Curr Treat Options Cardio Med (2015) 17: 10 DOI 10.1007/s11936-015-0368-z

Cerebrovascular Disease and Stroke (N Rost, Section Editor)

Multimodal Imaging in Acute Ischemic Stroke William A. Copen, MD Address *,1 Massachusetts General Hospital, Division of Neuroradiology, GRB-273A, 55 Fruit Street, Boston, MA 02114, USA Email: [email protected] 2 Harvard Medical School, Boston, MA 02115, USA

Published online: 4 March 2015 * Springer Science+Business Media New York 2015

This article is part of the Topical Collection on Cerebrovascular Disease and Stroke Keywords Stroke I Brain ischemia I Brain infarction I Diagnostic imaging I Neuroimaging I Magnetic resonance imaging

Opinion statement Recent years have seen the development of novel neuroimaging techniques whose roles in the management of acute stroke are sometimes confusing and controversial. This may be attributable in part to a focus on establishing simplified algorithms and terminology that omit consideration of the basic pathophysiology of cerebral ischemia and, consequently, of the full potential for optimizing patients’ care based upon their individual imaging findings. This review begins by discussing cerebral hemodynamic physiology and of the effects of hemodynamic disturbances upon the brain. Particular attention will be paid to the hemodynamic measurements and markers of tissue injury that are provided by common clinical imaging techniques, with the goal of enabling greater confidence and flexibility in understanding the potential uses of these techniques in various clinical roles, which will be discussed in the remainder of the review.

Introduction Laboratory experiments in the 1970s and 1980s enormously expanded scientific understanding of cerebral perfusion. In the late twentieth and early twenty-first centuries, researchers have brought the discoveries of that era to the bedside, in the form of widely available

imaging techniques that probe the effects of perfusion alterations upon the living human brain. These techniques’ potential roles in clinical care may be best understood by considering the physiologic principles upon which they are based.

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Imaging hemodynamic abnormalities Clinical evaluation of cerebral hemodynamics usually employs bolus-tracking CT or MR perfusion imaging (CTP and MRP). In both techniques, images of the brain are acquired repeatedly while an intravenous contrast agent bolus is injected. After image acquisition is complete, post-processing software assembles measurements of contrast concentration over time for each pixel location in the brain and uses these measurements to compute various hemodynamic measurements. These most commonly include cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and the time at which the deconvolved residue function reaches its maximum (Tmax). Measurements from individual locations are assembled into images, called Bmaps,^ in which the regional values of a particular hemodynamic parameter are depicted as different colors or shades of gray. Maps of all of available perfusion measurements should be interpreted together, in order to obtain as complete as possible an understanding of the hemodynamic status of a patient’s brain. Table 1 provides a suggested framework for doing this, and each of the commonly measured hemodynamic parameters is discussed in detail below.

Cerebral blood volume CBV is the volume occupied by blood in a particular part of the brain and is most commonly measured in milliliters of blood per 100 g of brain tissue. CBV may rise due to vasodilation, such as that which occurs as an autoregulatory response to a drop in cerebral perfusion pressure (CPP) [1–4]. This suggests that CBV maps might be used to detect autoregulatory vasodilation as evidence of reduced regional perfusion pressure. However, this is difficult in practice, for several reasons. First, the CBV changes that result from vasodilation are small and may be difficult to detect in CT- and MR-based CBV maps, which are fairly noisy. Second, autoregulatory vasodilation commonly persists for up to several weeks after CPP has been restored from below-normal levels. Therefore, CBV elevation may reflect a CPP reduction that has recently resolved, rather than an ongoing one [5–7]. Finally, some common CTP and MRP post-processing algorithms are prone to underestimating CBV in regions where the arrival of blood is delayed or its transit is prolonged [8•].

Cerebral blood flow CBF describes the rate at which blood passes through brain tissue, and is usually measured in milliliters of blood per 100 g of brain tissue per minute. CBF also reflects the rate of delivery of oxygen and glucose, and therefore is the commonly measured hemodynamic parameter that is most closely linked to cellular metabolism and viability. In modern usage, the term Bischemia^ usually refers to CBF reduction, and terms that describe perfusion quantitatively without further specification, such as Bhypoperfused,^ refer to changes in CBF. The effects of CBF reduction have been elaborated in detail by numerous laboratory studies [2, 9, 10]. When CBF is only slightly below normal levels, synaptic transmission is unaffected. However, if CBF falls below a Bthreshold of electrical function,^ synaptic transmission ceases and a neurologic deficit may

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Table 1. Hemodynamic states that can be identified by CT or MR perfusion imaging Normal Delayed arrival, preserved CPP Compensated low CPP Hypoperfusion Post-ischemic hyperperfusion

CBV

CBF

MTT

Tmax

— — ↑ ↑↓ ↑

— — — ↓ ↑

— — ↑ ↑↓ ↑↓

— ↑ ↑ ↑ —

Interpretation of the four most commonly produced perfusion maps may be simplified by using their findings to assign to each part of the brain, one of five hemodynamic states. In this table, up and down arrows signify that a hemodyamic parameter’s value is typically higher or lower, respectively, than its normal value. When both arrows appear, this indicates that the parameter may be either higher or lower than normal. A horizontal line indicates that the parameter’s value is apparently normal

appear. In the 1970s, researcher Lindsay Symon and his colleagues coined the term Bischemic penumbra^ to describe tissue in which ischemia has caused loss of electrical function, but transmembrane cellular ion gradients remain intact [10, 11]. Because membrane disruption had been observed to be a necessary step in ischemic cell death, tissue in the ischemic penumbra could persist indefinitely in this state, without risk of infarction. Noting that this mildly ischemic tissue often surrounded a central zone of more severe ischemia, researchers were reminded of the small bright zone surrounding the center of a candle flame, which is also called the penumbra. If CBF falls below a lower Bthreshold of viability,^ cells begin to accumulate ischemic damage that will eventually become irreversible, if CBF is not restored. Of critical importance in acute stroke care, the severity of the CBF reduction determines how much time must elapse before ischemic injury becomes irreversible. Whereas a complete absence of CBF is survivable for only a few minutes, the tissue may survive more moderate ischemia for a much longer time and still recover completely when CBF is restored. As discussed above, autoregulatory vasodilation commonly persists after restoration of CPP. When this occurs, higher-than-normal CBF may be present for up to several weeks, usually but not always in tissue that has survived its transient ischemic insult [5–7]. Regional hyperperfusion also may be seen in other disorders, such as seizures [12], tumors [13], or inflammatory disease [14].

Mean transit time MTT is the average time spent by blood in a particular part of the brain. MTT is normally approximately 6 s [15] but may reach 10–20 s [16] in the setting of reduced CPP. The relationship between CBV, CBF, and MTT is defined by the central volume principle [17]:

MTT ¼

CBV CBF

As discussed above, a fall in CPP may trigger vasodilation and therefore an increase in CBV. Whether or not CBF is maintained, there is prolongation of MTT, which is usually appreciable in MTT maps.

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Curr Treat Options Cardio Med (2015) 17: 10 Although many writers describe tissue with abnormally high MTT as Bischemic^ or Bunderperfused,^ i.e., suffering from reduced CBF [18–23], this is not necessarily correct. CBF may or may not be low in tissue with high MTT, depending upon the success of autoregulatory vasodilation in compensating for low CPP. It is also common to describe high-MTT tissue as being Bat risk of infarction.^ [24, 25] However, this too deserves further scrutiny. MTT elevation does not directly threaten tissue survival. Indeed, transit time prolongation can actually protect ischemic tissue, by allowing additional time for cells to extract a greater fraction of blood’s oxygen content [26, 27].

Time-to-maximum of the deconvolved response function Tmax is the time at which a maximum value is reached by the deconvolved tissue response function, a mathematical construct derived by CTP and MRP post-processing software [28, 29]. In theory, Tmax reflects arrival delay, i.e., the time that elapses between the arrival of blood in some index vessel, typically a normal-appearing artery and its initial arrival in another part of the brain. In reality, calculated Tmax values also may be influenced by other factors, such as bolus dispersion and MTT [30]. Prolongation of arrival time (and therefore Tmax elevation) often occurs when blood reaches the brain tissue via stenotic arteries, or via circuitous collateral pathways. Although some authors describe tissue with prolonged Tmax as Bhypoperfused,^ [22, 31–33, 34•, 35] this is not necessarily correct, and CBF is frequently normal in the presence of high Tmax. Many studies have described tissue with Tmax prolongation as Bat risk^ of infarction [36–40]; however, arrival delay per se is not known to threaten tissue metabolism or viability.

Imaging the effects of ischemia Whereas perfusion imaging studies the brain’s hemodynamic status at the time of imaging, other techniques detect the effects that sufficiently severe and prolonged ischemia have had upon brain tissue. Two such techniques are commonly used: diffusion-weighted magnetic resonance imaging (DWI) and non-contrast computed tomography (NCCT). The phenomena that these techniques detect are cytotoxic edema and ionic or vasogenic edema, respectively.

DWI: detecting cytotoxic edema Cytotoxic edema is different from the process that is usually denoted by the term Bedema,^ in which water moves from blood into the interstitial space of affected tissue [41]. In cytotoxic edema, water moves instead from the interstitial space to the intracellular space. This causes swelling of individual cells, however, because there is no addition of water to the tissue; there is no increase in its macroscopic size or mass. Cytotoxic edema is the eventual result of a sufficiently severe and prolonged reduction in CBF. Depletion of cellular energy stores ultimately causes failure of membrane energy-dependent ion pumps, the best known of which is

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sodium/potassium ATP-ase. The widespread failure of these pumps allows a net influx of ions into the cells. Water follows passively by osmosis, causing the cells to swell. Cytotoxic edema can be detected by DWI and not by any other common clinical imaging technique, because it imposes restrictions upon the Brownian motion, or Bself-diffusion,^ of water molecules [42, 43]. These restrictions are partly caused simply by net migration of water molecules to the inside of cells, where there are more physical obstacles to diffusion. DWI can detect cytotoxic edema within minutes of ischemic injury, identifying infarction with sensitivity and sensitivity close to 100 % [44–48].

NCCT: detecting ionic or vasogenic edema Cytotoxic edema causes no changes in the tissue’s overall atomic content, and therefore no change in its X-ray attenuation, which is the only characteristic of biologic tissues that can be depicted by NCCT. NCCT detects ischemic injury only if there is edema in the usual sense, i.e., movement of water from the blood vessels into the interstitial space. In stroke imaging, the term Bvasogenic edema^ is often used to distinguish this more conventional type of edema from cytotoxic edema. Some authors prefer a more restrictive definition of vasogenic edema, one that applies only when the extravasation of water is accompanied by leakage of large molecules, especially albumin, due to disruption of the blood-brain barrier. These authors use a different term, Bionic edema,^ to refer to the condition in which the blood-brain barrier is intact, but osmotically active ions in the interstitial space draw water out of the blood vessels. For clarity, this review will adhere to the more restrictive definition. In acute stroke, ionic edema begins shortly after the onset of cytotoxic edema, driven largely by the shifting of sodium ions from the interstitial space to the intracellular space in cytotoxic edema. This shift depletes normally high extracellular sodium concentrations and therefore draws sodium ions out of the blood. Water follows by osmosis, expanding the interstitial space [41]. Because water absorbs fewer X-rays than brain cells, the addition of new water to the tissue decreases its X-ray attenuation, making it appear slightly hypodense, or Bdark,^ in NCCT images. The quantities of water that leave the blood vessels in ionic edema are so small that their manifestations in NCCT images are extremely subtle and often are not visible at all. Various studies have reported approximately 39–45 % sensitivity for NCCT in detecting acute infarction, with fairly low inter- and even intra-rater agreement [48–53]. In one study, sensitivity increased from 38 to 52 % when the provided clinical history alerted the interpreting radiologist to the possibility of stroke [54]. Another study found that radiologists’ sensitivity for detecting acute infarction improved from 57 to 71 % when NCCT images were viewed with high-contrast window and level settings [55].

Clinical roles for imaging The above review of the hemodynamic changes that occur in acute cerebral perfusion disorders and the effects that they have upon the brain suggests

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Curr Treat Options Cardio Med (2015) 17: 10 several potential roles for neuroimaging in the care of patients with known or suspected ischemic stroke.

Exclusion of intracranial hemorrhage When a patient presents with a neurologic deficit of sudden onset, ruling out intracranial hemorrhage is of paramount importance. Although chronic hemorrhage is much more sensitively detected by MRI, acute hemorrhage may be diagnosed with by either NCCT or by MRI, with both modalities demonstrating sensitivity of 90 % in one study that compared them directly [56]. NCCT is used more commonly in excluding intracranial hemorrhage, because CT scanners are more widely available than MRI scanners in hospital emergency departments [57] and because CT scans can be completed more rapidly. As will be discussed in the next subsection, it is particularly important that NCCT is the first neuroimaging study for patients who are potential candidates for intravenous tissue plasminogen activator (tPA).

Determining eligibility for intravenous tissue plasminogen activator Current guidelines for treating acute ischemic stroke with intravenous tissue plasminogen activator (tPA) are based on the 1995 NIND [58] and 2008 ECASS [59] trials, which showed a significant benefit of therapy for patients treated within 3 and 4.5 h of onset of symptoms, respectively. Both trials required NCCT prior to treatment, chiefly in order to exclude intracranial hemorrhage, but did not include any other imaging study. Consequently, although centers vary in their preferences for the 3-h versus 4.5-h windows, acceptance of NCCT as the only imaging determinant of IV tPA eligibility is nearly universal. In order to maximize the potential benefit of tPA for appropriately selected acute stroke patients, its infusion should begin immediately after completion of the NCCT examination [60, 61]. Additional imaging studies are often undertaken subsequently, while the tPA infusion continues. As tPA’s purpose is to restore CPP, it is reasonable to hypothesize that the substantial risks of tPA administration should only assumed only when there is a potential benefit, i.e., when CTP or MRP provides evidence of focal CPP reduction. However, this hypothesis has not been tested. In current practice, most centers would consider acquisition of hemodynamic information prior to initiating tPA therapy to be a deviation from the standard of care that unacceptably delays treatment.

Diagnosing infarction As discussed above, the two current clinical imaging techniques that can diagnose cerebral infarction are NCCT and MRI. MRI is probably more sensitive than NCCT in diagnosing infarcts of all ages and in all anatomic locations. However, MRI is especially superior in diagnosing acute infarcts, in which vasogenic and ionic edema have not yet caused substantial hypodensity on CT, and in diagnosing infarcts that are small or are located in the posterior fossa, where beam-hardening artifacts caused by surrounding bones often obscure subtle findings [47, 51, 53, 62–64]. Because of MRI’s superior accuracy, it is preferable that patients with suspected infarction undergo brain MRI. However, as MRI scanners are not

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always immediately available, it is often necessary to begin evaluating patients with suspected infarction with CT and then proceed to MRI at a later time.

Vascular evaluation In patients with suspected cerebral ischemia, evaluation of the arteries of the head and neck is important for multiple reasons, the most urgent of which is often determining the patient’s potential eligibility for intra-arterial therapy (IAT). Interventional neuroradiologists now employ a variety of IAT techniques that can reopen occluded intracranial arteries via direct catheter access, all of which are employable only when there is a relatively proximal arterial lesion, as current microcatheter techniques usually can reach only primary or secondary intracranial arterial branches. Clinical IAT practices vary across institutions, but most centers reserve IAT for patients whose symptoms began less than 6–12 h prior to presentation. For patients who satisfy local clinical IAT criteria, imagingbased assessment of proximal arterial occlusion (PAO) must be performed emergently. Usually, this is done in the emergency department, prior to transport to the angiography suite, using CTA or MRA. CTA is slightly more accurate than MRA in diagnosing PAO, although both achieve high levels of sensitivity and specificity [65–67]. The preferred study in this setting is usually CTA, which can be performed more quickly, provides more detailed images of distal arterial branches, and is less prone to artifacts such as those caused by turbulent blood flow or patient motion. The only major advantage of MRA over CTA is MRA’s ability to produce angiographic images without the use of intravenous contrast material, which may be important in patients with contrast allergies or renal impairment. In patients with suspected cerebral perfusion disorders who are not IAT candidates, vascular evaluation should be performed promptly but need not be emergent. In such cases, the choice between CTA and MRA may be based upon the individual characteristics of the patient and/or scanner availability. Ideally, these patients should undergo brain MRI, which provides better evaluation of the brain parenchyma than CT. Therefore, it may be convenient to include vascular evaluation in an already ordered brain MRI study, by simply adding pulse sequences that provide MRA images of the head and neck. Questionable MRA findings may require additional evaluation with the more detailed images that CTA provides. Skipping MRA and proceeding directly to CTA may be indicated in some cases, such as when there is suspicion of arterial dissection or of unusual intracranial arterial pathology such as vasculitis or reversible cerebral vasoconstriction syndrome, whose detection may require CTA.

Measuring the core As has been discussed earlier, ischemic injury to brain tissue accumulates gradually and eventually becomes irreversible, after an amount of time that is inversely related to the severity of a CBF reduction. At any particular moment, the tissue that has accumulated irreversible ischemic injury is called the Binfarct core,^ or simply the Bcore.^ These terms are based upon the observation that core tissue sometimes lies near the center of a larger ischemic region. The term Bischemic core^ is sometimes used with equivalent meaning, although core tissue frequently is not actually ischemic, when reperfusion has occurred. If

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Curr Treat Options Cardio Med (2015) 17: 10 sufficiently severe ischemia exists outside of the core, the core may grow, over the hours and days following presentation, with a larger volume of tissue ultimately proceeding to infarction. Much recent research has focused on measuring the size of the core, particularly in selecting patients who might be most likely to benefit from IAT. Although some argue otherwise [68], mounting evidence suggests that recanalization therapy is unlikely to improve outcomes for patients whose core volumes are greater than 60–100 mL or approximately one third of the middle cerebral artery territory [31, 69–71]. Because core tissue by definition cannot be salvaged by therapeutic reperfusion, the potential benefit of reperfusion is limited in patients with large cores. Reperfusing large volumes of core tissue may actually worsen patient outcomes [34•], by exacerbating extravasation of edema fluid through damaged blood vessels or increasing the likelihood of hemorrhage [31, 72]. DWI is generally accepted as the preferred imaging technique for measuring the core. As discussed above, DWI detects cytotoxic edema, which results from sufficiently severe and prolonged ischemia, and DWI is highly sensitive in detecting ischemic brain injury even minutes after its onset. DWI is not a perfect indicator of the irreversibly injured core, as disappearance of DWI lesions does occur occasionally [73]. However, DWI lesion reversal typically involves a very small volume of tissue, most of which nevertheless ultimately proceeds to infarction [74–77]. Researchers debate whether the benefit of selecting patients for IAT based on core volume is sufficient to justify the additional time needed to complete DWI. It is possible that the answer to this question could vary among different institutions, where the time required to complete DWI could range from approximately ten minutes to many hours, depending upon scanner availability. The core can also be located with NCCT, though with much less sensitivity and precision than that of DWI during the first few hours of infarction. As discussed above, NCCT detects ionic and vasogenic edema, which physiologically accompany and follow cytotoxic edema, suggesting that the specificity of NCCT in detecting the core should be at least as great as that of DWI. However, in the first 6–12 h after the onset of ischemia, the quantity of water that exits from the blood vessels is so minute that it often cannot be appreciated in NCCT images. Therefore, although NCCT may provide insensitive and approximate estimates of the extent of acute infarction, volumetric core estimates are possible only with DWI. Many studies have attempted to use perfusion imaging to identify the infarct core [22, 24, 25, 35, 36, 38, 40, 78–86]. However, the above review of the physiology of ischemic injury should make clear that this is not possible. Perfusion imaging depicts instantaneous hemodynamic conditions within the brain, rather than the effects of ischemia that have accumulated prior to imaging. Ischemic tissue transitions over time from being potentially salvageable Bnon-core^ to being irreversibly injured Bcore,^ without any hemodynamic change taking place. Therefore there is no hemodynamic signature that can characterize the core. Furthermore, spontaneous reperfusion of infarcts is common and can cause the core tissue to appear normal in perfusion maps.

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The penumbra Another extremely active area in acute stroke imaging research is measurement of the so-called penumbra. The term Bpenumbra^ has its origins in the ischemic penumbra of the 1970s; however, the original meaning has been abandoned. Whereas the ischemic penumbra originally was defined as tissue that is electrically impaired because of ischemia but not in danger of infarction, researchers now define the penumbra as the tissue that is still viable (i.e., not part of the core) but that is likely to undergo infarction, if reperfusion is not achieved rapidly. The implication is that patients with larger penumbras are better candidates for tPA or IAT. Current studies usually identify the supposedly at-risk tissue of the penumbra using abnormalities of Tmax or MTT, which in fact do not entail any direct threat to tissue viability. This practice is based upon prior reports of statistically significant correlations between the volumes of tissue with Tmax or MTT abnormalities and various other adverse imaging findings. While it is intuitive that more severe imaging findings of all types would tend to co-occur with one another, a significant correlation between two measurements does not logically imply their interchangeability [87, 88]. Tmax or MTT prolongation does not necessarily imply the existence of ischemia (which may explain the waning use of the word Bischemic^ when discussing the penumbra), and many patients with chronic atherosclerotic disease manifest large Tmax and MTT abnormalities for years, without ever experiencing infarction. Some current studies label as the penumbra any tissue that appears subjectively abnormal in maps of Tmax or MTT, but normal in some other image that putatively identifies the core [89–94, 71, 95]. Other studies employ quantitative Tmax thresholds, for example, defining the penumbra as tissue with Tmax over 2 s [31, 33, 32, 96] 4 s [35, 97], 5.5 s [98, 99], or 6 s [34•, 35]. Still other studies have used quantitative MTT thresholds of 6 s [98], 7 s [80], or 145 % of normal values [24, 23, 35, 38, 80]. Researchers have not agreed upon a single imaging standard that should be used to identify the penumbra, and no such consensus is likely to be achievable, or even desirable, in the future. Any one universal perfusion imagingbased method could not take into account population-related differences among acute stroke patients who present to different institutions that might affect the prognostic implications of any particular perfusion imaging finding [90]. Even more significantly, the claim that any particular instantaneous hemodynamic condition can determine how much of an individual patient’s brain will undergo infarction in the future, if therapeutic recanalization is not achieved, ignores, and implicitly negates the potential impact of all other therapeutic decisions that have yet to be made. Despite these concerns and despite the existence of many conflicting proposed methods for defining the penumbra, an increasing number of publications now refer to the penumbra without stating a specific definition, [40] perhaps reflecting the absence of any one accepted definition, and the inconsistency of commonly used definitions with the fundamental understanding of cerebral hemodynamics that gave rise to the idea of the ischemic penumbra in the first place.

Management of patients with infarcts Current clinical stroke imaging research focuses largely upon optimizing selection of patients for emergent recanalization therapy, i.e., intravenous tPA or IAT. Although recanalization therapy potentially produces the most dramatic improvements in patient outcomes, only a small minority of patients meets even the most liberally defined clinical criteria for its use. For both these patients

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Curr Treat Options Cardio Med (2015) 17: 10 and the many more who do not qualify for tPA or IAT, neuroimaging studies could potentially help to guide hospital care in the hours and days following initial presentation in other ways. One largely unexplored role for neuroimaging in stroke care is that of blood pressure management. Although stroke patients’ systemic blood pressures are carefully monitored and controlled during their early treatment, extensive research has produced inconsistent conclusions regarding what blood pressure is optimal [84, 100]. A relatively high blood pressure may preserve tissue viability by mitigating low regional CPP, and some studies have found benefit in not merely allowing stroke patients’ blood pressures to rise but in therapeutically inducing hypertension using pressor agents [101]. On the other hand, spontaneous reperfusion of ischemic tissue is common [102–105], and in reperfused tissue that has already undergone infarction, higher blood pressure may worsen vasogenic edema [100] and increase the risk of hemorrhagic infarct transformation [106, 107]. Higher blood pressures may also worsen outcomes by injuring other organs, particularly the heart and the kidneys. It is reasonable to suppose that a single, somewhat high blood pressure goal may not be best for all stroke patients. Hypertension cannot help to mitigate low CPP, if CPP is not low. It is possible that a lower blood pressure may be better for patients whose infarcts have fully reperfused, and the significant minority of acute stroke patients whose infarcts have reperfused spontaneously prior to presentation could be identified by perfusion imaging. Perfusion imaging might further help by not merely helping to choose one of two blood pressure goals but perhaps by helping to establish individual blood pressure goals for individual patients. For example, identification of a hypoperfused region (i.e., low CBF) might suggest that raising blood pressure could help to preserve the viability of some tissue. In contrast, identification of only compensated low CPP (i.e., elevated MTT but normal CBF) might suggest that the current blood pressure is adequate. The distinction between reperfused and unreperfused infarcts potentially could be helpful not only in blood pressure management, but perhaps in other treatment decisions as well. For example, hyperosmolar therapy is sometimes employed to reduce vasogenic edema and reduce intracranial pressure in patients with large infarcts, but is only transiently effective [108, 109]. It is possible that its use might best be reserved until the onset of reperfusion, which tends to cause a rapid increase in vasogenic edema. As another example, hyperoxia therapy has been proposed as an experimental means of improving oxygenation of underperfused tissue [110] but also could be harmful, especially in the setting of reperfused infarcts, because of increased formation of reactive oxygen species [111]. Demonstration of the effectiveness of experimental therapies like hyperoxia could be assisted by imaging-based selection of patients who are most likely to benefit. None of these hypotheses has been tested empirically. In current practice, the roles of neuroimaging in the management of infarction are usually limited to the following. First, hemorrhagic transformation of an ischemic infarct may be detected with high sensitivity either by NCCT or MRI, and follow-up NCCT to exclude hemorrhage is recommended 24 h following treatment with intravenous tPA. Second, either NCCT or MRI may be used to assess mass effect that results from vasogenic edema, which tends to peak

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Fig. 1. Typical imaging protocols employed at the author’s institution for patients with suspected acute stroke or transient ischemic attack. These protocols are adapted from previously published guidelines [120] and have been expanded to encompass a wider variety of patient presentations.

approximately 3–5 days after infarction and may cause further perfusion impairment and potentially herniation. Third, enlargement of an existing infarct and/or development of new infarcts are common in the days following presentation. Although new infarction may be assessed either by NCCT or MRI, MRI provides greater sensitivity.

Transient ischemic attack Patients who may have experienced a transient ischemic attack (TIA) should undergo MRI for detection of any clinically silent infarcts that may have occurred during an ischemic event. Various studies have reported finding DWI abnormalities in between 34 and 67 % of TIA patients [112–119]. TIA patients

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Curr Treat Options Cardio Med (2015) 17: 10 also should undergo evaluation of the major cervicocranial arteries with CTA, MRA, or ultrasound, to help determine whether an intervention such as antiplatelet therapy or carotid endarterectomy is indicated as a means of preventing future infarction. Ideally, patients with suspected TIA should also undergo perfusion imaging. Approximately 25–30 % of patients with TIA symptoms and negative DWI demonstrate persistent hemodynamic abnormalities in early perfusion imaging [117, 119], and these sometimes provide the only objective confirmation that a TIA has occurred.

Conclusion Multimodal neuroimaging can contribute a wealth of complementary information to the care of the acute stroke patient, by excluding intracranial hemorrhage, detecting vascular lesions, evaluating those lesions’ hemodynamic consequences, and assessing the effects of ischemia upon tissue metabolism and viability. As a model, Fig. 1 presents typical acute stroke imaging protocols that are used at the author’s institution. The actual imaging studies selected for individual patients may vary greatly, and entirely different protocols may be preferable at other centers, where treatment options and scanner availability vary. At any institution, the selection and use of neuroimaging for an acute stroke patient should be based upon that individual patient’s presentation and upon an understanding of the fundamental physiologic principles of cerebral hemodynamics and ischemic brain injury.

Compliance with Ethics Guidelines Conflict of Interest Dr. William Copen declares no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not report any studies with human or animal subjects performed by any of the authors.

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