9
Neuroimaging in Acute Ischemic Stroke
Katie D. Vo, Weili Lin, and Jin-Moo Lee
I. What is the imaging modality of choice for the detection of intra- cranial hemorrhage?
A. Computed tomography B. Magnetic resonance imaging
II. What are the imaging modalities of choice for the identification of brain ischemia and the exclusion of stroke mimics?
A. Computed tomography B. Magnetic resonance imaging
III. What imaging modality should be used for the determination of tissue viability—the ischemic penumbra?
A. Magnetic resonance imaging B. Computed tomography
C. Positron emission tomography (PET)
D. Single photon emission computed tomography (SPECT) IV. What is the role of noninvasive intracranial vascular imaging?
A. Computed tomography angiography B. Magnetic resonance angiography
V. What is the role of acute neuroimaging in pediatric stroke?
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Issues
䊏 Noncontrast computed tomography (CT) is currently accepted as the gold standard for the detection of intracranial hemorrhage, though rigorous data is lacking (limited evidence). Magnetic resonance imaging (MRI) is equivalent to CT in the detection of intracranial hem- orrhage (strong evidence), but its role in the evaluation of throm- bolytic candidates has not been studied.
䊏 Noncontrast CT of the head should be performed in all patients who are candidates for thrombolytic therapy to exclude intracerebral hemorrhage (strong evidence).
䊏 Magnetic resonance (MR) (diffusion-weighted imaging) is superior to CT for detection of cerebral ischemia within the first 24 hours of symptom onset (moderate evidence); however, some argue that iden-
Key Points
Definition and Pathophysiology
This chapter focuses on imaging within the first few hours of stroke onset, where issues relating to the decision to administer thrombolytics are of paramount importance. Stroke is a clinical term that describes an acute neu- rologic deficit due to a sudden disruption of blood supply to the brain.
Stroke is caused by either an occlusion of an artery (ischemic stroke or cere- bral ischemia/infarction) or rupture of an artery leading to bleeding into or around the brain (hemorrhagic stroke or intracranial hemorrhage). The vast majority of strokes are ischemic (88%), whereas 9% are intracerebral hemorrhages and 3% are subarachnoid hemorrhages (1). Ischemic stroke can be divided into several subtypes based on etiology: small-vessel strokes (40%), large-vessel atherothrombotic strokes (20%), cardioembolic strokes (20%), and strokes from unknown etiologies (20%) (2). Risk factors for stroke include age, male gender, race (African American), previous history of stroke, diabetes, hypertension, heart disease, smoking, and alcohol. Treatment of ischemic stroke can be divided into acute therapies, consisting of thrombolysis with tissue plasminogen activator (tPA) and management of secondary complications (edema, herniation, hemor- rhage); and preventative therapies, aimed at reducing the risk of recurrent stroke.
Epidemiology
It is estimated that approximately 731,000 new or recurrent strokes occur annually, and that a new stroke occurs every 45 seconds in United States (1,3). This number is expected to increase as the population ages. The third leading cause of mortality after heart disease and cancer, stroke results in approximately 160,000 deaths per year, leaving 4.6 million stroke survivors in the United States. Fifteen to 30% of stroke survivors are permanently disabled or require institutional care, making it the leading cause of severe long-term disability and the leading diagnosis from hospital to long-term care (1,4,5).
Overall Cost to Society
The estimated direct and indirect costs of stroke are $53.6 billion in 2004, with 62% of the cost related directly to medical expenditures (1). Acute inpatient hospital costs account for 70% of the first-year post-stroke cost;
tification of ischemia merely confirms a clinical diagnosis and does not necessarily influence acute clinical decision making, or outcome.
䊏 Advanced functional imaging such as MR perfusion, MR spec- troscopy, CT perfusion, xenon CT, single photon emission computed tomography (SPECT), and positron emission tomography (PET) show promise in improving patient selection and individualizing therapeu- tic time windows (limited evidence), but the data are inadequate for routine use in the current management of stroke patients.
the contribution of diagnostic tests during the initial hospitalization accounts for 19% of total hospital costs (6). These diagnostic tests included MR or CT (91% of patients), echocardiogram (81%), noninvasive carotid artery evaluation (48%), angiography (20%), and electroencephalography (6%).
Goals
The primary goal of neuroimaging in patients presenting with acute neurologic deficits is to differentiate between ischemic and hemorrhagic stroke, and to exclude other diagnoses that may mimic stroke. Other emerging goals in acute stroke patients are to determine if brain tissue is viable and thereby amenable to interventional therapies, and to determine the localization of vascular occlusion.
Methodology
A comprehensive Medline search (United States National Library of Medicine database) for original articles published between 1966 and July 2004 using the Ovid and Pubmed search engines was performed using a combination of the following key terms: ischemic stroke, hemorrhage, diag- nostic imaging, CT, MR, PET, SPECT, angiography, gadolinium, circle of Willis, carotid artery, brain, technology assessment, evidence-based medicine, and cost.
The search was limited to English-language articles and human studies.
The abstracts were reviewed and selected based on well-designed method- ology, clinical trials, outcomes, and diagnostic accuracy. Additional rele- vant articles were selected from the references of reviewed articles and published guidelines.
I. What Is the Imaging Modality of Choice for the Detection of Intracranial Hemorrhage?
Summary of Evidence: Computed tomography (CT) is widely accepted as the gold standard for imaging intracerebral hemorrhage; however, it has not been rigorously examined in prospective studies, and thus the precise sensitivity and specificity is unknown (limited evidence). For the evalua- tion of thrombolytic candidates (exclusion of intracerebral hemorrhage), however, CT is clearly the modality of choice based on strong evidence (level I) from randomized controlled trials (7,8). By many measures MR is at least as sensitive as CT in the detection of intracerebral hemorrhage, and it is suspected to be more sensitive during the subacute and chronic phases.
A recent study indicates that the sensitivity and accuracy of MR in detect- ing intraparenchymal hemorrhage is equivalent to CT even in the hyper- acute setting (within 6 hours of ictus) (strong evidence) (9).
Supporting Evidence
A. Computed Tomography
It is essential that an imaging study reliably distinguish intracerebral hemorrhage from ischemic stroke because of the divergent management of these two conditions. This is especially critical for patients who present within 3 hours of symptom onset under consideration for thrombolytic
therapy. Noncontrast CT is currently the modality of choice for detection of acute intracerebral hemorrhage. Acute hemorrhage appears hyperdense for several days due to the high protein concentration of hemoglobin and retraction of clot, but becomes progressively isodense and then hypodense over a period of weeks to months from breakdown and clearing of the hematoma by macrophages. Rarely acute hemorrhage can be isodense in severely anemic patients with a hematocrit of less than 20% or 10 g/dL (10,11). Although it has been well accepted that CT can identify intra- parenchymal hemorrhage with very high sensitivity, surprisingly few studies have been conducted to support this (12,13). In 1974, shortly after the introduction of the EMI scanner, Paxton and Ambrose (14) diagnosed 66 patients with intracerebral hemorrhages with this novel modality; the study was observational, lacking autopsy confirmation, and thus accuracy was not determined (insufficient evidence). Subsequently, in an autopsy series of 79 patients, EMI did not detect four out of 17 patients with hem- orrhages—all were brainstem hemorrhages (limited evidence) (15). There is little doubt that the sensitivity of current third-generation CT scanners for the detection of intracerebral hemorrhage is far superior to the first- generation scanners; however, it is of interest that the precise sensitivity and specificity of this well-accepted modality is unknown, and the level of evidence supporting its use is limited (level III).
Four studies evaluating third-generation CT scanners in patients with nontraumatic subarachnoid hemorrhage identified by CT or cerebrospinal fluid (CSF) have been reported (16–19). The overall sensitivity of CT was 91% to 92%, but was dependent on the time interval between symptom onset and scan time. Sensitivity was 100% (80/80) for patients imaged within 12 hours, 93% (134/144) within 24 hours, and 84% (31/37) after 24 hours (level III) (18,19). These numbers were confirmed by two other studies that demonstrated a sensitivity of 98% (117/119) for scans obtained within 12 hours, 95% (1313/1378) within 24 hours, 91% (1247/1378) between 24 and 48 hours, and 74% after 48 hours (1017/1378) (moderate evidence) (16,17). These studies relied on a diagnosis made by CT, or by blood detected in CSF in the absence of CT findings. No studies with autopsy confirmation have been reported.
Therefore, although CT is commonly regarded as the modality of choice for imaging intracranial hemorrhage, the precise sensitivity and specificity is unknown and is dependent on time after onset, concentration of hemo- globin, and size and location of the hemorrhage (limited evidence).
B. Magnetic Resonance Imaging
Like CT, the appearance and detectability of hemorrhage on magnetic res- onance imaging (MRI) depends on the age of blood and the location of the hemorrhage (intraparenchymal or subarachnoid). In addition, the strength of the magnetic field, and type of MR sequence influences its sensitivity (20). As the hematoma ages, oxyhemoglobin in blood breaks down sequen- tially into several paramagnetic products: first deoxyhemoglobin, then methemoglobin, and finally hemosiderin. Iron in hemoglobin is shielded from surrounding water molecules when oxygen is bound, resulting in a molecule (oxyhemoglobin) with diamagnetic properties. As a result, the MR signal is similar to that of normal brain parenchyma, making it diffi- cult to detect on any MR sequence, including susceptibility weighted sequences (echo-planar imaging [EPI] T2* or gradient echo). In contrast,
iron exposed to surrounding water molecules in the form of deoxyhemo- globin creates signal loss, making it easy to identify on susceptibility- weighted and T2-weighted (T2W) sequences (21,22). Thus the earliest detection of hemorrhage depends on the conversion of oxyhemoglobin to deoxyhemoglobin, which was believed to occur after the first 12 to 24 hours (20,23). However, this early assumption has been questioned with reports of intraparenchymal hemorrhage detected by MRI within 6 hours, and as early as 23 minutes from symptom onset (24–26). One of the studies prospectively demonstrated that MRI detected all nine patients with CT-confirmed intracerebral hemorrhage (ICH), suggesting the potential of MRI for the hyperacute evaluation of stroke (limited evidence) (24–26).
More recently, a blinded study comparing MRI (diffusion-, T2-, and T2*- weighted images) to CT for the evaluation of ICH within 6 hours of onset demonstrated that ICH was diagnosed with 100% sensitivity and 100%
accuracy by expert readers using MRI; CT-detected ICH was used as the gold standard (strong evidence) (9).
Data regarding the detection of acute subarachnoid and intraventricular hemorrhage using MRI is limited. While it is possible that the conversion of blood to deoxyhemoglobin occurs much earlier than expected in hypoxic tissue, this transition may not occur until much later in the oxygen-rich environment of the CSF (20,27). Thus the susceptibility-weighted sequence may not be sensitive enough to detect subarachnoid blood in the hyper- acute stage. This problem is further compounded by severe susceptibility artifacts at the skull base, limiting detection in this area. The use of the fluid-attenuated inversion recovery (FLAIR) sequence has been advocated to overcome this problem. Increased protein content in bloody CSF appears hyperintense on FLAIR and can be readily detected. Three case-control series using FLAIR in patients with CT-documented subarachnoid or intra- ventricular hemorrhage demonstrated a sensitivity of 92% to 100% and specificity of 100% compared to CT and was superior to CT during the sub- acute to chronic stages (limited evidence) (28–30). Hyperintense signal in the CSF on FLAIR can be seen in areas associated with prominent CSF pul- sation artifacts (i.e., third and fourth ventricles and basal cisterns) and in other conditions that elevate protein in the CSF such as meningitis or after gadolinium administration (level III) (31–33); however, these conditions are not usually confused with clinical presentations suggestive of subarach- noid hemorrhage.
At later time points in hematoma evolution (subacute to chronic phase) when the clot demonstrates nonspecific isodense to hypodense appearance on CT, MRI has been shown to have a higher sensitivity and specificity than CT (limited evidence) (28,34,35). The heightened sensitivity of MRI susceptibility-weighted sequences to microbleeds that are not otherwise detected on CT makes interpretation of hyperacute scans difficult, espe- cially when faced with decisions regarding thrombolysis (Fig. 9.1). Patient outcome regarding the use of thrombolytic treatment in this subgroup of patients with microbleeds is not known; however, in one series of 41 patients who had MRI prior to intraarterial tPA, one of five patients with microbleeds on MRI developed major symptomatic hemorrhage compared to three of 36 without (36), raising the possibility that the presence of microbleeds may predict the subsequent development of symptomatic hemorrhage following tPA treatment. As this finding was not statistically significant, a larger study is required for confirmation.
II. What Are the Imaging Modalities of Choice for the Identification of Brain Ischemia and the Exclusion of Stroke Mimics?
Summary of Evidence: Based on moderate evidence (level II), MRI (diffusion-weighted imaging) is superior to CT for positive identification of ischemic stroke within the first 24 hours of symptom onset, allowing exclusion of stroke mimics. However, some argue that despite its superi- ority, positive identification merely confirms a clinical diagnosis and does not necessarily influence acute clinical decision making or outcome.
Supporting Evidence
A. Computed Tomography
Computed tomography images are frequently normal during the acute phase of ischemia and therefore the diagnosis of ischemic stroke is con- Figure 9.1. Microhemorrhages. Top row: Two sequential magnetic resonance (MR) images of T2* sequence show innumerable small low signal lesions scattered throughout both cerebral hemispheres compatible with microhemorrhages. Bottom row: Noncontrast axial computed tomography (CT) at the same anatomic levels does not show the microhemorrhages.
tingent upon the exclusion of stroke mimics, which include postictal state, systemic infection, brain tumor, toxic-metabolic conditions, positional vertigo, cardiac disease, syncope, trauma, subdural hematoma, herpes encephalitis, dementia, demyelinating disease, cervical spine fracture, con- version disorder, hypertensive encephalopathy, myasthenia gravis, and Parkinson disease (37). Based purely on history and physical examination alone without confirmation by CT, stroke mimics can account for 13% to 19% of cases initially diagnosed with stroke (37,38). Sensitivity of diagno- sis improves when noncontrast CT is used but still 5% of cases are misdi- agnosed as stroke, with ultimate diagnoses including paresthesias or numbness of unknown cause, seizure, complicated migraine, peripheral neuropathy, cranial neuropathy, psychogenic paralysis, and others (39).
An alternative approach to excluding stroke mimics, which may account for the presenting neurologic deficit, is to directly visualize ischemic changes in the hyperacute scan. Increased scrutiny of hyperacute CT scans, especially following the early thrombolytic trials, suggests that some patients with large areas of ischemia may demonstrate subtle early signs of infarction, even if imaged within 3 hours after symptom onset. These early CT signs include parenchymal hypodensity, loss of the insular ribbon (40), obscuration of the lentiform nucleus (41), loss of gray–white matter differentiation, blurring of the margins of the basal ganglia, subtle efface- ment of the cortical sulci, and local mass effect (Fig. 9.2). It was previously believed that these signs of infarction were not present on CT until 24 hours after stroke onset; however, early changes were found in 31% of CTs per- formed within 3 hours of ischemic stroke (moderate evidence) (42). In addi-
Figure 9.2. Early CT signs of infarction. A: Noncontrast axial CT performed at 2 hours after stroke onset shows a large low-attenuated area involving the entire right middle cerebral artery distribution (bounded by arrows) with associated effacement of the sulci and sylvian fissure. There is obscuration the right lentiform nucleus (*) and loss of the insular ribbon (arrowhead). B: Follow-up noncontrast axial image 4 days later confirms the infarction in the same vascular distribution. There is hemorrhagic conversion (*) in the basal ganglia with mass effect and subfalcine herniation.
tion, early CT signs were found in 81% of patients with CTs performed within 5 hours of middle cerebral artery (MCA) stroke onset (demonstrated angiographically) (moderate evidence) (43). Early CT signs, however, can be very subtle and difficult to detect even among very experienced readers (moderate evidence) (44–46). Moreover, the presence of these early ischemic changes in only 31% of hyperacute strokes precludes its reliabil- ity as a positive sign of ischemia.
Early CT signs of infarction, especially involving more than 33% of the MCA distribution, have been reported to be associated with severe stroke, increased risk of hemorrhagic transformation (46–49), and poor outcome (50). Because of these associations, several trials involving thrombolytic therapy including the European Cooperative Acute Stroke Study (ECASS) excluded patients with early CT signs in an attempt to avoid treatment of patients at risk for hemorrhagic transformation (8,46,51,52). Although ECASS failed to demonstrate efficacy of intravenous tPA administered within 6 hours of stroke onset, a marginal treatment benefit was observed in the target population (post-hoc analysis), excluding patients with early CT signs that were inappropriately enrolled in the trial (46). The National Institute of Neurological Disorders and Stroke (NINDS) t-PA stroke trial (7), which did demonstrate efficacy, did not exclude patients with early CT signs, and retrospective analysis of the data showed that early CT signs were associated with stroke severity but not with increased risk of adverse outcome after t-PA treatment (42). Thus, based on current data, early CT signs should not be used to exclude patients who are otherwise eligible for thrombolytic treatment within 3 hours of stroke onset (strong and moder- ate evidence) (7,42).
B. Magnetic Resonance Imaging
Unlike CT and conventional MR, new functional MR techniques such as diffusion-weighted imaging (DWI) allow detection of the earliest phy- siologic changes of cerebral ischemia. Diffusion-weighted imaging, a sequence sensitive to the random brownian motion of water, is capable of demonstrating changes within minutes of ischemia in rodent stroke models (53–55). Moreover, the sequence is sensitive, detecting lesions as small as 4 mm in diameter (56). Although the in vivo mechanism of signal alteration observed in DWI after acute ischemia is unclear, it is believed that ischemia-induced energy depletion increases the influx of water from the extracellular to the intracellular space, thereby restricting water motion, resulting in a bright signal on DW images (57,58). Diffusion-weighted imaging has become widely employed for clinical applications due to improvements in gradient capability, and it is now possible to acquire DW images free from artifacts with an echo planar approach. Because DW images are affected by T1 and T2 contrast, stroke lesions becomes pro- gressively brighter due to concurrent increases in brain water content, leading to the added contribution of hyperintense T2W signal known as
“T2 shine-through.” To differentiate between true restricted diffusion and T2 shine-through, bright lesions on DWI should always be confirmed with apparent diffusion coefficient (ADC) maps, which exclusively measure dif- fusion. For stroke lesions in adults, although there is wide individual vari- ability, ADC signal remains decreased for 4 days, pseudo-normalizes at 5
to 10 days, and increases thereafter (56). This temporal evolution of DWI signal allows one to determine the age of a stroke.
The high sensitivity and specificity of DWI for the detection of ischemia make it an ideal sequence for positive identification of hyperacute stroke, thereby excluding stroke mimics. Two studies evaluating DWI for the detection of ischemia within 6 hours of stroke onset reported an 88% to 100% sensitivity and 95% to 100% specificity with a positive predictive value (PPV) of 98.5% and negative predictive value (NPV) of 69.5%, using final clinical diagnosis as the gold standard (moderate and limited evi- dence) (59,60). In another study, 50 patients were randomized to DWI or CT within 6 hours of stroke onset, and subsequently received the other imaging modality with a mean delay of 30 minutes. Sensitivity and speci- ficity of infarct detection among blinded expert readers was significantly better when based on DWI (91% and 95%, respectively) compared to CT (61% and 65%) (moderate evidence) (61). The presence of restricted diffu- sion is highly correlated with ischemia, but its absence does not rule out ischemia: false negatives have been reported in transient ischemic attacks and small subcortical infarctions (moderate evidence) (60,62–64). False- positive DWI signals have been reported in brain abscesses (65), herpes encephalitis (66,67), Creutzfeldt-Jacob disease (68), highly cellular tumors such as lymphoma or meningioma (69), epidermoid cysts (70), seizures (71), and hypoglycemia (72) (limited evidence). However, the clinical history and the appearance of these lesions on conventional MR should allow for exclusion of these stroke mimics. Within the first 8 hours of onset, the stroke lesion should be seen only on DWI, and its presence on conventional MR sequences suggests an older stroke or a nonstroke lesion.
The DWI images, therefore, should not be interpreted alone but in con- junction with conventional MR sequences and within the proper clinical context.
Acute DWI lesion volume has been correlated with long-term clinical outcome, using various assessment scales including the National In- stitutes of Health Stroke Scale (NIHSS), the Canadian Neurologic Scale, the Barthel Index, and the Rankin Scale (moderate evidence) (73–77). This correlation was stronger for strokes involving the cortex and weaker for subcortical strokes (73,74), which is likely explained by a discordance between infarct size and severity of neurologic deficit for small subcorti- cal strokes.
In addition to DWI, MR perfusion-weighted imaging (PWI) approaches have been employed to depict brain regions of hypoperfusion. They involve the repeated and rapid acquisition of images prior to and follow- ing the injection of contrast agent using a two-dimensional (2D) gradient echo or spin echo EPI sequence (78,79). Signal changes induced by the first passage of contrast in the brain can be used to obtain estimates of a variety of hemodynamic parameters, including cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT, the mean time for the bolus of contrast agent to pass through each pixel) (79–81). These parame- ters are often reported as relative values since accurate measurement of the input function cannot be determined. However, absolute quantification of CBF has also been reported (82). Thus, hypoperfused brain tissue result- ing from ischemia demonstrates signal changes in perfusion-weighted images, and may provide information regarding regional hemodynamic status during acute ischemia (insufficient evidence).
III. What Imaging Modality Should Be Used for the Determination of Tissue Viability—the Ischemic Penumbra?
Summary of Evidence: Determination of tissue viability using functional imaging has tremendous potential to individualize therapy and extend the therapeutic time window for some. Several imaging modalities, including MRI, CT, PET, and SPECT, have been examined in this role. Operational hurdles may limit the use of some of these modalities in the acute setting of stroke (e.g., PET and SPECT), while others such as MRI show promise (limited evidence). Rigorous testing in large randomized controlled trials that can clearly demonstrate that reestablishment of perfusion to regions
“at risk” prevents progression to infarction is needed prior to their use in routine clinical decision making.
Supporting Evidence
A. Magnetic Resonance Imaging
The combination of DWI and PWI techniques holds promise in identify- ing brain tissue at risk for infarction. It has been postulated that brain tissue dies over a period of minutes to hours following arterial occlusion. Initially, a core of tissue dies within minutes, but there is surrounding brain tissue that is dysfunctional but viable, comprising the ischemic penumbra. If blood flow is not restored in a timely manner, the brain tissue at risk dies, completing the infarct (83). The temporal profile of signal changes seen on DWI and PWI follows a pattern that is strikingly similar to the theoretical construct of the penumbra described above. On MR images obtained within hours of stroke onset, the DWI lesion is often smaller than the area of perfusion defect (on PWI), and smaller than the final infarct (defined by T2W images obtained weeks later). If the arterial occlusion persists, the DWI lesion grows until it eventually matches the initial perfusion defect, which is often similar in size and location to the final infarct (chronic T2W lesion) (Fig. 9.3) (limited evidence) (84,85). The area of normal DWI signal but abnormal PWI signal is known as the diffusion-perfusion mismatch and has been postulated to represent the ischemic penumbra. Diffusion- perfusion mismatch has been reported to be present in 49% of stroke patients during the hyperacute period (0 to 6 hours) (limited evidence) (86).
Growth of the DWI lesion over time has been documented in a random- ized trial testing the efficacy of the neuroprotective agent citicoline. Mean lesion volume in the placebo group increased by 180% from the initial DWI scan (obtained within 24 hours of stroke onset) to the final T2W scan obtained 12 weeks later. Interestingly, lesion volume grew by only 34% in the citicoline-treated group, suggesting a treatment effect (moderate evi- dence) (87). However, efficacy of the agent was not definitively demon- strated using clinical outcome measures (88). The ultimate test of the hypothesis that mismatch represents “penumbra,” will come from studies that correlate initial mismatch with salvaged tissue after effective treat- ment. One small prospective series of 10 patients demonstrated that patients with successful recanalization after intraarterial thrombolysis showed larger areas of mismatch that were salvaged compared to patients that were not successfully recanalized (limited evidence) (89).
The promise of diffusion-perfusion mismatch is that it will provide an image of ischemic brain tissue that is salvageable, and thereby individual- ize therapeutic time windows for acute treatments. The growth of the lesion to the final infarct volume may not occur until hours or even days later in some individuals (limited evidence) (84,85), suggesting that tissue may be salvaged beyond the 3-hour window in some. One of the assump- tions underlying the hypothesis that diffusion-perfusion mismatch repre- sents salvageable tissue is that the acute DWI lesion represents irreversibly injured tissue. However, it has been known for some time that DWI lesions are reversible after transient ischemia in animal stroke models (90,91), and reversible lesions in humans have been reported following a transient ischemic attack (TIA) (92) or after reperfusion (93). These data suggest that at least some brain tissue within the DWI lesion may represent reversibly injured tissue.
Figure 9.3. Evolution of the right middle cerebral distribution infarction on mag- netic resonance imaging (MRI). A,B: MRI at 3 hours after stroke onset shows an area of restricted diffusion on diffusion-weighted imaging (DWI) (A) with a larger area of perfusion defect on perfusion-weighted imaging (PWI) (B). The area of normal DWI but abnormal PWI represents an area of diffusion-perfusion mismatch. C,D:
Follow-up MRI at 3 days postictus shows interval enlargement of the DWI lesion (C) to the same size as the initial perfusion deficit (B). There is now a matched dif- fusion-perfusion (C,D).
Additional new experimental MR techniques such as proton MR spec- troscopy (MRS) and T2 Blood Oxygen Level Dependent (BOLD) and 2D multiecho gradient echo/spin echo have also been explored for the iden- tification of salvageable tissue (94,95). Magnetic resonance spectroscopy is an MR technique that measures the metabolic and biochemical changes within the brain tissues. The two metabolites that are commonly measured following ischemia are lactate and N-acetylaspartate (NAA). Lactate signal is not detected in normal brain but is elevated within minutes of ischemia in animal models, remaining elevated for days to weeks (96). The lactate signal can normalize with immediate reperfusion (97). N-acetylaspartate, found exclusively in neurons, decreases more gradually over a period of hours after stroke onset in animal stroke models (98). It has been suggested that an elevation in lactate with a normal or mild reduction in NAA during the acute period of ischemia may represent the ischemic penumbra (94), though this has not been examined in a large population of stroke patients.
The cerebral metabolic rate of oxygen consumption (CMRO2) has been measured in acute stroke patients using MRI, and a threshold value has been proposed to define irreversibly injured brain tissue (level III) (82).
Though preliminary, these results appear to be in agreement with data obtained using PET (see below) (99,100). Measurement of CMRO2 has theoretical advantages over other measures (e.g., CBF, CBV), as the threshold value for irreversible injury is not likely to be time-dependent (101). Clearly research into the identification of viable ischemic brain tissue is at a preliminary stage. However, such techniques may be important for future acute stroke management. These new imaging approaches will require extensive validation and assessment in well-designed clinical trials.
B. Computed Tomography
In addition to anatomic information, CT is capable of providing some physiologic information, accomplished with either intravenous injection of nonionic contrast or inhalation of xenon gas. Like PWI, perfusion parameters can be obtained by tracking a bolus of contrast or inhaled xenon gas in blood vessels and brain parenchyma with sequential CT imaging. Using spiral CT technology, the study can be completed in 6 minutes.
Stable xenon (Xe) has been employed as a means to obtain quantitative estimates of CBF in vivo. Xenon, an inert gas with an atomic number similar to iodine, can attenuate x-rays like contrast material. However, unlike CT contrast, the gas is freely diffusable and can cross the blood–brain barrier. Sequential imaging permits the tracking of progres- sive accumulation and washout of the gas in brain tissue, reflected by changes in Hounsfield units over time, and quantitative CBF and CBV maps can be calculated (102). The quantitative CBF value from xenon- enhanced CT has been shown to be highly accurate compared with radioactive microsphere and iodoantipyrine techniques under different physiologic conditions and wide range of CBF rates in baboons (correla- tion coefficient r = 0.67 to 0.92, p < .01 and <.001) (103,104). The major advantage of the xenon CT is that it allows absolute quantification of the CBF, which may help to define a threshold value from reversible to
irreversible cerebral injury. Low CBF (<15mL/100g/min) correlated with early CT signs of infarction, proximal M1 occlusion, severe edema, and life- threatening herniation. Very low CBF values (<7mL/100g/min) predicted irreversibly injured tissue (105,106). In addition, xenon CT has been shown to be effective in obtaining cerebral vascular reserve (CVR) in patients with occlusive disease (107). Poor CVR has been shown to be a risk factor for stroke in patients with high-grade carotid stenosis or occlusion (108).
However, to ensure a sufficient signal-to-noise ratio for Xe-CT perfusion, a high concentration of Xe is needed, which itself may cause respiratory depression, cerebral vasodilation, and thus confound the measurements of CBF (109).
In addition to inhalation xenon gas, bolus nonionic contrast can also be used to generate a CT perfusion map. Rapid repeated serial images of the brain are acquired during the first-pass passage of intravenous contrast to generate relative CBF, CBV, and MTT. The CT perfusion maps obtained within 6 hours of stroke onset in patients with MCA occlusion had signif- icantly higher sensitivity for the detection of stroke lesion volume com- pared to noncontrast CT, and the perfusion volume correlated with clinical outcome (limited evidence) (105,110). Cerebral blood flow maps generated by CT perfusion in 70 acute stroke patients predicted the extent of cerebral infarction with a sensitivity of 93% and a specificity of 98% (limited evidence) (111). A major limitation to this technique is that only relative CBF map can be obtained, thus precluding exact determination of the tran- sition from ischemia to infarction.
C. Positron Emission Tomography (PET)
Positron emission tomography imaging has provided fundamental infor- mation on the pathophysiology of human cerebral ischemia. Quantitative measurements of cerebral perfusion and metabolic parameters can be obtained, namely CBF, CBV, MTT, oxygen extraction fraction (OEF), and CMRO2, using multiple tracers and serial arterial blood samplings. Based on the values of these hemodynamic parameters, four distinct successive pathophysiologic phases of ischemic stroke have been identified: autoreg- ulation, oligemia, ischemia, and irreversible injury (112). Oligemia (low CBF, elevated OEF with normal CMRO2) and ischemia (low CBF, elevated OEF but decreased CMRO2) are sometimes termed misery perfusion, and have been postulated to represent the ischemic penumbra (113). During misery perfusion, a decline in CMRO2heralds the beginning of a transi- tion from reversible to irreversible injury. Irreversible injury is reflected in tissue with CMRO2below 1.4 mL/100 g/min (99,100). In three serial obser- vational studies of acute ischemic stroke, elevation of OEF in the setting of low CBF has been suggested to be the marker of tissue viability in ischemic tissue (level II) (114–116). The CBF in ischemic tissue with elevated OEF is between 7 and 17 mL/100 g/min. Elevated OEF has been observed to persist up to 48 hours after stroke onset (115). Progression to irreversible injury is reflected in decreased OEF (114,115). Furthermore, in a prospec- tive blinded longitudinal cohort study of 81 patients with carotid occlu- sion, elevated OEF was found to be an independent predictor for subsequent stroke and potentially defining a subgroup of patients who may benefit from revascularization (moderate evidence) (117). However,
confirmation of tissue viability in the region of elevated OEF is best accom- plished by large randomized controlled trials that can clearly demonstrate that reestablishment of perfusion to this region prevents progression to infarction. Such studies have not been done and are difficult to implement since PET is limited to major medical centers and requires considerable expertise and time. Moreover, the requirement for intraarterial line place- ment precludes its use for evaluating thrombolytic candidates. Despite these hurdles one study assessed PET after thrombolysis in 12 ischemic stroke patients within 3 hours of symptoms onset (118). Due to the above- mentioned hurdles, only relative CBF was obtained prior to and follow- ing intravenous thrombolysis (118). In all patients, early reperfusion of severely ischemic tissue (<12mL/110g/min in gray matter) predicted better clinical outcome and limited infarction.
D. Single Photon Emission Computed Tomography (SPECT)
The most commonly used radiopharmaceutical agent for SPECT perfu- sion study is technetium-99 m pertechnetate hexamethyl-propylene amine oxime (99m Tc-HMPAO). This lipophilic substance readily crosses the blood–brain barrier and interacts with intracellular glutathione, which pre- vents it from diffusing back. However, due to technical problems includ- ing incomplete first-pass extraction from blood, incomplete binding to glutathione leading to back diffusion, and metabolism within the brain, absolute quantification of the CBF cannot be determined. However, SPECT technology is much more accessible than PET and is more readily avail- able. In a multicenter prospective trial with 99mTc-bicisate (99mTc-ECD, an agent with better brain-to-background contrast) of 128 patients with ischemic stroke and 42 controls, SPECT had a sensitivity of 86% and specificity of 98% for localization of stroke compared with final clinical, diagnostic, and laboratory studies (119). The sensitivity decreased to 58% for lacunar stroke (119). Perfusion studies with HMPAO-SPECT in early ischemic stroke demonstrated that patients with severe hypoperfu- sion on admission had poor outcome at 1 month (120). Furthermore, reperfusion of ischemic tissue with 65% to 85% reduction of regional CBF (rCBF) compared to the contralateral hemisphere decreased the final infarct volume but had no affect on regions with reduction greater than 85% (121).
IV. What Is the Role of Noninvasive Intracranial Vascular Imaging?
Summary of Evidence: With the development of different delivery approaches for thrombolysis in acute ischemic stroke, there is a new demand for noninvasive vascular imaging modalities. While some data are available comparing magnetic resonance angiography (MRA) and com- puted tomography angiography (CTA) to digital substraction angiography (DSA) (moderate and limited evidence), strong evidence in support of the use of such approaches for available therapies is lacking. Prospective studies examining clinical outcome after the use of screening vascular imaging approaches to triage therapy are needed.
Supporting Evidence
A. Computed Tomography Angiography
One advantage of CTA is that it can be performed immediately following the prerequisite noncontrast CT for all stroke patients. Using spiral CT, the entire examination can be completed in 5 minutes with 100 cc of nonionic intravenous contrast, with an additional 10 minutes required for image reconstruction. The sensitivity and specificity of CTA for trunk occlusions of the circle of Willis are 83% to 100% and 99% to 100%, respectively, com- pared to DSA in several case series (limited evidence) (122–126). Few studies have examined the sensitivity of CTA for distal occlusions. In one study the reliability in assessing MCA branch occlusion was significantly lower (123).
B. Magnetic Resonance Angiography
In addition to tissue evaluation, MR is capable of noninvasively assessing the intracranial vascular status of stroke patients using MRA. One of the most commonly used MRA techniques is the 2D or 3D time-of-flight tech- nique. Stationary background tissue is suppressed while fresh flowing intravascular blood has bright signal. The source images are postprocessed using a maximal intensity projection (MIP) to display a 3D image of the blood vessel. However, the sensitivity and specificity of MRA are some- what limited when compared to DSA. In a prospective nonconsecutive study of 50 patients, MRA had a sensitivity of 100% and a specificity of 95% for occlusion and 89% sensitivity and specificity for stenosis of the intracranial vessels compared to DSA (limited evidence) (127). In another study of 131 patients with 32 intracranial steno-occlusive lesions, MRA had a sensitivity of 85% and specificity of 96% for internal carotid artery (ICA) pathology, and for MCA lesions, 88% sensitivity and 97% specificity (moderate evidence) (128). A recent comparison of MRA and DSA in 24 children presenting with cerebral infarction demonstrated that all lesions detected on DSA were present on MRA; however, distal vascular lesions and the degree of stenosis were more accurately detected with DSA (moderate evidence) (129). In another study, DSA and MRA were com- pared to surgical and histologic findings of specimens removed during endarterectomy; MRA was 89% and DSA was 93% in agreement with histologic specimens in determining the degree of stenosis, and plaque morphology was in agreement in 91% of cases for MRA and 94% for DSA (130).
These findings are not surprising given the known technical limitations associated with MRA. First, the ability of MRA to accurately depict the vessel lumen is limited due to the fact that complete or partial signal voids in regions of high or turbulent flow normally occur (spin dephasing), leading to an overestimation of the extent of stenosis. Second, the inabil- ity to acquire high-resolution images due to limited signal-to-noise ratios and loss of contrast between blood and brain parenchyma for slow-flowing spins (spin saturation) makes it difficult for MRA to depict distal and small vessels. Therefore, while MRA is able to provide images of the cerebral vas- culature noninvasively, cautious interpretation of lumen definition is war- ranted. Although contrast-enhanced MRA of the extracranial arteries appears to be better at defining the degree of stenosis than the time-of-
flight MRA technique (131,132), assessment of the intracranial vessels with contrast is limited due to venous contamination. However, while it may be possible to overcome this limitation with new technical development including ultrafast imaging techniques and better timing of the arrival of contrast, data regarding its accuracy has not yet been defined (133).
Whether MRA can provide screening for future thrombolytic/interven- tional approaches remains to be seen.
V. What Is the Role of Acute Neuroimaging in Pediatric Stroke?
Summary of Evidence: Due to the low incidence of stroke in the pediatric population, few studies are available regarding risk factors, recurrence, and outcome. Moreover, the efficacy of acute therapies has not been exam- ined in this population, limiting the utility of acute neuroimaging in pedi- atric stroke for early therapeutic decision making.
Supporting Evidence: In contrast to stroke in the adult population, pediatric stroke is an uncommon disorder with a very different pathophysiology.
The overall incidence of ischemic stroke is 2 to 13 per 100,000 children, with the highest rate occurring in the perinatal period (26.4 per 100,000 infants less than 30 days old) (134). The incidence of ischemic stroke has increased over the past two decades, probably due to better population-based studies (the Canadian Pediatric Stroke Registry), more sensitive imaging tech- niques (fetal MR, DWI), and an increased survival of immature neonates due to improved treatment modalities (extracorporeal membrane oxy- genation). The etiologies of ischemic stroke in children are due to nonath- erosclerotic causes such as congenital heart disease, sickle cell anemia, coagulation disorders, arterial dissection, varicella zoster infection, inher- ited metabolic disorders, and moyamoya, and is found to be idiopathic in one third of the cases (134,135).
To date, there are no randomized clinical trials for the treatment of acute ischemic stroke in the pediatric population. Indeed, there is only one published randomized controlled trial for stroke prevention [the Stroke Prevention Trial (STOP) in Sickle Cell Anemia], which showed that blood transfusions greatly reduced the risk of stroke in children with sickle cell anemia who have peak mean blood flow velocities greater than 200 cm per second measured by transcranial Doppler ultrasonography in the ICA or proximal MCA (strong evidence) (136). Though there is no Food and Drug Administration (FDA)-approved treatment for children with acute ischemic stroke, several case reports have documented the use of intravenous tPA in this setting (insufficient evidence) (137–
139).
The lack of proven therapeutic interventions for acute pediatric stroke limits the utility of acute neuroimaging for early therapeutic decision making. However, the diagnosis and differentiation of stroke subtypes may still be important for preventative measures. This is true especially in neonates and infants, where neurologic deficits may be subtle and difficult to ascertain. In this regard, MRI (with T1W, T2W, FLAIR, as well as DWI) may be superior to CT in the early identification of ischemic lesions and exclusion of stroke mimics (extrapolated from adult data).
Acute Imaging Protocols Based on the Evidence
Head CT: indicated for all patients presenting with acute focal deficits Noncontrast examination
Sequential or spiral CT with 5-mm slice thickness from the skull base to the vertex
Head MR: indicated if stroke is in doubt
Axial DWI (EPI) with ADC map, GRE, or ep T2*, FLAIR, T1W Optional sequences (insufficient evidence for routine clinical practice):
MRA of the circle of Willis (3D TOF technique)
PWI (EPI FLASH, 12 slices per measurement for 40 measurements, with 10- to 15-sec injection delay, injection rate of 5 cc/sec with single or double bolus of gadolinium, followed by a 20-cc saline flush)
Axial T1W postcontrast
Areas of Future Research
• Use of neuroimaging to select patients for acute therapies:
䊊
Imaging the ischemic penumbra to extend the empirically determined therapeutic windows for certain individuals䊊
Predict individuals at high risk for hemorrhagic conversion䊊
As more therapies are made available, neuroimaging has the potential to help determine which modality might be most efficacious (e.g., imaging large vessel occlusions for use of intraarterial thrombolysis or clot retrieval).• Use of neuroimaging to predict outcome:
䊊
Useful for prognostic purposes, or for discharge planning䊊
Useful as a surrogate measure of outcome in clinical trialsTable 9.1. Diagnostic performance for patients presenting with acute neurological deficits
Sensitivity Specificity Reference Evidence Acute intraparenchymal hemorrhage (<6 hours)
CT 100%* 100%* *
MRI 100% 100% 61 Strong
Acute subarachnoid hemorrhage (<12 hours)
CT 98–100% 16,17 Moderate
MRI (FLAIR) 92–100% 100% 28–30 Limited
Acute ischemic infarction (<6 hours)
CT 61% 65% 9 Moderate
MRI 91% 95% 9 Moderate
* Although the exact sensitivity or specificity of CT for detecting intraparenchymal hemor- rhage is unknown (limited evidence), it serves as the gold standard for detection in compari- son to other modalities.
Take-Home Table
Table 9.1 summarizes sensitivity, specificity and strength of evidence of neuroimaging in acute intraporenchymal hemorrhage, acute subarachnoid hemorrhage, and acute ischemic infarction.
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