NCI 2018-4 by KAREPUBLISHING

P ISSN 2148–4902 E ISSN 2536–4553

NORTHERN CLINICS OF ISTANBUL • İSTANBUL KUZEY KLİNİKLERİ NORTHERN CLINICS OF ISTANBUL • İSTANBUL KUZEY KLİNİKLERİ

Vol. 5 • No. 4 • Year 2018

INDEXED IN WEB OF SCIENCE, EMERGING SOURCES CITATION INDEX, PUBMED, PUBMED CENTRAL, EUROPE PMC, EBSCO, DOAJ, TUBITAK TR INDEX, AND TURKIYE CITATION INDEX.

Journal Abbreviation: North Clin Istanb

Vol. 5 • No. 4 • Year 2018

KARE

The effects of shortterm use of granulocyte colony-stimulating factor on bone metabolism in child cancer patients • Impact of emergency room meetings on improvement of door-to-needle times in acute ischemic stroke patients • Bradyarrhythmia development and permanent pacemaker implantation

after cardiac surgery • Effect of increase in cortisol level due to stress in healthy young individuals on dynamic and static balance scores • Factors associated with problematic internet use among children and adolescents with Attention Deficit Hyperactivity Disorder • Efficacy of extracorporeal shockwave

rheumatic heart disease: A single center experience • Surgical treatment of type III acromioclavicular dislocation: Bosworth technique versus hook plating • Vitamin D status of children with cerebral palsy: Should vitamin D levels be checked in children with cerebral palsy? • Daytime sleepiness, functionality, and

therapy in patients with lateral epicondylitis: A randomized, placebocontrolled, double-blind clinical trial • Effects of long-term computer use on eye dryness • The association between aspirin resistance and extentand severity of coronary atherosclerosis • Subclinical

stress levels in chronic neck pain and effects of physical medicine and rehabilitation therapies on these situations • Intracranial abscess developed after ganciclovir treatment • Management of Transverse Testicular Ectopia with Persistent Mullerian Duct Syndrome • Parathyroid adenoma presenting with

multiple Brown tumors in an adolescent patient • Treatment choice in metaplastic breast cancer: A report of 5 cases • Bayés’ syndrome: Time to consider early anticoagulation? • How to get ethics committee approval for clinical trials in Turkey?

NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ

Editor Levent Doganay, M.D.

Associate Editors

Publıcatıon Coordınators

Berna Terzioglu Bebitoglu, M.D. Bekir Durmus, M.D.

Beril Tekay Umut Elmas

Betul Sozeri, M.D.

Asistant to the Edıtor

Managing Editor

Aysenur Aydin

Neslihan Buyukmurat, M.D.

Scientıfıc Commıttee* Didem Tuba Akcali, M.D.

Mehmet Zafer Goren, M.D.

Sait Naderi, M.D.

Ilknur Aktas, M.D.

Aysegul Gunduz, M.D.

Kemal Nas, M.D.

Mustafa Aldag, M.D.

Ozlem Guneysel, M.D.

Cagatay Nuhoglu, M.D.

Mustafa Aldemir, M.D.

Melek Gura Celik, M.D.

Tamer Okay, M.D.

Orhan Alimoglu, M.D.

Melih Atahan Guven, M.D.

Muhammed Fatih Onsuz, M.D.

Nuri Aydin, M.D.

Mert Ilker Hayiroglu, M.D.

Melike Ozcelik, M.D.

Ozlem Baysal, M.D.

Mine Hekimgil, M.D.

Kamil Ozdil, M.D.

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Mustafa Caliskan, M.D.

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Tarik Sapci, M.D.

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Ayse Banu Sarifakioglu, M.D.

Turhan Caskurlu, M.D.

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Ali Riza Cenk Celebi, M.D.

Semra Kayatas Eser, M.D.

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Umut Kefeli, M.D.

Ozlem Tanriover, M.D.

Tongabay Cumurcu, M.D.

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Gurkan Kiran, M.D.

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Sibel Dogan, M.D.

Cemal Kocaaslan, M.D.

Ismail Turkmen, M.D.

Mehmet Doganay, M.D.

O. Emek Kocaturk Goncu, M.D.

Sezgin Vatansever, M.D.

Dilek Erdogan Ari, M.D.

Sukran Kose, M.D.

Ayhan Verit, M.D.

Yuksel Ersoy, M.D.

Turkan Kudsioglu, M.D.

Destina Yalcin, M.D.

Duygu Geler Kulcu, M.D.

Kemal Memisoglu, M.D.

Tuba Yavuzsen, M.D.

Kaan Gideroglu, M.D.

Aysel Milanlioglu, M.D.

Sema Yilmaz, M.D.

Ahmet Gocmen, M.D.

Murat Muhcu, M.D.

Ebru Zemheri, M.D.

*The editorial board list is sorted alphabetically by surname.

NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ YEAR 2018 VOLUME 5 NUMBER 4

p ISSN 2148 - 4902 e ISSN 2536 - 4553

Ownership and Accountability for Contents on behalf of The Istanbul Health Directorate

Kemal Memisoglu, M.D.

Publicatıon Manager

Bekir Durmus, M.D.

Publicatıon Coordinators

Beril Tekay

Umut Elmas

Executive Office Umraniye Teaching and Research Hospital Elmalikent Mah., Adem Yavuz Cad. No: 1, 34764 Umraniye, Istanbul-Turkey Phone: +90 216 632 18 18 Fax: +90 216 632 71 24 http://www.kuzeyklinikleri.com e-mail: bilgi@kuzeyklinikleri.com Indexed in Web of Science, Emerging Sources Citation Index, PubMed, PubMed Central, Europe PMC, DOAJ, TUBITAK TR Index, CINAHL and Turkiye Citation Index.

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KARE PUBLISHING Dumlupinar Mah., Cihan Sok., No: 15, B Blok Da: 162 Kadikoy, Istanbul, Turkey Tel: +90 216 550 61 11 Fax: +90 216 550 61 12 http://www.kareyayincilik.com e-mail: kare@kareyayincilik.com

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YILDIRIM PRINTING HOUSE Yuzyil Mah., Massit Matbaacılar Sitesi, 1. Cad. No: 101, Bagcilar, Istanbul, Turkey Tel: +90 212 629 80 37 Fax: +90 212 629 80 39

Gurkan Kazanci

Northern Clinics of Istanbul (NCI) is a peer-reviewed journal published triannually. Materials published in the Journal is covered by copyright ©2018 NCI. All rights reserved. This publication is printed on paper that meets the international standard ISO 9706:1994. National Library of Medicine recommends the use of permanent, acid-free paper in the production of biomedical literature.

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Press date: December 2018 Circulation: 1000 Type of publication: Periodical

CONTENTS Vol. 5 • No. 4 • Year 2018 IV

Instructions for the authors

O R I G I N A L A RT I C LE S

277–281 The effects of short-term use of granulocyte colony-stimulating factor on bone metabolism

in child cancer patients

A. Bozkurt Turhan, C. Binay, O. Bor, E. Simsek

282–287 Impact of emergency room meetings on improvement of door-to-needle times in acute ischemic stroke patients: A single center’s experience

B. A. Acar

288–294 Bradyarrhythmia development and permanent pacemaker implantation after cardiac surgery

C. Turkkan, D. Osmanov, E. Yildirim, K. S. Ozcan, S. Altay, H. Hasdemir, A. T. Alper, N. Ozbilgin, I. C. Erdinler, K. Gurkan

295–301 Effect of increase in cortisol level due to stress in healthy young individuals on dynamic and static balance scores

M. Cay, C. Ucar, D. Senol, F. Cevirgen, D. Ozbag, Z. Altay, S. Yildiz

302–313 Factors associated with problematic internet use among children and adolescents with Attention Deficit Hyperactivity Disorder

F. H. Cakmak, H. Gul

314–318 Efficacy of extracorporeal shockwave therapy in patients with lateral epicondylitis: A randomized, placebo-controlled, double-blind clinical trial

N. Senol Guler, S. Sargin, N. Sahin

319–322 Effects of long-term computer use on eye dryness

S. Akkaya, T. Atakan, B. Acikalin, S. Aksoy, Y. Ozkurt

323–328 The association between aspirin resistance and extentand severity of coronary atherosclerosis

S. Kahraman, A. Dogan, M. Ziyrek, E. Usta, O. Demiroz, C. Ciftci

329–333 Subclinical rheumatic heart disease: A single center experience

S. Kayali, N. Belder

334–340 Surgical treatment of type III acromioclavicular dislocation: Bosworth technique versus hook plating

S. A. Gumustas, F. Saglam, B. Komur, A. G. Batmaz, I. Yukunc, H. B. Tosun, H. I. Bekler

341–347 Vitamin D status of children with cerebral palsy: Should vitamin D levels be checked in children with cerebral palsy?

P. Akpinar

348–352 Daytime sleepiness, functionality, and stress levels in chronic neck pain and effects of physical medicine and rehabilitation therapies on these situations

S. Sayilir

C A SE RE PO RTS

353–356 Intracranial abscess developed after ganciclovir treatment: A case report

M. Cansever, E. N. Ozmansur, A. Ozcan, Z. F. Kahraman, T. Patiroglu

357–360 Management of Transverse Testicular Ectopia with Persistent Mullerian Duct Syndrome

S. Cansaran, S. Moralioglu, A. Celayir, O. Bosnali, R. G. Yesiltepe Mutlu

361–364 Parathyroid adenoma presenting with multiple Brown tumors in an adolescent patient

S. Aslan, M. Ceyhan Bilgici, R. F. Bernay, H. M. Aydin, M. B. Selcuk

365–369 Treatment choice in metaplastic breast cancer: A report of 5 cases

T. Acar, N. Acar, G. Sezgin, M. Bekler Gokova, B. B. Kucukzeybek, M. Haciyanli

I N V I T E D RE V I E W

370–378 Bayés’ syndrome: Time to consider early anticoagulation?

A. Baranchuk, B. Alexander, G. Cinier, M. Martinez-Selles, A. I. Tekkesin, R. Elousa, A. B. De Luna

379–386 How to get ethics committee approval for clinical trials in Turkey?

H. Ilbars, B. Terzioglu Bebitoglu

INSTRUCTIONS FOR THE AUTHORS Northern Clinics of Istanbul - NCI is a peerreviewed, open-access, international journal published by the Istanbul Health Directorate (IHD). The NCI is printed 4 times a year. Free full-text articles in English are available at www.kuzeyklinikleri. com. The NCI is indexed in the Web of Science, Emerging Sources Citation Index, PubMed, PubMed Central, Europe PMC, DOAJ, ULAKBIM TR Index and Turkey Citation Index. The journal publishes research, interesting case reports, letters to the editor, review articles, editorial comments, medical news, and guidelines. The NCI accepts manuscripts written in Turkish and English. Opinions presented in published articles do not represent official endorsement of the IHD. Manuscripts should be prepared in accordance with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which is regularly updated by the International Committee of Medical Journal Editors (ICMJE), and available at http://www.icmje.org. ARTICLE TYPES

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ADDRESS OF CORRESPONDENCE KARE PUBLISHING Dumlupınar Mah. Cihan Sok. No: 15 B Blok Da 162, Kadikoy, Istanbul, Turkey Tel: 0216 550 61 11 Fax: 0216 550 61 12 E-mail: kare@kareyayincilik.com

Orıgınal Article

PEDIATRY

North Clin Istanb 2018;5(4):277–281 doi: 10.14744/nci.2017.59320

The effects of short-term use of granulocyte colony-stimulating factor on bone metabolism in child cancer patients Ayse Bozkurt Turhan,1

Cigdem Binay,2

Ozcan Bor,3

Enver Simsek2

Division of Pediatric Hematology-Oncology, Department of Pediatrics, Goztepe Training and Research Hospital of Istanbul Medeniyet

University, Istanbul, Turkey Division of Pediatric Endocrinology, Department of Pediatrics, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey

Division of Pediatric Hematology-Oncology, Department of Pediatrics, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey

ABSTRACT OBJECTIVE: The granulocyte colony-stimulating factor (G-CSF) is the most commonly used hematopoietic growth factor recombinant DNA technology. It affects bone metabolism by modulating both osteoclast and osteoblast functions. The aim of the present study was to investigate the effects of short-term use of G-CSF on bone metabolism in children with leukemia and solid tumors. METHODS: Thirty-six patients with a malignancy who received G-CSF therapy according to chemotherapy protocols and another 20 growth factor-free cancer patients who were enrolled as controls were included in the study. The serum osteocalcin and urinary free deoxypyridinoline levels were measured before the start of G-CSF therapy, on day 3 after treatment, and 7 days after G-CSF therapy was discontinued. In the control group, the measurements were made during corticosteroid and methotrexate-free chemotherapy. RESULTS: The mean osteocalcin level (8.6±2.3 ng/mL) from before the onset of treatment decreased significantly (7.7±2.3 ng/mL) on day 3 of G-CSF therapy and significantly increased after 7 days of G-CSF therapy (7.9±2.2 ng/mL) (p<0.001 and p<0.001, respectively), which was still significantly lower than the pre-G-CSF values (p<0.001). The urinary free deoxypyridinoline level significantly increased on day 3 of G-CSF treatment (25.6±6.5 nmol/mmol Cr) and significantly decreased after 7 days of G-CSF therapy (22.6±6.4 nmol/mmol Cr) (p<0.001 and p<0.001, respectively), which was still significantly higher than the values recorded before G-CSF therapy (p<0.001). CONCLUSION: The findings show that the short-term use of G-CSF in children with cancer can affect bone metabolism and can play a role in metabolic changes. Decreased osteoblastic activity and increased osteoclastic activity suggest that osteoporosis may be associated with bone pain in these patients. Keywords: Bone; cancer; granulocyte colony-stimulating factor; hematopoietic growth factor.

Cite this article as: Bozkurt Turhan A, Binay C, Bor O, Simsek E. The effects of short-term use of granulocyte colony-stimulating factor on bone metabolism in child cancer patients. North Clin Istanb 2018;5(4):277–281.

ematopoietic growth factors are glycoprotein hormones that regulate the proliferation and differentiation of mature blood and hematopoietic progenitor cells. The granulocyte colony-stimulating factor (G-CSF) prepared by recombinant DNA technology is the most

commonly used hematopoietic growth factor. G-CSF regulates the survival, proliferation, and differentiation of neutrophils and activates and stimulates the functions of mature neutrophils. It decreases the neutropenic period following intensive chemotherapy in children with

Received: Kasım 08, 2017 Accepted: Aralık 08, 2017 Online: December 03, 2018 Correspondence: Dr. Ayse BOZKURT TURHAN. Medeniyet Universitesi, Goztepe Egitim ve Arastirma Hastanesi, Cocuk Hematoloji Klinigi, Istanbul, Turkey. Tel: +90 532 724 71 80 e-mail: aysebturhan@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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acute leukemia and solid tumors and also decreases the frequency of infections and deaths due to infections [1]. Although G-CSF can be used intravenously and subcutaneously, subcutaneous use is preferred because it is less toxic and more effective [1]. The side effects of shortterm use of G-CSF are usually mild fever, fatigue, nausea, and bone pain. The most prevalent side effect is mild to moderate bone pain [2–3]. G-CSF affects bone metabolism by modulating both osteoclast and osteoblast functions. Bone morphogenetic protein 2, an effective inhibitor of the cartilage and bone, is also an effective regulator in the conduction pathway [4]. Bone metabolism is a continuous and dynamic process characterized with new bone formation by osteoblasts and bone resorption by osteoclasts [5]. Biochemical markers of bone production metabolism include serum alkaline phosphatase (ALP), serum osteocalcin, and serum procollagen type 1 peptides. Biochemical markers of bone resorption metabolism are urinary calcium, hydroxyproline, Ntelopeptide, C-telopeptide, pyridinoline, and deoxypyridinoline. Serum osteocalcin levels are indicative of osteoblastic activity reflecting bone mineralization rate. The level of urine deoxypyridinoline is considered to be a sensitive and specific indicator of osteoclastic activity [6–9]. Long-term treatment with G-CSF is characterized by clinically significant osteopenia, decreased bone mineral density, and compression fractures in the vertebra [10, 11]. The prevalence of osteopenia has been reported as 28% in children under chronic G-CSF treatment due to severe congenital neutropenia [10]. Not only long-term use but also short-term G-CSF treatment may affect bone metabolism. While long-term G-CSF treatment resulted in increased osteoclastogenesis, new evidence reveals that short-term administration of G-CSF reduces the number and activity of osteoblast [12–14]. It has been observed that the level of osteocalcin, which is one of the markers of bone formation, was significantly lower than baseline, whereas bone and bonespecific ALP levels significantly increased. It has been suggested that bone pain observed in patients receiving G-CSF may be due to the effect of osteoblastic activity, whereas short-term (3–7 days) G-CSF administration does not directly stimulate osteoclasts, and osteoporosis may occur indirectly via the activation of osteoclasts as a result of the stimulation of osteoblasts [2]. In healthy progenitor cells and stem cell donors, it has been observed that short-term (3–7 days) G-CSF treatment temporarily suppressed osteoblastic activity and

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increased osteoclastic activity [2, 12]. We aimed to investigate the effects of short-term GCSF use on bone metabolism in children with leukemia and solid tumors because of the small number of studies investigating the effects of short-term G-CSF treatment on bone metabolism. MATERIALS AND METHODS Fifty-six patients with hematological malignancies and solid tumors followed up by the Department of Pediatric Hematology–Oncology, Faculty of Medicine University of Eskisehir Osmangazi, including 36 patients receiving G-CSF therapy and 20 controls not receiving growth factor in compliance with chemotherapy protocols, were included in the study. Approval was obtained from the local ethics committee of the university where the present study was conducted. None of the solid tumor groups had bone involvement, and baseline calcium phosphorus and ALP values were within normal limits. Age, gender, diagnosis of primary disease, follow-up period, chemotherapy period, last chemotherapeutic drug received, development of neutropenia, and duration of G-CSF treatment were recorded. Among biochemical analyses, calcium, phosphorus, and ALP levels were analyzed for the estimation of bone metabolism. Serum osteocalcin and urine free deoxypyridinoline levels of the patients in the study group were measured before the beginning of G-CSF treatment, 3 days after onset of G-CSF therapy, and 7 days after discontinuation of G-CSF treatment. Serum osteocalcin and urine levels were measured in the control group during chemotherapy without corticosteroids and methotrexate that could affect bone metabolism. In the treated group, G-CSF chemotherapy protocol was started on day 3 after treatment and administered subcutaneously every morning at a dose of 5 μg/kg daily. Every morning, fasting blood samples were placed in heparinized tubes for the measurement of serum osteocalcin, and 10 cm3 urine samples were collected for the measurement of deoxypyridinoline and urine creatinine. Patients with abnormal parathormone or vitamin D levels who did not provide consent were excluded from the study. Data were analyzed by SPSS Windows 18 (SPSS Inc., Chicago, IL, USA). For descriptive statistical analysis, values were expressed as mean±standard deviation (minimum–maximum) using the one-way analysis of

Bozkurt Turhan et al., The effects of G-CSF on bone metabolism

Table 1. Demographic characteristics of the patients Characteristics

Patient Control group group (n=36) (n=20)

n % n %

Age (years), median (min.–max.) Gender (male) Diagnosis Acute lymphoblastic leukemia Lymphoma Acute myeloblastic leukemia Solid tumors

8.5 (1–17) 7 (2.1–15) 44.4 16 50 10 50.0 18 50.0 10 30.6 11 20.0 4 0 0 15.0 3 19.4 7 15.0 3

Min.: Minimum; Max.: Maximum.

variance for variables with normal distribution and median (25%–75%) for non-normally distributed variables, and the results were compared using the Mann–Whitney U test. Chi-square test or Fisher’s exact test was used for comparison of categorical data, and Student’s t-test was used for comparison of continuous data. A p value <0.05 was accepted as significant. RESULTS Fifty-six patients with G-CSF treatment and 20 controls without growth factor were included in the study. The me-

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dian ages of the patients and the control subjects were 8.5 (1–17) and 7 (2.1–15) years, respectively, with no statistically significant intergroup difference (p=0.24). The male gender ratios were 44.4% (n=16) in the patient group and 50% (n=10) in the control group with no statistically significant difference between the groups (p=0.69). The patients included in the study were followed up with the diagnoses of lymphoblastic leukemia (ALL) (n=18, 50%), lymphoma (including 11 (30.6%) patients with non-Hodgkin lymphoma), and solid tumors (n=7, 19.4%; including patients with neuroblastoma (n=3), Ewing’s sarcoma (n=2), Wilms tumor (n=1), and primitive neuroectodermal tumor (PNET) (n=1)) in the patient group, whereas the patients in the control group (n=20) were followed up with the diagnoses of acute ALL (n=10, 50%), acute myeloblastic leukemia (n=3, 15%), lymphoma (n=4, 20%; including 1 patient with non-Hodgkin lymphoma (n=1)), and solid tumors (n=3, 15%; including neuroblastoma (n=1), Wilms tumor (n=1), and PNET (n=1)). The median duration of G-CSF administration was 6.4 (3–11) days in the patient group. Table 1 shows the demographic data of the patient and control groups. When the average serum osteocalcin, serum ALP, and urine deoxypyridinoline levels were compared, there was no statistically significant difference between the pretreatment values of the G-CSF group and the levels of the control group (Table 2). Similarly, serum calcium, phosphorus, ALP, and vitamin D levels were not different between the groups.

Table 2. Comparison of serum osteocalcin, alkaline phosphatase, and urine deoxypyridinoline levels

Control group (n=20)

Pretreatment Serum osteocalcin level (ng/ml) Mean±SD (min.–max.) Urine deoxypyridinoline level (nmol/mmol Cr) Mean±SD (min.–max.) Serum alkaline phosphatase level (U/l) Mean±SD (min.–max.)

8.6±1.8 (5.4–11.7)€ 18.7±6.0 (9.0–30.6)€ 152±38 (93–222)€

G-CSF group (n=36) 3 days of treatment*

7 days after treatment£,¥

8.6±2.3 7.7±2.3 7.9±2.2 (5.2–13.4) (4.1–12.8) (4.3–12.9) 19.9±5.9 25.6±6.5 22.6±6.4 (9.3–30.6) (14.0–36.6)* (11.0–37.6)£,¥ 139±47 145±50 161±53 (56–250) (56–261) (58–313)α,β

G-CSF: Granulocyte colony-stimulating factor; Max.: Maximum; Min.: Minimum; SD: Standard deviation; €No difference when compared with pretreatment levels in the G-CSF group; *A significant difference when compared with pretreatment levels (p<0.001). £A significant difference when compared with 3-day levels (p<0.001); ¥ A significant difference when compared with pretreatment levels (p<0.001); αA significant difference when compared with 3-day levels (p=0.001); βA significant difference when compared with pretreatment levels (p=0.001).

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The mean osteocalcin level before onset of treatment (8.6±2.3 ng/ml) significantly decreased on day 3 of G-CSF treatment (7.7±2.3 ng/ml) and significantly increased 7 days after discontinuation of G-CSF therapy (7.9±2.2 ng/ml) (p<0.001 and p<0.001, respectively). However, they were still found to be significantly lower than the values before G-CSF treatment (p<0.001, Table 2). When we compared the mean urine free deoxypyridinoline levels on days 0, 3, and 7 after drug withdrawal, free urinary deoxypyridinoline level (19.9±5.9 nmol/mmol Cr) significantly increased on day 3 of G-CSF treatment (25.6±6.5 nmol/mmol Cr) and significantly decreased 7 days after discontinuation of G-CSF (22.6±6.4 nmol/ mmol Cr) (p<0.001 and p<0.001, respectively). However, it was still significantly higher than the values before the onset of G-CSF treatment (p<0.001) (Table 2). Serum ALP levels were significantly higher (145±50 U/l) on day 3 of G-CSF treatment (p<0.001 and p<0.001, respectively) than values before onset of treatment (139±47 U/l). While it remained at significantly higher levels at 7 days after discontinuation of G-CSF treatment (161±53 U/l) (p=0.001). DISCUSSION In the present study, it was found that the effects of short-term G-CSF treatment on bone metabolism in patients with pediatric cancer significantly changed the levels of biochemical markers related to bone formation and resorption. Osteoblasts provide regeneration of the bone tissue by proliferation, differentiation, and mineralization of the extracellular matrix. Osteocalcin is the major noncollagenous protein of the bone and is produced by osteoblasts during bone formation and binds to hydroxyapatite in the newly mineralized bone. Takamatsu et al. [12] reported that osteocalcin levels are significantly reduced on day 3 of G-CSF treatment and returned to baseline levels shortly after treatment. Serum ALP levels are associated with bone matrix formation and osteoblastic activity. ALP is produced by immature osteoblasts, and osteocalcin is produced by more mature osteoblasts [15]. It has been thought that the increase in ALP level and decrease in serum osteocalcin level after G-CSF treatment may be due to the downregulation of mature osteoblast and osteocalcin expressions [2]. Similarly, in our study, it was found

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that serum ALP levels increased, and osteocalcin levels decreased; these changes continued after termination of treatment in relation to G-CSF treatment. This condition has been associated with a decrease in osteoblastic activity, an increase in osteoblast turnover, an increase in osteoblast apoptosis, and a decrease in differentiation to mature osteoblasts after G-CSF treatment [16]. Cristopher et al. [16] reported that G-CSF treatment reduces the number of mature osteoblasts by increasing apoptosis and the number of osteoprogenitor cells in the bone marrow. Rapid recovery of osteoblastic activity after discontinuation of therapy is thought to occur due to the accumulation of these osteoblast precursors. As a result of long-term use of G-CSF treatment, it has been reported that significant degrees of osteopenia and osteoporosis developed, and bone mineral density values significantly decreased due to an increase in osteoclastic activity that may cause vertebral fractures [10, 17]. It has been detected that increased monocytic precursors with G-CSF treatment were the source of osteoclasts, and also osteoclast formation and activity increased with other direct or indirect mechanisms [10, 18, 19]. Dale et al. [10] proposed a reduction in the level of osteoprotegerin (OPG) regulated by osteoblasts in relation to increased osteoclastic activity, mechanisms such as disruption of the OPG/receptor activator of nuclear factor kappa-B ligand ratio. In the bone, collagen fibrils are cross-linked with deoxypyridinoline, such as dipyrimidine [20]. Deoxypyridinoline, especially in the bone and dentin, is released from bone collagen during bone resorption and excreted in urine without further deterioration. Therefore, the concentration of deoxypyridinoline in urine can be used as a specific symptom of bone resorption. Takamatsu et al. [12] showed that serum osteocalcin levels decrease, and urine deoxypyridinoline levels increase with 6 days of GCSF (10 μg/kg) treatment in patients with breast cancer. It has been observed that an increase in osteoclastic activity peaked at 7 days of treatment and coursed at high levels until at least 1 week after discontinuation of treatment. While with pamidronate treatment, an increased level of urine dihydropyridine was associated with GCSF treatment [12]. Although the G-CSF dose was lower in our study (5 μg/kg), we obtained similar results for osteoclastic activity. The findings of our study are similar to previous studies showing that prolonged administration of G-CSF in congenital neutropenia may stimulate osteoclast-medi-

Bozkurt Turhan et al., The effects of G-CSF on bone metabolism

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ated bone resorption [21, 22]. Similarly, significant expansion in bone space and a reduction in bone mass have been shown in transgenic mice with chronic and excessive G-CSF expressions [23]. These studies suggest that there may be a relationship between bone remodeling and mobilization of progenitor cells. Children are different from adults in terms of bone metabolism, and this difference may contribute to the variability of results. Although there are few studies on the effects of short-term G-CSF use on bone metabolism in the pediatric patient group [17], our study is one of the studies performed in children with cancer. In conclusion, our results showed that the use of short-term G-CSF in children with cancer may affect bone metabolism and may play a role in metabolic changes. A decrease in osteoblastic activity and an increase in osteoclastic activity suggest that osteoporosis in these patients may be associated with bone pain by contributing to osteoporosis in these patients. These findings should be warning signs for closer follow-up of the patients, and further studies should be performed with greater number of patients.

poros Int 1993;3:255–60. 7. Husain SM, Mughal Z, Williams G, Ward K, Smith CS, Dutton J, et al. Urinary excretion of pyridinium crosslinks in healthy 4-10 year olds. Arch Dis Child 1999;80:370–3. 8. Risteli L, Risteli J. Biochemical markers of bone metabolism. Ann Med 1993;25:385–93. 9. Romberg RW, Werness PG, Riggs BL, Mann KG. Inhibition of hydroxyapatite crystal growth by bone-specific and other calcium-binding proteins. Biochemistry 1986;25:1176–80. 10. Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol 2003;72:82–93. 11. Lee MY, Fukunaga R, Lee TJ, Lottsfeldt JL, Nagata S. Bone modulation in sustained hematopoietic stimulation in mice. Blood 1991;77:2135– 41. 12. Takamatsu Y, Simmons PJ, Moore RJ, Morris HA, To LB, Lévesque JP. Osteoclast-mediated bone resorption is stimulated during short-term administration of granulocyte colony-stimulating factor but is not responsible for hematopoietic progenitor cell mobilization. Blood 1998;92:3465–73. 13. Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 2006;124:407–21. 14. Semerad CL, Christopher MJ, Liu F, Short B, Simmons PJ, Winkler I, et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 2005;106:3020–7. 15. Delmas PD. Biochemical markers of bone turnover. J Bone Miner Res 1993;8 Suppl 2:S549–55. 16. Christopher MJ, Link DC. Granulocyte colony-stimulating factor induces osteoblast apoptosis and inhibits osteoblast differentiation. J Bone Miner Res 2008;23:1765–74. 17. Watanabe T, Suzuya H, Onishi T, Kanai S, Kaneko M, Watanabe H, et al. Effect of granulocyte colony-stimulating factor on bone metabolism during peripheral blood stem cell mobilization. Int J Hematol 2003;77:75–81. 18. Li S, Li T, Chen Y, Nie Y, Li C, Liu L, et al. Granulocyte Colony-Stimulating Factor Induces Osteoblast Inhibition by B Lymphocytes and Osteoclast Activation by T Lymphocytes during Hematopoietic Stem/Progenitor Cell Mobilization. Biol Blood Marrow Transplant 2015;21:1384–91. 19. Purton LE, Lee MY, Torok-Storb B. Normal human peripheral blood mononuclear cells mobilized with granulocyte colony-stimulating factor have increased osteoclastogenic potential compared to nonmobilized blood. Blood 1996;87:1802–8. 20. Morris HA, Chatterton BE, Ross PD, Durbridge TC. Diagnostic procedures. Metabolic Bone and Stone Disease. In: Need AG, Morris HA, editors. Metabolic Bone and Stone Disease. 3rd. Edinburgh: Churchill Livingstone; 1993. p. 339–79. 21. Bonilla MA, Dale D, Zeidler C, Last L, Reiter A, Ruggeiro M, et al. Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias. Br J Haematol 1994;88:723–30. 22. Bishop NJ, Williams DM, Compston JC, Stirling DM, Prentice A. Osteoporosis in severe congenital neutropenia treated with granulocyte colony-stimulating factor. Br J Haematol 1995;89:927–8. 23. Takahashi T, Wada T, Mori M, Kokai Y, Ishii S. Overexpression of the granulocyte colony-stimulating factor gene leads to osteoporosis in mice. Lab Invest 1996;74:827–34.

Conflict of Interest: The authors declare that they have not received any financial or any other support that might lead to any conflict of interest. Authorship Contributions: Concept – A.B.T., C.B., O.B., E.S.; Design – A.B.T., C.B., O.B., E.S.; Supervision – A.B.T.; Materials – A.B.T., C.B.; Data collection &/or processing – A.B.T., C.B.; Analysis and/or interpretation – A.B.T., O.B., E.S.; Writing – A.B.T., C.B., O.B., E.S.; Critical review – A.B.T.

REFERENCES 1. Lehrnbecher T, Welte K. Haematopoietic growth factors in children with neutropenia. Br J Haematol 2002;116:28–56. 2. Froberg MK, Garg UC, Stroncek DF, Geis M, McCullough J, Brown DM. Changes in serum osteocalcin and bone-specific alkaline phosphatase are associated with bone pain in donors receiving granulocytecolony-stimulating factor for peripheral blood stem and progenitor cell collection. Transfusion 1999;39:410–4. 3. Steward WP. Granulocyte and granulocyte-macrophage colony-stimulating factors. Lancet 1993;342:153–7. 4. Kuwabara H, Wada T, Oda T, Yoshikawa H, Sawada N, Kokai Y, et al. Overexpression of the granulocyte colony-stimulating factor gene impairs bone morphogenetic protein responsiveness in mice. Lab Invest 2001;81:1133–41. 5. Christenson RH. Biochemical markers of bone metabolism: an overview. Clin Biochem 1997;30:573–93. 6. Eastell R, Robins SP, Colwell T, Assiri AM, Riggs BL, Russell RG. Evaluation of bone turnover in type I osteoporosis using biochemical markers specific for both bone formation and bone resorption. Osteo-

Orıgınal Article

NEUROLOGY

North Clin Istanb 2018;5(4):282–287 doi: 10.14744/nci.2017.00378

Impact of emergency room meetings on improvement of door-to-needle times in acute ischemic stroke patients: A single center’s experience Bilgehan Atilgan Acar Department of Neurology, Sakarya University Faculty of Medicine, Sakarya, Turkey

ABSTRACT OBJECTIVE: One major limitation of the use of intravenous tissue plasminogen activator (IV-tPA) is the short treatment window of acute ischemic stroke (AIS). In this article, we analyze the impact of emergency room meetings on step-by-step improvement of door-to-needle times (DTN). METHODS: This study used prospectively recorded data of AIS patients treated with IV-tPA admitted to the Sakarya University Education and Research Hospital between January 2015 and August 2017. Time benchmarks of DTN were recorded on a case-by-case basis. Meetings were held in the emergency room if there was an increase of more than 25% in DTN of subsequent AIS patients treated with IV-tPA. Guideline-recommended stroke management methods and feedback from our previous DTN data were both considered. The goal was to improve DTN within 60 minutes for at least 50% of AIS patients. RESULTS: Mean DTN of 20 patients was 76.9±32.4 minutes. Nine patients experienced ≤60 minute DTN times, while two were under 30 minutes. Six meetings were conducted, with two each in 2015, 2016, and 2017. Without exception, there was a reduction in DTN after all meetings. Considering the intervals of the six meetings, the ratios of patients treated at ≤60 minutes were 0%, 0%, 60%, 66.6%, 40 and 100%, respectively. CONCLUSION: Meetings in the emergency room, when conducted according to certain rules, can be effective in improving DTN. Keywords: Acute stroke; door-to-needle time; emergency room.

Cite this article as: Acar BA. Impact of emergency room meetings on improvement of door-to-needle times in acute ischemic stroke patients: A single center’s experience. North Clin Istanb 2018;5(4):282–287.

troke is a leading cause of death and disability worldwide. Ischemic stroke is the most common type. Eligible patients presenting with acute ischemic stroke (AIS) are treatable via intravenous tissue plasminogen activator (IV-tPA) if the stroke is recognized early (up to 4.5 hours after symptom onset). Rapid treatment with IV-tPA with a specialized team improves recovery in patients with AIS [1]. This short time window is a major limitation to the benefits of IV-tPA and American Heart Association

(AHA)/American Stroke Association (ASA) Stroke Council recommendations of a door-to-needle time (DTN) of ≤60 minutes [2]. Although great importance is placed on improving the DTN in 60 minutes or less, fewer than one-third of AIS patients receiving IV-tPA are treated within this time [3]. This time target for treatment was later included in the AHA’s guidelines and has remained a metric in hospitals identified as primary or comprehensive stroke centers [4]. Emergency room (ER) crowding and frequent changes and rotations of

Received: September 08, 2017 Accepted: December 25, 2017 Online: September 10, 2018 Correspondence: Dr. Bilgehan Atilgan ACAR. Sakarya Universitesi Tip Fakultesi, Noroloji Anabilim Dali, Sakarya, Turkey. Tel: +90 505 657 91 70 e-mail: bilgehanacar@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Acar, Impact of emergency room meetings on improvement of door-to-needle times in acute ischemic stroke patients

emergency room doctors are the major obstacles to this goal. In order to overcome this problem, our stroke team held ER meetings if the DTN of subsequent patients exceeded 25%. The aim of these meetings was to improve DTN via education and motivation. In Turkey, rt-PA for treatment of acute ischemic stroke has been permitted by the Ministry of Health since 2006. The relatively late approval of use of IVtPA has resulted in obvious underuse of treatment [5]. Thrombolytic therapy in acute ischemic stroke is estimated to be at lower levels [6] than it should be, and the data are not sufficient in this regard. Very few studies have been reported on this issue [5, 7–11], many of which evaluated clinical outcomes of patients. However, the DTN have not been reviewed in detail. Our aim is to evaluate the DTN of all patients treated with IV-tPA in acute ischemic stroke in our hospital and to investigate the effect of the emergency room stroke meetings that organized by the stroke team in shortening this period. MATERIALS AND METHODS Twenty AIS patients who were treated with IV-tPA within 4.5 hours at Sakarya University Education and Research Hospital from January 2015 to August 2017 were admitted to the study. All the data in the study were obtained from hospital records and a stroke information database maintained progressively by the stroke neurologist. Assessment of the patient in an emergency room After entering the emergency gate, all patients suspected to be undergoing AIS were initially evaluated by an ER doctor. This period of time was expressed as “door to doctor”. After taking medical history, time last known well, symptom onset, vital assessment, fingertip glucose, and ordering laboratory work, patients underwent a head CT. If symptoms had begun within 4.5 hours, the ER doctor informed the stroke team neurologist. This period of time was expressed in terms of “access to neurologic expertise & laboratory /CT scan order”. ECG was performed before or after CT scan completion. After CT scan interpretation and laboratory results, the neurologist evaluated the eligibility of patients for IV-tPA treatment. Prior to administration of IV-tPA, patient condition was stabilized, especially if elevated blood pressure, a urinary catheter, and/or second vascular access were present. Administration of bolus dose began in the ER after the patient completed an informed consent form.

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The time period from the emergency gate to first bolus injection was expressed as “door to needle time” (DTN). Educational and motivational meetings The first meeting was held on 07 January 2015 in the Neurology Department with the participation of stroke team, consisting of neurology, emergency medicine, radiology, and cardiology doctors. The following five meetings were held in the emergency room if there was more than a 25% increase in DTN in subsequent AIS patients. The subjects of these meetings included acute ischemic stroke management, and our previous timeline metrics of DTN. Short presentations were used referring to guideline-recommended stroke management and focused attention on what we had done and what we could have done to improve DTN in our previous patients using feedback from our previous DTN data. The goal was to improve DTN within 60 minutes for at least 50% of acute ischemic stroke patients. Ethical approval was obtained from the Sakarya University Faculty of Medicine Ethics Committee in order to conduct the study. RESULTS Twenty AIS patients who received IV rt-PA between January 2015 and August 2017 were analyzed. Mean DTN was 76.9±32.4 minutes. Nine patients experienced ≤60 minutes of DTN, which was our goal, while only two were ≤30 minutes. After the initial meeting in the Neurology Department on 07 January 2015, five additional meetings were held due to a 25% increase in DTN in the emergency room. One meeting was held in 2015, two in 2016, and two in 2017 (Fig. 1). The first patient was treated with IV rt-PA about three and a half months after the first meeting with a DTN of 135 minutes. The second patient’s DTN was 75 minutes. When DTN extended to 155 minutes in the third patient (which was more than 100% range of the previous one), we held the second meeting. The fourth patient’s DTN was improved to 95 minutes. The durations of DTN in the 6th, 7th and 8th patients were 95, 100, and 83, respectively (Fig. 1). Due to the prolongation of the 9th patient’s DTN to 107 minutes (which was more than 25% range of the previous one), a third meeting was held. After the third meeting, the DTNs of the 10th, 11st, 12nd, and 13rd patients were 55, 53, 64, and 28 minutes respectively.

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Door to doctor Access to neurologic expertise & Laboratory/CT scan order CT scan completion CT scan interpretation/Laboratory results DNT (door to needle time) (door to treatment)

Minutes (mean)

140 120 100 80 60

) =5 =5

)

(n =4

5 th

In t

4 th

va l

In t

va l

)

va l er

In t 3 rd

2 nd

1 st

In t

va l(

40 20 0

Figure 1.

Mean stroke evaluation time benchmarks and door-to-needle times (DTN) of AIS patients at meeting intervals.

patients

Door to doctor Access to neurologic expertise & Laboratory/CT scan order CT scan completion

The shortest DTN was obtained with 28 minutes for the 12nd patient, which was a record low DTN duration. But this success did not continue, as the DTN of the 13rd patient was prolonged to 64 minutes (more than 25% longer than the previous). We thus held a fourth meeting (Fig. 1). After the fourth meeting, the DTNs of the 14th, 15th and 16th patients were 59, 56, and 115 minutes, respectively. The increase in DTN between the 15th and 16th patients was 105.3%, after which a fifth meeting was held (Fig. 1). After the fifth meeting, 4 patients (the 17th, 18th, 19th and 20th patients) received thrombolytic therapy with DTN of 60, 60, 30 and 50 minutes respectively. Finally, a sixth meeting was held due to 66.6% elongation of DTN for the last two patients (Fig. 1). Without exception, there was reduction in DTN times after all meetings. Details of the DTNs including timelines of the 20 patients and the dates of the 6 meetings are shown in Figure 1. Mean changes in the duration of DTN for each interval are shown in Figure 2. Considering the meeting intervals among the six meetings, the ratios of patients treated in â&#x2030;¤60 minutes were 0%, 0%, 60%, 66.6%, and 100%, respectively (Table 1).

CT scan interpretation/Laboratory results DNT (door to needle time) (door to treatment) DNT (door to needle time) (door to treatment)

20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1

5th Interval

4th Interval

3rd Interval

2nd Interval

1st Interval 0 minutes

100

120

140

150

Figure 2. Door-to-needle times (DTN) with stroke evaluation time benchmarks of 20 AIS patients and timedates of the meetings.

Access to CT scan neurologic completion expertise & (minutes)* Laboratory/CT scan order (minutes)*

CT scan interpretation/ Laboratory results (minutes)*

Door-to-Needle Time (DTN) (Door to treatment) (minutes)*

Ratio of Patients Treated ≤60 Minutes

Ratio of Patients Treated ≤30 Minutes

CT: Computer Tomography

*** According to American Heart Association/American Stroke Association’s Target: Stroke initiative [6]

** The ideal DTN which is less than or equal to 60 minutes

* Mean±SD

%50

9/20 2/20 20 10.3±7.6 18.5±14.2 50.7±26.6 61.7±29.4 76.9±32.4 14.07.2017 %45 %10

07.01.2015

Target***

Total

5th 09.03.2017 4/4 1/4 4 5.5±2.8 11.5±8 32.7±6.2 38.2±6.9 50±12.2** interval 14.07.2017 %100 %25

4th 25.12.2016 2/3 0/3 3 3.3±1.2 6.6±2.3 47±4.9 54.3±9.8 76.6±27.1 interval 08.03.2017 %66 %0

3rd 03.03.2016 3/5 1/5 5 8.2±1.9 14±3.5 30.2±13 38.8±12.7 52.8±13.1** interval 24.12.2016 %60 %20

02.07.2015

0/5 0/5 5 19±9.3 34.6±17.5 71.8±7.9 85±8.2 96±7.8 interval 02.03.2016 %0 %0

2nd

1st 07.01.2015 0/3 0/3 3 13.0±2.8 20.6±7.4 77.6±40.5 100±34.8 121.6±33.9 interval 01.07.2015 %0 %0

Meeting Dates Number of Door to Intervals of the patients doctor meetings treated (minutes)* with IV-tPA

Table 1. Mean stroke evaluation time benchmarks and door-to-needle times (DTN) of AIS patients at meeting intervals

Acar, Impact of emergency room meetings on improvement of door-to-needle times in acute ischemic stroke patients

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DISCUSSION Thrombolysis with IV-tPA is one of the most important reperfusion strategies that improves functional outcome after acute ischemic stroke. It is a first-line treatment worldwide [12]. A major goal in the treatment of acute ischemic stroke is the rapid improvement of blood flow. Every minute is golden to perform treatment without sequelae, as each minute 1.9 million neurons with 14 billion synapses are destroyed [13]. In hospitals with very busy emergency departments and high patient loads, these precious minutes can be wasted. Our hospital is the most central and comprehensive in Sakarya province, with an average of 30.000 patients admitted per month. At this intensity, catching treatable acute stroke patients requires more effort. The most important task of the hospital stroke team is to treat the AIS diagnosed patient as soon as possible when admitted to the hospital. Many studies have been published that consider the prevention of DTN delays for AIS patients. Fonarow et al. [3] demonstrated that fewer than one third of tPA receiving acute ischemic stroke patients are treated within guideline-recommended door-to-needle time. This demonstrates the a need for a targeted initiative to improve the timeliness of reperfusion in acute ischemic stroke. Following this, a national initiative known as Target: Stroke was established [14]. It was conceived in November 2009 by the American Heart Association/American Stroke Association in partnership with other organizations to increase the proportion of IV-tPA-treated patients who achieve guideline recommended door-to-needle time (≤60 minutes) for at least 50% of acute ischemic stroke patients with the following strategies: emergency medical service prenotification; a single call to activate the stroke team; rapid completion and interpretation of brain imaging; using specific protocols and 155 tools; premixing tPA; a team-based approach; and rapid data feedback [14]. Similar programs have been reported to improve DTN for AIS patients. Bhatt et al. [15] also highlighted strategies such as emergency medical service prenotification, activating the stroke team with a single call, rapid acquisition and interpretation of brain imaging, use of specific protocols and tools, premixing tPA, a team-based approach, and rapid data feedback. Thortveit et al. [16] reported that starting treatment in CT laboratory instead of emergency room contributed to reduced DTN. Tveiten et al. [17] reported that even an inexperienced stroke center can provide the necessary logistics for thrombolytic therapy, with short hospital delays to a large proportion

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of patients with acute stroke. They found that prenotification of a team and the initiation of thrombolytic treatment in the emergency room are the most important factors. Schrock et al. [18] reported that an ECG or a chest radiograph obtained before head CT increased CT times by 6 and 13 minutes, respectively, in AIS patients. Extensive work concerning this topic remains limited in Turkey. Öztürk et al. [7] published outcomes of 21 acute ischemic stroke patients who had undergone IV-tPA treatment between 2006 and 2008, but did not address the patient’s DTN. They emphasized that this practice is within a narrow treatment window and that well-equipped centers are needed. Tanrıverdi et al. [8] emphasized that they obtained successful results in accordance with the literature, with 15 patients who took this treatment between 2006 and 2012. Their mean reported DTN was 82.5 (45–145) minutes. Sorgun et al. [9] reported 32 patients who had received IV-tPA treatment between 2007 and 2012, with a mean DTN of 85±37 (15–165) minutes. They emphasized that the sooner treatment begins, the more positive the results. Oruç et al. [10] reported the data of 40 patients who received IV-tPA treatment between 2011–2015 in a university hospital, and highlighted that the treatment was reported to be safe and effective, as well as to reduce disability at the end of the third month. However this did not address the DTN data of the patients. In a more recent study, Kunt [11] reported the clinical outcome data of 25 patients who received IV-tPA treatment within 2.5 years from 2014 in a state hospital, and the mean DTN was 70±40 (20–195) minutes. Kutluk et al. [5] published the first and only nationwide registry on thrombolysis after the approval of IVtPA for the treatment of acute ischemic stroke in Turkey. This prospective multicenter hospital-based cohort study from 38 centers in 18 cities from 2006 to 2013 highlighted that the critical time limit of DTN, which is recommended to be 60 minutes, was reached at the end of the fourth year of the registry and despite the addition of new centers, the mean treatment time remained at 69 minutes. In this study, relationship between clinical experience and DTN were evaluated. “High-volume center” was defined as a center applying IV-tPA to 10 or more patients per year, while “low-volume center” was defined as a center applying IV-tPA to fewer than 10 patients per year. Authors reported that although the DTN durations of the high-volume centers were higher than low-volume centers initially, at the end of the study high-volume centers had better outcome for hemorrhage and DTN. Furthermore, they highlighted that this expe-

Acar, Impact of emergency room meetings on improvement of door-to-needle times in acute ischemic stroke patients

rience is also associated with decreased mortality. From this point of view, our center is a low-volume center. However, unlike others, DTN of our patients tended to decrease by year. This could be due to our emergency room meetings held to reduce the DTN. To decrease DTN after each period of meetings, we implemented these precautions: 1. Creating a stroke team with neurology, emergency medicine, radiology, and cardiology doctors. This includes using established specific protocols and guideline based algorithms, order sets, dosing charts and activating the stroke team with a smartphone application and recording detailed data of the patients prospectively and analyze them on further meetings; 2. Holding meetings in emergency room with the participation of emergency room doctors; and 3. Broadening the participation profile with emergency medical service staff and all newly-assigned or rotational emergency room doctors. Conclusion In addition to the effects of each factor summarized above, in our study two meetings were held each year. All meetings corresponded to the first and last half of each year. It may be concluded that educational and motivational meetings must be held biannually with regularity (at least twice a year). Educational and motivational meetings held in the emergency room are beneficial in improving DTN when repeated within a specified framework. Acknowledgement: I am thankful to my colleagues Semra Alacam Koksal, Turkan Acar, Aybala Neslihan Alagoz, Yesim Guzey Aras, Murat Yucel, Yusuf Yurumez, Alper Karacan, Ramazan Akdemir, Ayhan Boluk who provided expertise that greatly assisted the research. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Saver JL, Levine SR. Alteplase for ischaemic stroke-much sooner is much better. Lancet 2010;375:1667–8. 2. Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in

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Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 2007;115:e478–534. 3. Fonarow GC, Smith EE, Saver JL, Reeves MJ, Bhatt DL, Grau-Sepulveda MV, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation 2011;123:750–8. 4. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870–947. 5. Kutluk K, Kaya D, Afsar N, Arsava EM, Ozturk V, Uzuner N, et al. Analyses of the Turkish National Intravenous Thrombolysis Registry. J Stroke Cerebrovasc Dis 2016;25:1041–1047. 6. Kutluk K. Akut iskemik inmede intravenöz trombolitik tedavi: sorumluluğumuzun farkında mıyız? Türk Beyin Damar Hastalıkları Dergisi 2009:15:35–9. 7. Öztürk V, Yaka E, Uğurel B, Poyraz T, Men S, Kutluk K. Intravenous Thrombolysis in Acute Ischemic Stroke: Experiences in Dokuz Eylül University Hospital, Medical Faculty, Department of Neurology. J Neurol Sci [Turk] 2008;25:75–83. 8. Tanrıverdi Z, Örken DN, Aksoy S, Yükselen NP, Kargı EÖ, Mumcu S, et al. Intravenous thrombolytic theraphy in acute stroke: the experience of the neurology department of sisli etfal education and research hospital. Medical Bulletin of Sisli Etfal Hospital 2012;46:165–9. 9. Sorgun MH, Işıkay CT. Akut İskemik İnmede İntravenöz Trombolitik Tedavi. Ankara Üniversitesi Tıp Fakültesi Mecmuası 2012;65:103–106 10. Oruç S, Demirbaş H, Yaman M, Yılmaz Küsbeci Ö, Akpınar Oruç O, Tünay K, et al. Intravenous Thrombolytic Treatment Experiences In Patients With Acute Ischemic Stroke at The University of Kocatepe, Neurology Clinics. Türk Beyin Damar Hastalıkları Dergisi 2015;21:189–93. 11. Kunt R. Bir devlet hastanesi bakiş açisiyla akut iskemik inmede intravenöz trombolitik tedavi. Türk Beyin Damar Hastalıkları Dergisi 2016;22:91–9. 12. Wahlgren N, Ahmed N, Dávalos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITSMOST): an observational study. Lancet 2007;369:275–82. 13. Saver JL. Time is brain-quantified. Stroke 2006;37:263–6. 14. Fonarow GC, Smith EE, Saver JL, Reeves MJ, Hernandez AF, Peterson ED, et al. Improving door-to-needle times in acute ischemic stroke: the design and rationale for the American Heart Association/American Stroke Association’s Target: Stroke initiative. Stroke 2011;42:2983–9. 15. Bhatt A, Shatila A. Neurohospitalists Improve Door-to-Needle Times for Patients With Ischemic Stroke Receiving Intravenous tPA. Neurohospitalist 2012;2:119–122. 16. Thortveit ET, Bøe MG, Ljøstad U, Mygland A, Tveiten A. Organizational changes aiming to reduce iv tPA door-to-needle time. Acta Neurol Scand 2014;130:248–52. 17. Tveiten A, Mygland A, Ljøstad U, Thomassen L. Intravenous thrombolysis for ischaemic stroke: short delays and high community-based treatment rates after organisational changes in a previously inexperienced centre. Emerg Med J 2009;26:324–6. 18. Schrock JW, Lum M. Drill down analysis of door-to-needle time of acute ischemic stroke patients treated with intravenous tissue plasminogen activator. Am J Emerg Med 2014;32:1330–3.

Orıgınal Article

CARDIOLOGY

North Clin Istanb 2018;5(4):288–294 doi: 10.14744/nci.2017.20438

Bradyarrhythmia development and permanent pacemaker implantation after cardiac surgery Ceyhan Turkkan,1 Servet Altay,4

Damirbek Osmanov,2

Hakan Hasdemir,5

Izzet Celal Erdinler,6

Ersin Yildirim,3

Ahmet Taha Alper,1

Kazim Serhan Ozcan,1 Nazmiye Ozbilgin,1

Kadir Gurkan1

Department of Cardiology, Health Science University Dr. Siyami Ersek Training and Research Hospital, Istanbul, Turkey

Department of Cardiology, Bicard Clinic, Bishkek, Kyrgyzstan

Department of Cardiology, Umraniye Training and Research Hospital, Istanbul, Turkey

Department of Cardiology, Trakaya University Faculty of Medicine, Edirne, Turkey

Department of Cardiology, Istanbul Atakent Memorial Hospital, Istanbul, Turkey

Department of Cardiology, Istanbul Atasehir Memorial Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: Bradyarrhythmia is one of the complications that may develop after cardiac surgery. Only a few studies have previously dealt with this concern, and in our study, we investigated the factors affecting the development of atrioventricular block or sinus node dysfunction and the requirement of permanent pacemaker following cardiac surgery. METHODS: A total of 62 patients who developed the atrioventricular (AV) block or sinus node dysfunction and required a permanent pacemaker following cardiac surgery were included in the study. Among these, 31 patients were evaluated prospectively, and the information regarding 31 patients was evaluated retrospectively based on hospital records. Demographic, clinical, and surgical information was recorded. Patients were grouped according to the types of procedures, including the coronary artery bypass graft, valve surgery, congenital heart disease, and combinations of these. Patients were evaluated by standard 12-lead electrocardiogram and transthoracic echocardiography preoperatively. The postoperative development of bradyarrhythmia and requirement of permanent pacemaker were evaluated. RESULTS: The mean age of patients with preoperative conduction abnormality and wide QRS was statistically significantly higher than those without these disorders. The odds ratio for preoperative conduction abnormality risk in patients over 70 years of age was found as 4.429 (95% confidence interval, 1.40–13.93). There was no gender-related statistically significant difference in terms of left ventricular ejection fraction, left ventricular dilatation, interventricular septum thickness, the time interval from operation to the development of AV block, concomitant diseases, and complication rates. CONCLUSION: Preoperative conduction abnormality and wide QRS in patients over 70 years of age was determined as a risk factor. Keywords: Bradyarrhythmia; cardiac surgery; permanent pacemaker.

Cite this article as: Turkkan C, Osmanov D, Yildirim E, Ozcan KS, Altay S, Hasdemir H, et al. Bradyarrhythmia development and permanent pacemaker implantation after cardiac surgery. North Clin Istanb 2018;5(4):288–294.

everal rhythm abnormalities may occur following cardiac surgery. Although the most common arrhythmia is atrial fibrillation, ventricular arrhythmias

and conduction abnormalities may also be observed. Reported incidence of sustained ventricular arrhythmias after cardiac surgery ranges from 0.41% to 1.4%

Received: June 04, 2017 Accepted: October 06, 2017 Online: August 08, 2018 Correspondence: Dr. Ceyhan TURKKAN. Saglik Bilimleri Universitesi, Dr. Siyami Ersek Egitim ve Arastirma Hastanesi, Istanbul, Turkey. Tel: +90 216 542 44 35 e-mail: jjtkan@yahoo.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Turkkan et al., Bradyarrhythmia development and permanent pacemaker implantation after cardiac surgery

[1]. Persistent postoperative ventricular arrhythmias require aggressive treatment, and if the cause is not reversible, then the patient often needs an implantable cardioverter defibrillator (ICD). Advances in implantable electronic devices in the last 5 decades have been life saving for many patients. There is a slow but constant increase in pacemaker implantation rates, especially in developed countries with aging populations due to increasing life expectancy [2]. Temporary or permanent pacing may also be required in bradyarrhythmias. It has been reported that permanent pacing may be necessary in 0.8%–3.4% of the patients following coronary artery bypass graft (CABG) surgery for sinus node dysfunction or atrioventricular (AV) conduction abnormalities [1]. Permanent pacing may be required in 2%–4% of the patients after the valve surgery due to bradycardia associated with a complete or high-degree AV block. This rate may increase up to 20% in procedures associated with calcified aortic stenosis or tricuspid valve replacement (TVR) [1]. The sinus node dysfunction is relatively common following orthotopic heart transplantation, and permanent pacemaker implantation may be necessary in about 20% of the patients [1]. Although sustained ventricular arrhythmias do not occur very commonly, they are associated with a poor short- and long-term prognosis. The hospital mortality rate may reach 50% in these patients [1]. It is essential to define the risk factors to prevent these highly mortal arrhythmias or for early intervention. Not many studies have been previously conducted regarding factors determining the development of AV block or sinus node dysfunction and the necessity of permanent pacemaker following cardiac surgery. We aimed to investigate the risk factors affecting the development of conduction abnormalities or sinus node dysfunction and requirement of permanent pacemaker following cardiac surgery in this study. MATERIALS AND METHODS In our hospital, a tertiary cardiac center, 62 patients developing AV block or sinus node dysfunction and requiring permanent pacemaker following cardiac surgery were included in the study. A total of 31 patients operated between January 2008 and July 2009 were evaluated prospectively, and information regarding 31 patients operated before January 2008 was evaluated retrospectively based on hospital records. Demographic, clinical, and surgical information was recorded.

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Informed consent was obtained from each patient, and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in an a priori approval by the local ethics committee of Dr. Siyami Ersek Cardiovascular and Thoracic Surgery Training and Research Hospital. Patients were grouped according to the types of procedures, including CABG, valve surgery, congenital heart disease, and combinations of these. Patients were preoperatively evaluated for the types of conduction abnormality and QRS duration by standard 12-lead electrocardiogram (ECG). Preoperative transthoracic echocardiography was performed using the GE Vivid 3 and 7 devices and 2.5–3.5 MHz transducers. The standard parasternal short and long axis, as well as apical 4and 2-chamber views, were obtained. The left ventricle (LV) end-systolic and end-diastolic diameters, interventricular septum (IVS) thickness, and the presence of diastolic dysfunction were assessed. The measurement of systolic function was presented as the ejection fraction (EF) calculated by biplane Simpson method. Patients were followed-up for the development of bradyarrhythmia requirement of permanent pacemaker. The Number Cruncher Statistical System 2007 software (NCSS, Kaysville, Utah) and Power Analysis and Sample Size 2008 software (PASS, Kaysville, Utah) were used for the statistical analysis. In addition to descriptive statistical methods (mean, standard deviation), Student’s t-test was used to compare quantitative parameters with normal distribution between the groups. A chi-squared test was used to compare qualitative nonparametric variables. The statistical significance level was set at p<0.05. RESULTS The mean age of 62 patients was 58.69±17.97 years, and 64.5% were male. Nineteen patients (30.6%) were ≥70 years old. Preoperative conduction abnormality was present in 38.7% of the patients (n=24). General characteristics of the patients are presented in Table 1. As far as concomitant diseases are concerned, 17.7% of the patients (n=11) had diabetes mellitus, 53.2% (n=33) had hypertension, 6.5% (n=4) had chronic renal failure, 43.5% (n=27) had coronary artery disease, and 3.2% (n=2) had cerebrovascular event. Preoperative existing conduction abnormalities are shown in Table 2. Preoperative QRS duration of the patients ranged

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Table 1. General characteristics of the patients

Table 2. Preoperative existing conduction abnormalities

Mean±SD n %

Age (years) 58.69±17.97 <70 ≥70 Gender Female Male Hospital length of stay (days) 13.12±8.88 Preoperative conduction abnormality

43 69.4 19 30.6 22 35.5 40 64.5 24 38.7

SD: Standard deviation.

from 0.08 to 0.17 seconds (sec), with a mean value of 0.14±0.15 sec. While wide QRS (≥0.12 sec) was noted in 29% of the patients (n=18), QRS duration was <0.12 sec in 71% (n=44). While 87.1% of the patients (n=54) did not use heartrate-limiting medications preoperatively, 12.9% (n=8) did. Among 8 patients using these drugs, 5 were using beta blockers (3 metoprolol, 1 carvedilol, and 1 propranolol); 1 was using calcium channel blocker (diltiazem); and 2 were using beta blocker (metoprolol)+digoxin combination. Surgical interventions performed in the patients are summarized in Table 3. The mean time interval from the operation to the development of the block was 59.38±62.84 (0–324) months. Complete block was noted in 69.4% of the patients (n=43) postoperatively. Block developed perioperatively (during the operation or within postoperative 7 days) in 27.4% (n=17) and postoperatively (after postoperative 7 days) in 72.6% (n=45). Postoperative ECG findings are summarized in Table 4. An epicardial pacemaker was implanted in 6.5% (n=4), endocardial pacemaker was implanted in 88.7% (n=55), and no pacemaker was implanted in 4.8% (n=3) of patients. Among pacemakers implanted in 59 patients, 10.2% (n=6) were single-chamber rate-responsive pacemakers (the VVIR type), and 89.8% (n=53) were dual-chamber rate-responsive pacemakers (the DDDR type). Distribution of patient characteristics according to preoperatively existing conduction abnormalities is presented in Table 5. The mean age of patients with preoperative conduction abnormality was significantly higher than those

LBBB RBBB Incomplete LBBB Incomplete RBBB Bifascicular Trifascicular 2nd degree AV block

5 20.8 5 20.8 3 12.5 1 4.2 5 20.8 3 12.5 2 8.4

LBBB: Left bundle branch block; RBBB: Right bundle branch block; AV: Atrioventricular.

Table 3. Surgical interventions

CABG Valve surgery CABG + valve surgery Congenital heart disease Redo CABG Redo valve surgery Congenital heart disease + valve surgery

21 33.9 25 40.3 2 3.2 9 14.5 2 3.2 1 1.6 2 3.2

CABG: Coronary artery bypass grafting.

Table 4. Postoperative electrocardiographic findings

2nd degree Type 1 2nd degree Type 2 Complete block 2:1 block High degree Sinus node dysfunction

2 2 43 7 3 5

% 3.2 3.2 69.4 11.3 4.8 8.1

without. While conduction abnormality was present in 63.2% of the patients ≥70 years of age, it was present in only 27.9% of those younger than 70 years of age. The odds ratio for preoperative conduction abnormality risk in patients over 70 years of age was found as 4.429

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Table 5. Distribution of patient characteristics according to preoperatively existing conduction abnormalities

Preoperative conduction abnormality p Yes (n=24)

No (n=38)

n % n %

Age (years) 67.20±13.78 53.31±18.38 0.002 <70 12 27.9 31 72.1 ≥70 12 63.2 7 36.8 0.009 Pacemaker implant Epicardial 0 0 4 10.5 0.025 Endocardial 24 100 31 81.5 No implant 0 0 3 8 Pacemaker type DDDR 21 87.5 32 84.2 0.195 VVIR 3 12.5 3 7.9 No implant 0 0 3 7.9 Gender Female 7 31.8 15 68.2 0.409 Male 17 42.5 23 57.5 Block development Periop 6 35.3 11 64.7 0.734 Postop 18 40.0 27 60.0 QRS duration <0.12 sec 6 13.6 38 86.4 0.001 ≥0.12 sec 18 100.0 0 0.0 EF <50% 7 38.9 11 61.1 0.985 ≥50% 17 38.6 27 61.4 LV dilatation No 15 42.9 20 57.1 0.445 Yes 9 33.3 18 66.7 Thick IVS No 11 29.7 26 70.3 0.077 Yes 13 52.0 12 48.0 EF: Ejection fraction; IVS: interventricular septum; LV: left ventricle; The results are presented as mean±standard deviation or number (%).

(95% confidence interval, 1.40–13.93). Distribution of concomitant diseases and complications according to preoperative conduction abnormality status is presented in Table 6. The coronary artery disease rate in patients with preoperative conduction abnormality was significantly high. There was no significant difference between patients with or without preoperative conduction abnormalities in terms of concomitant disease and complication rates.

DISCUSSION The exact mechanism of bradyarrhythmias occurring after cardiac surgery is not fully understood. Approximately 0.8% to 4% of patients undergoing cardiac surgery require permanent pacemaker due to bradyarrhythmias that develop after the procedure. The pacemaker requirement was noted in 0.8% of the patients (25/2948) after CABG, 3.3% (30/923) after valve surgery, and 2.4% (11/450) for congenital heart disease surgery [3–8].

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Table 6. Distribution of concomitant diseases and complications according to preoperative conduction abnormality status

Preoperative conduction abnormality p Yes (n=24)

No (n=38)

n % n %

DM HT CRF CAD Complication

3 12.5 8 21.1 0.391 15 62.5 18 47.4 0.245 2 8.3 2 5.3 0.637 15 62.5 12 31.6 0.017 5 20.8 7 18.4 0.815

CAD: Coronary artery disease; CRF: Chronic renal failure; DM: Diabetes mellitus; HT: Hypertension.

Risk factors that have been reported in large-scale studies to be associated with the requirement of permanent pacemaker implantation following cardiac surgery include preexisting conduction disturbances, undergoing AVR, age, diuretic use, and cardiopulmonary bypass duration [9, 10]. The presence of preoperative rhythm and conduction abnormalities is a significant risk factor for the development of persistent block after the operation. Intra or infra-His bundle conduction abnormality has been found by electrophysiological evaluation in approximately 30% of patients with calcified aortic stenosis [8, 11, 12]. In a series of 120 patients who required postoperative permanent pacemaker implantation, it was also found that there were preoperatively existing rhythm and conduction abnormalities on ECG in 104 (87%) patients [3]. The number of patients with preoperative ECG rhythm and conduction abnormalities was 24 (38.7%) in our study. Merin et al. [9] evaluated data regarding 4999 patients undergoing cardiac surgery between 1993 and 2005 and found that 71% of the patients were men and the mean age was 64Âą12 years. The CABG was performed in 4071 patients (81%), AVR in 675 (14%), and mitral valve replacement (MVR) in 968 (18%). Permanent pacemaker implantation following surgery was required in 1.4% of the patients (n=72). Pacemaker indication was a complete AV block in 81.9% of these patients (n=59). On multivariate analysis, predictors for pacemaker requirement were found as the left bundle branch block (LBBB) and AVR. Raza et al. [10] evaluated 6268 patients undergoing cardiac surgery between 1987 and 2010 and reported that 141 patients (2.2%) re-

quired permanent pacemaker implantation, which were due to the AV block in 55% and bradycardia in 45%. Age, diuretic use, cardiopulmonary bypass time, and valve surgery were found as independent predictors of permanent pacemaker requirement. Dawkins et al. [13] evaluated potential risk factors associated with the requirement of permanent pacemaker implantation following isolated AVR in 342 patients. They found that preoperative conduction system abnormality was present in 26% of the patients. They noted postoperative pacemaker requirement in 29 patients (8.5%). The presence of preoperative conduction system abnormality was found as an independent predictor of permanent pacemaker requirement. Limongelli et al. [14] also evaluated risk factors for the requirement of permanent pacemaker implantation following AVR, and multivariate logistic regression analysis revealed that patients with previous aortic regurgitation, myocardial infarction, pulmonary hypertension, and postoperative electrolyte imbalance were at an increased risk for advanced AV block. Haworth et al. [15] also investigated potential predictors of permanent pacing following transcatheter aortic valve implantation and found the QRS morphology and increased annulus size as partial predictors. However, age, the baseline PR interval, and gender were not noted as predictors. Schurr et al. [16] reported that permanent pacemaker implantation was required in 6.6% of the 3534 patients undergoing AVR and stated that age was not an independent predictor, but that concomitant severe mitral valve insufficiency, CABG, subaortic stenosis, or re-do operations were independent predictors. In a multi-center study, arrhythmias were investigated in 556 adult patients who have undergone corrective surgery during childhood for

Turkkan et al., Bradyarrhythmia development and permanent pacemaker implantation after cardiac surgery

Fallot tetralogy. Among these, 102 patients (18.3%) had implanted cardiac rhythm devices, with pacemakers in 44 (7.9%) and ICDs in 58 (10.4%). Primary pacemaker indications were found as sinus node dysfunction in 8 patients (18.2%), AV block in 29 (65.9%), and tachycardia/bradycardia syndromes in 7 (15.9%). Moreover, the QRS width was ≥180 msec in 10 patients (37.0%), left ventricular EF was <35% in 4 (14.8%), and moderate or severe systolic right ventricular dysfunction was present in 14 (51.9%) as primary prevention indications [17]. In a Japanese multi-center study conducted in a similar group of patients, the prevalence of severe arrhythmias was found to be lower compared to those reported in Western countries, and better results may have been associated with the fact that QRS duration was <120 msec postoperatively in most of the patients (60%) [18]. Direct surgical damage to the AV node or bundle of His may explain the postoperative conduction abnormalities. Rarely, the sinus node may be traumatized during the cannulation procedure for cardiopulmonary bypass. Moreover, the sinus node or its vascularization may also be damaged during the Mustard and Senning procedures that are performed in transposition cases. Pathological changes include reversible elements such as edema. Repair of membranous ventricular septal defects (VSD) and atrial septal defects, as well as placement of mitral ring or prosthetic valves, may lead to edema of tissues surrounding the AV node and result in transient blocks [19, 20]. An advanced age [8, 21] and female gender [21] have previously been associated with postoperative development of permanent conduction block and permanent pacemaker implantation. The mean age was 58.69 years in our patient group and the advanced age was found to be the most significant risk factor. There were 22 women (35.5%) in our study group, and gender was not found to be a significant risk factor. We found that the permanent pacemaker requirement was most common following valve surgery (40.3%) in the adult population, and MVR (19.4%) was the most frequently associated procedure. According to previous literature, permanent pacemaker requirement was most common following the AVR (17.3%) and MVR plus TVR (17%) procedures [3]. Among congenital heart disease operations, the VSD repair (54.5%) has been reported as the procedure that is most frequently associated with permanent pacemaker requirement [8, 21]. Complete AV block was found to be the most fre-

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quent indication (69.4%) for permanent pacemaker implantation following surgery in our patients. In the series by Goldman et al. [8], the mean time interval between surgery and late development of block or sinus node dysfunction were reported as 4.7 years, which was similar to our finding of 5 years. As endocardial placement of the electrode and DDDR mode are the currently recommended settings for permanent pacemakers, we preferred endocardial placement in 88.7% of our patients and DDDR mode in 85.5%. As far as the timing of permanent pacemaker implantation after cardiac surgery is concerned, various opinions exist. Hancock [19] has recommended that permanent pacemaker be implanted if persistent high degree AV block is detected within 3 days after the surgical procedure, whereas Zakhia Doueihi et al. [7] have recommended that a permanent pacemaker be placed on the 10th day of postoperative heart block detection. In the recent American College of Cardiology/American Heart Association/North American Society of Pacing and Electrophysiology (ACC/AHA/NASPE) 2002 guideline, it has been concluded that AV blocks that develop following cardiac surgery have a variable course, and the decision of permanent pacemaker implantation is left to the physician [22]. It has also been mentioned in the guideline that permanent pacemaker is indicated in adults with AV blocks who are not expected to improve and in children and adolescents if the 2nd or 3rd degree AV block continues for 7 days or if the AV block is not expected to improve. In the present study, the mean postoperative hospital length of stay was 13 days in patients requiring permanent pacemaker. We believe that it would be better to reduce this period a bit more. In conclusion, we found that the presence of preoperative conduction abnormality and wide QRS in elderly patients were significant risk factors for the development of block following cardiac surgery. Further large-scale studies are needed to elucidate the exact mechanism of postoperative bradyarrhythmias. Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – C.T.; Design – C.T.; Supervision – C.T.; Materials – C.T., E.Y., K.S.O., S.A.; Data collection &/or processing – C.T., E.Y., K.S.O., S.A.; Analysis and/or interpretation – C.T., D.O., K.S.O., S.A, H.H., A.T.A., N.O., I.C.A, K.B.; Writing – C.T.; Critical review – I.C.E.

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REFERENCES 1. Chung MK. Cardiac surgery: postoperative arrhythmias. Crit Care Med 2000;28:N136–44. 2. Auricchio A, Moccetti T. Electronic cardiac medicine: present and future opportunities. Swiss Med Wkly 2010;140:w13052. 3. Glikson M, Dearani JA, Hyberger LK, Schaff HV, Hammill SC, Hayes DL. Indications, effectiveness, and long-term dependency in permanent pacing after cardiac surgery. Am J Cardiol 1997;80:1309–13. 4. Emlein G, Huang SK, Pires LA, Rofino K, Okike ON, Vander Salm TJ. Prolonged bradyarrhythmias after isolated coronary artery bypass graft surgery. Am Heart J 1993;126:1084–90. 5. Goldman BS, Hill TJ, Weisel RD, Scully HE, Mickleborough LL, Pym J, et al. Permanent cardiac pacing after open-heart surgery: acquired heart disease. Pacing Clin Electrophysiol 1984;7:367–71. 6. Keefe DL, Griffin JC, Harrison DC, Stinson EB. Atrioventricular conduction abnormalities in patients undergoing isolated aortic or mitral valve replacement. Pacing Clin Electrophysiol 1985;8:393–8. 7. Zakhia Doueihi R, Leloux MF, De Roy L, Krémer R. Permanent cardiac pacing for prolonged second and third degree atrioventricular blockcomplicating cardiac valve replacement. Acta Cardiol 1992;47:157–66. 8. Goldman BS, Williams WG, Hill T, Hesslein PS, McLaughlin PR, Trusler GA, et al. Permanent cardiac pacing after open heart surgery: congenital heart disease. Pacing Clin Electrophysiol 1985;8:732–9. 9. Merin O, Ilan M, Oren A, Fink D, Deeb M, Bitran D, et al. Permanent pacemaker implantation following cardiac surgery: indications and long-term follow-up. Pacing Clin Electrophysiol 2009;32:7–12. 10. Raza SS, Li JM, John R, Chen LY, Tholakanahalli VN, Mbai M, et al. Long-term mortality and pacing outcomes of patients with permanent pacemaker implantation after cardiac surgery. Pacing Clin Electrophysiol 2011;34:331–8. 11. Fukuda T, Hawley RL, Edwards JE. Lesions of conduction tissue complicating aortic valvular replacement. Chest 1976;69:605–14. 12. Friedman HS, Zaman Q, Haft JI, Melendez S. Assessment of atrioventricular conduction in aortic valve disease. Br Heart J 1978;40:911–7. 13. Dawkins S, Hobson AR, Kalra PR, Tang AT, Monro JL, Dawkins

North Clin Istanb KD. Permanent pacemaker implantation after isolated aortic valve replacement: incidence, indications, and predictors. Ann Thorac Surg 2008;85:108–12. 14. Limongelli G, Ducceschi V, D’Andrea A, Renzulli A, Sarubbi B, De Feo M, et al. Risk factors for pacemaker implantation following aortic valve replacement: a single centre experience. Heart 2003;89:901–4. 15. Haworth P, Behan M, Khawaja M, Hutchinson N, de Belder A, Trivedi U, et al. Predictors for permanent pacing after transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2010;76:751–6. 16. Schurr UP, Berli J, Berdajs D, Häusler A, Dzemali O, Emmert M, et al. Incidence and risk factors for pacemaker implantation following aortic valve replacement. Interact Cardiovasc Thorac Surg 2010;11:556–60. 17. Khairy P, Aboulhosn J, Gurvitz MZ, Opotowsky AR, Mongeon FP, Kay J, et al. Arrhythmia burden in adults with surgically repaired tetralogy of Fallot: a multi-institutional study. Circulation 2010;122:868– 75. 18. Nakazawa M, Shinohara T, Sasaki A, Echigo S, Kado H, Niwa K, et al; Study Group for Arrhythmias Long-Term After Surgery for Congenital Heart Disease: ALTAS-CHD study. Arrhythmias late after repair of tetralogy of fallot: a Japanese Multicenter Study. Circ J 2004;68:126– 30. Erratum in:Circ J 2004;68:403. 19. Hancock EW. AV block after aortic valve replacement. Hosp Pract (Off Ed) 1988;23:41,44,48. 20. Miller JM, Cossu SF, Josephson ME. Arrhythmias resulting from cardiac surgical procedures. In: Edmunds LH Jr, editors. Cardiac surgery in the adult. New York: Mc Graw-Hill; 1997. p. 731. 21. Del Rizzo DF, Nishimura S, Lau C, Sever J, Goldman BS. Cardiac pacing following surgery for acquired heart disease. J Card Surg 1996;11:332–40. 22. Gregoratos G, Abrams J, Epstein AE, Freedman RA, Hayes DL, Hlatky MA, et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation 2002;106:2145–61.

Orıgınal Article

BASIC MEDICAL SCIENCES

North Clin Istanb 2018;5(4):295–301 doi: 10.14744/nci.2017.42103

Effect of increase in cortisol level due to stress in healthy young individuals on dynamic and static balance scores Mahmut Cay,1

Cihat Ucar,2

Davut Ozbag,3

Zuhal Altay,4

Deniz Senol,3

Furkan Cevirgen,3

Sedat Yildiz5

Department of Anatomy, Usak University Faculty of Medicine, Usak, Turkey

Department of Physiology, Adiyaman University Faculty of Medicine, Adiyaman, Turkey

Department of Anatomy, Inonu University Faculty of Medicine, Malatya, Turkey

Department of Physical Medicine and Rehabilitation, Inonu University Faculty of Medicine, Malatya, Turkey

Department of Physiology, Inonu University Faculty of Medicine, Malatya, Turkey

ABSTRACT OBJECTIVE: Stress is a condition caused by various factors and characterized by imbalance in body functioning, impair in nervous system, and tension. The purpose of this study was to examine the effects of cortisol level, which increases in healthy young individuals due to stress, on dynamic and static balance scores as well as to present the results caused by high levels of stress. METHODS: In this study, 107 healthy medicine faculty students in their second year (who will take the same committee exam) aged between 19 and 23 years were included. The first balance measurements and saliva samples were taken 40 days before the committee exam, and this period was acknowledged as the relaxed period. The same students were considered for balance measurements again on the day of committee exam; saliva samples were collected, and cortisol concentration was determined. This period was acknowledged as the stressful period. The State-Trait Anxiety Inventory (STAI) was given to the participants in their relaxed and stressful periods. Dynamic balance scores were measured with Star Excursion Balance Test (SEBT). Static balance scores were measured with One Leg Standing Balance Test (OLSBT). RESULTS: The mean cortisol level was found to increase approximately 9 times in stressful periods compared with that in relaxed periods. STAI, which shows state anxiety, showed an increase supporting this increase. In stressful periods, dynamic balance scores showed obvious decrease in all directions. In addition, in stressful periods, an obvious decrease was observed in static balance scores compared with those in relaxed periods. CONCLUSION: This study showed that stress negatively affected dynamic and static balance, even for short periods of time. We believe that our study will form a positive source and basis when correlated with long terms stress and balance measurements. Keywords: Cortisol; dynamic balance; static balance; stress.

Cite this article as: Cay M, Ucar C, Senol D, Cevirgen F, Ozbag D, Altay Z, et al. Effect of increase in cortisol level due to stress in healthy young individuals on dynamic and static balance scores. North Clin Istanb 2018;5(4):295–301.

Received: May 17, 2017 Accepted: October 21, 2017 Online: May 29, 2018 Correspondence: Dr. Deniz SENOL. Inonu Universitesi Tip Fakultesi, Anatomi Anabilim Dali, Malatya, Turkey Phone: +90 506 447 06 86 e-mail: deniz.senol@inonu.edu.tr © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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a stabilized posture is an indispensable part of a great number of movement practices [13]. Balance control is a complex motor skill that includes planning and applying flexible movement figures as well as the integration of sensory input [14]. The integration of the information coming from sensory system gives information to a person about his/her orientation to maintain posture control in space that allows for regulatory reflexive movements [15]. However, sensory inputs are not responsible alone for the maintenance of postural control. Postural stability is bound to complete neural pathways for the integrity of muscle mass and efficiency of the muscles in the central nervous system for motor control [16]. Environmental components on balance include somatosensorial, visual, and vestibular systems. The central nervous system combines the environmental inputs coming from these systems and chooses the responses of many suitable muscles in order to control body position and posture on support basis [17, 18]. The purpose of this study is to examine the effects of cortisol level, which increases in healthy young individuals as a result of stress, on dynamic and static balance scores and to present the factors that caused by high levels of stress.

tress is a situation caused by various factors and characterized by an imbalance in body functioning, impair in the nervous system and tension [1]. An individual who is stressed because of an unpleasant event responds to this situation with physiological and emotional changes as well as changes in perception and behavior. Even though people may think that they are not very much affected by events, they may develop reactions without realizing [2]. Stress most frequently occurs in uncontrollable, unwanted situations and when a person has more workload than he can handle [3]. A chemical or physical imbalance that occurs in cells or tissue fluid as a result of a change in the body or in the external environment is called physiological stress. There are 3 components of physiological stress. These are exogenous or endogenous stress factors and chemical or physical imbalance caused by stress factors and the adaptation response of the body to these conditions [4]. The results of the researchers examined the association between stress and immune system and monoaminergic system show that 2 stress sensitive endocrine response systems are hypothalamic–pituitary– adrenal (HPA) axis and sympathetic adrenal medullary system [5]. When a person is faced with a stressor that he cannot control with existing cope mechanisms, HPA axis is activated through the association cortex, amygdala, and hippocampus, which causes the cortisol blood level to rise and brain functions to be affected through the neurons in the brain and glucocorticoid receptors in glial cells [6]. Cortisol is a steroid structured hormone released from the outer part of the cortex of suprarenal gland and exhibits glucocorticoid effect [7, 8]. Due to its small, fat-soluble structure (MW~362 Da), it passes from capillary vessels to cells primarily through passive diffusion [8, 9] and is distributed to body parts such as saliva, cerebrospinal fluid, sweat, hair, and urine [10]. Cortisol has circadian oscillation rhythm. While cortisol level in blood is high in the early hours of the morning, it drops to its lowest level at midnight [8–10]. While a major amount of the cortisol in blood is bound to corticosteroid-binding protein (CBG or transcortin) with high affinity, a small amount is carried as bound to albumin. Free cortisol is found in blood in a low rate (3–10% of the total cortisol) [8, 9]. Cortisol concentration in saliva has been reported to reflect the free cortisol in blood [8–11]. Salivary cortisol is used in psychoneuroendocrinological monitoring as an important parameter with reasons such as measuring the free cortisol level noninvasively, not causing pain, and allowing a person to get sample alone easily whenever wanted [12]. Maintaining balance and

MATERIALS AND METHODS This study was conducted with the 2016/45 numbered permission of the Clinical Researches Ethical Board. In this study, 107 medicine faculty students in their second year aged between 19 and 23 years, who did not drink or smoke, did not have any orthopedic diseases or surgical intervention, did not participate in any sportive exercises, and did not used any psychiatric drugs during the period measurements were made were included in the study voluntarily. Consent forms were taken from all the students. The first balance measurements and saliva samples were taken 40 days before the committee exam and this period was acknowledged as the relaxed period. The same students were taken for balance measurements again on the day of committee exam and saliva samples were collected and cortisol concentration was determined. This period was acknowledged as the stressful period. STAI was given to students in their relaxed or stressful periods. STAI is a scale that is frequently used to assess STAI anxiety [19]. Analysis of cortisol in saliva The passive droll method as described by Granger et al. [20] (2007) was used to collect saliva samples. The sam-

Cay et al., Effect of stress on balance scores

ples taken were kept at −20°C in a laboratory freezer. First, they were stored at thawing, then they were centrifuged for 10 min at 4000×g, and supernatants were analyzed with ELİSA. Assay buffer was used to dilute each sample 1:5 and all samples were assayed in triplicate. ELISA procedure; carbonate buffer, pH 9.6 was used to dilute cortisol-BSA stock solution (1 mg/mL) and at 200 μL/well it was added to a 96-well microtiter plate. The plate was incubated overnight at 4°C and using an 8-channel pipette, it was washed 5 times with wash buffer. The blocking buffer (200 μL/well) blocked some binding sites that were not occupied by the coating antigen 2 h at 37°C. After washing steps (5 times), standard solutions or samples (40 μL/well) and diluted 1st Ab (antiserum) (40 μL/well) were added in duplicate and incubated for 45 min at 37°C. Biotinylated anti-rabbit antibody was added (100 μL/well) after washing 5 times, and the plate was incubated for 30 min at 37°C. After the plate was washed 5 times, streptavidin peroxidase solution (100 μL/well) was added and the plate was incubated at 4°C for 15 min. Following this, the plate was washed again for 5 times, and then the substrate solution (150 μL/well) was added and incubated for 10 min in dark. Stop solution (50 μL/well) was added after incubation, and then using a microplate reader, the absorbance was measured at 450 nm. Intra-assay variation (CV) was found to be 5.6%, while inter-assay variation was found to be 7.8%. Balance measurements Dynamic balance scores were measured with SEBT. SEBT is a frequently used simple and reliable measurement method used in the assessment of dynamic postural control [21–23]. SEBT has been reported to have enough sensitivity to find out balance deficits associated with musculoskeletal injuries such as ankle instability by previous studies [24–26]. SEBT was used to assess dynamic balance. With the subjects standing in the middle of a grid constructed by 8 measure tapes extending out at 45° from each other, SEBT was performed. Along each of the 8 measure tapes, the subject had to reach as far as possible, touch the tape lightly, and then while maintaining a single-leg stance with the other leg in the center of the grid, he had to return the reaching leg back to the center. In order to complete the task, the subjects had to reach behind the stance leg while reaching in lateral and posterolateral directions. The subjects began with the anterior direction and continued clockwise around the grid. All subjects started in the center of the grid with a

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Table 1. Relaxed and stressed period cortisol levels, STAI

average±SD and results of Wilcoxon paired 2 sample test Parameter Relaxed Cortisol STAI

18.05±18.98 38.79±3.31

Stressed 159.83±460.36 42.71±4.23

p <0.001 <0.001

STAI: The State-Trait Anxiety Inventory; SD: Standard deviation.

right stance leg. Following the completion of the 3 trials in the 8 directions, a 5-min rest was given, after this rest, the test continued with a left stance leg. With a mark on the tape, each of the reach distances was recorded as the distance from the center of the grid to point of maximum excursion by the reach leg [27–30]. OLSBT was used to measure static balance. It was measured on stable platform with both eyes open for 60 s and closed for 30 s (EOSB; eyes open static balance, ECSB; eyes closed static balance), and the subjects were told to maintain their balance for maximum duration. When the stance foot shifted in any way or the non-stance foot touched the ground, the measurement was stopped [30–32]. Statistical analysis Shapiro–Wilk test was used to find out whether the data were normally distributed. They were found to be abnormally distributed. Wilcoxon paired 2 sample test was used for the analyzes of data. Correlations were calculated with Spearmen Rho coefficient. A level of p<0.05 was considered as statistically significant. IBM SPSS Statistics 22.0 for Windows package program was used for statistical analysis. RESULTS The average age of the 107 people who participated in the study was calculated as 20.5±1.36. Cortisol analyses in the saliva samples taken in both relaxed and stressful days and averages and±standard deviation of STAI were given in Table 1. Average cortisol level was found to increase approximately 9 times in stressful periods compared with that in relaxed periods. STAI, which shows state anxiety, showed an increase supporting this increase. In order to assess whether the difference between relaxed and stressful period cortisol and STAI scale increase was significant, Wilcoxon Paired 2 sample test was conducted on the data. According to analysis results, a statistically signifi-

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Table 2. Averages and±SD of relaxed and stressed period SEBT and Wilcoxon paired 2 sample test results SEBT A AM M PM P PL L AL

Right leg

Relaxed Stressed 57.41±12.07 57.74±13.67 46.55±15.43 55.18±14.57 55.97±13.43 55.50±13.50 56.31±14.22 57.81±13.77

46.49±10.93 45.00±11.56 33.75±12.38 43.39±12.22 44.65±11.95 46.40±11.53 47.11±11.87 46.22±11.98

p <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Left leg

Relaxed Stressed 57.85±13.94 56.01±13.28 49.39±14.50 55.00±15.47 55.72±15.19 55.21±14.48 56.01±15.81 57.62±14.06

45.29±11.17 43.67±11.78 35.17±11.92 43.60±12.39 44.54±11.83 44.84±11.07 46.78±10.87 45.28±11.62

p <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

SD: Standard deviation; SEBT: Star Excursion Balance Test; A: Anterior; AM: Anteromedial; M: Medial; PM: Posteromedial; P: Posterior; PL: Posterolateral; L: Lateral; AL: Anterolateral.

Table 3. Average and±SD of static balance scores measured by OLSBT OLSBT EOSB ECSB

Relaxed 54.14±10.89 18.37±7.69

Right leg Stressed

42.67±14.66 9.20±5.42

<0.001 <0.001

Left leg

Relaxed 53.94±9.80 17.72±8.21

Stressed

39.75±14.12 9.43±6.11

<0.001 <0.001

SD: Standard deviation; OLSBT: One Leg Standing Balance Test; EOSB: Eyes open static balance; ECSB: Eyes closed static balance.

cant (p<0.05) increase was found in cortisol and STAI scores during relaxed and stressful periods (Table 1). Table 2 gives the average±standard deviation of measurements conducted in relaxed and stressed periods in terms of right and left foot SEBT anterior (A), anteromedial (AM), medial (M), posteromedial (PM), posterior (P), posterolateral (PL), lateral (L), anterolateral (AL) directions. When SEBT was examined, it was found that for the right foot, dynamic balance scores showed 19% anterior, 22% anteromedial, 28% medial, 21% posteromedial, 20% posterior, 16% posterolateral, 12% lateral, and 20% anterolateral decreases in stressful periods compared with those in relaxed periods. For the left foot, dynamic balance scores showed 22% anterior, 22% anteromedial, 29% medial, 21% posteromedial, 20% posterior, 19% posterolateral, 17% lateral, and 21% anterolateral decreases in stressed periods compared with those in relaxed periods. According to Wilcoxon paired 2 sample test results, dynamic balance scores measured by SEBT

were found to be statistically significant for the right and left feet between relaxed and stressed periods (p<0.05). When Table 2 was examined, it was found that stress had a negative effect on individuals’ dynamic balance scores. In stressed periods, dynamic balance scores showed significant decreases in all directions. Table 3 gives the results of OLSBT and Wilcoxon paired 2 sample test results conducted showed that opening and closing of the eyes in relaxed and stressed periods for right and left foot. Eyes open stressed period right foot static balance scores showed 21% decrease when compared with relaxed period, while left foot static balance scores showed 26% decrease. Eyes closed stressed period right foot static balance scores showed 50% decrease when compared with relaxed period, while left foot static balance scores showed 47% decrease. According to Wilcoxon paired 2 sample test results, static balance scores measured by OLSBT were found to be statistically significant for the right and left feet between relaxed and stressed periods (p<0.05). When Table 3 was examined, it was found that exam stress had a nega-

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Table 4. Spearman Rho correlation analysis results (dynamic balance scores - static balance scores) Test

Right leg Cortisol

STAI

Left leg Cortisol STAI

A AM M PM Dynamic balance P PL L AL

r -0.366 0.222 -0.304 0.245 p <0.001 0.001 <0.001 <0.001 r -0.373 213 -0.308 213 p <0.001 0.234 <0.001 0.253 r -0.299 0.001 -0.295 0.000 p <0.001 213 <0.001 213 r -0.355 0.251 -0.373 0.251 p <0.001 <0.001 <0.001 <0.001 r -0.400 213 -0.304 213 p <0.001 0.255 <0.001 0.286 r -0.364 0.000 -0.308 0.000 p <0.001 213 <0.001 213 r -0.252 0.256 -0.269 0.225 p <0.001 <0.001 <0.001 0.001 r -0.286 213 -0.352 213 p <0.001 0.213 <0.001 0.252

EO Static balance EC

r p r p

-0.186 0.328 -0.322 0.365 0.006 <0.001 <0.001 <0.001 -0.107 0.336 -0.173 0.343 0.117 <0.001 0.011 <0.001

STAI: The State-Trait Anxiety Inventory; A: Anterior; AM: Anteromedial; M: Medial; PM: Posteromedial; P: Posterior; PL: Posterolateral; L: Lateral; AL: Anterolateral.

tive effect on students’ static balance scores. When static balance scores in stressed periods were compared with those in relaxed periods, an obvious decrease was found. Table 4 gives the dynamic balance scores measured by SEBT and Spearman Rho correlation analysis results connected on static balance scores measured by OLSBT. According to the results of the analysis, cortisol increase, which increased with stress, was found to correlate negatively with balance tests. It was found that cortisol increase due to stress affected balance negatively. Correlation analysis conducted with STAI state anxiety questionnaire was found to support this result. DISCUSSION Human body tries to adjust to stressful events with various responses. Individuals who face the effect of a stress stimulus, respond to this by taking a physiologi-

cal or psychological defense [33]. Stimulating messages from internal and external environments change a person’s balance and the organism tries to rebalance and maintain adjustment. If a person’s efforts are insufficient, his/her adjustment will be disrupted. The factors that disrupt adjustment put the organism in a difficult situation [34]. As long as a person adjusts to changes, he/ she can keep balance, order, happiness, and health and tries consciously or unconsciously to maintain this balance and order. Sometimes he/she will be successful in these efforts, keeps his/her old balance and order and maintain adjustment [35]. Maintaining balance and a stable posture is an indispensable part of many movement practices [13]. Balance control is a motor skill that includes planning and practicing flexible movements as well as integrating sensory inputs [14]. The integration of the information coming from perceptive systems gives information to a person about orientation to maintain posture control in space that allows regulatory reflexive movements [15]. However, sensory inputs alone are not responsible for maintaining postural control. Postural stability depends on the integrity of muscle mass, the efficiency of the systems in the central nervous system, and the complete neural pathways for motor control [16]. As a response to stress, the endocrine system begins to release cortisol, and a sudden increase in cortisol levels is an adaptive function [36]. In our study, we compared the cortisol concentration of individuals in their relaxed and stressed periods. In their study conducted with 35 medicine faculty students, Singh et al. [37] (2012) compared cortisol levels in relaxed and stressed periods and made measurements on exam stress. They found cortisol levels as 2.48±1.5 ng/ml in male students and 2.92±1.9 ng/ml in female students during relaxed periods, while the levels were 5.02±3.1 ng/ml in male students and 5.19±3.1 ng/ml in female students during stressed periods. In a previous study, Schoofs et al. [38] (2008) found that academic exams caused very high increases in salivary cortisol levels. In our study, cortisol levels in stressed period were found to increase about 9 times compared with relaxed periods. This result was expected and our values were in line with the literature. Some of the physical responses to stress are: shaking, muscle spasm, myotonia, cramps, numbness in fingers and toes [39–41]. Frequent physical symptoms and complaints during stress are pain in neck, nape, waist and back, spasm and arthralgia, imbalance and swaying while standing, sitting and walking [42]. In recent study with cyclists, Filho et al. [43] (2015) stated that stress factors

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differed in short-term period and these changes affected performance. Bali [44] (2015) stated that sportive performance was not just a biomechanical and physiological event, psychological factors also affected performance significantly and in addition more than optimum stress affected performance negatively. In previous study on young (22.3±3.6 years) and old (82.3±9.6 years) individuals, Sarabon and Rosker (2015) found dynamic balance scores they measured with SEBT as 76.2±6.78 cm in young individuals and 37.3±7.26 cm in old individuals in anterior direction; as 65.1±8.63 cm in young individuals, 30.3±7.36 cm in old individuals in lateral direction, as 77.9±11.0 cm in young individuals, and as 36.1±8.05 cm in old individuals in posterior direction [45]. The results of this study are in line with that by Sarabon and Rosker (2015) on young individuals. In literature, we could not find any studies similar to our study that is on static and dynamic balance test in stressed and relaxed periods. The results of our study showed that static and dynamic balances of individuals were worse in stressed period when compared with relaxed period. The results of static and dynamic balance test showed unstableness and swaying in postural balances in stressed periods of individuals and also it was seen that they could not stand for long periods of time. When SEBT scores were analyzed, 12% and 28% decrease was found in all directions in dynamic balance scores of stressed period for right foot when compared with relaxed period. For left foot, a decrease between 17% and 29% was found in SEBT scores of stressed period when compared with relaxed period. In addition, significant differences were found in OLSBT results we conducted eyes open and closed in relaxed and stressed periods. Static balance scores measured with OLSBT were found to have lower values in stressed period when compared with relaxed period. As a conclusion; dynamic and static balance scores between stressed period and relaxed period in healthy individuals seem to be a response for stress. It is not known whether cortisol increase in stressed period has an effect on balance center. Cortisol increase and balance disruption were not in the same rates in this period. Thus, it should be researched whether cortisol increase has a positive effect on balance centers. Does the disruption of balance trigger cortisol increase or does cortisol increase contribute to the disruption of balance? In addition, it has been reported in literature that extreme cortisol released in healthy individuals due to long-term stress can cause negative effects such as increase in blood pressure, atherosclerosis, diabetes, immune suppression, osteolysis,

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and myolysis [36]. As a result of the levels short-term stress affected static and dynamic balance in our study, we predict that long-term stress may cause permanent disruption of postural balance in young individuals. Further studies will present more obviously how long-term stress can affect postural balance in healthy individuals. We believe that our study will form a positive source and basis to new studies and contribute to literature. Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept – M.C., D.S.; Design – D.O., Z.A., S.Y.; Supervision – M.C.; Materials – C.U., F.C.; Data collection &/or processing – M.C., D.S.; Analysis and/or interpretation – D.S., S.Y.; Writing – M.C., D.S., C.U.; Critical review – D.O., Z.A., S.Y.

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Orıgınal Article

PSYCHIATRY

North Clin Istanb 2018;5(4):302–313 doi: 10.14744/nci.2017.92668

Factors associated with problematic internet use among children and adolescents with Attention Deficit Hyperactivity Disorder Fatma Hulya Cakmak,1

Hesna Gul2

Department of Child and Adolescent Psychiatry, Dr. Sami Ulus Children Hospital, Ankara, Turkey

Department of Child and Adolescent Psychiatry, Gulhane Research and Training Hospital, Ankara, Turkey

ABSTRACT OBJECTIVE: The aim of this study was to determine the association of problematic internet use with attention deficit hyperactivity disorder (ADHD), personal risk factors, and familial factors and compare with a healthy control group and investigate the risk factors. METHODS: The study sample consisted of 34 children aged 12–16 years and their families who applied to Ankara University Faculty of Medicine Department of Child and Adolescent Psychiatry with the diagnosis of ADHD. The control group consisted of 36 junior high and high school children aged 12–16 years and their families. The control group was matched with the ADHD group for age and sex. The Kiddie Schedule for Affective Disorders and Schizophrenia Present and LifetimeVersion (K-SADSPL) version was used according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for patients with ADHD and the control group. Internet/Computer Use Assessment Questionnaire for Children/Adolescents, the Strengths and Difficulties Questionnaire adolescent form (SDQ), and Online Cognition Scale (OCS) were applied to children. Internet/ Computer Use Assessment Questionnaire for Parents and SDQ-parent form and Family Assessment (FAS) were applied to the parents. RESULTS: Weekly internet usage was higher in the ADHD group than the control group. The OCS total scores and subscale scores were significantly higher in the ADHD group. The subscales of SDQ hyperactivity, conduct problems, and peer problems were significantly higher in the ADHD group. FAS-general functions, communication, roles and behavior control subscale scores were higher in the ADHD group. There was no significant difference between groups regarding the internet usage in the daily life, with the availability of a computer and internet at home. In the ADHD group, there was a significant correlation between the OCS scores, weekly internet usage, and psychiatric comorbidities Oppositional Defiant Disorder and Conduct Disorder. Also, affective responsiveness subscale scores of FAS were significantly correlated with OCS scores in the ADHD group. CONCLUSION: In this study, it was noted that problematic internet use was more frequent in ADHD. During ADHD treatment, problematic internet use may interfere in the treatment goals. Interventions to problematic internet use should consider familial emotional expression studies. Keywords: Attention Deficit Hyperactivity Disorder; child; family; risk factors; problematic internet use.

Cite this article as: Cakmak FH, Gul H. Factors associated with problematic internet use among children and adolescents with Attention Deficit Hyperactivity Disorder. North Clin Istanb 2018;5(4):302–313.

Received: August 17, 2017 Accepted: November 08, 2017 Online: August 09, 2018 Correspondence: Dr. Hesna GUL. Gulhane Egitim Arastirma Hastanesi, Cocuk Psikiyatrisi Klinigi, Ankara, Turkey. Tel: +90 507 152 39 52 e-mail: drhesnagul@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Cakmak et al., Problematic internet use in ADHD children

he use of computers and the internet has become an indispensable tool of life in the era of technology. Internet is a communication and data sharing platform that enables individuals to access all information easily and communicate quickly with other individuals irrespective of the distance between them [1, 2]. There are a number of risks of the internet even though it saves time, shortens distances, and makes life easier. The internet is regarded as a technological miracle supporting the individual development of children and adolescents, including their access to information, research, problem solving, creativity, and critical thinking [3, 4]. However, the internet has been stated to negatively affect the development of personal skills owing to the excessive, uncontrolled, and non-purposeful use [5, 6]. Although the problematic use of the internet can be seen at any age, adolescents are reported to be one of the major risk groups [7]. It has been stated that because of the adolescents’ proximity and attraction to technology, they use the internet more frequently than the other age groups. Adolescents’ continuing cognitive, emotional, and social developments are more prone to the problematic use of the internet in their developmental period [8–11]. Brown et al. pointed out that young people tend to use the internet as a form of socialization, and children and adolescents are more likely to exchange real life activities with the virtual reality and emotion [12]. In a study performed in adults, it has been reported that excessive internet use was associated with unemployment, marital problems, neglect of children, and sleep disorders [13]. Internet addiction in South Korea began to be regarded as a public health problem [10] after 10 cardiopulmonary deaths [14] and a murder [15] related to a game occurred [16]. Moreover, it has been reported that there is an inverse relationship between time spent with internet games and academic achievement, and a significant relationship between aggression and violent games [17]. According to literature reviews, one of the important conditions associated with problematic use of the internet, especially in the adult group, is Attention Deficit Hyperactivity Disorder (ADHD) [18–25]. Children and adolescents with internet addiction were reported to be 2.51 times more likely to have ADHD than their non-addicted peers [18, 21, 25]. Studies in adolescents and young adults have shown that there is no significant difference between age groups in relation to ADHD-internet addiction or dependency in these groups and that

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internet addiction is significantly more common in the male gender [18, 21, 22, 26–28]. In addition, many studies have determined that the scores of attention deficit and mobility, which are among the basic ADHD symptoms scores, were higher [20, 25, 29–32] in the internet addiction group. The issue has also attracted interest in Turkey in recent years. Population-based studies have been conducted in university and high school students [8, 33–37]. However, a limited number of studies have been performed in the smaller age groups in which ADHD was clinically diagnosed and supported by a detailed psychiatric examination. The purpose of this study was to investigate the relationship between personal risk factors, familial factors, ADHD, and the problematic use of the internet, which is increasingly seen in clinical practice in our country among children and early adolescents and compare them with a healthy control group to investigate the factors (if any). The hypotheses of this study were determined as follows: • Problematic internet use is more frequent in children and adolescents diagnosed with ADHD than in normal controls. • The presence of additional diagnoses, such as Oppositional Defiant Disorder (ODD) and Depression and Conduct Disorder, increases the frequency and severity of problematic internet use. • Broken familial rapport increases the frequency and severity of problematic internet use. MATERIALS AND METHODS Sampling Following the approval of the study reviewed by the ethics committee of the University of Ankara Faculty of Medicine, 34 children aged 12-16 years who were referred to and followed up with the diagnosis of ADHD by Polyclinic of Child and Adolescent Mental Health and Diseases of Psychiatry Department of Ankara University Faculty of Medicine between April 2013 and June 2013 and their families constituted the ADHD group, and 36 age-matched children selected among sixth, seventh, and eighth grade students of a primary school ninth and tenth grade students of a lycée and their families were included in the study as a control group. Individuals who were clinically thought to have mental

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retardation and those with medical conditions, including epilepsy, asthma, or physical disability, were not included in the study. Participants and their families were given detailed information about the survey and written consent was obtained indicating that they voluntarily agreed to participate in the survey. Data collection tools Sociodemographic Data Form: In this form prepared by the researcher, the sociodemographic characteristics of the child/adolescent and parents were questioned (parental age, education level and occupation, monthly income, family structure, number of siblings, and children). Internet/Computer Usage Assessment Questionnaire (Parent and Child form) for children and adolescents: It was prepared specifically for the research and included the following: • From where is the child connected to the internet? • What is the intention of top priority for using the internet? • For how long is the internet used (hour/week)? • What time of the day internet is used? • Which types of sites are preferred? • How many years are computer/internet being used? • School success? • Are there rules for internet use at home? Two separate forms have been prepared for parents and children. Strengths and Difficulties Questionnaire Forms (for parents, teachers, and adolescents): The Strengths and Difficulties Questionnaire (SDQ) is a 25-item Likert-type questionnaire developed by Robert Goodman in 1997 for the purpose of questioning emotional and behavioral problems together with some favorable characteristics of children and adolescents aged 4–16 years [38]. Questions on the scale are answered by parents, teachers, and adolescents as “not correct”, “partially correct,” and “absolutely correct” and scored “0”, “1,” and “2,” respectively. Questions 7, 11, 14, 21, and 25 of the scale are scored by reversing. It consists of five subscales related to emotional problems, conduct problems, and peer relationship problems. As the scores of hyperactivity subscales increase, predisposition to problematic clinical increases, and as the

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scores of social behavior subscales increase, predisposition to problematic clinical conditions decreases. As each subtitle is evaluated within itself, the sum of the first four subscale scores gives the “total difficulty score.” The total score obtained from the scale is between 0 and 40 points. A higher total score indicates increased frequency of problematic behaviors of the child or youth. The increase in social behavior subscale scores indicates that the child is less prone to clinical problems. Therefore, unlike the other subscale and total scores, increase in social behavior subscale score is a favorable indicator. Forms of this questionnaire designed for 4-16-year old individuals were to be responded by parents and teachers, and forms to be responded by 11-16-year -old adolescents themselves can be completed within nearly 5 minutes. The adaptation of SDQ to Turkish language was realized by Guvenir et al. in 2008 [39]. Online cognition scale Developed by Davis, the online cognition scale (OCS) consists of 36 items that question the thoughts, attitudes, and beliefs about the internet [40]. OCS is a 7 point Likert-type scale with scores ranging from “I absolutely disagree” (1 point) to “I strongly agree” (7 points). The Turkish validity-reliability study of the OCS scale was conducted in 2005. According to the result of our study, its reliability coefficient was α=0.93, and the test- retest reliability was r=0.87 [41]. There are four dimensions of the OCS: 1. Loneliness-Depression (2-, 22-, 23-, 24-, 25-, and 35-point items): The dimension of loneliness-depression includes depressive thoughts about excessive/ problematic/inappropriate use of internet. 2. Diminished Impulse Control (4-, 5-, 10-, 11-, 12-, 15-, 17-, 21-, 34-, and 36-point items): Diminished impulse control related to the use of the internet, failed attempts to limit the use of the internet, and tendency to engage in risky and dangerous behaviors. 3. Social Support Subdimension (1-, 3-, 6-, 7-, 8-, 9-, 13-, 14-, 16-, 18-, 19-, 26-, and 31-point items): Relates to the assumption that internet use of individuals may be associated with hypersensitivity to seeking social support or social rejection. 4. Distraction (2-, 27-, 28-, 29-, 30-, 32-, and 33-point items): Subdimension that expresses the situation related to avoidance of anticipated duties in relation to the person’s identity and responsibilities. It evaluates

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resorting to internet with the intention to postpone some tasks or jobs. In addition, item 12 is scored by reversing. The assessment of the scale is done by calculating total score and subscale scores. Generally, the high scores of the OCS give an idea of the value attributed to internet and the priority of the internet in the individual’s life. Family Assessment Scale Developed by Epstein and Bishop, Family Assessment Scale (FAS) is a measure of the extent to which the family can or cannot fulfill its functions on specific matters. It consists of 60 items. Family members rate each item with scores ranging between 1 and 4 points according to representability of each item, and they are asked to mark the items that most appropriately define their condition. Its translation to Turkish and the validity and reliability study was performed by Işıl Bulut. FAS consists of seven subscales. Seven subscales consist of problem solving, communication, roles, emotional responsiveness, paying required attention, behavioral control, and general functions [42]. Schedule for Affective Disorders and Schizophrenia for School Aged –Kiddie- Present and LifetimeVersion: Schedule for Affective Disorders and Schizophrenia for School Aged Children Kiddie-SADS Present and LifetimeVersion (K-SADS-PL) is a semi-structured diagnostic interview developed with the aim to assess the present and future psychopathology of children and adolescents according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) and DSM-IV diagnostic criteria. It was adapted from K-SADS-P in 1997 by Kaufman et al. [43]. The validity and reliability study of its Turkish adaptation was realized in 2004 by Gokler et al. [44]. The current psychiatric diagnosis of the children who participated in the study was determined according to the DSM-IV [45] diagnostic criteria using the MDQ-SCI. Statistical evaluation Statistical analyses were performed using the Statistical Package for Social Sciences, version 18.0, statistical package program. The Kolmogorov-Smirnov normality test was used for the analysis of fitness of the data to the normal distribution before starting the analyses. The Chi-square test and/or Fisher’s exact test were used

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Table 1. Sociodemographic Characteristics

ADHD

Control

Gender 0,741 Female 11 (32.4%) 13 (36.1%) Male 23 (67.6%) 23 (63.9%) Age, years 13.50±1.41 13.50±1.42 0.932 Education Mother 9.7±3.6 5.7±1.6 <0.001 Father 10.1±3.7 7.8±2.3 0.001 ADHD: Attention deficit hyperactivity disorder.

to compare categorical variables. The Student t-test was used to compare continuous variables, and the Mann– Whitney U test was used when normal distribution was not obtained. Pearson and Spearman correlation analysis methods were used to determine the correlation among continuous data. In all statistical evaluations, the level of statistical significance was accepted as p <0.05. RESULTS A total of 70 children and adolescents, including 34 ADHD (11 females and 23 males) and 36 healthy controls (13 females and 23 males), participated in the study. The mean age of the group of ADHD and control group was 13.50±1.4 years. There were no significant differences between groups in terms of age and gender. It was observed that the level of education of the parents of the children with ADHD was significantly higher than that of the control group, indicating a significant difference between the parents of the ADHD and control groups (Table 1). When the level of familiarity with internet and the intentions of its use in the groups were examined, it was observed that the ADHD group used computer for longer periods (p=0.008) and the weekly duration of internet use was significantly higher than that of the control group (p=0.009). When the purposes of internet use were compared, the ADHD group engaged more frequently in social sharing sites, e-mail, betting sites, online games, chatting sites, dating sites, shopping sites, web design, and media access such as TV and music videos. This difference was statistically significant in terms of usage of e-mail, online games, and chat sites. In contrast, the con-

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Table 2. Comparison of the levels of familiarity of children, and adolescents with Internet, and computer use

ADHD group

Control group

n % n %

Internet use 33 97.1 33 91.7 0.6151 Having computer at home 33 97.1 31 86.1 0.199¹ Uninterrupted internet access at home 28 82.4 25 69.4 0.208² How many years he/she is using computer? (mean±SD) 5.2±2.6 3.7±1.6 0.008³ Weekly internet use (hours) (mean±SD) 15.73±14.36 7.66±6.90 0.009³ Purposes of using Internet Social networking site 25 73.5 21 58.3 0.181 E-mailing 14 41.2 6 16.7 0.023¹ Search for information 21 61.8 30 83.3 0.043¹ Home works 26 76.5 35 97.2 0.012² Online gaming 19 55.9 7 19.4 0.002¹ Offline gaming 6 17.6 7 19.4 0.847 Chatting 17 50 5 13.9 0.001¹ Dating sites 1 2.9 0 0 0.486 Shopping sites 4 11.8 1 2.8 0.192 Web design, blogs 3 8.8 1 2.8 0.350 Pornographic sites 0 0 0 0 News portals 6 17.6 9 25 0.454 Media (TV, music, video etc) 21 61.8 17 47.2 0.222 Betting sites 3 8.8 2 5.6 0.669 Other 2 5.9 0 0 0.232 ADHD: Attention deficit hyperactivity disorder; SD: Standard deviation; 1Fisher’s exact test; 2Pearson chi-square test, 3Mann-Whitney U test.

trol group was found to be more frequently interested in searching information, using homework sites, loading offline games, and reading newspapers and news, and this difference was statistically significant in the fields of accessing information and homework sites (Table 2). When the scale scores of the groups were examined, it was found that in the subscale scores of “Communication,” “Roles,” “Behavior Control,” and “General Family Functions” of the FAS appeared to be statistically significantly higher in the ADHD group (Table 3). Parents of children in the ADHD group assigned significantly higher scores to all the subscale items of OCS compared with the control group (Table 3). Parents of children in the ADHD group assigned significantly higher scores to subscale items of “Strengths and Difficulties Questionnaire Problems,” including Conduct Problems, Hyperactivity, Peer Relationship Problems, and Prosocial Behaviors, than the parents of

the control group (Table 3). The rates of additional diagnoses in the ADHD group were investigated using K-SADS. Spearman correlation analyses showed a mild-to-moderate positive correlation between OCS scores and ODD and Conduct Disorders in the ADHD group. It was also determined that as the education level of the mother increased, the total scores of the OCS also increased, which indicated the presence of a weak correlation between these parameters (Table 4). The relationship between the total score of OCS and other subscale scores was examined using the Pearson correlation analysis. As the scores related to the problematic internet use increased, scores of dysfunction related to the emotional reactions in the family increased, and the adolescents using the internet had more frequently indicated emotional and conduct problems related to themselves.

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Table 3. Comparison of various scale scores of the groups FAS subscales Problem solving Communication Roles Emotional responsiveness Gereken ilgiyi gösterebilme Conduct control General family functionality OCS subscales Loneliness/depression Decreased impulse control Social support Distraction Total score GGA-Parents subscales Emotional problems Conduct problems Hyperactivity Peer relationship problems Social behaviours Total difficulty score SDQ-Adolescent Emotional problems Conduct problems Hyperactivity Peer relationship problems Social behaviours Total difficulty score

ADHD group Mean±SD

Control group Mean±SD

1.99±0.64 1.87±0.53 2.11±0.46 1.77±0.59 2.36±0.47 2.08±0.39 1.82±0.54

1.73±0.50 1.60±0.47 1.87±0.29 1.52±0.47 2.32±0.39 1.81±0.41 1.46±4.27

0.970 0.024 0.018 0.055 0.840 0.011 0.002

18.85±6.94 35.67±12.55 51.00±15.75 26.55±9.43 132.08±38.67

11.75±5.09 23.41±9.19 35.02±11.59 19.52±6.21 89.72±26.87

<0.001 <0.001 <0.001 0.001 <0.001

3.82±2.32 3.32±2.26 6.00±2.81 4.06±1.90 7.03±2.39 17.21±6.37

2.78±2.41 1.06±0.86 3.03±1.85 2.42±1.46 8.75±1.33 9.28±4.76

0.054 <0.001 <0.001 <0.001 0.001 <0.001

3.71±2.66 3.41±2.31 5.15±2.59 3.85±2.21 7.71±2.19 16.12±7.11

3.58±2.81 1.69±1.39 3.36±2.21 3.28±1.86 8.06±2.48 11.92±7.13

0.718 <0.001 0.005 0.181 0.205 0.012

SD: Standard deviation; OCS: Online Cognition Scale; SDQ: Strengths and Difficulties Questionnaire; FAS: Family Assessment Scale; ADHD: Attention deficit hyperactivity disorder; Mann-Whitney U test.

Problems related to problem solving, communication, and roles in family functionality were positively correlated with adolescent self-report and behavioral scores and negatively and moderately with SDQ-parents-social behavior scores. This situation was interpreted as the problems of the puberty increased when the problemsolving skill in the family decreased. In addition, negative relationships with the subscale of SDQ-parents-social behaviors, which reveal the social skills of adolescents, indicate that these problems in the family can lead to problems in social relations (Table 5).

DISCUSSION In our study, the factors related to problematic internet use by children and adolescents were investigated. Problematic internet use has been found to be more frequent in children and adolescents with ADHD. When the patterns of internet use among children and adolescents with ADHD were examined, it was found that the presence of accompanied ODD and Conduct Disorders (CD), longer periods of internet use, and disordered family functionality related to emotional reactions was associated with problematic internet use.

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Table 4. Relationship between the presence of additional

diagnosis,educational levels of the parents, and OCD scores in the ADHD group Presence of an additional diagnosis Depression Separation anxiety Phobia OCD ODD Conduct disorder SLD Educational level Mother Father

OCD (total score) r

0.451 0.007 0.170 0.337 0.096 0.591 0.134 0.450 -0.028 0.875 0.343 0.047 0.358 0.038 -0.182 0.303 .237 -.074

0.024 0.271

Spearman Correlation Analysis; ADHD: Attention deficit hyperactivity disorder; OCD: Obsessive compulsive disorder; ODD: Oppositional defiant disorder; SLD: Specific learning difficulty; OCS: Online cognition scale.

When patient groups were examined in terms of additional psychiatric disorders, 70.6% of the patients in the ADHD group had additional psychiatric diagnoses at a significantly higher rate relative to the control group. It has been suggested that 60–100% of ADHD patients have one or more additional psychiatric diagnoses [46]. The most common comorbidities in ADHD in order of their decreasing frequency are Oppositional Defiant Disorder (ODD), learning disorders, CD, anxiety disorders, and depression [47, 48]. In our study, ODD (26.5%), depression (23.5%), and CD (17.6%) were most frequently diagnosed in the ADHD group. When the levels of children and adolescents’ acquaintance with computer and internet were examined, no difference between both groups was noted in terms of the factors, such as using internet in daily life, having a computer, and internet access at home. These results are important in that they demonstrate that internet and the computer occupy an important part in the lives of children and young people, independent of the economic conditions of the family. In contrast, although the opportunities of internet access were reported as comparable, it has been determined that the ADHD group used computers and internet for statistically significantly longer periods compared to the control group, suggesting that access to computers, internet, and technology products

is easier and more frequent in recent years. However, it also reveals that ADHD children and their parents who are genetically predisposed to ADHD have been at increased risk for the problematic internet use. When the time spent by children and adolescents using the computer and internet was examined, it was found that the ADHD group spent significantly longer periods, with an average of 15.73±14.36 hours per week. Problematic internet use was reported as over 8.48 hours per week in a study performed by MorahanMartin and Schumaher [49]. In the study by Kelleci et al. performed in our country, it has been reported that the daily use of internet of over 2 hours is related to mental disorders [34]. In a study performed by Uneri et al. in high school students, it was stated that the increase in the time spent on the internet is related to internet dependency [36]. In a population-based study, Yolga-Tahiroglu et al. defined the use of internet for 12 hours or more per week as problematic internet use [35]. We found that children and adolescents with ADHD who participated in this study had clinically significant internet dependency with longer use per week compared with the control group When the children and adolescents were examined in terms of the places where internet and computer were used, the control group had more frequently used computers at school, while no statistically significant difference was detected in terms of other locations of computer use. In our study, the respective percentages of children and adolescents in the ADHD group stated that they preferred to use computer and internet at home (85.3%), internet café (17.6%), and school (8.8%). The children and adolescents in the control group stated that they preferred to use internet and computer at home (74.3%), internet café (17.1%), and school (31.4%). In a similar study conducted with male university students in our country, the respective percentages of students stated that they were using computer and internet at home (80.6%), school (8.7%), and internet café (9.2%) [50]. It is thought that the increased use of computer and internet at home among adolescents between the ages of 12 and 24 years has contributed to the higher frequency of internet use at home. When the children and adolescents were examined according to their purpose of using internet and computer, the patients in the ADHD group used internet more frequently for e-mailing, playing online games, and chatting. The control group used the internet more frequently than

2 3

5 6 7 8

Pearson Correlation Analysis; FAS: Family Assessment Scale; OCS: Online Cognition Scale.

1. OCS total – 2. FAS-Problem solving 0.13 – 3. FAS-Communication 0.26 .49** – 4. FAS-Roles 0.19 .57** .58** – 5. FAS-Emotional responsiveness 0.40** .43** .69** .59** – 6. FAS-Showing required affection 0.19 .51** .41* .56** .42* – 7. FAS-Conduct control 0.10 .48** .52** .61** .57** .22 – 8. FAS-General family functionality 0.24 .71** .64** .69** .63** .39* .46** – 9. SDQ-Parents Total score 0.27 .07 .48** .37* .53** -.03 .22 .51** – 10. SDQ-Parents-Emotional problems 0.30 -.11 .25 .18 .46** -.09 .14 .30 .65** – 11. SDQ-Parents-Conduct problems 0.25 .18 .52** .51** .35* .03 .23 .63** .75** .28 – 12. SDQ-Parents-Hyperactivity -0.02 .07 .40* .34* .30 .10 .24 .26 .71** .18 .48** – 13. SDQ-Parents-Peer relationship problem 0.26 -.06 .06 -.08 .33 -.19 -.06 .19 .57** .35* .27 .11 – 14. SDQ-Parents-Social behaviours 0.09 -.35* -.40* -.39* -.27 -.002 -.38* -.38* -.41** .05 -.47** -.44** -.20 – 15. SDQ-Adolescent-Total score 0.44** .00 .24 .26 .22 .05 .05 .34* .41* .33 .42** .06 .36* .15 – 16. SDQ-Adolescent-Emotional problems 0.47** -.15 .10 .17 .30 .07 -.03 .13 .18 .42* .06 -.22 .34* .27 .75** – 17. SDQ-Adolescent-Conduct problems 0.41** .41* .49** .44** .35* .21 .29 .59** .45** .10 .63** .24 .26 -.21 .64** .28 – 18. SDQ-Adolescent-Hyperactivity 0.31 -.17 .07 .16 .006 -.06 .09 .12 .32 .29 .26 .19 .14 .24 .75** .39* .32 – 19. SDQ-Adolescent-Peer relationship problem 0.52 -.04 .06 -.02 -.05 -.05 -.21 .17 .25 .11 .36* -.01 .30 .11 .74** .46** .30 .42* 20. SDQ-Adolescent-Social behaviours 0.28 -.16 -.20 -.09 -.007 .07 -.06 -.32 -.33 -.005 -.34* -.38* -.12 .39* -.11 .22 -.21 -.17 -.21 –

9 10 11 12 13 14 15 16 17 18 19 20

the ADHD group for searching information and doing homework. Social networking sites were used extensively by both groups, without any significant difference between them. Our results are also important in terms of demonstrating that online social media and gaming addiction, which are considered as new fads in recent years, carry a greater risk for adolescents with ADHD [25, 51–53]. Upon analysis, the mean OCS subscale and total scores rated by children and adolescents of the ADHD group were found to be significantly higher than those of the control group. Higher OCS scores give an idea about the value attributed to internet and the degree of its priority in the life of the individual. Based on this finding, it can be said that the ADHD group is more prone to use the internet problematically. In another study, OCS scores of age-matched children and adolescents with ADHD were reported to be significantly higher than the population in general [54]. The average weekly internet usage hours and OCS scores of children and adolescents with ADHD who participated in the study were significantly higher than those of the control group; however, extreme values were observed when the distribution intervals were examined. What are the differences between children and adolescents with and without problematic internet and computer in the ADHD group? What are the factors that lead to these differences? To investigate the answers to these questions, the ADHD group has been examined within itself in terms of internet usage patterns. In our study, it was determined that as the duration of internet and computer use of children and adolescents in the ADHD

Table 5. Relationship between OCS, and FAS Subscale Scores in the ADHD group

Cakmak et al., Problematic internet use in ADHD children

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group increased, OCS scores increased. In contrast, as the time spent on the computer and internet increases, the rate of problematic usage, personal importance attributed to the internet by the user, and its priority in the life of the person also increase. In a study conducted in university students, a significant relationship was found between the OCS scores and the duration of weekly internet use [50]. Our study also supports this finding. When the relationship between OCS scores and weekly internet usage was examined in the ADHD group, a statistical but moderately significant correlation was found between the duration of weekly internet use and loneliness/depression, decreased impulse control, social support subscales, and their total scores. The strongest relationship was between the loneliness/ depression subscale scores and the duration of internet use. In a recent review that evaluated 20 studies, depression (75%), anxiety (57%), obsessive-compulsive symptoms (60%), aggression (66%), and ADHD (100%) were detected in respective percentages of individuals with problematic internet use. In the light of the relevant literature, as was the case with other age groups, feelings of depression and loneliness were determined as important risk factors for the problematic internet use among adolescents with ADHD. When the familiarity levels of the cases in the ADHD group with internet and computer are examined in relation with internet usage patterns, a significant correlation between the factors, such as using internet in daily life, having a computer and internet access at home, OCS scores, and weekly internet use was not detected. Although the duration of computer use (year) of the ADHD group was higher than that of the control group, no correlation was found between the OCS scores and duration of weekly internet use. In a similar study performed with lyceĂŠ students, it has been reported that the presence of internet at home and youngster possessing a computer in his/her private room is not related to internet addiction [36]. In a study conducted with university students, no significant correlation was not found between the duration of internet use by the students in years, OCS scores, and duration of weekly internet use. Unlike our study, in this study, it was stated that young people with their own computers had higher OCS scores and weekly internet usage times [50]. When the relationship between the intention of using internet and computer and internet use patterns are examined in the ADHD group, online games were found

North Clin Istanb

to be moderately related to the OCS scores, while chatting was also moderately correlated with the duration of weekly use. In a population-based study, Kormas et al. reported that using the internet for interactive gaming, chatting, and searching for sexual information is a predictor of problematic internet use [55]. In the study by Mottram et al. performed in adults aged older than 17 years, using internet for gaming and non-business purposes and being affiliated with online groups predicted problematic internet use [56]. In his study with adult internet addicts, Bernardi et al. stated that the use of internet for chatting in women and its use for interactive gaming in men is related to internet dependency [57]. When the relationship between comorbid psychiatric disorders and internet use patterns in the ADHD group was examined, the additional diagnoses of ODD and CD were found to be significantly related to both the OCS scores and the duration of the weekly internet use. According to literature reviews, although the association between ADHD and other mental disorders had been mentioned, it was noticed that there were no studies related to the additional diagnoses of CD and ODD accompanying ADHD. This is thought to be due to the use of different diagnostic tools, the use of self-reporting scale in most studies, and the lack of diagnostic evidence of conduct problems within them, as a result of the differences in the study methods and assessment methods. In a recent study conducted in our country with clinical samples selected from adolescents and children aged 10-8 years who were diagnosed with internet addiction, ADHD was the most frequently diagnosed condition in 83.3% of the patients. In addition, incidence rates of ODD (23%) and CD (15%) were also consistent to the rates in our study, but it was not specified whether these diagnoses accompanied ADHD [58]. When the relationship between SDQ subscale scores and internet usage patterns was examined in the ADHD group, a moderately significant correlation between OCS scores and emotional and conduct problems and total difficulty subscale scores was detected. Only a moderately significant correlation was found between the duration of weekly use and the subscales of conduct problems in both SDQ-parent and SDQ-teacher forms. In the study by Kormas et al. where SDQ was used, the presence of a correlation between the conduct problems, hyperactivity subscale scores, and problematic internet use was indicated [55].

Cakmak et al., Problematic internet use in ADHD children

When the relationship between FAS subscale scores and internet use patterns was examined in the ADHD group, a statistically significant relationship was detected between OCS scores and emotional responsiveness subscale scores only. A moderately positive correlation between the OCS and this subscale indicates that the use of problematic internet increases when the unhealthy expression of emotional reactions in the family increases. This finding suggests that an adolescent who does not express his/her emotional reactions appropriately or an adolescent who does not receive appropriate emotional responses from his/her parents uses the internet more inefficiently. This is an important finding. Problems with internet use are commonly encountered in children with ADHD, and interventions to address this need should also address intrafamilial expressions of emotion. A statistically significant relationship was not found between the duration of weekly internet use and FAS subscale scores. It has been also observed that other difficulties in family functionality generally increase the parents’ negative scores in the SDQ regarding their children, and in this case, the adolescents themselves also overestimate conduct problems and mobility symptoms. This condition may be related to two important factors. Firstly, ADHD may be the cause of both maladjustment of family functionality and problematic use of the internet; secondly, a chaotic family structure of adolescents with ADHD may be an additional risk factor that increases the effect of ADHD on the problematic use of the internet. It seems further studies are required related to this issue. Our study has certain limitations. Only limited number of children were included in the study, which is not sufficient to generalize the results. In addition, the study group included cases with ADHD who were admitted to our clinic. Studies in the social sample can give different results. Another limitation is that the selected control group is at a lower socioeconomic level than the ADHD group. However, since the use of the internet has become widespread nowadays, the difference between the two groups is not important in terms of access to internet and computer use. Conclusion Our study is one of the first studies that compared the control group with ADHD group in terms of problematic internet use by youngsters in the early adolescence.

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It also evaluated family functionality and its relationship to internet usage patterns. We hope that this study will shed light on other studies and warrant further similar studies. Acknowledgment: We thank Prof. Dr Kagan Gurkan for his contribution to the collection, analysis and evaluation processes of the study data. Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – F.H.C., H.G.; Design – F.H.C., H.G.; Supervision – F.H.C., H.G.; Materials – F.H.C., H.G.; Data collection &/or processing – F.H.C., H.G.; Analysis and/or interpretation – F.H.C., H.G.; Writing – F.H.C., H.G.; Critical review – F.H.C., H.G.

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Orıgınal Article

PT&R

North Clin Istanb 2018;5(4):314–318 doi: 10.14744/nci.2017.82435

Efficacy of extracorporeal shockwave therapy in patients with lateral epicondylitis: A randomized, placebo-controlled, double-blind clinical trial Nilgun Senol Guler,1

Serdar Sargin,2

Nilay Sahin1

Department of Phisical Therapy and Rehabilitation, Balikesir University Faculty of Medicine, Balikesir, Turkey

Department of Orthopedics and Traumatology, Balikesir University Faculty of Medicine, Balikesir, Turkey

ABSTRACT OBJECTIVE: Lateral epicondylitis is a common elbow problem. Although extracorporeal shockwave therapy (ESWT) is widely used in the treatment of lateral epicondylitis, its efficacy is still controversial. Moreover, the number of prospective, randomized, controlled studies in the literature is not sufficient. Here, we intend to investigate the efficacy of ESWT. METHODS: The study was randomized, placebo-controlled, double-blind, and prospectively planned. Forty patients who met the inclusion criteria were divided into two groups, real ESWT (Group 1, n=20) and placebo ESWT (Group 2, n=20), in a 1: 1 randomized closed envelope manner. Patients were evaluated for Patient-Rated Tennis Elbow Evaluation-Turkish Version (PRTEE-T), visual analog scale (VAS) pain scores, and grip and pinching strengths. The evaluation were performed thrice before, at the end of treatment and 1 month after treatment. Both groups were treated with wrist splinting, ice treatment, and rest. RESULTS: There was no statistical difference between sex and dominant hand in both groups. There was no significant difference in the grasp and pinching strength between the measurements of the groups themselves (p>0.05). When examined in terms of VAS scores, only significant changes were found in the actual ESWT group (p<0.05). According to the PRTEE-T scores, both groups showed significant changes (p<0.05). No significant difference was found between post-treatment and control measures in the grip and pinching power between groups, VAS and PRTEE-T scores before treatment (p>0.05). CONCLUSION: Although pain and functional improvement were more prominent in our patients treated with ESWT than placebo, no statistically significant results were found. Keywords: Epicondylitis; high-energy shock waves; lateral humeral.

Cite this article as: Senol Guler N, Sargin S, Sahin N. Efficacy of extracorporeal shockwave therapy in patients with lateral epicondylitis: A randomized, placebo-controlled, double-blind clinical trial. North Clin Istanb 2018;5(4):314–318.

ateral epicondylitis (LE) is a common elbow problem and often affects active people aged 30–50 years [1, 2]. The incidence is 4/1000 people per year [3]. The definitive etiology is not fully understood, but it is thought that factors such as overuse injury and direct trauma on the lateral epicondyle play a role in the compulsive wrist extension [4]. The goal in LE treatment is to prevent loading into the arm, reduce pain, accelerate healing, and provide rapid

return to daily activities. Despite the availability of many studies on LE treatment in the literature, the most appropriate treatment is still controversial. Different treatment modalities are described in the literature, either alone or in combination. Various treatment modalities such as rest, activity modification and restriction, ice treatment, splinting, oral and topical nonsteroidal anti-inflammatory (NSAI) drugs, physical therapy, acupuncture, local injections (corticosteroids, platelet rich plasma), and

Received: September 06, 2017 Accepted: November 09, 2017 Online: December 03, 2018 Correspondence: Dr. Nilay SAHIN. Balikesir Universitesi Tip Fakultesi, Fizik Tedavi ve Rehabilitasyon Anabilim Dali, Balikesir, Turkey. Phone: +90 555 233 25 35 e-mail: nilaysahin@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Senol Guler et al., ESWT therapy on lateral epicondylitis

surgery are applied in LE treatment [5]. However, there is not enough scientific evidence to support the effectiveness of each treatment modality [6]. Extracorporeal shockwave therapy (ESWT) has been widely used in many musculoskeletal problems over the last 25–30 years [7, 8]. Though the exact effects have not been proven, it is suggested that shock waves accelerate tissue healing, reduce calcification, and inhibit pain receptors with denervation [9]. Despite the widespread use of ESWT in the treatment of LE, controversy regarding its efficacy still remains. There are publications in the literature that have different conclusions about the efficacy of ESWT. Furthermore, the number of prospective, randomized, controlled studies in the literature is not enough [10]. For this reason, we aimed to investigate whether ESWT is indeed effective in patients with LE in a prospective, randomized, double-blind, and placebocontrolled study. MATERIALS AND METHODS This study included patients who were referred to the orthopedics-traumatology and physical therapy rehabilitation clinic in 2014 and 2015 with the complaint of elbow pain and who were diagnosed with LE. Ethical consent was obtained from the ethics committee of the university, and informed consent form was obtained from each patient. The ethics committee approval number is 2014/35. The inclusion criteria were as follows: patients aged 18–65 years of age, sensitivity on the lateral epicondyle, positive diagnosis of LE, and no treatment for LE within the last 3 months. The exclusion criteria were the presence of any treatment for LE within the last 3 months, pregnancy, hemostatic disturbance, upper extremity tumor, local or systemic infection, pacemaker attachment, elbow arthritis, posterior interosseous nerve syndrome, and radiculopathy. The study included 100 patients with complaints of 3 weeks to 1 year who met the following diagnostic criteria. LE was diagnosed with ≥2 of the following prognostic tests with patient complaining of pain in the lateral epicondyle region. The provocative tests used in the study were as follows: 1. Lateral epicondyle sensitivity in palpation. 2. Positive Cozen’s test: pain during wrist extension against resistance.

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3. Moudley’s test: pain during middle finger extension against resistance. 4. Chair test: pain during lifting of weight of approximately 3–5 kg. This was a randomized, placebo-controlled, doubleblind, and prospective study. Forty patients who met the inclusion criteria were divided into two groups, real ESWT (Group 1, n=20) and placebo ESWT (Group 2, n=20), in a 1: 1 randomized closed envelope manner. Treatment and evaluation were done by different physicians. Patients were informed of the intent of studying after the diagnosis of the disease and comparing two separate treatment protocols, and their approval was obtained. Before the application, demographic data of the patients, the duration of illness, the side of complaint, the dominant side, and additional systemic diseases were recorded to the previously prepared forms. Evaluation Patients were evaluated with the Patient-Rated Tennis Elbow Evaluation-Turkish Version (PRTEE-T) [11]. The level of pain at rest, compression, and activity were assessed as 0–10 points (0, no pain; 10, very painful) using the visual analog scale (VAS). The Roles and Maudsley score was also taken. Scores were assesed thrice before, at the end of treatment and 1 month after treatment. Gripping and Pinching Forces Measure The maximal gripping and pinching forces were measured using Jamar dynamometer before, at the end of treatment and 1 month after treatment. Hand dynamometry ( Jamar dynamometer, Preston Healthcare, Jackson, USA) was used for the procedure. The patient was informed about how to perform the measurement with hand dynamometer before the procedure and confirmation regarding their understanding was taken. The measurement was performed by the same physician (SS, MT) who performed the examination. The procedure was performed while sitting in a chair and the forearm was in a comfortable position at 60° flexion on the table. The patient requested a maximum squeeze of the jammer. This process was repeated thrice and the average value was recorded. ESWT treatment ESWT procedure was performed by the same physiotherapist (NE). A BTL device (BTL 6000 SWT TOPLINE, UK) was used for ESWT. Without apply-

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ing local anesthesia to the marked area, an R15 applicator was used with a hand gun at 1500 pulse counts, a frequency of 15 Hz, and an energy density of 2.4 bar. The peripheral muscles were applied with a D35 applicator tipped hand gun at 1500 pulse counts, using a gel at the interface at an energy density of 1.8 bar and a frequency of 21 Hz. The placebo ESWT group was performing all steps as if it were being done. To be more convincing, the device provided sound at every shock, but no electric current was supplied. Both groups were treated with wrist splinting, ice, and rest, so that the placebo group would not be left without treatment. Statistical analyses Statistical analyses were performed using SPSS version 21.0 software. The normal distribution of variables was examined using visual (histogram and probability plots) and analytical methods (Kolmogorov–Smirnov/ Shapiro–Wilk tests). The pre-treatment, post-test, and control measures included changes in the groups themselves using the repaired measures ANOVA test. Paired t test was used to assess post-hoc Bonferroni adjustment if the results were significant. The ANCOVA test was used to compare changes between groups. Statistically significant results were obtained when the p-value was <0.05. RESULTS The demographic data of the patients are shown in Table

1. There was no statistical difference between sex and dominant hand in both groups. When statistical evaluation was made, changes within the groups themselves were evaluated first. For this, pre-treatment, post-treatment, and control outcomes were assessed using the repaired measures ANOVA test. There was no significant difference in the grasp and pinching strength between the measurements of the groups (p>0.05). Also, there was no statistically significant difference between post-treatment and control measures compared with pre-treatment grip and pinching power among the groups (p>0.05). Regarding VAS scores, significant changes were found in the real ESWT group (p<0.05). When examining the extent of this change, it was seen that the changes between pre-treatment and post-treatment control measures were significant (p<0.05). There was no significant difference between the groups in terms of VAS scores (p>0.05). According to PRTEE-T scores, both groups found significant changes in themselves (p<0.05). It was found that the changes between pre-treatment and post-treatment control measures in the real ESWT group were significant (p<0.05). Similarly, in the placebo ESWT group, the changes between before and after treatment and between pre-treatment and control measures were significant (p<0.05). However, there was no significant difference between the groups in terms of PRTEE-T scores (p>0.05).

Table 1. Collected data

Real ESWT group

Pseudo-ESWT group

Sex 6 male, 14 female 6 male, 14 female Age 46.3±8.09 45.8±10.8 BMI 28.6±4.1 27.3±3.4 Symptom 4.1±2.4 4.4±2.2 duration (month) Affected side 11 right, 9 left 13 right, 7 left

Preatment Control

VAS Score 5.8±1.8 4.3±2.1 PRTEE-Score 79.7±26.4 60.1±33.2 Grasping force 45.9±21.8 52.1±19.2 Pinch force 11.1±5.3 12.5±4.4

Preatment Control 6.1±1.6 5.3±1.8 76.7±19.7 64.7±20.2 47.05±14.4 49.4±16.07 11.9±2.6 12.3±3.7

BMI: Body mass index; ESWT: Extracorporeal shockwave therapy; PRTEE: Patient-rated tennis elbow evaluation; VAS: Visual Analog Scale.

Senol Guler et al., ESWT therapy on lateral epicondylitis

DISCUSSION This study compared actual ESWT and placebo ESWT results in patients with LE. According to our results, early recovery of ESWT treatment improved in grip strength, pinching strength, VAS, and PRTEE-T functional scoring in both groups, although it was more pronounced in the true ESWT group. However, there was no statistically significant difference between the groups in the changes (p>0.05). There are studies with similar results in literature [9, 12–15]. In some studies, ESWT is not effective or is even less effective than placebo [9, 12, 14, 16, 17]. Our study differs from these studies for the first time to assess grip strength as well as pinch strength and also to use a LE specific scoring system such as PRTEE-T. Three of these studies have been separated from our study due to chronic LE cases with similar outcomes and to patients after failed non-operative treatment [9, 12, 13]. Haake et al. [12] found that ESWT treatment in a multicenter, randomized, placebo-controlled, singleblind study was not as effective as placebo. The success rate of treatment administered under local anesthesia at 12 weeks was 25.8% in the ESWT group and 25.4% in the placebo group. Although consistent with the results of our study, there are differences in the dose of ESWT and method of application. In a prospective randomized double-blind study, Melikyan et al. [14] performed high-dose ESWT without local anesthesia, which is similar to that performed in our work. The difference is that the area to be applied ESWT is determined by USG. In this study, no statistically significant difference was found between the groups after 12 months. In the placebo-controlled study by Speed et al. [9], patients had a mean duration of 15.9 months in the ESWT group and 12 months in the placebo group. Similar to our study, they did not use local anesthesia during ESWT administration. The ESWT doses were applied at a rate of 0.18 mJ/mm2 at 1500 counts. Significant improvement was observed in the study in both groups over 2 months. However, similar to our study, there was no significant difference in pain scores between the groups. Rompe et al. [18] used Siemens Sonocur Plus unit device. The ESWT site, as in our study, determined where the pain was at the maximum; however, unlike our study, this study confirmed the point of application using USG. The results of this study are consistent to those in

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our study. Both groups showed improvement over time. However, no statistically significant difference was found between the groups. There is still confusion regarding the efficiency of ESWT in the treatment of LE [9, 12–14, 18–20]. Similar results have been reported in the review of Stasinopoulos et al. [10]. The reasons behind the different outcomes can be easily understood by analyzing the methods of the studies. Factors such as the use of different devices, variable doses and protocols, different patient selection criteria, follow-up times, and evaluation methods affect the outcomes of the studies. Therefore, good quality, standardized, prospective, randomized, double-blind studies are needed. There are also publications reporting the effectiveness of ESWT in the treatment of LE between 68% and 91% [18, 19, 21]. Rompe et al. [19] reported excellent results in 48% of patients in the low-energetic ESWT group and 100% of patients in the placebo-controlled chronic tennis elbow. On the other hand, in the placebo group, 6% and 24% reported acceptable and excellent results, respectively. Again, Rompe et al. [18] found that low-energy ESWT was statistically significantly more effective than the placebo group in our placebo-controlled trial of 78 patients. Wang et al. [21] compared 43 patients who were followed up for 1–2 years in the case series with six disease placebo control groups and achieved close to 90% good results. In a study by Spacca et al. [22], 31 patients were administered radial shock wave therapy (RSWT) 4 times a month at a rate of 2 beats per month in 31 prospective randomized controlled trials, and the control group was administered RSWT at a rate of 20 beats to 31 patients. Unlike our study, the clinical diagnosis of LE was confirmed by USG or MRI. Similar to this study, local anesthesia was not performed for RSWT. Unlike our study, patients who did not respond to treatment, treated with injection therapy, were included to study. Patients were evaluated thrice before treatment, at the end of treatment, and at the 6th month after treatment. Spacca et al. reported that RSWT is an effective treatment method that can be safely applied in the treatment of LE and is an alternative modality to low-energy ESWT. The limitations of our study include the number of cases, the short follow-up period, not using an imaging method such as USG or MRI to confirm the diagnosis, and not applying ESWT in USG guideline. For these 1-month follow-ups, Haake et al. [12] led us to hypothe-

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ses about spontaneous improvement in pain in the long term. The cost of using USG or MRI for diagnosis confirmation prevented cost and unnecessary work. The reason for using USG during the application was the lack of infrastructure such as the lack of our own USG device in our polyclinic. As a result, although pain and functional improvement were more prominent in our patients treated with ESWT treatment, no statistically significant differences were found between two groups. However, as per the literature, we think that ESWT can be performed before surgical treatment, especially when there are no local complications in low-energy ESWT and RSWT and the publications that give positive results. However, in the treatment of LE, there is a need for multicenter, placebo-controlled studies investigating the efficacy of ESWT. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – N.S.; Design – N.S.; Supervision – N.S.; Materials – N.S., S.S.; Data collection &/or processing – S.S.; Analysis and/or interpretation – S.S., N.S.G.; Writing – S.S., N.S.G.; Critical review – N.S.G.

REFERENCES 1. Wadsworth TG. Tennis elbow: conservative, surgical, and manipulative treatment. Br Med J (Clin Res Ed) 1987;294:621–4. 2. Shiri R, Viikari-Juntura E, Varonen H, Heliövaara M. Prevalence and determinants of lateral and medial epicondylitis: a population study. Am J Epidemiol 2006;164:1065–74. 3. Hay EM, Paterson SM, Lewis M, Hosie G, Croft P. Pragmatic randomised controlled trial of local corticosteroid injection and naproxen for treatment of lateral epicondylitis of elbow in primary care. BMJ 1999;319:964–8. 4. Nirschl RP, Pettrone FA. Tennis elbow. The surgical treatment of lateral epicondylitis. J Bone Joint Surg Am 1979;61:832–9. 5. Bisset L, Paungmali A, Vicenzino B, Beller E. A systematic review and meta-analysis of clinical trials on physical interventions for lateral epicondylalgia. Br J Sports Med 2005;39:411–22. 6. Labelle H, Guibert R, Joncas J, Newman N, Fallaha M, Rivard CH. Lack of scientific evidence for the treatment of lateral epicondylitis of the elbow. An attempted meta-analysis. J Bone Joint Surg Br

North Clin Istanb 1992;74:646–51. 7. Haupt G. Use of extracorporeal shock waves in the treatment of pseudarthrosis, tendinopathy and other orthopedic diseases. J Urol 1997;158:4–11. 8. Speed CA. Extracorporeal shock-wave therapy in the management of chronic soft-tissue conditions. J Bone Joint Surg Br 2004;86:165–71. 9. Speed CA, Nichols D, Richards C, Humphreys H, Wies JT, Burnet S, et al. Extracorporeal shock wave therapy for lateral epicondylitis-a double blind randomised controlled trial. J Orthop Res 2002;20:895–8. 10. Stasinopoulos D, Johnson MI. Effectiveness of extracorporeal shock wave therapy for tennis elbow (lateral epicondylitis). Br J Sports Med 2005;39:132–6. 11. Altan L, Ercan I, Konur S. Reliability and validity of Turkish version of the patient rated tennis elbow evaluation. Rheumatol Int 2010;30:1049–54. 12. Haake M, König IR, Decker T, Riedel C, Buch M, Müller HH; Extracorporeal Shock Wave Therapy Clinical Trial Group. Extracorporeal shock wave therapy in the treatment of lateral epicondylitis : a randomized multicenter trial. J Bone Joint Surg Am 2002;84-A:1982–91. 13. Crowther MA, Bannister GC, Huma H, Rooker GD. A prospective, randomised study to compare extracorporeal shock-wave therapy and injection of steroid for the treatment of tennis elbow. J Bone Joint Surg Br 2002;84:678–9. 14. Melikyan EY, Shahin E, Miles J, Bainbridge LC. Extracorporeal shockwave treatment for tennis elbow. A randomised double-blind study. J Bone Joint Surg Br 2003;85:852–5. 15. Chung B, Wiley JP. Effectiveness of extracorporeal shock wave therapy in the treatment of previously untreated lateral epicondylitis: a randomized controlled trial. Am J Sports Med 2004;32:1660–7. 16. Staples MP, Forbes A, Ptasznik R, Gordon J, Buchbinder R. A randomized controlled trial of extracorporeal shock wave therapy for lateral epicondylitis (tennis elbow). J Rheumatol 2008;35:2038–46. 17. Buchbinder R, Green SE, Youd JM, Assendelft WJ, Barnsley L, Smidt N. Shock wave therapy for lateral elbow pain. Cochrane Database Syst Rev 2005:CD003524. 18. Rompe JD, Decking J, Schoellner C, Theis C. Repetitive low-energy shock wave treatment for chronic lateral epicondylitis in tennis players. Am J Sports Med 2004;32:734–43. 19. Rompe JD, Hope C, Küllmer K, Heine J, Bürger R. Analgesic effect of extracorporeal shock-wave therapy on chronic tennis elbow. J Bone Joint Surg Br 1996;78:233–7. 20. Melegati G, Tornese D, Bandi M, Rubini M. Comparison of two ultrasonographic localization techniques for the treatment of lateral epicondylitis with extracorporeal shock wave therapy: a randomized study. Clin Rehabil 2004;18:366–70. 21. Wang CJ, Chen HS. Shock wave therapy for patients with lateral epicondylitis of the elbow: a one- to two-year follow-up study. Am J Sports Med 2002;30:422–5. 22. Spacca G, Necozione S, Cacchio A. Radial shock wave therapy for lateral epicondylitis: a prospective randomised controlled single-blind study. Eura Medicophys 2005;41:17–25.

Orıgınal Article

OPHTHALMOLOGY

North Clin Istanb 2018;5(4):319–322 doi: 10.14744/nci.2017.54036

Effects of long-term computer use on eye dryness Sezen Akkaya,

Tugba Atakan,

Banu Acikalin,

Sibel Aksoy,

Yelda Ozkurt

Department of Eye Diseases, University of Health Sciences Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: To evaluate the effects of long-term computer use on tear production and evaporation. METHODS: In this study, 30 eyes of 30 people using computer for 8 hours a day were taken as the study group. In the control group, 30 eyes of 30 healthy individuals who did not spend 1 hour using computer on a daily basis were evaluated. The cases were examined at 8 am and 5 pm. The Schirmer test, tear break-up time (TBUT), and ocular surface disease index (OSDI) were evaluated. RESULTS: There was no significant difference between the groups in terms of age and gender. The Schirmer test results, which measure the parameters of tear production, were 16.80±2.04 and 15.50±2.06 mm (p>0.05) in the study group, and 17.28±1.52 and 17.16±2.53 in the control group. The TBUT measurements were 9.15±2.93 and 6.80±1.11 sec in the study group. It was observed that the evening TBUT decreased (p<0.05). The TBUT measurements were 15.80±3.15 sec and 15.20±1.92 sec (p>0.05) in the control group. The OSDI scores were 26.7±3.36 and 28.3±1.19 in the study group, and 25.0±4.48 and 27.3±2.27 in the control group. CONCLUSION: As a result, it was found that a long-term computer use did not change the Schirmer test results significantly, but there were statistically significant changes in the tear break-up time (TBUT) results of the evaporative type eye dryness. According the our study results, long-term computer usage may cause an evaporative-type dry eye disease. Keywords: Dry eye disease; Schirmer test; TBUT; use of computer.

Cite this article as: Akkaya S, Atakan T, Acikalin B, Aksoy S, Ozkurt Y. Effects of long-term computer use on eye dryness. North Clin Istanb 2018;5(4):319–322.

ry eye disease is a multifactorial condition. Eye dryness is more common in elderly postmenopausal women, and it is becoming more frequent as the life span of people increases [1, 2]. In addition, the number of individuals using computer and display devices with a screen is increasing every day [3, 4]. Use of computers and display devices with a screen decreases the number of eye blinks, leading to incomplete blinking, evaporation of tears, and subsequently to dry eye disease. The most common type of dry eye disease is an evaporative type, and the use of computers is especially important in this group [5]. Computer vision syndrome, also referred to as digital eye fatigue, has been described by the American Op-

tometry Association as an eye and vision problem seen in long-term computer, tablet, and cell phone users [6]. The most frequent symptoms are eye fatigue, headache, blurred vision, and dry eyes. Double vision and head and neck pain can also be added [7]. Eye dryness is a very common eye disease nowadays, and it affects daily activities by decreasing the quality of life due to its symptoms. In addition, it has also become an important public health problem because of the increased treatment costs [1, 8]. In this study, we wanted to determine the points to be noted with regard to use of devices with screen display important for this public health problem by evaluating the results of the Schirmer test and tear break-up time,

Received: September 14, 2017 Accepted: December 22, 2017 Online: August 08, 2018 Correspondence: Dr. Sezen AKKAYA. Saglik Bilimleri Universitesi, Fatih Sultan Mehmet Egitim ve Arastirma Hastanesi, Goz Hastaliklari Klinigi, Istanbul, Turkey. Tel: +90 216 578 30 00 e-mail: drsezenakkaya@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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which are the parametres of dry eye disease related to a long-term computer use. MATERIALS AND METHODS In this study, 30 eyes of 30 persons using computer longterm for work were taken as the study group, and 30 eyes of 30 healthy individuals who did not work with devices with display screen were evaluated as the control group. The study was conducted in accordance with the Helsinki Declaration, and informed consent forms were obtained from patients. The study group consisted of staff working as secretary and information-processing officers in our hospital. Persons with systemic diseases other than eye diseases, or eye diseases that could not be corrected by using eyeglasses, individuals who experienced open or laser surgery for their eyes, and cases using ophthalmic medications, artificial tear drops, or contact lenses were excluded from the study. During the study, the right eye of the individuals was evaluated. Individuals included in the study were examined twice before starting work at 8 am and at 5 pm in the evening after at least 8 hours of computer use. The morning and evening tear break-up time (TBUT), results of the Schirmer test (with topical anesthesia), and ocular surface disease index (OSDI) scores were recorded. Dry eye symptoms of the cases were assessed using the OSDI questionnaire, which is a 12-item questionnaire that assesses dry-eye-related ocular symptoms and their visual functions. Questions cover the ocular symptoms, environmental stimuli, and visual functions. The Schirmer test was performed after applying topical anesthesia with proparacaine drops (proparacaine HCI, Alcaine 0.5%, Alcon) and after drying the excess tear drops. In this test, the Schirmer strip was placed on the-one third of the lateral part of the lower eyelid of the patient. The patient waited for 5 minutes and then was asked to look across and blink normally. Five minutes later, Schirmer strips were taken, and the the quantity of tears was recorded. To determine TUBT, fluorescein solution was dropped into patients’ eyes, and they were asked to blink three times and then look across with their eyes open. During the biomicroscopic examination, the integrity of the tears is lost under cobalt blue light, and the time to the formation of the dry spot on the cornea was recorded and evaluated. The obtained data were recorded in SPSS 16.0 (Sta-

North Clin Istanb

tistical Package for the Social Sciences, IBM). The chisquared test, Mann–Whitney U test, and Wilcoxon test were used for comparisons. The evaluations were made within the 95% confidence interval, and the p-value less than 0.05 was regarded as a statistically significant difference. RESULTS The average age of the study participants (17 women and 13 men) using computers for a long time was 29.92±4.25 years. The control group consisted of 30 healthy individuals (18 women and 12 men) with a mean age of 28.42±4.56 years. There was no difference in terms of age and gender between the two groups who were using or not using computers for a long time on a daily basis (p>0.05). Duration of daily computer use was 7.70±0.86 hours in the computer group and 0.72±0.68 hours in the control group (p<0.001) (Table 1). The Schirmer average value in the group using the computer for a long period of time per day was 16.80±2.04 mm at 8 am and at 15.00±2.06 mm at 5 pm at the end of the workday (p>0.05). In the control group, the Schirmer value was 17.28±1.52 in the morning, and the evening measurement was 17.16±2.53 mm (p>0.05) (Table 2). The study group had 9.15±2.93 seconds in the morning examination of TBUT measurements. At the end of the

Table 1. Daily computer use of the groups Daily duration of computer use (hours) Study group Control group

7.70±0.86 0.72±0.68

p <0.001*

*: Statistically significant.

Table 2. Morning and evening values of Schirmer test with anesthesia Study group Control group

Morning (mm)

Evening (mm)

16.80±2.04 17.28±1.52

15.50±2.06 17.16±2.53

>0.05 >0.05

Akkaya et al., Effects of long-term computer use on eye dryness

Table 3. Morning and evening tear break-up time values of the groups

Morning TBUT value

Evening TBUT value

Study group Control group

9.15±2.93 15.80±3.15 (<0.05)*

6.80±1.11 15.20±1.92 (<0.05)*

(<0.05)* (>0.05)

TBUT: Tear break-up time; p<0.05, level of statistical significance.

Table 4. Morning, and evening OSDI values of the groups

Morning OSDI value

Evening OSDI value

Study group Control group

26.7±3.36 25.0±4.48 (>0.05)

28.3±1.19 27.3±2.27 (>0.05)

(>0.05) (>0.05)

OSDI: Ocular surface disease index; p<0.05 level of statistical significance.

day, the TBUT value was determined as 6.80±1.11 sec. There was a statistically significant difference between these two values in the study group. A decrease in the evening TBUT value was observed (p<0.05). In the control group, the TBUT value was recorded as 15.80±3.15 sec in the morning and 15.20±1.92 sec in the evening (p>0.05). There was no statistically significant difference between these two values in the control group (Table 3). The OSDI score of the group using computers for a long time every day was 26.7±3.36 in the morning and 28.3±1.19 at the end of the workday (p>0.05). In the control group, it was 25.0±4.48 in the morning and 27.3±2.27 in the evening (p>0.05). There was no statistically significant difference between the two groups or OSDI scores, and between the evening and morning values (Table 4). There was no significant intergroup difference between the Schirmer test results and OSDI values measured in the morning and evening (Tables 2, 4), but the TBUT values were significantly different, and the TBUT values in the study group were significantly lower (Table 3). In addition, the evening TBUT values were significantly lower in the group using computer (Table 3).

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DISCUSSION It has been shown in our study that a long-term use of the computer caused instability in the distribution of tears on the ocular surface, leading to easy evaporation of the tear drops. The TBUT showing tear stability was found to be significantly lower in the group using computer compared to the control group. In addition, when the evening TBUT measurements were compared with the morning measurements, there was a significant decrease in the computer users group. Previous studies have shown that the use of computers causes tear evaporation, which is attributed to a reduction in the number of blinks and an incomplete blinking. Portello et al. found a positive correlation between the number of incomplete blinks and eye dyness symptoms of individuals. They found a negative correlation between the number of blinks and relevant symptoms [5, 9]. When we evaluated the results of the Schirmer test performed with topical anesthesia, which demonstrates the basal tear release in our study, we did not find any significant difference between the two groups and between the morning and evening values. This suggests that the mechanism of evaporation is more prevalent than the reduction of tear release in the dry eyes due to computer use. We did not find any statistically significant difference between the study and control groups in terms of OSDI scores in our study. Bayhan et al. previously reported that OSDI scores were significantly higher in the group using computers for a long time [10]. In our study, there was no statistically significant difference between morning and evening OSDI values. We think that the lack of any difference between OSDI scores among the study participants due to the fact that they had not complaints of eye dryness, and all of them were healthy individuals. A long-term computer use also affects the functions of accommodation and vergence functions, other than dry eye functions [11]. It has been reported that those who use computer for 4 hours or longer show convergence insufficiency, exosphoria, lower fusional convergence, and decrease in accommodation width [12]. An increasing use of devices with display screens at all ages is beginning to make computer vision syndrome an important public health problem. This problem affects both the eye health and job performance. There are environmental and personal precautions that can be taken to protect individuals from the com-

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puter vision syndrome and to reduce the eye fatigue. Some of them are 20–20–20 rules. A person who uses a computer for a long time should look at an object from 20 feet (6 m) away for 20 seconds every 20 minutes. Employees should be advised to blink their eyes frequently so as to prevent the evaporation of tear drops and to protect moisture. If the problem of refraction develops, it should be absolutely corrected [13]. The American Optometry Association recommends that the center of the computer monitor should be 15– 20 degrees (approximately 10–12.5 cm) below the eye level, and it should be 50–70 cm away from the eyes. Appropriate lighting should be provided in the environment, and the daylight should be received from one side if possible. Screen filtering can help reduce glare. In addition, 15 minutes of rest after 2 hours of work will both improve the work performance and provide protection from computer vision syndrome [6]. In addition, in a large-scale study by Buhargava et al., a total of 456 individuals with computer vision syndrome were divided into two groups: One group received an oral Omega-3 treatment, and the other group received placebo. The authors demonstrated the beneficial effects of Omega-3, which is used for the treatment of dry eyes due to computer vision syndrome. In the group that received oral Omega-3 preparations, the dry eye symptoms were alleviated, and the tear evaporation rate was decreased [14]. As a result, a prolonged computer use increases the eye evaporation rate and causes eye strain. Employees and employers should be warned in this regard and take necessary precautions and measures that will be effective in solving this public health problem. Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – S.A, S.Ak., Y.O.; Design – S.A., S.Ak., Y.O.; Supervision – B.A., Y.O.; Materials – S.A., S.Ak.;

North Clin Istanb Data collection &/or processing – S.A., S.Ak.; Analysis and/or interpretation – T.A.; Writing – T.A.; Critical review – B.A., Y.O.

REFERENCES 1. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:75–92. 2. Peck T, Olsakovsky L, Aggarwal S. Dry Eye Syndrome in Menopause and Perimenopausal Age Group. J Midlife Health 2017;8:51–54. 3. Nakamura S, Kinoshita S, Yokoi N, Ogawa Y, Shibuya M, Nakashima H, et al. Lacrimal hypofunction as a new mechanism of dry eye in visual display terminal users. PLoS One 2010;5:e11119. 4. van Tilborg MM, Murphy PJ, Evans KS. Impact of Dry Eye Symptoms and Daily Activities in a Modern Office. Optom Vis Sci 2017;94:688–93. 5. Portello JK, Rosenfield M, Chu CA. Blink rate, incomplete blinks and computer vision syndrome. Optom Vis Sci 2013;90:482–7. 6. Randolph SA. Computer Vision Syndrome. Workplace Health Saf 2017;65:328. 7. Munshi S, Varghese A, Dhar-Munshi S. Computer vision syndrome-A common cause of unexplained visual symptoms in the modern era. Int J Clin Pract 2017;71. 8. Ranasinghe P, Wathurapatha WS, Perera YS, Lamabadusuriya DA, Kulatunga S, Jayawardana N, et al. Computer vision syndrome among computer office workers in a developing country: an evaluation of prevalence and risk factors. BMC Res Notes 2016;9:150. 9. Hirota M, Uozato H, Kawamorita T, Shibata Y, Yamamoto S. Effect of incomplete blinking on tear film stability. Optom Vis Sci 2013;90:650–7. 10. Bayhan HA, Bayhan SA,Muhafız E, Gürdal C. Evaluation of the Dry Eye Parameters and Tear Osmolarity in Computer Users.Turkiye Klinikleri J Ophthalmol 2014;23:167–71. 11. Rosenfield M. Computer vision syndrome: a review of ocular causes and potential treatments. Ophthalmic Physiol Opt 2011;31:502–15. 12. Gur S, Ron S, Heicklen-Klein A. Objective evaluation of visual fatigue in VDU workers. Occup Med (Lond) 1994;44:201–4. 13. Tribley J, McClain S, Karbasi A, Kaldenberg J. Tips for computer vision syndrome relief and prevention. Work 2011;39:85–7. 14. Bhargava R, Kumar P, Phogat H, Kaur A, Kumar M. Oral omega-3 fatty acids treatment in computer vision syndrome related dry eye. Cont Lens Anterior Eye 2015;38:206–10.

Orıgınal Article

CARDIOLOGY

North Clin Istanb 2018;5(4):323–328 doi: 10.14744/nci.2017.26779

The association between aspirin resistance and extent and severity of coronary atherosclerosis Serkan Kahraman,1

Ali Dogan,2

Murat Ziyrek,1

Emrah Usta,3

Onder Demiroz,4

Cavlan Ciftci4

Department of Cardiology, Istanbul Silivri State Hospital, Istanbul, Turkey

Department of Cardiology, Istanbul Yeniyuzyil University Faculty of Medicine, Gaziosmanpasa Hospital, Istanbul, Turkey

Department of Cardiology, Baltalimani Training and Research Hospital, Istanbul, Turkey

Department of Cardiology, Istanbul Bilim University Faculty of Medicine, Istanbul, Turkey

ABSTRACT OBJECTIVE: Uncontrolled inflammatory responses could contribute to the pathogenesis of many leading causes of human morbidity and mortality. Aspirin is an anti-inflammatory and antithrombotic drug that is used in the primary and secondary protection in atherothrombotic diseases and complications. The aim of the present study was to analyze the effect of aspirin resistance on the extent and severity of atherosclerosis. METHODS: One hundred patients who underwent coronary angiography with suspected or known coronary artery disease and were using aspirin were enrolled in the study. RESULTS: Of these 100 patients, 30 (8 female and 22 male) formed the aspirin-resistant group (ARG), and 70 (22 female and 48 male) formed the control group. Gensini scoring system (GSS) was significantly higher in the ARG than in the control group (80.5 (36–166) vs. 45 (2–209); p<0.001). The number of percutaneous coronary intervention (PCI) patients was significantly higher in the ARG (13 of 30 (43.3%) ARG vs. 13 of 70 (18.6%) control group; p=0.01). Furthermore, when we evaluate the 16 reintervention patients, stent restenosis was significantly higher in the ARG (11 of 16 (68.75%) ARG vs. 5 of 16 (31.25%) control group; p=0.016). Multivariate logistic regression analysis revealed that GSS (p=0.038; 95% CI: 1.001–1.026) and PCI history (p=0.017; 95% CI: 1.182–89.804) were independent risk factors for aspirin resistance. CONCLUSION: In conclusion, atherosclerotic burden as calculated by the GSS is significantly higher in aspirin-resistant patients. According to this result, we suggest that aspirin treatment can be prescribed in higher doses in aspirin resistance patients with coronary events. Furthermore, GSS and PCI history could be independent predictors of aspirin resistance. Keywords: Aspirin resistance; atherosclerosis; coronary artery disease.

Cite this article as: Kahraman S, Dogan A, Ziyrek M, Usta E, Demiroz O, Ciftci C. The association between aspirin resistance and extent and severity of coronary atherosclerosis. North Clin Istanb 2018;5(4):323–328.

ncontrolled inflammatory responses could contribute to the pathogenesis of many leading causes of human morbidity and mortality [1]. Atherosclerosis, a chronic low-grade inflammatory state, is one of the most common causes of death in developed countries and an example of uncontrolled inflammation [2]. The clinical importance of atherosclerosis attracts much attention to the inflammation cascade. Arachidonic acid is a polyunsaturated fatty acid that accounts for 10%–20% of the

phospholipid fatty acid content on average [3]. Metabolites produced by the oxygenation of the arachidonic acid play a key role in the modulation of inflammation [4]. Cyclooxygenase (COX) and lipoxygenase (LOX) enzyme families degrade arachidonic acid to various proinflammatory metabolites. Thromboxane A2, which propagates strong vasoconstriction and platelet aggregation, is synthesized by COX-1 [5]. COX-2 enzyme catalyzes prostacyclin, one of the strongest vasodilator metabo-

Received: September 09, 2017 Accepted: September 21, 2017 Online: August 08, 2018 Correspondence: Dr. Serkan KAHRAMAN. Silivri Devlet Hastanesi, Kardiyoloji Klinigi, Istanbul, Turkey. Tel: +90 505 382 59 21 e-mail: serkankahraman_86@outlook.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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lites, synthesis reaction [6]. The second important pathway producing eicosanoids is catalyzed by the LOX enzyme family. Leukotriene B4 produced by this pathway is a known mediator of programmed apoptosis and atherosclerosis [7]. Owing to this close relationship between arachidonic acid metabolites and endothelial homeostasis, these enzymatic pathways deserve great attention. Aspirin is an important anti-inflammatory drug that directly inhibits the COX enzyme family. It is an effective antithrombotic drug that is used in the primary and the secondary protection in atherothrombotic diseases and complications [8, 9]. Aspirin resistance plays an important role on atherosclerosis. Two types of aspirin resistance are defined. The occurrence of new cardiovascular events in patients who are using aspirin is defined as “clinical resistance,” and the incomplete blockage of platelet activity in vitro is defined as “laboratory resistance” [10]. Since there is a well-known close relationship between atherosclerosis and inflammation, anti-inflammatory drugs inhibiting certain steps of the arachidonic acid pathway and resistance to them become trend topics of cardiology. The main purpose of the present study was to analyze the association between aspirin resistance and extent and severity of coronary atherosclerosis. MATERIALS AND METHODS Patient population One hundred patients with suspected coronary artery disease (CAD) due to typical chest pain or positive non-invasive cardiovascular stress testing who underwent cardiac catheterization between April 1, 2013 and November 30, 2013 were included in the study. Exclusion criteria were defined as follows: thrombocytopenia (<100,000/mm3), thrombocytosis (>400,000/mm3), end-stage renal disease, acute or chronic liver failure, hematologic diseases, history of malignant disease, active infection, intolerance or contraindication to aspirin, under treatment of glycoprotein IIb/IIIa inhibitors in the last 3 days, usage of antithrombotic or anticoagulant treatment other than aspirin in the last 30 days, regular use of nonsteroidal anti-inflammatory treatment in the last 3 months, and subjects <30 and >75 years old. One hundred patients with known or newly diagnosed CAD already using therapeutic doses of aspirin were included. Study protocol This was a prospective observational study. Basic demographic data of patients included age, gender, body mass

North Clin Istanb

index (BMI), glomerular filtration rate (GFR), presence of traditional major cardiovascular risk factors (age, sex, hypertension (HT), diabetes, dyslipidemia, family history of premature cardiovascular disease (CVD), and current smoking). The extent and severity of atherosclerosis was analyzed using the Gensini scoring system (GSS) [11]. Thereafter, venous blood samples were collected for biochemical analysis. The study was approved by the local ethics committee of Istanbul Bilim University (no. 44140529/2013-028). All patients were informed about the study. Written informed consent was obtained from the patients. Angiographic evaluation Angiographic evaluations were done by two different experienced cardiologists. The extent and severity of CAD was assessed by the GSS. The Gensini score was calculated by multiplying the severity coefficient assigned to each coronary stenosis according to the degree of luminal narrowing (reductions of 25%, 50%, 75%, 90%, and 99%, and complete occlusion was given Gensini scores of 1, 2, 4, 8, 16, and 32, respectively) by the coefficient identified based on the functional importance of the myocardial area supplied by that segment as follows: left main coronary artery, 5; proximal segment of the left anterior descending coronary artery, 2.5; mid-segment of the left anterior descending coronary artery, 1.5; apical segment of the left anterior descending coronary artery, 1; first diagonal branch, 1; second diagonal branch, 0.5; proximal segment of the circumflex artery, 2.5 (if right coronary artery dominancy existed, 3.5); distal segment of the circumflex artery, 1 (if dominant, 2); obtuse marginal branch, 1; posterolateral branch, 0.5; proximal segment of the right coronary artery, 1; mid-segment of the right coronary artery, 1; distal segment of the right coronary artery, 1; and posterior descending artery, 1. Biochemical analysis After terminating oral intake for 8–12 h, blood samples that are drawn from the brachial veins of all patients are injected into dry tubes, and samples are centrifuged before biochemical evaluation. Total cholesterol, low-density lipoprotein (LDL), very-low-density lipoprotein, high-density lipoprotein, triglyceride, fasting blood glucose, blood urea nitrogen, creatinine, and complete blood count were measured. In our study, aspirin resistance is evaluated by the “VerifyNow” system that is an adenosine diphosphate

Kahraman et al., The association between aspirin resistance and extent and severity of coronary atherosclerosis

(ADP) stimulation method. Aspirin inhibition levels are detected by extracting blood from patients who are taking therapeutic dose aspirin (at least 100 mg/day) after 12–24 h. “VerifyNow” is a system that is based on the stimulation of fibrinogen-coated particles in full blood with citrate by agonists, such as ADP, thrombin receptor-activating peptide, and arachidonic acid, in the mixing compartment. By adding anticoagulated blood into the mixing compartment, platelets are activated, and platelet aggregation occurs after the bonding between GPIIb/IIIa receptors on activated platelets and particles with fibrinogen. After this reaction, the change of light transmissions is defined as aspirin reaction unit (ARU). ARU >550 is considered as aspirin resistance [12, 13]. Statistical analysis All statistical analyses were performed using the SPSS 16.0 software (SPSS Inc., Chicago, IL, USA). Fitness to normal distribution was analyzed by the Kolmogorov– Smirnov test. Homogeneity of variances was calculated by the Levene test and the Lilliefors significance correction. Interobserver agreement between two cardiologists was calculated using the Bland–Altman analysis. Differences among two groups were analyzed by the Student’s t test or its non-parametric counterpart, Mann–Whitney U test. Categorical variables were analyzed by either chi-square test or Fisher’s exact test where appropriate. Multivariate logistic regression analysis was performed to explore the factors affecting aspirin resistance. Data were expressed as mean±standard deviation or median (minimum-maximum) where appropriate. A p value <0.05 was considered as statistically significant. RESULTS One hundred patients who underwent coronary angiography with suspected or known CAD and were using aspirin were enrolled in the study. Clinical and demographic characteristics of all subjects are given in Table 1. Of these 100 patients, 30 (8 female and 22 male) formed the aspirin-resistant group (ARG), and 70 (22 female and 48 male) formed the control group. There were no statistically significant differences in age, smoking, diabetes mellitus, HT, BMI, GFR levels, beta blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and statin usage between the ARG and the control group. Only LDL level was significantly higher in the ARG as shown in Table 2.

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Table 1. Clinical and demographic characteristics of all sub-

jects

n=100 % Age (years) 62.72±7.93 Gender (female) 30 Diabetes mellitus 45 Hypertension 75 Hyperlipidemia 95 Smoking 32 Stent history 26

There was no statistically significant difference in the GSS between two cardiologists (p=0.76). GSS was significantly higher in the ARG than in the control group (80.5 (36–166) vs. 45 (2–209); p<0.001) as shown in Figure 1. In addition to this, 26 of a total of 100 patients had first or repetitious percutaneous coronary intervention (PCI) history. There were no acute stent thrombosis patients, 10 (38.5%) patients had first PCI, and 16 (61.5%) patients had reintervention due to stent restenosis. The number of PCI patients was significantly higher in the ARG (13 of 30 (43.3%) ARG vs. 13 of 70 (18.6%) control group; p=0.01). Furthermore, when we evaluate the 16 reintervention patients, stent restenosis was significantly higher in the ARG (11 of 16 (68.75%) ARG vs. 5 of 16 (31.25%) control group; p=0.016) as shown in Table 3. There were statistically significant differences in LDL levels, GSS, and stent thrombosis between the ARG and the control group. However, multivariate logistic regression analysis revealed that only GSS (p=0.038; 95% CI: 1.001–1.026) and PCI history (p=0.017; 95% CI: 1.182–89.804) were independent risk factors for aspirin resistance as shown in Table 4. DISCUSSION In our recent study, we aimed to investigate the association between aspirin resistance and extent and severity of coronary atherosclerosis. Antiplatelet therapy remains the most important and effective management in the prevention of important clinical complications of atherothrombosis, namely acute coronary events, cerebral vascular accidents, and all other thrombotic events [7]. Aspirin is an important antiplatelet and anti-inflammatory drug that is fairly well analyzed ever. In the meta-

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North Clin Istanb

Table 2. Comparison of baseline characteristics of the ARG and control group Parameter

ARG (n=30) Mean±SD

Control (n=70) Mean±SD

n % n %

Age (years)* 63.3±6.70 62.47±8.43 0.635 Female (gender)† 8 26.7 22 31.4 0.634 Smoking† 10 33.3 22 31.4 0.852 Diabetes mellitus† 15 50 30 42.9 0.511 Hypertension† 22 73.3 53 75.7 0.601 Beta blocker† 13 43.3 43 61.4 0.095 † ACE inhibitor 7 23.3 22 31.4 0.414 Statin† 10 33.3 25 35.7 0.819 PPI† 5 16.7 6 8.6 0.236 BMI (kg/m2)* 27.12±1.29 26.85±1.51 0.402 * GFR (ml/min) 87.08±27.92 79.92±18.04 0.129 LDL (mg/dl)* 128.33±43.40 108.43±40.02 0.029 ARG: Aspirin resistant group; ACE: Angiotensin converting enzyme; PPI: Proton pump inhibitor; BMI: Body mass index; GFR: Glomerular filtration rate; LDL: Low density lipoprotein; *Student’s t test; †Chi-square test.

Table 3. Comparison of angiographic data and aspirin doses of the ARG and control group

100 p<0.001 Gensini score

Parameter

ARG Control p (n=30) (n=70)

Aspirin dose (mg/day)* 100 (100–300) 100 (80–300) 0.018 Gensini score* 80.5 (36–166) 45 (2–209) <0.001 No. of total PCI† 13 (%43.3) 13 (%18.6) 0.01 † No. of reintervention 11 (68.75%) 5 (31.25%) 0.016

40 20 0 ARG group

Control group

Figure 1. Comparison of the Gensini score between the aspirin resistance and non-resistance groups. ARG: aspirinresistant group. analysis of five randomized studies that included 9853 patients who were followed up with stable CVD, a 21% decrease in cardiovascular event risk (non-fatal myocardial infarction (MI), non-fatal stroke, and cardiovascular death) and a 13% decrease in all-cause mortality were found in patients who were taking low dose aspirin (75– 325 mg/day) [14]. In a review that included 287 randomized controlled studies with >200,000 patients (An-

ARG: Aspirin resistant group; PCI: Percutaneous coronary intervention; *Mann Whitney- U test; †Student’s t test.

ti-thrombotic Trialists’ Collaboration), a 22% decrease in the risk of cardiovascular event mortality was detected [9]. The effectiveness of regular aspirin usage in reducing the risk for MI, ischemic stroke, and fatal coronary events among patients with pre-existing atherosclerotic CVDs is well established [15]. Although cheap, effective, and easily accessible, aspirin resistance restricts the usage of this antiplatelet and anti-inflammatory drug. Aspirin resistance is defined as the incapacity of aspirin to decrease platelet production of thromboxane A2, and so platelets activate and aggregate [16]. The prevalence of aspirin resistance has been estimated to be between 5%

Kahraman et al., The association between aspirin resistance and extent and severity of coronary atherosclerosis

Table 4. Logistic regression analysis giving information

about the independent risk factors for aspirin resistance Parameter Gensini score LDL (mg/dl) PCI history Aspirin dose (mg/day)

Beta

CI (95%)

0.013 0.012 2.206 -0.009

0.041 0.073 0.034 0.062

1.001–1.026 0.999–1.025 1.182–89.804 0.991–0.997

CI: Confidence interval; LDL: Low density lipoprotein; PCI: percutaneous coronary intervention.

and 60% of aspirin-treated patients for secondary prevention [17]. That is why patients treated with aspirin still retain at substantial risk of clinically important CVDs due to insufficient inhibition of platelet aggregation via the thromboxane A2 pathway. The incidence of aspirin resistance was found to be 30% in our study, which is compatible with previous ones. It is obvious that patients with aspirin resistance are prone to atherothrombotic and atherosclerotic events. Krasopoulus et al. reported that long-term aspirin-treated patients who are resistant to aspirin are at a greater risk of important cardiac morbidity than patients who are sensitive to aspirin [18]. As we mentioned previously, atherosclerosis is a chronic low-grade inflammatory state. Aspirin, due to the COX enzyme inhibitor activity, is also a well-known anti-inflammatory drug. The influence of inflammation on the progression of atherosclerosis and rupture of atherosclerotic plaque opens a new therapeutic era for atherosclerosis. Not only aspirin but also some other drugs, such as statins, thiazolidinediones (glitazones), and renin–angiotensin aldosterone system blockers, exert their anti-atherosclerotic effect through the modulation of endothelial inflammation [19, 20]. In addition to this, in a recent study, it was found that antiplatelet agents, namely aspirin, clopidogrel, or ticagrelor, significantly reduce high sensitive C-reactive protein level, which is a key biomarker of inflammation [21]. In our study, there was no significant difference in statin and renin–angiotensin aldosterone system blocker usage between the ARG and the control group that can affect the inflammatory state. Furthermore, in a similar study, Li et al. showed that the anti-inflammatory effect of tanshinone IIA, one of the most abundant constituents of the root of the red sage, improves inflammation and increases atherosclerotic plaque stability [22]. In light of foregoing data, it is known that atherosclerosis is one of the reasons of in-

327

flammatory state, and anti-inflammatory agents, such as aspirin, could exert anti-atherosclerotic effect. We might conclude that patients with aspirin resistance could be more prone to atherosclerosis and atherothrombosis. As far as we see, there is hardly any literature assessment to analyze the relationship between GSS and aspirin resistance. In our study, we revealed that the GSS was significantly higher in aspirin-resistant patients, meaning that atherosclerotic burden is significantly higher in aspirin resistance. Furthermore, we found that coronary reintervention ratio is significantly higher in the ARG. We consider that aspirin has antiplatelet and anti-inflammatory effects, and in aspirin resistance patients, lack of these effects is the possible reasons of high GSS and coronary reintervention ratio. Although the possible mechanisms of aspirin resistance are beyond the scope of this article, the effect of aspirin dose on aspirin resistance could be discussible. Actually, Gengo et al. demonstrated that patients who are non-responsive to 81 mg/day dose of aspirin become responsive at 162 mg/day or at a greater dose [23]. In a similar study, Duzenli et al. revealed that increasing the aspirin dose to 300 mg/day or adding clopidogrel to aspirin can provide adequate platelet inhibition in a significant number of patients with impaired responses to low dose aspirin [24]. Interestingly, in our study, the mean aspirin dose in the control group was significantly higher than that in the ARG. In previous studies, non-responsive patients became aspirin responsive at doses >150 mg/day. In our study, although both groups’ aspirin doses were in therapeutic ranges, they were not in maximal doses. This could be the possible reason of this result. The prothrombotic and inflammatory state is related with aspirin resistance in patients with hyperlipidemia, and it is known that this relationship does not depend on LDL cholesterol levels. In our study, LDL level was significantly higher in the ARG. However, there were some other factors, such as statin usage, and other causes of inflammatory state could affect aspirin resistance [25]. Conclusion Our study concluded that atherosclerotic burden as calculated by the GSS is significantly higher in aspirin-resistant patients. According to this result, we suggest that aspirin treatment can be prescribed in higher doses in aspirin resistance patients with coronary events. Furthermore, Gensini score and PCI history could be independent predictors of aspirin resistance. Absolutely higher

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scaled studies are needed to further elucidate the clinical implications of these findings. Limitations of the study One of the limitations was the lack of basal ARU before aspirin treatment. However, all the patients were evaluated by VerifyNow, and ARU levels were obtained under therapeutic dose aspirin treatment, with a cut-off level of 550, which is considered as a critical level in most studies. This provides us to get over this limitation in a way. Another limitation was the small number of subjects in the ARG. In addition, low dose aspirin was used in the ARG than the control group, but both of them were in therapeutic ranges. Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – S.K. A.D. C.C.; Design – S.K., A.D., C.C.; Supervision – S.K., A.D., C.C.; Materials – S.K., M.Z., E.U., O.D., C.C.; Data collection &/or processing – S.K., M.Z., E.U., O.D., C.C.; Analysis and/or interpretation – S.K., A.D., C.C.; Writing – S.K., A.D., E.U., O.D., C.C.; Critical review – S.K., A.D., M.Z., C.C.

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North Clin Istanb 9. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. 10. Kuliczkowski W, Witkowski A, Polonski L, Watala C, Filipiak K, Budaj A, et al. Interindividual variability in the response to oral antiplatelet drugs: a position paper of the WorkingGroup on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventionsof the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the EuropeanSociety of Cardiology. Eur Heart J 2009;30:426–35. 11. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983;51:606. 12. Gachet C, Aleil B. Testing antiplatelet therapy. Eur Heart J Suppl 2008;10: A28–A34. 13. Michelson AD. Methods for the measurement of platelet function. Am J Cardiol 2009;103:20A–26A. 14. Berger JS, Brown DL, Becker RC. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. Am J Med 2008;121:43–9. 15. Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–60. 16. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet 2006;367:606– 17. 17. Heistein LC, Scott WA, Zellers TM, Fixler DE, Ramaciotti C, Journeycake JM, et al. Aspirin resistance in children with heart disease at risk for thromboembolism: prevalence and possible mechanisms. Pediatr Cardiol 2008;29:285–91. 18. Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ 2008;336:195–8. 19. Sukhova GK, Williams JK, Libby P. Statins reduce inflammation in atheroma of nonhuman primates independent of effects on serum cholesterol. Arterioscler Thromb Vasc Biol 2002;22:1452–8. 20. Husain K, Hernandez W, Ansari RA, Ferder L. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis. World J Biol Chem 2015;6:209–17. 21. Layne K, Di Giosa P, Ferro A, Passacquale G. LB03.03: Antı-ınflammatory effects of antı-platelet drugs: ımplıcatıon for atherosclerosıs. J Hypertens 2015;33:e126. 22. Li Y, Guo Y, Chen Y, Wang Y, You Y, Yang Q, et al. Establishment of an interleukin-1β-induced inflammation-activated endothelial cell-smooth muscle cell-mononuclear cell co-culture model and evaluation of the anti-inflammatory effects of tanshinone IIA on atherosclerosis. Mol Med Rep 2015;12:1665–76. 23. Gengo F, Westphal ES, Rainka MM, Janda M, Robson MJ, Hourihane JM, et al. Platelet response to increased aspirin dose in patients with persistent platelet aggregation while treated with aspirin 81 mg. J Clin Pharmacol 2016;56:414–21. 24. Duzenli MA, Ozdemir K, Aygul N, Soylu A, Tokac M. Comparison of increased aspirin dose versus combined aspirin plus clopidogrel therapy in patients with diabetes mellitus and coronary heart disease and impaired antiplatelet response to low-dose aspirin. Am J Cardiol 2008;102:396–400. 25. Cipollone F, Mezzetti A, Porreca E, Di Febbo C, Nutini M, Fazia M, et al. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation 2002;106:399–402.

Orıgınal Article

CHILD HEALTH&DISEASES

North Clin Istanb 2018;5(4):329–333 doi: 10.14744/nci.2017.73384

Subclinical rheumatic heart disease: A single center experience Seyma Kayali,1

Nuran Belder2

Department of Pediatric Cardiology, Kecioren Training and Research Hospital, Ankara, Turkey

Department of Pediatrics, Kecioren Training and Research Hospital, Ankara, Turkey

ABSTRACT OBJECTIVE: Rheumatic heart disease (RHD) is still a major cause of morbidity and mortality in developing countries. The aim of the present study was to investigate asymptomatic RHD cases diagnosed by echocardiography without any acute rheumatic fever (ARF) history and to present the follow-up results. METHODS: Children who had been admitted to the pediatric cardiology department between 2011 and 2017 for various reasons (e.g., sport participation and palpitation) and diagnosed with RHD by echocardiography without a history of ARF were included the study. Echocardiographic findings of the patients were evaluated retrospectively. RESULTS: A total of 75 (55 girls and 20 boys) patients were included in the study. The median age of the cases was 13.6 (minimum 5 and maximum 18) years. The median follow-up period was 19.2 months, whereas the longest follow-up period was 66 months. At the time of admission, pathological valvular insufficiency was present only in the mitral valve in 69 (89.3%) cases, only in the aortic valve in 2 (2.7%) cases, and in both aortic and mitral valve in 6 (8%) cases. Of the cases, 40 (60%) were diagnosed as borderline RHD at the time of admission, and 30 (40%) as definite RHD according to the World Heart Federation criteria. Of these cases, 88% remained the same as borderline RHD, and the findings of two patients improved from definite to borderline RHD. RHD of four patients deteriorated from borderline to definite RHD, and in two patients, valvular insufficiency completely resolved during the follow-up period. None of the cases needed valvular replacement. CONCLUSION: RHD is still a serious health problem in Turkey. The sensitivity of echocardiography in detecting subclinical mild or asymptomatic cases is well known. For this reason, although it is not yet applied as a routine study, it is important to start the nationwide echocardiographic screening program. Keywords: Asymptomatic; children; echocardiography; Rheumatic heart disease.

Cite this article as: Kayali S, Belder N. Subclinical rheumatic heart disease: A single center experience. North Clin Istanb 2018;5(4):329–333.

cute rheumatic fever (ARF) is an important public health problem in developing countries including Turkey [1–3]. Although ARF and rheumatic heart disease (RHD) are considered to be parts of the same whole, their evaluation per se provides benefit. Indeed, in some patients with ARF, cardiac involvement is not seen at all, and in the medical history of nearly 50% of cases with RHD, diagnosis of ARF is not encountered because of the silent progression of ARF or unmade diagnosis. This condition is termed as subclinical carditis and is considered to be the major finding in both low- and moderateand high-risk populations according to the Jones criteria, which were lastly readjusted in 2015 [4].

Diagnosis of cases with definite ARF story bearing morphological and functional features of rheumatic heart disease (RHD) is easy to make. In certain cases with a definite history of ARF, having any valvular structural/ functional impairment is RHD unless proven otherwise [5]. However, the subclinical course leads to delayed diagnosis and onset of secondary prophylaxis at baseline, resulting in increased morbidity and mortality due to RHD. Echocardiography is the most appropriate tool for the early diagnosis of subclinical RHD. In recent years, echocardiographic screening programs have been implemented in some countries in light of an increasing number of studies [6–8]. A guide was issued by the World

Received: September 15, 2017 Accepted: December 04, 2017 Online: August 13, 2018 Correspondence: Dr. Seyma KAYALI. Saglik Bilimleri Universitesi, Kecioren Egitim ve Arastirma Hastanesi, Cocuk Kardiyolojisi, Ankara, Turkey. Tel: +90 312 356 90 00 e-mail: ak-seyma@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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Table 1. The World Heart Federation echocardiographic diagnostic criteria of RHD for patients aged ≤20 years

Morphological changes

Pathological valvular insufficiency

Mitral valve RHD Thickening of the anterior mitral It should be observed in two different views valve leaflet (≥3 mm, age-specific) Thickening of the chordae tendineae Insufficiency jet length should be ≥2 cm in at least one view Reduced leaflet mobility The velocity in one complete envelope should be ≥3 m/s Extensive mobility of the Insufficiency jet should be pansystolic in leaflet tip during systole at least one envelope Aortic valve RHD Irregular or focal consolidation It should be observed in two different views Coaptation defect Insufficiency jet length should be ≥1 cm in at least one view Reduced leaflet mobility Velocity should be ≥3 m/s in early diastole Prolapse Insufficiency jet should be pandiastolic in at least one envelope Definite RHD (A, B, C, or D) A. Pathological MR and presence of at least two morphological features of RHD of the mitral valve B. Mitral stenosis (mean pressure gradient ≥4 mmHg) C. Pathological AI, and presence of at least two morphological features of RHD of the aortic valve D. Concomitant presence of borderline rheumatic involvement of both mitral and aortic valves Borderline RHD (A, B or C) A. Presence of at least two morphological features of rheumatic involvement of the mitral valve without pathological MS or MR B. Pathological MR C. Pathological AI AI: Aortic insufficiency; MR: Mitral regurgitation; MS: Mitral stenosis.

Heart Federation (WHF) for the rapid identification of RHD in patients without ARF to be used in these screening programs [9]. Table 1 summarizes the criteria found in this guideline. Knowing the diagnostic criteria for RHD is also very important in terms of our country. However, there is no new study to determine the prevalence of RHD in our country, and also a national echocardiographic screening program is not available. The aim of the present study was to analyze echocardiographically detected cases with RHD without ARF in light of the current diagnostic criteria of RHD and to share the follow-up results of these cases. MATERIALS AND METHODS Established cases with available echocardiographic evidence of pathological valve insufficiency under our surveillance without any history of ARF who were referred to the pediatric cardiology polyclinic between 2011 and 2017 with different clinical indications (e.g., participa-

tion in sport activities and palpitation) were included in the study. All patients underwent transthoracic echocardiography using a Vivid 3 Expert (General Electric Medical Systems, USA) device with 3 and 7 MHz probes by an experienced pediatric cardiologist. Mitral valve insufficiency jet was assessed throughout the systole in the apical four-chamber examination, and aortic valve insufficiency jet was assessed in the apical five-chamber examination throughout the diastole. For the echocardiographic diagnosis of pathological valve insufficiency, the criteria previously defined and then updated by the WHF in 2012 were used [9]. According to the criteria, for mitral valve insufficiency, the following should be present: insufficiency jet should be seen at least two different sections, jet length should be at least 2 cm, and peak flow rate should be at least 3 m/s during systole. However, the criteria for aortic valve insufficiency were as follows: insufficiency jet should be seen at least two different sections, jet length should be at least 1 cm, and peak flow velocity along the diastole should be >3 m/s. The presence of borderline and definite RHD was also

Kayali et al., Subclinical rheumatic heart disease: A single center experience

Table 2. Characteristic features of patients with rheumatic heart diseases (n=75)

Age (mean±SD) 13.6±3.3 years Gender, % (female/male) 73.3 /26.7 2 BMI (kg/m ) 19.4±3.6 Complaints (%) Chest pain 36 Palpitation 10.7 Murmur 9.3 Syncope 6.7 Other 37.3 Murmur, % (yes/no) 26.7/73.3 SD: Standard deviation; BMI: Body mass index.

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Table 3. Characteristic features of valvular involvement (n=75) Valvular involvement Isolated MR Isolated AI MR+AI Degree of valvular involvement Mild Moderate Severe Types of RHD Borderline Definite

67 2 6

89.3 2.7 8

65 10 0

86.7 13.3 0

45 30

60 40

AI: Aortic insufficiency; MR: Mitral regurgitation.

assessed according to the criteria including morphological valvular changes as determined by the WHF. The presence of mitral stenosis or at least two of the RHD morphological criteria in addition to pathological mitral regurgitation (MR) for the mitral valve was assessed to be sufficient for the definitive diagnosis of rheumatic mitral valve disease. For aortic valve insufficiency, the presence of at least two morphological criteria in the setting of pathological aortic regurgitation (AR) was assessed to be sufficient for the definitive diagnosis of rheumatic AR (Table 1). Data were analyzed using the SPSS 22.0 statistical package program (SPSS Inc., Chicago, IL, USA). The distribution pattern of the data was evaluated by the Shapiro–Wilk test. Qualitative variables were expressed as numbers and percentages. Quantitative variables were expressed as mean±standard deviation for normally distributed data. Descriptive analysis was performed for the clinical findings of the patients, such as age, gender, and clinical features. RESULTS During a 6-year period, RHD was diagnosed echocardiographically in a total of 75 patients who were referred to us for different clinical indications. In only 26.7% of the cases, physical examination detected heart murmurs. It was determined that the patients were mostly girls, and that the most frequent cause of referrals was chest pain. Clinical and demographic characteristics of the patients are given in Table 2. Echocardiographically, mostly pathological isolated MR was detected in patients (89.3%). In any one of the

patients, severe valve insufficiency was not observed. The characteristics of valvular deficiencies in patients are given in Table 3. However, morphological changes accompanying pathological valvular insufficiencies were detected in 30 (40%) patients and diagnosed with definite RHD, while 45 (60%) patients were diagnosed with borderline RHD. There was no difference between the age of diagnosis between patients with definite and borderline RHD. Penicillin prophylaxis was initiated for all patients who met the criteria for borderline or definitive echocardiographic diagnosis. While 44 of the 75 patients were followed up for >1 year, the median follow-up period was determined as 19.7 months. At the end of the follow-up period, echocardiographic improvement was not observed in the majority of the patients, and valvular insufficiency of two cases regressed completely. The findings of valve insufficiency of the patients after the followup period are given in Table 4. At the end of the follow-up period, 88% of the cases remained as borderline RHD at baseline, whereas findings of two cases regressed from definite RHD to borderline RHD, four cases with borderline RHD progressed to definite RHD, and two cases were completely normalized. When the patients progressed to definite RHD were examined, it was determined that the shortest and the longest follow-up periods were 6 and 66 months, respectively. In three of these patients, mitral valve thickening and prolapse of the anterior leaflet were detected by

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Table 4. Follow-up outcomes of the patients

Follow-up period (months) Disappearance of valvular insufficiency Improvement in valvular insufficiency Worsening of valvular insufficiency Unchanged valvular status

19.2±19.7 2 2.7 13 17.3 1 1.3 59 78.7

Expressed as mean±SD.

echocardiography, and pathological aortic insufficiency developed in one patient without prior relevant evidence. None of the patients developed valvular stenosis during follow-up. No patient needed replacement of the valve. DISCUSSION RHD is a major health problem in developing countries and is one of the leading causes of acquired heart disease worldwide [6, 10]. Early recognition of the disease is important because it is known that secondary prophylaxis with penicillin prevents the progression of RHD. In recent years, with the frequent use of echocardiography, diagnosis of subclinical cases and early detection of the disease have been made possible, emphasizing the fact that the frequency of RHD is much more higher than previously thought [8, 11]. It is known that echocardiography is more sensitive than physical examination in detecting mild or asymptomatic RHD [7]. For this reason, the WHF has developed echocardiographic screening programs specifically for use in endemic areas and recently published in 2012 consensus guidelines that allow the standardized definitions of RHD as “definite” or “borderline” in diagnostic echocardiography [9]. These guidelines include Doppler evaluation of mitral and aortic regurgitation along with morphological features that can be caused by RHD in the mitral and aortic valves (Table 1). The echocardiographic findings of cases with asymptomatic and non-ARF, whose information could be accessed during the 6-year period in our study, were evaluated in accordance with the current criteria of the WHF. To our knowledge, the present study is the first study performed in our country that evaluated asymptomatic cases in the pediatric age group according to

the current diagnostic criteria of the WHF. The most common isolated mitral valve involvement is RHD, but isolated aortic valve involvement can be seen in approximately 3%–5% of the patients [12, 13]. In our study, mitral valve was also mostly affected in 75 (89.5%) subclinical cases with RHD consistent with the literature. Isolated aortic valve involvement alone was found in 2.7% of the cases. Although there are no clear echocardiographic criteria for mitral valve prolapse (MVP) in children as in adults, MVP associated with pathological mitral valve insufficiency seen in RHD is well defined in various studies such as valve thickening,excessive movement at the leaflet tip, and restricted leaflet movement [14, 15]. Thus, it has been emphasized in children that irregular focal thickening of the mitral valve, especially the excessive mobility of the anterior leaflet in systole and its prolapse together with the eccentric insufficiency jet accompanying the restricted mobility of the posterior leaflet, should be evaluated in favor of rheumatic etiology [15]. In our study, valvular prolapse accompanied by pathological mitral valve insufficiency was evaluated as rheumatic MVP, and these cases were accepted as definite RHD. According to this, 26 (34.6%) patients were diagnosed with baseline echocardiography, and 3 (4%) patients with rheumatic MVP were detected by followup echocardiography. Although the persistence of valvular insufficiencies in subclinical carditis is often reported in various studies, the natural course of this condition is not yet known [12, 16]. In the RHEUMATIC study, one of the largest case series, 6270 children aged 5–15 years were screened, and subclinical RHD was found during echocardiographic examinations; in 128 patients (especially girls in families with low socioeconomic status) and 4% of these patients, the disease progressed within 3–27 months [17]. Similarly, in a different study by Figureo et al., patients were followed up for 5 years, valvular findings remained the same in 60% of the patients with subclinical carditis [18]. In our study, valvular insufficiency remained the same in 78.7% of the cases, 2.7% the patients were completely healed and in only one patient valvular insufficiency worsened. Taking into consideration the existing studies, conduction of a study with large case series with long-term follow-up results is needed so as to be able knowledgeable about the natural course of the disease. Nevertheless, the pediatric age group gains the most benefit from the secondary protection after early diagno-

Kayali et al., Subclinical rheumatic heart disease: A single center experience

sis of RHD, but typical valve pathologies may not be established due to their young age. For this reason, the definition of “borderline RHD” has been introduced with the current WHF diagnostic criteria, with the aim of increasing the diagnostic sensitivity especially in patients aged ≤20 years. Since our present study includes only pediatric cases, we advocate regular follow-up at certain intervals in cases of borderline RHD in childhood, especially in endemic regions, such as our country, and emphasize the necessity of launching nationwide screening programs for the early detection of these cases. Secondary prevention is absolutely necessary when diagnosing “subclinical definite RHD” using echocardiography. However, it is recommended in patients with borderline RHD in areas where the prevalence of RHD is too high with inadequate access to valve surgery [19]. In our study, secondary prophylaxis with penicillin was initiated in all cases with definite RHD and in patients diagnosed as borderline RHD due to the higher prevalence of RHD in our country, and recurrent episodes of ARF were not observed in any case during follow-up. Limitations of our study include the lack of a screening study, the limited number of patients, and the inadequate length of the follow-up period. As a result, RHD is a health problem that still retains seriousness in our country. The sensitivity of echocardiography in the detection of subclinical, mild, or asymptomatic cases is well known. Detection and follow-up of subclinical cases with RHD owing to the development of echocardiographic screening programs especially in an endemic region similar to our country are necessary to overcome this relevant lack of information. For this reason, although not a routine approach yet, it is important to launch nationwide echocardiographic screening programs. Conflict of Interest: The authors declare no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – S.K., N.B.; Design – S.K., N.B.; Supervision – S.K., N.B.; Materials – S.K., N.B.; Data collection &/or processing – S.K., N.B.; Analysis and/or interpretation – S.K., N.B.; Writing – S.K., N.B.; Critical review – S.K., N.B.

REFERENCES 1. Akalın F. Novelties in acute rheumatic fever. Turk Arch Ped 2007;42:85–93. 2. Ozer S, Hallioğlu O, Ozkutlu S, Celiker A, Alehan D, Karagöz T. Childhood acute rheumatic fever in Ankara, Turkey. Turk J Pediatr 2005;47:120–4. 3. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart dis-

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ease. Lancet 2012;379:953–64. 4. Gewitz MH, Baltimore RS, Tani LY, Sable CA, Shulman ST, Carapetis J, et al.; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young. Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation 2015;131:1806–18. 5. Eroğlu AG. Update on diagnosis of acute rheumatic fever: 2015 Jones criteria. Turk Pediatri Ars 2016;51:1–7. 6. Marijon E, Celermajer DS, Tafflet M, El-Haou S, Jani DN, Ferreira B, et al. Rheumatic heart disease screening by echocardiography: the inadequacy of World Health Organization criteria for optimizing the diagnosis of subclinical disease. Circulation 2009;120:663–8. 7. Mirabel M, Bacquelin R, Tafflet M, Robillard C, Huon B, Corsenac P, et al. Screening for rheumatic heart disease: evaluation of a focused cardiac ultrasound approach. Circ Cardiovasc Imaging 2015;8:pii:e002324. 8. Roberts K, Cannon J, Atkinson D, Brown A, Maguire G, Remenyi B, et al. Echocardiographic Screening for Rheumatic Heart Disease in Indigenous Australian Children: A Cost-Utility Analysis. J Am Heart Assoc 2017;6:pii:e004515. 9. Reményi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, et al. World Heart Federation criteria for echocardiographic diagnosis of rheumatic heart disease -an evidence-based guideline. Nat Rev Cardiol 2012;9:297–309. 10. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM; World Heart Federation. Position statement of the World Heart Federation on the prevention and control of rheumatic heart disease. Nat Rev Cardiol 2013;10:284–92. 11. Saxena A. Increasing detection of rheumatic heart disease with echocardiography. Expert Rev Med Devices 2014;11:491–7. 12. Caldas AM, Terreri MT, Moises VA, Silva CM, Len CA, Carvalho AC, et al. What is the true frequency of carditis in acute rheumatic fever? A prospective clinical and Doppler blind study of 56 children with up to 60 months of follow-up evaluation. Pediatr Cardiol 2008;29:1048–53. 13. Roodpeyma S, Kamali Z, Zare R. Rheumatic fever: the relationship between clinical manifestations and laboratory tests. J Paediatr Child Health 2005;4197–100. 14. Marcus RH, Sareli P, Pocock WA, Barlow JB. The spectrum of severe rheumatic mitral valve disease in a developing country. Correlations among clinical presentation, surgical pathologic findings, and hemodynamic sequelae. Ann Intern Med 1994;120:177–83. 15. Atalay S, Uçar T, Ozçelik N, Ekici F, Tutar E. Echocardiographic evaluation of mitral valve in patients with pure rheumatic mitral regurgitation. Turk J Pediatr 2007;49:148–53. 16. Tubridy-Clark M, Carapetis JR. Subclinical carditis in rheumatic fever: a systematic review. Int J Cardiol 2007;119:54–8. 17. Saxena A, Ramakrishnan S, Roy A, Seth S, Krishnan A, Misra P, et al. Prevalence and outcome of subclinical rheumatic heart disease in India: the RHEUMATIC (Rheumatic Heart Echo Utilisation and Monitoring Actuarial Trends in Indian Children) study. Heart 2011;97:2018– 22. 18. Figueroa FE, Fernández MS, Valdés P, Wilson C, Lanas F, Carrión F, et al. Prospective comparison of clinical and echocardiographic diagnosis of rheumatic carditis: long term follow up of patients with subclinical disease. Heart 2001;85:407–10. 19. Çağlı K, Gölbaşı Z. How to diagnose rheumatic heart disease with echocardiography? Turk Kardiyol Dern Ars 2016;44:440–4.

Orıgınal Article

ORTHOPEDICS & TRAUMATOLOGY

North Clin Istanb 2018;5(4):334–340 doi: 10.14744/nci.2017.65037

Surgical treatment of type III acromioclavicular dislocation: Bosworth technique versus hook plating Seyit Ali Gumustas,1 Ismail Yukunc,5

Fevzi Saglam,2

Baran Komur,3

Haci Bayram Tosun,6

Ahmet Guray Batmaz,4

Halil Ibrahim Bekler7

Department of Orthopaedics and Traumatology, Dr. Lutfi Kirdar Kartal Training and Research Hospital, Istanbul, Turkey

Department of Orthopaedics and Traumatology, Sultanbeyli State Hospital, Istanbul, Turkey

Department of Orthopaedics and Traumatology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey

Department of Orthopaedics and Traumatology, Istanbul Medipol University Faculty of Medicine, Istanbul, Turkey

Department of Orthopaedics and Traumatology, Yavuz Selim Bone disease and Rehabilitation Hospital, Trabzon, Turkey

Department of Orthopaedics and Traumatology, Adiyaman University Faculty of Medicine, Adiyaman, Turkey

Department of Orthopaedics and Traumatology, VM Medical Park Kocaeli Hospital, Kocaeli, Turkey

ABSTRACT OBJECTIVE: In this study, it was compared the clinical results of the Bosworth technique and hook plating in acromioclavicular (AC) dislocations. METHODS: 44 patients are retrospectively evaluated in this study whom diagnosed as type III AC dislocations and treated by two different surgical methods in two different clinics. The patients were 30 males and 14 females with a mean age of 44 years (range, 18–80 years). The patients were divided into 2 groups according to the applied surgical technique. Group I comprised 25 patients to whom coracoclavicular fixation was applied by using the Bosworth technique. Group II comprised 19 patients to whom acromioclavicular fixation was applied by using hook plate. All patients are evaulated by The University of California at Los Angeles Shoulder Score (UCLA) and The disabilities of the arm, shoulder and hand (DASH) scoring system. RESULTS: The mean follow-up period was 23 months (range, 12–42 months). A statistically significant diffference was determined between the surgical groups in respect of the modified UCLA scale (p=0.012) and Quick DASH score (p=0.008). Hook plating group had better clinical results according to Bosworth group in terms of both UCLA and DASH score. A statistically highly significant negative correlation was determined between the UCLA and DASH scores (r=0.677, p=0.000). CONCLUSION: Although hook plating had better clinic outcomes compared to Bosworth technique, there is not seen difference between two groups in terms of the time of return to work. Treatment of the AC dislocation should perform early reconstruction for better reduction, fewer complications and higher levels of patient satisfaction. Keywords: Acromioclavicular dislocation; bosworth technique; fixation; hook plating; results.

Cite this article as: Gumustas SA, Saglam F, Komur B, Batmaz AG, Yukunc I, Tosun HB, et al. Surgical treatment of type III acromioclavicular dislocation: Bosworth technique versus hook plating. North Clin Istanb 2018;5(4):334–340.

s one of the most important joints around the shoulder, injuries to the acromioclavicular joint (AC) are very important, as depending on the degree of injury, they cause restrictions to the daily life of the patient and workforce losses. Although several treatment methods have

been described in literature, it has not been fully clarified which type of treatment is recommended for which type of dislocation [1–6]. The degree of injury and the functional expectations of the patient are the primary indicators. In type III AC joint injuries, there is a severe trauma

Received: November 05, 2017 Accepted: December 29, 2017 Online: December 29, 2017 Correspondence: Dr. Haci Bayram TOSUN. Adiyaman Universitesi Tip Fakultesi, Ortopedi ve Travmatoloji Klinigi, Adiyaman, Turkey.

Gumustas et al., Surgical treatment of type III acromioclavicular dislocation: Bosworth technique versus hook plating

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Table 1. General characteristics of the patients according to the surgical group

Hook

Bosworth

Total

Age 46.05±7.28 40.80±9.09 0.053 43.06±8.67 Gender Female 10 (52.6) 4 (16) 0.01* 14 (31.8) Male 9 (47.4) 21 (84) 30 (68.2) Side Left 4 (21.1) 11 (44) 0.11 15 (34.1) Right 15 (78.9) 14 (56) 29 (65.9) Dominant side Left 2 (10.5) 5 (20) 0.68 7 (15.9) Right 17 (89.5) 20 (80) 37 (84.1) Trauma type Sport 4 (21.1) 6 (24) 10 (22.7) Traffic accident 5 (26.3) 4 (16) 0.70 9 (20.5) Fall 10 (52.6) 15 (60) 25 (56.8) Preoperative period (days) 2.57±1.01 4.32±1.49 0.001* 3.56±1.56 Hospitalization (days) 4.68±1.15 5.36±1.49 0.11 5.06±1.38 Follow-up (months) 20.84±7.04 25.12±9.72 0.16 23.27±8.84 *p<0.05

with joint dislocation from tears of the AC ligament and capsule and tears of the coracoclavicular (CC) ligament. If evaluation is only made radiologically without making a thorough physical examination, there is a high possibility that these types of injuries will be overlooked [2, 6–8]. In radiological comparison with the contralateral side, the CC ligament may be displaced by a distance of between 25%–100% [7, 9]. If adequate treatment is not applied to patients with type III AC injuries, it may be seen undesirable results such as pain, restricted movement of the shoulder joint, weakness around the shoulder, arthrosis in the AC joint, subluxation and re-dislocation, restriction of daily activities and sporting activities of the patient in the future. Therefore, it must be obtained stability of the AC joint without disrupting the movements and strenght of the shoulder in the ideal treatment [7]. In this study, we retrospectively evaluated the clinical results of Bosworth technique and hook plating in acromioclavicular (AC) dislocations. MATERIALS AND METHODS In this study, a retrospective examination was made of a total of 44 patients who were surgically treated for type III acromioclavicular joint dislocation. All patients were

given detailed information about this surgery, and approval was obtained. The patients were 30 males and 14 females with a mean age of 44 years (range, 18–80 years). Group I comprised 25 patients to whom coracoclavicular fixation was applied using malleolar screw in the Bosworth technique [6, 10]. Group II comprised 19 patients to whom acromioclavicular fixation was applied using hook plate with the AO technique [11]. The mechanism of injury was a fall in 25 cases, a sports injury in 10 and a traffic accident in 9. The injury was on the right side in 29 patients and on the left in 15 and the mean time to surgery was 4 days (range, 1–8 days). Exclusion criterias were conservative treatment, concomitant clavicular fractures, chronic cases and those who had less than 1 year of follow-up (Table 1). Postoperative functional evaluation was made using modified The University of California at Los Angeles Shoulder Score (UCLA) scale [12] and The disabilities of the arm, shoulder and hand (Quick DASH) scoring system [13]. In the modified UCLA scale 18–20 points was evaluated as very good, 15–17 points as good, 12– 14 points as fair and <11 points as poor. The patients in group I were operated on under general anaesthesia in the semi-seated position by the same orthopaedic surgeon (SAG). The skin layers over the

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Figure 1. Bosworth technique radiography. clavicle were entered with a parallel incision. After reduction of the AC joint, the clavicle and coracoid were drilled with a 3.2 mm drill. Only the superior cortex of the clavicle was hollowed with a 4.5 mm drill. Fixation was applied with one semi-cannulated spongeous screw (malleolar screw) of appropriate size and a washer (Fig. 1). In 3 patients, as there was a torn or subluxated disc which was preventing reduction of the AC joınt, the disc was excised by extending the incision. It was not applied the CC ligament repair in any patient.

Figure 2. Hook plate technique.

The patients in group II were operated on under general anaesthesia by another orthopaedic surgeon (İY). Entry was made with a straight incision of 5–6 cm starting from the distal of the clavicle and extending to the AC joint. After reduction of the joint by excision of the meniscus, fixation was applied with placement of a hook plate of appropriate size (Fig. 2). Postoperative rehabilition protocols were not applied the same for each groups and patients. A shoulder-arm sling was used the all patients in the both groups for post-

Gumustas et al., Surgical treatment of type III acromioclavicular dislocation: Bosworth technique versus hook plating

operative 3 weeks, but it was allowed to remove the sling 4 or 5 times a day to do pendulum exercises. All patients were referred for physical therapy and passive and active joint range of movement exercises were started. It was not allowed to weight lift any objects over 1–2 pounds and to elevate of operated arm above 90 degrees in any plane for a period of first 6 weeks. However, it was not allowed to elevate of operated arm above 90 degrees in any plane for patients in hook plate groups. The patients applied hook plate in contrast to Bosworth technique are not recommended the arm abduction over 90 degrees till implant removal. After 3 months, activities requiring strength were permitted. Complaints of excessive pain in the shoulder or restricted movement were considered to be due to the implant or insufficient material and after at least 6 months, all of the implants were removed. Statistical analysis of the data was made using SPSS 17.5 statistics software program. In the comparison of categorical variables, the Chi-square test was used. Continuous variables with normal distribution were compared with the T-test and those not with normal distribution with the Mann Whitney U-test. A value of p<0.05 was considered statistically significant.

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Table 2. Comparison of modified UCLA scala in Group I and Group II UCLA Very Good Count % within group Good Count % within group Moderate Count % within group Total Count % within group

Group

Hook Bosworth Total

10 52.6%

7 28.0%

17 38.6%

6 31.6%

16 64.0%

22 50.0%

3 15.8%

2 8.0%

5 11.4%

19 100.0%

25 100.0%

44 100.0%

UCLA: The University of California at Los Angeles Shoulder Score.

Table 3. Comparison between both groups of functional outcomes and time of return to work

RESULTS The mean follow-up period was 23 months (range, 12– 42 months). The general distribution and according to the surgical groups is shown in Table 1. Postoperatively, the mean modified UCLA scale value was 16.6 (range, 14–19), the mean Quick DASH score was 14.5 (range, 2.2–26.8). According to the modified UCLA scale, 17 (38.6%) patients were evaluated as very good, 22 (50.0%) patients as good and 5 (11.4%) patients as moderate (Table 2). No poor results were obtained in any patient. A statistically significant diffference was determined between the surgical groups in respect of the modified UCLA scale (p=0.012) and Quick DASH score (p=0.008). Hook plating group had better clinical results according to Bosworth group in terms of both modified UCLA and DASH score. A statistically highly significant negative correlation was determined between the UCLA and DASH scores (r=0.677, p=0.000) (Table 3). Mean time for return to work of all the patients was 3.3 months (range, 2–6 months). No statistically significant difference was determined between the two groups in respect of the return to work (p=0.58). Removal of the fixation material was applied at mean 4.6 months (4.2 months for Bosworth technique, 5.1 months for Hook plating). At the final physical examination, all patients

UCLA DASH Return to work (month)

Hook plating

Bosworth technique

17.42±1.80 16.12±1.26 0.012* 9.22±8.61 18.58±4.30 0.008* 3.42±1.26 3.24±0.72 0.58

UCLA: The University of California at Los Angeles Shoulder Score; DASH: The disabilities of the arm, shoulder and hand; *p<0.05; A highly significant negative correlation was determined between the UCLA and DASH scores (r=-0.677, p=0.000).

were observed to have full shoulder joint range of movement. During surgery, no complications such as vascular or nerve damage were encountered in any patient. A change in working or sporting activities had to be made in 3 (6.8%) patients. We observe 1 hook plate breaking and 1 superficial wound infection that treated by antibiotherapy. We observe 5 AC arthritis (4 was in hook plate group) and 3 reduction loss (2 in Bosworth group). DISCUSSION In this study, we compared the clinical outcomes of patients who underwent hook plating and Bosworth technique for type III AC dislocation. Hook plating group

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had better clinical results according to Bosworth group in terms of both modified UCLA (p=0.012) and DASH score (p=0.008). No statistically significant difference was determined between both groups in respect of the return to work (p=0.58). At the final physical examination after removal of implant, all patients were observed to have full shoulder joint range of movement. Typically, acromioclavicular injuries result from direct trauma to the shoulder from a fall or in contact sports when the arm is in an adducted position. The force pushes the acromion inferiorly while the clavicle maintains its anatomic position, resulting in a variable disruption of the acromioclavicular and coracoclavicular ligaments [12]. Treatments are based on one of three types of fixation: acromioclavicular, coracoclavicular, and dynamic muscle transfer. These procedures can all be combined with ligament augmentation and/or resection of the distal clavicle [4]. Some authors have advocated conservative treatment in cases of acute Type III dislocations and recommend 2–8 weeks immobilization following reduction in these patients [14, 15]. There are some studies reported that results of conservative treatment were better than those of surgical treatment [16, 17]. However, in young active patients with severe AC displacement of >2 cm, surgical treatment was recommended [6]. Galpin et al. [18] compared the conservative treatment method with surgical treatment using the Bosworth technique. They reported that the results of both techniques were reported to be similar even though there was a slight delay in return to work, sports and activity in the patients of the conservative treatment group [18]. Inadequate treatment results have been reported from conservative treatment characterized by pain, loss of strength and restricted movement in 20% of conservatively-treated patients with difficulties in tolerance and the development of cosmetic problems [6, 7, 15, 19, 20]. Therefore, many authors have advocated surgery in the treatment of acute AC dislocations [5–8]. Previous studies have shown the superiority of surgical treatment according to conservative treatment [14]. The basic aim of surgery is to obtain anatomic reduction and stable fixation. The disadvantages of surgery are the requirement for anaesthesia, the risk of infection and the possibility of degenerative arthritis [7, 20]. Superficial wound site infection following AC joint luxation has been reported in literature at rates of 0%–53% [1–3]. In our study, we carried out surgery for all Type III dislocations and observed one superficial infection whom healing by antibiotherapy.

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When patients with AC dislocation are performed early reconstruction, it will be obtained better reduction, fewer complications and higher levels of patient satisfaction [21]. Weinstein et al. reported that worse results were obtained in cases where a period of more than 3 months had elapsed before surgery [22]. In our study, surgical treatment was applied to patients who presented within 10 days of the trauma and were evaluated as an acute injury. We carried out surgery for acute dislocations when patients applied to us and we exclude the patients whom undergone for late surgery. Fukuda et al. emphasized that it is important the effects on stabilization and clinical outcomes of the ligament repair [23]. Ligament repair with the Bosworth technique is an effective technique in obtaining adequate shoulder functions with ease of application, a low complication rate and low rates of acromioclavicular joint arthritis [2, 3, 24]. The most common complication of surgical treatment is loss of reduction in the joint because of problems such as breakage or loosening of the screw [3, 6, 25]. Bektaser et al. [2] reported that it is seen recurrence of dislocation in only 8.8% of patients treated with the modified Bosworth technique [2]. Although it has been reported that there may be mild pain and discomfort in the follow-up of cases with subluxation, the results of most of these cases have been good, and no relationship has been determined between the amount of subluxation and the outcome [3, 26]. In our study, we didn’t apply coracoclavicular ligament repair to any patient. We observed reduction loss in 2 patients who was performed Bosworth technique. For this reason, we think ligaments repair is important at stability and re-dislocation. The rates of arthritis in the Bosworth technique are extremely low [3], but AC arthritis has been reported to be seen more often in cases where reduction could not be achieved [27]. Taft et al. [19] reported that in patients where anatomic reduction could not be achieved, although degenerative changes are generally seen radiographically, insufficient anatomic restoration did not effect the clinical results or patient satisfaction [19]. In our study, as there were complaints of excessive pain in one patients who developed arthritis following the Bosworth procedure, the material was removed. At 3 months postoperatively, the complaints of these patients were seen to have completely recovered. We observed AC arthritis in five patients but we did not perform acromioplasty to any patient. A limitation of the modified Bosworth technique is

Gumustas et al., Surgical treatment of type III acromioclavicular dislocation: Bosworth technique versus hook plating

the need for a second intervention to remove the screw [28]. A good balance must be struck between early removal of the screw to prevent breakage and the risk of deformity developing again. Otherwise, the recurrence of deformity may see at the high rate of 35% in literature (3/3). It is usually recommended that the screw is removed in the 8th week [6]. In our study, the screw was removed after the 3rd month (3–7 months). The hook-plate is a useful device for the treatment of unstable injuries in the acromioclavicular region. Although the main concern in the application of hook plate is subacromial impingement, good results have been obtained in many studies without this complication [29]. Koukakis et al. [30] suggested that extraction of the osteosynthetic material within 3 months because of the possibility of subacromial impingement. In our study, the plate was removed in one patient with pain due to the development of AC arthritis after hook plating, and the complaints were seen to recover. Biomechanical complications can be observed in both techniques. Kienast et al. [31] reported that it was developed complications in 24 (10.6%) of 225 patients, and the most common complication was reported to be redislocation after removal of the hook plate. Baets et al. [11] reported that despite AC joint changes and an increased CC distance compared to the healthy side, excellent and good clinical results after surgery were obtained. The clinical results of their study were reported to be better than the radiological results. Kezunović et al. [5] have compared these two techniques in 28 patients with AC dislocation. They reported that postoperative complications were seen in 8 of the 16 patients in the Bosworth group and seen in only 2 of the 12 patients in hook plate group, but it was not statistically significant difference. However, the patient satisfaction and Constant scores of the hook plate group were determined to be statistically significantly high. Broos et al. [27] reported that it was no statistically significant difference between the Bosworth technique and hook plating in a long-term study of 87 patients with AC dislocation. In their study, high complication rates (16% implant failure, 25% redislocation, 39% calcification, 41% arthritis) and low success rates (60% very good and good results) were obtained. In our study, better functional results were obtained in the hook plate group without additional soft tissue interventions. Previous studies have been generally recommended the application of a shoulder-arm sling for 1–4 weeks,

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but early functional motion is important and must avoid from limitations of shoulder motion [1, 3, 24]. In our study, a shoulder-arm sling was routinely applied for a period of 3 weeks postoperatively. During this period, shoulder pendulum exercises and wrist and elbow active exercises were permitted. Limitations of this study are lack of long-term results and there is no control group of conservative. Also, the groups were not randomised and the design of the study was retrospective. In conclusion, although hook plating had better clinic outcomes compared to Bosworth technique, there is no statistically significant difference between two groups in terms of the time of return to work. Treatment of the AC dislocation should perform early reconstruction for better reduction, fewer complications and higher levels of patient satisfaction. A good balance should be struck between the time of removal of the implants to prevent breakage of implant and recurrence of deformity. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – S.A.G., I.Y.; Design – S.A.G., I.Y.; Supervision – S.A.G., I.Y.; Materials – S.A.G., F.S., B.K., A.G.B., I.Y.; Data collection &/or processing – S.A.G., F.S., B.K., A.G.B., I.Y.; Analysis and/or interpretation – S.A.G., B.K., I.Y., H.B.T.; Writing – S.A.G., F.S., B.K., A.G.B., H.B.T.; Critical review – S.A.G., F.S., I.Y., H.B.T.

REFERENCES 1. Mardani-Kivi M, Mirbolook A, Salariyeh M, Hashemi-Motlagh K, Saheb-Ekhtiari K. The comparison of Ethibond sutures and semitendinosus autograft in the surgical treatment of acromioclavicular dislocation. Acta Orthop Traumatol Turc 2013;47:307–10. 2. Bektaşer B, Bozkurt M, Oçgüder A, Solak S, Oğuz T. Surgical treatment of type III acromioclavicular joint dislocations by a modified Bosworth technique. Ulus Travma Acil Cerrahi Derg 2004;10:245–9. 3. Esenyel CZ, Oztürk K, Bülbül M, Ayanoğlu S, Ceylan HH. Coracoclavicular ligament repair and screw fixation in acromioclavicular dislocations. Acta Orthop Traumatol Turc 2010;44:194–8. 4. Basyoni Y, El-Ganainy AE, Aboul-Saad M. Acromioclavicular joint reconstruction using anchor sutures: surgical technique and preliminary results. Acta Orthop Belg 2010;76:307–11. 5. Kezunović M, Bjelica D, Popović S. Comparative study of surgical treatment of acromioclavicular luxation. Vojnosanit Pregl 2013;70:292–7. 6. Bannister GC, Wallace WA, Stableforth PG, Hutson MA. The management of acute acromioclavicular dislocation. A randomised prospective controlled trial. J Bone Joint Surg Br 1989;71:848–50. 7. Kaplan H, Kiral A, Kuskucu M, Arpacioglu MO, Sarioglu A, Rodop O. Report of eight cases of humeral fracture following the throwing of

340 hand grenades. Arch Orthop Trauma Surg 1998;117:50–2. 8. Li X, Ma R, Bedi A, Dines DM, Altchek DW, Dines JS. Management of acromioclavicular joint injuries. J Bone Joint Surg Am 2014;96:73– 84. 9. Rockwood CA Jr. Injuries to the acromioclavicular joint. In: Rockwood CA Jr, Green DP. Fractures in adults. Vol 1. 2nd ed. Philadelphia: JB Lippincott; 1984. p 860–910. 10. Bosworth BM. Acromioclavicular separation: New method of repair. Surg Gynecol Obstet 1941;73:866–71. 11. De Baets T, Truijen J, Driesen R, Pittevils T. The treatment of acromioclavicular joint dislocation Tossy grade III with a clavicle hook plate. Acta Orthop Belg 2004;70:515–9. 12. Algarín JR, Salcedo JD, Rodríguez JO, Bello AG, Sancho FB. Grade III acromioclavicular dislocation treated with a minimally invasive approach. [Article in Spanish]. Acta Ortop Mex 2010;24:317–23. 13. Gummesson C, Ward MM, Atroshi I. The shortened disabilities of the arm, shoulder and hand questionnaire (QuickDASH): validity and reliability based on responses within the full-length DASH. BMC Musculoskelet Disord 2006;7:44. 14. Darrow JC Jr, Smith JA, Lockwood RC. A new conservative method for treatment of Type III acromioclavicular separations. Orthop Clin North Am 1980;11:727–33. 15. Schlegel TF, Burks RT, Marcus RL, Dunn HK. A prospective evaluation of untreated acute grade III acromioclavicular separations. Am J Sports Med 2001;29:699–703. 16. Glick JM, Milburn LJ, Haggerty JF, Nishimoto D. Dislocated acromioclavicular joint: follow-up study of 35 unreduced acromioclavicular dislocations. Am J Sports Med 1977;5:264–70. 17. Dias JJ, Steingold RF, Richardson RA, Tesfayohannes B, Gregg PJ. The conservative treatment of acromioclavicular dislocation. Review after five years. J Bone Joint Surg Br 1987;69:719–22. 18. Galpin RD, Hawkins RJ, Grainger RW. A comparative analysis of operative versus nonoperative treatment of grade III acromioclavicular separations. Clin Orthop Relat Res 1985:150–5. 19. Taft TN, Wilson FC, Oglesby JW. Dislocation of the acromioclavicular joint. An end-result study. J Bone Joint Surg Am 1987;69:1045–51. 20. Lancaster S, Horowitz M, Alonso J. Complete acromioclavicular separations. A comparison of operative methods. Clin Orthop Relat Res

North Clin Istanb 1987:80–8. 21. Rolf O, Hann von Weyhern A, Ewers A, Boehm TD, Gohlke F. Acromioclavicular dislocation Rockwood III-V: results of early versus delayed surgical treatment. Arch Orthop Trauma Surg 2008;128:1153–7. 22. Weinstein DM, McCann PD, McIlveen SJ, Flatow EL, Bigliani LU. Surgical treatment of complete acromioclavicular dislocations. Am J Sports Med 1995;23:324–31. 23. Fukuda K, Craig EV, An KN, Cofield RH, Chao EY. Biomechanical study of the ligamentous system of the acromioclavicular joint. J Bone Joint Surg Am 1986;68:434–40. 24. Weitzman G. Treatment of acute acromioclavicular joint dislocation by a modified Bosworth method. Report on twenty-four cases. J Bone Joint Surg Am 1967;49:1167–78. 25. Pavlik A, Csépai D, Hidas P. Surgical treatment of chronic acromioclavicular joint dislocation by modified Weaver-Dunn procedure. Knee Surg Sports Traumatol Arthrosc 2001;9:307–12. 26. Graupe F, Dauer U, Eyssel M. Late results of surgical treatment of Tossy III acromioclavicular joint separation with the Balser plate. [Article in German]. Unfallchirurg 1995;98:422–6. 27. Broos P, Stoffelen D, Van de Sijpe K, Fourneau I. Surgical management of complete Tossy III acromioclavicular joint dislocation with the Bosworth screw or the Wolter plate. A critical evaluation. [Article in German]. Unfallchirurgie 1997;23:153–9. 28. Law KY, Yung SH, Ho PY, Chang HT, Chan KM. Coracoclavicular ligament reconstruction using a gracilis tendon graft for acute type-III acromioclavicular dislocation. J Orthop Surg (Hong Kong) 2007;15:315–8. 29. Faraj AA, Ketzer B. The use of a hook-plate in the management of acromioclavicular injuries. Report of ten cases. Acta Orthop Belg 2001;67:448–51. 30. Koukakis A, Manouras A, Apostolou CD, Lagoudianakis E, Papadima A, Triantafillou C, et al. Results using the AO hook plate for dislocations of the acromioclavicular joint. Expert Rev Med Devices 2008;5:567–72. 31. Kienast B, Thietje R, Queitsch C, Gille J, Schulz AP, Meiners J. Mid-term results after operative treatment of rockwood grade III-V acromioclavicular joint dislocations with an AC-hook-plate. Eur J Med Res 2011;16:52–6.

Orıgınal Article

PT&R

North Clin Istanb 2018;5(4):341–347 doi: 10.14744/nci.2017.09581

Vitamin D status of children with cerebral palsy: Should vitamin D levels be checked in children with cerebral palsy? Pinar Akpinar Department of Physical Medicine and Rehabilitation, University of Health Science Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: We aimed to investigate the vitamin D status of children with cerebral palsy (CP). METHODS: A total of 274 children (111 females and 163 males), aged between 1 and 19 years with CP, who came to the Physical Medicine and Rehabilitation, Pediatric Rehabilitation Outpatient Clinic between October 2013 and March 2017, were included in our study. Demographics, data concerning the details of each child’s comorbidity, the Gross Motor Function Classification System (GMFCS), and Manual Ability Classification System (MACS) scores were recorded. The serum 25 hydroxy vitamin D [25(OH)D], calcium (Ca), phosphate (P), and parathormone (PTH) levels were also recorded. RESULTS: The mean age of children with CP was 7.59±6.09 years. The distribution by the CP type was 24.8% spastic unilateral, 59.8% spastic bilateral, 1.4% dyskinetic, 0.7% ataxic, 7.6% mixed, and 5.1% unclassified. The serum 25(OH) D levels of the 235 children with CP were measured. There were 79 children at the 25(OH)D level ≤12 ng/ml, regarded as vitamin D deficiency; 62 children at the 25(OH)D level 12-≤20 ng/ml, considered as vitamin D insufficiency, 43 children at the 25(OH)D level 20-≤30 ng/ml, considered as vitamin D sufficiency, and 15 children at the 25(OH)D level >30 ng/ml. A total of 36 children were already taking vitamin D supplements. There was a significant correlation between the 25(OH)D levels and GMFCS and MACS levels and associated impairments such as the epilepsy history, intellectual delay, teeth problems, and growth retardation (p<0.05). CONCLUSION: Our results revealed that the children with CP who are not ambulatory (GMFCS levels IV–V) and have associated impairments were prone to vitamin D deficiency, and thus should be checked for vitamin D. Keywords: Anti-epileptics; cerebral palsy; gross motor function classification system; vitamin D.

Cite this article as: Akpinar P. Vitamin D status of children with cerebral palsy: Should vitamin D levels be checked in children with cerebral palsy? North Clin Istanb 2018;5(4):341–347.

erebral palsy (CP) refers to a group of disorders in the development of motor and posture, occurring as a result of a non-progressive impairment of the brain, and it can have a wide range of consequences for the child. Various manifestations of the impaired brain may appear more significant in different children or at different life periods, for example, some aspects of the motor

impairment, sensory loss, intellectual disability, epilepsy, musculoskeletal dysfunction, and many others may be more prominent at different stages of the life of a child with CP [1]. Children with CP present as a heterogeneous population and often have associative and co-mitigating conditions that also impose additional challenges. There are

Received: December 05, 2017 Accepted: December 14, 2017 Online: August 08, 2018 Correspondence: Dr. Pinar AKPINAR. Fatih Sultan Mehmet Egitim ve Arastirma Hastanesi, Fiziksel Tip ve Rehabilitasyon Klinigi, H Blok, Atasehir, Istanbul, Turkey. Tel: +90 216 578 30 00 - 3439 e-mail: pinar.pinarakpinar@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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also many potential variables that may affect their growth and development of the bony skeleton. Children with CP can be prone to low bone mineral density (BMD) for several reasons, such as poor nutritional status, vitamin D deficiency, non-ambulation, reduced weight-bearing activity, anti-epileptic drug (AED) intake, and pubertal delay [2]. Vitamin D deficiency is one of the important causes of low BMD in children with CP. Children with CP have inadequate dietary intake of calcium and vitamin D, due to feeding problems. They are usually housebound and have poor sunlight exposure. Epilepsy frequently coexists with CP, and many studies reported that the AED use contribute to low vitamin D status [3–6]. Adequate vitamin D levels are essential for normal skeletal system development and mineralization. There isn’t enough scientific evidence on the prevalence and severity of the vitamin D deficiency in children with CP. We aimed to investigate the vitamin D status of children with CP and also its relation with the functional level and associated impairments. MATERIALS AND METHODS In this retrospective study, 274 children (111 females and 163 males), aged between 1 and 19 years with CP, who applied to the Physical Medicine and Rehabilitation, Pediatric Rehabilitation Outpatient Clinic between October 2013 and March 2017, were included. Demographics, data concerning the details of each patient’s comorbidity, Gross Motor Function Classification System (GMFCS), and Manual Ability Classification System (MACS) scores were recorded. The serum 25-hydroxy-vitamin D [25(OH)D], calcium (Ca), phosphate (P), and parathormone (PTH) levels during autumn, winter, and beginning of the spring (from October until the end of March) were recorded. Children whose serum 25(OH)D levels were measured during summer were not included. For the biochemical analysis, 10-hour fasting blood samples were collected in the morning using a vacutainer system (Becton–Dickinson, NJ, USA). The samples were then centrifuged for 10 minutes at 3000 rpm and further analyzed for biochemical parameters (Ca and P) using the Abbott Architect C16000 model autoanalyzer (Abbott Laboratories, Abbott Park, IL, USA). The PTH and 25(OH)D measurements were performed by the chemiluminescent microparticle immunoassay method using the ARCHITECT system brand kits on

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the Abbott brand i2000SR immunological analyzer. The serum 25(OH)D levels were considered deficient if 25(OH)D was ≤12 ng/ml, insufficient if 25(OH) D was in the range of 12–20 ng/ml, and sufficient if 25(OH)D was in the range of 20≤30 ng/ml [7]. The GMFCS-E&R is a widely used method for classifying the movement ability of children with cerebral palsy. It consists of 5 levels; Level I indicates independent mobility, and Level V indicates full dependency. The questionnaire is available for four different age groups: 2 to <4 years, 4 to <6 years, 6 to <12 years, and 12 to 18 years [8]. The Turkish version of the expanded and revised GMFCS was translated by Kerem-Gunel et al., and reliability was demonstrated by El et al. [9, 10]. The MACS was developed to describe how children with CP aged between 4 to 18 years use their hands when handling objects in daily activities [11]. Later on, the Mini-MACS for children with CP aged between 1 to 4 years was created by making adjustments to the MACS [12]. The MACS is a five-level system, where Level I represents the best manual ability, and Level V indicates that the child does not use his or her hands for functional purposes. Adaptation of the MACS to Turkish children with CP was done by Akpinar et al. [13]. Turkish versions of the MACS and the Mini-MACS can be found at www.macs.nu. This study was approved by the Institutional Ethics Committee, and informed consent was obtained from the parents of each child (Approval number: 2017/6). Statistical analysis Statistical analyses were performed using the IBM SPSS Statistics 22 software package (IBM Turk Limited Company, Istanbul, Turkey). The Shapiro–Wilk test was used to check whether the data were normally distributed. The chi-square test and Fisher Freeman Halton test were used for comparison of qualitative data, and Continuity (Yates) correction was used to determine the group causing the difference. A p-value of <0.05 was considered statistically significant. RESULTS The mean age of 274 children with CP was 7.59±6.09 years. The distribution by the CP type was 24.8% spastic unilateral, 59.8% spastic bilateral, 1.4% dyskinetic, 0.7% ataxic, 7.6% mixed, and 5.1% unclassified. One hundred ninety-six (71.5%) children with CP were ambulatory

Akpinar, Vitamin D status of children with cerebral palsy

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Table 1. Descriptive data of children (Types of CP and as-

Table 2. Serum 25(OH)D, PTH, Ca, and p levels

sociated impairments)

Types of CP Spastic unilateral (hemiplegic) CP Spastic bilateral Diplegic CP Quadriplegic CP Triplegic CP Dyskinetic CP Ataxic CP Mixed CP Unclassified CP Associated impairments Epilepsy Intellectual delay Hearing impairment Visual impairment Strabismus Growth retardation Behavioral problems Respiratory dysfunction Dysphagia Drooling Teeth problems Metabolic disorders

n=235

61 142 89 25 28 3 0 16 11

25.95 60.42

95 96 12 59 83 81 35 28 36 45 45 8

40.4 40.9 5.1 25.1 35.3 34.5 14.9 11.9 15.3 19.1 19.1 3.4

1.27 0.0 6.80 4.68

CP: Cerebral palsy; n: Number.

25(OH)D (ng/ml) (n=235) ≤12 >12 – ≤20 >20 – ≤30 >30 Taking already Ca (mg/dl) (n=83) Low Normal High P (mg/dl) (n=28) Low Normal High PTH (pg/ml) (n=50) Low Normal High

79 62 43 15 36

33.6 26.4 18.3 6.4 15.3

2 80 1

2.4 96.4 1.2

1 27 0

3.6 96.4 0

1 41 8

2.0 82.0 16.0

25(OH)D: 25-hydroxy-vitamin D; PTH: Parathormone; Ca: Calcium; P: Phosphor; n: Number.

Table 3. The GMFCS and MACS levels

(GMFCS Levels I–III), and 78 (28.5%) children were non-ambulatory (GMFCS Levels IV–V). The serum 25(OH)D levels of the 235 children with CP were recorded. The types of CP and associated impairments of these 235 children are shown at Table 1. There were 79 children at the 25(OH)D level ≤12 ng/ ml regarded as vitamin D deficiency, 62 children at the 25(OH)D level 12-≤20 ng/ml regarded as vitamin D insufficiency, 43 children at the 25(OH)D level 20-≤30 ng/ml regarded as vitamin D sufficient, and 15 children at the 25(OH)D level >30 ng/ml. Thirty-six children were already taking vitamin D supplements. The serum 25(OH)D, PTH, Ca, and P levels are shown in Table 2. The GMFCS and MACS levels are shown in Table 3. There was a significant correlation between the 25(OH) D levels and the GMFCS and MACS levels (p<0.05) (Table 4). Non-ambulatory children with CP had lower 25(OH)D levels than the ambulatory children. Chil-

GMFCS level I II III IV V MACS level I II III IV V

n=235

31 59 79 39 27

13.2 25.1 33.6 16.6 11.5

53 85 41 33 23

22.6 36.2 17.4 14 9.8

GMFCS: Gross motor function classification system; MACS: Manual ability classification system; n: Number.

dren who were at the MACS Levels I and III had higher serum 25(OH)D levels than the children who were at the MACS Levels IV and V. Children who have been already

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Table 4. Correlation between the 25(OH)D levels and GMFCS and MACS levels 25(OH)D (ng/ml)

≤12

12 – ≤20

>20

Taking already

n % n % n % n %

GMFCS level I 9 29 13 41.9 8 25.8 1 3.2 II 10 16.9 22 37.3 17 28.8 10 16.9 III 29 36.7 16 20.3 22 27.8 12 15.2 IV 18 46.2 9 23.1 8 20.5 4 10.3 V 13 48.1 2 7.4 3 11.1 9 33.3 p 0.002* Ambulatory (GMFCS I, II, III) 48 28.4 51 30.2 47 27.8 23 13.6 Non-ambulatory (GMFCS IV, V) 31 47 11 16.7 11 16.7 13 19.7 p 0.009* MACS level I 14 26.4 14 26.4 20 37.7 5 9.4 II 28 32.9 29 34.1 15 17.6 13 15.3 III 12 29.3 12 29.3 13 31.7 4 9.8 IV 14 42.4 4 12.1 8 24.2 7 21.2 V 5 47.8 3 13 2 8.7 7 30.4 p 0.002* *p<0.05; GMFCS: Gross motor function classification system; MACS: Manual ability classification system; 25(OH)D: 25-hydroxy-vitamin D; n: Number.

taking vitamin D were mostly at the MACS Level V. There wasn’t any correlation between the 25(OH) D levels and the CP types, except children classified as spastic bilateral CP had significantly lower vitamin D levels than the children classified as spastic unilateral CP (p<0.05). Table 5 shows significant relations between the 25(OH)D levels and the associated impairments. There was a significant correlation between the 25(OH)D levels and AED use. Children who used AEDs also had lower 25(OH)D levels than the children who did not use AEDs. Children who had intellectual delay, teeth problems, and growth retardation had lower 25(OH)D levels than the children who didn’t have intellectual delay, teeth problems, and growth retardation. Nine children with CP had a history of previous fracture. Six of the 9 children had vitamin D deficiency, 2 had vitamin D insufficiency, and 1 have already been taking vitamin D. Five of the 9 children had an epilepsy history. Five children were ambulatory, and 4 children were non-ambulatory.

DISCUSSION In this study, we investigated the vitamin D status of children with CP and its relation to the functional level and associated impairments to find an answer to the question if the investigation of vitamin D levels is necessary in this population. In our study population, 33.6% of the 235 children with CP were vitamin D deficient. Our results demonstrated that children with CP who were not ambulatory and had associated impairments such as epilepsy history, intellectual delay, teeth problems, and growth retardation were prone to vitamin D deficiency. This is in agreement with earlier studies, which revealed that non-ambulation and the AED use affect vitamin D levels [2, 3, 14]. Vitamin D deficiency is an increasing public health concern among individuals of all ages. The endocrine society recommends that children and adults at high risk of vitamin D deficiency, with factors or conditions that reduce the synthesis or intake of vitamin D, were candidates for preventative vitamin D supplementation [7].

Akpinar, Vitamin D status of children with cerebral palsy

345

Table 5. Correlation between the 25(OH)D levels and associated impairments 25(OH)D (ng/ml)

≤12

12 – ≤20

>20

Taking already

n % n % n % n %

Epilepsy (+) 45 47.4 26 27.4 6 6.3 18 18.9 (-) 34 24.3 36 25.7 52 37.1 18 12.9 p 0.001* Intellectual delay (+) 45 46.9 23 24 16 16.7 12 12.5 (-) 34 47.4 39 28.1 42 30.2 24 17.3 p 0.003* Growth retardation (+) 30 37 12 14.8 19 23.5 20 24.7 (-) 49 31.8 50 32.5 39 25.3 16 10.4 p 0.003* Teeth problems (+) 24 53.3 15 33.3 4 8.9 2 4.4 (-) 55 28.9 47 24.7 54 28.4 34 17.9 p 0.001* *p<0.05; 25(OH)D: 25-hydroxy-vitamin D; n: Number.

Neuromuscular conditions like CP may put an individual at higher calcium and vitamin D deficiency, as well as under-nutrition in general [4]. Thus, investigation of vitamin D status and addition of vitamin D supplements may be necessary in children with CP. For children with CP, skeletal maturation can be delayed or accelerated as a result of multiple factors that affect the onset of puberty, including hormonal imbalance, nutrition, and severity of impairment. Feeding problems due to swallowing difficulty, impaired control of the lips and tongue, dental problems, malabsorption syndromes, and hepatic, renal, and endocrine disorders may contribute to growth retardation and impaired skeletal development. Adequate vitamin D levels are essential for normal skeletal development and mineralization. In our study, children who had intellectual delay, teeth problems, and growth retardation had significantly lower 25(OH)D levels than the children who didn’t have intellectual delay, teeth problems, and growth retardation. Moreover, 29 of the 36 children who were already taking vitamin D supplements had dysphagia and teeth problems. Individuals with disabilities that limit mobility like

CP are often housebound and have reduced sunlight exposure. Thus, they are prone to low serum vitamin D concentrations [15]. The sun exposure is known to be a strong determinant of vitamin D status: More than 90% of people’s vitamin D requirement comes from casual exposure to sunlight [16]. In non-ambulatory patients with CP, the sunlight exposure is expected to be limited. In our study population, non-ambulatory children with CP had lower 25(OH)D levels than the ambulatory children with CP, which is parallel with the literature [3]. In addition, children with CP are already at an increased risk of developing symptomatic osteoporosis because of decreased weight bearing. Low vitamin D levels in children with CP are also associated with muscle weakness and with hypovitaminosis D myopathy, characterized by decreased muscle strength and balance, muscle pain, paresthesias, and poor muscular coordination [15, 17]. Vitamin D also plays a role in host defense, and hypovitaminosis D may predispose to infections [18]. Therefore, sufficient vitamin D supplementation may have significant health benefits. Furthermore, the AED intake can contribute to re-

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duced serum vitamin D concentrations. Vitamin D deficiency is common in children who use AEDs. The AEDs commonly reported to affect vitamin D levels and bone health are the inducers of cytochrome P450 enzyme: carbamazepine, phenytoin, phenobarbitone, and primidone. However, studies have found that even valproic acid, a P450 enzyme inhibitor, affects vitamin D levels apart from accelerating bone loss by activating the osteoclasts directly [3, 19]. Nettekoven et al. demonstrated vitamin D deficiency in 75% of children taking AEDs, and this deficiency was most pronounced in patients taking combinations of different AEDs [6]. In our study population, 40.4% of the 235 children with CP were applied AED, and 47.4% of them were vitamin D deficient. We found a significant correlation between the 25(OH)D levels and the AED use in line with the literature [3, 4]. Unfortunately, we didn’t report the types of AEDs used in our study. Another limitation of our study is that the serum PTH, Ca, and P levels were not measured for all children. We referred the children who had abnormal serum PTH, Ca, and P levels to the pediatric endocrinologist. Clarke and Page suggested prevention of fractures through the use of vitamin D supplementation in children with CP. They pointed out that the pathological fractures in this group of patients can be extremely difficult to treat conservatively or surgically [20]. The prophylactic use of vitamin D dramatically reduced the rate of pathological fractures in children with CP [21]. Only 9 patients had a history of previous fracture in our study population, but 6 of the 9 children had vitamin D deficiency, 2 had vitamin D insufficiency, and 1 has already been taking vitamin D. Although normal bone growth probably cannot be expected, facilitating bone development and reducing the fracture incidence is critical to ensure the optimal quality of life for these children. Clinical researches involving children with CP tend to focus on common symptoms, such as spasticity, pain, and mobility issues, and the viability and effectiveness of respective medical interventions. There has been very little attention on bone health in children with CP. Most clinicians who treat children with CP do not check vitamin D levels on a consistent basis. Our study showed that children with CP who are not ambulatory and have associated impairments such as epilepsy history, intellectual delay, teeth problems, and growth retardation should be checked for vitamin D deficiency. Prospective research is needed to determine the appropriate timing and dosing of vitamin D in children with CP.

North Clin Istanb

Conclusion Investigation of the vitamin D status and addition of vitamin D supplements may be necessary in children with CP, especially those who are not ambulatory and have associated impairments, such as an epilepsy history, intellectual delay, teeth problems, and growth retardation to maintain a good health. Acknowledgements: The author thanks all the children and their families who participated in this study for their contribution. Conflict of Interest: The author declares that there is no conflict of interest and no sources of financial assistance. Financial Disclosure: The author declared that this study has received no financial support.

REFERENCES 1. Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, et al. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl 2007;109:8–14. 2. Ozel S, Switzer L, Macintosh A, Fehlings D. Informing evidence-based clinical practice guidelines for children with cerebral palsy at risk of osteoporosis: an update. Dev Med Child Neurol 2016;58:918–23. 3. Seth A, Aneja S, Singh R, Majumdar R, Sharma N, Gopinath M. Effect of impaired ambulation and anti-epileptic drug intake on vitamin D status of children with cerebral palsy. Paediatr Int Child Health 2017;37:193–98. 4. Aronson E, Stevenson SB. Bone health in children with cerebral palsy and epilepsy. J Pediatr Health Care 2012;26:193–9. 5. Souverein PC, Webb DJ, Weil JG, Van Staa TP, Egberts AC. Use of antiepileptic drugs and risk of fractures: case-control study among patients with epilepsy. Neurology 2006;66:1318–24. 6. Nettekoven S, Ströhle A, Trunz B, Wolters M, Hoffmann S, Horn R, et al. Effects of antiepileptic drug therapy on vitamin D status and biochemical markers of bone turnover in children with epilepsy. Eur J Pediatr 2008;167:1369–77. 7. Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, et al. Global Consensus Recommendations on Prevention and Management of Nutritional Rickets. J Clin Endocrinol Metab 2016;101:394–415. 8. Palisano RJ, Rosenbaum P, Bartlett D, Livingston MH. Content validity of the expanded and revised Gross Motor Function Classification System. Dev Med Child Neurol 2008;50:744–50. 9. Gunel MK, Mutlu A, Tarsuslu T, Livanelioglu A. Relationship among the Manual Ability Classification System (MACS), the Gross Motor Function Classification System (GMFCS), and the functional status (WeeFIM) in children with spastic cerebral palsy. Eur J Pediatr 2009;168:477–85. 10. El O, Baydar M, Berk H, Peker O, Koşay C, Demiral Y. Interobserver reliability of the Turkish version of the expanded and revised gross motor function classification system. Disabil Rehabil 2012;34:1030–3. 11. Eliasson AC, Krumlinde-Sundholm L, Rösblad B, Beckung E, Arner M, Ohrvall AM, et al. The Manual Ability Classification System (MACS) for children with cerebral palsy: scale development and evidence of validity and reliability. Dev Med Child Neurol 2006;48:549–54.

Akpinar, Vitamin D status of children with cerebral palsy

12. Eliasson AC, Ullenhag A, Wahlström U, Krumlinde-Sundholm L. Mini-MACS: development of the Manual Ability Classification System for children younger than 4 years of age with signs of cerebral palsy. Dev Med Child Neurol 2017;59:72–78. 13. Akpinar P, Tezel CG, Eliasson AC, Icagasioglu A. Reliability and crosscultural validation of the Turkish version of Manual Ability Classification System (MACS) for children with cerebral palsy. Disabil Rehabil 2010;32:1910–6. 14. Baer MT, Kozlowski BW, Blyler EM, Trahms CM, Taylor ML, Hogan MP. Vitamin D, calcium, and bone status in children with developmental delay in relation to anticonvulsant use and ambulatory status. Am J Clin Nutr 1997;65:1042–51. 15. Kilpinen-Loisa P, Nenonen H, Pihko H, Mäkitie O. High-dose vitamin D supplementation in children with cerebral palsy or neuromuscular disorder. Neuropediatrics 2007;38:167–72. 16. Stamp TC, Haddad JG, Twigg CA. Comparison of oral 25-hydroxyc-

347 holecalciferol, vitamin D, and ultraviolet light as determinants of circulating 25-hydroxyvitamin D. Lancet 1977;1:1341–3. 17. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, Staehelin HB, Bazemore MG, Zee RY, et al. Effect of Vitamin D on falls: a meta-analysis. JAMA 2004;291:1999–2006. 18. Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 2004;80:6 Suppl:1717S–20S. 19. Sato Y, Kondo I, Ishida S, Motooka H, Takayama K, Tomita Y, et al. Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 2001;57:445–9. 20. Clarke NM, Page JE. Vitamin D deficiency: a paediatric orthopaedic perspective. Curr Opin Pediatr 2012;24:46–9. 21. Shellhaas RA, Barks AK, Joshi SM. Prevalence and risk factors for vitamin D insufficiency among children with epilepsy. Pediatr Neurol 2010;42:422–6.

Orıgınal Article

PT&R

North Clin Istanb 2018;5(4):348–352 doi: 10.14744/nci.2017.77992

Daytime sleepiness, functionality, and stress levels in chronic neck pain and effects of physical medicine and rehabilitation therapies on these situations Selcuk Sayilir Department of Physical Medicine and Rehabilitation, Mugla Sitki Kocman University Faculty of Medicine, Mugla, Turkey

ABSTRACT OBJECTIVE: To evaluate the relationship between symptom severity, daytime sleepiness, and perceived stress levels and the impact of physical medicine & rehabilitation (PMR) therapies on these situations in chronic neck pain (CNP) conditions. METHODS: The study included 54 patients with CNP and 20 healthy control individuals. Patients with CNP were divided into two groups: the PMR therapy group (n=34) and the CNP control group (n=20). The PMR therapy programs of the patients included TENS, hot packs, therapeutic ultrasound, and exercises. Visual analog scale (VAS) at activity and resting for neck pain, Neck Disability Index (NDI), Perceived Stress Scale (PSS), Epworth Sleepiness Scale, chin-manubrium distances (CMD), and tragus-wall distances (TWD) values were evaluated before and after the treatment programs. RESULTS: Significant differences were found between the CNP patients and healthy controls regarding PSS, TWD, and CMD values. Furthermore, significant differences were detected between the PMR group and the CNP control group in the final evaluation of the VASresting, VASactivity, PSS, and NDI levels. CONCLUSION: Evaluation of CNP from a single point of view can leave clinically missing points. Patients with CNP should be assessed for daytime sleepiness, stress levels, and functionality, and PMR therapies can be effective in relieving pain and psychological stress in patients with CNP. Keywords: Chronic neck pain; daytime sleepiness; functionality; rehabilitation; stress levels.

Cite this article as: Sayilir S. Daytime sleepiness, functionality, and stress levels in chronic neck pain and effects of physical medicine and rehabilitation therapies on these situations. North Clin Istanb 2018;5(4):348–352.

hronic spinal pain conditions can limit the activities of daily living, cause sleep disturbances, and increase stress levels. Chronic neck pain (CNP) can occur due to numerous reasons, including disk pathologies, degenerative changes, exercise habits, vertebrae alignment defects, and trauma [1]. It is a well-known fact that prolonged pain and disability rates in individuals with neck and back pain are high [2]. Development of chronic pain in individuals with neck and spine pain has been studied by numerous authors, and evaluation of risk for chronic spinal pain and how to approach this pain has been reported [3, 4]. Chronic spinal pain is related to the natural structure of the injury and the occupational, social, and psychoReceived: February 28, 2017 Accepted: October 19, 2017

logical states of the patients. The relationship between chronic spinal pain and psychosocial situations has shown that psychosocial status affects the development of chronic pain, and psychosocial problems can play a role in the chronicization of spinal pain [5]. Conversely, untreated pain can result in increased levels of stress, and heavy psychological burdens may appear in this case. Additionally, sleep disturbances are associated with daytime sleepiness, which may impair personal, social, and occupational activities, leading to the need for multidisciplinary treatment in patients with CNP. Treatment of CNP with physical agents and exercise has been performed for a long time. Superficial heaters Online: December 03, 2018

Correspondence: Dr. Selcuk SAYILIR. Mugla Sitki Kocman Universitesi Tip Fakultesi, Fiziksel Tip ve Rehabilitasyon Anabilim Dali, Mugla, Turkey. Tel: +90 252 214 13 26 e-mail: selcukssay@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Sayilir, Self reported symptoms in chronic neck pain

can contribute to the reduction of muscle spasms [6]. Previous studies have shown that therapeutic ultrasound is effective in reducing the musculoskeletal pain conditions [7]. In addition, transcutaneous electrical stimulation (TENS) is a widely used analgesic electrical current for relieving musculoskeletal spinal pain conditions [8, 9]. Many studies have reported the positive effects of exercise therapies for decreasing pain in patients with CNP [10, 11]. The present study aims to evaluate the relationship of symptom severity, daytime sleepiness, and perceived stress levels with the short-time impact of physical medicine & rehabilitation (PMR) therapy programs in patients with CNP. MATERIALS AND METHODS Fifty-four patients with CNP and 20 healthy controls were included to the study. Patients with CNP were divided into two groups: the PMR therapy group (n=34) and the CNP control group (n=20). Demographic and clinical features were evaluated. Patients with history of epidural or intramuscular corticosteroid injections, pregnancy, surgery history of the spine, skin problems around the neck, benign and malignant tumors, psychiatric problems, sleep problems, and night sleep less than 6 h/ day were excluded. Local ethics committee approval was obtained for the study. Informed consents were obtained from all the subjects. The PMR therapy program included TENS, hot pack application, therapeutic ultrasound, and exercises. In total, 10 sessions were performed for 2 weeks (5 days/ week). A two-channel portable machine was used for TENS applications. (BTL-4620, Czech Republic) on neck for 30 min, which delivered a premixed ampitude modulated current with 60ms pulse width and, 100 Hz frequency and intensity adjusted according to the threshold, without emerging pain or contractions for each participant. Electrodes were placed crosswise in the cervical paravertebral region. Hot packs (20 min/day) and therapeutic ultrasound (1-MHz frequency with 1 W/cm2 intensity, for 5 min) (BTL- 4000 professional, Czech Republic) were applied. Range of motion, stretching, and strengthening (neck region muscles) exercises were given to the patients for 15 min, 5 times/week. Visual analog scale (VAS) at activity and resting for neck pain, Epworth Sleepiness Scale (ESS) [12], Perceived Stress Scale-10 (PSS) [13, 14], Neck Disability Index (NDI) [15, 16], chin-manubrium distances (mouth closed) (CMD), and tragus-wall distances (TWD) were collected at baseline and after the therapy programs. Post-treatment evalua-

349

tions were performed on the first day following the end of the therapy programs. In addition, the CNP control group was evaluated twice: at baseline and 15 days after the first evaluation. Throughout the study, the patients were discouraged to use analgesics; however, they were allowed to use paracetamol daily if necessary. Statistical analysis Statistical analysis was conducted using SPSS for Windows, version 20.0 software program (SPSS Inc., Chicago, IL, USA). Descriptive results are shown as mean±standard deviation of continuous data or n (%) for categorical data. Baseline characteristics were compared using X2 and student’s t-tests where appropriate. Pre- and post-therapy results were evaluated through paired sample t-tests. The significant p value was evaluated as <0.05. RESULTS Fifty-four patients with CNP (mean age, 51.12±12.54 years) and 20 healthy controls (mean age, 51.45±7.74 years) were included in the study. Demographic and clinical features of the individuals are shown in Table 1. Significant differences were found between the CNP patients and healthy controls regarding PSS, TWD, and CMD

Table 1. Baseline demographic and clinical features of the CNP patients and the healthy controls CNP (n=54)

Healthy controls (n=20)

Age 51.1±12.5 51.4±7.7 >0.05 Sex M/F 13/41 5/15 >0.05 Disease 29.4±39.8 duration (mo) Neck pain (%) 54 (100) Radicular pain (%) 21 (39) VASresting 6.0±2.1 VASactivity 7.1±1.8 ESS 7±4.2 6.1±1.9 >0.05 NDI 56.7±12 PSS 22.4±3.9 18.5±4.8 <0.05 TWD (cm) 11.4±2.5 8.7±1.5 <0.05 CMD (cm) 1.6±1.2 0.9±0.7 <0.05 CNP: Chronic neck pain; mo: Month; VAS: Visual analog scale; ESS: Epworth sleepiness scale; NDI: Neck disability index; PSS: Perceived stres scale; TWD: tragus-wall distance; CMD: Chin-manubrium distance.

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values (Table 1). Significant improvements were detected in VASresting, VASactivity, PSS, and NDI levels in the PMR group than in the control CNP group after the therapies (Table 2). Significant improvements were detected in the VASactivity, VASresting, PSS, and NDI scores from baseline to post-therapy in the PMR group (Table 3). DISCUSSION CNP can severely limit activities of daily living as well as occupational and social activities. Especially, in the chronic period, pain may lead to sleep disorders. The prevalence of sleep disorders and daytime sleepiness is higher in patients with chronic pain conditions [17, 18]. It should be kept in mind that daytime sleepiness can lead to serious problems in workers who need attention; it may also lead to problems such as falls in elderly patients [19, 20]. Therefore, it is necessary to evaluate daytime sleepiness in pain clinics and take necessary precautions. In our study, daytime sleepiness in patients with

Table 2. Comparison of the demographic and clinical features of the baseline and second assessments of the PMR and control CNP groups Age (years) Disease duration (months) ESS first scores ESS second scores NDI first scores NDI second scores PSS first scores PSS second scores CMD first (cm) CMD second (cm) TWD first (cm) TWD second (cm) VAS activit y first VAS activity second VAS resting first VAS resting second

PMR group (n=34)

Control CNP (n=20)

52.3±13.8 49.1±11.3 >0.05 27.1±18.7 33.1±44.8 >0.05 6.9±6.1 6.3±3.7 58.1±12.1 43±14.7 23.1±3.4 19±5.8 1.7±1.5 1.6±1.4 11.8±1.6 11.2±2 7.2±1.9 4.7±1.7 6.1±3.1 3.9±1.8

7.1±0.8 >0.05 7.1±2.1 >0.05 54.3±4.4 >0.05 56.1±5.3 <0.05 21.3±1.9 >0.05 21.2±2 <0.05 1.5±0.9 >0.05 1.6±0.9 >0.05 10.9±1.4 >0.05 10.8±1.4 >0.05 6.9±1.8 >0.05 6.3±2 <0.05 5.8±1.8 >0.05 5.1±2.1 <0.05

PMR: Physical medicine & rehabilitation; CNP: Chronic neck pain: VAS; Visual analog scale; ESS: Epworth sleepiness scale; NDI: Neck disability index; PSS: Perceived stres scale; TWD: Tragus-wall distance; CMD: chin-manubrium distance.

CNP and acute effects of PMR therapies on this condition were evaluated using the ESS, which is a widely used tool in the field of sleep medicine for subjective measurement of daytime sleepiness [21]. In the present study, we did not find higher levels of daytime sleepiness in patients with CNP than in healthy controls. Furthermore, no significant improvement in the ESS scores was found after PMR therapies. Although, the relationship between daytime sleepiness and aging has been reported [22] and aging is evaluated as a risk factor for CNP, the present study did not show CNP as an independent risk factor for daytime sleepiness due to outcomes. The relationship between chronic pain and psychosocial problems has been reported, and it has been pointed out that many psychological problems, especially depression, can coexist with chronic pain conditions [23]. Perceived stress levels of patients with chronic pain can be high, and at the same time, patients may begin to use emotional words to describe pain in these processes [24]. Perceived stress levels were significantly higher in patients with CNP than in healthy controls. This outcome indicates the vicious circle of the pain and increased stress levels in patients with CNP. The present study showed significant improvements in the perceived stress levels after the acute period of PMR therapies. This result shows that PMR therapies could be one of the beneficial components of the multidisciplinary approach for management of psychological stress in the treatment of CNP conditions. Inter-group evaluation of the neck disability scores showed a significant difference between the PMR group

Table 3. Comparison of the clinical features at baseline and after PMR therapies in the PMR group

Baseline (n=34) ESS scores 6.9±6.1 NDI scores 58.1±12.1 PSS scores 23.1±3.4 TWD (cm) 11.8±1.6 CMD (cm) 1.7±1.5 VASresting 6.1±3.1 VASactivity 7.2±1.9

After treatment (n=34)

6.3±3.7 43±14.7 19±5.8 11.2±2 1.6±1.4 3.9±1.8 4.7±1.7

>0.05 <0.05 <0.05 >0.05 >0.05 <0.05 <0.05

PMR: Physical medicine & rehabilitation; VAS: Visual analog scale; ESS: Epworth sleepiness scale; NDI: Neck disability index; PSS: Perceived stres scale; TWD: tragus-wall distance; CMD: Chin-manubrium distance.

Sayilir, Self reported symptoms in chronic neck pain

and the CNP control group at the final evaluation. In addition, a significant improvement in NDI scores was detected after PMR therapies. These results indicate the negative effects of CNP on the quality of life while highlighting the short-term effectiveness of PMR therapies in replacing personal, occupational, and social functional losses due to neck pain. TWD and CMD values were measured, and no significant improvement was detected in these functional parameters after PMR therapies. This outcome can be attributed to the fact that the mean age of the participants was high, and, thus, the risk of age-related degenerative processes could be high in the study group. Increased rates of analgesic utilization in chronic pain conditions have been reported [25]. Self-reported beliefs were detected as decreased necessity of analgesics in the individuals for whom PMR therapies were performed; however, the formal data for this result were not properly collected. Besides, this result can encourage further studies to investigate the possible effects of reducing the utilization of analgesics in PMR therapies. Conversely, a large proportion of the CNP patients reported that they chose the analgesic drugs based on their neighborhood or friends’ recommendations instead of doctor recommendations, but similarly, the data were not clear for a statistical assessment. Furthermore, none of the individuals participating in the study had visited a neck & back school anytime in their life; this situation predicts the importance of neck & back schools for preventing inappropriate approaches for CNP. The present study has some limitations: Although, our sample size is small, it is acceptable compared with that of the previous studies. All the participants were enquired about the previous sleep and psychiatric disorders (especially depression); however, the data were limited as the clinical tests for these conditions were not performed (e.g., depression questionnaires). Thus, further studies with larger sample sizes and longer follow-up periods will be beneficial to evaluate the relationship of CNP with stress levels, quality of life, and daytime time sleepiness and to evaluate the short- and long-term effects of PMR therapies on these situations. Conclusion Evaluation of CNP from a single point of view can leave clinically missing points as patients with CNP face many problems. These patients should be assessed for daytime sleepiness, stress levels, and functionality. PMR therapies can be effective in relieving pain and psychological stress in patients with CNP.

351 Conflict of Interest: No conflict of interest was declared by the author. Financial Disclosure: The author declared that this study has received no financial support.

REFERENCES 1. Gore DR, Sepic SB, Gardner GM, Murray MP. Neck pain: a long-term follow-up of 205 patients. Spine (Phila Pa 1976) 1987;12:1–5. 2. Sturzenegger M, Radanov BP, Di Stefano G. The effect of accident mechanisms and initial findings on the long-term course of whiplash injury. J Neurol 1995;242:443–9. 3. Fransen M, Woodward M, Norton R, Coggan C, Dawe M, Sheridan N. Risk factors associated with the transition from acute to chronic occupational back pain. Spine (Phila Pa 1976) 2002;27:92–8. 4. Valat JP, Goupille P, Védere V. Low back pain: risk factors for chronicity. Rev Rhum Engl Ed 1997;64:189–94. 5. Linton SJ. A review of psychological risk factors in back and neck pain. Spine (Phila Pa 1976) 2000;25:1148–56. 6. Fountain FP Gersten JW, Senger O. Decrease in muscle spasm produced by ultrasound, hot packs and IR. Arch Phys Med Rehabil 1960:41:293–9. 7. Robertson VJ, Baker KG. A review of therapeutic ultrasound: effectiveness studies. Phys Ther 2001;81:1339–50. 8. Sayilir S, Yildizgoren MT. The medium-term effects of diadynamic currents in chronic low back pain; TENS versus diadynamic currents: A randomised, follow-up study. Complement Ther Clin Pract 2017;29:16–19. 9. Jensen I, Harms-Ringdahl K. Strategies for prevention and management of musculoskeletal conditions. Neck pain. Best Pract Res Clin Rheumatol 2007;21:93–108. 10. Weinstein SM, Herring SA, Cole AJ. Rehabilitati-on of the patient with spinal pain. in DeLisa JA, Gans BM (Eds): Rehabilitation Medicine: Principles and Practice. Philadelphia: Lippincott-Raven Pub; 1998. p. 1423–51. 11. Highland TR, Dreisinger TE, Vie LL, Russell GS. Changes in isometric strength and range of motion of the isolated cervical spine after eight weeks of clinical rehabilitation. Spine (Phila Pa 1976) 1992;17:S77– 82. 12. Yildirim Y, Ergin G. A validity and reliability study of the Turkish Multidimensional Assessment of Fatigue (MAF) scale in chronic musculoskeletal physical therapy patients. J Back Musculoskelet Rehabil 2013;26:307–16. 13. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983;24:385–96. 14. Eskin, M, Harlak H, Demirkıran F, Dereboy Ç. The adaptation of the perceived stress scale into Turkish: A reliability and validity analysis [Article in Turkish]. New/Yeni Symposium Journal 2013;51:132–40. 15. Wheeler AH, Goolkasian P, Baird AC, Darden BV 2nd. Development of the Neck Pain and Disability Scale. Item analysis, face, and criterionrelated validity. Spine (Phila Pa 1976) 1999;24:1290–4. 16. Bicer A, Yazici A, Camdeviren H, Erdogan C. Assessment of pain and disability in patients with chronic neck pain: reliability and construct validity of the Turkish version of the neck pain and disability scale. Disabil Rehabil 2004;26:959–62. 17. Rose AR, Catcheside PG, McEvoy RD, Paul D, Kapur D, Peak E, et al. Sleep disordered breathing and chronic respiratory failure in patients with chronic pain on long term opioid therapy. J Clin Sleep Med

352 2014;10:847–52. 18. Guilleminault C, Cao M, Yue HJ, Chawla P. Obstructive sleep apnea and chronic opioid use. Lung 2010;188:459–68. 19. Ancoli-Israel S, Cooke JR. Prevalence and comorbidity of insomnia and effect on functioning in elderly populations. J Am Geriatr Soc 2005;53:264–71. 20. Gooneratne NS, Weaver TE, Cater JR, Pack FM, Arner HM, Greenberg AS, et al. Functional outcomes of excessive daytime sleepiness in older adults. J Am Geriatr Soc 2003;51:642–9. 21. Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth Sleepiness Scale. Chest 1993;103:30–6. 22. Bixler EO, Vgontzas AN, Lin HM, Calhoun SL, Vela-Bueno A, Kales

North Clin Istanb A. Excessive daytime sleepiness in a general population sample: the role of sleep apnea, age, obesity, diabetes, and depression. J Clin Endocrinol Metab 2005;90:4510–5. 23. Elliott TE, Renier CM, Palcher JA. Chronic pain, depression, and quality of life: correlations and predictive value of the SF-36. Pain medicine 2003;4:331–9. 24. Carmody J, Ruth AB. Relationships between mindfulness practice and levels of mindfulness, medical and psychological symptoms and wellbeing in a mindfulness-based stress reduction program. J Behav Med 2008;31:23–33. 25. Stovitz SD, Johnson RJ. NSAIDs and musculoskeletal treatment: what is the clinical evidence? Phys Sportsmed 2003;31:35–52.

Case Report

CHILD HEALTH&DISEASES

North Clin Istanb 2018;5(4):353–356 doi: 10.14744/nci.2017.13284

Intracranial abscess developed after ganciclovir treatment: A case report Murat Cansever,1

Elif Nurdan Ozmansur,2

Zehra Filiz Kahraman,4

Alper Ozcan,3

Turkan Patiroglu1

Department of Pediatric Immunology and Allergy, Erciyes University Faculty of Medicine, Kayseri, Turkey

Department of Pediatric, Erciyes University Faculty of Medicine, Kayseri, Turkey

Department of Henatology and Oncology, Erciyes University Faculty of Medicine, Kayseri, Turkey

Department of Pediatric Radiology, Erciyes University Faculty of Medicine, Kayseri, Turkey

ABSTRACT In this report, we examine severe neutropenia secondary to ganciclovir treatment and associated intracranial abscess in a patient with respiratory insufficiency who required intubation due to cytomegalovirus (CMV) pneumonitis. Secondary neutropenia is a condition encountered more frequently than primary neutropenia, and additional risk factors may lead to vital complications, independent of the presence of additional risk factors. Keywords: Cranial abscess; cytomegalovirus; ganciclovir; secondary neutropenia.

Cite this article as: Cansever M, Ozmansur EN, Ozcan A, Kahraman ZF, Patiroglu T. Intracranial abscess developed after ganciclovir treatment: A case report. North Clin Istanb 2018;5(4):353–356.

eutropenia is defined as the absolute neutrophil count (ANC) below 1500 cells/mm3. The severity of neutropenia is associated with the ANC. It can be classified as severe neutropenia (ANC, <500/mm3), moderate neutropenia (ANC, <500–1000/mm3), and mild neutropenia (ANC, <1000–1500/mm3) [1]. The classification of neutropenia can be done in several different ways, taking into account different characteristics. Acute neutropenia is defined as a neutropenia lasting less than 3 months, and chronic neutropenia lasts longer than 3 months. Congenital causes constitute primary neutropenia, while acquired causes lead to secondary neutropenia [2–4]. Neutropenia is a life-threatening condition that can cause serious infections. Secondary neutropenia is more frequently encountered than primary neutropenia. A number of different etiologies have been shown to cause secondary neutropenia. Some of these are infectious agents, drugs, malnutrition, metabolic diseases, and environmental factors [5, 6]. Drug-related neutropenia is a common condition that can be seen at any age. Drug-related neu-

tropenia may manifest itself through many mechanisms. Neutropenia can manifest itself through the immune mechanism, and it can be seen following direct suppression of the precursors in the bone marrow. The first approach to treatment is to discontinue neutropenic drugs and to treat it with the granulocyte-colony-stimulating factor (G-CSF) [7, 8]. Herein, we would like to present a case of intracranial abscess associated with neutropenia following ganciclovir treatment in a case with normal neutrophil counts. CASE REPORT A 6-month-old previously healthy male patient was admitted to the emergency center with cough and respiratory distress. Posteroanterior chest X-ray demonstrated increased aeration and infiltration in the reticular pattern that established the diagnosis of bronchopneumonia, and treatment was initiated. In the follow-up, the postero-anterior lung graft suggested progression to respiratory distress syndrome, so acyclovir and oseltamivir were added to

Received: March 17, 2017 Accepted: October 01, 2017 Online: August 09, 2018 Correspondence: Dr. Murat CANSEVER. Erciyes Universitesi Tip Fakultesi, Fevzi Mercan Cocuk Hastanesi, Cocuk Immunoloji Departamani, 38039 Kayseri, Turkey. Phone: +90 352 207 66 66 e-mail: mcansever66@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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Table 1. Hemogram, immunoglobulins, and subgroups of lymphocytes WBC Hb Plt ANC ALC Hemogram (mm3) (gr/dl) (mm3) (mm3) (mm3) Immunoglobulins

4500 9600

9.5 10.2

445000 355000

470 4550

3360 4700

IgG IgM IgA IgE Eosinophil (mg/dl) (mg/dl) (mg/dl) (mg/dl) %/(mm3) 609

17.3

5.81

18.5

0.9/100

Subgroups of lymphocytes

CD3 CD4 CD8 CD19 NK (%)/(mm3) (%)/(mm3) (%)/(mm3) (%)/(mm3) (%)/(mm3)

69.7/3275 39.6/1861 25.2/1184 22.8/1071 5/235

WBC: White blood cell; Hgb: Hemoglobulin; Plt: Platelet; ANC: Absolute neutrophil count; ALC: Absolute lymphocyte count; NK: Natural killer.

the treatment. On the 7th day of the follow-up, the patientâ&#x20AC;&#x2122;s general condition deteriorated, and he was taken into the intensive care unit because of the necessity of intubation. On the respiratory tract pathogenetic agent panel, upon cytomegalovirus (CMV), and CMV PCR positivity, we switched from acyclovir to ganciclovir treatment 4 weeks after the initiation of ganciclovir therapy. The CMV PCR negativity was detected, so the treatment was discontinued. The patient experienced seizures, and the head control was difficult during extubating and weaning from mechanical ventilation while he was followed up in the intensive care unit. Therefore, cranial magnetic resonance imaging (MRI) was obtained which revealed a 4.5x3 cm lesion with restricted diffusion consistent with the abscess formation. The patient was operated with the indication of cranial abscess. Bacterial growth was not detected in the cultures of the abscess material, and gram staining did not reveal the presence of any infectious agent. The CMV-PCR test result of the abscess material was reported as negative. The patient was referred to the Pediatric Immunology Clinic for further investigation of possible underlying immunodeficiency. The first physical examination of the patient did not reveal any pathology regarding skin, cardiovascular and respiratory systems, and pulmonary vasculature. Lymphadenopathy, hepatosplenomalgy, and microcephaly were not observed, and examinations of other systems were unremarkable. To differentiate between congenital and acquired CMV infection of the patient, eye examination, hearing

test, cranial magnetic resonance (MR), and CMV avidity tests were performed. Calcification was not observed on cranial MR in the patient, whose ocular examination and hearing test results were within the normal limits. The CMV avidity test result was negative. The patient was evaluated in terms of genetics and neurometabolism. In the evaluation of pediatric neurology, no pathology was detected, and the convulsion experienced was interpreted as a manifestation of the secondary to intracranial abscess. Metabolic tests were normal. A broad-spectrum antibiotherapy (meropenem, vancomycin) was initiated based on the blood culture results. The hemogram of the patient was reported as follows: WBC, 4500/mm3; neutrophils, 470/mm3; lymphocytes, 3360/mm3; Hgb, 9.5 gr/dl; and Plt, 445,000/mm3. On peripheral smear, atypical cells were not detected, and only few neutrophils and toxic granulation were observed. Immunoglobulin results were the following: IgG, 609 mg/dl; IgM, 17.3 mg/dl; IgA, 5.81 mg/dl. Lymphocyte subgroups were CD3, 69.7%; CD4, 39.6%; CD8, 25.2%; CD19, 22.8%; and NK, 5.0% (Table 1). The dihydrorodamine test was normal. Repeated control MRI obtained in our clinic was evaluated in favor of bleeding (Figure 1). The patient was consulted to neurosurgery for operation. During the operation, pus was drained from the area, and it was interpreted as hemorrhage. The operation was completed by placing the catheter in the loge. Microbiological examination of the material collected during the operation, and abscess material retrieved from the catheter were unremarkable. Gram staining and antibiogram could not reveal any bac-

Cansever et al., Intracranial abscess developed after ganciclovir treatment

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Figure 1. Cranial magnetic resonance T1-weighted contrasted and non-contrasted, T2-weighted images of the patient. terial growth in both specimens. Neutropenia was not detected in the evaluation of whole blood counts calculated during healthy periods of the patient, and at the starting time of his first complaints (WBC, 9600/mm3; lymphocytes, 4700/mm3; neutrophils: 4550/mm3). The bone marrow aspiration was performed to exclude the primary etiologies, drug-related secondary neutropenia was considered, and maturation arrest was not observed. The samples were sent for genetic analysis to exclude possible congenital causes of neutropenia, and the result was reported as normal. The cyclic pattern was not observed in the weekly hemogram follow-ups performed to detect cyclic neutropenia. After the exclusion of primary etiologies, since the number of neutrophils calculated during the clinical follow-up was within the normal limits, infection associated with drug-related secondary neutropenia was considered in the patient who developed neutropenia after the CMV infection and ganciclovir treatment. It is thought that the cranial abscess developed secondary to these risk factors because of the presence of risk factors such as intubation in the intensive care conditions during this period of neutropenia. Ganciclovir treatment was continued with the CMV PCR follow-ups, and when the CMV PCR results became negative, neutropenia resolved spontaneously. The patient whose lung infection and cranial abscess treatment completed was discharged with cure. Neutropenia was not detected during the clinical follow-up. DISCUSSION The etiology of acquired neutropenia involves destruction or consumption of peripheral neutrophils, which leads to

the shortening of the neutrophil life. The bone marrow is normal, or the maturation is late in the metamyelocyte/ band stage. The risk of developing infections in acquired neutropenia is significantly less than in other neutropenias [9–11]. Secondary neutropenia can be caused by infections, drugs, and autoimmune and isoimmune etiologies [12]. In childhood, the most common etiologies are infections of the secondary neutropenia (viral, bacterial, and parasitic). The most common causes of acute secondary neutropenia are viral infections: CMV, the Epstein– Barr virus, hepatitis A and B, influenza A and B viruses, measles, parvovirus B19, rubella, and chicken pox [13]. Mechanisms of neutropenia secondary to infection involve the passage of neutrophils from circulation into the marginal pool, sequestration, increased consumption, or a decrease in the bone marrow reserves [14]. Neutropenia usually begins 24 hours following infection and lasts for 3–8 days in patients who have or had an infection [5]. Infection with CMV leads to neutropenia, through decreased production and increased destruction of neutrophils [12]. The G-CSF can be used in neutropenic conditions due to depletion and inadequate production of bone marrow reservoir pools in severe sepsis [10]. Since in our case neutropenia developed at the time of detection of the CMV infection, and other possible causes have been ruled out, we interpreted the infection in favor of secondary neutropenia. Drug-related secondary neutropenia may be caused by many drugs. The most frequent causative drug groups include chemotherapy drugs, analgesics and anti-inflammatory agents, antipsychotics, antiepileptics, antithyroids, cardiovascular agents, and antibiotics [14].

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Mechanisms of neutropenia associated with drugs include the idiosyncratic suppression of myeloid production, dose-dependent suppression, suppression due to individual differences in drug metabolisms, and drughapten disease-induced destruction [15]. Diagnostic criteria of drug-related neutropenia include neutrophil count below 500 cells/mm3, the hemoglobin level above 10 gr/dl, platelet count above 100,000 cells/mm3, and drug use history without a causative agent that may cause secondary neutropenia [16, 17]. Ganciclovir idiosyncratically suppresses myeloid production and causes neutropenia [15]. With the use of medications, neutropenia usually develops within 2 to 3 months and is expected to resolve within 10 days after the discontinuation of drug application. However, sometimes this period can be shorter or longer [12]. In our case, after all other causes were excluded, we thought of secondary neutropenia due to ganciclovir treatment for infection because of its myelosuppressive effects in the bone marrow. In our case, neutropenia resolved within 7–10 days after complete control of the infection and cessation of ganciclovir treatment, and neutropenia did not recur during the follow-up period. Secondary neutropenia due to autoimmune causes is more common in adults, and it constitutes a part of autoimmune diseases. If rheumatologic diseases are not considered in the presence of secondary autoimmune neutropenia in children, autoimmune lymphoproliferative syndrome and Evans syndrome should first come to mind [18]. Both diseases had findings of lymphadenopathy, splenomegaly, and autoimmunity, which were not detected in our patient. Neutropenia is a serious, lifethreatening condition and can cause serious complications. Agranulocytosis increases the susceptibility to many bacterial and fungal infections [19]. Conclusion Neutropenia is a serious clinical condition with congenital or acquired causes. Clinicians are more likely to encounter secondary neutropenia, and it should be kept in mind that life-threatening complications such as primary causes may develop in these patients. Informed Consent: Written informed consent was obtained from the patient for the publication of the case report and the accompanying images. Conflict of Interest: No conflict of interest was declared by the authors.

North Clin Istanb Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – M.C.; Design – M.C.; Supervision – M.C.; Materials – M.C., E.N.O., Z.F.K; Data collection &/ or processing – E.N.O., Z.F.K; Analysis and/or interpretation – M.C., Z.F.K.; Writing – M.C.; Critical review – M.C., A.O., T.P.

REFERENCES 1. Menell JS. Disorders of white blood cells. In: Lanzowsky P. Manual of Pediatric Hematology and Oncology. 5th ed. Amsterdam: Academic Press/Elsevier; 2011. p. 272–320. 2. Clay ME, Schuller RM, Bachowski GJ. Granulocyte serology: current concepts and clinical signifcance. Immunohematology 2010;26:11–21. 3. Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol 2013;50:198–206. 4. Walkovich K, Boxer LA. How to approach neutropenia in childhood. Pediatr Rev 2013;34:173–84. 5. Husain EH, Mullah-Ali A, Al-Sharidah S, Azab AF, Adekile A. Infectious etiologies of transient neutropenia in previously healthy children. Pediatr Infect Dis J 2012;31:575–7. 6. Andrés E, Maloisel F. Idiosyncratic drug-induced agranulocytosis or acute neutropenia. Curr Opin Hematol 2008;15:15–21. 7. Palmblad J, Papadaki HA, Eliopoulos G. Acute and chronic neutropenias. What is new? J Intern Med 2001;250:476–91. 8. Rudolph CD, Rudolph AM, Lister GE, First LR, Gershon AA. Rudolph Pediatri. In: Yudarök M, translation editor. Ankara: Güneş Tıp Kitabevi; 2013. p. 1592. 9. Boxer LA. How to approach neutropenia. Hematology Am Soc Hematol Educ Program 2012;174–82. 10. Berliner N, Horwitz M, Loughran TP Jr. Congenital and acquired neutropenia. Hematology Am Soc Hematol Educ Program 2004:63–79. 11. Fioredda F, Calvillo M, Bonanomi S, Coliva T, Tucci F, Farruggia P, et al; Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica). Congenital and acquired neutropenias consensus guidelines on therapy and follow-up in childhood from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica). Am J Hematol 2012;87:238–43. 12. Celkan T, Koç BS. Approach to the patient with neutropenia childhood. Turk Pediatri Ars 2015;50:136–44. 13. Boxer L, Dale DC. Neutropenia: causes and consequences. Semin Hematol 2002;39:75–81. 14. Aydoğdu S, Çelik A, Karakaş Z. An Approach to Neutrophenia [Article in Turkish]. J Child 2015;15:3–9 15. Devecioğlu Ö, Gümüş S. Approach to Childhood Neutropenia. J Child 2012;12:53–9. 16. Andres E, Zimmer J, Affenberger S, Federici L, Alt M, Maloisel F. Idiosyncratic drug-induced agranulocytosis: Update of an old disorder. Eur J Intern Med 2006;17:529–35. 17. van der Klauw MM, Goudsmit R, Halie MR, van’t Veer MB, Herings RM, Wilson JH, et al. A population-based case-cohort study of drugassociated agranulocytosis. Arch Intern Med 1999;159:369–74. 18. Farruggia P, Dofour C. Diagnosis and management of primary autoimmune neutropenia in children: insights for clinicians. Ther Adv Hematol 2015;6:15–24. 19. Palmblad J, Papadaki HA, Eliopoulos G. Acute and chronic neutropenias. What is new? J Intern Med 2001;250:476–91.

Case Report

PEDIATRIC SURGERY

North Clin Istanb 2018;5(4):357–360 doi: 10.14744/nci.2018.22755

Management of Transverse Testicular Ectopia with Persistent Mullerian Duct Syndrome Sabri Cansaran,1 Oktav Bosnali,1

Serdar Moralioglu,1

Aysenur Celayir,1

Rahime Gul Yesiltepe Mutlu2

Department of Pediatric Surgery, University of Health Sciences, Istanbul Zeynep Kamil Maternity and Children’s Diseases Training and

Research Center, Istanbul, Turkey Pediatric Endocrinology, University of Health Sciences, Istanbul Zeynep Kamil Maternity and Children’s Diseases Training and Research

Center, Istanbul, Turkey

ABSTRACT According to additional anomalies, transverse testicular ectopia (TTE) is classified into three groups. Type-2 TTE, accompanied by persistent mullerian duct syndrome, constitutes approximately 20% of the patients. Surgical treatment should be planned after careful physical examination, ultrasonography, and genetic/endocrinologic evaluation. Herniorrhaphy, orchiopexy with testicular biopsy, and excision of the mullerian structures are the most appropriate surgical approaches in cases of TTE with persistent mullerian duct syndrome. We aimed to share our approach to the diagnosis and treatment of a patient with type-2 TTE. Possibility of TTE should be kept in mind in children with nonpalpable testis on one side and inguinal hernia on the other side. Keywords: Child; male pseudohermaphroditism; orchiopexy; Persistent Mullerian Duct Syndrome; Testicular Ectopia.

Cite this article as: Cansaran S, Moralioglu S, Celayir A, Bosnali O, Yesiltepe Mutlu RG. Management of Transverse Testicular Ectopia with Persistent Mullerian Duct Syndrome. North Clin Istanb 2018;5(4):357–360.

ransverse testicular ectopia (TTE) is a rare anomaly in boys in which both testes pass through the same inguinal canal, and it is usually accompanied by an inguinal hernia [1–5]. The majority of patients present with ipsilateral inguinal hernia and contralateral nonpalpable testis [1–4, 6–8]. TTE is often accompanied by inguinal hernia, hydrocele, persistent mullerian duct syndrome (PMDS), disorders of sex development (DSD), and karyotype abnormalities [6, 7]. PMDS is seen in approximately 20% of cases with TTE [2–6]. TTE is also called as crossed testicular ectopia, testicular pseudoduplication, unilateral double testis, and transverse aberrant testicular maldescent [3, 4]. Ectopic testis lies in the opposite hemiscrotum, inguinal canal, or deep inguinal ring [1, 2, 7].

PMDS may occur due to MIS (mullerian inhibiting substance) and MISR-II (mullerian inhibiting substance—type II receptor) gene mutations. It has autosomal recessive transmission [1, 4, 6, 8–10]. Uterus, fallopian tubes, and upper two-third of vagina persist in a normal, virilized male. Karyotype is 46, XY [4–6, 8] Herein, we aimed to share our experience and discuss our surgical treatment method in a case with TTE and PMDS. CASE REPORT Two-month-old male patient was admitted to our pediatric surgery department due to antenatally diagnosed bilateral hydronephrosis. There was no history of uri-

Received: November 02, 2017 Accepted: January 22, 2018 Online: August 08, 2018 Correspondence: Dr. Sabri CANSARAN. Saglik Bilimleri Universitesi, Istanbul Zeynep Kamil Kadin ve Cocuk Hastaliklari Saglik Uygulama ve Arastirma Merkezi, Cocuk Cerrahisi Klinigi, Istanbul, Turkey. Phone: +90 2016 391 06 80 - 2022 e-mail: sabrican@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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nary tract infection during postnatal follow-ups. Right inguinal hernia and left nonpalpable testis were determined by physical examination, and two testes were in the right inguinal region. One of them was closer to the entrance of scrotum. Our pre-diagnosis was TTE, and the patient was also evaluated by a pediatric endocrinologist. Ultrasound examination showed grade 3 ectasia on right kidney, and grade 2 ectasia on left kidney in that period. Urethra was normal, and there was no vesicoureteral reflux in voiding cystourethrography. Kidneys had no abnormality, and drained normally in mercaptoacetyltriglycine scintigraphy. Right testicle 9.4×7.1 mm and left testicle 9.7×7.7 mm were measured in size and ovoid, 24×4.5 mm in size, suspicious uterine-like structure was present behind the bladder on scrotal and pelvic ultrasonography respectively. Karyotype analysis of the patient was reported as 46, XY. Anti-mullerian hormone 7.6 ng/ml (normal range 28–142 ng/ml), dihydrotestosterone 32.8 pg/ml (normal range 250–990 pg/ml), androstenedione <0.3 ng/ ml (normal range 0.6–3.1 ng/ml), and total testosterone 0.13 ng/ml (normal range 1.66–8.11ng/ml) were found in low levels. The patient was also diagnosed as PMDS. Surgical treatment was planned according to the decision of Gender Research Committee. The patient was operated when he was ten months old. Ureteral catheter was inserted by cystoscopy through the opening of utriculus prostaticus (Figure 1). Right/left testes and their cord structures, and rudimentary structures of the mullerian ducts were seen during inguinal exploration via right groin incision (Figure 2). All patent mullerian structures were excised after the right inguinal hernia repair. Left testicle was brought down to the left hemiscrotum transseptally through the right inguinoscrotal canal. Then, the right testis was brought down to the right hemiscrotum via the right inguinoscrotal canal, and bilateral orchiopexy was completed. An illustrative picture of the operation is shown in Figure 3. Preoperative biopsies were taken from each testis. Testicular biopsies were reported as normal testicular tissue, while rudimentary structure was reported as uterus with inactive endometrium. Early postoperative period was uneventful, and testes were in the scrotum bilaterally at 1 year of age. Scrotal ultrasonography showed homogeneous appearance of testes. Right (7.3×8.6×12.7 mm) and left (7.6×8.2×15 mm) testes were reported in normal size.

North Clin Istanb

Figure 1. Ureteral catheter was inserted through an opening in utriculus.

Figure 2. Both testes, epididymis, spermatic cords, vessels, and rudimentary structures were seen in right side inguinal exploration.

Figure 3. Illustration of the operation: Both testes, epididymis, spermatic cords, and vessels were passed from right inguinal canal to the right scrotum and transseptally to the left scrotum. All rudimentary structures were excised from right inguinal groin incision.

Cansaran et al., Management of Transverse Testicular Ectopia with Persistent Mullerian Duct Syndrome

DISCUSSION There are many factors that are thought to play a role in the TTE etiology. Development of both testes from the same germinal ridge, early fusion of Wolffian ducts, testicular adherence to mullerian structures, and obstruction of the inguinal ring are suggested as causative in failure of testicular descent. The most widely accepted theory is abnormal attachment of gubernaculum which was proven by experimental studies [3–5, 7,10]. The TTE classification is made according to associated anomalies. Type I is only accompanied by inguinal hernia (40%–50%). Type II is accompanied by PMDS (20%–30%). Type III is accompanied by other anomalies such as DSD, hypospadias, scrotal abnormalities, seminal vesicle cysts, common deferent duct, and horseshoe kidney [2, 3, 5–7]. Based on this information, it can be said that our patient is type II TTE. Because of the presentation with undescended testis or symptomatic inguinal hernia, TTE is detected during the surgery in many patients [1, 2, 5, 7]. Sometimes, both testes may be palpated on the same side with ipsilateral inguinal hernia and contralateral unpalpable testis, as in our patient. PMDS with TTE is a rare form of internal male pseudohermaphroditism that is caused by mullerian inhibiting factor (MIF) deficiency. Both testes are on the same side, and the mullerian duct remnants (fallopian tubes, uterus, upper part of vagina, etc.) are present in normally virilized XY patients. mullerian derivatives may be localized intraabdominally, as in our patient, or herniate from the inguinal canal [4–6]. PMDS can be sporadic, but most commonly, it occurs due to MIS and MISR-II gene mutation that has autosomal recessive transmission [1, 6, 8, 10]. In our patient, there was no gene mutation in the genetic tests. TTE is often accompanied by ipsilateral inguinal hernia and contralateral nonpalpable testicle. Both TTE and PMDS are usually detected incidentally during inguinal hernia or undescended testis operations. Preoperative diagnosis requires a high level of suspicion. If necessary, imaging methods should be used to support diagnosis [1, 3, 5, 7]. The optimal surgical approach in cases of TTE with PMDS should be protective for vas deferens, and include herniorrhaphy, orchiopexy, or orchiectomy (if the testicle cannot be brought down), excision of mullerian remnants and testicular biopsies [1, 3, 4, 6]. Right and left or-

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chiopexies can be performed by passing through separate inguinal canals from separate groin incisions. Transseptal orchiopexy is easier because both testes have already passed through the same inguinal canal [2, 7]; whereas in bilateral orchiopexy, there is also a risk of damaging the vessels of the ectopic testis with the additional contralateral incision. In our case, access to the posterior urethral region was easy following the high ligation of the right hernia sac through the right inguinal groin incision. Mullerian remnants and each ductus deferens were observed clearly. Both testes were easily brought down through the same inguinal canal, and spermatic cord length of the ectopic testis was sufficient to perform a transseptal orchiopexy. The surgical management of PMDS remains controversial. Some authors refrain from recommending the removal of patent mullerian structures due to the risk of injury to vas deferens and the lack of the risk of developing malignancy [5, 10]. However, recent studies have shown that remaining patent mullerian structures have a malignancy potential [8,9]. Orchiectomy (if necessary) or excision of mullerian remnants are deemed useful in preventing malignancies [3, 6, 8, 9]. For reasons discussed above, all mullerian remnant structures were excised just proximal to the urethral connection using a gentle technique to protect the vas deferens before adulthood. Conclusion In cases of TTE with PMDS, the length of the cord and vessels of the ectopic testis is the major factor in deciding whether to bring down the testis ipsilaterally or contralaterally. If bringing down the ectopic testis is not possible due to short cord and vessels, excision may be considered due to risk of possible malignancy. Informed Consent: Written informed consent was obtained from the patient for the publication of the case report and the accompanying images. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – S.C., S.M., A.C., O.B., R.Y.M.; Design – S.C., S.M., A.C., O.B., R.Y.M.; Supervision – S.C., S.M., A.C., O.B., R.Y.M.; Materials – S.C., S.M., A.C., O.B., R.Y.M.; Data collection &/or processing – S.C., S.M., A.C., O.B., R.Y.M.; Analysis and/or interpretation – S.C., S.M., A.C., O.B., R.Y.M.; Writing – S.C.; Critical review – S.M., A.C.

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REFERENCES 1. Patil V, Muktinaini S, Patil R, Verma A. Persistent müllerian duct syndrome: a case report. Indian J Surg 2013;75(Suppl 1):460–2. 2. Akin M, Erginel B, Bilici S, Gedik S, Yıldız A, Karadağ CA, et al. Crossed testicular ectopia: Report of six cases. Afr J Paediatr Surg 2014;11:269–72. 3. Karakuş SC, Kılınçaslan H, Ertaşkın I, Koku N, Deliağa H. Delayed and incidental diagnosis of transverse testicular ectopia. Balkan Med J 2012;29:447–9. 4. Deepika, Kumar A. Persistent mullerian duct syndrome with transverse testicular ectopia: rare entity. J Clin Diagn Res 2014;8:162–3. 5. Alamsahebpour A, Blachman-Braun R, Gupta A, Castellan M, Campos S J, Gosalbez R. Laparoscopy and transseptal orchiopexy in the management of transverse testicular ectopia. Curr Urol Rep 2015;16:48. 6. Telli O, Gökçe MI, Haciyev P, Soygür T, Burgu B. Transverse testicular

North Clin Istanb ectopia: a rare presentation with persistent Müllerian duct syndrome. J Clin Res Pediatr Endocrinol 2014;6:180–2. 7. Farikullah J, Ehtisham S, Nappo S, Patel L, Hennayake S. Persistent Müllerian duct syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Müllerian remnants. BJU Int 2012;110:E1084–9. 8. Wei CH, Wang NL, Ting WH, Du YC, Fu YW. Excision of Mullerian duct remnant for persistent Mullerian duct syndrome provides favorable short- and mid-term outcomes. J Pediatr Urol 2014;10:929–33. 9. Wuerstle M, Lesser T, Hurwitz R, Applebaum H, Lee SL. Persistent mullerian duct syndrome and transverse testicular ectopia: embryology, presentation, and management. J Pediatr Surg 2007;42:2116–9. 10. Naouar S, Maazoun K, Sahnoun L, Jouini R, Ksia A, Elezzi O, et al. Transverse testicular ectopia: a three-case report and review of the literature. Urology 2008;71:1070–3.

Case Report

RADIOLOGY

North Clin Istanb 2018;5(4):361–364 doi: 10.14744/nci.2018.35693

Parathyroid adenoma presenting with multiple Brown tumors in an adolescent patient Serdar Aslan,1

Meltem Ceyhan Bilgici,1

Hasan Murat Aydin,3

Riza Ferit Bernay,2

Mustafa Bekir Selcuk1

Department of Radiology, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey

Department of Pediatric Surgery, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey

Department of Pediatrics, Ondokuz Mayis University Faculty of Medicine, Samsun, Turkey

ABSTRACT Parathyroid glands are endocrine glands that secrete parathyroid hormone (PTH) and regulate calcium-phosphor metabolism. The overexpression of PTH is called hyperparathyroidism (HPT), and is classified as primary, secondary, and tertiary. Primer HPT (PHPT) is the most common cause of parathyroid adenomas (80%–85%). Development of juvenile PHPT during adolescence is rare. The incidence of bone lesions in all age groups is reported to be 10%–20% in the patients with PHPT, and 5% in patients with juvenile PHPT. In patients with bone lesions, regression occurs in lesions after parathyroidectomy. In this case report, we aimed to present the imaging findings of long bones and left fifth metacarpal bone multiple Brown tumors, which is a rare presentation of parathyroid adenoma in adolescent patient and regression after parathyroidectomy. Keywords: Adolescent; Brown tumor; primary hyperparathyroidism.

Cite this article as: Aslan S, Ceyhan Bilgici M, Bernay RF, Aydin HM, Selcuk MB. Parathyroid adenoma presenting with multiple Brown tumors in an adolescent patient. North Clin Istanb 2018;5(4):361–364.

arathyroid glands are two endocrine glands, which are usually located in vicinity of the upper and lower poles of the thyroid gland. Parathyroid glands secrete parathormone (PTH) and regulate calcium-phosphorus metabolism. PTH plays an important role in bone mineral balance. The overexpression of PTH is termed as hyperparathyroidism (HPT), and it is classified as primary, secondary, and tertiary hyperparathyroidism. Primary HPT (PHPT) develops as a result of adenoma (80%–85%), hyperplasia (10%–15%), and parathyroid carcinoma (<0.5%) [1]. Secondary HPT develops due to overexpression of PTH secondary to hypocalcemia or vitamin D deficiency. Tertiary HPT develops as a result of autonomy acquired by the parathyroid glands as a result of long-lasting secondary HPT [2]. Juvenile PHPT in the adolescent period is very rare, and only a limited number of cases have been reported in the literature [3].

The incidence of bone lesions in PHPT was reported to be 10%–20%, and in juvenile PHPT as 5% [4]. The most commonly identified bone lesions are bone resorption, bone cysts, Brown tumors, and generalized osteopenia. Bone lesions are often seen in facial bones, ribs, and pelvic bones. They are rarely seen in long bones. Brown tumors are reactive lesions that result in disruption of the balance between bone formation and destruction in favor of bone resorption due to the direct effect of PHT. Diagnosis is difficult, and is radiologically confused with giant cell tumor, bone metastasis, or multiple myeloma [5]. In this case report, we aimed to present the imaging findings of a large number of Brown tumors in the long bones and the fifth metacarp of the left hand, which have a rare manifestation of parathyroid adenoma in the adolescent patient that regresses after parathyroidectomy.

Received: October 08, 2017 Accepted: January 02, 2017 Online: August 09, 2018 Correspondence: Dr. Serdar ASLAN. Ondokuz Mayis Universitesi Tip Fakultesi, Radyoloji Anabilim Dali, 55139 Samsun, Turkey. Phone: +90 544 885 22 76 e-mail: serdaraslan28@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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Figure 1. A bone lesion measuring 71×30 mm (white arrow) on the proximal metaphysis of the left tibia and the other one measuring 87×44 mm in size (red arrow) in the distal metaphysis of the right femur are observed.

Figure 2.

A bone lesion measuring 66×30 mm (white arrow) in the proximal metaphysis of the left tibia and the other one measuring 80×36 mm in the distal metaphysis of the right femur (red arrow) are observed.

CASE REPORT A 14-year-old girl was admitted to the outpatient orthopedic clinic with complaints of increasing pain and

North Clin Istanb

Figure 3.

Parathyroid adenoma-compatible lesion (white arrow) in the size of 11,5×5,5×19,5 mm is seen in the inferior lobe of the left thyroid gland.

fatigue on her left knee for one month. On physical examination, the patient’s weight (40 kg (<3p) and height 146 cm (<3p) were measured. Her left knee movements were minimally limited. Bilateral knee Xray and lower extremity long bone radiograms were obtained, and the patient was referred to us. Radiograms revealed radiolucent bone lesions proximal to the left tibia and distal to the right femur and extensive decrease in bone densities (Fig. 1). Other bones were scanned to detect the presence of bone lesion. A bone lesion with similar appearance was observed in distal part of the fifth metacarp of the left hand. Lowdose computed tomography (CT) of both lower extremities was performed to aid in differential diagnosis. Likewise, CT demonstrated expansile, hypodense bone lesions at a location proximal to the left tibia and distal to the right femur (Fig. 2, remarkable laboratory findings were as follows: calcium, 13.4 mg/dL (8.6–10 mg/dL); phosphorus, 2.22 mg/dL (2.6–4 mg/dL); alkaline phosphatase 636 IU/L (73–189 IU/L); 25-OH Vitamin D3 1.25 μg/L (10–55 μg/L), and PTH 1441 pg/mL (10–65 pg/mL). With available findings, lesions were thought to be Brown tumors due to PHPT. Neck ultrasonography (USG) and parathyroid scintigraphy (Tc99m sestamibi) were performed to investigate the etiology. In the neck US, a lesion compatible with parathyroid adenoma was observed near the lower left thyroid gland (Fig. 3). Sintigraphy also showed findings consistent with parathyroid

Aslan et al., Parathyroid adenoma presenting with multiple Brown tumors in an adolescent patient

Figure 4. Decreases in the dimensions of the Brown tumors localized in the tibia and femur are observed on the control knee radiograms.

adenoma. The patient was diagnosed with parathyroid adenoma and Brown tumor developed secondary to parathyroid adenoma. Parathyroid adenoma was removed by the department of surgery. The calcium and PTH levels were normal after parathyroidectomy. The patient had no complaints at 1-month follow-up; and the calcium, PTH, and phosphorus levels were normal. The size of the lesions seen in the knee radiogram also decreased (Fig. 4). Thus, without the need for biopsy, it was proved that the lesions were Brown tumor, and they developed due to parathyroid adenoma. DISCUSSION We presented an adolescent patient who presented with left knee pain, and had multiple Brown tumors in the long bones of the lower extremities. Radiographically detected bone lesions and laboratory findings supporting PHPT primarily suggested us the presence of Brown tumor. Normalization of PTH after parathyroidectomy and decrease in the size of the lesions in the control imaging performed one month later confirmed our diagnosis without the necessity of biopsy or surgical intervention. The Brown tumor is a slowly growing, occasionally painful, and locally aggressive bone lesion without metastatic potential. The incidence of Brown tumor in PHPT is reported to range between 1.5% and 1.7% [6]. It is frequently seen in adults over the age of 50 years, but the appearance of Brown tumors secondary to parathy-

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roid adenoma in the adolescence period is very rare [7]. The imaging findings of the Brown tumor are not specific. They are frequently seen as bone lesions with lytic or sclerotic contours that do not cause cortical erosion, inflammatory changes, or periosteal reaction [8]. They are rarely localized in long bones, and they are seldom seen in multiple numbers. It may be confused with giant cell tumor, aneurysmal bone cyst, giant cell granuloma, or cherubism when it develops in the mandible, and it may be confused also with metastasis when it is seen in multiple numbers [6]. In the literature, most of the cases of the Brown tumor have been presented in a single bone and mostly in the mandibula and palate [9]. It is difficult to make the diagnosis of Brown tumor in biopsy materials histopathologically, and diagnosis can be frequent indicated if clinical manifestations of HPT are found. In cases of suspect Brown tumor, the presence of parathyroid adenoma should be investigated before resorting to biopsy and surgical intervention. If parathyroid adenoma is detected, parathyroidectomy is the most appropriate option. With parathyroidectomy, the PTH levels are kept under control, and also existing Brown tumors are treated [4, 10]. Tumors that grow despite treatment or do not change in size during the 6-month period after treatment, and lesions that impair the functions of the affected bone, or those associated with fractures require interventional treatment [10]. In conclusion, Brown tumor is a rare bone lesion that develops secondary to PHPT in adolescents, and it can be anticipated in cases with prolonged PHT elevation. Imaging methods are important diagnostic tools. When suspect lesions are revealed by imaging modalities, the patients should not be immediately directed to biopsy, differential diagnosis should be considered, biochemical values should be reviewed, and the presence of parathyroid adenoma should be investigated. Informed Consent: Written informed consent was obtained from the patient for the publication of the case report and the accompanying images. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – S.A.; Design – S.A.; Supervision – S.A.; Materials – S.A.; Data collection &/or processing – M.C.B., R.F.B., H.M.A., M.B.S.; Analysis and/or interpretation – M.C.B., R.F.B., H.M.A., M.B.S.; Writing – S.A.; Critical review – S.A.

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REFERENCES 1. Kanaan I, Ahmed M, Rifai A, Alwatban J. Sphenoid sinus brown tumor of secondary hyperparathyroidism: case report. Neurosurgery 1998;42:1374–7. 2. Som PM, Lawson W, Cohen BA. Giant-cell lesions of the facial bones. Radiology 1983;147:129–34. 3. Monneuse O, Causeret S, Lifante JC, Berger N, Lapras V, Peix JL. Primary juvenile hyperparathyroidism. Report of 24 cases. Ann Chir 2002;127:276–80. 4. Yamazaki H, Ota Y, Aoki T, Karakida K. Brown tumor of the maxilla and mandible: progressive mandibular brown tumor after removal of parathyroid adenoma. J Oral Maxillofac Surg 2003;61:719–22. 5. Ahmad R, Hammond JM. Primary, secondary, and tertiary hyperparathyroidism. Otolaryngol Clin North Am 2004;37:701–13.

North Clin Istanb 6. Atabek ME, Pirgon O, Sert A, Esen HH. Extensive brown tumors caused by parathyroid adenoma in an adolescent patient. Eur J Pediatr 2008;167:117–9. 7. Hoshi M, Takami M, Kajikawa M, Teramura K, Okamoto T, Yanagida I, et al. A case of multiple skeletal lesions of brown tumors, mimicking carcinoma metastases. Arch Orthop Trauma Surg 2008;128:149–54. 8. Daniels JS. Primary hyperparathyroidism presenting as a palatal brown tumor. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98:409–13. 9. Cupisti K, Raffel A, Dotzenrath C, Krausch M, Röher HD, Schulte KM. Primary hyperparathyroidism in the young age group: particularities of diagnostic and therapeutic schemes. World J Surg 2004;28:1153–6. 10. Pallan S, Rahman MO, Khan AA. Diagnosis and management of primary hyperparathyroidism. BMJ 2012;344:e1013.

Case Report

GENERAL SURGERY

North Clin Istanb 2018;5(4):365–369 doi: 10.14744/nci.2018.09124

Treatment choice in metaplastic breast cancer: A report of 5 cases Turan Acar,1

Nihan Acar,1

Betul Bolat Kucukzeybek,3

Gulten Sezgin,2

Melek Bekler Gokova,1

Mehmet Haciyanli1

Department of General Surgery, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey

Department of Interventional Radiology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey

Department of Pathology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey

ABSTRACT Metaplastic breast carcinoma (MBC) is a general term defining a heterogeneous group that includes biphasic lesions, with both malignant epithelial and mesenchymal tissue components. Although its clinical findings are similar to those present in invasive ductal carcinoma, it rarely presents with the findings of inflammatory breast cancer. It is generally seen in the fifth decade. MBC spreads via lymph and blood circulation. Most common distant metastasis areas include lungs and the bone. Although the treatment generally relies on the same principles applied in invasive ductal carcinoma, a more aggressive treatment should be employed in at-risk groups due to higher rates of local recurrence. In this study, we aimed to discuss clinicopathological features and treatment approach in 5 women with MBC. Keywords: Breast; cancer; lymph; metaplastic; node; sentinel.

Cite this article as: Acar T, Acar N, Sezgin G, Bekler Gokova M, Kucukzeybek BB, Haciyanli M. Treatment choice in metaplastic breast cancer: A report of 5 cases. North Clin Istanb 2018;5(4):365–369.

etaplastic breast carcinoma (MBC) is a rare lesion, comprising less than 1% of all malignant breast tumors [1, 2]. It is a biphasic tumor, containing both malignant epithelial and mesenchymal tissue components [2]. The World Health Organization classifies metaplastic breast carcinoma into 2 groups: epithelial and mixed type [3]. However, the more popular Wargotz–Norris [4, 5] classification divides MBC into 4 subtypes: spindle cell, squamous cell, carcinosarcoma, and matrix-producing type. This tumor is generally large in size and has a poor prognosis [6]. The lymph node involvement is less common when compared to other breast cancers [7]. The treatment strategy is very important, especially for patients with local recurrence and poor prognosis. Therefore, in this paper, we aim to discuss clinicopathological features and treatment approaches to MBC using records of 5 patients.

CASE REPORT Table 1 presents the clinical and morphological findings of patients. One hundred and 10 patients with breast cancer were operated between November 2010 and December 2014. Metaplastic breast carcinoma was diagnosed in 5 of these patients. All relevant patient files were reviewed retrospectively. There were 5 women with the mean age of 52.2 years (36–63 years) in this case series. Four of them were postmenopausal women. A common complaint was a palpable mass, which had been there for a long time, but started growing rapidly in the recent period. Only 1 patient had positive family history (her sibling underwent surgery with the diagnosis of breast cancer) as a risk factor. On physical examination, there was a firm, solid,

Received: August 17, 2017 Accepted: February 01, 2018 Online: August 08, 2018 Correspondence: Dr. Turan ACAR. Izmir Katip Celebi Universitesi, Ataturk Egitim ve Arastirma Hastanesi, Genel Cerrahi Klinigi, Izmir, Turkey. Phone: +90 232 329 35 35 e-mail: drturanacar1982@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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Table 1. Demographic characteristics and morphological findings

Case 1

Case 2

Case 3

Case 4

Case 5

Gender Female Female Female Female Female Age 61 63 46 55 36 Family history – – + – – Localization Left upper-outer Right upper-outer Left upper-outer Right upper-inner Right upper-outer quadrant quadrant quadrant quadrant quadrant Mammography findings BI- RADS 4 BI- RADS 5 BI- RADS 4 BI- RADS 5 BI- RADS 5 Fine-needle aspiration Suspicious Malignant Biphasic tumor Malignant Malignant biopsy/ cytology cytology (fibroadenoma or cytology cytology Tru-Cut biopsy phyllodes tumor) (Tru-Cut biopsy) Treatment Segmental Mastectomy **BCS ***MRM MRM MRM + *SLNB Tumor diameter 20 25 75 10 25 (mm) Axilla 0/4 1/19 2/14 0/16 0/21 Metaplastic Matrix-producing Matrix-producing – – Squamous cell component type type carcinoma Stage T2N0M0 T2N1M0 T3N1M0 T1N0M0 T3N0M0 Estrogen receptor – – + – – Progesterone receptor – – + – – cerbB2 – – – – – Systemic treatment RT**** KT +RT *****KT – Neo-adjuvant KT + (Adjuvant) (Adjuvant) (Adjuvant) Adjuvant RT Follow-up (months) 40 40 23 56 11 Local recurrence – – – – – Distant metastasis – – – + (bone) + (bone) *SLNB: Sentinel lymph node biopsy; **BSS: Breast sparing surgery; ***MRM: Modified radical mastectomy; ****RT: Radiotherapy; *****CT: Chemotherapy.

fixed, and palpable lump at the upper-outer quadrant in the left breast in 3 patients; at the upper-outer quadrant in the right breast in 1 patient; and at the upper-inner quadrant in the right breast in 1 patient. The Breast Imaging-Reporting and Data System (BI-RADS) Category 4 breast lesions were detected in 2 patients, and the BI-RADS Category 5 breast lesions were detected in 3 patients on the mammogram (Fig. 1). The neo-adjuvant chemotherapy (CT) was planned for 1 patient due to locally advanced disease. The patient was referred to neo-adjuvant CT after confirmation of diagnosis by TruCut biopsy. A fine-needle aspiration biopsy (FNAB) was performed in remaining patients. Malignant cytology was revealed in 2 patients, suspicious cytology in 1 patient, and suspicion regarding biphasic tumor (fibroadenoma or phyllodes tumor) in 1 patient. Neo-adjuvant chemotherapy was offered to patient whose tumor was 75 mm in

diameter, but she chose surgery as the primary treatment. No distant metastases were detected by screening tests. Modified radical mastectomy (MRM) was performed in 2 patients, 1 who underwent neo-adjuvant CT and 1 who had diffuse ductal carcinoma in situ (DCIS) areas in the frozen section; while the left-segmental mastectomy and sentinel lymph node biopsy (SLNB) were performed in 1 patient and breast conserving surgery (BCS) in 1 patient. According to a histopathological evaluation, a matrix-producing subtype was detected in 2 patients, and squamous cell carcinoma was detected in 1 patient, while histological subtype was not reported in remaining 2 patients (Fig. 2). Four patients were estrogen-receptor(ER), progesterone-receptor- (PR), and HER2-negative, while 1 patient was ER and PR positive, but HER2 negative. The mean follow-up duration was 34 months (11–56 months). None of the patients experienced a lo-

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Figure 1. (A) On mammography, a high-intensity mass-like opacity (5x4 mm in size) with relatively irregular margins was seen at the upper-outer quadrant next to the axillary tail in the right breast (marked with a circle). (B) On sonography, it was seen that the opacity on the mammography represents a heterogeneous, hypoechoic solid mass lesion (51x32x26 mm in size) with cystic appearance at inferior and malignant features (marked with a circle). cal recurrence during their follow-up, while further treatment was planned due to bone metastases in 2 patients. Written informed consent was obtained from all patients. DISCUSSION MBC is a rare, high-grade, biphasic breast cancer, which contains both malignant epithelial and mesenchymal A

tissue components. These tumors show no specific appearance on neither mammogram nor sonography. It is mandatory to identify both histological components together for diagnosis. For this reason, it is extremely difficult to diagnose by a FNAB. Most tumors are sporadic, but they also may originate from previous lesions, such as spindle cell carcinoma, papilloma, complex sclerosing lesion, or fibroadenoma [8]. MBC contains sarcoma-like spindle cell areas and areas with squamous, chondroid, osseous differentiation together with adenocarcinoma. MBC is divided into 4 subtypes according to the Wargotzâ&#x20AC;&#x201C;Norris [4, 5] classification: spindle cell, squamous cell, carcinosarcoma, and matrix-producing type. It is essential to make this classification, because prognosis varies between subtypes, with the squamous subtype having the worst prognosis. MBC mostly occurs in the fifth decade, just as invasive ductal carcinomas [9]. The patients most commonly present with large tumors varying from 1.4 to 9.5 cm (mean, 3.7 cm) in diameter [10]. As seen in our cases, majority of patients are ER-, PR-, and HER2-negative [9, 11]. Therefore, they are termed â&#x20AC;&#x153;triple negative.â&#x20AC;? It is known that there is a high p53 gene expression, which plays an important role in epithelial proliferation and differentiation. Higher expression of p53 is a poor prognostic factor. In addition, these tumors stain for S100, actin, desmin, vimentin, EMA , and keratin in varying degrees. In our cases, tumors stained positively for S100, vimentin, actin, and keratin in general. MBC spreads through the lymph and blood circulation. Early hematogenous spreading frequently involves lungs and the bone. The hematogenous spreading route is particularly more common in the subtypes with predominant sarcomatoid spectrum. When compared to adenocarcinomas, the risk of distant metastasis is higher, C

Figure 2. (A) Tumor composed of squamous cells showing features (H&Ex10). (B) Tumor composed of squamous cells showing features (H&Ex4). (C) Positive cytokeratin 5/6 staining by immunohistochemically (Cytokeratin 5/6x10).

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while the risk of lymph node involvement is lower in MBCs [12, 13]. In a case series, the rate of lymph node metastasis was reported as 8%. Rates of axillary metastasis vary depending on tumor morphology. We performed the axillary dissection in 4 of our patients and detected metastatic lymph node involvement in 2 of these patients. The SLNB was performed in remaining 1 patient. In addition, bone metastases had occurred in 2 patients at an early period during 32 months of the mean follow-up, while remaining 3 patients showed no local recurrence or distant metastasis. The 3-year disease-free survival (DFS) of MBC patients varies from 15% to 76%, and the 3-year overall survival (OS) varies from 48% to 91% [13, 14]. In another series [15], the 5-year OS rates were reported as 73%, 59%, 4%, and 0% in the order of stages I, II, III, and IV, respectively. These rates reveal that MBC has a poorer prognosis than infiltrative ductal carcinoma. The tumor size is a more valuable prognostic feature than the axillary lymph node metastasis. Considering the fact that patients with larger tumors have higher recurrence rates and poorer prognosis, mastectomy is recommended rather than BCS [6, 16]. The selection of surgical procedure may affect the 5-year DFS [17]. In the literature [17, 18], it has been suggested that adjuvant hormonotherapy (HT), and CT would be more effective according to the receptor status of primary tumor and prognostic criteria. Radiotherapy has an important role in adjuvant treatment, particularly in those who underwent BCS. Adjuvant CT is still controversial. There are several studies that support adjuvant CT, especially in Stage 1 and Stage 2 patients. On the contrary, Bae et al. showed that there is no survival benefit of adjuvant CT in metaplastic carcinoma [19]. None of our patients received adjuvant CT or RT. Adjuvant RT is also recommended in patients who underwent breast sparing surgery, just as in patients with invasive ductal carcinoma and those patients with tumors of 4 cm or larger and/or with 4 or more lymph node metastases, according to the study by Tseng et al. [20]. The Tumor–Node–Metastasis Classification of Malignant Tumor (TNM) was used for staging, and they were the following in our patients (in order): IIA, IIB, IIIA, IA, and IIA. All patients were informed comprehensively regarding their diseases. Only 1 patient underwent segmental mastectomy and SLNB due to having an early stage disease, while BCS was performed in 1 patient,

North Clin Istanb

and MRM was performed in 3 patients—1 who received neo-adjuvant CT and 2 who had diffuse DCIS areas. Conclusion Although the MBC treatment shares similar principles with the infiltrative ductal carcinoma treatment, more aggressive treatments should be applied in groups with risk features due to higher rates of local recurrence and poorer prognosis. However, because of lower axillary metastasis rates, the SLNB will be a more appropriate approach, rather than routine axillary dissection, to reduce postoperative morbidity. Acknowledgments: The authors thank all the general surgery staff for their cooperation. The authors have no conflict of interest and no financial issues to disclose. All the authors read and approved the paper. All human breast tissues were collected with written informed consent from patients prior to participation in the study. Informed Consent: Written informed consent was obtained from the patient for the publication of the case report and the accompanying images. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – T.A.; Design – T.A.; Supervision – T.A.; Materials – T.A., G.S., M.B.G.; Data collection &/or processing – T.A.; Analysis and/or interpretation – T.A. G.S., M.H.; Writing – T.A., B.B.K.; Critical review – N.A., B.B.K., M.H.

REFERENCES 1. Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ. WHO classification of tumors of the breast World Health Organization classification of tumours. 4th. Lyon: IARC Press; 2012. p. 48–52. 2. Breast Cancer from Molecular Point of View: Pathogenesis and Biomarkers.Available at: https://www.intechopen.com/books/breast-cancer-focusing-tumor-microenvironment-stem-cells-and-metastasis/ breast-cancer-from-molecular-point-of-view-pathogenesis-andbiomarkers. Accessed July 5, 2018. 3. DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin 2014;64:52–62. 4. Luini A, Aguilar M, Gatti G, Fasani R, Botteri E, Brito JA, et al. Metaplastic carcinoma of the breast, an unusual disease with worse prognosis: the experience of the European Institute of Oncology and review of the literature. Breast Cancer Res Treat 2007;101:349–53. 5. Yang WT, Hennessy B, Broglio K, Mills C, Sneige N, Davis WG, et al. Imaging differences in metaplastic and invasive ductal carcinomas of the breast. AJR Am J Roentgenol 2007;189:1288–93. 6. Lai HW, Tseng LM, Chang TW, Kuo YL, Hsieh CM, Chen ST, et al. The prognostic significance of metaplastic carcinoma of the breast (MCB)--a case controlled comparison study with infiltrating ductal carcinoma. Breast 2013;22:968–73. 7. Song Y, Liu X, Zhang G, Song H, Ren Y, He X, et al. Unique clini-

Acar et al., Metaplastic breast cancer

copathological features of metaplastic breast carcinoma compared with invasive ductal carcinoma and poor prognostic indicators. World J Surg Oncol 2013;11:129. 8. Leddy R, Irshad A, Rumboldt T, Cluver A, Campbell A, Ackerman S. Review of metaplastic carcinoma of the breast: imaging findings and pathologic features. J Clin Imaging Sci 2012;2:21. 9. Choi BB, Shu KS. Metaplastic carcinoma of the breast: multimodality imaging and histopathologic assessment. Acta Radiol 2012;53:5– 11. 10. Kuo SH, Chen CL, Huang CS, Cheng AL. Metaplastic carcinoma of the breast: analysis of eight Asian patients with special emphasis on two unusual cases presenting with inflammatory-type breast cancer. Anticancer Res 2000;20:2219–22. 11. Tse GM, Tan PH, Putti TC, Lui PC, Chaiwun B, Law BK. Metaplastic carcinoma of the breast: a clinicopathological review. J Clin Pathol 2006;59:1079–83. 12. Park HS, Park S, Kim JH, Lee JH, Choi SY, Park BW, et al. Clinicopathologic features and outcomes of metaplastic breast carcinoma: comparison with invasive ductal carcinoma of the breast. Yonsei Med J 2010;51:864–9. 13. Gultekin M, Eren G, Babacan T, Yildiz F, Altundag K, Guler N, et al. Metaplastic breast carcinoma: a heterogeneous disease. Asian Pac J

369 Cancer Prev 2014;15:2851–6. 14. Esbah O, Turkoz FP, Turker I, Durnali A, Ekinci AS, Bal O, et al. Metaplastic breast carcinoma: case series and review of the literature. Asian Pac J Cancer Prev 2012;13:4645–9. 15. Ilhan E, Vardar E, Ozkok G, Sezgin A, Sahin S, Teker K, et al. A rare tumour of the breast: carcinosarcoma. J Clin Med Res 2010;2:96–8. 16. Nelson RA, Guye ML, Luu T, Lai LL. Survival outcomes of metaplastic breast cancer patients: results from a US population-based analysis. Ann Surg Oncol 2015;22:24–31. 17. Lee H, Jung SY, Ro JY, Kwon Y, Sohn JH, Park IH, et al. Metaplastic breast cancer: clinicopathological features and its prognosis. J Clin Pathol 2012;65:441–6. 18. Brown-Glaberman U, Graham A, Stopeck A. A case of metaplastic carcinoma of the breast responsive to chemotherapy with Ifosfamide and Etoposide: improved antitumor response by targeting sarcomatous features. Breast J 2010;16:663–5. 19. Bae SY, Lee SK, Koo MY, Hur SM, Choi MY, Cho DH, et al. The prognoses of metaplastic breast cancer patients compared to those of triple-negative breast cancer patients. Breast Cancer Res Treat 2011;126:471–8. 20. Tseng WH, Martinez SR. Metaplastic breast cancer: to radiate or not to radiate? Ann Surg Oncol 2011;18:94–103.

Invited Review

CARDIOLOGY

North Clin Istanb 2018;5(4):370–378 doi: 10.14744/nci.2017.60251

Bayés’ syndrome: Time to consider early anticoagulation? Adrian Baranchuk,1

Bryce Alexander,1

Ahmet Ilker Tekkesin,2

Roberto Elousa,4

Goksel Cinier,2

Manuel Martinez-Selles,3

Antoni Bayes De Luna5

Department of Cardiology, Kingston General Hospital, Queen’s University, Kingston, Ontario, Canada

Department of Cardiology, Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey

Department of Cardiology, Hospital Universitario Gregorio Marañón, CIBERCV, Universidad Complutense, Universidad Europea, Madrid, Spain

Hospital de la Santa Creu i Sant Pau, Cardiovascular Research Center, CSIC-ICCC, Barcelona, Spain

Department of Cardiology, Hospital del Mar Medical Research Institute, Barcelona, Spain

ABSTRACT In the past few decades, extensive research has been conducted on atrial conduction disorders and their clinical relevance. An association between interatrial block (IAB) and supraventricular arrhythmias [most commonly atrial fibrillation (AF)] has been discovered and extensively investigated. We coined the term “Bayés Syndrome” to describe this association, and the medical community has accepted the eponym in recognition to the scientist who discovered most of the aspects associated with it. In this non-systematic review, we will focus on the association between IAB and AF, with special emphasis on the value of the surface 12-lead ECG as a valid tool to predict AF. Keywords: Atrial fibrillation; bayes syndrome; interatrial block.

Cite this article as: Baranchuk A, Alexander B, Cinier G, Martinez-selles M, Tekkesin AI, Elousa R, et al. Bayés’ syndrome: Time to consider early anticoagulation? North Clin Istanb 2018;5(4):370–378.

nteratrial block (IAB) is a distinct electrocardiographic pattern that has been studied with growing interest since it was first described in 1979 by Bayés de Luna [1]. The conduction delay seen in IAB is thought to be mediated by the Bachmann region, which is the largest and most common anatomical route for interatrial conduction during a normal sinus rhythm [2–6]. IAB results from a conduction delay between the atria, and like other blocks can be classified into degrees [6]. Partial (first degree) IAB (pIAB), which is much more common, manifests as a prolongation of the P-wave (Pwave duration ≥120 ms) (measured in the inferior leads: II, III, and aVF) without any other significant abnormality [6, 7]. This prolongation is thought to occur when the electrical impulses from the right atrium continue

to conduct via a partially blocked Bachmann region [7]. Advanced (third degree) IAB (aIAB) is less frequent and is represented on ECG as a biphasic (±) P-wave in the inferior leads in addition to the elongated P-wave described above (Fig. 1). aIAB is thought to occur when the sinus impulses can no longer pass via the Bachmann region or other preferential conduction tracts. Instead, the net electrical vector goes toward the AV node as the right atrium depolarizes through the internodal pathways, following which the left atrium is depolarized in a caudocranial direction starting at a crossing point at the inferior aspect of the left atrium near the atrioventricular node (most frequently the coronary sinus, and in small proportion, the fossa ovalis) [7]. This superior-inferiorsuperior activation pattern is what is thought to result

Received: September 10, 2017 Accepted: October 10, 2017 Online: May 23, 2018 Correspondence: Dr. Goksel CINIER. Dr. Siyami Ersek Gogus Kalp ve Damar Cerrahisi Egitim ve Arastirma Hastanesi, Kardiyoloji Klinigi, Istanbul, Turkey. Tel: +90 216 542 44 44 e-mail: cinierg@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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P-IAB

A-IAB

I I II II

III

aVR

III

aVR

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changes to the atria that result in IAB may be reversed with specific therapies. A reduction in the P-wave duration has been noted in several studies, indicating that the pathological process leading to IAB may be dynamic. This reverse atrial remodeling supports the idea that the development and progression of IAB depends on insults to the atrium in a time-dependent manner and is not a single permanent event. The recent demonstration of the atrial fibrotic process using cardiac magnetic resonance reconfirms the ECG/VCG observations [10, 11]. More recently, sophisticated echocardiographic studies using “speckle tracking” have also demonstrated the activation pattern and physiopathological mechanisms described above [12].

Pathophysiology aVL

aVL

aVF aVF

Figure 1. The most common types of IAB are partial (P-IAB) and advanced (A-IAB). Note the calipers simultaneously measuring the P-wave onset and P-wave offset in all lead limbs in the biphasic (±) P-wave seen on the inferior leads [6] (Fig. 2). Although few studies have examined the histological and pathophysiological changes that accompany partial or complete blockade of this interatrial conduction pathway, it is reasonable to believe the same underlying structural remodeling process may be responsible for both partial and advanced IAB. There is emerging evidence that atrial remodeling resulting from progressive fibrosis of the interatrial conduction system or from changes in the electrical properties of the atrial myocytes play a role [8, 9] (Fig. 3). If IAB is truly a progressive process, temporal modification of the P-wave would be expected to occur, a phenomenon which has been documented in several studies and case reports. Interestingly, there is recent evidence that in certain conditions, the

Atrial conduction The Bachmann Bundle (BB), first described in 1916, is the most common anatomical route for interatrial conduction during sinus rhythm [2–5]. BB (although we consider that the proper term should be “Bachmann region”) is a broad, muscular band that originates from the anterior internodal pathway as it emerges from the anterior lip of the sinoatrial node. It is composed of a trapezoid, band-like bundle of parallel fibers that follow the superior segment of the interatrial sulcus [13]. The role of this bundle is to allow for rapid conduction between the atria, allowing for synchronously timed atrial contraction [8]. Additional interatrial conduction routes have also been described at the level of the fossa ovalis [14, 15] and coronary sinus [16–18], which may also play a role in electrical impulse propagation between the atria [19]. BB is thought to mediate IAB because the experimental interruptions of BB in a canine model reproduced the classic wide P-waves with±morphology of aIAB [20]. Among other evidence, a study by Cosio et al. [4] showed that in two human cases with ECG evidence of advanced atrial block, the timing of activation over the left atrial roof was consistent with a block of the Bachmann region. While the macro scale conduction disturbances of IAB have been well correlated with a disruption of the Bachmann region, few studies have observed the mechanism through which this disruption occurs. Structural atrial remodeling Reduced atrial contractility, fibrosis development, and atrial enlargement are the main components of atrial structural remodeling [21]. The ability of atrial fibrosis to delay cardiac electrical conduction has been well documented [22–24]. It has been demonstrated in humans

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Scheme of atrial activation

P loop in F.P.

P wavw in lead ‘y’

Partial block Advenced block

N.A.C.

Partial I.A.B

Advenced I.A.B with R.C.L.A.

Figure 2. Traditional diagram from the original papers of Bayés de Luna to explain the delay of conduction in the Bachmann region and the retrograde activation of the left atrium. Evaluate ECG-VCG diagnostic criteria; To study the prevalence; Relationship with LAE; Relationship with P.T.

Figure 3. Progressive IAB. Note the prolongation of the Pwave and the appearance of the final negative component over time that reactive fibrosis accompanying the reparative fibrosis of degenerating myocytes can cause interstitial expansion, which in turn can cause a separation of surviving myocytes and a deterioration of intermyocyte coupling, creating a barrier to impulse propagation [22–24]. Atrial fibrosis is the common end pathway for various cardiac

insults, which share common molecular fibrotic pathways [22]. The cellular mechanisms underlying atrial fibrosis are not entirely clear; however, there is emerging evidence that a multifactorial process involving complex interactions between neurohormonal and cellular mediators is responsible [24]. It has been hypothesized that IAB results from fibrotic atrial remodeling due to reduction of the blood supply (ischemia) to the Bachmann region [8, 25]. Supporting this hypothesis, coronary artery disease and hypertension have been described as leading risk factors for IAB [25]. The sinoatrial nodal (SAN) artery and its branches provide the main arterial blood supply to this region [26]. The SAN artery may arise from the proximal or mid portions of the right coronary or left circumflex arteries [8]; however, the majority of the time the origin is the right coronary artery [26]. Ariyarajah et al. [26] demonstrated in 2007 that in patients with significant coronary artery disease (>70% stenosis) and IAB, RCA (compared with LCx) was the artery affected in the majority of cases. Since

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this correlates with a blockage of the most common blood supply of the Bachmann region, the authors postulated that ischemia of the Bachmann region and resulting fibrosis predispose the development of IAB. In 2008, Saremi et al. performed a retrospective trial using computed tomographic angiography [8, 27]. They found that patients with severe coronary artery disease and IAB or atrial fibrillation (AF) had higher structural changes and a less well-visualized Bachmann region8. Although the role of atrial fibrosis in the development of interatrial block is still unproven, it is a leading candidate among possible structural etiologic agents.

Figure 4. AHRE episode detected by a dual-chamber pacemaker. Note AF in the electrogram recorded and stored by the device. AR: atrial refractory; AS: atrial sensing; VP: ventricular pacing; VS: ventricular sensing

Activation of fibroblasts (age, HTA, diabetes, HF, etc)

Genetics

Triggers (prem.atrial.com)

ATRIAL REMODELING

FIBROTIC ATRIAL CM ATRIAL FIBRILLATION

A-LAB (risk factor for AF)

LA hypocontractile ‘‘f’’ (waves)

LA with abnormal contractility and flow velocity in LAA

ATRIAL REMODELING Activation PAR for thrombin

ATRIAL REMODELING

Blood stasis Hypercogulation ATRIAL FIBROSIS

Thrombogenic cascade SYSTEM EMBOLISM

Figure 5.

Diagram integrating IAB, atrial fibrosis, and the activation of pro-coagulation states and AF.

CM: Cardiomyopathy; HF: Heart failure; AF: Atrial fibrillation

How to measure the P-wave? In the surface ECG, the measurement of the P-wave and the diagnosis of IAB can be done at the first glance if the ECG recording and morphology in leads II, III, and aVF is clear and free of artifacts or pacing spikes. The diagnosis of aIAB may be done after the consensus paper published in 20126 following the criteria established by Bayés de Luna already in 19891. To be sure about the measurement of the P-wave in difficult cases (and for research purposes), consistency in the measurements is key. Analyzing digitalized ECG images using amplification as well as using ECG systems that allow at least three simultaneous channels (six or 12 channels are ideal) is paramount (Fig. 1). Particular attention should be given to the six leads of the frontal plane simultaneously because it is where we will better identify the changes to the P-wave duration and morphology produced by IAB. However, the horizontal plane leads, particularly lead V1, are also important (Morris index and P-terminal force in lead V1) and should be checked for the possible diagnosis of associated LA enlargement. To perform a good measurement of the P-wave duration, it is important to check and define the interval between the earliest detection of the P-wave (onset) in any lead of the frontal plane and the latest one (offset). Once these two points are defined with lines, the P-wave duration can be measured using calipers or semi-automatic calipers [28]. Bayés Syndrome: IAB as a predictor of AF general considerations The association between IAB and supraventricular arrhythmias (mostly AF) has been initially described by Bayés de Luna and subsequently demonstrated in many different clinical scenarios. This association, recently termed as “Bayés Syndrome,” has important clinical implications [28–32]. The early identification of the ECG

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pattern would prompt more extensive cardiac monitoring searching for AF. This would allow early initiation of oral anticoagulation to prevent stroke. An interesting hypothesis has been advanced to consider early full oral anticoagulation in patients with aIAB but non-documented AF (NDAF). In this section, we will review the relationship between IAB and AF in different clinical scenarios. IAB as a predictor of post-cardioversion AF recurrence In 2014, Enriquez et al. [33] conducted a study to determine whether IAB predicted AF recurrence following pharmacological cardioversion. They included 61 patients with recent-onset AF and no structural heart disease who recently underwent cardioversion with one of the two antiarrhythmic drugs. Thirty-one patients received a single oral dose of propafenone, whereas 30 patients received IV vernakalant. A 12-lead ECG following conversion was evaluated for the presence of partial or advanced IAB. Clinical follow-up and electrocardiographic recordings were performed for a 12-month period. aIAB was present in 18% of the population and partial IAB in 16.4% of the population. Overall AF recurrence was 36%, with a 90.9% recurrence in patients with aIAB versus 70% in those with partial IAB. In patients without IAB, there was a 12.5% recurrence rate (p=0.001) [33]. A multivariate analysis found IAB to be independently associated with AF recurrence (odds ratio, 18.4) [33]. The study confirms that aIAB is strongly associated with a higher risk of AF recurrence 1 year following pharmacological cardioversion, independent of the antiarrhythmic drug used. IAB as a predictor of post-pulmonary vein isolation AF recurrence Pulmonary vein isolation is only successful in 70%–80% of cases and often requires a repeat procedure, indicating that electrical abnormalities outside of the pulmonary veins may be involved in the pathogenesis of recurrent paroxysmal AF in this population. Caldwell et al. [34] studied a cohort of 114 patients who underwent pulmonary vein isolation to test the hypothesis that patients with IAB have a higher rate of paroxysmal AF recurrence than those without IAB. They analyzed 12-lead ECGs for all patients for the presence of IAB as well as P-wave dispersion and followed patients for paroxysmal AF recurrence. They found that patients with aIAB had a higher rate of paroxysmal AF recurrence than those without IAB (66.6% vs. 40.3%; p=<0.05), indicating that IAB is a predictor of AF in the post-pulmonary vein isolation population [34].

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IAB as a predictor of post-atrial flutter ablation AF recurrence Cavotricuspid isthmus ablation is the first-line curative therapy for typical atrial flutter and has a success rate of >90%. Enriquez et al. [35] hypothesized that aIAB is associated with an elevated risk of AF in patients who underwent catheter ablation for typical atrial flutter. They studied a cohort of 187 patients with typical atrial flutter and no AF history. Patients with repeat ablations or no evidence of bidirectional block were excluded from the study. The mean age of the population was 67 years. Over a mean follow-up period of 24.2 months, they found that patients with aIAB had a higher rate of recurrence of new-onset AF than those without aIAB (64.7% vs. 29.4%; p=<0.001)[35]. After a comprehensive multivariate analysis, aIAB was determined to be the strongest predictor of AF (odds ratio, 4.2; 95% confidence interval, 1.9–9.3; p=<0.001). Therefore, this study indicates that IAB is a predictor of new-onset AF in the post-cavotricuspid isthmus ablation population [35]. IAB as a predictor of new-onset AF in patients with chagas disease Chagas cardiomyopathy is an endemic disease in Latin America. Patients with Chagas cardiomyopathy usually present with a low ejection fraction, and some patients have an ICD device implanted for primary or secondary prevention. A significant proportion of these patients develop AF, which may result in stroke, embolism, and inappropriate ICD shock. This is associated with increased morbidity and/or mortality. For this reason, Enriquez et al. investigated IAB as a possible predictor for AF in this population [36]. They conducted a retrospective study of patients with Chagas cardiomyopathy and ICDs from 14 centers in Latin America. The presence of advanced or partial IAB was identified, and the patients were followed up over a 33-month period for evaluating new-onset AF36. The mean age was 54.6 years, the mean ejection fraction was 49%, and the presence of IAB was 18.8% (10% advanced, 8.8% partial). During the follow-up period, AF occurred in 13.8% of the patients and was significantly greater in the group with IAB (advanced and partial) than in the group without IAB (73.3% vs. 0%; p<0.0001). The number of inappropriate ICD shocks was significantly higher in the group with IAB (p=0.014). In conclusion, IAB predicts new-onset AF in patients with Chagas’ cardiomyopathy and ICDs [36].

Baranchuk et al., Bayés’ syndrome: Time to consider early anticoagulation?

IAB as a predictor of new-onset AF in patients with NSTEMI IAB is thought to occur via partial or complete blockade of BB, the largest and most common anatomical route for conduction between the atria. It has been suggested that fibrotic remodeling of the atria may lead to IAB. Alexander et al. [25] hypothesized that a higher burden of coronary artery disease is associated with a higher prevalence of IAB in patients who present with NSTEMI due to fibrotic ischemic atrial remodelling. As a secondary outcome, they hypothesized that IAB is associated with new-onset AF in this population. They analyzed 322 consecutive patients who presented with NSTEMI and underwent both coronary angiography and a baseline ECG at a single center. The mean age of the population was 65.4 years. They found that the presence of diffuse coronary artery disease defined as >1 significant coronary artery lesion (≥70% occlusion) was associated with the presence of IAB (69.8% vs. 48.1%; p=0.026). In addition, they found that patients with IAB had a higher incidence of new-onset AF within 1 year than those without IAB (55.9% vs 36.1%; p=0.021) [25]. This study shows that in the general NSTEMI population, IAB is associated with the development of new-onset AF [25].

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population. The study included 112 patients with severe HF receiving an implanted cardiac resynchronization device. These patients had no AF history and 65% of HF was due to ischemic heart disease. The mean age was 67 years, and 37.2% of patients had aIAB. After 30 months of follow-up, new-onset AF occurred in 29% of the patients. The prevalence of AF was significantly higher in the group with aIAB than in the group without aIAB (50% vs. 17% respectively; p<0.001) [38]. In a multivariate analysis, older age (OR, 1.06; 95% CI, 1.002–1.130; p=0.04) and aIAB (OR, 4.91; 95% CI, 2.06–11.69; (p<0.001) were independent predictors of AF occurrence. In summary, IAB was detected in more than one third of this population. It was an independent predictor of AF in patients with severe HF undergoing cardiac resynchronization device implantation with no AF history [38].

IAB as a predictor of post-transcatheter aortic valve replacement new-onset AF The transcatheter aortic valve replacement (TAVR) procedure was first performed in 2002 and has since become an increasingly popular procedure for those deemed to be at a high risk for TAVR. Alexander et al. [37] conducted a retrospective study of one hospital in Canada and one hospital in Spain to examine the association of aIAB and new-onset AF in the TAVR population. ECGs were analyzed for the presence of IAB. Patients were followed up for a minimum of 1 year to determine the incidence of new-onset AF. The population had a mean age of 83 years. New-onset AF occurred more frequently in patients with aIAB at baseline than those without aIAB (42.9% vs. 22.9%; p=0.14) [37]. This study indicates that aIAB is associated with new-onset AF in the postTAVR population [37].

IAB as a predictor of atrial high-rate episodes in patients with cardiac devices Recent studies suggest that asymptomatic paroxysmal atrial fibrillation (PAF) episodes occur more frequently than symptomatic PAF [39]. Technological advances in long-term ECG monitoring particularly in patients with cardiac implantable electronic devices enabled clinicians to diagnose asymptomatic PAF episodes, namely atrial high-rate episodes (AHRE) (Fig. 4). Subsequent studies established the predictive role of AHRE as a harbinger of future symptomatic AF and ischemic stroke [39–41]. Tekkesin et al. [42] evaluated the predictive value of IAB on the occurrence of AHRE in 367 patients with dualchamber pacemakers implanted due to sinus node dysfunction. Standard 12-lead surface ECG was performed to patients before device implantation to diagnose IAB. AHRE was detected in 107 patients (30.1%) during device interrogation 6 months after the implantation. Study patients were divided into two groups according to the presence of AHRE in their device interrogation. Sixty-seven (27%) patients in AHRE (−) group had IAB, whereas 48 (44.9%) patients had in AHRE (+) group (p<0.01) [42]. This initial experience suggested that IAB was a predictor of future symptomatic as well as asymptomatic AF.

IAB as a predictor of new-onset AF in patients with severe heart failure Sadiq Ali et al. [38] further evaluated IAB in patients with advanced heart failure (HF) requiring cardiac resynchronization therapy (CRT). They sought to determine whether IAB could predict new-onset AF in this

IAB as a predictor of AF in the general population P-wave prolongation has shown a strong association with the development of AF in the general population. The two epidemiological studies that more clearly showed the relation of IAB with the risk of AF are the Atherosclerosis Risk in Communities (ARIC) study [43] and

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the Copenhagen ECG Study [44]. In both cases, it was shown that IAB, particularly aIAB, is associated with an increased risk of AF. Also, in the ARIC cohort, the risk factors for developing aIAB were similar to those for developing AF.

Aging with IAB Aging gradually modifies the specialized cardiac conducting system, creating a milieu that facilitates the appearance of IAB [45]. IAB is related to atrial fibrosis, which produces a slowing of electrical transmission and atrial activation. The progressive degree of atrial fibrosis probably plays a central role in the increase of IAB prevalence with age [7]; moreover, fibrosis is associated with age and is per se a risk factor for stroke [46]. The P-wave duration is positively correlated to age, even in infancy [47]. IAB, practically inexistent in healthy children, is rare in younger adults (except in the case of cryptogenic stroke and patent foramen ovale), with a prevalence of only 16% in a control group with a mean age of 37 years. However, the prevalence of IAB increases with age [48, 49]. In septuagenarians, the prevalence is almost 40%50 and is >50% in those aged >80 years [48]. In the case of aIAB, the relation with age is even clearer. In the ARIC study [43], performed in a global population with mean age of 54 years, only 0.5% had aIAB at baseline; however, age had a strong effect as 1.3% developed aIAB during the mean 6-year follow-up. These authors found an incidence of 2.3 per 1.000 person-years for aIAB. This association with age is probably related to the fact that aging increases not only the rate of elderly population but also the prevalence of cardiovascular disease, a strong predictor of IAB. Moreover, the recent advances in the management of cardiac conditions are increasing the survival of patients with heart disease, particularly those who already have IAB or will acquire it during the course of their disease.

IAB and stroke The relevance of IAB is mainly related to its association with stroke, an association particularly strong in patients with aIAB [50, 51]. This association could be related, at least in part, to supraventricular arrhythmias and poor left atrium contractility. Conversely, IAB could just be a marker for the overall burden of cardiovascular disease. In the Cardiac and Clinical Characterization of Centenarians (4C) registry [49], the incidence of previous stroke in centenarians with IAB was high (reaching almost 30% in patients with aIAB). In the 4C registry,

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the relatively low incidence of stroke in centenarians with AF was probably related to the fact that patients with AF frequently benefit from anticoagulation therapy, whereas this is not the case in those with aIAB. Centenarians with IAB also presented a higher rate of dementia than those with a normal P-wave, a possible consequence of cerebral microinfarcts.

The BAYES registry An International Registry has been launched in October 2016 with almost 40 centers from all around the world looking after almost 700 patients, the BAYES (Interatrial Block and Yearly Events) registry [52]. This work will provide further insight into the ability of IAB to predict AF (in elderly populations with structural heart disease) using a simple and economical method such as the 12lead ECG. Patients are enrolled in three groups: normal P-wave, pIAB, or aIAB. More than 450 patients had been enrolled by September 2017, and we are collecting outcomes on new-onset AF, stroke, and dementia (using the Pfeiffer Score). We hope the registryâ&#x20AC;&#x2122;s results will contribute with data to support a randomized control trial of full oral anticoagulation vs. placebo in this population.

Is it time to consider oral anticoagulation in patients with IAB and NDAF? This is an attractive hypothesis [53]. The rationale relies in a series of observations that could lead us to believe that a randomized control trial for elderly patients with aIAB may be suitable: 1. Recently, implantable devices have demonstrated a lack of a clear temporal relationship between cryptogenic stroke and paroxysmal AF [54â&#x20AC;&#x201C;56]. Therefore, AF may not necessarily be the cause of stroke but rather another clinical risk factor. 2. There are many clinical and physiopathological similarities between AF and aIAB: a) Both processes increase with age b) Both processes present the same anatomical substrate: fibrotic atrial cardiomyopathy (CM) [57] c) Fibrotic atrial CM and atrial remodeling induce blood stasis, hypercoagulation, and more atrial fibrosis (Fig. 5) d) Finally, both AF and aIAB are risk factor for stroke [58] Before advancing a new recommendation for oral anticoagulation, a randomized controlled clinical tri-

Baranchuk et al., Bayés’ syndrome: Time to consider early anticoagulation?

al comparing the efficacy of NOACs in preventing stroke in patients with NDAF and aIAB is needed. If the results of this study are positive, a global strategy for anticoagulation to prevent stroke in patients with NDAF should be considered. Conclusions Bayés syndrome is a clinical electrocardiographic entity that encompasses the presence of IAB in the surface ECG and the detection of clinical or asymptomatic AF. IAB is a strong predictor of AF and stroke in many different clinical scenarios. Its proper identification may help prevent stroke in several patients, if early anticoagulation is considered. This hypothesis should be tested with a randomized control trial. Conflict of Interest: No conflict of interest was declared by the authors. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – A.B., G.C., A.B.L., M.M.S.; Design – A.B., B.A., A.I.T.; Supervision – R.E., A.B., A.B.L.; Materials – A.B., G.C.; Data collection &/or processing – A.B., B.A.; Analysis and/or interpretation – G.C., A.I.T.; Writing – A.B.; Critical review – A.B., A.B.L.

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Invited Review

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North Clin Istanb 2018;5(4):379–386 doi: 10.14744/nci.2018.68815

How to get ethics committee approval for clinical trials in Turkey? Hilal Ilbars,1

Berna Terzioglu Bebitoglu2

Turkish Medicines and Medical Devices Agency, Ankara, Turkey

Department of Medical Pharmacology, Istanbul Medeniyet University Faculty of Medicine, Istanbul, Turkey

ABSTRACT The “ethics committee approval” required to conduct clinical trials can be difficult to obtain for researchers due to problems with their time management, evaluating clinical investigations as a routine process as a part of their work; confusions regarding the concepts of treatment, interference, research and intervention, and sometimes due to lack of knowledge. Ethics committee approval process in our country is discussed by informing the investigators who want to conduct clinical research, about the issues that should be considered in accordance with the current legal regulations related to the clinical trials involving human volunteers. Keywords: Ethics committee; clinical trial; Turkey.

Cite this article as: Ilbars H, Terzioglu Bebitoglu B. How to get ethics committee approval for clinical trials in Turkey? North Clin Istanb 2018;5(4):379–386.

n this paper, within the frame of current legal regulations in Turkey, we mentioned about some issues which should be paid attention by those who want to conduct clinical trials, and discuss the ways of obtaining ethics committee approval. To obtain “ethics committee approval” required to conduct clinical researches can be difficult for researchers due to problems with their time management, evaluating clinical investigations as a part of their routine work; confusions regarding the concepts of treatment, interference, research and intervention, and sometimes due to lack of knowledge. Sometimes a critical perspective may be displayed against members of ethics committees. Ethics committees specified as “independent committees established to give scientific and ethical opinion about the trial to protect rights, safety and well-being of participants who are willing to participate in the trial” [1–3]. Why do we participate in clinical trials? Why there are

so many documents and rules? First of all, we need to understand the answers to these questions. The researcher may participate in clinical trials to gain experience about current applications, to have international recognition, to be able to follow studies performed in international area, to prepare his/her specialty thesis, to contribute to science, and to gain early access into new scientific information. From the perspective of participants, they wish to reach earlier to new information, researches, and treatment alternatives, to be able to be followed up by his/her physician more closely, and to lower his/her healthcare costs because the sponsors cover expenses of many required tests, examinations, and treatments [4]. Before starting to perform a new clinical trial, the researchers should apply to the ethics committee, and should know some concepts related to ethical rules, clinical trial regulations, ethical rules, and how to access them. Primarily one should discriminate between the concepts of “treatment” with “research”, and “interference” with

Received: February 15, 2018 Accepted: March 19, 2018 Online: December 11, 2018 Correspondence: Dr. Hilal ILBARS. Dr. Turkiye Ilac ve Tibbi Cihaz Kurumu, Ankara, Turkey. Tel: +90 551 554 71 70 e-mail: hilalilbars@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

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“intervention”. Turkish Linguistic Society defined these terms as follows [5]; Treatment: 1. noun: to cure or mitigate the disease using various methods, management, therapy 2. dealing with an issue in an attempt to correct or improve it Research: 1. noun: the act of investigating, search, examination, inspection 2. methodological study in the field of science and art, investigation Interference: 1. noun: undertaking, enterprise, attempt 2. physics: the process of coming together of two or more than two waves to the same point with resultant reinforcement or cancellation each other (interference). Some definitions found in the Dictionary of Medical Terms: Intervention: Interference, interposition, involvement; the approach of a psychoanalyst to a patient with suggestions so as to resolve his/her psychological problem. In psychiatry, the physician’s interference with the mental world of the patient so as to effect his/her way of conduct or thinking. The acts of a living creature aiming to change its environment or its relations with it [6]. Medical Intervention: Any kind of activity realized by legally authorized health professionals so as to diagnose, treat any physical and/or mental deficiency, disorder or disease, if not possible alleviate, prevent its progression, and worsening, its potential complications to be manifest in the future, and relieve pain in compliance with general rules, and principles demanded by the science of medicine. Medical intervention aims to protect health of an individual from harm, essentially it is directed at physical integrity of a person. This approach determined the relation between the physician, and the patient. Enlightment is the debt to be paid by the physician, but it is a right for a patient. Since each intervention performed by the physician will be illegal if informed consent of the patient is not obtained priorly, informed consent of the patient is the basic prerequisite for the compliance of medical intervention with relevant laws. Both the researhers and ethics committe members should know these terminology well and use them correctly and evaluate the study by knowing the Turkish equivalents of the English terms “invasive” and “intervention”. The researchers should not think that there is no

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need for gathering information, and submitting and documents such as budget, and ethics committee approval with the thought of “the study participant would already receive this treatment”, or “these interventions will be applied anyhow”, These concepts should be differentiated from each other, and essentials of legal regulations implemented in Turkey should be known even though not in detail. It is possible to access into regulations concerning clinical trials in Turkey from following links: www.mevzuat. gov.tr; www.resmigazete.gov.tr; www.titck.gov.tr. In general, some Laws, International Contracts, Regulations, Implementing Regulations, Legislations, Directives, Circular, Guidelines, Guiding documents and related articles are indicated in Table 1 [7–10]. It is obvious that researchers in Turkey do not know exactly where to apply for ethics committe approval and how to apply, which documents are required [11]. According to current regulations there exists three different ethics committee; “Clinical Trials Ethics Committee”, “Bioavailability/Bioequivalence Ethics Committee” and “Ethics Committees of Cosmetic Clinical Research Studies”. Apart from these, the “Ethics Committee of Non-Interventional Studies”, whose name is contraversial, is available in many academic institutions and often gives approval even for those interventional studies according to legislation that should be approved by “Clinical Trial Ethics Committee”. Besides, there are many boards with names “Ethics committee of clinical trials with non-pharmaceutical products”, “Ethics commissions”, that provide ethics committee approvals for clinical researches with human volunteers. However as stated above only three ethics committees evaluate researches covered by relevant regulations. The locations of ethics committees can be found in the website “www. titck.gov.tr”. However this website should be updated with links of ethics committees and their updated contact information. According to the “Health Services Fundamental Law” Article 10-(Annex: 6/4/2011-6225/8) (Amended section: 2/1/2014-6514/45); “use of any treatment method or tools or even approved and licenced drugs, and their preparations, medical, and biological products, herbal products, cosmetics products, and their raw materials, and medical devices, on human beings with the intention of scientific research requires approvals granted by Ministry of Health and affiliated establishments……..” for the use of each indicated item necessitates interim arrangements. Currently, regulations concerning drugs, medical, and biological products, cosmetics products,

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Table 1. Legal regulations, and guide documents concerning clinical researches in our country Law, international conventions, legislations

• • • • • • •

Constitution (item 17) Human Rights, and Biomedicine Convention The Law on the Practice of Medicine and Medical Sciences (issue no: 14/04/1928-863: item no: 70) Fundamental Law on Health Services Amendment no:10 Turkish Criminal Law (2004/Amended 2005 –issue no: 5237: item no: 90) Protection of Personal Data Act (6698) (04/07/2016–issue no: 29677) Medical Deontology Legislation (19/02/1960-10436 issue no: items: 10 and 11)

Regulations

• • • • •

Regulation of Clinical Investigations with Drugs and Biological Products Regulation on Clinical Trials on Medical Devices Regulation on Traditional and Complementary Medicine Practices (27/10/2014-29158) Regulation on Processing and Protecting The Privacy of Personal Health Data (20/10/2016-29863) Regulation on Clinical Researches on Effectiveness and Safety Studies on Cosmetic Products and their Raw Materials

Guidelines

• Good Clinical Practices Guideline • Guideline for Observational Drug Studies • Guideline for the Application to Ethics Committees for Clinical Researches, and Bioavailability-Bioequivalency Studies • Procedure of Application to Directorate of Department of Clinical Researches of Turkish Medicines, and Medical Devices Agency • Standard Working Procedures of Ethics Committees for Clinical Researches, Bioavailability–Bioequvalence Studies • Guideline for Ethical Approaches to Clinical Trials Conducted in Pediatric Population • Guideline for Essentials, and Principles of Good Clinical Practices applied for Advanced Treatment Products • Guideline for the Management of Biological Materials in Clinical Researches • Guideline for the Insurance Coverage to be Performed in Clinical Trials • Guideline for Reports on Safety Issues in Clinical Trials • Guideline for Reports on Development, Safety, Updating in Clinical Trials • Guideline for The Application to The Assembly ofClinical Researchers • Guideline for Principles of Programming and Evaluating of Training in ClinicalTrials • Guideline for The Essential Principles of Central Organization Management in Clinical Trials • Guideline for Independent Data Monitoring Committee • Guideline for The Structure, and Essential Principles of Procedures, and Principles of Bioethics Committee • Guideline on the Essentials of The Standard Working Method of Advisory Committee of Clinical Trials • Guideline for the Storage, and Distribution of Investigational Products used in Clinical Trials • Guideline for Principles of Archiving in Clinical Trials • Guideline for Efficacy, and Safety Trialsof Cosmetic Products or Raw Materials performed with Volunteers