優秀論文獎

混合型腦出血患者之腦部小血管病變：類澱粉正子攝影之研究
蔡欣熹 1, 2、Marco Pasi 3、蔡力凱 2、陳雅芳 4、李柏青 4、湯頌君 2、Panagiotis Fotiadis 3、黃晨祐 5、
顏若芳 6、鄭建興 2、Edip Gurol 3
1
台大醫院北護分院神經內科
2
台大醫院神經內科
3
美國麻州總醫院腦出血研究中心
4
台大醫院影像醫學科
5
台大醫院心臟內科
6
台大醫院核子醫學科暨正子攝影中心

Microangiopathy Underlying Mixed-location Intracerebral Hemorrhages/

Microbleeds: A PiB-PET Study
Hsin-Hsi Tsai1, 2, Marco Pasi3, Li-Kai Tsai2, Ya-Fang Chen4, Bo-Ching Lee4, Sung-Chun Tang2,
Panagiotis Fotiadis3, Chen-Yu Huang5, Ruoh-Fang Yen6, Jiann-Shing Jeng2, M. Edip Gurol3
1
Departments of Neurology, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan
2
Departments of Neurology, National Taiwan University Hospital, Taipei, Taiwan
3
Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital
Stroke Research Center, Harvard Medical School, Boston, MA, USA
4
Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan
5
Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
6
Department of Nuclear Medicine, National Taiwan University Hospital, Taipei, Taiwan

Objective: To test the hypothesis that patients with concomitant lobar and deep intracerebral
hemorrhages/microbleeds (mixed ICH) have predominantly hypertensive small vessel disease
(HTN-SVD) rather than cerebral amyloid angiopathy (CAA), using in vivo amyloid imaging.
Methods: Eighty Asian patients with primary ICH without dementia were included in this
cross-sectional study. All patients underwent brain MRI and 11C-Pittsburgh compound B
(PiB)-PET imaging. The mean cortical standardized uptake value ratio (SUVR) was calculated
using cerebellum as reference. Forty-six patients (57.5%) had mixed ICH. Their demographic
and clinical profile as well as amyloid deposition patterns were compared to those of 13
patients with CAA-ICH and 21 patients with strictly deep microbleeds and ICH (HTN-ICH).
Results: Patients with mixed ICH were younger (62.8 ± 11.7 vs 73.3 ± 11.9 years in CAA, p
= 0.006) and showed a higher rate of hypertension than patients with CAA-ICH (p < 0.001).
Patients with mixed ICH had lower PiB SUVR than patients with CAA (1.06 [1.01–1.13] vs
1.43 [1.06–1.58], p = 0.003). In a multivariable logistic regression model, mixed ICH was
associated with hypertension (odds ratio 8.9, 95% confidence interval 1.4–58.4, p = 0.02) and
lower PiB SUVR (odds ratio 0.03, 95% confidence interval 0.001–0.87, p = 0.04) compared
to CAA after adjustment for age. Compared to HTN-ICH, mixed ICH showed a similar
mean age (62.8 ± 11.7 vs 60.1 ± 14.5 years in HTN-ICH) and risk factor profile (all p > 0.1).
Furthermore, PiB SUVR did not differ between mixed ICH (values presented above) and
HTN-ICH (1.10 [1.00–1.16], p = 0.45).
Conclusions: Patients with mixed ICH have much lower amyloid load than patients with
CAA-ICH, while being similar to HTN-ICH. Overall, mixed ICH is probably caused by HTN-
SVD, an important finding with clinical relevance.

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Rivaroxaban與apixaban於亞洲心房纖維顫動族群之濃度分析
林欣儀 1, 2、郭錦樺 2、葉馨喬 3、蔡力凱 3、劉言彬 4、黃織芬 1, 2、湯頌君 3、鄭建興 3
1
台大醫院藥劑部
2
台灣大學藥學專業學院藥學系
3
台大醫院神經部腦中風中心
4
台大醫院內科部心血管中心

Real World Rivaroxaban and Apixaban Levels in Asian Patients with Atrial
Fibrillation
Shin-Yi Lin, MS1, 2; Ching-Hua Kuo, PhD2; Shin-Joe Yeh, MD PhD3; Li-Kai Tsai MD, PhD3;
Yen-Bin Liu, MD, PhD4; Chih-Fen Huang, PhD1, 2; Sung-Chun Tang, MD, PhD3;
Jiann-Shing Jeng, MD, PhD3
1
Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan.
2
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
3
Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
4
Department of Internal Medicine, Cardiovascular Center and Division of Cardiology, National
Taiwan University Hospital, Taipei, Taiwan.

Introduction: Although the therapeutic index for non-vitamin K antagonist oral anticoagulants
(NOAC) is wide, measuring NOAC level remains the most arbitrary method for evaluating
the pharmacologic effect. The study aims to measure the plasma levels of rivaroxaban and
apixaban among Asian atrial fibrillation (AF) patients and compare the results with expected
drug levels from clinical studies.
Methods: AF patients aged more than 20 years who took rivaroxaban or apixaban for more
than 7 days were enrolled. Peak and trough levels were collected at 1-4 hours after medication
ingestion and right before the next dose, respectively. Samples were measured using ultra-high
performance liquid chromatography with tandem mass spectrometry.
Results: A total of 178 patients were enrolled, 73 who took rivaroxaban (15 mg daily, 34
patients; 10 mg daily, 39 patients) and 105 who took apixaban (5 mg twice daily, 44 patients;
2.5 mg twice daily, 61 patients). Patients in the apixaban group were more likely to be
ordered an inappropriately-adjusted dose compared to those in the rivaroxaban group (37.5%
versus 22.5%, p = 0.046). The percentage of those with drug levels within the expected
range reported in clinical studies was significantly higher in the apixaban group than in the
rivaroxaban group, both for trough (84.8% versus 64.4%, p = 0.002) and peak level (76.9%
versus 33.8%, p < 0.001). After adjusting for age, sex, kidney function, appropriate dose and
adherence, patients in the rivaroxaban group were still less likely to have peak and trough
levels within the expected drug levels (odds ratio [OR] for trough 0.279, 95% confidence
interval [CI] = 0.13–0.62, P = 0.002; for peak, OR = 0.172, 95% CI = 0.08–0.35, P < 0.001).
Conclusion: Our real world data suggests that Asian patients taking rivaroxaban are more
likely to have out-of-expected drug levels than those taking apixaban.

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急性缺血性腦中風取栓試驗之非劣性臨界值之探討
林浚仁 1、Jeffrey L. Saver 2
1
臺北榮民總醫院
2
美國加州大學洛杉磯分校

Noninferiority Margins in Trials of Thrombectomy Devices for Acute Ischemic

Stroke : Is the Bar Being Set Too Low?
Chun-Jen Lin1, Chun-Jen Lin2
1
Division of Cerebrovascular Diseases, Neurological Institute, Taipei Veterans General Hospital, Taiwan
2
Comprehensive Stroke Center and Department of Neurology, David Geffen School of Medicine,
University of California, Los Angeles, USA

Background and Purpose: Novel endovascular thrombectomy (EVT) devices for acute
ischemic stroke are often cleared by regulatory agencies on the basis of noninferiority trials.
The relation between the noninferiority margins used in trials and the minimal clinically
important differences (MCIDs) determined by experts have not been systematically
investigated.
Methods: Systematic searches were performed to identify (1) all noninferiority design
or noninferiority-presented stroke-EVT trials for acute ischemic stroke, (2) all studies
determining the MCIDs for the same outcomes, and (3) all noninferiority coronary
revascularization trials. Stroke-EVT trial results were reanalyzed using the broad
noninferiority margins originally used and narrower noninferiority margins derived from
formal MCID studies.
Results: We identified 7 noninferiority-designed or noninferiority-interpreted stroke-EVT
controlled trials, enrolling 1766 patients, variously comparing coil retrievers, first- and
second-generation stent retrievers, and aspiration devices. In 6 trials, the primary outcome was
achievement of reperfusion, using noninferiority margins of 15% (3 trials), 10% (2 trials), and
8% (1 trial). In contrast, a stroke expert survey identified the MCID for reperfusion as 3.1% to
5%, and cardiac trials used noninferiority margins of 3.5% to 4.4%. In one stroke-EVT trial,
the primary outcome was functional independence, using a noninferiority margin of 15%.
However, 2 stroke expert survey studies identified MCIDs for functional independence as
having lower values, 5% and 1% to 1.5%. For both reperfusion and functional independence
outcomes, all 7 trials demonstrated noninferiority with the broadest noninferiority margin,
but only 4 and 3 trials demonstrated noninferiority with actual expert-derived margins for
reperfusion and functional independence, respectively.
Conclusions: Noninferiority margins used in EVT device trials have regularly exceeded
the MCIDs determined by stroke experts, as well as margins used for cardiac devices.
New approaches, such as the use of reasonably adequate performance margins, rather than
noninferiority margins, are needed to optimize stroke-EVT trial design integrity and trial
performance feasibility.

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芳香烴受體調節成鼠急性腦中風後之神經發炎與神經新生
陳琬慈 1、張立鑫 2、黃相碩 4、黃昱傑 1、池春蓮 5、郭紘志 6、李怡萱 1, 3、李怡慧 2, 3, 7
1
陽明大學生理學研究所
2
陽明大學腦科學研究所
3
陽明大學腦科學研究中心
4
中山醫學大學醫學 系藥理學科
5
振興醫院
6
中央研究院細胞與個體生物學研究院
7
台北榮總神經醫學中心腦血管科

Aryl Hydrocarbon Receptor Modulates Stroke-induced Astrogliosis and Neurogenesis

in the Adult Mouse Brain
Wan-Ci Chen1, Li-Hsin Chang2, Shiang-Suo Huang4, Yu-Jie Huang1, Chun-Lien Chih5,
Hung-Chih Kuo6, Yi-Hsuan Lee1, 3, I-Hui Lee2, 3, 7
1
Department and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
2
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
3
Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
4
Department of Pharmacology, Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan.
5
Cheng Hsin General Hospital, Taipei, Taiwan.
6
Stem Cell Program, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
7
Division of Cerebrovascular Diseases, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription

factor activated by environmental agonists and dietary tryptophan metabolites for the immune
response and cell cycle regulation. Emerging evidence suggests that AHR activation after
acute stroke may play a role in brain ischemic injury. However, whether AHR activation alters
poststroke astrogliosis and neurogenesis remains unknown.
Methods: We adopted conditional knockout of AHR from nestin-expressing neural stem/
progenitor cells (AHRcKO) and wild-type (WT) mice in the permanent middle cerebral artery
occlusion (MCAO) model. WT mice were treated with either vehicle or the AHR antagonist
6,2′,4′-trimethoxyflavone (TMF, 5 mg/kg/day) intraperitoneally. The animals were examined
at 2 and 7 days after MCAO.
Results: The AHR signaling pathway was significantly upregulated after stroke. Both TMF-
treated WT and AHRcKO mice showed significantly decreased infarct volume, improved
sensorimotor, and nonspatial working memory functions compared with their respective
controls. AHR immunoreactivities were increased predominantly in activated microglia
and astrocytes after MCAO compared with the normal WT controls. The TMF-treated WT
and AHRcKO mice demonstrated significant amelioration of astrogliosis and microgliosis.
Interestingly, these mice also showed augmentation of neural progenitor cell proliferation at
the ipsilesional neurogenic subventricular zone (SVZ) and the hippocampal subgranular zone.
At the peri-infarct cortex, the ipsilesional SVZ/striatum, and the hippocampus, both the TMF-
treated and AHRcKO mice demonstrated downregulated IL-1β, IL-6, IFN-γ, CXCL1, and
S100β, and concomitantly upregulated Neurogenin 2 and Neurogenin 1.
Conclusion: Neural cell-specific AHR activation following acute ischemic stroke increased
astrogliosis and suppressed neurogenesis in adult mice. AHR inhibition in acute stroke may
potentially benefit functional outcomes likely through reducing proinflammatory gliosis and
preserving neurogenesis.

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手術前後出現之心房顫動與後續中風及死亡風險：後設分析
林孟昕1、 Hooman Kamel、 Daniel E. Singer3、吳宜玲4、李孟1、 Bruce Ovbiagele5
1
嘉義長庚醫院神經部
2
Department of Neurology, Weill Cornell Medical College, New York.
3
Division of General Internal Medicine, Massachusetts General Hospital and Harvard Medical School, Boston.
4
國家衛生研究院群體健康科學研究所
5
Department of Neurology, University of California, San Francisco.

Perioperative/Postoperative Atrial Fibrillation and Risk of Subsequent Stroke

and/or Mortality A Meta-Analysis
Meng-Hsin Lin, MD1; Hooman Kamel, MD2; Daniel E. Singer, MD3; Yi-Ling Wu, DrPH4;
Meng Lee, MD1; Bruce Ovbiagele, MD, MS5
1
From the Department of Neurology, Chang Gung University College of Medicine, Chang Gung
Memorial Hospital, Chiayi, Taiwan
2
Department of Neurology, Weill Cornell Medical College, New York.
3
Division of General Internal Medicine, Massachusetts General Hospital and Harvard Medical School, Boston.
4
Institute of Population Health Sciences, National Health Research Institutes, Miaoli County, Taiwan.
5
Department of Neurology, University of California, San Francisco.

Background and Purpose: Although believed to be transient and self-limiting, new-

onset perioperative/postoperative atrial fibrillation (POAF) might be a risk factor for stroke
and mortality. We conducted a systematic review and meta-analysis to qualitatively and
quantitatively evaluate the relationship of POAF with early and late risks of mortality and
stroke.
Methods: We searched Pubmed, EMBASE, and Cochrane Library (1966 through March
2018) to identify cohort studies that reported stroke and mortality associated with POAF. We
computed a random-effects estimate based on the Mantel- Haenszel method. Odds ratios with
95% CI were used as a measure of the association between POAF and early (in- hospital or
within 30 days of surgery) stroke and mortality, while hazard ratios (HR) were used for long-
term outcomes.
Results: Our analysis included 35 studies with 2 458 010 patients. Pooling the results from the
random-effects model showed that POAF was associated with increased risks of early stroke
(odds ratio, 1.62; 95% CI, 1.47–1.80), early mortality (odds ratios, 1.44; 95% CI, 1.11–1.88),
long-term stroke (HR, 1.37; 95% CI, 1.07–1.77), and long-term mortality (HR, 1.37; 95% CI,
1.27–1.49). Analyses focusing on high-quality studies obtained similar results. In subgroup
analyses, POAF was more strongly associated with stroke in patients undergoing noncardiac
surgery (HR, 2.00; 95% CI, 1.70–2.35) than in patients undergoing cardiac surgery (HR, 1.20;
95% CI, 1.07–1.34).
Conclusions: New-onset POAF is associated with an increased risk of stroke and mortality,
both in the short-term and long- term. The best strategy to reduce stroke risk among these
patients needs to be determined.

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機械取栓術後短期內再發缺血性中風的臨床探討
薛頌儒 1, 3、李崇維 2、湯頌君 1、鄭建興 1
1
臺大醫院神經部
2
臺大醫院影像醫學部
3
臺大醫院雲林分院神經部

Early Recurrent Stroke in Patients Receiving Mechanical Thrombectomy

Sung-Ju Hsueh1, 3, Chung-Wei Lee2, Sung-Chun Tang1, Jiann-Shing Jeng1
1
Department of Neurology, National Taiwan University Hospital, Taiwan.
2
Department of Radiology, National Taiwan University Hospital, Taiwan.
3
Department of Neurology, National Taiwan University Hospital Yun-Lin Branch, Taiwan.

Background: Mechanical thrombectomy for acute ischemic stroke is a proven technique

effective in selective patients. This study described the incidence and clinical characteristics
of early recurrent stroke (ERS) in patients receiving mechanical thrombectomy from a single
center in Taiwan.
Methods: We retrospectively reviewed patients who had acute ischemic stroke and received
mechanical thrombectomy from January 2015 to September 2018 at National Taiwan
University Hospital. ERS was defined as newly developed neurological deficit localized a
different vascular territory and not caused by hemorrhage within the 21 days after the onset of
index stroke. Good functional outcome was defined as modified Rankin Scale ≤ 2 at 3 months
after stroke.
Results: During the period, 200 patients (mean age 71.62 ± 12.34 years, male 49.0%) received
mechanical thrombectomy. 17 patients (mean age 65.0 ± 15.54 years, male 35.3%) developed
ERS (8.50%, 95% confidence interval 5.39- 13.39%.) The stroke etiologies of those with
ERS were cardioembolism in 10 (58.8%) patients, active cancer with positive disseminated
intravascular coagulation profiles in 4 patients (23.5%), catastrophic antiphospholipid
syndrome in 1 (5.9%) patient, and large artery atherosclerosis in 2 (11.8%) patients. 10
(58.8%) of them received repeated mechanical thrombectomy, all achieving successful
revascularization and none developed symptomatic hemorrhage. The patients with and without
ERS had comparable good functional outcome (29.4% versus 41.0%, p = 0.31).
Conclusion: ESR in stroke patients with mechanical thrombectomy was not rare, and repeated
mechanical thrombectomy could be effective and feasible in subjects with ERS.

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近端主動脈剝離患者的長期腦中風發生率
許晉譯 1、劉安邦 1, 2、蘇圓智 3, 4、鄭文立 1,5
1
花蓮慈濟醫院神經內科
2
慈濟大學醫學系
3
中國醫藥大學醫學院
4
中國醫藥大學大數據中心
5
美國加州大學舊金山分校全球腦健康研究機構

Long-term stroke incidence in proximal thoracic aortic dissection survivors: a

nationwide population-based cohort study
Jin-Yi Hsu1, An-Bang Liu1, 2, Yuan-Chih Su3, 4 and Boon Lead Tee1, 5
1
Buddhist Tzu Chi General Hospital, Department of Neurology, Hualien, Taiwan R.O.C.;
2
Buddhist Tzu Chi University, Department of Medicine, Hualien, Taiwan R.O.C.;
3
China Medical University Hospital, Management Office for Health Data, Taichung, Taiwan R.O.C.;
4
China Medical University, College of Medicine, Taichung, Taiwan R.O.C.;
5
Global Brain health institute, Atlantic Fellows for Equity in Brain Health, San Francisco, USA

Background: Proximal thoracic aorta dissection (pTAD) is a fatal disease, but the
advancement in surgical repair technique increase overall survival rate. Studies have
demonstrated that there are increase perioperative risk for stroke incidence after pTAD surgery.
However, there lacks evidence illustrating the long-term stroke incidence in pTAD individuals,
that impact the long-term morbidity, mortality, and usage of antithrombotic agents.
Method: Using Taiwan National Health Insurance Research Database (NHIRD), a nationwide
population-based cohort, we recruited 3,501 pTAD survivors hospitalized from January 1st,
2000 to December 31th, 2012. To ensure study cohort quality, only patients that underwent
aortic dissection repair surgery and age 20 and above are included. The control cohort is
identified by matching background features (comorbidities, age, gender) at a 1:4 ratio through
the use of propensity score. The primary outcomes include ischemic stroke and intracranial
hemorrhage incidence 30 days after surgery.
Results: Compared to the control cohort, pTAD survivor had higher risk for intracranial
hemorrhage (adjusted hazard ratio [aHR]: 2.09; 95% confidence interval [CI]: 1.57–2.78),
ischemic risk (aHR:1.82; 95%CI: 1.55–2.14). Risk factors for intracranial hemorrhage include
middle age (45-64 year-old) and dyslipidemia and risk factors for ischemic stroke include
young age (<45 year-old) and chronic kidney disease.
Conclusion: Despite surviving the acute aortic dissection and surgical repair surgery, our
study suggests that pTAD patients may still face an increased risk of intracranial hemorrhage
and ischemic stroke in the future. Further research and guideline are warranted to prevent such
occurrence.

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