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Magnetic Resonance Imaging of Cerebrovascular Diseases Maarten G. Lansberg, Max Wintermark, Chelsea S. Kidwell, Steven Warach, Gregory W. Albers

KEY POINTS • The MRI acute stroke protocol includes T2, FLAIR, GRE, MRA, DWI, and PWI and can be acquired in 15–20 minutes. • Diffusion-weighted MRI (DWI) is an excellent tool to detect acute cerebral infarcts, and to distinguish these from chronic infarcts, in patients with stroke or TIA. • MRI has great promise as a tool to select patients who are the optimal candidates for acute stroke therapy. • MRI is as reliable as CT in the identification of acute intracerebral hemorrhage and can therefore be used as the sole imaging modality for evaluating patients with acute stroke. • MRI is superior to CT in identifying the underlying cause of intracerebral hemorrhage. • MR angiography and venography are ideal imaging modalities for evaluation of cerebrovascular pathology such as arterial stenosis or occlusions, dissections, aneurysms, and venous thrombosis.

Nuclear magnetic resonance imaging (MRI) techniques were first employed in the 1940s. The first MR images were obtained in the 1970s. In the 1980s structural MRI emerged as a clinically useful diagnostic modality for stroke and other neurologic disorders.1–5 In the detection of ischemic stroke lesions MRI is more sensitive than computed tomography (CT), particularly for small infarcts and in sites such as the cerebellum and brainstem and deep white matter.6–8 In the investigation of ischemic stroke, conventional structural MRI techniques, such as T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and fluid-attenuated inversion recovery (FLAIR) imaging, reliably detect ischemic parenchymal changes beyond the first 12–24 hours after stroke onset. These methods can be combined with MR angiography (MRA) to non-invasively assess the intracranial and extracranial vasculature. However, within the critical first 3–6 hours, the period of greatest therapeutic opportunity, these methods do not adequately assess the extent and severity of ischemic changes. The 1990s witnessed the development of diffusionweighted imaging which is sensitive and specific for delineating irreversibly injured ischemic brain tissue within the first 6 hours from stroke onset.9,10 Around the same time, contrastbased MR perfusion (MRP) techniques gained popularity to delineate hemodynamic changes.11,12 These two techniques were recognized for their potential clinical utility in the early detection and investigation of patients with stroke.13,14 That initial optimism began to bear fruit as further technical developments, most notably echoplanar imaging (EPI),15 made

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diffusion and perfusion MRI feasible in routine clinical practice. The detection of hyperacute intraparenchymal hemorrhagic stroke by susceptibility-weighted MRI also has been established as comparable to CT. In combination with MRA, the multimodal stroke MRI examination opened the door for the detection of the site, age, extent, mechanism, and tissue viability of acute stroke lesions in a single imaging study. A number of potential clinical applications have emerged that could allow therapeutic and clinical decisions to be based on the physiologic state of the tissue in addition to clinical assessment. Stroke MRI is applied as a multimodal examination to evaluate the stroke patient for arterial pathology, hemodynamic changes, hyperacute parenchymal injury, subacute and chronic infarct, and evidence of acute or chronic hemorrhage (Fig. 48-1). Beyond its role as an aid in routine clinical diagnosis, the most promising applications of current MRI methodology are as a patient selection tool for experimental and interventional therapies and as a biomarker of therapeutic response in clinical trials. In this review, we describe the applications of structural and functional MR techniques in cerebrovascular diseases. First, the general MRI principles and pulse sequences are discussed, followed by clinical applications of MRI in the evaluation of patients with TIA, ischemic stroke, intracranial hemorrhage and cerebrovascular pathology. Broader applications of MRI to specific cerebrovascular topics are illustrated in the other chapters of this book. A fuller treatment of the technical topics discussed in this chapter may be found elsewhere.16,17

GENERAL PRINCIPLES OF MAGNETIC RESONANCE IMAGING Routine MR imaging is based on the interaction of radio waves with atomic nuclei (most commonly protons or hydrogen nuclei) in tissue. Hydrogen is present in nearly all of the organs of the body. Protons have a net magnetic moment such that when they are placed in a magnetic field they align with the magnetic field and can be excited by radiofrequency (RF) pulses. Water and fat protons are the most extensively imaged nuclei. Other nuclei can be imaged, such as phosphorus, sodium, and fluorine, but these are much less abundant than hydrogen and have no current clinical application to stroke. When undergoing an MRI study, the patient is placed in a strong magnetic field. In general, this main magnetic field is always on, so safety precautions around the MRI scanner are essential even when a scan is not being performed. The strength of the magnetic field depends on the specific scanner. In practice, a number of the current clinical MRI are performed at 1.5 Tesla (1.5 T), but lower and higher field strength scanners are also in use. Over the past decade clinical 3T MRI has become commonplace. The next decade may see 7T MRI become a product for routine clinical use.18 In general, for brain and cerebrovascular imaging, higher field strengths give greater signal-to-noise ratio, which is advantageous for



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T2-weighted

FLAIR

DWI

MTT

ADC

CE-MRA

GRE

TOF MRA

Figure 48-1.  Multimodal MRI of acute stroke. Arrows point to the sequence-specific acute cerebrovascular pathology. T2-weighted image from the b0 images of the diffusion-weighted imaging (DWI) sequence appears normal. DWI image shows acute ischemic injury as a region of relative hyperintensity. The apparent diffusion coefficient (ADC) is reduced, as is characteristic of hyperacute stroke. The gradient recalled echo (GRE) image illustrates the susceptibility blooming of an acute thrombus (arrow). Fluid-attenuated inversion recovery (FLAIR) image shows hyperintense middle cerebral artery (MCA) distal to the occlusion. The mean transit time (MTT) map of the perfusion-weighted image illustrates delayed perfusion in the right MCA territory. The contrast-enhanced (CE) and time-of-flight (TOF) MR angiograms identify the site of occlusion in the right MCA.

reducing scanning time and improving spatial resolution. Higher field strengths also come with challenges, including those related to susceptibility. To acquire images, RF pulses are applied at the Larmor frequency of hydrogen, the proton’s resonant spin frequency. The energy from the RF pulses is absorbed and then released until the tissue being scanned has reemitted the energy absorbed and undergone relaxation. The echo time (TE) is the time the machine waits after the applied RF pulse to receive the RF echo from the patient. The repetition time (TR) is the time between RF pulses. The energy released occurs over a short time according to two relaxation constants, known as T1 (longitudinal relaxation constant) and T2 (transverse relaxation constant). Varying the TE and TR enables images of different contrast to be obtained, depending on which of the constants is dominant in the tissue. Spatial localization of the signal source from the tissue is achieved by the superimposition of brief gradient magnetic field pulses. In the sections below, the most commonly used MR pulse sequences are reviewed. Conventional MRI pulse sequences include T2WI, T1WI, proton density (PD) imaging, and FLAIR imaging. These are of most value in the evaluation of subacute and chronic stroke. The conventional sequences are based on two families of sequences termed spin echo (or fast spin echo) and gradient echo. In the former, the energy is refocused with the use of a series of RF pulses, whereas the latter uses a reversal of the magnetic field gradient to refocus the energy. The gradient echo sequences are most useful for MR angiography and

hemorrhage detection. Supplementing the anatomical information obtained from conventional sequences, contemporary MR protocols also include diffusion-weighted imaging (DWI), diffusion kurtosis imaging (DKI), MR perfusion (MRP), and MR-angiography (MRA). These sequences allow a multimodal evaluation of the patient with acute stroke by imaging tissue injury, perfusion, and the vasculature within the short period feasible for an acute stroke evaluation.

T1-Weighted Images T1WIs are based on the longitudinal relaxation of spins. They are generated primarily from sequences of short TE and short TR; the shorter the TE and TR, the more T1-weighted the image is. On T1WI, the cerebrospinal fluid (CSF) has low signal intensity, whereas fat has high signal intensity. Gray matter appears less intense (darker) than white matter. Ischemic infarcts appear hypointense on T1WI. The T1WI is not an essential part of the multimodal stroke MRI examination but is valuable in specific cases: axial fat-suppressed T1WI of neck soft tissue can identify the intramural thrombus of an arterial dissection.19

T2-Weighted Images T2WIs are based on the transverse relaxation of spins. They are generated from sequences of long TE and long TR. On T2WI, the CSF signal is hyperintense. Gray matter appears

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less intense (darker) than white matter. Ischemic lesions also appear hyperintense and may be difficult to distinguish from normal CSF spaces, a potential problem for smaller lesions.

PD images are generated with long TR and short TE, and the CSF and fat are of similar signal intensity. One advantage of PD imaging is that lesions appear hyperintense relative to CSF, although in practice PD imaging has been supplanted by FLAIR imaging.

examination, because of the diagnostic advantages of the latter for non-cerebrovascular pathologies. Unique features of FLAIR sequences for acute stroke imaging include hyperintensity of extra-axial blood (e.g., subarachnoid hemorrhage [SAH],20 subdural hematoma, Figs 48-2A, B) and delayed gadolinium enhancement of intrasulcal CSF, indicative of early blood– brain barrier disruption (Fig. 48-2C).21 FLAIR imaging may also depict hyperintense arterial signal indicative of very slow flow associated with acute occlusions or severe stenosis (Figs 48-1, 48-3)22–25 A disadvantage of FLAIR imaging is its high sensitivity to pulsation artifacts of CSF that may mimic SAH, for instance in the basilar cisterns.

Fluid-attenuated Inversion Recovery Images

Diffusion-weighted Imaging

On FLAIR, an additional RF pulse (inversion pulse) is applied with the purpose of nulling signal from the normal CSF. As applied in routine practice, on T2-weighted FLAIR imaging the CSF signal is nearly fully suppressed and appears dark as in T1WI, but the lesions appear bright, as in T2WI, allowing better visualization of cortical lesions and periventricular lesions. In practice, FLAIR imaging is used in place of PD imaging and often preferred to T2WI, although FLAIR acquisition times are somewhat longer. Some radiologists prefer both FLAIR imaging and T2WI for the comprehensive head MRI

DWI has transformed the diagnosis of ischemic stroke in its earliest stage, from reliance on a mostly clinical inference about the presence, localization, and size of an ischemic lesion, to imaging confirmation of the infarct. This technique is the only brain imaging method to reliably demonstrate ischemic parenchymal impact within the first minutes to hours after onset, well before changes are detectable on CT and T2WI or FLAIR MR images (Figs 48-1, 48-4). DWI detects the self-diffusion of water, which is the mobility of water molecules among other water molecules (brownian

Proton Density Images

A

B

C

Figure 48-2.  Extra-axial hyperintensity on fluid-attenuated inversion recovery (FLAIR). A, An example of a subdural hematoma seen on fluidattenuated inversion recovery image (FLAIR) (arrow), with clear contrast between the hyperintensity of the blood and the background tissue. This small subdural hematoma was not seen on CT. B, FLAIR images from a 47-year-old man with a subarachnoid hemorrhage. Blood appears hyperintense in the subarachnoid space at multiple levels. C, FLAIR images showing gadolinium enhancement of cerebrospinal fluid in hemispheric sulci (arrows) after intravenous tissue-type plasminogen activator (t-PA) treatment. This is the hyperintense acute reperfusion marker (HARM) sign, which indicates early blood–brain barrier disruption in stroke and is associated with reperfusion and increased risk of hemorrhagic transformation. The HARM sign is more likely to be seen following thrombolytic therapy. The main imaging differential is blood, which can be ruled out by gradient recalled echo MRI or CT.

Figure 48-3.  Fluid-attenuated inversion recovery (FLAIR) hyperintense vessel sign. Left, Hyperintense vessel sign on FLAIR imaging in a patient with a 2-hour-old occlusion of the left internal carotid artery (arrow). Note the normal flow void (hypointensity) of the contralateral carotid artery. Right, Hyperintense vessel (arrows) sign in branches of the right middle cerebral artery territory distal to an occlusion, indicating slow flow in a patient with penumbral flow in that territory.

DWI DWI

FLAIR

A

B

DWI-HR

C Figure 48-4.  Detection of hyperacute ischemic stroke with diffusion-weighted imaging (DWI). A, The characteristic MRI pattern of hyperacute ischemic stroke, which is DWI-positive (arrow) and fluid-attenuated inversion recovery (FLAIR)-negative. B, High-resolution DWI (DWI-HR) may reveal punctate acute ischemic lesions not seen on the more typical lower-resolution DWI. The use of DWI-HR may further reduce the probability of false-negative DWI in stroke. C, Acute ischemic lesions (arrows) in multiple arterial territories suggestive of cardioembolic mechanism.

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motion).9,26 With use of single-shot echoplanar imaging, whole-brain DWI of stroke can be obtained in a scanning time as short as 2 seconds;27 in current practice, however, multiple DWI acquisitions are obtained and combined for greater signal-to-noise ratio. The typical DWI pulse sequence actually acquires two sets of images, one with and the other without diffusion weighting. An EPI T2WI sequence is set without diffusion weighting. A bipolar pair of diffusion-sensitizing magnetic field gradient pulses to the T2WI pulse sequence cause a dephasing and then rephasing of the spinning protons in water molecules.26 Where there has been net displacement of a water molecule (i.e., protons) between application of the two diffusion gradient pulses (on the order of tens of milliseconds), there is a net dephasing and subsequent signal loss in the resulting image. The more the water has moved, the greater the signal loss, so that signal intensity is reduced everywhere but relatively less where water movement is restricted. CSF appears very dark, normal brain appears intermediate, and ischemic brain, where parenchymal diffusion is reduced, appears relatively bright. DWI is quantitative in that it both measures a physiologic parameter – the apparent diffusion coefficient (ADC) of water in mm2/second – and can define the acute ischemic lesion volume, which can be used to study ischemic pathophysiology in vivo. The ADC is calculated from the reduction in signal intensity that occurs with diffusion weighting. Thus a DWI pulse sequence usually contains at least two sets of images, one without diffusion weighting, a T2WI, and one with high diffusion weighting. The strength of diffusion weighting is described by a set of pulse sequence features called the b-value, so these two sets of images may be referred to as b0, indicating the T2WI without diffusion weighting, and the b1000, referring to the most commonly used b-value in practice. DWI measurements also contain geometric information, primarily axonal orientation, because DWI acquires its information in one direction at a time. This anisotropy results in higher signal perpendicular to fiber tracts and lower signal parallel to them. For routine stroke imaging, it is preferable to minimize anisotropy by effectively averaging the diffusion measurements across three orthogonal directions, reducing the hyperintensity not due to ischemia, a potential

confounding factor for small ischemic lesion in white matter tracts. These averaged images are often referred to as isotropic DWI. Diffusion tensor imaging (DTI)28,29 is a type of DWI that, rather than eliminate anisotropy, uses this information to determine the direction and integrity of degenerated white matter tracts. There are emerging data suggesting that DTI can be used to assess stroke recovery.30,31 In acute cerebral ischemia, the ischemic lesion appears hyperintense (bright) on DWI and hypointense (dark) on an ADC map (see Figs 48-1, 48-4). This appearance reflects cytotoxic edema, and a reduction in the volume and increased tortuosity of the extracellular space. As the ischemic lesion evolves through the phases of cytotoxic edema, vasogenic edema, tissue necrosis, and cavitation, the ADC normalizes and then becomes elevated in the chronic phase of stroke.32 This feature makes it possible to distinguish old ischemic lesions from new by calculation of the ADC value. As a rule of thumb, DWI hyperintensity without T2WI or FLAIR changes usually implies reduced ADC and can be taken as evidence of acute ischemic impact. Signal hyperintensity on DWI can persist during later stages of stroke (the “T2 shine-through” effect) and cannot by itself be evidence of acute ischemic stroke. In addition, non-ischemic pathologies may be associated with DWI hyperintensity.33 For these reasons, in patients with suspected ischemic stroke, DWI should always be interpreted with T2WI and FLAIR and ideally with a calculation of the ADC maps.

Magnetic Resonance Perfusion Imaging Brain perfusion, defined in the broadest sense as some aspect of cerebral circulation, may be studied by various MRI strategies. Two categories of MRI methods, one requiring the injection of contrast agent and the other not, have been used to study abnormal perfusion in human stroke (mainly ischemic) (Fig. 48-5). The first strategy, which is the standard method in clinical practice, is dynamic susceptibility contrast (DSC) imaging, involves a bolus injection of gadolinium and the rapid acquisition of a series of susceptibility-weighted or T2*-weighted images repeated every 1 to 2 seconds through an entire brain volume.11,12 The intravascular passage of

Figure 48-5.  MR perfusion imaging. A, Acute ischemic changes in left middle cerebral artery territory on diffusion-weighted imaging (DWI). B, Larger region of ischemia on perfusion mean transit time (MTT) map using the standard dynamic susceptibility contrast (DSC) method. C, MR perfusion without gadolinium is acquired using arterial spin labeling (ASL), showing a comparable perfusion defect on this relative cerebral blood flow map obtained 1 hour 40 minutes after stroke onset. Arrows point to regions of abnormality.

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gadolinium in sufficiently high concentration distorts the local magnetic field owing to magnetic susceptibility effects, causing dephasing of spins in brain tissue adjacent to the blood vessels and therefore results in signal loss. The amount of signal loss over time in a series of rapidly acquired images has been shown to be proportional to cerebral blood volume (CBV) in healthy brain tissue. The time it takes for the change in signal intensity to reach a maximum is the time to peak (TTP) and is related to the Tmax and mean transit time (MTT) of an idealized bolus of contrast agent. Because cerebral blood flow (CBF) in these intravascular models equals the ratio CBV/ MTT, information about cerebral blood flow can potentially be inferred with this technique. In patients with acute stroke, perfusion maps of the relative MTT, Tmax, CBV, and CBF can be generated, permitting visualization of perfusion defects in acute infarcts, tissue reperfusion occurring after recanalization of blood vessels, and hyperperfusion of subacute infarcts that have reperfused. Postprocessing of the MRP images occurs within minutes of image acquisition at the scanner and so the images are rapidly available to the treating physician. The optimal and accurate assessment of these and other perfusion parameters is an area of intense investigation,34–40 but in clinical practice, the MRP source images and scanner-generated perfusion maps are sufficient to determine the presence or absence of acute focal ischemia. For cases in which patient head movement during MRP acquisition renders the maps inadequate for diagnosis, assessment of the individual source MRP images can be useful, because these EPI source images are virtually unaffected by patient motion. Because of the recognized toxicity of gadolinium-based contrast agents in patients with renal failure, which is not uncommon in older stroke patients, there has been increased interest in MR perfusion methods that do not require contrast agent administration. The second MR perfusion strategy involves arterial spin labeling (ASL) methods, which use RF inversion pulses to magnetically label spins in the arterial supply to brain regions, using arterial water as an endogenous diffusible tracer.41–44 It can be applied either as pulsed,45,46 as continuous labeling,47 or as a combination of both. In ischemic stroke, ASL appears to give comparable diagnostic information to that from the gadolinium bolus tracking methods (see Fig. 48-5),48 although the reduced signal-to-noise ratio requires averaging of multiple acquisitions, requiring longer acquisition times, and thus is more vulnerable to motion artifacts. However, the more straightforward quantitative measurement of tissue perfusion with ASL49,50 is an advantage of this methodology over the bolus tracking method. Innovations have now permitted multiple brain slices to be imaged with ASL,51 and ASL perfusion methods are available for routine imaging on most MRI scanners.

inspection of the source images is often necessary to evaluate subtle or ambiguous findings, and most scanners permit scrolling through a reformatted slab of source MRA images for this purpose (see Fig. 48-1). For imaging of the arteries of the circle of Willis, 3D rather than 2D TOF MRA is the most common method of MRA in clinical practice, since it gives superior spatial resolution and is less prone to signal loss from turbulent flow at sites of stenoses. Limitations of TOF MRA are its tendency to overestimate the degree of stenosis (particularly when there is slow or turbulent flow or calcifications) and its insensitivity to collateral sources of flow. Its advantages include greater spatial resolution than CE-MRA for the intra­cranial circulation and its application to the imaging of the cerebral venous system (MR venography). TOF is an alternative for patients unable to receive gadolinium-based contrast agents. Notwithstanding its tendency to overestimate the degree of stenosis, MRA rivals CT angiography and conventional angiography for the detection of arterial stenoses, occlusions, and dissections.52–55 The sensitivity of MRA to detect aneurysm after SAH is estimated to be 69–100%, with a specificity of 75–100%.56 The sensitivity for smaller aneurysms is less.57

Magnetic Resonance Angiography In cerebrovascular diagnosis, MRA with contrast-enhanced (CE) or time-of-flight (TOF) methods are the standard approaches. In CE-MRA, a rapid MR acquisition is timed to a bolus injection of contrast agent over a large field of view, permitting routine imaging of the vasculature from the aortic arch through to the branches of the circle of Willis (see Fig. 48-1). The vascular anatomy is outlined by the blood containing the contrast agent. In TOF MRA, no contrast agent injection is required, and the vascular signal depends on direction and velocity of blood flowing into the plane of imaging. The magnetization of protons in stationary tissue occurs through saturation by repeated low-flip-angle RF pulses, whereas protons in the vessels flowing into the tissue remain unsaturated and appear relatively bright. The data are then postprocessed for an angiographic reconstruction. In practice,

Susceptibility-weighted Imaging SWI refers to a family of MRI sequences in which the tissue contrast is based on magnetic susceptibility differences between different tissue types. Magnetic susceptibility is the property of matter that distorts an applied magnetic field. Although often a source of artifacts at the interface of differing tissue types or in the presence of metal, this principle can be used to make pulse sequences sensitive to hemorrhage, to functional changes in blood oxygenation, and to hemodynamic parameters. The conventional GRE pulse sequence (commonly called T2*weighted images) is sensitive to the susceptibility effects of paramagnetic molecules such as gadolinium-containing contrast agents as well as deoxyhemoglobin and other hemoglobin breakdown products that are present during all stages of intracranial hemorrhage. Single-shot EPI has intrinsic susceptibility weighting, and EPI using a GRE technique, as in MRP, is the most sensitive of all to susceptibility effects in routine clinical practice. A specific variation of GRE, termed simply SWI, measures phase differences and may be more sensitive than conventional GRE in the detection of acute hemorrhage, chronic microbleeds, and cerebral veins.58–60

Magnetic Resonance Spectroscopy MRS allows the non-invasive in vivo assessment of brain chemistry by measuring resonances from important metabolites. Clinical studies of MRS have been performed predominantly on 1H nuclei (proton MRS), for which there is a relatively favorable signal-to-noise ratio compared with MRS of other nuclei. Although data collection from single voxels (single voxel spectroscopy) is more straightforward, differences between tissue compartments following stroke are more easily appreciated with chemical shift imaging (CSI). In CSI, spectra from multiple voxels within a grid corresponding to one or more slices are displayed. Typically metabolite peaks are presented as a spectrum in the “frequency domain” on a scale expressed in parts per million (ppm), which conventionally runs from right to left. CSI data can also be displayed as a color-coded “map” overlying a structural image, but it should be stressed that analysis of individual spectra is mandatory. Although a large number of metabolites can be detected, particularly in those studies using a short TE, stroke studies have focused on metabolites with large peaks including N-acetyl-L-aspartate (NAA) at 2.01 ppm, lactate at 1.33 ppm, and, to a lesser extent, choline at 3.22 ppm and

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creatine at 3.03 ppm. Values of metabolite peaks can be expressed in relative terms, for example, as a ratio to another metabolite within the same voxel, or to the same metabolite in a voxel in the contralateral hemisphere. Absolute concentrations may be derived by using the signal from water as an internal reference61 or, less commonly, by using a reference solution placed in the scanner external to the patient. MRS spectroscopy is time-consuming and therefore has limited clinical applications for acute stroke imaging.

CLINICAL APPLICATIONS OF MRI IN PATIENTS WITH CEREBROVASCULAR DISEASE The objective of multimodal MRI of acute stroke, also referred to as the stroke MRI examination, is to obtain diagnostic information about the acute parenchymal injury, subacute or chronic infarct, arterial pathology, tissue perfusion, and presence of hemorrhage. In this section the clinical application of multimodal MRI in the diagnostic work-up of patients with transient ischemic attacks, ischemic stroke, intracranial hemorrhage, and vascular pathology is discussed. Finally, we describe the utility of MRI as a tool to guide acute stroke therapy. The full multimodal MR sequences listed in Table 48-1 can be acquired within 15–20 minutes of scanning. All patients must be screened by MRI personnel for safety related to metal or electronic devices. Updated online resources relating to MRI safety are available (e.g., www.mrisafety.com). Approximately, 10–15% of patients suspected of acute stroke are unable to undergo MRI because of contraindications. In 2006, a link between gadolinium-based contrast agents and nephrogenic systemic fibrosis (NSF), a potentially debilitating fibrosing disease of the skin and viscera occurring in patients with chronic kidney disease was recognized. Readers are referred to European and North American guidelines for specific management recommendations.62,63 In general, caution is recommended when the glomerular filtration rate (GFR) is between 30 and 60 mL/min/1.73 m2 in the patient with chronic kidney disease, but local hospital policies may differ. Gadolinium TABLE 48-1  MRI Sequences in Acute Stroke Sequence

Primary Diagnostic Use in Cerebrovascular Disease

Diffusion-weighted imaging (DWI)

Hyperacute acute ischemic lesions Distinguish old lesions from new by apparent diffusion coefficient (ADC) imaging

T2-weighted imaging (T2WI)

Subacute and chronic ischemic lesions Rule out non-cerebrovascular pathology

Fluid-attenuated inversion recovery (FLAIR)

Subacute and chronic ischemic lesions Rule out non-cerebrovascular pathology Hyperintense vessel sign Blood–brain barrier breakdown

Gradient recalled echo (GRE)

Acute intracranial hemorrhage Hemorrhagic transformation Microbleeds Intravascular thrombus

MR angiography (MRA)

Acute arterial occlusion Other arterial lesions: stenosis, dissection, aneurysm MR venogram for sinus and cerebral venous thrombosis

Perfusion-weighted imaging (PWI)

Focal hemodynamic defect Diffusion–perfusion mismatch as marker of ischemic penumbra

should not be used when the GFR is less than 30 mL/ min/1.73 m2 or if the patient is dialysis-dependent. Estimated GFR based on serum creatinine is used to screen patients undergoing MRI for this risk.

Transient Ischemic Attacks Conventional MRI Conventional MRI (e.g., T2WI) is more sensitive than CT in identifying both new and preexisting ischemic lesions in patients with transient ischemic attacks (TIAs) (employing the classic definition of TIA as a focal neurologic deficit of vascular etiology that resolves within 24 hours). One of the earliest studies reported that 77% of patients had focal ischemic changes on MRI compared with 32% on CT.64 In subsequent studies, the percentage of TIA patients with at least one infarct on conventional MRI varies from 46% to 81%, but the majority of lesions do not correlate with symptomatology.65,66 The percentage of patients with an infarct on MRI in a location that could have accounted for the deficits observed during the TIA varies from 31% to 39% on conventional MRI.65,67 With conventional MRI it is difficult to determine what proportion of these appropriately localized infarcts occurred at the time of the index TIA and what proportion existed prior to the presenting event. Contrast-enhanced MRI studies can help determine the acuity of the lesion. In series of TIA patients who underwent contrast-enhanced MRI, contrast enhancement of an infarct was observed in 11–39%.65,65

Diffusion-weighted MRI Newer MRI techniques, including diffusion weighting and perfusion have revolutionized the MRI assessment of patients with TIA (Fig. 48-6).68–75 The high sensitivity and specificity of DWI for detection of acute infarcts has been particularly useful in the work-up of TIA patients. In a pooled analysis of 19 studies, the aggregate rate of DWI positivity was 39%, with frequency ranging from 25% to 67%.76 In studies that also obtained a follow-up MRI, 56–80% of patients demonstrated a subsequent infarct in the region corresponding to the original DWI abnormality (Fig. 48-7).68,80 Several studies have demonstrated that DWI positivity is associated with specific clinical characteristics, including longer symptom duration, motor deficits, aphasia, and largevessel occlusion demonstrated on MRA.68,77–79 A study exploring the characteristics of “DWI-negative” patients with TIA, found that patients with brainstem location ischemia or lacunar syndromes were most likely to have a negative initial DWI result and a positive follow-up imaging result.81 Identification of DWI-positive lesions in TIA patients is often clinically relevant. For patients who have multiple lesions on T2WI, DWI helps to clarify whether the lesions were related to a recent ischemic event in 31%,79 and the DWI image alters the physician’s opinion regarding vascular localization and probable TIA mechanism in also approximately one-third of patients.68 It has also been shown that patients with TIA who have abnormalities on DWI scans have a higher risk of recurrent ischemic events than those without such abnormalities.74,78,82 The presence of a DWI lesion alone or in combination with clinical variables such as the ABCD score (age, blood pressure, type of symptoms and symptom duration) is a strong predictor of 7-day and 3-month stroke risk.74,83

MR Perfusion Several studies have demonstrated that MRP can provide additive value to DWI and in some cases is more sensitive than DWI in detecting acute ischemic changes in patients with TIA.



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DWI positive TIA (FLAIR negative)

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Figure 48-6.  Diffusion-weighted imaging (DWI) of a patient with a transient ischemic attack (TIA). MRI findings in a 63-year-old man with a 30-minute episode of left arm weakness, imaged 4 hours after resolution. Left, DWI sequence shows right periventricular white matter lesion (arrow) not apparent on the fluid-attenuated inversion recovery (FLAIR) sequence (right, arrow).

DWI

ADC

Baseline T2

Follow-up T2

Figure 48-7.  Baseline and follow-up MRI in a patient with TIA. An acute ischemic lesion is evident on the baseline MRI as a bright lesion on the DWI sequence (top left) and as a dark lesion on the ADC map (top right), but is inconspicuous on the T2 sequence. Follow-up imaging demonstrates a subsequent infarct in the region corresponding to the original diffusion-weighted imaging (DWI) abnormality. TIA, transient ischemic attack; ADC, apparent diffusion coefficient.

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Because MRP is able to detect regions of relative hypoperfusion that do not reach the threshold of tissue bioenergetic compromise required to cause a lesion on DWI, a greater number of patients with modest degrees of ischemia may be detected with MRP. In series of TIA patients evaluated with MRP within 48 hours of symptom onset, approximately 33% of patients had a perfusion lesion.73,84 The percentage of patients with a DWI lesion was also approximately 33% and the combined yield of DWI plus MRP was 51%.73

Implications of MRI for Transient Ischemic Attack Definition and Clinical Guidelines TIAs are “brief episodes of neurological dysfunction resulting from focal cerebral ischemia not associated with permanent cerebral infarction.”76 Historically, transient episodes of neurological dysfunction lasting less than 24 hours have been considered TIAs. However, the MRI studies discussed above have shown that 30–50% of patients with short spells sustain permanent injury as evidenced by the presence of acute infarcts. Because of this, a new definition for TIA that includes imaging criteria has been proposed. This defines TIA as “a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction”.76,85 Given the utility of MRI imaging in the work-up of patients with TIA, the AHA/ASA states that “TIA patients should undergo neuroimaging evaluation within 24 hours of symptom onset, preferably with magnetic resonance imaging, including diffusion sequences; noninvasive imaging of the cervical vessels should be performed and noninvasive imaging of intracranial vessels is reasonable”.76,85

Ischemic Stroke Conventional MRI

of ischemic lesions are evident on both CT and conventional MRI by 24 hours, standard MRI is superior to CT in identifying lesions earlier as well as lesions that are smaller or in the posterior fossa.6,7 Whereas ischemic parenchymal changes are not apparent on conventional sequences in the first few hours, intravascular signs of acute stroke may be apparent. Specific findings include: absence of arterial flow void on T2WI, the hypointense intravascular sign due to acute thrombus on GRE sequences (Figs 48-1, 48-8),86,87, and intravascular hyperintensity on FLAIR (Figs 48-1, 48-3).22–25 This hyperintense vessel sign on FLAIR is indicative of slow anterograde flow through an incomplete occlusion, or slow retrograde flow via lep­ tomeningeal collaterals. This finding is associated with large diffusion–perfusion mismatch, but is not predictive of response to thrombolytic therapy.22,23,88,89 Similarly, after the administration of gadolinium, enhancement of the blood vessels in the area of infarction can be seen on T1WI, indicating slow flow within these vessels. On FLAIR imaging, CSF signal is suppressed which makes this sequence very sensitive to blood or gadolinium-based contrast agents in the CSF. SAH and subdural hemorrhage can therefore readily be detected on FLAIR. Leakage of gadolinium contrast into the CSF space in stroke patients with early disruption of their blood–brain barrier can be detected on postcontrast FLAIR images. It is characterized by a hyperintensity of the sulci.21 Such enhancement – termed hyperintense acute reperfusion marker, or HARM – is associated with reperfusion, thrombolytic therapy, an increase in the risk of hemorrhagic transformation, and an increase in plasma matrix metalloproteinase-921,90–92 (Fig. 48-2). The Subacute Stroke Stage.  When infarcts evolve their MR characteristics gradually change. Subacute infarcts are characterized by varying amounts of vasogenic edema and sometimes hemorrhagic transformation. Vasogenic edema is maximum between 1 and 6 days but persists to varying degrees

The Acute Stroke Stage.  Early MRI findings in patients with acute stroke are summarized in Box 48-1. Within the first few hours of ischemia, standard MRI sequences (T1WI, T2WI, and FLAIR) are relatively insensitive to ischemia, showing abnormalities in less than 50% of cases.84 The earliest changes, seen as increased signal on T2WI and FLAIR sequences, are due to a net increase in overall tissue water content, a process which takes several hours to develop to levels visible on MR. These changes are uncommon prior to 6 hours from onset but can be readily appreciated by 12–24 hours. Although the majority

BOX 48-1  Early MRI Findings in Acute Ischemic Stroke • Hyperintensity on diffusion-weighted imaging, with minimal or no changes on T2-weighted imaging (T2WI) or fluid-attenuated inversion recovery (FLAIR) imaging • Hypointensity on apparent diffusion coefficient (ADC) imaging • Hypointense (“blooming”) artery sign of acute intravascular thrombus on gradient recalled echo (GRE) imaging • Arterial occlusion on MR angiography • Absence of arterial flow-void, indicative of occlusion, on T2WI or FLAIR imaging • Hyperintense vessel sign, indicative of slow or collateral flow, on FLAIR imaging • Focal reduction or absence of contrast on dynamic perfusion source images • Focal reduction or absence of perfusion on perfusion parameter maps

Figure 48-8.  The blooming hypointensity of an acute arterial thrombus on gradient recalled echo (GRE) MRI (large arrow). The small arrows point to dilated veins commonly seen on GRE within the penumbral region, as defined on diffusion–perfusion mismatch (not shown).

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for 3 or 4 weeks. This edema appears as a hyperintense signal on T2-weighted and FLAIR images and as hypointense on T1WI. Subacute strokes are also characterized by breakdown of the blood–brain barrier. This breakdown results in gadolinium enhancement. The typical sequence of enhancement of the infarct is that enhancement is uncommon in the first 6 days, is most common between 7 and 30 days and disappears after that but can persist for up to 6 weeks.93 Two patterns of enhancement have been seen, a slowly progressive form that follows the T2WI changes and then an early form of enhancement which may be associated with better outcome. Occasionally a fogging effect may be seen in this phase or in the acute phase that is postulated to be due to developing hemorrhagic infarction.

superiority of DWI in a broad, representative sample.113 The sensitivity of DWI for ischemic acute stroke ranged from 73% (within 3 hours after the event) to 92% (more than 12 hours). By contrast, the sensitivity of CT at these times was 12% and 16%, respectively. The specificity of MRI for stroke detection was 92% (at 3 hours) and 97% (more than 12 hours).113 The superiority of DWI over CT was observed regardless of clinical severity or time from stroke onset to scan. A study comparing DWI lesions with pathologically confirmed infarction at autopsy also demonstrated an overall accuracy of 95%.114 Despite the high sensitivity of DWI, false-negative results might occur: Mild or small infarcts, early imaging, and brainstem location are factors associated with false-negative scans, and the false-negative rate is higher when patients have two or more of these factors than when individuals have one or none.81,113 The reported rate of false-negative results with DWI in consecutive patients assessed for acute stroke was 17% (versus 84% for CT) for the entire sample and 27% (versus 88% for CT) for patients imaged within the first 3 hours.113 False-positive DWI lesions are rare, but occasionally, DWI hyperintensities may be seen in other cerebral disorders, including status epilepticus, tumors, infections, and Creutzfeldt-Jakob disease. Given the overall excellent test characteristics of DWI for detection of acute infarcts, the 2010 practice guideline of the American Academy of Neurology states that DWI should be performed for the most accurate diagnosis of acute ischemic stroke.115

The Chronic Stroke Stage.  In the chronic stage of stroke the edema that was present in the subacute phase has resolved. At very late time points there may be atrophy and cavity formation. At this stage infarcts appear hyperintense on T2-weighted and FLAIR imaging. On T1WI, infarcts are hypointense and no longer have contrast enhancement. On DWI there is the T2 shine-through pattern and the ADC is elevated. Also at this stage, Wallerian degeneration may be seen as a secondary phenomenon in the white matter tracts.94 Ischemic Lesions on MRI in Patients without a Clinical Stroke.  Focal hyperintensities in the subcortical white matter demonstrated by T2-weighted or FLAIR images are a common incidental finding in patients undergoing brain MRI for indications other than stroke. They are indicative of chronic microvascular disease. These white matter hyperintensities are an indication of chronic cerebrovascular disease. They are associated with advanced age, history of hypertension, and pathologic changes such as arteriosclerosis, dilated perivascular spaces, and vascular ectasia.142–145,148–151 These white matter lesions may progress in number and frequency. Their clinical significance in the asymptomatic patient for cognitive decline or risk of stroke, independent of the other coexisting stroke risk factors, is uncertain.

Diffusion-Weighted MRI DWI allows visualization of regions of ischemia within minutes of symptom onset.95 DWI lesions follow a relatively consistent pattern of growth during the first 3 days, followed by a subsequent gradual decrease in size.96–100 The increased (bright) signal on DWI reflects restricted diffusion of water molecules in areas with cytotoxic edema. This can be quantitatively measured on the ADC maps, where darker areas represent decreased diffusion. The increase in signal on DWI may persist for several weeks or longer partially owing to a T2 effect. The average ADC, however, remains reduced for only 4 to 7 days then returns to normal or supranormal levels within 7 to 10 days from ischemia onset.32,101,102 This feature makes it possible to distinguish old ischemic lesions from new by calculating the ADC. Although the average ADC generally follows this pattern, studies have now clearly demonstrated that marked heterogeneity of the ADC value can occur within the ischemic lesion, even in the hyperacute time window.103 Test Characteristics of DWI.  DWI has a high degree of sensitivity (88% to 100%) and specificity (95% to 100%) for acute cerebral ischemia, even at very early time points.104–107 Studies performed in the acute stroke setting have consistently demonstrated marked superiority in accuracy of diagnosis of ischemic change for DWI (95% to 100%) over that for CT (42% to 75%) or standard MRI sequences such as FLAIR (46%).108–112 A prospective, blinded comparison of DWI with non-contrast CT in a consecutive series of 356 patients referred for emergency assessment of suspected acute stroke proved the

Clinical Utility of DWI.  DWI’s high sensitivity and specificity for identifying acute infarcts and its ability to distinguish acute from chronic infarcts can provide important diagnostic and prognostic information.116–119 The neuroanatomic site and the vascular territory of acute infarcts can almost always be demonstrated with DWI. Knowledge about the location of the acute infarcts can provide insight into stroke etiology, because certain lesion patterns are associated with specific stroke subtypes.120,121 Multiple lesions in the unilateral anterior circulation, and small scattered lesions in one vascular territory, particularly in a watershed distribution, are typically related to large-artery atherosclerosis.121,122 The presence of multiple acute lesions in different vascular territories in patients who have only one clinically symptomatic acute insult suggests an embolic stroke mechanism. This pattern may be seen in 3–5% of patients.120 These imaging patterns, together with information obtained from other MRI sequences, such as MRA, might help in the selection of the most appropriate measures for secondary prevention of stroke. DWI lesion characteristics can also be used to help determine the age of a stroke in patients with unwitnessed onset of stroke, including individuals whose deficits are present on awakening. A DWI lesion without a matching hyperintensity on FLAIR imaging suggests that the stroke occurred within 6 hours. Acute stroke studies are ongoing that use this pattern as a selection criterion for study enrollment.123–126 The volume of the baseline DWI lesion provides prognostic information regarding final infarct volume and neurologic and functional outcomes in patients with stroke affecting the anterior circulation but not the posterior circulation99,127–134 Prognostic accuracy is improved when DWI volume data are combined with clinical variables.135 The number of acute DWI lesions can also be used prognostically, as the presence of multiple DWI lesions is associated with an increased risk of future ischemic events.136–138

MR Perfusion MR bolus perfusion imaging (MRP) is playing an ever more important role in the initial evaluation of the patient with acute stroke. Perfusion measures that can be derived from this

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technique include mean transit time (MTT), time to peak (TTP), time to maximum of the residue function (Tmax), cerebral blood volume (CBV), and cerebral blood flow (CBF).35,38,139,140 Controversy persists regarding which perfusion measure is optimal for identification of critically hypoperfused tissue in the acute stroke setting. The role of perfusion imaging in the assessment of the acute stroke patients is discussed in detail in the section on MRI-guided acute stroke therapy at the end of this chapter.

Magnetic Resonance Spectroscopy MRS provides an opportunity to study brain biochemistry in vivo after stroke. This technique may be used to image the ischemic penumbra, provide prognostic information, and may offer additional imaging endpoints in clinical trials. MRS, however, has a number of limitations. First, even under ideal conditions, signal-to-noise ratio is limited by the low concentration of brain metabolites relative to water. Second, movement of patients during scanning not only may distort spectra and introduce confounding signal from scalp lipid, but also may displace the head from its original position, thereby limiting the spatial sensitivity of the technique. Third, interpretation of metabolite ratios requires an appreciation that all major metabolites may change after stroke and with aging.141 Finally, MRS is time-consuming and therefore not practical in the acute stroke setting. In the paragraphs below, we describe the expected changes in the major metabolites following stroke that can be measured with MRS. NAA is considered a marker of neuronal integrity142 on the basis of its predominantly neuronal localization.143 NAA values fall after stroke,144–150 with greater decreases in the center than in the periphery of the infarct.157,161 The early reduction of NAA can be as much as 20% within an hour151 and 50% within 6 hours.152 NAA levels continue to decrease in the first 2 weeks after stroke,150 and remain chronically low or absent thereafter. Low NAA levels have therefore been implied as a marker of the ischemic core. The creatine peak is influenced by both creatine and phosphocreatine and therefore is considered a marker of energy stores. Reductions in this peak are seen after stroke,144,145,147,149 but are less dramatic than the reduction in NAA.146 Lactate levels are raised within the infarct and manifest as a “doublet” peak at 1.33 ppm, projecting above and below the baseline at long and intermediate TEs, respectively. Lactate production results from anaerobic glycolysis and is generally considered to be undetectable in the healthy brain, although

low levels of lactate may be detectable in older healthy adults153 and in the hemisphere contralateral to stroke lesions.150 Animal studies of ex vivo and in vivo MRS demonstrate that lactate is present within minutes of ischemia and that lactate levels continue to increase over hours, particularly in the center of the ischemic lesion.151,152,154 Reperfusion after focal ischemia precipitates a gradual decrease in lactate over days151,155 but a decline in lactate is also seen in permanent MCA occlusion models.151 Clinical studies are consistent with these findings. High levels of lactate are present in the infarct of patients imaged in the hyperacute phase.156,157 Subsequently, lactate levels fall during the first week145,146 and are undetectable after 2 weeks.147,150 Measurements after a number of months have shown a second rise in lactate levels,150 consistent with the presence of inflammatory infiltrate. Changes in the choline peak, which represents total choline levels and is a marker of cell membrane turnover are more variable. Choline levels after stroke can be decreased,144,149 unchanged,147 or increased.145 Although decreases may represent cell loss, it has been postulated that increases may represent myelin damage in infarct regions with a significant proportion of white matter.148 Clinical Utility of MR Spectroscopy in Stroke.  While MR spectroscopy can theoretically be used to refine the MR definition of “tissue at risk”,156 its clinical applicability in the acute stroke setting is limited because MR spectroscopy is timeconsuming. It has been hypothesized that tissue with a raised lactate but normal NAA levels may indicate metabolically compromised yet intact neurons, and therefore the ischemic penumbra (Fig. 48-9).148 One human MRS study of acute stroke patients confirmed that the MRP–DWI mismatch region has raised lactate levels and normal NAA levels.156 Another study showed less lactate and more NAA in the ischemic penumbra compared to the ischemic core.157 MRS studies also have the potential to provide markers of the efficacy of stroke therapy. This may include the measurement of brain temperature in different tissue compartments,158,159 assessment of the interplay between ischemia and redox status,160 or, theoretically, even the demonstration that certain drugs have actually reached the target tissues. In addition, MRS could be used to evaluate the effect of revascularization procedures such as endarterectomy or EC–IC bypass surgery. MRS studies have shown a reduction of NAA, an increase in choline, and sometimes an increase in lactate in the hemisphere ipsilateral to an internal carotid artery stenosis.161,162 Such changes can be reversed with carotid

Lactate

A

B

C

D

Figure 48-9.  Identification of lactate in 2-hour acute stroke in diffusion-negative, perfusion-positive region, preceding the diffusion-weighted imaging (DWI) lesion. A, Baseline DWI with magnetic resonance spectroscopy (MRS) grid overlaid. B, MRS abscissa from highlighted voxels in A, which shows the presence of lactate (arrow). C, Baseline lesion on mean transit time (MTT) map. D, Follow-up DWI demonstrating lesion in region on early lactate peak.



Magnetic Resonance Imaging of Cerebrovascular Diseases

779

TABLE 48-2  Appearance of Hemorrhage on Various MRI Sequences

48

Stage

T1-Weighted

T2-Weighted

Fluid-Attenuated Inversion Recovery

Hyperacute (<12 hour)

Isointense or mildly hyperintense

Hyperintense

Hyperintense

Hypointense rim

Acute (12 hour to 2 days)

Isointense or hypointense

Hypointense

Hypointense

Hypointense rim gradually progressing centrally

Early subacute (2–7 days)

Hyperintense

Hypointense

Hypointense

Hypointense

Late subacute (8 days to 1 month)

Hyperintense

Hyperintense

Hyperintense

Hypointense

Chronic (>1 month to years)

Isointense or hypointense

Hypointense

Hypointense

Slit-like hyperintense or isointense core surrounded by a hypointense rim

endarterectomy, particularly in patients who do not have lactate in the lesion prior to surgery,161 and in those in whom the postoperative CBV is demonstrably improved.163 Finally, MRS may play a role in assessing prognosis after stroke, as lactate-to-choline ratios164 and changes in NAA165 correlate with clinical outcome.

Head CT

Gradient Recalled Echo or T2*

MRI GRE

MRI SWI

Intracranial Hemorrhage Although non-contrast CT has traditionally been considered the gold standard for the assessment of hemorrhage, advances in MRI techniques have provided both improved diagnostic capabilities for detection of intracranial hemorrhage and better understanding of the underlying pathophysiology, etiology, and prognosis of these disorders. The appearance of blood on various MRI sequences depends on the stage of evolution of the blood breakdown products (Table 48-2).166 The hemoglobin that is present in freshly extravasated blood exists primarily in the form of oxyhemoglobin, which is non-paramagnetic. However, conversion of intracellular oxyhemoglobin to deoxyhemoglobin likely begins at the periphery of the hematoma almost immediately. Deoxyhemoglobin contains four unpaired electrons, making it highly paramagnetic. Around days 2 or 3, deoxyhemoglobin is converted to methemoglobin, which initially is formed intracellularly then becomes extracellular as the red blood cells lyse. Around day 7, macrophages and phagocytes begin transforming the methemoglobin to hemosiderin and ferritin. Conventional T1- and T2-weighted MRI sequences are highly sensitive for the detection of subacute and chronic blood, but they are less sensitive to parenchymal hemorrhage less than 6 hours old. Studies now suggest that hyperacute parenchymal blood can be accurately detected using standard or echoplanar imaging T2*-weighted sequences, including gradient recalled echo (GRE) and susceptibility-weighted imaging (SWI).167–169 Echoplanar T2*-weighted imaging can be performed with a very low acquisition time (seconds), representing a significant advantage in patients with acute intracranial hemorrhage who are unable to cooperate or lie still for extended periods of time. The hallmark of hyperacute hemorrhage on T2*-weighted sequences is a rim of hypointense signal surrounding an isointense core (Fig. 48-10). Subsequently, in the acute and sub­ acute stages, the hematoma becomes diffusely hypointense, and in the chronic stage, the hematoma appears as a slit-like signal with a hyperintense or isointense core with a rim of hypointensity. Several large multicenter prospective studies have demonstrated that these MRI sequences are as reliable as CT in the

CT – 1 hr 16 min after symptom onset MRI – 1 hr 37 min after symptom onset

A

B Figure 48-10.  A, An example of an acute intraparenchymal hematoma, less than 2 hours from onset, on CT as well as gradient recalled echo (GRE) MRI and MRI using echoplanar imaging (EPI) and susceptibility weighted imaging (SWI). Note on MRI the appearance of a hetero­ geneous central hypointense periphery of the hematoma, surrounded by the hyperintense rim of edema. B, In a hematoma at a later point, approximately 3 hours from onset in this figure, hypointensity predominates.

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identification of acute blood, and superior to CT for detection of chronic blood including microbleeds and chronic hemorrhages.113,170,171 In some cases, MRI detects hemorrhages that are not evident on CT.170,172 These findings have allowed MRI to be employed as the sole imaging modality to evaluate patients with acute stroke at capable centers. However, up to 20% of patients with acute stroke may not tolerate or may have contraindications to MRI.173

Intraparenchymal Hemorrhage The most frequent underlying etiologies of adult primary intracerebral hemorrhage (ICH) are hypertension and cerebral amyloid angiopathy (CAA), and MRI findings can often assist in making this determination. Primary ICH associated with hypertension most often occurs in deep brain structures (e.g., putamen, thalamus, cerebellum, and pons), and is often accompanied by deep microbleeds. In contrast, primary ICH occurring in lobar regions, particularly in the elderly, is most commonly related to CAA but may also be associated with hypertension.174 CAA-related hemorrhage is frequently characterized by a distinct pattern of lobar microbleeds. MRI is superior to CT in identifying underlying structural lesions that are less frequent causes of parenchymal ICH (e.g., arteriovenous malformations, tumors) and in quantifying the amount and extent of perihematomal edema (fluid attenuated inversion recovery [FLAIR] sequence). A contrast study (highest yield in subacute phase once edema has dissipated and blood been reabsorbed) is indicated in patients without a clear underlying etiology or in hemorrhages occurring in unusual locations.175 MRI techniques have provided new insights into the underlying pathophysiology of ICH, specifically the role of ongoing secondary neuronal injury in the perihematomal region. A number of studies (but not all) have demonstrated perihematomal regions of hypoperfusion, bioenergetic compromise, or both.176,177 These MRI studies have suggested that approximately one-third of patients imaged in the acute phase may have reduced perihematomal ADC values.176,178,179 Further studies have characterized the evolving time course, with ADC values being low within the first day and then gradually elevated, likely reflecting the evolution of perihematomal edema. In aggregate, these studies suggest that there may be a subset of patients with a rim of perihematomal hypoperfusion and possibly ischemia in the hyperacute phase. It is likely that this region rapidly disappears in the subacute phase as edema and inflammation evolve.177,180 The development of

edema and toxicity from blood breakdown products are the most significant contributors to ongoing perihematomal injury. MRI studies thus have the potential to monitor the impact of these findings on recovery and in the future may be used as surrogate outcome markers for studies of putative interventions.181,182 Recently, a series of studies have reported a high frequency of small acute ischemic lesions visualized on DWI in the acute and subacute periods following the onset of primary ICH. These lesions are remote from the index hemorrhage and have been reported in approximately one-quarter to one-third of patients with primary ICH due to either hypertensive disease or cerebral amyloid angiopathy.183–188 Several of the studies have found an association with blood pressure reductions or fluctuations in the acute hospital setting184,188,189 and they have also been associated with the presence of microbleeds, white matter disease, and prior stroke.185,186,188 Notably, a number of these studies have also found an association between remote ischemic lesions on DWI and poor functional outcome or death following primary ICH.184,186,190

Microbleeds T2*-weighted MRI sequences have the ability to detect clinically silent prior microbleeds, not visualized on CT (Figs 48-11, 48-12). Microbleeds are defined as punctate, homogeneous, rounded, hypointense parenchymal lesions, usually

Figure 48-11.  Gradient recalled echo MRI sequence demonstrating multiple scattered old microbleeds (punctate hypointensities) from a patient with cerebral amyloid angiopathy.

A

P

P

Figure 48-12.  Example of GRE from a patient with ICH attributable to hypertensive disease, in whom microbleeds are most commonly found in deep and infratentorial regions.

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Magnetic Resonance Imaging of Cerebrovascular Diseases

less than 5–10 mm in size. A number of studies have demonstrated that the pathologic correlate of GRE-visualized microbleeds is a region with hemosiderin-laden macrophages that occurs adjacent to small vessels. These findings are indicative of previous extravasation of blood at the vessel wall.191 Studies have suggested that the ability to detect microbleeds is greater with higher magnet strength, high-resolution 3D T2*-weighted imaging, and/or the use of susceptibility-weighted imaging sequences compared to standard GRE; however, the clinical relevance of these differences remains unclear.192–195 A number of standardized approaches and scoring systems have been proposed for quantifying microbleed burden, including automated or semi-automated approaches.196–200 MRI evidence of microbleeds is seen in 38–80% of patients with primary ICH, in 21–26% of patients with ischemic stroke, and in 5–6% of asymptomatic individuals.201–203 In the Rotterdam study of a general elderly population, prevalence of microbleeds increased from 24.4% to 38% over a 3-year interval.204 Hypertension and/or blood pressure variability, CAA, and advancing age are the most commonly reported risk factors for microbleeds.205–210 Chronic kidney disease, statin use, antithrombotic use, elevated blood inflammatory markers, and elevated serum uric acids levels have also been reported as independent risk factors for microbleeds.211–217 In one study, microbleeds have been found to be more prevalent in black patients with primary ICH (74%) than in whites (42%) (P = 0.005).218 Microbleeds have also been found to occur more commonly in persons with greater white matter and small-vessel disease.219 Less common risk factors are cerebral autosomal dominant arteriopathy with silent infarcts and leukoaraiosis (CADASIL)210 moyamoya disease,220 and SAH where they were associated with the presence of ischemic DWI lesions.221 A growing body of evidence indicates that microbleeds represent a marker of a bleeding-prone angiopathy as well as an active, dynamic small-vessel disease process.222–226 Several case reports and small series suggested that patients with microbleeds may be at increased risk for development of hemorrhage following antithrombotic or thrombolytic therapies. In contrast, two large series did not show an increased risk of hemorrhage in patients treated with intravenous tissue plasminogen activator (t-PA).227,228 However, in both of these studies, very few patients were included who had a large microbleed burden, thus representing a potentially biased sample. A more recent meta-analysis did report a significant relationship between increasing microbleed burden and symptomatic hemorrhage post thrombolysis.229 One study found that almost 5% of patients treated with intravenous thrombolysis developed new microbleeds.230 The pattern of microbleed topography can provide insights into the underlying risk factors and etiology, particularly in patients with primary ICH. It has been shown that microbleeds are a common occurrence in patients with CAA and most frequently are found in lobar regions (see Fig. 48-11).205 A pattern of multiple lobar microbleeds in the setting of a lobar ICH is highly suggestive of CAA as the underlying etiology. However, a recent study found that both small-vessel disease and CAA contribute to the pathogenesis of lobar micro­bleeds.231 In contrast, in patients with ICH attributable to hypertensive disease, microbleeds are most commonly found in deep and infratentorial regions, although it is likely that hypertension may also contribute to lobar-located microbleeds (see Fig. 48-12).208 A number of studies have suggested an association between microbleeds and apolipoprotein genotype status, with increased rates in persons with apolipoprotein ε4 and ε4 alleles, particularly in CAA-related lobar microbleeds.232–234 The presence of microbleeds and the overall microbleed burden appear to have important prognostic significance. One

study demonstrated that the total number of microbleeds predicts risk of future symptomatic hemorrhage in patients with probable CAA.207 In addition, new microbleeds demonstrated on repeat MRI were found to also predict increased risk of future symptomatic ICH.235 Several studies have shown a correlation between microbleeds and new vascular events.206,236,237 In patients with TIA or stroke, microbleeds have been associated with an increased risk of future stroke in general but not symptomatic ICH.238,239 The presence of prior microbleeds has also been associated with development of new microbleeds both in ischemic disease and ICH. Moreover, microbleed burden and rate of accumulation have been found to predict cognitive decline and poor neurologic or functional outcome in this population, and even vascular death.240–243 In particular, microbleeds have been found to be associated with executive dysfunction.244,245 In patients with TIA or stroke, microbleeds have been associated with an increased risk of future stroke in general but not symptomatic ICH.238,239

Hemorrhagic Transformation Hemorrhagic transformation (HT) of an ischemic infarction is a common occurrence, visualized in up to 42% of patients in pathologic series. The MRI evolution of blood breakdown products in HT is similar to that seen with primary ICH (see Table 48-2). However, T2*-weighted MR sequences often demonstrate regions of petechial hemorrhage not visualized with CT or standard MR sequences. Prospective studies, employing serial MRI with gradient echo sequences, are required to clarify the frequency of these findings in various stroke subtypes with and without reperfusion treatments, and their role in antithrombotic treatment decisions. The most commonly used radiologic classification system for rating the type and severity of hemorrhagic transformation was developed for head CT scans and divides hemorrhage into two major categories, hemorrhagic infarct (HI) and parenchymal hematoma (PH), each with two subcategories based on severity.246 However, it is important to note that the application of this classification system to MRI has not been fully validated. One small study suggested that T2*-weighted GRE was the most reproducible method to categorize HT with excellent reliability for severe parenchymal hematoma category.247 A modified classification system has also been developed with high rates of interobserver agreement.248 MRI information can, however, assist in distinguishing hemorrhagic transformation of an ischemic infarct from a primary hematoma. Most hemorrhagic transformations are smaller than the field of the ischemic infarct as seen on DWI. Primary hematomas also tend to have rounder edges and often have a greater amount of surrounding edema than would be seen in an ischemic stroke. Finally, hematomas frequently do not respect vascular territories. A growing number of studies have evaluated the clinical and radiologic (including MRI) predictors of HT in the setting of thrombolytic therapy. Contrast agent extravasation visualized on FLAIR, T1-weighted, or T2*-weighted sequences has been identified as an important marker of blood–brain barrier disruption, and therefore a predictor of HT.218,249–253 Several studies have also suggested that a large baseline DWI lesion, low ADC values, and very low cerebral blood volume are also independent predictors of subsequent symptomatic hemorrhage.254–258 Some studies,259 but not all,260 suggest that early infarct FLAIR hyperintensity is associated with increased rates of hemorrhagic transformation following thrombolysis. Higher rates of HT have been reported in patients treated with intravenous thrombolysis and with enlargement of medullary veins visualized on T2*-weighted sequences.261 These findings provide potential imaging biomarkers for testing of treatments

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SECTION V  Diagnostic Studies

designed to minimize risk of blood–brain barrier opening and subsequent hemorrhagic transformation.

Subarachnoid Hemorrhage Later studies have explored the clinical utility of MRI sequences in patients with subarachnoid hemorrhage (SAH). Although standard spin-echo sequences are relatively insensitive to subarachnoid blood, newer sequences, including FLAIR and gradient echo T2* imaging, have been shown to have modest sensitivity, particularly in the subacute phase when the CT result is often negative.262–264 Subarachnoid blood appears as a region of high signal intensity relative to normal CSF on FLAIR sequences and as a region of hypointensity on gradient echo images. Overall, studies have suggested that FLAIR imaging is as sensitive as CT for acute SAH, but compared with the findings at lumbar puncture, the findings on FLAIR imaging are not definitive in excluding acute SAH.263,265–267 Evaluation of patients with SAH and vasospasm is an emerging role for multimodal MRI. Several reports have demonstrated that patients with vasospasm secondary to aneurysmal SAH demonstrate a high rate of DWI lesions, often indicative of silent ischemia.268,269 In studies employing perfusion imaging, these ischemic lesions were associated with regions of hemodynamic compromise and angiographic evidence of vessel vasospasm.270–272 Later studies have employed combined diffusion and perfusion imaging to characterize the pathophysiology and evolution of ischemia due to vasospasm.273,274

Superficial Siderosis Superficial siderosis (or hemosiderosis) is defined as hemosiderin deposition within the subpial brain layers due to chronic iron deposition in subarachnoid or CSF spaces that can be visualized on T2*-weighted sequences. It can be caused by or associated with other forms of CNS hemorrhage including SAH, SDH, and primary intraparenchymal hemorrhage or intraventricular hemorrhage. Superficial siderosis is a common finding in cerebral amyloid angiopathy and has been associated with a clinical presentation of transient focal neurological episodes.275–277 Cortical superficial siderosis in this population may be associated with an increased risk of symptomatic ICH.278

Subdural and Epidural Hematomas Subdural hematomas appear as crescent-shaped lesions adjacent to the brain parenchyma. The MRI appearance depends on the age of the hematoma and the sequences acquired. In the acute stage, subdural hemorrhages appear as hyperintense on FLAIR and T2-weighted sequences. On GRE sequences, they may be isointense or hypointense in the acute stage, on the basis of the stage of blood breakdown products. In the subacute stage, they appear hypointense. In the chronic stage, subdural hematomas appear as either isointense or mixed signals, depending on the degree of blood reabsorption. Epidural hematomas appear as lentiform (biconvex) extraaxial lesions adjacent to the brain parenchyma. The displaced dura appears as a thin line of low signal intensity between the brain and hematoma. Rapid enlargement may lead to significant midline shift, often associated with herniation. MRI signal intensities usually follow the previously described temporal evolution of intraparenchymal ICH.

Cerebrovascular Pathology Arterial Stenosis and Occlusion MRA rivals conventional angiography and CT angiography for the detection of arterial stenoses and occlusions,52–55,279 but

there is a tendency of MRA, especially TOF, to overestimate the degree of stenosis because of dephasing of protons caused by turbulent flow or calcifications at the site of the stenosis. Smaller intracranial vessels are not well visualized with routine applications of MRA, however, ultra-high field MRA at 7 Tesla has shown promising results to reliably visualize small, microvessels at a sensitivity approaching that of angiography.280 A normal screening MRA of the extracranial carotid is reliable to exclude hemodynamically significant stenosis but falsepositive results can arise when the degree of carotid stenosis is overestimated. This can occur when the carotid artery is kinked or changes direction abruptly, when assessing stenosis of the distal ICA as it enters the carotid canal (owing to susceptibility artifact between vessel and bone), and when assessing stenosis in the presence of surgical clips. A false-positive occlusion on MRA is usually deducible by the reconstitution of flow distal to the point of signal loss. Sensitivity and specificity for carotid occlusion have been found to be 100% for most studies. In general, if MRA shows no stenosis or a stenosis of less than 70%, no further evaluation is necessary. If MRA shows a stenosis of 70% or more, duplex ultrasonography should be performed. If results of the two studies agree, no further evaluation is suggested,281,282 and appropriate management can be provided. If MRA and duplex ultrasonography do not agree, then further evaluation with conventional angiography is recommended. A promising new approach is contrastenhanced MRA of the carotid arteries, in which a more rapid MR acquisition is timed to a bolus injection of contrast agent over a larger field of view in less than 1 minute. This technique compares favorably to conventional angiography for the diagnosis of carotid stenosis.283–286 The accuracy of contrast-enhanced MRA for the detection of vascular disease of the vertebral artery origins and the aortic arch is being investigated.

Arterial Plaque Morphology A newer application of vascular imaging with MRI is high spatial resolution multimodal imaging of the carotid plaque to identify the various components, such as lipid deposits, fibrous caps, calcium, and thrombus.287 Although not yet a routine practice, high-resolution carotid plaque imaging appears promising as a way to document decreased lipid content and plaque stabilization following lipid-lowering therapy288 and to identify a ruptured fibrous cap associated with a recent history of TIA or stroke.287 Technical developments in high-resolution MR imaging of MCA stenosis have the potential to yield excellent visualization of intracranial stenosis and atherosclerotic plaque.289

Arterial Dissection The diagnosis of dissection of the internal carotid or vertebral artery can be made with MRI and MRA.290–293 Findings suggestive of dissection on MRI are increased signal from parts of, or the entire, vessel wall on axial T1-weighted images (with fat suppression) consistent with hematoma (Fig. 48-13), a border of increased signal surrounding the lumen with luminal narrowing, poor or absence of visualization of the vessel, or significant compromise of the vessel lumen by adjacent abnormally increased signal tissue. If a false lumen with an intimal flap is present, it is best appreciated on the T2WI. Vessel abnormalities such as narrowings, aneurysmal dilatation, and a second lumen may be demonstrable by MRA. When a TOF technique is used, MRA may show a normal or simply widened outer contour of the vessel at the site of dissection. This is caused by the addition of signal from the vessel wall due to methemoglobin in the hematoma, and by the high-flow lumen. False-negative MRI/MRA assessments for dissection

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occur, and CT angiography is recommended if there is a high degree of clinical suspicion and the MR results are negative. Review of the literature indicates that, in general, the positivepredictive and negative-predictive values of MRI combined with MRA were similar to those of CTA for diagnosis of dissection of the carotid and vertebral arteries.294

projection) algorithm. The use of MRA as a routine screening test for the detection of aneurysms is controversial.298,299 If aneurysm size is the only factor, the insensitivity to small aneurysms may not be of clinical consequence. The accuracy of MRA in detecting small aneurysms is likely to improve as techniques are further refined.

Aneurysms

Venous Thrombosis

MRA has a sensitivity of 92–95% for the detection of intra­ cranial aneurysms.240,241 False-negative and false-positive aneurysms detected on MRA are mainly located at the skull base and middle cerebral artery.295 The sensitivity of MRA to detect aneurysm after SAH is 69–100%, with a specificity of 75–100%.56 The sensitivity of this technique for the detection of small aneurysms is lower.57 Lesions as small as 2–3 mm in diameter have been shown by MRA, and the technique has occasionally demonstrated small aneurysms missed on conventional angiography.296 However, aneurysms smaller than 5 mm may be missed with MRA. Slow flow and turbulence within small aneurysms may interfere with their detection in up to 27% of cases, leading to limitation in study interpretation.297 These problems can be partially overcome by using intravenous contrast media. Small aneurysms may be difficult to differentiate from vessel loops because, unlike with conventional angiography, there is no increase in signal at the point of vessel overlap with use of an MIP (maximum intensity

Although diagnosis of cerebral venous thrombosis remains a diagnostically challenging entity, advances in MRI have substantially aided in the ability of physicians to perform a rapid, non-invasive, and comprehensive neuroimaging evaluation. The combination of brain MRI with MR venography (MRV) has a sensitivity of up to 95% in detecting cerebral venous sinus thrombosis.300 Moreover, MRI has provided further insight into the underlying differences in the pathophysiologic processes involved in venous versus arterial infarction. In cerebral venous thrombosis, breakdown of the blood–brain barrier combined with venous congestion leads to a unique combination of coexistent vasogenic and cytotoxic edema, which in turn often leads to frank infarction, hemorrhage, or both. MRI studies are able to visualize venous congestion, venous infarction, and hemorrhage. Venous hypertension may produce cytotoxic edema, vasogenic edema, or a combination of the two. These changes can be visualized as hyperintensity on T2-weighted or FLAIR images. If venous hypertension is mild, no signal abnormalities may occur. In patients with superior sagittal sinus thromboses, parasagittal lesions are common and may be bilateral. Transverse sinus thrombosis frequently causes posterior temporal lobe lesions, whereas thrombosis of the deep sinus system often causes bithalamic lesions. With contrast agent administration, there may be lesion enhancement in a tumorlike pattern. Hemorrhagic transformation of venous infarction occurs frequently and has the typical MR appearance of hemorrhage based on the stage of the blood breakdown product (see earlier discussion of hemorrhage). Venous sinus occlusion is usually well demonstrated by MR venography (MRV) (Fig. 48-14), making conventional angiography unnecessary in the majority of cases. MRV has been accepted as the procedure of choice in the diagnosis of sagittal sinus thrombosis.301,302 Direct findings of cerebral thrombosis by MRV include lack of typical high flow signal from a sinus and direct visualization of thrombus on individual frames of the 2D slices. These must be distinguished from an aplastic or hypoplastic sinus and from the appearance of a sinus after recanalization. Thrombosed veins and/or sinuses may also be

Figure 48-13.  MR images from a 48-year-old man with dissections (arrows) of bilateral carotid and vertebral arteries. Left, Power-injector contrast-enhanced neck MR angiogram shows an intimal flap in the left vertebral artery as well as progressive tapering of the distal internal carotid arteries. Right, A T1-weighted axial MR image through the internal carotid artery illustrates the pathognomonic crescent sign of dissection. In this image, the blood within the vessel wall of the right internal carotid artery appears hyperintense.

A

B

Figure 48-14.  A, Normal MR venogram of the brain. B, Straight sinus thrombosis. Note the lack of flow signal in the straight sinus, lateral sinus, vein of Galen, and internal cerebral veins.

48

MRI-Guided Acute Stroke Therapy The role of MRI in acute stroke management is an area of intense research. The results from MRI-based clinical trials are helping to refine the mismatch concept, and penumbral imaging is a promising tool that has the potential to identify individuals who might benefit from reperfusion therapies at extended time windows.312–318 There has been extensive research focused on the optimal MRI criteria to identify the ischemic penumbra. DWI is generally felt to be the gold standard for the ischemic core, but animal studies and case series in humans have shown that a limited volume of the early diffusion abnormalities can be temporarily or permanently reversed with early reperfusion319–321 (Figs 48-15–48-17). ADC values may predict which portion of the early DWI lesion is most likely to be permanently reversible, and one recent study identified an ADC of ≤620 × 10−6 mm2/seconds as the optimal threshold for identification of ischemic core (sensitivity 69% and specificity 78%).322 Studies that focus on identifying PWI criteria that mark the outer border of the ischemic penumbra (i.e., the border between tissue that is critically hypoperfused and tissue with benign oligemia) have typically optimized perfusion thresholds that predict final infarct size in patients without reperfusion. The underlying rationale for this approach is that, in the absence of reperfusion, the infarct grows to consume the entire penumbra to the benign oligemia border (see Fig. 48-16).323–326 Because the baseline perfusion lesion identifies tissue that is likely to infarct if vessel recanalization does not occur, its volume correlates well with final infarct volume as well as neurologic and functional outcomes and, in fact, correlates better than the baseline diffusion lesion volume.128,130,133,327 DEFUSE, Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) and DEFUSE 2 used the perfusion parameter Tmax (time to maximum of tissue residue function) and found that a Tmax contrast arrival delay of >4–6 seconds predicts ischemic tissue destined to become infarcted in acute stroke patients who do not experience reperfusion.328,329 A Tmax threshold of 5–6 seconds has also been

12 hr post treatment

visualized on axial gradient echo T2*-weighted sequences with greater conspicuity than standard T1- and T2-weighted scans.303,304 One group reported that the sensitivity of T2*WI and T1WI sequences to detect clot in the sinuses or veins was estimated at 90% and 71%, respectively, between days 1 and 3.305 Cerebral veins have a smaller caliber that the cerebral sinuses and there is more variability in terms of their anatomic location. As a result, the cerebral veins are more difficult to visualize on MRV than the cerebral sinuses. However, 97% of thrombosed cortical veins have been detected on T2*SWI, even in the absence of visible occlusion on MRV. Studies now suggest that the majority of cases of cerebral venous sinus thrombosis can be initially diagnosed by a combination of MRI studies, including T1WI, T2WI, DWI, GRE, FLAIR, MRA, and MRV, and that MRI provides a useful means for follow-up.306,307 Several reports have begun to elucidate the diffusion–perfusion MR characteristics of venous sinus thrombosis. Abnormal DWI signal intensity may be associated with low ADC values indicative of cytotoxic edema, high ADC values indicative of vasogenic edema, or mixed values indicative of a combination of both vasogenic and cytotoxic edema.301,308,309 Consequently, MR lesions caused by venous thrombosis are more frequently reversible than those due to arterial ischemia, because of the reversibility of vasogenic edema. Several groups have also demonstrated perfusion imaging abnormalities, including increased MTT310 and increased CBV.311

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DWI 9 mL

MRP 79 mL

DWI 0 mL

MRP 0 mL

5 -dat follow-up

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FLAIR 9 mL Figure 48-15.  The baseline MRI scan (top row) in a patient with a left MCA stroke shows a large mismatch between the diffusion and the perfusion lesion. The diffusion lesion (pink) is segmented based on a ADC threshold <620 × 10−6 mm2/second. The perfusion lesion (green) is segmented based on a Tmax>6 second threshold. The patient underwent successful endovascular therapy resulting in complete recanalization of the middle cerebral artery. A follow-up MRI obtained 12 hours after endovascular therapy (middle row) demonstrates complete reperfusion and complete reversal of the initial DWI lesion. The 5-day follow-up MRI (bottom panel) demonstrates an infarct in the location of the baseline DWI lesion which illustrates the transient nature of DWI reversal following endovascular reperfusion.

shown to approximate penumbral cerebral blood flow values on positron emission tomography.330 Serial diffusion/perfusion MR studies have demonstrated that the natural history of diffusion MRI abnormalities is to grow over time, particularly in patients with a large perfusion–diffusion mismatch imaged early after symptom onset.96,97,99,100,130,331–333 As the diffusion lesion grows, the extend of the mismatch decreases and, as a result, it is less common to see a substantial mismatch when the MRI is obtained later after symptom onset. Nevertheless, a substantial percentage of patients in whom the diffusion lesion grows slowly, still have regions of mismatch 24 hours after symptom onset.332,334 An altered evolution of infarction can be visualized on serial diffusion and perfusion imaging studies. Inhibition of lesion growth has been demonstrated in patients experiencing reperfusion in comparison with patients with persistent perfusion deficits or vessel occlusions.335–338 These studies suggest that it is feasible and potentially advantageous to use diffusion–perfusion MRI to select patients for thrombolytic therapy.

Magnetic Resonance Imaging of Cerebrovascular Diseases

DWI 47 mL

MRP 112 mL

DWI 67 mL

MRP 178 mL

5 -dat follow-up

12 hr post treatment

Baseline



FLAIR 288 mL Figure 48-16  The baseline MRI (top row) of a 42-year-old man with a left MCA occlusion shows a moderate-size ischemic core (pink lesion measuring 47 ml on DWI) and a larger territory of critical hypoperfusion (green lesion measuring 112 ml on the MRP [Tmax>6 second] map). Based on these numbers the patient has a MRP–DWI mismatch ratio of 2.4. Endovascular therapy was unsuccessful as evidenced by a persistent perfusion deficit on early follow-up imaging. In the absence of reperfusion, the ischemic core has grown some between baseline (47 ml) and early follow-up (67 ml). At 5-day follow-up there has been further expansion of the infarct into the perfusion lesion.

DWI

ADC

PWI

Pretreatment

Post-treatment

Figure 48-17  Examples of diffusion-weighted (DWI) and perfusionweighted (PWI) imaging from a patient treated with intra-arterial thrombolytic therapy for a right middle cerebral artery occlusion. Top row shows pretreatment images, and bottom row, early post-treatment images. Perfusion images are in the form of color-coded maps of the time to peak of the residue function (Tmax) with red indicating greatest delay. The intra-arterial treatment resulted in complete recanalization which is evidenced by near-complete reversal of the baseline PWI lesion. There is accompanying complete reversal of the initial DWI and apparent diffusion coefficient (ADC) abnormalities.

785

The combination of DWI and perfusion imaging allows the identification of several different patterns that appear to have prognostic significance. In about 50% of patients studied within 24 hours of symptom onset, there is a “perfusion– diffusion mismatch” (Fig. 48-16). It has been proposed that patients with a mismatch are the patients who are most likely to respond favorably to reperfusion. In other patients, the DWI lesion is larger than the perfusion lesion (presumably a result of early reperfusion), and in about 10–15%, the DWI and perfusion lesions are of similar size (likely indicating that little or no salvageable tissue is present and operationally defined as a completed infarct). Some patients (about 10%) rapidly develop very large DWI lesions (>70–100 ml) and/or very large and severe perfusion lesions, presumably related to the combination of poor collaterals and a large-vessel occlusion. These patients have been termed “Malignant profile” and appear to have very poor outcomes regardless of early reperfusion.339,340 In addition to predicting response to reperfusion, there is a growing body of data suggesting that baseline MRI characteristics may be used to predict risk of hemorrhagic transformation.222,341 Moreover, follow-up MRI imaging obtained after reperfusion therapy can provide insights into the evolving pathophysiology of human ischemia. The phenomenon of postischemic hyperperfusion has been demonstrated in approximately half of patients undergoing successful vessel recanalization with intra-arterial thrombolysis.342 Late secondary ischemic injury has been demonstrated on DWI and ADC maps in humans and in animal models, following vessel recanalization.222 These findings may become important targets for neuroprotective therapy in the future. The use of MRI signatures to select patients for reperfusion therapy may extend the time window for treatment beyond current standards and improve safety by enabling treatment decisions to be based on individual patient pathophysiology rather than rigid time windows.

Clinical Trials of Intravenous Thrombolysis Multimodal MRI for acute stroke can now be performed and interpreted rapidly and the additional diagnostic information obtained has the potential to improve both patient selection as well as cost-effectiveness of thrombolytic therapy.343–348 Several large stroke centers rely on MRI to screen patients for thrombolytic or endovascular therapies and many have contributed to clinical trials evaluating various MR imaging techniques.349 The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) as well as the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE), Desmoteplase in Acute Ischemic Stroke (DIAS), and Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS) studies showed that in patients with a DWI–MR perfusion mismatch, reperfusion following intravenous thrombolytic therapy was strongly associated with favorable clinical outcomes even in extended time windows.312–315,350 The DEFUSE study involved stroke patients treated with intravenous alteplase 3 to 6 hours after onset of symptoms. These patients were not selected on the basis of the DWI–MR perfusion mismatch; however, early reperfusion in patients with a mismatch (an MR perfusion lesion of at least 10 mL and ≥20% larger than the DWI lesion) was associated with a favorable clinical outcome, and the benefit of reperfusion appeared to be enhanced in patients with the Target mismatch profile (neither DWI nor MR perfusion with severe delay [Tmax > 8 seconds] exceeded 100 mL). In patients without a mismatch, there was no association between reperfusion and favorable clinical outcomes.312 In the EPITHET, treatment with intravenous alteplase vs placebo led to attenuation of some measures of infarct

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volume growth in patients with a mismatch, and similar to DEFUSE, there was a strong association between reperfusion and favorable clinical outcomes in patients with the Target mismatch profile.313 The trials of desmoteplase (DIAS and DEDAS) enrolled patients in whom a DWI–MR perfusion mismatch was detected 3–9 hours from onset of symptoms. The DIAS and DEDAS studies showed a positive dose–response relationship for desmoteplase on early reperfusion and beneficial clinical effects were seen in patients treated with desmoteplase.314,315 DIAS-2, a phase 3 study, did not confirm the clinical benefit of desmoteplase;316 although, in a subgroup analysis, patients with a large mismatch (>60 mL) had more favorable outcomes in the desmoteplase vs placebo group.351 Results of these late thrombolysis trials are encouraging, but larger clinical trials, such as the ongoing EXTEND study, are required to establish the role of the diffusion– perfusion mismatch in selecting patients for intravenous thrombolysis.352

therapy in DEFUSE 2 had more favorable clinical outcomes than the endovascular-treated penumbral group in MR RESCUE (Rankin 0–2 outcomes at 90 days occurred in 46% in DEFUSE 2 vs 21% in MR RESCUE). Among DEFUSE patients who achieved complete reperfusion, Rankin 0–2 outcomes at 90 days were achieved in 75%.356 The disparities in outcomes between DEFUSE 2 and MR RESCUE may be explained by differences in baseline imaging characteristics as well as reperfusion rates obtained. The estimated infarct core volumes in the MR RESCUE “penumbral pattern” groups (medians 36 and 37 mL) were substantially larger than the “Target Mismatch” group of DEFUSE 2 (13 mL). Of note, the EPITHET trial documented a substantial reduction in favorable clinical outcomes at core volumes >25 mL.357 A number of ongoing trials are using a variety of different imaging selection techniques to clarify which imaging patterns will identify patients who are likely to benefit from endovascular therapy.

Endovascular Therapy

The complete reference list can be found on the companion Expert Consult website at www.expertconsult.inkling.com.

The role of multimodal MR imaging in selecting patients for endovascular therapy was evaluated in the recently reported MR RESCUE and DEFUSE 2 studies. MR RESCUE was a randomized multi-center study in which patients with a largevessel anterior circulation stroke were randomized to embolectomy vs standard care within 8 hours of symptom onset.353 To be eligible for enrollment, multimodal MRI or CT perfusion was required and randomization was stratified based on imaging finding of a “favorable penumbral pattern”, defined as infarct core <90 mL and substantial salvageable tissue vs a non-penumbral pattern, defined as large core or small/absent penumbra. MRI was the primary imaging modality employed; however, CT perfusion was also allowed towards the end of the study and was used in about 20% of the patients. To assess salvageable tissue, an automated software program was employed and the penumbral pattern defined based on a voxel-by-voxel algorithm which included measures of the apparent diffusion coefficient, cerebral blood flow, mean transit time, and Tmax for the MRI model.354 One-hundred and eighteen patients eligible were recruited from 22 North American Stroke Centers between 2004 and 2011. Functional outcomes at 3 months were not different in the embolectomy vs standard care groups, irrespective of penumbral vs nonpenumbral pattern. Potential explanations for the failure of this trial to demonstrate benefits of embolectomy include the fact that the median predicted infarct core volume at the time of baseline imaging was large, 60 mL (34.1–107), there was a delay of 2 hours between start of imaging and femoral puncture, and the rate of good reperfusion (TICI 2b/3) achieved in the endovascular group (27%) was low. DEFUSE 2 was a prospective cohort study in which patients received an MRI scan prior to endovascular therapy.355 Onehundred and thirty-eight patients were enrolled at nine stroke centers over 3 years. The definition of the Target mismatch pattern was an MR perfusion lesion (Tmax > 6 seconds) that was at least 1.8 times larger than the DWI lesion (defined by an ADC value <600) and the absence of a “Malignant profile” defined as either DWI >70 mL or an MR perfusion lesion with severe delay (Tmax >10 seconds) exceeding 100 mL. The rate of TICI 2b/3 reperfusion obtained in DEFUSE 2 was 46%. DEFUSE 2 demonstrated that patients with a “Target Mismatch” pattern who experienced early reperfusion after endovascular therapy had significantly more favorable clinical outcomes. There was no association between reperfusion and favorable outcomes in the “No Target Mismatch” group. Comparing outcomes in MR RESCUE and DEFUSE 2, it is apparent that the Target mismatch group who underwent endovascular

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141. Haga KK, Khor YP, Farrall A, et al. A systematic review of brain metabolite changes, measured with 1H magnetic resonance spectroscopy, in healthy aging. Neurobiol Aging 2009;30: 353–63. 147. Gideon P, Henriksen O, Sperling B, et al. Early time course of N-acetylaspartate, creatine and phosphocreatine, and compounds containing choline in the brain after acute stroke. A proton magnetic resonance spectroscopy study. Stroke 1992;23: 1566–72. 150. Munoz Maniega S, Cvoro V, Chappell FM, et al. Changes in NAA and Lactate following ischemic stroke. A serial MR spectroscopic imaging study. Neurology 2008;71:7. 155. Allen K, Busza AL, Crockard HA, et al. Acute cerebral ischaemia: Concurrent changes in cerebral blood flow, energy metabolites, pH, and lactate measured with hydrogen clearance and 31P and 1H nuclear magnetic resonance spectroscopy. III. Changes following ischaemia. J Cereb Blood Flow Meta 1988;8:816–21. 156. Nicoli F, Lefur Y, Denis B, et al. Metabolic counterpart of decreased apparent diffusion coefficient during hyperacute ischemic stroke: A brain proton magnetic resonance spectroscopic imaging study. Stroke 2003;34:e82–7. 158. Karaszewski B, Wardlaw JM, Marshall I, et al. Measurement of brain temperature with magnetic resonance spectroscopy in acute ischemic stroke. Ann Neurol 2006;60:438–46. 161. van der Grond J, Balm R, Klijn CJ, et al. Cerebral metabolism of patients with stenosis of the internal carotid artery before and after endarterectomy. J Cereb Blood Flow Metab 1996;16: 320–6. 166. Kidwell CS, Wintermark M. Imaging of intracranial haemorrhage. Lancet Neurol 2008;7:256–67. 170. Kidwell CS, Chalela JA, Saver JL, et al. Comparison of MRI and CT for detection of acute intracerebral hemorrhage. JAMA 2004;292:1823–30. 174. Lang EW, Ren Ya Z, Preul C, et al. Stroke pattern interpretation: The variability of hypertensive versus amyloid angiopathy hemorrhage. Cerebrovasc Dis 2001;12:121–30. 175. Broderick J, Connolly S, Feldmann E, et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: A guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group. Stroke 2007;38:2001–23. 176. Kidwell CS, Saver JL, Mattiello J, et al. Diffusion-perfusion MR evaluation of perihematomal injury in hyperacute intracerebral hemorrhage. Neurology 2001;57:1611–17. 177. Butcher KS, Baird T, MacGregor L, et al. Perihematomal edema in primary intracerebral hemorrhage is plasma derived. Stroke 2004;35:1879–85. 180. Herweh C, Juttler E, Schellinger PD, et al. Evidence against a perihemorrhagic penumbra provided by perfusion computed tomography. Stroke 2007;38:2941–7. 183. Prabhakaran S, Naidech AM. Ischemic brain injury after intracerebral hemorrhage: a critical review. Stroke 2012;43:2258–63. 185. Gregoire SM, Charidimou A, Gadapa N, et al. Acute ischaemic brain lesions in intracerebral haemorrhage: multicentre crosssectional magnetic resonance imaging study. Brain 2011;134(Pt 8):2376–86. 188. Menon RS, Burgess RE, Wing JJ, et al. Predictors of highly prevalent brain ischemia in intracerebral hemorrhage. Ann Neurol 2012;71:199–205. 191. Fazekas F, Kleinert R, Roob G, et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: Evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol 1999;20:637–42. 193. Goos JD, van der Flier WM, Knol DL, et al. Clinical relevance of improved microbleed detection by susceptibility-weighted magnetic resonance imaging. Stroke 2011;42(7):1894–900. 199. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol 2009;8(2):165–74. 204. Poels MM, Ikram MA, van der Lugt A, et al. Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study. Stroke 2011;42(3):656–61.

219. van Es AC, van der Grond J, de Craen AJ, et al. Risk factors for cerebral microbleeds in the elderly. Cerebrovasc Dis 2008;26(4): 397–403. 222. Kidwell CS, Saver JL, Villablanca JP, et al. Magnetic resonance imaging detection of microbleeds before thrombolysis: An emerging application. Stroke 2002;33:95–8. 226. Lee SH, Lee ST, Kim BJ, et al. Dynamic temporal change of cerebral microbleeds: long-term follow-up MRI study. PLoS ONE 2011;6(10):e25930. 228. Fiehler J, Albers GW, Boulanger JM, et al. Bleeding risk analysis in stroke imaging before thromboLysis (BRASIL): Pooled analysis of T2*-weighted magnetic resonance imaging data from 570 patients. Stroke 2007;38:2738–44. 229. Shoamanesh A, Kwok CS, Lim PA, et al. Postthrombolysis intracranial hemorrhage risk of cerebral microbleeds in acute stroke patients: a systematic review and meta-analysis. Int J Stroke 2013;8(5):348–56. 231. Park JH, Seo SW, Kim C, et al. Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. Ann Neurol 2013;73(5):584–93. 234. Maxwell SS, Jackson CA, Paternoster L, et al. Genetic associations with brain microbleeds: Systematic review and metaanalyses. Neurology 2011;77(2):158–67. 235. Gregoire SM, Brown MM, Kallis C, et al. MRI detection of new microbleeds in patients with ischemic stroke: five-year cohort follow-up study. Stroke 2010;41(1):184–6. 238. Kwa VI, Algra A, Brundel M, et al. Microbleeds as a predictor of intracerebral haemorrhage and ischaemic stroke after a TIA or minor ischaemic stroke: a cohort study. BMJ Open 2013;3(5). 239. Thijs V, Lemmens R, Schoofs C, et al. Microbleeds and the risk of recurrent stroke. Stroke 2010;41(9):2005–9. 250. Bang OY, Buck BH, Saver JL, et al. Prediction of hemorrhagic transformation after recanalization therapy using T2*permeability magnetic resonance imaging. Ann Neurol 2007; 62:170–6. 254. Lansberg MG, Thijs VN, Bammer R, et al. Risk factors of symptomatic intracerebral hemorrhage after tPA therapy for acute stroke. Stroke 2007;38:2275–8. 255. Singer OC, Humpich MC, Fiehler J, et al. Risk for symptomatic intracerebral hemorrhage after thrombolysis assessed by diffusion-weighted magnetic resonance imaging. Ann Neurol 2007. 257. Campbell BC, Christensen S, Parsons MW, et al. Advanced imaging improves prediction of hemorrhage after stroke thrombolysis. Ann Neurol 2013;73:510–19. 259. Kufner A, Galinovic I, Brunecker P, et al. Early infarct FLAIR hyperintensity is associated with increased hemorrhagic transformation after thrombolysis. Eur J Neurol 2013;20(2):281–5. 260. Campbell BC, Costello C, Christensen S, et al. Fluid-attenuated inversion recovery hyperintensity in acute ischemic stroke may not predict hemorrhagic transformation. Cerebrovasc Dis 2011;32(4):401–5. 262. Singer MB, Atlas SW, Drayer BP. Subarachnoid space disease: Diagnosis with fluid-attenuated inversion-recovery MR imaging and comparison with gadolinium-enhanced spin-echo MR imaging—blinded reader study. Radiology 1998;208:417–22. 263. Mitchell P, Wilkinson ID, Hoggard N, et al. Detection of subarachnoid haemorrhage with magnetic resonance imaging. J Neurol Neurosurg Psychiatry 2001;70:205–11. 270. Rordorf G, Koroshetz WJ, Copen WA, et al. Diffusion- and perfusion-weighted imaging in vasospasm after subarachnoid hemorrhage. Stroke 1999;30:599–605. 275. Charidimou A, Peeters A, Fox Z, et al. Spectrum of transient focal neurological episodes in cerebral amyloid angiopathy: multicentre magnetic resonance imaging cohort study and meta-analysis. Stroke 2012;43(9):2324–30. 278. Charidimou A, Peeters AP, Jager R, et al. Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral amyloid angiopathy. Neurology 2013;81(19):1666–73. 280. Kang CK, Park CW, Han JY, et al. Imaging and analysis of lenticulostriate arteries using 7.0-Tesla magnetic resonance angiography. Magn Reson Med 2009;61:136–44. 282. Long A, Lepoutre A, Corbillon E, et al. Critical review of non- or minimally invasive methods (duplex ultrasonography, MR- and

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CT-angiography) for evaluating stenosis of the proximal internal carotid artery. Eur J Vasc Endovasc Surg 2002;24:43–52. 286. Randoux B, Marro B, Koskas F, et al. Carotid artery stenosis: Prospective comparison of CT, three-dimensional gadoliniumenhanced MR, and conventional angiography. Radiology 2001;220:179–85. 287. Yuan C, Zhang SX, Polissar NL, et al. Identification of fibrous cap rupture with magnetic resonance imaging is highly associated with recent transient ischemic attack or stroke. Circulation 2002;105:181–5. 288. Zhao XQ, Yuan C, Hatsukami TS, et al. Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: A case-control study. Arterioscler Thromb Vasc Biol 2001;21:1623–9. 289. Degnan AJ, Gallagher G, Teng Z, et al. MR angiography and imaging for the evaluation of middle cerebral artery atherosclerotic disease. AJNR Am J Neuroradiol 2012;33:1427–35. 290. Sue DE, Brant-Zawadzki MN, Chance J. Dissection of cranial arteries in the neck: Correlation of MRI and arteriography. Neuroradiology 1992;34:273–8. 294. Provenzale JM, Sarikaya B. Comparison of test performance characteristics of MRI, MR angiography, and CT angiography in the diagnosis of carotid and vertebral artery dissection: a review of the medical literature. AJR Am J Roentgenol 2009;193: 1167–74. 295. Sailer AM, Wagemans BA, Nelemans PJ, et al. Diagnosing Intracranial Aneurysms With MR Angiography: Systematic Review and Meta-Analysis. Stroke 2014;45:119–26. 298. Ronkainen A, Puranen MI, Hernesniemi JA, et al. Intracranial aneurysms: MR angiographic screening in 400 asymptomatic individuals with increased familial risk. Radiology 1995;195: 35–40. 300. Qu H, Yang M. Early imaging characteristics of 62 cases of cerebral venous sinus thrombosis. Exp Ther Med 2013;5:233–6. 302. Yuh WT, Simonson TM, Wang AM, et al. Venous sinus occlusive disease: MR findings. AJNR Am J Neuroradiol 1994;15: 309–16. 307. Bousser MG, Ferro JM. Cerebral venous thrombosis: An update. Lancet Neurol 2007;6:162–70. 309. Ducreux D, Oppenheim C, Vandamme X, et al. Diffusionweighted imaging patterns of brain damage associated with cerebral venous thrombosis. AJNR Am J Neuroradiol 2001;22: 261–8. 312. Albers GW, Thijs VN, Wechsler L, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: The diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006;60: 508–17. 313. Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): A placebo-controlled randomised trial. Lancet Neurol 2008;7:299–309. 314. Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): A phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005;36:66–73. 315. Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): Evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006; 37:1227–31. 316. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusiondiffusion weighted imaging or perfusion CT (DIAS-2): A prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009;8:141–50. 317. Donnan GA, Baron JC, Ma H, et al. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol 2009;8:261–9. 319. Kidwell CS, Saver JL, Mattiello J, et al. Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/ perfusion magnetic resonance imaging. Ann Neurol 2000;47: 462–9. 322. Purushotham A, Campbell BC, Straka M, et al. Apparent diffusion coefficient threshold for delineation of ischemic core. Int J Stroke 2013.

324. Thijs VN, Adami A, Neumann-Haefelin T, et al. Relationship between severity of MR perfusion deficit and DWI lesion evolution. Neurology 2001;57:1205–11. 325. Rose SE, Chalk JB, Griffin MP, et al. MRI based diffusion and perfusion predictive model to estimate stroke evolution. Magn Reson Imaging 2001;19:1043–53. 329. Wheeler HM, Mlynash M, Inoue M, et al. Early diffusionweighted imaging and perfusion-weighted imaging lesion volumes forecast final infarct size in defuse 2. Stroke 2013;44: 681–5. 330. Zaro-Weber O, Moeller-Hartmann W, Heiss WD, et al. Maps of time to maximum and time to peak for mismatch definition in clinical stroke studies validated with positron emission tomography. Stroke 2010;41:2817–21. 331. Sorensen AG, Copen WA, Ostergaard L, et al. Hyperacute stroke: Simultaneous measurement of relative cerebral blood volume, relative cerebral blood flow, and mean tissue transit time. Radiology 1999;210:519–27. 334. Darby DG, Barber PA, Gerraty RP, et al. Pathophysiological topography of acute ischemia by combined diffusion-weighted and perfusion MRI. Stroke 1999;30:2043–52. 335. Jansen O, Schellinger P, Fiebach J, et al. Early recanalisation in acute ischaemic stroke saves tissue at risk defined by MRI. Lancet 1999;353:2036–7. 339. Mlynash M, Lansberg MG, De Silva DA, et al. Refining the definition of the malignant profile: Insights from the defuse-epithet pooled data set. Stroke 2011;42:1270–5. 342. Kidwell CS, Saver JL, Mattiello J, et al. Diffusion-perfusion MRI characterization of post-recanalization hyperperfusion in humans. Neurology 2001;57:2015–21. 345. Kohrmann M, Juttler E, Fiebach JB, et al. MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: A cohort study. Lancet Neurol 2006;5:661–7. 349. Hjort N, Butcher K, Davis SM, et al. Magnetic resonance imaging criteria for thrombolysis in acute cerebral infarct. Stroke 2005;36: 388–97. 350. Lansberg MG, Lee J, Christensen S, et al. Rapid automated patient selection for reperfusion therapy: A pooled analysis of the echoplanar imaging thrombolytic evaluation trial (epithet) and the diffusion and perfusion imaging evaluation for understanding stroke evolution (defuse) study. Stroke 2011;42: 1608–14. 351. Warach S, Al-Rawi Y, Furlan AJ, et al. Refinement of the magnetic resonance diffusion-perfusion mismatch concept for thrombolytic patient selection: Insights from the desmoteplase in acute stroke trials. Stroke 2012;43:2313–18. 352. Ma H, Parsons MW, Christensen S, et al. EXTEND investigators. A multicentre, randomized, double-blinded, placebo-controlled Phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND). Int J Stroke 2012;7(1):74–80. 353. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914–23. 354. Kidwell CS, Wintermark M, De Silva DA, et al. Multiparametric MRI and CT models of infarct core and favorable penumbral imaging patterns in acute ischemic stroke. Stroke 2013;44: 73–9. 355. Lansberg MG, Straka M, Kemp S, et al. MRI profile and response to endovascular reperfusion after stroke (defuse 2): A prospective cohort study. Lancet Neurol 2012;11:860–7. 356. Inoue M, Mlynash M, Straka M, et al. DEFUSE 1 and 2 Investigators. Clinical outcomes strongly associated with the degree of reperfusion achieved in target mismatch patients: pooled data from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution studies. Stroke 2013;44(7):1885–90. 357. Parsons MW, Christensen S, McElduff P, et al. Pretreatment diffusion- and perfusion-mr lesion volumes have a crucial influence on clinical response to stroke thrombolysis. J Cereb Blood Flow Metab 2010;30:1214–25.

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226. Lee SH, Lee ST, Kim BJ, et al. Dynamic temporal change of cerebral microbleeds: long-term follow-up MRI study. PLoS ONE 2011;6(10):e25930. 227. Kakuda W, Thijs VN, Lansberg MG, et al. Clinical importance of microbleeds in patients receiving IV thrombolysis. Neurology 2005;65:1175–8. 228. Fiehler J, Albers GW, Boulanger JM, et al. Bleeding risk analysis in stroke imaging before thromboLysis (BRASIL): Pooled analysis of T2*-weighted magnetic resonance imaging data from 570 patients. Stroke 2007;38:2738–44. 229. Shoamanesh A, Kwok CS, Lim PA, et al. Postthrombolysis intracranial hemorrhage risk of cerebral microbleeds in acute stroke patients: a systematic review and meta-analysis. Int J Stroke 2013;8(5):348–56. 230. Kimura K, Aoki J, Shibazaki K, et al. New appearance of extraischemic microbleeds on T2*-weighted magnetic resonance imaging 24 hours after tissue-type plasminogen activator administration. Stroke 2013;44(10):2776–81. 231. Park JH, Seo SW, Kim C, et al. Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment. Ann Neurol 2013;73(5):584–93. 232. Kim M, Bae HJ, Lee J, et al. APOE epsilon2/epsilon4 polymorphism and cerebral microbleeds on gradient-echo MRI. Neurology 2005;65(9):1474–5. 233. Loehrer E, Ikram MA, Akoudad S, et al. Apolipoprotein E genotype influences spatial distribution of cerebral microbleeds. Neurobiol Aging 2013. 234. Maxwell SS, Jackson CA, Paternoster L, et al. Genetic associations with brain microbleeds: Systematic review and metaanalyses. Neurology 2011;77(2):158–67. 235. Gregoire SM, Brown MM, Kallis C, et al. MRI detection of new microbleeds in patients with ischemic stroke: five-year cohort follow-up study. Stroke 2010;41(1):184–6. 236. Boulanger JM, Coutts SB, Eliasziw M, et al. Cerebral microhemorrhages predict new disabling or fatal strokes in patients with acute ischemic stroke or transient ischemic attack. Stroke 2006; 37:911–14. 237. Imaizumi T, Horita Y, Hashimoto Y, et al. Dotlike hemosiderin spots on T2*-weighted magnetic resonance imaging as a predictor of stroke recurrence: A prospective study. J Neurosurg 2004;101:915–20. 238. Kwa VI, Algra A, Brundel M, et al. Microbleeds as a predictor of intracerebral haemorrhage and ischaemic stroke after a TIA or minor ischaemic stroke: a cohort study. BMJ Open 2013; 3(5). 239. Thijs V, Lemmens R, Schoofs C, et al. Microbleeds and the risk of recurrent stroke. Stroke 2010;41(9):2005–9. 240. Greenberg SM, Eng JA, Ning M, et al. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke 2004;35:1415–20. 241. Altmann-Schneider I, Trompet S, de Craen AJ, et al. Cerebral microbleeds are predictive of mortality in the elderly. Stroke 2011;42(3):638–44. 242. Qiu C, Cotch MF, Sigurdsson S, et al. Cerebral microbleeds, retinopathy, and dementia: the AGES-Reykjavik Study. Neurology 2010;75(24):2221–8. 243. van Norden AG, van den Berg HA, de Laat KF, et al. Frontal and temporal microbleeds are related to cognitive function: the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) Study. Stroke 2011;42(12): 3382–6. 244. Gregoire SM, Smith K, Jager HR, et al. Cerebral microbleeds and long-term cognitive outcome: longitudinal cohort study of stroke clinic patients. Cerebrovasc Dis 2012;33(5):430–5. 245. Patel B, Lawrence AJ, Chung AW, et al. Cerebral microbleeds and cognition in patients with symptomatic small vessel disease. Stroke 2013;44(2):356–61. 246. Berger C, Fiorelli M, Steiner T, et al. Hemorrhagic transformation of ischemic brain tissue: asymptomatic or symptomatic? Stroke 2001;32(6):1330–5. 247. Renou P, Sibon I, Tourdias T, et al. Reliability of the ECASS radiological classification of postthrombolysis brain haemorrhage: a comparison of CT and three MRI sequences. Cerebrovasc Dis 2010;29(6):597–604.

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Magnetic Resonance Imaging of Cerebrovascular Diseases

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789.e8 SECTION V 

Diagnostic Studies

314. Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): A phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005;36:66–73. 315. Furlan AJ, Eyding D, Albers GW, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): Evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006;37: 1227–31. 316. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusiondiffusion weighted imaging or perfusion CT (DIAS-2): A prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol 2009;8:141–50. 317. Donnan GA, Baron JC, Ma H, et al. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol 2009;8: 261–9. 318. Merino JG, Latour LL, An L, et al. Reperfusion half-life: A novel pharmacodynamic measure of thrombolytic activity. Stroke 2008;39:2148–50. 319. Kidwell CS, Saver JL, Mattiello J, et al. Thrombolytic reversal of acute human cerebral ischemic injury shown by diffusion/ perfusion magnetic resonance imaging. Ann Neurol 2000;47: 462–9. 320. Lutsep HL, Nesbit GM, Berger RM, et al. Does reversal of ischemia on diffusion-weighted imaging reflect higher apparent diffusion coefficient values? J Neuroimaging 2001;11:313–16. 321. Uno M, Harada M, Okada T, et al. Diffusion-weighted and perfusion-weighted magnetic resonance imaging to monitor acute intra-arterial thrombolysis. J Stroke Cerebrovasc Dis 2000; 9:113–20. 322. Purushotham A, Campbell BC, Straka M, et al. Apparent diffusion coefficient threshold for delineation of ischemic core. Int J Stroke 2013. 323. Grandin CB, Duprez TP, Smith AM, et al. Which MR-derived perfusion parameters are the best predictors of infarct growth in hyperacute stroke? Comparative study between relative and quantitative measurements. Radiology 2002;223:361–70. 324. Thijs VN, Adami A, Neumann-Haefelin T, et al. Relationship between severity of MR perfusion deficit and DWI lesion evolution. Neurology 2001;57:1205–11. 325. Rose SE, Chalk JB, Griffin MP, et al. MRI based diffusion and perfusion predictive model to estimate stroke evolution. Magn Reson Imaging 2001;19:1043–53. 326. Liu Y, Karonen JO, Vanninen RL, et al. Cerebral hemodynamics in human acute ischemic stroke: A study with diffusion- and perfusion-weighted magnetic resonance imaging and SPECT. J Cereb Blood Flow Metab 2000;20:910–20. 327. Tong DC, Yenari MA, Albers GW, et al. Correlation of perfusionand diffusion-weighted MRI with NIHSS score in acute (<6.5 hour) ischemic stroke. Neurology 1998;50:864–70. 328. Olivot JM, Mlynash M, Thijs VN, et al. Optimal tmax threshold for predicting penumbral tissue in acute stroke. Stroke 2009; 40:469–75. 329. Wheeler HM, Mlynash M, Inoue M, et al. Early diffusionweighted imaging and perfusion-weighted imaging lesion volumes forecast final infarct size in defuse 2. Stroke 2013; 44:681–5. 330. Zaro-Weber O, Moeller-Hartmann W, Heiss WD, et al. Maps of time to maximum and time to peak for mismatch definition in clinical stroke studies validated with positron emission tomography. Stroke 2010;41:2817–21. 331. Sorensen AG, Copen WA, Ostergaard L, et al. Hyperacute stroke: Simultaneous measurement of relative cerebral blood volume, relative cerebral blood flow, and mean tissue transit time. Radiology 1999;210:519–27. 332. Neumann-Haefelin T, Wittsack HJ, Wenserski F, et al. Diffusionand perfusion-weighted MRI. The DWI/PWI mismatch region in acute stroke. Stroke 1999;30:1591–7. 333. Karonen JO, Vanninen RL, Liu Y, et al. Combined diffusion and perfusion MRI with correlation to single-photon emission CT in acute ischemic stroke. Ischemic penumbra predicts infarct growth. Stroke 1999;30:1583–90. 334. Darby DG, Barber PA, Gerraty RP, et al. Pathophysiological topography of acute ischemia by combined diffusion-weighted and perfusion MRI. Stroke 1999;30:2043–52.

335. Jansen O, Schellinger P, Fiebach J, et al. Early recanalisation in acute ischaemic stroke saves tissue at risk defined by MRI. Lancet 1999;353:2036–7. 336. Schellinger PD, Jansen O, Fiebach JB, et al. Monitoring intravenous recombinant tissue plasminogen activator thrombolysis for acute ischemic stroke with diffusion and perfusion MRI. Stroke 2000;31:1318–28. 337. Marks MP, Tong DC, Beaulieu C, et al. Evaluation of early reperfusion and i.v. tPA therapy using diffusion- and perfusionweighted MRI. Neurology 1999;52:1792–8. 338. Taleb M, Lovblad KO, El-Koussy M, et al. Reperfusion demonstrated by apparent diffusion coefficient mapping after local intra-arterial thrombolysis for ischaemic stroke. Neuroradiology 2001;43:591–4. 339. Mlynash M, Lansberg MG, De Silva DA, et al. Refining the definition of the malignant profile: Insights from the defuse-epithet pooled data set. Stroke 2011;42:1270–5. 340. Yoo AJ, Verduzco LA, Schaefer PW, et al. MRI-based selection for intra-arterial stroke therapy: Value of pretreatment diffusionweighted imaging lesion volume in selecting patients with acute stroke who will benefit from early recanalization. Stroke 2009;40:2048–54. 341. Tong DC, Adami A, Moseley ME, et al. Prediction of hemorrhagic transformation following acute stroke: Role of diffusionand perfusion-weighted magnetic resonance imaging. Arch Neurol 2001;58:587–93. 342. Kidwell CS, Saver JL, Mattiello J, et al. Diffusion-perfusion MRI characterization of post-recanalization hyperperfusion in humans. Neurology 2001;57:2015–21. 343. Kang DW, Chalela JA, Dunn W, et al. MRI screening before standard tissue plasminogen activator therapy is feasible and safe. Stroke 2005;36:1939–43. 344. Schellinger PD, Jansen O, Fiebach JB, et al. Feasibility and practicality of MR imaging of stroke in the management of hyperacute cerebral ischemia. AJNR Am J Neuroradiol 2000;21: 1184–9. 345. Kohrmann M, Juttler E, Fiebach JB, et al. MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: A cohort study. Lancet Neurol 2006;5: 661–7. 346. Schellinger PD, Thomalla G, Fiehler J, et al. MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: An analysis of 1210 patients. Stroke 2007;38:2640–5. 347. Earnshaw SR, Jackson D, Farkouh R, et al. Cost-effectiveness of patient selection using penumbral-based MRI for intravenous thrombolysis. Stroke 2009;40:1710–20. 348. Solling C, Hjort N, Ashkanian M, et al. Safety and efficacy of MRI-based selection for recombinant tissue plasminogen activator treatment: Responder analysis of outcome in the 3-hour time window. Cerebrovasc Dis 2009;27:223–9. 349. Hjort N, Butcher K, Davis SM, et al. Magnetic resonance imaging criteria for thrombolysis in acute cerebral infarct. Stroke 2005;36: 388–97. 350. Lansberg MG, Lee J, Christensen S, et al. Rapid automated patient selection for reperfusion therapy: A pooled analysis of the echoplanar imaging thrombolytic evaluation trial (epithet) and the diffusion and perfusion imaging evaluation for understanding stroke evolution (defuse) study. Stroke 2011;42: 1608–14. 351. Warach S, Al-Rawi Y, Furlan AJ, et al. Refinement of the magnetic resonance diffusion-perfusion mismatch concept for thrombolytic patient selection: Insights from the desmoteplase in acute stroke trials. Stroke 2012;43:2313–18. 352. Ma H, Parsons MW, Christensen S, et al. EXTEND investigators. A multicentre, randomized, double-blinded, placebo-controlled Phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND). Int J Stroke 2012;7(1):74–80. 353. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914–23. 354. Kidwell CS, Wintermark M, De Silva DA, et al. Multiparametric MRI and CT models of infarct core and favorable penumbral imaging patterns in acute ischemic stroke. Stroke 2013;44:73–9.

789.e9



Magnetic Resonance Imaging of Cerebrovascular Diseases

355. Lansberg MG, Straka M, Kemp S, et al. MRI profile and response to endovascular reperfusion after stroke (defuse 2): A prospective cohort study. Lancet Neurol 2012;11:860–7. 356. Inoue M, Mlynash M, Straka M, et al. DEFUSE 1 and 2 Investigators. Clinical outcomes strongly associated with the degree of reperfusion achieved in target mismatch patients: pooled data

from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution studies. Stroke 2013;44(7):1885–90. 357. Parsons MW, Christensen S, McElduff P, et al. Pretreatment diffusion- and perfusion-MR lesion volumes have a crucial influence on clinical response to stroke thrombolysis. J Cereb Blood Flow Metab 2010;30:1214–25.

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