Christopher T. Whitlow, MD, PhD

CT perfusion for stroke leaped from clinical discussion forums to the front pages in the last 13 months. First, the FDA revealed in October 2009 that Cedars-Sinai Medical Center may have exposed more than 200 stroke patients to eight times the normal dose of ionizing radiation for CT perfusion brain scans. Then, in July an article featured in The New York Times concluded that overdoses from CT perfusion brain scans are far more common than even the FDA recognized.

The New York Times article prompted a letter to the editor from Dr. George Lantos, vice chair of radiology and director of neuroradiology at North Bronx Healthcare Network, arguing that CT perfusion for stroke should be performed only in the setting of a clinical trial. He agreed to expand on his comments for Diagnostic Imaging. To get the other side of the story we turned to Dr. Carol Geer and Dr. Christopher Whitlow, assistant professors of radiology in the neuroradiology division at Wake Forest University.

Finally, we asked Dr. William G. Bradley Jr., chair of radiology at the University of California, San Diego what it will take to move MR into a more prominent position on stroke imaging.

How to treat stroke is a crucial issue in ER departments across the nation, and CT imaging remains a common gateway. It is our hope that this contrast of views will contribute to the discussion of this topic.

NO: Routine clinical use of CT perfusion, 				MR diffusion/perfusion is not ready for prime time

Until phase III results are in, perfusion scans should not be used except within the context of clinical trials

In our field of diagnostic imaging, no one wants to be involved in a controversy and land on the front page of The 

. Yet that is what happened in the case of CT perfusion this summer.

 reported that in the investigation of acute stroke, a number of patients undergoing this procedure, known to involve radiation levels higher than most other diagnostic imaging tests even when properly performed, actually suffered radiation burns to their skin. Some of the subjects received far more radiation than intended. Clearly, there is potential for permanent brain damage in these patients as well as radiation-induced neoplasms in the decades to come.

The article prompted me to write a letter to the editor.

 My intent was not to join others decrying the excessive radiation; it’s obvious that CT scanners must be programmed and radiologists and technologists must be trained to avoid overdoses of radiation. Rather, I wanted to point out that since there is no current FDA-approved therapy that utilizes the information from CT perfusion or MRI perfusion/diffusion studies in the setting of acute stroke therapy, these advanced imaging techniques should be performed only in the context of clinical investigation. I thank the editors of Diagnostic Imaging for the opportunity to expand on these views.

To understand the role of imaging in acute stroke management, it’s useful to review some pathophysiology. It is well known that cerebral ischemia initiates a number of damaging cellular events called the ischemic cascade.

 These cellular events include acidosis due to a switch from aerobic to anaerobic metabolism, release of the amino acid glutamate and consequent excitotoxicity, elevation of intracellular calcium, and production of toxic substances including nitric oxide and free radicals. Ultimately, cell death results from these events.

The brain tissue that suffers irreversible necrosis is referred to as the ischemic core. Reviewing their own and others’ physiologic studies of cerebral ischemia, the concept of a penumbra in acute stroke was first advanced by Astrup and his colleagues in 1981.

 Penumbra refers to the poorly perfused and therefore nonfunctioning brain substance surrounding the core; but though the tissue is nonfunctioning, it has not suffered permanent damage. The situation is similar to that in the case of myocardial infarction, where permanently damaged myocardium is surrounded by nonfunctioning (or hibernating), but nonetheless viable, tissue.

Strategies directed at limiting ischemic brain damage as much as possible can therefore be divided into two broad categories. One is neuroprotection. The various stages in the damaging ischemic cascade, for example, provide attractive targets for neuroprotective agents that could potentially be deployed against one or more of the toxic chemical species produced during a stroke. Various strategies have been tried to limit these cell-damaging events. However, despite much effort in both the basic science and clinical trial spheres, and for a variety of reasons including timing of therapy, to date no neuroprotective agent has been shown to have definite clinical efficacy.

The other broad category of strategies is the attempted restoration of cerebral blood flow and perfusion, the earlier the better, to minimize irreversibly damaged tissue. In 1995, the National Institute of Neurological Disease and Stroke published a landmark multi-institution study on the intravenous injection of recombinant tissue plasminogen activator (rtPA, or simply tPA) in acute stroke therapy.

 This was followed the next year by FDA approval of the drug. Fifteen years later, tPA is still the only FDA-approved drug for the treatment of acute stroke. A variety of clinical parameters must be met prior to administration of tPA. These include the passage of no more than three hours since the patient was last known to be neurologically normal, as well as absence of significant bleeding diathesis and severe hypertension and other clinical features.

It turns out that the three-hour window for administration of tPA is the most limiting factor, making most patients who present with ischemic stroke ineligible.

 Although recent evidence indicates that this window can be extended to 4.5 hours,

 many patients will likely still be disqualified because they present too late.

Imaging needed for the use of tPA is quite simple. A noncontrast CT scan is performed to exclude hemorrhage and nonstroke pathology. In addition, tPA is not administered if there is a well-formed infarct in the area of clinical concern not consistent with a duration less than three hours. Evidence from the European Cooperative Acute Stroke Study indicates that involvement of more that one-third of the middle cerebral artery territory results in a 3.5-fold risk of parenchymal hemorrhage following administration of tPA.

A routine noncontrast CT scan is a blunt instrument with which to assess the rapidly changing pathophysiologic events involved in an ischemic stroke. It cannot distinguish tissue destined to undergo irreversible damage from potentially salvageable surrounding penumbra. Although noncontrast CT can disclose the presence of thrombus in a major vessel-for example, the dense middle cerebral artery sign first reported by Gacs et al

-it cannot depict the level of detail of cerebral arterial supply that one would like to have in order to restore regional perfusion by opening a cerebral arterial branch via either thrombolysis or mechanical clot retrieval.

Both CT and MRI methods have been developed for the study of regional brain perfusion as well as depiction of the details of brain arterial supply. The merits of each modality have been debated in the recent literature.

 While these tests undoubtedly provide the radiologist and clinician with a great deal of information, such diagnostic methods are currently far ahead of approved therapy. There is a strong rationale for treating patients with a mismatch between an already infarcted core and surrounding poorly perfused but viable penumbra, particularly with drugs that would work outside the tPA window of up to 4.5 hours. Unfortunately, there has already been a false start along this road. Hacke and colleagues conducted promising trials with the novel thrombolytic agent desmoteplase, selecting patients for treatment on the basis of a mismatch between diffusion and perfusion on MRI.

 But later studies with larger numbers of patients failed to confirm the benefit of desmoteplase in the initial trials.

There is also a strong rationale for using the information from MR or CT angiography to treat patients with major intracranial arterial occlusions or stenoses with thrombolysis, stenting, or clot retrieval. Again, strong rationale does not equate to solid evidence from well-done clinical trials.

I believe that before we put a diagnostic modality or therapy into routine clinical use, we should require the best possible evidence for its efficacy. Guidelines for the evaluation of various acute stroke therapies have been published (see table). Lest we fall into the trap of “knowing” that a particular approach is correct, we must remember that the history of medicine is replete with things we thought we knew that turned out to be wrong.

One example in the stroke field is extracranial-intracranial bypass surgery for carotid occlusive disease, first described by Donaghy and Yasargil in the 1960s.

 I worked with a neurosurgeon in the 1980s who performed these operations and who “knew” they were effective in reducing the long-term risk of stroke. He was so certain that he refused to include his patients in the definitive prospective randomized clinical trial of this procedure,

 although two of our patients were randomized to medical therapy in that study. Unfortunately for stroke patients, the study showed that after the initial surgical mortality and morbidity is taken into account, the benefits of surgery never caught up with those accorded to the medically treated group.

This operation is still being performed for stroke in selected situations and various other conditions, including cases where the internal carotid or other major artery has to be sacrificed in aneurysm or skull-base surgery. There is presently no justification for performing it in otherwise unselected patients with occlusive disease. However, it remains possible that there is a subset of patients who could be identified by modern physiologic perfusion imaging and benefit from this procedure. A recent study published by the Cochrane group made the recommendation that this possibility should be investigated.

Getting back to the issue of routine use of perfusion imaging in the setting of acute stroke, I’d like to summarize by quoting the conclusion of a recent meta-analysis of the literature on mismatch-based stroke therapy conducted by several leading neurologists working in this field:

Delayed thrombolysis amongst patients selected according to mismatch imaging is associated with increased reperfusion/recanalization. Recanalization/reperfusion is associated with improved outcomes. However, delayed thrombolysis in mismatch patients was not confirmed to improve clinical outcome, although a useful clinical benefit remains possible. Thrombolysis carries a significant risk of symptomatic intracerebral hemorrhage and possibly increased mortality. Criteria to diagnose mismatch are still evolving. Validation of the mismatch selection paradigm is required with a phase III trial. Pending these results, delayed treatment, even according to mismatch selection, cannot be recommended as part of routine care.

At this writing, I’m not aware of any prospective, randomized, controlled phase III studies that have shown a superior outcome in acute stroke patients selected with either CT perfusion or MR perfusion for treatment with any modality. Of course, if treatment doesn’t depend on the results, then there’s really no reason to perform these tests in routine clinical practice outside the context of clinical trials.

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 16. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009;8(2):141-150.
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YES: CT perfusion proves its value in planning treatment for acute ischemic stroke

Careful patient selection is crucial, but CT perfusion can be key in making a decision whether to proceed with intravascular tPA

BY CAROL P. GEER, M.D., AND CHRISTOPHER T. WHITLOW, M.D., Ph.D.

Ischemic stroke remains a common cause of substantial morbidity and mortality in the U.S., and great effort has been expended to better evaluate and treat affected patients. The FDA has approved the use of intravenous tissue plasminogen activator in eligible patients presenting for treatment of ischemic stroke within three hours of symptom onset and without evidence of intracerebral hemorrhage on CT of the brain, which has improved clinical outcomes in some patients.

However, there remain a significant number of patients who do not derive benefit from IV tPA, possibly due to substantial clot burden in larger vessels, such as the internal carotid artery and proximal middle cerebral artery (MCA). There are also a number of patients who present to the healthcare system after the three-hour-or now the 4.5-hour-window has passed.

 Although many patients present outside of the standard treatment window for IV tPA, there is evidence that delayed recanilization may have clinical benefit in some of these patients. Of these, patients who have brain tissue that is ischemic but not irreversibly damaged, or so-called ischemic penumbra, are those who stand to benefit most. Diagnostic imaging methods designed to accurately measure penumbra and therapies directed at preserving this tissue in patients who present after the IV tPA window are targets of active research across the globe.

CT perfusion has become a key imaging modality to qualitatively determine the amount of penumbra present relative to completed infarct in patients with occlusive cerebrovascular thrombus.

 CT perfusion defines penumbra as a mismatch between the mean transit time (MTT) and cerebral blood volume (CBV).

 Cerebral blood flow (CBF) is subsequently calculated from the measured MTT and CBV. MRI diffusion and perfusion imaging has also been used to evaluate for significant salvageable brain tissue.

 But in most emergency departments, CT perfusion can be obtained more quickly.

Patients presenting with stroke symptoms generally first undergo head CT without contrast to evaluate for the presence of intracranial hemorrhage and imaging signs of acute ischemia. In many centers, including ours, patients then undergo head and neck CT angiography to evaluate for occlusive cerebrovascular thrombus. Because the patient is already on the CT table, obtaining CT perfusion data to evaluate for penumbra, as opposed to transferring the patient for MRI examination, makes good clinical sense, given that time is the critical factor for preserving brain. The main disadvantages to obtaining CT perfusion rather than MRI diffusion-perfusion data are the radiation exposure and the IV contrast administration. The critical question faced by diagnostic and treating clinicians is whether the decrease in radiation and contrast exposure gained by performing MRI diffusion-perfusion rather than CT perfusion is worth the increase in time to reperfusion and potential infarct expansion.

Indeed, several studies have demonstrated that there is an increased risk of infarct expansion if there is a large penumbra.

 Furthermore, some recently published data suggest that patients presenting with large penumbra and relatively small completed infarcts longer than eight hours after symptom onset, as well as some patients with wake-up strokes, may benefit from intra-arterial thrombolysis.

 This being so, many centers, including our own, have started to be more aggressive in treating patients with substantial ischemic penumbra, using intra-arterial thrombolysis to recanalize obstructed arteries.

The critical information necessary for evaluating the viability of intra-arterial thrombolysis as a treatment option is based on perfusion imaging data and includes penumbra size and degree of completed tissue infarction. Endovascular recanalization of patients who already have a large completed infarct increases their risk of complications due to edema and reperfusion hemorrhage.

 CT perfusion and MRI data, therefore, are used to identify patients who may benefit from intra-arterial thrombolysis, and those in whom recanalization may be of questionable benefit or even be harmful. Although CT and MRI can both be useful for evaluation of penumbra and infarct completion, in our hospital and many others, it is much faster to obtain CT perfusion. MRI scanners at our institution are not located in, or even very close to, our emergency department, making transport time a serious issue.

Given the necessity for CT perfusion in the evaluation of ischemic stroke, at our institution we attempt to employ strict adherence to ALARA (as low as reasonably achievable) principles. In particular, we have optimized our CT scan technique to use a low-dose perfusion protocol that maintains a radiation dose at less than 200 mGy. Attention to technique, as well as oversight by experienced radiologists and a dedicated physicist, are critical elements we have employed to avoid the complications that other centers have reported with radiation exposure, including hair loss and scalp injury.

Furthermore, we work in close collaboration with the primary clinical referral services at our institution (emergency medicine, neurology, and neurosurgery) to carefully select patients in whom the use of CT perfusion is important for treatment planning. Indeed, performing CT perfusion on every stroke patient as a standard protocol is probably not good medicine and is not being responsible with radiation exposure. Using CT perfusion in a careful and judicious manner, when the results may change clinical management, is likely to be the safest and most efficacious way to use this technology.

To elucidate the above discussion, we present examples in which CT perfusion data were collected during the evaluation of two patients presenting to our hospital for treatment of acute ischemic stroke 4.5 hours after symptom onset.

: A 64-year-old woman presented with acute left hemiplegia and neglect four hours and 46 minutes after symptom onset. Head CT was negative for acute hemorrhage, and no large area of low density was identified to suggest infarct. Head and neck CTA demonstrated a large occlusive thrombus in the M1 segment of the right MCA. CT perfusion demonstrated elevated MTT in the entire right MCA, with only a small area of decreased blood volume in this vascular territory, compatible with a large penumbra (

). Studies have shown these patients to have an increased risk of infarct expansion. This patient was, therefore, recanalized using a combination of intra-arterial tPA and mechanical thrombolysis, including the Penumbra System (Penumbra, Alameda, CA) and balloon angioplasty. She made a complete recovery.

: An 84-year-old man presented with acute right hemiplegia, aphasia, and neglect four hours and 30 minutes after symptom onset. Head CT was negative for acute hemorrhage, and no large area of low density was identified to suggest infarct. Head and neck CTA demonstrated a large occlusive thrombus in the left M1 segment. CT perfusion was obtained, but due to a computer malfunction immediately after the study was acquired, the data could not be processed and viewed. The patient was nonetheless taken for intra-arterial recanalization, as the head CT suggested the absence of a large completed infarct, and we could not wait any longer for the perfusion data. Recanalization of the left MCA was performed using mechanical thrombolysis.

Following the procedure, the computer was fixed and the CT perfusion data were processed and subsequently reviewed. They demonstrated elevated MTT in the entire distribution of the left MCA with a matched decrease in CBV and CBF, suggesting completed infarct (

). Postoperatively, the patient developed severe edema in the left MCA distribution and expired.

Although outcomes from these two cases, and others in the literature, are certainly insufficient to direct policy and change standards of care, they do highlight the potential clinical utility of CT perfusion data in directing the delayed recanalization of occlusive cerebrovascular thrombus, and serve as a basis for further evaluation of these technologies. Case 2 is particularly important, as it demonstrates the importance of careful patient selection before application of endovascular recanalization techniques. Indeed, had the CT perfusion data driven subsequent management of this patient, intra-arterial thrombolysis would not have been performed, given the presence of a large completed infarct. The patient in case 2 was obviously not helped by recanalization, and it is possible that intra-arterial treatment resulted in worsening cerebral edema, among other negative consequences, such as raising false hope among the family, and adding unnecessary expense to the healthcare system.

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CT perfusion for stroke leaped from clinical discussion forums to the front pages in the last 13 months.

Christopher T. Whitlow, MD, PhD

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CT perfusion for stroke: Should you use it?