436
Advanced Imaging in Acute Ischemic Stroke Shlee S. Song, MD1 1 Department of Neurology, Cedars-Sinai Medical Center, Los Angeles,
California
Address for correspondence Shlee S. Song, MD, Department of Neurology, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, A6600- Rm 404, Los Angeles, CA 90048 (e-mail: [email protected]).
Abstract
Keywords
► acute stroke ► perfusion imaging ► computed tomography ► magnetic resonance imaging ► reperfusion ► ischemic Penumbra
Advances in stroke neuroimaging have evolved from excluding acute intracranial hemorrhage on computed tomography (CT) to now using perfusion studies (PWI) and magnetic resonance imaging (MRI) to possibly expand thrombolytic treatment to patients most likely to benefit from reperfusion therapy. Advanced imaging has also helped identify those at high risk for hemorrhage and poor outcome so appropriate treatment can occur with fewer complications. Identifying those who can benefit from endovascular recanalization using advanced neuroimaging techniques is particularly useful because endovascular treatment is often initiated much later than intravenous thrombolytic treatment due to logistical constraints. Using imaging markers of tissue injury may eventually lead to a paradigm shift from time-based treatment eligibility in acute stroke reperfusion treatment as the sensitivity and specificity to identify ischemic penumbra improves and correlation with clinical outcomes becomes clearer.
Neuroimaging is an important tool for confirming diagnosis and determining treatment decisions in the evaluation of patients with acute ischemic stroke. There are various imaging modalities available to distinguish ischemia versus hemorrhage and methods to determine pathology in blood flow and identify at-risk penumbral or salvageable tissue. The preferred imaging modality for acute ischemic stroke varies across stroke centers, but the most common is still computed tomography (CT). Computed tomography is readily available, quick, and accurately excludes acute intracranial hemorrhage in thrombolytic treatment-eligible patients. However, CT is not sensitive in the identification of acute cerebral ischemia, while magnetic resonance imaging (MRI) offers the advantage of more accurately identifying ischemic stroke from noncerebrovascular causes.1,2 To improve sensitivity of CT in the evaluation of acute ischemic stroke, systematic quantitative scoring using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) has been shown to identify early ischemia and is comparable to diffusion-weighted imaging (DWI) MRI. However, lower ASPECTS were seen with DWI lesions, which implies higher sensitivity for smaller lesions with DWI.3 In another comparison study because of concerns regarding sensitivity of MRI in detecting acute intracranial hemorrhage, Chalela and col-
Issue Theme Advanced Cerebrovascular Disease Management; Guest Editor, Jason Mackey, MD, MS
leagues prospectively assessed patients in the emergency setting using both MRI and CT.4 When compared with the final clinical diagnosis of stroke, blinded readers diagnosed acute ischemic stroke with higher sensitivity using MRI than CT (89% vs. 54%, respectively). Magnetic resonance imaging was comparable to CT for the detection of acute intracranial hemorrhage. Interestingly, MRI was superior to CT in the detection of all forms of intracranial hemorrhage, either acute or chronic. With evidence of better overall sensitivity of MRI, some tout MRI as the preferred imaging modality for acute stroke patients. Magnetic resonance imaging has its own limitations. Treatment times may be longer using this imaging protocol. Many patients are also excluded from MRI because of implanted devices such as pacemakers. Some acutely ill patients cannot tolerate MRI because of respiratory instability or remain still without sedation. In clinical practice, emerging data suggest either MR perfusion or CT perfusion can help identify at-risk or penumbral tissue when considering reperfusion therapy beyond approved treatment time windows or thrombectomy. Prolonged transit times of cerebral blood flow in which cerebral blood volumes are preserved are defined as areas of salvageable tissue or ischemic penumbra (►Fig. 1). Matched areas with lack of blood flow and volume are considered areas of
Copyright © 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1364214. ISSN 0271-8235.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Semin Neurol 2013;33:436–440.
Song
Fig. 1 Ischemic penumbra. Example of computed tomography perfusion study showing increased time to peak (TTP; top row, right corner) and mean transit time (MTT; bottom row, middle) in the right middle cerebral artery territory with relative preservation of cerebral blood volume (CBV; top row, middle).
core infarct.5 The optimal threshold to find critically underperfused tissue is a major challenge. Time-to-maximum (Tmax) delay between 2 to 8 seconds has been used to identify hypoperfused tissue.6–8 However, because some delayed areas of reperfusion will do well regardless of recanalization, efforts were made to reduce the capture of benign oligemia in ischemic penumbra calculations. In a separate analysis of the DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) Study, after multiple Tmax delay evaluations (> 2, 4, 6, or 8 seconds), it was determined Tmax > 4 seconds was the accurate predictor of final infarct volume.8 The arbitrary and generally used mismatch criteria for most clinical trials is a perfusion lesion volume 20% larger than the diffusion lesion.9 The role of neuroimaging in predicting progression from ischemia to infarction is controversial, and whether these imaging findings translate to prediction of clinical outcome is unclear and depends upon an interpretation of what is considered salvageable versus infarcted tissue. Tests need to be reliable for imaging studies to be useful in clinical practice. Targeting therapy to those with imaging profiles indicating salvageable tissue limits treatment to patients most likely to benefit with reperfusion therapy. Identifying patients with irreversible injury or core infarction who are unlikely to benefit from reperfusion treatment due to further risk of
hemorrhage and edema is just as important in real time when decisions need to be made for patients regarding thrombolytic treatment. Large-volume severe ischemia with DWI MRI greater than 100 mL (►Fig. 2) or PWI greater than 100 mL using Tmax > 8 seconds has been described as a malignant profile in the DEFUSE study.6 Further analysis including the EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial) database refined the definition as a PWI volume > 85 mL when using a Tmax delay of > 8 seconds as the optimum threshold to identify patients with poor outcome despite reperfusion therapy. However, the PWI volume deficit was not applicable or a significant predictor in the nonreperfused patients.10 Exclusion of malignant-profile patients may improve the safety profile of reperfusion therapy. Nevertheless, excluding these patients a priori before testing the penumbral imaging selection criteria has been controversial without a control-based study. Since the National Institute of Neurological Disorders and Stroke tPA ischemic stroke treatment trial in 199511 (which showed benefit of thrombolytic treatment in those patients receiving tPA within 3 hours of stroke onset) and ECASSIII in 200812 (which extended the thrombolytic treatment time window from 3 to 4.5 hours in select patients), surrogate imaging markers have been sought to help identify and include more ischemic stroke patients that could possibly benefit with Seminars in Neurology
Vol. 33
No. 5/2013
437
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Advanced Imaging in Acute Ischemic Stroke
Advanced Imaging in Acute Ischemic Stroke
Song
Fig. 2 Example image of a malignant profile6 on diffusion-weighted magnetic resonance imaging (lesion volume > 100 mL).
acute therapies beyond currently accepted treatment-time windows. In the DEFUSE study,6 acute ischemic stroke patients at 3 to 6 hours from stroke onset with a perfusion-diffusion mismatch profile showed clinical benefit with early reperfusion treatment. A subsequent prospective study13 sought to use this mismatch profile to help identify patients who would likely benefit with endovascular reperfusion treatment out to 12 hours from stroke onset. Identifying those who can benefit from endovascular recanalization is particularly useful because endovascular treatment is often initiated much later than intravenous thrombolytic treatment due to logistical constraints. The disease progression from ischemia to infarction in the early hours of ischemic injury varies,14 and this dynamic process is often attributed to variable collateral blood flow patterns.15,16 Similar findings were demonstrated in the EPITHET study,17 where clinical benefit was seen with reperfusion in perfusion-diffusion mismatch patients at 3 to 6 hours from stroke onset. In keeping with the hypothesis Seminars in Neurology
Vol. 33
No. 5/2013
that recanalization leads to favorable outcomes in mismatch patients, patients with mismatch profiles who did not recanalize had significant growth in infarct volumes and subsequent poorer clinical outcomes. In contrast to the findings in these prior prospective studies, the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) study18 found that penumbral mismatch pattern did not help select patients who would benefit from endovascular therapy. In contrast to DEFUSE and EPITHET, MR RESCUE included nonpenumbralpattern subjects as a control to help determine whether imaging studies could identify patients who would benefit with endovascular treatment. The pretreatment penumbral pattern (mismatch vs. nonmismatch) did not identify patients who would benefit from endovascular treatment. Contributing factors to the negative results may be the low recanalization rate in the intervention group, the use of first-generation devices, and the heterogeneous imaging protocol including
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
438
Song
Fig. 3 Example images of three qualitative ratings of diffusion-weighted imaging- (DWI) positive with none, subtle, and bright fluid-attenuated inversion recovery (FLAIR) hyperintensity. DWI-positive scans without FLAIR hyperintensity were seen between 0 to 6 hours from stroke onset. Subtle FLAIR hyperintensity scans could be seen as early as 1.3 hours. Bright FLAIR hyperintensity occurred after 9 hours from stroke onset. (Adapted from Song SS, Latour LL, Ritter CH, et al. A pragmatic approach using magnetic resonance imaging to treat ischemic strokes of unknown onset time in a thrombolytic trial. Stroke 2012;43(9):2331–2335)
both CT and MRI. Some work suggests that patients with favorable mismatch imaging profiles with preservation of cerebral blood volumes with collateral circulation may have better clinical outcomes regardless of intervention.19 The results of recent negative endovascular trials such as MR RESCUE and Interventional Management of Stroke III (IMS-III)20 studies highlight the importance of further research to better select patients who can benefit with reperfusion therapy. A common thread in these negative trials18,20,21 was that if reperfusion therapy was implemented too late, the potential benefit or efficacy time window is lost. An emphasis on shorter time-to-intervention coupled with more effective recanalization techniques using newergeneration devices in a randomized trial will help answer whether imaging selection criteria can better select patients for effective recanalization treatment.22,23 Recent studies suggest select neuroimaging studies such as CT with CT perfusion24 and DWI and fluid-attenuated inversion recovery (FLAIR) MRI can be used as a tissue clock when time of stroke onset is unknown.25 This may be particularly useful for patients who “wake up” with stroke symptoms whose last known well time puts them outside the guidelines for the approved use of tPA. The Abciximab in Emergency Stroke Treatment Trial (AbESTT)-II14 investigators found that the symptomatic intracerebral hemorrhage rate in reperfused patients was much higher in wake-up patients than nonwake-up patients. Clinical outcomes were significantly worse
in the wake-up patients independent of treatment arm. This may be explained by baseline CT showing wake-up patients had higher frequency of prior strokes and new abnormal CT findings consistent with new stroke. This unfavorable riskbenefit profile led to the halt of further wake-up patient study enrollment after 43 patients were enrolled. Current trials such as MR WITNESS (Phase IIa safety study of intravenous thrombolysis with alteplase in MRI-selected patients)26 and WAKE-UP (investigator-initiated randomized controlled trial of MRI-based thrombolysis in patients)27 are using DWI-positive, FLAIR-negative MRI profiles to estimate time of stroke onset to evaluate whether such imaging findings are safe to treat for reperfusion therapy (►Fig. 3).28 Using imaging markers of tissue injury may eventually lead to a paradigm shift from time-based treatment eligibility in acute stroke reperfusion treatment as the sensitivity and specificity to identify ischemic penumbra improves, safety margins increase, and correlation with clinical outcomes becomes clearer. These future developments in acute stroke imaging may help clinicians treat more eligible patients for reperfusion therapy with fewer complications.
References 1 Barber PA, Darby DG, Desmond PM, et al. Identification of major
ischemic change. Diffusion-weighted imaging versus computed tomography. Stroke 1999;30(10):2059–2065 Seminars in Neurology
Vol. 33
No. 5/2013
439
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Advanced Imaging in Acute Ischemic Stroke
Advanced Imaging in Acute Ischemic Stroke
Song
2 González RG, Schaefer PW, Buonanno FS, et al. Diffusion-weighted
15 Liebeskind DS. Collateral circulation. Stroke 2003;34(9):2279–2284
MR imaging: diagnostic accuracy in patients imaged within 6 hours of stroke symptom onset. Radiology 1999;210(1):155–162 Barber PA, Hill MD, Eliasziw M, et al; ASPECTS Study Group. Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diffusion-weighted imaging. J Neurol Neurosurg Psychiatry 2005;76(11):1528–1533 Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet 2007;369(9558):293–298 Heiss WD. Flow thresholds of functional and morphological damage of brain tissue. Stroke 1983;14(3):329–331 Albers GW, Thijs VN, Wechsler L, et al; DEFUSE Investigators. 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(5):508–517 Davis SM, Donnan GA, Parsons MW, et al; EPITHET investigators. 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(4):299–309 Olivot JM, Mlynash M, Thijs VN, et al. Optimal Tmax threshold for predicting penumbral tissue in acute stroke. Stroke 2009;40(2): 469–475 Donnan GA, Baron JC, Ma H, Davis SM. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol 2009;8(3): 261–269 Mlynash M, Lansberg MG, De Silva DA, et al; DEFUSE-EPITHET Investigators. Refining the definition of the malignant profile: insights from the DEFUSE-EPITHET pooled data set. Stroke 2011; 42(5):1270–1275 Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333(24):1581–1587 Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359(13):1317–1329 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):1885–1890 Fisher M, Albers GW. Advanced imaging to extend the therapeutic time window of acute ischemic stroke. Ann Neurol 2013;73(1):4–9
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of hyperacute stroke over 6 hours using serial MR perfusion and diffusion maps. J Magn Reson Imaging 2009;29(6): 1262–1270 Nagakane Y, Christensen S, Brekenfeld C, et al; EPITHET Investigators. EPITHET: Positive Result After Reanalysis Using Baseline Diffusion-Weighted Imaging/Perfusion-Weighted Imaging CoRegistration. Stroke 2011;42(1):59–64 Kidwell CS, Jahan R, Gornbein J, et al; MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368(10):914–923 Shuaib A, Butcher K, Mohammad AA, Saqqur M, Liebeskind DS. Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target. Lancet Neurol 2011;10(10):909–921 Broderick JP, Palesch YY, Demchuk AM, et al; Interventional Management of Stroke (IMS) III Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368(10):893–903 Ciccone A, Valvassori L; SYNTHESIS Expansion Investigators. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368(25):2433–2434 U.S. National Institutes of Health. Solitaire™ FR as primary treatment for acute ischemic stroke. http://clinicaltrials.gov/show/ NCT01657461 U.S. National Institutes of Health. Assess the Penumbra System in the treatment of acute stroke. http://clinicaltrials.gov/show/ NCT01429350 Michel P, Ntaios G, Reichhart M, et al. Perfusion-CT guided intravenous thrombolysis in patients with unknown-onset stroke: a randomized, double-blind, placebo-controlled, pilot feasibility trial. Neuroradiology 2012;54(6):579–588 Thomalla G, Rossbach P, Rosenkranz M, et al. Negative fluidattenuated inversion recovery imaging identifies acute ischemic stroke at 3 hours or less. Ann Neurol 2009;65(6):724–732 U.S. National Institutes of Health. A study of intravenous thrombolysis with Alteplase in MRI-selected patients. http://clinicaltrials.gov/show/NCT01282242 U.S. National Institutes of Health. Efficacy and safety of MRI-based thrombolysis in wake-up stroke. http://clinicaltrials.gov/show/ NCT01525290 Song SS, Latour LL, Ritter CH, et al. A pragmatic approach using magnetic resonance imaging to treat ischemic strokes of unknown onset time in a thrombolytic trial. Stroke 2012;43(9): 2331–2335
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Advanced Imaging in Acute Ischemic Stroke Shlee S. Song, MD1 1 Department of Neurology, Cedars-Sinai Medical Center, Los Angeles,
California
Address for correspondence Shlee S. Song, MD, Department of Neurology, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, A6600- Rm 404, Los Angeles, CA 90048 (e-mail: [email protected]).
Abstract
Keywords
► acute stroke ► perfusion imaging ► computed tomography ► magnetic resonance imaging ► reperfusion ► ischemic Penumbra
Advances in stroke neuroimaging have evolved from excluding acute intracranial hemorrhage on computed tomography (CT) to now using perfusion studies (PWI) and magnetic resonance imaging (MRI) to possibly expand thrombolytic treatment to patients most likely to benefit from reperfusion therapy. Advanced imaging has also helped identify those at high risk for hemorrhage and poor outcome so appropriate treatment can occur with fewer complications. Identifying those who can benefit from endovascular recanalization using advanced neuroimaging techniques is particularly useful because endovascular treatment is often initiated much later than intravenous thrombolytic treatment due to logistical constraints. Using imaging markers of tissue injury may eventually lead to a paradigm shift from time-based treatment eligibility in acute stroke reperfusion treatment as the sensitivity and specificity to identify ischemic penumbra improves and correlation with clinical outcomes becomes clearer.
Neuroimaging is an important tool for confirming diagnosis and determining treatment decisions in the evaluation of patients with acute ischemic stroke. There are various imaging modalities available to distinguish ischemia versus hemorrhage and methods to determine pathology in blood flow and identify at-risk penumbral or salvageable tissue. The preferred imaging modality for acute ischemic stroke varies across stroke centers, but the most common is still computed tomography (CT). Computed tomography is readily available, quick, and accurately excludes acute intracranial hemorrhage in thrombolytic treatment-eligible patients. However, CT is not sensitive in the identification of acute cerebral ischemia, while magnetic resonance imaging (MRI) offers the advantage of more accurately identifying ischemic stroke from noncerebrovascular causes.1,2 To improve sensitivity of CT in the evaluation of acute ischemic stroke, systematic quantitative scoring using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) has been shown to identify early ischemia and is comparable to diffusion-weighted imaging (DWI) MRI. However, lower ASPECTS were seen with DWI lesions, which implies higher sensitivity for smaller lesions with DWI.3 In another comparison study because of concerns regarding sensitivity of MRI in detecting acute intracranial hemorrhage, Chalela and col-
Issue Theme Advanced Cerebrovascular Disease Management; Guest Editor, Jason Mackey, MD, MS
leagues prospectively assessed patients in the emergency setting using both MRI and CT.4 When compared with the final clinical diagnosis of stroke, blinded readers diagnosed acute ischemic stroke with higher sensitivity using MRI than CT (89% vs. 54%, respectively). Magnetic resonance imaging was comparable to CT for the detection of acute intracranial hemorrhage. Interestingly, MRI was superior to CT in the detection of all forms of intracranial hemorrhage, either acute or chronic. With evidence of better overall sensitivity of MRI, some tout MRI as the preferred imaging modality for acute stroke patients. Magnetic resonance imaging has its own limitations. Treatment times may be longer using this imaging protocol. Many patients are also excluded from MRI because of implanted devices such as pacemakers. Some acutely ill patients cannot tolerate MRI because of respiratory instability or remain still without sedation. In clinical practice, emerging data suggest either MR perfusion or CT perfusion can help identify at-risk or penumbral tissue when considering reperfusion therapy beyond approved treatment time windows or thrombectomy. Prolonged transit times of cerebral blood flow in which cerebral blood volumes are preserved are defined as areas of salvageable tissue or ischemic penumbra (►Fig. 1). Matched areas with lack of blood flow and volume are considered areas of
Copyright © 2013 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0033-1364214. ISSN 0271-8235.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Semin Neurol 2013;33:436–440.
Song
Fig. 1 Ischemic penumbra. Example of computed tomography perfusion study showing increased time to peak (TTP; top row, right corner) and mean transit time (MTT; bottom row, middle) in the right middle cerebral artery territory with relative preservation of cerebral blood volume (CBV; top row, middle).
core infarct.5 The optimal threshold to find critically underperfused tissue is a major challenge. Time-to-maximum (Tmax) delay between 2 to 8 seconds has been used to identify hypoperfused tissue.6–8 However, because some delayed areas of reperfusion will do well regardless of recanalization, efforts were made to reduce the capture of benign oligemia in ischemic penumbra calculations. In a separate analysis of the DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) Study, after multiple Tmax delay evaluations (> 2, 4, 6, or 8 seconds), it was determined Tmax > 4 seconds was the accurate predictor of final infarct volume.8 The arbitrary and generally used mismatch criteria for most clinical trials is a perfusion lesion volume 20% larger than the diffusion lesion.9 The role of neuroimaging in predicting progression from ischemia to infarction is controversial, and whether these imaging findings translate to prediction of clinical outcome is unclear and depends upon an interpretation of what is considered salvageable versus infarcted tissue. Tests need to be reliable for imaging studies to be useful in clinical practice. Targeting therapy to those with imaging profiles indicating salvageable tissue limits treatment to patients most likely to benefit with reperfusion therapy. Identifying patients with irreversible injury or core infarction who are unlikely to benefit from reperfusion treatment due to further risk of
hemorrhage and edema is just as important in real time when decisions need to be made for patients regarding thrombolytic treatment. Large-volume severe ischemia with DWI MRI greater than 100 mL (►Fig. 2) or PWI greater than 100 mL using Tmax > 8 seconds has been described as a malignant profile in the DEFUSE study.6 Further analysis including the EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial) database refined the definition as a PWI volume > 85 mL when using a Tmax delay of > 8 seconds as the optimum threshold to identify patients with poor outcome despite reperfusion therapy. However, the PWI volume deficit was not applicable or a significant predictor in the nonreperfused patients.10 Exclusion of malignant-profile patients may improve the safety profile of reperfusion therapy. Nevertheless, excluding these patients a priori before testing the penumbral imaging selection criteria has been controversial without a control-based study. Since the National Institute of Neurological Disorders and Stroke tPA ischemic stroke treatment trial in 199511 (which showed benefit of thrombolytic treatment in those patients receiving tPA within 3 hours of stroke onset) and ECASSIII in 200812 (which extended the thrombolytic treatment time window from 3 to 4.5 hours in select patients), surrogate imaging markers have been sought to help identify and include more ischemic stroke patients that could possibly benefit with Seminars in Neurology
Vol. 33
No. 5/2013
437
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Advanced Imaging in Acute Ischemic Stroke
Advanced Imaging in Acute Ischemic Stroke
Song
Fig. 2 Example image of a malignant profile6 on diffusion-weighted magnetic resonance imaging (lesion volume > 100 mL).
acute therapies beyond currently accepted treatment-time windows. In the DEFUSE study,6 acute ischemic stroke patients at 3 to 6 hours from stroke onset with a perfusion-diffusion mismatch profile showed clinical benefit with early reperfusion treatment. A subsequent prospective study13 sought to use this mismatch profile to help identify patients who would likely benefit with endovascular reperfusion treatment out to 12 hours from stroke onset. Identifying those who can benefit from endovascular recanalization is particularly useful because endovascular treatment is often initiated much later than intravenous thrombolytic treatment due to logistical constraints. The disease progression from ischemia to infarction in the early hours of ischemic injury varies,14 and this dynamic process is often attributed to variable collateral blood flow patterns.15,16 Similar findings were demonstrated in the EPITHET study,17 where clinical benefit was seen with reperfusion in perfusion-diffusion mismatch patients at 3 to 6 hours from stroke onset. In keeping with the hypothesis Seminars in Neurology
Vol. 33
No. 5/2013
that recanalization leads to favorable outcomes in mismatch patients, patients with mismatch profiles who did not recanalize had significant growth in infarct volumes and subsequent poorer clinical outcomes. In contrast to the findings in these prior prospective studies, the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) study18 found that penumbral mismatch pattern did not help select patients who would benefit from endovascular therapy. In contrast to DEFUSE and EPITHET, MR RESCUE included nonpenumbralpattern subjects as a control to help determine whether imaging studies could identify patients who would benefit with endovascular treatment. The pretreatment penumbral pattern (mismatch vs. nonmismatch) did not identify patients who would benefit from endovascular treatment. Contributing factors to the negative results may be the low recanalization rate in the intervention group, the use of first-generation devices, and the heterogeneous imaging protocol including
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
438
Song
Fig. 3 Example images of three qualitative ratings of diffusion-weighted imaging- (DWI) positive with none, subtle, and bright fluid-attenuated inversion recovery (FLAIR) hyperintensity. DWI-positive scans without FLAIR hyperintensity were seen between 0 to 6 hours from stroke onset. Subtle FLAIR hyperintensity scans could be seen as early as 1.3 hours. Bright FLAIR hyperintensity occurred after 9 hours from stroke onset. (Adapted from Song SS, Latour LL, Ritter CH, et al. A pragmatic approach using magnetic resonance imaging to treat ischemic strokes of unknown onset time in a thrombolytic trial. Stroke 2012;43(9):2331–2335)
both CT and MRI. Some work suggests that patients with favorable mismatch imaging profiles with preservation of cerebral blood volumes with collateral circulation may have better clinical outcomes regardless of intervention.19 The results of recent negative endovascular trials such as MR RESCUE and Interventional Management of Stroke III (IMS-III)20 studies highlight the importance of further research to better select patients who can benefit with reperfusion therapy. A common thread in these negative trials18,20,21 was that if reperfusion therapy was implemented too late, the potential benefit or efficacy time window is lost. An emphasis on shorter time-to-intervention coupled with more effective recanalization techniques using newergeneration devices in a randomized trial will help answer whether imaging selection criteria can better select patients for effective recanalization treatment.22,23 Recent studies suggest select neuroimaging studies such as CT with CT perfusion24 and DWI and fluid-attenuated inversion recovery (FLAIR) MRI can be used as a tissue clock when time of stroke onset is unknown.25 This may be particularly useful for patients who “wake up” with stroke symptoms whose last known well time puts them outside the guidelines for the approved use of tPA. The Abciximab in Emergency Stroke Treatment Trial (AbESTT)-II14 investigators found that the symptomatic intracerebral hemorrhage rate in reperfused patients was much higher in wake-up patients than nonwake-up patients. Clinical outcomes were significantly worse
in the wake-up patients independent of treatment arm. This may be explained by baseline CT showing wake-up patients had higher frequency of prior strokes and new abnormal CT findings consistent with new stroke. This unfavorable riskbenefit profile led to the halt of further wake-up patient study enrollment after 43 patients were enrolled. Current trials such as MR WITNESS (Phase IIa safety study of intravenous thrombolysis with alteplase in MRI-selected patients)26 and WAKE-UP (investigator-initiated randomized controlled trial of MRI-based thrombolysis in patients)27 are using DWI-positive, FLAIR-negative MRI profiles to estimate time of stroke onset to evaluate whether such imaging findings are safe to treat for reperfusion therapy (►Fig. 3).28 Using imaging markers of tissue injury may eventually lead to a paradigm shift from time-based treatment eligibility in acute stroke reperfusion treatment as the sensitivity and specificity to identify ischemic penumbra improves, safety margins increase, and correlation with clinical outcomes becomes clearer. These future developments in acute stroke imaging may help clinicians treat more eligible patients for reperfusion therapy with fewer complications.
References 1 Barber PA, Darby DG, Desmond PM, et al. Identification of major
ischemic change. Diffusion-weighted imaging versus computed tomography. Stroke 1999;30(10):2059–2065 Seminars in Neurology
Vol. 33
No. 5/2013
439
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Advanced Imaging in Acute Ischemic Stroke
Advanced Imaging in Acute Ischemic Stroke
Song
2 González RG, Schaefer PW, Buonanno FS, et al. Diffusion-weighted
15 Liebeskind DS. Collateral circulation. Stroke 2003;34(9):2279–2284
MR imaging: diagnostic accuracy in patients imaged within 6 hours of stroke symptom onset. Radiology 1999;210(1):155–162 Barber PA, Hill MD, Eliasziw M, et al; ASPECTS Study Group. Imaging of the brain in acute ischaemic stroke: comparison of computed tomography and magnetic resonance diffusion-weighted imaging. J Neurol Neurosurg Psychiatry 2005;76(11):1528–1533 Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet 2007;369(9558):293–298 Heiss WD. Flow thresholds of functional and morphological damage of brain tissue. Stroke 1983;14(3):329–331 Albers GW, Thijs VN, Wechsler L, et al; DEFUSE Investigators. 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(5):508–517 Davis SM, Donnan GA, Parsons MW, et al; EPITHET investigators. 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(4):299–309 Olivot JM, Mlynash M, Thijs VN, et al. Optimal Tmax threshold for predicting penumbral tissue in acute stroke. Stroke 2009;40(2): 469–475 Donnan GA, Baron JC, Ma H, Davis SM. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol 2009;8(3): 261–269 Mlynash M, Lansberg MG, De Silva DA, et al; DEFUSE-EPITHET Investigators. Refining the definition of the malignant profile: insights from the DEFUSE-EPITHET pooled data set. Stroke 2011; 42(5):1270–1275 Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333(24):1581–1587 Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359(13):1317–1329 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):1885–1890 Fisher M, Albers GW. Advanced imaging to extend the therapeutic time window of acute ischemic stroke. Ann Neurol 2013;73(1):4–9
16 Harris AD, Kosior RK, Chen HS, Andersen LB, Frayne R. Evolution
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