Jin Soo Lee

Autologous mesenchymal stem cell transplantation in stroke patients.

Mesenchymal stem cell (MSC) transplantation improves recovery from ischemic stroke in animals. We examined the feasibility, efficacy, and safety of cell therapy using culture‐expanded autologous MSCs in patients with ischemic stroke. We prospectively and randomly allocated 30 patients with cerebral infarcts within the middle cerebral arterial territory and with severe neurological deficits into one of two treatment groups: the MSC group (n = 5) received intravenous infusion of 1 × 108 autologous MSCs, whereas the control group (n = 25) did not receive MSCs. Changes in neurological deficits and improvements in function were compared between the groups for 1 year after symptom onset. Neuroimaging was performed serially in five patients from each group. Outcomes improved in MSC‐treated patients compared with the control patients: the Barthel index (p = 0.011, 0.017, and 0.115 at 3, 6, and 12 months, respectively) and modified Rankin score (p = 0.076, 0.171, and 0.286 at 3, 6, and 12 months, respectively) of the MSC group improved consistently during the follow‐up period. Serial evaluations showed no adverse cell‐related, serological, or imaging‐defined effects. In patients with severe cerebral infarcts, the intravenous infusion of autologous MSCs appears to be a feasible and safe therapy that may improve functional recovery. Ann Neurol 2005;57:874–882

A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke.

We previously evaluated the short‐term follow‐up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long‐term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open‐label, observer‐blinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long‐term side effects, and new‐onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow‐up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log‐rank; p = .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow‐up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0–3 increased in the MSC group (p = .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell‐derived factor‐1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long‐term follow‐up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients. Stem Cells 2010;28:1099–1106

Stroke Statistics in Korea: Part I. Epidemiology and Risk Factors: A Report from the Korean Stroke Society and Clinical Research Center for Stroke

The aim of the Part I of Stroke Statistics in Korea is to summarize nationally representative data of the epidemiology and risk factors of stroke in a single document. Every year, approximately 105,000 people experience a new or recurrent stroke and more than 26,000 die of stroke, which indicates that every 5 minutes stroke attacks someone and every 20 minutes stroke kills someone in Korea. Stroke accounts for roughly 1 of every 10 deaths. The estimated stroke prevalence is about 795,000 in people aged ≥30 years. The nationwide total cost for stroke care was 3,737 billion Korean won (US

Frequency and mechanisms of stroke recurrence after cryptogenic stroke

3.3 billion) in 2005. Fortunately, the annual stroke mortality rate decreased substantially by 28.3% during the first decade of the 21th century (53.2/100,000 in 2010). Among OECD countries, Korea had the lowest in-hospital 30-day case-fatality rate for ischemic stroke and ranked third lowest for hemorrhagic stroke in 2009. The proportion of ischemic stroke has steadily increased and accounted for 76% of all strokes in 2009. According to hospital registry studies, the 90-day mortality rate was 3-7% for ischemic stroke and 17% for intracerebral hemorrhage. For risk factors, among Korean adults ≥30 years of age, one in 3-4 has hypertension, one in 10 diabetes, and one in 7 hypercholesterolemia. One in 3 Korean adults ≥19 years of age is obese. Over the last 10 years, the prevalence of hypertension slightly decreased, but the prevalence of diabetes, hypercholesterolemia, and obesity increased. Smoking prevalence in men has decreased, but is still as high as 48%. This report could be a valuable resource for establishing health care policy and guiding future research directions.

Chronic cerebral hypoperfusion in a mouse model of Alzheimer's disease: an additional contributing factor of cognitive impairment.

The purpose of this study was to better understand the frequency and mechanisms of stroke recurrence after the stroke with no determined cause (NC). We prospectively studied consecutive patients with acute cerebral infarcts. We divided the patients into five groups (large artery disease [LAD], cardioembolism [CE], small artery disease [SAD], two or more causes [TMC], and NC) and registered recurrent strokes and prognosis for 1 year. Those in the NC group were compared with other subtypes. A total of 204 patients were included; 56 LAD, 22 CE, 62 SAD, 27 TMC, and 37 NC. During follow‐up, there were 7 deaths and 31 first recurrent strokes. Patients of the NC group showed a significantly higher rate (30%) of recurrent stroke than those of other subtypes (LAD 16%; CE 14%; SAD 2%), and it was associated with the existence of mild stenosis (≤50%) on relevant artery or the stenosis of greater than 50% on nonrelevant artery. Occlusive lesions other than significant stenosis of relevant artery may play an important role in the development of stroke recurrence in patients of the NC group. Therefore, from the therapeutic and prognostic point of view, the detection of such occlusive lesions in patients with cryptogenic stroke may be needed.Ann Neurol 2003

Stroke Statistics in Korea: Part II Stroke Awareness and Acute Stroke Care, A Report from the Korean Stroke Society and Clinical Research Center For Stroke.

The purpose of the present study was to evaluate whether chronic cerebral hypoperfusion would affect cognitive status in an Alzheimer mouse model. Behavioral tests and histological evaluations were performed using female Tg2576 mice eight weeks after right common carotid artery occlusion (rCCAO), which is known to induce a type of vascular dementia without neuronal necrosis in nontransgenic mice. Positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) was utilized to evaluate metabolic status in the rCCAO-operated brain of nontransgenic mice. Escape latency from the Morris water maze test was not significantly different between rCCAO- and sham-operated mice. However, the learning curve was impaired in rCCAO-operated transgenic mice while it was preserved in sham-operated transgenic or rCCAO-operated nontransgenic mice. Histological examination revealed no evidence of cell death in the rCCAO-operated brains, and the extent of amyloid deposition was not different in rCCAO- and sham-operated mice. The brain of rCCAO-operated mice showed metabolic deficits in the ipsilateral parietal cortex through FDG-PET. In conclusion, further cognitive decline which is more comparable to typical Alzheimers disease was induced by chronic cerebral hypoperfusion in an Alzheimer mouse model. This aggravation might be associated with hypometabolism via chronic cerebral hypoperfusion.

Circulating beta amyloid protein is elevated in patients with acute ischemic stroke

The aim of the current Part II of Stroke Statistics in Korea is to summarize nationally representative data on public awareness, pre-hospital delay, thrombolysis, and quality of acute stroke care in a single document. The publics knowledge of stroke definition, risk factors, warning signs, and act on stroke generally remains low. According to studies using open-ended questions, the correct definition of stroke was recognized in less than 50%, hypertension as a stroke risk factor in less than 50%, and other well-defined risk factors in less than 20%. Among stroke warning signs, sudden paresis or numbness was best appreciated, with recognition rates ranging in 36.9-73.7%, but other warning signs including speech disturbance were underappreciated. In addition, less than one third of subjects in a representative population survey were aware of thrombolysis and had knowledge of the appropriate act on stroke, calling emergency medical services (EMS). Despite EMS being an essential element in the stroke chain of survival and outcome improvement, EMS protocols for field stroke diagnosis and prehospital notification for potential stroke patients are not well established. According to the Assessment for Quality of Acute Stroke Care, the median onset-to-door time for patients arriving at the emergency room was 4 hours (mean, 17.3 hours) in 2010, which was not reduced compared to 2005. In contrast, the median door-to-needle time for intravenous tissue plasminogen activator (IV-TPA) treatment was 55.5 minutes (mean, 79.5 minutes) in 2010, shorter than the median time of 60.0 minutes (mean, 102.8 minutes) in 2008. Of patients with acute ischemic stroke, 7.9% were treated with IV-TPA in 2010, an increase from the 4.6% in 2005. Particularly, IV-TPA use for eligible patients substantially increased, from 21.7% in 2005 to 74.0% in 2010. The proportion of hospitals equipped with a stroke unit has increased from 1.1% in 2005 to 19.4% in 2010. Performance, as measured by quality indicators, has steadily improved since 2005, and the performance rates for most indicators were greater than 90% in 2010 except for early rehabilitation consideration (89.4%) and IV-TPA use for eligible patients (74.0%). In summary, the current report indicates a substantial improvement in in-hospital acute stroke care, but also emphasizes the need for enhancing public awareness and integrating the prehospital EMS system into acute stroke management. This report would be a valuable resource for understanding the current status and implementing initiatives to further improve public awareness of stroke and acute stroke care in Korea.

Standard vs Modified Antiplatelet Preparation for Preventing Thromboembolic Events in Patients With High On-Treatment Platelet Reactivity Undergoing Coil Embolization for an Unruptured Intracranial Aneurysm: A Randomized Clinical Trial

Summary.Recent clinical and experimental studies suggest that ischemic strokes may play an important role in the pathogenesis of Alzheimer’s disease (AD). Beta amyloid (Aβ), a major component of senile plaque in AD, is known to be derived from ischemic brain or activated platelets. We prospectively enrolled 62 patients with acute ischemic stroke and 27 age-matched controls. The serum Aβ and P-selectin levels were determined using the Sandwich-ELISA. We divided ischemic strokes into subgroups according to the clinical syndrome, pathogenesis, and infarct size, and compared the Aβ level between each subgroup. The Aβ1–40 level was markedly elevated in ischemic stroke patients, as compared to controls (140.2 ± 54.0 vs 88.44 ± 34.96 pg/ml, p<0.001). Cardioembolic and larger artery atherosclerotic infarcts had higher Aβ1–40 level than small vessel disease (p = 0.001). Both infarct size and the initial NIHSS score had significantly positive correlations with the serum level of Aβ1–40 (r = 0.539, p<0.001 and r = 0.425, p = 0.001, respectively). However, the P-selectin level was not significantly correlated with serum Aβ1–40. Our data suggest that elevated circulating Aβ1–40 in ischemic stroke patients may be derived from brain as a consequence of ischemic insults.

Primary Stent Retrieval for Acute Intracranial Large Artery Occlusion Due to Atherosclerotic Disease

IMPORTANCE Thromboembolism is the most common complication in coiling for an unruptured aneurysm and is frequent in patients with high on-treatment platelet reactivity (HTPR) who are prescribed a standard antiplatelet preparation for its prevention. OBJECTIVE To evaluate the effect of a modified antiplatelet preparation compared with a standard preparation in patients with HTPR undergoing coiling. DESIGN, SETTING, AND PARTICIPANTS A prospective randomized open-label active-control trial with blinded outcome assessment at the Seoul National University Bundang Hospital from May 27, 2013, to April 7, 2014. Patients with HTPR were randomly assigned (1 to 1) to the standard or modified preparation group. Patients without HTPR were assigned to the non-HTPR group. A total of 228 patients undergoing coiling for unruptured aneurysms were enrolled and allocated to the study, 126 in the HTPR group (63 to the standard preparation group and 63 to the modified preparation group) and 102 to the non-HTPR group. Intent-to-treat analysis was performed. INTERVENTIONS The modified preparation (HTPR to aspirin, 300 mg of aspirin and 75 mg of clopidogrel bisulfate; and HTPR to clopidogrel, 200 mg of cilostazol added to the standard regimen) was performed before coiling in the modified preparation group. Standard preparation (100 mg of aspirin and 75 mg of clopidogrel) was maintained in the standard preparation and non-HTPR groups. MAIN OUTCOMES AND MEASURES The primary outcome was a thromboembolic event defined as thromboembolism during coiling and a transient ischemic attack or ischemic stroke within 7 days after coiling. The principal secondary outcome was a bleeding complication according to Thrombolysis in Myocardial Infarction bleeding criteria within 30 days after coil embolization. RESULTS The thromboembolic event rate was low in the modified preparation group (1 of 63 [1.6%]) compared with the standard preparation group (7 of 63 [11.1%]; adjusted risk difference, -11.7% [95% CI, -21.3% to -2.0%]; P = .02), which had a higher thromboembolic risk than the non-HTPR group (1 of 102 [1.0%]; adjusted risk difference, 8.6% [95% CI, 1.0% to 16.3%]; P = .03). All bleeding complications were of minimal grade according to Thrombolysis in Myocardial Infarction bleeding criteria. The bleeding rate was not different between the modified (6 of 63 [9.5%]) and standard (4 of 63 [6.3%]) preparation groups (adjusted risk difference, 5.6% [95% CI, -4.2% to 15.4%]; P = .26). CONCLUSIONS AND RELEVANCE Modified antiplatelet preparation for patients with HTPR compared with standard antiplatelet preparation reduced the thromboembolic event rate in coiling for an unruptured aneurysm without increasing bleeding. TRIAL REGISTRATION Clinical Research Information Service Identifier: KCT0000804.

Periodic limb movements in sleep after a small deep subcortical infarct

Background and Purpose The goal of stent retriever–based thrombectomy is removal of embolic clots in patients with intracranial large artery occlusion. However, outcomes of stent retrieval may differ between acute arterial occlusions due to intracranial atherosclerotic disease (IAD) and those due to embolism. This case series describes the outcomes of stent retriever–based thrombectomy and rescue treatments in 9 patients with IAD-related occlusion. Methods Among patients who underwent endovascular treatment for acute intracranial large artery occlusion, those in whom stent retrieval was attempted as first-line treatment were included in this review. IAD was defined as significant fixed focal stenosis at the occlusion site, which was evident on final angiographic assessment or observed during endovascular treatment. Results Median number of stent retriever passes was 2 (range, 1-3), and temporary bypass was seen in all patients. Immediate partial recanalization (arterial occlusive lesion grade 2-3) was observed in 7 patients. Immediate modified thrombolysis in cerebral infarction grade 2b-3 was seen in 6 patients, but the lesions often required rescue treatment due to reocclusion or flow insufficiency. In terms of rescue treatments, angioplasty and intra-arterial tirofiban infusion seemed to be effective. Conclusions Our findings suggest that stent retrieval can effectively remove thrombi from stenotic lesions and achieve partial recanalization despite the tendency toward reocclusion in most patients with IAD-related occlusion. Further research into the use of rescue treatments, such as tirofiban infusion and angioplasty, is warranted.