Impact of Recanalization, Reperfusion, and Collateral Flow on Clinical Efficacy
2013; Lippincott Williams & Wilkins; Volume: 44; Issue: 6_suppl_1 Linguagem: Inglês
10.1161/strokeaha.111.000258
ISSN1524-4628
Autores Tópico(s)Stroke Rehabilitation and Recovery
ResumoHomeStrokeVol. 44, No. 6_suppl_1Impact of Recanalization, Reperfusion, and Collateral Flow on Clinical Efficacy Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBImpact of Recanalization, Reperfusion, and Collateral Flow on Clinical Efficacy Gregory W. Albers, MD Gregory W. AlbersGregory W. Albers From the Department of Neurology and Neurological Sciences, Stanford Stroke Center, Stanford University Medical Center, Palo Alto, CA 94305. Originally published1 Jun 2013https://doi.org/10.1161/STROKEAHA.111.000258Stroke. 2013;44:S11–S12IntroductionThe goal of acute stroke therapy is reperfusion of salvageable ischemic tissue. Acute stroke trials have typically focused on inclusion of patients who present within a short time after the onset of symptoms. The assumption underlying this approach is that the time from symptom onset is a surrogate for the volume of salvageable tissue. It has been estimated that in patients with a large vessel occlusion presenting with acute ischemic stroke, about 120 million neurons die each hour.1 However, more recent data support the concept that the rate at which ischemic neurons become irreversibly injured after stroke onset is actually highly variable and depends on numerous factors, including the site of occlusion and the extent of collateral circulation. It seems that some patients lose neurons at an alarmingly high rate and that even very early reperfusion may be futile. In contrast, there seems to be a subgroup of stroke patients in whom irreversible ischemic injury evolves over many hours. These patients may be ideal candidates for reperfusion therapies administered at late time points.Diffusion-Weighted Imaging and Irreversible InjuryAlthough there has been controversy regarding the accuracy of acute diffusion-weighted imaging (DWI) for identification of irreversible ischemic injury, recent clinical and laboratory studies have confirmed that permanent and complete tissue salvage in regions of early DWI positivity is limited to no more than a few milliliters of tissue in the vast majority of large artery infarcts.2,3 Reports of large volume reversal may be explained by the fact that apparent diffusion coefficient (ADC) values transiently rise after reperfusion, but this transient rise does not denote tissue salvage. Therefore, obtaining follow-up imaging within 12 to 24 hours of reperfusion may suggest a reversal of DWI changes that later imaging, or pathological examination, confirm to be irreversible neuronal injury. An additional important concept is that DWI reversal is not an all or nothing phenomenon. It is not uncommon for regions of DWI reversal after reperfusion to subsequently demonstrate subtle abnormalities on delayed T2 or fluid attenuated inversion recover imaging. On the basis of data from animal models, these subtle lesions seem to represent selective neuronal necrosis rather than infarction. Lesions with lower ADC values also reflect more severe reductions in cerebral blood flow (CBF) and ADC values less than ≈600×10–6 mm2/s provide more reliable evidence of irreversible injury than milder ADC reductions. Therefore, although acute DWI lesions can overestimate irreversible injury, the volume of overestimation is rarely >10 mL and consequently a large DWI lesion with low ADC values can be considered a highly reliable indicator that a large volume of irreversible injury has occurred.Perfusion Imaging and Critically Hypoperfused TissueCritically hypoperfused tissue can be defined as tissue with a reduction in CBF sufficient to cause irreversible injury if reperfusion does not occur. A limitation of both perfusion-weighted MRI (PWI) and computed tomography perfusion is that they do not provide quantitative CBF values. Many perfusion imaging techniques identify tissue that is relatively hypoperfused; yet, CBF is not low enough to cause irreversible injury. Therefore, these techniques have had a propensity to overestimate critical hypoperfusion. More recently, specific perfusion thresholds have been applied to exclude ischemic tissue with modest blood flow reduction. Recent studies using perfusion parameters that detected delays in contrast bolus arrival time compared with the nonischemic tissue have generated encouraging results. For example, a Tmax delay of >5 to 6 s is predictive of ischemic tissue likely destined to irreversible injury if reperfusion does not occur.4 In addition, a Tmax delay of 5 to 6 s correlates well with critical hypoperfusion as defined by positron emission tomography.5 Therefore, patients who demonstrate a mismatch between the volume of the early DWI lesion and an appropriately thresholded PWI lesion are likely to have penumbral tissue.Clinical ObservationsStroke Centers that routinely perform MRI in acute stroke have noted that some patients with middle cerebral artery or internal carotid artery occlusion rapidly develop very large DWI lesions, whereas other patients with identical vessel occlusion develop large DWI lesions over a considerably longer time period. Patients with rapid DWI growth typically have severe perfusion lesions characterized by very low CBF values and substantial delays in the arrival of a contrast bolus (Tmax delays >10 s) to the ischemic region. These patients have been referred to as having a malignant profile and can be identified by both MRI and computed tomography perfusion. These patients seem to have very poor clinical outcomes even when reperfusion therapy has been administered early.6 It has been estimated that ≈10% of acute stroke patients who present within 3 hours of symptom onset may have already sustained a large volume of irreversible injury.EPITHET and the DEFUSE 1 and 2 StudiesIn the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) studies,7,8 patients underwent DWI and PWI imaging before treatment with intravenous tissue-type plasminogen activator (DEFUSE 1 and EPITHET) or endovascular therapy (DEFUSE 2). DEFUSE 1 and EPITHET found that patients with a PWI/DWI mismatch had better clinical outcomes and less lesion growth if reperfusion occurred after intravenous tissue-type plasminogen activator treatment in the 3- to 6-hour time window. An exception to this precept was patients with the malignant profile who demonstrated a very high rate of brain hemorrhage and severe disability/death after reperfusion even if they had a mismatch.9 Mismatch patients who do not have the malignant profile were termed target mismatch. In a pooled analysis of DEFUSE and EPITHET, target mismatch patients had a 5-fold increase in favorable clinical response at 90 days if they reperfused. For patients who did not have a mismatch, there was no association between reperfusion and clinical outcomes or infarct growth.The DEFUSE 2 study8 confirmed the concepts demonstrated in DEFUSE 1 and EPITHET in a longer time window (up to 12 hours from symptom onset). Target mismatch patients who reperfused had a substantial reduction in infarct growth and more favorable clinical outcomes. Among patients who did not have target mismatch, there was no association between reperfusion and favorable outcomes or infarct growth. Of note, in patients treated with endovascular therapy between 6 and 12 hours from symptom onset, the odds ratio for favorable clinical response in target mismatch patients with reperfusion versus those without was 8.5 (95% confidence interval, 2.1–35.1). The robust response to reperfusion in these late-treated patients may be explained by the observation that infarct growth is considerably slower in these late-arriving patients who still have a PWI/DWI mismatch. This slower growth rate implies that less infarct progression will occur during the time required to achieve reperfusion. However, if reperfusion is not achieved, the DEFUSE 2 data indicate that infarct progression continues in these patients and clinical outcomes are poor.ConclusionsRandomized controlled trails are required to conclusively prove that advanced imaging techniques can identify a subset of patients who will benefit from reperfusion therapy at delayed time points. Ongoing studies with these objectives are currently in progress. Validated imaging techniques also have the potential to identify patients who have poor collateral circulation and experience rapid infarct growth. Alternatives treatments, rather than reperfusion, may be more appropriate for these patients.DisclosureDr Albers has equity interest in iSchemaView and has received consulting fees from Lundbeck, Covidien, Genentech and Concentric.FootnotesCorrespondence to Gregory W. Albers, MD, Stroke Center, Stanford University Medical Center, 1215 Welch Road, Modular D, Stanford, CA 94305. E-mail [email protected]References1. Saver J. Time is brain—quantified.Stroke. 2006; 37(1):10LinkGoogle Scholar2. Chemmanam T, Campbell BC, Christensen S, Nagakane Y, Desmond PM, Bladin CF, et al.; EPITHET Investigators. Ischemic diffusion lesion reversal is uncommon and rarely alters perfusion-diffusion mismatch.Neurology. 2010; 75:1040–1047.CrossrefMedlineGoogle Scholar3. Campbell BC, Purushotham A, Christensen S, Desmond PM, Nagakane Y, Parsons MW, et al.; EPITHET–DEFUSE Investigators. The infarct core is well represented by the acute diffusion lesion: sustained reversal is infrequent.J Cereb Blood Flow Metab. 2012; 32:50–56.CrossrefMedlineGoogle Scholar4. Olivot JM, Mlynash M, Thijs VN, Kemp S, Lansberg MG, Wechsler L, et al. Optimal Tmax threshold for predicting penumbral tissue in acute stroke.Stroke. 2009; 40:469–475.LinkGoogle Scholar5. Zaro-Weber O, Moeller-Hartmann W, Heiss WD, Sobesky J. Maps of time to maximum and time to peak for mismatch definition in clinical stroke studies validated with positron emission tomography.Stroke. 2010; 41:2817–2821.LinkGoogle Scholar6. Inoue M, Mlynash M, Straka M, et al. Patients with the Malignant Profile within 3 hours of symptom onset have very poor outcomes following IV tPA therapy.Stroke.2012; 43:2494–2496.LinkGoogle Scholar7. Lansberg MG, Lee J, Christensen S, Straka M, De Silva DA, Mlynash M, et al. RAPID automated patient selection for reperfusion therapy: a pooled analysis of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study.Stroke. 2011; 42:1608–1614.LinkGoogle Scholar8. Lansberg MG, Straka M, Kemp S, Mlynash M, Wechsler LR, Jovin TG, et al.; DEFUSE 2 Study Investigators. MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study.Lancet Neurol. 2012; 11:860–867.CrossrefMedlineGoogle Scholar9. Mlynash M, Lansberg MG, De Silva DA, Lee J, Christensen S, Straka M, et al.; DEFUSE-EPITHET Investigators. Refining the definition of the malignant profile: insights from the DEFUSE-EPITHET pooled data set.Stroke. 2011; 42:1270–1275.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Chen Y, Zhang Y, Guo Z, Liu L, Gao F, Lv Y, Zhang M, Sun X, Obenaus A, Yang Y, Tang J, Feng H and Zhang J (2019) Neurovascular Network as Future Therapeutic Targets Cerebral Venous System in Acute and Chronic Brain Injuries, 10.1007/978-3-319-96053-1_1, (1-47), . Motyer R, Asadi H, Thornton J, Nicholson P and Kok H (2017) Current evidence for endovascular therapy in stroke and remaining uncertainties, Journal of Internal Medicine, 10.1111/joim.12653, 283:1, (2-15), Online publication date: 1-Jan-2018. Villringer K, Serrano-Sandoval R, Grittner U, Galinovic I, Schneider A, Ostwaldt A, Brunecker P, Rocco A and Fiebach J (2015) Subtracted Dynamic MR Perfusion Source Images (sMRP-SI) provide Collateral Blood Flow Assessment in MCA Occlusions and Predict Tissue Fate, European Radiology, 10.1007/s00330-015-3927-5, 26:5, (1396-1403), Online publication date: 1-May-2016. Tóth M, Little P, Arnberg F, Häggkvist J, Mulder J, Halldin C, Gulyás B and Holmin S (2015) Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking, Brain Structure and Function, 10.1007/s00429-014-0970-y, 221:3, (1279-1290), Online publication date: 1-Apr-2016. Menon B, Qazi E, Nambiar V, Foster L, Yeatts S, Liebeskind D, Jovin T, Goyal M, Hill M, Tomsick T, Broderick J and Demchuk A (2015) Differential Effect of Baseline Computed Tomographic Angiography Collaterals on Clinical Outcome in Patients Enrolled in the Interventional Management of Stroke III Trial, Stroke, 46:5, (1239-1244), Online publication date: 1-May-2015. Man S, Aoki J, Hussain M, Wisco D, Tateishi Y, Toth G, Hui F and Uchino K (2015) Predictors of Infarct Growth after Endovascular Therapy for Acute Ischemic Stroke, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2014.09.004, 24:2, (401-407), Online publication date: 1-Feb-2015. Möhlenbruch M (2015) Interventionelle neuroradiologische Techniken NeuroIntensiv, 10.1007/978-3-662-46500-4_25, (361-375), . Jansen O and Rohr A (2013) Neurothrombectomy in the treatment of acute ischaemic stroke, Nature Reviews Neurology, 10.1038/nrneurol.2013.204, 9:11, (645-652), Online publication date: 1-Nov-2013. June 2013Vol 44, Issue 6_suppl_1 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.111.000258PMID: 23709700 Manuscript receivedNovember 23, 2012Manuscript acceptedMarch 13, 2013Originally publishedJune 1, 2013 Keywordscollateral flowperfusion MRIreperfusiondiffusion MRIbrain ischemiaPDF download Advertisement SubjectsCerebrovascular ProceduresTreatment
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