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The Changhua Journal of Medicine

Publisher Honorary Editor Editor-in-ChiefChanghua Christian Hospital Shou-Jen Kuo Chin-San Liu

Deputy Editors-in-Chief Rei-Cheng Yang Cho-Yu Chan Wen-Sheng Huang

Editorial Board Cho-Yu Chan Tung-Hao Chang Shu-Chen Chang Jui-Chih Chang

Yao-Li Chen Mu-Kuan Chen Hsiu-Chu Chen San-Ni Chen

Chang-Hua Chen Ching-Pei Chen Shou Tung Chen Hsiao-Neng Chen

Ming Chen Yan-Yu Chen Yi-Nan Chen Ching-Yuan Cheng

Chun-Yuan Cheng Jien-Wen Chien Su-Yu Chien Nan-Ying Chiu

Hsien-Chang Chou Chu-Chung Chou Ya-Hui Chou Chih-Yuan Chung

Yi-Hsuan Hsiao Min-Chia Hsieh Kuo-Cheng Hsieh Tien-Cheng Hsui

Ching-Shan Huang Yao-Ting Huang Ya-Wen Kuo Su-Feng Kuo

Chin-Chun Lan Chien-Hsing Lee Chin-Hsing Li Su-Fen Liao

Yi-Cheng Liao Chang-Ping Lin Ching-Hsiung Lin Jen-Tsun Lin

Ping-Yi Lin Lun-Chien Lo Gwo-Chin Ma Ming-Ching Shen

Mao-Soan Soon Mou-Jong Soon Che-Chun Su Jenn-Cheng Su

Shih-Li Su Alan-Ronald Talbot Feng-Cheng Tang Horng-Der Tsai

Yi-Giien Tsai Ling-Jane Tsai Lon-Yen Tsao Shih-Chung Wang

Chu-Hsien Wang Ta-Sen Wei Yung-Sung Wen Hong-Ming Wu

Shey-Lin Wu Ruei-Cheng Yang Kuang Tao A. Yang Chih-Chuan Yang

Kuo-Chia Yang

Advisory Editorial Board Yuan-Shiun Chang Tsung-Lin Cheng Fu-Chou Cheng

Jong-Ling Fuh Ming-Feng Hou Ming-Li Hsieh

Alex Ye-Chen Huang Chih-Hsing Hung Jiunn-Liang Ko

Wei-Yong Lin Kai-Li Liu Ashraf Mina

Hsiu-Ting Tsai Fong Y Tsai Bao-Tyan Wang

Yau-Huei Wei Lee-Jun C. Wong Ching-yee Oliver Wong

Chung-Ho Chang

Li-Chi Chiang

Ching-Liang Hsieh

Ie-Bin Lian

Kang Shentu

Tsu-Shing Wang

Lian Xing Wu Shun-Fa Yang

Editorial Secretaries Chih-Cheng Lin Jeffrey Conrad Li-Hsin Yu Pao-Chin Lin

Editorial Office Changhua Journal of Medicine (CJM)

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ISSN 1680-1504 VOL 12 NO 1 March 2014

CONTENTS

Original Articles Predictor for survival outcomes of young adult patients after hepatectomy for hepatocellular carcinoma Chih-Jan Ko, Kuo-Hua Lin, Ping-Yi Lin, Tung-Yi Ko, Yao-Li Chen, Shou-Jen Kuo 1

Effects of lamotrigine monotherapy on lipid peroxidation and the antioxidant defense system in patients with newly diagnosed epilepsy Wan-Yu Huang, Chin-San Liu, Jing-Jane Tsai, Hung-Ming Wu 9

Tl-201 myocardial SPECT is an effective imaging modality for differentiating Ischemic from non-ischemic dilated cardiomyopathy in patients with left ventricular dysfunction Ching-Pei Chen, Ching-Hui Huang,Chiang-Hsuan Lee,Ming-Che Chang,Chao-Wei Yang,Guang-Uei Hung,Wen-Sheng Huang 17

學齡期高功能自閉症兒童的心智理論能力表現

(Theory of mind in school-age children with high-functioning autism) Chun-Ling Hsu, Pei-Zhen Chen 24

Case Reports Unusual rib metastatic patterns on bones scans in a patient with breast cancer: A case report Po-Ling Chang, Yue-Chong Wu, Liang-Yuan Wong, Kuang-Tao Yang, Shou-Dong Chen, Wen-Sheng Huang 30

Sympathetic ophthalmia following vitreoretinal surgery Chen-Cheng Chao, San-Ni Chen 34

Intensity-modulated radiation therapy is an effective treatment for optic nerve sheath meningioma Chen-Cheng Chao, Sung-Tsang Hsieh, Ya-Fang Chen, Jieh-Ren Jou 40

Letter to the Editor Hyperdense basilar artery sign is predictive of brain stem infarction Chih-Ming Lin, Chi-Kuang Liu 47

The Changhua Journal of Medicine (2014) 12, 1-8

Original article

Predictors of survival among young adult patients with early recurrence of hepatocellular carcinoma after hepatectomy Chih-Jan Ko1, Kuo-Hua Lin1, Ping-Yi Lin2, Tung-Yi Ko1, Yao-Li Chen1, 3, 4*, Shou-Jen Kuo1

1Department of General Surgery, Changhua Christian Hospital, Changhua, Taiwan 2Transplant Medicine & Surgery Research Center, Changhua Christian Hospital, Changhua, Taiwan 3School of Medicine, Chung Shan Medical University, Taichung, Taiwan 4School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Received 5 Feburary 2014; accepted 24 March 2014

Abstract Background: Studies have shown that young adults with hepatocellular carcinoma (HCC), espe-cially those ≤ 40 years, are at high risk of recurrence after hepatectomy even though most of them have adequate residual liver function. The aim of this study was to analyze the risk factors asso-ciated with early recurrence of HCC in young adults after hepatectomy. Methods: We enrolled 45 patients with resectable HCC who underwent hepatectomy at a single medical center during the period March 1997 to November 2010. All patients were ≤ 40 years at the time of diagnosis. Prognostic factors of overall survival were examined using a proportional hazard regression model. The independent t test and the Pearson chi-squared test were used to examine differences in demographic and clinical characteristics between patients with HCC recur-rence one year after surgery and those without recurrence. The prognostic factors were studied using the Kaplan-Meier method with the log-rank test to detect differences in cumulative survival rates of young adult patients with HCC. Results: During the follow-up period, the rate of post-resection HCC recurrence was 53.5% (24 of 45). Univariate analysis revealed that tumor size > 5.0 cm, the presence of HCV infection, recur-rence of HCC within 12 months after surgery, and specimen margin < 1 cm were predictors of poor survival after hepatectomy. Univariate analysis revealed that tumor size, serum alpha fetoprotein, the type of operation, and tumor stage were significant predictors of recurrence one year after he-patectomy. Conclusion: Large tumor size is predictive of early tumor recurrence and poor survival after sal-vage interventions in young adults.

* Corresponding author. Yao-Li Chen, M.D. Department of General Surgery, Changhua Christian Hospital. 135 Nanxiao St. Chang-Hua 50006, Taiwan, ROC

E-mail address: [email protected]

Copyright © 2014, Changhua Christian Hospital.


journal homepage: http://www2.cch.org.tw/7477

KEYWORDS Hepatocellular carcinoma; Young adult patients; Early recurrence; Hepatectomy; Tumor size

2 C. -J. Ko et al.

Introduction

Hepatocellular carcinoma (HCC) is the leading cause of cancer death in men and the second leading cause in women [1]. Hepatitis B is endemic in Taiwan and many HBV carriers acquired the infection via the perinatal route or horizontal transmi-ssion. The lifetime risk of developing HCC among HBV carriers is esti-mated to be 0.5% per year [2,3,4]. Al-though hepatic resection is the first-line treatment for HCC in patients with preserved liver function, the rate of recurrence of HCC after resection is as high as 82% and the 5-year survival rate approaches 50% [5-7]. Understanding the factors that are associated with tumor recurrence can lead to early detection and treatment, thereby improving the prognosis and survival of patients after curative re-section. In this study, we investigated the clinical and pathological features associated with tumor recurrence after hepatectomy in young adults with HCC.

Methods

Patients, Surgery, and Follow-up

In this retrospective cross-sectional study, we enrolled all patients aged between 20 and 40 years with a preoperative diagnosis of HCC who received hepa-tectomy during the period March 1997 to November 2010 at the Changhua Christian Hospital. Clinical data were obtained through chart review. Pre-operative eva-luation of patients included liver function tests, determi-nation of hepatitis B or C status, measurement of alpha-fetoprotein (AFP) level, abdominal ultrasonography (US), computed tomography (CT), and chest radio-graphy with or without liver biopsy according to the diagnostic criteria of the American Association for the Study of Liver Diseases (AASLD) [8]. Treatment of HCC followed the Barcelona Clinic Liver Cancer (BCLC) staging system, which links the stage of the disease to a specific treatment strategy [9]. The types of hepatectomy performed during the study period included major hepatectomy and minor hepatectomy, depending on the size and location of the tumor. Minor hepatecto-my was defined as the resection of one or two segments according to Couinaud’s classification and major hepa-tectomy was defined as the resection of three or more segments. HCC was diagnosed based on the results of pathological examinations of resected specimens. Op-eration-related factors such as type of hepatectomy and surgical outcome were analyzed to identify the impact of

tumor size on tumor recurrence. The study was approved by the Institutional Review Board of the Changhua Christian Hospital.

Definition for Tumor Recurrence and Tumor size

After curative hepatectomy, AFP level was mea-sured and image studies were performed in all patients at 3-month intervals during the first two years and at 6-month intervals in the following years. If elevated AFP levels or abnormal image findings were found during the follow-up period, patients underwent more advanced image studies, such as CT, magnetic resonance imaging, bone scan, or positron emission tomography to investi-gate the presence of recurrence. Tumor recurrence was defined in patients with evidence of intrahepatic recu-rrence in the remnant liver or extrahepatic recurrence. Tumor size was based on the largest diameter of the tumor specimen measured during the pathological exa-mination.

Treatment of Tumor Recurrence

Patients with recurrent HCC who had preserved liver function underwent re-resection. However, patients in whom re-resection was contraindicated were treated with local regional therapy such as transarterial che-moembolization (TACE), percutaneous ethanol injection (PEI), or radiofrequency ablation (RFA). After repeat hepatectomy or local regional therapy, patients received regular follow-up and were evaluated for tumor recur-rence.

Analysis of Factors Influencing Recurrence and Survival

We evaluated factors that are possibly related to overall survival and tumor recurrence, such as patient characteristics, tumor-related factors, and treatment-related variables. Patient characteristics included gender, age, and AFP level (less than or greater than 400 ng/ml). Tumor-related factors included tumor size, tumor num-ber, the presence or absence of capsular invasion, the presence or absence of vascular invasion, staging of the tumor (AJCC 7th Edition) [10], and histological charac-teristics. Treatment-related variables included the type of resection (major hepatectomy or minor hepatectomy), clearance of resected margins (less than or greater than 1 cm), and blood loss.

Statistical Analysis

All data were recorded on a computer database. Continuous variables are expressed as mean ± standard deviation (S.D.). Prognostic factors of overall survival were examined by univariate analysis using a propor-

Larger tumor size in hepatocellular carcinoma is predictive of earlier recurrence 3

tional hazard regression model. The independent t test and Pearson chi-squared test were used to examine dif-ferences in demographic and clinical characteristics be-tween patients with evidence of recurrence and patients without evidence of recurrence one year after surgery. Prognostic factors were studied using the Kaplan-Meier method with the log-rank test to detect differences in cumulative survival rates. P values less than 0.05 were considered to be statistically significant. All statistical analyses were performed on a personal computer with the statistical package SPSS for Windows (Version 16.0, SPSS, Chicago, USA).

Results

During the period March 1997 to November 2010, a total of 48 patients aged between 20 and 40 years un-derwent liver resection for hepatic tumor at the Chang-hua Christian Hospital. However, three of those patients were lost to follow-up and, therefore, were excluded from the study. Descriptive statistics of the study partic-ipants are presented in Table 1. Of the 45 patients in-cluded in the study, the mean age was 34 years (range, 20-40 years) and the majority (75.6%, 34 of 45) of pa-tients were men. With the exception of one patient with combined HBV and HCV infection, all patients had he-patitis B infection. Most of the patients had good liver function according to Child Pugh classification (Child-Pugh class A, n=42; Child-Pugh class B, n=2) and a slight majority had post-operative AFP levels greater than 400 ng/ml (51.1%, 22 of 45). Major hepatectomy was performed in 22 patients and minor hepatectomy was performed in 23 patients. The average tumor size was 6.16 cm (SD, 4.55 cm). There were no deaths with-in 30 days of surgery; however, during the follow-up

period (mean, 5.06 years; SD, 3.81 years), 16 patients died due to HCC recurrence or complications. Of the 45 patients, 14 developed early recurrence after hepatecto-my. Pathological examination of resected specimens revealed stage I HCC in 20 patients (44.4%), stage II HCC in 14 patients (31.1%), stage III HCC in 10 pa-tients (22.2%), and stage IV HCC in one patient. Vascu-lar invasion was found in 20 patients (44.4%). Table 2 shows the prognostic factors examined by univariate analysis using a proportional hazard regression model. Of the clinical and pathological variables, univariate analysis revealed that tumor size > 5.0 cm, the presence of HCV infection, recurrence of HCC within 12 months after surgery, and specimen margin < 1 cm were nega-tive predictors of overall survival after hepatectomy. Analysis of overall survival revealed that patients with large-size tumors had a significantly higher risk of death than patients with small-sized tumors (Hazard ratio (HR), 1.110; 95% confidence interval [CI], 1.016-1.213; p=0.021). Of the 24 patients with tumor recurrence, 10 required local regional therapy (TACE, RFA or PEI), two required excision of extrahepatic tumors and radio-therapy or chemotherapy for extrahepatic metastasis, four received repeat hepatectomy for intrahepatic HCC recurrence, and eight required excision of extrahepatic tumors. Table 3 shows the characteristics and tumor features of the patients with early tumor recurrence. Pa-tients with early tumor recurrence had larger tumor size, higher AFP levels, a higher rate of major resection, and more advanced tumor stage. Tumor size is an important risk factor for early tumor recurrence after hepatectomy. Therefore, we analyzed the tumor size cutoff points as-sociated with the highest risk of poor survival. The re-sults of our analysis showed that patients with a tumor measuring > 5.5 cm were at a higher risk of death than patients with a tumor size < 5.5 cm (Fig. 1).

4 C. -J. Ko et al.

Table 1. Characteristics and clinical features of patients Characteristics N= 45 Mean age (SD) 34(5) Tumor size cm (SD) 6.16(4.55) Gender (%) Female 11(24.4) Male 34(75.6) T stage I

II III IV

20(44.4) 14(31.1) 10(22.2) 1(2.2)

Histology Well Moderate Poor

1(2.2) 32(71.1) 12(26.7)

Child-Pugh

A B

43(95.6) 2(4.4)

Vascular invasion

No Yes

25(55.6) 20(44.4)

Margin < 1cm ≥ 1cm

12(26.7) 33(73.3)

Operation type

Minor Major

23(51.1) 22(48.9)

HBsAg Positive Negative

44(97.8) 1(2.2)

HCVAb

Positive Negative Unknown

1 (2.3) 43(97.7) 1

HBV or HCV

Positive Negative

44(97.8) 1(2.2)

Tumor Capsule No Yes

23(51.1) 22(48.9)

Tumor Capsule Invasion No Yes

33(73.3) 12(26.7)

Tumor Rupture No Yes

41(91.1) 4(8.9)

Preoperative TACE No Yes

33(73.3) 12(26.7)

AFP (%)

<400 ng/mL ≥400 ng/mL

23(51.1) 22(48.9)

GOT (SD; U/l ) 50.8(38.5) GPT (SD; U/l) 52.8(30.7) Albumin level (SD; g/dL) Mean ± SD 4.2(0.5) Total Bilirubin level (SD; mg/dL) Mean ± SD 2.8(12.9) Blood loss (mL) Mean ± SD 663.10 ± 807.364 Recurrence No

Yes 21(46.7) 24(53.3)

Early recurrence ≤1 year 14(31.1) 5-year disease-free survival 37.3% 10-year disease-free survival 34.2% 5-year overall survival 68.7% 10-year overall survival 57.0% Average follow-up years (SD) 5.06(3.81)

SD: standard deviation


Table 2. List of prognostic factors examined by univariate analysis using proportional hazard regression

Overall Survival

Variable

Hazard Ratio

95% CI

p value

Clinical factors Gender Male vs. Female 0.283 (0.062-1.278) 0.101 Age ≥ 30 vs. < 30 0.641 (0.232-1.769) 0.390 Tumor Size 1.110 (1.016-1.213) 0.021* Tumor No. ( >1 vs. ≤1) 1.809 (0.504-6.488) 0.363 Child-Pugh B vs. A 0.454 (0.047-4.355) 0.494 HBV Positive vs. Negative 0.224 (0.028-1.798) 0.159 HCV Positive vs. Negative 9.980 (1.115-89.329) 0.040* AFP >400 vs. ≤400 1.972 (0.710-5.477) 0.192 Operation Type Major vs. Minor 2.126 (0.769-5.878) 0.146 Tumor Capsule Yes vs. No 0.383 (0.132-1.110) 0.077 Tumor Capsule Invasion Yes vs. No 1.620 (0.501-5.239) 0.420 Tumor Rupture Yes vs. No 0.312 (0.036-2.703) 0.290 Preoperative TACE Yes vs. No 1.079 (0.343-3.400) 0.896 1-year recurrence Yes vs. No 3.952 (1.142-13.676) 0.030* Pathologic factors Stage (II,III,IV vs. I) 1.305 (0.481-3.539) 0.602 Vascular Invasion Yes vs. No 2.059 (0.764-5.545) 0.153 Margin ≥ 1cm vs. < 1cm 0.283 (0.099-0.808) 0.018* Histology Moderate, Poor vs. Well - - -

*p < 0.05

6 C. -J. Ko et al.

Table 3. Characteristics and tumor features of young adult HCC patients with early recurrence

Characteristics

1-year recurrence rate (%)

p-value

Clinical factors 14/24 Gender Male

Female 12(85.7) 2(14.3)

0.262

Tumor Size (cm) Mean ± SD 8.78 ± 4.65 0.009a

Tumor Size (cm) >5 ≤5

10(28.6) 4(71.4)

0.041

Tumor Size (cm) >6 ≤6

9(64.3) 5(35.7)

0.080

Tumor No. >1 ≤1

4(28.6) 10(71.4)

0.685

Child-Pugh B A

0(0) 14(100)

1

HBV Positive Negative

14(100) 0(0)

1

HCV Positive Negative

1(7.1) 13(92.9)

0.412

AFP >400 ng/mL ≤400 ng/mL

11(78.6) 3(21.4)

0.006

Operation type Major Minor

10(71.4) 4(28.6)

0.041

Pathologic factors Stage II,III,IV

I 11(78.6) 3(21.4)

0.036

Vascular invasion Yes No

9(64.3) 5(35.7)

0.094

Margin ≥1cm <1cm

12(85.7) 2(14.3)

0.431

Histology Well Moderate Poor

1(7.2) 10(71.4) 3(21.4)

0.462a

a Data are shown as mean±standard deviation (SD) and were compared using the Independent T test. b Data are shown as n (%) and were compared using the Fisher’s exact test.

Figure 1. Overall Survival of young HCC patients by tu-mor size classification (> 5.5 cm vs. ≤ 5.5 cm)

Discussion

Age is one of many factors that influence the risk of developing HCC, especially in countries with a high prevalence of HBV infection [11]. It has been shown that age < 40 years is associated with worse 1-year sur-vival and that the recurrence of HCC is one of the major risk factors for poor prognosis after hepatectomy [12]. The overall rate of HCC recurrence after hepatectomy ranges from 58% to 82% in Asia [5,6]. In the present study, we investigated the risk factors associated with early recurrence (< 1 year) of HCC in young adult pa-tients. We found that more than half of our patients had


tumor recurrence within one year after curative resection, even though most of them had normal liver function and non-cirrhotic livers. Poon et al. showed that those tumor characteristics were not risk factors for recurrence in young adult patients [13]. The effect of chronic liver damage in young adults with HCC is usually mild, and most have better liver function after hepatectomy than patients of advanced age.

The lifetime risk of developing HCC among HBV carriers is high. Kim et al. found that patients with an HBV viral load of more than 2000 IU/mL were at signif-icantly higher risk of HCC recurrence after resection [14]. In addition, Kuzuya et al. reported that control of HBV by antiviral therapy did not produce significant improvement in the recurrence rate of HCC [15]. In our study, most of the patients were HBV carriers. Thus, the role HBV infection plays in tumor recurrence in young HCC patients requires further study. In this study, we found that tumor size was an important factor in the de-velopment of early HCC recurrence. Tumor size is a known prognosticator of poor survival and early recur-rence following hepatectomy [16,17,18]. Chen et al. reported that tumors greater than 3 cm correlated with worse overall survival in young patients with HCC [12] and Roayaie et al. found that tumor size greater than 5 cm was associated with early recurrence and worse sur-vival in patients with HCC after liver transplantation [19]. These results support our findings. In young adult patients, greater tumor size influences early recurrence and survival.

The mechanisms governing hepatocarcinogenesis have been shown to differ between different age groups [20]; however, few studies have explored the relation-ship between early recurrence of HCC and tumor size in young adult patients with HCC. It has been reported that high preoperative serum AFP levels are predictive of early postoperative recurrence [21]. In our study, we also found that young adult patients with early recur-rence of HCC tended to have a high AFP level (AFP > 400 μg/dl). In addition, we found that those patients had a more advanced tumor stage and greater tumor size (8.78 ± 4.65 cm). Although re-operation was performed in patients with early tumor recurrence, all of them tended to have poor survival outcomes. Evidence from our study indicates that greater tumor size is a risk factor for poor overall survival in young adults with HCC. In-terestingly, vascular invasion was not associated with the risk of early recurrence and did not play a role in the overall survival in our study. Although some studies have shown that HCC recurrence can be controlled with repeat hepatectomy [22], other studies have shown that multi-disciplinary local regional therapy, targeted thera-py [23], and other strategies are not effective in prevent-ing early or late recurrence [24,25,26,27].

In conclusion, large tumor size is predictive of ear-ly tumor recurrence and poor survival after salvage in-terventions in young adults.

Limitations This study is limited by its retrospective nature and

its small sample size. Nonetheless, HCC in young adults is rare and our data were collected from a cohort of 45 HCC patients. Thus, we believe that our results provide a meaningful correlation between tumor recurrence fol-lowing hepatectomy and survival outcomes in young adult patients.

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Original article

Effects of lamotrigine monotherapy on lipid peroxidation and the antioxidant defense system in patients with newly diagnosed epilepsy Wan-Yu Huang1, Chin-San Liu2, Jing-Jane Tsai3, Hung-Ming Wu2*

1Department of Pediatrics, Kuang-Tein General Hospital, Taichung, Taiwan 2Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan 3Department of Neurology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan Received 29 January 2014; accepted 24 March 2014

Abstract Background: Conventional antiepileptic drugs can induce oxidative stress. We investigated the effects of lamotrigine (LTG) monotherapy on lipid peroxidation and the antioxidant defense system in patients with epilepsy. Methods: This prospective study comprised 17 patients with newly diagnosed epilepsy and 20 age- and sex-matched controls without evidence of epilepsy. Levels of oxidative stress markers, including plasma malondialdehyde (MDA), total blood glutathione, and non-glutathione free sulfhy-dryl (thiol) compounds in whole blood, as well as the activities of antioxidant defense enzymes, including copper-zinc superoxide dismutase (CuZnSOD), glutathione peroxidase (GSHPx), and glutathione S-transferase in plasma and erythrocytes were measured at baseline in patients and controls, at the end of a 3-month LTG monotherapy regimen (short-term), and at the end of a 36-month LTG monotherapy regimen (long-term). Results: There were no significant differences between patients and controls in baseline levels of the measured oxidative stress markers or activities of antioxidant defense enzymes. There were also no significant differences in levels or activities between controls at entry into the study and patients after 3 months of LTG monotherapy. However, after 36 months of monotherapy, the activi-ties of CuZnSOD and GSHPx in erythrocytes were significantly lower and the concentration of total glutathione was significantly higher than baseline values in patients and controls. No differences in MDA were noted between the groups at any time point. Conclusion: LTG monotherapy has an insignificant effect on lipid peroxidation in young patients with partial epilepsy.

* Corresponding author. Hung-Ming Wu, Department of Neurology, Changhua Christian Hospital. 135 Nanxiao St. Chang-Hua 50006, Taiwan, ROC





KEYWORDS Lamotrigine; Antioxidant; Epilepsy

10 W.-Y. Huang et al.

Introduction

Pharmacotherapy with antiepileptic drugs (AEDs) is the mainstay of epilepsy treatment. Although AEDs can successfully control up to 80% of epileptic sei-zures[1,2], most patients need to take one or more AEDs for many years before symptoms stabilize and the drugs can be withdrawn. The use of some AEDs has been shown to result in acute idiosyncratic reactions, ranging from skin rash to Stevens-Johnson syndrome[3,4]. Chronic latent side effects have also been reported, such as immunological deficiency and teratogenecity[5]. Little is known about the mechanisms governing the adverse effects induced by AEDs. Studies have shown that free radicals play an important role, either directly or indirectly, in the development of toxicity and side effects of AEDs[6,7]. Most AEDs are metabolized in the liver by hydroxylation (phase 1) or conjugation (phase 2). When a reactive metabolite is formed during hepatic metabolism, oxidative stress may occur. It has been found that some conventional AEDs can enhance lipid peroxidation, resulting in altered enzymatic activities related to free radical scavengers in patients with epilep-sy[8,9]. Although lamotrigine (LTG) is a US Federal Drug Administration (FDA)-approved broad-spectrum AED, 10-20% of patients taking LTG suffer from idio-syncratic reactions[10,11]. Risk factors include young age, high starting dose, rapid escalation, and increased cytochrome P450 (CYP)-catalyzed metabolism[10-12]. Studies have shown that arene oxide, the reactive metabolite of LTG, can result in oxidative stress and hence an idiosyncratic reaction to the drug. Although the mechanism governing the teratogenecity of AEDs is still under investigation, oxidative stress has been proposed as one of the leading pathways. The aim of this study was to investigate whether LTG monotherapy induces oxidative stress in patients with epilepsy.

Materials and Methods

Patients

Patients were recruited from the Departments of Neurology and Pediatrics, Kuang-Tein General Hospital, Taichung, Taiwan. Inclusion criteria included: (1) patients aged 18 to 25 years; (2) patients with a history of partial seizures with or without secondary generaliza-tion; (3) patients with newly diagnosed epilepsy without a history of taking AEDs; (4) patients with no evidence o f systemic, psychiatric or progressive neurological

diseases; and (5) patients without a history of long-term vitamin supplementation or herbal drug use. The control group comprised 20 age- and sex-matched individuals without a history of epilepsy. Informed consent to participate in the study was provided by the participants or by the parent(s) of the participants.

Administration of LTG and clinical assess-ments

After a baseline observation period of 8 weeks, patients with epilepsy received LTG at a daily dose of 25 mg for two weeks, followed by an 8-week titration at increments of 50 mg/week up to a maximum daily dose of 450 mg, unless the patient was unable to tolerate the regimen. The titration phase was terminated in patients who showed signs of early adverse reactions, such as skin rash and leukopenia. After LTG titration, patients entered a short-term 3-month LTG maintenance period followed by a long-term 36-month LTG maintenance period. Patients or their parents were instructed to record both seizure frequency and treatment-emergent adverse events during LTG therapy.

Measurement of antioxidant enzymes

Before measurement of antioxidant enzymes, we ensured that none of the patients had evidence of trauma or epileptic seizure one week prior to blood sample collection. In those patients, blood was drawn in the morning after an overnight fast for laboratory studies at the end of the baseline observation period, at the end of short-term LTG therapy, and at the end of long-term LTG therapy. Whole blood (10 mL) was drawn from an antecubital vein and delivered into a heparin-containing plastic tube and an EDTA-containing plastic tube. Plas-ma was immediately obtained by centrifugation, divided into several aliquots, and stored at – 800C in metal-free plastic tubes. The activities of antioxidant enzymes, namely copper-zinc superoxide dismutase (CuZnSOD), , g l u t a t h i o n e p e r o x i d a s e ( G S H P x ) , a n d glutathione S-transferase, and the concentrations of non-enzymatic small-molecular weight antioxidants such as malondialdehyde (MDA), glutathione, and non-glutathione free sulfhydryl (thiol) compounds in plasma were determined within 3 days to avoid interference of free radical scavenger enzymes or lipid peroxidation product formation. Plasma lipid peroxidase activity was monitored by measuring the level of MDA, one of the end products of lipid peroxidation. The activity of free radical scavenging enzymes including CuZnSOD, GHSPx, and GST in erythrocytes (r) and plasma (p), as well as nonenzymatic components including total blood glutathione (tGSH) and non-glutathione free sulfhydryl

Lamotrigine monotherapy on lipid peroxidation in patients with epilepsy 11

(thiol) componts (fSH) in whole blood, which are often involved in detoxification of reactive metabolites of LTG to nonreactive metabolites, was measured in patients receiving LTG and in age- and sex-matched controls at study entry.

Determination of CuZnSOD in erythro-cytes

Red blood cells (RBCs) and plasma were separated by centrifugation. RBCs were then washed three times with cold physiological saline and then lysed with demi-neralized water prior to analysis of rCuZnSOD activity. The enzymes were measured spectrophotome-trically according to the BIOXYTECH® SOD-525™ method (BIOXYTECH S.A. (Cedex, France). The acti-vity of rCuZnSOD is expressed as KU/g Hb.

Determination of tGSH and non-GSH fSH in whole blood

Measurement of tGSH and fSH in whole blood was performed as previously described [13]. Briefly, 0.1mL of whole blood was suspended in 0.05 mL of 10% perchloric acid. After deproteination, total free GSH in the PCA-soluble fraction was measured using an enzymatic recycling assay, which employs glutathione reductase to induce a kinetic colorimetric reaction of DTNB (5,5’ –dithiobis-(2-nitrobenzoic acid)) [14]. The rate of change of the absorbance at 412 nm was moni-tored at 300C for 5 min. The concentration of tGSH in blood was calculated from a standard curve. For fSH measurements, the PCA-soluble supernatant added to DTNB solution was left standing at room temperature. DTNB was allowed to react with the sulfhydryl com-pounds for 30 min, at which time the final absorbance at 412 nm was recorded. The concentration of fSH was calculated by subtracting the concentration of GSH from that of tGSH. The blood concentrations of tGSH and fSH are expressed as µg/mL.

Measurement of GSHPx activities in plasma and erythrocytes

GSHPx activity was assayed as previously reported, with minor modifications [13]. Briefly, we added a sui-table portion of plasma or hemolyzed erythrocytes to 0.9 mL of 50 mM phosphate buffer (pH 7.0) with 0.24 units of glutathione reductase and 1 mM GSH. This mixture was then incubated at 370C for 10 min. NADPH was then added to the solution (final concentration, 0.2 mM). The hydroperoxide-independent consumption of NADPH was monitored by measuring the change in

absorbance at 340 nm for 3 min. Finally, the overall reaction was initiated by adding 100 µl of 12 mM t-butylhydroperoxide. Changes in absorbance during the first five minutes were measured at 340 nm [15]. GSHPx activity, calculated from the hydroperoxide-dependent NADPH consumption rate, is expressed as U/liter or U/g Hb.

Measurement of GST in plasma and erythro-cytes

GST activity in plasma and in erythrocytes was measured using 1-chloro-2,4-dinitrobenzene (CDNB) as a substrate as previously described [16]. The final con-centrations of the reagents in the reaction mixture were 0.2M phosphate buffer (pH 6.5), 0.95 mM CDNB, 0.95 mM GSH, and 0.5 mL plasma or lysed erythrocytes. The reaction was initiated by the addition of the electrophilic s u b s t r a t e C D N B a n d w a s m o n i t o r e d spectro-photometrically at 250C by measuring the change in absorbance relative to said change in the test sample. GST activity is expressed as U/liter or U/g Hb.

Measurement of lipid peroxidase activity in plasma

MDA level was measured as a proxy of lipid perox-idase activity in plasma as previously described, with a few modifications [17]. Blood was drawn into a he-pa rinized tube with 10 µL of 2 mM butylated hy-droxytoluene and then immediately centrifuged. Then, a 20-µL aliquot of plasma was mixed with 2 mL of 0.1 N HCL, 0.3 ml of 10% phosphotungstic acid, and 1 ml of 0.7% 2-thiobarbituric acid (TBA). The mixture was heated in boiling water for 60 min and then exposed to 5 mL 1-butanol to extract the MDA-TBA adduct. After centrifugation, the fluorescence intensity of the MDA-TBA complex in the 1-butanol layer was measured in a fluorescence spectrophotometer with an excitation wa-velength of 525 nm and an emission wavelength of 550 nm. The concentration of lipid peroxidase in plasma is expressed as nmol MDA /mL. A calibration curve was constructed for each run using 1,1,3,3-tetraethoxypropane as the standard.

Statistical analyses

Experimental data were analyzed by the paired Student’s t-test and independent Student’s t-test. The results are expressed as mean ± SD. A P value of <0.05 was considered to indicate statistical significance. All statistical analyses were performed on a personal com-puter with the statistical package SAS for Windows (Version 9.3, SAS Institute, Cary, NC).


Results

The clinical features of the patients and controls in this study are described in Table 1. Of the 19 patients with newly diagnosed epilepsy, two discontinued LTG treatment within the first three months due to skin rash and dizziness and were, therefore, excluded from the study. A total of 17 patients completed the three-month regimen of LTG monotherapy and 15 of them completed the 36–month course. The maintenance dose of LTG ranged from 200 mg/day to 450 mg/day (mean, 300 ± 68.5 mg/day). Mean seizure frequency after three months of LTG treatment (1.4 ± 1.8 seizures/month) was significantly lower than that at baseline (2.8 ± 2.7 seizures/month) (p<0.01). No significant differences in mean seizure frequency were observed between patients who received short-term LTG therapy and patients who received long-term LTG therapy. Also, there were no significant differences in activities of measured antioxi-dant enzymes or MDA levels between controls and

patients at study entry. In addition, there were no significant differences between patient baseline values and those measured in patients after three months of LTG therapy (Table 2). In patients who completed the 36-month LTG monotherapy regimen, the average con-centration of tGSH was significantly higher and the mean activities of CuZnSOD and GSHPX in erythro-cytes were significantly lower than baseline values (P <0.05). Furthermore, the activities of rCuZnSOD, rGSHPx, and tGSH in all seven of the female patients who received long-term LTG therapy tended to be lower than those in the paired female controls at baseline (rCuZnSOD: 89.5 ± 9.0 KU/g Hb vs 103.0 ± 7.5 KU/g Hb, P = 0.01; rGSHPx: 50.7 ± 8.3 U/g Hb vs 58.8 ± 10.2 U/g Hb, P = 0.17; tGSH: 268.1 ± 27.2μg/mL vs 224.5 ± 49.6 µg/mL, P = 0.06). However, the mean level of MDA, a product of lipid peroxidation, after long-term LTG treatment did not differ significantly from that after short-term treatment.

Table 1. Clinical features of controls and patients with epilepsy.

Control group (n = 20) LTG-0 group (n = 17)

Sex (Male/Female)

Age (year)*

Onset of seizure (year)*

Duration (year)*

Etiology

Idiopathic

Cryptogenic

Symptomatic

Seizure type+

Simple partial seizure

Complex partial seizure

Secondary generalization

Seizure frequency (fit/month)*

9/11

21.7 ± 3.9

-

-

-

-

-

-

-

-

-

7/10

21.0 ± 4.7

16.7 ± 4.5

3.5 ± 4.0

-

15

2

8

14

6

2.8 ± 2.7

Control group indicates age-matched control subjects; LTG-0 group indicates patients under lamotrigine monotherapy at entry. * Arithmetic mean ± SD. Seizure type+, some patients had more than one seizure type.


Table 2. Concentrations of antioxidants in plasma and erythrocytes in patients with epilepsy receiving short- and long-

term lamotrigine monotherapy and in age- and sex-matched controls

Controla

(n = 20)

LTG-0a

(n = 17)

LTG-3moa

(n = 17)

LTG-36moa

(n = 15)

rCuZnSOD (KU/g Hb)

tGSH (µg/ml)

fSH (µg/ml)

pGSHPx (U/Liter)

rGSHPx (U/g Hb)

pGST (U/Liter)

rGST (U/g Hb)

MDA (nmol/mL)

101.5 ± 7.4

229.0 ± 40.0

338.6 ± 50.2

688.8 ± 113.6

55.3± 8.2

7.0 ± 0.7

6.4 ±1.3

1.1± 0.3

99.0 ± 8.8

231.1 ± 50.7

333.5 ± 71.1

664.8 ± 107.0

56.0 ± 8.3

6.6 ± 0.9

5.5 ± 1.6

1.0 ± 0.3

98.5 ± 12.4

236.9 ± 40.3

346.1 ± 60.3

667.3 ± 68.0

55.4 ± 8.6

6.8 ± 1.5

5.6 ± 1.7

1.1 ± 0.3

89.2 ± 7.5*#

262.0 ±34.2*#

339.7 ± 32.2

674.4 ± 59.9

48.8 ± 7.8*#

6.7 ± 0.5

5.7 ± 1.7

1.0 ± 0.4

Control, age-matched control group; LTG-0, lamotrigine monotherapy group at entry; LTG-3mo, 3-month regimen of lamotrigine monotherapy; LTG-36mo, 36-month regimen of lamotrigine monotherapy. a Arithmetic mean ± SD. *, P < 0.05, compared with control by unpaired Student’s t test. #, P < 0.05, compared with LTG-0 by paired Student ‘s t test.

Discussion

Many studies have shown that conventional antiepileptic drugs can alter lipid peroxidation and endogenous antioxidant defense mechanisms [18]. However, most of those studies were not prospective and did not investigate the effects of monotherapy. Therefore, we conducted a prospective study to inves-tigate the effects of LTG monotherapy on lipid peroxi-dation and the antioxidant defense system in patients with newly diagnosed epilepsy and found that long-term LTG monotherapy suppressed the activities of CuZn-SOD and GSHPx in erythrocytes and resulted in elevated levels of tGSH after 10 months of treatment.

Oxidative stress is involved in the pathophysiology of many chronic inflammatory diseases [19,20]. In addition, an abundance of evidence indicates that immune and inflammatory reactions occur in brain in various central nervous system (CNS) diseases, inclu-ding epilepsy [21,22]. Epilepsy is one of the most com-mon chronic neurological disorders and studies have shown that reactive oxygen species play a role in the development of seizures [23]. There is also increasing evidence that oxidative stress and lipid peroxidation increase during seizures [24]. Thus, it is important to assess the association between oxidative stress and epilepsy. Yuksel et al. found that levels of lipid peroxi-dation in serum were increased in young patients (age

range, 11 months to 15 years) with epilepsy who did not receive AEDs [25]. In addition, Turkdogan et al. re-vealed that plasma lipid peroxidation was detected in epileptic children with CNS structural abnormalities after receiving AEDs but not in patients without brain structural lesions [26]. In our study, we found that there were no significant differences in lipid peroxide levels or activities of antioxidant enzymes between patients with newly diagnosed epilepsy and healthy sex- and age-matched controls.

The antioxidant enzymes CuZnSOD and GSHPx play important roles in protecting cells from damage caused by reactive oxygen species [27] CuZnSOD breaks down superoxide anion into oxygen and hydro-gen peroxide whereas GSHPx catalyses the reduction of hydrogen peroxide to water, with the simultaneous con-version of reduced glutathione to oxidase glutathione and lipid hydroperoxides, the latter of which reduce lipid peroxidation. In this study, we revealed that CuZnSOD and GSHPx activities were significantly decreased in patients receiving long-term LTG monotherapy. The mechanisms governing the effects induced by LTG are still unknown. Graf et al. found that the activities of CuZnSOD and GSHPx were lower in patients who received long-term treatment with valproic acid (VPA) and stated that the reason could be due to a lack of GSHPx and CuZnSOD cofactors (e.g. selenium, copper, and zinc) in said patients [28]. LTG is metabolized in liver, where it undergoes glucuronidation on the


2-nitrogen atom of the triazine ring [29]; however, Maggs et al reported that cytochrome P450 (CYP) also plays a role in the metabolism of LTG and that CYP-catalyzed metabolism results in the formation of arene oxide, a potent reactive oxygen species [12]. Similarly, VPA metabolism has been shown to occur via glucuronosyltransferase-catalyzed glucuronide conjuga-tion and beta-oxidation, with minor CYP-dependent metabolism [30]. Although metabolism of these two drugs is not completely identical, it is hypothesized that the compromised antioxidant defense system induced by LTG might be associated with alteration of the metabol-ism of trace elements in patients on long-term LTG ther-apy. An alternative explanation may be that LTG and similar antiepileptic drugs enhance hemoglobin auto-oxidation, which is accompanied by the generation of superoxide and hydrogen peroxide [29,30]. Increased generation of reactive oxygen species may, therefore, inhibit the activities of GSHPx and CuZnSOD in patients who are exposed to said drugs for a prolonged period of time [33].

Glutathione, an important water-phase antioxidant and an essential cofactor for antioxidant enzymes, is widely distributed in animals, plants, and micro-organisms. Glutathione participates in various antioxi-dant mechanisms, particularly in the detoxification of xenobiotics [34], and protects cells against the toxic effects of reactive oxygen species and other organic hydroperoxides by serving as a substrate for GSHPx and GST during removal of metabolic intermediates and waste products of xenobiotics, drugs, chemicals, and environmental pollutants.

Glutathione status is homeostatically controlled, being continually self-adjusting with respect to the balance between glutathione synthesis, its recycling from glutathione disulfide, and its utilization. When the status is disturbed by deficiency of the enzymes in the metabolic pathway of glutathione biosynthesis, lipid peroxidation will occur. Previous studies have shown that phenytoin can induce lipid peroxidation in patients with epilepsy due to inadequate supply of antioxidants [8]. However, recent evidence suggests that antioxidant factors are modified to a compensatory level (e.g. gluta-thione) enough to attenuate oxidative challenge, thereby inhibiting lipid peroxidation [35,36]. One of the major factors is the age-associated decrease in activity of the endogenous antioxidant defense system. Al-Turk et al. found that the activity of GSH synthesis begins to de-crease staring in the fourth decade of life [19]. Other studies have demonstrated that higher levels of gluta-thione can be induced in tissues exposed to oxidative stress in young individuals but not in people of advanced age [13,37]. In this study, we found that the level of

tGSH was increased after long-term LTG therapy, which could represent a compensatory defense mechanism that protects against oxidative stress induced by LTG meta-bolic processes, thereby preventing the enhancement of lipid peroxidation in young patients (mean age, 21 ± 4.7 years) but not in older patients. On the other hand, one possible hypothesis for the increased levels of tGSH is the development of selective enzyme inhibitors or enhancers involved in glutathione metabolism and syn-thesis during LTG therapy.

A number of studies have shown that LTG does not induce significant lipid peroxidation in patients [38,39], a finding consistent with that in the present study. Child-ren born to mothers with epilepsy are at greater risk for birth defects, such as facial, cardiac, urogenital and neurological anomalies, which have been shown to be related to exposure to antiepileptic drugs during pre-gnancy [40,41]. Studies have shown that the teratogenic effects of AEDs are mediated by the formation of free radical intermediates during embryonic development [6,7]. Therefore, it is necessary to choose an optimal AED for patients with epilepsy before they become pregnant.

In conclusion, our prospective study shows that LTG monotherapy has an insignificant effect on lipid peroxidation in young patients with partial epilepsy and is, therefore, a relatively safe compound for treatment of epilepsy.

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Original article

Tl-201 myocardial SPECT is an effective imaging modality for differentiating ischemic from non-ischemic dilated cardiomyopathy in patients with left ventricular dysfunction Ching-Pei Chen1,2, Ching-Hui Huang1, Chiang-Hsuan Lee3, Jhi-Joung Wang3, Ming-Che Chang4, Chao-Wei Yang4, Guang-Uei Hung5**, Wen-Sheng Huang4* 1Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan 2Chienkuo Technology University. Changhua, Taiwan 3Departments of Nuclear Medicine and Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan 4Department of Nuclear Medicine, Changhua Christian Hospital, Changhua, Taiwan 5Department of Nuclear Medicine, Chang-Bing Show Chwan Memorial Hospital, Changhua, Taiwan Received 12 March 2014;accepted 24 March 2014

Abstract Background: The presence of perfusion defects on Thallium-201 (Tl-201) myocardial perfusion imaging (MPI) makes it difficult to differentiate non-ischemic dilated cardiomyopathy (DCM) from ischemic cardiomyopathy (ICM) in patients with left ventricular dysfunction. The purpose of this study was to investigate Tl-201 MPI-related factors that can discriminate ICM from DCM. Materials and Methods: We retrospectively reviewed the medical records of 21 patients with echocardiograph-ic evidence of severe left ventricular dysfunction (ejection fraction <40%) who underwent TI-201 single-photon emission computed tomography (SPECT) and coronary angiography procedures within a one-month period. Of them, 12 patients had ICM (defined as stenosis >70% in at least one coronary artery on coronary angiography) and 9 patients had DCM (defined as no evidence of stenosis > 70% in any coronary artery). SPECT was inter-preted using a 17-segment model and a 0 to 4 scoring system. Perfusion defects with a score of 3 or more in a single segment were considered “severe” and those that presented in 3 or more consecutive segments were considered “large”. Summed stress score (SSS) and summed rest score (SRS) were also generated for semi-quantitative analysis of perfusion defects. Results: There was no significant difference in frequency of perfusion defects between patients with ICM and patients with DCM (100% vs. 78%, p > 0.05). Nonetheless, the mean SSS was significantly higher in the ICM group (27.9 ± 13.3) than in the DCM group (8.7 ± 7.9) (p < 0.001). Although there was no significant difference in frequency of large defects between patients with ICM (n=12, 100%) and those with DCM (n=6, 67%) (p > 0.05), there were significant differences in frequency between patients with severe defects in the ICM group (n=10, 83%) and those in the DCM group (n=2, 22%; p = 0.005) and in the frequency of large and severe de-fects between patients with ICM (n=10, 83%) and those with DCM (n=1, 11%; p < 0.001). Receiver operating characteristic (ROC) curve analysis revealed that the optimal diagnostic cut-off values for SSS and SRS were 19 and 8, respectively. In addition, both scores had a sensitivity of 83% and a specificity of 89%. In contrast, visual interpretation of the presence of perfusion defects had a sensitivity of 100% and a specificity of 22% while the sensitivity and specificity associated with the presence of large or severe defects were 83% and 89%, re-spectively. Conclusion: Perfusion defects in patients with ICM are more severe than those in patients with DCM. We found that Tl-201 SPECT was a helpful modality for discriminating ICM from DCM, regardless of whether semi-quantitative analyses of SSS and SRS or visual determination of defects was used.

**Corresponding author. Guang-Uei Hung, M.D., Department of Nuclear Medicine, Chang Bing Show Chwan Memmorial Hospital, 6 Lukon Road, Lukong Town, Chang-Hua 50006, Taiwan ROC

E-mail address: [email protected] *Corresponding author. Wen-Sheng Huang, M.D., Department of Nuclear Medicine and Molecular Image Center, Changhua Christian Hospital. 135 Nanxiao St. Chang-Hua 50006, Taiwan, ROC

E-mail: [email protected] Copyright © 2014, Changhua Christian Hospital.



KEYWORDS Ischemic Cardiomyopathy; Dilated Cardiomyopathy; Thallium-201; Myocardial perfusion imaging

18 C.-H. Lee et al.

Introduction

Myocardial perfusion imaging (MPI) coupled with thallium-201 (Tl-201) or technetium (Tc)-99m single-photon emission computed tomography (SPECT) can accurately diagnose coronary artery disease (CAD) [1]. In patients with left ventricular dysfunction, however, perfusion defects can also be found in those with non-ischemic dilated cardiomyopathy (DCM). Although some earlier studies showed that MPI with Tl-201 could differentiate between ischemic cardiomyopathy (ICM) and DCM, others found that the modality was not relia-ble [2-5]. Recent studies on Tc-99m SPECT showed that perfusion defects in patients with ICM were significant-ly more severe than those in patients with DCM and that MPI could accurately distinguish between ICM and DCM [6, 7]. However, Wu et al reported that Tl-201 SPECT was unable to reproduce that result [8].

Compared with Tc-99m-labeled tracers, SPECT with Tl-201 acquires relatively lower photon count den-sity because of the limitation of radiation dosimetry. Although some studies suggested that gated SPECT using Tl-201 tracers could assess left ventricular fun-ction equally as well as SPECT using Tc-99m tracers [9, 10], others found that Tl-201 SPECT provided limited reproducibility due to lower counts [11, 12]. In our pre-vious study we used a modified imaging protocol to obtain higher count statistics and validated the perfor-mance of Tl-201 gated SPECT in the assessment of left ventricular function [13]. We also showed the feasibility of Tl-201 SPECT in evaluating early post-stress function [14-16]. In this study, we assessed whether Tl-201 SPECT could discriminate ICM from DCM using a modified imaging protocol.

Materials and methods

Patients

We retrospectively reviewed the records of 21 pa-tients who underwent Tl-201 myocardial perfusion SPECT and cardiac catheterization procedures within a one-month period. All patients had echocardiographic evidence of severe left ventricular dysfunction (ejection fraction <40%). None of the patients had primary valvu-lar heart disease. Of the 21 patients, 12 had at least one coronary artery with a stenotic diameter greater than 70%; of them, six had 3-vessel disease and five had 2-vessel disease. Those patients were considered to have

ICM. The remaining nine patients had no significant coronary disease and were considered to have non-ischemic cardiomyopathy.

Tl-201 myocardial perfusion SPECT

Patients fasted for at least 4 hours and were asked to abstain from caffeine-containing foods and beverages as well as medications containing methylxanthine for 24 hours before the procedure. Dipyridamole was admini-stered intravenously at a rate of 0.14 mg/kg/min for 4 minutes. Tl-201 (3 mCi) was then injected 3 minutes after the end of the dipyridamole infusion. Blood pre-ssure and heart rate were recorded every 1 minute. Ami-nophylline was given to patients with evidence of chest pain, dyspnea, nausea, vomiting, severe bradycardia (heart rate less than 40 beats per minute), second or third degree atrioventricular block, ST depression, or frequent premature ventricular contractions.

All SPECT scans were acquired with the patient in the supine position. Stress SPECT scans were taken 5 minutes after Tl-201 injection and rest SPECT scans were taken 4 hours after injection. A dual-head gamma camera (Millennium MG, GE, Haifa, Israel) equipped with a low-energy/general-purpose collimator was used. Thirty-two projections (70 seconds per projection) were obtained over a 180° arc extending from the 45° right anterior oblique position to the 45° left posterior oblique position. A 20% window was centered over the 72 and 167 keV Tl-201 photopeaks. The projection images were generated in 64 x 64 matrices with a 1.60 acquisi-tion zoom and were reconstructed by filtered backpro-jection with a Butterworth filter (order 10 and cut-off frequency 0.35 cycle/pixel).

Interpretation of SPECT images

The left ventricle was divided into 17 segments and perfusion defects in all segments were semi-quantitatively scored on a 5-point scale (0, normal; 1, mildly reduced; 2, moderately reduced; 3, severely re-duced; and 4, no uptake). The summed stress score (SSS) and the summed rest score (SRS) were the sum of the scores of 17 segments on stress and rest images, respec-tively. The sum of the difference between each of the 17 segments on the stress and rest images was defined as the summed difference score (SDS). Perfusion defects with a score of 3 or more in a single segment were con-sidered “severe” and those that presented in 3 or more consecutive segments were considered “large”.

Statistical Analysis

Continuous variables are expressed as mean ± SD and were tested by the Student’s t-test. ROC curve ana-lysis was performed to generate optimal cut-off values

Tl-201 SPECT in differentiating dilated cardiomyopathy 19

of SSS and SRS in the diagnosis of ICM. Non-continuous variables are expressed as frequency and percentage and were tested by the Chi-square test. A p value less than 0.05 was considered to represent statis-tical significance. To determine the clinical performance of different SPECT criteria for diagnosing ICM, the sensitivity, specificity, and positive and negative predic-tive values were calculated.

Results

Clinical Characteristics

The clinical characteristics of patients are shown in Table 1. There were no differences in age, male gender, hypertension, diabetes, hyperlipidemia, family history, smoking history, or left ventricular ejection fraction be-tween the ICM and DCM groups. Five (42%) of the patients with ICM had a history of myocardial infarction (MI) and none of the patients with DCM had a history of MI (p = 0.027).

Tl-201 myocardial perfusion SPECT

Perfusion parameters in both groups are shown in Table 2. Perfusion defects were found in all 12 patients with ICM and in 7 of the 9 patients with DCM (100% vs. 78%, p > 0.05). The rate of defects seen only in the infe-rior wall was significantly higher in the DCM group (n=5, 71%) than in the ICM group (n=0, 0%) (p < 0.001).

Reversible stress-induced perfusion defects were found in 9 patients in the ICM group and in 5 patients in the DCM groups (75% vs. 56%, p > 0.05). The SSS, SRS and SDS of the ICM and DCM groups were 27.9 ± 13.3 vs. 8.7 ± 7.9 (p < 0.001), 17.5 ± 9.4 vs. 5.1 ± 4.9 (p = 0.002) and 11.3 ± 11.9 vs. 3.6 ± 5.0 (p >0.05), respec-tively. In the ROC curve analyses of SSS and SRS for the diagnosis of ICM, the areas under the curves were 0.91 (95% confidence interval [CI], 0.71 to 0.99) and 0.88 (CI, 0.66 to 0.98), respectively. The optimal cut-off values were 19 for SSS and 8 for SRS, and the sensitivi-ty and specificity for both were 83% and 89%, respec-tively.

Large defects were found in all patients with ICM and in 6 of the 9 patients with DCM (100% vs. 67%, p >0.05). Severe defects were found in 10 patients with ICM and in 2 patients with DCM (83% vs. 22%, p = 0.005), and large and severe defects were found in 10 patients with ICM and in 1 patient with DCM (83% vs. 11%, p < 0.001).

The diagnostic performance of different perfusion criteria is shown in Table 3. For the diagnosis of ICM, the presence of perfusion defects had a sensitivity of 100% but a specificity of only 22%. When using large and severe defects for detecting ICM, the sensitivity slightly decreased to 83% but the specificity significant-ly increased to 89%. The presence of large and severe defects had a 91% predictive value for ICM and the ab-sence of perfusion defects had a 100% predictive value for DCM.

Figure 1. Representative images of a patient with ischemic cardiomyopathy (left panel) and a patient with non-ischemic cardiomyopathy (right panel). In the left panel, large and severe perfusion defects involving the apex and anteroseptal, inferoseptal, and inferior walls are noted on stress SPECT images with slight redistribution on rest. Coronary angiogra-phy reveals critical stenosis in the left anterior descending and right coronary arteries. In the right panel, SPECT images reveal fixed, large but moderate perfusion defects in the apex and inferior wall. No significant stenosis is visible on coro-nary angiography. Both patients had a severely dilated left ventricle.

20 C.-H. Lee et al.

Table 1. Clinical characteristics

ICM (n = 12)

DCM (n = 9) p Value

Age 67.7 ± 13.9 60.4 ± 10.9 NS

Male 10 (83%) 6 (67%) NS

Hypertension 8 (67%) 8 (89%) NS

Diabetes 6 (50%) 4 (44%) NS

Hyperlipidemia 4 (33%) 6 (67%) NS

Family history 2 (17%) 2 (22%) NS

Smoking history 8 (67%) 3 (33%) NS

MI history 5 (42%) 0 (0%) 0.027

LV EF 31.4 ± 5.2 32.3 ± 6.9 NS

Values are mean ± SD or n (%) ICM, ischemic cardiomyopathy; DCM, idiopathy dilated cardiomyopathy; MI, myocardial infarction; LV EF, left ven-tricular ejection fraction

Table 2. Tl-201 SPECT results

Ischemic DCM (n=12)

Non-ischemic DCM (n=9) p Value

Perfusion defect 12 (100%) 7 (78%) NS

Inferior wall only 0 (0) 5 (71%) < 0.001

Redistribution 9 (75%) 5 (56%) NS

Large defect 12 (100%) 6 (67%) NS

Severe defect 10 (83%) 2 (22%) 0.005

Large severe defect 10 (83%) 1 (11%) < 0.001

SSS 27.9 ± 13.3 8.7 ± 7.9 < 0.001

SRS 17.5 ± 9.4 5.1 ± 4.9 0.002

SDS 11.3 ± 11.9 3.6 ± 5.0 NS

Values are mean ± SD or n (%) SSS, summed stress scores; SRS, summed rest scores; SDS, summed difference scores


Table 3. Clinical use analysis Perfusion defect Large defect Severe defect Large Severe defect

Sensitivity 100% (12/12) 100% (12/12) 83% (10/12) 83% (10/12)

Specificity 22% (2/9) 33% (3/9) 78% (7/9) 89% (8/9)

PPV 63% (12/19) 67% (12/18) 83% (10/12) 91% (10/11)

NPV 100% (2/2) 100% (2/2) 78% (7/9) 80% (8/10)

Values are % (n) PPV, Positive predictive value; NPV, Negative predictive value

Discussion

In comparison with Tc-99m-labeled tracers, Tl-201 has some physical drawbacks, including lower photon energy, longer half-life, and limited injection dose due to higher radiation burden. Nonetheless, Tl-201 remains the most widely used tracer for MPI in many Asian countries, including Taiwan, because it only requires a single injection for stress/rest protocols and has the ability to assess myocardial viability when necessary. Other reasons for its use include lower cost and lower radiation burden to nuclear medicine personnel.

In order to optimize the image quality of Tl-201 MPI, we modified the imaging protocol to obtain higher count statistics. First, the Tl-201 dose used in this study for routine stress/redistribution SPECT scans was 3 mCi, which is slightly higher than that used in most nuclear laboratories in Taiwan but is still in accordance with the procedural guidelines of the American Society of Nuc-lear Cardiology [17]. Second, the acquisition time used in this study was 70 seconds per view, which is much longer than that used in ordinary protocols (30-40 seconds per view). With this protocol, we have found that variables of left ventricular function (LVEF and volumes) obtained from Tl-201-gated SPECT correlate very well with those obtained from echocardiography and that the reproducibility and repeatability are similar to those in studies using Tc-99m sestamibi [13].

Danias et al found that patients with ICM had sig-nificantly higher SSS values than patients with DCM (32.9 ± 7.7 vs. 6.9 ± 3.8, p < 0.001) on Tc-99m sestami-bi SPECT scans, indicating that Tc-99m SPECT can reliably distinguish between the two conditions [6]. Wu et al performed a similar study using Tl-201 as the tracer but found considerable overlap between ICM and DCM (SSS: 27.9 ± 9.4 vs. 20.6 ± 8.6, p = 0.04) [8]. The favor-able imaging characteristics of Tc-99m over Tl-201 are one of the major reasons for the discrepancy between the two studies. In this study, we found that the difference in SSS between ICM and DCM was profound (27.9 ± 13.3

vs. 8.7 ± 7.9, p < 0.001), a finding that supports the re-sults reported by Danias et al [6]. In addition, our study confirmed that the presence of large and severe defects on Tl-201 SPECT scans are not only specific but also sensitive markers for ICM, which is consistent with the findings reported by Tauberg et al. [5]. Semi-quantitative analysis also revealed higher cut-off values (SSS ≥ 19 and SRS ≥ 8) than traditionally used values (SSS ≥ 4) for predicting the presence of significant co-ronary stenoses on coronary angiography [1]. Our study indicates that Tl-201 SPECT, using our imaging proto-col combined with more rigorous interpretation criteria, is useful in differentiating ICM from DCM in patients with left ventricular dysfunction.

The underlying mechanisms of perfusion defects in DCM remain unclear. Postulated hypotheses include partial volume effects secondary to large ventricular volume [18], tracer non-homogeneity due to myocardial fibrosis [19], and altered tracer uptake by impaired cel-lular metabolism [20]. In this study and in other pre-vious studies, it was found that these perfusion defects were usually mild to moderate [5, 6]. In addition, in this study we observed that the frequency of perfusion de-fects seen only in the inferior wall was much higher in patients with DCM than in patients with ICM (71% vs. 0%, p < 0.001). It is known that the majority of diaph-ragmatic attenuation artifacts encountered do not pro-duce severe defects [17]; however, artifacts can appear somewhat more intense in low-count density tomograms [21]. Therefore, it is not surprising to see severe “arti-facts” in the inferior walls of patients with DCM when using a lower injection dose and shorter acquisition time.

There are some limitations in this study. First, at-tenuation correction was not performed. Attenuation artifacts can cause perfusion defects; however, their im-pact on the visual assessment in this study should be similar in the ICM and DCM groups. Second, the num-ber of patients studied was relatively small and might have led to selection bias. Our results need to be tested prospectively using a larger patient population. Third, the perfusion defects were subjectively scored with vis-

22 C.-H. Lee et al.

ual interpretation, leading to potential bias; however, the reader was blinded from the catheterization information.

Conclusions

Perfusion defects in patients with ICM are signifi-cantly more severe than those in patients with DCM on Tl-201 SPECT images. We found that more rigorous interpretation criteria (SSS ≥ 19 or SRS ≥ 8, or the pres-ence of large and severe perfusion defects) can differen-tiate between ICM and DCM in patients with left ventri-cular dysfunction.

Acknowledgement

The authors thank Ms. Chia-Chi Chang for her technical assistance. This work was supported in part by grants from the Changhua Christian Hospital (102-CCH-IRP-060 and CMNDMC10101-13).

References

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[3] Doi YL, Chikamori T, Takata J, et al. Prognostic value of thallium-201 perfusion defects in idiopathic dilated cardiomyopathy. Am J Cardiol 1991;67: 188-93.

[4] Chikamori T, Doi YL, Yonezawa Y, et al. Value of dipyridamole thallium-201 imaging in noninvasive differentiation of idiopathic dilated cardiomyopathy from coronary artery disease with left ventricular dysfunction. Am J Cardiol 1992;69: 650-3.

[5] Tauberg SG, Orie JE, Bartlett BE, et al. Usefulness of thallium-201 for distinction of ischemic from idi-opathic dilated cardiomyopathy. Am J Cardiol 1993;71: 674-80.

[6] Danias PG, Ahlberg AW, Clark BA III, et al. Com-bined assessment of myocardial perfusion and left ventricular function with exercise technetium-99m sestamibi gated single-photon emission computed tomography can differentiate between ischemic and nonischemic dilated cardiomyopathy. Am J Cardiol 1998;82: 1253–8.

[7] DaniasPG, Papaioannou GI, AhlbergAW, et al.Usefulness of electrocardiographic-gated stress techne-tium-99m sestamibi single-photon emission com-puted tomography to differentiate ischemic from Non-ischemic cardiomyopathy. Am J Cardio 12004;94:14-9.

[8] Wu YW, Yen RF, Chieng PU, et al.Tl-201 myocar-dial SPECT in differentiation of ischemic from noni-schemic dilated cardiomyopathy in patients with left ventricular dysfunction. J Nucl Cardiol 2003;10: 369-74.

[9] He ZX, Cwajg E, Preslar JS, et al. Accuracy of left ventricular ejection fraction determined by gated myocardial perfusion SPECT with Tl-201 and Tc-99m sestamibi: comparison with first-pass radionuc-lide angiography. J Nucl Cardiol 1999;6: 412–7.

[10] Bacher-Stier C, Muller S, Pachinger O, et al. Thal-lium-201 gated single-photon emission tomography for the assessment of left ventricular ejection frac-tion and regional wall motion abnormalities in comparison with two-dimensional echocardio-graphy. Eur J Nucl Med 1999;26:1533–40.

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[14] Hung GU, Lee KW, Chen CP, et al. Relationship of transient ischemic dilation in dipyridamole myo-cardial perfusion imaging and stress-induced changes of functional parameters evaluated by Tl-201 gated SPECT. J Nucl Cardiol 2005;12:268-75.

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Original Article

學齡期高功能自閉症兒童的心智理論能力表現

許君翎﹡, 陳姵瑱

彰化基督教醫院兒童發展中心 Received 2 December 2013;accepted 24 March 2014

Abstract

本研究為了解學齡期高功能自閉症兒童與一般正常兒童在不同層次心智理論能力上的表現

差異及得分型態的不同。共有 27 名高功能自閉症學齡兒童及 27 名一般兒童參與研究，

受試者接受心智理論測驗以評估其三個層次的心智理論能力，所得結果再以 t 檢定及卡方

考驗進行統計分析。結果顯示高功能自閉症兒童的各項得分皆顯著低於一般兒童。得分型

態方面，解讀他人諷刺言詞的真正含意時，以問答方式得分的比率，自閉症兒童為

68.35%，一般兒童為 90.48%。在理解隱喻的動機推論部份，以問答方式得分的比率，自

閉症兒童為 9.52%，一般兒童則為 50%。可見高功能自閉症兒童到了學齡期，各層次的

心智理論能力仍有缺損，且較難自行進行心智理論推測，比起一般同齡者更需要透過提示

來正確推論他人的想法與動機。 * Corresponding author. 許君翎彰化市南校街 135 號





KEYWORDS 高功能自閉症心智理論學齡兒童

http://www2.cch.org.tw/7477

C.-L. Hsu et al. 25

前言

心智理論意指推測他人之想法、信念、慾望、感受及意圖等等…心理狀態，並以此預測和理解其行為的能力[1]，屬於社會認知能力的一部份[2]。Flavell、Miller 與 Miller 於 1993 年曾提出心智理論能力的五階段理論，階段一至三屬於心智理論的前備技能，約於五歲前發展出來；階段四為開始出現真正的心智理論能力，出現在六歲左右；階段五是更為成熟的心智理論能力，在七歲後才逐漸發展[3]。

研究證實各種智力水準的自閉症者皆普遍存在著心智理論能力的缺陷，並因此導致患者在語言、想像力及社會功能領域的損傷[4,5]，如：無法了解他人的行為動機、難以站在他人立場思考、社會互動能力差、缺乏溝通人際需求的能力等… [6]。Baron-Cohen、Leslie 與 Frith 是最早以心智理論缺損來解釋自閉症患者社會功能損傷的學者，他們比較了高功能自閉症兒童（High-Functioning Autism，簡稱 HFA）、唐氏症及正常兒童，發現在排除語言理解、記憶及猜測等干擾因素後，HFA 兒童通過第一順位錯誤信念測驗的比率仍比唐氏症及學前兒童低[7]。Buitelaar、Wees、Swaab-Barneveld 與 Gaag 比較 HFA 及正常學齡兒童的情緒辨識能力後指出，HFA 者的平均智力和語文能力雖正常，但辨識臉部情緒及情境相關情緒的能力卻比正常兒童差[8]。Muris 等人以學齡期高功能廣泛性發展疾患為研究對象，也有相同發現[3]。

針對自閉症者各階段心智理論能力的其他研究，結果一致指出 HFA 兒童及青少年推測第一順位錯誤信念的能力比心智年齡相當的控制組差[9,10]，甚至低於更為年幼的正常兒童[8,11]。自閉症患者第二順位錯誤信念推測能力不但比心智年齡相當的正常人差[11,12,13,14]，也低於心智年齡較低的唐氏症與正常兒童[15]，Gillott、Furniss 與 Walter 發現 HFA 兒童在理解諷刺、假裝、玩笑及說謊等高層次的心智理論能力明顯比同齡兒童差 [6]。Baron-Cohen、O ’Riordan、Stone、Jones 與 Plaisted 指出智力正常且能通過第二順位錯誤信念測驗的 HFA 及亞斯伯格兒童，偵測失禮的能力卻比同齡兒童低落，甚至比年幼者差[16]。

因此，HFA 的異常行為和社會功能缺損與心智理論能力缺陷有密切關係，且此缺陷遍及各個年齡層。患者在心智理論各階段的發展不但比正常同齡者差，甚至不及年幼者，以及智力較低的唐氏症患者。此種缺損，亦無法完全以智力及語言能力等其他認知功能損傷做解釋。

但過去研究多有研究對象、程序及測驗工具的問題，如未區分不同診斷的廣泛性發展疾患[3]、混用不同的診斷準則[12]、測驗內容未涵蓋不同發展階段的心智理論能力[5,16]等。因此，本研究的研究對

象皆經過專科醫師以 DSM-IV 的標準確診為 HFA，並依據 Flavell 等人提出的心智理論能力五階段理論[3]，修訂編製涵蓋三大層次心智理論能力的測驗。本研究的主要目的為了解 HFA 兒童在各層次心智理論上的得分是否與一般兒童有所差異，再者，探討HFA 兒童的得分型態是否異於一般兒童。以期，得知 HFA 者的心智理論整體發展與教學介入時所需的提示程度。

方法

1. 研究對象本研究自中部地區某醫學中心招募實驗組受試，

由兒童心智科或小兒神經科專科醫師確診，並排除有腦傷、重大神經或生理疾病、智商低於 70 分、嚴重語言障礙、情緒、社會剝奪及被虐者。控制組受試招募自某國小，由學校老師挑選無智能障礙者，且年級分佈與實驗組相同。經篩選後，共有 27 名HFA 學齡兒童及 27 名一般正常兒童參與。 2. 研究工具

2.1 魏氏兒童智力量表第四版（中文版）：魏氏兒童智力量表第四版（WISC-IV）（中文版）

是一套用以評估 6 歲至 16 歲 11 個月兒童認知能力的個別化測驗，具有良好的心理計量特性。共包含14 項分測驗[17]，收案時施測 10 項分測驗，所得分數經轉換後即可得到全量表智商、語文理解、知覺推理、工作記憶及處理速度等五項分數。

2.2 心智理論測驗：本測驗是參考 Happé[18]、Adachi 等人 [19]、

Muris 等人[3]及 Baron-Cohen 等人[16]所發展測量心智理論的幾項測驗後，由鳳華和許君翎編製完成。用以評估兒童的心智理論前備技能、真正心智理論能力的出現，及更為成熟的心智理論能力。共包含 7項分測驗，分屬於三大層次，層次一為基本心智發展（含慾望或情境引起的情緒與信念分測驗）；層次二為進階心智發展（含基本信念及第一順位錯誤信念兩項分測驗）；層次三則為高層次心智發展（含第二順位錯誤信念、理解諷刺、理解隱喻及分辨失禮等四項分測驗）。本測驗有良好的內部一致性，α係數介於.59~.86 之間[20]。

統計方法

本研究使用以 t 檢定與卡方考驗進行統計分析。

結果

參與本研究的受試者共 54 名，包含 27 名 HFA兒童及 27 名一般正常兒童，兩組人的年級分佈無顯著差異(χ2 (5)=,000，p＞.05)(表 1)。

26 TOM ability in children with HFA

表 1 受試者的年級分配與適合度考驗年級一般組 HFA X2 p

人數 % 人數 % .000 1.000 一 2 7.4 2 7.4 二 6 22.2 6 22.2 三 5 18.5 5 18.5 四 6 22.2 6 22.2 五 4 14.8 4 14.8 六 4 14.8 4 14.8

心智理論測驗部分，兩組受試者的各項平均得

分皆逹.05 以上的顯著差異。層次一基本心智發展部份，HFA 兒童在層次一總分、慾望或情境引起的情緒與信念分測驗、層次一辨識能力及層次一確認能力得分皆顯著低於一般兒童。層次二進階心智發展部份，HFA 兒童在層次二總分、基本信念分測驗、第一順位錯誤信念分測驗、層次二辨識能力及層次

二確認能力的得分皆顯著低於一般兒童。層次三高層次心智發展及測驗總分部份，HFA 兒童在全量表總分、層次三總分、第二順位錯誤信念分測驗、理解諷刺分測驗、理解隱喻分測驗、分辨失禮分測驗、層次三辨識能力及層次三確認能力的得分皆顯著低於一般兒童(表 2)。

表 2. 受試者在心智理論測驗上的表現一般組 HFA t 平均數標準差平均數標準差

層次一總分 11.93 .27 10.54 2.12 3.31** 慾望或情境引起的情緒與信念 11.93 .27 10.54 2.12 3.31**

層次一辨識 6.00 .00 5.50 1.14 2.27* 層次一確認 5.93 .27 5.04 1.83 3.74** 層次二總分 8.74 1.87 5.93 2.67 4.98*** 基本信念 5.07 1.33 4.00 1.57 2.72**

第一順位錯誤信念 3.67 .92 1.93 1.41 5.38*** 層次二辨識 4.48 .89 3.41 1.05 4.06*** 層次二確認 4.26 1.06 2.52 1.50 4.92*** 層次三總分 44.22 5.81 28.50 12.47 5.65***

第二順位錯誤信念 1.81 .88 .30 .01 7.38*** 理解諷刺 16.81 2.34 11.25 5.86 4.35*** 理解隱喻 19.70 4.36 12.00 6.91 4.90*** 分辨失禮 5.89 .32 3.42 2.34 5.14*** 層次三辨識 15.89 1.95 11.46 4.41 4.54*** 層次三確認 28.33 4.29 17.04 8.41 5.93***

總分 64.89 6.41 45.08 15.60 6.14*** * p<.05,** p<.01,*** p<.001

得分型態方面，一般兒童與 HFA 兒童有明顯的

不同，解讀他人諷刺言詞的真正含意時，一般兒童相較於 HFA 兒童多以問答方式得分。在理解隱喻的

動機推論部份，HFA 兒童以問答方式得分的比例明顯低於一般兒童，多數需透過選答方式才能得分(表 3 )。

表 3 受試者的應答型態與百分比同質性考驗應答型態一般組 HFA X2 p

人次％人次％ 14.323 .000 解讀諷刺問答 95 90.48 54 68.35

選答 10 8.52 25 31.65 推論隱喻動機問答 53 50 8 9.52 35.222 .000

選答 53 50 76 90.48

C.-L. Hsu et al. 27

討論

本研究結果與國外針對學齡期 HFA 兒童所做的研究相似[3,6,8,9,10]，也支持 Baron-Cohen 等人所提出的自閉症心智理論能力缺損假說[7]。HFA 兒童到了學齡期，在各層次心智理論能力上仍有明顯缺損，且心智理論能力的發展層次愈高，HFA 兒童與一般兒童的差異也愈大。即使是推論情緒及信念此些五歲之前即開始發展的心智理論前備技能也顯著落後一般同齡者，要發展出角色取替、理解弦外之音、分辨聲音表情及不合宜言行等層次較高的心智理論能力則更為困難。從得分型態的分析顯示，HFA 兒童較難獨立推測他人的心理狀態，比起一般同齡者更需要透過提示才能正確推論他人的想法與動機。

就本研究的 HFA 受試而言，雖然平均智力有中等水準，有些受試甚至可達優秀程度。但在進行心智理論測驗時，表現仍不如以其智力所做的預期，他們比起一般兒童更常出現無法理解他人意圖的反應，難以站在他人的立場來進行思考，有困難從聲音表情中去解讀出他人真正的情緒與心理狀態，而且極容易相信表面說辭，不懂當他人所言與事實不符時，應從聲音表情去判斷發言者的情緒狀態與意圖，也不太能區辨不禮貌的言行。

心智理論能力的不足，使得 HFA 兒童難以判斷他人的情緒、想法及動機，故較無法預測和理解別人的行為，進而調整自己的言行，使得社交互動更為順暢。建議在進行自閉症者社交訓練時，需加入心智理論能力教學，並可使用選答或給予其他提示等方式來促進其理解教學內容，以建立成功經驗。

參考文獻

[1] Kleinman J, Marciano PL, Ault RL. Advanced Theo-ry of Mind in High-Functioning Adults with Autism. J Autism Dev Disord 2001;31:29-36.

[2] Adolphs R. The neurobiology of social cognition. Curr Opin Neurobiol 2001;11:231-9. Baron-Cohen S. The Autistic Child’s Theory of Mind: a Case of Spe-cific Developmental Delay. J Child Psychol Psychia-try 1989;30:285-97.

[3] Muris P, Steerneman P, Meesters C, et al. The TOM Test: A New Instrument For Assessing Theory of Mind in Normal Children and Children with Perva-sive Developmental Disorder. J Autism Dev Disord 1999;29:67-80.

[4] Frith U. Social communication and its disorder in autism and Asperger syndrome. J Psychopharmacol 1996;10:48-53.

[5] Steele S, Joseph RM, Tager-Flusberg H. Brief Re-port: Developmental Change in Theory of Mind Ability in Children with Autism. J Autism Dev Disord 2003;33:461-7.

[6] Gillott A, Furniss F, Walter A. Theory of mind abil-ity in children with specific language impairment. Child Lang Teach Ther 2004;20:1-11.

[7] Baron-Cohen S, Leslie AM, Frith U. Does the autis-tic child have a “theory of mind”? Cognition 1985;21:37-46.

[8] Buitelaar JK, Wees MVD, Swaab-Barneveld H et al. Theory of mind and emotion-recognition functioning in autistic spectrum disorders and in psychiatric con-trol and normal children. Dev Psychopathol 1999;11:39-58.

[9] Pilowsky T, Yirmiya N, Arbelle S, et al. Theory of mind abilities of children with schizophrenia, chil-dren with autism, and normally developing children. Schizophr Res 2000;42:145-55.

[10] Peterson C. Mind and Body: Concepts of Human Cognition, Physiology and False Belief in Children with Autism or Typical Development. J Autism Dev Disord 2005;35:487-97.

[11] Dissanayake C, Macintosh K. Mind Reading and Social Functioning in Children with Autistic Disor-der and Asperger’s Disorder. In: Repacholi B, Slaughter V, editors. Individual Differences in Theory of Mind: Implications for Typical and Atypical Development. New York: The Psychology Press; 2003, p. 213-39.

[12] Dahlgren SV, Trillingsgaard A. Theory of Mind in Non-Retarded Children with Autism and Asper-ger’s Syndrome. A Research Note. J Child Psychol Psychiatry 1996;37:759-63.

[13] Shields J, Varley R, Broks P et al. Social Cognition in Developmental Language Disorders and High-Level Autism. Dev Med Child Neurol 1996;38: 487-95.

[14] Bauminger N, Kasari C. Brief Report: Theory of Mind in High-Functioning Children with Autism. J Autism Dev Disord 1999;29:81-6.

[15] Baron-Cohen S. The Autistic Child’s Theory of Mind: a Case of Specific Developmental Delay. J Child Psychol Psychiatry 1989;30:285-97.

[16] Baron-Cohen S, O’Riordan M, Stone V et al. Recognition of Faux Pas by Normally Developing Children and Children with Asperger Syndrome or High-Functioning Autism. J Autism Dev Disord 1999;29:407-18.

[17] 陳榮華、陳心怡，主編。魏氏兒童智力量表第四版中文版指導手冊。台北市：中國行為科學社股份有限公司，2007。

28 TOM ability in children with HFA

[18] Happé FGE. An Advanced Test of Theory of Mind: Understanding of Story Characters’ Thoughts and Feelings by Able Autistic, Mentally Handicapped and Normal Children and Adults. J Autism Dev Disord 1994;24:129-54.

[19] Adachi T, Koeda T, Hirabayashi S et al. The meta-phor and sarcasm scenario test: a new instrument to

help differentiate high functioning pervasive devel-opmental disorder from attention defi-cit/hyperactivity disorder. Brain Dev 2004;26:301-6.

[20] 鳳華。中部地區亞斯伯格症者心智理論之發展現況及心智理論社會技巧教學成效結案報告。2008。NSC-95-2413-H-018-003。

C.-L. Hsu et al. 29

Theory of mind in school-aged children with high-functioning autism

Chun-Ling Hsu* , Pei-Zhen Chen

Child Development Center, Changhua Christian Hospital,Changhua county, Taiwan

Abstract This study examined differences in scoring patterns and performance on the Theory of Mind test between 27 school-aged chil-dren with a diagnosis of high-functioning autism and 27 age-matched normal children. Researchers recorded and scored the children’s oral responses and data were analyzed by the t-test and chi-square test. We found that the scores of children with high-functioning autism were significantly lower than those of normal children. In addition, we found that 68.4% of children with high-functioning autism could explain the meaning of sarcasm compared with 90.5% of normal children. Moreover, only 9.5% of children with autism could explain the meaning of metaphors compared with 50% of normal children. These findings reveal that the theory of mind is impaired in school-aged children with high-functioning autism. Our results also show that these children require more prompts to understand others’ thoughts and motivations correctly than normal children at the same age. Keywords: High-Functioning Autism, Theory of Mind, school-age children

* Corresponding author. Chun-Ling Hsu, 135 Nanxiao St. Changhua City, Changhua County 500, Taiwan



Case Report

Unusual rib metastatic patterns on bones scans in a patient with breast cancer: A case report Po-Ling Chang1, Yue-Chong Wu2, Shou-Jen Kuo2, Kuang-Tao Yang1, Shou-Dong Chen2*, Wen-Sheng Huang1,3*

1Department of Nuclear Medicine, Changhua Christian Hospital, Changhua, Taiwan 2Breast Center and Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan 3Molecular imaging Center, Changhua Christian Hospital, Changhua, Taiwan Received 8 January 2014;accepted 24 March 2014

Abstract

Focal uptake in the costochondral junction seen on bone scintigraphy is usually indicative of be-

nign disease. A 42-year-old woman with breast cancer underwent Tc-99m MDP whole-body bone

scintigraphy. Scans revealed focal uptake in the left sixth costochondral junction; however, chest

X-ray did not reveal any abnormalities. A benign lesion, possibly due to traumatic injury, was diag-

nosed. The patient subsequently underwent neoadjuvant chemotherapy and partial mastectomy.

At five-month follow-up, scintigraphy revealed decreased tracer uptake. However, bone scintigra-

phy performed at two-year follow-up showed an extended band-like uptake pattern at the sixth

costochondral junction and abnormal bony uptake elsewhere. Those findings in conjunction with a

progressive increase in serum levels of CA15-3 and evidence of cancer on FDG PET scans indi-

cate that breast cancer had metastasized to the left sixth rib. * Corresponding author. Wen-Sheng Huang, M.D. Department of Nuclear Medicine, Changhua Christian Hospital. 135 Nanxiao St.

Chang-Hua 50006, Taiwan, ROC Email: [email protected]

* Corresponding author. Shou-Dong Chen, M.D. Department of General Surgery, Changhua Christian Hospital. 135 Nanxiao St. Chang-Hua 50006, Taiwan, ROC Email: [email protected]




KEYWORDS Rib metastasis Breast cancer Bone scintigraphy FDG PET

P.-L. Chang et al. 31

Introduction

Breast cancer is the most frequently diagnosed can-cer and is the leading cause of cancer death in women, accounting for 23% of total cancer cases and 14% of cancer deaths [1, 2,3]. About 20% of patients will de-velop metastases during the course of their disease and 50% of them will develop bone metastases [4,5]. Tc-99m methylene diphosphonate (MDP) bone scintigraphy and F-18-fluorodeoxyglucose positron emission tomo-graphy (FDG PET) are useful imaging modalities for detecting bony metastasis [6]. However, the uptake cha-racteristics differ between the two techniques.

Bone scintigraphy reflects the osteoblastic reaction of bone to the presence of tumor cells whereas FDG PET shows the metabolic activity of metastatic tumors. While the sensitivity of both imaging modalities is simi-lar, ranging from 57% to 100%, the specificity of FDG PET is better than that of bone scintigraphy, approach-ing 100% [5]. Pure osteolytic lesions in patients with breast cancer can be difficult to detect on bone scinti-graphy scans, leading to false negative findings, but are easily detected on FDG PET scans [5]. Herein, we report on a case of unusual bone scan patterns in a patient with breast cancer.

Case Report

A 42-year-old woman was diagnosed as having stage IA invasive ductal carcinoma in the left breast. Immunohistochemical analysis of biopsy specimens revealed the presence of estrogen receptor (ER) but no evidence of progesterone receptor (PR) or human epi-dermal growth factor receptor 2 (HER2). Specimens taken from sentinel lymph node biopsy showed no evi-dence of lymph node involvement. The patient was, therefore, referred to the Department of Nuclear Medi-cine for Tc-99m MDP whole-body bone scintigraphy. A spot-like uptake was found at the left sixth costochon-dral junction (Figure 1 A); however, chest X-ray did not reveal any abnormalities. A benign lesion, possibly due to traumatic injury, was diagnosed [7]. The patient re-ceived neoadjuvant chemotherapy and partial mastecto-my as well as post-operative anti-hormone therapy (ta-moxifen and goserelin). Follow-up bone scan 5 months later revealed decreased uptake at the sixth rib lesion, providing further evidence that the lesion had been caused by a traumatic injury and that the wound was healing (Figure 1 B) [8]. The level of tumor marker CA15-3 in serum at five-month follow-up was within

normal range (7.2 µg/mL). At two-year follow-up, the patient presented with increased serum titers of CA15-3 (11.2 µg/mL) and whole-body bone scintigraphy re-vealed increased uptake of tracer at the original left six rib lesion (C, arrow). In addition, abnormal uptake was noted in the left seventh rib (D, arrow heads), the first thoracic vertebra, and the sacrum (Figure 1E). Those findings combined with positive FDG PET findings and the increased serum CA15-3 level indicate that the le-sion at the left sixth costochondral junction was not due to a traumatic injury but was a metastatic lesion. (Figure 2)

Discussion

The detection rate of bone metastases using bone scintigraphy ranges from 0.8% to 40.5%, depending on cancer stage [9, 10]. Studies have shown that up to 47% of patients with bone metastases show a solitary rib hot spot on bone scans [11, 12]. In our patient, the decreased uptake on the bone scan performed after neoadjuvant chemotherapy and mastectomy might indicate a partial response to treatment [13]. The third bone scan revealed recurrence with metastases. Post-mortem studies have shown that up to 70% of patients with breast cancer have evidence of metastasis to bone [14, 15]. In addition, Koizumi et al. found that a solitary bony metastasis was an independent risk factor for the development of mul-tiple bony metastases in patients with breast cancer [16].

Molecular subtypes of breast cancer are related to underlying tumor biology. Jatoi et al. found that patients with ER-positive breast cancer tend to have a steady rate of recurrence over time (2% per year) whereas patients with other breast cancer subtypes tend to show a rate of recurrence that peaks early but declines in frequency thereafter [17]. Patients with ER-positive breast cancer have a significantly higher incidence of bony metastasis than patients with ER-negative cancers. In addition, me-tastasis in ER-positive patients normally occurs in pa-tients with recurrent disease [18, 19]. Although ER-positive cancers are associated with a steady recurrence rate over time, patients with ER-positive breast cancer generally have a good prognosis and are less likely to develop recurrence or to die due to their disease than patients with other subtypes [20]. Studies have shown that patients with ER-positive breast cancer that co-expresses PR have the best outcome, probably because ER/PR-expressing cancers are more responsive to hor-mone therapy than other subtypes [17, 21].

Triple negative breast cancer (TNBC), characte-rized by lack of expression of ER, PR, and HER2 is an aggressive subtype of breast cancer. Compared with other subtypes, TNBC is associated with increased local

32 Unusual bone metastasis in breast cancer

recurrence and frequency of brain and lung metastases (but a lower frequency of bone metastasis (10% vs. 40% of non-TNBC)) [22], shorter survival after metastasis is diagnosed [23], and significantly higher risk of develop-ing metastasis in the first 5 years after diagnosis [22, 24, 25]. Dent et al. reported that recurrence of breast cancer occurred within eight years after diagnosis in all patients with TNBC whereas recurrence in patients with other types of breast cancer occurred up to 17 years after diag-

nosis [24]. Understanding the biological subtypes of breast cancer and possible clinical courses can aid in the interpretation of imaging findings.

In conclusion, follow-up bone scintigraphy show-ing decreased tracer uptake at a lesion that had originally showed increased uptake and which was diagnosed as being the result of trauma could indicate a malignant tumor that has responded to therapy.

Figure 1. Panel A (arrow): initial scintigraphy scan shows spot-like uptake at the left sixth costochondral junction. Panel B (arrow): follow-up bone scan 5 months after neoadjuvant chemotherapy and partial mastectomy shows decreased uptake at the sixth costochondral junction. Panels C-E: scintigraphy scan carried out at two-year follow-up shows increased uptake at the original rib lesion site (C, arrow) with additional abnormal uptake in the left seventh rib (D, arrow heads), the first thoracic vertebra and the sacrum (E, arrow heads).

Figure 2. The focal uptake at the sixth rib seen on bone scintigraphy is also visible on FDG PET/CT.

P.-L. Chang et al. 33

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Case report

Sympathetic ophthalmia following vitreoretinal surgery Chen-Cheng Chao, San-Ni Chen﹡

Department of Ophthalmology, Changhua Christian Hospital, Changhua, Taiwan Received 23 January 2014;accepted 24 March 2014

Abstract Sympathetic ophthalmia is a bilateral, diffuse, granulomatous intraocular inflammation normally induced by trauma or surgery. Symptoms of this rare, yet potentially blinding condition can occur days to years after trauma onset. In this study, we present the clinical courses of three patients who developed sympathetic ophthalmia following vitreoretinal surgery. Patient I presented with sudden onset of deteriorating vision in both eyes after multiple surgeries for recurrent retinal de-tachment complicated by proliferative vitreoretinopathy in the left eye. Neither exudative retinal detachment nor a subretinal fluid pocket was present. Color fundus photography showed peripapil-lary subretinal fibrin deposition and optical coherence tomography (OCT) revealed choroidal thick-ening and disruption of the inner and outer segment junctions. Fluorescein angiography (FA) showed multiple hyperfluorescent spots and disc staining and indocyanine green (ICG) angiogra-phy showed multiple hypofluorescent spots. Patient II underwent vitrectomy, lensectomy and sili-con oil infusion for complicated retinal detachment and vitreous hemorrhage after eye ball perfora-tion. Six years later, the patient presented with sudden onset of decreased visual acuity in the fel-low eye. OCT revealed choroid folding and ICG angiography showed multiple hypofluorescent spots. Patient III underwent pars plana vitrectomy with internal tumor excision and silicone oil infu-sion for choroidal melanoma. Acute vision loss in the fellow eye was noted 2 months after vitrec-tomy. FA showed multiple areas of pinpoint leakage and subretinal fluid pooling at the posterior pole in the fellow eye. The three patients in this study received systemic corticosteroid therapy combined with azathioprine and mycophenolate. Sympathetic ophthalmia should be considered in the differential diagnosis when patients present with sudden deterioration of vision after vitreoretin-al surgery.

* Corresponding author. San-Ni Chen Department of Ophthalmology, Changhua Christian Hospital. 135 Nanxiao St. Chang-Hua 50006, Taiwan, ROC





KEYWORDS Sympathetic ophthalmia; Vitreoretinal surgery; Immunomodulatory therapy

C. –C. Chao et al. 35

Introduction

Sympathetic ophthalmia (SO) is a rare, yet poten-tially blinding bilateral diffuse granulomatous intraocu-lar inflammation that occurs after either surgical or acci-dental penetrating trauma to one eye. Ocular inflamma-tion in the fellow eye can present within days or months after injury, although onset in 80%-90% of cases occurs within 3 months to one year [1,2]. SO is often accompa-nied by conjunctival injection and a granulomatous ante-rior chamber reaction with mutton-fat keratic precipi-tates (KPs) on the corneal endothelium. The inflamma-tion can be so mild that the term “sympathetic irritation” is occasionally used to describe the condition. In the posterior segment, the extent of inflammation can range from vitritis and retinal vasculitis to choroiditis and pa-pillitis. The extent of inflammation can signify serous retinal detachment or optic nerve swelling in affected patients. White-yellowish choroidal lesions are more common in the peripheral fundus of patients with SO (Dalen–Fuchs nodules).

Although penetrating trauma is the most common precipitating event, sympathetic ophthalmia can also be caused by vitreoretinal surgery [3]. In this study, we present the clinical courses of three patients who devel-oped sympathetic ophthalmia following vitreoretinal surgery.

Case reports

Case 1

A 56-year-old woman presented with loss of vision in the left eye in June 2011. Visual acuity (VA) was 20/25 in the right eye (RE) and 20/200 in the left eye (LE). Dilated fundus examination revealed rhegmato-genous retinal detachment in the LE. During the period June-December 2011, the patient underwent six intra-ocular operations, including placement of an encircling band, pars plana vitrectomy (PPV), silicone oil injection, and endolaser photocoagulation because of recurrent retinal detachment and macular puckering. Good retinal-vitreous attachment was noted after the last surgery; however, four months later, visual acuity in the LE de-creased to light perception only and that in the fellow eye (RE) had fallen to 20/40. Examination of the RE revealed a swollen, hyperemic disc accompanied by 1+ cells in the anterior chamber and vitreous cavity (Fig. 1A). Fluorescein angiography (FA) demonstrated hyperfluorescent spots and disc staining and indocyanine green (ICG) angiography also revealed hypofluorescent spots (Fig. 1B, C). Results of a blood workup, serum immune test, chest x-ray, and magnetic resonance imag-ing (MRI) of brain revealed no evidence of systemic infection or inflammation. SO was diagnosed. Pulse steroid therapy with systemic methylprednisolone 250 mg every 6 hours for 3 days together with topical stero-ids and cycloplegics halted the inflammatory process. However, her vision deteriorated after tapering of stero-id therapy. Her vision finally stabilized after intravitreal injection of triamcinolone acetonide 4 mg combined with systemic administration of prednisolone, cyclospo-rine, and mycophenolate sodium. A quiet fundus in the RE was observed at the most recent follow-up visit.

Figure1. Color fundus phototograph in panel A reveals disc swelling and hyperemia accompanied by vitreous cells in the RE and multiple Dalen-Fuchs spots throughout the fundus. Fluorescein angiography (FA) in panel B reveals hyperfluorescent spots and disc staining and indocyanine green (ICG) angiography in panel C shows hypofluorescent spots.

36 Atypical SO following vitreoretinal surgery

Case 2

A 72- year-old man presented with acute globe rup-ture in the right eye in 2007. The injury was treated with primary suture. Approximately one month later, he re-ceived pars plana vitrectomy, lensectomy and silicon oil infusion for complicated retinal detachment. The retina in the right eye was only partially attached after the sur-geries and his visual acuity had deteriorated to no light perception by April 2012. Visual acuity in the left eye was normal (20/20). In December 2013, the patient presented with sudden onset of blurred vision in the left eye. Visual acuity at that time was 20/32. Dilated fundus examination revealed choroidal folding at the posterior

pole with the presence of vitreous cells. B-scan showed diffuse choroidal thickening but no evidence of a solita-ry choroidal mass. Orbital MRI revealed no evidence of retro-orbital lesions. FA showed multiple hyperfluores-cent leakage sites and multifocal hypofluorescent spots were noted on ICG angiography. Optical coherence to-mography (OCT) showed choroidal folding (Figure.2). SO was diagnosed. The patient received pulse steroid therapy with methylprednisolone 250 mg every 6 hours for 3 days combined with oral immunomodulators (cyc-losporine 25 mg twice daily and mycophenolate 500 mg twice daily). Visual acuity in the LE increased to 20/25 and the choroidal fold became flattened.

Figure 2. Color fundus photograph in panel A shows choroid folding. B-scan in panel B reveals choroid thickening; FA in panel C shows hyperfluorescent spots; and indocyanine green angiography in panel D reveals hypofluorescent spots. Panels E and F demonstrate the structure of the choroid before (E) and after (F) treatment.


Case 3

A 39-year-old man with choroidal melanoma and complicated cataract in the right eye underwent pars plana vitrectomy with internal tumor excision, silicon oil infusion, and phacoemulsification with intraocular lens implantation in March 2007. The patient was lost to fol-low-up until August 2009, at which time total retinal detachment of the RE was noted on dilated fundus ex-amination. VA was light perception only in the right eye and 20/20 in left eye. In January 2011, the patient pre-sented with sudden deterioration of vision in the left eye (20/100) and fundus examination revealed serous de-tachment at the posterior pole. FA revealed multiple

pinpoint leakage sites and dye pooling and ICG angio-graphy revealed multiple hypofluorescent spots. In addi-tion, subretinal fluid was noted on OCT (Figure 3). Sympathetic ophthalmia in the left eye was diagnosed and the patient was treated with oral prednisolone 100 mg per day. Visual acuity in the left eye increased to 20/25 within one month. Recurrent SO with subretinal fluid accumulation was noted in May 2011 and in Octo-ber 2011. In both instances, the patient responded well to oral steroid and immunomodulator therapy (cyclospo-rine 100 mg twice daily and mycophenolate 500 mg twice daily). At the most recent follow-up, visual acuity in the left eye was 20/25.

Figure3. Color fundus photograph in panel A reveals serous retinal detachment in the sympathetic eye. FA in panel B shows multiple pinpoint leakage spots and hypofluorescent spots on indocyanine green angiography. OCT in panel C shows evidence of subretinal fluid.

Discussion

The incidence of SO is variable and appears to be declining because of the increased understanding of the disease and improved surgical techniques. The true inci-dence is unknown because of lack of pathologic proof, the difficulty in studying sufficiently large case series, and the fact that most data are from dated literature that often confused SO with other forms of uveitis [4]. In 1982, Gass reported that the incidence of SO was 0.01% following pars plana vitrectomy and 0.06% after non-surgical penetrating ocular trauma [5]. Other studies have shown that the incidence of OS is 0.2% to 0.5% after non-surgical penetrating ocular injuries and 0.01% after intraocular surgery [6,7].

Kilmartin et al. [8] reported that the most frequent cause of SO was retinal surgery and that gender was not associated with the likelihood of developing the condi-tion. They gathered data from nine patients with newly diagnosed SO and found that retinal surgery was the causative ocular injury in all patients. Interestingly, five of the nine patients had undergone pars plana vitrectomy. The authors concluded that the risk of developing SO after vitrectomy was twice that of developing the condi-

tion after external retinal detachment repair. Immuno-genic risks associated with pars plana vitrectomy are likely due to increased retinal manipulation and break-down of the blood–retinal barrier. Abu El Asrar et al. [9] reported that most patients who developed SO after pars plana vitrectomy for rhegmatogenous retinal detachment had a history of penetrating ocular injury. In contrast, Pollack et al. [10] found that development of OS after pars plana vitrectomy was not associated with a history of penetrating ocular trauma. In their study, the time from vitrectomy to the onset of symptoms ranged from 2 months to longer than 2 years. In our patients, SO de-veloped after a single vitrectomy in two patients and after multiple procedures in one patient. In addition, the onset of symptoms ranged from 3 months to more than 6 years after pars plana vitrectomy.

In our three patients, we found that the anterior segment was not always involved, a finding consistent with that reported by Gupta et al. [11]. Furthermore, the posterior segment may show signs of papillitis, vitritis, serous retinal detachment or choroid folding due to lym-phoid hyperplasia.

Diagnosis of sympathetic ophthalmia is based on history and clinical examination as there are no specific laboratory studies to establish the diagnosis; however, focused clinical testing can be used to rule out other

38 Atypical SO following vitreoretinal surgery

disease entities with a similar clinical picture. FA and indocyanine green angiography are useful adjuncts in establishing the extent and severity of SO. Fluorescein angiography typically demonstrates multiple hyperfluo-rescent leakage sites at the retinal pigment epithelium (RPE) during the venous phase that persist into the late frames of the study and ICG angiography studies tend to show multifocal hypofluorescent spots that become more prominent as the study progresses. These lesions are thought to be reflective of inflammatory cell infiltra-tion into the choroid [12,13].

The differential diagnosis of SO includes all dis-eases that can present as panuveitis. However, history of previous penetrating ocular injury or intraocular surgery is suggestive of the disease. Occasionally, it is difficult to distinguish SO from Vogt–Koyanagi–Harada (VKH) disease. However, patients with VKH normally do not have a history of surgery or trauma. In addition, VKH typically presents as bilateral granulomatous panuveitis with prominent choroidal involvement. Other diseases that need to be distinguished from SO include lympho-ma, syphilis, tuberculosis, and sarcoidosis. If lymphoma is suspected, a careful systemic workup should be per-formed, and if necessary, a vitreous sample must be ob-tained for diagnostic purposes. Tuberculosis, sarcoidosis, and syphilis are usually accompanied by constitutional signs and symptoms of the underlying systemic disease. These features, combined with appropriate testing for tuberculosis (PPD skin testing and chest radiograph), sarcoidosis (serum angiotensin-converting enzyme and lysozyme, and chest radiograph), and syphilis (Rapid plasma reagin and Fluorescent Treponemal Antibody-absorption) can distinguish these systemic infections from SO.

Treatment of SO is primarily medical. Systemic corticosteroids are the first-line therapy for SO; however, in patients that are non-responsive to steroid therapy, immunosuppressive agents such as cyclosporine and azathioprine can be used for long-term immunomodula-tory therapy. Corticosteroids may be given topically, by sub-tenon or transseptal injection, or systemically. Oral prednisone is most frequently employed in the treatment of SO. In severe cases, intravenous pulse steroid therapy can be employed. Administration of steroid-sparing im-munomodulators such as cyclosporine, chlorambucil, cyclophosphamide, azathioprine, mycophenolate or ta-crolimus may be more advantageous in patients who are steroid-resistant or have intolerable side effects from corticosteroids [14-16]. In our patients, we used steroid therapy as our primary regimen combined with an im-munomodulatory agent such as cyclosporine or myco-phenolate if the SO was refractory to steroid treatment or if the patient was likely to develop steroid-induced

hyperglycemia. Our regimen was well tolerated in all three patients and prevented SO from destroying the ocular structure.

In conclusion, sympathetic ophthalmia should be considered in the differential diagnosis when patients present with sudden deterioration of vision after vitreo-retinal surgery.

References

[1] Lubin JR, Albert DM, Weinstein M. Sixty-five years of sympathetic ophthalmia. A clinicopathologic re-view of 105 cases (1913-1978). Ophthalmology 1980; 87:109-21.

[2] Goto H, Rao NA. Sympathetic ophthalmia and Vogt-Koyanagi-Harada syndrome. Int Ophthalmol Clin 1990; 30:279-85.

[3] Kilmartin DJ, Dick AD, Forrester JV. Prospective surveillance of sympathetic ophthalmia in the UK and Republic of Ireland. Br J Ophthalmol 2000; 84:259-63.

[4] Power WJ, Foster CS. Update on sympathetic oph-thalmia. Int Ophthalmol Clin 1995; 35:127-137.

[5] Gass JD. Sympathetic ophthalmia following vitrec-tomy. Am J Ophthalmol 1982; 93:552-558.

[6] Makley TA,Azar A. Sympathetic ophthalmia. A long-term follow-up. Arch Ophthalmol 1978; 96:257-62.

[7] Marak GE. Recent advances in sympathetic oph-thalmia. Surv Ophthalmol 1979; 24:141-156.

[8] Kilmartin DJ, Dick AD, Forrester JV. Sympathetic ophthalmia risk following vitrectomy: should we counsel patients? Br J Ophthalmol 2000; 84:448-9.

[9] Abu El-Asrar AM, Al Kuraya H, Al-Ghamdi A. Sympathetic ophthalmia after successful retinal reat-tachment surgery with vitrectomy. Eur J Ophthalmol 2006; 16:891-4.

[10] Pollack AL, McDonald HR, Ai E, Green WR, et al. Sympathetic ophthalmia associated with pars plana vitrectomy without antecedent penetrating trauma. Retina 2001; 21:146-54.

[11] Gupta V, Gupta A, Dogra MR. Posterior sympa-thetic ophthalmia: a single centre long-term study of 40 patients from North India. Eye (Lond) 2008; 22:1459-64.

[12] Bernasconi O, Auer C, Zografos L, Herbort CP. Indocyanine green angiographic findings in sympa-thetic ophthalmia. Graefes Arch Clin Exp Oph-thalmol 1998; 236:635-8.

[13] Moshfeghi AA, Harrison SA, Ferrone PJ. Indocya-nine green angiography findings in sympathetic


ophthalmia. Ophthalmic Surg Lasers Imaging 2005; 36:163-6.

[14] Tessler HH, Jennings T. High-dose short-term chlo-rambucil for intractable sympathetic ophthalmia and Behcet's disease. Br J Ophthalmol 1990; 74:353-7.

[15] Lau CH, Comer M, Lightman S. Long-term effica-cy of mycophenolate mofetil in the control of se-

vere intraocular inflammation. Clin Experiment Ophthalmol 2003; 31:487-91.

[16] Ishioka M, Ohno S, Nakamura S, Isobe K, Wata-nabe N, Ishigatsubo Y, et al. FK506 treatment of noninfectious uveitis. Am J Ophthalmol 1994; 118:723-9.


Case report

Intensity-modulated radiation therapy is an effective treatment for optic nerve sheath meningioma Chen-Cheng Chao1, Sung-Tsang Hsieh2, Ya-Fang Chen3, Jieh-Ren Jou1*

1Department of Ophthalmology, Changhua Christian Hospital, Changhua , Taiwan 2Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan 3Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan Received 5 Feburary 2014; accepted 24 March 2014

Abstract

A 39-year-old woman presented to our clinic with a two-week history of blurred vision in the right

eye. Best corrected visual acuity was 20/25 in the right eye (RE) and 30/20 in the left eye (LE).

Visual field (VF) test revealed an inferior altitudinal defect in the RE. Magnetic resonance imaging

(MRI) of brain and orbit demonstrated an enlarged right intraorbital optic nerve sheath complex

measuring 2 cm in length and 7 mm in diameter with prominent enhancement, findings consistent

with optic nerve sheath meningioma (ONSM). The patient underwent intensity-modulated radiation

therapy (IMRT), receiving a total dose of 54 Gy in 30 fractions over a period of 42 days. At four-

month follow-up, visual acuity in the RE was 20/20 and the altitudinal defect had resolved. At 30-

month follow-up, serial VF showed progressive resolution of scotoma. IMRT provided effective

treatment for ONSM in our patient; however, long-term monitoring is warranted. * Corresponding author. Jieh-Ren Jou Department of Ophthalmology, Changhua Christian Hospital. 135 Nanxiao St. Chang-Hua 50006, Taiwan, ROC





KEYWORDS Intensitymodulated radiation therapy; Magnetic resoance imaging; Optic nerve sheath meningioma

C.-C. Chao et al. 41

Introduction

Primary optic nerve sheath meningiomas (ONSMs) account for approximately one-third of all primary optic nerve tumors. They are also the second most common type of optic nerve tumor after optic glioma and the most common tumors of the optic nerve sheath [1]. In-tensity-modulated radiation therapy (IMRT), a refined type of three-dimensional conformal radiation therapy that allows for the sparing of healthy tissue and for mod-ifications of radiation dose during treatment, has been shown to be an effective treatment for primary ONSM [2]. Herein, we report the two-year follow-up results of IMRT as primary treatment for ONSM in a middle-aged woman.

Case report

A 39-year-old woman presented to our clinic with a two-week history of blurred vision in the right eye. Her medical and surgical history included receipt of thyroi-dectomy for hyperthyroidism nine years prior to this presentation and receipt of laser in situ keratomileusis (LASIK) for myopia 10 years prior to this presentation. Ophthalmological examination revealed a best corrected visual acuity of 20/25 in the right eye (RE) and 30/20 in the left eye (LE). Pupils were isocoric, yet a relative afferent pupillary defect was noted in the RE. Extraocu-lar motility and exophthalmometric measurements were normal. The cornea, anterior chamber, iris, lens, and fundus of both eyes were also normal (Figure 1). Acute retrobulbar optic neuritis was suspected initially.

Visual field (VF) test revealed an inferior altitudin-al defect in the RE (Mean deviation, -13.26 dB) (Figure 2), and magnetic resonance imaging (MRI) of brain and orbit revealed an enlarged right intraorbital optic nerve sheath complex measuring 2 cm in length and 7 mm in diameter with prominent enhancement, findings consis-tent with ONSM (Figure 3). Visual evoked potential (VEP) revealed a decreased amplitude in the RE (Figure 4).

Figure.1 Color fundus photographs reveal a normal cornea, anterior chamber, iris, lens, and fundus in the right eye (left panel) and left eye (right panel).

RE RE LE LE

Figure 2. Visual field examination reveals an inferior altitudinal defect in the right eye; the visual field of the left eye was normal.

42 Excellent visual outcome in ONSM by IMRT

Figure 3. Panels A-E are brain MR images revealing an enlarged right intraorbital optic nerve sheath complex. Optic nerve compression and lateral displacement are visible. Panel A shows pre-radiotherapy coronal short tau inversion recovery (STIR) and panel B shows a gadolinium-enhanced, fat–saturated T1-weighted image. Panel C demonstrates a pre-radiotherapy axial STIR and panel D shows a gadolinium-enhanced, fat–saturated T1-weighted image. Panel E shows a pre-radiotherapy axial T2-weighted image and panel F shows a gadolinium-enhanced, fat–saturated T1-weighted image. Panel G demonstrates an axial STIR image at 30-month follow-up and panel H shows a gadolinium-enhanced, fat–saturated T1-weighted image taken at 30-month follow-up.


Figure 4. VEP patterns before (upper) and 11 months after IMRT (lower). Left: right eye, right: left eye. Decrease in VEP amplitude in the RE was found. Note that after IMRT, VEP amplitude in the RE improved.

One month later, the patient visited the Walter

Reed National Army Medical Center in Washington, D.C, USA, where she underwent IMRT. The patient received a total dose of 54 Gy in 30 fractions over a pe-riod of 42 days. At four-month follow-up, visual acuity in the RE was 20/20 and the altitudinal defect had re-

solved (Mean deviation: -3.03 dB). However, the size of the meningioma on the optic nerve sheath remained the same. At 30-month follow-up, serial VF showed pro-gressive resolution of scotoma (Figure 5), although MR images revealed that the tumor had not reduced in size.

Pre-IMRT Post-IMRT 4 Ms Post-IMRT 18Ms Post-IMRT 30 Ms

MD: -13.26dB MD: -3.03dB MD: -2.84dB MD: -0.68dB Figure 5. Serial VF shows resolution of visual field defect during follow-up


Discussion

Primary ONSMs derive from a proliferation of me-ningothelial cap cells of the arachnoid villi within the optic nerve sheath and account for one third of primary optic nerve tumors, 5-10% of orbital tumors, and 1-2% of all meningiomas. These tumors can develop any-where along the course of the optic nerve, although 92% arise from the intraorbital nerve sheath and only 8% are intracanalicular in origin. Only 5% of primary ONSMs are bilateral. Secondary ONSMs typically originate intracranially from dura or near the planum sphenoidale, from where they spread anteriorly within the confines of the optic nerve sheath through the optic canal, eventual-ly surrounding the orbital portion of the nerve [3,4]. Both primary and secondary ONSMs occur most com-monly in middle-aged women [1].

Decreased visual acuity is the most common symp-tom in patients with ONSM. For example, Saeed et al reported that most patients with ONSM (49%) have a visual acuity of 20/50 or better on initial examination, 17% present with a visual acuity ranging from 20/60 to 20/200, and about a third of patients with ONSM have a visual acuity of less than 20/200 (16). Initial symptoms include disturbances of color vision and visual field defects. Less common symptoms include periocular or retrobulbar pain or discomfort, double vision, proptosis, transient visual obscurations, and mechanical restriction of ocular motility [5-7]. Almost all patients with unila-teral ONSM have an ipsilateral relative afferent pupil-lary defect (RAPD) and optic disc swelling without pe-ripapillary hemorrhages or exudates [6-7]. In the late stage of ONSM, the presence of visual loss, optic disc pallor, and retinochoroidal shunts is almost always pa-thognomonic [8]. Our patient had unilateral ONSM with an ipsilateral RAPD, but no evidence of optic disc swel-ling or exudate.

The diagnosis of an ONSM can be made by various imaging studies, including computerized tomography (CT) scanning, MRI, and ultrasonography, although MRI has been shown to provide better detail and hence to be superior to the other two modalities in diagnosing the disease [5]. The pattern of ONSM can be tubular, globular, fusiform or focal and is typically isointense or slightly hypointense to optic nerve tissue on T1- weighted images and hyperintense or hypointense on T2-weighted images. ONSMs typically present as a ho-mogeneous intense enhancement often suggesting in appearance a "tram track" around the hypointense optic nerve in axial sequences [9,10]. It is not always possible to differentiate ONSM from other lesions involving the

optic nerve and meninges, such as optic nerve glioma, optic neuritis, infiltrative optic neuropathy, and orbital pseudotumor/lymphoma.

Optic nerve gliomas typically occur during the first decade of life and can be differentiated from ONSMs by their characteristic fusiform appearance associated with enlargement of the nerve on MR images. Other findings characteristic of optic nerve gliomas include the appear-ance of a downward kink in the mid-orbit, isointensity or hypointensity on T1-weighted images, hyperintensity on T2-weighted images, and homogeneous enhancement [11]. Gliomas also typically respond well to steroid ther-apy.

MR image findings characteristic of optic neuritis include focal or diffuse thickening of the optic nerve with increased signal intensity on T2-weighted images and plaques of multiple sclerosis seen on gadolinium-enhanced, fat–saturated T1-weighted MR images. De-creased visual acuity or visual field over hours to days may also be noted. Orbital pseudotumor is an idiopathic inflammatory process that may involve all intraorbital structures and is often mistaken for orbital lymphoma [12]. Orbital lymphoma infiltrates the perioptic nerve sheath and is similar in presentation to meningiomas in this location. Lymphoma accounts for approximately 10% of orbital masses and most commonly presents in the sixth and seventh decades with insidious painless onset of a lesion that moulds itself to orbital structures [13].

Management of ONSM includes observation, sur-gery, radiation, and combined therapy. Treatment must be initiated in patients when visual acuity progressively falls below 20/40 or the visual field is constricting [14]. Biopsy is rarely required for the diagnosis as image find-ings of ONSM are unambiguous. However, biopsy in addition to MRI should be performed in patients who present with sudden or rapidly progressive visual loss [15]. Attempts to excise these tumors without damaging the optic nerve are usually unsuccessful [16-18]. Turbin et el reported that radiotherapy alone results in good visual outcome in ONSM patients with a visual acuity of better than light perception [23].

Radiotherapy techniques for treating optic nerve tumors include stereotactic radiosurgery, stereotactic fractionated radiation (SFR), and IMRT. Stereotactic radiosurgery applies high single radiation doses in one or a few boluses, which can damage adjacent cerebral structures, the optic nerve, or the retina [20]. The total dose of radiation applied to the optic nerve and other CNS structures is a critical determinant for late toxicity of treatment. The tolerance dose of the optic nerve has been estimated to be approximately 54 Gy given in 30 fractions for fractionated irradiation [21]. In Paulsen’s


series, they found that gender, primary or secondary ONSM, tumor size and treatment at primary diagnosis were not related to visual outcome following fractio-nated stereotactic radiotherapy [15]. Adams et el re-ported that a longer time from the onset of symptoms to the start of radiotherapy is predictive of worse visual outcome [1]. Miller et al reported that the overall re-sponse rate among 70 patients with primary ONSM who received SFR was 94.3% and that 54.7% of patients showed signs of improved visual function within the first three months of treatment [14]. In Liu’s study of five patients with ONSM, serial MRI revealed no changes in the size of the tumor in the five patients stu-died and dramatic improvement in visual acuity, visual field and color vision in four of the five patients after stereotactic radiotherapy [24]. None of their patients had evidence of tumor enlargement during follow-up, and no severe or permanent complications were noted. We postulate that subtle changes in tumor size after radio-therapy, such as decreases in edematous tissue and fi-brotic changes of solid tumors led to the apparent func-tional improvement in Liu’s study.

Grant and Cain were the first to report that IMRT is an effective treatment for primary ONSM [25]. IMRT is increasingly used to treat meningiomas and provides higher dose conformality, improved target coverage, and better sparing of critical structures compared with 3-dimensional conformal radiation therapy (3D-CRT). IMRT enables the delivery of higher radiation doses to the lesion while sparing the organs and tissues at risk, thus enhancing the therapeutic ratio. In addition, IMRT modulates the intensity of the photon beam across the treatment portal. This means that instead of delivering an irregularly shaped beam of uniform intensity (as used for CRT), multiple subfields, each of irregular shape, are delivered one after another, creating an intensity pattern similar to a checkerboard with different levels of shad-ing [26]. When performing 3D-CRT, however, it is dif-ficult to protect the retina from radiation exposure. That is not the case for IMRT [27]. Based on the above-mentioned findings and the results from this study, IMRT is an effective treatment for ONSM. However, further long-term follow-up studies are needed.

Acknowledgments

We would like to thank Prof. Yung-Feng Shih for revising our manuscript.

References

[1] Adams G, Roos DE, Crompton JL. Radiotherapy for optic nerve sheath meningioma: a case for earlier in-tervention, Clin Oncol (R Coll Radiol) 2013; 25:356-61.

[2] Jeremic B, Pitz S, editors. Primary Optic Nerve Sheath Meningioma. Springer Berlin Heidelberg. 2008; 95-03

[3] Aoyama H, Westerly DC, Mackie TR, et al. Integral radiation dose to normal structures with conformal external beam radiation. Int J Radiat Oncol Biol Phys 2006; 64: 962-7.

[4] Backhouse O, Simmons I, Frank A, et al. Optic nerve breast metastasis mimicking meningioma. Aust N Z J Ophthalmol 1998; 26: 247-9.

[5] Cristante L. Surgical treatment of meningiomas of the orbit and optic canal: a retrospective study with particular attention to the visual outcome. Acta Neu-rochir (Wien) 1994; 126: 27-32.

[6] Dutton JJ. Optic nerve sheath meningiomas. Surv Ophthalmol 1992; 37: 167-83.

[7] Goldsmith BJ, Rosenthal SA, Wara WM, et al. Optic neuropathy after irradiation of meningioma. Radiol-ogy 1992; 185: 71-6.

[8] Grant W,3rd, Cain RB. Intensity modulated confor-mal therapy for intracranial lesions. Med Dosim 1998; 23: 237-41.

[9] Kondziolka D, Niranjan A, Lunsford LD, et el. Ste-reotactic radiosurgery for meningiomas. Neurosurg Clin N Am 1999; 10: 317-25.

[10] Mafee MF, Goodwin J, Dorodi S. Optic nerve sheath meningiomas. Role of MR imaging. Radiol Clin North Am 1999; 37: 37-58.

[11] Miller NR. New concepts in the diagnosis and management of optic nerve sheath meningioma. J Neuroophthalmol 2006; 26: 200-8.

[12] Burgener FrancisA, Meyers StevenP, editors. Diffe-rential diagnosis in Magnetic Resonance Imaging. Stuttgart: Thieme; 2002: 215-7

[13] Selva D, Rootman J, Crompton J. Orbital lympho-ma mimicking optic nerve meningioma. Orbit 2004;23: 115-20.

[14] Miller NR. The evolving management of optic nerve sheath meningiomas. Br J Ophthalmol 2002; 86: 1198.

[15] Paulsen F, Doerr S, Wilhelm H, et al. Fractionated stereotactic radiotherapy in patients with optic nerve sheath meningioma. Int J Radiat Oncol Biol Phys 2012; 82:773-8.

[16] Saeed P, Rootman J, Nugent RA, et al. Optic nerve sheath meningiomas. Ophthalmology 2003; 110:2019-30.


[17] Sarkies NJ. Optic nerve sheath meningioma: diag-nostic features and therapeutic alternatives. Eye (Lond) 1987; 1:597-02.

[18] Selva D, Rootman J, Crompton J. Orbital lympho-ma mimicking optic nerve meningioma. Orbit 2004; 23:115-20.

[19] Shapey J, Danesh-Meyer HV, Kaye AH. Diagnosis and management of optic nerve glioma. J Clin Neu-rosci 2011; 18: 1585-91.

[20] Sibony PA, Krauss HR, Kennerdell JS, et al. Optic nerve sheath meningiomas. Clinical manifestations. Ophthalmology 1984; 91: 1313-26.

[21] Thorne JE, Volpe NJ, Wulc AE, et al. Caught by a masquerade: sclerosing orbital inflammation. Surv Ophthalmol 2002; 47: 50-4.

[22] Turbin RE, Pokorny K. Diagnosis and treatment of orbital optic nerve sheath meningioma. Cancer Control 2004; 11: 334-41.

[23] Turbin RE, Thompson CR, Kennerdell JS, et al. A long-term visual outcome comparison in patients with optic nerve sheath meningioma managed with observation, surgery, radiotherapy, or surgery and radiotherapy. Ophthalmology 2002; 109: 890-9.

[24] Liu JK, Forman S, Hershewe GL, et al. Optic nerve sheath meningiomas: visual improvement after ste-reotactic radiotherapy. Neurosurgery 2002; 50:950-5

[25] Grant W 3rd, Cain RB. Intensity modulated con-formal therapy for intracranial lesions. Med Dosim 1998l; 23: 237-41.

[26] Pirzkall A, Debus J, Haering P, et el. Intensity modulated radiotherapy (IMRT) for recurrent, resi-dual, or untreated skull-base meningiomas: prelim-inary clinical experience. Int J Radiat Oncol Biol Phys 2003; 55: 362-72.

[27] Wilson WB. Meningiomas of the anterior visual system. Surv Ophthalmol 1981; 26: 109-27.


Letter to the Editor

Hyperdense basilar artery sign is predictive of brain stem Infarction Chih-Ming Lin1*, Chi-Kuang Liu2

1Department of Neurology, Chunghua Christian Hospital, Chunghua, Taiwan 2Department of Neuro-imaging, Chunghua Christian Hospital, Chunghua, Taiwan

Received 5 Feburary 2014; accepted 24 March 2014

A

To the Editor

Stroke is a leading cause of death and morbidity in the United States and Taiwan.[1]Risk factors for stroke include advanced age and the presence of chronic dis-ease. Of the various types of stoke, brain stem infarction is associated with ominous outcome and often gives rise to permanent neurological deficits. Studies have shown that intracranial stenosis is more common in Asians than in Caucasians, who are more prone to developing extrac-ranial artery stenosis[2,3].

A previously healthy 29-year-old man presented to our emergency department with a two-hour history of sudden onset of disturbance of consciousness. On arrival, his vital signs were relatively stable (temperature, 36.2 °C; pulse rate, 89 beats per minute; respiratory rate, 27 breaths per minute). Neurologic examination revealed a patient in a comatose state with right-to-left conjugate eye movements and ocular bobbing. Deep tendon re-flexes were absent in all four extremities. Non-contrast computed tomography of brain revealed a hyperdense basilar artery (Figure 1). The preliminary diagnosis was brain stem infarction. Tissue plasminogen activator (t-PA) was administered intravenously but resulted in lim-ited neurological improvement. Angiographic examina-tion revealed a basilar artery occlusion extending dis-tally from the mid-portion of the vessel (Figure 2A). Therefore, emergency intra-arterial thrombolysis with

urokinase (540,000 units) was performed via a trans-femoral approach. Angiographic imaging after the pro-cedure revealed recanalization of the basilar artery (Fig-ure 2B). Follow-up brain magnetic resonance imaging revealed a right-sided pontine infarction and a patent basilar artery (Figure 3A and 3B ). The patient regained consciousness one week after admission and began a rehabilitation program. Upon discharge from the hospi-tal approximately three weeks after admission, he had left-sided hemiparesis and required a cane to assist him with walking.

Figure 1 Cranial computed tomography without contrast shows a hyperdense basilar artery (black arrow).

*Corresponding author. Chih Ming Lin, Department of Neurology, Changhua Christian Hospital. 135 Nanxiao St. Chang-Hua 50006,

Taiwan, ROC



E-mail address: [email protected] Copyright © 2014, Changhua Christian Hospital.

http://www2.cch.org.tw/7477

48 C.-M. Lin et al.

2A 2BFigure 2A and 2B Percutaneous angiography before and after intra-arterial thrombolysis therapy. Angiography before the procedure (Panel 2A) reveals a basilar artery occlusion extending distally from the mid-portion of the vessel (black arrow).Angiography after the procedure (Panel 2B) shows recanalization of the basilar artery.

3A 3BFigure 3A and 3B Diffusion-weighted magnetic resonance imaging shows a right-sided pontine infarction (Panel 3A, black arrow). Magnetic resonance angiography in panel 3B shows a patent basilar artery.

In our patient, cranial CT without contrast demon-strated a hyperdense basilar artery, a finding characteris-tic of brain stem infarction. However, most patients with that type of stroke are of advanced age (>60 years) and have a history of long-term chronic disease[1, 3,4-6]. Interestingly, our patient was young and did not have any underlying disease that might complicate the intrac-ranial vasculature.

References

[1] Tsai YF, Su CT, Chor-Ming Lin A. Hyperdense basilar sign: an early computed tomography finding of acute ischemia. J Emerg Med 2012; 43:1077-8.

[2] Connell L, Koerte IK, Laubender RP, et al. Hyper-dense basilar artery sign-a reliable sign of basilar ar-tery occlusion. Neuroradiology 2012; 54:321-7.

Although the appearance of a hyperdense basilar artery is predictive of brain stem infarction, advanced imaging studies are needed to arrive at a definitive diag-nosis. Early detection of brain stem ischemic changes, as in our patient, allows for timely intra-arterial thromboly-sis therapy to be performed so that the obstructed basilar artery can be recanalized [6,7].

[3] Mortimer AM, Saunders T, Cook JL. Cross-sectional imaging for diagnosis and clinical outcome predic-tion of acute basilar artery thrombosis. Clin Radiol 2011; 66:551-8.

Hyperdense basilar sign in a young Asian man 49

[4] Tan X, Guo Y. Hyperdense basilar artery sign diag-noses acute posterior circulation stroke and predicts short-term outcome. Neuroradiology 2010; 52:1071-8.

[5]Goldmakher GV, Camargo EC, Furie KL, et al. Hy-perdense basilar artery sign on unenhanced CT pre-dicts thrombus and outcome in acute posterior circu-lation stroke. Stroke 2009; 40:134-9.

[6] Segura T, Abad L, Parras P. Hyperdense basilar artery sign . Neurologia 2004; 19:321-2.

[7] Ehsan T, Hayat G, Malkoff MD, et al. Hyperdense basilar artery. An early computed tomography sign of thrombosis. J Neuroimaging 1994; 4:200-5.

Changhua Journal of Medicine (CJM)

Instruction for Authors

The Changhua Journal of Medicine (CJM) is the official peer-reviewed journal published quarterly by Changhua Chris-tian Hospital (CCH) and ACMSR-Taiwan Branch. The Journal aims to publish reviews, original articles, case report, short communications, technical notes and letters on all fields of medicine and related disciplines that are of topical in-terest to the medical profession. The Editorial Board requires authors to be in compliance with the Uniform Require-ments for Manuscripts Submitted to Biomedical Journals (URMs), which are compiled by the International Committee of Medical Journal Editors (ICMJE); current URMs are available at http://www.icmje.org. These Instructions to authors might be revised periodically by the Editors as needed. Authors should consult a recent issue of the Journal or visit www2.cch.org.tw/7477 for the latest version of these instructions. Any manuscript not pre-pared according to these instructions will be returned immediately to the author(s) without review.

1. Manuscript Submission

1.1. Submission Manuscripts (meaning all submission items, including all text, tables, artwork, cover letter, conflicts of interest dis-

closures, and any other required documents/material) must be submitted online to the CJM Editorial Office: Editorial Office, Changhua Journal of Medicine (CJM) Changhua Christian Hospital 135, Nanhsiao Street, Changhua, 50006 Taiwan E-mail: [email protected] Tel:+886-4-7238595 ext 4367 Fax:+886-4-7238595 ext 4364 If assistance is required, please visit www2. cch.org.tw/7477 or contact the Editorial Office.

1.2. Important Information Articles should be in Microsoft Word document format and prepared in the simplest form possible. Authors are required to check spelling and grammar before submission. We will add in the correct font, font size, margins and so on according to the journal’s style.

You may use automatic page numbering, but do NOT use other kinds of automatic formatting such as footnotes, headers and footers.

Put text, references, table headings and tables, and figure legends in one file. Figures must be submitted as separate picture files, at the correct resolution and named according to the figure number, e.g., “Fig1.tif”, “Fig2.jpg”. Please see section 6.8. for more information.

1.3. Supporting Documents 1.The following documents must be included in your submission (refer also to the Checklist that follows these au-

thor instructions). Items (1), (2) and (3) are mandatory. Items (4), (5), (6) and (7) are required only if they are applicable to your manuscript. Cover Letter. This must include the following information:

title of the manuscript names (spelled out in full) of all authors*, and the institutions with which they are affiliated; indicate all affiliations with a superscripted lowercase letter after the author's name and in front of the matching af-filiation (*the name of each author should be written with the family name last, e.g., Wan-Lin Chang)

corresponding author details (name, e-mail, mailing address, telephone and fax numbers) Chinese authors should provide their names, affiliations and contact details in both English and Chinese characters

a statement that the material contained in the manuscript has not been previously published and is not be-ing concurrently submitted elsewhere

persons who do not fulfill the requirements to be listed as authors but who nevertheless contributed to the manuscript (such as those who provided writing assistance, for example) should be disclosed

the signature of the first author or the corresponding author

2. Authorship & Conflict of Interest Statement. Each author's contribution to the manuscript should be listed. Any and all potential and actual conflicts of interest should also be listed (see Section 2 for more information). Please use the CJM Authorship & Conflicts of Interest Statement form that follows these author instructions and that is also provided on the Journal's website at ww2.cch.org.tw/7477 Your signature and those of ALL your coauthors must be included.

3.Copyright Transfer Agreement. In the event that your manuscript is accepted for publication in the CJM, you are required to transfer all copyright ownership in and relating to the work to CCH. Please use the CJM Copyright Transfer Agreement form that follows these author instructions and that is also provided on the Journal’s web-site at www2.cch.org.tw/7477 Your signature and those of ALL your coauthors must be included.

4.Ethics Statement. Articles covering the use of human or animal samples in research, or human or animal experi-ments must be accompanied by a letter of approval from the relevant review committee or authorities.

5.Consolidated Standards of Reporting Trials (CONSORT) flow chart for randomized controlled trials submitted for publication.

6.Signed Statement of Informed Consent. Articles where human subjects can be identified in descriptions, photo-graphs or pedigrees must be accompanied by a signed statement of informed consent to publish (in print and on-line) the descriptions, photographs and pedigrees from each subject who can be identified.

7.Copyright Permission. If you have reproduced or adapted material from other copyrighted sources, the letter(s) of permission from the copyright holder(s) to reproduce or adapt the copyrighted sources must be supplied. Otherwise, such material must be removed from your manuscript. You may use the Permission Request and Li-cense form that follows these author instructions and that is also provided on the Journal's website at www2.cch.org.tw/7477 in your communication with the copyright holder(s).

2. Disclosure of Conflicts of Interest

A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. CJM Editors strive to ensure that what is pub-lished in the Journal is as balanced, objective and evidence-based as possible. Since it is difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any po-tential conflicts of interest.

Conflicts of interest may be financial or non-financial. Financial conflicts include financial relationships such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock own-ership, or other equity interest; expert testimony or patent-licensing arrangements. Non-financial conflicts include per-sonal or professional relationships, affiliations, academic competition, intellectual passion, knowledge or beliefs that might affect objectivity.

Please ensure that the name of each author listed in your manuscript appears in either Section I or Section II of the CJM Conflicts of Interest Statement form (an author’s name cannot appear in both Section I and Section II of the form).

3. Identification of Patients in Descriptions, Photographs and Pedigrees

A signed statement of informed consent to publish (in print and online) patient descriptions, photographs and pedi-grees should be obtained from all persons (parents or legal guardians for minors) who can be identified (including by the patients themselves) in such written descriptions, photographs or pedigrees. Such persons should be shown the ma-nuscript before its submission. Omitting data or making data less specific to de-identify patients is acceptable, but changing any such data is not acceptable.

4. Previous Publication or Duplicate Submission

Submitted manuscripts are considered with the understanding that they have not been published previously in print or electronic format (except in abstract or poster form) and are not under consideration in totality or in part by another

publication or electronic medium.

5. Article Categories

5.1. Review Articles These should aim to provide the reader with a balanced overview of an important and topical subject in medicine,

emphasizing factors such as cause, diagnosis, prognosis, therapy or prevention. They should cover aspects of a topic in which scientific consensus exists as well as aspects that remain controversial and are the subject of ongoing scientific research. All articles and data sources reviewed should include information about the specific type of study or analysis, population, intervention, exposure, and tests or outcomes. All articles or data sources should be selected systematically for inclusion in the review and critically evaluated.

While review articles are usually submitted by invitation only, unsolicited review articles will also be given due consideration. Typical length: 2000-3500 words.

5.2. Original Articles These articles typically include randomized trials, intervention studies, studies of screening and diagnostic tests,

laboratory and animal studies, cohort studies, cost-effectiveness analyses, case-control studies, and surveys with high response rates, which represent new and significant contributions to the field.

Section headings should be: Abstract, Introduction, Methods, Results, Discussion, Conflicts of Interest Statement (if any), Acknowledgments (if any), and References.

The Introduction should provide a brief background to the subject of the paper, explain the importance of the study, and state a precise study question or purpose.

The Methods section should describe the study design and methods (including the study setting and dates, pa-tients/participants with inclusion and exclusion criteria, patient samples or animal specimens used, the essential features of any interventions, the main outcome measures, the laboratory methods followed, or data sources and how these were selected for the study), and state the statistical procedures employed in the research.

The Results section should comprise the study results presented in a logical sequence, supplemented by tables and/or figures. Take care that the text does not repeat data that are presented in tables and/or figures. Only emphasize and summarize the essential features of the main outcome measures, and the main results.

The Discussion section should be used to emphasize the new and important aspects of the study, placing the results in context with published literature, the implications of the findings, and the conclusions that follow from the study re-sults.

Typical length: 2000-3000 words and not more than 40 references.

5.3. Case Report These are short discussions of a case or case series with unique features not previously described that make an im-

portant teaching point or scientific observation. Section headings should be: Abstract, introduction, Case Presentation, Discussion, Acknowledgments (if applicable), Conflict of Interest(if any), References. There should be no more than 6 authors. Typical length: 1000-1500 words and not more than 25 references.

5.4. Short Communications and Technical Notes These reports should be concise presentations of preliminary experimental results or technical aspects of clinical or

experimental practice that are not fully investigated, verified or perfected but which may be of widespread interest or application.

Typical length: 1000-1500 words and not more than 25 references.

5.5. Letters to the Editor Letters are welcome in response to previously published CJM articles and may also include interesting case reports,

as well as other brief technical or clinical notes of general interest. Letters should have a title, no more than five authors, include appropriate references and the corresponding author's mailing and e-mail addresses. Letters are edited, some-times extensively, to sharpen their focus. They may be sent for peer review at the discretion of CJM Editors. Letters are selected based on clarity, significance, and space.

Typical length: 500 words and not more than 5 references (1 table or figure may be included).

6. Manuscript Preparation

Text should be typed double-spaced on one side of white A4 (297 × 210 mm) paper, with outer margins of 2.5 cm. A manuscript should include a title page, abstract, text, references, conflicts of interest statement (if any), acknowledg-ments (if any), and figures and tables as appropriate. Each section of the manuscript should begin on a new page. Pages should be numbered consecutively, beginning with the title page.

6.1. Title Page The title page should contain the following information (in order, from the top to bottom of the page):

article category article title running title not exceeding 50 characters IMPORTANT: please do NOT include any author names and affiliations or corresponding author infor-

mation on the title page (this information should be listed in your cover letter instead) because the CJM follows a double-blind peer review process

6.2. Abstract and Keywords An unstructured abstract (i.e., in one single paragraph with no subheadings), of no more than 500 words in length,

and 3-5 relevant keywords (in alphabetical order) are required for the following article categories: Review Articles, Original Articles, and Short Communications.

Keywords should be taken from the Medical Subject Headings (MeSH) list of Index Medicus ( http://www.nlm.nih.gov/mesh/meshhome.html).

No abstract or keywords are required for Letters to the Editor.

6.3. Main Text The text for Original Articles should be organized into the following sections: Introduction, Methods, Results,

Discussion, and References. Each section should begin on a new page.

6.3.1. Abbreviations Where a term/definition will be continually referred to, it must be written in full when it first appears in the text,

followed by the subsequent abbreviation in parentheses. Thereafter, the abbreviation may be used. An abbreviation should not be first defined in any section heading; if an abbreviation has previously been defined in the text, then the abbreviation may be used in a subsequent section heading. Restrict the number of abbreviations to those that are abso-lutely necessary.

6.3.2. Numbers Numbers that begin a sentence or those that are less than 10 should be spelled out using letters. Centuries and dec-

ades should be spelled out, e.g., the Eighties or nineteenth century. Laboratory parameters, time, temperature, length, area, mass, and volume should be expressed using digits.

6.3.3. Units Système International (SI) units must be used, with the exception of blood pressure values which are to be reported

in mmHg. Please use the metric system for the expression of length, area, mass, and volume. Temperatures are to be given in degrees Celsius.

6.3.4. Names of drugs, devices and other products Use the Recommended International Nonproprietary Name (rINN) for medicinal substances, unless the specific

trade name of a drug is directly relevant to the discussion. Generic drug names should appear in lowercase letters in the text. If a specific proprietary drug needs to be identified, the brand name may appear only once in the manuscript in parentheses following the generic name the first time the drug is mentioned in the text.

For devices and other products, the specific brand or trade name, the manufacturer and their location (city, state, country) should be provided the first time the device or product is mentioned in the text, for example, "...SPSS version 11 was used (SPSS Inc., Chicago, IL, USA)". Thereafter, the generic term (if appropriate) should be used.

6.3.5. Gene nomenclature Current standard international nomenclature for genes should be adhered to. For human genes, use genetic notation

and symbols approved by the HUGO Gene Nomenclature Committee ( http://www.genenames.org). You may also refer to the resources available on PubMed at http://www.ncbi.nlm.nih.gov/guide/genes-expression. The Human Genome Variation Society has a useful site that provides guidance in naming mutations at http://www.hgvs.org/mutnomen/ index. html. In your manuscript, genes should be typed in italic font and include the accession number.

6.3.6. Statistical requirements Statistical analysis is essential for all research papers. Use correct nomenclature of statistical methods (e.g., two

sample t test, not unpaired t test). Descriptive statistics should follow the scales used in data description. Inferential sta-tistics are important for interpreting results and should be described in detail.

All p values should be presented to the third decimal place for accuracy. The smallest p value that should be ex-pressed is p < 0.001, since additional zeros do not convey useful information; the largest p value that should be ex-pressed is p > 0.99.

6.3.7. Personal communications and unpublished data These sources cannot be included in the references list but may be described in the text. The author(s) must give

the full name and highest academic degree of the person, the date of the communication, and indicate whether it was in oral or written (letter, fax, e-mail) form. A signed statement of permission should be included from each person identi-fied as a source of information in a personal communication or as a source for unpublished data.

6.5. Acknowledgments After the Conflicts of Interest Statement, general acknowledgments for consultations and statistical analysis should

be listed concisely, including the names of the individuals who were directly involved. Consent should be obtained from those individuals before their names are listed in this section. All financial and material support for the research, work, writing and editorial assistance from internal or external agencies, including commercial companies, should be clearly and completely identified.

6.6. References Authors are responsible for the accuracy and completeness of their references and for correct in-text citation.

6.6.1. In the main text, tables, figure legends References should be indicated by numbers in square brackets in line with the text, numbered consecutively in order of appearance, and placed before punctuation. [The actual authors can be referred to, but the reference number(s) must always be given.]

References cited in tables or figure legends should be included in sequence at the point where the table or figure is first mentioned in the main text.

Do not cite abstracts unless they are the only available reference to an important concept. Do not cite uncom-pleted work or work that has not yet been accepted for publication (i.e., “unpublished observation”, “personal communication”) as references. Also see Section 6.3.7.

6.6.2. In the references list References should be limited to those cited in the text and listed in numerical order, NOT alphabetical order. References should include, in order, authors’ surnames and initials, article title, abbreviated journal name, year, volume and inclusive page numbers.

The surnames and initials of all the authors up to 3 should be included, but when authors number 4 or more, list the first 3 authors only followed by “et al”.

Abbreviations for journal names should conform to those used in MEDLINE. If citing a website, provide the author information, article title, website address and the date you accessed the information.

Reference to an article that is in press must state the journal name and, if possible, the year and volume. Examples of the most common reference types are provided below. (Please pay particular attention to the format-

ting, word capitalization, spacing and style.)

Standard journal articles

Impara JC, Plake BS. Teachers’ ability to estimate item difficulty: A test of the assumptions inn the Angoff standard setting method. J Educ Measu 1998;35:69-81.

Hsu SW, Shu K, Lee WC, et al. Adrenal myelolipoma: A 10-year single-center experience and literature review. Kao- hsiung J Med Sci 2012;28:377-82.

Journal supplement Kaplan NM. The endothelium as prognostic factor and therapeutic target: what criteria should we apply? J Cardiovasc Pharmacol 1998;32(Suppl 3):S78–80.

Journal article not in English but with English abstract Kawai H, Ishikawa T, Moroi J, Hanyu N, Sawada M, Kobayashi N, et al. Elderly patient with cerebellar malignant as-trocytoma. No Shinkei Geka 2008;36:799-805. [In Japanese, English abstract]

Book with edition Bradley EL. Medical and surgical management. 2nd ed. Philadelphia: Saunders; 1982, p. 72–95.

Book with editors Letheridge S, Cannon CR, editors. Bilingual education: Teaching English as a second language. New York: Praeger; 1980.

Book chapter in book with editor and edition Greaves M, Culligan DJ. Blood and bone marrow. In: Underwood JCE, editor. General and systematic pathology. 4th ed. London: Churchill Livingstone; 2004, p. 615–72.

Book series with editors Wilson JG, Fraser FC, editors. Handbook of teratology, vols. 1-4. New York: Plenum Press; 1977-1978.

Bulletin World Health Organization. World health report 2002: reducing risk, promoting healthy life. Geneva, Switzerland: World Health Organization; 2002.

Electronic publications Duchin JS. Can preparedness for biological terrorism save us from pertussis? Arch Pediatr Adolesc Med 2004;158:106–7. Available at http://archpedi.amaassn.org/cgi/content/full/158/2/106. Accessed June 12, 2004.

Smeeth L, Iliffe S. Community screening for visual impairment in the elderly. Cochrane Database Syst Rev 2002(2):CD001054. doi:10.1002/14651858. CD1001054.

Theses Ayers AJ. Retention of resin restorations by means of enamel etching and by pins. MSD thesis, Indiana University, In-dianapolis, 1971.

Website American Association of Oral and Maxillofacial Surgeons. Wisdom teeth. Rosemont, IL: AAOMS, 2008. Available at http://www.aaoms.org/wisdom_teeth.php. Accessed November 15, 2008.

Company/manufacturer publication/pamphlet Eastman Kodak Company, Eastman Organic Chemicals. Catalog no. 49. Rochester, NY: Eastman Kodak; 1977, p. 2–3.

6.7. Tables Tables should supplement, not duplicate, the text. They should have a concise table heading, be self-explanatory,

and numbered consecutively in the order of their citation in the text. Items requiring explanatory footnotes should be denoted using superscripted lowercase letters (a, b, c, etc.), with the footnotes arranged under the table in alphabetical order. Asterisks (*, **) are used only to indicate the probability level of tests of significance. Abbreviations used in the table must be defined and placed after the footnotes in alphabetical order. If you include a block of data or table from another source, whether published or unpublished, you must acknowledge the original source.

6.8. Figures

6.8.1. General guidelines The number of figures should be restricted to the minimum necessary to support the textual material. Figures

should have an informative figure legend and be numbered in the order of their citation in the text. All symbols and ab-breviations should be defined in the figure legend in alphabetical order. Items requiring explanatory footnotes should follow the same style as that for tables as described in Section 6.7.

Patient identification should be obscured. All lettering should be done professionally and should be in proportion to the drawing, graph or photograph. Photomicrographs must include an internal scale marker, and the legend should state the type of specimen, original magnification and stain.

Figures must be submitted as separate picture files at the correct resolution (see Section 6.8.2 below). The files should be named according to the figure number and format, e.g., “Fig1.tif”, “Fig2.jpg”.

6.8.2. Formats Regardless of the application used, when your electronic artwork is finalized, please “save as” or convert the images to one of the following formats (note the resolution requirements for line drawings, halftones, and line/halftone combinations given below): EPS: Vector drawings. Embed the font or save the text as “graphics”.

TIFF: Color or grayscale photographs (halftones) — always use a minimum of 300 dpi. TIFF: Bitmapped line drawings — use a minimum of 1000 dpi. TIFF: Combination of bitmapped line/half-tone (color or grayscale) — a minimum of 600 dpi. DOC, XLS or PPT: If your electronic artwork is created in any of these Microsoft Office applications, please supply “as is”.

Please do not: Supply files that do not meet the resolution requirements detailed above; Supply files that are optimized for screen use (such as GIF, BMP, PICT, WPG) as the resolution is too low; Submit graphics that are disproportionately large for the content.

A detailed guide on electronic artwork is available at http://www2.cch.org.tw/7477

7. Preparation for Publication Once a manuscript has been accepted for publication, authors should submit the final version of their manuscript in

MS Word format, with all tables/figures as applicable to the Editorial Office. Accepted manuscripts are then copyedited according to the Journal’s style and the galley proofs in the form of a

PDF file are sent by the Publisher to the corresponding author for final approval. Authors are responsible for all state-ments made in their work, including changes made by the copy editor.

Proofreading is solely the authors' responsibility. Note that the Editorial Board reserves the right to make revisions to the manuscript and the Publisher may proceed with the publication of your article if no response from the author(s) is received.


CHECKLIST

Only complete manuscript submissions will be considered for publication. Complete submission must include the following documents:

□ Cover letter signed by the first author or the corresponding author (Chinese authors should provide their names, affiliations and contact details in both English and Chinese characters)

□ Authorship & conflicts of interest statement signed by all authors listed in the manuscript □ Copyright transfer agreement signed by all authors listed in the manuscript □ Manuscript in MS Word format

AND, where applicable □ Letter of approval from review committee for use of human samples in research and human experiments □ Letter of approval from relevant authority for use of animals in experiments □ CONSORT flow chart for randomized controlled trial □ Signed consent to publish (in print and online) from human subjects who can be identified in your manuscript □ Title page (double spaced)*

〇 Article category 〇 Article title 〇 Running title not exceeding 50 characters

□ Abstract and keywords (double spaced) required for: Review Articles, Original Articles, Short Communications, and Case Reports 〇 Abstract is unstructured (i.e., in one single paragraph with no subheadings) and no more than 500 words in

length 〇 3–5 keywords are arranged in alphabetical order (MeSH terms are recommended; see

http://www.ncbi.nlm.nih.gov/mesh?term) □ Main text (double spaced) □ References (double spaced) in the correct format, cited in numerical order, and all references in the List are cited in

the Text/Tables/Figures and vice versa

AND, where applicable □ Conflicts of interest statement □ Acknowledgments □ Table headings and tables (double spaced), each on a new page □ Figure legends (double spaced), on a new page □ Electronic picture files of all figures; resolution of 300 dpi for halftone images, 600 dpi for combination art (half-

tone + line art), and 1000 dpi for line art

Further considerations: □ Manuscript has been spell-checked □ List of color figures to be converted into grayscale for publication in the print Journal (please list out the figure

numbers clearly in this space provided)**:

_______, _______ , _______ , _______ , ________

**Explanation: authors will be charged US$67 (NT$2000) per illustration, figure or table that is printed in color. Therefore, if authors want their color artwork to be converted into grayscale for publication in the print Journal (which would be free), the figure number(s) should be listed in the space above. Note that the Editors reserve the right to over-rule the request to conversion to grayscale if it is deemed that color reproduction would better aid readers’ interpretation of the artwork.


PERMISSION REQUEST AND LICENSE

Date:

To: NAME / COMPANY / ADDRESS / E-MAIL

From/Return to: NAME / E-MAIL / TEL / ADDRESS

Changhua Journal of Medicine (CJM) requests permission to republish the materials identified in this request, per the terms below, in the CJM. Full credit to the original source will be given.

If you do not control the rights to this material, please supply the name, address and e-mail of the person to whom requests should be directed.

ORIGINAL SOURCE INFORMATION

Work/Product Title:

Author(s):

Volume/Edition No./Other:

Figure/Table & Page No./Other:

Article/Chapter Title/Other:

Publisher & Year of Copyright:

APPROVAL OF REQUEST

The undersigned grants and assigns the non-exclusive permission to reproduce (and if necessary to redraw or modi-fy) the material listed above in this and all subsequent editions, revisions, versions, derivative works, translations, an-cillaries, adaptations, supplementary materials, custom editions, and in advertising and promotion thereof, in all lan-guages, in all formats and media now known or hereafter developed, throughout the world and in perpetuity to CCH and its licensees, affiliates and successors. The undersigned rights holder has the right to grant this permission and represents that the use of the material as set forth herein will not infringe the rights of any third party. In the event that use of the material exceeds the rights granted herein, the sole obligation of CCH to the rights holder shall be to pay for such additional use in accordance with the rights holder’s standard fees for such use, and the terms and conditions of this Permission Request and License shall apply to such additional uses.

Name: _______________________; Signature:_____________________

Company: _____________________; Date: _________________________


COPYRIGHT TRANSFER AGREEMENT

Changhua Christian Hospital (CCH) will be pleased to publish your article

(“the Work”), tentatively entitled: ___________________________________________________

________________________________________________________________________in the Changhua Journal of Medicine (“the Journal”) if the Work is accepted for publication. The undersigned authors transfer all copyright ownership in and relating to the Work, in all forms and media, to CCH in the event that the Work is published in the Journal. However, this agreement will be null and void if the Work is not published in the Journal.

The undersigned authors warrant that the Work is original, is not under consideration by another journal, and has not been previously published.

(This agreement must be signed by all authors listed in the Work. A photocopy of this form may be used if there are more than 10 authors.)

___________________________ ____________________________ Author’s name & signature Date Author’s name & signature Date





Changhua Journal of Medicine

AUTHORSHIP & CONFLICTS OF INTEREST STATEMENT

Manuscript title: __________________________________________________________________________________

________________________________________________________________________________________________

AUTHORSHIP All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated suffi-ciently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript. Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication. Please Indicate the specific contributions made by each author (list the authors’ initials followed by their surnames, e.g., Y.L. Chang). The name of each author must appear at least once in each of the three categories below.

Category 1 Conception and design of study: _______________, _______________, ______________, _____________ acquisition of data: _________________, _________________, ________________, ________________ analysis and/or interpretation of data:______________, _____________, _____________, _____________

Category 2 Drafting the manuscript: ________________, ________________, _______________, _______________ revising the manuscript critically for important intellectual content: ___________, ___________, __________

Category 3 Approval of the version of the manuscript to be published (the names of all authors

must be listed): __________, __________, _________, _________, __________, __________, _________ Acknowledgments All persons who have made substantial contributions to the work reported in the manuscript (e.g., technical help, writ-ing and editing assistance, general support), but who do not meet the criteria for authorship, are named in the Acknowl-edgments and have given us their written permission to be named. If we have not included an Acknowledgments, then that indicates that we have not received substantial contributions from non-authors. CONFLICTS OF INTEREST A conflict of interest occurs when an individual’s objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. CJM Editors strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any poten-tial conflicts of interest.

Section I (No conflicts of Interest) The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Author names:

Section II (With conflicts of Interest) The authors whose names are listed immediately below report the following details of affiliation or involvement in an organization or entity with a financial or non-financial interest in the subject matter or materials discussed in this ma-nuscript. Please specify the nature of the conflict on a separate sheet of paper if the space below is inadequate.

Author names and details of the conflict(s) of interest:

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This Authorship & Conflicts of Interest Statement is signed by the corresponding auther on behalf of all the listed au-thors in the manuscript. The corresponding author certifies that all the information contained in this statement is true, correct and agreed on by all the listed authors. Corresponding author’s name(typed) Corresponding author’s signature Date

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