Emergent Recanalization with Stenting for Acute Stroke due to Athero-Thrombotic Occlusion of the Cervical Internal Carotid Artery : A Single Center Experience

Objective

The purpose of this study is to demonstrate the technical feasibility and clinical efficacy of emergent carotid angioplasty and stenting (CAS) for acute stroke due to athero-thrombotic occlusion of the cervical internal carotid artery (ICA).

Methods

Review of medical records identified 17 patients who underwent emergent CAS for treatment of athero-thrombotic occlusion of the cervical ICA with acute stroke between 2009 and 2013. Eleven patients (64.7%) presented with concomitant intracranial artery occlusion, which was treated primarily by mechanical thrombectomy after CAS.

Results

Successful revascularization of the cervical ICA with emergent CAS was achieved in all patients. After CAS, intracranial recanalization with Thrombolysis in Cerebral Infarction ≥2b flow was achieved in four of the 11 patients (36.4%). The overall recanalization rate (cervical ICA and intracranial artery) was 10 of 17 patients (58.8%). Symptomatic intracranial hemorrhage occurred in two patients (11.8%), resulting in death. Ten patients (58.8%) showed improvement (decrease in NIHSS score of ≥4 points) at seven days after recanalization. Nine patients (52.9%) showed a favorable outcome (mRS ≤2) at the last follow-up. A favorable outcome (mRS ≤2) was obtained in four of the six patients with isolated cervical ICA occlusion (4/6, 66.7%) and five of 11 patients with intracranial tandem occlusion (5/11, 45.5%).

Conclusion

Emergent CAS for acute stroke due to athero-thrombotic occusion of the cervical ICA showed a good technical feasibility and favorable clinical outcome.     

The Effectiveness of Additional Treatment Modalities after the Failure of Recanalization by Thrombectomy Alone in Acute Vertebrobasilar Arterial Occlusion

Objective

Acute vertebrobasilar artery occlusion (AVBAO) is a devastating disease with a high mortality rate. One of the most important factors affecting favorable clinical outcome is early recanalization. Mechanical thrombectomy is an emerging treatment strategy for achieving a high recanalization rates. However, thrombectomy alone can be insufficient to complete recanalization, especially for acute stroke involving large artery atheromatous disease. The purpose of this study is to investigate the safety and efficacy of mechanical thrombectomy in AVBAO.

Methods

Fourteen consecutive patients with AVBAO were treated with mechanical thrombectomy. Additional multimodal treatments were intra-arterial (IA) thrombolysis, balloon angioplasty, or permanent stent placement. Recanalization by thrombectomy alone and multimodal treatments were assessed by the Thrombolysis in Cerebral Infarction (TICI) score. Clinical outcome was determined using the National Institutes of Health Stroke Scale (NIHSS) at 7 days and the modified Rankin Scale (mRS) at 3 months.

Results

Thrombectomy alone and multimodal treatments were performed in 10 patients (71.4%) and 4 patients (28.6%), respectively. Successful recanalization (TICI 2b-3) was achieved in 11 (78.6%). Among these 11 patients, 3 (27.3%) underwent multimodal treatment due to underlying atherosclerotic stenosis. Ten (71.4%) of the 14 showed NIHSS score improvement of >10. Overall mortality was 3 (21.4%) of 14.

Conclusion

We suggest that mechanical thrombectomy is safe and effective for improving recanalization rates in AVBAO, with low complication rates. Also, in carefully selected patients after the failure of recanalization by thrombectomy alone, additional multimodal treatment such as IA thrombolysis, balloons, or stents can be needed to achieve successful recanalization.     

Multimodal Therapy for Patients with Acute Ischemic Stroke : Outcomes and Related Prognostic Factors

Objective

The objectives of this study were to analyze the recanalization rates and outcomes of multimodal therapy that consisted of sequential intravenous (IV)/intra-arterial (IA) thrombolysis, mechanical thrombolysis including mechanical clot disruption using microcatheters and microwires, balloon angioplasty, and stenting for acute ischemic stroke, and to evaluate the prognostic factors related to the outcome.

Methods

Fifty patients who were admitted to the hospital within 8 hours from ischemic symptom onset were retrospectively analyzed. Initial IV thrombolysis and subsequent cerebral angiography were performed in all patients. If successful recanalization was not achieved by IV thrombolysis, additional IA thrombolysis with mechanical thrombolysis, including balloon angioplasty and stenting, were performed. The outcomes were assessed by the National Institute of Health Stroke Scale (NIHSS) change and modified Rankin scale (mRS) and prognostic factors were analyzed.

Results

Successful recanalization was achieved in 42 (84%) of 50 patients, which consisted of 8 patients after IV thrombolysis, 19 patients after IA thrombolysis with mechanical clot disruption, and 15 patients after balloon angioplasty or stenting. Symptomatic hemorrhage occurred in 4 (8%) patients. Good outcomes were achieved in 76% and 70% of patients upon discharge, and 93% and 84% of patients after 3 months according to the NIHSS change and mRS. The initial clinical status, recanalization achievement, and presence of symptomatic hemorrhage were statistically related to the outcomes.

Conclusion

Multimodal therapy may be an effective and safe treatment modality for acute ischemic stroke. Balloon angioplasty and stenting is effective for acute thrombolysis, and produce higher recanalization rates with better outcomes.     

Comparative Analysis of Endovascular Stroke Therapy Using Urokinase,Penumbra System and Retrievable (Solitare) Stent

Background

Higher reperfusion rates have been established with endovascular treatment for acute ischemic stroke patients. There are limited data on the comparative performance of mechanical thrombectomy devices. This study aimed to analyse the efficacy and safety of the stent retriever device (Solitaire stent) by comparing procedure time, angiographic outcome, complication rate and long term clinical outcome with previous chemical thrombolysis and mechanical thrombectomy using penumbra system.

Methods

A retrospective single-center analysis was undertaken of all consecutive patients who underwent chemical thrombolysis and mechanical thrombectomy using Penumbra or Solitaire stent retriever from March 2009 to March 2014. Baseline characteristics, rate of successful recanalization (modified Thrombolysis in Cerebral Infarction score 2b-3), symptomatic intracerebral hemorrhage, procedure time, mortality and independent functional outcomes (mRS ≤2) at 3 month were compared across the three method.

Results

Our cohort included 164 patients, mechanical thrombectomy using stent retriever device had a significant impact on recanalization rate and functional independence at 3 months. In unadjusted analysis mechanical thrombectomy using Solitaire stent retriever showed higher recanalization rate than Penumbra system and chemical thrombolysis (75% vs. 64.2% vs. 49.4%, p=0.03) and higher rate of functional independence at 3 month (53.1% vs. 37.7% vs. 35.4%, p=0.213). In view of the interrelationships between all predictors of variables associated with a good clinical outcome, when the chemical thrombolysis was used as a reference, in multiple logistic regression analysis, the use of Solitaire stent retriever showed higher odds of independent functional outcome [odds ratio (OR) 2.62, 95% confidence interval (CI) 0.96-7.17; p=0.061] in comparison with penumbra system (OR 1.57, 95% CI 0.63-3.90; p=0.331).

Conclusion

Our initial data suggest that mechanical thrombectomy using stent retriever is superior to the mechanical thrombectomy using penumbra system and conventional chemical thrombolysis in achieving higher rates of reperfusion and better outcomes. Randomized clinical trials are needed to establish the actual benefit to specific patient populations.     

Critical Use of Balloon Angioplasty after Recanalization Failure with Retrievable Stent in Acute Cerebral Artery Occlusion

Objective

Sudden major cerebral artery occlusion often resists recanalization with currently available techniques or can results in massive symptomatic intracranial hemorrhage (sICH) after thrombolytic therapy. The purpose of this study was to examine mechanical recanalization with a retrievable self-expanding stent and balloon in acute intracranial artery occlusions.

Methods

Twenty-eight consecutive patients with acute intracranial artery occlusions were treated with a Solitaire retrievable stent. Balloon angioplasty was added if successful recanalization was not achieved after stent retrieval. The angiographic outcome was assessed by Thrombolysis in Cerebral Infarction (TICI) and the clinical outcomes were assessed by the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS).

Results

At baseline, mean age was 69.4 years and mean initial NIHSS score was 12.5. A recanalization to TICI 2 or 3 was achieved in 24 patients (85%) after stent retrieval. Successful recanalization was achieved after additional balloon angioplasty in 4 patients. At 90-day follow-up, 24 patients (85%) had a NIHSS improvement of ≥4 and 17 patients (60%) had a good outcome (mRS ≤2). Although there was sICH, there was one death associated with the procedure.

Conclusion

Mechanical thromboembolectomy with a retrievable stent followed by additional balloon angioplasty is a safe and effective first-line therapy for acute intracranial artery occlusions especially in case of unsuccessful recanalization after stent thrombectomy.     

Regionwide Retrospective Survey of Acute Mechanical Thrombectomy in Tama,Suburban Tokyo: A Preliminary Report

Background and Purpose

To improve results of acute thrombectomy, the time from stroke onset to efficient recanalization must be minimized. Studies have confirmed the importance of rapid treatment, workflow, and efficient team-based care for acute thrombectomy in large vessel occlusion. This study examined the challenges facing mechanical thrombectomy in the Tama area (population, 4.3 million), a densely populated urban area of Tokyo, Japan, and analyzed retrospective data from the Tama-REgistry of Acute endovascular Thrombectomy.

The Comparison of Outcome between Thromboaspiration and Aggressive Mechanical Clot Disruption in Treating Hyperacute Stroke Patients

Objective

Stroke is the third leading cause of death in the Republic of Korea. Time is the most important factor in hyperacute stroke. Yet, there had been no protocol for mechanical thrombolysis. We have treated patients with hyperacute stroke by mechanical thrombolysis for 3 years. In current study, we analyzed the outcome of mechanical thrombolysis.

Methods

From March 2008 to February 2011, 36 patients were treated with mechanical thrombolysis. Initially we treated the patients by aggressive mechanical clot disruption (AMCD) who were admitted within 6 hours after the symptom onset. If revascularization was not achieved, balloon angioplasty was performed, followed by stenting or temporary endovascular bypass was performed. The result in 15 cases was not so successful. Since then, we started using the thromboaspiration method as the first line treatment of the mechanical thrombolysis.

Results

After using the thromboaspiration, we had better results in recanalization rate, modified Rankin Score (mRS) and reperfusion injury compared to AMCD. The recanalization rate was 80.85%, mRS is 2.85, and there was only 0.09% hemorrhagic formation.

Conclusion

Even though thromboaspiration is not statistically significant due to the limited numbers of patients enrolled in this study, we think it is a good way in mechanical thronbolysis for hyperacute stroke.     

Angiographic Blush after Mechanical Thrombectomy is Associated with Hemorrhagic Transformation of Ischemic Stroke

Background and Purpose

Risk factors for hemorrhagic transformation of ischemic stroke after mechanical thrombectomy (MT) are not well established. We conducted a study to determine if prominent angiographic cerebral vascularity following recanalization with thrombectomy (angiographic blush) is associated with hemorrhagic transformation.

Emergency Microsurgical Embolectomy for the Treatment of Acute Intracranial Artery Occlusion: Report of Two Cases

Background

The main treatment for acute arterial ischemic stroke is intravenous or intra-arterial thrombolysis within a particular time window. Endovascular mechanical embolectomy is another treatment option in the case of major artery occlusion. Endovascular mechanical embolectomy is a useful technique for restoring blood flow in patients with large-vessel occlusion, and especially in those who are contraindicated for thrombolytics or in whom thrombolytic therapy has failed.

Case Report

We report herein two cases of emergency microsurgical embolectomy for the treatment of acute middle cerebral artery and internal carotid artery occlusion as an alternative treatment for major artery occlusion.

Conclusions

Emergency microsurgical mechanical embolectomy may be an alternative treatment option for restoring blood flow in selected patients with large-vessel acute ischemic stroke.     

Multicenter initial experience with the EmboTrap device in acute anterior ischemic stroke

Background and purpose

Mechanical thrombectomy predominantly using stent retrievers effectively restores cerebral blood flow and improves functional outcomes in patients with acute ischemic stroke. We sought to determine the safety and efficacy of mechanical thrombectomy using the EmboTrap device.

Unresolved Issues in Thrombectomy

Purpose of Review

Trials demonstrating marked benefit of mechanical thrombectomy (MT) for acute stroke caused by large vessel occlusion (LVO) in the anterior circulation have been the most significant advance in acute ischemic stroke in the past 20 years. However, despite this marked advance, there are still many hurdles to improving access to thrombectomy worldwide. Additionally, despite these advances, a substantial portion of patients with LVO still are left disabled.

Recent Findings

The major randomized trials focused on patients within 6 h from symptom onset, with occlusion of the ICA or proximal MCA, small amount of permanently damaged brain, and a moderate to large clinical deficit. We will explore the role of thrombectomy outside of these areas, but also explore larger issues as they pertain to re-organization of stroke systems of care to improve access to this remarkable therapy.

Summary

Now that we have proven, without a shadow of doubt, that rapid revascularization with mechanical thrombectomy improves outcomes in LVO stroke, we must reorganize our systems of care to improve access and assess the role for MT outside of the patients who meet trial criteria.

     

Various Techniques of Stent-Assisted Coil Embolization of Wide-Necked or Fusiform Middle Cerebral Artery Aneurysms : Initial and Mid-Term Results

Objective

To evaluate the feasibility and clinical and angiographic outcomes of stent-assisted embolization for complex middle cerebral artery (MCA) aneurysms.

Methods

The records of 23 consecutive patients with 24 MCA aneurysms, who underwent stent-assisted embolization of the aneurysm, were retrospectively evaluated.

Results

Fifteen aneurysms were treated with one stent and 8 were treated using more than two stents (5 a stent-within-a-stent, 1 triple stents, and two Y-stent). Angiographically, complete or near complete occlusion was achieved in 15 aneurysms (65.2%), residual neck in five (21.7%), and residual aneurysm in three (13.1%). Five aneurysms demonstrated thrombosis within the stent during the procedure and hospitalization, and were resolved by intraarterial and intravenous Tirofiban injection. Symptomatic thromboembolic complications were developed in five patients and permanent deficits demonstrated in two patients with modified Rankin Scale 1 and 2, respectively. Treatment-related permanent morbidity and mortality rates were 8.3% and 0% with relatively high complication rate. Angiographic follow-up was available in 17 aneurysms at 6-31 months (mean, 13.2 months) and showed stable or improved in 15 (88.2%) and major and minor recurrence in one, respectively.

Conclusion

Complex MCA aneurysms could be treated by stent-assisted coiling and showed lower recanalization rate during mid-term follow-up by effective flow diversion due to various stent-assisted techniques. Our results warrant further study with a longer follow-up period in a larger sample.     

Outcomes of Endovascular Mechanical Thrombectomy and Intravenous Tissue Plasminogen Activator for the Treatment of Vertebrobasilar Stroke

Background and Purpose

Aggressive treatment of posterior-circulation occlusions is important due to the high rates of morbidity and mortality associated with these infarctions. A large administrative database was evaluated to determine the outcomes of mechanical thrombectomy and intravenous tissue plasminogen activator (IV-tPA) for the treatment of posterior-circulation (vertebrobasilar) strokes. Outcomes were compared across age groups.

Methods

The United States Nationwide Inpatient Sample was used to evaluate the outcomes of patients treated for posterior-circulation acute ischemic stroke between 2006 and 2010. Patients who underwent endovascular mechanical thrombectomy and IV-tPA were selected. Primary outcomes were discharge status and mortality; secondary outcomes were length of stay, rate of intracranial hemorrhage, tracheostomy, and percutaneous endoscopic gastrostomy/jejunostomy tube placement. Outcomes were grouped according to age (i.e., <50, 50-64, and ≥65 years). Chi-squared test and Student''s t-test were used for comparisons of categorical and continuous variables, respectively.

Results

During 2006-2010 there were 36,675 patients who had discharge International Classification of Diseases (9th edition) codes indicating posterior-circulation strokes. Of these, 631 (1.7%) underwent mechanical thrombectomy and 1554 (4.2%) underwent IV-tPA. The in-hospital mortality rate for mechanical thrombectomy patients was significantly lower for those aged <50 years than for those aged 50-64 years (30.4% versus 47.4%, p<0.01) and those aged ≥65 years (30.4% versus 43.0%, p≤0.01). Age had no effect on the in-hospital mortality for IV-tPA patients, with an incidence of 22.7% for patients aged <50 years, compared to 25.4% for patients aged 50-64 years (p=0.46) and 23.0% for patients aged ≥65 years (p=0.92).

Conclusions

Patients requiring IV-tPA and/or mechanical thrombectomy for the treatment of posterior-circulation strokes suffer from high mortality rates. Increased age is associated with significantly higher mortality rates among posterior-circulation stroke patients who require mechanical thrombectomy.     

Urgent Recanalization with Stenting for Severe Intracranial Atherosclerosis after Transient Ischemic Attack or Minor Stroke

Objective

Stenting of symptomatic intracranial stenosis has recently become an alternative treatment modality. However, urgent intracranial stenting in patients with intracranial stenosis following a transient ischemic attack (TIA) or minor stroke is open to dispute. We sought to assess the feasibility, safety, and effectiveness of urgent intracranial stenting for severe stenosis (>70%) in TIA or minor stroke patients.

Methods

Between June 2009 and October 2010, stent-assisted angioplasty by using a balloon-expandable coronary stent for intracranial severe stenosis (>70%) was performed in 7 patients after TIA and 5 patients after minor stroke (14 stenotic lesions). Technical success rates, complications, angiographic findings, and clinical outcomes were retrospectively analyzed.

Results

Stenting was successful in all 12 patients. The mean time from symptom onset to stenting was 2.1 days (1-8 days). Post-procedural angiography showed restoration to a normal luminal diameter in all patients. In-stent thrombosis occurred in one patient (n=1, 8.3%), and was lysed with abciximab. No device-related complications, such as perforations or dissections at the target arteries or intracranial hemorrhaging, occurred in any patient. The mortality rate was 0%. No patient had an ischemic event over the mean follow-up period of 12.5 months (range, 7-21 months), and follow-up angiography (n=7) revealed no significant in-stent restenosis (>50%).

Conclusion

Urgent recanalization with stenting is feasible, safe, and effective in patients with TIA or acute minor stroke with intracranial stenosis of ≥70%.     

Mechanical thrombectomy for pediatric acute stroke and ventricular assist device

Background

Certain pediatric populations have increased risk of ischemic strokes, including those with cardiac disease and those dependent on mechanical circulatory devices such as ventricular assist devices. Due to their need for chronic anticoagulation, patients with mechanical circulatory devices are not candidates for systemic thrombolysis and thus treatment of acute ischemic stroke is limited.

Multimodal MRI for Ischemic Stroke: From Acute Therapy to Preventive Strategies

Background and Purpose

Conventional therapies for ischemic stroke include thrombolytic therapy, prevention of inappropriate coagulation and thrombosis, and surgery to repair vascular abnormalities. Over 10 years have passed since the US Food and Drug Administration approved intravenous tissue plasminogen activator for use in acute stroke patients, but most major clinical trials have failed during the last 2 decades, including large clinical trials for secondary prevention and neuroprotection. These results suggest the presence of heterogeneity among stroke patients. Neuroimaging techniques now allow changes to be observed in patients from the acute to the recovery phase. The role of MRI in stroke evaluation and treatment is discussed herein.

Main Contents

Three MRI strategies are discussed with relevant examples. First, the following MRI strategies for acute ischemic stroke are presented: diffusion-perfusion mismatch, deoxygenation (oxygen extraction and cerebral metabolic rate of oxygen), and blood-brain barrier permeability derangement in selected patients for recanalization therapy. Second, multimodal MRI for identifying stroke mechanisms and the specific causes of stroke (i.e., patent foramen ovale, infective endocarditis, and nonbacterial thrombotic endocarditis) are presented, followed by MRI strategies for prevention of recurrent stroke: plaque images and flow dynamics for carotid intervention.

Expectations

The studies reviewed herein suggest that using MRI to improve the understanding of individual pathophysiologies will further promote the development of rational stroke therapies tailored to the specifics of each case.     

Gender Differences in the Functional Recovery after Acute Stroke

Background and Purpose

PurposezzInterest in gender differences in the effects of acute stroke is growing worldwide. However, gender differences in functional recovery after acute stroke in the Korean population have yet to be evaluated. The aim of this investigation was to compare long-term functional outcomes between male and female after acute stroke.

Methods

Patients with acute stroke were enrolled prospectively between January 2005 and January 2009. Baseline characteristics, risk factors, stroke subtypes, time delay from onset to arrival at a hospital, active treatment, and stroke severity were compared between male and female. Differences in mortality and disability at discharge, and at 3 months and 1 year after stroke onset were also investigated. Functional disabilities were categorized into two groups: good outcome (score on modified Rankin scale ≤2) and poor outcome (score on modified Rankin scale >2).

Results

Among 1,055 patients with acute stroke, 575 were male (aged 64.83±11.98 years, mean±SD) and 480 were female (aged 70.09±13.02 years). There were no gender differences in mortality at 3 months and 1 year after stroke. The frequency of poor outcomes was higher in female patients than in male patients at discharge (39.8% versus 30.9%, respectively; p=0.003), the 3 months follow-up (32.3% versus 20.8%, respectively; p<0.001), and the 1 year follow-up (31.1% versus 18.7%, respectively; p=0.001). After adjusting for multiple confounding factors including age and stroke severity, the female gender persisted as a predictor of poor functional outcome at 3 months and 1 year after stroke.

Conclusions

Female patients have greater difficulty than male patients in recovering from a disabled state after acute stroke. Future studies should investigate the causes of this gender difference.     

Validation of iScore and PLAN Score for Death in Thrombectomy in Acute Stroke Due to Anterior Circulation Large Artery Occlusion

Background

To validate iScore and PLAN score in acute anterior circulation large vessel occlusion stroke patients undergoing thrombectomy.

Process Improvement to Enhance Existing Stroke Team Activity Toward More Timely Thrombolytic Treatment

Background and Purpose

Process improvement (PI) is an approach for enhancing the existing quality improvement process by making changes while keeping the existing process. We have shown that implementation of a stroke code program using a computerized physician order entry system is effective in reducing the in-hospital time delay to thrombolysis in acute stroke patients. We investigated whether implementation of this PI could further reduce the time delays by continuous improvement of the existing process.

Methods

After determining a key indicator [time interval from emergency department (ED) arrival to intravenous (IV) thrombolysis] and conducting data analysis, the target time from ED arrival to IV thrombolysis in acute stroke patients was set at 40 min. The key indicator was monitored continuously at a weekly stroke conference. The possible reasons for the delay were determined in cases for which IV thrombolysis was not administered within the target time and, where possible, the problems were corrected. The time intervals from ED arrival to the various evaluation steps and treatment before and after implementation of the PI were compared.

Results

The median time interval from ED arrival to IV thrombolysis in acute stroke patients was significantly reduced after implementation of the PI (from 63.5 to 45 min, p=0.001). The variation in the time interval was also reduced. A reduction in the evaluation time intervals was achieved after the PI [from 23 to 17 min for computed tomography scanning (p=0.003) and from 35 to 29 min for complete blood counts (p=0.006)].

Conclusions

PI is effective for continuous improvement of the existing process by reducing the time delays between ED arrival and IV thrombolysis in acute stroke patients.     

Non-cardioembolic Mechanisms in Cryptogenic Stroke: Clinical and Diffusion-weighted Imaging Features

Background

The role of several cardiogenic risk factors, including patent foramen ovale, in patients with cryptogenic stroke has been extensively studied. However, little attention has been paid to the role of non-cardioembolic causes of cryptogenic stroke. We therefore sought to identify the characteristics of cryptogenic stroke.

Methods

We studied 832 patients with acute infarction in the middle cerebral arterial territory. We divided the patients into four subtypes: 402 with large artery atherosclerosis (LAA), 133 with cardioembolism, 182 with small arterial occlusion (SAO), and 115 with cryptogenic stroke. We compared risk factors and lesion patterns observed by diffusion-weighted imaging (DWI) between patients with cryptogenic stroke and those with stroke of other subtypes.

Results

Both risk factors and DWI lesion patterns differed between the cryptogenic and cardioembolic groups (P<0.05). Risk factors for cryptogenic stroke were similar to those for the LAA and SAO groups. Similarly, DWI lesion patterns for cryptogenic stroke were similar to LAA patients. Large cortical infarcts on DWI were more common in the cardioembolic group than in the LAA or cryptogenic groups (P<0.001). In contrast, deep, non-lacunar (OR 5.02; 95% CI 2.68~9.40; P<0.001) and superficial perforator infarcts (OR 2.23; 95% CI 1.08~4.59; P=0.029) were independently associated with the cryptogenic group.

Conclusions

Our results indicate that non-cardioembolic causes, such as macro- and microangiopathy, are important mechanisms in the pathogenesis of cryptogenic stroke.