Applied Radiology

Dr. Bochar received her MD from the University of Illinois College of Medicine in 1997. She is currently a third-year radiology resident at Emory University School of Medicine, Atlanta, GA.

Ischemic stroke is an important cause of morbidity and mortality worldwide; it is the third leading cause of death ¹ and affects more than 400,000 individuals per year in the United States. ² Until recently, there has been no approved treatment for acute ischemic cerebral infarction. Although neuroprotective agents have been shown to be beneficial in animal models with middle cerebral artery occlusion, ³ no significant benefits have been proven in humans. In 1996, intravenous (IV) tissue plasminogen activator (t-PA) became the first United States Food and Drug Administration (FDA)-approved medication for the treatment of acute stroke. This approval was prompted by the results of the National Institute of Neurologic Disorders and Stroke (NINDS) t-PA Study Group, which demonstrated improvement in clinical outcome when IV t-PA was administered within 3 hours of the onset of acute stroke. ⁴ The first European Cooperative Acute Stroke Study (ECASS I) demonstrated improvement in clinical outcome and some functional measures in a subgroup of stroke patients without computed tomography (CT) signs of extensive infarction when IV recombinant t-PA (rt-PA) was administered within 6 hours from the onset of symptoms. ⁵ Given the narrow window of 3, or potentially 6, hours from the onset of stroke symptoms to the administration of IV t-PA, the timely diagnosis of acute ischemic stroke is essential. With the recent development of improved magnetic resonance (MR) techniques, including new diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) techniques, the rapid and accurate detection of acute infarction is now possible.

Imaging techniques

Diffusion-weighted imaging --Diffusion-weighted MR technology has been available for several decades. Stejskal and Tanner ⁶ described diffusion-weighted sequences as early as 1965. Although the clinical application of DWI in evaluating neurologic disorders was first reported in the mid 1980s, ⁷ DWI has only recently become practical in the clinical setting. This is largely a result of the development of echo-planar diffusion sequences, which have dramatically decreased imaging times and motion artifacts. DWI is now a rapid imaging modality, with the ability to obtain images of the whole brain in less than a minute. DWI can also detect hyper-acute ischemic changes promptly after the onset of ischemic stroke. In animal models, ischemic changes have been observed on DWI within minutes, ^8-10 and in humans, changes have been reported as early as 30 minutes after the onset of stroke symptoms. ¹¹ The lesions on diffusion-weighted images have been shown to correlate with regions of ischemia and infarction on histologic and cytologic evaluation. ⁸

DWI is based on the microscopic movement (Brownian motion) of water molecules. By applying strong MR diffusion-sensitizing gradient pulses, water protons can be labeled during dephasing and subsequent rephasing. ^11-16 In normal diffusion, water protons move between the dephasing and the rephasing gradients, resulting in signal attenuation. If there is restricted diffusion, such as in acute infarction, the signal attenuation is decreased, resulting in hyperintensity on diffusion-weighted images.

The degree of diffusion-weighting is called the b value. If the b value is zero, there is no diffusion weighting. The images are similar to T2-weighted images, and the cerebral spinal fluid (CSF) appears bright. Conversely, if the b value is high, there is heavy diffusion-weighting. The CSF appears dark since the water molecules in the CSF have unrestricted diffusion.

It is important to note that diffusion-weighted images are a combination of diffusion information and T2 signal intensity. If a lesion, such as a chronic infarct, is hyperintense on T2-weighted images, the lesion may also appear hyperintense on DWI despite a lack of restricted diffusion. This phenomenon has been referred to as "T2 shine-through" ¹⁷ and can be eliminated by the generation of an apparent diffusion coeffient (ADC) map.

The apparent diffusion coeffient is a measure of water diffusion and is calculated by differences in the rate of change of signal intensity at various b values. ¹⁵ It is termed "apparent" because the measured value does not indicate pure diffusion, but reflects capillary perfusion and other processes. ⁷ An ADC map is created by having signal intensities that are equal to the magnitude of the ADC values. ¹² Low ADC values reflect restricted diffusion and appear hypointense on an ADC map (but hyperintense on DWI). Likewise, nonrestricted diffusion appears hyperintense on an ADC map (but hypointense on DWI). ADC values in acute ischemic lesions are often compared with the ADC values of the nonaffected contralateral brain parenchyma, and the ratio of the two is referred to as the ADC ratio (ADCr). ADC values in acute ischemic lesions are typically 30% to 40% lower than in the contralateral brain parenchyma. ^15,18,19 Serial evaluations of cerebral infarcts in humans have demonstrated a decrease in the ADC values in the first week, followed by a period of "pseudonormalization" of the ADC values around 5 to 10 days. After the first week, the ADC values may become elevated, corresponding to increased diffusion secondary to encephalomalacia as seen histologically. ^20,21 By utilizing the ADC values and maps in combination with the diffusion-weighted images, acute ischemic lesions can readily be distinguished from chronic ones (figure 1).

Anisotropy is the phenomenon in which diffusion is not equal in all directions. In the brain, increased diffusion is seen along white matter tracts. Greater diffusion is observed when the diffusion-sensitizing gradients are applied parallel to the white matter tracts, and slower diffusion is observed when the gradients are applied perpendicular to the white matter tracts. ²² Diffusion anisotropy may result in hyperintensity when the gradients are applied perpendicular to the white matter tracts, and this may lead to the misinterpretation of the diffusion-weighted images. A simple way to counteract the effects of anisotropy is to combine the individual, mutually orthogonal diffusion-weighted images, resulting in a "trace" isotropic image. ^11,23

The exact mechanism of restricted diffusion during acute ischemia is unclear, but appears to be related to the failure of cellular energy metabolism. ^24-26 Sodium-potassium adenosine-triphosphatase (Na-K ATPase) within the cell membrane is disrupted by ischemia. Absolute tissue perfusion under 15 to 20 cc/100g/min is the threshold for Na-K ATPase dysfunction and has also been shown to be the threshold for restricted diffusion. In the presence of Na-K ATPase dysfunction, there is influx of sodium and water into the cells, with resulting cytotoxic edema, "compartmentalization" of the water molecules, and restricted diffusion.

Perfusion-weighted imaging --PWI is also referred to as perfusion imaging (PI) or hemodynamically weighted imaging (HWI). It evaluates the blood flow in the cerebral microvasculature and detects areas of perfusion abnormalities. There are two major methods currently used to determine PWI: bolus-tracking PWI (BT-PWI) and arterial spin-labeling techniques (ASL-PWI). ^12,16,27 Bolus-tracking, which is also called first-pass bolus method or susceptibility-based perfusion imaging, requires the IV injection of a paramagnetic contrast agent, namely a gadolinium chelate. The difference between the increased magnetic susceptibility of the gadolinium and the lower susceptibility of the surrounding tissues creates local field inhomogeneities, which result in signal loss on T2*-weighted images (figure 2). From the data obtained, time-signal intensity curves are created, and various hemodynamic parameters can be calculated. The most common parameters to evaluate perfusion on PWI are time-to-peak (TTP), mean transit time (MMT), and regional or relative cerebral blood flow (rCBF) and volume (rCBV). Although absolute CBF and CBV can be calculated experimentally, ²⁸ these parameters require the calculation of arterial input as well as lengthy processing.

Arterial spin-labeling PWI is also known as spin-tagging or time-of-flight PWI. It is termed noninvasive, as exogenous contrast is not required. Water protons in arterial blood are labeled with an inversion pulse and compared to a control image without an inversion pulse. ^12,16 ASL-PWI results in a more direct measurement of CBF than bolus-tracking and provides quantification of CBF and qualitative CBF mapping. ^29-31

Diagnostic performance

DWI has been shown to be very accurate in the diagnosis of acute cerebral infarction, ^17,32-34 with reported sensitivities of 88% to 100% and specificities of 86% to 100% in clinical studies. Lansberg et al ³⁵ compared DWI with CT within 7 hours of stroke onset. CT was observed to have only a 42% to 63% sensitivity, compared with 100% sensitivity for DWI in this series. A strong correlation was also noted between the final infarct volumes and the acute DWI lesion volumes, but no correlation was noted between the CT volumes and the final infarct volumes. Lansberg et al ³⁶ also compared DWI to conventional MRI within 48 hours of acute stroke. DWI correctly identified at least one lesion in 94% of the patients, compared to 71% to 80% for conventional MRI. Inter-rater reliability was also observed, and was reported to be good (kappa=0.8) for DWI, but only moderate (kappa=0.5-0.6) for conventional MRI. Lesion conspicuity and observer confidence were also significantly improved by the addition of DWI.

Although the sensitivity and specificity of DWI in the detection of acute ischemic stroke are very high, false-negatives and false-positives have been observed. Ay et al ³⁷ reported 27 of 782 consecutive patients with stroke-like deficits who had normal DWI images. When compared with the final diagnosis, 37% of these 27 patients were found to have a "stroke-mimic," including migraine, seizure, functional disorder, transient global amnesia, and brain tumors. The remaining 63% were shown to have ischemic events including transient ischemic attacks, prolonged reversible deficits, and brainstem lacunar (3/27) and hemispheric (3/27) infarctions. All three of the patients with hemispheric infarctions but normal initial diffusion-weighted images had abnormalities on PWI. Presumably, the tissues in the region of the PWI abnormalities were ischemic but viable, and in the presence of prolonged ischemia, the lesions progressed to infarction. This emphasizes the importance of the addition of PWI to DWI. Other investigators have also described false-negative DWI in patients with presumed very small brainstem and deep gray nuclei infarctions, ^32,34,36,38 potentially because these tiny lacunar infarctions may be below the resolution of DWI. ³⁷ False-positive diffusion-weighted images have been seen in patients with tumor or cerebral abscess. ¹¹ These two disease entities can usually be easily distinguished from acute ischemic stroke when conventional MR images, including T1- and T2-weighted images, are obtained in combination with the diffusion-and perfusion-weighted images.

Lesion volumes and clinical outcomes

The evaluation of ischemic lesion volumes with DWI and PWI has proven to be significant in several regards. Both techniques have provided an insight into the dynamic nature of infarct evolution. Schwamm et al ¹⁸ reported that infarctions tend to increase in size during the first several days after stroke onset and reach a maximum volume at an average of 70 hours, and that final infarct volumes tended to be smaller than the maximum infarct volumes. Numerous investigations have shown that both DWI and PWI are good predictors of final infarct volumes, with a strong correlation existing between lesion volumes on initial diffusion- and perfusion-weighted images and final infarct volumes (r values ranging from 0.479 to 0.99). ^18,38-43 Karonen et al ⁴¹ specifically observed that of the various perfusion parameters, the final infarct volumes correlated best with rCBV. The degree of DWI-PWI mismatch also correlates well with infarct growth. Finally, lesion volumes on DWI and PWI have been shown to have an excellent correlation with clinical outcomes.

Several stroke scales have been devised to provide an index of the neurologic status of patients after ischemic stroke. Such scales can be used to assess the severity of the stroke, that is, the neurological impairment, within the first few days. When applied after the first few months of a stroke, the stroke scales can quantify both functional outcomes and neurologic recovery. ⁴⁴ Some of the more common stroke scales include the National Institutes of Health Stroke Scale (NIHSS), the Canadian Neurologic Scale, The Middle Cerebral Artery Neurologic Score, the Barthel Index, the Rankin Scale, and the European Stroke Scale. There is a good correlation (with r values of 0.44 to 0.88) between the DWI and PWI lesion volumes and the stroke scale severity and outcome scores. ^{18,38,42,43,45,46} The correlation is weaker in penetrator artery disease, but stronger in cortical infarction.

DWI-PWI mismatch

When PWI is performed in combination with DWI, different patterns of abnormalities are seen. ^{18,39,41-43,47,48} The most common pattern is one in which the perfusion abnormality is larger than, and surrounds, the DWI abnormality. This is referred to as a DWI-PWI mismatch, and is often associated with large vessel (such as proximal middle cerebral artery [MCA]) occlusion. The area of abnormal perfusion surrounding the infarcted DWI core is thought to represent ischemic tissue at risk for infarction, or the "ischemic penumbra." ⁴⁹ This tissue is potentially viable if perfusion is restored. ^50-52 The degree of initial DWI-PWI mismatch correlates well with the degree of infarct growth. Barber et al ⁴³ reported that the presence of a DWI-PWI is a significant predictor of infarct growth, and in the absence of a DWI-PWI mismatch, no significant lesion enlargement occurred.

Other common patterns of DWI-PWI abnormalities include a DWI lesion that is equal to or larger than the perfusion abnormality and a DWI lesion in the absence of a perfusion abnormality. In the presence of small vessel disease (such as distal MCA or perforator infarctions), the initial PWI lesion volumes approximate the initial DWI lesion volumes, and there is only slight infarct growth with time. The finding of a DWI abnormality without a perfusion abnormality suggests presence of infarction with reperfusion. No significant infarct growth occurs in this situation. These findings again emphasize the importance of combining perfusion imaging along with diffusion imaging to potentially viable tissues that are at risk for infarction.

Therapeutic implications

DWI and PWI play a major role in the evaluation and follow-up of patients for thrombolytic therapy. Since t-PA is associated with an increased risk of intracranial hemorrhage, ^4,5,53 it is important to select patients who will most likely benefit from treatment and who are the least likely to experience complications. Patients who are the most likely to benefit from IV t-PA include those with an acutely occluded major intracranial vessel, especially an occluded proximal MCA; and patients with "tissue at risk," as demonstrated by DWI and PWI. ^47,54 Preliminary studies have shown that early recanalization after thrombolytic therapy can save tissues at risk for further infarction. Patients with early recanalization demonstrated significantly smaller infarct volumes and significantly better outcomes when compared with patients with vessel occlusion without recanalization. ^47,50

In addition to aiding in the selection of patients who may benefit from thrombolytic therapy, DWI and PWI may help exclude patients who are at an increased risk for complications. The presence of intracranial hemorrhage, brain edema or mass effect, and involvement of >33% of an MCA territory are all contraindications to IV t-PA. ^4,5,53 Preliminary investigations of standardized multimodality stroke protocols including DWI, PWI, conventional MRI, and magnetic resonance angiography (MRA) found MRI to be as reliable as CT in the detection of acute intracranial hemorrhage (ICH), ^55,56 thus potentially eliminating the need for CT in the evaluation of acute stoke. Additionally, there is an increased sensitivity in DWI when compared with CT for the detection of >33% MCA territory involvement. ³⁵ DWI can also differentiate acute from chronic lesions, ⁵⁷ which is essential since only acute lesions can benefit from thrombolytic therapy.

Besides facilitating patient selection for thrombolytic administration, DWI and PWI are also helpful in patient follow-up after such therapy. When combined with conventional MRI, DWI and PWI can evaluate for potential complications including intracranial hemorrhage. DWI and PWI can also determine the efficacy of thrombolytic therapy by evaluating lesion volumes following treatment.

Since the therapeutic window for IV t-PA is very narrow, at 3, or potentially 6, hours from the onset of symptoms, diagnostic images must be obtained quickly. Sunshine et al ⁵⁸ reported "ultrafast MR imaging" of stroke patients. In this series, the mean time from entering the emergency department to the beginning of imaging was < 45 minutes, and the mean imaging time was < 15 minutes, including DWI, PWI, conventional MRI, and post-processing. Although these time frames seem idealistic and not practically obtainable, it is hoped that in the future there will be widespread availability of emergency MR imaging, including DWI and PWI, to rapidly and accurately diagnose acute ischemic infarctions.

Cost effectiveness

While the cost effectiveness of IV t-PA has been established, ⁵⁹ as of yet, no published investigations have determined the cost effectiveness of DWI and PWI in the evaluation of acute ischemic stroke. There are, however, several theoretical cost benefits associated with the use of DWI and PWI. First, expenses may be reduced by potentially eliminating the need for CT to exclude intracranial hemorrhage. Second, DWI and PWI may aid in the appropriate selection of patients for thrombolytic therapy. Patients without a DWI-PWI mismatch are much less likely to have "tissue at risk" for infarction, and the expense and unnecessary risk of IV t-PA may be spared in these patients. Patients with an unacceptably increased risk for complications from thrombolytic therapy can be identified, and the potential for intracranial hemorrhage can be prevented. Finally, since DWI combined with PWI is very sensitive at detecting acute ischemic lesions and since there is a strong correlation between the perfusion and diffusion lesion volumes and the final infarct volumes, the number of follow-up studies with CT or conventional MRI may be reduced. Large-scale investigations are required to validate these hypotheses.

Conclusion

In summary, DWI and PWI are relatively new and accurate imaging modalities for the timely diagnosis of acute ischemic infarction and hypoperfusion. Lesions on diffusion- and perfusion-weighted images have been found to correlate well with infarct growth, final infarct volume, stroke severity, and clinical outcomes. DWI and PWI may eventually become incorporated into acute stroke management algorithms for evaluating potential candidates for thrombolytic therapy by detecting "tissue at risk" for infarction and by identifying patients at an increased risk for complications. DWI and PWI can also be utilized for patient follow-up after thrombolytic therapy to exclude potential complications and to evaluate the response to treatment. Further studies are needed to confirm the sensitivity and specificity of DWI and PWI in combination with multimodality MRI to exclude intracranial hemorrhage; to evaluate the change in perfusion and diffusion abnormalities following thrombolytic therapy and recanalization; and to determine the cost effectiveness of DWI and PWI in the evaluation of acute ischemic stroke.

Acknowledgements

I am very grateful to Chad Holder, MD, and Richard Woodcock, MD, (both from Emory University School of Medicine, Atlanta, GA) for their thoughtful input and for providing images for this manuscript.