Clinical Characteristics of Patients with Embolic Stroke of Undetermined Source Treated by Endovascular Recanalization Therapy

Transcription

1 DOI: /jnet.oa Clinical Characteristics of Patients with Embolic Stroke of Undetermined Source Treated by Endovascular Recanalization Therapy Ryota Kurogi, 1 Tomoyuki Tsumoto, 1 Yuichi Miyazaki, 1 Takahiro Kuwashiro, 2 Masahiro Yasaka, 2 and Yasushi Okada 2 Objective: This study was carried out to evaluate the clinical characteristics of patients with embolic stroke of undetermined source () treated by endovascular reperfusion therapy for emergent large vessel occlusion (ELVO). Subjects and Methods: Of 87 consecutive acute ischemic stroke patients with ELVO treated by endovascular reperfusion therapy, clinical characteristics, treatments, and outcomes were compared in 14 patients diagnosed with at discharge and 42 patients with cardioembolic stroke (). Results: In the group, the patients were younger (63.9 vs years, P <0.05), and the percentage of males was lower (21.4% vs. 64.3%, P <0.05), than in the group. Most patients in both groups received mechanical thrombectomy, and there was no significant difference in the National Institutes of Health Stroke Scale (NIHSS) score on admission (median: 17 vs. 18), diffusion weighted image-alberta Stroke Program Early CT score (DWI-ASPECTS) (median: 8 vs. 7), or successful reperfusion (thrombolysis in cerebral infarction [TICI] grade 2b or 3) rate (78.6% vs. 61.9%). Favorable outcome (modified Rankin Scale [mrs] score of 0-2 at discharge) tended to be more frequent in the group (71.4% vs. 42.9%, P = 0.06). Conclusion: The relatively younger age of the group compared with the group is considered to have contributed to the more favorable outcome. Keywords embolic stroke of undetermined source, endovascular recanalization therapy, cryptogenic stroke, paroxysmal atrial fibrillation, transesophageal echocardiography Introduction The cause of about 1/4 of strokes has not been identified despite appropriate examinations, and they have been 1 Department of Neuroendovascular Surgery, National Hospital Organization, Clinical Research Institute, Kyushu Medical Center, Fukuoka, Fukuoka, Japan 2 Department of Cerebrovascular Medicine and Neurology, National Hospital Organization, Clinical Research Institute, Kyushu Medical Center, Fukuoka, Fukuoka, Japan Received: September 12, 2017; Accepted: April 3, 2018 Corresponding author: Ryota Kurogi. Department of Neuroendovascular Surgery, National Hospital Organization, Clinical Research Institute, Kyushu Medical Center, Jigyohama, Chuo-ku, Fukuoka, Fukuoka , Japan kurogi1982@yahoo.co.jp This work is licensed under a Creative Commons Attribution-NonCommercial- NoDerivatives International License The Japanese Society for Neuroendovascular Therapy called cryptogenic strokes. As understanding of the pathology has advanced with improvements in diagnostic imaging techniques, embolism has begun to be considered the mechanism of many cryptogenic strokes, and embolic stroke of undetermined source () has been proposed as a new clinical construct. 1) Stroke by an embolic mechanism also occurs in cardioembolic stroke () but its clinical characteristics and prognosis differ. 2) Recently, a large number of clinical studies of have been reported, 3) but reports on patients treated by endovascular reperfusion therapy for emergent large vessel occlusion (ELVO) have been scarce. 4,5) We retrospectively investigated the characteristics and outcomes of patients by comparing patients diagnosed with at discharge with those of patients with among those who were treated with endovascular reperfusion therapy at our institution. We also evaluated the detection of embolic source during hospitalization in patients eventually diagnosed with. 1

2 Kurogi R, et al. Table 1 Diagnostic definition of embolic stroke of undetermined source Diagnostic definition Nonlacunar infarct on imaging studies Patency of the main artery proximal to infarct ( 50%) No major intracardiac embolic sources Absence of special conditions that may cause brain infarction (angiitis, arterial dissection, migraine, vasospasm, drug abuse, etc.) Necessary examinations CT or MRI of the head to demonstrate nonlacunar infarct Transthoracic echocardiography ECG or 24-hour or longer cardiac monitoring Imaging examinations of the intra- and extracranial arteries that supply the ischemic area of the brain Transesophageal echocardiography or close examination of the aortic arch is not required ECG: electrocardiogram Subjects and Methods Of 87 acute ischemic stroke patients with ELVO treated by endovascular reperfusion therapy between January 2012 and April 2016 in our institute, 14 patients met the definition of 1) ( group) and 42 patients diagnosed with cardioembolic stroke ( group) at discharge. The definition of is given in Table 1. The diagnostic criteria for were those with high-risk cardioembolic source according to the The trial of Org in Acute Stroke Treatment (TOAST) classification. 6) The patient characteristics, treatments, and outcomes were compared between the and groups using medical records, and retrospective analyses were performed. Comparison of diffusion weighted image-alberta Stroke Program Early CT score (DWI-ASPECTS) was made only in patients with ELVO in the anterior circulation who underwent MRI on admission. Of the treatments, procedures using the Merci retriever (Concentric Medical, Mountain View, CA, USA), Penumbra aspiration catheter (Penumbra Inc., Alameda, CA, USA), or stent retrievers (Solitaire FR: Medtronic, Minneapolis, MN, USA; Trevo XP: Stryker Neurovascular, Fremont CA, USA; Revive: Codman, Johnson & Johnson, Miami, FL, USA) were collectively defined as mechanical thrombectomy. All endovascular procedures performed in each patient were counted. Postprocedural bleeding was defined as symptomatic intracranial hemorrhage when the National Institutes of Health Stroke Scale (NIHSS) score decreased by 4 or more. For statistical analyses, the χ 2 -test and t-test were performed using JMP 11.0 software (SAS Institute Inc., Cary, NC, USA). A of <0.05 was regarded as significant. In the group, the percentages of patients who underwent 24-hour Holter electrocardiogram (ECG), transthoracic echocardiography, transesophageal echocardiography, and ultrasonography of the lower extremity veins during hospitalization were studied, and significant findings related to the diagnoses of suspected underlying disorders were evaluated. Results The and groups consisted of 14 and 42 patients, respectively. The embolic source was undetected on admission in 20 patients. Six of these patients were diagnosed as, when transient atrial fibrillation was detected by 24-hour Holter ECG or continuous ECG monitoring during hospitalization. Table 2 shows the baseline characteristics of the and groups. In the group, the patients were younger (63.9 ± 22.3 vs ± 8.8 years, P <0.05), and the proportion of male patients was lower (21.4% vs. 64.3%, P <0.05), than in the group. No significant difference was noted in hypertension, dyslipidemia, diabetes, or smoking history, and the proportion of patients with atrial fibrillation were higher in the group (0% vs. 95.2%, P <0.05). The most frequent occluded vessel was the middle cerebral artery in both groups (42.9% vs. 64.3%), followed by the internal carotid artery (28.6% vs. 23.8%) and vertebral or basilar artery (21.4% vs. 9.5%), with no significant difference. The median NIHSS score on admission (17 vs. 18) or the median DWI-ASPECTS in patients with anterior circulation occlusion (8 vs. 7) did not differ significantly. The time from the onset to puncture was 8 hours or less in most patients of both groups (92.3% vs. 85.7%). The mean brain natriuretic peptide (BNP) level on admission was higher in the group, but the difference was not significant (117.2 vs pg/ml, P = 0.07). Table 3 shows the treatments of and patients receiving endovascular reperfusion therapy. There was no significant difference in the proportion of patients who underwent intravenous thrombolysis with recombinant 2

3 Embolic Stroke of Undetermined Source and Endovascular Therapy Table 2 Baseline characteristics of and patients receiving endovascular reperfusion therapy Baseline characteristics n = 14 n = 42 Age, year, mean ± SD 63.9 ± ± 8.8 <0.05 Sex (male), n (%) 3 (21.4) 27 (64.3) <0.05 Risk factors Hypertension, n (%) 8 (57.1) 30 (71.4) 0.32 Diabetes mellitus, n (%) 1 (7.1) 9 (21.4) 0.23 Hyperlipidemia, n (%) 4 (28.6) 13 (31.0) 0.87 Smoking, n (%) 4 (28.6) 15 (36.6) 0.59 Atrial fibrillation, n (%) 0 (0) 40 (95.2) <0.05 Occlusion site, n (%) 0.25 Common carotid artery 0 (0) 1 (2.4) Internal carotid artery 4 (28.6) 10 (23.8) Anterior cerebral artery 1 (7.1) 0 (0) Middle cerebral artery 6 (42.9) 27 (64.3) Vertebral or basilar artery 3 (21.4) 4 (9.5) Baseline NIHSS, median (1st 4th quartile) 17 (11 22) 18 (13 22) 0.44 DWI-ASPECTS, median (1st 4th quartile) n = 11 vs (7 9) 7 (5 8) 0.16 Onset to puncture time, n (%) 0.61 <8 hour 13 (92.3) 36 (85.7) 8 24 hour 0 (0) 2 (7.1) <24 hour 1 (7.7) 2 (7.1) Brain natriuretic peptide, pg/ml, mean ± SD ± ± : cardioembolic stroke; DWI-ASPECTS: diffusion weighted image-alberta Stroke Program Early CT score; : embolic stroke of undetermined source; NIHSS: National Institutes of Health Stroke Scale Table 3 Treatment of and patients receiving endovascular reperfusion therapy Treatment n = 14 n = 42 Intravenous rt-pa, n (%) 6 (42.9) 17 (40.5) 0.88 All treatment procedure or device Thrombectomy *, n (%) 12 (85.7) 35 (92.9) 0.42 Manual aspiration, n (%) 0 (0) 5 (11.9) 0.18 Percutaneous transluminal angioplasty, n (%) 1 (7.1) 2 (4.8) 0.73 Urokinase, n (%) 2 (14.3) 0 (0) <0.05 * Thrombectomy include Merci, Penumbra, and Stent retrievers. : cardioembolic stroke; : embolic stroke of undetermined source; rt-pa: recombinant tissue-type plasminogen activator Table 4 Outcomes of and patients receiving endovascular reperfusion therapy Outcomes n = 14 n = 42 TICI 2b, n (%) 11 (78.6) 26 (61.9) 0.25 TICI 2b (post-aprroval of stent retrievers), n (%), n = 5 vs (80.0) 17 (100) 0.05 Onset or LKN to recanalization time, min, mean ± SD, n = 11 vs ± ± Puncture to recanalization time, min, mean ± SD, n = 11 vs ± ± Discharge mrs 0 2, n (%) 10 (71.4) 18 (42.9) 0.06 Symptomatic intracerebral hemorrhage, n (%) 1 (7.1) 1 (2.4) 0.41 : cardioembolic stroke; : embolic stroke of undetermined source; LKN: last known normal; TICI: thrombolysis in cerebral infarction; mrs: modified Rankin Scale tissue plasminogen activator (rt-pa) (42.9% vs. 40.5%). Of the endovascular procedures, thrombectomy was performed most frequently in both groups (85.7% vs. 92.9%). Table 4 shows the outcomes in the and groups. There was no significant difference in the successful reperfusion (thrombolysis in cerebral infarction [TICI] grade 2b or 3) rate (78.6% vs. 61.9%). After the introduction of stent retrievers in Japan, there was also no significant difference in the successful reperfusion (TICI grade 2b or 3) rate (80.0% vs. 100%). The time from puncture to successful reperfusion was longer in the group than in the group (88.2 vs min), but no significant 3

4 Kurogi R, et al. Table 5 Characteristics of and patients achieved TICI 2b-3 reperfusion Outcomes n = 11 n = 26 Occlusion site, n (%) 0.45 Internal carotid artery 3 (27.3) 7 (26.9) Anterior cerebral artery 1 (9.0) 0 Middle cerebral artery 5 (45.5) 15 (57.7) Vertebral or basilar artery 2 (18.2) 4 (15.4) Number of pass, mean ± SD 2.2 ± ± Number of treatment procedure or device, mean ± SD 1.4 ± ± Phase 0.10 pre-aprroval of stent retrievers, n (%) 7 (63.6) 4 (36.4) post-aprroval of stent retrievers, n (%) 9 (34.6) 17 (65.4) : cardioembolic stroke; : embolic stroke of undetermined source; TICI: thrombolysis in cerebral infarction difference was observed in the time from the onset or the last known normal time to successful reperfusion (494.3 vs min). Favorable outcome (modified Rankin Scale [mrs] score of 0 2 at discharge) tended to be more frequent in the group (71.4% vs. 42.9%, P = 0.06). There was no significant difference in the rate of symptomatic intracerebral hemorrhage (7.1% vs. 2.4%). Table 5 shows the characteristics of the patients in the and groups achieved a successful reperfusion (TICI grade 2b or 3). The occluded vessel was most frequently the middle cerebral artery in both groups (45.5% vs. 57.7%), followed by the internal carotid artery (27.3% vs. 26.9%) and vertebral or basilar artery (18.2% vs. 15.4%), with no significant difference. There was no significant difference in the number of passes (2.2 vs. 2.2) or devices (1.4 vs. 1.5). The endovascular treatment in the group was performed more frequently after approval of stent retrievers in Japan (34.6% vs. 65.4%). Table 6 shows the characteristics of the diagnostic tool (24-hour Holter ECG, transthoracic echocardiography, transesophageal echocardiography, and lower limb venous ultrasound) and the findings in 14 patients. Both 24-hour Holter ECG and transthoracic echocardiography, which were included in the diagnostic criteria for, were performed in all 14 patients. Transesophageal echocardiography was performed in 78.6% (11/14), and lower limb venous ultrasound was performed in 71.4% (10/14). In the group that underwent 24-hour Holter ECG, high frequency of ventricular premature contractions were observed in two patients. In the group that underwent transthoracic echocardiography, one patient showed enlargement of the left atrium. In the group that underwent transesophageal echocardiography, a decreased left atrium appendage flow velocity and smoke-like echo, which were regarded as a low-risk embolic source in the TOAST classification system, were noted in one patient each, and patent foramen ovale was observed in three patients. In the group that underwent lower limb venous ultrasound, a thrombus was detected in a lower extremity vein in one of the three patients with patent foramen ovale. Discussion In this study, clinical characteristics, treatments, and outcomes in patients diagnosed with treated by endovascular reperfusion therapy were compared with those in patients with. In the group, no significant difference was observed in the characteristics on admission except age, sex, and presence of atrial fibrillation. Despite the difference of embolic source, the treatment and successful reperfusion rate were similar. The frequency of in all strokes varies among reports from 7% 42%. 3) In Japan, the multicenter collaborative study about ELVO patients also reported that others/unclassified corresponding to accounted for 9.1%. 7) The frequency of in the present study (16.1%) is almost similar to that of the previous reports. 7) Yoshimura et al., reported that the proportion of cardioembolism was 71.0%, and the mean age of the patients was 75.5 years, 7) which was similar to those in our group. Generally, the patients with is considered to be younger than those with other types of brain infarction, 3) same as our results. This is because atrial fibrillation is less prevalent in younger patients. 8) On the other hand, the frequency of male in the patients is lower in our series, although the frequency of male in the patients is considered higher than other stroke types generally. 3) In our study, 7 of 14 patients (50%) in the group showed no abnormality in 24-hour Holter ECG, transthoracic echocardiography, transesophageal echocardiography, or lower limb venous ultrasound 4

5 Embolic Stroke of Undetermined Source and Endovascular Therapy Table 6 Diagnostic tool and findings in 14 patients Remarks Lower limb venous ultrasound Transesophageal echocardiography Transthoracic echocardiography Age Sex 24 hour Holter ECG Patient no Female WNL WNL NP NP 2 80 Female VPC, beats/day WNL PFO Thrombus 3 72 Male WNL WNL WNL WNL 4 64 Female WNL WNL WNL WNL 5 13 Male WNL WNL WNL WNL 6 74 Female WNL WNL Decreased LAA flow velocity WNL 7 28 Female WNL WNL WNL NP 8 80 Female WNL WNL NP NP 9 79 Female WNL WNL NP Thrombus Detection of right-to-left shunts using TCD Female WNL WNL PFO WNL WNL WNL WNL Female Nine consecutive VPC; VPC, 563 beats/day Female WNL WNL PFO WNL Female WNL LAD, 49 mm Spontaneous echo contrast NP Detection of Paf after 1 month of discharge Male WNL WNL WNL WNL ECG: electrocardiography; : embolic stroke of undetermined source; LAA: left atrial appendage; LAD: left atrial dimension; NP: not performed; PFO: patent foramen ovale; TCD: transcranial doppler; VPC: premature ventricular contraction; WNL: within normal limit echography, or did not undergo these examinations. These patients may have affected the differences in age and sex proportion between and groups. Young females who were diagnosed with frequently have coagulation disorders, such as antiphospholipid antibody syndrome, 9) and they may not have been detected in this study. The etiologies underlying include primarily heart diseases not established as embolic sources, covert atrial fibrillation, cancer, arteriogenic emboli, and paradoxical embolism. 1) The Athens Stroke Registry revealed that are caused by transient atrial fibrillation in more than 40% of the patients. 10) In our group, transient atrial fibrillation was detected 1 month after discharge in a patient who showed left atrial enlargement and smoke-like echo (Patient 13). Recently, long-time ECG monitoring has been shown to be useful for the detection of transient atrial fibrillation. In unexplained stroke, the detection rate of atrial fibrillation is only about 6% by 24-hour Holter ECG, but this rate increases to 22% when monitoring is continued for 1 week. 11) In addition, atrial fibrillation was reported to be detected in 29% of patients during a follow-up period of 3.2 years. 10) Also, in Japan, the Reveal LINQ system; insertable cardiac monitoring system (Medtronic, Dublin, Ireland) was approved in March ) On the other hand, we note the fact that the group differs in age and sex compared with the groups and includes many patients with non-cardiogenic underlying diseases. Transesophageal echocardiography is reportedly useful for the diagnosis of. 13) In earlier reports concerning patients, patent foramen ovale was noted in 25% 14) and 28% 13) of the patients which is similar to our study. In one patient (Patient 2), a thrombus was detected by lower limb venous ultrasound in addition to patent foramen ovale, and the patient was diagnosed as paradoxical cerebral embolism. Anticoagulants have been commonly used for the secondary prevention of paradoxical cerebral embolism, but as closure of patent foramen ovale has been recently reported to be also effective. 15) Thus, transesophageal echocardiography is an important examination for considering treatment option against the secondary prevention of paradoxical cerebral embolism. However, we could not perform the examination in all patients despite its effectiveness for the search of the embolic source partly because of our hesitation to perform it in patients with severe impairment. There have also been reports of complications of transesophageal echocardiography, such as airway obstruction, which occurred in 1 5.5% of the patients. 16) Since the patients with ELVO sometimes takes a serious 5

6 Kurogi R, et al. course, 17) further evaluation is necessary on whether transesophageal echocardiography should be performed in all patients. We performed primarily thrombectomy in both groups, and the reperfusion rate was similar between the and groups. Comparison of thrombi by mechanical thrombectomy between and groups was reported that those were similar in the proportion of erythrocytes, leukocytes, fibrin, and platelets in both groups. 4) If the composition of thrombi is similar, the effectiveness of thrombectomy would also be similar. In this study, the reperfusion rate was comparable, and this may be related to the similarity of the composition of thrombi. However, the time to reperfusion tended to be longer in the group. Evaluation with standardization of therapeutic procedures and devices is necessary for more precise evaluation of therapeutic results. Despite the relatively longer time up to reperfusion, the percentage of patients with an mrs score of 0 2 at discharge tended to be higher in the group. This may be explained by the difference in age, that is, the mean age was 13 years lower in the group than in the group. In the meta-analysis of five randomized controlled trials that evaluated the efficacy of thrombectomy devices for ELVO of the anterior circulation by Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke trials (HERMES) collaborators, 17) the percentage of patients with an mrs score of 0 2 at 90 days after endovascular treatment was 51.9, 43.1, and 29.8% in those aged 60 69, 70 79, and years, respectively. These results suggest that age is an important determinant of the outcome in patients treated by endovascular reperfusion therapy for ELVO. In the Athens Stroke Registry, the percentage of patients with an mrs score of 0 2 at the last follow-up period was 63% in the group, 10) a figure comparable to 71.4% in the group of our study. Exact comparison of the outcomes between the Athens Stroke Registry and our study is impossible due to differences in patient characteristics. However, considering that the patients in this study had severe cerebral infarction accompanied by ELVO, it is conceivable that endovascular reperfusion therapy is an effective treatment for ELVO due to. A limitation of this study was the small sample size of patients, and further accumulation of cases is necessary. Conclusion In the patients who underwent endovascular treatment (EVT) for ELVO, the NIHSS score and DWI- ASPECTS on admission and the successful reperfusion rate were similar to those in the group, However, they were younger and had more favorable outcomes in the group. EVT is effective for ELVO due to, same as to. Disclosure Statement Masahiro Yasaka has received lecture fees from Nippon Beohringer Ingelheim Co., Ltd., Bayer, and Daiichi Sankyo, Inc. The other authors have no conflicts of interest to declare. References 1) Hart RG, Diener HC, Connolly SJ: Embolic strokes of undetermined source: support for a new clinical construct authors reply. Lancet Neurol 2014; 13: ) Arauz A, Morelos E, Colín J, et al: Comparison of functional outcome and stroke recurrence in patients with embolic stroke of undetermined source () vs. cardioembolic stroke patients. PLoS ONE 2016; 11: e ) Hart RG, Catanese L, Perera KS, et al: Embolic stroke of undetermined source: a systematic review and clinical update. Stroke 2017; 48: ) Boeckh-Behrens T, Kleine JF, Zimmer C, et al: Thrombus histology suggests cardioembolic cause in cryptogenic stroke. Stroke 2016; 47: ) Boeckh-Behrens T, Schubert M, Förschler A, et al: The impact of histological clot composition in embolic stroke. Clin Neuroradiol 2016; 26: ) Adams HP Jr, Bendixen BH, Kappelle LJ, et al: Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org in acute stroke treatment. Stroke 1993; 24: ) Yoshimura S, Sakai N, Okada Y, et al: Efficacy of endovascular treatment for acute cerebral large-vessel occlusion: analysis of nationwide prospective registry. J Stroke Cerebrovasc Dis 2014; 23: ) Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke 1991; 22: ) Stadler K, Mutzenbach JS, Kalss G, et al: Therapeutic challenges after successful thrombectomy in a patient with an antiphospholipid syndrome associated M1-occlusion: a case report. Interv Neuroradiol 2015; 21:

7 Embolic Stroke of Undetermined Source and Endovascular Therapy 10) Ntaios G, Papavasileiou V, Milionis H, et al: Embolic strokes of undetermined source in the athens stroke registry: an outcome analysis. Stroke 2015; 46: ) Higgins P, MacFarlane PW, Dawson J, et al: Noninvasive cardiac event monitoring to detect atrial fibrillation after ischemic stroke: a randomized, controlled trial. Stroke 2013; 44: ) Toyoda K, Okumura K, Hashimoto Y, et al: Identification of covert atrial fibrillation in cryptogenic ischemic stroke: current clinical practice in Japan. J Stroke Cerebrovasc Dis 2016; 25: ) Katsanos AH, Bhole R, Frogoudaki A, et al: The value of transesophageal echocardiography for embolic strokes of undetermined source. Neurology 2016; 87: ) Perera KS, Vanassche T, Bosch J, et al: Embolic strokes of undetermined source: prevalence and patient features in the global registry. Int J Stroke 2016; 11: ) Saver JL, Carroll JD, Thaler DE, et al: Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017; 377: ) Hilberath JN, Oakes DA, Shernan SK, et al: Safety of transesophageal echocardiography. J Am Soc Echocardiogr 2010; 23: ; quiz ) Goyal M, Menon BK, van Zwam WH, et al: Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387: