The window expands for more effective stroke treatment

Buffalo psychologist Jamie Shiffner, Ph.D., beat the odds. The acute stroke patient was lucky enough to have everything go right after being struck down. With ischemic stroke, time is brain. Within moments of Shiffner's collapse at home on the evening of April 11, 2005, millions of neurons in his brain began dying every minute. The left side of Shiffner's body went numb, and attempts to talk resulted in nonsense phrases.

A race against the clock began, and recovering these functions was the prize. Blood flow had to be restored to ischemically injured neurons in Shiffner's brain to prevent their death and to avoid damage to blood vessels and the blood-brain barrier. The risk of potentially fatal brain hemorrhage increased with time, making tissue plasminogen activator therapy more dangerous. The standard protocol, established by the FDA in 1996, gives physicians just three hours from the onset of symptoms to intravenous administration of tPA.

Over the past 10 years, only 4% of potentially qualified patients have actually received tPA treatment. Patients often don't recognize the symptoms of stroke or understand the importance of immediate emergency treatment. Transport or emergency room response can be too slow. CT, an essential tool in screening patients for IV tPA, may be unavailable or lack staffing in off-hours.

Shiffner was lucky. His wife, Cathy Carter, Ph.D., also a psychologist, immediately dialed 911, and an ambulance arrived in 10 minutes. Five minutes later, he arrived in the ER of Millard Fillmore Gates Circle Hospital, a designated primary stroke center. Shiffner recalls a rush of activity. Neurologist Dr. E. Mark Hekler treated him in stocking feet. A head CT was completed and read in 40 minutes. Hemorrhagic stroke was ruled out and intravenous tPA administered less than 90 minutes after Shiffner had crumpled to the floor.

The end result was complete recovery. Hemiparesis and aphasia disappeared within four hours. To acknowledge the first anniversary of the event, the 53-year-old Shiffner will walk an American Stroke Association marathon in June.

Many of the 700,000 U.S. residents who suffer a stroke annually are not so fortunate. About 157,000 die, making stroke the third leading cause of death in the U.S. behind heart disease and all forms of cancer.

Medical progress and new institutional protocols made in the past year are widening the window of opportunity to safely administer intra-arterial thrombolyis and perform interventional revascularizations long after the FDA-mandated three-hour window has closed, delivering IV tPA to more qualified patients.

Diagnostic imaging is playing a role on two fronts. Institutionally, designated primary stroke centers sanctioned by the Joint Commission on Accreditation of Healthcare Organizations must meet criteria for fast imaging turnaround and 24/7 imager staffing. More than 230 hospitals have qualified for primary stroke center designation since program implementation in 2004.

Medically, several large clinical trials published since September 2005 have shown how functional MR and CT help more patients qualify for symptom-reversing therapies through better patient selection. University-based comprehensive stroke centers are increasingly performing intra-arterial thrombolysis and clot-clearing interventions with stents or FDA-approved Merci clot removal systems.

Results of the Multi-MERCI (Mechanical Embolus Removal in Cerebral Ischemia) Trial, announced in February, found the mechanical corkscrew device reestablished flow in large-vessel strokes among 111 patients who were ineligible for tPA or had undergone ineffective thrombolysis. Dr. Wade Smith, principal investigator of the 11-center trial, reported good functional outcomes in 34% of cases after 90 days. The Merci Extractor, made by Concentric Medical of Mountain View, CA, was awarded FDA clearance in 2004.

Investigational antithrombolytic agents such as desmotoplase used in combination with functional imaging have shown promise in clinical trials in stretching the treatment window to as long as nine hours. Imaging researchers have known since the 1990s that a mismatch finding between diffusion and perfusion MRI can isolate a stroke penumbra, the region of ischemic brain that will recover if reperfused. That capability, since extended to perfusion CT imaging, is key to recent developments.

"The whole idea is to use imaging to identify patients who are appropriate for treatment, independent of the time of onset of their stroke," said Dr. Michael Lev, director of emergency neuroradiology at Massachusetts General Hospital. "It has been long said that time is brain. We are trying to coin a new phase, 'Mismatch is brain.'"

FDA DEFINES TREATMENT TERMS

Except at a few academic institutions, however, first-response stroke treatment is still defined by the results of the 1995 National Institute of Neurological Disorders (NINDS) acute stroke trial (NEJM 1995;333:1581-1588). Patients treated with tPA were at least 30% more likely to have minimal or no disability after three months than patients given a placebo, but a 6.4% rate of symptomatic intracerebral hemorrhage led the FDA in 1996 to limit tPA administration to within three hours of symptom onset.

As a result, tPA is administered infrequently. A study by Mathew Reeves, Ph.D., of Michigan State University, published in Neurology in February, found that only 2% of stroke patients at 15 Michigan hospitals received the clot-busting treatment. A survey of North Carolina hospitals in 2000 (Stroke 2000;31:66-70) found that 66% of hospitals did not have stroke protocols, and 82% did not have rules for rapidly identifying patients experiencing a stroke.

Even under ideal conditions, some ER physicians do not order the drug. From survey responses of 1105 ER physicians in 2005, Dr. William G. Barsan, chair of emergency medicine at the University of Michigan, learned that 24% of respondents would probably not administer tPA even with access to CT, neuroradiology and neurology support, and an appropriate candidate. Two-thirds of its opponents cited the risk of brain hemorrhage for withholding treatment. About one-quarter doubted its effectiveness (Ann Emerg Med 2006;47(3):297).

The Brain Attack Coalition began to change this dismal tPA scenario. The coalition published groundbreaking guidelines for primary stroke centers in 2000 (JAMA 2000;283(23):3102-3109), and the JCAHO program put those recommendations into action.

To earn a JCAHO primary stroke center designation, hospitals must organize acute stroke teams available around the clock to respond to stroke patients as they arrive in the ER and coordinate care. Written protocols for that initial response must be implemented, and emergency medical services personnel in ambulances are taught to identify probable stroke cases and determine where those patients should be transported.

Emergency CT or MR services must be staffed day and night and procedures streamlined to differentiate between hemorrhagic and ischemic stroke within 25 minutes after the order has been written. A physician must interpret the results onsite or via teleradiology within 20 minutes of the scan's completion.

First-year results show that hospitals become more responsive after earning primary stroke center designation, according to Jean Range, executive director of JCAHO disease-specific care certification. Based on the experience of 30 designated primary stroke centers in 2005, Range found that tPA administration rates rose 18.3% from 65.7% to 84% of stroke patients arriving at the hospital within 2.5 hours.

Because of extensive community outreach, two-thirds of the stroke patients at El Camino Hospital in Mountain View, CA, arrive within 2.5 hours, said Dr. Ronald Hess, director of neurology. The hospital earned its JCAHO designation in February. Educational efforts have resulted in half of the arriving patients potentially qualifying for tPA, and 80% of that group are imaged and evaluated in time to receive thrombolysis. Overall, 13.7% of El Camino's stroke patients received tPA in 2005. The average time between arrival and drug treatment was 45 minutes.

ER PROTOCOLS

The reasons for improvement have been both psychological and social. Better training and protocols at El Camino made ER personnel more attuned to possible cases of stroke. They realized that walk-in patients need to be assessed as attentively as those arriving in an ambulance.

"If you arrive in an ambulance, you'll be rolled straight to the CT scanner, but if you walk in complaining of a weak arm, you could be given forms and told to take a seat," Hess said.

FDA limitations govern El Camino's approach to stroke imaging (Figures 1 and 2). Head CT is performed to distinguish between hemorrhagic and ischemic stroke, and tPA is administered intravenously for qualified patients within the three-hour window. Thereafter, tPA is not an option at El Camino and other community hospitals, although academic services administer intra-arterial tPA up to six hours after onset, Hess said.

"At present, no evidence is available to show that intra-arterial thrombosis is superior to intravenous treatment," he said. "Therapy should not be withheld for treatment of patients who are eligible for intravenous thrombolysis so that medication can be administered intra-arterially, except in the setting of a comparative research clinical trial."

Hess's opinion was seconded by Dr. Steve Warach, section chief of stroke, diagnostics, and therapeutics at NINDS.

"I'd say that is the right attitude," Warach said. "Our view is that, except in very rare cases, using intra-arterial thrombolysis to go beyond three hours should be done in the context of clinical trials."

Intra-arterial thrombolysis and other clot removal methods are frequently performed later than three hours at comprehensive stroke centers involved in clinical trials, however.

Of 628 stroke patients treated in 2005 at Millard Fillmore's Kaleida Stroke Care Center in Buffalo, 85 underwent an interventional procedure. Thirty-six received IV tPA and 48 received intra-arterial tPA, stent placements, or Merci retriever clot removal. Stenting was performed on one patient after unsuccessful intravenous tPA.

"To be a comprehensive stroke center, you need to have intra-arterial capabilities 24/7," said Dr. Elad Levy, an associate professor of neurosurgery and radiology at the University of Buffalo, a Kaleida affiliate.

It also helps to participate in clinical trials and have independent review board authorization to bend FDA rules that apply to community-based hospitals like El Camino. With informed consent, Levy can enroll patients into one of several trials that are testing ways to stretch the time window.

Patients with NIH stroke severity scores of less than 8 and onset within three hours usually receive intravenous thrombolysis at Millard Fillmore. Patients with stroke scores of 8 or greater, regardless of observed speech impairment, receive intra-arterial tPA. It is performed on patients with salvageable brain up to eight hours after onset, Levy said.

"If the brain is not infarcted-if it is not yet dead-we will then try to open the vessel," he said.

IMPORTANCE OF PATIENT SELECTION

Although Hess complains about a lack of evidence justifying intra-arterial thrombosis, a growing body of data support its use for some patients. Careful patient selection using either functional MRI or CT as a guide is essential, however, as indicated in recent clinical trials showing that it can reduce considerably the risk of intracranial hemorrhage from intra-arterial procedures performed three to nine hours after onset.

The Desmoteplase in Acute Ischemic Stroke (DIAS) Trial, published in November 2005, was a watershed in confirming the importance of patient selection with diffusion-perfusion MRI, according to Dr. R. Gilberto Gonzalez, director of neuroradiology at MGH.

Desmoteplase is the subject of considerable interest in its own right. Originally discovered in the saliva of the vampire bat, desmoteplase specifically activates plasminogen bound to fibrin. Once activated, plasminogen is converted to plasmin, which in turn dissolves clots by digesting the fibrin matrix. The DIAS phase II dose escalation trial was published last November (Stroke 2005;36:66-73).

The spectacular nature of the results can be seen when they are compared with the 10-year-old NINDS trial for tPA, Gonzalez said. More than 600 patients were needed in the NINDS trial to reveal a statistically significant difference between patients who received the drug or a placebo, but only 57 were sufficient in the DIAS trial performed on patients three to nine hours after onset to demonstrate its effectiveness with absolute statistical certainty. Far fewer patients were needed because of the huge gap in response between the desmoteplase and placebo patients. Sixty percent of the patients treated with 120 microg of desmoteplase experienced favorable 90-day clinical outcomes, compared with 22% for the placebo-treated patients.

Reasons for the big difference were not limited to the superior performance of the experimental drug, Gonzalez said. Equally important was the use of perfusion-diffusion imaging to select patients for therapy. Patients had to have a region of abnormal perfusion that was at least 30% larger than the region of abnormal diffusion on MRI for enrollment in the trial.

"That's a paradigm shift," Gonzalez said. "Imaging was used to identify the ischemic penumbra-the region of vulnerable but salvageable tissue. It shows you can rationally select the right patients instead of shooting gunk in everybody's veins."

Two more studies published after the DIAS Trial reinforced the argument for patient selection with perfusion-diffusion mismatch. Dr. Marc Bio, neurology director at Hospital Universitari de la Vall d'Hebron in Barcelona, demonstrated that the 50% success rate of tPA during the first three hours after onset also applies to patients in the three to six-hour period, when treatment is restricted to patients with an ischemic penumbra revealed with perfusion-diffusion MRI.

STRETCHING WINDOW TO SIX HOURS

In the seven-center Diffusion-weighted imaging Evaluation For Understanding Stroke Evolution (DEFUSE) Study, Dr. Michael Marks, director of neuroradiology at Stanford University, confirmed the ability of MRI perfusion-diffusion mismatch to extend the treatment window for IV tPA to six hours (Figure 3). About 37% of patients with early vessel reopening had favorable clinical outcomes as seen on NIH stroke severity scores, compared with 28% of those without early reopening. Follow-up evaluation showed that 50% to 60% of patients with demonstrated penumbra had good outcomes.

"All these studies tell us that what we really want to treat are patients with penumbra. It doesn't matter what time it is. It is not the time after the stroke. It is whether they have a penumbra," Gonzalez said. "If the patient has a penumbra, you better do something."

The identification of penumbra need not be limited to MRI, which is still difficult for community hospitals to perform quickly and to staff around the clock. The work of Dr. Pamela Schaefer and Lev at MGH suggests that perfusion CT can be nearly as powerful as MRI in identifying the presence and extent of salvageable tissue (Figures 4 through 6). Their preliminary study of 14 patients in the first six hours after onset found that most tissue in regions of the brain with less than a 50% reduction in cerebral blood flow survived regardless of whether the vessel was recanalized. Tissues involving a 70% or greater reduction in blood flow, measured with perfusion CT, necrosed even with successful early reperfusion. Regions with a blood flow between these thresholds are the perfusion CT equivalent of MRI mismatch.

Symptomatic hemorrhage rarely occurs when there is a substantial penumbra, Gonzalez said. Either diffusion MRI or perfusion CT will reveal the characteristic large hypodensity indicating the presence of a developed ischemic stroke that is vulnerable to intracerebral hemorrhage and compromised blood-brain barrier.

Many academic hospitals employ both MR and CT for stroke assessment. The University of Wisconsin Clinic in Madison favors MR because it provides full-brain perfusion-diffusion coverage compared with the 2 to 3.2-cm slabs acquired during multislice CT perfusion imaging. To accommodate the slower acquisition times of MR, protocols have been streamlined to allow assessment of the brain parenchyma with diffusion, head and neck vasculature with MR angiography, and potential penumbra with perfusion, according to Dr. Howard A. Rowley, chief of neuroradiology.

The clinic's ability to perform these exams in less than 15 minutes requires postprocessing of functional MR data sets in real-time. The staff developed software that generates a color perfusion parameter map in less than a minute. The data are transmitted to the reading room where interpretation is often completed before the patient is wheeled out the imaging suite door, Rowley said.

CT assumes a more prominent role at nonacademic hospitals such as St. Francis Medical Center in Indianapolis. The center's emergency brain attack protocol begins with noncontrast CT to rule out hemorrhage. For ischemic stroke, head and neck CT angiography localizes the clot, and perfusion CTA characterizes the presence and extent of salvageable tissue, said Dr. Vincent P. Mathews, a neuroradiologist associated with the Northwest Radiology Network. Candidates for intra-arterial tPA are identified by a mean transit time above 5 mL/100 g/min and cerebral blood volume below 10 mL/g/min.

Images are transmitted to the reading room where a neuroradiologist performs interpretation, often a few seconds after acquisition. Technologists who prepare the perfusion maps aim at completing them within 20 minutes.

STENTING OCCLUDED ARTERIES

Through its association with the University of Buffalo School of Medicine, Millard Fillmore has pursued research on the use of carotid stenting for emergency stroke intervention (Figures 7 and 8). Candidates for these investigational procedures are selected with diagnostic angiography. Intra-arterial contrast released distal and proximal to blockage defines the borders of dead space, showing the length of the clot. Stenting is performed on occlusions that are less than 16 mm long. The success rate for recanalization at Millard Fillmore using conventional coronary artery stents is 80%. The department recently submitted an application to the FDA to conduct multicenter trials to test stents specifically designed for intracranial applications.

Levy argues that intra-arterial interventions are the future of stroke therapy.

"For strokes that lead to catastrophe, you've got to get in there and treat the clot directly. Otherwise, the likelihood of opening the vessel is pretty small," he said.

Levy uses the Merci extraction device to treat large vessel occlusions, especially T-occlusions involving both internal carotid and cerebral arteries. Recanalization was achieved in 48% of patients, with procedures limited to occlusion in the M1 segment of the middle cerebral artery or the basilar and vertebral arteries within eight hours.

"Merci is a great device when it works, but a soft clot may not respond as well as hard clots. You may not be able to hold on to it," Levy said.

Other innovations under development promise to stretch the window far behind current clinical limits. A general linear model, developed by Dr. Gregory Sorensen and Dr. Ona Wu at MGH performs pixel-by-pixel probability analysis based on MR blood flow, blood volume, and mean transit times, creating color-coded maps that illustrate the likelihood of neuronal death following stroke (Figure 9). A perfusion CT version of the general linear model is in development. The preliminary work may lead to intelligent computer-assisted diagnoses, as the attending physician can quickly prescribe therapy with the help of color-coded diffusion-perfusion mapping.

Advanced research in Warach's lab at NINDS in Bethesda aims to combine the use of several antithrombolytic drugs to stretch the therapeutic window out to 24 hours. An early phase analysis suggests the blood-thinning cocktail is safe enough to proceed with more testing.

While such advanced techniques are perfected, millions of U.S. residents will encounter the telltale signs of stroke. But new measures may mean more stroke patients, like Jamie Shiffner, can tell their tale.

"I remember feeling euphoric just a few hours after the stroke, thinking about how quickly my symptoms had resolved," he said.

Mr. Brice is senior editor of Diagnostic Imaging.

SYMPTOMS OF STROKE

Sudden numbness or weakness of face, arm, or leg, especially on one side of the body

Sudden confusion and/or trouble speaking or understanding

Sudden difficulty in seeing in one or both eyes

Sudden trouble walking, dizziness, and/or loss of balance or coordination

Sudden severe headache with no known cause

(Source: American Stroke Society)