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Retrievable, Detachable Stent-Platform-Based Thrombectomy Device (Solitaire™ FR) for Acute Stroke Revascularization
First Demonstration of Feasibility in a Canine Stroke Model
First Demonstration of Feasibility in a Canine Stroke Model
Abstract
Objective. We sought to report the successful intracranial placement of the Solitaire FR device (ev3, Inc., Irvine, California), a self-expanding stent-platform-based thrombectomy device that is fully recoverable after deployment, effecting complete recanalization of soft and firm clots in a canine stroke model. Methods. Soft and firm clots were introduced in the target vessel to occlude the vessels completely in a mongrel dog. The clot was crossed with a SilverSpeed guidewire (ev3) and over the wire with a Rebar microcatheter (ev3). The Solitaire FR was deployed. The Solitaire FR and Rebar microcatheter were removed into the guide catheter while constant slow suction was maintained on the guide catheter. Angiographic runs were performed after deployment and retrieval of the Solitaire FR to assess recanalization, distal emboli, vessel damage, thrombosis and vasospasm. Results. Successful delivery of the device with immediate thrombolysis in myocardial infarction (TIMI) 3 recanalization after deployment was achieved once in the intracranial anterior spinal artery (1.6 mm) and thrice in the extracranial vertebral artery (2.3–2.7 mm). In the case of the anterior spinal artery and when a soft clot was used in the vertebral artery, a second pass was required for complete clot recovery. No difficulty was encountered with respect to flexibility or maneuverability of the device. The distal markers were visible; the device was able to be reliably deployed and recovered within 2–4 minutes. Conclusions. Use of this device in the intracranial vasculature of a canine stroke model was technically feasible and associated with a high success rate of recanalization after clot retrieval.
Key words: canine stroke model, clot retrieval, Solitaire™ FR Revascularization Device, stent platform, thrombectomy device
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Introduction
Reestablishment of flow to perfuse salvageable brain tissues has been shown to significantly reduce the morbidity and mortality of ischemic stroke.1,2 The Merci® mechanical clot retriever (Concentric Medical, Mountain View, California) and the Penumbra device (Penumbra, Inc., Alameda, California) are thrombectomy devices that have increased the ability to recanalize acute thromboembolic occlusion in patients with ischemic stroke.3,4 Self-expanding intracranial stents are being evaluated in this setting and their use has resulted in higher recanalization rates, albeit in small case series.5–8 Concerns over stent-assisted recanalization are the need for dual antiplatelet therapy and the possibility of late in-stent stenosis. Hauck et al9 and Kelly et al10 reported the use of the Enterprise Stent (Codman Neurovascular, Raynham, Massachusetts) as a temporary endovascular bypass in acute stroke. In both reported cases, the stent was partially deployed for some time and then retrieved, with successful recanalization of the occluded vessel. The Solitaire™ FR Revascularization Device (ev3, Inc., Irvine, California) (Figure 1) is a recoverable self-expanding thrombectomy device that can also be used as a temporary endovascular bypass. The Solitaire FR was developed as a result of the experience with the Solitaire™ AB Neurovascular Remodeling Device (ev3), which has been used for stent-assisted coiling.11–13 We report the first successful delivery and recovery of the Solitaire™ FR Revascularization Device in the intracranial and extracranial vessels after the introduction of clots of varying consistencies in a canine stroke model.
Materials and Methods
The Solitaire FR Revascularization Device is packaged in a single unit consisting of the ev3 Solitaire AB stent, an introducer sheath and a detachable push wire. The stent is laser-cut from nickel-titanium alloy (nitinol). It is attached to a nitinol pushwire and has a closed-cell design and a slit along its longitudinal axis throughout its length. The slit allows the two circumferential ends of the stent to overlap when placed in a vessel. The extent of overlap depends on the extent of oversizing. As the deployed device traverses from a small vessel to a large vessel, its cell shape and configuration are retained, and the device unrolls to change the extent of overlap. This unique feature and resulting cell stability allow this device to reliably retain clot while traversing the vessel. The thickness of the stent wall is 50–70 microns, creating minimal intrusion on the lumen of the target vessel. The outer diameter of the stent is small enough to allow delivery through a 0.021- or 0.027-inch inner-diameter microcatheter for its 4 or 6 mm diameter sizes, respectively. It can be used with any appropriate microguidewire. The stent has a radiopaque marker at its proximal end and three or four radiopaque markers on its distal end for its 4 mm or 6 mm diameter sizes, respectively. The radial force per unit length is 0.011 Newtons (N)/mm and is comparable to that of the Wingspan stent (0.012 N/mm). The study was performed with the approval of the Animal Care and Use Committee at our institution in accordance with guidelines established by the Animal Welfare Act.14 A mongrel dog (weight 20 kg) was placed under general anesthesia with 1.5–2.5% isoflurane. Therapeutic systemic anticoagulation was achieved by administering sufficient heparin (2500–3000 units) to produce an activated coagulation time of > 250 seconds. An 8 French (Fr) arterial access sheath was used to perform diagnostic cerebral angiography. Baseline angiographic images were acquired, with measurements obtained of the target vessels (left VA, 2.3–2.7 mm in diameter; and intracranial ASA, 1.6 mm in diameter) and distal vasculature. Soft and firm clots were created (approximately 2.5 mm and 8 mm in diameter in vitro) with a combination of barium sulfate, fibrinogen, thrombin and porcine blood, as reported previously.15 A 7 Fr balloon guide catheter was used to introduce clot into the intracranial ASA, and an 8 Fr balloon guide catheter was used to introduce clots into the left VA. The Y-connector was removed from the balloon guide catheter, and the clot was injected into a tube that was attached directly to the hub of the balloon guide catheter. The syringe attached to the clot tube was slowly depressed to introduce the clot at the desired location under fluoroscopic guidance. Angiography was performed to confirm clot position and vessel occlusion (thrombolysis in myocardial infarction [TIMI] grade 0).16 The 7 or 8 Fr balloon guide catheter used to introduce the clot was removed from the arterial access sheath and replaced with an 8 Fr balloon guide catheter a few minutes later. The clot was crossed with a SilverSpeed 0.014-inch guidewire. The clot was then crossed over the wire with a Rebar-18 microcatheter (for a 4 x 20 mm Solitaire FR) or with a Rebar-27 microcatheter (for a 6 x 30 mm Solitaire FR). Crossing of the clot with the device was confirmed when a puff of contrast material was seen distally. The guidewire was removed, and the Solitaire FR system was advanced to the distal tip of the Rebar microcatheter through the guide catheter. When the working length of the Solitaire FR was across the clot, the microcatheter tip was withdrawn to 1 cm proximal to the clot. Angiographic runs were performed to assess recanalization, distal emboli, vessel damage, thrombosis and vasospasm. The balloon catheter was inflated. The microcatheter was advanced over the Solitaire FR until the distal marker of the microcatheter was aligned with the proximal marker of the Solitaire FR. The Solitaire FR and Rebar microcatheter were removed as a system into the guide catheter and while constant slow suction was maintained on the guide catheter with a syringe. Angiographic runs were done again to assess recanalization, distal emboli, vessel damage, thrombosis and vasospasm.
Results
Successful delivery and retrieval of the Solitaire FR with immediate TIMI 3 recanalization16 after deployment were achieved once in the intracranial ASA (1.6 mm) and thrice in the extracranial VA (2.3–2.7 mm), as shown in Table 1. In the case of the ASA, a small part of the distal clot was left in the artery during the recovery but was retrieved completely with a second pass of the Solitaire FR (Figure 2). When a soft clot was used in the VA, a second pass was required for complete removal of the clot. In the other two cases, the clot was completely removed in the first pass (Figure 3). A photograph of the device with the removed clot is shown in Figure 4. No difficulty was encountered with respect to the flexibility or maneuverability of the thrombectomy device to the target vessel. The distal markers were visible; the device could be reliably deployed and recovered within 2–4 minutes. TIMI 3 flow was achieved in every case immediately after device deployment. Minimal residual vasospasm in the target vessel developed in both cases in which two passes of the device were made and was relieved by intra-arterial infusion of 25 mg of nitroglycerin. All devices and catheters were removed, and the dog was euthanized with pentobarbital (100 mg/kg).
Discussion
Clot-retrieval devices. Intra-arterial therapies for acute stroke have evolved rapidly in recent years. Mechanical revascularization with devices such as the Merci4 and Penumbra17 have improved recanalization rates to 70–80%. However, this rate is only marginally superior to the 66% recanalization rate in the Prolyse in Acute Cerebral Thromboembolism II trial.18 Concerns about the limited treatment window and associated hemorrhage risk of pharmacological thrombolysis and the higher yet not 100% rates of recanalization reported with mechanical thrombectomy have prompted interest in intracranial stenting.
Stent-assisted revascularization. Although use of self-expanding stents is being evaluated with enthusiasm, there is some skepticism regarding the incidence of in-stent stenosis and the use of antiplatelet therapy after stent placement in the acute stroke patient and, thus, the possibility of an increase in hemorrhage rates. Disappointingly high rates of recurrent stenosis (25–29.7%) have been described for midterm results after use of Wingspan self-expanding stents (Boston Scientific, Natick, Massachusetts) for chronic intracranial stenosis.19–22 Although most patients with in-stent stenosis remain asymptomatic, in-stent stenosis can cause neurologic symptoms and may require target-vessel recanalization.21,23 Zaidat et al8 reported 1 case (11%) of immediate in-stent restenosis after acute stroke treatment. The risk of in-stent stenosis may be higher in the setting of symptomatic intracranial stenosis or acute stroke as compared with the “natural history” of intracranial stents placed for aneurysm treatment.24 The need for aggressive antiplatelet and/or anticoagulant therapy associated with intracranial stent placement5,7–10,22,25–28 is a second major disadvantage if stent placement is used as a treatment technique in the setting of acute stroke. Patients treated for the prevention of recurrent stroke with aspirin face a hemorrhagic complication rate of 2.22 per 100 patient-years.29 With dual antiplatelet therapy or antiplatelets plus anticoagulation, the risk is increased.30–33 Zaidat et al8 reported an 11% hemorrhage rate associated with stent placement for acute stroke. Moreover, Levy et al7 reported lethal hemorrhages as a complication in 11% of patients treated with stent placement for acute stroke. Hauck et al9 and Kelly et al10 reported that use of the Enterprise stent as a temporary endovascular bypass in acute stroke provided the advantages of stent-assisted revascularization without the need for antiplatelet therapy and avoided the complication of in-stent restenosis. In both these cases, the Enterprise stent was partially deployed for some time and retrieved with successful recanalization of the occluded vessel. A retrievable stent-platform-based device like the Solitaire FR could be used in these situations.
Solitaire FR revascularization device. The Solitaire FR Revascularization Device is a thrombectomy device based on the Solitaire AB Neurovascular Remodeling Device that takes advantages of the high recanalization rate of stent-assisted revascularization and lower hemorrhage rate and increased time window of treatment with a mechanical thrombectomy device, while eliminating the disadvantages of placing a permanent implant in the neurovasculature, such as the need for antiplatelet therapy and avoidance of in-stent stenosis. In the present study, successful complete recanalization was achieved immediately after Solitaire FR deployment in every instance, although a second pass was required in two instances for complete clot retrieval after the device was recovered. The average estimated recanalization time with the Merci retrieval device in a previous animal study was 13 minutes,34 whereas the average time with the Solitaire FR thrombectomy device was 4 minutes. In the case of the soft clot, a longer interval between device deployment and recovery could have allowed complete clot retrieval during one pass. In both instances in which a second pass was attempted, mild vasospasm occurred, which was relieved by vasodilators. The device markers were visible, and the device was reliably deployed and recovered in the target vessels. The main advantage of this device is that it can be deployed as an intracranial stent, used as a temporary endovascular bypass and a clot retriever device on a case-by-case basis.
Study limitations. The main limitation of this study is that it was done in a single animal. Investigations in additional animals would allow evaluation of anatomic variations and clots of different ages. In the setting of human stroke, procedures are performed on thrombi that are not visible and can be depicted only indirectly and might change shape and position during the recovery procedure. Procedures in this study are not directly comparable to those in stroke patients as they were performed with visible thrombi (due to the barium sulfate), allowing optimal placement of the devices at and inside the thrombus. Although further evaluation of the Solitaire FR is necessary before clinical use, this is the first reported instance of safe and effective deployment and retrieval of this device in the intracranial circulation of a canine model for acute revascularization of ischemic stroke. Moreover, this study provides proof of the concept of a retrievable stent-platform-based thrombectomy device.
Conclusion
A retrievable, self-expanding stent platform-based thrombectomy device, the Solitaire FR Revascularization device, represents a novel interventional treatment option for acute stroke. The use of this device in the intracranial vasculature of a canine stroke model was technically feasible and had a high success rate of recanalization after clot retrieval. This thrombectomy device has the advantages of a clot-retrieval device, the immediate recanalization effectiveness of a self-expanding stent and can be used as a temporary endovascular bypass when necessary, while eliminating the need for aggressive antiplatelet therapy and the risk of in-stent stenosis associated with permanent deployment of that device. Although this new technology is exciting, further data are needed to assess the safety and efficacy of this device.
COMPLETE FIGURE LEGENDS
Figure 1. Illustration showing (A) an occlusive clot in the vessel that has been crossed by the Rebar microcatheter (ev3). The microwire has been exchanged with the Solitaire device (ev3) that is being deployed in the direction shown by the arrows. (B) The Solitaire device is completely deployed and pushes the clot to the side, restoring blood flow immediately in the occluded vessel. (C) The Solitaire with the clot and the Rebar are pulled with the clot into the guide catheter with constant syringe aspiration from the guide catheter.
Figure 2. Angiographic images showing (A) Baseline anatomy of the canine posterior circulation showing the right VA (A, 2.7 mm in diameter), proximal ASA (B, 1.8 mm in diameter) and distal ASA (C, 1.6 mm) in diameter. (B) TIMI 0 occlusion of the ASA after placement of a firm clot. (C) Placement of a Rebar 18 microcatheter in the ASA. (D) A 4- x 20-mm Solitaire FR device is deployed in the ASA. (E) TIMI 2 restoration of flow after deployment of Solitaire FR. (Arrows showing proximal and distal markers of the Solitaire FR device in D and E.) (F) TIMI 1 flow (arrow) in the ASA after recovery of the Solitaire FR due to a remnant thrombus in the proximal ASA. (G) Second pass of the 4- x 20-mm Solitaire FR establishing immediate TIMI 3 flow. (Arrows showing proximal and distal markers of the Solitaire FR device.) (H) TIMI 3 flow after recovery of the Solitaire FR.
Figure 3. Angiographic images showing (A) Left VA injection (proximal A, 2.4 mm; middle B, 2.7 mm; and distal C, 2.8 mm in diameter). (B) A Rebar 27 microcatheter (arrows) is shown to have crossed the clot. (C) Contrast puff through the Rebar showing distal patency (arrow). (D) Deployment of a 6- x 30-mm Solitaire FR device. (E) Immediate restoration of TIMI 3 flow post deployment. (Arrows showing proximal and distal markers of the Solitaire FR device in Figures D and E.) (F) TIMI 3 flow after recovery of the Solitaire FR device (shown by arrow).
Figure 4. Photographs showing the Solitaire FR device with the retrieved clot (actual size).
References
1. Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: The diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60:508–517.
2. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: A meta-analysis. Stroke 2007;38:967–973.
3. Bose A, Henkes H, Alfke K, et al. The Penumbra System: A mechanical device for the treatment of acute stroke due to thromboembolism. Am J Neuroradiol 2008;29:1409–1413.
4. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: Final results of the Multi MERCI trial. Stroke 2008;39:1205–1212.
5. Chiam PT, Samuelson RM, Mocco J, et al. Navigability trumps all: Stenting of acute middle cerebral artery occlusions with a new self-expandable stent. Am J Neuroradiol 2008;29:1956–1958.
6. Imai K, Mori T, Izumoto H, et al. Transluminal angioplasty and stenting for intracranial vertebrobasilar occlusive lesions in acute stroke patients. Am J Neuroradiol 2008;29:773–780.
7. Levy EI, Mehta R, Gupta R, et al. Self-expanding stents for recanalization of acute cerebrovascular occlusions. Am J Neuroradiol 2007;28:816–822.
8. Zaidat OO, Wolfe T, Hussain SI, et al. Interventional acute ischemic stroke therapy with intracranial self-expanding stent. Stroke 2008;39:2392–2395.
9. Hauck EF, Mocco J, Snyder KV, Levy EI. Temporary endovascular bypass: A novel treatment for acute stroke. Am J Neuroradiol 2009;30:1532–1533.
10. Kelly ME, Furlan AJ, Fiorella D. Recanalization of an acute middle cerebral artery occlusion using a self-expanding, reconstrainable, intracranial microstent as a temporary endovascular bypass. Stroke 2008;39:1770–1773.
11. Liebig T, Henkes H, Reinartz J, et al. A novel self-expanding fully retrievable intracranial stent (SOLO): Experience in nine procedures of stent-assisted aneurysm coil occlusion. Neuroradiology 2006;48:471–478.
12. Wakhloo AK, Gounis MJ. Retrievable closed cell intracranial stent for foreign body and clot removal. Neurosurgery 2008;62:ONS390–394.
13. Yavuz K, Geyik S, Pamuk AG, et al. Imsmediate and midterm follow-up results of using an electrodetachable, fully retrievable SOLO stent system in the endovascular coil occlusion of wide-necked cerebral aneurysms. J Neurosurg 2007;107:49–55.
14. Congress of the United States: Animal Welfare Act, Regulations, and Standards. https://wwwaphisusdagov/animal_welfare/ [Accessed September 28, 2009].
15. Levy EI, Sauvageau E, Hanel RA, et al. Self-expanding versus balloon-mounted stents for vessel recanalization following embolic occlusion in the canine model: Technical feasibility study. Am J Neuroradiol 2006;27:2069–2072.
16. TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med 1985;312:932–936.
17. McDougall CG, Clark W, Mayer T, et al. for the Penumbra Stroke Trial Investigators. The Penumbra Stroke Trial: Safety and effectiveness of a new generation of mechanical devices for clot removal in acute ischemic stroke. International Stroke Conference 2008 2008: New Orleans, LA, February 22.
18. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: A randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999;282:2003–2011.
19. Albuquerque FC, Levy EI, Turk AS, et al. Angiographic patterns of Wingspan in-stent restenosis. Neurosurgery 2008;63:23–28.
20. Turk AS, Levy EI, Albuquerque FC, et al. Influence of patient age and stenosis location on Wingspan in-stent restenosis. Am J Neuroradiol 2008;29:23–27.
21. Levy EI, Turk AS, Albuquerque FC, et al. Wingspan in-stent restenosis and thrombosis: Incidence, clinical presentation, and management. Neurosurgery 2007;61:644–651.
22. Zaidat OO, Klucznik R, Alexander MJ, et al. The NIH registry on use of the Wingspan stent for symptomatic 7–99% intracranial arterial stenosis. Neurology 2008;70:1518–1524.
23. Fiorella DJ, Levy EI, Turk AS, et al. Target lesion revascularization after Wingspan: Assessment of safety and durability. Stroke 2009;40:106–110.
24. Fiorella D, Albuquerque FC, Woo H, et al. Neuroform in-stent stenosis: Incidence, natural history, and treatment strategies. Neurosurgery 2006;59:34–42.
25. Bose A, Hartmann M, Henkes H, et al. A novel, self-expanding, nitinol stent in medically refractory intracranial atherosclerotic stenoses: The Wingspan study. Stroke 2007;38:1531–1537.
26. Fiorella D, Levy EI, Turk AS, et al. US multicenter experience with the Wingspan stent system for the treatment of intracranial atheromatous disease: Periprocedural results. Stroke 2007;38:881–887.
27. Hahnel S, Ringleb P, Hartmann M. Treatment of intracranial stenoses using the Neuroform stent system: Initial experience in five cases. Neuroradiology 2006;48:479–485.
28. Kurre W, Berkefeld J, Sitzer M, et al. Treatment of symptomatic high-grade intracranial stenoses with the balloon-expandable Pharos stent: Initial experience. Neuroradiology 2008;50:701–708.
29. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444–1451.
30. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008;71:1084–1089.
31. Kjaer J, Larsen CH, Poulsen TS, et al. Bleeding complications after treatment with clopidogrel and acetylsalicylic acid after acute coronary syndrome. Ugeskr Laeger 2006;168:3209–3214.
32. Reaume KT, Regal RE, Dorsch MP. Indications for dual antiplatelet therapy with aspirin and clopidogrel: Evidence-based recommendations for use. Ann Pharmacother 2008;42:550–557.
33. Aronow HD, Steinhubl SR, Brennan DM, et al. Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: Insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J 2009;157:369–374.
34. Brekenfeld C, Schroth G, El-Koussy M, et al. Mechanical thromboembolectomy for acute ischemic stroke: Comparison of the catch thrombectomy device and the Merci Retriever in vivo. Stroke 2008;39:1213–1219.
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From the aDepartments of Neurosurgery and bRadiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University New York; cDepartment of Neurosurgery, Millard Fillmore Gates Hospital, Kaleida Health; and Toshiba Stroke Research Center, dUniversity at Buffalo, State University of New York, Buffalo New York.
Disclosures: This study was funded by ev3, Inc. Dr. Hopkins receives research study grants from Abbott (ACT 1 Choice), Boston Scientific (CABANA), Cordis (SAPPHIRE WW), and ev3 (CREATE) and a research grant from Toshiba (for the Toshiba Stroke Research Center); has an ownership/financial interest in AccessClosure, Boston Scientific, and Micrus; serves on the Abbott Vascular Speakers’ Bureau; receives honoraria from Bard, Boston Scientific, Cordis, and from the following for speaking at conferences – Complete Conference Management, Cleveland Clinic, and SCAI; serves as a consultant to or on the advisory board for Abbott, AccessClosure, Bard, Boston Scientific, Cordis, Gore, Lumen Biomedical, Micrus, and Toshiba; and serves as the conference director for Nurcon Conferences/Strategic Medical Seminars LLC. Dr. Levy receives research grant support (principal investigator: Stent-Assisted Recanalization in acute Ischemic Stroke, SARIS), other research support (devices), and honoraria from Boston Scientific and research support from Micrus Endovascular and ev3; has ownership interests in Intratech Medical Ltd. and Mynx/Access Closure; serves as a consultant on the board of Scientific Advisors to Codman Neurovascular/Cordis Corporation; serves as a consultant per project and/or per hour for Micrus Endovascular, ev3, and TheraSyn Sensors, Inc.; and receives fees for carotid stent training from Abbott Vascular and ev3. Dr. Levy receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr. Natarajan reports no conflict of interest regarding the content herein. Dr. Siddiqui has received research grants from the University at Buffalo and from the National Institutes of Health (NINDS 1R01NS064592-01A1, Hemodynamic induction of pathologic remodeling leading to intracranial aneurysms); is a consultant to Codman Neurovascular/Cordis Corporation, Concentric Medical, ev3, and Micrus Endovascular; serves on speakers’ bureaus for Codman Neurovascular/Cordis Corporation and Genentech; and has received honoraria from Genentech, Neocure Group LLC, an American Association of Neurological Surgeons’ course, and an Emergency Medicine Conference and from Codman Neurovascular/Cordis Corporation for training other neurointerventionists. Dr. Siddiqui receives no consulting salary arrangements. All consulting is per project and/or per hour.
Address for correspondence: Elad I. Levy, MD, Millard Fillmore Gates Hospital, Kaleida Health, Departments of Neurosurgery & Radiology and Toshiba Stroke Research Center, University at Buffalo, State University of New York, 3 Gates Circle, Buffalo, NY 14209. E-mail: elevy@ubns.com
