Improvement in Delivery of Ischemic Stroke Treatments but Stagnation of Clinical Outcomes in Young Adults in South Korea.

BACKGROUND: There is limited information on the delivery of acute stroke therapies and secondary preventive measures and clinical outcomes over time in young adults with acute ischemic stroke. This study investigated whether advances in these treatments improved outcomes in this population. METHODS: Using a prospective multicenter stroke registry in Korea, young adults (aged 18-50 years) with acute ischemic stroke hospitalized between 2008 and 2019 were identified. The observation period was divided into 4 epochs: 2008 to 2010, 2011 to 2013, 2014 to 2016, and 2017 to 2019. Secular trends for patient characteristics, treatments, and outcomes were analyzed. RESULTS: A total of 7050 eligible patients (mean age, 43.1; men, 71.9%) were registered. The mean age decreased from 43.6 to 42.9 years (Ptrend=0.01). Current smoking decreased, whereas obesity increased. Other risk factors remained unchanged. Intravenous thrombolysis and mechanical thrombectomy rates increased over time from 2008 to 2010 to 2017 to 2019 (9.5%-13.8% and 3.2%-9.2%, respectively; Ptrend<0.01). Door-to-needle time improved (Ptrend <.001), but onset-to-door and door-to-puncture times remained constant. Secondary prevention, including dual antiplatelets for noncardioembolic minor stroke (26.7%-47.0%), direct oral anticoagulants for atrial fibrillation (0.0%-56.2%), and statins for large artery atherosclerosis (76.1%-95.3%) increased (Ptrend<0.01). Outcome data were available from 2011. One-year mortality (2.5% in 2011-2013 and 2.3% in 2017-2019) and 3-month modified Rankin Scale scores 0 to 1 (68.3%-69.1%) and 0 to 2 (87.6%-86.2%) remained unchanged. The 1-year stroke recurrence rate increased (4.1%-5.5%; Ptrend=0.04), although the difference was not significant after adjusting for sex and age. CONCLUSIONS: Improvements in the delivery of acute stroke treatments did not necessarily lead to better outcomes in young adults with acute ischemic stroke over the past decade, indicating a need for further progress.

Frequency, management, and outcomes of early neurologic deterioration due to stroke progression or recurrence.

OBJECTIVE: The frequency, management, and outcomes of early neurologic deterioration (END) after ischemic stroke specifically due to stroke progression or stroke recurrence have not been well delineated. MATERIALS AND METHODS: In a multicenter, nationwide registry, data on END due to stroke progression or recurrence confirmed by imaging were collected prospectively between January 2019 and July 2020. Patient characteristics, management strategies, and clinical outcomes were analyzed. RESULTS: Among 14,828 consecutive ischemic stroke patients, 1717 (11.6%) experienced END, including 1221 (8.2%) with END due to stroke progression (SP) or stroke recurrence (SR). Active management after END was implemented in 64.2% of patients. Active management strategies included volume expansion (29.2%), change in antithrombotic regimen (26.1%), induced hypertension (8.6%), rescue reperfusion therapy (6.8%), intracranial pressure lowering with hyperosmolar agents (1.5%), bypass surgery (0.6%), and hypothermia (0.1%). Active management strategies that varied with patient features included volume expansion and induced hypertension, used more often in large artery atherosclerosis and small vessel occlusion, and rescue endovascular thrombectomy, more common in other (dissection), cardioembolism, and large artery atherosclerosis. Active management was associated with higher rates of freedom from disability (modified Rankin Scale, mRS, 0-1; 24.3% vs. 16.6%) and functional independence (mRS, 0-2; 41.6% vs. 27.7%) at 3 months. CONCLUSION: END specifically due to stroke progression or recurrence occurs in 1 in 12 acute ischemic stroke patients. In this observational study, active management, undertaken in two-thirds of patients, was most often hemodynamic or antithrombotic and was associated with improved functional outcomes.

Prevalence of Mutations in Mendelian Stroke Genes in Early Onset Stroke Patients.

OBJECTIVE: Heritability of stroke is assumed not to be low, especially in the young stroke population. However, most genetic studies have been performed in highly selected patients with typical clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population. METHODS: We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGVs) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP) using a customized, targeted next generation sequencing panel. RESULTS: Among 1,033 patients, 131 (12.7%) had 28 CRGVs, most frequently in RNF213 (n = 59), followed by ABCC6 (n = 53) and NOTCH3 (n = 15). The frequency of CRGVs differed by ischemic stroke subtypes (p < 0.01): the highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51 to 55 years (17.1% vs 9.3%, p = 0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUSs) were found in 15.4% patients. INTERPRETATION: CRGVs in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGVs did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGVs or VUSs should be explored. ANN NEUROL 2023;93:768-782.

Stroke of Other Determined Etiology: Results From the Nationwide Multicenter Stroke Registry.

BACKGROUND: Stroke of other determined etiology (OE) includes patients with an uncommon cause of stroke. We described the general characteristics, management, and outcomes of stroke in OE and its subgroups. METHODS: This study is a retrospective analysis of a prospective, multicenter, nationwide registry, the Clinical Research Center for Stroke-Korea-National Institutes of Health registry. We classified OE strokes into 10 subgroups according to the literature and their properties. Each OE subgroup was compared according to clinical characteristics, sex, age strata, lesion locations, and management. Moreover, 1-year composites of stroke and all-cause mortality were investigated according to the OE subgroups. RESULTS: In total, 2119 patients with ischemic stroke with OE types (mean age, 55.6±16.2 years; male, 58%) were analyzed. In the Clinical Research Center for Stroke-Korea-National Institutes of Health registry, patients with OE accounted for 2.8% of all patients with stroke. The most common subtypes were arterial dissection (39.1%), cancer-related coagulopathy (17.3%), and intrinsic diseases of the arterial wall (16.7%). Overall, strokes of OE were more common in men than in women (58% versus 42%). Arterial dissection, intrinsic diseases of the arterial wall and stroke associated with migraine and drugs were more likely to occur at a young age, while disorders of platelets and the hemostatic system, cancer-related coagulopathy, infectious diseases, and hypoperfusion syndromes were more frequent at an old age. The composite of stroke and all-cause mortality within 1 year most frequently occurred in cancer-related coagulopathy, with an event rate of 71.8%, but least frequently occurred in stroke associated with migraine and drugs and arterial dissection, with event rates of 0% and 7.2%, respectively. CONCLUSIONS: This study presents the different characteristics, demographic findings, lesion locations, and outcomes of OE and its subtypes. It is characterized by a high proportion of arterial dissection, high mortality risk in cancer-related coagulopathy and an increasing annual frequency of cancer-related coagulopathy in patients with stroke of OE.

Association of ischemic stroke onset time with presenting severity, acute progression, and long-term outcome: A cohort study.

BACKGROUND: Preclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke. METHODS AND FINDINGS: In a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules. CONCLUSIONS: Night-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis after BNT162b2 COVID-19 Vaccination.

After the coronavirus disease 2019 (COVID-19) pandemic emerged, the development of vaccines was accelerated. Neurologic complications of COVID-19 vaccination had been reported, which included encephalitis. In this study, we report a very rare case of a female with anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma that would be triggered by BNT162b2 m-RNA COVID-19 vaccination.

Diabetes is not protective against the formation of unruptured cerebral aneurysm.

OBJECTIVES: Diabetes appears to decrease the risk of subarachnoid hemorrhage. However, it is not clear whether diabetes decreases the risk of aneurysm formation. The aim of our study to evaluate the risk of unruptured cerebral aneurysm in patients with diabetes mellitus. METHODS: We used data from participants who underwent brain magnetic resonance angiography (MRA) and laboratory tests at the Healthcare System Gangnam Center of Seoul National University Hospital between January 2010 and December 2013. From the 17,368 participants who underwent brain MRA, we analyzed 16,337 subjects whose diabetes status could be identified. RESULTS: The number of participants with diabetes was 2299 (14.1%). The proportion of participants with cerebral aneurysms was 2.3% in the diabetic group and 2.7% in the non-diabetic group, which was not significantly different (P = 0.225). There were no significant differences in the size, location, and multiplicity of aneurysms between the diabetes and control groups. In multivariate logistic regression, older age showed significant risk effects on cerebral aneurysms, but female sex, hypertension, diabetes, obesity, and smoking did not show significant risk effects. CONCLUSION: In this study, diabetes did not affect the risk of cerebral aneurysm formation. In addition, neither smoking, nor hypertension was a significant risk factor for unruptured cerebral aneurysms. The lack of association between cerebral aneurysm and the traditional risk factors for subarachnoid hemorrhage requires further study. Risk factors for cerebral aneurysm development and those for cerebral aneurysm rupture may be different.

Executive Summary of Stroke Statistics in Korea 2018: A Report from the Epidemiology Research Council of the Korean Stroke Society.

Despite the great socioeconomic burden of stroke, there have been few reports of stroke statistics in Korea. In this scenario, the Epidemiologic Research Council of the Korean Stroke Society launched the "Stroke Statistics in Korea" project, aimed at writing a contemporary, comprehensive, and representative report on stroke epidemiology in Korea. This report contains general statistics of stroke, prevalence of behavioral and vascular risk factors, stroke characteristics, pre-hospital system of care, hospital management, quality of stroke care, and outcomes. In this report, we analyzed the most up-to-date and nationally representative databases, rather than performing a systematic review of existing evidence. In summary, one in 40 adults are patients with stroke and 232 subjects per 100,000 experience a stroke event every year. Among the 100 patients with stroke in 2014, 76 had ischemic stroke, 15 had intracerebral hemorrhage, and nine had subarachnoid hemorrhage. Stroke mortality is gradually declining, but it remains as high as 30 deaths per 100,000 individuals, with regional disparities. As for stroke risk factors, the prevalence of smoking is decreasing in men but not in women, and the prevalence of alcohol drinking is increasing in women but not in men. Population-attributable risk factors vary with age. Smoking plays a role in young-aged individuals, hypertension and diabetes in middle-aged individuals, and atrial fibrillation in the elderly. About four out of 10 hospitalized patients with stroke are visiting an emergency room within 3 hours of symptom onset, and only half use an ambulance. Regarding acute management, the proportion of patients with ischemic stroke receiving intravenous thrombolysis and endovascular treatment was 10.7% and 3.6%, respectively. Decompressive surgery was performed in 1.4% of patients with ischemic stroke and in 28.1% of those with intracerebral hemorrhage. The cumulative incidence of bleeding and fracture at 1 year after stroke was 8.9% and 4.7%, respectively. The direct costs of stroke were about ₩1.68 trillion (KRW), of which ₩1.11 trillion were for ischemic stroke and ₩540 billion for hemorrhagic stroke. The great burden of stroke in Korea can be reduced through more concentrated efforts to control major attributable risk factors for age and sex, reorganize emergency medical service systems to give patients with stroke more opportunities for reperfusion therapy, disseminate stroke unit care, and reduce regional disparities. We hope that this report can contribute to achieving these tasks.

Recurrent Stroke, Myocardial Infarction, and Major Vascular Events during the First Year after Acute Ischemic Stroke: The Multicenter Prospective Observational Study about Recurrence and Its Determinants after Acute Ischemic Stroke I.

BACKGROUND: Patients with acute ischemic stroke (AIS) are at high risk of subsequent vascular events. The aim of this study was to estimate rates of recurrent stroke, myocardial infarction (MI), and major vascular events during the first year after AIS in Korea. METHODS: Through a multicenter stroke registry in Korea, 12,227 consecutive cases of AIS were identified between November 2010 and May 2013 and were followed up for recurrent stroke, MI, and major vascular events up to 1 year after stroke. RESULTS: Cumulative 30-day, 90-day and 1-year rates were 2.7%, 3.9%, and 5.7% for recurrent stroke; .1%, .3%, and .5% for MI; and 8.1%, 10.6%, and 13.7% for major vascular events, indicating that the early period is at high risk of recurrent stroke and major vascular events. The risk of recurrent stroke was substantially higher than the risk of MI: 13.0 times at 90 days and 11.4 times at 1 year. Compared to those with small-vessel occlusion (SVO), those with ischemic stroke subtypes other than SVO had a higher risk of recurrent stroke as well as major vascular events. Other common independent predictors for recurrent stroke and major vascular events were diabetes and prior stroke history. CONCLUSIONS: During the first year after AIS, one in 18 had recurrent stroke and one in 7 major vascular events. More than two thirds of recurrent stroke and three quarters of major vascular events developed within 90 days in a Korean cohort of stroke patients. Better prevention strategies are required for high-risk patients during this high-risk period.

Contralateral referred pain in a patient with intramedullary spinal cord metastasis from extraskeletal small cell osteosarcoma.

CONTEXT: Referred pain has been observed in some patients after cordotomy, wherein noxious stimulus applied to a region rendered analgesic by cordotomy produces pain at a spot different from the one where the noxious stimulus is applied. We report a patient who had intramedullary spinal cord metastasis of extraskeletal small cell osteosarcoma, a rare form of metastatic disease, and experienced contralateral referred pain. FINDINGS: Initially, the patient had a mass in the left posterior neck region and later developed a large extradural mass at the C3-C7 level. The masses were excised, and the histological findings led to a diagnosis of small cell osteosarcoma. He underwent chemotherapy and radiation therapy. He experienced numbness in his left leg; subsequently, the numbness slowly spread up the thigh to the left side of the abdomen. When pinched in the numb area on the left side of the body, he felt as though he had been pinched in both that area and the corresponding area on the right side. A magnetic resonance imaging scan showed an enhancing lesion in the right side of the cord at the C6-C7 level. CONCLUSION/CLINICAL RELEVANCE: An intramedullary spinal cord metastasis can arise from primary extraskeletal small cell osteosarcoma and cause contralateral referred pain, especially in a mirror-image location. Contralateral referred pain may be caused by a subsidiary pathway comprising ascending chains of short neurons that link the dorsal horn neurons longitudinally and latitudinally.

Effect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: a randomized controlled trial.

OBJECTIVE: Acute kidney injury after cardiac surgery with cardiopulmonary bypass is closely related to systemic inflammatory reactions and oxidative stresses. Remote ischemic preconditioning is a systemic protective strategy whereby brief limb ischemia confers systemic protection against prolonged ischemia and inflammatory reactions in distant organs. This study investigated whether remote ischemic preconditioning provides systemic protective effect on kidneys that are not directly exposed to ischemia-reperfusion injury during complex valvular heart surgery. METHODS: Seventy-six adult patients undergoing complex valvular heart surgery were randomly assigned to either remote ischemic preconditioning group (n = 38) or control group (n = 38). Remote ischemic preconditioning consisted of 3 10-minute cycles of lower limb ischemia and reperfusion with an automated cuff inflator. Primary end points were comparisons of biomarkers of renal injury including serum creatinine, cystatin C and neutrophil gelatinase-associated lipocalin, and incidence of acute kidney injury. Secondary end points were comparisons of myocardial enzyme release and pulmonary parameters. RESULTS: There were no significant differences in serum levels of biomarkers of renal injury between groups throughout the study period. The incidence of acute kidney injury did not differ between groups. Creatine kinase isoenzyme MB at 24 hours after surgery was lower, and intensive care unit stay was shorter in the remote ischemic preconditioning group than in the control group. CONCLUSIONS: In patients undergoing complex valvular heart surgery, remote ischemic preconditioning did not reduce degree of renal injury or incidence of acute kidney injury whereas it did reduce myocardial injury and intensive care unit stay.

Distribution and in situ proliferation patterns of intravenously injected immortalized human neural stem-like cells in rats with focal cerebral ischemia.

Neural stem cells are considered as a candidate for cell replacement therapy in various neurological diseases. To investigate whether human neural stem cells can migrate into the adult ischemic rat brain, we transplanted immortalized human neural 'tem-like' cells intravenously 24 h after focal cerebral ischemia. The intravenously injected human neural stem-like cells were found around the infarcted area, differentiated into neurons and astrocytes in the lesioned areas, and survive up to 56 days after transplantation. The number of the injected cells increased between 7 and 14 days after transplantation with incorporating BrdU. Our findings show that intravenously injected human neural stem-like cells may incorporate into the ischemic brain, and undergo proliferation responding to the endogenous mitotic signal during the acute period of focal ischemia.