Friday, April 26, 2019

Dedication and commitment to supporting life after stroke in Japan

In March 2019 I was invited to speak about patient involvement at the Non-Communicable Disease (NCD) Global Forum for Civil Society in Tokyo, organised by the Health and Global Policy Institute. I also took the opportunity to visit some inspiring stroke support organisations.

Sarah Belson, International Development Manager, World Stroke Organization and Stroke Association UK

NCD Global Forum for Civil Society
Takenori Yamaguchi, Executive Director
Japan Stroke Association
Following the recent passing of Japan's new Basic Act on Cardiovascular Diseases, the March session of the NCD Global Forum focused on heart disease, stroke and other cardiovascular diseases. The Basic Act aims to ensure a comprehensive and systematic response to cardiovascular diseases across the country. With the Government, healthcare professionals and patient organisations beginning to work on implementation plans for each health condition, the NCD Global Forum was an opportunity to share experiences and insights from patients, legislators, healthcare professionals and international organisations.

I spoke about strengthening patient advocacy and stressed the importance of ensuring meaningful involvement is at the heart of an organisation’s mission and strategic priorities; highlighting the World Stroke Organization’s priority to strengthen global capacity to reduce the burden of stroke, and the UK Stroke Association’s strategic goal to partner with people and communities to help them take action on stroke.

There are lots of great examples from across the World Stroke Organization and its members of meaningful involvement: the Global Stroke Bill of Rights built consensus across experience and contexts to develop advocacy messages; the activities of the Stroke Association of Kenya are guided by the lived experience of stroke survivors; and Stroke Action Nigeria supports stroke survivors to develop local stroke services as a business.

Inspiring stroke support in Tokyo and Osaka

I spent some time with Naomi Sonoda, a dedicated stroke advocate and Director of the Language Support Centre in Tokyo. Naomi was motivated to start this Centre and also the Japan Aphasia Circle, a peer support group, following her husband's stroke nearly 20 years ago. The Language Centre runs daily speech therapy sessions and has four speech and language therapists and 66 members.

In Osaka, I had the most wonderful welcome at the Sumomo Club for people with aphasia. The club is really vibrant, with skilled and committed staff. Established in 2005, the Sumomo Club has 65 members ranging in age from 30 to 90, and runs group activities as well as outreach to families and schools. Its mission is to provide a therapeutic environment for people with aphasia and other communication disorders to be able to participate, communicate and engage in creative activities. Its approach is to reinforce what you can do, not what you can’t. This wonderful video captures the spirit of the club.

The Japan Stroke Association sees its role as promoting and supporting long term care for people affected by stroke. Although this stroke support organisation only has one full time staff member and relies on volunteers, it delivers activities across the 47 prefectures of Japan, which include a helpline and peer support groups.  The Japan Stroke Association has been involved in the Basic Act, in particular consulting with patient groups, and will certainly be actively involved in the development of the implementation plan.

Thank you to everyone I met for such a warm welcome to Japan; at the policy and service level there is a lot to be positive about for people affected by stroke, and it's clear that there is a strong commitment to continue to ensure that people affected by stroke access the long term support that they need.

Staff of the Sumomo Club, Osaka

Monday, April 15, 2019

Thrombolysis, Thrombectomy and Acute Stroke Therapy. Series. Part 6

Series 6 

Thrombolysis, Thrombectomy and Acute Stroke Therapy. Series. Part 6

A summary of this meeting, and an extended report are available in the International Journal of Stroke, the flagship publication of the World Stroke Organization.  

Speeding thrombolysis and thrombectomy

How can we expand telestroke and other innovations?
Teddy Wu, Lee Schwamm, Larry Wechsler

Stroke is a rare event, accounting for less than 5% of emergency medical dispatches, emergency department visits and hospital admissions. Telestroke extends the reach of acute stroke expertise to rural and community hospitals increasing appropriate delivery of thrombolytic therapy and identifying patients eligible for mechanical thrombectomy.  Most telestroke networks limit evaluations to the acute stroke setting either in the emergency department or in-house stroke alerts. When patients remain at originating hospitals after acute evaluation subsequent hospital care may not be the same as care delivered by vascular neurologists at a stroke center. Providing telestroke follow-up throughout the episode of care for stroke patients promotes efficient and cost-effective testing and selection of optimal treatment, reducing length of stay and improving outcomes.

Advancement of stroke care is dependent on completion of clinical trials. Traditional ways of patient recruitment into acute ischemic stroke trials at tertiary care centers can be inefficient and often patients at remote hospitals lack access to such trials. Transfer delays from remote hospitals to larger tertiary centers may preclude enrollment of these patients into time-sensitive acute stroke clinical trials. Telemedicine has the potential to enable stroke specialist to conduct acute stroke trials at remote hospitals to potentially enhance enrollment while also increasing access and opportunities for stroke patients at rural and community hospitals to receive promising new therapies. 

Mobile Stroke Units—status and future perspective
Klaus Fassbender, Steve Davis, Anne W. Alexandrov

Many advantages of Mobile Stroke Units (MSUs) have already been noted in previous sections on systems of care. In addition to speeding tPA treatment into the first “golden hour”, MSUs should improve both the speed and accuracy of pre-hospital patient triage for thrombectomy. While MSUs are proliferating, cost-effectiveness remains to be established, and is being tested in the ongoing BEST-MSU study in the US. 

An important component of cost is staffing. Staffing on MSUs varies among existing programs, and is dependent on manpower availability, technology requirements, and regulatory and credentialing mandates. Programs should consider models that are sustainable based on personnel expense and the local availability of expertise. Most countries and local governing authorities will require at least the presence of a licensed prehospital provider, such as a paramedic and/or emergency medical technician on board any vehicle that is licensed as an ambulance. CT technologists are required to perform all CT imaging acquisition functions. The main difference between MSU program staffing lies in the area of stroke expertise, with use of vascular neurologists, nurse practitioners, or telemedicine operations. Regardless of the staffing model utilized, MSU teams must collaborate closely to support optimal stroke diagnostic and treatment outcomes.  

Discussion Panel
Martin Ebinger, Sandy Middleton, Silke Walter

The discussion evolved around the role of nurses in future stroke care. Patients cared for in stroke units who received facilitated implementation to manage fever, hyperglycemia and swallowing using the FeSS Protocols (fever, sugar, swallow) had 16% reduced death and disability107, with a sustained effect in terms of 20% increased likelihood of being alive out to a median of four years.108 It also has been shown to result in a $AUD 281M saving if only 60% of all eligible patients received this care over 12 months.109 This is as a result of evidence-based nursing care. Further, stroke unit coordinators, most usually nurses, have been shown to improve uptake of evidence-based stroke care and improve patient outcomes.110 However, the QASC Europe study is demonstrating the variable level of autonomy of stroke nurses across the world. Advancing stroke nursing care requires active support by neurologists. How can neurologists advance the role of the stroke nurse within their services? Can they identify nurses with potential who could lead FeSS protocol implementation and support introduction of other evidence-based stroke care processes to improve patient outcomes? 

Involving stroke nurses in MSUs would support autonomy of nurses and strengthen their role in the service.22,111 In addition, a recent good example of the multifaceted uses of MSUs took place in Houston in 2017, when Hurricane Harvey caused power breakdown of a hospital. The Mobile Stroke Unit partly replaced the emergency department in this exceptional situation providing head CT imaging. This report sparked a discussion about Mobile Stroke Units replacing Stroke Units in underserved areas, though the panelists also reminded the audience that a Stroke Unit is more than the CT-scanner and a laboratory. Apart from nurses and doctors, Stroke Units consist of a dedicated team that also includes physiotherapists, occupational therapists, speech therapists, and social workers.

Key Points:

Implementation of evidence-based nursing care can improve patient outcomes but requires multi-disciplinary support.
Telemedicine and MSUs shrink the gap between patient, provider, and treatment.
The cost effectiveness of MSU implementation needs evaluation.
Nurses and advanced practice providers are well suited for deployment in these roles. 

Other approaches to increasing perfusion 
Andrei Alexandrov, Italo Linfante, Rolf Blauenfeldt 

Placing the head of the bed at zero degrees may be the most important step in managing an LVO, since this significantly increases blood flow to ischemic regions. Use of this rescue maneuver has yet to be tested in LVO patients presenting in the hyperacute phase. The ZODIAC trial (NCT03728738) will examine the efficacy and safety of zero degree head positioning in hyperacute LVOs while being transferred for thrombectomy procedures.

The principle behind remote ischemic conditioning (RIC) is based in applying short-lasting, non-lethal ischemia in a distant tissue to protect against long-lasting ischemic injury in the brain. In practice, it is applied by inflating a cuff to a supra-systolic pressure on a extremity and holding that pressure for 5 minutes. This is followed by a reperfusion phase of 5 minutes. These 2 stages are one cycle, and it is then repeated for a total of 4 to 5 cycles. RIC seems to target multiple neuroprotectant mechanisms and cause an anti-inflammatory shift, as showed in many preclinical studies.112 
Major ongoing RIC Trials
RICA– This clinical trial is being conducted in China. It is the largest trial looking at a population with either AIS or TIA with symptomatic intracranial atherosclerotic disease. Patients are treated with RIC once daily for one year and were then followed up to assess for stroke recurrence. Sample size is 2600 with its enrollment almost completed. Results are expected to be published in 2020.
RESCUE BRAIN – Clinical trial in France, with 10 participating centers where RIC is given within 6 hours from symptom onset in the in-hospital setting for AIS patients treated with either alteplase or intra-arterial treatment. Primary endpoint is infarct growth rate and enrollment has been completed. Results are expected early in 2019.
REMOTE-CAT – Pre-hospital trial (Catalonia, Spain) in which RIC is started within 8 hours from symptom onset in the ambulance. Target population is AIS patients who do or don’t receive reperfusion therapy. Primary endpoint is dichotomized modified Rankin Scale.  
ReCAST-2 – Dose escalation study in the United Kingdom looking at the application of RIC in the in-hospital setting for AIS patients. Enrollment has been completed and results will be analyzed and depending on these planning of a large efficacy trial (ReCAST-3).
RESIST – Danish trial for pre-hospital RIC given within 4 hours from symptom onset in patients presenting with stroke symptoms. If patients are confirmed of having an AIS or ICH, patients are treated once again in-hospital after 6 hours. Current enrollment is 170 patients out of 1500 patients. Primary endpoint is modified Rankin Scale (shift analysis).

The effect of improved functional outcome is likely to be small, but RIC treatment is a cheap and feasible therapy without serious adverse events risk. Questions regarding which subset of patients will benefit from this intervention, standardized timing and dosing of cycles, and other applications beyond ischemic stroke are yet to be answered. 

Recent data showing increasing blood flow in the leptomeningeal anastomosis by administering Hemoglobin Oxygen Carriers and Carboxyhemoglobin Transporters in MCAO may represent a way to slow down core progression by increasing collateral circulation and transporting oxygen in acute ischemic brain tissue. 

Another proposed pathway to enhance collateral circulation is through sphenopalatine ganglion (SPG) stimulation. SPG stimulation, when started within 24 hours of symptom onset enhances the ipsilateral collateral flow of the anterior circulation and may reduce disability and increase the proportion of patients with good functional outcome.113,114 The Implant for Augmentation of Cerebral Blood Flow Trial, Effectiveness and Safety in a 24 Hour Window Study (ImpACT-24B - NCT00826059) involved 1000 patients at 73 centers in 18 countries, with a primary endpoint of improvement beyond expectations on the modified Rankin Scale at 3 months. A statistically significant relative improvement in outcome in the treatment was observed with similar results to previous trials. 

Sonothrombolysis is another approach for improved thrombolytic efficacy.  CLOTBUSTER (NCT01098981) had a signal of efficacy for in subgroup analysis (publication pending). A new phase III international trial called TRUST (NCT03519737) will assess the efficacy and safety of transcranial ultrasound using the Sonolysis Headframe as an adjunctive therapy to intravenous alteplase treatment in patients that arrive within conventional time window at spoke hospitals and are transferred for mechanical thrombectomy. The primary end-point is recanalization on diagnostic catheter angiography assessment prior to mechanical thrombectomy. The lead-in phase testing a novel therapeutic ultrasound device is being launched now at 4 US hub-and-spokes systems.

Other new and exciting updates
Pat Lyden, Dileep Yavagal, Simon de Meyer 

Reperfusion of the ischemic territory that occurs too late can also exacerbate tissue damage by reperfusion injury. This problem does not only occur after successful thrombolysis but also often complicates stroke outcome after successful mechanical thrombectomy. Hence, there continues to be a critical need for novel therapies for AIS, including better ways for thrombolysis and better ways to guarantee neuroprotection upon recanalization.
Many previous neuroprotectant failures (promising drugs emerge from pre-clinical development only to fail in large stroke patient trials) might be traced to a fundamental dogmatic misconception of the mammalian brain. New understanding of the neurovascular unit indicates the brain uses at least 7 main categories of cell types: neurons, astrocytes, endothelial cells, oligodendroglia, pericytes, ependymal cells and microglia. Recently, emerging data suggests the elements of the neurovascular unit respond to injury (ischemia, trauma) and to treatment differently. Understanding this differential susceptibility to injury—and subsequent differential response to therapy—has led to a novel, striking re-interpretation of prior clinical therapeutic trial failures. 
In some patients however, alteplase can cause internal bleeding and other complications. 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis associated hemorrhage. 3K3A-APC’s cytoprotective properties may be useful in protecting ischemic brain tissue from further damage, while reducing the risk of treatment-related bleeding. The NeuroNEXT trial NN104 (RHAPSODY) trial established the safety, tolerability and activity of 3K3A-APC, following the use of alteplase in subjects who have experienced moderately severe acute hemispheric ischemic stroke. Results were presented at the International Stroke Conference in January 2018 and confirmed that 3K3A-APC appears safe and tolerable, and that a suggestion of vascular protection (reduced hemorrhage) requires confirmation in a larger trial. The next phase of development includes further pre-clinical development, hopefully via the new Stroke Pre-clinical Assessment Network (SPAN) and further dose finding studies in patients via StrokeNET. Together, these development efforts will not only advance one drug to Phase 3 trial, these joint efforts among SPAN and StrokeNET will establish the validity of rigorous pre-clinical development in parallel and in concert with early proof of efficacy in stroke patients. The paradigm challenges the dogma “bench-to-bedside-to-bench” in favor of a more realistic, collaborative joint development effort in which basic and translational scientists work together in real-time. 

The natural history of stroke recovery depends on endogenous stems cells in the adult and pediatric brain. This recovery is incomplete in most patients and exogenous cell-based therapy shows great promise to significantly enhance this stroke recovery. Among different cell types, mesenchymal stem cells (MSCs) are most attractive for clinical translation. MSCs are adult stem cells that are multipotent, non-hematopoietic stem cells found in the stromal fraction of the bone marrow, along with the connective tissue of most organs. They are an appealing cell source due to the relative ease in which they can be retrieved, developed, and expanded for therapeutic application. Among various routes of cell delivery for ischemic stroke, the intra-arterial route of stem cell transport is most attractive as it targets delivery of cells to the ischemic brain bypassing systemic trapping of cells seen with intravenous delivery and much less invasive than direct stereotactic or intraventricular delivery. Furthermore, intra-arterial delivery of cells leads to a wide distribution of cells in the ischemic brain as MSCs home in to ischemic tissue via the vasculature using the CXCR4-SDF-1 signaling pathway. Thus, intra-arterial cell delivery leads to a substantial number of MSCs in the core and penumbra of the infarct optimizing the trophic mechanism of benefit for stroke recovery: anti-inflammation, neuroprotection and stimulation of endogenous stem cells. This suggests great potential for clinical translation of intra-arterial delivered MSCs for ischemic stroke, especially considering the growing clinical application of endovascular treatment for AIS. 

A major concern for intra-arterial delivery of cells is the potential for brain ischemia that could result from administered cells compromising blood flow in the microcirculation. Pre-clinical work addressing this issue shows that such ischemia depends on the dose of intra-arterial delivery and can be fully mitigated by lowering cell doses in small and larger animal models. Furthermore, the lower (MTD) dose of cells, when given at 24-48 hours after stroke onset is efficacious for functional recovery and reduction of infarct volume in rodent stroke models. The first randomized trial (Phase 2a) of intra-arterial cell therapy in 48 patients, RECOVER-Stroke was presented at the European Stroke Conference in 2015 and recently accepted for publication. The study showed safety of autologous intra-arterial cell delivery in anterior circulation ischemic stroke at a median of 18 days from stroke onset with no difference in efficacy. A larger phase 2b clinical trial with allogenic MSCs given between 24-36 hours is planned to move towards clinical translation of this this promising approach. 

Limited data exist on clot composition and detailed characteristics of arterial thrombi associated with large vessel occlusion in acute ischemic stroke. Advances in endovascular thrombectomy and related imaging modalities have created a unique opportunity to analyze thrombi removed from cerebral arteries. Insights into thrombus composition may lead to future advancements in acute ischemic stroke treatment and improved clinical outcomes. Such detailed information can reveal novel insights and open improved recanalization. Some thrombi are particularly rich in von Willebrand factor, leading to the concept of developing a novel thrombolytic strategy using the von Willebrand factor-cleaving enzyme ADAMTS13. Similarly, the remarkable amount of extracellular DNA (derived from neutrophil extracellular traps) had led to using DNase1 as a prothrombolytic drug in experimental studies. The testing hypothesis that will be presented is one of using a thrombolytic cocktail (alteplase + ADAMT13 + DNAse) instead of alteplase alone.

Discussion Panel
E. Clarke Haley, Antoni Davalos, Markku Kaste, Chris Levi  

Key Points: 

Existing treatment with thrombolysis and thrombectomy still leaves half of patients with disability and substantial room for new experimental approaches. Initial optimal head positioning in LVO patients is being determined in an ongoing trials.
Ongoing approaches along this line include remote ischemic preconditioning, enhancing collaterals through oxygen carriers or sonothrombolysis, targeting the multiplicity of vulnerable cell populations in the neurovascular unit, stem cells, and a better understanding of clot composition.    
These new approaches in acute stroke care and their potential applications are of importance in regions with no access to either thrombolysis or mechanical thrombectomy.           

1. Thrift AG, Thayabaranathan T, Howard G, Howard VJ, Rothwell PM, Feigin VL, Norrving B, Donnan GA, Cadilhac DA. Global stroke statistics:. International Journal of Stroke. 2017;12:13–32. 
2. Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA, Barker-Collo S, Moran AE, Sacco RL, Truelsen T, Davis S, Pandian JD, Naghavi M, Forouzanfar MH, Nguyen G, Johnson CO, Vos T, Meretoja A, Murray CJL, Roth GA, GBD 2013 Writing Group, GBD 2013 Stroke Panel Experts Group. Update on the Global Burden of Ischemic and Hemorrhagic Stroke in 1990-2013: The GBD 2013 Study. Neuroepidemiology. 2015;45:161–176. 
3. Feigin VL, Norrving B, Mensah GA. Global Burden of Stroke. Circ. Res. 2017;120:439–448. 
4. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, Naghavi M, Mensah GA, Murray CJL. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015;372:1333–1341. 
5. Kim AS, Cahill E, Cheng NT. Global Stroke Belt: Geographic Variation in Stroke Burden Worldwide. Stroke. 2015;46:3564–3570. 
6. Howard G, Goff DC. Population shifts and the future of stroke: forecasts of the future burden of stroke. Ann. N. Y. Acad. Sci. 2012;1268:14–20. 
7. Scott PA, Temovsky CJ, Lawrence K, Gudaitis E, Lowell MJ. Analysis of Canadian population with potential geographic access to intravenous thrombolysis for acute ischemic stroke. Stroke. 1998;29:2304–2310. 
8. Schwamm LH, Ali SF, Reeves MJ, Smith EE, Saver JL, Messe S, Bhatt DL, Grau-Sepulveda MV, Peterson ED, Fonarow GC. Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With The Guidelines-Stroke hospitals. Circ Cardiovasc Qual Outcomes. 2013;6:543–549. 
9. Smith EE, Saver JL, Cox M, Liang L, Matsouaka R, Xian Y, Bhatt DL, Fonarow GC, Schwamm LH. Increase in Endovascular Therapy in Get With The Guidelines-Stroke After the Publication of Pivotal Trials. Circulation. 2017;136:2303–2310. 
10. Bartig D, Kitzrow M, Brassel F, Busch EW, Nolden-Koch M, Reimann G, Weimar C, Weber R, Eyding J. Verfügbarkeit der mechanischen Thrombektomie bei akutem Hirninfarkt. Der Nervenarzt. 2017;88:1–9. 
11. Yusuf S, Reddy S, Ôunpuu S, Circulation SA, 2001. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. 
12. Zhao D, Liu J, Wang W, Zeng Z, Cheng J, Liu J, Sun J, Wu Z. Epidemiological transition of stroke in China: twenty-one-year observational study from the Sino-MONICA-Beijing Project. Stroke. 2008;39:1668–1674. 
13. CDC. Stroke Hospitalization Rates, 2013-2015 Adult Medicare Beneficiaries, Ages 65+, by County. 2018;:1–1. 
14. Johnston SC, Mendis S, Mathers CD. Global variation in stroke burden and mortality: estimates from monitoring, surveillance, and modelling. The Lancet Neurology. 2009;8:345–354. 
15. Odutayo A, Gill P, Shepherd S, Akingbade A, Hopewell S, Tennankore K, Hunn BH, Emdin CA. Income Disparities in Absolute Cardiovascular Risk and Cardiovascular Risk Factors in the United States, 1999-2014. JAMA Cardiol. 2017;2:782–790. 
16. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillum RF, Kim Y-H, McAnulty JH Jr, Zheng Z-J, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJL. Worldwide Epidemiology of Atrial Fibrillation. Circulation. 2014;129:837–847. 
17. Goyal M, Menon BK, van Zwam WH, Dippel DWJ, Mitchell PJ, Demchuk AM, Dávalos A, Majoie CBLM, van der Lugt A, de Miquel MA, Donnan GA, Roos YBWEM, Bonafe A, Jahan R, Diener H-C, van den Berg LA, Levy EI, Berkhemer OA, Pereira VM, Rempel J, Millán M, Davis SM, Roy D, Thornton J, Román LS, Ribó M, Beumer D, Stouch B, Brown S, Campbell BCV, van Oostenbrugge RJ, Saver JL, Hill MD, Jovin TG. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. The Lancet. 2016;387:1723–1731. 
18. Ornello R, Degan D, Tiseo C, Di Carmine C, Perciballi L, Pistoia F, Carolei A, Sacco S. Distribution and Temporal Trends From 1993 to 2015 of Ischemic Stroke Subtypes. Stroke. 2018;49:814–819. 
19. Noorian AR, Sanossian N, Shkirkova K, Liebeskind DS, Eckstein M, Stratton SJ, Pratt FD, Conwit R, Chatfield F, Sharma LK, Restrepo L, Valdes-Sueiras M, Kim-Tenser M, Starkman S, Saver JL. Los Angeles Motor Scale to Identify Large Vessel Occlusion. Stroke. 2018;49:565–572. 
20. Adeoye O, Albright KC, Carr BG, Wolff C, Mullen MT, Abruzzo T, Ringer A, Khatri P, Branas C, Kleindorfer D. Geographic access to acute stroke care in the United States. Stroke. 2014;45:3019–3024. 
21. Kim J, Hwang Y-H, Kim J-T, Choi N-C, Kang S-Y, Cha J-K, Ha YS, Shin D-I, Kim S, Lim B-H. Establishment of government-initiated comprehensive stroke centers for acute ischemic stroke management in South Korea. Stroke. 2014;45:2391–2396. 
22. Ebinger M, Kunz A, Wendt M, Rozanski M, Winter B, Waldschmidt C, Weber J, Villringer K, Fiebach JB, Audebert HJ. Effects of Golden Hour Thrombolysis. JAMA Neurol. 2015;72:25–6. 
23. Katz BS, Adeoye O, Sucharew H, Broderick JP, McMullan J, Khatri P, Widener M, Alwell KS, Moomaw CJ, Kissela BM, Flaherty ML, Woo D, Ferioli S, Mackey J, Martini S, De Los Rios la Rosa F, Kleindorfer DO. Estimated Impact of Emergency Medical Service Triage of Stroke Patients on Comprehensive Stroke Centers: An Urban Population-Based Study. Stroke. 2017;48:2164–2170. 
24. Martinez B, Owings JT, Hector C, Hargrove P, Tanaka S, Moore M, Greiffenstein P, Giaimo J, Talebinejad S, Hunt JP. Association Between Compliance with Triage Directions from an Organized State Trauma System and Trauma Outcomes. J. Am. Coll. Surg. 2017;225:508–515. 
25. Lassen JF, Bøtker HE, Terkelsen CJ. Timely and optimal treatment of patients with STEMI. Nat Rev Cardiol. 2013;10:41–48. 
26. Chen J, Krumholz HM, Wang Y, Curtis JP, Rathore SS, Ross JS, Normand S-LT, Schreiner GC, Mulvey G, Nallamothu BK. Differences in patient survival after acute myocardial infarction by hospital capability of performing percutaneous coronary intervention: implications for regionalization. Arch. Intern. Med. 2010;170:433–439. 
27. Cournoyer A, Notebaert É, de Montigny L, Ross D, Cossette S, Londei-Leduc L, Iseppon M, Lamarche Y, Sokoloff C, Potter BJ, Vadeboncoeur A, Larose D, Morris J, Daoust R, Chauny J-M, Piette É, Paquet J, Cavayas YA, de Champlain F, Segal E, Albert M, Guertin M-C, Denault A. Impact of the direct transfer to percutaneous coronary intervention-capable hospitals on survival to hospital discharge for patients with out-of-hospital cardiac arrest. Resuscitation. 2018;125:28–33. 
28. Concannon TW, Kent DM, Normand S-L, Newhouse JP, Griffith JL, Cohen J, Beshansky JR, Wong JB, Aversano T, Selker HP. Comparative effectiveness of ST-segment-elevation myocardial infarction regionalization strategies. Circ Cardiovasc Qual Outcomes. 2010;3:506–513. 
29. Aguiar de Sousa D, Martial von R, Abilleira S, Gattringer T, Kobayashi A, Gallofré M, Fazekas F, Szikora I, Feigin V, Caso V, Fischer U. Access to and delivery of acute ischaemic stroke treatments: A survey of national scientific societies and stroke experts in 44 European countries. European Stroke Journal. 2018;:239698731878602–16. 
30. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018;49. 
31. Maas MB, Jaff MR, Rordorf GA. Risk Adjustment for Case Mix and the Effect of Surgeon Volume on Morbidity. JAMA Surg. 2013;148:532–536. 
32. Holt PJE, Poloniecki JD, Loftus IM, Thompson MM. The Relationship between Hospital Case Volume and Outcome from Carotid Endartectomy in England from 2000 to 2005. European Journal of Vascular and Endovascular Surgery. 2007;34:646–654. 
33. Cross DT, Tirschwell DL, Clark MA, Tuden D, Derdeyn CP, Moran CJ, Dacey RG. Mortality rates after subarachnoid hemorrhage: variations according to hospital case volume in 18 states. J. Neurosurg. 2003;99:810–817. 
34. Prabhakaran S, Fonarow GC, Smith EE, Liang L, Xian Y, Neely M, Peterson ED, Schwamm LH. Hospital case volume is associated with mortality in patients hospitalized with subarachnoid hemorrhage. Neurosurgery. 2014;75:500–508. 
35. Leake CB, Brinjikji W, Kallmes DF, Cloft HJ. Increasing treatment of ruptured cerebral aneurysms at high-volume centers in the United States. J. Neurosurg. 2011;31:1179–1183. 
36. Boogaarts HD, van Amerongen MJ, de Vries J, Westert GP, Verbeek ALM, Grotenhuis JA, Bartels RHMA. Caseload as a factor for outcome in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J. Neurosurg. 2014;28:605–611. 
37. Berman MF, Solomon RA, Mayer SA, Johnston SC, Yung PP. Impact of Hospital-Related Factors on Outcome After Treatment of Cerebral Aneurysms. Stroke. 2003;34:2200–2207. 
38. Johnston SC. Effect of endovascular services and hospital volume on cerebral aneurysm treatment outcomes. Stroke. 2000;31:111–117. 
39. McNeill L, English SW, Borg N, Matta BF, Menon DK. Effects of institutional caseload of subarachnoid hemorrhage on mortality: a secondary analysis of administrative data. Stroke. 2013;44:647–652. 
40. Rush B, Romano K, Ashkanani M, McDermid RC, Celi LA. Impact of hospital case-volume on subarachnoid hemorrhage outcomes: A nationwide analysis adjusting for hemorrhage severity. J Crit Care. 2017;37:240–243. 
41. Kumbhani DJ, Bittl JA. Much Ado About Nothing? The Relationship of Institutional Percutaneous Coronary Intervention Volume to Mortality. Circ Cardiovasc Qual Outcomes. 2017;10. 
42. Fanaroff AC, Zakroysky P, Dai D, Wojdyla D, Sherwood MW, Roe MT, Wang TY, Peterson ED, Gurm HS, Cohen MG, Messenger JC, Rao SV. Outcomes of PCI in Relation to Procedural Characteristics and Operator Volumes in the United States. J. Am. Coll. Cardiol. 2017;69:2913–2924. 
43. Adamczyk P, Attenello F, Wen G, He S, Russin J, Sanossian N, Amar AP, Mack WJ. Mechanical thrombectomy in acute stroke: utilization variances and impact of procedural volume on inpatient mortality. J Stroke Cerebrovasc Dis. 2013;22:1263–1269. 
44. Neal D FK. A Nationwide Inpatient Sample Study of Stroke Outcomes Based on Aggressiveness to Pursue Thrombectomy: The Thrombectomy/Thrombolysis Ratio. J Neurol Disord. 2015;03:1–7. 
45. Sablot D, Dumitrana A, Leibinger F, Khlifa K, Fadat B, Farouil G, Allou T, Coll F, Mas J, Smadja P, Ferraro-Allou A, Mourand I, Dutray A, Tardieu M, Jurici S, Bonnec J-M, Olivier N, Cardini S, Damon F, Van Damme L, Aptel S, Gaillard N, Marquez A-M, Them LN, Ibanez M, Arquizan C, Costalat V, Bonafe A. Futile inter-hospital transfer for mechanical thrombectomy in a semi-rural context: analysis of a 6-year prospective registry. J NeuroIntervent Surg. 2018;:neurintsurg–2018–014206. 
46. Mokin M, Gupta R, Guerrero WR, Rose DZ, Burgin WS, Sivakanthan S. ASPECTS decay during inter-facility transfer in patients with large vessel occlusion strokes. J NeuroIntervent Surg. 2017;9:442–444. 
47. Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, Cheripelli B, Cho T-H, Fazekas F, Fiehler J, Ford I, Galinovic I, Gellissen S, Golsari A, Gregori J, Günther M, Guibernau J, Häusler KG, Hennerici M, Kemmling A, Marstrand J, Modrau B, Neeb L, Perez de la Ossa N, Puig J, Ringleb P, Roy P, Scheel E, Schonewille W, Serena J, Sunaert S, Villringer K, Wouters A, Thijs V, Ebinger M, Endres M, Fiebach JB, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Gerloff C. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018;379:611–622. 
48. Amiri H, Bluhmki E, Bendszus M, Eschenfelder CC, Donnan GA, Leys D, Molina C, Ringleb PA, Schellinger PD, Schwab S, Toni D, Wahlgren N, Hacke W. European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND. Int J Stroke. 2016;11:260–267. 
49. Ma H, Parsons MW, Christensen S, Campbell BCV, Churilov L, Connelly A, Yan B, Bladin C, Phan T, Barber AP, Read S, Hankey GJ, Markus R, Wijeratne T, Grimley R, Mahant N, Kleinig T, Sturm J, Lee A, Blacker D, Gerraty R, Krause M, Desmond PM, McBride SJ, Carey L, Howells DW, Hsu CY, Davis SM, Donnan GA, EXTEND investigators. A multicentre, randomized, double-blinded, placebo-controlled Phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND). Int J Stroke. 2012;7:74–80. 
50. Schlemm L, Ebinger M, Nolte CH, Endres M. Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment. Stroke. 2018;49:439–446. 
51. Belt GH, Felberg RA, Rubin J, Halperin JJ. In-Transit Telemedicine Speeds Ischemic Stroke Treatment: Preliminary Results. Stroke. 2016;47:2413–2415. 
52. Nogueira RG, Silva GS, Lima FO, Yeh Y-C, Fleming C, Branco D, Yancey AH, Ratcliff JJ, Wages RK, Doss E, Bouslama M, Grossberg JA, Haussen DC, Sakano T, Frankel MR. The FAST-ED App: A Smartphone Platform for the Field Triage of Patients With Stroke. Stroke. 2017;48:1278–1284. 
53. Kettner M, Helwig SA, Ragoschke-Schumm A, Schwindling L, Roumia S, Keller I, Martens D, Kulikovski J, Manitz M, Lesmeister M, Walter S, Grunwald IQ, Schlechtriemen T, Reith W, Fassbender K. Prehospital Computed Tomography Angiography in Acute Stroke Management. Cerebrovasc Dis. 2017;44:338–343. 
54. Smith EE, Kent DM, Bulsara KR, Leung LY, Lichtman JH, Reeves MJ, Towfighi A, Whiteley WN, Zahuranec DB, American Heart Association Stroke Council. Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke. 2018;49:e111–e122. 
55. Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, Yan B, Bush SJ, Dewey HM, Thijs V, Scroop R, Simpson M, Brooks M, Asadi H, Wu TY, Shah DG, Wijeratne T, Ang T, Miteff F, Levi CR, Rodrigues E, Zhao H, Salvaris P, Garcia-Esperon C, Bailey P, Rice H, de Villiers L, Brown H, Redmond K, Leggett D, Fink JN, Collecutt W, Wong AA, Muller C, Coulthard A, Mitchell K, Clouston J, Mahady K, Field D, Ma H, Phan TG, Chong W, Chandra RV, Slater L-A, Krause M, Harrington TJ, Faulder KC, Steinfort BS, Bladin CF, Sharma G, Desmond PM, Parsons MW, Donnan GA, Davis SM. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018;378:1573–1582. 
56. Tsivgoulis G, Katsanos AH, Schellinger PD, Köhrmann M, Varelas P, Magoufis G, Paciaroni M, Caso V, Alexandrov AW, Gurol E, Alexandrov AV. Successful Reperfusion With Intravenous Thrombolysis Preceding Mechanical Thrombectomy in Large-Vessel Occlusions. Stroke. 2018;49:232–235. 
57. Scott PA, Xu Z, Meurer WJ, Frederiksen SM, Haan MN, Westfall MW, Kothari SU, Morgenstern LB, Kalbfleisch JD. Attitudes and Beliefs of Michigan Emergency Physicians Toward Tissue Plasminogen Activator Use in Stroke. Stroke. 2010;41:2026–2032. 
58. Dhamoon MS, Moon YP, Paik MC, Sacco RL, Elkind MSV. Trajectory of Functional Decline Before and After Ischemic Stroke. Stroke. 2012;43:2180–2184. 
59. Levine DA, Galecki AT, Langa KM, Unverzagt FW, Kabeto MU, Giordani B, Wadley VG. Trajectory of Cognitive Decline After Incident Stroke. JAMA. 2015;314:41–51. 
60. Doyle KP, Quach LN, Solé M, Axtell RC, Nguyen T-VV, Soler-Llavina GJ, Jurado S, Han J, Steinman L, Longo FM, Schneider JA, Malenka RC, Buckwalter MS. B-Lymphocyte-Mediated Delayed Cognitive Impairment following Stroke. J. Neurosci. 2015;35:2133–2145. 
61. Shibata D, Cain K, Tanzi P, Zierath D, Becker K. Myelin basic protein autoantibodies, white matter disease and stroke outcome. J. Neuroimmunol. 2012;252:106–112. 
62. Parsons MW, Miteff F, Bateman GA, Spratt N, Loiselle A, Attia J, Levi CR. Acute ischemic stroke: imaging-guided tenecteplase treatment in an extended time window. Neurology. 2009;72:915–921. 
63. Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, O'Brien B, Bladin C, McElduff P, Allen C, Bateman G, Donnan G, Davis S, Levi C. A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke. 2012;366:1099–1107. 
64. Durand A, Chauveau F, Cho T-H, Kallus C, Wagner M, Boutitie F, Maucort-Boulch D, Berthezene Y, Wiart M, Nighoghossian N. Effects of a TAFI-inhibitor combined with a suboptimal dose of rtPA in a murine thromboembolic model of stroke. Cerebrovasc Dis. 2014;38:268–275. 
65. Schattauer GmbH, Jamasbi J, Ayabe K, Goto S, Nieswandt B, Peter K, Siess W. Platelet receptors as therapeutic targets: Past, present and future. Thromb Haemost. 2017;117:1249–1257. 
66. Denorme F, Langhauser F, Desender L, Vandenbulcke A, Rottensteiner H, Plaimauer B, François O, Andersson T, Deckmyn H, Scheiflinger F, Kleinschnitz C, Vanhoorelbeke K, De Meyer SF. ADAMTS13-mediated thrombolysis of t-PA resistant occlusions in ischemic stroke in mice. Blood. 2016;127:blood–2015–08–662650–2345. 
67. Martinez de Lizarrondo S, Gakuba C, Herbig BA, Repessé Y, Ali C, Denis CV, Lenting PJ, Touzé E, Diamond SL, Vivien D, Gauberti M. Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi. Circulation. 2017;136:646–660. 
68. Ducroux C, Di Meglio L, Loyau S, Delbosc S, Boisseau W, Deschildre C, Ben Maacha M, Blanc R, Redjem H, Ciccio G, Smajda S, Fahed R, Michel J-B, Piotin M, Salomon L, Mazighi M, Ho-Tin-Noe B, Desilles J-P. Thrombus Neutrophil Extracellular Traps Content Impair tPA-Induced Thrombolysis in Acute Ischemic Stroke. Stroke. 2018;49:754–757. 
69. Laridan E, Denorme F, Desender L, François O, Andersson T, Deckmyn H, Vanhoorelbeke K, De Meyer SF. Neutrophil extracellular traps in ischemic stroke thrombi. Ann. Neurol. 2017;82:223–232. 
70. Brott TG, Haley EC, Levy DE, Barsan W, Broderick J, Sheppard GL, Spilker J, Kongable GL, Massey S, Reed R. Urgent therapy for stroke. Part I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992;23:632–640. 
71. Haley EC, Levy DE, Brott TG, Sheppard GL, Wong MC, Kongable GL, Torner JC, Marler JR. Urgent therapy for stroke. Part II. Pilot study of tissue plasminogen activator administered 91-180 minutes from onset. Stroke. 1992;23:641–645. 
72. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587. 
73. Yamaguchi T, Mori E, Minematsu K, DelZoppo GJ. Thrombolytic therapy in acute ischemic stroke III. 2012. 
74. Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, Shinohara Y. Alteplase at 0.6 mg/kg for Acute Ischemic Stroke Within 3 Hours of Onset. Stroke. 2006;37:1810–1815. 
75. Nakagawara J, Minematsu K, Okada Y, Tanahashi N, Nagahiro S, Mori E, Shinohara Y, Yamaguchi T, J-MARS Investigators. Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice: the Japan post-Marketing Alteplase Registration Study (J-MARS). Stroke. 2010;41:1984–1989. 
76. Toyoda K, Koga M, Naganuma M, Shiokawa Y, Nakagawara J, Furui E, Kimura K, Yamagami H, Okada Y, Hasegawa Y, Kario K, Okuda S, Nishiyama K, Minematsu K, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement Study Investigators. Routine use of intravenous low-dose recombinant tissue plasminogen activator in Japanese patients: general outcomes and prognostic factors from the SAMURAI register. Stroke. 2009;40:3591–3595. 
77. Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. The Lancet. 2007;369:275–282. 
78. Anderson CS, Robinson T, Lindley RI, Arima H, Lavados PM, Lee T-H, Broderick JP, Chen X, Chen G, Sharma VK, Kim JS, Thang NH, Cao Y, Parsons MW, Levi C, Huang Y, Olavarría VV, Demchuk AM, Bath PM, Donnan GA, Martins S, Pontes-Neto OM, Silva F, Ricci S, Roffe C, Pandian J, Billot L, Woodward M, Li Q, Wang X, Wang J, Chalmers J. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. 2016;374:2313–2323. 
79. Cheng J-W, Zhang X-J, Cheng L-S, Li G-Y, Zhang L-J, Ji K-X, Zhao Q, Bai Y. Low-Dose Tissue Plasminogen Activator in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis. J Stroke Cerebrovasc Dis. 2018;27:381–390. 
80. Wang X, You S, Sato S, Yang J, Carcel C, Zheng D, Yoshimura S, Anderson CS, Sandset EC, Robinson T, Chalmers J, Sharma VK. Current status of intravenous tissue plasminogen activator dosage for acute ischaemic stroke: an updated systematic review. Stroke Vasc Neurol. 2018;3:28–33. 
81. Logallo N, Novotny V, Assmus J, Kvistad CE, Alteheld L, Rønning OM, Thommessen B, Amthor K-F, Ihle-Hansen H, Kurz M, Tobro H, Kaur K, Stankiewicz M, Carlsson M, Morsund Å, Idicula T, Aamodt AH, Lund C, Næss H, Waje-Andreassen U, Thomassen L. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. The Lancet Neurology. 2017;16:781–788. 
82. Zarich SW, Kowalchuk GJ, Weaver WD, Loscalzo J, Sassower M, Manzo K, Byrnes C, Muller JE, Gurewich V. Sequential combination thrombolytic therapy for acute myocardial infarction: results of the pro-urokinase and t-PA enhancement of thrombolysis (PATENT) trial. J. Am. Coll. Cardiol. 1995;26:374–379. 
83. Zhu W, Churilov L, Campbell BCV, Lin M, Liu X, Davis SM, Yan B. Does large vessel occlusion affect clinical outcome in stroke with mild neurologic deficits after intravenous thrombolysis? J Stroke Cerebrovasc Dis. 2014;23:2888–2893. 
84. Nedeltchev K, Schwegler B, Haefeli T, Brekenfeld C, Gralla J, Fischer U, Arnold M, Remonda L, Schroth G, Mattle HP. Outcome of stroke with mild or rapidly improving symptoms. Stroke. 2007;38:2531–2535. 
85. Kim J-T, Park M-S, Chang J, Lee JS, Choi K-H, Cho K-H. Proximal Arterial Occlusion in Acute Ischemic Stroke with Low NIHSS Scores Should Not Be Considered as Mild Stroke. PLoS ONE. 2013;8:e70996. 
86. Heldner MR, Jung S, Zubler C, Mordasini P, Weck A, Mono M-L, Ozdoba C, El-Koussy M, Mattle HP, Schroth G, Gralla J, Arnold M, Fischer U. Outcome of patients with occlusions of the internal carotid artery or the main stem of the middle cerebral artery with NIHSS score of less than 5: comparison between thrombolysed and non-thrombolysed patients. J Neurol Neurosurg Psychiatry. 2015;86:755–760. 
87. Sarraj A, Hassan A, Savitz SI, Grotta JC, Cai C, Parsha KN, Farrell CM, Imam B, Sitton CW, Reddy ST, Kamal H, Goyal N, Elijovich L, Reishus K, Krishnan R, Sangha N, Wu A, Costa R, Malik R, Mir O, Hasan R, Snodgrass LM, Requena M, Graybeal D, Abraham M, Chen M, McCullough LD, Ribó M. Endovascular Thrombectomy for Mild Strokes: How Low Should We Go? Stroke. 2018;49:2398–2405. 
88. Messer MP, Schönenberger S, Möhlenbruch MA, Pfaff J, Herweh C, Ringleb PA, Nagel S. Minor Stroke Syndromes in Large-Vessel Occlusions: Mechanical Thrombectomy or Thrombolysis Only? AJNR Am J Neuroradiol. 2017;38:1177–1179. 
89. Rai AT, Domico JR, Buseman C, Tarabishy AR, Fulks D, Lucke-Wold N, Boo S, Carpenter JS. A population-based incidence of M2 strokes indicates potential expansion of large vessel occlusions amenable to endovascular therapy. J NeuroIntervent Surg. 2018;10:510–515. 
90. Zaidat OO, Castonguay AC, Gupta R, Sun C-HJ, Martin C, Holloway WE, Mueller-Kronast N, English JD, Linfante I, Dabus G, Malisch TW, Marden FA, Bozorgchami H, Xavier A, Rai AT, Froehler MT, Badruddin A, Nguyen TN, Taqi MA, Abraham MG, Janardhan V, Shaltoni H, Novakovic R, Yoo AJ, Abou-Chebl A, Chen PR, Britz GW, Kaushal R, Nanda A, Issa MA, Nogueira RG. North American Solitaire Stent Retriever Acute Stroke registry: post-marketing revascularization and clinical outcome results. J NeuroIntervent Surg. 2014;6:584–588. 
91. Saver JL, Goyal M, van der Lugt A, Menon BK, Majoie CBLM, Dippel DW, Campbell BC, Nogueira RG, Demchuk AM, Tomasello A, Cardona P, Devlin TG, Frei DF, Mesnil de Rochemont du R, Berkhemer OA, Jovin TG, Siddiqui AH, van Zwam WH, Davis SM, Castaño C, Sapkota BL, Fransen PS, Molina C, van Oostenbrugge RJ, Chamorro A, Lingsma H, Silver FL, Donnan GA, Shuaib A, Brown S, Stouch B, Mitchell PJ, Dávalos A, Roos YBWEM, Hill MD, for the HERMES Collaborators. Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis. JAMA. 2016;316:1279–10. 
92. Froehler MT, Saver JL, Zaidat OO, Jahan R, Aziz-Sultan MA, Klucznik RP, Haussen DC, Hellinger FR, Yavagal DR, Yao TL, Liebeskind DS, Jadhav AP, Gupta R, Hassan AE, Martin CO, Bozorgchami H, Kaushal R, Nogueira RG, Gandhi RH, Peterson EC, Dashti SR, Given CA, Mehta BP, Deshmukh V, Starkman S, Linfante I, McPherson SH, Kvamme P, Grobelny TJ, Hussain MS, Thacker I, Vora N, Chen PR, Monteith SJ, Ecker RD, Schirmer CM, Sauvageau E, Abou-Chebl A, Derdeyn CP, Maidan L, Badruddin A, Siddiqui AH, Dumont TM, Alhajeri A, Taqi MA, Asi K, Carpenter J, Boulos A, Jindal G, Puri AS, Chitale R, Deshaies EM, Robinson DH, Kallmes DF, Baxter BW, Jumaa MA, Sunenshine P, Majjhoo A, English JD, Suzuki S, Fessler RD, Delgado Almandoz JE, Martin JC, Mueller-Kronast NH, STRATIS Investigators. Interhospital Transfer Before Thrombectomy Is Associated With Delayed Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke). Circulation. 2017;136:2311–2321. 
93. Hastrup S, Damgaard D, Johnsen SP, Andersen G. Prehospital Acute Stroke Severity Scale to Predict Large Artery Occlusion: Design and Comparison With Other Scales. Stroke. 2016;47:1772–1776. 
94. Kellner CP, Sauvageau E, Snyder KV, Fargen KM, Arthur AS, Turner RD, Alexandrov AV. The VITAL study and overall pooled analysis with the VIPS non-invasive stroke detection device. J NeuroIntervent Surg. 2018;10:1079–1084. 
95. Lapergue B, Blanc R, Gory B, Labreuche J, Duhamel A, Marnat G, Saleme S, Costalat V, Bracard S, Desal H, Mazighi M, Consoli A, Piotin M, ASTER Trial Investigators. Effect of Endovascular Contact Aspiration vs Stent Retriever on Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion: The ASTER Randomized Clinical Trial. JAMA. 2017;318:443–452. 
96. Wintermark M, Albers GW, Alexandrov AV, Alger JR, Bammer R, Baron J-C, Davis S, Demaerschalk BM, Derdeyn CP, Donnan GA, Eastwood JD, Fiebach JB, Fisher M, Furie KL, Goldmakher GV, Hacke W, Kidwell CS, Kloska SP, Köhrmann M, Koroshetz W, Lee T-Y, Lees KR, Lev MH, Liebeskind DS, Ostergaard L, Powers WJ, Provenzale J, Schellinger P, Silbergleit R, Sorensen AG, Wardlaw J, Wu O, Warach S. Acute stroke imaging research roadmap. 2008. p. 1621–1628.
97. Wintermark M, Albers GW, Broderick JP, Demchuk AM, Fiebach JB, Fiehler J, Grotta JC, Houser G, Jovin TG, Lees KR, Lev MH, Liebeskind DS, Luby M, Muir KW, Parsons MW, Kummer von R, Wardlaw JM, Wu O, Yoo AJ, Alexandrov AV, Alger JR, Aviv RI, Bammer R, Baron J-C, Calamante F, Campbell BCV, Carpenter TC, Christensen S, Copen WA, Derdeyn CP, Haley EC Jr, Khatri P, Kudo K, Lansberg MG, Latour LL, Lee T-Y, Leigh R, Lin W, Lyden P, Mair G, Menon BK, Michel P, Mikulik R, Nogueira RG, Ostergaard L, Pedraza S, Riedel CH, Rowley HA, Sanelli PC, Sasaki M, Saver JL, Schaefer PW, Schellinger PD, Tsivgoulis G, Wechsler LR, White PM, Zaharchuk G, Zaidat OO, Davis SM, Donnan GA, Furlan AJ, Hacke W, Kang D-W, Kidwell C, Thijs VN, Thomalla G, Warach SJ. Acute Stroke Imaging Research Roadmap II. Stroke. 2013;44:2628–2639. 
98. Warach SJ, Luby M, Albers GW, Bammer R, Bivard A, Campbell BCV, Derdeyn C, Heit JJ, Khatri P, Lansberg MG, Liebeskind DS, Majoie CBLM, Marks MP, Menon BK, Muir KW, Parsons MW, Vagal A, Yoo AJ, Alexandrov AV, Baron J-C, Fiorella DJ, Furlan AJ, Puig J, Schellinger PD, Wintermark M, Stroke Imaging Research (STIR) and VISTA-Imaging Investigators. Acute Stroke Imaging Research Roadmap III Imaging Selection and Outcomes in Acute Stroke Reperfusion Clinical Trials: Consensus Recommendations and Further Research Priorities. Stroke. 2016;47:1389–1398. 
99. Fiehler J, Albers GW, Boulanger J-M, Derex L, Gass A, Hjort N, Kim JS, Liebeskind DS, Neumann-Haefelin T, Pedraza S, Rother J, Rothwell P, Rovira A, Schellinger PD, Trenkler J, MR STROKE Group. Bleeding risk analysis in stroke imaging before thromboLysis (BRASIL): pooled analysis of T2*-weighted magnetic resonance imaging data from 570 patients. Stroke. 2007;38:2738–2744. 
100. Neumann-Haefelin T, Hoelig S, Berkefeld J, Fiehler J, Gass A, Humpich M, Kastrup A, Kucinski T, Lecei O, Liebeskind DS, Rother J, Rosso C, Samson Y, Saver JL, Yan B, MR STROKE Group. Leukoaraiosis is a risk factor for symptomatic intracerebral hemorrhage after thrombolysis for acute stroke. Stroke. 2006;37:2463–2466. 
101. Schröder J, Cheng B, Ebinger M, Köhrmann M, Wu O, Kang D-W, Liebeskind DS, Tourdias T, Singer OC, Christensen S, Campbell B, Luby M, Warach S, Fiehler J, Fiebach JB, Gerloff C, Thomalla G, STIR and VISTA Imaging Investigators. Validity of acute stroke lesion volume estimation by diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomographic Score depends on lesion location in 496 patients with middle cerebral artery stroke. Stroke. 2014;45:3583–3588. 
102. Iturria-Medina Y, Carbonell FM, Evans AC, Alzheimer's Disease Neuroimaging Initiative. Multimodal imaging-based therapeutic fingerprints for optimizing personalized interventions: Application to neurodegeneration. Neuroimage. 2018;179:40–50. 
103. Sherif T, Rioux P, Rousseau M-E, Kassis N, Beck N, Adalat R, Das S, Glatard T, Evans AC. CBRAIN: a web-based, distributed computing platform for collaborative neuroimaging research. Front. Neuroinform. 2014;8:1472. 
104. Copen WA, Yoo AJ, Rost NS, Morais LT, Schaefer PW, Gonzalez RG, Wu O. In patients with suspected acute stroke, CT perfusion-based cerebral blood flow maps cannot substitute for DWI in measuring the ischemic core. PLoS ONE. 2017;12:e0188891. 
105. Borst J, Berkhemer OA, Roos YBWEM, van Bavel E, van Zwam WH, van Oostenbrugge RJ, van Walderveen MAA, Lingsma HF, van der Lugt A, Dippel DWJ, Yoo AJ, Marquering HA, Majoie CBLM, MR CLEAN Investigators. Value of Computed Tomographic Perfusion-Based Patient Selection for Intra-Arterial Acute Ischemic Stroke Treatment. Stroke. 2015;46:3375–3382. 
106. Nagel S, Sinha D, Day D, Reith W, Chapot R, Papanagiotou P, Warburton EA, Guyler P, Tysoe S, Fassbender K, Walter S, Essig M, Heidenrich J, Konstas AA, Harrison M, Papadakis M, Greveson E, Joly O, Gerry S, Maguire H, Roffe C, Hampton-Till J, Buchan AM, Grunwald IQ. e-ASPECTS software is non-inferior to neuroradiologists in applying the ASPECT score to computed tomography scans of acute ischemic stroke patients. International Journal of Stroke. 2017;12:615–622. 
107. Middleton S, McElduff P, Ward J, Grimshaw JM, Dale S, D'Este C, Drury P, Griffiths R, Cheung NW, Quinn C, Evans M, Cadilhac D, Levi C, QASC Trialists Group. Implementation of evidence-based treatment protocols to manage fever, hyperglycaemia, and swallowing dysfunction in acute stroke (QASC): a cluster randomised controlled trial. Lancet. 2011;378:1699–1706. 
108. Middleton S, Coughlan K, Mnatzaganian G, Low Choy N, Dale S, Jammali-Blasi A, Levi C, Grimshaw JM, Ward J, Cadilhac DA, McElduff P, Hiller JE, D'Este C. Mortality Reduction for Fever, Hyperglycemia, and Swallowing Nurse-Initiated Stroke Intervention: QASC Trial (Quality in Acute Stroke Care) Follow-Up. Stroke. 2017;48:1331–1336. 
109. Australian Commision on Safety and Quality in Health Care. Economic evaluation of investigator-initiated clinical trials conducted by networks [Internet]. 2017 [cited 2019 Jan 4];:1–74. Available from:
110. Cadilhac DA, Purvis T, Kilkenny MF, Longworth M, Mohr K, Pollack M, Levi CR, New South Wales Strokes Services Coordinating Commitee, Agency for Clinical Innovation. Evaluation of rural stroke services: does implementation of coordinators and pathways improve care in rural hospitals? Stroke. 2013;44:2848–2853. 
111. Walter S, Kostopoulos P, Haass A, Keller I, Lesmeister M, Schlechtriemen T, Roth C, Papanagiotou P, Grunwald I, Schumacher H, Helwig S, Viera J, Körner H, Alexandrou M, Yilmaz U, Ziegler K, Schmidt K, Dabew R, Kubulus D, Liu Y, Volk T, Kronfeld K, Ruckes C, Bertsch T, Reith W, Fassbender K. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. The Lancet Neurology. 2012;11:397–404. 
112. Vaibhav K, Braun M, Khan MB, Fatima S, Saad N, Shankar A, Khan ZT, Harris RBS, Yang Q, Huo Y, Arbab AS, Giri S, Alleyne CH, Vender JR, Hess DC, Baban B, Hoda MN, Dhandapani KM. Remote ischemic post-conditioning promotes hematoma resolution via AMPK-dependent immune regulation. J Exp Med. 2018;215:2636–2654. 
113. Khurana D, Kaul S, Bornstein NM, ImpACT-1 Study Group. Implant for augmentation of cerebral blood flow trial 1: a pilot study evaluating the safety and effectiveness of the Ischaemic Stroke System for treatment of acute ischaemic stroke. Int J Stroke. 2009;4:480–485. 
114. Bar-Shir A, Shemesh N, Nossin-Manor R, Cohen Y. Late stimulation of the sphenopalatine-ganglion in ischemic rats: improvement in N-acetyl-aspartate levels and diffusion weighted imaging characteristics as seen by MR. J Magn Reson Imaging. 2010;31:1355–1363. 

About: International symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy 

The 14thInternational Symposium on Thrombolysis, Thrombectomy and Acute Stroke Therapy (TTST) took place in Houston, Texas on October 21stand 22nd, 2018. TTST meetings began in 1990 during the initial simultaneous clinical investigations into thrombolysis taking place in the United States, Europe, and Japan. Since then, TTST has brought together invited experts on reperfusion therapy for acute stroke every two years, and rotates among venues in Europe, North America, and Asia. TTST has provided opportunities for stimulating controversial discussions on data from recent clinical trials, the status of major ongoing studies, and priorities for future research. Initially focused on thrombolytic therapy, recent TTST conferences have helped lay the groundwork for the success of thrombectomy clinical research. 

Tuesday, April 9, 2019

Hope and support on Stroke Survivors' Day in Ghana

16th March is National Stroke Survivors' Day in Ghana and this year, stroke support organisation Stroke Association Support Network Ghana (SASNET Ghana), ensured that the day was full of hope and support for people affected by stroke. 

SASNET Ghana is a stroke support organisation member of the World Stroke Organization and a member of the Ghana NCD Alliance. SASNET Ghana wants a nation that recognises stroke and other non-communicable diseases (NCDs) as a public health priority. Its aim is that all Ghanaians are educated about the risk factors and signs of stroke, and all those affected by stroke have access to the best possible treatment and rehabilitation. SASNET Ghana campaigns for better stroke services and provides prevention awareness and rehabilitation recovery support services for stroke survivors.

2019 marked the second National Stroke Survivors' Day and SASNET Ghana used the day to promote the message that there is life after stroke and that with the right information, treatment, care and support, people affected by stroke can have improved outcomes. The day was also an opportunity for SASNET Ghana to mobilise the general population to support people affected by stroke and to challenge stigma and discrimination.

As part of their activities for the day SASNET Ghana held a Community NCD Awareness Forum in partnership with the Ghana NCD Alliance. In his welcome  address, Mr. Ad Adams Ebenezer, Vice Chairman of the Ghana NCD Alliance and Director of Operations for SASNET Ghana, focused on NCD risk factors and the increasing incidence of hypertension and stroke across the country. Ad Adams emphasized the need for a multi-stakeholder approach to combat NCDs, including the Government, health sector, civil society organisations and citizens working together.

During the Forum people living with NCDs shared their experiences. Mr. Samuel Sedodo talked about the effects he has experienced due to his stroke. He highlighted that caring for people affected by stroke is challenging and that there needs to be increased support from the Government for long term care. He also called on young people to take their health seriously.

Featured Post

Epidemiologic profiling for stroke in Nepal: Endeavour towards establishing database

Resha Shrestha  @avi_neuro. , MS 1 , Avinash Chandra, MD 1 , Samir Acharya, MS 1 , Pranaya Shrestha, MS 1 , Pravesh Rajbhandari, MS 1 , Re...