Evaluation of the CT High-density Area after Endovascular Treatment for Acute Ischemic Stroke

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1 Journal of Neuroendovascular Therapy 2017; 11: Online January 30, 2017 DOI: /jnet.oa Evaluation of the CT High-density Area after Endovascular Treatment for Acute Ischemic Stroke Jun Takei, 1 Koreaki Irie, 1 Toshihide Tanaka, 1 Kenji Okuno, 2 Izumu Hasegawa, 2 Takashi Shimoyama, 3 Hiroshi Yaguchi, 3 Keisuke Hatano, 1 Fumiaki Maruyama, 1 Youhei Yamamoto, 1 Satoru Tochigi, 1 Yuzuru Hasegawa, 1 and Yuichi Murayama 4 Objective: To evaluate the relationship between the incidence of the CT high-density area that appears immediately after endovascular treatment for acute ischemic stroke with postprocedural hemorrhagic transformation and its significance in the clinical outcome. Methods: Ten patients with ischemic stroke of the anterior circulation encountered between May 2014 and December 2015 in whom recanalization could be achieved within 8 hours after the onset were retrospectively analyzed. In addition, 695 patients presented in 13 reports were divided into thrombolysis and mechanical thrombectomy groups, and the postprocedural incidence of CT high-density areas was compared between the two groups. Results: Postprocedural CT high-density areas were observed in six (60%) of our patients. Hemorrhagic transformation occurred in three of them, but no exacerbation of neurological symptoms was noted. The incidence of postprocedural CT high-density areas was 43.1% (191/443) in the thrombolysis group and 71.8% (188/262) in the mechanical thrombectomy group including our patients, being significantly higher in the latter group (p <0.01). Conclusion: Although CT high-density areas appear more frequently after mechanical thrombectomy than after thrombolysis, they are considered to be infrequently developed into hemorrhagic transformation and exert relatively few negative effects on the neurological outcome. Keywords acute ischemic stroke, intra-arterial revascularization, hyperdense areas, contrast staining, thrombectomy Introduction There have been incessant attempts to recanalize large vessel occlusion in acute ischemic stroke and improve the functional outcome. Intravenous thrombolysis with 1 Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan 2 Department of Emergency Medicine, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan 3 Department of Neurology, Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan 4 Department of Neurosurgery, Jikei University School of Medicine, Tokyo, Japan Received: May 8, 2016; Accepted: November 28, 2016 Corresponding author: Jun Takei. Department of Neurosurgery, Jikei University Kashiwa Hospital, Kashiwashita, Kashiwa, Chiba , Japan jun.takei1986@gmail.com This work is licensed under a Creative Commons Attribution-NonCommercial- NoDerivatives International License The Japanese Society for Neuroendovascular Therapy recombinant tissue plasminogen activator (IV-tPA) has been established as a treatment. 1) In patients who do not respond to, or have no indication for IV-tPA, endovascular procedures, such as intra-arterial thrombolysis (IAT) using urokinase or tpa, 2) mechanical clot disruption, 2,3) and mechanical thrombectomy using MERCI retrievers 4) were alternative options. From the results of randomized clinical trials including MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, and REVASCAT, the usefulness of thrombectomy using stent retrieval devices has been demonstrated, and this approach is expected to improve the outcome of ischemic stroke. 5 9) High-density areas occasionally appear on head CT performed early after endovascular treatment for acute ischemic stroke. However, there is no consensus as to the cause of these findings, which have been described as hyperdense areas (HA), 10) hemorrhage/contrast staining areas, 11) contrast enhancement and contrast extravasation, 12) and contrast staining, 13) or their relationship with the clinical outcome. We evaluated the incidence of HA, their relationship with hemorrhagic transformation after treatment, and their 227

2 Takei J, et al. impact on the clinical outcome by reviewing the literature and retrospectively analyzing our patients. Subjects and Methods In total, 14 patients underwent endovascular treatment for acute ischemic stroke between May 2014 and December 2015 at our department. Ten of these patients with ischemic stroke of the anterior circulation in whom recanalization could be achieved within 8 hours after the onset were analyzed by excluding three with occlusion of the posterior circulation or cervical internal carotid artery and one who underwent percutaneous transluminal angioplasty (PTA) for arterial stenosis. The initial imaging evaluation was performed using CT and MRI, and IV-tPA was administered as the first-line treatment for patients with indications according to the second edition of the guidelines for the intravenous application of recombinant tpa (alteplace) in Japan. 14) Thrombectomy was indicated for patients with an National Institute of Health Stroke Scale (NIHSS) score of 4 or higher at the initial examination confirmed to have large vessel occlusion such as the internal carotid artery and the M1-M2 segment of the middle cerebral artery. The treatment was indicated when the Alberta Stroke Programme Early CT score on diffusion-weighted imaging (DWI-ASPECTS) was 5 or higher in principle, but the final judgment was made by the endovascular interventionist in consideration of the onset to revascularization time (OtoR). CT images immediately after treatment were evaluated using flat panel detector CT (FPCT; Artis zee BA Twin, Siemens, Munich, Germany) in nine patients and using a conventional CT system (Aquilion64SC, Toshiba Medical Systems, Tochigi, Japan) in one patient. Follow-up head CT examination was performed within 24 hours after the initial CT examination. These treatment groups were evaluated retrospectively with regard to the following items: Sex, age, site of occlusion, presence or absence of tpa administration, preprocedural NIHSS score, preprocedural DWI-ASPECTS, onset to puncture time (OtoP), OtoR, device used, thrombolysis in cerebral infarction (TICI) classification, presence or absence of HA, changes in HA on follow-up CT, presence or absence of hemorrhagic transformation, and modified Rankin Scale (mrs) score at 90 days after the onset. In our patients, HA was defined as a condition that met all the following criteria in those who showed high-density areas on the first CT after the recanalization procedure: 1) Hounsfield units (HU) of 40, 2) clearly demarcated from the surrounding structures, 3) no mass effect, and 4) no surrounding cerebral edema. 13) Hemorrhagic transformation was rated as hemorrhagic infarction (HI) type 1 or 2 and parenchymal hematomas (PH) type 1 or 2 following the classification by Berger et al. 15) According to our review, 14 articles published between 1993 and 2015 were found. After excluding one article not providing details of the recanalization procedure, a total of 705 patients consisting of those reported in the remaining 13 articles and our patients were analyzed ,16 25) Concerning the recanalization procedure, the method for endovascular treatment differed after the report in 2012, and the treatments described in the 13 reports that we reviewed were IAT or clot disruption alone before 2012 and mechanical thrombectomy alone after IV-tPA was performed concomitantly in both groups. The patients were classified into those who underwent thrombolysis before 2012 (thrombolysis group) and those who underwent mechanical thrombectomy after 2012 (thrombectomy group), CT high-density areas that appeared after the recanalization procedure were defined as HA, and the frequency of their occurrence was analyzed. Statistical analysis The incidence of HA was compared between the thrombolysis and thrombectomy groups according to Pearson s chisquare test. Excel was used for statistical procedures. The level of statistical significance was P value of <5%. Results Table 1 summarizes the details of our 10 patients. They consisted of five males and five females with a mean age of 65.9 (range; 40 83) years. The site of occlusion was the middle cerebral artery in six patients and internal carotid artery in four patients. IV-tPA was administered before the endovascular procedure in six patients. The mean preprocedural NIHSS score was 18.2 (10 24). The mean preprocedural DWI-ASPECTS was 6.3 (3 8). The mean OtoP was 3.7 ( ) hours, and the mean OtoR was 4.8 ( ) hours. The device used was Merci retriever (Stryker, Kalamazoo, MI, USA) in one patient, Trevo provue (Stryker) in nine patients. The recanalization grade was TICI 2a in 1, 2b in 4, 3 in 5, and TICI2b or higher recanalization was achieved in 9 (90%). On CT examination immediately after the recanalization procedure, HA were noted in six patients (60%), of whom four patients (40%) were administered IV-tPA. 228

3 Evaluation of the CT High-density Area Table 1 Summary of our cases treated by thrombectomy with or witout thrombolysis mrs 90 days after onset Hemorrhagic transformation Transformation of HA on follow-up CT Area of HA TICI grade OtoR (hours) OtoP (hours) DWI- ASPECTS tpa Device NIHSS Age/ Sex Occlusion site Case number 1 Rt. MCA (M1) 40/F + Merci b Rt putamen Infarction None 2 2 Lt. MCA (M1) 66/M + Trevo Lt caudate head Iso density Hemorrhage (PH-2) 5 3 Rt. ICA 45/F - Trevo Rt putamen Infarction None 4 4 Lt. MCA (M1) 83/M + Trevo b None None 4 5 Lt. MCA (M1) 66/F - Trevo None None 6 Hemorrhage (HI-2) 4 Hemorrhage (HI-2) 6 Rt. MCA (M2) 73/F + Trevo b Rt striate/ Rt temporal cortex 7 Rt. MCA (M1) 71/M - Trevo a Rt stiate Infarction None 5 8 Lt. ICA 63/F - Trevo None None 5 Hemorrhage (PH-1) 0 Hemorrhage (PH-1) 9 Lt. ICA 75/M + Trevo b Lt striate/ Lt frontal cortex 10 Lt. ICA 77/M + Trevo None None 6 DWI-ASPECTS: Alberta Stroke Programme Early CT score on diffusion-weighted imaging; F: female; HA: hyperdense areas; HI: hemorrhagic infarction; ICA: internal carotid artery, Lt: left; M: male; MCA: middle cerebral artery; mrs: modified Ranking Scale; NIHSS: National Institute of Health Stroke Scale; OtoP: onset to puncture; OtoR: onset to revasculization; PH: parenchymal hematoma; Rt: right; TICI: thrombolysis in cerebral infarction; tpa: tissue plasminogen activator. brain CT 12 hours after intervention. hemmorrhage in a remote area from HA. On follow-up head CT, HA developed into cerebral infarction in three patients (50%), hemorrhagic transformation in two patients (33%), and isodensity in one patient (17%). The patient in whom HA changed to isodensity developed remote hemorrhagic transformation at a different site from HA. Of our 10 patients, hemorrhagic transformation was noted in three patients (30%), who all showed HA. HI-1 and PH-1 occurred in HA, but PH-2 occurred at sites distant from HA. None of the patients showed symptomatic hemorrhage with 4 points or more increase in the NIHSS score. The mrs score at 90 days after the onset was 0 in 1, 2 in 1, 4 in 3, 5 in 3, and 6 in 2. The favorable outcome was achieved (mrs score 2) in two patients (20%). According to our review, 13 articles have been published concerning HA after thrombolysis or mechanical thrombectomy for acute ischemic stroke (Table 2). When the reported cases and our patients were combined, the incidence of HA was 53.8% (379/705). The incidence of HA after the recanalization procedure was 43.1% (191/443) in the thrombolysis group and 71.8% (188/262) in the thrombectomy group including our patients (Table 3). The incidence of HA was significantly higher in the thrombectomy group (Pearson s chi-square test: p <0.01). Case Presentation (Case No. 9) The patient was a 75-year-old male with a history of untreated paroxysmal atrial fibrillation. He developed disturbance of consciousness and right hemiparesis including the face and arrived at the hospital 53 minutes after the onset. The NIHSS score was 21, high signal on DWI was noted in the left precentral gyrus and left corona radiate, and the DWI-ASPECTS was 8 (Fig. 1). MRA disclosed occlusion of the left terminal internal carotid artery. IV-tPA was initiated 118 minutes after the onset. The NIHSS score improved to 10 two minutes after the administration, and cerebral angiography and mechanical thrombectomy were subsequently performed. Interventional procedure A 8 Fr-90 cm OPTIMO (Tokai Medical Products, Aichi, Japan) was placed in the left internal carotid artery, and occlusion of a proximal part of the left middle cerebral artery was confirmed. TrevoPro18 microcatheter (Stryker) was navigated to the inferior trunk of the left middle cerebral artery, and the 229

4 Takei J, et al. Table 2 The list of reported cases treated with thrombolysis/thrombectomy with or without hyperdense areas Symptomatic hemorrhage HA as a risk factor for symptomatic hemorrhage? No. of cases HA (+) HA (-) HA (+) HA (-) Procedure/Device of surgery Authors Year Thrombolysis group Komiyama M 20) 1993 IA-tPA N.D. Yes Wildenhain SL 24) 1994 IA-UK No Yokogami K 25) 1996 IA-UK, IA-tPA Yes Mericle RA 22) 2000 IA-UK N.D. N.D. No a Nakano S 10) 2001 PTA, IA-UK, IV-tPA Yes Yoon W 12) 2004 IA-UK Yes b Jang YM 17) 2006 IA-UK, MCD N.D. N.D. No Ghobrial GM 16) 2011 IA-thrombolysis No Kim JT 19) 2012 IA-UK, MCD, PTA, Stenting No Thrombectomy group Parrilla G 11) 2012 SR N.D. No Lummel N 21) 2014 Retriever, AT No Song SY 23) 2015 SR, AT N.D. N.D. Yes c Kim JM 18) 2015 SR, AT Yes d AT: aspiration thrombectomy; HA: hyperdense areas; HU: hounsfield unit; IA-tPA: intraarterial tissue plasminogen activator; IA-UK: intraarterial urokinase; IV-tPA: intravenous tissue plasminogen activator; MCD: mechanical clot disruption; N.D.: not described; PTA: percutaneous transluminal angioplasty; SR: stent retriever; a) HU >150 is a risk factor for poor outcome; b) HU >90 and persisting 24 hours are a risk factor; c) Only large HA is a risk factor; d) HA involved the cortex is a risk factor Table 3 Incidence of hyperdense areas in each group HA positive HA negative Thrombolysis group (n = 443) Thrombectomy group (n = 262) p <0.01 Pearson s chi-square test. HA: hyperdense areas distal part of the thrombus was secured. Trevo Provue retriever was deployed, and, after waiting for 5 minutes, the balloon of the guiding catheter was dilated. Then, Trevo Provue was retrieved while aspirating the thrombus. The thrombus was captured in the stent and guiding catheter. The stent could not be navigated to the superior trunk of the left middle cerebral artery, and the procedure was terminated 270 minutes after the onset. The recanalization grade was TICI2b (Fig. 2). FPCT was performed immediately after surgery, highdensity areas (mean HU: 80) unaccompanied by mass effect were noted in the left striate and frontotemporal cortex, and a diagnosis of HA was made. Postprocedural course On head CT performed on the day after endovascular treatment, high-density areas persisted in the areas consistent with HA, and it was diagnosed as a hemorrhagic transformation (PH1) (Fig. 3). Motor aphasia was noted, and the patient was transferred to a rehabilitation hospital on the 17th hospital day. The mrs score at 90 days after the onset was 0. Discussion Komiyama et al. 20) first reported the appearance of high-density areas on CT examination early after endovascular treatment for acute ischemic stroke. Thereafter, Wildenhain et al. 24) reported six patients who developed HA immediately after thrombolysis and concluded that patients in whom HA disappeared early showed a favorable outcome. Also, hemorrhagic transformation after thrombolysis accompanied by exacerbation of neurological symptoms was reported to be significantly related to the appearance of HA. 10) Parrilla et al. 11) first reported HA immediately after mechanical thrombectomy but observed that their appearance was unrelated to the clinical outcome and was not a prognostic factor. HA have been suggested to be caused by multiple factors including contrast enhancement due to the 230

5 Evaluation of the CT High-density Area Fig. 1 Case No. 9. (A) Brain CT scan 1 hour after onset showing no Early CT signs. (B) DWI immediately after CT showing high intensity in the territory of the left middle cerebral artery. DWI: diffusion-weighted imaging Fig. 2 (A) Left internal carotid artery angiogram showing a contrast defect from the origin of the left middle cerebral artery. (B) Left internal carotid artery angiogram after the procedure showing revascularization of inferior trunk of the left middle cerebral artery. contrast medium, contrast extravasation into the brain parenchyma, and hemorrhage, and no consensus has been established. Mechanisms such as disruption of the blood brain barrier (BBB) caused by reperfusion and influx of a highconcentration contrast medium, and stagnation of the contrast medium due to insufficient recanalization of the capillaries despite recanalization of the major artery ( noreflow phenomenon ) have been proposed. 13) Iwata et al. 26) reported patients who developed HA after coil embolization for unruptured cerebral aneurysms and speculated that they were caused by disruption of the BBB by the contrast medium. Although CT was used for intracranial evaluation after recanalization in the past studies, we used primarily FPCT in this study. Irie et al. 27) performed intracranial evaluation using FPCT after craniotomy and endovascular treatment and reported its usefulness. The quality of FPCT images is sufficient for the assessment of novel lesions after endovascular treatment for acute ischemic stroke, but it is insufficient for the differentiation between hemorrhage and contrast extravasation similar to conventional CT. 28) Recently, the 231

6 Takei J, et al. Fig. 3 (A) Flat panel detector CT immediately after revascularization showing high density in the territory of the left middle cerebral artery and perforators. (B) Brain CT the next day after revascularization demonstrating high density with surrounding low density. use of dual energy CT (DE-CT) has been reported to be useful for the differentiation of hemorrhage and contrast extravasation. 29) Renú et al. 30) reported that they used DE-CT for the evaluation after thrombectomy and concluded that contrast extravasation and intracranial hemorrhage were related to a poor prognosis. Dinkel et al. 31) reported some technical problems as well as the neuroradiological usefulness of DE-CT. Presently, however, DE-CT is not a standard method for the intracranial evaluation after thrombectomy and the evaluation using conventional CT or FPCT is still important. According to our review of the literature, 13 articles have been published concerning HA after thrombolysis or mechanical thrombectomy for acute ischemic stroke (Table 2). Regarding the recanalization procedure for large vessel occlusion, mechanical thrombectomy has been performed in all reports since the one by Parrilla in Therefore, we evaluated the incidence of HA by classifying the patients into those who underwent thrombolysis before 2012 (thrombolysis group) and those who underwent mechanical thrombectomy after 2012 (thrombectomy group) and found that it was significantly higher in the thrombectomy group (p <0.01). The incidence of HA is considered to have been higher in the thrombectomy group for the following three reasons: First, in the thrombectomy group, the incidence of HA may have increased due to contrast enhancement or contrast extravasation as a result of an improvement in the recanalization rate. 11) Second, involvement of IV-tPA. In this study, HA occurred in four (67%) of the six patients in whom IV-tPA was performed concomitantly. Although there have been no reports that IV-tPA increased the incidence of HA, this possibility cannot be excluded since IV-tPA is frequently used with mechanical thrombectomy. Third, the effect of the procedure using a stent retriever. For mechanical thrombectomy, a stent retriever has been used in 87% 100% of our patients and patients reported to have been treated with a known device. 11,23) Since the thrombectomy procedure using a stent retriever involves mechanical injury of the intracranial vessels with the stent and multiple intracranial injections of the contrast medium through the microcatheter, the differences in the procedure may have contributed to an increase in the incidence of HA. The definition of HA has not been established. The thrombolysis group included many patients from studies classifying HA as CT high-density areas that appeared after the recanalization procedure and evaluating the relationships of the outcome with the site of HA and HU. 10,17) There have also been reports in which the disappearance of HA on CT at 24 hours after the recanalization procedure was defined as contrast enhancement and no disappearance of HA as contrast extravasation. 12,22) 232

7 Evaluation of the CT High-density Area In the thrombectomy group, HA were defined as CT high-density areas after the recanalization procedure, and the relationships of the outcome with the site of HA and HU were evaluated similarly to earlier reports. 11,18,23) Lummel et al. 21) classified the disappearance of HA on CT performed 24 hours after the recanalization procedure as contrast extravasation and no disappearance as hemorrhagic transformation and evaluated the relationship of this classification with the outcome. There is a discrepancy among reports concerning the relationship between HA and symptomatic hemorrhage as an adverse prognostic factor (Table 2). According to two reports, there was no relationship between the presence or absence of HA and the outcome in the thrombectomy group, and symptomatic hemorrhage was rare. 11,21) Another report, in which risk factors were extracted by directing attention to characteristics of images of HA, observed that brain edema was more likely to occur with exacerbation of the prognosis when HA were distributed over 20% or more of the cerebral hemisphere. 23) In addition, HA extending to the cerebral cortex was reported to be more often complicated by PH2 symptomatic hemorrhage and to be related to a poor outcome. 18) Of our patients, two patients (20%) developed hemorrhagic transformation in HA, and it was HI2 and PH1. In one patient (10%), PH2 intracranial hemorrhagic was noted at a site other than HA. None of the patients suffered exacerbation by 4 points or more on the NIHSS score during the course, and no symptomatic hemorrhage that lead to a poor outcome was noted. Regarding the relationship between the presence or absence of HA and OtoP, HA were reported to have occurred more frequently when the interval between the onset and treatment was short, 13) but no correlation was observed between the presence or absence of HA and OtoP or OtoR in our patients. Although statistical analysis could not be performed, according to this analysis of a small number of patients and a review of the literature, HA observed after mechanical thrombectomy are considered unlikely to develop into PH2 symptomatic hemorrhage. However, HA covering 20% or more of the unilateral cerebral hemisphere or extending to the cerebral cortex may lead to brain edema or PH2 symptomatic hemorrhage and requires caution. 18,23) Conclusion The incidence of HA was significantly higher in the thrombectomy group than in the thrombolysis group. HA after mechanical thrombectomy evaluated by conventional CT or FPCT is unlikely to develop into PH2 intracranial hemorrhage unless they extend over 20% or more of the unilateral cerebral hemisphere or to the cerebral cortex and is considered to have little significance as a prognostic factor. Disclosure Statement Coauthor Yuichi Murayama is an advisor for Asahi Intecc (Aichi), Brain Lab (München, Germany), and Stryker. He is provided with research funds from Asahi Intecc, Stryker, and Siemens (Munich, Germany) and is receiving a patent royalty from Stryker. The first author and other coauthors have no conflicts of interest to declare. References 1) Nakagawara J, Minematsu K, Okada Y, et al: Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice: the Japan post-marketing Alteplase Registration Study (J-MARS). Stroke 2010; 41: ) IMS II Trial Investigators: The Interventional Management of Stroke (IMS) II Study. Stroke 2007; 38: ) Yoon W, Park MS, Cho KH: Low-dose intra-arterial urokinase and aggressive mechanical clot disruption for acute ischemic stroke after failure of intravenous thrombolysis. AJNR Am J Neuroradiol 2010; 31: ) Smith WS, Sung G, Saver J, et al: Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke 2008; 39: ) Berkhemer OA, Fransen PS, Beumer D, et al: A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015; 372: ) Goyal M, Demchuk AM, Menon BK, et al: Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372: ) Campbell BC, Mitchell PJ, Kleinig TJ, et al: Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372: ) Saver JL, Goyal M, Bonafe A, et al: Stent-retriever thrombectomy after intravenous t-pa vs. t-pa alone in stroke. N Engl J Med 2015; 372: ) Jovin TG, Chamorro A, Cobo E, et al: Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372: ) Nakano S, Iseda T, Kawano H, et al: Parenchymal hyperdensity on computed tomography after intra-arterial reperfusion therapy for acute middle cerebral artery occlusion: incidence and clinical significance. Stroke 2001; 32:

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