Miracles of Modern Medicine: Advances in Stroke Management

Dr. David Guzick, M.D., Ph.D.

February 23, 2009

JD is an 80 y/o woman who developed acute confusion, aphasia, quadriparesis and cortical blindness early one morning in 2006. Her husband called 911 and she was taken to SMH where she was immediately evaluated by physicians from Emergency Medicine and the Stroke Service and was found to have a severe stroke (NIH Stroke Scale Score = 15). She underwent laboratory studies and a head CT scan prior to being treated with a thrombolytic agent, intravenous tissue plasminogen activator (t-PA) within 2 hours of her onset of symptoms. Her MRI scan of the brain subsequently revealed infarctions in the right thalamus and both occipital lobes. While on the Stroke Unit, JD underwent diagnostic testing and evaluations by several therapists. Her symptoms gradually improved over the next 3-4 days and she was discharged to a skilled nursing facility for continued rehabilitation. Two weeks later, she was transferred to an assisted living facility. She is currently independent in all of her activities and was recently cleared for driving again.

ST is a 38 year-old woman with prior heart disease who, a few months ago, arrived at the SMH Emergency Department one hour after the onset of a stroke. Examination revealed right hemiplegia, aphasia, gaze deviation, and facial droop; she had a severe stroke (NIH Stroke Scale = 16). She underwent immediate CT angiography and CT perfusion, demonstrating an occlusion of her left middle cerebral artery (MCA), with corresponding reduction in MCA blood flow and a large ischemic area in that territory of her brain. In light of ST’s severe stroke and large vessel occlusion, the endovascular team was rapidly assembled, simultaneous with administration of intravenous tPA. Unfortunately, ST did not show improvement in response to medical therapy. She therefore underwent a form of endovascular treatment in which a special catheter (Mechanical Embolus Removal in Cerebral Ischemia or “MERCI” retriever) was threaded to the point of occlusion, and the clot was removed. With her cerebral artery thus re-canalized, the patient experienced a rapid postoperative recovery and was essentially back to normal at 3 month follow-up clinic visit.

This newsletter is the story of the amazing progress that has been made in the evaluation and treatment of stroke. Strokes that would have led to serious and long-term impairment or death a few years ago can now be treated, as in the cases above, in a manner that allows virtually complete recovery.

Stroke, also known as cerebrovascular accident (CVA) or "brain attack," is a syndrome caused by a disruption in the flow of blood to part of the brain due to either occlusion of a blood vessel (ischemic stroke) or rupture of a blood vessel (hemorrhagic stroke). The interruption in blood flow deprives the brain of nutrients and oxygen, resulting in injury to cells in the affected vascular territory of the brain. When brain cells die, the function of the body parts they control is impaired or lost.

According to the latest epidemiologic data from the American Heart Association (Circulation 2009;119:e1-e161), stroke is the third leading cause of death in the United States after heart disease and cancer. On average, every 40 seconds, someone in the United States has a stroke. Stroke is the number one cause of disability: 20% of patients need help walking, 70% cannot return to their previous jobs, and 51% are unable to return to work. Each year, 55,000 more women than men have a stroke, and African Americans have a risk of first-ever stroke that is almost twice that of Whites.

Of all strokes, 87% are ischemic, 10% are associated with intracerebral hemorrhage, and 3% are associated with subarachnoid hemorrhage. Focal neurologic symptoms such as diploplia, weakness on one side, loss of sensation, aphasia and visual field defects are suggestive of ischemic stroke, while symptoms such as severe headache, seizures, alterations in consciousness, and vomiting are more likely to reflect hemorrhagic stroke.

The patients described above had ischemic stroke. It is truly a credit to our team that they were able to respond so quickly and effectively. With a cerebral artery occlusion like the one suffered by ST, it has been estimated that 32,000 neurons, 230 million synapses and 200 meters of myelinated fibers are lost with each passing second. With every passing hour, 120 million neurons are lost, as are 830 billion synapses and 714 kilometers of myelinated fibers. Moreover, with each passing hour it is estimated that aging is accelerated by 3.6 years. Only with rapid treatment like that described above is there any hope of full recovery.

The turning point in stroke therapy (and indeed in mindset and approach of stroke specialists and the physician community at large) occurred in 1995 with publication of the NINDS trial of intravenous thrombolysis with tPA, which demonstrated significant benefit in the treatment of acute stroke. Indeed, when the FDA approved Activase (t-PA) in 1996 on the basis of this study, it was the first drug approved to treat acute ischemic stroke. Made by Genentech, the drug is given intravenously to dissolve the clot or clots that are keeping blood from flowing to the brain. It improves the chance of recovery by up to 30 percent when used correctly. But there are two major limitations--the need to begin the treatment within three hours, and the risk of intracranial bleeding. Of note, promising results from a large, European trial in which patients were treated up to 4.5 hours after symptom onset may prompt expansion of the time window here in the U.S. to 4.5 hours. This change in the time threshold for treatment has not occurred in the U.S. as yet, however.

Despite initial controversy, the NINDS results have now been replicated in large community-based registries across North America and Europe; thus, IV tPA now represents the minimum standard of care in the treatment of acute stroke within 3 hours. Strict limitations on the therapeutic time-window and numerous exclusions for eligibility have led to thrombolysis rates of <2% across most North American hospitals, however. These factors, coupled with diminished efficacy of intravenous tPA in large-vessel and/or severe (NIHSS≥10) stroke, have prompted a search for alternative or complementary approaches.

One such approach has been to capitalize on the growing experience and advances with endovascular treatment of cerebrovascular disease over the past two decades, in combination with improvements in imaging studies. Beginning with treatment of brain aneurysms and arteriovenous malformations, endovascular specialists and device manufacturers have worked together to make minimally invasive intra-arterial treatment of such lesions a mainstream option. A pivotal point in the application of such technology to the treatment of acute ischemic stroke was publication of the PROACT-II trial in 1999, showing efficacy of intra-arterial pro-urokinase in MCA occlusion. While FDA approval was not granted at that time, this spurred rapid advances in (off-label) use of intra-arterial thrombolysis, mechanical clot disruption with microwires/snares, ultrasound-tipped infusion microcatheters, thrombolysis with glycoprotein inhibitors, and eventually intracranial angioplasty and stenting for both acute and chronic cerebrovascular ischemia.

This evolution has heralded a new dawn in treatment of stroke by offering focal, targeted treatments that can overcome prior time-window and exclusionary limitations of systemic thrombolysis. Recent trials have begun to address these advances in stroke treatment by examining the combination of “bridging” intravenous tPA with intra-arterial therapy in the treatment of severe stroke, with systemic thrombolysis administered as the patient is prepared for endovascular treatment. Phase 2 trials (Interventional Management of Stroke-II) have shown improved outcomes with this approach when compared with a matched historical cohort from the NINDS intravenous tPA trial, and URMC is in the planning stages of joining IMS-III, a large ongoing phase III trial comparing intravenous tPA alone versus combined tPA and endovascular therapy within three hours of stroke onset.

In parallel, acute stroke therapy is now increasingly guided by new imaging modalities that overcome reliance on pure time-based windows, and instead directly image the ischemic brain to rapidly determine site of occlusion and the volume of “infarcted core” (dead brain) versus “ischemic penumbra” surrounding the core (salvageable brain). Such an approach provides rapid diagnosis and triage of patients in the ED. With institution of a new CT Acute Stroke Protocol at the Strong ED over the past few months, emergency physicians and stroke specialists now can rapidly determine physiology and anatomy of cerebral blood flow in each stroke patient, guiding a tailored approach to each individual. This has promoted an interdepartmental collaborative effort between Emergency Medicine, Neurology, Neurosurgery, Neuroradiology, and Critical Care Medicine; with 24/7 in-house resident presence across all specialties. This includes round-the-clock access to stroke and endovascular fellows and attendings, an aggressive “level-1 stroke center” approach (modeled on trauma) to providing acute stroke care to all surrounding institutions and community hospitals in the region, and institution of a separate on-call nursing and technologist team for the neuroendovascular angiosuite. Progress in developing this “Brain Attack Team” at URMC is expected to improve outcomes from acute stroke and diminish the soaring burden of cerebrovascular disease in our community.

Whereas both thrombolysis and mechanical clot extraction aim to restore blood flow in the patient with an acute ischemic stroke, additional treatment strategies target injured but potentially salvageable cells in the ischemic penumbra. The ideal neuroprotectant will either arrest or reverse cellular processes initiated by hypoxic-ischemic injury that lead to immediate or delayed cell death. Unfortunately, none of the agents tested thus far in humans have proved efficacious and safe. Reasons for this lack of success have been varied: the time window for treatment was too long, side effects were toxic, clinical trials were underpowered, or the pre-clinical data were insufficient to warrant a Phase III clinical trial. Nevertheless, the search continues for a neuroprotectant that can be administered either alone or ideally in combination with a thrombolytic agent.

Work by Berislav Zlokovic, MD, PhD, Professor of Neurosurgery, and his colleagues has demonstrated that activated Protein C (APC) has both direct neuronal and vascular anti-apoptotic activities, and when tested in multiple animal models of ischemic stroke, APC reduces infarct size, improves behavioral outcome, controls t-PA-induced neurotoxicity, and increases cerebral blood flow. Specifically, APC inhibits hypoxia-induced apoptosis in mouse and human brain endothelial cells and blocks apoptotic pathways in stressed cortical neurons both in vitro and in vivo after ischemic stroke. Based on these findings, Curtis Benesch, Associate Professor of Neurology, successfully secured funding from the NHLBI to conduct a clinical trial using APC in patients with acute ischemic stroke. The “APC in Acute Stroke Trial” (APCAST) is a multi-center, dose-escalation, safety and feasibility trial of APC administered within 6 hours of symptom onset. The study is currently enrolling subjects at URMC along with 5 other sites.

According to Latha Stead, Professor and Chair of Emergency Medicine, “it is an exciting time to be at URMC where there is a multidisciplinary effort towards the management of acute stroke, involving specialists from the emergency department, imaging sciences, neurology, neurosurgery, and rehabilitation medicine.” Indeed, it appears that a critical mass has developed by the combination of longstanding and new faculty. Dr. Benesch, noted for his research on the medical management of stroke, has been the long-term Director of the Stoke Service in the Department of Neurology. John DeVeikis, MD, Professor of Radiology, has been performing endovascular treatment of stroke for many years in the context of a broad-based practice in neuroradiology. Babak Jahromi, MD, PhD, Assistant Professor of Neurosurgery, who has been at URMC since August, 2008, recently completed a fellowship focused on state-of-the-art endovascular treatment of stroke, and Latha Stead, MD, Professor and Chair of Emergency Medicine, who just arrived on January 1 from Mayo Clinic, has devoted her research efforts to developing stroke management protocols from the perspective of patients who present to the E.D.

Dr. Stead continues, “We are not only collaborating to provide state of the art care to URMC patients, but are also launching a city-wide stroke collaborative designed to optimize and streamline care via standardization of care protocols. EMS crews will be trained by Dr. Jeremy Cushman in the recognition of a stroke via use of the Cincinnati prehospital stroke scale, and will alert the hospital communications centers that an acute stroke is on the way. This will allow mobilization of the multidisciplinary team to the bedside upon the patient’s arrival, so that no time is wasted, as ‘time is brain.’ In the ED, a 12 step protocol is being deployed that allows for rapid evaluation to determine the best type of intervention.” This protocol is based on the one developed by Dr. Stead at Mayo Clinic, and termed BEST for “Better Early Stroke Treatment.” Dr. Stead concludes that “we are fortunate to have a stellar duo of neuroendovascular specialists in Drs. Jahromi and Devaikis, who are available 24/7 to provide this important time sensitive treatment option for our patients. They employ state of the art imaging technology in the form of CT perfusion, the protocol for which has been perfected by Dr. Jahromi in order to decipher whether the stroke is amenable and best treated by a catheter based intervention. Studies support that such interventions are associated with better outcomes when compared to the natural history of the event.”

Strong Memorial Hospital is an accredited Stroke Center by the Joint Commission and has been designated as a Primary Stroke Center by the New York State Department of Health. In addition, the Strong Stroke Center has recently received the American Heart Association Gold Performance Achievement Award based on outstanding adherence to established performance standards. What this award truly recognizes is the exemplary day-to-day work of the nurses, therapists and staff of the Stroke Unit on 5-1600, the efforts of Stroke Nurse Practitioners, Ann Leonhardt and Lynne Massaro-Baker, and the leadership of Justine Zentner, N.P., Stroke Program Coordinator. The Stroke Service at URMC performs over 700 consultations annually on patients with cerebrovascular disease.

With the combination of state-of-the-art imaging, specialized neurological and endovascular surgical talent, a well-coordinated E.D. protocol and a team of seasoned nurses and technicians committed to exemplary care, URMC is now one of the few institutions in the country capable of managing cases like JD and ST with the speed and expertise needed to obtain their superb outcomes. We should all take great pride in their extraordinary devotion and achievement.

Meliora,

David S. Guzick, MD, PhD
Dean, School of Medicine and Dentistry
University of Rochester

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