Comprehensive Stroke Imaging: The Time is Now
Disclosure: Dr. Rowley would like to acknowledge with gratitude his NIH grant. In addition, Dr. Rowley receives modest research support from General Electric and has modest Speaker's Bureau/Honoraria relationships with Carestream and Bracco.
Pub Date: Monday, September 28, 2009
Author: Howard A. Rowley, MD
Latchaw RE, Alberts MJ, Lev MH, et al. on behalf of the American Heart Association Council on Cardiovascular Radiology and Intervention, Stroke Council, and the Interdisciplinary Council on Peripheral Vascular Disease. Recommendations for imaging of acute ischemic stroke: a scientific statement from the American Heart Association. Stroke 2009. Published online before print, September 24, 2009. 10.1161/STROKEAHA.108.192616.
Latchaw and colleagues are to be congratulated for their comprehensive review of acute stroke imaging guidelines and recommendations. This paper helps refresh our thinking about the role of imaging in stroke and our overall approach to stroke triage in clinical practice. The data presented invite us to consider evidence-based, logical ways to harness the full potential of neurovascular imaging to help reduce suffering and improve patient outcomes in stroke--our ultimate shared goal.
The promise of tissue plasminogen activator (tPA) to improve stroke outcomes has been delivered in practice, resulting in 30% lower likelihood of neurologic disability at 90 days compared with placebo treatment. This remains the first and only proven specific medical therapy for stroke, with clinical benefit confirmed by multiple postapproval studies.[2-4] Forward-thinking centers have successfully geared up, educated the public and local healthcare professionals, prepared emergency responders, and developed streamlined workflow to identify and treat patients quickly. But there is still much room for improvement: 13 years after tPA approval, only about 4% of acute stroke patients actually get treated with the drug, and 65% of hospitals in the United States have never treated a single patient.[5,6] Only about one-fifth of stroke patients arrive within the Food and Drug Administration-approved 3-hour treatment window, a major obstacle. Fear of postthrombolytic hemorrhage and lack of efficacy are further limitations cited by tPA critics, despite evidence to the contrary. Newly published evidence of clear tPA clinical benefit as late as 4.5 hours after symptom onset, the establishment of Stroke Centers of Excellence, the American Heart Association's "Get with the Guidelines" initiatives, "TeleStroke" remote treatment programs, and opening of dedicated stroke units are helping consolidate progress in the field.[7,8]
Rapid advances in imaging technology and development of endovascular interventions now give us new options to consider and incorporate into acute stroke triage and treatment algorithms. Noncontrast computed tomography (CT) triage was the only practical imaging approach available when the tPA studies were designed 20 years ago. As neurologist Dr. Lou Caplan has so eloquently pointed out, the clinical guidelines for tPA use have not kept up with the rapid pace of new developments in medical imaging. Intravenous tPA patient selection guidelines are still based on noncontrast head CT screening and symptom duration (less than 3 hours), but without knowledge of (or even regard for) the vascular site of occlusion. A few minutes of additional neurovascular imaging in the acute setting could refine patient selection and therefore become the next major practical advance in stroke treatment.
We now have the ability to accurately assess relevant anatomic and physiologic characteristics in individual patients in real-time as part of the acute triage process. Modern CT and magnetic resonance imaging protocols can provide comprehensive parenchymal, vascular, and perfusion information in less than 15 minutes. Stroke is ultimately caused by clot in a blood vessel, and thrombolytic agents are prescribed specifically to attack that clot. Therefore, the presence or absence of a thrombus, and site of any vascular occlusion are directly relevant to accurate diagnosis and treatment decisions. It has been repeatedly shown that large vessel clots or proximal occlusions respond poorly to intravenous (IV) tPA, but can be safely and effectively reopened using endovascular lytics and devices. For example, the CLOTBUST trial showed that middle cerebral artery (MCA) occlusions treated with IV tPA within 3 hours have sustained complete recanalization only 13% of the time. In contrast, the PROACT trial showed that intra-arterial (IA) lytics could open proximal MCA occlusions 66% of the time, even at a 6-hour time window and with improved patient outcomes. Similar efficacy for opening vessels has been shown with IA urokinase and using endovascular devices (MERCI and PENUMBRA).[12-14] However, the stroke community has been slow to embrace IA therapies and has shown resistance to incorporation of vascular imaging in the acute setting. Some stroke neurologists argue that they do not even want to look at the vessels because tPA guidelines do not require it. Many also do not feel the evidence for IA treatment is compelling, so they await larger confirmatory studies before they will alter their practices. Additional resistance stems from the legitimate concern that adding more imaging will be costly and cause delay in the triage and treatment of IV tPA candidates.
With this background, it is most noteworthy that among the key recommendations in this paper--and immediately relevant to daily clinical practice--the new guidelines provide solid evidence that vascular imaging studies should be routinely incorporated into acute stroke imaging protocols. The authors show that vascular imaging assessment in the emergent setting is appropriate for patients seen either before or after 3 hours of symptom onset in centers where IA thrombolytic therapy is available. They also summarize evidence that perfusion studies may be used to determine suitability for IV thrombolytic treatment beyond 3 hours and for triage to IA interventions. It seems logical that even for centers without inhouse interventionalists, vascular screening would be appropriate if rapid transfer to an advanced stroke center is feasible.
In a patient presenting with a transient ischemic attack (TIA) or stroke, it can be strongly argued that the global neurovascular assessment should be done right in the emergency department at first encounter. Traditionally, there has justifiably been an emphasis on the noncontrast head CT used for tPA consideration, while critical vascular imaging is delayed or even forgotten. If a test is indicated eventually, why not do it in the first hour, and have the benefit of more accurate diagnosis and the chance to definitively direct treatment? Upfront imaging is important not only for acute triage and treatment but also for determining root cause of stroke. It is efficient from the standpoint of the patient and the medical team. A large minority of strokes can be traced to carotid disease. Earlier triage to specialty clinics and avoiding delay to endarterectomy can reduce the risk of second events.[15-17] In the case of TIAs, patients with positive diffusion scans acutely have higher risk for recurrence than those without and can be triaged for more intensive immediate evaluation.[18,19]
The evidence for vascular imaging in stroke is stronger than that for perfusion imaging, at least for the moment. But these are really complementary techniques providing independently valuable, clinically relevant anatomic and physiologic data for individual patients. Stroke is caused by vascular occlusion, but ultimate brain damage depends on the degree and duration of perfusion deficit, which is impossible to predict based on vascular anatomy alone. Even with identical occlusion sites (e.g., internal carotid artery or M1 MCA), one patient may be asymptomatic while another may die of malignant infarction, in large part due to highly variable individual differences in compensatory collateral flow. Perfusion assessment helps in multiple ways: confirmation of diagnosis, estimation of the extent of severely oligemic tissue, and operationally defining penumbra, tissue at risk. Perfusion metrics add both sensitivity (dynamic maps such as mean transit time, Tmax, and first moment transit time) and specificity (low blood volume) to the diagnosis and prognosis of brain regions affected by acute stroke. Used in acute triage perfusion studies help on both sides of the selection equation: simultaneously helping to exclude those with large strokes unlikely to benefit or patients who have already spontaneously recanalized, while including others based on demonstrable tissue at risk, a rational target for acute revascularization. Vascular studies complement perfusion in defining the site of occlusion and therefore best therapeutic options for revascularization (IV, IA, blood pressure support, etc.). Stroke mimics, such as migraine, encephalitis, and "transient tumor attacks," are more easily excluded with comprehensive protocols. In short, more complete imaging correlated with proper clinical assessment can help pick the best candidates for intervention and save others the risk of intervention when there is little reasonable hope.
Accumulating trial evidence shows perfusion triage has potential to safely and effectively push therapy with IV tPA out to 6 hours, may help select a subset of patients most likely to benefit from revascularization devices, and does help rationally identify potential acute therapy candidates among late-arriving patients, including those with wake-up strokes. There was disappointment in the negative results of magnetic resonance (MR) or CT perfusion-screened DIAS-2 (IV desmoteplase) trial, which some have viewed as a "nail in the coffin" for penumbral selection. But careful reading of the DIAS-2 paper shows that the small sample size, unexpectedly mild stroke population with small strokes and small mismatch, unusually good placebo response, and late unrelated nonneurologic deaths in the high-dose drug tier may have produced a negative result by chance alone.
Further support for the use of advanced MR with perfusion selection comes from several recent series and small trials. In a recent large clinical series reported by Schellinger, 1,210 acute stroke patients treated with tPA were variously screened by noncontrast CT within 3 hours, or using MR perfusion-diffusion stroke protocol either before or after 3 hours. Compared with traditional treatment using CT under 3 hours, the authors show comparable or better clinical outcomes and lower hemorrhage rates in the MR-screened subjects, whether treated before or after 3 hours. In another clinical series of 97 patients, advanced MR vascular and perfusion triage lead to a change in diagnosis in 21% and altered management plans in 26% of the patients compared with information from noncontrast CT imaging alone. The 3 to 6 hour window IV tPA DEFUSE [24-27] and EPITHET [28-30] trial data also support the safety and efficacy of advanced MR triage, with several secondary analyses from these trials now proposing refined selection criteria that will be tested in larger upcoming randomized trials.
From the standpoint of the neuroradiologist or radiologist in practice, the movement toward comprehensive acute stroke imaging is a welcome development we should embrace. This is valuable information that our patients and referring clinicians deserve to have. We are in the enviable position of having two excellent, widely available modalities, CT and MR, capable of providing comprehensive neurovascular information in the acute setting. Each modality has its advantages and disadvantages as outlined in the paper.[31,32] However, this is not a competition: each is useful and may be chosen based on a host of practical factors, including the exact question at hand, local expertise, machine and technologist availability at the time of presentation, and patient compatibility. A suggested general algorithm for either CT or MR imaging triage in acute stroke is shown in the diagram below (Figure 1).
Figure 1. Comprehensive Acute Stroke Imaging Triage. The first priority is to quickly screen the brain for hemorrhage, extended infarct signs, or stroke mimics so that intravenous tissue plasminogen activator (IV tPA) can be delivered according to approved guidelines. In the same acute session, vascular imaging is performed to identify candidates for endovascular revascularization or bridging IV-intra-arterial therapies. For patients presenting beyond the tPA-approved time window (3 or 4.5 hours), perfusion is also added to assess penumbra and collateral compensation. Comprehensive acute imaging data facilitate accurate diagnosis and guide rationale, patient-specific management.
Most practices in the United States are already equipped with multidetector CT scanners and power injectors, routinely used in trauma settings and acute neuro and body vascular protocols. Modern generation MR scanners already in place are also capable of performing these comprehensive protocols. What is needed is attention to protocol development and every step of workflow, including user-friendly (or fully automated) postprocessing software (Figure 2). Stroke cases must be handled with the highest priority to insure rapid triage for IV tPA candidates while simultaneously providing vascular imaging and, preferably, perfusion studies as well. Incorporating comprehensive stroke protocols with vascular imaging and perfusion takes time, effort, and money. Such an approach will cost more in terms of diagnostic testing but would be projected to be offset by improved patient outcomes and by reducing the frequency and costs related to futile interventions. There are costs of knowing and not knowing.
Figure 2. Emergency Stroke Magnetic Resonance Protocol. Comprehensive neurovascular data can be obtained and postprocessed in less than 15 minutes. This patient with acute left hemiparesis had already received intravenous tissue plasminogen activator (IV tPA) at an outside hospital before transfer but remained densely plegic on arrival. Gradient echo T2* images (scan duration, 1.5 minutes) show susceptibility artifact from clot in the right middle cerebral artery (MCA) (arrow). Diffusion-weighted images (DWI, 40 seconds) and apparent diffusion coefficient maps (ADC) confirm early ischemic changes in the right frontal lobe and basal ganglia. Dynamic contrast enhanced perfusion data (1.5 minutes) are postprocessed at the scanning console with automated arterial input selection and deconvolution to produce color parameter maps (inhouse, University of Wisconsin software, 1 minute). Perfusion maps show a severely oligemic core [low cerebral blood flow and volume, cerebral blood flow (CBF) and cerebral blood volume (CBV)] similar to DWI, with an even larger area of delayed transit times (Tmax) indicative of tissue at risk. A dynamic contrast enhanced magnetic resonance angiography (MRA) (CE-MRA, TRICKS protocol, 50 seconds) shows right internal carotid occlusion (arrow) extending intracranially into the MCA. There was no further attempted revascularization due to the large and severely oligemic core as well as the location and length of persistent clot. He initially decompensated and went on the infarct the entire right MCA territory, but his status improved after craniectomy. Imaging triage provides a rational basis to both select and exclude patients for a range of potential interventions.
Adoption of advanced imaging triage also requires dedication and retraining of technologists and physicians. Perfusion imaging is relatively early in development and its complexity is at first anxiety-provoking compared with mature and familiar CT and MR exams. A standardized approach to acquisition, postprocessing, and interpretation needs to be developed for physicians in each practice. However, the efforts in developing ischemic stroke protocols also pay off in other areas. Advanced imaging protocols are directly applicable to patients with CNS hemorrhage and high-risk trauma evaluations. For example, the computed tomography angiography (CTA) spot sign (contrast extravasation into a hematoma) is useful in predicting which patients are at high risk for parenchymal hematoma expansion in the first hours.[34,35] CTA provides a noninvasive, accurate way to evaluate aneurysms in acute subarachnoid hemorrhage (SAH) , and CT perfusion can be used to predict and monitor for SAH-related vasospasm. CTA also provides an excellent way to screen high-risk trauma patients for vascular injury (e.g., displaced or high cervical fractures, skullbase fractures). The methods of CTA, magnetic resonance angiography (MRA), and perfusion are becoming indispensible tools that need to be learned, taught in our residencies and fellowships, and deployed in practice.
Comprehensive neurovascular assessment, including vascular imaging and perfusion, are appropriate to incorporate into acute triage in advanced stroke centers now. Additional large, well-designed, controlled studies are clearly needed (and some are underway) to refine these methods, standardize the approaches, and prove clinical impact for various treatment scenarios. The accumulated evidence already provides a solid basis for our adoption of these techniques today. Waiting for the highest levels of evidence in every clinical setting is not practical, sensible, or justified. If we are to get beyond the current stagnant situation, where over 95% of acute patients are not treated with a proven therapy, we must engage these advanced techniques and dedicate ourselves to this effort.
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-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association --