Pioneering Research at UB's Toshiba Stroke Research Center

More often than not, scientific advances come slowly and incrementally, each step dependent upon the work of earlier researchers whose focus, patience and plodding zeal were guided by a shared vision that at times may have seemed over-reaching, perhaps even a bit surreal.

In cases where these incremental steps are successful, however, there comes a turning point when the quiet, behind-the-scenes evolutionary work reaches a critical mass and becomes revolutionary in its impact.

Nowhere is this phenomenon better exemplified than in the work of neurosurgeons who over the past several decades have collaborated with other clinical specialists and basic scientists to make real the vision of treating stroke and other cerebral vascular diseases with minimally invasive surgical techniques. These techniques involve taking advantage of the body's circulation system to navigate micro-thin devices through the large artery in the groin until they reach injured or blocked vessels in the brain or neck, where treatment is provided using procedures and devices specially designed for endovascular surgery.

Bolstered by ongoing iterative advances in the miniaturization and visualization of these devices-and the testing and perfecting of them in a large number of clinical trials-minimally invasive approaches to cerebral vascular diseases not only are here to stay, but within the decade are expected by many to become the gold standard for a growing number of neurological conditions requiring surgery. The reasons for this are numerous: Because the endovascular approach is less invasive-requiring only a needle puncture in the groin as opposed to opening the skull-the risk of infection is lower, postoperative recuperation is faster, hospital stays are shorter, expenses are reduced and the emotional stress on patients and their families is significantly decreased.

A widely recognized leader in the field of neuroendovascular surgery is L. N. "Nick" Hopkins III, MD, chair and professor of neurosurgery and professor of radiology in the University at Buffalo School of Medicine and Biomedical Sciences, who also serves as director of the UB Toshiba Stroke Research Center. Inspired by cardiologists, whom he readily credits with pioneering the concept of endovascular intervention, Hopkins has long made it his mission to take minimally invasive techniques as they apply to coronary arteries and adapt them for use in the more delicate, convoluted and difficult-to-access blood vessels in the brain.

"While the concept is the same, the devices, techniques and training required to treat cerebral vascular disease with endovascular approaches are quite different from those used to treat coronary artery disease," he explains. "The intracranial circulation is much more tortuous and difficult to navigate, and the blood vessels in the brain are much thinner."

Undaunted by the challenge of discovering new or better ways to safely navigate micro-devices deep within the brain, Hopkins, in collaboration with his UB colleagues, has been at the forefront of efforts to develop and test many of these devices and procedures and has meticulously built an Endovascular Surgical Neuroradiology Service at Kaleida Health's Millard Fillmore Hospital in Buffalo that is a magnet for patients from all over the United States. In addition, the service has become a top draw for talented residents and fellows seeking to learn advanced neuroendovascular surgical skills and to participate in groundbreaking research projects in collaboration with scientists at the Toshiba Stroke Research Center.

Hopkins attributes the success of UB's neurosurgery program to its three-pronged approach of clinical care, research and education, as well as to the fact that the faculty is multidisciplinary.

"We have always had very strong vascular surgery and neurosurgery here," he notes. "However, I think that the addition of the endovascular approach has made our center a leader because we can offer both traditional, open surgery, as well as endovascular surgery interchangeably, with no bias. By this I mean that all services are provided by one group of physicians, so there's not one specialist saying, 'I can do it better with open surgery' and another saying, 'I can do it better with endovascular surgery.'

"As you might imagine," he continues, "as the less-invasive endovascular techniques continue to mature and gain popularity, this is a very important advantage because there are centers where the two approaches are separated and it's getting to be a competition between endovascular and traditional surgical techniques. In our department, because we're a multidisciplinary team, there's no competition, so we can avoid bias in deciding the best way to treat patients."

The synergy among clinical specialists in the department is further enhanced by the fact that basic-science faculty in the Toshiba Stroke Research Center also represent a broad spectrum of disciplines, including radiation physics, biomedical and aerospace engineering and polymer chemistry.

"One of the things I'm most proud of is that our program, because of the Toshiba Stroke Research Center, has always been in the lead in terms of research-mostly translational-type research-that goes hand in hand with the development of new techniques," says Hopkins.

The concept of the Toshiba Stroke Research Center was originated by Lee Guterman, PhD, MD '89, according to Hopkins (see article on page XX).

"Over the years, it's been a truly exciting thing for me to be associated with great people, and my partner, Lee Guterman, has been one of those people," says Hopkins. "Back when he was a medical student and resident at UB, Lee kept saying, 'We've got to be doing some research here.' And that led directly to the multidisciplinary team we put together in the early 1990s and, eventually, to our developing the concept of the Toshiba Stroke Research Center.

"The ability to do the preliminary work at the research center and then to transfer, or translate, that research into the clinical setting very quickly has been a huge opportunity for us to have both a strong clinical and teaching program," he adds.

The Ins and Outs of Stenting and Coiling

Two endovascular procedures that today have the potential to revolutionize the treatment of stroke are "stenting," which is used to prevent ischemic stroke (blockage of brain blood vessels), and "coiling," which is used to prevent hemorrhagic stroke, or aneurysm (burst blood vessels in the brain). Hopkins and his group have been involved in long-term clinical and laboratory studies that have directly contributed to the development of both of these procedures, neither of which has escaped growing pains as it inches its way toward winning acceptance as standard treatment for carefully defined patient populations.

The primary cause of ischemic stroke is a buildup of plaque in the carotid arteries on each side of the neck, which supply blood to the brain.

If patients present with TIAs, or transient-ischemic attacks (mini-strokes) and are found by Doppler ultrasound studies to have significant plaque build-up in their carotid arteries, the standard treatment over the past 50 or more years has been endarterectomy, a surgical procedure in which the artery is opened and the plaque is peeled out. Traditionally, the procedure has been performed by vascular surgeons; however, it is not uncommon for neurosurgeons to perform endarterectomy as well.

Although safe and effective for many patients, endarterectomy does cause significant scarring and is a high-risk procedure for patients with severe medical co-morbidities, such as coronary artery disease or pulmonary disease, according to Hopkins, who began performing the operation about 25 years ago.

In the early 1980s, Hopkins became convinced that alternatives to endarterectomy had to be found for high-risk patients, when he operated on the father of a friend. The patient was a physician who had severe diabetes, coronary disease and pulmonary disease and was obese. In addition, he presented with mini-strokes, which pointed to a severe blockage of his carotid artery.

"All this meant that it was going to be a difficult operation," recalls Hopkins, "but we didn't have an alternative. So I operated on him and he made it through the procedure, but it was difficult. To make a long story short, he never made it out of the ICU. Right then, I said there has to be a better way."

Shortly thereafter, a French surgeon began pioneering the use of balloon angioplasty for treatment of carotid artery disease. By the mid-1990s, surgeons were placing a tiny mesh cylinder, called a stent, over the balloon, so that when the balloon was inflated at the site of the occlusion, it expanded the stent, which then braced open the artery and maintained blood flow to the brain. Traditionally, this stenting procedure has been performed by interventional cardiologists and neuroradiologists.

Until recently, a serious drawback to the stenting approach was the tendency for pieces of plaque to be dislodged during the procedure and migrate up to the brain and cause a mini-stroke. This risk has been significantly reduced by the development of a tiny filter that is placed distal to the stent to collect any debris that is released during the procedure, after which it is removed.

Over the past five years, there have been ongoing studies assessing the safety and efficacy of stents in carotid artery disease, and the UB group has been involved in six of them, with either Hopkins or Guterman serving as principal investigator.

One of the most important trials to date is the SAPPHIRE (Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy) Trial, in which patients considered at high risk for surgery were randomized to receive either surgery or stents.

"Stents won overwhelmingly," says Hopkins, noting that the results of the study were reported at an American Heart Association meeting in November 2002. "It proved for the first time that stenting is safer and better for surgery in patients who are at high risk."

Currently, Hopkins is co-principal investigator for a study called CREST (Carotid Revascularization Endarterectomy vs. Stent), which is comparing endarterectomy with stenting in patients who are not at high risk for surgery.

"One of the things I think is important to emphasize is that all the way along in the development of this technology, our group has been extremely conservative in the way we have used it," Hopkins notes. "We don't use carotid stenting in the normal low-risk patients for which the FDA [Food and Drug Administration] has not approved a product. We reserve it for the high-risk patients. I think there are a lot of places where people have been using this technology pretty willy-nilly. We're just not ready for that yet. We don't know for sure that carotid stenting is as safe as carotid endarterectomy, which is still a great operation. More studies, like the CREST, need to be done."

As is the case with carotid artery disease, clinicians are determined to expand viable treatment options for patients with hemorrhagic cerebral aneurysm, a devastating condition that affects some 30,000 Americans a year, 15 percent of whom die within minutes and 50 percent, within a month.

For the past three decades, an intracranial surgical procedure called clipping has been the standard treatment for aneurysms. This involves a neurosurgeon opening the skull, finding the location of the bleeding vessel in the brain and placing a clamp on the section of artery that has become weakened and has bulged out owing to pressure from the circulating blood. (In some cases, the clip is applied to the parent vessel of the unruptured aneurysm-as opposed to the bleeding vessel-to prevent a future rupture.)

Over the past 12 years, an endovascular approach called coiling has come into its own as a technique that might someday supplant the need for invasive surgery to treat aneurysms.

Performed by either a neurosurgeon or a neuroradiologist, coiling involves the use of computer-aided X-ray imaging to navigate a catheter from the groin up into the brain to the site of the aneurysm, where micro-thin Slinky-like devices called coils are gently packed inside the aneurysm, where they form a dense mesh catacomb that clots off the bleeding.

Coil-type devices have been around for approximately 20 years; however, the technology was given a formidable boost in 1990, when Guido Guglielmi-a neurosurgeon and neuroradiologist with electrical expertise (then at the University of California at Los Angeles)-invented a coil that detaches from the catheter when zapped by a small electrical current.

Over the past decade, however, coiling has not flourished as much in the United States as it has in Europe owing to concerns that U.S. physicians have about the long-term efficacy of the procedure, as well as to differences in European and American health-care delivery and reimbursement systems.

Questions concerning the efficacy of the procedure were recently addressed in a landmark European study funded by the Medical Research Council (the British equivalent of the FDA) that compared coiling to surgery for the treatment of aneurysms. As reported in the October 26, 2002, issue of The Lancet, the ISAT (International Subarachnoid Aneurysm Trial) was halted early when results after a year showed that 31 percent of patients who underwent surgery for aneurysm were disabled or had died compared with 24 percent who had undergone the coiling procedure. Although these results are promising, U. S. physicians are calling for additional studies that will address specific long-range concerns they have regarding the question of recurrent hemorrhage after coiling compared to surgery.

While the neurosurgeons are participating in ongoing trials to examine the efficacy of coiling and coiling devices, they are also working with their UB colleagues at the Toshiba Stroke Research Center to develop improvements to existing coiling technology, as well as next-generation devices and procedures that have the potential to someday supplant coiling itself.

One such improvement that was developed at the center is the idea of using specialized neuro stents to overcome a significant problem that had precluded coiling from being used to treat aneurysms that have a wide neck (the opening from the normal blood vessel into the bulge). For these types of aneurysms (an estimated 30 to 40 percent of all aneurysms), coiling doesn't work because the devices cannot be held in place-they slip out through the wide neck.

Several years ago, Guterman and his colleague Ajay Wakhloo, MD, PhD, (now director of interventional radiology at the University of Miami) developed the concept of placing a stent at the base of a wide-necked aneurysm to hold the coils in place.

Owing to the development of this new technique, which is now in clinical use, neurosurgeons and neuroradiologists can effectively treat a larger number of aneurysms using less invasive endovascular procedures.

"The technique accomplishes three things," explains Guterman, UB assistant professor of neurosurgery and co-director for device development at the Toshiba Stroke Research Center. "One, it enables us to confine the coil within the aneurysm; two, it actually shapes the flow of blood, which is funneled by the stent back into the normal artery; and three, it straightens out a segment of the artery where the aneurysm is, which gives the blood a further hemodynamic boost."

Image Is Everything

The idea to develop a next-generation device that might someday supplant coiling has evolved from a seemingly unrelated but highly successful area of research at the Toshiba Stroke Research Center that promises to advance all aspects of neuroendovascular surgery: the development of a prototype camera that can turn blurred X-ray images of tiny blood vessels and micro-devices into high-resolution images that can detect a structure as fine as a single strut on a neuro stent.

Called a "high-resolution region-of-interest microangiographic digital detector," the camera, which was patented by UB in September 2002, is close to being ready to test in the clinic, according to Stephen Rudin, PhD, UB professor of radiology and physics, codirector of the center's Imaging Division and lead researcher on the project.

Having clear X-ray images of vessels and instruments is critical to reaching a damaged or occluded site in the brain without injuring vessels along the way. Once at the site, improved visualization greatly enhances a clinician's ability to place or reposition a device.

Work on the camera began in 1999 with the support of a three-year, $1.2 million grant from the National Institute of Neurological Disorders and Stroke. Much progress has been made since that time.

"We started with an existing camera chip that had about a centimeter-by-centimeter field of view, which is very impractical," explains Rudin.

"We now have a five-centimeter-by-five-centimeter field of view and can correct for artifacts and nonlinearities, something we couldn't do before," he continues. "Also, we are able to take pictures at five frames per second, at 50-micron pixel sizes. Since the images are digital-just like you'd get from any digital camera-we can place them in files in a computer, where they can be processed, displayed and manipulated. These are all things that conventional equipment can do at rough resolution; we are doing them at high resolution."

While the current camera is in the final phase of being readied for testing in the clinic, a new camera is under development that the researchers hope will move the technology forward from five frames per second to 30.

"This is the subject of one of our graduate student's thesis," says Rudin-"to be able to go to 30 frames a second, which is real-time."

Another more long-term goal for the team is to take the camera, which is designed only for angiography, and develop it to a point where it can be integrated into a single device that can perform angiography in combination with fluoroscopy.

"Normally what the surgeons do is switch back and forth between the fluoroscopy, which provides real-time, low-resolution imaging, and angiography, which provides good-quality images at somewhat higher exposure, but not the continuous, real-time imaging that you get with fluoroscopy," explains Rudin. "What they'd really like-and what we'd like to develop for them-is one device that can switch back and forth between the two.

"To do that requires a non-trivial step from where we are," he adds with a chuckle. "However, we do have all the elements of technology in place; they've been tested, and are successful enough at this point to make it feasible for one of our students to earn his PhD on the topic."

Almost as exciting to Rudin and the research team at the Toshiba Stroke Research Center is a new capability they have discovered for the camera-it allows them to see well enough to rotate a stent on its axis.

This realization has led the scientists to formulate a concept that may lead to the development of a new endovascular treatment for aneurysm: If stents can be clearly visualized and manipulated, why not create a stent that has a low-porosity patch on it that can be maneuvered up against the neck of an aneurysm to seal it and thereby prevent it from growing and hemorrhaging?

"Aneurysms are bulges in the vessel, and these bulges are not symmetrical," explains Rudin. "The advantage now is that we can use the camera to not only see at high resolution things as small as a strut [on a stent], but we feel that we can rotate the stent on its axis, and if there's any asymmetry, we'll be able to localize it and wall off the aneurysm with the low-porosity patch."

This approach, Rudin and his group theorize, might someday make coils superfluous.

"In the past, people hadn't thought of this approach because there was no way to control the stent because you couldn't see it clearly enough," explains Rudin.

"We would have to be very precise, very targeted when we're positioning these patches over the aneurysm," adds Guterman. "It can't be done sloppily because there are problems with putting low-porosity regions in neurovasculature. For example, there are tiny perforator vessels that come off of the main vessels. You don't want to cover these up because they lead directly into brain tissue, and if you cover them up and stop the flow, you can cause severe damage. So the placement of this type of stent will require very careful guidance, which means you have to be able to see what you're doing, which means you have to have high resolution, which we now have with the new camera."

A patent application has been submitted for the new device, called an asymmetric low-porosity stent, and in January 2002 the researchers received a $75,000 grant from the UB Office of Science, Technology Transfer and Economic Outreach (STOR) that will enable them to buy equipment needed for the fabrication of an array of prototype devices.

Teaching the Teachers

These and other clinical-research endeavors serve to attract the best and brightest residents and fellows from around the world, who, in turn, continuously reinfuse the UB neurosurgery group with energy, ideas and talent.

Each year, the department accepts one or two residents; it also offers a two-year fellowship in endovascular surgical neuroradiology that is open to two individuals at a time. (Other fellowship training is offered in neurooncology and in critical care and stroke.) To date, some 25 fellows have graduated from the UB program.

"All of our alumni are out there starting their own programs, and that's even more exciting," says Hopkins. "This [training] is one of the main reasons why our service is strong. Because when there is a difficult decision to be made at the angiography table, we have the most incredible team of young people standing there kicking ideas around.

"These kids are so smart that I find that after the first six months I'm learning as much from them as they are learning from me," he continues. "Oh sure, I've got a few gray hairs and when one of them gets into a technically difficult situation, I can sometimes go in and show them a little trick or two, but these young people are phenomenal. Every one of them has come to me with recommendations from their chair, saying: 'This is the best student I have ever trained,' and they send them here.

"So I have been absolutely privileged to be able to teach and collaborate with the talented young people who choose to come here. They've given up two years to learn these new endovascular techniques because they feel, as I do, that the future of neurosurgery in the vascular area is going to be endovascular."

Currently, the senior fellow in endovascular surgical neuroradiology at UB is Elad Levy, MD, who earned his medical degree at George Washington University and has completed two years of residency training in neurosurgery at the University of Pittsburgh.

"I think everyone [in the field] considers this to be the number-one endovascular fellowship in neurosurgery in the country," says Levy, who will complete his training at UB in June 2003, after which he will return to the University of Pittsburgh to finish his residency. "Dr. Hopkins has been a pioneer in the past decade. He's really considered by many to be the 'father' of neuroendovascular surgery; he's constantly pushing the envelope. Most importantly, however, he is a mentor in every sense of the word. He teaches us not only about neuroendovascular surgery, but about patient care and about judgement. Judgement comes from experience, and I don't think anyone else has as much experience as Dr. Hopkins does."

In terms of advances in clinical research, Levy says "Buffalo is the leader in intracranial stenting," and he explains why he thinks now is a particularly exciting time to be involved in neuroendovascular surgery.

"As recently as two years ago, stents really had a lot of trouble going around the C-1 arch, where the vertebral artery takes a very sharp turn before going into the skull base, or the intracranial cavity," he says.

The reason for this is that the stents were designed for the heart, so were not delicate or pliable enough for neuroendovascular surgery, according to Levy. Today, however, finer, more pliable stents designed for neurologic applications can navigate vessels as small as two millimeters.

"Essentially, you can just about go wherever microcatheters go [within the body's vascular system]; that's how soft these stents are," notes Levy. "So, if a catheter can get in there, so can a stent."

Levy is enthusiastic about the research opportunities he has had through his fellowship and is eager to describe a UB study he recently collaborated on that was published in the December 2002 (Vol. 97) issue of the Journal of Neurosurgery.

The study pertained to stenting for atherosclerotic disease in intracranial vessels using what Levy refers to as "a revolutionary technique."

"Traditionally, surgeons just go in and stent the lesion, but there is a high incidence of dislodging plaque, which goes upstream and causes strokes," he explains.

Under Hopkins leadership, the UB study group examined whether they could treat vertebrobasilar atherosclerotic disease with staged stent-assisted angioplasty, according to Levy. "The idea was to first treat the plaque with angioplasty to open up the vessel to give it a little bit more blood flow, then let it heal before returning in a month or two-after there had been some scar formation and protection-and then treat with stenting to provide the best revascularization.

"Our question was: 'Is this a safer approach?' And there were no strokes in the subgroup of patients that we treated with this 'staged-stenting' approach."

While large-scale, multiple-center trials need to be conducted before the efficacy of this new approach can be determined, Levy is convinced that studies like this are pointing to where his field is moving in the future.

He is also convinced that his work on these studies is helping him to develop the endovascular expertise he will need as a neurosurgeon.

"There's no such thing as a magic bullet, so the more tools surgeons have to treat neurovascular disease, the better position they are in, and the better surgeon they will be," says Levy. "And this removes bias. Most people [in the field] can do one or the other: Typically the endovascular procedures are done by neuroradiologists, and surgery is done by neurosurgeons. So there's always the possibility that there will be a clinical bias, a lack of information, or even a financial bias to treat your patients one way or another. But if you have a variety of tools, a variety of skills, it helps you to individualize patient care."

Collaboration Among Specialists

As technical barriers continue to fall, clearing the way for a future that is sure to include endovascular approaches to cerebral vascular diseases, it will be physicians like Levy and his peers who will have to resolve the thorny, long-term issues related to which specialists will provide such care and, subsequently, which will reap the economic rewards-issues that, over the years, have evolved parallel to the technology.

Leaders today, like Hopkins, can strive to lay a foundation but, ultimately, it will be the current generation of students, residents and fellows who will decide what the future will hold.

"Over the years, I've tried to build bridges," says Hopkins. "In our service, and on more and more services throughout the country, neurosurgeons are working hand in hand with neuroradiologists to manage the whole schema of care for the neuroendovascular patient, from diagnoses through preoperative and postoperative care. This, I feel, is what the blueprint should be for the future.

"From the patient's perspective," he adds, "it will be critical for specialists to find synergistic ways to provide these really wonderful new neuroendovascular techniques, many of which are certain to become standard care over the next decade."

The neuroendovascular surgical services and research programs described in this article represent just one area of focus in the University at Buffalo's Department of Neurosurgery.

To learn more about the full spectrum of technologically advanced services provided by UB's neurosurgical faculty-as well as state-of-the art research programs they are conducting in spine surgery, skull base surgery, neurooncology, pediatric neurosurgery, and cell implantation and regeneration-visit the Department of Neurosurgery's Web site at http://www.neurosurgerybuffalo.com/.