Northern Clinics of İstanbul 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. 3 • 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. 3 • Year 2018

KARE

Effect of intra-abdominally administered mesalazine (5-aminosalicylic acid) in experimental peritonitis • Sciatic nerve injury following analgesic drug injection in rats: A histopathological examination • Systemic inflammatory activation in patients with acute coronary syndrome secondary

to nonatherosclerotic spontaneous coronary artery dissection • Outcomes of surgery for gallbladder cancer: A single-center experience • Evaluation of the attitudes of specialist and family physicians regarding rational drug selection • Evaluation of childhood solid pseudopapillary tumors of the pancreas •

success in ectopic pregnancy: A single-center tertiary study • The relationship between joint hypermobility and subacromial impingement syndrome and adhesive capsulitis of the shoulder • Ear atresia: Is there a role of apoptosis-regulating miRNAs? • A patellar tendon length conservation method: Biplanar retrotubercle

Vitelline duct pathologies in neonates • Validity and reliability of geriatric depression scale-15 (short form) in Turkish older adults • Ischemic colitis following infrarenal abdominal aortic aneurysm treatment: Results from a tertiary medical center • Predictive factors of methotrexate treatment

open-wedge proximal tibial osteotomy • Subclavian vein puncture-induced massive pulmonary hemorrhage and hemoptysis during pacemaker implantation • Infliximab use in ulcerative colitis flare with Clostridium difficile infection: A report of two cases and literature review • Open repair of a type Ia endoleak with a giant

abdominal aortic aneurysm sac • Difficult management of a patient presenting with recurrent syncope caused by diffuse vasospasm • The use of neodymium magnets in healthcare and their effects on health • The effects of neuromonitorization in thyroidectomies can be safely evaluated with the standardized techniques

NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ Editor

Associate Editors

Levent Doganay, M.D.

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

Publıcatıon Coordınator Beril Tekay

Asistant to the Edıtor Aysenur Aydın

Betul Sozeri, M.D.

Managing Editor Neslihan Buyukmurat, M.D.

Scientıfıc Commıttee Abdullah Aydin, M.D. Adem Ozkan, M.D. Afitap Icagasioglu, M.D. Ahmet Gocmen, M.D. Alaattin Ozturk, M.D. Ali Ihsan Dokucu, M.D. Ali Ozdemir, M.D. Ali Riza Cenk Celebi, M.D. Ali Riza Odabas, M.D. Asiye Kanbay, M.D. Atakan Yesil, M.D. Ateş Kadioglu, M.D. Atilla Polat, M.D. Ayhan Verit, M.D. Aysel Milanlioglu, M.D. Ayse Cikim Sertkaya, M.D. Ayse Serap Karadag, M.D. Aysegul Gunduz, M.D. Aysenur Celayir, M.D. Aytekin Guven, M.D. Aytekin Oguz, M.D. Ayten Kadanali, M.D. Baris Onder Pamuk, M.D. Bekir Atik, M.D. Beyhan Cengiz Ozyurt, M.D. Birsen Yurugen, M.D. Canan Agalar, M.D. Cevdet Ugur Kocogullari, M.D. Derya Buyukkayhan, M.D. Destina Yalcin, M.D. Didem Akcali, M.D. Didem Korular Tez, M.D. Dilaver Tas, M.D. Duygu Geler Kulcu, M.D. Ebru Zemheri, M.D. Emek Kocaturk Goncu, M.D. Emin Evren Ozcan, M.D. Emine Samdanci, M.D. Ercan Madenci, M.D.

Eren Gozke, M.D. Eren Ozek, M.D. Eyup Gumus, M.D. Fahri Ovali, M.D. Fatih Goktay, M.D. Fatih Saygili, M.D. Fatma Eti Aslan, M.D. Ferruh Isman, M.D. Filiz Akyuz, M.D. Filiz Topaloglu Demir, M.D. Fugen Aker, M.D. Fusun Mayda Domac, M.D. Gizem Dinler Doganay, M.D. Gozde Kir Cinar, M.D. Gulbahar Sarac, M.D. Gulendam Kocak, M.D. Gulnur Tokuc, M.D. H. Muammer Karakas, M.D. Hakan Erdogan, M.D. Hale Akbaylar, M.D. Haluk Vahaboglu, M.D. Hamit Okur, M.D. H. Isin Ozisik Karaman, M.D. Hasan Bombaci, M.D. Hasan Borekci, M.D. Haydar Sur, M.D. Hilmi Ciftci, M.D. Hulya Apaydin, M.D. Huseyin Bayramlar, M.D. Ibrahim Akalin, M.D. Ibrahim Ali Ozemir, M.D. Ibrahim Ikizceli, M.D. Ihsan Karaman, M.D. Ihsan Metin Leblebici, M.D. Ilknur Aktas, M.D. Ismail Islek, M.D. Kadriye Avci, M.D. Kamil Ozdil, M.D. Kaya Saribeyoglu, M.D.

Kazim Capaci, M.D. Kemal Memisoglu, M.D. Kemal Nas, M.D. Kemalettin Koltka, M.D. Leyla Karadeniz Bilgin, M.D. Lutfullah Orhan, M.D. Mahmut Durmuş, M.D. Mehmet Ali Ozcan, M.D. Mehmet Doganay, M.D. Mehmet Eren, M.D. Mehmet Kanbay, M.D. Mehmet Selcuki, M.D. Mehmet Tayyar, M.D. Mehmet Tunca, M.D. Melek Celik, M.D. Melek Gura, M.D. Melih Atahan Guven, M.D. Metin Akbulut, M.D. Metin Kapan, M.D. Mine Hekimgil, M.D. Muhammed Fatih Onsuz, M.D. Muhammet Tekin, M.D. Murat Acar, M.D. Murat Muhcu, M.D. Mustafa Aldemir, M.D. Mustafa Caliskan, M.D. Mustafa Girgin, M.D. Nelgin Gerenli, M.D. Nezih Ozkan, M.D. Nihat Aksakal, M.D. Nilay Sahin, M.D. Nuri Aydin, M.D. Nusret Acikgoz, M.D. Onur S. Goksel, M.D. Orhan Alimoglu, M.D. O. Emek Kocaturk Goncu, M.D. Ozge Ecmel Onur, M.D. Ozlem Baysal, M.D. Ozlem Guneysel, M.D.

Ozlem Tanriover, M.D. Recep Alp, M.D. Remzi Cevik, M.D. S. Tahir Eren, M.D. Sabahat Aksaray, M.D. Sait Naderi, M.D. Salih Boluk, M.D. Salih Cetinkursun, M.D. Sarenur Gokben, M.D. Sahin Senay, M.D. Selcuk Mistik, M.D. Semra Kayatas Eser, M.D. Serhat Citak, M.D. Seyhan Hidiroglu, M.D. Seyhun Kurşat, M.D. Sibel Dogan, M.D. Selami Sozubir, M.D. Sema Yilmaz, M.D. Sevki Erdem, M.D. Soner Sanioglu, M.D. Sukran Kose, M.D. Tamer Okay, M.D. Tarik Sapci, M.D. Tayfun Kirazli, M.D. Tongabay Cumurcu, M.D. Tolga Baglan, M.D. Tolga Canbak, M.D. Tuba Tulay Koca, M.D. Tuba Yavuzsen, M.D. Turhan Caskurlu, M.D. Turkan Kudsioglu, M.D. Umut Kefeli, M.D. Veli Citisli, M.D. Volkan Ince, M.D. Yasar Bukte, M.D. Yesim Tuncok, M.D. Yurdanur Kilinc, M.D. Yuksel Altintas, M.D. Yuksel Ersoy, M.D.

NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ YEAR 2018 VOLUME 5 NUMBER 3

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 Elmalıkent 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.

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

DESIGN Ali Cangul kare@kareyayincilik.com

Press

Info

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

English Editing by Gurkan Kazanci Susan Atwood

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.

KARE PUBLISHIN G

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

CONTENTS Vol. 5 • No. 3 • Year 2018 IV

Instructions for the authors

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

171–175 Effect of intra-abdominally administered mesalazine (5-aminosalicylic acid) in experimental peritonitis A. Sener, A. Sahbaz, L. Turker Sener, M. Soluk Tekkesin, B. Kaya 176–185 Sciatic nerve injury following analgesic drug injection in rats: A histopathological examination H. Bostan, M. Cabalar, S. Altinay, Y. Kalkan, L. Tumkaya, A. Kanat, S. Balik, A. Erkut, D. Altuner, Z. Salihoglu, A. Kocer 186–194 Systemic inflammatory activation in patients with acute coronary syndrome secondary to nonatherosclerotic spontaneous coronary artery dissection Y. Canga, T. S. Guvenc, A. N. Calik, M. B. Karatas, T. Bezgin, T. Onuk, A. O. Uzun, V. O. Tanik, B. Gungor, O. Bolca 195–198 Outcomes of surgery for gallbladder cancer: A single-center experience A. Baskiran, E. Sahin, N. Karadag, T. T. Sahin, B. Barut, D. Ozgor, A. Dirican 199–206 Evaluation of the attitudes of specialist and family physicians regarding rational drug selection A. Akici, V. Aydin, S. Mollahaliloglu, S. Ozgulcu, A. Alkan 207–210 Evaluation of childhood solid pseudopapillary tumors of the pancreas A. Ozcan, C. Arslanoglu, E. Unal, T. Patiroglu, M. A. Ozdemir, K. Deniz, S. S. Ozcan, M. Karakukcu 211–215 Vitelline duct pathologies in neonates S. Celebi, S. Ozaydin, E. Polat, C. Basdas, E. R. Alim, S. Sander 216–220 Validity and reliability of geriatric depression scale-15 (short form) in Turkish older adults B. Durmaz, P. Soysal, H. Ellidokuz, A. T. Isik 221–226 Ischemic colitis following infrarenal abdominal aortic aneurysm treatment: Results from a tertiary medical center U. Aday, E. Gundes, D. A. Cetin, H. Ciyiltepe, A. S. Senger, S. Gulmez, M. Akbulut, E. Polat 227–231 Predictive factors of methotrexate treatment success in ectopic pregnancy: A single-center tertiary study C. Pulatoglu, O. Dogan, A. Basbug, A. Ellibes Kaya, A. Yildiz, O. Temizkan 232–237 The relationship between joint hypermobility and subacromial impingement syndrome and adhesive capsulitis of the shoulder A. Atici, I. Aktas, P. Akpinar, F. U. Ozkan 238–245 Ear atresia: Is there a role of apoptosis-regulating miRNAs? E. Aslan, E. Akbas, S. Yilmaz, A. S. Karaoglu, U. Telli, S. Yildirim, H. Gudek, M. T. Kalcioglu, S. Yilmaz, I. Akalin 246–253 A patellar tendon length conservation method: Biplanar retrotubercle open-wedge proximal tibial osteotomy I. Turkmen, I. Esenkaya

CA SE R E PO RTS

254–255 Subclavian vein puncture-induced massive pulmonary hemorrhage and hemoptysis during pacemaker implantation N. S. Yelgec, A. Osken, C. Turkkan, A. T. Alper 256–260 Infliximab use in ulcerative colitis flare with Clostridium difficile infection: A report of two cases and literature review B. S. Romana, A. A. Albarrak, M. H. Yousef, V. Tahan 261–263 Open repair of a type Ia endoleak with a giant abdominal aortic aneurysm sac C. Kocaaslan, M. Aldag, T. Kehlibar, M. Yilmaz, E. Aydin, B. Ketenci 264–267 Difficult management of a patient presenting with recurrent syncope caused by diffuse vasospasm A. Uslu, S. Demir, M. Sari, C. Dogan, O. Akgun, M. Celik, T. Akgun

INVITED REVIEW

268–273 The use of neodymium magnets in healthcare and their effects on health C. Yuksel, S. Ankarali, N. A. Yuksel

Let t er to t he E di tor

274–275 The effects of neuromonitorization in thyroidectomies can be safely evaluated with the standardized technique M. Tanal, M. Uludag

A ut hors Reply

275–276 S. Demiryas, T. Donmez, E. Cekic

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

The NCI publishes the kinds of articles briefly described below.

Research Articles: These are articles on original clinical (conducted with healthy subjects or patients) or experimental (human, animal or in-vitro trials) research performed in all fields. Case Reports: This section contains reports on interesting, instructive or rarely seen cases. Review Articles: Reviews are usually written at the invitation of the editors. The NCI publishes clinical review articles related to the natural course of diseases, updated diagnostic and therapeutic approaches of concern to clinicians and specialists in basic sciences that encompass genetic, physiological, and pharmacological aspects of the underlying mechanisms of diseases, and reviews about state-ofthe art treatment strategies, technological advancements, and newly approved drugs. Editorial Comments: This section contains editors’ comments, reviews, and other relevant items. Letters to the Editor: These are com-

ments, criticism and contributions in response to a paper published in the NCI. The author(s) of a criticized article has the right to reply. The article that is the subject of the comments should be listed in the references section. Letters must be sent to the editor within 4 weeks following publication of the subject article in the NCI. PREPARATION OF MANUSCRIPT

General Format: All manuscripts should be typewritten on A4 white paper, and 2.5 cm-wide margins should be left on all sides. The references should be numbered consecutively in the order of their first mention in the text. All text material, including references, footnotes, and table and figure legends, should be typed using double-spacing in an 11 point font with left alignment and without hyphenated line breaks. The fonts Times New Roman or Arial should be used in the text, for symbols, and all other special characters. Please use the editing features of your word processing program to type bold or italic letters, mathematical symbols, Greek letters, subscript and superscript characters. Please take care not to confuse the letters O and I with the numerals 0 and 1. To set a left indent for a paragraph, click the TAB button once. Only the International System of Units (SI) should be used for units of measurement. Abbreviations and acronyms should be written in parentheses following the full name or an explanation of the usage should be provided just after the first appearance in the text. Please review the final version of the manuscript very carefully, especially for formatting and editing errors. All pages of the manuscript should be consecutively numbered starting from the title page (page 1, title page; page 2, Turkish abstract; page 3, English abstract, etc.). Page numbers should be indicated on the upper right-hand corner of each page. Final version of the manuscript should be in “.doc” or “.rtf” format. Manuscripts submitted in “.pdf” format will not be accepted.

Manuscript Sections: All research articles must contain the following sections: (1) Title page, (2) Abstract with keywords, (3) Introduction, (4) Methods, (5) Results, (6) Discussion, (7) Acknowledgements, (8) Conflict of interest, (9) Funding re-

sources, (10) References, (11) Legends of the figures, (12) Tables, (13) Figures. In case of need, presentation of Methods, Results, and Discussion sections under subheadings is preferred. Case reports should be presented following abstract section, under headings of introduction, case presentation, and discussion. In review articles, appropriate headings can be used in accordance with the development of the manuscript. Sections of the manuscript in order of their appearance in the text with relevant explanations are listed below.

Title Page: The title page should contain the following information: (1) article title, (2) full name and academic title of all participating authors, (3) department and institution of all authors, including the city and country, (4) name, full mailing address, phone and fax numbers, and e-mail address of the corresponding author, and (5) word count (including title page, abstracts, explanatory notes for figures and tables). If the study was presented elsewhere, those details should be indicated on the title page. Abstract: The abstract should be written on a separate page. It should contain at most 250 words, and be structured as follows: (1) Objective, (2) Methods, (3) Results, and (4) Conclusion. Under these headings, briefly describe the subject of the article, methods used for the study, basic findings, and author’s conclusion. No subtitles may be used in the abstract of a case report. A minimal number of abbreviations and/or acronyms should be used. Abstracts should not contain any references. A maximum of 5 keywords should be included at the end of the abstract. The Medical Subject Headings (MeSH) prepared by the US National Library of Medicine (NLM) may be used as a reference for keywords. Introduction: State the specific purpose and available data relevant to the study. Methods: All methods used to select participants and conduct the study should be described in detail. Known methods should be cited. Novel or modified methods used should be described in detail. Doses, concentrations, routes, and duration of administration of drugs and chemical agents should be indicated. A concise

INSTRUCTIONS FOR THE AUTHORS report of all statistical methods used for summarizing available data and for testing the proposed hypothesis should be provided under a subtitle, including the p value criteria determined for statistically significant difference. Statistical evaluation conducted should be explained in detail. Standard statistical methods should be used as much as possible. If rarely employed or novel statistical methods were used, then the relevant references should be cited. When necessary, more detailed explanations about unusual, complex or new statistical methods can be provided in separate files for readers as online supplementary data. The commercial name and version number of any statistical software package program used should be provided. For statistical evaluation, the recommendations in the statistics section of the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication” (http://www.ICMJE.org) should be taken into consideration.

Results: The study results should be presented in logical sequence and in detail. The findings should be supported by figures and tables. Information given in figures and tables should not be repeated in the text unless absolutely required. Discussion: Data relevant to the study subject matter should be examined, evaluated, and substantiated with references from domestic and international sources. General information irrelevant or superfluous to the report should not be included. Acknowledgement: The names of individuals who contributed to the study but who fail to meet the criteria of authorship should be mentioned in this section. The written consent of all individuals mentioned should be obtained. Conflict of Interest: All potential conflicts of interest should be declared under this heading. All affiliations with pharmaceutical firms, biomedical device manufacturers, and other service or product procurers relevant to the subject matter of the study should be explicitly indicated. If no conflict of interest exists, this should be stated as “none declared.” Declarations related to conflicts of interest should be placed at the bottom of a separate page after the acknowledgements and before

the references. A Conflict of Interest Form will be sent to the authors of accepted papers.

Funding sources: The full name of any sponsoring foundation or institution should be provided. References: References should be listed consecutively in the order of their first appearance in the text. All sources the authors made direct use of should be included as references, excluding unpublished results and personal communications. During the preparation of the manuscript for publication, additional information regarding any unconfirmed references will be requested from the authors. Titles of journals should be abbreviated as indicated in the Index Medicus. If that is not possible, then the full name of the journal should be provided. In the references, a maximum of 6 authors should be cited for any 1 article with their full surname, and then the initial(s) of their first name. If more than 6 authors contributed to the cited article, then after the name of the sixth author, the abbreviation “et al.” should be added to indicate that there are additional authors. The notation and listing of references should comply with the following sample reference citations: 1. Journal: Balci NC, Sirvanci M, Tüfek I, Onat L, Duran C. Spontaneous retroperitoneal hemorrhage secondary to subcapsular renal hematoma: MRI findings. Magn Reson Imaging 2001;19:1145-8. 2. Articles in press: Roten L, Derval N, Sacher F, Pascale P, Wilton SB, Scherr D, et al. Ajmaline attenuates electrocardiogram characteristics of inferolateral early repolarization. Heart Rhythm 2011 Sep 19 [E-pub ahead of print], doi:10.1016/j.hrthm.2011.09.013. 3. Book: Brown AM. Physiology of the liver. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2003. 4. Chapter in book: Anderson JL, Muhlestein JB. The role of infection. In: Theroux P, editor. Acute coronary syndromes: a companion to Braunwald’s Heart Disease. Philadelphia: W.B. Saunders; 2003. p. 88-107. 5. Web page: Nainggolan L. New salt paper causes controversy. Heartwire. May 3, 2011. Available at: http://

www.theheart.org/article/1220043. do. Accessed: June 12, 2011.

Figure Legends: Explanatory notes for each figure should be submitted on a separate page in order of their appearance in the text immediately after the references section under the heading “figure legends.” All abbreviations and symbols used in the figure should be defined in alphabetical order. Figures: The manuscript will not be evaluated until all figures cited in the text are submitted. The number of figures provided should be in accordance with the content and data presented in the text, and table data should not be repeated in figures. All figures should be sent in individual electronic file format ready for publication with maximum dimensions of 125 cm x 180 cm. Illustrations in color should be in CMYK format and have a minimum resolution of 300 DPI suitable for publication. Figures depicted in gray scale should have a minimum resolution of 600 DPI, and the minimum resolution required for black and white illustrations is 1200 DPI. All figures should be in TIFF format. Figures must not disclose or imply the identity of a specific individual without the written consent of the individual in question. Tables: Each table should be typed or printed with double-spacing on a separate sheet of paper. Tables should be numbered consecutively in the order of their first citation in the text. The number and title of the table should be placed just above the table. Do not use vertical lines between columns. Horizontal lines should be used only above and below the headings of the columns, and at the bottom of the table. If required, explanatory notes regarding table data should be written in footnotes. All abbreviations and acronyms used in the table should also be explained in alphabetical order in footnotes. ETHICAL POLICY

NCI follows the ethics flowcharts developed by the Committee on Publication Ethics (COPE) for dealing with cases of possible scientific misconduct and breaches of publication ethics. For detailed information please visit www.publicationethics.org.

INSTRUCTIONS FOR THE AUTHORS All submitted manuscripts are screened with plagiarism software (iThenticate) to detect instances of overlapping and similar text during the evaluation process. All manuscripts presenting data obtained from research involving human subjects must include a statement that the written informed consent of the participants was obtained and that the study was approved by an institutional review board or an equivalent body. This institutional approval should be submitted with the manuscript. Authors of case reports must submit the written informed consent of the subject(s) of the report or of the patient’s legal representative. Manuscripts with human and animal studies should describe the steps taken to eliminate pain and suffering. AUTHORSHIP

All individuals listed as “author” in the submitted manuscript must make an adequate contribution to the study, meet the criteria of authorship, and take responsibility for their part of the manuscript. For the sake of the outcomes and the integrity of the study, at least one author should be responsible for each section of the manuscript. All authors mentioned in the cover letter must meet all of the following criteria: (1) substantial contribution to conception, design of the study, analysis, and interpretation of data, or all of these criteria; (2) significant contribution to the drafting of the article or revision of its scientific content; (3) approval of the final version of the article to be published. In multicentered studies, all individuals who are named as authors under the title of the article should meet all the abovementioned requirements of authorship. Seeking or providing financial support for the study, and/or data collection do not satisfy the criteria of authorship per se, nor does general support or guidance provided to the study investigators. Individuals who contributed to the study in various ways but who fail to meet the criteria of authorship may be included in the acknowledgements with their written consent. Please refer to the ICMJE website for more information about authorship. Increasing the number of authors unnecessarily is not ethical conduct and to prevent any attempt to seek undue academic prestige or other unethical advantages, the editor may request a decla-

ration from the authors of their individual contributions to the article and publish this information, if deemed appropriate. The sequence of authors’ names should be based on a consensus reached by all the participating authors. Due to different specifications for the sequencing of authors, the order provided will be used unless otherwise stated. Authors may explain the rationale for a different sequence in a footnote. COVER LETTER

Each manuscript should be sent with a cover letter that must contain the following explicit declarations: (1) all authors meet the criteria of authorship; (2) the submitted manuscript was not simultaneously sent to another journal and it is not presently being evaluated by another journal; (3) no part of the content of the manuscript has been previously published elsewhere; and (4) the manuscript has been read and approved of by all authors. The name, full address, phone and fax number(s), and e-mail address of the corresponding author to whom all editorial correspondence will be directed must be provided. A brief paragraph describing the scientific significance of the manuscript may also be included. SUBMISSION OF THE MANUSCRIPT

All manuscripts should be submitted to the NCI via the online submission system. For questions or requests related to the submission and evaluation process of manuscripts, the editorial office may be contacted by e-mail at bilgi@kuzeyklinikleri.com. In compliance with the journal’s publication rules, the current status of the manuscript will not be discussed on the phone prior to acceptance for publication. First-time users of the online submission system will need to register. A user name and a code specific to the user will be sent by e-mail. For further details please consult the online manuscript submission page.

gin until a document with the signed approval of all authors has been received. During typesetting and other preparation of the manuscript for publication, a Copyright Transfer Form will be sent to the primary author(s) (“guarantors”) who will assume responsibility for the manuscript. All submitted manuscripts are first evaluated by the editorial board. At this stage, manuscripts not deemed suitable for publication in NCI, including those not complying with the requirements or without adequate scientific content, will be returned to the authors. Manuscripts found suitable for publication will be sent to reviewers for more detailed evaluation. Acceptability of manuscripts is dependent on originality, scientific content, and the subject of the study, in accordance with the publication protocol of the journal. All research articles deemed suitable for publication are subjected to a detailed statistical evaluation. The authors are informed of the editors’ decision on the acceptability of the manuscript via e-mail, usually within 6 weeks of its submission. The editors do not discuss their decision on the phone. All objections and requests should be communicated to the editors in a written format. If deemed necessary, the editorial board has the right to make modifications to the text without altering the main concept of the manuscript. An offprint of the manuscript will not be sent to the author(s). OPEN ACCESS

NCI is a fully open access journal. All articles published in NCI are available on the internet to all users immediately upon publication. Non-commercial use and distribution in any medium is permitted, provided the author and the journal are properly credited. PUBLISHING FEE

REVIEW OF MANUSCRIPTS

NCI is an open access journal. Manuscripts can be reached from the web page of journal without any fees. No additional fee is required from the authors for accepted manuscripts.

In order for an article to be published in the journal it should not be published elsewhere, and must be deemed suitable for publication by the editorial board selected by the NCI Executive Committee. All responsibility for the manuscript belongs to the author(s). The evaluation process of the submitted manuscript will not be-

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

BASIC MEDICAL SCIENCES

North Clin Istanb 2018;5(3):171–175 doi: 10.14744/nci.2017.48379

Effect of intra-abdominally administered mesalazine (5-aminosalicylic acid) in experimental peritonitis Aziz Sener,1 Alper Sahbaz,1 Leyla Turker Sener,2 Merva Soluk Tekkesin,3 Bulent Kaya4 Department of General Surgery, H.S.U Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey

Department of Biophysics, Istanbul University Faculty of Medicine, Istanbul, Turkey

Department of Institute of Oncology, Istanbul University, Istanbul, Turkey

Department of General Surgery, H.S.U Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: In this study,the effect of mesalazine was studied on TNF alpha IL-1 beta, IL-6, and C-reactive protein (CRP) levels and inflammatory changes in rat lungs with experimental peritonitis. METHODS: In total, 24 male Sprague–Dawley rats weighing 250–280 g were used in the study.The rats were divided into three groups based on no irrigation or irrigation with isotonic solution or mesalazine. Secondary peritonitis was generated by cecum penetrations. Group I, no irrigation was given after the development of peritonitis; Group II, irrigation was performed using isotonic solution 24 h after the development of peritonitis; Group III: irrigation was performed using mesalazine 24 h after the development of peritonitis. Blood samples were taken in the 48th hour for measuring TNF alpha, IL-1 beta, IL-6, and CRP levels. Lung tissue samples were taken for examining the effect of mesalazine in the development of systemic sepsis. RESULTS: TNF alpha, IL-1 beta, and CRP levels were significantly low in Group III than in the other groups (p<0.005). In the histologic examination, leucocyte infiltration in the lung was found low in Group III. CONCLUSION: TNF alpha, IL-1 beta, and CRP levels and leucocyte infiltration in the lung were found to be low in rats that were administered peritoneal irrigation using mesalazine after the development of secondary peritonitis. Peritoneal irrigation using mesalazine may be useful in patients requiring surgery due to secondary peritonitis. Keywords: Peritonitis; TNF alfa; IL-1 beta; IL-6; mesalazine.

Cite this article as: Sener A., Sahbaz A., Turker Sener L., Soluk Tekkesin M., Kaya B. Effect Of Intra-Abdominally Administered Mesalazine (5-Aminosalicylic Acid) In Experimental Peritonitis. North Clin Istanb 2018;5(3):171–175.

epsis is a serious pathology with significant morbidity and mortality [1]. Some proinflammatory mediators indirectly cause sepsis as a response against exposure to microbial products. Cytokine response is associated with morbidity and mortality in sepsis [2, 3]. Microbial products include liposaccharides (endotoxins or lipopolysaccharides) produced by gram-negative microorganisms, peptidoglycans and teichoic acids produced by gram-positive micro-organisms, cell-wall components and many others produced by fungi and yeasts.

Secondary peritonitis is a common morbidity that requires surgical intervention. Gastrointestinal system-related intra-abdominal contamination initiates the cytokine synthesis. Cytokines TNFα and IL-1β lead the pathogenesis of sepsis.These cytokines increase in the first 4 h after the development of sepsis. They reach the highest level in the 24th hour. C-reactive protein (CRP) is an acute-phase reactant, and CRP levels increase in sepsis. Mesalazine or 5-aminosalicylic acid (5-ASA) is an anti-inflammatory and antioxidant drug that has been

Received: August 15, 2017 Accepted: October 10, 2017 Online: June 08, 2018 Correspondence: Dr. Aziz SENER. H.S.U Kanuni Sultan Suleyman Egitim ve Arastirma Hastanesi, Genel Cerrahi Anabilim Dali, Istanbul, Turkey Phone: +90 532 436 05 53 e-mail: drazizsener@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

172

used in treatment of inflammatory bowel diseases for approximately 50 years [4, 5]. 5-ASA is a small hydrophilic organic acid and is well absorbed from the intestines. It is rapidly transformed to N-acetyl in the intestinal epitelium and liver, and the inactive molecule N-acetyl5-ASA is generated. Some parts of the inactive metabolite are secreted back to the lumen and removed from the body by feces. Some parts of 5-ASA are metabolized in the liver and extracted by the kidney. However, the clinical effect of 5-ASA is not associated with systemic absorption and redistribution on target organs; its topical effect is observed in the colon. There are various views on the effect mechanisms of 5-ASA compelexes. It was stated that 5-ASA complexes inhibit IL-1 and IL-2 synthesis in the inflammatory period. It was also proved that they inhibit TNF-α synthesis [6]. The aim of the present study was to investigate the effect of intra-abdominally administered mesalazine on cytokines (TNF-α, IL-1β, and IL-6) and on the level of acute-phase reactant CRP during sepsis due to secondary peritonitis. MATERIALS AND METHODS Animal study The study was conducted at the Institute of Experimental Medicine, Istanbul Faculty of Medicine, Istanbul University. The study protocol was approved by the Animal Care Ethics Committee. All procedures were conducted in accordance with the ethics guidelines for the treatment and welfare of experimental animals by the Istanbul Faculty of Medicine, Istanbul University, and Helsinki decleration. In total, 24 male Sprague–Dawley rats weighing 250–280 g were used in this study. The animals were housed at 21°C and were given tap water and standard rat food ad libitum. Surgical procedure The animals were anesthetized via an intramuscular injection of ketamine hydrochloride (50–100 mg/kg of body weight). Twenty-four male rats were randomly assigned to three groups. Group I, no irrigation after the development of peritonitis; Group II, irrigation using isotonic solution in the 24th hour after the development of peritonitis; and Group III, irrigation using mesalazine solution in the 24th hour after the development of peritonitis. Peritonitis was generated by small holes on the cecums of rats using a 22-G needle after laparotomy. Ten

North Clin Istanb A

Figure 1. (A, B) Midlinere laparotomy (C) Peritoneal lavage with mesalazine (D) Closure of the abdominal cavity. milliliter isotonic solution was abdominally administered to Group II and mesalazine (0.2 g/10mL) to Group III 24 h later (Fig. 1). A second laparotomy was performed in the 48th hour. Intracardiac blood samples were taken. Blood samples were collected for the measurement of TNFα, IL-1β, ΙL6, and CRP levels. All rats were sacrificed 48 h after the first laparotomy. Tissue samples were taken from the lung. Cytokines measurement Samples were collected in serum separator tubes. After clot formation, samples were centrifuged at 1000×g for 10 min, and serum was collected. Serum was stored at −40°C until required for analysis. Cell signal proteins were assessed in the top supernatant of blood by TNF-α, IL-1β, IL-6, and CRP levels using an enzyme-linked immunosorbent assay kit in accordance with the manufacturer’s guidelines. Histologic analysis Lung tissue samples were taken from the rats for histopathologic investigation because the risk of development of multiple organ failure was mainly in the lung in sepsis. For histologic assessments, lung samples were obtained from eight anesthetized rats is each group at 48 h through excisional biopsy. All specimens were fixed in 10% buffered formalin. Paraffin blocks were prepared from routinely processed specimens, and 5-μm sections were cut and deparaffinized. The sections were stained using hematoxylin–eosin (H&E). Histopathologic examinations were performed by a blinded pathologist with light microscopy at ×200 magnification.

Sener et al., Effect of intra-abdominaly mesalazine in peritonitis

173

Table 1. Characteristics of groups

Mean

Median

St. Dev.

Min.

Max.

TNF IL-6 IL-1beta CRP Lenfosit Nötrofil Lökosit

18 18 18 18 14 13 14

227.4 9.8 1827.8 184.2 48.4 19.4 6.9

227.3 9.8 1767.5 198.1 39.5 11.4 7.2

27.8 1.3 196.9 31.3 24.1 21.7 2.6

185.1 7.9 1556.3 128 9.0 1.5 3.0

175.4 12.6 2271.0 237.4 92.6 63.5 12.3

Table 2. Post-hoc test TNF IL-1beta CRP

1-2 1-3 2-3 1-2 1-3 2-3 1-2 1-3 2-3

p 0.073* 0.003* 0.038* 0.214* 0.419* 0.914* 0.808* 0.001* 0.114*

*Mann-Whitney U p value.

Statistical method Descriptive statistics were used to describe continuous variables (mean, standard deviation, minimum, maximum, and median). Comparison of three independent and non-normally distributed continuous variables was performed using the Kruskal–Wallis test. For significant results of the Kruskal–Wallis and Mann–Whitney U test, Bonferroni correction was used as a post-hoc analysis test. Statistical significance level was set at 0.05. Statistical analyses were performed using MedCalc Software version 12.7.7 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2013). RESULTS Intracardiac blood samples were taken 48 h after the operation for TNF-α, IL-1β, ΙL-6, and CRP measurement. TNF-α, IL-1β, and CRP levels were detected at a significantly lower level in Group III than in the other two

groups (Kruskal–Wallis, p<0.05) (Table 1). According to the the post-hoc test results, the differences stemmed from Groups I and III (Mann–Whitney U, p<0.016, Bonferroni correction) (Table 2). There is significant difference between TNF and Group. (Kruskal-Wallis p<0.05) According to the PostHoc test results, the differences stems from 1. and 3. groups. There is significant difference between II-1beta and Group. (Kruskal-Wallis p=0.041) According to the Post-Hoc test results, the differences are not caused by two groups. There is significant difference between CRP and Group. (Kruskal-Wallis p=0.011) According to the Post-Hoc test results, the differences stems from 1. and 3. groups (Mann-Whitney U p<0.016 Bonferroni correction) (Table 3). The histologic sections were examined under light microscopy and assessed for inflammation in lung tissue, which can be an indirect sign of sepsis. Slight differences of inflammatory reactions were determined between the groups. Group I showed more inflammatory infiltration than Groups II and III. Group III showed relatively lesser inflammatory infiltration than Group II (Fig. 2). DISCUSSION Secondary peritonitis is one of the main causes of sepsis and multiple organ failure. Its mortality rate is still high [7]. Elevated plasmacytokine levels have been related to the development of systemic inflammatory response syndrome, sepsis, and organ dysfunction. TNF-α has been associated with patients at high-risk for sepsis after abdominal surgery and is a predictor of mortality [8, 9]. Qui P et al. [10] investigated the therapeutic role of anti-TNFagents in a meta-analysis study. They searched 15 studies and concluded that anti-TNF agents produced a modest but significant decrease in

174

North Clin Istanb

Figure 2. Lung tissue of Group I (A), Group II (B), and Group III (C). Leucocyte infiltration can be seen in Group I. A decrease in leucocyte infiltration can be seen in Groups II and III.

Table 3. Comparison of TNF, IL-1beta, IL-6 and CRP levels parameters according to the groups TNF IL-1beta IL-6 CRP

Group

Mean

Median

St. Dev.

Min.

I II III I II III I II III I II III

248.8 225.1 200.4 1936.2 1866.9 1657.3 9.3 10.6 9.9 200.7 196.3 154.1

251.1 226.8 196.3 1933 1859.2 1677.3 9.4 10.3 9.9 202.7 206.5 163.4

21.4 13.0 16.9 216.8 116.7 55.2 1.0 1.7 1.3 11.1 43.9 19.3

213.9 209.8 185.1 1631.2 1758.8 1556.3 7.9 9 8.0 175.6 134.9 128.0

Max.

275.4 <0.05* 237.0 229.9 2271.0 0.041* 1990.7 1710.9 10.6 0.424* 12.6 12.0 210.9 0.011* 327.4 170.5

0.073

0.003

0.038

0.214

0.419

0.914

0.808

0.001

0.114

*Kruskal Wallis p value; 1I vs. II, 2I vs. III, 3I vs. II (Mann-Whitney U p value).

mortality in patients with sepsis. High levels of CRP are caused by infections and many inflammatory diseases. The relationship between intraabdominal infections and CRP is well established [11]. K. Mulari analyzed 66 patients with secondary peritonitis due to gastrointestinal tract perforation and investigated risk factors for hospital mortality. It was concluded that elevated CRP levels and high Mannheim peritonitis index score in the early postoperative phase had a prognostic significance [12]. Peritoneal lavage is described as the washing of the peritoneal space with high volumes of saline. Different agents have been used for peritoneal lavage in the literature. Povidioneâ&#x20AC;&#x201C;iodine (PVI) and saline are well-known agents that are used for this purpose. Araujo ID et al. investigated peritoneal lavage with PVI in rats with exper-

imental peritonitis. Lavage of the peritoneal cavity with PVI demonstrated no beneficial effect in local control of peritonitis [13]. Camargo M et al, showed a beneficial effect of peritoneal lavage with bupovacaine in rats with fecal peritonitis [14]. Peritoneal irrigation was performed in cases of severe pancreatitis and morbidity and mortality rates decreased in this patient group [15]. Coumarin, which has an immunostimulant effect, was used in peritonitis without any beneficial effect [16, 17]. Peritoneal irrigation performed with a local anesthetic agent, 0.2% ropivacarine, in rats with fecal peritonitis decreased the histologic changes that occurred due to inflammation [18]. In our study, Groups II and III underwent the proposed therapeutic process (peritoneal lavage with isotonic solution and mesalazine). The effects of peritoneal lavage with isotonic solution and mesalazine was exam-

Sener et al., Effect of intra-abdominaly mesalazine in peritonitis

ined objectively. The mean CRP level was found statistically significantly lower in Group III than in the other groups. TNFα and IL-1β levels were also lower in Group III. The decrease in TNF-α levels in Group III was statistically significant. We examined the lung tissues to show the systemic effect of intra-abdominal infection. The degree of inflammatory reaction was found lower in Group III, indicating that lavage using mesalazine may have a protective effect on the lung tissue. CONCLUSION In rats with intra-abdominal sepsis, TNF-α and CRP levels significantly decreased in the mesalazine group. There were also decrease in leukocyte infiltration in the lungs of rats treated with mesalazine. So, it may be suggested that the use of mesalazine in clinical practice may decrease the sepsis-related morbidity and mortality. 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 – A.S.; Design – A.S.; Supervision – B.K.; Materials – A.S., M.S.T., L.T.S., B.K.; Data collection &/ or processing – L.T.S.; Analysis and/or interpretation – M.S.T., L.T.S., A.S.; Writing – A.S., M.S.T., L.T.S., A.S., B.K.; Critical review – A.S.

REFERENCES 1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303–10. 2. Palmiere C, Augsburger M. Markers for sepsis diagnosis in the forensic setting: state of the art. Croat Med J 2014;55:103–14. 3. Hatamkhani S, Karimzadeh I, Elyasi S, Farsaie S, Khalili H. Carnitine and sepsis: a review of an old clinical dilemma. J Pharm Pharm Sci 2013;16:414–23. 4. Campieri M, Lanfranchi GA, Bazzocchi G, Brignola C, Sarti F, Franzin

175 G, et al. Treatment of ulcerative colitis with high-dose 5-aminosalicylic acid enemas. Lancet 1981;2:270–1. 5. Svartz M. The treatment of 124 cases of ulcerative colitis with salazopyrine and attempts of desensibilization in cases of hypersensitiveness to sulfa. Acta Med Scand 1948;131:465–72. 6. Koelink PJ, Hawinkels LJ, Wiercinska E, Sier CF, ten Dijke P, Lamers CB, et al. 5-Aminosalicylic acid inhibits TGF-beta1 signalling in colorectal cancer cells. Cancer Lett 2010;287:82–90. 7. Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, et al; Academic Medical Center Consortium Sepsis Project Working Group. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 1997;278:23–40. 8. Davis MG, Hagen PO. Systemic inflammatory response syndrome. Br J Surg 1997;84:920–35. 9. Oda S, Hirasawa H, Shiga H, Nakanishi K, Matsuda K, Nakamua M. Sequential measurement of IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS)/sepsis. Cytokine 2005;29:169–75. 10. Qiu P, Cui X, Sun J, Welsh J, Natanson C, Eichacker PQ. Antitumor necrosis factor therapy is associated with improved survival in clinical sepsis trials: a meta-analysis. Crit Care Med 2013;41:2419–29. 11. Kørner H, Nielsen HJ, Søreide JA, Nedrebø BS, Søreide K, Knapp JC. Diagnostic accuracy of C-reactive protein for intraabdominal infections after colorectal resections. J Gastrointest Surg 2009;13:1599–606. 12. Mulari K, Leppäniemi A. Severe secondary peritonitis following gastrointestinal tract perforation. Scand J Surg 2004;93:204–8. 13. Araujo ID, Grossi GC, Diniz SO, Nunes TA, Braga EA, Cardoso VN. Effects of the povidone-iodine (PVPI) in treatment of bacterial peritonitis induced in rats. Acta Cir Bras 2010;25:322–7. 14. Camargo MG, Fagundes JJ, Leal RF, Ayrizono Mde L, Rossi DH, Oliveira Pde S, et al. Influence of the peritoneal lavage with bupivacaine on the survival and resistance of colonic anastomoses performed under fecal peritonitis in rats. Acta Cir Bras 2013;28:783–7. 15. Matsumoto K, Miyake Y, Nakatsu M, Toyokawa T, Ando M, Hirohata M, et al. Usefulness of early-phase peritoneal lavage for treating severe acute pancreatitis. Intern Med 2014;53:1–6. 16. Sortini D, Feo CV, Maravegias K, Carcoforo P, Pozza E, Liboni A, et al. Role of peritoneal lavage in adhesion formation and survival rate in rats: an experimental study. J Invest Surg 2006;19:291–7. 17. Creagh TA, Leahy AL, McNamara E, Bouchier-Hayes DJ. Local beneficial effect of coumarin in experimental peritonitis. Ir J Med Sci 1991;160:385–6. 18. Brocco MC, Gomez RS, Paulo DN, Almeida CE, Baptista JF. Histological features of peritoneal lavage with ropivacaine in rats with fecal peritonitis. Acta Cir Bras 2012;27:193–9.

Orıgınal Article

NEUROLOGY

North Clin Istanb 2018;5(3):176–185 doi: 10.14744/nci.2017.28190

Sciatic nerve injury following analgesic drug injection in rats: A histopathological examination Habib Bostan,1 Murat Cabalar,1 Serdar Altinay,2 Yildiray Kalkan,3 Levent Tumkaya,3 Ayhan Kanat,4 Sabri Balik,5 Adem Erkut,5 Dudu Altuner,6 Ziya Salihoglu,1 Abdulkadir Kocer7 Department of The Ministry of Justice, Council of Forensic Medicine, Istanbul, Turkey

Department of Pathology, Selcuk University Faculty of Medicine, Konya, Turkey

Department of Histology, Recep Tayyip Erdogan University Faculty of Medicine, Rize, Turkey

Department of Neurosurgery, Recep Tayyip Erdogan University Faculty of Medicine, Rize, Turkey

Department of Orthopaedic Surgery, Recep Tayyip Erdogan University Faculty of Medicine, Rize, Turkey

Department of Pharmacology, Rize University Faculty of Medicine, Rize, Turkey

Department of Neurology, Medeniyet University Faculty of Medicine, Istanbul, Turkey

ABSTRACT OBJECTIVE: Sciatic nerve neuropathy can be observed following intramuscular gluteal injections. The histopathological examination of sciatic nerve damage following intramuscular injection in the gluteal region for acute pain treatment is not feasible in humans due to the inability to dissect and examine the nerve tissue. To overcome this issue, we used a rat model for demonstrating damage to the sciatic nerve tissue after the application of commonly used drug injections. METHODS: We investigated possible damage following the intramuscular injection of diclofenac, lornoxicam, morphine, and pethidine in a rat model based on histopathological characteristics such as myelin degeneration, axon degeneration, epineurium degeneration, fibrosis, epineurium thickening, perineurium thickening, lymphocyte infiltration, vacuolization, and edema. RESULTS: All the analgesic drugs used in our study induced histopathological changes in the sciatic nerve. Anti-S100 positivity, showing nerve damage, was found to be the lowest in the group treated with diclofenac. Neurotoxic effects of diclofenac on the sciatic nerve were greater than those of the other drugs used in the study. Lornoxicam induced the least histopathological changes in the nerve. CONCLUSION: Diclofenac induced severe nerve damage not only after direct injection in the sciatic nerve but also after injection in the area around the nerve. Thus, we recommend restricting the use of intramuscular gluteal injections of diclofenac. Intramuscular use of morphine and pethidine should also be overviewed. Keywords: Acute pain treatment; sciatic neuropathy; diclofenac; lornoxicam; morphine; pethidine.

Cite this article as: Bostan H., Cabalar M., Altinay S., Kalkan Y., Tumkaya L., Kanat A., Balik S., Erkut A., Altuner D., Salihoglu Z., Kocer A. Sciatic nerve injury following analgesic drug injection in rats: A histopathological examination. North Clin Istanb 2018;5(3):176–185.

ntramuscular drug injection is preferred over oral drug administration in patients with pain complaints due to its observed immediate effects. Intramuscular drug administration is usually performed in the gluteal region [1, 2]. Even if the correct site, the correct method, a suitable injector, and an ideal dose are selected, sciatic nerve neu-

ropathy can be observed following intramuscular gluteal injections. The composition of the drug, the selection of an unsuitable injection site, unsterile conditions, the use of inappropriate tools, the level of technical skills and ability of the medical staff, as well as the condition of the patient may contribute to the undesirable results. In de-

Received: February 25, 2017 Accepted: November 05, 2017 Online: May 29, 2018 Correspondence: Dr. Abdulkadir KOCER. Medeniyet Universitesi Tip Fakultesi Noroloji Anabilim Dali, Istanbul, Turkey Phone: +90 505 426 28 28 e-mail: abdulkadirkocer@yahoo.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Bostan et al., Sciatic nerve injury following injection

veloping countries lacking adequate healthcare facilities, the risk of sciatic nerve neuropathy after an intramuscular injection is higher [3–5]. The drugs most commonly causing sciatic neuropathy via the intramuscular route are antibiotics and analgesics [5, 6]. The histopathological examination of sciatic nerve damage following intramuscular injection in the gluteal region for acute pain treatment is not feasible in humans due to the inability to dissect and examine the nerve tissue. In this study, we compared the pathological effects of intramuscular drugs commonly used in medical practice, including diclofenac, lornoxicam, morphine, and pethidine, on the sciatic nerve in a rat model. In this animal model, the histopathological effects depending on the drug type and the selection of injection site were compared. MATERIALS AND METHODS Histopathological changes in the sciatic nerve can be identified by examining the nerve tissue, and sciatic nerve damage can be easily shown in a rat model. In this study, we investigated possible damage following the intramuscular injection of diclofenac, lornoxicam, morphine, and pethidine for acute pain treatment in a rat model. The histopathological characteristics evaluated for the assessment of the neural defect included myelin degeneration, axon degeneration, epineurium degeneration, fibrosis, epineurium thickening, perineurium thickening, lymphocyte infiltration, vacuolization, and edema. The study was conducted at the Istanbul Bagcilar Education and Research Hospital Animal Laboratory Section between June 1, 2013 and June 1, 2014. In this study, 50 male Sprague Dawley rats (weighing 180–200 g) were used. All animals were fed with 7–8 mm rat chow pellets ad libitum and water. White fluorescent light controlled with automated photoperiod was used to provide a 12-h light and 12-h dark environment, and ambient temperature and humidity were set at 21°C±2°C and 55%–60%, respectively. The methods used for animal experiments were adjusted according to the protocols of the National Institute of Health Guide for the Care and Use of Laboratory Animals. The necessary permissions were obtained from the Local Ethics Committee for Animal Experiments of the Istanbul Bagcilar Education and Research Hospital (Date: 12.27.2012, Issue no: 63). In total, 10 groups of animals, including control (saline) and drug-treated groups, each containing five subjects were evaluated.

177

The administered drugs, drug administration route, and drug doses were as follows [7–10]: Diclofenac injection in the sciatic nerve, 2 mg/kg/ 0.5 ml; Lornoxicam injection in the sciatic nerve, 1.3 mg/kg/0.5 ml; Morphine injection in the sciatic nerve, 0.2 mg/kg/0.5 ml; Pethidine injection in the sciatic nerve, 3 mg/kg/0.5 ml; Diclofenac injection in the surrounding muscle tissue of the sciatic nerve, 2 mg/kg/0.5 ml; Lornoxicam injection in the surrounding muscle tissue of the sciatic nerve, 1.3 mg/kg/0.5 ml; Morphine injection in the surrounding muscle tissue of the sciatic nerve, 0.2 mg/kg/0.5 ml; Pethidine injection in the surrounding muscle tissue of the sciatic nerve, 3 mg/kg/0.5 ml; Saline (a mixture of sodium chloride in water) injection in the sciatic nerve, 0.5 ml; and Saline injection in the surrounding muscle tissue of the sciatic nerve, 0.5 ml. The rats were anesthetized with ketamine and xylazine. Thereafter, the sciatic nerve was exposed after dissecting through the gluteal muscles. The analgesics and saline were injected in the sciatic nerve and the muscles adjacent to the sciatic nerve. Subsequently, the gluteal muscles and skin tissues were sutured. After this, the rats were kept for 7 days in cages. Later, all the animals were decapitated under deep anesthesia with sodium pentothal (50–60 mg/kg), and the sciatic nerves were removed. The removed sciatic nerve tissues were used for histopathological and immunohistochemical examination, and the samples were stained within 24 h. For staining, the labeled sciatic nerve tissues were fixed in 10% neutral buffered formalin. After keeping for 24 h in the fixative, the samples were washed for about 6–8 h in running water, following which the tissue tracking and processing were performed using an automatic device (Citadel 2000, Thermo Fisher Scientific Shandon, England) passing the samples through ethanol–xylene series. Later, the samples were embedded in liquid paraffin. The tissues were sectioned 4–6-μm thick for routine hematoxylin–eosin staining and 3–4-μm thick for immunohistochemical staining. The cut sections for immunohistochemical staining were incubated for 20 min in xylene and kept in 3% H2O2 solution for 10 min after passing through the series of alcohol (70%–99%). After washing with PBS, the sections were heated in the citrate buffer solution for 5–10 min at 600–800 W; they

178

were allowed to stand for 10 min in the secondary blocking agent. Each slide was held for 60–75 min in various dilutions (1/100–1/300) of the primary antibody (Anti-S100-Coder: ab66041, Abcam plc, Cambridge CB4 0FL UK). Diaminobenzidine (DAB) solution was used as the chromogen, and Mayer’s hematoxylin was used for counterstaining. PBS was used for negative controls. After 1 month, the samples were examined within the same day. The appropriate slide regions under the light microscope were examined at different magnifications, and their pictures were taken. The blind reading and grading of slides were made by two histologists and by a pathologist. The positivity according to the percentage values was categorized in four grading categories: mild (+), moderate (++), severe (+++), and very severe (++++). The histopathological findings such as myelin degeneration, axon degeneration, epineurium degeneration, fibrosis, epineurium thickening, perineurium thickening, lymphocytic infiltration, vacuolization, and edema were evaluated. Additionally, these histopathological findings were divided into four grading categories according to the positivity for anti-S100: mild (+), moderate (++), severe (+++), and very severe (++++). The observed histopathological findings in the groups with drug injections in the sciatic nerve were statistically compared with those in the control groups with saline injections in the sciatic nerve (Table 1). The observed histopathological findings in the groups with drug injections in the muscles adjacent to the sciatic nerve were statistically compared with those in the control groups with saline injections in the muscles adjacent to the sciatic nerve (Table 2). The groups with injections in the sciatic nerve and the ones with injections in the muscles adjacent to the sciatic nerve were also statistically compared with each other in terms of histopathological findings for each drug (Table 3). The groups with drug injections in the sciatic nerve were statistically compared with the control groups with saline injections in the sciatic nerve in terms of anti-S100 positivity. Statistical analysis The statistical analysis and assessment of the study findings were performed using Number Cruncher Statistical System 2007 and Power Analysis and Sample Size 2008 Statistical Software (NCSS LLC, Kaysville, Utah, USA). Mann–Whitney U test was used for comparisons of abnormally distributed parameters between the

North Clin Istanb

groups. The results were evaluated at 95% confidence interval and at p<0.05 level of significance. RESULTS Histopathological results On evaluating the damage after drug injection in the sciatic nerve, axon and myelin degeneration was observed to be greater in the diclofenac group (Table 1). In the epineurium of the nerve, moderate cell degeneration and edema were detected (Figure 1C, D). In the lornoxicam group, nerve fascicular structures comprising myelinated and non-myelinated nerve fibers were shown to preserve their round morphology with distinct borders. In the mor-

CONTROL

Figure 1. (A,

B) Histopathological changes after injection in the muscle tissue adjacent to the sciatic nerve: epi, epineurium; e, edema; v, vacuolization; l, lymphocyte infiltration; star, normal axons; arrow head, degenerated axons; s, swollen Schwann cells; thick arrow, myelin degeneration; hematoxylin–eosin staining, ×40. (C, D) Histopathological changes after injection in the sciatic nerve: epi, epineurium; e, edema; v, vacuolization; l, lymphocyte infiltration; star, normal axons; arrow head, degenerated axons; s, swollen Schwann cells; thick arrow, myelin degeneration; hematoxylin–eosin staining, ×40. Control: star, normal axons; arrow head, mildly degenerated axons; s, normal Schwann cells; hematoxylin–eosin staining, ×40.

Bostan et al., Sciatic nerve injury following injection

CONTROL

Figure 2. (A,

B) Histopathological changes after injection in the muscle tissue adjacent to the sciatic nerve detected using anti-S100 immunohistochemical staining: arrow head, degenerated axons; s, swollen Schwann cells; short arrow, immunopositive cells; v, vacuolization; immunoperoxidase staining. (C, D) Histopathological changes after injection in the sciatic nerve detected using anti-S100 immunohistochemical staining: arrow head, degenerated axons; s, swollen Schwann cells; short arrow, immunopositive cells; v, vacuolization; epi, epineurium; e, edema; immunoperoxidase staining. Control: star, normal axons; short arrow, moderate immunopositive cells; s, intense immunopositive Schwann cells; immunoperoxidase.

phine group, axon and myelin degeneration was present at a certain rate around the epineurium. In the pethidine group, axon and myelin degeneration was observed. The degenerated regions between the epineurium and endoneurium showed a gradual increase. On evaluating the samples where drug was injected in the tissue adjacent to the sciatic nerve, axon degeneration, abundant lymphocyte infiltration, edema and vacuolization, and thickening at perineural areas, fibrosis, and granulation tissue formation at injection sites were observed in the diclofenac group. Inflammation around the axons and mild degeneration of the myelin sheath were observed in the lornoxicam group. In the muscles, vacuolization areas increased but lacked a homogeneous distribution throughout (Fig. 1A, B). In the morphine group, dense edema, vacuolization, fibrosis, and granulation tissue formation were observed (Fig. 1A, B). Myelin degeneration around

179

the epineurium was increased and both edema and degeneration were observed in the pethidine group (Fig. 1C, D). In group where saline was injected in the sciatic nerve, swelling surrounding the axons of some nerve fibers, formation of degenerated regions in the myelin sheaths, separation of the lamellae of myelin from each other, and mild degeneration of axons in some nerve fibers were detected, but significant number of myelinated nerve fibers presented with normal morphological features (Fig. 1, Control). In the group where saline was injected adjacent to the sciatic nerve group, no histopathological changes were observed on the examination of the sciatic nerves using light microscopy. Immunohistochemical results Immunohistochemical staining performed using the immunoperoxidase method in the groups in which injections were performed in the sciatic nerve yielded the following results for anti-S immunopositivity: (+) 60% and (++) 40% in the diclofenac group; (++) 60% and (+++) 40% in the lornoxicam group; (+) 40%, (++) 40%, and (+++) 20% in the morphine group; and (++) 20% and (+++) 40% in the pethidine group(+++). Furthermore, anti-S immunopositivity was (+++) 40% and (++++) 60% in the saline group (Fig. 2Aâ&#x20AC;&#x201C;D-Control). Statistical Findings Myelin degeneration Myelin degeneration was found to be significantly higher in the groups in which drugs were injected directly in the sciatic nerve than in the groups in which saline was injected (p<0.05) (Table 1). Furthermore, myelin degeneration was significantly greater in the groups in which drugs (except pethidine) were injected around the sciatic nerve than in the groups in which saline was injected around the sciatic nerve (p<0.05) (Table 2). In the diclofenac and pethidine groups, myelin degeneration was shown to be significantly higher than that in the diclofenac and pethidine groups in which drugs were injected in the tissue adjacent to the sciatic nerve (p<0.05) (Table 3). Axon degeneration In the diclofenac and pethidine groups, axon degeneration was found to be significantly higher than that in the group in which saline was injected directly in the sciatic nerve (p<0.05) (Table 1). The axon degeneration with the injection of any drug except pethidine in the tissue adjacent

180

North Clin Istanb

Table 1. The assessment of histopathological damage comparing saline with other drugs when the agents were injected in the sciatic nerve

Pathological Changes Level Myelin degeneration None +1 +2 +3 +4 Median (Min-Max) Axon degeneration None +1 +2 +3 +4 Median (Min-Max) Epineurium degeneration None +1 +2 +3 Median (Min-Max) Fibrosis None +1 +2 +3 Median (Min-Max) Epineurium thickening None +1 +2 +3 Median (Min-Max) Perineurium thickening None +1 +2 +3 Median (Min-Max) Lymphocyte infiltration None +1 +2 +3 +4 Median (Min-Max) Vacuolisation None +1 +2 +3 +4

Saline (n)

Morphine (n)

Pethidine (n)

Diclofenac (n)

Lornoxicam (n)

1 3 1 0 0 1 (0-2) 1 3 1 0 0 1 (0-2) 0 4 1 0 1 (1-2)

0 0 3 2 0 2 (2-3) 0 2 0 3 0 3 (1-3) 0 3 2 0 1 (1-2)

0 0 1 2 2 3 (2-4) 0 0 0 4 1 3 (3-4) 0 1 3 1 2 (1-3)

0 0 0 2 3 4 (3-4) 0 0 0 2 3 4 (3-4) 0 0 1 4 3 (2-3)

0 0 4 1 0 2 (2-3) 0 2 1 2 0 2 (1-3) 0 1 4 0 2 (1-2)

3 2 0 0 0 (0-1) 3 2 0 0 0 (0-1)

0 0 4 1 2 (2-3) 0 5 0 0 1 (1-1)

0 0 1 4 3 (2-3) 0 0 3 2 2 (2-3)

0 0 1 4 3 (2-3) 0 0 2 3 3 (2-3)

0 1 3 1 2 (1-3) 0 2 3 0 2 (1-2)

0 4 1 0 1 (1-2) 0 4 1 0 0 1 (1-2) 0 2 3 0 0

0 3 2 0 1 (1-2) 0 0 0 3 2 3 (3-4) 0 0 4 1 0

0 1 2 2 2 (1-3) 0 0 0 3 2 3 (3-4) 0 0 2 1 2

0 0 5 0 2 (2-2) 0 0 0 0 5 4 (4-4) 0 0 0 1 4

0 2 3 0 2 (1-2) 0 0 4 1 0 2 (2-3) 0 1 2 1 1

A-B p=0.016* A-C p=0.010* A-D p=0.007** A-E p=0.018*

A-B p=0.090 A-C p=0.006** A-D p=0.007** A-E p=0.116

A-B p=0.513 A-C p=0.065 A-D p=0.007** A-E p=0.072 A-B p=0.006** A-C p=0.006** A-D p=0.006** A-E p=0.013* A-B p=0.048* A-C p=0.007** A-D p=0.007** A-E p=0.020*

A-B p=0.513 A-C p=0.054 A-D p=0.014* A-E p=0.221

A-B p=0.006** A-C p=0.006** A-D p=0.004** A-E p=0.015*

A-B p=0.093 A-C p=0.033* A-D p=0.006** A-E p=0.214

Bostan et al., Sciatic nerve injury following injection

181

Table 1. CONT. Pathological Changes Level Median (Min-Max) Edema None +1 +2 +3 +4 Median (Min-Max)

Saline (n)

2 (1-2) 1 3 1 0 0 1 (0-2)

Morphine (n)

2 (2-3) 0 0 0 0 5 4 (4-4)

Pethidine (n)

3 (2-4) 0 0 2 2 1 3 (2-4)

Diclofenac (n)

4 (3-4) 0 0 0 0 5 4 (4-4)

Lornoxicam (n)

2 (1-4) 0 0 2 2 1 3 (2-4)

A-B p=0.005** A-C p=0.013* A-D p=0.005** A-E p=0.013*

n: number of subjects with pathological changes, Mann Whitney U test; * p<0.05 **p<0.01.

to the sciatic nerve was significantly higher than that with the injection of saline in the tissue adjacent to the sciatic nerve (p<0.05) (Table 2). Similar to myelin degeneration results, axon degeneration was found to be significantly higher in the diclofenac and pethidine groups in which the drugs were injected directly in the sciatic nerve than in those in which the drugs were injected in the tissue adjacent to the sciatic nerve (p<0.05) (Table 3). Epineurium degeneration Epineurium degeneration in the diclofenac group was significantly higher than that in the saline group (p<0.05) (Table 1). The degeneration was found to be significantly higher with the injection of any drug in the tissue adjacent to the sciatic nerve than with the injection of saline in the tissue adjacent to the sciatic nerve (p<0.05) (Table 2). Even epineurium degeneration was found to be greater in the group in which saline was directly injected in the sciatic nerve than in the group in which saline was injected in the tissue adjacent to the sciatic nerve (p<0.05) (Table 3). Fibrosis In comparison with saline, all drugs injected directly in the sciatic nerve resulted in a greater level of fibrosis (p<0.05) (Table 1). Similar findings were observed in the groups in which injection was performed in the tissue adjacent to the sciatic nerve (p<0.05) (Table 2). Greater fibrosis was observed in the groups in which morphine and pethidine were injected directly in the nerve than in those in which morphine and pethidine were injected in the tissue adjacent to the sciatic nerve (p<0.05) (Table 3).

Epineurium thickening Compared with saline, all drugs injected directly in the sciatic nerve resulted in greater epineurium thickening (p<0.05) (Table 1). Similar findings were observed in the groups in which injection was performed in the tissue adjacent to the sciatic nerve (p<0.05) (Table 2). Saline injected directly in the sciatic nerve caused more epineurium problems compared with that injected in the tissue adjacent to the nerve (p<0.05) (Table 3). Perineurium thickening Although any type of diclofenac injection resulted in greater perineurium thickening, lornoxicam injection in the area adjacent to the sciatic nerve resulted in greater perineurium thickening compared with saline injection (p<0.05) (Table 1 and 2). Perineurium thickening was greater in the groups in which pethidine and saline were directly injected in the sciatic nerve than in those in which pethidine and saline were injected in the tissue adjacent to the sciatic nerve (p<0.05) (Table 3). Lymphocyte infiltration Lymphocyte infiltration in all the groups in which drugs were directly injected in the sciatic nerve was significantly higher than that in the groups in which saline was injected (p<0.05) (Table 1). On comparing the different drugs injected in the tissue adjacent to the sciatic nerve, the diclofenac and lornoxicam groups showed higher lymphocyte infiltration than the saline-injected groups (p<0.05) (Table 2). The injections of diclofenac, morphine, or pethidine in the sciatic nerve caused higher lymphocyte infiltration than those in the tissue adjacent to the sciatic nerve (p<0.05) (Table 3).

182

North Clin Istanb

Table 2. The assessment of histopathological damage comparing saline with other drugs when the agents were injected in the muscle tissue adjacent to the sciatic nerve Pathological Changes Level Myelin degeneration None +1 +2 +3 +4 Median (Min-Max) Axon degeneration None +1 +2 +3 +4 Median (Min-Max) Epineurium degeneration None +1 +2 +3 Median (Min-Max) Fibrosis None +1 +2 +3 Median (Min-Max) Epineurium thickening None +1 +2 +3 Median (Min-Max) Perineurium thickening None +1 +2 +3 Median (Min-Max) Lymphocyte infiltration None +1 +2 +3 +4 Median (Min-Max) Vacuolisation None +1 +2 +3

Saline (n)

3 2 0 0 0 0 (0-1) 4 1 0 0 0 0 (0-1) 4 1 0 0 0 (0-1) 4 1 0 0 0 (0-1) 4 1 0 0 0 (0-1) 3 2 0 0 0 (0-1) 2 3 0 0 0 0 (0-1) 3 2 0 0

Morphine (n) CPethidine (n)

0 3 1 1 0 1 (1-3) 0 3 1 1 0 1 (1-3) 0 3 2 0 1 (1-2) 0 4 1 0 1 (1-2) 0 4 0 1 1 (1-3) 1 4 0 0 1 (0-1) 0 4 1 0 0 1 (1-2) 0 3 2 0

2 2 1 0 0 1 (0-2) 2 2 1 0 0 1 (0-2) 0 3 2 0 1 (1-2) 0 4 1 0 1 (1-2) 0 3 1 1 1 (1-3) 2 3 0 0 1 (0-1) 0 3 2 0 0 1 (1-2) 1 3 1 0

Diclofenac (n)

0 0 2 3 0 3 (2-3) 0 0 3 2 0 2 (2-3) 0 0 4 1 2 (2-3) 0 0 4 1 2 (2-3) 0 0 2 3 3 (2-3) 0 2 3 0 2 (1-2) 0 0 2 3 0 3 (2-3) 0 0 3 2

Lornoxicam (n)

0 2 1 2 0 2 (1-3) 0 2 2 1 0 2 (1-3) 0 3 2 0 1 (1-2) 0 3 2 0 1 (1-2) 1 3 1 0 1 (0-2) 0 2 2 1 2 (1-3) 0 0 3 2 0 2 (2-3) 0 1 3 0

A-B p=0.032* A-C p=0.419 A-D p=0.007** A-E p=0.021*

A-B p=0.014* A-C p=0.189 A-D p=0.006** A-E p=0.012* A-B p=0.014* A-C p=0.014* A-D p=0.005** A-E p=0.014* A-B p=0.015* A-C p=0.015* A-D p=0.005** A-E p=0.014* A-B p=0.015* A-C p=0.014* A-D p=0.006** A-E p=0.065 A-B p=0.221 A-C p=0.549 A-D p=0.020* A-E p=0.021*

A-B p=0.093 A-C p=0.058 A-D p=0.007** A-E p=0.007** A-B p=0.031* A-C p=0.166 A-D p=0.007** A-E p=0.013*

n: number of subjects with pathological changes, Mannâ&#x20AC;&#x201C;Whitney U test; * p<0.05, **p<0.01.

Vacuolization Vacuolization was significantly higher in the diclofenac and pethidine groups in which drugs were directly injected in

the sciatic nerve than in the saline group (p<0.05) (Table 1). Furthermore, vacuolization was significantly higher in the diclofenac, morphine, and lornoxicam groups in which

Bostan et al., Sciatic nerve injury following injection

183

Table 3. The comparison of histopathological damage after the injection of agents in the sciatic nerve and in the muscle tissue adjacent to the nerve

Morphine

Pethidine

Diclofenac

Lornoxicam

Saline (SF)

Miyelin Degeneration Axon Degeneration Epineurium Degeneration Fibrosis Epineurium Thickening Perineurium Degeneration Lymphocyte Infiltration Vacuolisation Edema

0.121 0.356 1.000 0.015* 0.317 0.093 0.006** 0.042* 0.005**

0.011* 0.007** 0.166 0.007** 0.121 0.017* 0.007** 0.013* 0.023*

0.031* 0.020* 0.072 0.072 1.000 0.134 0.005** 0.011* 0.005**

0.734 0.74 0.221 0.166 0.166 0.729 0.513 0.736 0.142

0.166 0.065 0.015* 0.513 0.513 0.042* 0.093 0.020* 0.166

Mann Whitney U test; * p<0.05 **p<0.01.

drugs were injected in the tissue adjacent to the sciatic nerve than in the saline groups (p<0.05) (Table 2). On comparing the different injection sites, the vacuolization in the diclofenac, morphine, pethidine, and saline groups was found to be significantly higher (p<0.05) (Table 3). Edema Edema in all the groups in which drugs were directly injected in the sciatic nerve was significantly higher than that in the groups in which saline was injected (p<0.05) (Table 1). On comparing different injections in the tissue adjacent to the sciatic nerve, the diclofenac and lornoxicam groups showed greater edema than the saline-injected groups (p<0.05) (Table 2). The injection of diclofenac, morphine, and pethidine in the sciatic nerve causes higher edema than that in the tissue adjacent to the sciatic nerve (p<0.05) (Table 3). Anti-S100 positivity The level of anti-s100 positivity was the highest in the saline group (p<0.05). It was the lowest in the diclofenac group. DISCUSSION The sciatic nerve is prone to injury following drug injection, and the proportion of sciatic nerve damage resulting from intramuscular injections is reported to be high (86% of all cases) [11]. Sciatic nerve damage arises from an injection either directly in the sciatic nerve or in the surrounding tissue [12–19]. Inappropriate drug injec-

tion in the gluteal region can result in direct damage to the sciatic nerve. The mechanism of injury appears to be a direct toxic effect of the injected compound on the neural tissue [12–20]. During injection in the sciatic nerve, the drug sometimes may get injected between the nerve and the sheath or between the fascicles. In these cases, neuronal damage occurs due to the effect of the drug rather than a physical damage to the nerve. Furthermore, the accumulation of the drug around the sciatic nerve or at an epineural level may result in sciatic nerve damage [12–14, 20, 21]. The neurological defects following drug injection directly in the sciatic nerve are observed depending on the level of damage induced by the specific agent injected [14, 15]. In addition, the quantity of the drug injected is important in determining the degree of injury [18]. The most severe injuries are associated with widespread axon and myelin degeneration, and the pathological alterations in the nerve are evident as early as 30 min following the injury due to the injection [17, 18]. In their study investigating the toxic effect of non-steroidal anti-inflammatory drugs during development, Canan et al reported that axon loss was significantly prominent in rats exposed to diclofenac sodium [20]. In our study, we demonstrated that analgesic drug or saline injection directly in the sciatic nerve caused nerve damage. This result was similar to the report by Canan et al. [20]. The histopathological changes were most prominent in the diclofenac group and least prominent in the lornoxicam group, as shown in Table 1. The diclofenac group showed many types of pathological changes, including axon damage in the subjects in which drugs or saline were injected in the tissue adjacent to the sciatic nerve, although the

184

other drug groups did not show any prominent findings related to the nerve damage (Table 2). All these findings supported the fact that nerve damage resulted from injection either directly in the sciatic nerve or in the tissue adjacent to the nerve. As another important finding of our study, we have shown toxic effects of all the drugs, although we used the lowest dosages reported in the literature [7–10, 19]. The intramuscular use of diclofenac, lornoxicam, morphine, and pethidine has been well established for the treatment of acute pain [22–31]. Among these, diclofenac and pethidine have both analgesic and anti-inflammatory effects [26–29]. Morphine and pethidine are narcotic drugs with analgesic effects [30, 31]. There is currently no report demonstrating the histopathological effects of diclofenac on the sciatic nerve, although diclofenac has been reported to induce anaphylaxis after intramuscular injection for acute pain treatment [28]. In our study, the histopathological changes observed with the injection of diclofenac in the sciatic nerve were more than those with the other drugs. Compared with other drugs, diclofenac induced more histopathological changes after injection in not only the sciatic nerve but also the tissue adjacent to the nerve. It is known that the protein level of S-100 decreases, and it can be demonstrated using immunohistochemical staining when there is nerve damage [32]. In the present study, anti-s100 positivity, showing nerve damage, was found to be the lowest in the diclofenac group with direct injection in the sciatic nerve. This observation indicates that diclofenac is the most toxic agent among the drugs injected in this study. Milder histopathological changes were observed on evaluating the toxic effects of the other drugs. Lornoxicam seems to be one of the drugs that can be intramuscularly used for acute pain treatment, and there are no reports on sciatic nerve damage induced by an intramuscular injection of this drug in the gluteal region or its histopathological effects on the sciatic nerve [24, 25]. Lornoxicam injection in the sciatic nerve resulted in greater damage supported based on the histopathological evidence, and anti-S100 positivity was detected to be lower in the lornoxicam group with injection in the sciatic nerve than in the control group with serum physiological injection in the sciatic nerve. This data suggests that the histopathological effects of lornoxicam on the sciatic nerve were more than those of serum physiological but milder than those of diclofenac. Both morphine and pethidine are administered intramuscularly in the gluteal region for acute pain treatment [22, 29–31]. Morphine is a narcotic analgesic lacking

North Clin Istanb

anti-inflammatory properties and is known to suppress respiration at higher doses and to pose an addiction risk. [22]. In our study, the histopathological changes were more severe in the morphine and pethidine groups in which the drugs were directly injected in the sciatic nerve than in the groups in which these drugs were injected in the tissue adjacent to the nerve. The anti-S100 positivity was found to be lower in the groups in which morphine and pethidine were directly injected in the sciatic nerve than in the groups in which serum physiological was injected. This proved the histopathological effects of morphine and pethidine on the sciatic nerve; however, their effects were found to be milder than those of diclofenac. Compared with the other drug injections, pethidine injection in the muscle tissue adjacent to the nerve resulted in less damage. Anti-S100 positivity in the group with pethidine injected in the sciatic nerve was found to be lower than that in the group injected with serum physiological ; this supports the evidence for the histopathological effects of pethidine on the sciatic nerve. Moreover, the injection of pethidine resulted in minor histopathological changes compared with that of other drugs. To our knowledge, these are the first results of damage after direct injections in the sciatic nerve or the tissue adjacent to the nerve; thus, no laboratory or clinical study is available in the literature to compare our findings. CONCLUSION In conclusion, the site of injection is the most crucial factor in determining the degree of nerve injury. Most widely used analgesic drugs can easily induce damage-related changes in the sciatic nerve when the drug is directly injected in the sciatic nerve or in the tissue adjacent to the sciatic nerve. Neurotoxic effects of diclofenac on the sciatic nerve were detected to be greater than those of other drugs used in the present study. Thus, we recommend that the use of diclofenac intramuscularly should be restricted in emergency units and even inpatient clinics. Additionally, lornoxicam, morphine, and pethidine have been demonstrated to have neurotoxic effects on the sciatic nerve tissue despite lack of relevant studies. Lornoxicam, with anti-inflammatory effects, has also been shown to exert neurotoxic effects on the sciatic nerve, although its effects were the mildest. Furthermore, we suggest that intramuscular use of morphine and pethidine should be overviewed. Acknowledgment: This study was partially presented at National Neurology Congress 20016, Antalya-Turkey.

Bostan et al., Sciatic nerve injury following injection

Ethics: The necessary permissions were obtained from the Local Ethics Committee for Animal Experiments of the Istanbul Bagcilar Education and Research Hospital (Date: 12.27.2012, Issue no: 63). 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 – H.B., A.K.; Design – H.B., A.K., M.C., L.T., Y.K.; Supervision – H.B., L.T., Y.K.; Materials – H.B., L.T., Y.K., A.K., S.B., A.E.; Data collection &/or processing – H.B., D.A., L.T., Y.K., A.K., S.B., A.E.; Analysis and/or interpretation – H.B., M.C., D.A., L.T., Y.K., A.K., S.B., A.E.; Writing – A.K., H.B., M.C., Z.S.; Critical review – A.K., H.B.

REFERENCES 1. Aysegul G, Nurten U, Nevzat A, Kiziltan ME. Injection Neuropathies of the Sciatic Nerve: Experience of an Electrophysiology Laboratory and Medicolegal Approach in Turkey. Noropsikiyatri Arsivi 49:208–11. 2. Nicoll LH, Hesby A. Intramuscular injection: An integrative research review and guideline for evidence-based practice. Applied Nursing Res 2002;15:149–62. 3. Mishra P, Stringer MD. Sciatic nerve injury from intramuscular injection: a persistent and global problem. Int J Clin Pract 2010;64:1573–9. 4. Idowu AO, Ogunrinu AE, Akinremi A, Aladeyelu OE, Kaka B, Adelugba JK. Injection-induced Sciatic Nerve Injury Among. Children Managed in a Nigerian Physiotherapy. Clinic: A five-year review. AJPARS 2011;3:13–6. 5. Bağış S, Adam M, Leblebici ÜB, Karataş M, Güven AZ, Çelikler AR. Sciatic nerve injury due to intramuscular injection: electrophysiological findings and one-year follow-up. Turk J Med Sci 2012;42:913–7. 6. Dönertaş B, Alkan A, Mollahaliloğlu S, Seçkin C, Akıcı A. Investigation of paranteral drug use in family health care centers across 32 provinces of Turkey. Anatolian J Clin Invest 2013;7:31–40. 7. Peris-Ribera JE, Torres-Molina F, Garcia-Carbonell MC, Aristorena JC, Pla-Delfina JM. Pharmacokinetics and bioavailability of diclofenac in the rat. J Pharmacokinet Biopharm 1991;19:647–65. 8. Topcu I, Vatansever S, Bayram E, Var A, Cetin I, Civi M. The effects of lornoxicam on neuroprotection following diffuse traumatic brain injury in rats. Turk Neurosurg 2013;23:764–71. 9 Thomas A, Miller A, Roughan J, Malik A, Haylor K, Sandersen C, et al. Efficacy of Intrathecal Morphine in a Model of Surgical Pain in Rats. PLoS One 2016;11:e0163909. 10. Randolph BC, Peters MA. Analgesic effectiveness of ketorolac compared to meperidine in the rat formalin test. Anesthesia Prog 1997;44:11–6. 11. Huang Y, Yan Q, Lei W. Gluteal sciatic nerve injury and its treatment [Article in Chinese]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2000;14:83–6. 12. Mayer M, Romain O. Sciatic paralysis after a buttock intramuscular injection in children: an ongoing risk factor [Article in French]. Arch Pediatr 2001;8:321–3. 13. Gentili F, Hudson AR, Hunter D, Kline DG. Nerve injection injury with local anesthetic agents: a light and electron microscopic, fluorescent microscopic, and horseradish peroxidase study. Neurosurgery 1980;6:263–72. 14. Kline DG, Kim D, Midha R, Harsh C, Tiel R. Management and results of

185 sciatic nerve injuries: a 24-year experience. J Neurosurg 1998;89:13–23. 15. Kline DG. Diagnostic approach to individual nerve injuries. In: Wilkins R, Rengachary S, editors. Neurosurgery. 2nd ed. New York: McGrawHill; 1996. p. 3125–46. 16. Todd PA, Sorkin EM. Diclofenac sodium. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1988;35:244–85. 17. Yaffe B, Pri-Chen S, Lin E, Engel J, Modan M. Peripheral nerve injection injury: an experimental pilot study of treatment modalities. J Reconstr Microsurg 1986;3:33–7. 18. Gentili F, Hudson A, Kline DG, Hunter D. Peripheral nerve injection injury: an experimental study. Neurosurgery 1979;4:244–53. 19. Strasberg JE, Atchabahian A, Strasberg SR, Watanabe O, Hunter DA, Mackinnon SE. Peripheral nerve injection injury with antiemetic agents. J Neurotrauma 1999;16:99–107. 20. Canan S, Aktaş A, Ulkay MB, Colakoglu S, Ragbetli MC, Ayyildiz M, et al. Prenatal exposure to a non-steroidal anti-inflammatory drug or saline solution impairs sciatic nerve morphology: a stereological and histological study. Int J Dev Neurosci 2008;26:733–8. 21. Emir A, Kalkan Y, Bostan H. Histopathological effects of intramuscular metamizole sodium on rat sciatic nerve. Iran J Basic Med Sci 2016;19:829–36. 22. Holdgate A, Pollock T. Nonsteroidal anti-inflammatory drugs (NSAIDs) versus opioids for acute renal colic. Cochrane Database Syst Rev 2004:CD004137. 23. Renal colic in adults: NSAIDs and morphine are effective for pain relief. Prescrire Int 2009;18:217–21. 24. Balfour JA, Fitton A, Barradell LB. Lornoxicam. A review of its pharmacology and therapeutic potential in the management of painful and inflammatory conditions. Drugs 1996;51:639–57. 25. Radhofer-Welte S, Dittrich P, Simin M, Branebjerg PE. Comparative bioavailability of lornoxicam as single doses of quick-release tablet, standard tablet and intramuscular injection: a randomized, open-label, crossover phase I study in healthy volunteers. Clin Drug Investig 2008;28:345–51. 26. Dash A, Maiti R, Akantappa Bandakkanavar TK, Arora P. Intramuscular drotaverine and diclofenac in acute renal colic: a comparative study of analgesic efficacy and safety. Pain Med 2012;13:466–71. 27. Zippel H, Wagenitz A. A multicentre, randomised, double-blind study comparing the efficacy and tolerability of intramuscular dexketoprofen versus diclofenac in the symptomatic treatment of acute low back pain. Clin Drug Investig 2007;27:533–43. 28. Colak S, Gunes H, Afacan MA, Kandis H, Erdogan MO, Ayranci M, et al. Anaphylaxis after intramuscular injection of diclofenac sodium. Am J Emerg Med 2014;32:815.e1–2. 29. Maurset A, Skoglund LA, Hustveit O, Oye I. Comparison of ketamine and pethidine in experimental and postoperative pain. Pain 1989;36:37–41. 30. Pincus DF. When and why I use pethidine. Aust Fam Physician 1991;20:392–4. 31. Bardo MT, Hughes RA. Exposure to a nonfunctional hot plate as a factor in the assessment of morphine-induced analgesia and analgesic tolerance in rats. Pharmacol Biochem Behav 1979;10:481–5. 32. Rezajooi K, Pavlides M, Winterbottom J, Stallcup WB, Hamlyn PJ, Lieberman AR, et al. NG2 proteoglycan expression in the peripheral nervous system: upregulation following injury and comparison with CNS lesions. Mol Cell Neurosci 2004;25:572–84.

Orıgınal Article

CARDIOLOGY

North Clin Istanb 2018;5(3):186–194 doi: 10.14744/nci.2017.59244

Systemic inflammatory activation in patients with acute coronary syndrome secondary to nonatherosclerotic spontaneous coronary artery dissection Yigit Canga,1 Tolga Sinan Guvenc,1 Ali Nazmi Calik,1 Mehmet Baran Karatas,1 Tahir Bezgin,2 Tolga Onuk,1 Ahmet Okan Uzun,1 Veysel Ozan Tanik,1 Baris Gungor,1 Osman Bolca1 Department of Cardiology, Siyami Ersek Cardiovascular and Thoracic Surgery Center, Istanbul, Turkey

Department of Cardiology, Gebze Fatih State Hospital, Izmit, Turkey

ABSTRACT OBJECTIVE: Pathological studies have suggested that local inflammation, particularly eosinophilic infiltration of the adventitia, could be related to nonatherosclerotic spontaneous coronary artery dissection (NA-SCAD). However, the role of systemic inflammation in the pathogenesis of NA-SCAD remains unknown. Our aim was to investigate systemic inflammatory activation in patients with an acute coronary syndrome (ACS) secondary to NA-SCAD. METHODS: The institutional electronic medical database was reviewed, and 22 patients with NA-SCAD-ACS were identified after the review. Furthermore, 30 random patients with CAD-ACS and 30 random subjects without any history of CAD or ACS with demographic and clinical characteristics similar to those of NA-SCAD-ACS patients were identified from the institutional database to be included in the study. RESULTS: Patients with NA-SCAD-ACS and those with CAD-ACS both had higher white blood cell and neutrophil counts than controls. Neutrophil–lymphocyte ratio (NLR) and C-reactive protein (CRP) levels were only significantly higher in the NA-SCADACS group [2.01 (1.54–6.17) for NLR and 0.70 (0.13–2.70) for CRP] than in the controls [1.55 (1.27–2.13), p=0.03 for NLR and 0.15 (0.10–0.43), p=0.049 for CRP]; however, there were no differences between the NA-SCAD-ACS and CAD-ACS groups [1.91 (1.41–2.78) for NLR and 0.41 (0.09–1.10) for CRP, p>0.05 for both comparisons] regarding all tested parameters. CONCLUSION: The degree of inflammatory activation in NA-SCAD-ACS patients was similar to, or even greater than, that in CAD-ACS patients; thus, suggesting a role of inflammation in the pathophysiology of NA-SCAD-ACS. Keywords: Acute coronary syndrome; inflammation; spontaneous coronary artery dissection.

Cite this article as: Canga Y., Güvenc T. S., Calik A. N., Karatas M. B., Bezgin T., Onuk T., Uzun A. O., Tanik V. O., Gungor B., Bolca O. Systemic inflammatory activation in patients with acute coronary syndrome secondary to nonatherosclerotic spontaneous coronary artery dissection. North Clin Istanb 2018;5(3):186–194.

pontaneous coronary artery dissection (SCAD) is a rare coronary pathology that is caused by a non-provoked separation of the medial and adventitial layers of the coronary artery secondary to an intimal tear or hemorrhage within the vessel wall. While SCAD could affect both atherosclerotic and non-atherosclerotic coronary

arteries, atherosclerotic SCAD is generally considered a variant of atherosclerotic coronary artery disease (CAD) as the dissection is related to the rupture of the atheroma and is limited to a short segment of the coronary artery as the progression is impeded by medial scarring secondary to CAD [1]. Nonatherosclerotic SCAD (NA-

Received: June 06, 2017 Accepted: September 20, 2017 Online: May 24, 2018 Correspondence: Dr. Yigit CANGA. Siyami Ersek Gogus Kalp ve Damar Cerrahisi Egitim ve Arastirma Hastanesi, Kardiyoloji Bolumu, Istanbul, Turkey. Phone: +90 216 459 27 66 e-mail: canga81@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Canga et al., Inflammation in patients with spontaneous coronary artery dissection

SCAD) comprises 0.1%–0.28% of all angiographicallyproven myocardial infarctions [2] and is more frequently observed in women, especially during peripartum period but may also affect older women [3]. Several autopsy reports and studies have associated inflammation, especially eosinophilic infiltration of the outer media and adventitia of the coronary vessel, with the occurrence of NA-SCAD [4, 5]. A noteworthy similarity exists between the eosinophilic coronary periarteritis (ECPA) and NA-SCAD, as both conditions are characterized by eosinophilic infiltration with mast cell degranulation in relatively short segments of the coronary arteries [6]. Other manifestations of systemic allergy or inflammation, such as asthma, may or may not accompany NA-SCAD and ECPA, but eosinophilia or widespread arteritis in systemic vessels is usually missing, suggesting that these phenomena may represent a standalone disorder [6, 7]. Besides these observations, however, an evaluation of hematologic or circulatory markers of inflammation was not attempted in patients with NASCAD. Systemic inflammation is a well-known feature of atherosclerotic CAD as inflammation plays a crucial role in the evolution of atheroma from the initial “fatty streak” lesions to complex atherosclerotic plaques responsible for acute coronary events [8]. We hypothesized that systemic inflammation may also play a role in NA-SCAD due to the association of this condition with periarterial inflammation. In this retrospective analysis, we aimed to investigate the presence of systemic inflammatory markers in NA-SCAD patients with a diagnosis of acute coronary syndrome (NA-SCAD-ACS) and compare our findings with age- and sex-matched subjects with ACS secondary to atherosclerotic coronary disease (CAD-ACS) and healthy individuals. As a secondary aim, we investigated the angiographic characteristics, management strategies, and in-hospital outcomes in NA-SCAD-ACS and CAD-ACS patients. MATERIALS AND METHODS All coronary angiographies performed between 2011 and 2015 and stored in the institutional database were reviewed for angiography reports containing the words “coronary” and “dissection.” Among 30255 coronary angiography reports, 187 met the criteria. Stored angiographic images for these reports were then evaluated by two cardiologists experienced in invasive procedures (YÇ and MBK). NA-SCAD was defined as an intraluminal

187

filling defect during contrast injection or persistent staining of the artery following contrast injection that was not interpreted as an obstructive coronary atheroma or intracoronary thrombus, and the artery in which the dissection was observed should be free from any coronary atherosclerotic plaque. To be eligible for inclusion in the study, dissection should be evident in at least two angiographic projections. In case of disagreement between two investigators, a third investigator (TSG) evaluated the angiogram in question and decided whether the patient would be included in the analysis. Patients in whom the intimal tear was in close proximity to the catheter tip were excluded due to the possibility of iatrogenic dissection. Other exclusion criteria included known inflammatory diseases, an acute infection at the time of angiography, known hematologic disorders that affect white blood cells, known malignancy, prior splenectomy, and additional exclusion criteria specified in the “laboratory analysis” section. While age was not an exclusion criterion, none of the patients were aged under 18 years as these patients were not accepted in the adult cardiology unit. Finally, patients diagnosed with NA-SCAD under non-emergent conditions (i.e., an evaluation for stable angina) were excluded due to the possibility of different inflammatory conditions in stable patients. Of the initial 187 patients, 22 met the inclusion criteria and were included in the study (Fig. 1). In addition to the patients with NA-SCAD, records for two additional Initial Screening Out of 30255 coronary angiography reports, 187 contained words ‘‘coronary’’ and ‘‘dissection’’ Exclusion Criteria -Known inflammatory diseases -Acute infection at the time of angiography -Known hemologic disorders that affect white blood cells Application of Exclusion Criteria -Know malignancy 22 patients were found eligible for study. -Prior splenectomy 30 patients with acute coronary seyndrome -Nonacute presensecondary to atherosclerosis and 30 controls tation without coronary artery disease were included. -Unavaliable laboratory data Fetching of Clinical and Laboratory Data Statistical Analysis Results Visual Evaluation of Angiograms Patients with atherosclerotic coronary dissections or iatrogenic dissections were excluded at this stage. 30 patients had nonatherosclerotic spontaneous coronery artery dissection.

Figure 1. Flow diagram of the study.

188

groups of subjects were collected to compare the degree of inflammation in patients with NA-SCAD. In the first group, records of 30 age- and gender-matched patients who were hospitalized in the study institution and who underwent coronary angiography for ACS [either STsegment elevation myocardial infarction (STEMI) or unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI)] and were diagnosed with CAD-ACS were collected to form CAD-ACS group. Records of a second set of 30 age- and sex-matched subjects without a cardiovascular disease who were admitted to the study institution for a routine check-up were collected to serve as controls. Subjects in the CAD-ACS and control groups were randomly selected using computer-generated numbers, and aforementioned exclusion criteria were also applied to the CAD-ACS and control groups. All the records were retrieved using institutional electronic medical database (EMD). In addition to the angiographic records, patients’ demographic characteristics, prior medical history, laboratory values, and data on inhospital outcomes were retrieved from EMD. This analysis was performed according to the principles of the Declaration of Helsinki, and a local Ethics Committee had approved the study. Laboratory analysis Per institutional protocol, blood is withdrawn for complete blood count and biochemical analysis from all patients who undergo coronary angiography. The blood is withdrawn and studied one day before coronary angiography for patients undergoing elective angiography. For patients undergoing emergent angiography, the blood is withdrawn immediately before angiography. For this analysis, complete blood count and C-reactive protein (CRP) values that preceded angiography were used if the blood was withdrawn within 24 h before angiography. Laboratory analyses performed using blood withdrawn >24 h before angiography or blood withdrawn following the study were not used. Laboratory records were not used if the laboratory had indicated possible hemolysis of the sample, and the patient was excluded from the study if there were no other laboratory analyses that preceded angiography. For healthy controls, blood that was analyzed during check-up was used for statistical analyses. As an institutional protocol, blood withdrawn from the patients was collected into an EDTA -containing tube for complete blood count evaluation and into a dry

North Clin Istanb

tube for biochemical analysis. All the samples collected for analysis were studied within half an hour of the blood withdrawal. An automatic Coulter analyzer was used for evaluating complete blood counts (Beckman Coulter LH 750, Fullerton, CA). CRP levels were determined using a BN II model Nephelometer (Dade Behring, Marburg, Germany). Statistical analysis All statistical analyses were performed using SPSS 17.0 statistical analysis software (IBM Inc, USA). Continuous variables were presented as mean±SD if distributed normally, while median and interquartile ranges were provided in case of a heterogenous distribution. Categorical variables were provided as percentages; Kolmogorov– Smirnov and Levene tests were used to test for normal distribution and homogeneity of data, respectively. A one-way ANOVA was preferred for parameters with a homogenous distribution, and post-hoc analyses were performed with Tukey’s HSD. For parameters with a heterogenous distribution or in case of an inequality of variances, Kruskal–Wallis test was used; Mann–Whitney U test was used for analysis of subgroups. For categorical variables, χ2 test or Fisher’s exact test was preferred according to the observed and expected cell counts. A univariate analysis was performed to determine significant predictors for SCAD. For all comparisons, a p value of <0.05 was accepted as the cut-off value for significance. RESULTS Demographic, clinical, and laboratory findings are presented in Table 1. There were no differences between the groups regarding age, gender, or risk factors for atherosclerotic CAD. Both the NA-SCAD-ACS and CAD-ACS groups had higher absolute total leucocyte and neutrophil counts than the control group. In contrast, both neutrophil–lymphocyte ratio (NLR) and CRP levels were significantly higher in the NA-SCADACS group than in the control group (p=0.009 and p=0.007, respectively); however, both NLR and CRP levels were not different between the CAD-ACS and control groups (p=0.07 and p=0.24, respectively) (Fig. 2). Neither the absolute eosinophil count nor the lymphocyte count differed between the groups, yet the percentages of eosinophils and lymphocytes were significantly lower in the NA-SCAD-ACS group than in the control group (p=0.048 and p=0.027, respectively). No significant differences were observed between the CAD-

Canga et al., Inflammation in patients with spontaneous coronary artery dissection

189

Table 1. Summary of demographic, clinical and laboratory variables between study groups Parameter Demographic and Clinical Variables Age (y) Gender (Female) n (%) Hypertension n (%) Diabetes n (%) Hyperlipidemia n (%) Smoking n (%) Laboratory Variables WBC (103/mm3) PNL (103/mm3) PNL (%WBC) Eosinophile (103/mm3) Eosinophile (WBC%) Lymphocyte (103/mm3) Lymphocyte (WBC%) NLR ELR C-Reactive Protein (mg/dl)

NASCAD-ACS (n=22)

CAD-ACS (n=30)

Control (n=30)

47.0±12.3 50 25 16 5 32

48.5±0.1 40 36 17 17 40

45.6 ± 9.1 40 30 13 6 17

0.53 0.72 0.85 0.91 0.27 0.13

9.68±3.44† 6.55±3.30 † 63.61±14.55 † 0.15±0.12 1.76±1.50 † 2.18±0.79 26.77±14.25 † 2.01 (1.54-6.17) † 0.07±0.05 0.70 (0.13-2.70) †

9.39±2.80 † 5.79±2.73 † 59.99±11.53 0.17±0.13 1.86±1.31 2.71±0.99 30.28±10.39 1.91 (1.41-2.78) 0.06±0.05 0.41 (0.09-1.10)

6.91±1.70 3.81±1.28 54.45±8.59 0.19±0.12 2.71±1.46 2.36±0.65 34.70±7.56 1.55 (1.27-2.13) 0.08±0.04 0.15 (0.10-0.43)

<0.001 <0.001 0.02 0.52 0.03 0.07 0.03 0.03 0.32 0.049

WBC; White blood cell, PNL; polymorphonuclear leucocytes, NLR, neutrophil-to-lymphocyte ratio, ELR; eosinophile-to-lymphocyte ratio; †: Significantly different at p<0.05 level as compared to control group.

ACS and control groups regarding the latter parameters. For all the comparisons presented in Table 1, no significant differences were found between the NA-SCADACS and CAD-ACS groups. Table 2 summarizes the angiographic characteristics, in-hospital management, and outcomes in the NASCAD-ACS and CAD-ACS groups. Multivessel disease and left circumflex lesions were less frequent in the NA-SCAD-ACS group, but the length of the dissected segments was longer than that of the atherosclerotic lesions, thus, necessitating longer stents if percutaneous intervention was chosen for management. However, a conservative strategy was much more common in the NA-SCAD-ACS group compared with that in the CADACS group. All patients managed with an initial conservative strategy in the NA-SCAD-ACS group presented with unstable angina or non-ST elevation MI as opposed to STEMI (44% vs. 0%). For both the NA-SCAD-ACS and CAD-ACS groups, the in-hospital mortality rate was 0%, with only one patient in each group experiencing a MACE. While an initial conservative strategy was the more common management strategy in the NA-SCADACS group, the frequency of in-hospital major cardio-

vascular events did not differ between the groups; however, the ejection fraction in the NA-SCAD-ACS group was significantly lower than that in the CAD-ACS group (Table 2). Finally, major cardiovascular events were similar in NA-SCAD-ACS groups managed conservatively or invasively (0% in the conservative group vs. 12.5% in the early invasive group, p=0.36), and there were no differences in the ejection fraction between these groups before discharge (49.28±12.69% in the conservative group vs. 48.75±11.57% in the early invasive group, p=0.87). On univariate analysis, none of the demographic, clinical, or laboratory parameters appeared to have sufficient discriminative capacity to differentiate the NA-SCADACS group from the CAD-ACS group; thus, a multivariate analysis was not attempted. DISCUSSION The major findings of the present study can be summarized as follows: i) similar to CAD-ACS patients, systemic inflammatory markers were increased in NASCAD-ACS patients; ii) while CRP levels and NLR were higher in the NA-SCAD-ACS group, there were no

North Clin Istanb

12.00

10.00

11.00

Neutrophil/Lymphocyte ratio

96% CI White blood cell count (x103/mm3)

190

10.00 9.00 8.00 7.00 6.00 Acute coronary synAcute coronary drome secondary to syndrome secondary spontaneus coronary to atherosclerotic artery dissection coronary artery disease

8.00

6.00

4.00

2.00

0.00 Control group

Acute coronary synAcute coronary drome secondary to syndrome secondary spontaneus coronary to atherosclerotic artery dissection coronary artery disease

Control group

C-Reative protein (CRP) (mg/dl)

10.00

8.00

6.00

4.00

2.00

0.00

Acute coronary synAcute coronary drome secondary to syndrome secondary spontaneus coronary to atherosclerotic artery dissection coronary artery disease

Control group

significant differences between the NA-SCAD-ACS and CAD-ACS groups regarding inflammatory biomarkers; iii) the percentage of eosinophils in the peripheral blood was decreased in NA-SCAD-ACS patients; and iv) a conservative approach was more frequently preferred in NA-SCAD-ACS patients, and this management strategy does not appear to increase in-hospital events. This last observation, however, should be interpreted with extreme caution due to the low sample size and retrospective nature of the study. Inflammation is a major pathophysiologic factor that affects all phases of atherosclerotic CAD [9]. Subjects with elevated levels of inflammatory biomarkers, including CRP, serum amyloid-associated protein, or inter-

Figure 2. White blood cell count (A), neutrophil–lymphocyte ratio (NLR) (B) and C-reactive protein (CRP) levels (C) among the study groups. Patients with an ACS secondary to spontaneous coronary artery dissection (NA-SCAD-ACS) had significantly higher white blood cell counts, NLR, and CRP levels as than the controls, whereas only total white blood cell count was significantly higher in patients with an acute coronary syndrome secondary to atherosclerotic coronary artery disease (CAD-ACS). None of the parameters, however, differed between the NA-SCAD-ACS and CAD-ACS groups. See text for details. leukin-6 were at risk for future ischemic events [10–14]. Following ST- and non-ST elevation myocardial infarction, several inflammatory biomarkers including (but not limited to) CRP levels, total white blood cell count, and NLR were associated with the risk of mortality and future cardiovascular events [15–21]. It is postulated that inflammation modulates the tendency of an atherosclerotic lesion to rupture, thus, increasing the vulnerability of an individual plaque [22]. A similar pathophysiologic mechanism was proposed for acute arterial dissection, where inflammation was hypothesized to increase the risk for intimal tears [23–26]. The role of inflammation in patients with other types of arterial dissection, such as SCAD, is less clear. Present findings showed that the

Canga et al., Inflammation in patients with spontaneous coronary artery dissection

191

Table 2. Angiographic characteristics, in hospital management strategies and in-hospital outcomes for study groups. Parameter

NASCAD-ACS (n=22)

CAD-ACS (n=30)

18.2 81.8 13.6 40.9 9.1 59.1 13.6 2.79±0.47 26.5±18.7

20 80 3.3 63.3 50 46.7 40 2.83±0.37 17.1±7.1

1.0 1.0 0.17 0.10 0.002 0.38 0.04 0.71 0.03

36.4 31.8 31.8

6.7 73.3 13.3

0.01 0.003 0.11

49.1±12.0 0 4.5

56.0±7.9 0 3.3

0.04 N/A 1.0

Lesion Characteristics Presentation (STEMI) n (%) Presentation (UA/NSTEMI) n (%) Involvement of LMCA n (%) Involvement of LAD n (%) Involvement of LCx n (%) Involvement of RCA n (%) Multivessel Disease n (%) Reference Diameter (mm) Lesion Length (mm) In-Hospital Management Conservative n (%) Percutaneous Intervention n (%) CABG n (%) In-Hospital Follow-Up Predischarge EF n (%) In-Hospital Mortality n (%) In-Hospital MACE n (%)

STEMI; ST-elevation myocardial infarction, UA/NSTEMI; unstable angına or non-ST elevation myocardial infarction, LMCA; left main coronary artery, LAD; left anterior descending artery, LCX; left circumflex artery, RCA; right coronary artery, CABG; coronary artery bypass grafting, EF; ejection fraction, MACE; major cardiovascular adverse effects.

degree of inflammation in NA-SCAD-ACS was similar to that in CAD-ACS, as no significant differences were found between these two conditions regarding the inflammatory biomarkers. While this preliminary study suggests that inflammation is present in NA-SCADACS, the pathophysiologic and clinical relevance of inflammation in NA-SCAD-ACS remains obscure, thus, necessitating further studies to better understand the role of inflammation in NA-SCAD-ACS. As mentioned before, previous studies have found that virtually all biomarkers of inflammation, including CRP levels and NLR, are elevated in CAD-ACS patients, and the magnitude of inflammation is associated with the outcomes in CAD-ACS. In the present study, we found that both CRP levels and NLR were higher in the CAD-ACS group than in the controls; however, the difference was not significant. As the levels of other biomarkers of inflammation were significantly higher in the CAD-ACS group (Table 1), we assume that the cause of this latter finding is the low statistical power of the study rather than a true lack of difference between the groups. It is worth noting that the mean NLR and

CRP levels in the NA-SCAD-ACS group were higher than those in the CAD-ACS group, although this finding did not reach significance. Whether this difference represents a higher degree of inflammatory reaction in NA-SCAD-ACS patients or simply represents a random effect could not be inferred from the present study due to its low statistical power and retrospective design. In our opinion, this latter observation deserves further research as a better understanding of the role of inflammation in NA-SCAD-ACS might have therapeutic value. A further concern regarding the inflammation in patients with NA-SCAD is the location and type of inflammatory reaction in the affected vessel. Several case studies have reported periarterial inflammation, most notably eosinophilic infiltration, as a postmortem finding in patients with NA-SCAD [6, 27]. It has been hypothesized that the proteolytic enzymes originating from eosinophils cleave collagen and elastin within the tunica media, thus, weakening the vessel wall and facilitating coronary dissection [28]. However, it is unknown whether these findings represent a cause-and-effect relationship or merely a reactive phenomenon secondary to

192

dissection [4, 29]. Pathologic findings in patients with NA-SCAD share several similarities with ECPA, which is postulated as a specific type of monoarteritis confined to coronary arteritis [30]. Our findings imply that eosinophilia is not a common condition in patients with NA-SCAD (Table 1). Hypereosinophilia increases the tendency for eosinophilic involvement in several organs including skin, lung, or the myocardium, but hypereosinophilia is not a prerequisite for isolated eosinophilic inflammation in individual tissues. Considering the findings of the present study and those of previous autopsy studies together, it can be suggested that coronary involvement in NA-SCAD is not caused by hypereosionphilia, but it is rather a result of an organ-specific disease. The importance of relative eosinopenia observed in NA-SCAD-ACS patients is unclear because the absolute eosinophil count was similar among the groups and there was a similar tendency for relative eosinopenia in the CAD-ACS group. These findings suggest that the cause of relative (but not absolute) eosinopenia could be an increase in the absolute neutrophil count secondary to ACS, thus, reducing the percentage of eosinophils in circulation. Randomized controlled trials performed within the last 20 years have proved that an immediate reperfusion strategy for STEMI and an early invasive strategy for US/NSTEMI reduces mortality and improves outcomes. Such strategies, however, were tested in patients with atherothrombotic lesions and should not be necessarily generalized to patients with other types of acute coronary events. Several studies have, in fact, reported that outcomes of a conservative strategy in NA-SCADACS are non-inferior to those of an early invasive strategy [3, 31]. Present findings suggest that in-hospital mortality or major cardiovascular events in NA-SCADACS patients were similar to those of an age- and gendermatched sample of patients with CAD-ACS, although an early reperfusion strategy was not considered in 63% of the patients with NA-SCAD. However, ejection fraction before discharge was lower in the NA-SCADACS group, which may increase the overall risk for adverse events in patients with NA-SCAD-ACS when the strong prognostic impact of left ventricular contractility on long-term survival is considered [32]. As in-hospital cardiovascular adverse effects and predischarge ejection fraction were similar between patients managed conservatively and those managed with an invasive strategy, it is unclear why patients with NA-SCAD-ACS had a lower predischarge ejection fraction than CAD-ACS patients.

North Clin Istanb

Finally, it should be emphasized that the present study is grossly underpowered to detect the differences in outcomes or mortality, and the retrospective nature of the study prevents making healthy comparisons between the two management strategies. Therefore, our results should be interpreted with extreme caution as there are no definitive randomized controlled trials that compare an early invasive vs. conservative strategy in patients with NA-SCAD-ACS. These latter results should not be generalized to NA-SCAD-ACS patients with STEMI as all patients with STEMI were managed with immediate reperfusion strategy rather than conservative management. As the management strategies may differ for NASCAD-ACS and CAD-ACS patients, distinguishing between these two conditions prior to obtaining an angiogram could aid management decisions. Previous studies have indicated that NA-SCAD patients are younger and predominantly females, although this latter finding is controversial as recent studies have demonstrated that NA-SCAD could be frequently present in males as well [31]. As these patients were younger, it is considered that risk factors for CAD are less frequently present in patients with NA-SCAD, although a control group was not used and the findings were based on individual case series [33]. Compared with an age- and gender-matched CAD-ACS population, however, we did not find any differences regarding the frequency of conventional coronary risk factors in NA-SCAD-ACS patients, suggesting that conventional risk factors were inadequate to discriminate between these two conditions. Similarly, inflammatory markers including total leucocyte count, neutrophil or eosinophil count, NLR, and CRP levels had an inadequate discriminatory capacity for distinguishing NA-SCAD-ACS from CAD-ACS. As the primary aim of the present study was to assess the presence of inflammation and these analyses were secondary, the reported findings should be regarded as preliminary and not definitive. Study limitations The present study is a retrospective analysis of a small number of NA-SCAD-ACS cases obtained from the database of a single study center. A major limitation of this study is the lack of data on intracoronary imaging studies such as intravascular ultrasound or optical coherence tomography, as these studies were not routinely performed in all the patients. Invasive coronary angiography is an inadequate tool for the diagnosis of intra-

Canga et al., Inflammation in patients with spontaneous coronary artery dissection

coronary dissections, and only angiographically visible (type I) coronary dissections could be diagnosed using angiographic data. Therefore, our results should not be generalized to all coronary dissections. A conventional method was used for CRP level measurements in the study period; thus, the findings could be different if the analyses were repeated using a high-sensitivity CRP kit. As mentioned before, the sample size of the study is severely limited to make assumptions on outcomes or management strategies, and the retrospective nature of the study prevents making direct comparisons between conservative and early invasive strategies. Furthermore, the results have indicated that there was a tendency toward more frequent presence of atherosclerotic risk factors in the CAD-ACS group; thus, a type II error secondary to low sample sizes could not be excluded for these comparisons. Inflammatory biomarkers were not limited to the ones that were studied in the present work; thus, potential differences in other biomarkers could not be excluded. Because the number of variables evaluated in the present study was severely limited, it could not be assumed that NA-SCAD-ACS or CAD-ACS could not be excluded using other demographic, clinical, laboratory or imaging parameters. Changes in the levels of inflammatory markers during an acute coronary event are not only caused by local reactions within the arterial wall but are also a consequence of the ischemia of the myocardium. Thus, present findings should not necessarily reflect local inflammatory reactions within the coronary vessels, but should be interpreted as changes in the systemic inflammatory biomarkers secondary to all causes of inflammation in ACS. CONCLUSION Similar to the patients with an acute coronary event secondary to coronary atherothrombosis, patients with NA-SCAD demonstrate a systemic inflammatory response during ACS. The degree of inflammation is at least comparable to CAD-ACS and could be even higher in NA-SCAD-ACS, yet the present study could not definitively prove this last assertion. We did not find any evidence for hypereosinophilia despite previous evidence for periarterial eosinophilic infiltration, which suggests that coronary infiltration could be an isolated phenomenon rather than being part of a multiorgan involvement syndrome. In-hospital outcomes in NA-SCAD-ACS patients were not different from those in CAD-ACS patients, although the majority of NA-SCAD-ACS pa-

193

tients were followed up conservatively. As the number of biomarkers tested in the present study was limited due to the retrospective nature of the study, further research on this subject could shed more light on the role of systemic inflammation in the pathophysiology of NA-SCAD. 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.B.; Design – A.N.C., Y.C., T.S.G.; Supervision – M.B.K.; Materials – T.O.; Data collection &/or processing – A.O.U., V.O.T.; Analysis and/or interpretation – B.G.; Writing – Y.C., T.S.G.; Critical review – O.B.

REFERENCES 1. Isner JM, Donaldson RF, Fortin AH, Tischler A, Clarke RH. Attenuation of the media of coronary arteries in advanced atherosclerosis. Am J Cardiol 1986;58:937–9. 2. Aqel RA, Zoghbi GJ, Iskandrian A. Spontaneous coronary artery dissection, aneurysms, and pseudoaneurysms: a review. Echocardiography 2004;21:175–82. 3. Saw J, Aymong E, Sedlak T, Buller CE, Starovoytov A, Ricci D, et al. Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes. Circ Cardiovasc Interv 2014;7:645–55. 4. Robinowitz M, Virmani R, McAllister HA. Spontaneous coronary artery dissection and eosinophilic inflammation: a cause and effect relationship? Am J Med 1982;72:923–8. 5. Bateman AC, Gallagher PJ, Vincenti AC. Sudden death from coronary artery dissection. J Clin Pathol 1995;48:781–4. 6. Kajihara H, Tachiyama Y, Hirose T, Takada A, Saito K, Murai T, et al. Eosinophilic coronary periarteritis (vasospastic angina and sudden death), a new type of coronary arteritis: report of seven autopsy cases and a review of the literature. Virchows Arch 2013;462:239–48. 7. Kobayashi M, Cohle SD. A case of sudden cardiac death due to eosinophilic coronary periarteritis: possible significance of coexisting atherosclerosis and eosinophilic inflammation of the esophagus. Cardiovasc Pathol 2016;25:67–71. 8. Crea F, Liuzzo G. Pathogenesis of Acute Coronary Syndromes. J Am Coll Cardiol 2013;61:1–11. 9. Libby P. Inflammation in atherosclerosis. Nature 2002;420:868–74. 10. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in “active” coronary artery disease. Am J Cardiol 1990;65:168–72. 11. Tomoda H, Aoki N. Prognostic value of C-reactive protein levels within six hours after the onset of acute myocardial infarction. Am Heart J 2000;140:324–8. 12. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, et al. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994;331:417– 24. 13. Liuzzo G, Biasucci LM, Gallimore JR, Caligiuri G, Buffon A, Rebuzzi AG, et al. Enhanced inflammatory response in patients with preinfarction unstable angina. J Am Coll Cardiol 1999;34:1696–703. 14. Biasucci LM, Vitelli A, Liuzzo G, Altamura S, Caligiuri G, Monaco

194 C, et al. Elevated levels of interleukin-6 in unstable angina. Circulation 1996;94:874–7. 15. Barron HV, Harr SD, Radford MJ, Wang Y, Krumholz HM. The association between white blood cell count and acute myocardial infarction mortality in patients > or =65 years of age: findings from the cooperative cardiovascular project. J Am Coll Cardiol 2001;38:1654–61. 16. Cannon CP, McCabe CH, Wilcox RG, Bentley JH, Braunwald E. Association of white blood cell count with increased mortality in acute myocardial infarction and unstable angina pectoris. OPUS-TIMI 16 Investigators. Am J Cardiol 2001;87:636–9. 17. Yen MH, Bhatt D, Chew DP, Harrington RA, Newby LK, Ardissino D, et al. Association between admission white blood cell count and oneyear mortality in patients with acute coronary syndromes. Am J Med 2003;115:318–21. 18. Grau AJ, Boddy AW, Dukovic DA, Buggle F, Lichy C, Brandt T, et al; CAPRIE Investigators. Leukocyte count as an independent predictor of recurrent ischemic events. Stroke 2004;35:1147–52. 19. Toss H, Lindahl B, Siegbahn A, Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. Circulation 1997;96:4204–10. 20. Sawant AC, Adhikari P, Narra SR, Srivatsa SS, Mills PK, Srivatsa SS. Neutrophil to lymphocyte ratio predicts short- and long-term mortality following revascularization therapy for ST elevation myocardial infarction. Cardiol J 2014;21:500–8 21. Park JJ, Jang HJ, Oh IY, Yoon CH, Suh JW, Cho YS, et al. Prognostic value of neutrophil to lymphocyte ratio in patients presenting with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am J Cardiol 2013;111:636–42. 22. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89:36–44. 23. Isselbacher EM. Thoracic and abdominal aortic aneurysms. Thoracic and abdominal aortic aneurysms. Circulation 2005;111:816–28.

North Clin Istanb 24. He R, Guo DC, Estrera AL, Safi HJ, Huynh TT, Yin Z, et al. Characterization of the inflammatory and apoptotic cells in the aortas of patients with ascending thoracic aortic aneurysms and dissections. J Thorac Cardiovasc Surg 2006;131:671–8. 25. Weis-Müller BT, Modlich O, Drobinskaya I, Unay D, Huber R, Bojar H, et al. Gene expression in acute Stanford type A dissection: a comparative microarray study. J Transl Med 2006;4:29. 26. Sakalihasan N, Limet R, Defawe OD. Abdominal aortic aneurysm. Lancet 2005;365:1577–89. 27. Koller PT, Cliffe CM, Ridley DJ. Immunosuppressive Therapy for Peripartum-Type Spontaneous Coronary Artery Dissection: Case Report and Review. Clin Cardiol 1998;21:40–6. 28. Biswas M, Sethi A, Voyce SJ. Spontaneous Coronary Artery Dissection: case report and review of literature. Heart Views 2012;13:149– 54. 29. Dowling GP, Buja LM. Spontaneous coronary artery dissection occurs with and without periadventitial inflammation. Arch Pathol Lab Med 1987;111:470–2. 30. Kajihara H, Kato Y, Takanashi A, Nakagawa H, Tahara E, Otsuki T, et al. Periarteritis of coronary arteries with severe eosinophilic infiltration. A new pathologic entity (eosinophilic periarteritis)? Path Res Pract 1989;184:46–52 31. Alfonso F, Paulo M, Lennie V, Dutary J, Bernardo E, Quevedo PJ, et al. Spontaneous coronary artery dissection: long-term follow-up of a large series of patients prospectively managed with a “conservative” therapeutic strategy. JACC Cardiovasc Interv 2012;5:1062–70. 32. Ng VG, Lansky AJ, Meller S, Witzenbichler B, Guagliumi G, Peruga JZ, et al. The prognostic importance of left ventricular function in patients with ST-segment elevation myocardial infarction: the HORIZONSAMI trial. Eur Heart J Acute Cardiovasc Care 2014;3:67–77. 33. Tweet MS, Hayes SN, Pitta SR, Simari RD, Lerman A, Lennon RJ, et al. Clinical features, management, and prognosis of spontaneous coronary artery dissection. Circulation. 2012;126:579–88.

Orıgınal Article

NEUROLOGY

North Clin Istanb 2018;5(3):195–198 doi: 10.14744/nci.2017.69320

Outcomes of surgery for gallbladder cancer: A single-center experience Adil Baskiran,1 Emrah Sahin,1 Nese Karadag,2 Tevfik Tolga Sahin,1 Bora Barut,1 Dincer Ozgor,1 Abuzer Dirican1 Department of Surgery, Inonu University Institute of Liver Transplantation, Malatya, Turkey

Department of Pathology, Inonu University, Malatya, Turkey

ABSTRACT OBJECTIVE: Gallbladder cancer (GBC) is a rare clinical entity that has a poor prognosis. Radical resection with meticulous lymph node dissection is the only treatment option. The aim of the present study is to evaluate the efficacy of radical resection for GBC in the early postoperative period with the viewpoint of clinicopathological correlation. METHODS: Patients (n=24) who underwent radical resection with lymph node dissection for GBC between 2015 and 2017 were included. Demographic data, histopathologic tumor type, preoperative tumor markers, pathologic tumor size/stage (depth of invasion), lymph node metastasis and metastasis rates, and postoperative early mortality were evaluated. The patients were grouped in two groups according to lymph node metastases: Group 1 (without lymph node metastasis) and Group 2 (with lymph node metastasis). RESULTS: The median age of the patients in Group 1 and Group 2 was 65 (range, 42–89) years and 68 (range, 48–87) years, respectively (p>0.05). The female/male ratio in Group 1 and Group 2 was 4/4 and 13/3, respectively (p>0.05). There was a tendency for increased metastasis in Group 2 compared with Group 1 (31% vs. 0%) (p>0.05). Also, 88% of the tumors in Group 2 were in the advanced stage, whereas the rate was 37% in Group 1 (p<0.05). There was early postoperative mortality in seven patients who underwent resection. Four of the seven patients (43%) were from Group 2 and three (37%) from Group 1 (p>0.05). CONCLUSION: Lymph node metastasis in GBC indicates advanced tumor stage. This causes a more complex surgical resection and therefore results in higher early postoperative mortality. Keywords: Gallbladder cancer; radical resection; lymph node dissection; lymph node metastasis; extrahepatic biliary tree resection.

Cite this article as: Baskiran A., Sahin E., Karadag N., Sahin T. T., Barut B., Ozgor D., Dirican A. Outcomes of surgery for gallbladder cancer: A single-center experience. North Clin Istanb 2018;5(3):195–198.

allbladder cancer (GBC) has extremely poor prognosis. Its worldwide incidence is 1.1%–2%, with a slightly higher incidence in Asian countries. Its prevalence increases with increasing patient age. Women are more frequently affected, and the prevalence is five times higher in female patients. It is the 5th most prevalent gastrointestinal cancer in patients aged >65 years [1]. The five-year survival rates of untreated cases are reported

to be 5%, and the median patient survival in untreated cases is reported to be approximately 8 months. GBC is associated with gallbladder stone in 1%–3% cases and anomalous pancreaticobiliary duct junction in 10%–18% cases. The common denominator is the inflammation of the gallbladder mucosa leading to atypia to dysplasia and cancer sequence [2]. Radical resection and regional lymph node dissection with clear surgical margins (R0)

Received: October 31, 2017 Accepted: November 17, 2017 Online: May 24, 2018 Correspondence: Dr. Adil BASKIRAN. Inonu Universitesi, Karaciger Nakli Enstitusu, Cerrahi Anabilim Dali, Malatya, Turkey. Tel: +90 505 853 10 02 e-mail: dr.adil.baskiran@gmail.com © Copyright 2018 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

196

are the only treatment options in these patients. However, even in cases with R0 resection, the five-year survival rate is approximately 20% [3]. The extent of surgical resection and lymph node dissection and the resultant stage of the disease after pathologic evaluation are the main determinants of patient outcomes. Furthermore, lymph node metastasis seems to play a pivotal role in the determination of the overall survival of patients, and to achieve a reliable result, lymph node dissection should be meticulous [4]. Our liver transplantation institute is a high-volume center in the eastern part of Turkey, with particular focus on hepatobiliary surgery. The aim of the present study is to share the early postoperative results of patients with GBC who underwent radical resection at our institute and also to correlate the data of the patients with results of pathologic evaluation following resection. MATERIALS AND METHODS Selection of the patients and design of the study groups Patients who underwent resection for gall bladder cancer at our institute between 2015 and 2017 were included. In addition to the preoperative demographic data such as age and sex, histopathologic tumor type, preoperative tumor markers (AFP, CEA, Ca 19-9, Ca15-3, and Ca 125), pathologic tumor size/stage (depth of invasion), lymph node metastasis and metastasis rates, and postoperative early mortality were evaluated. The patients were grouped according to the presence of lymph node metastasis. Group 1 included patients without lymph node metastasis, and Group 2 included patients with lymph node metastasis. Pathologic staging of the tumors The tumors were staged according to the American Joint Committee on Cancer (AJCC) 7th edition of tumor node metastasis (TNM) staging manual [5]. According to this manual, the lymph node metastasis gains importance and has a direct effect on patient survival. Surgical resection All the patients underwent a preoperative detailed workup including tumor marker assessment and abdominal computerized tomography, and a surgery was planned for each patient with the suspicion of GBC. An open approach with a “hockey-stick” incision was used in each

North Clin Istanb

patient. We routinely perform regional lymph node dissection, but we do not perform para-aortic lymph node dissection or sampling. Generous Kocher maneuver is performed, and regional lymph nodes were dissected. The gallbladder was resected together with the segment 4 and 5 using a cavitary ultrasonic aspirator (CUSA excel, Integra). The distal surgical margin was routinely studied. If invasion to neighboring tissues was suspected, concomitant bile duct and duodenal wall resection was also performed. In cases with extrahepatic biliary tree resection, hepaticojejunostomy involving Roux-en-Y Limb was performed. Sump drainage of the sub-hepatic area was performed, and the operation was terminated. Statistical analysis The variables were not normally distributed, and therefore, the continuous variables are expressed as median (range). Data that require rate are expressed in percentages. The dependent and independent data are evaluated using Mann–Whitney U test. Any p-value <0.05 was considered as statistically significant. All the statistical analysis was performed using Statistics Software Program for Social Sciences version 22 (SPSS v22, IBM, USA). RESULTS Demographic data of the patients A total of 24 patients were operated for gall bladder adenocarcinoma at our institute between 2015 and 2017. Only two patients among the whole study group showed neuroendocrine differentiation, and one patient had adenosquamous differentiation. There were eight patients in Group 1 and sixteen in Group 2. The data of the patients in the study groups are summarized in Table 1. Briefly, the median age of the patients in Group 1 and Group 2 was 65 (range, 42–89) years and 68 (range, 48–87) years, respectively (p=0.697). The female/male ratio in Group 1 and Group 2 was 4/4 and 13/3, respectively (p=0.238). The two groups were similar in terms of demographic characteristics. Tumor-related characteristics of patients’ tumors There was a tendency for increased systemic metastasis rate in Group 2 compared with Group 1 (31% vs. 0%), but this did not reach a statistical significance (p=0.238). Also, 88% of the tumors in Group 2 were in the advanced

Baskiran et al., Outcomes of surgery for gallbladder cancer: A single-center experience

197

Table 1. Demographic data of the patients in the study group Age (years) [median (range)] Female/Male Systemic Metastasis Rate (%) AFP (IU/mL) [median (range)] CEA (IU/mL) [median (range)] CA125 (IU/mL) [median (range)] CA199 (IU/mL) [median (range)] CA153 (IU/mL) [median (range)]

Group 1 (n=8)

Group 2 (n=16)

65 (42-89) 4/4 0 590.36 (0.8-4712) 21.91 (1.5-151) 43.25 (5.6-108) 255.30 (10.8-1320) 21.66 (7.7-39.9)

68 (48-87) 13/3 31 1126.51 (1.4-17995) 19.30 (1.1-165) 84.33 (3.6-506) 1558.98 (2.5-16315) 34.83 (6.6-145)

0.697 0.238 0.238 0.928 0.653 0.417 0.928 0.528

gan resection rates in the patients without postoperative early mortality were 29% and 35%, respectively. Although the patients with early postoperative mortality tended to have a higher rate of complex surgeries, this did not reach a statistical significance (p=0.418).

Postoperative early mortality of the patients There was early postoperative mortality in seven patients who underwent resection. Four of the seven patients (43%) were from Group 2 and 3 (37%) from Group 1. Although patients with lymph node metastasis tended to have higher early postoperative mortality, this difference did not reach a statistical significance (p=0.653). When these subgroups of the patients were analyzed, it was seen that 57% (n=4) patients underwent concomitant organ resection. In addition, Roux-en-Y biliary reconstruction was performed in 71% (n=5) patients. The concomitant Roux-en-Y hepaticojejunostomy reconstruction and or-

DISCUSSION

Percentage of Patients (%)

stage (T4 according to TNM staging), whereas the rate was 37% in Group 1. Therefore, the tumors in Group 2 had a statistically significant tendency to have more advanced stages than those in Group 1 (p=0.045). The tumor size/stages are summarized in Figure 1.

120 100

p=0.045

80 60 40 20 0

Tumor size stage=4 (% of patients) Tumor size stage<4 (% of patients)

Group 1 (n=8) 37 63

Group 2 (n=16) 88 12

Figure 1. The effect of lymph node metastasis on the tumor size of the patients.

We routinely perform radical resection and regional lymphadenectomy in patients with suspected GBC in the preoperative workup. GBC is a rare clinical entity in Turkey, and our institute is one of the referral centers draining the eastern part of Turkey. Therefore, we analyzed the adequacy of extent of the resection performed at our institute by correlating our results with a clinicopathologic correlation. In our study, one important observation was that patients with lymph node metastasis regardless of the location and number of the involved lymph nodes are a risk factor for advanced tumor size stage of patients with gallbladder tumors. This means that if the patient has lymph node metastasis, the tumor is more invasive and has a propensity to microscopically or microscopically invade the adjacent organs. Therefore, more complex surgeries were needed in these patients, leading to high rates of concomitant adjacent organ resections and hepaticojejunostomies. Therefore, this resulted in a higher frequency of early postoperative mortalities in these patient subpopulations. This is a unique finding because until now, the long-term prognostic significance of lymph node metastases has been analyzed in the current literature; however, our study is the first one to analyze the early postoperative effects of the advanced stages of the disease. The reported rates of postoperative mortality and morbidi-

198

ties ranged between 10% and 20% in various studies [6, 7]. However, these complications were observed following major abdominal surgery, and a stage-related correlation has not been done. It has been previously reported by Oh et al. [8] that lymph node metastasis reduced the overall survival of patients from 67.6 months to 56.1 months. Therefore, they emphasized the role of lymph node metastasis in patients with GBC. They concluded that lymph node dissection was imperative for adequate staging and allocation of the patients to certain prognostic groups. This concept was also supported by Liu et al. [9], where they emphasized that lymph node metastasis but not the totally harvested lymph node number together with metastatic lymph node ratio was important in determining the prognoses of patients. However, they have not emphasized the early postoperative mortality or morbidity in their study [8, 9]. Vascular endothelial growth factors, vascular endothelial growth factor receptor 2 (VEGFR-2), and stromal cell-derived factor 1 (SDF1)α have been analyzed in advanced biliary tact cancers for susceptibility to targeted chemotherapy with combination of gemcitabine and sorafenib [10]. However, the diagnostic efficacy of serum tumor markers has not been evaluated. In our study, we have found a tendency of serum tumor markers AFP, CEA, Ca 19-9, Ca15-3, and Ca 125 to be elevated in patients with lymph node metastases. This difference did not reach a statistical significance. We believe that this difference will be more pronounced when the number of patients is increased. One limitation of our study is that the patient number was low. However, this a preliminary report of the early results of an ongoing study, and as the patient number is increased, better and clear results will be obtained. In conclusion, lymph node metastasis indicates poor prognosis in the long term and has an impact on the early postoperative period by increasing the early postoperative mortality. Furthermore, lymph node metastases regardless of the location and number of the involved lymph nodes indicate advanced tumor depth stage for GBCs.

North Clin Istanb 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.; Design – A.B., E.S.; Supervision – A.D., D.O.; Materials – T.T.S.; Data collection &/or processing – E.S., A.B., T.T.S.; Analysis and/or interpretation – N.K., A.D.; Writing – A.B., T.T.S.; Critical review – A.D.

REFERENCES 1. Lee SE, Kim KS, Kim WB, Kim IG, Nah YW, Ryu DH, et al; Korean Association of Hepato-Biliary and Pancreas Surgery. Practical guidelines for the surgical treatment of gallbladder cancer. J Korean Med Sci 2014;29:1333–40. 2. Reid KM, Ramos-De la Medina A, Donohue JH. Diagnosis and surgical management of gallbladder cancer: a review. J Gastrointest Surg 2007;11:671–81. 3. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg 2000;232:557–69. 4. Todoroki T, Kawamoto T, Takahashi H, Takada Y, Koike N, Otsuka M, et al. Treatment of gallbladder cancer by radical resection. Br J Surg 1999;86:622–7. 5. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471–4. 6. Oertli D, Herzog U, Tondelli P. Primary carcinoma of the gallbladder: operative experience during a 16 year period. Eur J Surg Acta Chir 1993;159:415–20. 7. Piccolo G, Piozzi GN. Laparoscopic Radical Cholecystectomy for Primary or Incidental Early Gallbladder Cancer: The New Rules Governing the Treatment of Gallbladder Cancer. Gastroenterol Res Pract 2017;2017:8570502. 8. Oh TG, Chung MJ, Bang S, Park SW, Chung JB, Song SY, et al. Comparison of the sixth and seventh editions of the AJCC TNM classification for gallbladder cancer. J Gastrointest Surg 2013;17:925–30. 9. Liu GJ, Li XH, Chen YX, Sun HD, Zhao GM, Hu SY. Radical lymph node dissection and assessment: Impact on gallbladder cancer prognosis. World J Gastroenterol WJG 2013;19:5150–8. 10. Moehler M, Maderer A, Schimanski C, Kanzler S, Denzer U, Kolligs FT, et al; Working Group of Internal Oncology. Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme. Eur J Cancer 1990 2014;50:3125– 35.

Orıgınal Article

BASIC MEDICAL SCIENCES

North Clin Istanb 2018;5(3):199–206 doi: 10.14744/nci.2017.82788

Evaluation of the attitudes of specialist and family physicians regarding rational drug selection Ahmet Akici,1 Volkan Aydin,1 Salih Mollahaliloglu,2 Senay Ozgulcu,3 Ali Alkan4 Department of Medical Pharmacology, Marmara University Faculty of Medicine, Istanbul, Turkey

Department of Public Health, Yildirim Beyazit University Faculty of Medicine, Ankara, Turkey

Department of Zoonotic and Vector Borne Diseases, Turkish Public Health Institution, Ministry of Health, Ankara, Turkey

Department of Economical Assessments & Drug Supply Management, Turkish Medicines and Medical Devices Agency, Ministry of Health,

Ankara, Turkey

ABSTRACT OBJECTIVE: Physicians’ personal (P) drugs, which were ranked by priority, may show variations even for the same indication. We aimed to evaluate physicians’ knowledge and attitudes regarding P-drug list preparation with respect to the rational use of medicine context. METHODS: A total of 1062 family physicians (FPs) and 562 specialist physicians (SPs) were interviewed and questioned about their knowledge and attitude regarding P-drug list preparation. RESULTS: Compared with SPs (64.9%), significantly more number of FPs (72.8%) prepared a P-drug list. Women were more likely to prepare the P-drug list in both groups; gender comparison showed that significantly more number of female FPs (75.9%) exhibited this attitude than female SPs (67.8%) (p=0.002). Among SPs, the trend for P-drug list preparation attitude decreased with increasing age (p=0.006), and significantly less number of senior physicians showed this attitude compared with junior physicians (p=0.007). The most common source of information referred to by FPs (78.9%) and SPs (74.3%) during P-drug list preparation was “pharmaceutical company activities.” More than 80% of responders (80.9% of FPs and 83.6% of SPs) specified that a difference “exists” or “partially exists” between original and generic drugs. Approximately one in 10 physicians in both groups stated that they “rarely/never” consider their patients’ “liver/kidney disease” during prescribing. CONCLUSION: More prominently in male and senior physicians, the attitude of P-drug list preparation remained lower than expected. Moreover, it is remarkable that pharmaceutical company promotions are the most common source of information for drug selection. These findings disclose the need for the rational use of medicine dissemination interventions for all physicians focusing on more effective use of P-drug list. Keywords: Family physician; personal drug list; rational use of medicine; specialist physician.

Cite this article as: Akici A., Aydin V., Mollahaliloglu S., Ozgulcu S., Alkan A. Evaluation of the attitudes of specialist and family physicians regarding rational drug selection. North Clin Istanb 2018;5(3):199–206.

rescribing, with its multivariable nature, is a medical practice compelling physicians in an incremental way. For this, the rational use of medicine (RUM) concept, as described by World Health Organization, helps physicians overcome difficulties in their pharmacotherapy practices [1]. Any practice apart from RUM

principles constitutes irrational use of medicines (IUM), which may ultimately cause increased workload and financial loss. Though these issues have many addressees, physicians play the key role in resolving IUM. The primary expectation from physicians regarding RUM is a well-structured drug selection, where physicians and

Received: June 28, 2017 Accepted: November 03, 2017 Online: May 25, 2018 Correspondence: Dr. Ahmet AKICI. Marmara Universitesi Tip Fakultesi, Tibbi Farmakoloji Anabilim Dali, Istanbul, Turkey. Phone: +90 216 421 22 22 e-mail: ahakici@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

200

medical students were shown to utilize alternative techniques and sources of information and encounter various difficulties [1–4]. Before meeting patients, a preliminary preparation guide for common indications helps the physicians in drug selection at the time of prescription regarding RUM. Using the “efficacy, safety, suitability, and cost” criteria, physicians can select their personal (P)-treatment and P-drugs, which they consider as the most appropriate in comparison to their alternatives for the diseases they manage [2–4]. P-drugs are defined as the top-ranking drugs in the P-drug list (PDL), wherein physicians categorize and prioritize drugs by indications. P-drugs may show variations among physicians even for the same indication [2–5]. Moreover, if P-drug selection is practiced by “informal” ways, these variations may become so diversified that they complicate rational pharmacotherapy. Although numerous studies have reported about the consequences of physicians’ prescribing behaviors, data regarding drug selection reflecting the background of such behaviors remains insufficient. Indeed, an unmet need in this area is evident by the lack of comprehensive studies, even though a quarter century has passed since the introduction of PDL concept. This study aimed to evaluate the knowledge and attitudes of family physicians (FP) and specialist physicians (SP) about PDL preparation in terms of RUM and to compare these findings within and between these groups stratified by their general and occupational characteristics that may influence their RUM approaches. MATERIALS AND METHODS This descriptive study was performed in 12 provinces of Turkey with 1624 physicians [1062 FPs (65.4%) and 562 SPs (34.6%)]. The survey was conducted through face-to-face interviews with the physicians. The knowledge, attitude, and experiences of FPs and SPs working in randomly selected family health centers and state hospitals, respectively (both in rural and urban areas) were identified in terms of RUM (response rates: 97.2% and 74.8%, respectively). The survey began with the questions about demographic and occupational characteristics followed by questions about physicians’ knowledge, attitudes, and experiences reflecting RUM. These data were also compared with some demographic and occupational characteristics of FPs and SPs.

North Clin Istanb

Data were collected after preparations and interviewer training was completed. Data were analyzed using Microsoft Excel and SPSS 11.5 Statistics Pack software. Chi-square test was used for detection of any association between data of FPs and SPs. An overall 5% type I error level was used to infer statistical significance. This study was approved by the Ministry of Health (MoH). Approval by ethics committee was not required for this questionnaire study. RESULTS Male physicians constituted 70.7% of the study population, and the number of female physicians was lesser than that of male physicians for both FPs (31.1%) and SPs (25.8%). The majority of FPs and SPs belonged to the 36–45-years-old group (57.6% and 40.0%, respectively), followed by the “≤35-years-old group” (28.7% and 33.0%, respectively) and the “>45-years-old group” (13.7% and 27.0%, respectively). The majority of FPs (69.0%) and SPs (74.4%) reported the duration elapsed after graduation as “>10 years.” The majority of FPs (72.8%) and SPs (64.9%) declared that “they prepare PDL for common diseases,” which was significantly higher in FPs than in SPs (p=0.001). PDL preparation attitude was compared within FP and SP groups and with each other stratified by some of their characteristics. In both groups, the number of female physicians preparing PDL was higher; FPs exhibited a significantly more positive attitude than SPs (75.9% and 67.8%, respectively) (p=0.002). However, the intragroup comparisons of FPs and SPs did not show a statistical difference by gender (p>0.05), (Table 1). In terms of age stratum, the percentage of FPs preparing PDL was higher than that of SPs in all age groups (p<0.001). Although it was not different by the age groups within FPs, this attitude exhibited a significant decreasing trend in SPs as their age increased (p=0.006) (Table 1). PDL preparation attitude also significantly differed between the groups with respect to physicians’ working duration (p<0.001). Intragroup comparisons revealed this attitude to be significantly different in only SPs; the percentage of senior SPs preparing PDL was lower than that of junior SPs (p=0.007) (Table 1). SPs were stratified and compared by their places of residency and specialties in terms of PDL preparation for commonly encountered diseases, and no statistically significant difference was detected in either comparison (Table 2).

Akici et al., Evaluation of the attitudes of specialist and family physicians regarding rational drug selection

201

Table 1. Comparisons of physicians’ personal drug list preparation attitudes for commonly encountered diseases using their demographic and occupational characteristics

Stratum

Personal drug list preparation for commonly encountered diseases

Family physician Specialist physician

Yes No

Gender Male n 519 208 263 % 71.4 28.6 63.8 Female n 246 78 97 % 75.9 24.1 67.8 P 0.147 0.447 Age (years) ≤35 n 225 76 130 % 74.8 25.2 71.4 36-45 n 430 174 147 % 71.2 28.8 66.2 >45 n 110 36 83 % 75.3 24.7 55.0 P 0.398 0.006 Working duration (years) Junior (≤10 years) n 312 99 260 % 75.9 24.1 68.6 Senior (>10 years) n 453 187 100 % 70.8 29.2 56.8 p 0.075 0.007

149 36.2 46 32.2

52 28.6 75 33.8 68 45.0

119 31.4 76 43.2

0.002

<0.001

Table 2. Comparison of specialist physicians regarding PDL preparation attitude based on their places of residency and specialty Place of residency Specialty training University Training and Surgical Internal Hospital Research Sciences Sciences Hospital Personal drug list preparation attitude n % n % n % for commonly encountered diseases Yes 199 64.2 159 65.4 127 67.2 No 111 35.8 84 34.6 62 32.8 P 0.762 0.307

FPs and SPs stated that the most common source of information that they referred to for selecting drugs during PDL preparation was “pharmaceutical company (PC) activities” (78.9% and 74.3%, respectively), fol-

221 62.8 131 37.2

lowed by “treatment guidelines” (74.4% and 69.3%, respectively) (Table 3). The most considered criterion for drug selection during PDL preparation was “efficacy” for both FPs (97.4%)

202

and SPs (97.3%), followed by “safety, personal experience, cost, and suitability” for FPs and “personal experience, safety, suitability, and cost” for SPs. One-fifth of both groups included “PC promotions and patients’ demands” among the criteria they considered in drug selection (Table 3). When the participants were questioned about the drug-related factors they regarded as necessary to consider during prescribing, FPs prioritized them as “safety, efficacy, and suitability” and SPs as “efficacy, safety, and suitability.” The majority of physicians in both groups stated that they considered that the drug they pre-

North Clin Istanb

scribed should not be generic (64.9% and 67.0%, respectively). When participants were queried about “any existence of difference between original and generic drugs,” 80.9% of FPs and 83.6% of SPs stated that a difference “exists” or “partially exists.” Even few number of physicians did not have such knowledge (2.6% and 3.1%, respectively), (Table 3). In terms of medical history data used during prescribing, more than three-fourth of both FPs and SPs declared that the information they “always” used was “age and pregnancy/lactation.” About one in 10 physicians in both groups stated that they “rarely/never” consider

Table 3. The approaches of the physicians for the selection of drugs they prescribed (*multiple choices allowed) Parameters Family Specialist Physician Physician

Sources of information consulted during drug selection* Pharmaceutical company activities 663 78.9 300 Treatment guidelines 625 74.4 280 Vademecum 227 27.0 118 National drug formulary 196 23.3 102 Colleague experiences 214 25.5 82 Criteria considered for drug selection during personal drug list preparation* Efficacy 1029 97.4 543 Safety 886 83.9 430 Personal experience 880 83.3 474 Cost 795 75.3 373 Suitability 739 70.0 386 Pharmaceutical company promotions 234 22.2 129 Patients’ requests 227 21.5 107 Drug-related factors regarded as necessary during prescribing* Efficacy 1041 98.6 544 Safety 1046 98.9 542 Suitability 1031 97.4 527 Suitability of pharmaceutical form 1003 94.8 514 High bioavailability 938 88.7 478 Cost 895 84.6 444 Broad indication 760 71.8 382 Being a non-generic drug 687 64.9 369 Being known and commonly used drug 567 53.6 304 Is there any difference between original and generic drugs in terms of efficacy? Yes 245 23.3 152 Yes, in some drugs 607 57.6 312 No 174 16.5 74 I don’t know 27 2.6 17 Total 100.0 100.0

% 74.3 69.3 29.2 25.2 20.3 97.3 77.1 84.9 66.8 69.2 23.1 19.2 98.7 98.2 95.6 93.3 86.8 80.6 69.2 67.0 55.2 27.4 56.2 13.3 3.1

Akici et al., Evaluation of the attitudes of specialist and family physicians regarding rational drug selection

“liver/kidney disease” of their patients during prescribing. The percentage of FPs and SPs who “rarely/never” conceived their patients’ “social insurance” was 20.1% and 34.8%, respectively. The participants declaring to “rarely/ never” use “affordability” information during prescribing constituted 14.0% of FPs and 31.9% of SPs (Table 4). DISCUSSION Drug selection is one of the most critical steps of RUM practices. Provided that physicians prepare their own personal formularies before encountering their patients, the care they will provide could be more successful. A

203

personal formulary prepared by PDL in accordance with RUM confers significant advantages to physicians, e.g., prescribing in line with indication and individual characteristics of the patient or utilizing solid criteria and sparing time for drug selection [2–5]. This study showed that despite being partially better than the literature, the physicians were worse than expected in PDL preparation, an important component of RUM, with some differences based on their demographic and occupational characteristics. Our study revealed that FPs (72.4%) were significantly more likely to prepare PDL than SPs (64.9%). No data directly comparing these groups were present in the

Table 4. Frequency of utilization of anamnesis data while prescribing, stratified by physician groups (multiple choices allowed) Patients’ Information Age n % Gender n % Concomitant drugs n % Drug allergy n % Liver disease n % Kidney disease n % Other chronic conditions n % Pregnancy and lactation n % Social insurance n % Affordability n %

Family Physician

Specialist Physician

Always

Frequently

Rarely

Never

Always

Frequently

Rarely

Never

881 84.2

151 14.4

14 1.4

0 0

434 78.5

98 17.7

13 2.4

8 1.4

507 48.8

356 34.2

158 15.2

19 1.8

249 45.2

132 24.0

118 21.4

52 9.4

572 54.6

439 42.0

34 3.3

1 0.1

282 51.1

221 40.0

37 6.7

12 2.2

704 67.1

282 26.9

56 5.3

7 0.7

360 65.8

141 25.8

41 7.5

5 0.9

479 45.9

447 42.9

114 10.9

3 0.3

312 56.7

176 32.1

53 9.7

8 1.5

481 46.5

451 43.6

98 9.5

4 0.4

313 57.1

166 30.3

57 10.4

12 2.2

498 48.2

476 46.1

57 5.5

2 0.2

290 53.0

185 33.8

60 11.0

12 2.2

869 83.6

158 15.1

9 0.9

4 0.4

429 78.0

87 15.8

14 2.5

20 3.7

393 37.9

436 42.0

171 16.5

38 3.6

150 27.3

208 37.9

122 22.2

69 12.6

415 40.3

471 45.7

118 11.4

27 2.6

163 29.5

213 38.6

123 22.3

53 9.6

204

literature. A study performed with resident physicians and SPs in a tertiary center of Turkey in 2012 reported that 59% of participants prepared PDL [6]. This approach was exhibited by 20% of resident physicians and SPs as reported by an Indian study [7]. A study performed in Australia reported that general practitioners used personal formularies for certain drug groups, e.g., 70% had personal formulary for nonsteroidal anti-inflammatory drugs [8]. We propose that the physicians in our study are better in PDL preparation than those in the literature. The lower percentage of PDL preparation attitude in compared to FPs, a consistent finding in all age groups, is among striking aspects of this study. It is assumed that the number of diseases managed by SPs within their branch is lesser than that managed by FPs. Although this may imply that SPs prepare PDL more easily, the opposite was observed in our study, which may be linked to the diversity of the diseases covered. Unlike FPs who are responsible for managing many conditions, SPs may skip the practical benefits of PDL preparation due to the limited spectrum of indications. Toward the 2000s, awareness regarding PDL preparation in accordance with RUM officially started to spread [1, 4, 5]. Some SPs might have received their specialty training before this critical time-point. It is assumed that SPs are older than FPs due to the time required for their specialty training. Considering that the percentage of the “>45-year-old group” among SPs (27.0%) doubles that in FPs (13.7%), relative elderliness of SPs may account for one of the reasons for their lower capability in terms of PDL preparation. This association is supported by relevant data comparing the age groups and occupational experiences of the physicians. In our study, SPs exhibited a decreasing trend for PDL preparation with increasing age. In parallel, this attitude was less adopted among senior SPs than among junior SPs. In two Indian studies assessing PDL preparation attitudes, older and senior physicians were reported to practice less PDL preparation than their younger and inexperienced counterparts, respectively [7, 9]. These findings, consistent with our results, might be explained by the recent increase in RUM training courses for physicians [3–5, 10]. Female physicians showed more PDL preparation attitudes in both groups. Although no generalization exists, some evidence suggests that women have a more positive attitude than men in various medical practices [7, 11, 12]. For instance, a Swedish study concluded that female practitioners appreciated information from public authorities more than their male colleagues and that male

North Clin Istanb

practitioners had a more affirmative approach toward the industry-based data [11]. In another study, female physicians were reported to practice more RUM than males, without gender difference in P-drug selection [7]. Physicians acquire some of the drug information via PC activities. It is unfavorable that physicians frequently and unrestrainedly use this industry-based information with questionable objectivity and biased presentation [2, 13]. The fact that the most common source of information referred by FPs and SPs during PDL preparation was PC activities is challenging. Two Indian studies addressing the same issues reported that physicians most frequently benefited from “PC activities” during drug selection [7, 9]. In another study performed in Cyprus and Greece, the frequency of using “PC representatives” for prescribing were at second and fourth rank, respectively [14]. In previous studies performed in Turkey, benefiting from “PC activities” during selecting or prescribing drugs varied between 14%–34%, where none of which was at first rank (ranging third–seventh), [15–17, 6, 18]. Although less favorable than those published in Turkey, our findings either overlap or show some similarities with those in other countries. This discloses the heavy influence of the drug companies on the physicians in drug selection and indicates the necessity of a more careful evaluation by the physicians for using this potentially biased and questionable source. Physicians are expected to prepare PDL using the “efficacy, safety, suitability, and cost” criteria according to evidence-based objective findings during RUM-compliant drug selection [2]. The physicians in our study appeared to prioritize “efficacy” in drug selection, which was consistent with the literature [14, 15]. In contrast, they seemed to undervalue drug selection criteria other than efficacy, as evidenced by insufficient recognition of suitability by one-third of physicians. While physicians’ preference toward efficacy is a positive approach, other drug selection criteria should not be ignored according to the RUM principles. By asking specific questions to the patient, a physician who prepares PDL determines the suitability of the drugs that she/he included to the list for that indication [2]. Therefore, beside “drug selection” criteria, “drug-related factors regarded as necessary during prescribing” were also questioned to evaluate this attitude. While “efficacy, safety, and suitability” were again ranked among top factors, around seven out of 10 physicians in both groups regarded “broad indication” as necessary. Despite appearing to be advantageous in terms of “efficacy” at first

Akici et al., Evaluation of the attitudes of specialist and family physicians regarding rational drug selection

sight, it may be undesirable for certain therapies like antibiotics, where “broad-spectrum” preference might not necessarily be rational [19]. In our study, >80% of physicians in both groups stated that “original and generic drugs differ or partially differ in terms of efficacy.” A Saudi Arabian study conducted in 2007 reported that 67% of physicians thought that generic drugs were equal to original drugs in terms of efficacy [20]. In a US study, 67% of physicians were reported to “partially or strongly” agree that generic drugs were as efficacious as the originals [21]. In a Turkish study, 55% of physicians stated that there were differences between some generic and original drugs [22]. Generic drugs prove themselves as therapeutically equivalent to the original drugs whose efficacy and safety were determined through rigorous assessments. A retrospective analysis of 2.070 bioequivalence studies approved by FDA showed that original and generic drugs only had a mean of 3.56% bioavailability difference [23]. Both our study and the literature showed high prevalence of the misbelief about efficacy difference, which addresses the lack of knowledge of physicians and warrants the need for informative and awareness-oriented interventions. History taking provides important clues to physician during prescribing, thus requiring all relevant patient data to be used sufficiently. Prescribing a drug within PDL without using past medical history predisposes to adverse effects. About 10% of our participants in both groups declared that they “rarely/never” considered “liver/kidney disease” status of their patients while prescribing. Previous studies in Turkey showed that during prescribing, 11%–49% of physicians did not ask for the presence of liver disease [15, 16, 6] and 12%–42% did not question the presence of kidney disease [15, 6, 16]. While these conditions should be routinely considered during writing a prescription, they need more attention in special situations such as older age, where hepatic biotransformation and renal function diminish [24]. A US study performed in a tertiary healthcare center reported that the leading cause of clinically relevant medication errors were decreased kidney and liver functions [25]. In a Dutch study performed with around 30.000 primary care patients, 15% of those with eGFR ≤40 were detected to have medication errors, most of which were classified as significant or potentially serious adverse drug events [26]. When making treatment decisions, physicians are definitely expected to consider such critical organ impairments, which may increase the likelihood of occurrence of serious adverse events and negatively influence therapeutic outcomes. A substantial number of

205

physicians in our study ignored the liver or kidney status during prescribing, which is an example for IUM and reflects the need for improvement. Though history taking deems essential for “suitability” criterial “cost” is also adversely affected by the lack of this information. In our study, up to one-fifth of FPs and one-third of SPs appeared to “rarely/never” use “social insurance” and “affordability” data of their patients during prescribing. Previous studies in Turkey showed great variations in terms of questioning “social insurance” and “affordability” by the physicians [6, 15, 16]. A US primary care study reported 68% of physicians to show regard to cost of the drug even in Medicare patients [27]. Regarding RUM, physicians should consider the cost of the drug during prescribing for all patients regardless of social insurance. Consideration of treatment cost is not only essential for sustainable and high-quality healthcare service but also for access of drugs to those affording the treatment by themselves. In fact, a US study reported that two-thirds of patients who found prescribed drugs expensive did not tell their physicians that they would underuse those drugs [28]. Educational and informative interventions regarding drug costs were reported to make physicians to pay more attention to cost issues during prescribing, regardless of the social insurance status of their patients [29]. The fact that physicians in our study considered “cost” lower than expected warrants the need for educational activities regarding this issue. Our study has some limitations. The survey applied to SPs did not contain PDL questions specific to each specialty. Albeit weakly, there is possibility that some detailed characteristics of FPs and SPs and their institutions other than those questioned in the survey might influence their responses. CONCLUSION In conclusion, our findings suggest that PDL preparation is somewhat lower than expected, where women and younger physicians prove to be more successful than male and older physicians who practiced less PDL, respectively. It is remarkable that physicians considered efficacy at most during PDL preparation and prescribing, although they insufficiently used patient’s history, regard PC promotions as the most referred source of information, and have lack of knowledge about generic drugs. These approaches regarding PDL appear to be influenced by some of their demographic characteristics or being an FP or SP. The importance of using PDL has become more conspicuous nowadays, since the number

206

and knowledge of drug is continuously expanding every day and IUM hurdles are mounting gradually. Benefiting from the significant findings of the study contributes to more effective use of PDL during planning the treatment and hence dissemination of RUM. Acknowledgments: The authors thank Turkish MoH, RSHCP School of Public Health/General Directorate of Health Research, for their contributions in preparation of the research report, which is the basis of this article, and in the process of this article’s publication. The assistance of H. Gursoz, H.G. Oncul, M.N. Dogukan, and the Provincial Health Directors and their staff in collecting and evaluating the data for this study is also acknowledged. 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 – Ah.A., A.A.; Design – Ah.A., S.H., V.A.; Materials – Ah.A., S.H., S.O.; Data collection &/or processing – Ah.A., V.A., A.A.; Analysis and/or interpretation – Ah.A., V.A., S.H.; Writing – Ah.A., V.A.; Critical review – Ah.A., V.A., S.H., S.O., A.A.

REFERENCES 1. World Health Organization. Promoting rational use of medicines: core components. WHO Policy Perspectives on Medicines: Geneva; 2002. Available at: http://archives.who.int/tbs/rational/h3011e.pdf. Accessed May 3, 2018. 2. De Vries TPGM, Henning RH, Hogerzeil HV, Fresle DA. Guide to Good Prescribing – Apractical Manual. WHO/DAP/94.11. Available at: http://apps.who.int/iris/bitstream/handle/10665/59001/ WHO_DAP_94.11.pdf;jsessionid=4962B1470FDC15490E60C061 0AD680B3?sequence=1. Accessed May 3, 2018. 3. De Vries TP, Daniels JM, Mulder CW, Groot OA, Wewerinke L, Barnes KI, et al. Should medical students learn to develop a personal formulary? An international, multicentre, randomised controlled study. Eur J Clin Pharmacol 2008;64:641–6. 4. Akici A, Kalaca S, Goren MZ, Akkan AG, Karaalp A, Demir D, et al. Comparison of rational pharmacotherapy decision-making competence of general practitioners with intern doctors. Eur J Clin Pharmacol 2004;60:75–82. 5. Hogerzeil HV, Barnes KI, Henning RH, Kocabasoglu YE, Moller H, Smith AJ, et al. Teachers’ guide to good prescribing. Geneva: World Health Organization; 2001. 6. Filiz Basaran N, Akici A. Aspects of physicians’ attitudes towards the rational use of drugs at a training and research hospital: a survey study. Eur J Clin Pharmacol 2013;69:1581–7. 7. Mahajan R, Singh NR, Singh J, Dixit A, Jain A, Gupta A. Current scenario of attitude and knowledge of physicians about rational prescription: A novel cross-sectional study. J Pharm Bioallied Sci 2010;2:132–6. 8. Robertson J, Fryer JL, O’Connell DL, Smith AJ, Henry DA. Personal formularies. An index of prescribing quality? Eur J Clin Pharmacol 2001;57:333–41. 9. Banjara SK, Bhukya KD. To evaluate awareness of essential medicines, p-drug concept among clinicians in a teaching hospital. International Journal of Scientific Research 2014;9:347–9. 10. Holloway K, van Dijk L. The World Medicines Situation. 3rd ed. Geneva: World Health Organization; 2011. Available at: http://www.

North Clin Istanb who.int/medicines/areas/policy/world_medicines_situation/WMS_ ch14_wRational.pdf. Accessed May 3, 2018. 11. Skoglund I, Björkelund C, Mehlig K, Gunnarsson R, Möller M. GPs’ opinions of public and industrial information regarding drugs: a crosssectional study. BMC Health Serv Res 2011;11:204. 12. Roter DL, Hall JA, Aoki Y. Physician gender effects in medical communication: a meta-analytic review. JAMA 2002;288:756–64. 13. Lieb K, Scheurich A. Contact between doctors and the pharmaceutical industry, their perceptions, and the effects on prescribing habits. PLoS ONE 2014;9:e110130. 14. Theodorou M, Tsiantou V, Pavlakis A, Maniadakis N, Fragoulakis V, Pavi E, et al. Factors influencing prescribing behaviour of physicians in Greece and Cyprus: results from a questionnaire based survey. BMC Health Serv Res 2009;9:150. 15. Ergin A, Büyükakın B, Kortunay S, Bozkurt Aİ. The Knowledge and Attitudes About Rational Use of Drugs of Medical Residents Working in Pamukkale University Hospital [Article in Turkish]. Tıp Eğitimi Dünyası 2014;40:29–38. 16. Akıcı A, Uğurlu MÜ, Gönüllü N, Oktay Ş, Kalaça S. Pratisyen hekimlerin akılcı ilaç kullanımı konusunda bilgi ve tutumlarının değerlendirilmesi. Sted 2002;11:253–7. 17. Saygılı M, Özer Ö. An Evaluation on Levels of Knowledge, Attitude and Behavior of Physician About Rational Drug Use [Article in Turkish]. Hacettepe Sağlık İdaresi Dergisi 2015;18:35–46. 18. Vançelik S, Çalıkoğlu O, Güraksın A, Beyhun E. The Basic Factors that Impact the Prescibing and the Status of Consideration of the Rational Drug Usage Criterias of General Practitioners [Article in Turkish]. ATÜD 2006;38:7–12. 19. Niederman MS. Principles of appropriate antibiotic use. Int J Antimicrob Agents 2005;26 Suppl 3:S170–5. 20. Alghasham AA. Generic drug prescribing in central Saudi Arabia: perceptions and attitudes of physicians. Ann Saudi Med 2009;29:24–9. 21. Shrank WH, Liberman JN, Fischer MA, Girdish C, Brennan TA, Choudhry NK. Physician perceptions about generic drugs. Ann Pharmacother 2011;45:31–8. 22. Toklu HZ, Dülger GA, Hıdıroğlu S, Akici A, Yetim A, Gannemoğlu HM, et al. Knowledge and attitudes of the pharmacists, prescribers and patients towards generic drug use in Istanbul - Turkey. Pharm Pract (Granada) 2012;10:199–206. 23. Davit BM, Nwakama PE, Buehler GJ, Conner DP, Haidar SH, Patel DT, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother 2009;43:1583–97. 24. Nobili A, Garattini S, Mannucci PM. Multiple diseases and polypharmacy in the elderly: challenges for the internist of the third millennium. J Comorb 2011;1:28–44. 25. Lesar TS, Briceland L, Stein DS. Factors related to errors in medication prescribing. JAMA 1997;277:312–7. 26. Joosten H, Drion I, Boogerd KJ, van der Pijl EV, Slingerland RJ, Slaets JP, et al. Optimising drug prescribing and dispensing in subjects at risk for drug errors due to renal impairment: improving drug safety in primary healthcare by low eGFR alerts. BMJ Open 2013;3:pii:e002068. 27. Reichert S, Simon T, Halm EA. Physicians’ attitudes about prescribing and knowledge of the costs of common medications. Arch Intern Med 2000;160:2799–803. 28. Piette JD, Heisler M, Wagner TH. Cost-related medication underuse: do patients with chronic illnesses tell their doctors? Arch Intern Med 2004;164:1749–55. 29. Korn LM, Reichert S, Simon T, Halm EA. Improving physicians’ knowledge of the costs of common medications and willingness to consider costs when prescribing. J Gen Intern Med 2003;18:31–7.

Orıgınal Article

CHILD HEALTH & DISEASES

North Clin Istanb 2018;5(3):207–210 doi: 10.14744/nci.2017.27443

Evaluation of childhood solid pseudopapillary tumors of the pancreas Alper Ozcan,1 Ceyda Arslanoglu,2 Ekrem Unal,1 Turkan Patiroglu,1 Mehmet Akif Ozdemir,1 Kemal Deniz,3 Serdal Sadet Ozcan,4 Musa Karakukcu1 Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, Faculty of Medicine, Kayseri, Turkey

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

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

Department of Pathology, Training and Research Hospital, Kayseri, Turkey

ABSTRACT OBJECTIVE: Solid pseudopapillary tumor (SPT) of the pancreas is an extremely rare primary tumor in the pediatric age group. It has a low malignant potential and the prognosis is good if radical resection of the tumor is performed. Local recurrence and distant metastasis has only rarely been reported following incomplete resection. METHODS: A retrospective review of the medical records of 6 patients diagnosed as SPT according to a histopathological examination at the Children’s Hospital of Erciyes University School of Medicine between 2010 and 2017 was performed. Demographic characteristics, tumor localization and size, diagnostic method, immunohistochemical staining features, and medical and surgical treatments employed were recorded. RESULTS: There were 4 girls and 2 boys with the diagnosis of SPT included in this study. The mean age of the patients was 14 years (min-max: 13–16 years). The most common presenting complaint was abdominal pain. The mass lesion was at the head of the pancreas in 3 cases (50%) and the tail of the pancreas in the remaining 3 patients (50%). A Whipple procedure was performed in 3 cases, a distal pancreatectomy in 1, a distal pancreatectomy plus splenectomy in 1, and a subtotal pancreatectomy in 1patient. Immunohistochemistry revealed positive staining for beta-catenin, keratin, CD56, vimentin, and CD10 in all cases. CONCLUSION: SPT is a rarely seen pancreatic mass with low rate of malignancy. Diagnosis may be delayed due to its asymptomatic nature in most cases and a lack of descriptive symptoms. The survival rate is quite high after radical resection. Keywords: Child; pancreas; pseudopapillary tumor.

Cite this article as: Ozcan A., Arslanoglu C., Unal E., Patiroglu T., Ozdemir M. A., Deniz K. Evaluation of childhood solid pseudopapillary tumors of the pancreas. North Clin Istanb 2018;5(3):207–210.

olid pseudopapillary tumor (SPT) is one of the rarely seen primary tumors of the pancreas. In all age groups they constitute 2–3% of all primary pancreatic tumors [1]. They are more frequently seen in the second, and third decades of life, and in female children [2]. It was firstly defined by Frantz in the year 1959, and it was termed as papillary cystic tumor, solid cystic tumor, Frantz’s tumor

[3]. In the year 1996, the World Health Organization designated the term “solid pseudopapillary tumor” for this tumor [4]. It has lower malignancy potential, and its prognosis is very good after radical resection. However local recurrence, and also distant metastasis were reported following incomplete resection [5]. Its pathogenesis has not been clarified completely yet. Some authors claimed that

Received: August 15, 2017 Accepted: October 03, 2017 Online: April 18, 2018 Correspondence: Dr. Musa KARAKUKCU. Erciyes Universitesi Tıp Fakultesi, Pediatrik Hematoloji ve Onkoloji Anabilim Dali, Kayseri, Turkey. Phone: +90 532 381 71 20 e-mail: mkkukcu@yahoo.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

208

North Clin Istanb

this tumor has a hormonal origin, some others advocated that these tumors originate from ductal, acinar or primitive cells. Characteristically these tumors are bulky, however they are asymptomatic or have mild symptoms [6]. In this study, clinical characteristics, results of pathophysiologic, immunohistochemical analyses, and surgical treatment have been ivestigated.

location, and size of the tumor, diagnostic methods, immunohistochemical staining characteristics, medical, annd surgical treatments applied were recorded. For immunohistochemical staining, beta-catenin, keratin, chromogranin, CD56, synaptophysin, vimentin, CD10, and cyclinD1 were used.

MATERIALS AND METHODS

Six patients (4 female, and 2 male patients with a male/ female ratio of 1:2) with a mean age of 14 (min-max 13â&#x20AC;&#x201C;16) years who were histopathologically diagnosed as SPT between 2010, and 2017 were included in the study. Admission complaint of 5 (88%) patients was abdominal pain. Abdominal ultrasound (US) performed with the indication of hirsutismus revealed the presence of a mass which established the diagnosis of SPT. The mass lesion was localized on the head (n=3; 50%), and

In this study the files of 6 patients who were diagnosed as SPT based on the histopathological examination of the specimen in Erciyes University Faculty of Medicine, Hospital of Childrenâ&#x20AC;&#x2122;s Health and Diseases between the years 2010, and 2017 were retrospectively screened. Approval of Ethics Committee of Erciyes University Faculty of Medicine was obtained. Demographic characteristics,

RESULTS

Table 1. The characteristic features of the patients in the pediatric age group followed up with the diagnosis of SPT Case Age Gender

Admission Location Size (cm) complaint

Imaging modality

Followup period (months)

1 13 K Abdominal Tail of the 10 US-MRI 43 pain pancreas 2 13 E Abdominal Tail of the 10 US-MRI 76 pain pancreas 3 15 K Abdominal Head of the 9 CT-MRI 85 pain pancreas 4 16 K Hirsutism Head of the 5 US-MRI 96 pancreas 5 16 K Abdominal pain Head of the 6 US-MRI 99 pancreas 6 11 E Abdominal pain Tail of the 5 US-CT-MRI 30 pancreas

Treatment

Distal pancreatectomy + splenectomy Distal pancreatectomy Whipple surgery Whipple surgery Whipple surgery Subtotal pancreatectomy

Table 2. The immunohistochemical characteristics of the patients in the pediatric age group followed up with the diagnosis

of SPT Case

Beta-catenin

Ceratin

Chromogranin

CD56

Synaptophysin

Vimentin

1 2 3 4 5 6

+ + + + + +

- + - - - -

+ + + + + +

+ + - - - +

+ + + + + +

CD10

Cyclin D1

+ + + + + + +

NSE +

Ozcan et al., Solid pseudopapillary tumors

tail (n=3; 50%) of the pancreas. US, and computed tomography (CT) were performed for the identification of the mass. All patients also additionally underwent magnetic resonance imaging (MRI). Median tumor diameter was 16.5 (5–10) cm. Liver function tests, cholestatic, and pancreatic enzymes were within normal limits The patients were followed up for a median of 71.5 (30–96) months. We performed Whipple surgery (n=3), distal pancreatectomy (n=1), distal pancreatectomy and splenectomy (n=1), and subtotal pancreatectomy (n=1). Complication developed in one patient, and formation of a pseudocyst was also observed (Table 1). Samples harvested from 6 patients were subjected to immunohistochemical analyses. In all patients beta- catenin, ceratin, CD56, vimentin CD 10 staining positivity was detected In one (16.3%) patient chromogranin, and in 3 (50%) patients synaptophysin positivity were detected (Table 2). DISCUSSION SPT is rarely seen in infants, and children, and constitutes 2–3% of all pancreatic tumors. Pediatric patients have a more improved prognosis when compared with adults [1]. Ten years ago very few studies were available on this subject. Standardization of terminology, and increase in the use of immunohistochemical staining, the level of awareness concerning these tumors has increased [8]. In a review performed with 292 patients with SPT median age of the patients at the time of the identification of the tumor was detected as 23.9 years with a male/ female ration of 1:9.4 [9]. In two separate studies performed on children, male/female ratios were found to be 1:27, and 1:2, respectively [8, 10]. In our study this ratio was 1:2, in compliance with the literature. SPT generally leads an asymptomatic course or causes inexplicit symptoms as abdominal pain, and distension. Therefore they are incidentally detected during physical examination or with imaging modalities [11]. Liver function test results, levels of cholestatic, and pancreatic enzymes, and serum tumor markers are usually within normal limits [12]. In these patients exocrine, and endocrinological insufficiency has not been detected up to now [13]. Our five cases presented with nonspecific complaints as abdominal pain, and only physical examination, and imaging modalities revealed this intraabdominal mass. In our one patient with hirsutismus, polycystic ovary syndrome, incidental abdominal US detected an intraabdominal mass. Liver function test results, cholestatic, and pancreatic enzymes, hormonal evaluation of the all patients were found to be within

209

Figure 1. On axial T2- weighted images hyperintense heterogenous giant solid mass in the body, and tail of the pancreas. normal limits, and consistent with the diagnosis of polycystic ovary syndrome. In the determination of pancreatic mass lesions, US is the first-line preference because of its lower cost, and lack of radiation exposure US may aid in the determination of the association of the mass with mesenteric, and splenic vessels, and Doppler US helps us to identify intratumoral vascularization [14]. Procacci et al. estimated diagnostic accuracy of CT in pancreatic tumors with cystic component as 60 percent. Although CT plays a major role in the diagnostic evaluation of cystic lesions of pancreas, when compared with MRI, some disadvantages of CT have been reported in demonstrating tissue characteristics as bleeding, cystic degeneration, and presence of a capsule [15, 16]. In our patients, firstly mass lesion was detected using US or CT, then MRI was used to make an initial radiological diagnosis of SPT (Fig. 1). In children tumor is more frequently (60–70%) localized on the head of the pancreas contrary to its location in adults, In children SPT is localized in the head of the pancreas. However in adult patients SPT is mostly (80%) localized in the body, and the tail of the pancreas [17]. In the present study, contary to literature findings mass lesion was located in the head of the pancreas in 50%, and in the tail of the pancreas also in 50% of the patients. It has been reported that pancreatic SPT cells express exocrine, endocrine, mesenchymal, and epithelial cell markers in varying amounts [8]. SPT has a complex immune profile. In previous studies respective percentages of patients demonstrated positive staining with NSE (93%), vi-

210 A

North Clin Istanb B

S.S.O.; Data collection &/or processing – C.A., A.O., S.S.O., K.D.; Analysis and/or interpretation – A.O., M.K., E.U.; Writing – A.O., C.A., S.S.O.; Critical review – T.P., M.A.O.

REFERENCES

Figure 2. Microscopic appearance of pseudopapilllary component of the tumor (A) staining with HE (B) Positive staining with vimentin (C) Nuclear, and cytoplasmic positive staining with B catenin (D) Negative staining with chromogranin.

mentin (90%), chromogranin A, cytokeratin, and synaptophysin [2, 8]. In another study performed with 11 pediatric patients with SPT, respective percentages of patients displayed positive staining with NSE (36%), chromogranin A (91%) [8]. However in the present study only one patient (16.3%) manifested positive staining with chromogranin. In all patients, positive staining with beta-catenin, keratin, CD56, vimentin CD 10 was detected. Synaptophysin positivity was detected in 3 (50%) patients (Fig. 2). Surgical resection constitutes the basis of treatment.. In cases of radical resection of the tumor prognosis is generally good. Long-term survival, and recurrence rates were reported as 90, and 10%, respectively [18]. In 6 cases total surgical resection was achieved. Physical, and US examinations were maintained during follow-up period. During our average follow-up of 6 years any recurrence was not detected. In conclusion, SPT is a rarely seen pancreatic mass with lower malignancy rates. Since it has nondescriptive characteristics, and asymptomatic course, diagnosis may be delayed. Survival rates are at a higher level when total surgical resection was performed. 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.O., E.U., C.A.; Design – S.S.O., A.O.; Supervision – A.O., M.K., E.U.; Materials – C.A., K.D.,

1. Sur YK, Lee JH, Kim JK, Park MJ, Kim B, Park MS, et al. Comparison of MR imaging features of solid pseudopapillary neoplasm of pancreas between male and female patients. Eur J Radiol 2015;84:2065–70. 2. Branco C, Vilaça S, Falcão J. Solid pseudopapillary neoplasm-Case report of a rare pancreatic tumor. Int J Surg Case Rep 2017;33:148–50. 3. Divarcı E, Dökümcü Z, Çetingül N, Nart D, Barbet FY, Ergün O, et al. Radical resection of the pancreas should not always be necessary in the surgical management of pancreatic solid pseudopapillary tumor in children. Turk J Gastroenterol 2017;28:214–8. 4. Klöppel G, Solcia E, Longnecker DS, Capella C, Sobin L. Histological Typing of Tumours of the Exocrine Pancreas. 2nd ed. Springer-Verlag Berlin Heidelberg; 1996. 5. Morita K, Urushihara N, Fukumoto K, Miyano G, Yamoto M, Nouso H, et al. Solid pseudopapillary tumor of the pancreas in children: surgical intervention strategies based on pathological findings. Pediatr Surg Int 2014;30:253–7. 6. Spătaru RI, Enculescu A, Popoiu MC. Gruber-Frantz tumor: a very rare pathological condition in children. Rom J Morphol Embryol 2014;55:1497–501. 7. Rebhandl W, Felberbauer FX, Puig S, Paya K, Hochschorner S, Barlan M, et al. Solid-pseudopapillary tumor of the pancreas (Frantz tumor) in children: report of four cases and review of the literature. J Surg Oncol 2001;76:289–96. 8. Park JY, Kim SG, Park J. Solid pseudopapillary tumor of the pancreas in children: 15-year experience at a single institution with assays using an immunohistochemical panel. Ann Surg Treat Res 2014;86:130–5. 9. Veras E, Mao TL, Ayhan A, Ueda S, Lai H, Hayran M, et al. Cystic and adenofibromatous clear cell carcinomas of the ovary: distinctive tumors that differ in their pathogenesis and behavior: a clinicopathologic analysis of 122 cases. Am J Surg Pathol 2009;33:844–53. 10. Jung SE, Kim DY, Park KW, Lee SC, Jang JJ, Kim WK. Solid and papillary epithelial neoplasm of the pancreas in children. World J Surg 1999;23:233–6. 11. Parelkar SV, Oak SN, Kapadnis SP, Sanghvi BV, Joshi PB, Sathe P, et al. Solid pseudo papillary tumor of the pancreas: An unusual tumor in children. J Indian Assoc Pediatr Surg 2013;18:38–40. 12. Erkılıç S, Özsaraç C, Güldür E. Solid-Pseudopapillary Neoplasm of Pancreas: A Case report. Turk Patoloji Derg 2003;19:3–4. 13. Raffel A, Cupisti K, Krausch M, Braunstein S, Tröbs B, Goretzki PE, et al. Therapeutic strategy of papillary cystic and solid neoplasm (PCSN): a rare non-endocrine tumor of the pancreas in children. Surg Oncol 2004;13:1–6. 14. Shet NS, Cole BL, Iyer RS. Imaging of pediatric pancreatic neoplasms with radiologic-histopathologic correlation. AJR Am J Roentgenol 2014;202:1337–48. 15. Salvia R, Festa L, Butturini G, Tonsi A, Sartori N, Biasutti C, et al. Pancreatic cystic tumors. Minerva Chir 2004;59:185–207. 16. Cantisani V, Mortele KJ, Levy A, Glickman JN, Ricci P, Passariello R, et al. MR imaging features of solid pseudopapillary tumor of the pancreas in adult and pediatric patients. AJR Am J Roentgenol 2003;181:395–401. 17. Escobar MA, Bond BJ, Schopp J. Solid pseudopapillary tumour (Frantz’s tumour) of the pancreas in childhood. BMJ Case Rep 2014;2014. pii: bcr2013200889. 18. Çolak B, Çakır M, Çolak MH. Solid pseudopapillary tumor of the pancreas: A Case Report. Genel Tıp Derg 2013;23:23–5.

Orıgınal Article

CHILD SURGERY

North Clin Istanb 2018;5(3):211–215 doi: 10.14744/nci.2017.60590

Vitelline duct pathologies in neonates Suleyman Celebi,1 Seyithan Ozaydin,1 Esra Polat,2 Cemile Basdas,1 Elmas Reyhan Alim,1 Serdar Sander1 Department of Pediatric Surgery, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey Department of Pediatric Gastroenterology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: The aim of this study was to review the management of pediatric cases of vitelline duct pathology (VDP) detected surgically or incidentally during the neonatal period and the outcomes. METHODS: The data of newborns who were symptomatic and underwent VDP resection or who were incidentally diagnosed with VDP at a single institution between 1985 and 2015 were retrospectively analyzed in terms of age, sex, clinical features, treatment, perioperative findings, ectopic tissue pathology, and postoperative follow-up information. RESULTS: Among the 36 newborns enrolled in this study, 26 were male and 10 were female (2.6:1). The median weight was 2400 g (range: 800–3090 g). In 16 cases (14 males and 2 females; 7:1) the VDP was surgically repaired. Pathological evaluation indicated that 43% (n=7) of the cases had ectopic gastric mucosa. VDP was incidentally discovered in 12 males and 8 females (1.5:1). VDP was removed in 10 cases (50%) and left intact in others. Ectopic gastric mucosa was observed in 10% of the VDP removal cases. Ectopic gastric tissue was more prevalent in the surgical VDP cases than in the incidentally discovered and VDP removal cases (p<0.05). Male predominance was greater in the surgically repaired cases than in the incidentally discovered cases (p<0.05). One patient whose VDP was discovered incidentally was admitted 3 years later with obstruction due to intussusception caused by Meckel’s diverticulum, and 1 patient was admitted with rectal bleeding at 11 years of age. CONCLUSION: Symptomatic VDP in the newborn demonstrates a significant gender difference. Symptomatic cases are more likely to have ectopic gastric tissue than non-symptomatic cases. Incidentally detected cases without removal should be followed closely for future complications. Keywords: Meckel’s diverticulum; neonates; vitelline duct pathologies.

Cite this article as: Celebi S., Ozaydin S., Polat E., Basdas C., Alim E. R., Sander S. Vitelline duct pathologies in neonates. North Clin Istanb 2018;5(3):211–215.

he vitelline duct (VD) is an embryonic structure providing communication from the yolk sac to the midgut during fetal development [1]. Normally, it obliterates spontaneously and separates from the intestine between approximately the 5th and 9th weeks of gestation [2]. The obliterative process begins at the umbilical end of the duct and extends toward the intestine. Disruption of this process results with intestinal end or residents, causing vitelline duct pathology (VDP)[3]. VDP could occur in a variety of abnormalities, such as Meckel’s diverticulum, vitelline cyst, persistent fibrous cord, or

umbilical sinus; Alternatively, VD may be patent and present as an omphaloileal fistula and after birth, the infant presents with umbilical discharge resembling small bowel content [4]. VD remnants are said to be present in 2%–4% of all routine postmortem examinations [5, 6]. The complications are common in infants and male children, which can be serious [7, 8] but most reports focus on VD on symptomatic Meckel’s diverticulum, whereas other anomalies are given little attention. Our newborn series is one of the largest series in the literature.

Received: April 28, 2017 Accepted: October 04, 2017 Online: April 21, 2018 Correspondence: Dr. Suleyman CELEBI. Kanuni Sultan Suleyman Egitim ve Arastirma Hastanesi, Cocuk Cerrahisi Anabilim Dali, Istanbul, Turkey. Phone: +90 505 745 65 77 e-mail: celebisuleyman@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

212

North Clin Istanb

Table 1. Clinical characteristics of surgically repaired VDP Surgical Cases All patients Age (n=16) (postnatal day) Patent Vitelline duct Volvulus Ileal dysgenesis Littre hernia MD perforation

11 2 1 1 1

4-17 2.5 4 7 3

Gender Simple (male: diverticulectomy female) (n=2) 10:1 1:1 1:0 1:0 1:0

Wedge-shaped excision (n=3)

2 0 0 0 0

2 0 0 1 0

Segmental bowel Ectopic Gastric resection (n=11) tissue (n)

7 2 1 0 1

5 0 1 0 1

Surgical repaired cases has statistically significant male predominance (p<0.05)

The objective of this study was to review the management and outcomes of surgically and incidentally diagnosed VDP in the neonatal period, using contemporary data from an institutional database. MATERIALS AND METHODS Newborn patients who underwent surgery due to VDP or who were incidentally diagnosed at a single institution from 1985 to 2015 were retrospectively analyzed. After approval of the study by the Institutional Review Board of Medical Ethics Committee, informed consent was obtained from the children’s parents. Patient-related information included gender, the postnatal day at presentation and surgery, clinical features, laboratory data, and perioperative findings, including operative procedures, pathology, and postoperative follow-up. Based on the diagnoses at presentation, the enrolled patients were divided into two groups. Group 1 consisted of surgical cases due to VDP that was resected in all cases. Group 2 consisted of incidentally discovered cases of patients who had undergone surgery for other newborn pathologies. In Group 1, VDP was classified as the presence of patent VD, a cyst, and a fıstula, as diagnosed by a physician. In Group 2, VDP was classified as having been discovered incidentally during surgery for other congenital gastrointestinal malformations. The clinical manifestations were also included if there was intestinal hemorrhage, inflammation, and intestinal obstruction. Intestinal obstruction was defined when VD was presented with bilious vomiting and when intussusception, adhesion ileus, hernia, torsion, or other mechanical intestinal obstructions were found during surgery. Statistical analysis was performed using SPSS soft-

ware (version 17.0; SPSS Inc., Chicago, IL, USA). Continuous variables were presented as means and standard deviations. Qualitative variables were presented as total numbers and percentages. The continuous variables were compared using the Mann–Whitney U-test for nonparametric variables. The statistical significance level was set at p<0.05. RESULTS Among the 36 newborns enrolled, 26 were male and 10 were female. There were 16 patients (14 boys, two girls) who had surgery for VDP so the male-to-female ratio was 7:1. Median weight was 2,400 g (range: 800–3090 g). Median age was 6 days (0–17 days). Eleven newborns had a patent vitelline duct (PVD). The main complaint was watery and mucous discharge from the umbilicus. One patient with PVD had an associated anomaly (intestinal malrotation). Other surgical cases were two patients with volvulus, one with ileal dysgenesis and segmental mega-ileum within MD, and one with inguinal hernia in which MD was inside the hernia sac and was strangulated, being discovered during surgery (Table 1). One patient was operated on because of MD perforation (Fig. 1). Two of the 16 patients who were operated on because of VDP had multiple organ failure and died of cardiopulmonary arrest; the other 14 (87%) patients were discharged without additional complications. Ectopic gastric mucosa was detected in histopathological evaluations in seven (43%) histopathological cases. Twenty cases were found incidentally, 12 males and eight females. The male-to-female ratio of asymptomatic cases was 1.5:1. The sex discrepancy was higher in the surgically repaired category than in the incidental

Celebi et al., Vitelline duct pathologies

213

Figure 1. (A) Perforation due to Meckel Diverticulitis in newborn patient. Patient was born as a result of in vitro fertilization twin pregnancies at 36 weeks gestational age. Twins are one male and one female. Male patient was operated on because of MD (B) MD underwent segmental bowel resection.

Table 2. Clinical characteristics of Incidentally discovered cases of VDP Total Patient (n) Male: Female Abdominal Wall Defect (AWD) AWD with Intestinal perforation Gastrointestinal anomaly Ileal atresia Duodenal atresia Pouch colon Malrotation Anal atresia Congenital Diaphragmatic Hernia Surgery (n) Ectopic Gastric Tissue Ectopic Tissue Surgical repaired- Incidental Discovered

20 3: 2 12 (60%) 3 (15%) 2 2 1 1 1 1 10 (50%) 1 (10%) 4:1

discovered cases (male-to-female 7:1 vs 1.5:1, p<0.05). Twelve newborns in this group were diagnosed during surgery for abdominal wall defects. Three patients in this group had an concominant intestinal perforation at the same time. Among the 10 cases of VDP removal, two were diagnosed during surgery for ileal atresia, two were diagnosed during surgery for duodenal atresia, one was diagnosed during surgery for pouch colon, one was diagnosed during surgery for malrotation, one was diagnosed during surgery for anal atresia, one was diagnosed during surgery for diaphragmatic hernia. VDP in the other discovered cases was left intact (Table 2). Ectopic gastric

mucosa was present in 10% cases. Ectopic tissues were more prevalent in symptomatic VDP cases than incidental discovered and VDP removal cases (43%: 10%, p<0.05). One patient who was discovered incidentally and leaved intact during follow-up was admitted with obstruction due to Meckelâ&#x20AC;&#x2122;s diverticulum when he was 3 years old and underwent surgery for an intussusception. The other one presented with an intestinal hemorrhage when the patient was 11 years old, and diverticulitis was discovered during the surgery. There were 13 (50%) patients who underwent segmental bowel resection of an ileal segment, nine (34%) who underwent wedge-shaped resection, and four (15%) who underwent simple diverticulectomy In the neonatal period, the following pathological findings were reported: predominantly mucosal congestion with VDP, edema, hemorrhage, or ischemic changes. In histopathological examinations for ectopic tissue, 11 cases had gastric mucosa. With regard to the pathology, six cases did not have clearly defined findings and intense inflammation of the diverticulum mucosa due to necrosis was reported. All cases of MD containing gastric mucosa were symptomatic, and one patient who was diagnosed incidentally, during follow-up was operated on because of bleeding when he was 11 years old. This patient also had ectopic gastric mucosa in the pathological examination. DISCUSSION The VD is the embryonic communication between the yolk sac and the midgut, but it normally closes and disappears during the development process [9, 10]. A persistent intestinal end or residents can cause VDPs. Clinical presentations in decreasing order of likelihood include intestinal obstruction, gastrointestinal bleeding, acute intraabdominal inflammation, and umbilical anomalies that have junction with the ileum [11, 12]. Symptomatic presentation of VDP in neonates is rare [13]. Thus, our study focused on VDP discovered in newborns. In this study, the most common pathology in newborns was patent VD and secondly incidentally discovered cases during omphalocele, gastroschisis and umbilical cord prolapse repairs and one patient who had a Littre hernia was admitted with strangulated hernia. Segmental ileum dilatation (SID), an anomaly also known as ileal dysgenesis, was found in one patient.

214

There were eight cases of SID associated with VD reported till now; only three were in neonates [14]. Neonatal VDP can also present as ileal volvulus with resultant infarction of the diverticulum [15] and the ileum, similar to the pathology in two of our cases. Looking at the other presentations, we found 12 cases of neonatal Meckel’s diverticulum with perforation that have been described in the literature [16]. The causes of perforation include spontaneous inflammatory ulceration with heterotopic mucosa, congenital muscle defect, or perforation secondary to Hirschsprung’s disease. Our case series has one such case. We had incidentally discovered VDs during repair of the newborn congenital anomalies, and some were left intact according to surgeon preference. Two of these cases were readmitted during follow-up–one of them was admitted with intussusception at the age of 3 years and the other with bleeding 11 years later. Ectopic tissue could be detected in VDP [3]. Numerous explanations have been put forward to account for the presence of aberrant elements. The most acceptable is the endothelial lining of the embryo forms cell groups which function as a primitive digestive system and that, while normally this system regresses as soon as its function ceases, occasionally “a vestige of heterotopic tissue remains as a consequence of retarded retrogression of the vitellointestinal duct [17]. Ectopic tissue detection rate in VDs is higher in children than in adults [3]. It is known that if the ectopic tissue contains gastric mucosa, it has a greater chance to become symptomatic than those without gastric mucosa MD [18]. Heterotopic gastric mucosa (HGM) can be symptomatic more frequently in younger and male patients (e.g., bleeding), usually derived from an adjacent ileal mucosal ulceration, intestinal obstruction, and diverticulitis [19]. There is convincing evidence for MD removal in young patients with suspicion of ectopic mucosa. Rutherford and Aker observed ectopic gastric mucosa in all symptomatic patients. [20] Only a 6% incidence of heterotopic tissue was found in autopsy specimens of asymptomatic diverticulum. In one study among 30 gastric-mucosa-containing MD, 25 (83%) were found in the pediatric group and five (17%) were found in the adult group [21]. In our study, nearly half of the surgically repaired group had ectopic tissue; the inflammation in the rest may have prevented the pathological confirmation of ectopic gastric mucosa. One of the ınfants in our study who weighed 2,300 g had an early postnatal volvulus. Volvulus occurs when

North Clin Istanb

the small bowel twists around a fibrous cord, or Meckel’s band, tethering MD to the umbilicus. In addition, MD could be complicated with intestinal obstruction secondary to internal hernia, as observed in one of our cases. Male patients were more likely to have HGM than female patients; hence, symptomatic VDP patients were more likely to be male [3]. Even with no difference in the prevalence of asymptomatic MD between males and females, symptomatic MD has a male predominance, with a male-to-female ratio ranging from 2:1 to 5:1 in children [22, 23]. In our study including only newborns, we found major male dominance, with a ratio of almost 7:1. Case reports in the literature on neonatal MD almost all males [15]. One of the largest series from the Mayo Clinic reported that the diverticulum containing ectopic or abnormal tissue is associated with symptomatic diverticulum in male patients, and they suggests resection in such cases [3]. In our one patient. This patient was born as a result of in vitro fertilization twin pregnancies at 36 weeks gestational age. Twins are one male and one female. Male patient was operated on because of MD perforation. But female has no MD symptoms. Bleeding in ectopic gastric mucosa was secondary to the ileal mucosal breakdown as a result of acid-producing parietal cells within MD [3]. The theory is based on the inheritance of an acid-secreting ability, possibly a parietal cell mass at the top of the normal range and the consequence of hyperacidity [20]. Those reported cases of ulcers involving gastric mucosa are of doubtful validity, and Gezer [24] suggested that the actual ulceration occurs in an island of ileal mucosa within the gastric rest. According to Gezer, the neck of the diverticulum is the most common site for the ulcer, followed by the body, the tip, and lastly the immediately neighboring ileum. One of our incidentally discovered cases was admitted because of bleeding 11 years later during follow-up; the pathology in case was ectopic gastric tissue. Omphalomesenteric duct anomalies occur in approximately 2% of newborns. In 6% of these infancts, the duct remains patent. In a study of approximately 1,000 umbilical cords and placentas, microscopic analysis revealed embryonic remnants of 23.1% samples. Furthermore, up to 6.6% of these omphalomesenteric were VD remants [24]. When connected to the ileum, a PVD may have a wide lumen or be a high-output fistula. This may lead to fluid and electrolyte loss, especially in neonates, and treatment should be expeditious. Early surgical manage-

Celebi et al., Vitelline duct pathologies

ment is important as it may cause severe complications, which may result in mortality in up to 18% cases, especially in the newborn period [25]. In our series it is striking to see high rates of gastroschisis and omphalocele in VDPs. The most recent hypothesis was sectional by Stevenson et al. [26], who suggested that the defect in the gastroschisis is caused by the failure of the yolk sac and related vitelline structures to be incorporated into the umbilical stalk. In addition to the umbilicus, the abdominal wall has a second opening through which the midpoint of the gut (Meckel’s point) is attached to the exteriorized vitelline structures. Gastroschisis and omphaloceles that we see with VDP supports the Stevenson’s hypothesis that midline with such pathology. CONCLUSION The VD complications to which they are subject are serious and are commonest in newborns. Presenting symptoms were related to age, ectopic tissue, and showing gender differences. Male predominance in newborns is higher than children and adults. 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.O.; Design – S.C., E.S., C.B., S.S.; Supervision – S.C., E.A., C.B., S.S.; Materials – S.C., E.A., E.R.A., S.S.; Data collection &/or processing – S.C., S.O., E.P., E.S., S.S.; Analysis and/or interpretation – S.C., C.B., E.P., E.R.A., S.S.; Writing – S.C., E.P.; Critical review – S.C., E.P., S.S.

REFERENCES 1. Yahchouchy EK, Marano AF, Etienne JC, Fingerhut AL. Meckel’s diverticulum. J Am Coll Surg 2001;192:658–62. 2. Sagar J, Kumar V, Shah DK. Meckel’s diverticulum: a systematic review. J R Soc Med 2006;99:501–5. 3. Park JJ, Wolff BG, Tollefson MK, Walsh EE, Larson DR. Meckel diverticulum: the Mayo Clinic experience with 1476 patients (1950-2002). Ann Surg 2005;241:529–33. 4. Kadian YS, Verma A, Rattan KN, Kajal P. Vitellointestinal Duct Anomalies in Infancy. J Neonatal Surg 2016;5:30. 5. Menezes M, Tareen F, Saeed A, Khan N, Puri P. Symptomatic Meckel’s diverticulum in children: a 16-year review. Pediatr Surg Int 2008;24:575–7.

215 6. Stone PA, Hofeldt MJ, Campbell JE, Vedula G, DeLuca JA, Flaherty SK. Meckel diverticulum: ten-year experience in adults. South Med J 2004;97:1038–41. 7. Tseng YY, Yang YJ. Clinical and diagnostic relevance of Meckel’s diverticulum in children. Eur J Pediatr 2009;168:1519–23. 8. St-Vil D, Brandt ML, Panic S, Bensoussan AL, Blanchard H. Meckel’s diverticulum in children: a 20-year review. J Pediatr Surg 1991;26:1289–92. 9. Cserni G. Gastric pathology in Meckel’s diverticulum. Review of cases resected between 1965 and 1995. Am J Clin Pathol 1996;106:782–5. 10. Gandy J, Byrne P, Lees G. Neonatal Meckel’s diverticular inflammation with perforation. J Pediatr Surg 1997;32:750–1. 11. Elsayes KM, Menias CO, Harvin HJ, Francis IR. Imaging manifestations of Meckel’s diverticulum. AJR Am J Roentgenol 2007;189:81–8. 12. Baker Al Jr, Marshall SF. Meckel’s diverticulum: a report of ninety-three cases. Am Surg 1955;21:1173–81. 13. Ko SF, Tiao MM, Huang FC, Hsieh CS, Huang CC, Ng SH, et al. Internal hernia associated with Meckel’s diverticulum in 2 pediatric patients. Am J Emerg Med 2008;26:86–90. 14. Ojha S, Menon P, Rao KL. Meckel’s diverticulum with segmental dilatation of the ileum: radiographic diagnosis in a neonate. Pediatr Radiol 2004;34:649–51. 15. Sy ED, Shan YS, Tsai HM, Lin CH. Meckel’s diverticulum associated with ileal volvulus in a neonate. Pediatr Surg Int 2002;18:529–31. 16. Chang YT, Lin JY, Huang YS. Spontaneous perforation of Meckel’s diverticulum without peritonitis in a newborn: report of a case. Surg Today 2006;36:1114–7. 17. Cullen JJ, Kelly KA, Moir CR, Hodge DO, Zinsmeister AR, Melton LJ 3rd. Surgical management of Meckel’s diverticulum. An epidemiologic, population-based study. Ann Surg 1994;220:564–8. 18. Matsagas MI, Fatouros M, Koulouras B, Giannoukas AD. Incidence, complications, and management of Meckel’s diverticulum. Arch Surg 1995;130:143–6. 19. Çelebi S. Male predominance in Meckel’s diverticulum: A hyperacidity hypotheses. Med Hypotheses 2017;104:54–7. 20. Rutherford RB, Akers DR. Meckel’s diverticulum: a review of 148 pediatric patients, with special reference to the pattern of bleeding and to mesodiverticular vascular bands. Surgery 1966;59:618–26. 21. Dumper J, Mackenzie S, Mitchell P, Sutherland F, Quan ML, Mew D. Complications of Meckel’s diverticula in adults. Can J Surg 2006;49:353–7. 22. Ymaguchi M, Takeuchi S, Awazu S. Meckel’s diverticulum. Investigation of 600 patients in Japanese literature. Am J Surg 1978;136:247–9. 23. Levy AD, Hobbs CM. From the archives of the AFIP. Meckel diverticulum: radiologic features with pathologic Correlation. Radiographics 2004;24:565–87. 24. Gezer HÖ, Temiz A, İnce E, Ezer SS, Hasbay B, Hiçsönmez A. Meckel diverticulum in children: Evaluation of macroscopic appearance for guidance in subsequent surgery. J Pediatr Surg 2016;51:1177–80. 25. Rao PL, Mitra SK, Pathak IC. Patent vitello-intestinal duct. Indian J Pediatr 1979;46:215–8. 26. Stevenson RE, Rogers RC, Chandler JC, Gauderer MW, Hunter AG. Escape of the yolk sac: a hypothesis to explain the embryogenesis of gastroschisis. Clin Genet 2009;75:326–33.

Orıgınal Article

GERIATRICS

North Clin Istanb 2018;5(3):216–220 doi: 10.14744/nci.2017.85047

Validity and reliability of geriatric depression scale-15 (short form) in Turkish older adults Busra Durmaz,1 Pinar Soysal,2 Hulya Ellidokuz,3 Ahmet Turan Isik2 Department of Neuroscience, Health Science Institute, Dokuz Eylul University, Izmir, Turkey

Department of Geriatric Medicine, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey

Department of Biostatistics, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey

ABSTRACT OBJECTIVE: The present study aimed to assess the validity and reliability of Geriatric Depression-15 Scale (GDS-15) in Turkish older adults and to compare the results with Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) depression criteria. METHODS: A total of 329 outpatients were enrolled. In the first step, the patients underwent the Mini-Mental State Examination. After assessing whether the patients meet the diagnosis of depression based on DSM-5 diagnostic criteria, another researcher applied the long form of GDS. After sorting the items of short form out of the long form, two separate scores were obtained. The scores of GDS-30 and GDS-15 scales were compared with the scores of DSM-5. RESULTS: The correlation of GDS-30 with GDS-15 was r=0.966 (p<0.001). The analysis performed considering DSM-5 criteria revealed that the sensitivity, specificity, positive predictive value, and negative predictive value of GDS-15 in determining depression were 92%, 91%, 76%, and 97%, respectively, when the cutoff value was taken as ≥5. The area under the receiver operating characteristics curve [95% confidence interval (CI)] was 0.97 (95% CI=0.947–0.996) for GDS-15 (p<0.001). The Cronbach alpha coefficient for the total scale was 0.920. CONCLUSION: GDS-15, just as GDS-30, is a beneficial scale in determining depression in older adults. This study provides an evidence for the validity and reliability of GDS-15 in Turkish elderly population and primary care centers. Keywords: Depression; DSM-5; GDS-15; geriatrics; Turkey.

Cite this article as: Durmaz B., Soysal P., Ellidokuz H., Isik A. T. Validity and reliability of geriatric depression scale-15 (short form) in Turkish older adults. North Clin Istanb 2018;5(3):216–220.

epression is a serious health problem in older adults. Although depression is seen in all age groups, geriatric depression may be associated with devastating outcomes such as falls, sleep disorders, cognitive deficiency, malnutrition, self-neglect, and increased risk of morbidity and mortality. Moreover, depression in advanced ages might be the initial sign of other diseases [1]. Therefore, early diagnosis and treatment of depression is important for geriatric practice. However, it is difficult to diagnose geriatric depression because the affective symptoms are

uncommon in elderly compared with adults and children, the disease may frequently present itself with cognitive or somatic symptoms, or the clinicians may usually attribute the symptoms to senility or existing comorbidities [2, 3]. Therefore, screening for geriatric depression is important in clinical practice, and screening tools that would enable rapid and reliable detection of depression in older adults are needed. For this purpose, the initial form of Geriatric Depression Scale (GDS) comprising 30 items was developed by

Received: August 03, 2017 Accepted: November 13, 2017 Online: May 30, 2018 Correspondence: Dr. Ahmet Turan ISIK. Dokuz Eylul Universitesi Tip Fakultesi, Geriatri Bilim Dali, Izmir, Turkey. Phone: +90 232 412 43 41 e-mail: atisik@yahoo.cm © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Durmaz et al., Validity and reliability of geriatric depression scale-15 (short form) in Turkish older adults

Yesavage JA et al. [4] in 1983, and it was validated for Turkish older adults by Ertan et al. [5]. However, GDS30 is a time-consuming screening tool for both clinicians and patients. The short form of GDS comprising 15 items (GDS-15), which is effective for the diagnosis of depression in elderly, is more simple, brief, and timeeffective than GDS-30. Because of these characteristics, GDS-15 has been validated and is being widely used in many different populations all over the world. America, China, Israel, Greece, United Kingdom, Lebanon, and Brazil are some of the countries where the short form of the scale has been validated [6–12]. The present study aimed to validate GDS-15 and make it available for Turkish older adults. MATERIALS AND METHODS Procedure The study comprised the patients aged ≥65 years who visited a geriatric outpatient clinic of a university hospital between November 2015 and May 2016 for any reason. In the first step, the patients underwent the Mini-Mental State Examination (MMSE) and Cognitive State Test (COST) [13]. After assessing whether the patients meet the DSM-5 diagnostic criteria for depression, another researcher applied the long form of GDS. Sorting the items of the short form out of the long one, two separate scores were obtained. Any translation procedure was not considered necessary during the validation phase as the validation of the long form was done in 1997 by Ertan et al., and the items of short form were sorted out of the long form using exactly the same structures of items. The protocol for this study was approved by the local Ethics Committee. All participants signed informed consent forms. Participants Patients who had cognitive deficiency (Alzheimer disease, frontotemporal dementia, Lewy body dementia, and so on), delirium, or psychotic disorder; have had acute disease within the last two weeks (those with the history of serious disease that impairs general health status such as acute coronary syndrome, acute cerebrovascular accident, and gastrointestinal hemorrhage or staying in the intensive care unit); have been using drugs likely to influence emotional state such as benzodiazepine and antipsychotics; and who were alcohol and substance addicts were excluded. Finally, 329 patients meeting the criteria were enrolled.

217

Measures The Geriatric Depression Scale (GDS-30) was developed in 1983 by Yesavage JA et al. [3]. The primary target of this scale, which consists of self-reported 30 questions, is to contain easy-to- answer questions for elderly. While scoring this scale comprising questions with only “yes” or “no” as answers, 1 point is given to each answer that suggest depression and 0 is given for the other answers, and final score is considered as the depression score. The sensitivity and specificity of this initial form consisting of 30 questions were found to be 80% and 100%, respectively, when the cutoff value was taken as 14. A cutoff value of 0–11 was defined as the absence of depression, 11–14 as “probable depression,” and ≥14 as “definite depression” [5]. Geriatric Depression Scale-Short Form (GDS-15): The validity and reliability of this 15-question short form was performed in 1991 by Burke et al. for ease of use [14]. The GDS-15, which was used in the present study, consists of 15 questions inquiring the patient’s mood. Answers are given based on the feelings in the last week; answers are in the form of “yes” or “no” just as in the long form, and 1 point is given either to the answer “yes” or to the answer “no” depending on the question.

Table 1. Characteristics of the participants (n=329) Characteri̇ cti̇ cs Age - Mean, (SD) Sex % Female Male Level of education % <8 years >8 years Marital status % Married Widowed Unmarried Comorbidities % Hypertension Hyperlipidemia Coronary artery disease Congestive heart failure Hypothyroidism Chronic obstructive pulmonary disease Having hearing difficult Cataract Hypertension Hyperlipidemia

Value 74.4 (8.5) 61.4 38.6 61.1 38.9 55.9 39.2 3.9 68.4 21.0 20.4 4.9 18.2 7.0 9.7 18.2 68.4 21.0

218

North Clin Istanb

RESULTS In the present study, a total of 329 participants were evaluated. The mean age was 74.4 years, and 61.4% was female. The characteristics and comorbidities of the participants are demonstrated in Table 1. The mean score (SD) was 8.21 (7.3) for GDS-30 and 3.21 (3.5) for GDS-15; the mean score of MMSE was 26.6 (2.3). The correlation of GDS-30 (Pearson) with GDS-15 was r=0.966 (p<0.001). Patients with and without depression based on the DSM-5 criteria, GDS-15, and GDS-30 are demonstrated in Table 2. The prevalence of major depression was 24.6% according to DSM-5. Kappa analyses performed for the consistency between the items of DSM-5 and GDS-15 are demonstrated in Table 3. Accordingly, the items 7, 3, and 5 of GDS-15 make the highest contribution to the measuring tool. The Cronbach alpha coefficient for the total scale was 0.920.

ROC analysis for GDS-15 revealed an optimal balance of sensitivity and specificity in distinguishing the patients with depression from those without depression at a cutoff value of 5 points with AUC of 0.971 (95% CI=0.947–0.996), P<0.001 (Fig. 1) and with a sensitivity and specificity of 92% and 91%, respectively (Table 4). The cutoff values show no variation according to the education level and existing comorbidities (Charlson Comorbidity Index) of the participants. The sensitivity, specificity, and PPV and NPV of GDS-15 are presented in Table 4. DISCUSSION The present study demonstrated that GDS-15 is a valid and reliable screening tool for depression in elderly Turkish outpatients without cognitive impairment and shows strong correlation with DSM-5 criteria in patients with depression. Similar to the earlier studies, the present study determined significantly high correlation between GDS-15 and GDS-30 and DSM-5 in distinguishing the patients with depression [15–17]. When the cutoff value is taken as ≥5, the sensitivity, specificity, PPV, and NPV of GDS15, Turkish version, are 92%, 91%, 76%, and 97%, respectively, in successfully distinguished the patients with 1.0

0.8

Sensitivity

Statistical analysis Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) 17.0 as well as Power Analysis and Sample Size (PASS) 2008 Statistical Software (NCSS, Kaysville, UT). Demographic characteristics of participants were analyzed using descriptive statistics. The Kappa consistency test was used to evaluate the consistency between Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) criteria and the items of GDS-15. The cutoff scores were assessed by the receiver operating characteristics (ROC) curve. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for different cutoff scores. In all analyses, P<0.05 was considered to indicate statistical significance. A sample size of 153 participants was calculated to ensure that the minimum required size was within a 95% confidence interval (CI) and 5% of the true proportion.

0.6

0.4

Table 2. Comparisons of the YGDS-15 and YGDS-30 with

0.2

Depression

0.0

DSM-5

No, % Depression, %

YGDS-15

YGDS-30

DSM-5

70.8 29.2

72.2 27.8

75.4 24.6

YGDS-15: Yesavage Geriatric Depression Scale 15 item; YGDS-30: Yesavage Geriatric Depression Scale 30 item; n: number of patients

0.0

0.2

0.4 0.6 1 - Specificity

0.8

1.0

Figure 1. ROC analysis for GDS-15 Receiver operating characteristic curve (ROC) analysis of the YGDS15 total scores to detect depression (AUC=0.971, p<0.001).

Durmaz et al., Validity and reliability of geriatric depression scale-15 (short form) in Turkish older adults

219

Table 3. The Kappa values for each items of Geriatric Depression Scale-15 Item 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Kappa Are you basically satisfied with your life? Have you dropped many of your activities and interest? Do you feel that your life is empty? Do you often get bored? Are you in good spirits most of the time? Are you afraid that something bad is going to happen to you? Do you feel happy most of the time? Do you often feel helpless? Do you prefer to stay at home, rather than going out and doing new thing? Do you feel you have more problems with memory than most? Do you think it is wonderful to be alive now? Do you feel pretty worthless the way you are now? Do you feel full of energy? Do you feel that your situation is hopeless? Do you think that most people are beter off than you are?

0.446* 0.564* 0.580* 0.508* 0.572* 0.224* 0.631* 0.504* 0.334* 0.215* 0.244* 0.539* 0.495* 0.482* 0.434*

*p<0.001.

Table 4. Discriminant validity of the YGDS-15 for depression Cut-off Sensitivity (%) Specificity (%) PPV (%) NPV (%) value

4 5 6 7

96 92 87 87

84 91 97 99

64 76 91 100

99 97 95 91

PPV: Positivepredictivevalue; NPV: Negativepredictivevalue.

depression from others. These results are consistent with the cutoff values found in the earlier studies from various countries, which have been performed for the validation of the short form; however, the present study used the same cutoff value with a validation study conducted in the United Kingdom (sensitivity=80%, specificity=77%) [10] and a study conducted in the United States in patients receiving homecare (sensitivity=71.8%, specificity=78.2%) [18]. Contrarily, the cutoff value was 3 (sensitivity=84%, specificity=64%) in a validation study conducted in Puerto Rico in patients aged ≥50 years [19], and it was 6 (sensitivity=81% specificity=75%) in a study from New York [20]. In addition, the present study demonstrated that the cutoff value does not change depending on education and comorbidity in older adults,

which may be an advantage while using GDS-15. GDS15 has several advantages, such as reduced respondent burden, shorter administration time, and less staff time required to help complete the scale over the more widely used GDS-30 or similar longer scales. GDS-15 can be used conveniently instead of GDS-30. These advantages may be important for outpatients as well as for frail and dependent nursing home residents and may enhance working capacity of health professionals. The prevalence of geriatric depression was reported to be 4.5%–37.4% among patients aged ≥65 years [21, 22]; likewise, the prevalence was demonstrated as 24.6% in the study. Therefore, validated GDS-15 may be quite helpful for our geriatric practice. The strength of the present study is the larger sample size than the other studies as well as the fact that diagnosis of depression has been made based on the DSM5 diagnostic criteria. The major limitation is the study group’s consisting of patients of a single outpatient clinic. Accordingly, it is partially representative of the whole population. Enrolling only the cognitively normal older subjects is another limitation, since many elderly people are cognitively impaired. However, it would be extremely important to assess the effectiveness of GDS-15 in such patients, who as well are usually depressed.

220

CONCLUSION In conclusion, GDS-15 is a valid and reliable screening tool for geriatric depression and is highly correlated with GDS-30 and DSM-5. It could be used for rapid and reliable detection of depression in elderly Turkish older adults, particularly in primary care. 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.T.I.; Design – A.T.I., P.S.; Supervision – P.S., A.T.I.; Materials – P.S., B.D.; Data collection &/or processing – B.D., P.S.; Analysis and/or interpretation – H.E., P.S., A.T.I.; Writing – P.S., B.D., A.T.I.; Critical review – P.S., A.T.I.

REFERENCES 1. Blazer DG. Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci 2003;58:249–65. 2. Fiske A, Wetherell JL, Gatz M. Depression in older adults. Annu Rev Clin Psychol 2009;5:363–89. 3. Bae JN, Cho MJ. Development of the Korean version of the Geriatric Depression Scale and its short form among elderly psychiatric patients. J Psychosom Res 2004;57:297–305. 4. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1983;17:37–49. 5. Ertan T, Eker E, Şar V. Geriatrik depresyon ölçeğinin. Türk yaşlı nüfusunda geçerlilik ve güvenilirliği. Nöropsikiyatri Arşivi 1997;34:62– 71. 6. Chiang KS, Green KE, Cox EO. Rasch Analysis of the Geriatric Depression Scale-Short Form. Gerontologist 2009;49:262–75. 7. Wong MT, Ho TP, Ho MY, Yu CS, Wong YH, Lee SY. Development and inter-rater reliability of a standardized verbal instruction manual for the Chinese Geriatric Depression Scale-short form. Int J Geriatr Psychiatry 2002;17:459–63. 8. Zalsman G, Aizenberg MD, Sigler MD, Nahshoni E, Weizman MD. Geriatric Depression Scale-Short Form–Validity and Reliability of the Hebrew Version. Clin Gerontol 1998;18:3–9.

North Clin Istanb 9. Fountoulakis KN, Tsolaki M, Iacovides A, Yesavage J, O’Hara R, Kazis A, et al. The validation of the short form of the Geriatric Depression Scale (GDS) in Greece. Aging (Milano) 1999;11:367–72. 10. Shah A, Phongsathorn V, Bielawska C, Katona C. Screening for depression among geriatric inpatients with short versions of the geriatric depression scale. Int J Geriatr Psychiatry 1996;11:915–8. 11. Chaaya M, Sibai AM, Roueiheb ZE, Chemaitelly H, Chahine LM, AlAmin H, et al. Validation of the Arabic version of the short Geriatric Depression Scale (GDS-15). Int Psychogeriatr 2008;20:571–81. 12. Castelo MS, Coelho-Filho JM, Carvalho AF, Lima JW, Noleto JC, Ribeiro KG, et al. Validity of the Brazilian version of the Geriatric Depression Scale (GDS) among primary care patients. Int Psychogeriatr 2010;22:109–13. 13. Babacan-Yildiz G, Isik AT, Ur E, Aydemir E, Ertas C, Cebi M, et al. COST: Cognitive State Test, a brief screening battery for Alzheimer disease in illiterate and literate patients. Int Psychogeriatr 2013;25:403– 12. 14. Burke WJ, Roccaforte WH, Wengel SP. The short form of the Geriatric Depression Scale: a comparison with the 30-item form. J Geriatr Psychiatry Neurol 1991;4:173–8. 15. Yesavage JA, Sheikh JI. 9/Geriatric Depression Scale (GDS) Recent evidence and development of a shorter. Clinical Gerontologist 1986;5:165–73. 16. Alden D, Austin C, Studeon R. A correlation between the Geriatric Depression Scale long and short forms. J Gerontol 1989;44:124–5. 17. Lesher EL, Berryhill JS. Validation of the Geriatric Depression ScaleShort Form among inpatients. J Clin Psychol 1994;50:256–60. 18. Marc LG, Raue PJ, Bruce ML. Screening performance of the 15-item geriatric depression scale in a diverse elderly home care population. Am J Geriatr Psychiatry 2008;16:914–21. 19. Robison J, Gruman C, Gaztambide S, Blank K. Screening for depression in middle-aged and older puerto rican primary care patients. J Gerontol A Biol Sci Med Sci 2002;57:M308–14. 20. Friedman B, Heisel MJ, Delavan RL. Psychometric properties of the 15-item geriatric depression scale in functionally impaired, cognitively intact, community-dwelling elderly primary care patients. J Am Geriatr Soc 2005;53:1570–6. 21. Luppa M, Sikorski C, Luck T, Ehreke L, Konnopka A, Wiese B, et al. Age- and gender-specific prevalence of depression in latest-life--systematic review and meta-analysis. J Affect Disord 2012;136:212–21. 22. Soysal P, Isik AT, Usarel C, Kaya D, Ellidokuz H, Grossberg GT. Validity and reliability of “AM SAD”, a short geriatric depression screening tool, in Turkish elderly people. Bulletin of Clinical Psychopharmacology 2016;26:175–80.

Orıgınal Article

GENERAL SURGERY

North Clin Istanb 2018;5(3):221–226 doi: 10.14744/nci.2017.80774

Ischemic colitis following infrarenal abdominal aortic aneurysm treatment: Results from a tertiary medical center Ulas Aday,1 Ebubekir Gundes,1 Durmus Ali Cetin,1 Huseyin Ciyiltepe,1 Aziz Serkan Senger,1 Selcuk Gulmez,1 Mustafa Akbulut,2 Erdal Polat1 Department of Gastroenterological Surgery, Kartal Kosuyolu High Speciality and Training Hospital, Istanbul, Turkey

Department of Cardiovascular Surgery, Kartal Kosuyolu High Speciality and Training Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: The aim of this study was to investigate the effects of ruptured aneurysm on morbidity and mortality in patients with ischemic colitis (IC) and resection following infrarenal abdominal aortic aneurysms (AAA) surgery. METHODS: Between January 2012 and December 2016, patients who underwent resection for ischemic colitis in our clinic were retrospectively reviewed. Data on the ruptured condition of the aneurysm, the emergency or elective form of aneurysm surgery, treatment method for the aneurysm (EVAR-open) were obtained. The patients were compared and divided into two groups as those with ruptured aneurysm and those without. RESULTS: A total of 275 infrarenal AAA cases were treated by the cardiovascular surgery clinic between January 2012 and December 2016. Fourteen patients (5%) developed ischemic colitis requiring resection. Four (1.8%) patients with EVAR and 10 (17.5%) patients with open surgery were operated because of IC. No statistically significant difference was observed between the two groups in terms of demographic data and surgical procedures. The intergroup comparison did not reveal any statistically significant difference among gastrointestinal (GIS) symptoms, the time period until surgery, the involved colon segment, and the surgical procedures performed. The mortality rate in ruptured AAA group was 83.3%, while it was 62.5% in the non-ruptured AAA group. In spite of the fact that the mortality rate was high in the ruptured group, it was not statistically significant (p=0.393). CONCLUSION: IC is a complication of AAA surgery with a high mortality rate. Rupture in abdominal aortic aneurysm increasing mortality in IC patients. This complication with a high mortality rate following open AAA surgery should be noted by surgeons and we believe that the liberal utilization of laparotomy and early intervention in suspected cases will decrease mortality rates. Keywords: Abdominal aortic aneurysms; ischemic colitis; ruptured aneurysm; surgery.

Cite this article as: Aday U., Gundes E., Cetin D. A., Ciyiltepe H., Senger A. S., Gulmez S., Akbulut M., Polat E. Ischemic colitis following infrarenal abdominal aortic aneurysm treatment: Results from a tertiary medical center. North Clin Istanb 2018;5(3):221–226.

schemic colitis (IC) is a complication with a very high mortality rate that may develop following the repair of abdominal aortic aneurysms (AAA) by open and endovascular (EVAR) methods [1, 2]. The rates of resection performed because of IC in ruptured AAA surgery

can go as high as 14%. Currently, endovascular aortic repair (EVAR) is commonly used as a minimally invasive method for aneurysm treatment. The IC rates following EVAR have considerably decreased [3, 4]. Severe IC results in full-thickness necrosis perforation of the bowel

Received: June 05, 2017 Accepted: October 30, 2017 Online: May 25, 2018 Correspondence: Dr. Ulas ADAY. Kartal Kosuyolu Yuksek Ihtisas Egitim ve Arastirma Hastanesi, Gastroenteroloji Cerrahi Klinigi, Istanbul, Turkey Phone: +90 216 500 50 01 e-mail: ulasaday@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

222

wall, and its rapid clinical progress gives way to multiple organ failure and mortality [5]. Resection and frequent stoma formation by early identification are crucial in the management of this picture with a high mortality rate [6]. Studies have identified many risk factors for IC. It has been observed that conditions such as old age, female sex, renal failure, ruptured aneurysm, emergency surgery, inotropic support, massive blood loss, prolonged surgery, duration of aortic clamping, open surgery, diabetes mellitus (DM), coronary artery disease (CAD), hypertension, chronic obstructive pulmonary disease (COPD), smoking, shaggy aorta, and occluded inferior mesenteric artery (IMA) increased the risk of IC and mortality [1– 3, 6–9]. Most of the studies have presented more than one risk factor. The presence of more than one comorbid condition, previous history of major abdominal vascular surgery, time between the diagnosis and teratment of IC, and additional surgical load like laparotomy and resection in such patients render very high mortality rates [1, 9]. IC frequently manifests with segmental and left colon involvement. It has been reported that the rate of IC was as high as 42% as seen in colonoscopic controls following emergency procedures because of ruptured AAA. Cases with ruptured AAA frequently receive emergency surgical procedures; it has also been stated that IC and mortality rates were higher and thus had negative effects on prognosis [1, 3, 6, 10, 11]. A majority of these cases were IC cases limited to the mucosa and muscular layer (Grade I–II), and the rate of severe IC (Grade III) has been reported to be between 8.9% and 14% [5, 10, 11]. Cessation of food intake, intravenous fluid replacement, measures taken against thromboemboli, antibiotherapy, and achievement of sufficient cardiac output in Grade I– II IC are curative in most of the cases. Patients are closely followed up for severe IC development. It is also suggested that the gangrenous segment is resected as soon as possible by laparotomy in severe IC cases [1, 5, 11]. Treatment options for emergency and elective AAA have been frequently utilized at our hospital. A significant portion of these has recently been EVAR. The aim of this study was to investigate the effect of a ruptured abdominal aortic aneurysm on IC development, morbidity, and mortality. MATERIALS AND METHODS Patients Between January 2012 and December 2016, patients who underwent resection for IC at our clinic were retro-

North Clin Istanb

spectively reviewed. The study included patients with infrarenal AAA surgery, those who underwent a resection because of IC, and those whose data were obtained. IC cases following suprarenal and thoracic aortic aneurysm surgery were excluded from the study. Furthermore, IC patients who underwent resections because of mesenteric ischemia, cardiac surgery, inflammatory bowel disease, abdominal surgery, volvulus and adhesions were excluded from the study. The consent of the Board of Ethics at Kartal Kosuyolu Higher Specialty Training and Research Hospital was also obtained. Data collection Data on the patients were collected through the investigation of the hospital’s electronic archive system and patients’ files. Basic data such as patients’ age, sex, and body mass index (BMI) were recorded in addition to their comorbid conditions like hypertension, DM, smoking, CAD, peripheral vascular disease (PVD), COPD, and ASA (American Society of Anesthesiologists) scores. Data on the ruptured condition of an aneurysm, emergency or elective form of aneurysm surgery, and treatment method for an aneurysm (EVAR-open) were obtained from the surgical and epicrisis reports of the cardiovascular surgery (CVS) clinic. Data like inotropic support, amount of blood loss, and duration of surgery (min) during the surgical procedure for the treatment of aneurysm were obtained through the investigation of surgical notes and anesthesia follow-up forms. After aneurysm treatment, the first 24-h unfractionated heparin infusion was provided to patients without active bleeding. Aspirin and low-molecular-weight heparin were then administered during hospitalization and discharged with aspirin. Thromboembolism prophylaxis was performed similarly for IC. Laboratory values before and 24 h after aneurysm surgery were recorded. Complications other than IC and related to AAA surgery [renal failure, hemorrhage, superior mesenteric artery occlusion, sepsis, lower extremity vascular obstruction, adult respiratory distress syndrome (ARDS), multiorgan failure syndrome (MOFS), pneumonia, wound site infection, spinal cord ischemia, cerebrovascular event] were recorded as well. The number of full blood and erythrocyte suspension administered to the patients during hospitalization was established through the comparison of data from the blood bank and the blood product confirmation form for the patient. Symptoms were seen prior to the gastrointestinal system (GIS) surgery, duration of

Aday et al., Ischemic colitis following infrarenal abdominal aortic aneurysm treatment: Results from a tertiary medical center

the surgical procedures performed because of IC, and the aneurysm surgery were recorded (in days). The duration of hospitalization was set as the time from AAA surgery to discharge while mortality was set as mortality during hospitalization. The patients were compared and divided into 2 groups: those with a ruptured aneurysm and those without the aneurysm. Statistical analyses The Statistical Package for the Social Sciences (Chicago, IL, USA) software was utilized for biostatistical analyses. The data of the patients covered by the study were given in minimum and maximum values as well as in percentages, where necessary. Categorical groups were compared by the chi-squared test. Binary group comparisons of numeric data were performed by the Mann–Whitney U-test. Statistical significance was set at the p<0.05 level. RESULTS A total of 275 infrarenal AAA cases were treated by the cardiovascular surgery clinic between January 2012 and December 2016. Fifty-seven (20.7%) of these patients were treated by open surgery, while 218 (79.2%) were treated by the EVAR method. Fourteen patients (5%) developed IC requiring resection. Four (1.8%) patients with EVAR and 10 (17.5%) patients with open surgery were operated because of IC. The median age of the patients was 62.5 (40–85) years, and all were males. The most frequent comorbid conditions included hypertension (12/14), CAD (10/14), DM (5/14), and PVD (4/14). The ASA score of the patients was mostly III and IV. The results of the intergroup comparison demonstrated that all the patients with PVD were in the group with no ruptures (p=0.04). There was no statistically significant difference between the groups with regards to age, other comorbid conditions, smoking, and ASA scores (Table 1). Due to the ruptured aneurysm, 6 (42.86%) patients were all treated under emergency conditions and 2 were treated by EVAR and 4 by an open surgical procedure. All 8 patients (57.14%) without a ruptured aneurysm were scheduled operated. While the aneurysms of 2 of these patients were repaired by EVAR, 6 were repaired by open surgery. No statistically significant difference was found between the ruptured AAA group and the nonrupture group with regards to intraoperative blood loss, duration of operation, intraoperative inotropic support,

223

Table 1. The demographic data of the patients Variable

Without rupture (n=8, 100%)

With rupture (n=6, 100%)

Median age, 60 (48-85) 65 (40-82) years (min-max) Sex M 8 (%) 6 (%) F 0 (%) 0 (%) Comorbidities HTN 6 (75%) 6 (100%) CAD 6 (75%) 4 (66.7%) DM 3 (37.5%) 2 (33.3%) CHF 1 (12.5%) 2 (33.3%) PVD 4 (50%) 0 AF 1 (12.5%) 0 COPD 1 (12.5%) 1 (16.7%) Cigarette smoking 4 (50%) 2 (33.2%) 23.8 (18.5-30.4) 27.2 (22.4-30.8) BMI (m2/kg) ASA score 1 0 0 2 2 (25%) 0 3 4 (50%) 2 (33.3%) 4 2 (25%) 4 (66.7%)

0.998

0.186 0.733 0.872 0.347 0.04* 0.369 0.825 0.533 0.194 0.211

AF, atrial fibrillation; ASA, American Society of Anesthesiologists; BMI, body massindex (m2/kg); CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; F, female; HTN, hypertension; M, male; PVD, peripheral vasculer disease;*, p<0.05.

and the number of blood transfusions. The ruptured cases, however, were all taken into emergency surgery (Table 2). Table 3 presents the comparison of laboratory parameters of both groups before the aneurysm surgery and 24 h after surgery. The preoperative WBC value was 8.3×109/L (6.2–10.8) in the non-rupture group, while it was 11.4×109/L (8.4–15.9) in the rupture group and the difference between the 2 groups was statistically significant (p=0.01). The measured lactate value was 2.6 mmol/L (1.1–10.7) in the ruptured AAA group, while it was 1.1 mmol/L (0.8–5.4) in the non-rupture group and the difference between the 2 was statistically significant as well (p=0.038) (Table 3). Among the symptoms seen prior to GIS surgery, the most common ones were abdominal pain and distension. The median value of the time between aneurysm surgery and GIS surgery was 5 (1–150) days in the rupture group, while it was 6 (3–90) days in the non-rupture group and the results were similar in both groups. One patient from both groups was operated on late due to

224

North Clin Istanb

stenosis. Five (62.5%) patients in the non-rupture group received the Hartmann procedure, 2 (25%) patients underwent right colectomy with partial small bowel resection, and 1 patient underwent total colectomy. Five (83.3%) patients in the rupture group received the Hart-

Table 2. Data related to aneurysm surgery Variable

Without Rupture (n=8, 100%)

With Rupture (n=6, 100%)

EVAR** 2 (25%) 2 (33.3%) Open surgery 6 (75%) 4 (66.7%) Emergency 0 6 (100%) Elective 8 (100%) 0 Intraoperative 1050 (340-2500) 1250 (350-3200) blood loss (ml) Inotrop support 1 (12.5%) 2 (33.3%) Surgery time 340 (120-560) 270 (140-600) (minute) Transfusion 3 (0-61) 12 (6-32) (unit)

0.733 0.733 0.001* 0.001* 0.897 0.347 0.438 0.196

**, EVAR, endo vasculer aneurysm repair; *, p<0.05.

mann procedure, while one patient had right colectomy alongside with segmental small bowel resection. Two patients had segmental small bowel resection by relaparatomy. The intergroup comparison did not reveal any statistically significant difference among GIS symptoms, the time period until surgery, the involved colon segment, and the surgical procedures performed (Table 4). All the patients contracted complications, except IC, following aneurysm surgery. Renal failure was seen in 10 patients, while sepsis in 7, MOFS in 4, bleeding in the early postoperative period in 3, wound site infection and evisceration in 3, pneumonia in 3, spinal cord ischemia in 2, and SVO in 2 patients was observed. Table 5 summarizes the data on all complications. Both groups had similar durations of intensive care and hospitalization. Five patients in each group had mortality. The mortality rate in ruptured AAA group was 83.3%, while it was 62.5% in the non-ruptured AAA group. In spite of the fact that the mortality rate was high in the ruptured group, it was not statistically significant (p=0.393).

Table 4. Symptoms, surgical procedures and results of ischemic colitis

Table 3. Laboratory data before and 24 hours after aneurysm surgery in groups Variable

Without Rupture With Rupture (n=8) (n=6)

Preoperative 8.3 (6.2-10.8) WBC (×109/L) Htc (%) 38 (26-45) 229 (21-354) Platalet (×109/L) Lactate (mmol/L) 1.1 (0.8-5.4) Urea (mg/dL) 42 (22-55) Creatinine (mg/dL) 1.1 (0.6–1.4) CRP (mg/dl) 2 (0,2-19) Postoperative (After 24 hours) 14.8 (11.2-17.7) WBC (×109/L) Htc (%) 31 (24-36) 118 (70-138) Platalete (×109/L) Lactate (mmol/L) 2.8 (1.2-7.9) Urea (mg/dL) 52 (35-88) Creatinine (mg/dL) 1.5 (1-2.3) CRP (mg/dL) 14 (4-26)

11.4 (8.4-15.9) 41 (26-48) 220 (139-233) 2.6 (1.1-10.7) 54 (25-67) 1.4 (0.9-1.8) 1 (0.3-5)

12.6 (5.2-20.1) 31 (18-42) 140 (76-251) 2.9 (1.8-24) 177 (41-145) 1.6 (1.1-3.4) 10 (1-24)

0.01* 0.651 0.606 0.038 0.053 0.169 0.699

0.560 0.99 0.064 0.841 0.358 0.998 0.467

CRP: C-reactive protein (normal range: 0-0.34 mg/dL).Htc: Hematocrite (normal range: 33-54%), WBC: Peripheral white blood cell count: *, p<0.05.

Variable Abdominal pain Distension Rectal bleeding Intestinal contents coming from the incision Time between aneurysm surgery and gastrointestinal surgery (day) Surgical procedure Hartman procedure Right colectomy+ small bowel resection Total colectomy Stoma Days in ICU (day) Length of stay in hospital (day) Mortalite ICU, Intensive care unit.

Without rupture With rupture (n=8, 100 %) (n=6, 100%)

6 (75%) 4 (50%) 1 (12.5%) 1 (12.5%)

2 (33.3%) 4 (66.7%) 0 1 (16.7%)

0.119 0.533 0.369 0.825

6 (3-90)

5 (1-150)

0.399

5 (62.5%) 2 (25%)

5 (83.3%) 1 (16.7%)

0.393 0.707

1 (12.5%) 7 (87.5%) 13 (1-37) 15 (5-49)

0 6 (100%) 16 (2-39) 17 (2-39)

0.369 0.369 0.605 0.983

5 (62.5%)

5 (83.3%)

0.393

Aday et al., Ischemic colitis following infrarenal abdominal aortic aneurysm treatment: Results from a tertiary medical center

DISCUSSION The full-thickness colon necrosis with AAA perforation, which has high rates of morbidity and mortality, still proves to be a significant complication. Ruptured AAA and emergency surgical procedures increase the risk of IC [6, 12]. IC still continues to be an important cause of deaths in aortic aneurysm surgery based on its low incidence rate, challenging diagnosis, and destructive results. It has to be identified early giving way to the resection of the gangrenous segment with maximal borders before MOFS develops [1, 13]. The incidence of IC has decreased considerably as the utilization of EVAR as a treatment modality has increased. IC is seen between 0.5% and 4% after EVAR [11, 14]. In our study, 14 patients (5%) developed IC requiring resection. Four (1.8%) patients with EVAR and 10 (17.5%) patients with open surgery were operated because of IC. Open surgery is frequently performed on patients with ruptured AAA who are generally hemodynamically unstable under emergency conditions, which in turn increases the incidence of IC. In a study by Champagne et al [10], the authors reported that 14% of 88 patients, who had an emergency open surgery because of ruptured AAA, had Grade III IC. Becquemin et al. [2] also stated that 12.5% of the patients in their ruptured AAA group had IC, while 2% of the patients in the non-rupture group had IC. The formation of colonic ischemia has been explained by many factors. The closure of the IMA, microembolization, embolization of the hypogastric artery, placement of cross-clamp into the aorta, intraoperative traumatization of the colon, compressive effect because of retroperitoneal hematoma, prolonged hypotension, and ischemia-reperfusion damage are listed among its causes [1, 2, 8, 11, 13, 15]. Many risk factors in the formation of IC have also been reported in various studies. In their study with a large population, Moghadamyeghaneh et al. [3] ascertained that preoperative rupture of an aneurysm, the need for blood transfusion, aneurysmâ&#x20AC;&#x2122;s going above the renal level, renal failure, diabetes, and female sex were determinant in IC formation. In a current meta-analysis by Lee et al. [6], the authors stated that emergency presentation and open surgery proved to be 2 significant risk factors in IC formation. The same meta-analysis also referred to old age, female sex, hypotension, and the need for massive blood transfusion as risk-increasing factors. Our study was not appropriate to determine risk factors as no comparisons were made with patients who did not undergo surgery because of IC. Ten (71.4%) patients with IC, however, had

225

aneurysm repair by open surgery. Ruptured aneurysm was not ascertained to be a risk factor for IC in this study. Some studies have reported that lactate levels >2.5 mmol/L in IC cases were related to mortality [9, 16]. It was seen in our study that lactate levels and WBC counts measured before aneurysm surgery in the rupture group were significantly higher than those of the non-rupture group (P value=0.038 and 0.01 respectively). This difference, however, was observed on the first postoperative day, and it was seen that it had no effect on the results. A total of 46 complications occurred in 14 patients who underwent surgery for IC. (Table 5). Among the complications observed and proved to be significant included renal failure in 10 patients, sepsis in 7, MOFS in 4, bleeding in the early postoperative period in 3, wound site infection and evisceration in 3, pneumonia in 3, spinal cord ischemia in 2, SVO in 2, and ARDS in 2. Alongside with the fact that IC on its own is an important cause of mortality, these complications are also serious problems contributing to the increase in mortality. It was seen that mortality was higher (83.3% vs. 62.5%) in the ruptured aneurysm group but this difference was not statistically significant (p=0.393). Our study has serious limitations among which it being retrospective, limited

Table 5. Postoperative complications Complications

Acut renal failure Sepsis MOFS Hemorrhage Pneumonia Evisceration Wound infection ARDS SVE Spinal cord ischemia Myocardial infarction SMA occlusion Lower Extremity arterial thrombosis Thoracotomy (hemorrhge) DIC Ventricular fibrillation Decubitus ulcers

10 7 4 3 3 3 3 2 2 2 1 1 1 1 1 1 1

ARDS, Adult respiratuar distress syndrome; DIC, disseminated intravascular coagulation; MOFS, Multiorgan failure syndrome; SMA, Superior mesenteric artery; SVE, Cerebrovascular event.

226

number of cases, absence of data on IC patients not necessitating resection, inability to compare data with the non-IC group, and the absence of long-term follow-up results can be listed. CONCLUSION IC is a complication of AAA surgery with a high mortality rate. Mortality is increased in patients who develop IC in a ruptured abdominal aortic aneurysm. Its incidence with EVAR is quite rare and it still is a frequent problem in open aneurysm surgery. This complication with a high mortality rate following open AAA surgery should be noted by surgeons and we believe that the liberal utilization of laparotomy and early intervention in suspected cases will decrease mortality rates. 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 – U.A., E.B., E.P.; Design – U.A., D.A.C., H.C., A.S.S., S.G.; Supervision – E.P., M.A., E.G., A.S.S.; Materials – U.A., M.A., S.G., D.A.C.; Data collection &/or processing – U.A., E.P., M.A., S.G., H.C., D.A.C.; Analysis and/or interpretation – U.A., E.G.,H.C.; Writing – U.A., E.G., D.A.C.; Critical review – E.P., A.S.S., S.G.

REFERENCES 1. Steele SR. Ischemic colitis complicating major vascular surgery. Surg Clin Am 2007;87:1099–114. 2. Becquemin JP, Majewski M, Fermani N, Marzelle J, Desgrandes P, Allaire E, et al. Colon ischemia following abdominal aortic aneurysm repair in the era of endovascular abdominal aortic repair. J Vasc Surg 2008;47:258–63. 3. Moghadamyeghaneh Z, Sgroi MD, Chen SL, Kabutey NK, Stamos MJ, Fujitani RM. Risk factors and outcomes of postoperative ischemic colitis in contemporary open and endovascular abdominal aortic

North Clin Istanb aneurysm repair. J Vasc Surg 2016;63:866–72. 4. Davidovic LB, Maksic M, Koncar I, Ilic N, Dragas M, Fatic N, et al. Open repair of AAA in a high volume center. World J Surg 2017;41:884–91. 5. Moszkowicz D, Mariani A, Trésallet C, Menegaux F. Ischemic colitis: the ABCs of diagnosis and surgical management. J Visc Surg 2013;150:19–28. 6. Lee MJ, Daniels SL, Drake TM, Adam IJ. Risk factors for ischaemic colitis after surgery for abdominal aortic aneurysm: a systematic review and observational meta-analysis. Int J Colorectal Dis 2016;31:1273– 81. 7. Neary P, Hurson C, Briain DO, Brabazon A, Mehigan D, Keaveny TV, et al. Abdominal aortic aneurysm repair and colonic infarction: a risk factor appraisal. Colorectal Dis 2007;9:166–72. 8. Toya N, Baba T, Kanaoka Y, Ohki T. Embolic complications after endovascular repair of abdominal aortic aneurysms. Surg Today 2014;44:1893–9. 9. Genstorfer J, Schafer J, Kettelhack C, Oertli D, Rosenthal R. Surgery for ischemic colitis: outcome and risk factors for in-hospital mortality. Int J Colorectal Dis 2014;29:493–503. 10. Champagne BJ, Darling RC, Daneshmand M, Kreienberg PB, Lee EC, Mehta M, et al. Outcome of aggressive surveillance colonoscopy in ruptured abdominal aortic aneurysm. J Vasc Surg 2004;39:792–6. 11. Brandt LJ, Feuerstadt P, Longstreth GF, Boley SJ; American College of Gastroenterology. ACG clinical guideline: epidemiology, risk factors, patterns of presentation, diagnosis, and management of colon ischemia (CI). Am J Gastroenterol 2015;110:18–44. 12. Perry RJ, Martin MJ, Sohn VY, Steele SR. Colonic ischemia complicating open vs endovascular abdominal aortic aneurysm repair. J Vasc Surg 2008;48:272–7. 13. Darras S, Paineau J, Patra P, Goueffic Y. Prognostic factors of ischemic colitis after infrarenal aortic surgery. Ann Vasc Surg 2011;25:612–9. 14. Reimerink JJ, Hoornweg LL, Vahl AC, Wisselink W, van den Broek TA, Legemate DA, et al; Amsterdam Acute Aneurysm Trial Collaborators. Endovascular repair versus open repair of ruptured abdominal aortic aneurysms: a multicenter randomized controlled trial. Ann Surg 2013;258:248–56. 15. Miller A, Marotta M, Scordi-Bello I, Tammaro Y, Marin M, Divinp C. Ischemic colitis after endovascular aortoiliac aneurysm repair: a 10-year retrospective study. Arch Surg 2009;144:900–3. 16. Reissfelder C, Sweiti H, Antolovic D, Rahbari NN, Hofer S, Büchler MW, et al. Ischemic colitis: Who will survive? Surgery 2011;149:585– 91.

Orıgınal Article

GYNECOLOGY & OBSTETRICS

North Clin Istanb 2018;5(3):227–231 doi: 10.14744/nci.2017.04900

Predictive factors of methotrexate treatment success in ectopic pregnancy: A single-center tertiary study Cigdem Pulatoglu,1 Ozan Dogan,2 Alper Basbug,3 Aski Ellibes Kaya,3 Ahmet Yildiz,4 Osman Temizkan2 Department of Obstetrics and Gynecology, Bayburt Government Hospital, Bayburt, Turkey

Department of Obstetrics and Gynecology, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul

Department of Obstetrics and Gynecology, Duzce University Hospital, Duzce, Turkey

Department of Gynecology and Obstetrics, Sakarya University Faculty of Medicine, Sakarya, Turkey

ABSTRACT OBJECTIVE: It is controversial whether medical or surgical treatment options have more successful results in ectopic pregnancy treatment. Although high pretreatment serum hCG levels have been known to be the most important predictor, the appropriate treatment modality for a specific range of hCG level remains unclear. Furthermore, the variables that make a patient a bad candidate for single-dose methotrexate treatment is unclear. The aim of this study was to identify predictive factors associated with the success of single-dose methotrexate treatment in women with ectopic pregnancy. METHODS: In this retrospective study, 101 women with tubal ectopic pregnancies who had been treated with single-dose methotrexate were selected. The gestational ages, pretreatment hCG values, ectopic mass size, and fluid presence in the abdomen were compared between the groups. RESULTS: The mean age of the patients was 30.6±5.8 (range, 19–42) years, and the gestational age at first injection was 7.0±2.13 (range, 2.3–13.6) weeks. The overall treatment success rate was 77.2% (n=79). The mean duration of hospital stay was 4.21±1.89 days in the successfully treated group and 6.92±2.13 days in the failure group (p<0.05). The rate of treatment failure in patients with abdominal fluid was 37.8%, and it was 12.7% in the non-fluid group (p=0.03). hCG values on days 1, 4, and 7 were significantly higher in the unsuccessful group (3887–2589 mIU/mL, 2814–1287 mIU/mL, and 1119–285 mIU/mL, respectively; p<0.05). The cutoff hCG value, which determined the failure of methotrexate treatment, was found to be 1362 mIU/mL. CONCLUSION: In present study, patients with hCG value <1362 mIU/mL were found to be good candidates for methotrexate treatment. Although not strictly decisional, this hCG threshold level can be used to decide on the likelihood of methotrexate success or failure. Detection of abdominal fluid on ultrasonography also can be assessed as a bad prognostic factor, but size of ectopic mass does not correlate with methotrexate treatment success. Keywords: Ectopic pregnancy; methotrexate; single-dose treatment.

Cite this article as: Pulatoglu C., Dogan O., Basbug A., Ellibes Kaya A., Yildiz A., Temizkan O. Predictive factors of methotrexate treatment success in ectopic pregnancy: A single-center tertiary study. North Clin Istanb 2018;5(3):227–231.

ctopic pregnancy occurs when the developing blastocyst gets implanted at a site other than the endometrium of the uterine cavity. The most common extrauterine location is the fallopian tube, which accounts for 98% of all ectopic gestations [1]. Ectopic pregnancy is a potentially life-threat-

ening condition and accounts for 4%–6% of all maternal death [2]. Although surgical approaches are the mainstay of treatment, advances in early diagnosis facilitated the introduction of medical treatment with methotrexate (MTX) for unruptured ectopic pregnancy [3].

Received: October 03, 2017 Accepted: October 11, 2017 Online: May 23, 2018 Correspondence: Dr. Ozan DOGAN. Sisli Hamidiye Etfal Egitim ve Arastirma Hastanesi, Kadin Hastalikları ve Dogum Klinigi, Istanbul, Turkey. Phone: +90 505 506 07 20 e-mail: ozandogan02@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

228

MTX is an antimetabolite chemotherapeutic agent that binds to the enzyme dihydrofolate reductase, which is involved in the synthesis of purine nucleotides. This interferes with deoxyribonucleic acid synthesis and disrupts cell multiplication. Its effectiveness on trophoblastic tissue has been well established and is derived from experience gained in using MTX in the treatment of hydatiform moles and choriocarcinomas. MTX is used in the treatment of ectopic pregnancy as single or multiple intramuscular injections [4–6]. The 2 most commonly used protocols for MTX administration are single-dose and multiple-dose regimens (4 MTX doses that alternate with oral leucovorin). A meta-analysis reported that using a single-dose regimen is associated with a higher failure rate than using the multidose regimen (12% vs. 7%) [7]. Previous studies have also reported similar effectiveness between single-dose and multi-dose treatments [8]. Moreover, single-dose regimen is found to be less expensive, requires less intensive monitoring, and does not require folinic acid rescue [7]. Although high pretreatment serum human chorionic gonadotropin β subunit (hCG-β) levels have been known to be the most important predictor associated with medical treatment failure, which treatment modality is appropriate for a specific range of pretreatment serum hCG level remains unclear [9]. The aim of this study was to identify predictive factors associated with the success of response to treatment with single-dose MTX regimen in women with tubal ectopic pregnancy. MATERIALS AND METHODS We conducted a retrospective study of 101 consecutive women with tubal ectopic pregnancies who had been treated with single-dose MTX from November 2015 to July 2016 at Sisli Hamidiye Etfal Training and Research Hospital in Istanbul, Turkey. The study was approved by the local ethics committee, and the study protocol adhered to the tenets of the Declaration of Helsinki. Patients who were >18 years old, hemodynamically stable with unruptured tubal ectopic pregnancy, did not have hepatic, hematologic, or renal disease, and treated with intramuscular MTX were included. Patients who were <18 years old, hemodynamically unstable, had other localizations of ectopic pregnancy (abdominal, ovarian, cervical, cesarean scar), had unknown treatment results, or underwent surgery directly before medical treatment were excluded. Patients who had ectopic focus with positive fetal cardiac activity direct underwent surgery and

North Clin Istanb

were not included in the study. Demographic data such as age, parity, gestation week by last menstrual period, previous infertility treatment, previous history of ectopic pregnancy, use of intrauterine contraceptive device, and clinical presentation such as abdominal pain, vaginal bleeding, and amenorrhea were documented from patients’ medical files. Initial free hCG-β levels of all patients who had been treated with a single 50 mg/m2 (body surface area) dose of intramuscular MTX according to the tubal ectopic pregnancy treatment protocol [10, 11] were recorded. The size of ectopic mass, presence of ectopic cardiac activity, and presence of abdominal fluid around the liver and between the loops of intestine that have been detected by both abdominal and vaginal ultrasonographic examination were documented. Following MTX administration, serum hCG levels on days 4 and 7 were recorded. If the decrease in hCG level between days 4 and 7 after MTX administration was >15%, it was accepted as successful medical treatment. hCG levels were monitored weekly until it was undetectable. If hCG level between days 4 and 7 failed to fall >15% of the previous serum hCG level, treatment with single-dose MTX was considered unsuccessful and a second dose was administered. No complications or side effects were observed among patients treated with MTX. When the patient exhibited signs or symptoms of ruptured ectopic pregnancy, had persistence of ectopic cardiac activity, or showed insufficient fall or rise of serum hCG levels, medical treatment was considered unsuccessful and surgery was indicated. The statistical analyses were obtained using Statistical Package for the Social Sciences software, version 17.0. Results were considered as statistically significant when the P-value was <0.05. RESULTS A total of 101 patients who received MTX treatment for ectopic pregnancy in the 9-month period were included in the study. The mean age of the patients was 30.6±5.8 years. The mean gestational age at first MTX injection was 7.0±2.13 weeks. Of the 101 patients, 34 were multiparous, 26 were primiparous, and 41 were nulliparous. Six of the nulliparous patients were found to be primer infertile. The symptoms of patients at the time of admission to hospital were metrorrhagia for 46 (45.5%) patients and pain for 29 (28.7%) patients. Twenty-six (25.7%) patients presented to the hospital just for abnormal hCG levels although they were asymptomatic. Ectopic focus was observed in 75% of patients. Overall,

Pulatoglu et al., Predictive factors of methotrexate treatment success in ectopic pregnancy: A single-center tertiary study

229

Table 1. Characteristics of patients and ectopic pregnancy Characteristics Age (years) Gravidity Parity D1 hCG level (mIU/mL) D4 hCG level (mIU/mL) D7 hCG level (mIU/mL) Size of ectopic focus (mm) Gestational ages (weeks) Duration of hospital stay (days) Presence of fluid in the abdomen (%)

Failure of MTX treatment; n=22

Successful MTX treatment; n=79

30.68 2.65 0.97 3887 2814 1119 28.45 7.02 6.92 37.8

30.45 2.32 0.86 2589 1287 285 24.70 6.91 4.21 12.7

0.41 0.387 0.61 0.017 0.002 0.001 0.521 0.47 <0.05 0.03

Significant scores with p<0.05 are bolded; D0: the day of first MTX injection.

nificantly higher in the unsuccessful group (3887–2589 mIU/mL, 2814–1287 mIU/mL, and 1119–285 mIU/ mL) (p<0.05) (Table 1). The cutoff hCG value, which determined the failure of MTX treatment with 71.8% sensitivity and 68.2% specificity in the ROC curve analysis, was found to be 1362 mIU/mL. In patients with hCG levels >1362 mIU/mL, the failure rate was 23.9%, while at lower values, the failure rate was 17.9%, which was not significant (Fig. 1). ROC Curve

1.0

0.8

Sensitivity

28% of the patients had an ectopic focal size >3.5 cm in diameter, and 37% had fluid in their abdomen. The mean pretreatment hCG level for all patients was 2874 (±2277) mIU/mL. The MTX doses used ranged from 50 to 100 mg, with a mean of 71.37±18.40 mg. Overall, 14% of the patients needed a second MTX dose. Second doses were administered after a mean of 7.8 (±6.9) days, when needed. Overall, 28.4% of patients who had received a second MTX dose required surgical treatment. A total of 22 patients underwent surgical treatment after an average of 4.8±3.1 (range, 2–9) days due to findings of ectopic pregnancy rupture or unresponsiveness to medical treatment. The overall success rate of medical treatment with MTX was 77.2% (n=79). In patients in whom medical treatment failed, the hCG level at first day of injection was 3887±3300 mIU/mL, whereas in the successfully treated group, this value was found to be 2589±1784 mIU/mL. The hCG levels were significantly different between the 2 groups (p<0.017). The mean duration of hospital stay was 4.21±1.89 days in the successfully treated group and 6.92±2.13 days in the group with unsuccessful medical treatment (p<0.05). In both groups, there was no statistically significant difference in terms of the mean age of patients (30.4 and 30.68 years), the gestational age at time of diagnosis, size of ectopic focus, number of pregnancies, infertility, abortion, and ectopic pregnancy history (p>0.05). There was significant difference between the 2 groups in terms of fluid presence in the abdomen, as detected by ultrasonography with abdominal probe. The rate of failure of medical treatment in patients with fluid in the ultrasonography was 37.8% and 12.7% in the non-fluid group (p=0.03). hCG values on days 1, 4, and 7 were sig-

0.6

0.4

0.2

0.0 0.0

0.2

0.4 0.6 1 - Specificity

0.8

1.0

Figure 1. ROC curve for the prognostic value of baseline hCG level (IU/L). Test Result Variables: hCG at the day of first injection: 0.397.

230

DISCUSSION Medical treatment of ectopic pregnancy with MTX has become the treatment of choice for hemodynamically stable patients [12]. In our study, the success rate of MTX treatment was found to be 78% in 101 patients. There are many studies in the literature evaluating the success rates of medical treatment of ectopic pregnancy; it ranges between 75% and 95% [13–15]. Rabischong et al. [14], reported a success rate of 75.4% in a series of 419 patients. In our study, the mean age of patients was 30.6±5.8 years, and there was no correlation between MTX treatment success and maternal age. The mean age of patients in a study conducted by Mirbolouk et al. [16] was 29.34±5.57 years, and it was similar in both medical treatment success and failure groups. Another study revealed that increased maternal age reduces MTX treatment success [17]. We found no difference in both groups in terms of gestational age (7.0±2.13). In the study designed by Mirbolouk et al. [16], the mean gestational age of patients at the time of diagnosis was 6.99 weeks in the successful group and 7.05 weeks in the treatment failure group. In the same study, it has been shown that there was no difference between groups in terms of gravidity and ectopic pregnancy history, similar to those in the present study. However, unlike our study, they found that the number of abortions was significantly higher in the unsuccessful group (0.41 and 0.22; p=0.03). The hCG levels on days 1, 4, and 7 in the present study were significantly higher in the treatment failure group (3887–2589 mIU/mL, 2814–1287 mIU/mL, and 1119–285 mIU/mL, respectively; p=0.002). Similarly, hCG levels on days 1, 4, and 7 were significantly higher in the treatment failure group in Mirbolouk’s study (2541– 1167 mIU/mL, 2807–1132 mIU/mL, and 2723–931 mIU/mL, respectively, p=0.000). There are other studies showing that hCG levels on days 1, 4, and 7 are higher in the MTX treatment failure group [16, 18]. One of the known factors associated with MTX treatment success is the pretreatment hCG levels, but thresholds reported in the literature vary from 1000 IU/l to as much as 5000 IU/l. We found that the cutoff hCG value to predict MTX treatment failure was 1362 mIU/ mL with 68.8% sensitivity and 71.8% specificity. In patients with hCG level >1362 mIU/mL, the failure rate was 23.9%, whereas in patients with lower hCG levels, the failure rate was 17.9%; however, it was not statisti-

North Clin Istanb

cally significant. In a study, the failure rate of MTX treatment was 13% at hCG levels between 5000 and 9999 mIU/mL, 18% at hCG levels between 10000 and 14999 mIU/mL, and 32% at hCG levels >15000 mIU/mL [5]. Our threshold value of was similar to Rabischong et al. [14] retained 1300 IU/L for their 2011 study . The study conducted by Markwitz et al. [19] revealed the cutoff hCG level for determining MTX treatment failure as 1790 mIU/mL with a sensitivity and specificity of 81% and 78%, respectively. In the study by Vaswani et al. [20], the cutoff hCG level was 5921 mIU/mL with a sensitivity of 100% and specificity of 93.3%. In our study, no significant correlation was found between ectopic focus size and treatment success. This result may be due to the fact that the proportion of patients (72%) with ectopic focus <3.5 cm was too large in our study. Gnisci et al. [21] demonstrated that as the size of ectopic mass increased, so did the failure rates, but this association was not statistically significant. In some studies, the use of MTX treatment has been shown to have a higher success rate when the treatment was limited to patients with ectopic focus size <3–4 cm [4]. The ectopic focus size was found to be 28.30 mm in the treatment success group and 30.2 mm in the treatment failure group in Mirbolouk’s study [16]. Peritoneal fluid, detected by ultrasonography, may be the finding of tubal rupture or tubal abortion and used frequently as an exclusion criterion for MTX treatment. As a result of culdocentesis performed in ectopic pregnancies, blood was detected in 70%–83% of the patients and tubal rupture was observed in only 50%–62% of them [17–22]. In our study, the rate of failure of medical treatment in patients with abdominal fluid, as detected by ultrasonography, was found to be 37.8% (12.7%, p<0.03). In a large case series, free fluid in the abdomen was not associated with medical treatment failure [4]. The main limitations of our study are its retrospective nature and small number of patient series. CONCLUSION The patients who will respond well to MTX treatment for ectopic pregnancy can be chosen by the initial serum B-hCG levels. Better results can be expected from patients with hCG levels <1362 mIU/mL. Although not strictly decisional, this hCG threshold level can be used to decide on the likelihood of MTX success or failure. Presence of abdominal fluid on ultrasonography can be assessed as a bad prognostic factor for medical treatment.

Pulatoglu et al., Predictive factors of methotrexate treatment success in ectopic pregnancy: A single-center tertiary study

Size of ectopic mass was not statistically correlated with MTX treatment success. The retrospective nature of the study and small sample size were the limitations of this study. Prospective studies with larger populations are required to support our findings. 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 – C.P.; Design – C.P., O.T.; Supervision – A.B.; Materials – C.P.; Data collection &/or processing – C.P., O.D.; Analysis and/or interpretation – A.E.K., O.T.; Writing – C.P., O.D.; Critical review – A.Y.

REFERENCES 1. Bouyer J, Coste J, Fernandez H, Pouly JL, Job-Spira N. Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases. Hum Reprod 2002;17:3224–30. 2. Centers for Disease Control and Prevention (CDC). Ectopic pregnancy mortality - Florida, 2009-2010. MMWR Morb Mortal Wkly Rep 2012;61:106–9. 3. Oron G, Tulandi T. A pragmatic and evidence-based management of ectopic pregnancy. J Minim Invasive Gynecol 2013;20:446–54. 4. Hoover KW, Tao G, Kent CK. Trends in the diagnosis and treatment of ectopic pregnancy in the United States. Obstet Gynecol 2010;115:495–502. 5. Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril Mar 2007;87:481–4. 6. Thurman AR, Cornelius M, Korte JE, Fylstra DL. An alternative monitoring protocol for single-dose methotrexate therapy in ectopic pregnancy. Am J Obstet Gynecol 2010;202:139.e1–6. 7. Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing “single dose” and “multidose” regimens. Obstet Gynecol 2003;101:778–84. 8. Guvendag Guven ES, Dilbaz S, Dilbaz B, Aykan Yildirim B, Akdag D, Haberal A. Comparison of single and multiple dose methotrexate therapy for unruptured tubal ectopic pregnancy: a prospective randomized study. Acta Obstet Gynecol Scand 2010;89:889–95.

231

9. Helmy S, Bader Y, Pablik E, Tiringer D, Pils S, Laml T, et al. Cut-off value of initial serum β-hCG level predicting a successful MTX therapy in tubal ectopic pregnancy: a retrospective cohort study. Eur J Obstet Gynecol Reprod Biol 2014;179:175–80. 10. Barnhart KT. Clinical practice. Ectopic pregnancy. N Engl J Med 2009;361:379–87. 11. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 94: Medical management of ectopic pregnancy. Obstet Gynecol 2008;111:1479–85. 12. Lipscomb GH, Stovall TG, Ling FW. Nonsurgical treatment of ectopic pregnancy. N Engl J Med 2000;343:1325–9. 13. Lipscomb GH, Givens VM, Meyer NL, Bran D. Comparison of multidose and single-dose methotrexate protocols for the treatment of ectopic pregnancy. Am J Obstet Gynecol 2005;192:1844–8. 14. Rabischong B, Tran X, Sleiman A.A, Larraín D, Jaffeux P, Aublet-Cuvelier B, et al. Predictive factors of failure in management of ectopic pregnancy with single-dose methotrexate: a general population-based analysis from the Auvergne register, France. Fertil Steril 2011;95:401–4. 15. Orozco EM, Sánchez-Durán MA, Bello-Muñoz JC, Sagalá J, Carreras E, Roura LC. ß-hCG and prediction of therapeutic success in ectopic pregnancies treated with methotrexate, results from a prospective observational study. J Matern Fetal Neonatal Med 2015;28:695–9. 16. Mirbolouk F, Yousefnezhad A, Ghanbari A. Predicting factors of medical treatment success with single dose methotrexate in tubal ectopic pregnancy: a retrospective study. Iran J Reprod Med 2015;13:351–4. 17. Panti A, Ikechukwu NE, lukman OO, Yakubu A, Egondu SC, Tanko BA. Ectopic pregnancy at Usmanu Danfodiyo University Teaching Hospital Sokoto: a ten-year review. Annals of Nigerian Medicine 2012;6:87–91. 18. Cohen A, Bibi G, Almog B, Tsafrir Z, Levin I. Second-dose methotrexate in ectopic pregnancies: the role of beta human chorionic gonadotropin. Fertil Steril 2014;102:1646–9. 19. Nowak-Markwitz E, Michalak M, Olejnik M, Spaczynski M. Cutoff value of human chorionic gonadotropin in relation to the number of methotrexate cycles in the successful treatment of ectopic pregnancy. Fertil Steril 2009;92:1203–7. 20. Vaswani PR. Predictors of success of medical management of ectopic pregnancy in a tertiary care hospital in United Arab Emirates. J Clin Diagn Res 2014;8:OC04–8. 21. Gnisci A, Stefani L, Bottin P, Ohannessian A, Gamerre M, Agostini A. Predictive value of hemoperitoneum for outcome of methotrexate treatment in ectopic pregnancy: an observational comparative study. Ultrasound Obstet Gynecol 2014;43:698-701. 22. Cartwright PS, Vaughn B, Tuttle D. Culdocentesis and ectopic pregnancy. J Reprod Med 1984;29:88–91.

Orıgınal Article

PHYSICAL THERAPY & REHABILITATION

North Clin Istanb 2018;5(3):232–237 doi: 10.14744/nci.2017.35119

The relationship between joint hypermobility and subacromial impingement syndrome and adhesive capsulitis of the shoulder Arzu Atici, Ilknur Aktas, Pinar Akpinar, Feyza Unlu Ozkan Department of Physical Medicine and Rehabilitation, Universıty of Health Sciences, Fatih Sultan Mehmet

Training and Research Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: Joint hypermobility (JH) is a clinical condition in which the joints move beyond the expected physiological range of motion. JH can be accompanied by many musculoskeletal complaints. One of the common causes of musculoskeletal pain is shoulder pain. The aim of this study was to investigate the relationship between subacromial impingement syndrome (SAIS), shoulder adhesive capsulitis (AC), and JH in patients with shoulder pain. METHODS: Patients aged between 18 and 70 years who presented at the physical medicine and rehabilitation outpatient clinic and who were diagnosed with SAIS or AC in a clinical and physical examination were included in the study. Patients in the same age group without musculoskeletal system pain were included in a control group. All of the cases were assessed for hypermobility using the Beighton score for generalized joint hypermobility (GJH), and the revised 1998 Brighton criteria for benign joint hypermobility syndrome (BJHS). RESULTS: Of the 124 cases included in the study, 71 (57.3%) were female and 53 (42.7%) were male. There was no case of GJH in the AC group. There were 2 (4.50%) cases in the SAIS group and 3 (7.5%) in the control group. BJHS was found in 4 (10%) cases in the AC group, 6 (13.63%) in the SAIS group, and 2 (5%) cases in the control group. There was no statistically significant difference between groups in terms of JH (p>0.05). The Beighton scores of the AC group were statistically lower those of the control group (p<0.05). CONCLUSION: The results of this study indicated no significant difference between the SAIS group, the AC group, and the control group in terms of GJH and BJHS. The fact that Beighton scores were lower in the AC group than in the control group suggests that the probability of developing AC in those with JH may be lower. Keywords: Adhesive capsulitis of the shoulder; joint hypermobility; subacromial impingement syndrome.

Cite this article as: Atici A., Aktas I., Akpinar P., Unlu Ozkan F. The relationship between joint hypermobility and subacromial impingement syndrome and adhesive capsulitis of the shoulder. North Clin Istanb 2018;5(3):232–237.

oint hypermobility ( JH) is a clinical condition characterized an excess range of motion in a joint beyond the physiological range of motion [1]. When the condition is asymptomatic, it is termed generalized joint hypermobility (GJH); however, when it is associated with symptoms such as arthralgia, soft tissue damage, and joint instability, it is referred to as benign joint hypermobility syndrome

(BJHS) [2]. JH is more common in young people; the incidence decreases with age. The incidence in the general population has been reported to range between 10% and 20% [3]. An increase in the proportion of collagen or collagen subtypes, such as type III/type I has been detected in JH [4, 5]. This abnormal collagen structure causes joint laxity, and fragility of the connective tissue increases. This

Received: July 24, 2017 Accepted: October 17, 2017 Online: April 16, 2018 Correspondence: Dr. Arzu ATICI. Saglik Bilimleri Universitesi Fatih Sultan Mehmet Egitim ve Arastirma Hastanesi, Fiziksel Tip ve Rehabilitasyon Anabilim Dali, Istanbul, Turkey. Phone: +90 216 578 30 00-3745 e-mail: drsusin@mynet.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Atici et al., Joint hypermobility and shoulder

condition predisposes the individual to musculoskeletal pathologies. Shoulder pain is one of the widely seen causes of musculoskeletal system pain, and affects some 7% to 34% of the population [6]. Subacromial impingement syndrome (SAIS) and adhesive capsulitis (AC) of the shoulder are the most common causes of shoulder pain. SAIS occurs as a result of impingement of soft tissues, especially the supraspinatus muscle, the subacromial bursa, and the biceps tendon between the humerus and the coracoacromial arch [7]. SAIS may develop secondary to structural or functional etiologies [8]. In the literature, it has been suggested that JH may contribute to clinical manifestations of SAIS [9]. AC is a disease characterized by shoulder pain and a restricted range of joint motion which affects a reported 2% to 5% of the population [10]. AC may manifest without any etiology, or it may develop secondary to a local problem (shoulder rotator cuff rupture, calcific tendonitis, trauma) or systemic disease (diabetes mellitus, hypo- or hyperthyroidism) [11, 12]. The basic event in its pathogenesis is the development of fibrosis in the joint capsule as a result of an accumulation of fibroblasts and myofibroblasts in type I and type III collagen tissue [13, 14]. As a result, the range of motion of the joint is both actively and passively restricted. Both SAIS and AC cause pain and disability. In this study, the aim was to investigate the association of SAIS and AC, which are etiological agents of joint pain with different pathophysiological mechanisms, with JH. MATERIALS AND METHODS A total of 124 patients aged between 18 and 70 years who presented at the outpatient clinic of physical medicine and rehabilitation with complaints of shoulder pain and who were diagnosed with SAIS or AC based on their medical history and a clinical examination, and agematched healthy control subjects without any musculoskeletal complaints were enrolled in the study. Before the research was initiated, the participants were informed about the study design, and written informed consent was obtained. The subacromial injection test (SET) was administered to cases with positive Hawkins-Kennedy test, Neer test, and painful arc test results. SET-positive patients were included in the SAIS group. SET was performed using an anterior approach after injecting 5 cc 1% lidocaine solution with a 21-G needle tip inserted just below the acromion and advanced into the subacromial space. The SET test was considered positive if the pa-

233

Table 1. Beighton hypermobility score

Right Left

Dorsiflexion of the fifth metocarpal joint (˃90˚) Passive apposition of the thumb to the flexor aspect of the forearm Passive hyperextension of the elbow (˃10˚) Passive hyperextension of the knee(˃10˚) Palms of the hands resting flat on the floor with the patient standing erect with fully extended knees Total

1 1

1 1 1

1 1

tient’s pain was relieved and active and/or passive range of motion of the affected shoulder improved 80% [15, 16]. For the diagnosis of AC, the diagnostic criteria defined by Bulgen et al. [17] were used: shoulder pain persisting for at least 1 month, nighttime pain or the inability to lie on the affected side, restriction of active and passive range of motion of the shoulder joint in all directions, and at least 50% restriction of external rotation in the affected shoulder compared with the normal contralateral shoulder [17, 18]. Patients with a history of inflammatory disease, malignancy, shoulder trauma within the previous 6 months, shoulder surgery, or a plain radiogram that revealed the presence of osteoarthritis or calcification of the shoulder joint were not included in the study. Demographic data of all of the study participants were recorded. The duration of the shoulder pain and characteristics of the shoulder pain (activity pain, nighttime pain) of the cases diagnosed as AC and SAIS were noted. The Beighton hypermobility scoring system was used to evaluate GJH, and a score of ≥4 points was accepted as indicative of GJH (Table 1). BJHS was evaluated based on the revised 1998 Brighton criteria (Table 2) [19, 20]. The ethics committee of Istanbul Fatih Sultan Mehmet Training and Research Hospital approved of this study. Statistical analyses IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis of the study data. Normal distribution was evaluated using the Shapiro-Wilk test. Descriptive statistics of mean, SD, and frequencies were calculated. A one-way analysis of variance was used for intergroup comparisons of quantitative data with a normal distribution pattern. For intergroup comparisons of parameters with non-normal distribution, the Kruskal-Wallis and Mann-Whitney

234

North Clin Istanb

Table 2. Revised 1998 Brighton criteria Major criteria: Beighton score of 4/9 or greater (either currently or historically) Arthralgia for longer than 3 months in 4 or more joints Minor criteria: Beighton score of 1,2, or 3/9 (0,1,2 ,or 3/9 if aged >50 years) Arthralgia in one to three joints or back pain for more than 3 months, spondylolysis, spondylolysis/spondylolisthesis Dislocation/subluxation in more than one joint or in one joint on more than one occasion Soft tissue rheumatism with >3 lesions (e.g., bursitis, tenosynovitis, epicondylitis) Marfanoid habitus (tall, slim, span/height ratio >1.03, upper/lower segment ratio <0.89, arachnodactyly (positive Steinberg/wrist signs) Cutaneous lesions: striae, hyperextensibility, thin skin Eye signs: Drooping eyelids, myopia, or antimongoloid slant Varicose veins or hernia or uterine/rectal prolapse Required diagnostic criteria: 2 major criteria 1 major and 2 minor criteria 4 minor criteria Presence of BJHS in first degree relatives and 2 minor criteria *diagnosis of joint hypermobility syndrome is ruled out in the presence of collagen tissue diseases, such as Marfan syndrome and Ehler-Danlos syndrome. *Criteria Major 1 and Minor 1 are mutually exclusive, as are Major 2 and Minor 2.

U tests were used. A chi-square test and the Fisher-Freeman-Halton exact test were applied to compare qualitative data. Statistical significance was evaluated at p<0.05. RESULTS A total of 124 (female: n=71, 57.3%; male: n=53, 42.7%) participants were included in the study. The mean age

was 54.69±9.07 years (range: 29–70 years). The cases were divided into AC (n=40), SAIS (n=44), and healthy control (n=40) groups. No statistically significant intergroup difference was found with regard to mean age, gender, or hand dominance (p>0.05). (Table 3) In addition, no statistically significant intergroup difference was detected between the AC and SAIS groups with respect to duration of the

Table 3. Demographic and clinical characteristics of the groups Age (years; mean±SD) Gender Female Male Dominant hand Right Left

AC group

SAIS group

Control group

57.55±7.65

53.57±10.54

53.08±8.14

0.051

18 (45%) 22 (55%)

27 (61.36%) 17 (38.63%)

26 (65%) 14 (35%)

0.154

38 (95%) 2 (5%)

43 (97.72%) 1 (2.27%)

37 (92.5%) 3 (7.5%)

0.519

AC: Adhesive capsulitis; SAIS: Subacromial impingement syndrome

Atici et al., Joint hypermobility and shoulder

235

Table 4. Characteristics of pain encountered in the AC and SAIS groups Region, n (%) Right shoulder Left shoulder Both shoulders Duration of pain (months; mean±SD) Shoulder pain, n (%) Nighttime pain Activity pain Both nighttime and activity pain

AC group

SAIS group

20 (50%) 19 (47.50%) 1 (2.50%) 7.58±8.5 (5.5)

22 (50%) 19 (43.18%) 3 (6.81%) 14.73±27.03(4)

5 (12.50%) 3 (7.50%) 32 (80%)

9 (20.45%) 3 (6.81%) 32 (72.72%)

0.635 0.715 0.620

AC: Adhesive capsulitis; SAIS: Subacromial impingement syndrome

Table 5. Comparison of Beighton score, GJH, and BJHS between groups

AC group

SAIS group

Control group

Beighton score (mean±SD) GJH n (%) Present Absent BJHS n (%) Present Absent

0.28±0.64

0.68±1.18

0.93±1.27 (0)

0.045*

0 (0%) 40 (100%)

2 (4.5%) 42 (95.5%)

3 (7.5%) 37 (92.5%)

0.279

4 (10%) 36 (90%)

6 (13.6%) 38 (86.4%)

2 (5%) 38 (95%)

0.482

*p<0.05 AC: Adhesive capsulitis; BJHS: Benign joint hypermobility syndrome; GJH: Generalized joint hypermobility; SAIS: Subacromial impingement syndrome

shoulder pain, or the occurrence of nighttime and activity pain (p>0.05) (Table 4 ). In the entire study group, 5 (4.03%) cases of GJH were observed and 12 (9.68%) cases of BJHS. GJH was seen in 2 (4.50%) SAIS patients and in 3 (7.5%) controls; no cases of GJH were detected in the AC group. BHJS was present in 4 (10%) patients in the AC group, 6 (13.63%) of the SAIS group, and 2 (5%) of the controls. No statistically significant intergroup difference was found between the GJH and BJHS groups (p>0.05). However, the Beighton hypermobility scores of the AC patients were statistically significantly lower than those of the control group (p<0.05) (Table 5). DISCUSSION We investigated the association between SAIS and AC, the most frequently encountered shoulder diseases in our

clinical practice, and JH. No relationship with JH was observed in the 2 patient groups or the control group; however, the Beighton hypermobility score was significantly lower in the AC group compared with the control group. As an asymptomatic condition, GJH may confer advantages in activities as dance and gymnastics [21]. When it becomes symptomatic, it is called BJHS and may include musculoskeletal problems. Aktas et al. [22] detected a positive correlation between carpal tunnel syndrome and BJHS. In another study, BJHS was described as a potential risk factor for lumbar disc herniation [23]. Higher rates of JH have been reported in fibromyalgia patients relative to a control group [24, 25]. Gürer et al. [26] asserted that GJH may increase the risk of knee osteoarthritis. Joint injuries related to hypermobility are often seen. In a study performed with professional football players, the incidence of injuries to the lower extremities,

236

and particularly femur and ankle traumas, was greater in individuals with GJH [27]. GJH increases the risk of musculoskeletal system injuries and adversely affects the recovery period and the quality of healing due to the impaired collagen structure [20]. The shoulder is one of the joints most often affected by hypermobility. In a study conducted by Tobias et al. [28], the authors reported that in cases of GJH in adolescents, it was most frequently accompanied by shoulder, knee, or ankle pain. In another study, it was reported that the incidence of generalized body pain was higher in a group of patients diagnosed with BJHS and Hypermobile Type Ehler-Danlos Syndrome when compared with a healthy control group. The patients also frequently experienced neck pain, followed by shoulder pain. The Western Ontario Instability Index (WOSI) scores used to evaluate shoulder function in these patients were lower than those recorded in the control group [29]. The risk of joint instability increases in cases with JH. Although subluxations are not a specific characteristic of BJHS, recurrent subluxations indicate the severity of laxity and local muscular weakness [21]. Cameron et al. [30] detected a correlation between GJH and glenohumeral joint instability independent of gender or race and suggested the use of GJH scoring as a risk factor for joint instability. Similarly to our study, Terzi et al. [31] investigated the impact of GJH on the etiopathogenesis of AC, and compared cases with AC and SAIS with respect to JH. They detected lower rates of GJH and BJHS in the AC group, and suggested that GJH might be a protective factor against the development of AC in cases with joint pain. In our study we did not find any statistically significant difference between cases with SAIS and AC in terms of GJH. The Beighton hypermobility scores in the SAIS group were not significantly different from those of the control group, but were lower in the AC group. This finding suggests a potentially lower risk of developing AC in cases with JH. However, this subject requires additional studies performed with a larger number of cases. The incidence of JH decreases with age. Since the median age of our study population was 54 years, we might have observed a smaller percentage of GJH in our study participants. Monitoring young individuals with JH may enable a healthier solution for shoulder complaints in later years. In conclusion, we did not detect any difference in GJH and BJHS between the SAIS and AC groups. The lower Beighton hypermobility scores in the AC group

North Clin Istanb

relative to the control group suggest that there may be a lower risk of AC in cases with JH. 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.A., I.A.; Design – I.A., P.A.; Supervision – A.A., F.U.O.; Materials – A.A., P.A.; Data collection &/or processing – P.A., F.U.O.; Analysis and/or interpretation – A.A., P.A.; Writing – A.A, P.A; Critical review – I.A., F.U.O.

REFERENCES 1. Simmonds JV, Keer RJ. Hypermobility and the hypermobility syndrome. Man Ther 2007;12:298–309. 2. Ross J, Grahame R. Joint hypermobility syndrome. BMJ 2011;342:c7167. 3. Hakim A, Grahame R. Joint hypermobility. Best Pract Res Clin Rheumatol 2003;17:989–1004. 4. Simpson MR. Benign joint hypermobility syndrome: evaluation, diagnosis, and management. J Am Osteopath Assoc 2006;106:531–6. 5. Toprak Celenay S, Ozer Kaya D. Effects of spinal stabilization exercises in women with benign joint hypermobility syndrome: a randomized controlled trial. Rheumatol Int 2017;37:1461–8. 6. Reilingh ML, Kuijpers T, Tanja-Harfterkamp AM, van der Windt DA. Course and prognosis of shoulder symptoms in general practice. Rheumatology (Oxford) 2008;47:724–30. 7. Akgün K, Birtane M, Akarirmak U. Is local subacromial corticosteroid injection beneficial in subacromial impingement syndrome? Clin Rheumatol 2004;23:496–500. 8. Page P. Shoulder muscle imbalance and subacromial impingement syndrome in overhead athletes. Int J Sports Phys Ther 2011;6:51–8. 9. Cowderoy GA, Lisle DA, O’Connell PT. Overuse and impingement syndromes of the shoulder in the athlete. Magn Reson Imaging Clin N Am 2009;17:577–93. 10. Bagheri F, Ebrahimzadeh MH, Moradi A, Bidgoli HF. Factors Associated with Pain, Disability and Quality of Life in Patients Suffering from Frozen Shoulder. Arch Bone Jt Surg 2016;4:243–7. 11. Nagata H, Thomas WJ, Woods DA. The management of secondary frozen shoulder after anterior shoulder dislocation - The results of manipulation under anaesthesia and injection. J Orthop 2015;13:100–5. 12. Tamai K, Akutsu M, Yano Y. Primary frozen shoulder: brief review of pathology and imaging abnormalities. J Orthop Sci 2014;19:1–5. 13. Uppal HS, Evans JP, Smith C. Frozen shoulder: A systematic review of therapeutic options. World J Orthop 2015;6:263–8. 14. Bunker TD, Reilly J, Baird KS, Hamblen DL. Expression of growth factors, cytokines and matrix metalloproteinases in frozen shoulder. J Bone Joint Surg Br 2000;82:768–73. 15. Caliş M, Akgün K, Birtane M, Karacan I, Caliş H, Tüzün F. Diagnostic values of clinical diagnostic tests in subacromial impingement syndrome. Ann Rheum Dis 2000;59:44–7. 16. Cadogan A, McNair PJ, Laslett M, Hing WA. Diagnostic Accuracy of Clinical Examination and Imaging Findings for Identifying Subacromial Pain. PLoS One 2016;11:e0167738. 17. Bulgen DY, Binder AI, Hazleman BL, Dutton J, Roberts S. Frozen shoulder: prospective clinical study with an evaluation of three treatment regimens. Ann Rheum Dis 1984;43:353–60. 18. Robinson PM, Norris J, Roberts CP. Randomized controlled trial of su-

Atici et al., Joint hypermobility and shoulder

pervised physiotherapy versus a home exercise program after hydrodilatation for the management of primary frozen shoulder. J Shoulder Elbow Surg 2017;26:757–65. 19. Grahame R, Bird HA, Child A. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol 2000;27:1777–9. 20. Grahame R. Joint Hypermobility Syndrome Pain. Current Pain and Headache Reports 2009;13:427–33. 21. Baeza-Velasco C, Gély-Nargeot MC, Pailhez G, Vilarrasa AB. Joint hypermobility and sport: a review of advantages and disadvantages. Curr Sports Med Rep 2013;12:291–5. 22. Aktas I, Ofluoglu D, Albay T. The relationship between benign joint hypermobility syndrome and carpal tunnel syndrome. Clin Rheumatol 2008;27:1283–7. 23. Aktaş İ, Ofluoğlu D, Akgün K. Relationship Between Lumbar Disc Herniation and Benign Joint Hypermobility Syndrome. Turk J Phys Med Rehab 2011;57:85–8. 24. Ofluoglu D, Gunduz OH, Kul-Panza E, Guven Z. Hypermobility in women with fibromyalgia syndrome. Clin Rheumatol 2006;25:291–3. 25. Sendur OF, Gurer G, Bozbas GT. The frequency of hypermobility and its relationship with clinical findings of fibromyalgia patients. Clin

237 Rheumatol 2007;26:485–7. 26. Gürer G, Bozbas GT, Tuncer T, Unubol AI, Ucar UG, Memetoglu OI. Frequency of joint hypermobility in Turkish patients with knee osteoarthritis: a cross sectional multicenter study. Int J Rheum Dis 2016 Jul 27 [Epub ahead of print], doi: 10.1111/1756-185X.12883. 27. Konopinski MD, Jones GJ, Johnson MI. The effect of hypermobility on the incidence of injuries in elite-level professional soccer players: a cohort study. Am J Sports Med 2012;40:763–9. 28. Tobias JH, Deere K, Palmer S, Clark EM, Clinch J. Joint hypermobility is a risk factor for musculoskeletal pain during adolescence: findings of a prospective cohort study. Arthritis Rheum 2013;65:1107–15. 29. Johannessen EC, Reiten HS, Løvaas H, Maeland S, Juul-Kristensen B. Shoulder function, pain and health related quality of life in adults with joint hypermobility syndrome/Ehlers-Danlos syndrome-hypermobility type. Disabil Rehabil 2016;38:1382–90. 30. Cameron KL, Duffey ML, DeBerardino TM, Stoneman PD, Jones CJ, Owens BD. Association of generalized joint hypermobility with a history of glenohumeral joint instability. J Athl Train 2010;45:253–8. 31. Terzi Y, Akgün K, Aktaş İ, Palamar D, Can G. The Relationship Between Generalized Joint Hypermobility and Adhesive Capsulitis of the Shoulder. Turk J Rheumatol 2013;28:234–41.

Orıgınal Article

GENETICS & MOLECULAR MEDICINE

North Clin Istanb 2018;5(3):238–245 doi: 10.14744/nci.2017.26680

Ear atresia: Is there a role of apoptosis-regulating miRNAs? Ezgi Aslan,1 Emre Akbas,1 Sena Yilmaz,1 Ahmet Salih Karaoglu,1 Ubeyde Telli,1 Salih Yildirim,1 Hilal Gudek,1 Mahmut Tayyar Kalcioglu,2 Sarenur Yilmaz,3 Ibrahim Akalin3 Istanbul Medeniyet University Faculty of Medicine, Istanbul, Turkey

Department of Otorhinolaryngology, Istanbul Medeniyet University Faculty of Medicine, Istanbul, Turkey

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

ABSTRACT OBJECTIVE: The molecular events underlying ear development involve numerous regulatory molecules; however, the role of microRNAs (miRNAs) has not been explored in patients with ear atresia. Here, we aimed to investigate the expressions of 20–22 nucleotide noncoding RNAs. METHODS: We selected 12 miRNAs that function to control post-transcriptional gene expression in different pathways, including apoptosis, angiogenesis, and chondrogenesis. The altered miRNA expressions were analyzed by real-time PCR from serum samples of 7 patients with ear atresia and 8 controls. RESULTS: We found that the expression of apoptosis-regulating miRNAs was significantly downregulated in patients with ear atresia. TThe expressions of miR126, miR146a, miR222, and miR21 were significantly decreased by 76.2-(p=0.041), 61.8(p=0.000), 30.5-(p=0.009), and 71.21-fold (p=0.042), respectively, compared with controls. CONCLUSION: Abnormal ear development in ear atresia patients, could possibly be due to the reduced expression of apoptosis regulating miRNAs. Changes in the regulation of tumor protein p53 (TP53), p53 upregulated modulator of apoptosis (PUMA), Fas cell surface death receptor (FAS), FAS ligand (FasL), and phosphatase and tensin homolog (PTEN) directly or within the apoptosis-related cascades may play important roles during development, particularly in the external ear. This is the first report to present the possible association between apoptosis-regulating miRNAs and ear atresia/microtia. Keywords: Apoptosis; ear atresia; miRNA; miR21; miR146a; miR126b; miR222.

Cite this article as: Aslan E., Akbas E., Yilmaz S., Karaoglu A.S., Telli U., Yildirim S., Gudek H., Kalcioglu M.T., Yilmaz S., Akalin I. Ear atresia: Is there a role of apoptosis-regulating miRNAs? North Clin Istanb 2018;5(3):238–245.

ar atresia is a spectrum of ear deformities, commonly coexisting with unilateral or bilateral microtia (MIM 600674, MIM 251800). Its prevalence is between 0.8 and 17.4 in 10,000 individuals in different populations [1, 2]. It involves the failure of the development of the external auditory canal (EAC), and its surgical treatment is considered to be one of the most complex and demanding surgeries in otorhinolaryngology. Moreover, this malformation may be associated with other congenital anomalies, including the CHARGE syndrome [3, 4].

Development of the ear is a continuous complex process that begins during early embryonic life within three compartments and is completed till the first decade [5]. Briefly, in the 4th to 5th week of embryogenesis, the ectoderm of the first branchial groove elongates to form the primitive EAC and oppose to the endoderm of the first pharyngeal pouch to form a prototympanic membrane where the mesoderm intervenes between them thereafter. By this time, the epithelial plate produced by the proliferation of the ectodermal cells lining the primitive

Received: August 02, 2017 Accepted: December 11, 2017 Online: September 13, 2018 Correspondence: Dr. Ibrahim AKALIN. Istanbul Medeniyet Universitesi Tip Fakultesi, Tibbi Genetik Anabilim Dali, Istanbul, Turkey. Phone: +90 216 595 40 00 e-mail: ibrahimakalin@yahoo.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Aslan et al., Apoptosis regulating miRNAs in ear atresia

EAC first occludes the primitive EAC in the 8th week of gestation and is eventually split by apposed epithelial cells for subsequent recanalization to secondary EAC by approximately 19th–21st week of gestation. Toward the end of the 28th week, the tissue is progressively absorbed from the tympanic space and branchial groove to open the external canal in essence with the remaining tympanic membrane [6] and closely allied with the development of the middle ear space and ear bones from the branchial apparatus [7, 8]. The remarkable role of programmed cell death, the-socalled apoptosis, in ear development has been deduced by advances in recent technology. It aids in normal development by eradicating unwanted cells during morphogenesis. Neural tube, palate, heart, duodenal mucosa, and limb bud are the clarified examples in which apoptosis occurs [9, 10]. Likewise, Nishizaki et al. [8] (1998) showed that apoptosis is involved in the mouse EAC development. Microribonucleic acids (miRNAs) are highly conserved, small, noncoding RNA molecules, which are approximately 21–24 nucleotides in length, and control post-transcriptional gene expression in a wide variety of cellular processes, including cell proliferation, differentiation, cell fate determination, signal transduction, organ development, angiogenesis, tumorigenesis, and apoptosis [11–13]. Many miRNAs are involved in regulating either intrinsic or extrinsic apoptotic pathways [14]. The normal development of the ear consists of complex succession of events occupying three embryonic germ cell layers. Factors leading to ear atresia by ceasing the contemporaneous aural developmental course are yet

to be clarified. Nishikazi et al. [8] (1998) showed that in mouse, the apposed epithelium of EAC is eliminated by apoptosis. Hence, in this study, we aimed to investigate the expression of miRNAs regulating several pathways, including apoptosis, and for the first time achieved significantly altered expressions of miRNAs in the serum of patients with ear atresia, up to the literature. MATERIALS AND METHODS Patient and control groups and miRNA In our study, we included 7 patients and 8 controls who were age- and sex-matched after obtaining local ethical committee approval (2013–0007) and informed consents. The mean age of the patients was 14.3±7.9 years (minimum, 5 years; maximum, 27 years). Four patients had unilateral ear atresia, while the rest had bilateral ear atresia. The investigated miRNAs regulating different mechanisms are shown in Table 1. Isolation of miRNA-enriched total RNA MiRNAs were isolated from the serum samples of the patients and controls using the miRNeasy Serum/Plasma Kit (Qiagen) according to manufacturer’s instructions. Briefly, 1 ml of QIAzol Lysis Reagent was added to 200 µl of the serum sample by pipetting up and down for efficient lysis of fatty and standard tissues before RNA isolation. The homogenate was incubated at room temperature for 5 minutes. Then, 3.5 µl of miRNeasy Serum/Plasma Spike-In Control (at 1.6 × 108 copies/µl) was added and mixed thoroughly. Next, 200 µl chloroform was added to

Table 1. miRNA regulating different mechanisms in ear atresia

Apoptosis Regulator

Endodermal Developer

Angiogenesis

hsa-mir-143 X hsa-mir-146a X hsa-mir-92a X hsa-mir-181b X hsa-mir-210 X hsa-mir-106b X hsa-mir-183 X hsa-mir-375 X hsa-mir-126 X hsa-mir-222 X hsa-let-7f hsa-mir-21 X

Chondrogenesis

North Clin Istanb

the lysate tube, vortexed for 15 seconds, and incubated at room temperature for 2 minutes. This was followed by the separation of the phases by centrifugation at 12000 × g at 4°C for 15 minutes. Then, 600 µl of the upper aqueous phase was transferred to a new collection tube by avoiding the transfer of any interphase solution. Ethanol (900 µl) was added and mixed thoroughly using a pipette. Next, 700 µl of the sample was added onto an RNeasy MinElute spin column in a 2-ml collection tube and centrifuged at ≥8000 × g for 15 seconds at room temperature. Buffers RWT (700 µl), and RPE (500 µl) and 80% ethanol (500 µl) prepared with RNase-free water were added to the RNeasy MinElute spin column and centrifuged for 15 seconds at ≥8000 × g, followed by additional 2 minutes of centrifugation at full speed for 5 minutes to dry the membrane. The filtrate and collection tube were discarded at each step. Finally, the microRNA-enriched total RNA was eluted by centrifugation for 1 minute at full speed using 14 µl of RNase-free water. Complementary DNA (cDNA) synthesis cDNA was randomly primed using miScript II Reverse Transcription (RT) Kit (Qiagen) using 5 μg of miRNAenriched total RNA. Briefly, RT-PCR was set up with 4 µl of 5 × miScript HiSpec Buffer, 2 µl of 10 × Nucleic Mix, 1 µl of miScript Reverse Transcriptase Mix, 8 µl of RNasefree water, and 5 µl of template RNA in a 20-µl reaction tube. Reverse transcription was carried out at 37°C for 60 minutes and 95°C for 5 minutes. cDNA was then diluted with 200 µl of nuclease free water for further use in realtime polymerase chain reaction (RT-PCR). RT-PCR Mature miRNAs were expressed using Rotor-Gene® Q instrument with software 2.1.0.9 and quantitative RTPCR (RT-qPCR) with QuantiTech SYBR Green PCR Kit (Qiagen). RT-PCR was performed in duplicate after optimization, including minus reverse transcription controls to assess any DNA and nontemplate controls for ensuring the lack of background signal. The RT-PCR reaction was set up with mild modifications of manufacturer’s instructions as follows: 5 µL of 2 × QuantiTect SYBR Green PCR Master Mix , 1 µL of 10 × miScript Universal Primer, 1 µL of 10 × primer assay, and 1 µL of RNase-free water. Thirteen miRNAs covering a variety of miRNA sequence features (Table 1), including Ce miR-39, were selected, and SNORD61, SNORD68, and SNORD95 were used as housekeeping genes. Shortly after the hot start Taq polymerase activation at 95°C

for 10 minutes, reaction was carried out with 40 cycles of 95°C for 15 seconds, 55°C for 30 seconds, and 72°C for 15 seconds, followed by melting reaction ramps from 55°C–95°C at the acquisition of Melt A on Green. For TP53 mRNA expression, forward and reverse primers 5’-CGACAGAGCGAGATTCCATCTCAA-3’ and 5’-GCCCCAATTGCAGGTAAAACAGTC-3’ were used, respectively. Data analysis and statistics The threshold was manually determined as 0.025 in all the reactions, and standards were imported from the previous study as conc =10ˆ (−0.328 × Ct+11.903) with cycle threshold (Ct) values of −3.050 × log(conc)+36.302 and R2 of 0.99974. Ct values of miRNA expressions were exported from the instrument after normalization with dynamic tube using slope correct options of the real-time cycler software. Ct values and calculated concentrations according to the standards were entered into an Excel spreadsheet, and the average Ct value was converted to quantities for SABiosciences analysis. The quality of expended mature miRNAs was checked with melt analyses on Green. Then, the Ct data of miRNAs and TP53 mRNA were analyzed according to fold change [2-ΔΔCT] using online miScript miRNA PCR Array Data Analysis Tool (www.qiagen.com). For TP53 mRNA expression analyses, the Student’s t-test was used. A p-value of 0.05 was considered statistically significant. RESULTS RT-qPCR analysis of serum miRNA To explore the possible effects of microRNAs in the ear atresia, 13 microRNA expression profiles were analyzed in the serum of patients and control group. We found the expression patterns of pro-apoptotic microRNA’s downregulated in the patients. Among them, miR-126, miR146a and miR-222 and miR-21 were significantly 76.2 (p=0.041), 61.8 (p=0.000), 30.5 (p=0.009) and 71, 21 (p=0.042) fold decreased compared to controls, respectively (Table 2 and Fig. 1). TP53 mRNA expression analysis To explore the effects of downregulated pro-apoptotic miRNAs on apoptosis, we analyzed the expression levels of TP53 mRNA in the patient’s serum. We found that TP53 mRNA expression was significantly downregulated (31.7-fold; p=0.036; CI95%, 0.00001–0.09) in patients with ear atresia compared with controls. (Figs. 2, 3).

Aslan et al., Apoptosis regulating miRNAs in ear atresia

Table 2. Fold-regulation results and p-values of miRNAs expression levels of the ear atresia and control groups. Statistically significant and lower miRNAs expressions according to the control group are indicated with ‘‘a’’ symbol and ‘‘-,’’ respectively.

Fold Change 95% CI Ear Atresia/Control

hsa-mir-39ce hsa-mir-143 hsa-mir-210 hsa-mir-375 hsa-mir-146aa hsa-mir-222a hsa-mir-106b hsa-let-7f hsa-mir-183 hsa-mir-181b hsa-mir-126a hsa-mir-92a SNORD68 hsa-mir-21a SNORD61

1 0.37 2.66 0.03 0.02a 0.03a 0.31 0.70 0.59 0.24 0.01a 0.01 1.04 0.014a 1.55

(1.00-1.00) (0.00001-0.90) (0.00001-9.28) (0.00001-0.06) (0.00001-0.04)a (0.00001-0.09)a (0.00001-0.80) (0.00001-3.06) (0.00001-1.57) (0.00001-0.74) (0.00001-0.04)a (0.00001-0.02) (0.00001-2.89) (0.00001-0.04)a (0.18-2.93)

Fold Regulation Ear Atresia/Control

1 -2.7 2.6 -33.8 -61.8a -30.5a -3.1 -1.4 -1.7 -4.1 -76.2a -130 1 -71.2a 1.55

0 0.34 0.96 0.11 0.0003a 0.009a 0.31 0.21 0.35 0.14 0.041a 0.07 0.36 0.042a 0.79

CI: Confidence Interval

Control Group Group 1

DISCUSSION

hsa-miR-143-3p hsa-miR-210-3p hsa-miR-375 hsa-miR-146a-5p hsa-miR-222-3p hsa-miR-106b-5p hsa-let-71-3p hsa-miR-183-2p hsa-miR-181b-5p hsa-miR-126-5p hsa-miR-92a-3p SNORD68 Magnitude of gene expression min

Figure 1.

avg

max

Clustergram of miRNA expressions in patients with ear atresia compared with controls. This clustergram was created with online QIAGEN miScript Primer Assay, Data Analysis Center. Accordingly, expression levels of 10 miRNAs were decreased (green) in the patients compared with the control group (red). The decreased expression levels of miR146a (p=0.000), miR222 (p=0.009), and miR126 (p=0.041) were statistically significant.

The underlying effect of miRNA on the development of ear atresia was our major query in this study. Because miRNAs have an essential role in the developmental processes, including organogenesis, we aimed to explore a possible association between miRNAs regulating inflammation, apoptosis, angiogenesis, and chondrogenesis and ear atresia to detect whether any miRNA could be responsible for the developmental defects in ears (Table 1). Here, we noticed that there was a significant expression difference for several miRNAs between patients and healthy controls. Because the ears continue to develop during the lifetime [5], and ear atresia not only presents with external ear anomaly or microtia but also affects middle and inner compartments, we decided to use the serum samples of patients to investigate miRNA expression levels at the time of diagnoses instead of taking biopsy samples from the patients’ external ear. We found that the expressions of four miRNAs miR222, miR146a, miR126, and miR21 among the 12 miRNAs were significantly downregulated in patients with ear atresia. Remarkably, these miRNAs are particularly known to regulate apoptosis in human cancers. Few studies in the literature have addressed the ques-

Control Group Group 1

North Clin Istanb

Ear Atresia 60

SNORD61-11 p53 hsa-miR-21 hsa-miR-222-5p

max

Figure 2. Clustergram of TP53 mRNA and miR-21 expressions in patients with ear atresia compared with the control group. Average TP53 mRNA and miR21 (p=0.042) concentrations were determined in ear atresia and control groups by quantitative real-time PCR. The TP53 mRNA expressions of both the groups were compared using the t-test. TP53 (p=0.04) and miR21 (p=0.042) expressions were decreased significantly in the ear atresia group compared with the control group. There was no significant difference between the control and ear atresia groups in terms of SNORD61 (housekeeping gene) expression. tion of miRNA involvement in ear atresia, but they were mostly performed on experimental animals [15–18]. In the current literature, there are clues of the possible effects of miRNAs that could play a role in normal ear development. For example, Soukup et al. [18] reported the possible role of miRNAs in ear development and that miR183 expression was closely associated with the degree of hair cell and sensory epithelium differentiation in mice. Additionally, Li et al. [17] showed that knockdown of miR183, miR96, and miR182 resulted in decreased number of hair cells in the inner ear, smaller statoacoustic ganglion, defects in semicircular canals, and abnormal neuromasts on the posterior lateral line. Moreover, Li et al. [19] (2013) showed that in the cartilages of microtia, miR451 and miR486 expressions were significantly upregulated, whereas miR200c was significantly downregulated compared with controls. Hence, these studies provided insights regarding the control of miRNAs in ear development; however, which pathways are controlled by these miRNAs needs to be explored and is essential for normal development in humans. However, our study was the first to link apoptosis-regulating miRNAs with the pathogenesis of ear atresia. miRNA expression analyses in this study revealed that significantly decreased expressions of apoptosis-regulating miRNAs may have a role in the pathogenesis of ear atresia through different loci of the apoptosis pathway (Table 2).

Copies/ul

avg

Control

Magnitude of gene expression min

p53 expression in ear atresia

40 30 20 10 0

p53

SNORD61

Figure 3. Comparison of SNORD61 (housekeeping gene) and TP53 mRNA expression levels (copy number/µl) in the serum of ear atresia and control groups. TP53 mRNA expression levels were decreased 31.7-fold (statistically significant; p=0.04) in the ear atresia group compared with the control group. To discuss in more detail, the extrinsic apoptotic pathway starts with binding of FasL (death Ligand) to its receptor (Fas), and FasL has been reported to be a direct target of miR21 [14]. It has been reported that by targeting FasL, serum miR21 serves as a predictor for chemosensitivity and chemoresistance in advanced pancreatic cancers [20]. Moreover, miR21 promotes cell survival by inhibiting FasL expression in acute myeloid leukemia. Because we significantly found miR21 to be 71.2fold downregulated (95% CI: 0.00001–0.04, p=0.042), decreased inhibition of FasL due to underexpression of miR21 could activate the apoptosis cascade through the initial step of the extrinsic apoptotic pathway. Moreover, miR21 has been reported to control the key regulators of apoptosis, such as SMAD proteins, which are the critical mediators of tumor growth factor beta (TGF-β)-induced pro-apoptotic signaling. By binding to the 3’- untranslated region (3’-UTR) of SMAD7 mRNA, miR21 inhibits its translation [21]. Thus, decreased inhibition of SMAD7 mRNA could directly result in increased apoptosis. Another anti-apoptotic miRNA was miR146a, and together with miR196b, functioned as a potent suppres-

Aslan et al., Apoptosis regulating miRNAs in ear atresia

sor of Fas expression [22]. Forced miR146a expression causes autoimmune lymphoproliferative syndrome in mice via the downregulation of Fas in germinal center B cells [22, 23]. FAS is a death receptor, and its upregulation through decreased miR146a expression levels (Table 2: 61.8-fold downregulation, p<0.001; 95% CI, 0.00001–0.04) might induce developmental meatal cells to undergo early apoptosis. In addition, defects in cell migration or cell death could be attributed to underlying mechanisms for congenital diseases during the developmental process of embryogenesis [24, 25]. CHARGE syndrome is a multiple anomaly disorder that presents with a variety of phenotypes besides ear abnormalities [4]. Although 70%–90% of CHARGE syndrome case result from mutations in ATP-dependent chromatin remodeler CHD7 gene, Van Nostrand et al. (2014) showed surprising results using a knock-in mutant mouse strain expressing a stabilized and transcriptionally dead variant of the p53 tumor suppressor protein along with a wildtype p53 allele. They stated that the embryos represented characteristic phenotypes of CHARGE syndrome, including inner and

outer ear malformations besides coloboma, heart outflow tract defects, and craniofacial defects [26]. They reported that p53 mutant protein could stabilize or hyperactivate wildtype p53 to inappropriately induce apoptosis during development. Moreover, they stated that due to CHD7 binding to the p53 promoter, thereby causing inappropriate p53 activation due to CHD7 loss, could contribute to CHARGE syndrome phenotypes [26]. According to these striking findings [26] and few published data supporting the critical role for p53 in developmental processes of ears [8], we speculated that dysregulation of p53 through the downregulation of apoptosis-controlling miRNAs (miR21, miR146, miR126, and miR222) by altering the timing or intensity of apoptosis, particularly in the outermost epithelial cells during auditory meatal development [8], may beget the ear abnormalities, including ear atresia and/or microtia (Fig. 4). Furthermore, miR21 can affect cells by regulating major cascades of autophagy. Autophagy is a cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles in its own lysosomal system in eukaryotic cells. Different signaling pathways, including

mir-21

↓

↑→ Extrinsic Apoptotic Pathway ↑ PTEN ↑→ PI3K-I ↓→ mTORCH1 ↓/ ↑ Ras, Raf, MEK1/2, ERK1/2 → Autophagy ↑ SMAD7 Activation ↑→ Extrinsic Apoptotic Pathway ↑

mir-222

↓

PUMA

FasL

↑→

Intrinsic Apoptotic Pathway

↑

mir-146a

↓

FasR

mir-126

↓

Improper migration and timing of apoptotic cells

Extrinsic Apoptotic Pathway

↑

Changes in Timing and Intensity of Apoptosis

Ear Atresia

Inappropriate p53 Activation

Figure 4. Representation of downregulated miRNAs resulting in ear atresia through the regulation of the apoptosis pathway. The significantly decreased expressions of miRNAs (miR21, miR146a, miR126, and miR222) may be related with apoptotic pathways in the pathogenesis of ear atresia.

North Clin Istanb

mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase-I (PI3K-I)/PKB, Ras GTPases, calcium, and protein synthesis, play important roles in regulating autophagy [27, 28]. PTEN, a negative regulator of the PI3K signaling pathway, is a hot target for a number of miRNAs, including miR21, which are involved in the regulation of several cancer types [29, 30]. By the downregulation of miR21, PTEN more actively participates as a negative regulator of the PI3K signaling pathway [14]. Additionally, miR21 controls the major members of the Ras-Raf-1-MEK1/2-ERK1/2 signaling pathway [31, 32], particularly Ras expression in tumor suppression. Decreased expression of miR-21 may also serve as the negative regulator for autophagy either through Ras or PTEN within the cascade. miR222 is encoded in tandem on the Xp11.3 chromosome in humans and is highly conserved in vertebrates similar as pri-miRNA of miR221 [33]. The tumor suppressor and angiogenesis genes have been identified as miR221/222 targets in several cancers [34]. Polliseno reported that miR221/222 family modulates the angiogenic activity of stem cell factor by targeting its receptor c-Kit and consequently promotes invasion and metastasis [28]. In other study, miR222 was reported to directly induce apoptosis by targeting the binding sites on mRNA 3’-UTR of mitochondrial apoptotic protein PUMA, which has recently been identified as a critical mediator of p53-associated apoptosis [35]. Hence, based on our results, we assumed that the downregulation of miR222 could be related to ear atresia by leading over-induced apoptosis through excessive activity of PUMA on mitochondrial apoptotic pathway. In case of the downregulation of PUMA repressing factors, such as miR222, more apoptosis than it necessitates may have occurred during external and middle ear development. At this point, p53 could be a good mediator associated with miR222 and PUMA; however, we found its expression significantly decreased in the ear atresia patient group (Fig. 2). Thus, we assert that ear atresia may also develop due to increased apoptosis in concurrence with decreased autophagy. However, how can decreased autophagy result in ear atresia? PUMA is a direct transcriptional target of p53 and binds Bcl-2, which is localized in the mitochondria, induces cytochrome c release, and activates the rapid induction of apoptosis [36]. In our study, p53 was significantly downregulated; therefore, we assumed that downregulation of miR222 may activate PUMA regardless of p53.

Finally, miR126 is a cell growth suppressor that targets IRS-137, and ectopic expression of miR126 in SGC7901 gastric cancer cells potently inhibits cell growth by inducing cell cycle arrest in the G0/G1 phase. miR126 may also lead to the inhibition of migration and invasion in vitro as well as tumorigenicity and metastasis in vivo [38]. Taken together, our results suggested that the possible causes of ear atresia may include underexpression of miR126 by improper migration and timing of apoptotic cells. Thus, decreased expressions of apoptosis-controlling miRNAs may lead to inappropriate apoptosis at inappropriate settling in the ear. CONCLUSION The pathways underlying the development of ear atresia with diverse phenotypes remain poorly understood. With our study, we for the first time reported the significantly decreased expressions of miRNAs (miR21, miR146a, miR126, and miR222) in the serum of patients with ear atresia, thus suggesting that miRNA-mediated control of apoptotic pathways may be responsible for the pathogenesis of ear atresia. Further studies are needed to identify the effects of miRNAs and their target genes in altered developmental processes. Acknowledgment: This project was supported by the Research Fund of Istanbul Medeniyet University Project # TSG-2013-333. We would like to thank Associate Prof. Serdar Ceylaner, MD, for his kind supply of the TP53 forward and reverse primers used in RT-PCR experiments. Among the authors, EA, EA, SY, ASK, UT, SY, and HG are members of the Project Machine as Medical Students. The authors declare no conflict of interest. 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 – I.A., S.Y., M.T.K., E.As., E.A.; Design – I.A., E.As., A.S.K.; Supervision – I.A., M.T.K.; Materials – M.T.K., I.A.; Data collection &/or processing – E.As., E.A., S.Y., A.S.K., U.T., S.Y., H.G., M.T.K., I.A.; Analysis and/or interpretation – E.As., E.A., S.Y., A.S.K., U.T., S.Y., H.G., I.A.; Writing – E.As., E.A., S.Y., U.T., M.T.K., I.A.; Critical review – E.A., I.A.

REFERENCES 1. Nager GT. Congenital aural atresia: anatomy and surgical management. Birth Defects Orig Artic Ser 1971;07:33–51. 2. Castilla EE, Orioli IM. Prevalence rates of microtia in South America. Int J Epidemiol 1986;15:364–8. 3. Dostal A, Nemeckova J, Gaillyova R, Vranova V, Zezulkova D, Lejska M, et al. Identification of 2.3-Mb gene locus for congenital aural atresia

Aslan et al., Apoptosis regulating miRNAs in ear atresia

in 18q22.3 deletion: a case report analyzed by comparative genomic hybridization. Otol Neurotol 2006;27:427–32. 4. Jones KL, Jones MC, Del Campo M. Smith’s reconnisable patterns of human malformations. 7th ed. Philadelphia: Elsevier Saunders; 2013. 5. Wright CG. Development of the human external ear. J Am Acad Audiol 1997;8:379–82. 6. Peck JE. Development of hearing. Part II. Embryology. J Am Acad Audiol 1994;5:359–65. 7. Kenna MA. Embryology and developmental anatomy of the ear. In: Bluestone CD, Stool SE, editors. 2nd ed. Philadelphia: WB Saunders; 1990. p. 77–87. 8. Nishizaki K, Anniko M, Orita Y, Masuda Y, Yoshino T, Kanda S, et al. Programmed cell death in the development of the mouse external auditory canal. Anat Rec 1998;252:378–82. 9. Gerschenson LE, Rotello RJ. Apoptosis: a different type of cell death. FASEB J 1992;6:2450–5. 10. Wyllie AH. Apoptosis (the 1992 Frank Rose Memorial Lecture). Br J Cancer 1993;67:205–8. 11. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116:281–97. 12. Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 2010;11:597–610. 13. Huang Y, Shen XJ, Zou Q, Wang SP, Tang SM, Zhang GZ. Biological functions of microRNAs: a review. J Physiol Biochem 2011;67:129–39. 14. Su Z, Yang Z, Xu Y, Chen Y, Yu Q. MicroRNAs in apoptosis, autophagy and necroptosis. Oncotarget 2015;6:8474–90. 15. Rudnicki A, Isakov O, Ushakov K, Shivatzki S, Weiss I, Friedman LM, et al. Next-generation sequencing of small RNAs from inner ear sensory epithelium identifies microRNAs and defines regulatory pathways. BMC Genomics 2014;15:484. 16. Kersigo J, D’Angelo A, Gray BD, Soukup GA, Fritzsch B. The role of sensory organs and the forebrain for the development of the craniofacial shape as revealed by Foxg1-cre-mediated microRNA loss. Genesis 2011;49:326–41. 17. Li H, Kloosterman W, Fekete DM. MicroRNA-183 family members regulate sensorineural fates in the inner ear. J Neurosci 2010;30:3254– 63. 18. Soukup GA, Fritzsch B, Pierce ML, Weston MD, Jahan I, McManus MT, et al. Residual microRNA expression dictates the extent of inner ear development in conditional Dicer knockout mice. Dev Biol 2009;328:328–41. 19. Li C, Hao S, Wang H, Jin L, Qing F, Zheng F, et al. MicroRNA expression profiling and target genes study in congenital microtia. Int J Pediatr Otorhinolaryngol 2013;77:483–7. 20. Wang P, Zhuang L, Zhang J, Fan J, Luo J, Chen H, et al. The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol Oncol 2013;7:334–45. 21. Li Q, Zhang D, Wang Y, Sun P, Hou X, Larner J, et al. MiR-21/Smad 7 signaling determines TGF-β1-induced CAF formation. Sci Rep

2013;3:2038. 22. Guo Q, Zhang J, Li J, Zou L, Zhang J, Xie Z, et al. Forced miR146a expression causes autoimmune lymphoproliferative syndrome in mice via downregulation of Fas in germinal center B cells. Blood 2013;121:4875–83. 23. Li Z, Huang H, Chen P, He M, Li Y, Arnovitz S, Jiang X, et al. miR196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia. Nat Commun 2012;3:688. 24. Nussbaum RL, McInnes RR, Willard HF. Thompson and Thompson Genetics in Medicine. 7th ed. Saunders: 2007. 25. Mirkes PE. 2001 Warkany lecture: to die or not to die, the role of apoptosis in normal and abnormal mammalian development. Teratology 2002;65:228–39. 26. Van Nostrand JL, Brady CA, Jung H, Fuentes DR, Kozak MM, Johnson TM, et al. Inappropriate p53 activation during development induces features of CHARGE syndrome. Nature 2014;514:228–32. 27. LeBlanc VC, Morin P. Exploring miRNA-Associated Signatures with Diagnostic Relevance in Glioblastoma Multiforme and Breast Cancer Patients. J Clin Med 2015;4:1612–30. 28. Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, et al. MicroRNAs modulate the angiogenic properties of HUVECs. Blood 2006;108:3068–71. 29. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007;133:647–58. 30. Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN, Acerbi I, et al. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat Med 2014;20:360–7. 31. Deng M, Tang H, Zhou Y, Zhou M, Xiong W, Zheng Y, et al. miR216b suppresses tumor growth and invasion by targeting KRAS in nasopharyngeal carcinoma. J Cell Sci 2011;124:2997–3005. 32. Hatley ME, Patrick DM, Garcia MR, Richardson JA, Bassel-Duby R, van Rooij E, et al. Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell 2010;18:282–93. 33. Garofalo M, Quintavalle C, Romano G, Croce CM, Condorelli G. miR221/222 in cancer: their role in tumor progression and response to therapy. Curr Mol Med 2012;12:27–33. 34. Zhang CZ, Zhang JX, Zhang AL, Shi ZD, Han L, Jia ZF, et al. MiR221 and miR-222 target PUMA to induce cell survival in glioblastoma. Mol Cancer 2010;9:229. 35. Zhang C, Zhang J, Zhang A, Wang Y, Han L, You Y, et al. PUMA is a novel target of miR-221/222 in human epithelial cancers. Int J Oncol 2010;37:1621–6. 36. Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell 2001;7:683–94. 37. Zhang J, Du YY, Lin YF, Chen YT, Yang L, Wang HJ, et al. The cell growth suppressor, mir-126, targets IRS-1. Biochem Biophys Res Commun 2008;377:136–40. 38. Feng R, Chen X, Yu Y, Su L, Yu B, Li J, et al. miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett 2010;298:50–63.

Orıgınal Article

ORTHOPEDICS&TRAUMATOLOGY

North Clin Istanb 2018;5(3):246–253 doi: 10.14744/nci.2018.52243

A patellar tendon length conservation method: Biplanar retrotubercle open-wedge proximal tibial osteotomy Ismail Turkmen,1

Irfan Esenkaya2

Department of Orthopaedics and Traumatology, Health Sciences University Umraniye Training and Research Hospital, Istanbul, Turkey

Department of Orthopaedics and Traumatology, Istnbul Medeniyet University Faculty of Medicine, Istanbul, Turkey

ABSTRACT OBJECTIVE: The early-period results of our technique for performing a medial biplanar retrotubercle open-wedge proximal tibial osteotomy for the surgical treatment of varus gonarthrosis were evaluated and compared with those reported in the literature. METHODS: The clinical and radiological results of a medial biplanar retrotubercle open-wedge proximal tibial osteotomy performed on 23 knees in 22 patients with medial gonarthrosis with varus alignment were analyzed. RESULTS: Twenty patients were female and 2 were male. At the time of surgery, the mean age was 56.22 years (44–66 years), the mean body mass index was 31.95 kg/m2 (23.4–44.9 kg/m2), and the mean Hospital for Special Surgery (HSS) score was 68.7 (48–83). The mean preoperative femorotibial anatomical axis angle was 186.39° (173–194°), and the mean Insall-Salvati index value was 1.04 (0.94–1.171). The mean length of follow-up was 30.19 months (6–42 months). At the last follow-up examination, the mean HSS score was 86.48 (74–100), the mean femorotibial anatomical axis angle was 175° (168–171°), and the mean Insall-Salvati index value was 1.06 (0.857–1.32). Comparison of the final follow-up values with the preoperative values demonstrated significant improvement in the HSS score and femorotibial anatomical axis angle, but no significant difference in the Insall-Salvati index value. CONCLUSION: The results of this study indicated that frontal and sagittal plane deformities in patients with varus gonarthrosis can be treated with biplanar retrotubercle open-wedge proximal tibial osteotomy with good clinical results that achieve patellar tendon length stability and avoid patellofemoral problems. Keywords: Biplanar; open-wedge osteotomy; patellar tendon; retrotubercle.

Cite this article as: Turkmen I., Esenkaya I. A patellar tendon length conservation method: Biplanar retrotubercle open-wedge proximal tibial osteotomy. North Clin Istanb 2018;5(3):246–253.

everal alternative treatments are available for medial gonarthrosis. They include proximal tibial osteotomy (PTO), which is a “biological treatment” option often used for relatively young patients. PTO techniques have also been modified many times. Recently, medial openwedge osteotomies have been preferred because they produce very good clinical results [1]. However, patients

may have patellofemoral problems when the osteotomy is performed only in a single plane [2]. The purpose of this study was to demonstrate that good clinical results were obtained when treating a frontal plane deformity with our technique of medial biplanar retrotubercle open-wedge PTO, without changing the length of the patellar tendon in the sagittal plane.

Received: November 04, 2017 Accepted: February 27, 2018 Online: August 31, 2018 Correspondence: Dr. Ismail TURKMEN. Saglik Bilimleri Universitesi, Umraniye Egitim ve Arastirma Hastanesi, Ortopedi ve Travmatoloji Klinigi, Istanbul, Turkey. Tel: +90 530 462 21 07 e-mail: dr.ismailturkmen@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Turkmen et al., A patellar tendon length conservation method: Biplanar retrotubercle open-wedge proximal tibial osteotomy

247

MATERIALS AND METHODS The ethics committee of Istanbul Medeniyet University, Goztepe Training and Research Hospital approved a review and analysis of patients diagnosed with medial gonarthrosis. Informed consent was obtained from each patient. The results of medial biplanar retrotubercle openwedge PTO performed on patients with medial gonarthrosis and varus alignment who were treated in the clinic were examined. A single surgeon, who is the developer of the technique and one of the authors, performed the operation on all of the patients. The technique is a modification of the method defined by Gaasbeek et al. [2, 3]. The study inclusion criteria were knee pain, arthrosis in the medial compartment of the knee, varus alignment, and nonresponse to conservative treatment. Exclusion criteria were grade 3 or 4 chondropathy in the lateral compartment according to the Outerbridge classification as determined by arthroscopy or magnetic resonance imaging (MRI) [4], knee flexion contracture >15°, knee flexion <90°, femoral varus deformity, or serious arterial or venous insufficiency. Initially, 30 patients with medial gonarthrosis and varus malalignment were included. Six patients were excluded after the first step of the surgery due to the observation of grade 4 chondropathy on the lateral side of the knee during arthroscopy or they had not undergone an osteotomy. Two patients were also lost to follow-up. Thus, the study was completed with the data of 23 knees of 22 patients. The clinical examination included details obtained from the patients’ medical records and history: the nature of each patient’s complaint, date of onset, history of prior medication use, previous treatment, presence of other diseases, and the use of cigarettes. Each patient’s height, weight, and body mass index (BMI) was also recorded. The Hospital for Special Surgery Knee Rating Sheet (HSS score) was used to assess knee function [5]. The radiological assessment consisted of anteroposterior (AP) and lateral radiographs of both knees taken while the patient was in the standing and 30° flexion positions. Orthoroentgenography was performed in both lower extremities in the routine manner. If not performed previously, MRI and computed tomography imaging were completed before surgery as usual. Before surgery, the femoral and tibial anatomical axes, the angle between the femoral condyle and the tibial plateau (FCTPa), the angle between the tibial plateau and the

Figure 1. The appearance of the osteotomy line on the bone model - anterior side.

tibial axis (TPTAa), the tibial slope, and Insall-Salvati index parameters were measured. All of the patients underwent arthroscopy before the osteotomy. Microfracture surgery and chondroplasty were performed on patients with grade 4 chondropathy in the medial compartment. Once the decision was made to perform an osteotomy, an approximately 8-cm anterior longitudinal skin incision was made immediately below the area between the tuberositas tibia and the lower pole of the patella (this incision shape does not prevent possible future total knee prosthesis placement). The tibial periosteum and pes anserinus were elevated in an inverse “L” shape. The superficial fibers of the medial collateral ligament were cut. In the first scope control, the first Kirschner wire (K-wire) was passed from the medial region of the proximal tibial metaphysis (4 cm below the joint line) toward the lateral cortex such that it stayed 1 to 1.5 cm distal to the joint and about 1 cm medial to the lateral cortex. If it was passed at a right angle in the AP or lateral plane, the wire was shortened and additional Kwires were passed accordingly. The K-wires were placed so that they would stay in the proximal tibial tubercle and the osteotomy would be biplanar. The anterior wire

248

North Clin Istanb

Figure 2.

The appearance of the osteotomy line on 3-dimensional computed tomography - lateral side.

Figure 3. A 58-year-old male patient who was operated on from the left side due to bilateral genu varum.

was left in the anterior third of the tibial metaphysis. The incisional peak behind the tubercle should be at least 2.5 cm and the angle between the horizontal and vertical osteotomy lines should be 110 to 120° (Figs. 1, 2) [3, 6]. If the angle is smaller, the tibial tubercle may break; if the angle is larger, the application of a double plate is more difficult, due to the decreased bone angle [3]. The vertical osteotomy line was osteotomized with the thinnest osteotome. The posterior tibial cortex was dissected with a specially designed blunt-ended osteotome to protect posterior neurovascular structures. The horizontal osteotomy line was opened using a triple osteotome technique or a specially designed distractor [7]. The amount of correction was planned preoperatively, and distraction at the osteotomy site was performed according to the preoperative plan. The wedge-shaped gap remaining after fixation was filled with a bicortical autograft taken from the iliac crest. Fixation was enabled through specially designed wedge plates [3, 6, 8–10]. Tibial tubercules could not be fixed. The medialized distal end of the tibial tubercule was trimmed (Fig. 4). RESULTS Twenty patients in this study group were female and 2

HSS TFAAaº FCTPaº TPTAa SLOPE INSALL PLATE

Preoperative

(mm)

186

1.00 9+11

Postoperative 91

173

1.05

Preoperative anteroposterior graphy in a standing position. FCTPa: Angle between the femoral condyle and tibial plateau; HSS: Hospital for Special Surgery; Insall: Insall-Salvati index; TFAAa: Tibiofemoral anatomic axis angle; TPTAa: Angle between the tibial plateau and the tibial axis; Slope: Tibial slope.

were male. The right knee of 12 patients, the left knee of 9 patients, and both knees of 1 patient were operated on. The arthroscopic findings of the patients were evaluated and are presented in Table 1. The postoperative HSS scores were significantly higher than the preoperative scores (p<0.05). The postoperative mean flexion and extension values showed no significant change from the baseline figures (both p>0.05; Table 2). The mean preoperative TPTAa was 97.17±3.85° (median: 98°) and the mean TPTAa at the final follow up was 88.09±5.23° (median: 88°). The mean change was –9.09±5.28° (–17° to 7°; median: –10°; Table 3). No meaningful correlation was found between the change in HSS score (postoperative vs. pre-

Turkmen et al., A patellar tendon length conservation method: Biplanar retrotubercle open-wedge proximal tibial osteotomy

249

Figure 4. (A) Left knee lateral graphy. (B) Postoperative month 9 anteroposterior standing graphy. (C) Postoperative month 9 left knee lateral graphy.

Table 1. Arthroscopic findings in 23 knees of 22 patients Chondropathy in FMC G3/3–4 G 4 Chondropathy in TMP G 3 G 4 Medial meniscus lesion Lateral meniscus lesion Retropatellar chondropathy Trochlear chondropathy

7 16

30.4 69.6

ACL rupture PCL rupture

1 0

4.3 0.0

8 15 14 5 5 4

34.8 65.2 60.9 21.7 21.7 17.4

Plica Ligamentum mucosum Microfracture

4 0 21

17.4 0.0 91.3

ACL: Anterior cruciate ligament; FMC: Femoral medial condyle; PCL: Posterior cruciate ligament; TMP: Tibial medial plateau.

operative) and the change in flexion, extension, TFAAa, FCTPa, TPTAa, tibial slope, or Insall-Salvati index value (all p>0.05; Table 4). Complications: The following complications occurred in this sample of 23 knees in 22 patients: non-fatal pulmonary embolism (n=1), deep vein thrombus 1 year after surgery (n=1), temporary sensory nerve injury (n=2; lateral femoral cutaneous nerve hypoesthesia in 1 patient and hypoesthesia in the infrapatellar branch of the saphenous nerve in 1 patient), rhabdomyolysis (n=1), and loss (recurrence) at a recoverable level (n=1). No surface or deep infection, lateral tibial cortex or plateau fracture, tibial tubercle fracture, or plate or screw breakdown was observed.

DISCUSSION Patients who undergo PTO may have deformities in not just the frontal plane, but also in the sagittal plane [11]. After medial open-wedge PTO, the tibial slope tends to increase [12]. Giffin et al. [13] reported a 4.4° increase in slope postoperatively compared with the preoperative value, Naudie et al. [14] reported a 7.7° increase, and Bombaci et al. [15] reported a mean increase of 3.6°. Insufficiency of the posterior cortex and insufficient loosening of the posterior soft tissues play a role in this change [12]. The increase in tibial slope increases anterior subluxation of the tibia. Whereas this increase is positive in cases of a posterior cruciate ligament failure, a

250

North Clin Istanb

Table 2. Comparison of the preoperative and postoperative Hospital for Specıal Surgery scores and the flexion and extension assessments

Mean±SD

Median

Min.–Max.

HSS score

Preoperative

68.70±11.68

48–83

Postoperative

86.48±9.05

66–100

Amount of change

17.78±10.23

-4–39

0.000 E

Flexion

Preoperative

110.65±15.32

120

70–130

Postoperative

114.13±11.55

120

85–130

Amount of change

3.48±12.65

-15–30

0.275

1.000

Extension

Preoperative

-0.43±2.09

-10–0

Postoperative

-0.43±1.44

-5–0

Amount of change

0.00±1.51

-5–5

SD: Standard deviation; Min.: Minimum; Max.: Maximum; HSS: Hospital for special surgery.

Table 3. The postoperative and preoperative TFAAa, FCTPa, TPTAa, slope, and Insall-Salvati index change

Mean±SD

Median

Min.–Max.

TFAAa

Preoperative

186.39±4.45

186

173–194

Postoperative

175.00±5.54

175

168–191

Amount of change

-11.39±5.06

-10

-23–-3 2–10

0.000 E

FCTPa

Preoperative

6.22±2.24

Postoperative

4.09±1.73

1–7

Amount of change

-2.13±1.55

-2

-6–0

0.000 E

TPTAa

Preoperative

97.17±3.85

91–105

Postoperative

88.09±5.23

80–106

Amount of change

-9.09±5.28

-10

-17–7

0.000

0.560

0.057

Tibial slope

Preoperative

12.96±4.38

12.0

7.0–24.0

Postoperative

13.70±5.71

13.0

7.0–36.0

Amount of change

0.74±5.99

0.0

-5.0–25.0

Insall-Salvati index

Preoperative

1.04±0.08

1.1

0.9–1.2

Postoperative

1.06±0.13

1.1

0.9–1.3

Amount of change

0.03±0.07

0.0

-0.1–0.2

SD: Standard deviation; Min.: Minimum; Max.: Maximum; HSS: Hospital for special surgery; E: Matched sample t-test; FCTPa: Angle between the femoral condyle and the tibial plateau; TFAAa: Tibiofemoral anatomic axis angle; TPTAa: Angle between the tibial plateau and the tibial axis.

Turkmen et al., A patellar tendon length conservation method: Biplanar retrotubercle open-wedge proximal tibial osteotomy

251

Table 4. The relationship between radiological and clinical findings in the preoperative and postoperative periods

Preoperative /Postoperative change

Change r p Change r p Change r p Change r p Change r p Change r p Change r p

HSS score

Flex

Preoperative/Postoperative change Ext.

TFAAa

FCTPa

TPTAa

Slope

- flex -0.054 0.808 - extension 0.324 0.131

-0.060 0.787

0.000 1.000

0.125 0.569

0.060 0.787

0.102 0.645

0.175 0.424

-0.390 0.066

-0.111 0.613

0.180 0.412

0.212 0.331

0.285 0.187

0.618 -0.46 0.002 0.026

0.117 0.595

0.033 0.879

0.729 0.000

0.382 0.072

-0.470 0.563 0.024 0.005

0.065 0.768

0.155 0.479

0.307 0.154

0.180 0.412

-0.278 0.198

-TFAAa

- FCTPa

-TPTAa

- slope

-Insall-Salvati index 0.252 0.246

0.426 0.043

Pearson/Spearman correlation; FCTPa: Angle between the femoral condyle and tibial plateau; HSS: Hospital for Special Surgery; TFAAa: Tibiofemoral anatomic axis angle; TPTAa: Angle between the tibial plateau and the tibial axis; Slope: Tibial slope.

decrease in tibial slope is positive in cases of anterior cruciate ligament failure and extension limitation [11, 12]. In 2006, Esenkaya and Elmali [16] reported that they used a technique involving placement of a plate with a small (2–2.5 mm) wedge in front of the osteotomy line to prevent an increase in the tibial slope. We also used this technique to avoid changing the tibial slope. There is no need to change the slope in patients who have full knee extension. If there is a desire to increase or decrease the tibial slope, a double plate technique should be used. Otherwise, a single rectangular plate can be used. In our study, the difference between preoperative and postoperative tibial slope was not significant (p=0.560). One patient had a partial anterior cruciate ligament rupture, but no instability; thus, we did not change the tibial slope in this patient. Medial open-wedge osteotomy is used for acute fixation [1–3, 6, 10, 12, 14–17] and gradual fixation [18].

Fixation plates are used for acute fixation [2, 3, 6, 10, 12, 14, 17] and external fixation systems are used for gradual fixation [18]. Acute fixation is divided into monoplanar [10, 15–17] and biplanar [2, 3, 6, 11] types. Biplanar osteotomy can preserve the proximal [2, 3, 6] or distal [11] tibial tubercle. The use of retrotubercle osteotomy began because this technique does not change the location of the patella or the Q angle [2, 3]. Murphy [19] preferred this type of osteotomy for wedge closure. Then, Gaasbeek et al. [2] used this technique in an open-wedge osteotomy. In a medial open-wedge osteotomy performed from the proximal tibial tubercle, the tubercle is reduced by half of the deformity degree [20]. Thus, narrowing of the patellar tendon and patella infera can be observed [21]. This increases retropatellar pressure and causes patellofemoral arthrosis [3, 22]. Patella infera can create technical problems for total knee prosthesis surgery [2]. To avoid patellar tendon length shortening, Hernigou et

252

al. [1] oriented the graft with the greatest wedge height to the far back of the osteotomy, and used grafts with shorter (2 mm) wedges in the middle and at the far front. However, because this technique does not involve the use of a fixation plate after the osteotomy, tibial slope change is inevitable. In patients with patellofemoral arthrosis or the need for <15° fixation, an osteotomy that preserve the location of the proximal patellar tendon attachment is preferred [3]. In our study, we used a technique developed by Gaasbeek et al. [2] that was modified by the senior surgeon/author, with wedge plates designed by the senior surgeon/author (patent number: TR2002 02021Y). The Insall-Salvati index was used to evaluate the change in patellar tendon size. The mean preoperative and postoperative Insall-Salvati index value, as calculated from radiographs, was 1.04±0.08° (median: 1.1°) and 1.06±0.13° (median: 1.1°), respectively. The difference was not significant (p=0.057). One patient had recoverable loss, with a change in the sagittal plane and an increased Insall-Salvati index score. The inclusion of data from this patient in the statistical analysis did not change the mean statistical result. In our study, 1 (4.5%) patient had a non-fatal pulmonary embolism, 1 (4.5%) patient developed deep vein thrombus 1 year after surgery, 2 (9.1%) patients had temporary sensory nerve injury (lateral femoral cutaneous nerve hypoesthesia in 1 patient and hypoesthesia in the infrapatellar branch of the saphenous nerve in the other patient), 1 (4.5%) patient had rhabdomyolysis, and 1 (4.5%) patient had loss (recurrence) at a recoverable level; in total, this amounted to 6 (27.2%) complications in 22 patients. The pulmonary embolism caused no serious clinical issue, and no thrombus was present in the leg veins at the time of diagnosis. When the embolism occurred, the patient received 0.4 mL enoxaparin sodium daily. The deep vein thrombus occurring 1 year after surgery was treated symptomatically. Nerve injury was determined in the nerves feeding the related sensory areas and was resolved without treatment. One patient was found to have rhabdomyolysis, which began with oliguria and was detected with renal function tests on postoperative day 2. This patient was treated with early dialysis. The clinical view had improved markedly at postoperative month 7, but the femoral muscles were atrophied compared with the other side. We associated the formation of rhabdomyolysis with the use of a tourniquet [23]. We observed a loss in the degree of improvement in 1 patient. Loading was not performed with this patient, who had a high BMI, but no implant insufficiency was

North Clin Istanb

observed. Retrospective examination revealed that a 30cc allograft was used in this patient. We found no fracture or implant insufficiency in any patient. Although the plates we used were not locking plates, no screw loss occurred. The plates had a thin profile, and none of our patients developed skin problems. Our study has some limitations. First, it was retrospective and lacked a control group. Although a followup period of 6 months is sufficient to assess early clinical results, a longer period would make the study more valuable. Although our study included more patients than some other studies, the sample size was still small. In the surgical treatment of varus gonarthrosis, PTO may be considered before prosthesis options. PTOs can be applied with different shapes, grafts, and implants. Our study findings indicate that frontal and sagittal plane deformities in patients with varus gonarthrosis can be treated with biplanar retrotubercle open-wedge PTO, which can achieve patellar tendon length stability, avoid patellofemoral problems, and obtain good clinical results. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/irLeN5 Conflict of Interest: All authors declare that there is no conflict of interest. Financial Disclosure: The authors declared that this study has received no financial support. Authorship Contributions: Concept – I.E., Design – I.T.; Supervision – I.E.; Materials – I.T.; Data collection &/or processing – I.T.; Analysis and/or interpretation – I.E.; Writing – I.T.; Critical review – I.E.

REFERENCES 1. Hernigou P, Medevielle D, Debeyre J, Goutallier D. Proximal tibial osteotomy for osteoarthritis with varus deformity. A ten to thirteen-year follow-up study. J Bone Joint Surg Am 1987;69:332–54. 2. Gaasbeek RD, Sonneveld H, van Heerwaarden RJ, Jacobs WCH, Wymenga AB. Distal tuberosity osteotomy in open wedge high tibial osteotomy can prevent patella infera: a new technique. Knee 2004;11:6:457–61. 3. Esenkaya I, Unay K. Proximal medial tibial biplanar retrotubercle open wedge osteotomy in medial knee arthrosis. Knee 2012;19:416–21. 4. Outerbridge RE. The etiology of chondromalacia patellae. J Bone Joint Surg Br 1961;43:752–7. 5. Insall JN, Dorr LD, Scott RD, Scott WN. Rationale of the Knee Society clinical rating system. Clin Orthop Relat Res 1989;248:13–4. 6. Esenkaya I, Unay K, Turkmen I. Retro Tubercle Open Wedge Osteotomy in Medial Gonarthrosis. Turkiye Klinikleri J Orthop & Traumatol-Special Topics 2013;6:79–85.

Turkmen et al., A patellar tendon length conservation method: Biplanar retrotubercle open-wedge proximal tibial osteotomy

7. Esenkaya I. A new distractor with angle-scale for proximal tibia medial opening wedge osteotomy. Knee Surg Sports Traumatol Arthrosc 2006;14:443–6. 8. Esenkaya I, Misirlioglu M, Kelestemur MH, Elmali N, Fadillioglu E. Biomechanical evaluation of different fixation plates in medial opening upper tibial osteotomy. Knee 2007;14:46–50. 9. Yardimeden A, Kelestemur MH, Esenkaya I. Biomechanical comparison of the wedge supported plates at PTO. Archives of Material Science Engineering 2007;28:495–8. 10. Staubli AE, Simoni CD, Babst R, Lobenhoffer P. TomoFix: a new LCPconcept for open wedge osteotomy of the medial proximal tibia--early results in 92 cases. Injury 2003;34:55–62. 11. Lobenhoffer P, De Simoni C, Staubli AE. Open-wedge high-tibial osteotomy with rigid plate fixation. Tech Knee Surg 2002;1:93–105. 12. Marti CB, Gautier E, Wachtl SW, Jacob RP. Accuracy of frontal and sagittal plane correction in open-wedge high tibial osteotomy. Arthroscopy 2004;20:366–72. 13. Giffin JR, Vogrin TM, Zantop T, Woo SL, Harner CD. Effects of increasing tibial slope on the biomechanics of the knee. Am J Sports Med 2004;32:376–82. 14. Naudie DDR, Amendola A, Fowler PJ. Opening wedge high tibial osteotomy for symptomatic hyperextension-varus thrust. Am J Sports Med 2004;32:60–70. 15. Bombaci H, Canbora K, Onur G, Görgeç M. The effect of open wedge osteotomy on the posterior tibial slope. Acta Orthop Traumatol Turc

253

2005;39:404–10. 16. Esenkaya I, Elmali N. Proximal tibia medial open-wedge osteotomy using plates with wedges: early results in 58 cases. Knee Surg Sports Traumatol Arthrosc 2006;14:995–61. 17. Koshino T, Murase T, Saito T. Medial opening-wedge high tibial osteotomy with use of porous hydroxyapatite to treat medial compartment osteoarthritis of the knee. J Bone Joint Surg Am 2003;85:78–85. 18. Catagni MA, Guerreschi F, Ahmad TS, Cattaneo R. Treatment of genu varum in medial compartment osteoarthritis of the knee using the Ilizarov method. Orthop Clin North Am 1994;25:509–14. 19. Murphy SB. Tibial osteotomy for genu varum. Indications, preoperative planning, and technique. Orthop Clin North Am 1994;25:477–82. 20. Franco V, Cerullo G, Cipolla M, Gianni E, Puddu G. Open wedge high tibial osteotomy. Tech Knee Surg. 2002;1:43–53. 21. Elmali N, Esenkaya I, Can M, Karakaplan M. Monoplanar versus biplanar medial open-wedge proximal tibial osteotomy for varus gonarthrosis: a comparison of clinical and radiological outcomes. Knee Surg Sports Traumatol Arthrosc 2013;21:2689–95. 22. Esenkaya I, Elmali N, Mısırlıoğlu M, Ertem K, Atasever A. The Medial Opening Wedge Osteotomy in Which The Tibial Tubercle Remains Attached to the Proximal Fragment: An Anatomıc Study [Article in Turkish]. İnönü Üniversitesi Tıp Fakültesi Dergisi 2005;12:153–7. 23. Türkmen İ, Esenkaya İ, Unay K, Akçal MA. Rhabdomyolysis after tourniquet use in proximal tibial osteotomy: a case report and review of the literature. Acta Orthop Traumatol Turc 2015;49:338–41.

Case Report

CARDIOLOGY

North Clin Istanb 2018;5(3):254–255 doi: 10.14744/nci.2017.86619

Subclavian vein puncture-induced massive pulmonary hemorrhage and hemoptysis during pacemaker implantation Nizamettin Selcuk Yelgec, Altug Osken, Ceyhan Turkkan, Ahmet Taha Alper Department of Cardiology, Siyami Ersek Thoracic and Cardiovascular Surgery Center, Training and Research Hospital, Istanbul, Turkey

ABSTRACT We present a rare and interesting case of subclavian vein puncture-induced focal intraparenchymal lung hemorrhage and massive hemoptysis developed during CRT-D implantation. Clinical picture advanced to pulmonary edema in seconds. A noncontrast multiple-detector computed tomography scan revealed focal alveolar hemorrhage in the lung tissue right under the pacemaker pocket, but remarkably, there was no pneumothorax. This case shows that if cough and hemoptysis suddenly develop during subclavian puncture, injury of the adjoining lung because of parenchymal puncture should be considered as a complication. Keywords: Hemoptysis; pacemaker; pulmonary hemorrhage.

Cite this article as: Yelgec N. S., Osken A., Turkkan C., Alper A. T. Subclavian vein puncture-induced massive pulmonary hemorrhage and hemoptysis during pacemaker implantation. North Clin Istanb 2018;5(3):254–255.

ermanent pacemaker implantation remains one of the core skills of cardiologists. Implantation of a pacemaker lead via subclavian puncture carries a small but significant risk of access-related complications. Although hemoptysis related to the injury of lung parenchyma is a rare complication of subclavian vein access and is usually self-limited, it can affect prognosis in critically ill patients. We report a case of hemoptysis occurring during the vein puncture for cardiac resynchronization therapy defibrillator (CRT-D) implantation. CASE REPORT

A 59-year-old patient who had had a coronary artery bypass graft and prosthetic mitral valve replacement 5 years ago was admitted to our hospital because of bradycardia-induced syncope. His electrocardiogram showed A-V dissociation, 3rd degree A-V block, and left bundle branch block with QRS greater than 150 msn. His escape rhythm was about 40 beats per minute with a nor-

mal sinus node activity. Echocardiographic examination revealed diffuse hypokinesis and an ejection fraction of about 35%. His New York Heart Association functional class was III under optimal medical therapy. A decision to implant a CRT-D pacemaker was taken. He was under warfarin treatment because of the mechanical valve, and his INR was 1.7 on the day of the operation. After the patient was prepared for surgery, a leftarm contrast venography was obtained to be used as a roadmap for the venous puncture. This was the preferred method for venous access in our department. The first puncture of the atrial lead was accomplished successfully. While trying for the second puncture for ventricular lead, the patient began to cough. At the beginning, it seemed an unimportant nonspecific cough. But a few minutes later, the patient started to have massive hemoptysis and dyspnea and became cyanotic, orthopneic, and anxious. Fluoroscopy showed no signs of pneumothorax. The clinical picture was compatible with an acute pulmonary edema. We intervened with oxygen, diuretics, morphine, and head elevation. The patient became confused and agitated and tried to sit on the operation table. The im-

Received: May 15, 2017 Accepted: December 11, 2017 Online: May 29, 2018 Correspondence: Dr. Altug OSKEN. Siyami Ersek Gogus Kalp ve Damar Cerrahisi Egitim ve Arastirma Hastanesi, Kardiyoloji Klinigi, Istanbul, Turkey. Phone: +90 216 542 44 44 e-mail: alosk@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Yelgec et al., Subclavian vein puncture-induced massive pulmonary hemorrhage and hemoptysis during pacemaker implantation

plantation procedure was stopped as it was impossible to continue. We removed the wires and quickly closed the pocket. The patient was then managed in the intensive care unit. Multiple-detector computed tomography (MDCT) scans revealed no pneumothorax but localized pulmonary hemorrhage in the lung parenchyma under the newly fashioned pacemaker pocket. On noncontrast scans, there was hyperdense airspace consolidation in the left upper lung parenchyma within the alveolar space (Fig. 1). After medical therapy for respiratory distress and stabilization of heart failure, CRT-D was implanted uneventfully, and the patient was discharged without any problem. DISCUSSION Subclavian vein puncture is the most frequently practiced approach for pacemaker lead insertion because it is simple and suitable for multiple-lead insertion [1]. However, the debate regarding the safety and efficacy of this method remains unresolved. The possible shortterm complications of this approach are pneumothorax, hemothorax, and lung parenchymal puncture [1]. If the cephalic subclavian vein or cephalic vein access is difficult, there is a risk of the adjoining lung being accidentally punctured during the procedure. Contrast venography might help to localize the subclavian vein. Alternatively, the use of wire-guided venous access through a superficial brachial vein, either by the cephalic or basilic vein has been suggested [2]. The wire is pushed into the subclavian vein, and so subclavian puncture under fluoroscopy is made easier and safer.

255

Although there is 1%–3% risk of pneumothorax and hemothorax, a literature review revealed that the risk of subclavian vein puncture-induced parenchymal injury resulting in pulmonary hemorrhage without pneumothorax is extremely rare during subclavian puncture [2–3]. The outcome is usually benign, but it can be more lethal in patients with heart failure, chronic lung disease, or coagulopathy. The patient’s high INR on the day of operation probably facilitated the occurrence of the massive pulmonary hemorrhage. Additionally, the presence of serious heart failure caused serious respiratory distress and finally pulmonary edema. CONCLUSION Possible access-related complications during pacemaker implantation include pneumothorax, hemopneumothorax, lung laceration, inadvertent arterial puncture, air embolism, arteriovenous fistula, thoracic duct injury, and brachial plexus injury. In patients with respiratory disease, heart failure and coagulopathy some of these complications might cause severe respiratory distress. An absence of pneumothorax does not eliminate the possibility of lung injury during pacemaker insertion. Patients with respiratory distress after pacemaker implantation who do not show any pneumothorax on initial chest x-ray should be further evaluated using MDCT. Informed Consent: Written informed consent was obtained from the patient who participated in this study. 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.Y., A.O.; Design – N.S.Y.; Supervision – N.S.Y., A.O.; Materials – N.S.Y., A.O.; Data collection &/or processing – A.O., C.T.; Analysis and/or interpretation – N.S.Y., A.O.; Writing – N.S.Y.; Critical review – C.T., A.T.A.

REFERENCES

Figure 1.

Noncontrast chest CT revealing localized alveolar hemorrhage under newly fashioned pacemaker pocket on the left without pneumothorax.

1. Littleford PO, Parsonnet V, Spector SD. Method for the rapid and atraumatic insertion of permanent endocardial pacemaker electrodes through the subclavian vein. Am J Cardiol 1979;43:980–2. 2. Kossaify A, Nicolas N, Edde P. Hemoptysis after subclavian vein puncture for pacemaker implantation: importance of wire-guided venous puncture. Clin Med Insights Case Rep 2012;5:119–22. 3. Goldberg A, Rosenfeld I, Marmor A. Hemoptysis-a rare complication of pacemaker implantation. Indian Pacing Electrophysiol J 2008;8:75– 6.

Case Report

GASTROENTEROLOGY

North Clin Istanb 2018;5(3):256–260 doi: 10.14744/nci.2017.79446

Infliximab use in ulcerative colitis flare with clostridium difficile infection: A report of two cases and literature review Bhupinder S. Romana, Abdulmajeed A. Albarrak, Mohamad H. Yousef, Veysel Tahan Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri, USA

ABSTRACT Clostridium difficile infection (CDI) is a major cause of morbidity and mortality in patients with inflammatory bowel disease (IBD), especially in ulcerative colitis (UC). The incidence and severity of CDI in IBD has shown an increasing trend in the last two decades. Patients with IBD are predisposed to CDI secondary to the recurrent use of antibiotics, corticosteroids, and immunosuppressants and secondary to dysbiosis. It is clinically challenging to distinguish the symptoms of CDI from an IBD flare. The worsening of IBD symptoms demands escalation of steroids or initiation of biologics. However, the management of CDI in IBD, not responding to antibiotics, is not well described beyond a few case reports. We report two cases of CDI with active UC flare. The patients did not respond to antibiotics or intravenous corticosteroids but had rapid resolution of CDI symptoms after receiving infliximab infusion. The optimal dosing and infusion frequency of infliximab in management of CDI in UC/IBD remains to be established. Keywords: Clostridium difficile; comorbidity; dual; infliximab; tumor necrosis; treatment; ulcerative colitis.

Cite this article as: Romana B. S., Albarrak A. A., Yousef M. H., Tahan V. Infliximab use in ulcerative colitis flare with clostridium difficile infection: A report of two cases and literature review. North Clin Istanb 2018;5(3):256–260.

nflammatory bowel disease (IBD) patients, especially those with ulcerative colitis (UC), are at a high risk of developing Clostridium difficile infection (CDI) and related complications. CDI has been reported in 1.8%–5.7% of the patients hospitalized for UC [1]. IBD patients with CDI have poor outcomes with increased severity of relapse, longer hospital stay, and high rates of colectomy and mortality [2]. Approximately 10% of IBD patients develop CDI at the time of diagnosis or during the course of their disease [3, 4]. Colon involvement increases the risk of CDI by several fold compared with small bowel disease. Probably due to this reason, UC patients have a higher risk of developing CDI compared to Crohn’s disease (CD) patients [1]. IBD patients also have a higher rate (8% vs 1%) of asymptomatic carriage of C. difficile than the general healthy population

[5]. The management of CDI in IBD, not responding to antibiotics, is a challenge. Here we report two cases of UC flare secondary to CDI. CASE REPORTS Case 1 – A 21-year-old female with the history of panUC presented with bloody diarrhea. She was having approximately 20 bowel movements a day along with lower abdominal pain, fever, tenesmus, and urgency. The patient was diagnosed with pan-UC 3 years ago using colonoscopy and mucosal biopsies. She achieved clinical remission with high prednisone dose for 3 weeks with a gradual tapering off and was on maintenance therapy with azathioprine and mesalamine. Due to financial

Received: September 05, 2017 Accepted: November 09, 2017 Online: May 25, 2018 Correspondence: Dr. Veysel TAHAN. Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri, USA. Phone: +1 573 884-6044 e-mail: tahanv@health.missouri.edu © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Romana et al., Ulcerative colitis flare with Clostridium difficile infection

reasons, she discontinued all her medications after a few months of remission. She stayed in remission until 3 months ago when she was admitted to an outside hospital with fever, abdominal pain, and bloody stools. Stool studies were negative for infection including that with C. difficile. Colonoscopy showed mucosal inflammation in the rectum and sigmoid and descending colon. Mucosal biopsies indicated acute or chronic colitis without dysplasia. Intravenous steroids were initiated, and the patient was discharged on oral prednisone with a gradual tapering off. Prior to the current admission, she received two doses of infliximab. Patient appeared sick on initial presentation. She was afebrile and tachycardic with a heart rate of 112/min and had soft blood pressure of 98/49 mmHg without orthostatic hypotension and 95% oxygen saturation. Her bowel sounds were hypoactive, and the abdomen was diffusely tender to palpation. Laboratory workup was significant for an elevated white blood cell (WBC) count of 21,000/ÂľL with left shift, microcytic anemia with hemoglobin of 11 g/dL, erythrocyte sedimentation rate (ESR) 29 mm/h, and Creactive protein (CRP) 18 mg/dL. Other renal and liver chemistries were normal. Stool polymerase chain reaction (PCR) was positive for toxin-producing C. difficile with a negative hyper-virulent 027-NAP1-B1 strain. Computed tomography of the abdomen with intravenous contrast (Fig. 1A, B) showed multifocal, moderate mural thickening throughout the colon, most pronounced in the ascending colon. The appendix was dilated with mild periappendiceal fat stranding along with enlarged right lower quadrant mesenteric lymph nodes. Flexible sigmoidoscopy (Fig. 2) showed friable, granular mucosa with pseudo membrane formation, which was consistent with Mayo Class 2 endoscopic disease activity. Mucosal biopsies showed chronic active colitis with moderate ac-

257

tivity and granulation tissue. The test for cytomegalovirus stain showed negative results. Treatment was initiated with oral vancomycin and intravenous metronidazole along with aggressive intravenous hydration. General surgery department was consulted, and it recommended against acute surgical intervention. Patient failed to improve over the next 72 h; thus, a decision was made to start intravenous methyl prednisone 40 mg daily with a gradual tapering off. WBC count, ESR, and CRP levels started improving, but diarrhea persisted. Infliximab levels were less than 1 mcg/mL. The patient received a dose of 10 mg/kg infliximab, resulting in the resolution of diarrhea over the next 24 h. She successfully completed a 2-week course of vancomycin and metronidazole and had completely recovered from the flare at a follow-up visits after 2 and 6 weeks. Case 2 â&#x20AC;&#x201C; A 19-year-old male with a history of pan-UC presented with diarrhea and abdominal pain. He complained of watery diarrhea, on and off mixed with blood, associated with urgency and lower abdominal pain. The patient was diagnosed with pan-UC 4 months ago using colonoscopy and mucosal biopsies. Oral mesalamine was initiated, and he achieved a clinical remission within few weeks. He had experienced two episodes of CDI since the onset of UC. The first episode was treated with oral metronidazole and the second with a 4-week taper

Figure 1. CT

scan of abdomen and pelvis with intravenous contrast shows moderate wall thickening throughout the colon, most pronounced in the ascending colon.

Figure 2. Endoscopic view of sigmoid colon showing friable, granular mucosa with pseudo membrane formation consistent with severe Clostridium difficile infection.

258

of oral vancomycin. He remained asymptomatic for more than a month. Patientâ&#x20AC;&#x2122;s vital signs were stable on presentation. There was no fever, tachycardia, or hypotension. Abdomen was tender to palpation with normal bowel sounds. Laboratory workup showed hemoglobin levels of 10 g/dL and ESR 25 mm/h. Other hematology and biochemistries were within the normal range. Stool PCR was positive for toxin-producing C. difficile with a negative hyper-virulent strain. Treatment was initialed with oral vancomycin and intravenous steroids. Patient had resolution of hematochezia, but severe diarrhea persisted. He received 5 mg/kg infliximab infusion after 5 days, resulting in complete resolution of diarrhea within 24 h. He was re-evaluated in the clinic after 3 months and continues to do well on infliximab infusion every 8 weeks. DISCUSSION

C. difficile is a gram-positive, anaerobic, spore-forming, toxin-producing bacillus transmitted through the fecaloral route. In the late 1970s, it was first recognized as a causative agent of antibiotic-related pseudomembranous colitis [6]. It slowly emerged as the leading cause of gastroenteritis-related mortality, and the incidence of CDI has been steadily rising over the decades. In 2011, C. difficile was responsible for approximately half a million cases of infection and 29.000 deaths in the US [7]. Since 2005, the hyper-virulent strain of C. difficile, commonly referred as NAP1/B1/027, has been responsible for frequent outbreaks in North America, England, Europe, and parts of Asia [8]. Community-acquired CDI is seen in the absence of antibiotic use. It is also emerging in increasing proportions; a 2011 US study reported an adjusted national rate of 51.9 per 100.000 population [7]. Dysbiosis appears to play a vital role in the pathogenesis of both IBD and CDI [9]. Dysregulation of immune tolerance to the commensal gut microbiota possibly leads to mucosal inflammation in IBD. Reduced microbiota diversity also promotes C. difficile transmission and germination. The cytotoxic effects of C. difficile toxin damage the epithelial barrier, promote bacterial adhesion, and increase mucosal permeability, thus, contributing to the pathogenesis of IBD [10]. The fundamental question of whether CDI is a cause or outcome of IBD still remains unanswered. CDI may cause superimposed colitis in IBD or might precipitate an IBD flare with two sepa-

North Clin Istanb

rate, but simultaneous, ongoing inflammatory processes [10]. Probably this is the reason that UC flare patients co-infected with C. difficile have poorer long-term outcomes than those not infected with this bacterium [11]. Another hypothesis is that C. difficile might be just a colonizer in IBD patients, and disease flares are completely independent of its presence [10]. It is a diagnostic dilemma to differentiate whether the symptoms are due to a flare of chronic IBD or new CDI. American Collage of Gastroenterology (ACG) 2013 guidelines recommend that all IBD patients with a disease flare or new-onset diarrhea must be tested for CDI (12). PCR detects toxin-producing genes and is currently the preferred test for CDI. It is a rapid test with high sensitivity (>90%) and high specificity (>95%) [13]. Enzyme immunoassay detects toxins A and B in stools. It is rapid, cost effective, and has variable sensitivity (63%â&#x20AC;&#x201C;94%) and specificity (75%â&#x20AC;&#x201C;100%) [14]. It is important to emphasize that PCR can detect C. difficile isolates that contain inactive toxin genes, which are not actively transcribing toxins, leading to false-positive tests. A positive PCR also cannot differentiate between an asymptomatic carrier and an active infection. Testing should be performed only on unformed stool to reduce the false-positive rates. An American Gastroenterology Association expert review recommends that IBD should be considered as a severity marker of CDI and vancomycin or fidaxomicin should be considered as first-line antibiotics. Patients with mild to moderate disease are treated with 125 mg oral vancomycin four times a day. Those with severe or complicated disease should be given a higher oral dose of 500 mg vancomycin four times a day combined with 500 mg intravenous metronidazole 8 hourly and vancomycin enemas along with early surgery consultation [12]. The second important decision is regarding the management of immune suppression with ongoing infection. ACG 2013 guidelines recommend simultaneously starting empirical therapy for CDI and IBD flare in cases of severe colitis while awaiting C. difficile test results. The ongoing immunosuppressive medications should be continued while treating CDI. The initiation of corticosteroids or anti-tumor necrosis factor (TNF) therapy is discouraged in the first 72 h [12]. Using a combination of immunomodulators and antibiotics in CDI tends to have worse outcomes than using antibiotics alone [15]. Intravenous corticosteroids are commonly the first choice in escalation of immunosuppression when CDI

Romana et al., Ulcerative colitis flare with Clostridium difficile infection

symptoms do not improve with antibiotics alone. The patient should be monitored closely for worsening of CDI symptoms or impending complications like toxic megacolon or perforation. Infliximab is a chimeric Ig G4 monoclonal antibody targeting TNF-alpha (TNF-α). It is frequently used for induction of rapid remission in patients with fulminant UC. However, it has not been very well studied for use in UC flare secondary to CDI [16]. Induction of TNF-α by C. difficile toxins A and B in addition to other cytokines in causing inflammation suggests the potential role of anti-TNF therapy in CDI [17]. Anti-TNF therapy was found to be protective against CDI in a study [18]. In another population-based study, infliximab was not found to be associated with an increased risk of developing CDI [19]. Infliximab infusion resulting in therapeutic trough levels resulted in resolution of recurrent CDI symptoms in a single reported case of UC [20]. Infliximab drug level of less than 0.5 μg/mL requires dose escalation or shortening of interval between the infusions [21]. Contrary to the above evidence, Razik et al. reported more episodes of recurrent CDI in IBD patients on infliximab, whereas those on adalimumab did not show an increased risk. Azathioprine, methotrexate, and cyclosporine did not increase the risk of recurrent CDI [22]. Similarly, Zhang et al. [23] showed an increased risk of CDI in IBD patients on infliximab and antibiotics. A recent population-based study in Canada showed increased risk of CDI among IBD patients who were on corticosteroids or anti-TNF agents [24]. Immunotherapy, with intravenous immunoglobulin (IVIG), has been attempted in recurrent CDI with limited success in small studies [25, 26]. The rationale is that patients with severe or recurrent CDI have lower serum antitoxin antibody levels [27]. Fecal microbiota transplantation is less effecttive in clearing recurrent CDI in IBD patients than in patients without IBD (74.4% vs 92.1%) [28]. It was also associated with IBD flare in onefourth of the patients in the same study. There is a paucity of literature on the use of corticosteroids, infliximab, or IVIG in CDI associated with IBD. Furthermore, there is contradicting data on the beneficial effect of infliximab in CDI. Both of our patients did not respond to antibiotics and corticosteroids for 72 h but showed rapid improvement with infliximab infusion. Checking serum infliximab levels during a flare might be useful in guiding further therapy for CDI. Prospective studies in the future will likely provide more insight on the use of biologics in IBD flare associated with CDI.

259

Informed Consent: Written informed consent was obtained from the patient who participated in this study. 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 – B.S.R., A.A.A., M.H.Y., V.T.; Design – B.S.R., A.A.A., M.H.Y., V.T.; Supervision – B.S.R., A.A.A., M.H.Y., V.T.; Materials – B.S.R., A.A.A., M.H.Y., V.T.; Data collection &/ or processing – B.S.R., A.A.A., M.H.Y., V.T.; Analysis and/or interpretation – B.S.R., A.A.A., M.H.Y., V.T.; Writing – B.S.R., A.A.A., M.H.Y., V.T.; Critical review – V.T.

REFERENCES 1. Nguyen GC, Kaplan GG, Harris ML, Brant SR. A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am J Gastroenterol 2008;103:1443–50. 2. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut 2008;57:205–10. 3. Rodemann JF, Dubberke ER, Reske KA, Seo DH, Stone CD. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin Gastroenterol Hepatol 2007;5:339–44. 4. Binion DG. Clostridium difficile Infection in Patients with Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2012;8:615–7. 5. Clayton EM, Rea MC, Shanahan F, Quigley EM, Kiely B, Hill C, et al. The vexed relationship between Clostridium difficile and inflammatory bowel disease: an assessment of carriage in an outpatient setting among patients in remission. Am J Gastroenterol 2009;104:1162–9. 6. Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med 1978;298:531–4. 7. Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015;372:825–34. 8. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431–55. 9. Tamboli CP, Neut C, Desreumaux P, Colombel JF. Dysbiosis in inflammatory bowel disease. Gut 2004;53:1–4. 10. Bien J, Palagani V, Bozko P. The intestinal microbiota dysbiosis and Clostridium difficile infection: is there a relationship with inflammatory bowel disease? Therap Adv Gastroenterol 2013;6:53–68. 11. Jodorkovsky D, Young Y, Abreu MT. Clinical outcomes of patients with ulcerative colitis and co-existing Clostridium difficile infection. Dig Dis Sci 2010;55:415–20. 12. Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013;108:478– 99. 13. Deshpande A, Pasupuleti V, Rolston DD, Jain A, Deshpande N, Pant

260 C, et al. Diagnostic accuracy of real-time polymerase chain reaction in detection of Clostridium difficile in the stool samples of patients with suspected Clostridium difficile Infection: a meta-analysis. Clin Infect Dis 2011;53:e81–90. 14. Merz CS, Kramer C, Forman M, Gluck L, Mills K, Senft K, et al. Comparison of four commercially available rapid enzyme immunoassays with cytotoxin assay for detection of Clostridium difficile toxin(s) from stool specimens. J Clin Microbiol 1994;32:1142–7. 15. Ben-Horin S, Margalit M, Bossuyt P, Maul J, Shapira Y, Bojic D, et al; European Crohn’s and Colitis Organization (ECCO). Combination immunomodulator and antibiotic treatment in patients with inflammatory bowel disease and clostridium difficile infection. Clin Gastroenterol Hepatol 2009;7:981–7. 16. Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P, Grännö C, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005;128:1805–11. 17. Flegel WA, Müller F, Däubener W, Fischer HG, Hadding U, Northoff H. Cytokine response by human monocytes to Clostridium difficile toxin A and toxin B. Infect Immun 1991;59:3659–66. 18. Ananthakrishnan AN, Oxford EC, Nguyen DD, Sauk J, Yajnik V, Xavier RJ. Genetic risk factors for Clostridium difficile infection in ulcerative colitis. Aliment Pharmacol Ther 2013;38:522–30. 19. Schneeweiss S, Korzenik J, Solomon DH, Canning C, Lee J, Bressler B. Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infections. Aliment Pharmacol Ther 2009;30:253–64. 20. Seicean A, Moldovan-Pop A, Seicean R. Ulcerative colitis worsened after Clostridium difficile infection: efficacy of infliximab. World J Gas-

North Clin Istanb troenterol 2014;20:5135–40. 21. Steenholdt C, Bendtzen K, Brynskov J, Thomsen OØ, Ainsworth MA. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn’s disease. Scand J Gastroenterol 2011;46:310–8. 22. Razik R, Rumman A, Bahreini Z, McGeer A, Nguyen GC. Recurrence of Clostridium difficile Infection in Patients with Inflammatory Bowel Disease: The RECIDIVISM Study. Am J Gastroenterol 2016;11:1141–6. 23. Zhang T, Lin QY, Fei JX, Zhang Y, Lin MY, Jiang SH, et al. Clostridium Difficile Infection Worsen Outcome of Hospitalized Patients with Inflammatory Bowel Disease. Sci Rep 2016;6:29791. 24. Singh H, Nugent Z, Yu BN, Lix LM, Targownik LE, Bernstein CN. Higher Incidence of Clostridium difficile Infection Among Individuals With Inflammatory Bowel Disease. Gastroenterology 2017;153:430– 8.e2. 25. Abougergi MS, Broor A, Cui W, Jaar BG. Intravenous immunoglobulin for the treatment of severe Clostridium difficile colitis: an observational study and review of the literature. J Hosp Med 2010;5:E1–9. 26. McPherson S, Rees CJ, Ellis R, Soo S, Panter SJ. Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea. Dis Colon Rectum 2006;49:640–5. 27. Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001;35:189–93. 28. Khoruts A, Rank KM, Newman KM, Viskocil K, Vaughn BP, Hamilton MJ, et al. Inflammatory Bowel Disease Affects the Outcome of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection. Clin Gastroenterol Hepatol 2016;14:1433–8.

Case Report

CARDIAC SURGERY

North Clin Istanb 2018;5(3):261–263 doi: 10.14744/nci.2017.79037

Open repair of a type Ia endoleak with a giant abdominal aortic aneurysm sac Cemal Kocaaslan,1 Mustafa Aldag,1 Tamer Kehlibar,2 Mehmet Yilmaz,2 Ebuzer Aydin,1 Bulend Ketenci2 Department of Cardiovascular Surgery, Istanbul Medeniyet University Faculty of Medicine, Istanbul, Turkey

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

ABSTRACT Endovascular aneurysm repair (EVAR) has been widely accepted as a safe and effective treatment for abdominal aortic aneurysm. Endoleaks are the most common complication after EVAR and require urgent interventions. Usually endoleaks can be treated with endovascular procedures using a variety of techniques. Despite these interventions, if the endoleak still persists, conventional open surgery should be evaluated. A 67-year-old man had been treated with EVAR after a ruptured abdominal aortic aneurysm 7 years ago. Later on, a type II endoleak was detected due to the inferior mesenteric artery and treated with coil embolization at the first follow-up year. The patient was admitted to our emergency department due to abdominal pain. Computed tomography angiography demonstrated a type Ia endoleak from the posterior side of the graft with a huge abdominal aortic aneurysm sac (22.9 cm) without rupture. The patient was hemodynamically unstable, and open surgical repair was performed via left anterolateral thoracotomy and laparotomy. Here we report a case where we performed open repair of a type Ia endoleak and discuss the repairing techniques for type Ia endoleak in the light of the literature. Keywords: Abdominal aortic aneurysm; endovascular procedures; reoperation; type Ia endoleak.

Cite this article as: Kocaaslan C., Aldag M., Kehlibar T., Yilmaz M., Aydin E., Ketenci B. Open repair of a type Ia endoleak with a giant abdominal aortic aneurysm sac. North Clin Istanb 2018;5(3):261–263.

ndovascular aortic aneurysm repair (EVAR) is a less invasive technique than open surgery and has been widely accepted as a safe and effective treatment for abdominal aortic aneurysms (AAA); it offers several potential benefits over conventional surgical procedures and was first reported by Parodi et al. [1] in 1991. Despite the advancements in endovascular technology and the growing experience of physicians, endoleaks remain to be the complex complications after endovascular AAA repairs. Type Ia endoleak is defined as persistent blood flow into the aneurysmal sac from proximally. Incomplete proximal sealing results in type Ia endoleak in about 4% of all patients treated with EVAR [2]. In addition, type I endoleak is associated with an increased

risk of post-procedural aneurysm and late aneurysm-related mortality, and re-intervention is recommended as soon as possible after diagnosis [3]. Most endoleaks can be successfully treated using endovascular methods, but open conversion can be required with a rate of 2.1% as reflected in the European Collaborators on Stent Graft Techniques for Aortic Aneurysm Repair Registry [4]. Stent-graft extension combined with visceral artery bypass and use of chimney or periscope grafts to extend landing zones may be considered in open surgery [5]. Here we report the case of a patient who underwent open surgical treatment of a type Ia endoleak after EVAR with a 22.9-cm abdominal aortic aneurysm sac.

Received: May 08, 2017 Accepted: July 07, 2017 Online: May 24, 2018 Correspondence: Dr. Cemal KOCAASLAN. Istanbul Medeniyet Universitesi Tip Fakultesi, Kalp Damar Cerrahisi Anabilim Dali, Istanbul, Turkey. Phone: +90 505 391 98 12 e-mail: cemalkocaaslan@yahoo.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

262

North Clin Istanb

CASE REPORT A 67-year-old male patient was admitted to another surgery institution with a ruptured infrarenal abdominal aortic aneurysm (6.2 cm) 7 years ago. Left iliac artery occlusion and femorofemoral bypass were performed with right aortoiliac graft insertion. Afterwards, a type II endoleak was detected due to the inferior mesenteric artery and was treated with coil embolization at the first followup year, after which the patient was lost to follow-up. The patient was admitted to our emergency department due to abdominal pain. Computed tomography angiography demonstrated a type Ia endoleak from the posterior side of the graft with a huge aneurysm sac (22.9 cm) without rupture (Fig. 1A, B). His right kidney was atrophic, and the hemoglobin level was detected to be 8.1 g/dL. Endovascular repair techniques were considered first, but the proximal neck length was <6 mm, which was very near to the left renal artery; the vascular team lacked the experience of endovascular repair techniques for type Ia endoleaks, so the conventional open surgery was immediately planned. The patient was hemodynamically unstable, and inotropic drug infusion was initiated before the surgery. The proximal side of the endovascular graft was at the juxtarenal part of the aorta, and clamping by abdominal incision could be complicated; thus, left anterolateral thoracotomy was performed for safe clamping. The endovascular graft and the surrounding aortic tissue were resected with a wide laparotomy (Fig. 2A, B). An aortobifemoral bypass was performed using a Dacron graft. The proximal anastomosis was done with end-to-end configuration just below the superior mesenteric artery, and left renal artery bypass was established with the saphenous vein. The right renal artery was ligated as the right kidney was known to be atrophic. The patient was transferred to the intensive care unit after A

Figure 1. CT angiography showed a huge aneurysm sac and endovascular graft in the coronal plane (A) and horizontal plane (B).

the surgery; he died postoperative 6th hour due to persistent deep asidosis. Visceral or renal protection could not be provided during the surgery; total operation time was nearly 6 h, and four erythrocyte suspensions were replaced during the surgery and follow up. This study was approved ethically by Institutional Board. DISCUSSION Multiple techniques for the treatment of type Ia endoleak have been described in the literature with variable success rates. Usually, endoleaks can be treated with endovascular procedures. Standard endovascular treatment options for type Ia endoleaks include insertion of an aortic cuff to extend the endograft coverage more proximally or repeated ballooning or placement of a large-caliber, balloon-expandable stent inside the proximal endograft [6, 7]. Despite these interventions, if the endoleak still persists, conventional open surgery should be considered. Early detection and classification of the endoleaks are crucial for proper management and treatment. In the present case, the patient underwent open A

Figure 2. A huge aneurysm sac is seen after laparotomy (A); endovascular graft after resection (B).

Kocaaslan et al., Open repair of a type Ia endoleak with a giant abdominal aortic aneurysm sac

repair of a type Ia endoleak because the proximal neck length of the aneurysm was under 6 mm, which was very near to the left renal artery; moreover, the patient was hemodynamically unstable, and inotropic drug infusion had to be initiated before the surgery. Tan et al. [8] reported that type I endoleaks occur in up to 3% patients after EVAR and are associated with an increasing age, female gender, large endograft diameter, and unplanned graft extension. However, an increase in the diameter of aneurysmal sac due to other types of endoleaks could be a major reason for type I endoleak as seen as in the present case. In addition, when a type I endoleak is detected late, it is typically secondary to a caudad migration of the stent graft or continued dilatation of the neck [9]. The largest diameter of a giant unruptured AAA has been reported to be 25 cm in literature [10]. We observed a giant AAA sac 22.9 cm in diameter, which occurred due to a type Ia endoleak. Both endovascular and conventional open surgical procedures should be considered for type Ia endoleaks, but overcoming these complex complications remains a challenge. We did not get the expected result in this case, and the patient died. This is attributable to the preoperative conditions of the patient such as having cardiac inotropic support and being hemodynamically unstable. With the growing experience of physicians and development of new graft technologies, type Ia endoleaks are expected to be more successfully treated using endovascular techniques or hybrid procedures. Informed Consent: Written informed consent was obtained from the patient who participated in this study. 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.

263

Authorship Contributions: Concept – C.K., B.K.; Design – M.A., T.K., M.Y.; Supervision – E.A., B.K.; Materials – C.K., T.K., M.Y.; Data collection &/or processing – C.K., M.A.; Analysis and/or interpretation – C.K., M.A.; Writing – C.K., M.A.; Critical review – E.A., B.K.

REFERENCES 1. Parodi JC, Palmaz JC, Barone HD.Transfemoral intraluminal graft implantation for abdominal aortic aneurysms. Ann Vasc Surg 1991;5:491–9. 2. Chuter TA, Faruqi RM, Sawhney R, Reilly LM, Kerlan RB, Canto CJ, et al. Endoleak after endovascular repair of abdominal aortic aneurysm. J Vasc Surg 2001;34:98–105. 3. van Marrewijk C, Buth J, Harris PL, Norgren L, Nevelsteen A, Wyatt MG. Significance of endoleaks after endovascular repair of abdominal aortic aneurysms: The EUROSTAR experience. J Vasc Surg 2002;35:461–73. 4. Harris PL, Vallabhaneni SR, Desgranges P, Becquemin JP, van Marrewijk C, Laheij RJ. Incidence and risk factors of late rupture, conversion, and death after endovascular repair of infrarenal aortic aneurysms: the EUROSTAR experience. European Collaborators on Stent/graft techniques for aortic aneurysm repair. J Vasc Surg 2000;32:739–49. 5. Chun JY, Morgan R. Transcatheter Embolisation of type 1 endoleaks after endovascular aortic aneurysm repair with Onyx: When no other treatment option is feasible. Eur J Vasc Endovasc Surg 2013;45:141–4. 6. Tzortzis E, Hinchliffe RJ, Hopkinson BR. Adjunctive procedures for the treatment of proximal type I endoleak: the role of peri-aortic ligatures and Palmaz stenting. J Endovasc Ther 2003;10:233–9. 7. Veith FJ, Baum RA, Ohki T, Amor M, Adiseshiah M, Blankensteijn JD, et al. Nature and significance of endoleaks and endotension: summary of opinions expressed at an international conference. J Vasc Surg 2002;35:1029–35. 8. Tan TW, Eslami M, Rybin D, Doros G, Zhang WW, Farber A. Outcomes of patients with type I endoleak at completion of endovascular abdominal aneurysm repair. J Vasc Surg 2016;63:1420–7. 9. Fairman RM. Abdominal Aortic Aneurysms: Endovascular Treatment. In: Cronewett JL, Johston KW, editors. Rutherford’s Vascular Surgery, 2-Volume Set. 8th ed. Philadelphia: Elsevier/Saunders; 2014. p. 2046– 50. 10. Krievins D, Thora S, Zarins CK. Gigantic 25-cm abdominal aortic aneurysm. J Vasc Surg 2015;61:1067.

Case Report

CARDIOLOGY

North Clin Istanb 2018;5(3):264–267 doi: 10.14744/nci.2017.82160

Difficult management of a patient presenting with recurrent syncope caused by diffuse vasospasm Abdulkadir Uslu, Serdar Demir, Munevver Sari, Cem Dogan, Ozge Akgun, Mehmet Celik, Taylan Akgun Department of Cardiology, Health Sciences University, Kartal Kosuyolu Training and Research Hospital, Istanbul, Turkey

ABSTRACT Spontaneous and simultaneous multivessel coronary artery spasm may present with multisite myocardial ischemia, atrioventricular block, acute lung edema, cardiogenic shock, or ventricular fibrillation. In a case of syncope caused by vasospasm, the underlying mechanism may be complex, such as atrioventricular block and/or ventricular arrhythmia. Dual implantable cardioverter defibrillator (ICD) placement should be considered along with optimal medical treatment. This report is a description of a 57-year-old male patient who was admitted to the hospital with chest pain followed by loss of consciousness. As the patient had bradycardia, a diffuse spasm, and life-threatening ventricular arrhythmia during ischemic episodes, a dual ICD device was implanted. ICD treatment may be a good option in cases with a diffuse spasm that is hard to control with medical treatment due to the risk of life-threatening ventricular arrhythmia. Keywords: Complete atrioventrikuler block; syncope; vasospasm.

Cite this article as: Uslu A., Demir S., Sari M., Dogan C., Akgun O., Celik M., Akgun T. Difficult management of a patient presenting with recurrent syncope caused by diffuse vasospasm. North Clin Istanb 2018;5(3):264–267.

oth coronary vasospasms and beta blockers can cause cardiac syncope. Here, we present the case of a patient with recurrent syncope suspected due to sinus bradycardia caused by the chronic use of beta blockers. However, we noticed that the underlying mechanism of syncope was diffuse vasospasm causing complete atrioventricular block and ventricular arrhythmia. The patient was successfully managed with dual implantable cardioverter-defibrillator (ICD) implantation as well as oral nitrate and high-dose nondihydropyridine calcium channel blocker administration. In the case of syncope caused by vasospasm, the underlying mechanism may be complex, involving atrioventricular block and/or ventricular arrhythmias. Hence, dual ICD implantation should be considered along with optimal medical treatment.

CASE REPORT A 57-year-old male was admitted to our hospital with chest pain followed by loss of consciousness. It was stated that loss of consciousness was not related to the patient’s position, and according to the eyewitness’ statement, the patient’s eyes were open at that time. Episodes lasted for approximately 2–3 min. During the episode, fecal and urinary incontinence, tongue-biting, and tonic–clonic seizures were not observed. The medical history revealed that the patient was taking 5 mg amlodipine and 50 mg metoprolol succinate due to hypertension; there was no history of alcohol or cigarette consumption. The patient was then hospitalized and admitted to the cardiology department. Sinus bradycardia (45/min) was detected on electrocardiogram (ECG) at admission, and the patient’s blood pressure was 165/63 mmHg. Then, beta blocker

Received: October 21, 2017 Accepted: November 27, 2017 Online: September 13, 2018 Correspondence: Dr. Abdulkadir USLU. Saglik Bilimleri Universitesi Kartal Kosuyolu Yuksek Ihtisas Egitim ve Arastirma Hastanesi Istanbul, Turkey. Phone: +90 505 421 21 06 e-mail: dr.akadiruslu@gmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Uslu et al., An unusual case of coronary vasospasm

treatment was stopped. There were also no electrolyte disturbances on admission. No other pathology except sinus bradycardia was detected during 24-h ambulatory rhythm monitoring. On the third day of hospitalization, ST segment elevation at DII-DIII as well as aVF derivations and complete atrioventricular (AV) block were detected on ECG (Fig. 1). Emergency coronary angiography was performed, and diffuse spasm was detected at the left anterior descending, circumflex, and right coronary arteries (Fig. 2). After intracoronary administration of 300 mcg nitrate, vasospasm disappeared and ST elevation and AV block regressed (Figs. 3, 4). Because the patient had bradycardia, diffuse spasm, and life-threatening ventricular arrhythmia during ischemic episodes, dual implantable cardioverter-defibrillator (ICD) was implanted. Then, 50 mg isosorbid 5-mononitrate and 90 mg diltiazem 2Ă&#x2014;1 po treatment was initiated. Episodes of syncope continued, and ventricular fibrillation reoccurred during an ischemic episode because of vasospasm. During follow-up, the diltiazem dose was increased up to 480 mg, and episodes were taken under control . In the A

265

sixth-month follow-up, the patient had no complaints of angina and syncope and his vasospastic episodes were under control with treatment. DISCUSSION Here, we present the case of a patient with recurrent syncope suspected due to sinus bradycardia caused by the chronic use of beta blockers. However, we noticed that the underlying mechanism of syncope was in fact diffuse vasospasm causing high-grade AV block treated with oral

Figure 3. After intracoronary nitrate injection, ST segment elevation and atrioventricular block are resolved.

Figure 1. (A)

Electrocardiogram with ST segment elevation and complete atrioventricular block. (B) Coronary angiographic views that show diffuse coronary vasospasm.

Figure 2. After intracoronary nitrate injection, coronary vasospasm is released.

Figure 4. Electrocardiogram with ST segment elevation and complete atrioventricular block on inferior derivations.

266

nitrate and high-dose nondihydropyridine calcium channel blocker administration. The patient’s arrhythmias were successfully managed with dual ICD implantation. Endothelial dysfunction and enhanced vascular smooth muscle contractility are considered the major underlying mechanisms for the pathogenesis of coronary artery spasm; however, the variant angina has not been fully elucidated. In the literature, many primary pathophysiologic mechanisms that cause coronary vasospasms have been listed, such as imbalanced autonomic nervous activity, increased oxidative stress, chronic low-grade inflammation, magnesium deficiency, and genetic susceptibility [1, 2]. It is known that in a population with coronary artery disease with minimal atherosclerotic changes or even completely normal coronary arteries, myocardial ischemia associated with typical coronary vasospasm can result in severe clinical outcomes, such as SCD [2, 3]. Cardiac arrhythmias associated with myocardial ischemia have an important role in adverse cardiovascular events in patients with vasospastic angina. In their ambulatory ECG follow-up study, Onaka et al.[3] stated that vasospasm in multivessels or differentially localized coronary arteries is possible and that these patients can experience sudden cardiac death and malign arrhythmias. In a case presented by Ghadri et al. that includes a patient admitted with typical angina and high-grade AV block, coronary arteries were normal after nitrate administration, and they successfully treated the patient with long-term calcium channel blocker and nitrate administration [4]. In a case presented by Chuang et al., [5] a case with VF arrest due to vasospastic angina and a course of pulmonary edema, it was seen that coronary anatomy was normal after nitrate administration, and treatment was performed with high-dose calcium channel blocker administration and ICD implantation. In patients with vasospastic angina who are admitted with multivessel vasospasm and cardiac arrhythmia, in addition to the traditional treatment methods of calcium channel blocker and nitrate administration, dual ICD implantation has also been listed as a good treatment option in the literature. Similarly, Gul et al. successfully managed a patient who had recurrent angina attacks by bosentan therapy (an endothelin receptor antagonist), differently from conventional vasospastic angina treatment [6]. Simcha et al. reported on a patient with variant angina complicated by VF who was at a life-long risk for sudden death when exposed to myocardial ischemia [7, 8]. Although there are similar cases in the literature, our case differs. This is because after our patient was repeatedly examined with

North Clin Istanb

isolated syncope and his treatment was discontinued due to the risk of beta blocker-dependent bradycardia, his heart rhythm recovered, and we were planning his discharge when underlying Prinzmetal angina emerged and completely changed the course of clinical diagnosis and treatment. Therefore, we believe that it will be particularly helpful for clinicians to investigate the etiology of syncope in patients. In addition, during treatment management, it should be kept in mind that low-dose calcium channel blocker administration can be insufficient, as was the case in our patient, and ICD implantation should lower the rate of cardiovascular mortality that is unwanted in the long term. CONCLUSION Coronary vasospasm is one of the causes of cardiovascular syncope, and it is difficult to definitely diagnose the condition when it occurs in an angiographically normallooking vessel. Due to the risk of life-threatening ventricular arrhythmia, ICD implantation can be performed in cases with diffuse spasm that is hard to control with medical treatment. In these patients, standard doses of calcium channel blockers are frequently insufficient, and high-dose nondihydropyridine calcium channel blocker administration is required. Informed Consent: Written informed consent was obtained from the patient who participated in this study. 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.U., T.A.; Design – S.D., M.S., A.U., T.A.; Supervision – S.D., M.S., A.U., T.A.; Materials – S.D., M.S., A.U., T.A.; Data collection &/or processing – A.U., T.A.; Analysis and/or interpretation – A.U., T.A.; Writing – A.U., T.A.; Critical review – A.U., T.A.

REFERENCES 1. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Angina pectoris. I. A variant form of angina pectoris; preliminary report. Am J Med 1959;27:375–88. 2. Kusama Y, Kodani E, Nakagomi A, Otsuka T, Atarashi H, Kishida H, et al. Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology, and management. J Nippon Med Sch 2011;78:4–12. 3. Onaka H, Hirota Y, Shimada S, Kita Y, Sakai Y, Kawakami Y, et al. Clinical observation of spontaneous anginal attacks and multivessel spasm in variant angina pectoris with normal coronary arteries: evaluation by 24-hour 12-lead electrocardiography with computer analysis. J

Uslu et al., An unusual case of coronary vasospasm

Am Coll Cardiol 1996;27:38–44. 4. Ghadri JR, Ruschitzka F, Lüscher TF, Templin C. Prinzmetal angina. QJM 2014;107:375–7. 5. Chuang YT, Ueng KC. Spontaneous and simultaneous multivessel coronary spasm causing multisite myocardial infarction, cardiogenic shock, atrioventricular block, and ventricular fibrillation. Circ J 2009;73:1961–4. 6. Gül I, Aykan AC, Gökdeniz T, Celik S. A new hope in the treatment of coronary vasospasm: bosentan. Turk Kardiyol Dern Ars

267 2013;41:633–7. 7. Meisel SR, Mazur A, Chetboun I, Epshtein M, Canetti M, Gallimidi J, et al. Usefulness of implantable cardioverter-defibrillators in refractory variant angina pectoris complicated by ventricular fibrillation in patients with angiographically normal coronary arteries. Am J Cardiol 2002;89:1114–6. 8. Yasue H, Takizawa A, Nagao M, Nishida S, Horie M, Kubota J, et al. Long-term prognosis for patients with variant angina and influential factors. Circulation 1988;78:1–9.

Invıted Review

BASIC MEDICAL SCIENCES

North Clin Istanb 2018;5(3):268–273 doi: 10.14744/nci.2017.00483

The use of neodymium magnets in healthcare and their effects on health Cengiz Yuksel,1 Seyit Ankarali,2 Nehir Aslan Yuksel1 Department of Physiology, Institute of Health Sciences, Duzce University, Duzce, Turkey

Department of Physiology, Istanbul Medeniyet University Faculty of Medicine, Istanbul, Turkey

ABSTRACT The strong magnetic field properties of magnets have led to their use in many modern technologies, as well as in the fields of medicine and dentistry. Neodymium magnets are a powerful type of magnet that has been the subject of recent research. This review provides a brief explanation of the definition, history, and characteristics of rare earth magnets. In addition, a broad overview of results obtained in studies performed to date on the effects of magnets, and neodymium magnets in particular, on body systems, tissues, organs, diseases, and treatment is provided. Though they are used in the health sector in various diagnostic devices and as therapeutic tools, there is some potential for harmful effects, as well as the risk of accident. The research is still insufficient; however, neodymium magnets appear to hold great promise for both diagnostic and therapeutic purposes. Keywords: Health; magnet; neodymium.

Cite this article as: Yuksel C., Ankarali S., Aslan Yuksel N. The use of neodymium magnets in healthcare and their effects on health. North Clin Istanb 2018;5(3):268–273.

eodymium is a chemical element that was discovered in 1885. This element (atomic number 60) has a silvery-white metallic color and belongs to the group of lanthanides, which is a subgroup of rare earth elements (atomic numbers 57–71) in the periodic table and rapidly oxidizes in air. Lanthanides play important roles in new technological developments, such as wind turbines, electronic hybrid vehicles, and in the defense industry. In nature, neodymium does not exist in metallic or in mixed forms with other lanthanides but is refined for general use and has been mined in the USA, Brazil, India, Australia, Sri Lanka, and predominantly in China. Neodymium-iron-boron magnets were developed by General Motors and Hitachi in the 1980s. Because it provides high magnetic force even in lesser amounts, it has been increasingly given a more prominent role in the manufacture of strong permanent magnets made up of rare earth elements. In the field of information technol-

ogy, neodymium magnets are particularly used in hard disc drives, mobile phones, video and audio systems of television [1]. Neodymium magnets are also commonly used in magnetic separators, filters, ionizers, in production of on–off buttons, safety sector and security systems. Grease filter producers use neodymium magnets in metal separators to more effectively filter out iron powder in oil. Additionally, they are beneficial in covering machines, cars with awning and in the production of magnetic tool belts. They are also used in jewelry clips, identification badges and in the production of baby strollers that are attached to carriers via magnets. The health sector is another field where neodymium magnets are incorporated in medical devices for example in magnetic resonance imaging devices to diagnose and treat chronic pain syndrome, arthritis, wound healing, insomnia, headache, and several other diseases due to their

Received: June 01, 2017 Accepted: August 05, 2017 Online: April 12, 2018 Correspondence: Dr. Seyit ANKARALI. Istanbul Medeniyet Universitesi Tip Fakültesi, Fizyoloji Anabilim Dali, Istanbul,Turkey. Phone: +90 216 280 40 19 e-mail: seyitankarali@hotmail.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Yuksel et al., Effects of neodymium magnets on health

269

ability to generate a static magnetic field. An increase in their usage has been observed over the last decade [2]. These magnets are thought to have a curing effect and are therefore sometimes called â&#x20AC;&#x153;magic magnetsâ&#x20AC;?. NASA uses neodymium magnets to maintain the muscular tonus of astronauts during space flights [2]. Neodymium magnets have pushâ&#x20AC;&#x201C;pull forces and have been used as a motion-generating device in orthodontic treatments; molar distillation, and palatal expansion [3, 4]. Static magnetic field has been reported to stimulate bone formation via osteoblastic differentiation or activation [5, 6]. The amount of neodymium magnets used in all these areas has risen from 1 ton to 60.000 tons between 1983 and 2007. Since 1990, China has been predominant in the mining of rare earth elements. The mining of rare elements has various environmental impacts because of the low concentration of these substances; therefore, many countries have stopped the mining of rare elements and almost all countries depend on imports from China [1].

equal-sized, and same-weight platters were attached in the other group. The arteriole and venule diameters of the mice exposed to static magnetic field generated by neodymium magnets were demonstrated to be considerably reduced [10]. Another study, conducted in 2015, where the portal veins of dogs were cut and reconstructed, the anastomosis in one group was performed using traditional manual sutures and that in the other group was by covering it with rings comprising of neodymium magnets. In the latter, the recovery lasted for a considerably short time and the intima was smoother and regularly formed than in the former [11]. Bipolar ablation catheters, unipolar ablation catheters and bipolar catheters with magnets attached to them have been tried in thick and tight tissues where it is hard to create a full-thickness lesion like in the left ventricular wall. Both the transmural passage and the thickness of the lesion formed by the magnetized bipolar catheter were found to be higher than others [12].

Effects of neodymium magnets on health and medical usage Cardiovascular system

Neural system Magnets can be used to generate magnetic fields in neural electrical activity research. The effect of magnetic fields created using neodymium magnets on neural damage was examined in a study where they were applied on 17 healthy volunteers for 2 hours. Neuron specific enolase which is the determinant of neuronal damage and S100 blood levels were studied, the test conducted to measure mental ability revealed that the parameters tested on the 17 volunteers were not affected by the magnetic fields and to generate a magnetic field with neodymium magnets seemed to be safe on these parameters [13]. Recurrent transcranial magnetic stimulation (rTMS) is an approved and effective treatment method for major depression. Synchronized TMS (sTMS), which is the modified form of rTMS, has also been tried for the treatment of the same. A study conducted in 2014 revealed that while the occurrence rate of patients who suffered from major depression and treated with sTMS declined by 48%, it declined by 19% in the control group, and this difference was statistically significant. Neodymium magnets are used in TMS to generate magnetic fields and In contrast to electroconvulsive treatment for major depression, TMS does not require anesthesia [14]. Further, another study conducted in 2015 revealed the use of sTMS to be effective in the treatment of major depression [15]. Placing of magnets on upper and lower eyelids in the

In a study conducted in 2004, laser doppler was reported to significantly reduce blood flow and skin blood perfusion (SBF) in the 2nd and 4th fingers of the non-dominant hands of both poles of the neodymium magnet [7]. Another study indicated that neodymium magnetic fields increases the nail bed microcirculation although this study conflicted with other studies [8]. The flow of red blood cells in the skeletal muscle capillaries exposed to strong static magnetic fields has been reported to be reduced [9], Intra tumoral microcirculation is characterized by tortuous micro vessels with chaotic structures and unstable irregular blood flow. A study has reported a decrease in the blood stream and blood vessel density in tumors that were treated using static magnetic fields. In the same study, it was shown that in non-tumoral skeletal muscles exposed to static magnetic fields, platelet activation and adhesion increased [9]. The magnetic field generated by neodymium magnets is thought to increase microcirculation but the effects on this are not clearly known. In a study, a special device was surgically placed on the backs of laboratory mice. Neodymium magnets were attached to the device in one group, and non-magnetic,

270

treatment of lagophthalmos has obtained successful results [16]. Alternative treatment methods including magnetic therapy have been researched on menopause vasomotor symptoms and it has been found that they are not effective in the treatment of these symptoms [17]. In another study, to ensure glottis aperture in bilateral vocal cord paralysis, magnets were placed ex vivo in sheep larynx had the gap widened. The device provide a suitable glottis aperture that benefit from magnets and this may be used in the future [18]. Skeleton, muscle, and joints system The effect of neodymium magnet implants placed in rabbit tibia and that of non-magnetic implants on bone tissue have been compared. Magnetic implants reinforced both medulla and cortex around the bone tissue and the increase in the medulla was statistically significant [19]. In another study conducted using a trabecular damaged rabbit model, a magnetic scaffold was placed in the damaged area of the distal femoral epiphysis and cylindrical neodymium magnets (NdFeB) were placed in a nearby area, the interaction observed. At the end of the experiment, it was found that NdFeB protects against micro movements by keeping the magnetic scaffold constant and it is important in maintaining regular tissue regeneration [20]. In a randomized double blind placebo controlled research, the curing effect of neodymium magnets on osteoarthritis symptoms was investigated; participants were made to try on four types of wrist straps. During the comparison, magnetic neodymium wrist straps were used as an experimental device, and low magnified, demagnetized, and coppery wrist straps were used as control devices. The WOMAC Osteoarthritis Index, McGill Pain Questionnaire-Pain Rating Index (PRI), visual analog scale, and medicine intake were evaluated. Among these scales, only PRI subscales revealed statistically significant difference. Therapeutic benefits of wrist straps have attributable placebo effect. These devices have no major adverse effects therefore can be used for placebo effect [21]. In another study, the difficulty of forming a control group where magnetic bracelets tested, addressed that giving a weakly effective wristband to the control group might not be effective in relieving pain in arthritis as the participant could test the strength of the wrist [22].

North Clin Istanb

In a research in which the role of static magnetic field in carpal tunnel treatment was researched on, the effects of two different magnetic field levels on the median nerve were evaluated. In a randomized double blind placebo controlled research, 12-week long observation was performed after a 6-week long interference. Participants who were diagnosed with carpal tunnel syndrome using electrophysiological tests wore neodymium magnets and non-magnetic disks all night long. Boston Carpal Tunnel Questionnaire, symptom severity score (SSS), function severity score (FSS), and four parameters measuring the median neural activity were used. These parameters included sensory distal latency, sensory nerve action potential amplitude, motor distal latency, and compound motor action potential amplitude. Among the groups, no significant difference was found in SSS and FSS median nerve conduction. A recovery in symptoms was observed in a 6-week period for SSS and FSS in both groups. The change of symptoms in both magnetic and non-magnetic disc groups occurred in the same direction and size [23]. In two systematic reviews conduced in 2012 in which magnetic wristbands and several other alternative treatments were examined for arthritis, by citing the lack of enough research on the subject, it was concluded that there was no consistent evidence that it was effective for rheumatoid arthritis and osteoarthritis treatment [24, 25]. In a study, the effect of static magnetic field on the treatment of delayed onset muscle soreness revealed no difference with that of a placebo [26]. Gastrointestinal system In a study conducted in 2012, neodymium magnets were used to fix endoscopically determined colon tumors. During the laparoscopic surgery performed without tools such as fluoroscopy or ultrasonography, the magnets were used for an easy access to the tumor. The intraoperative localization of marked lesions was successful in 27 (96%) of 28 patients [27]. In an animal study, ring-shaped magnets were endoscopically used for magnetic compression anastomosis (magnamosis), being placed opposite to each other in the targeted areas [28, 29]. Magnets have also been surgically used in humans; unwanted tissues in the operative area were safely removed using magnetic forceps in 44 laparoscopic operations, including cholecystectomy, gastrojejunostomy, and splenectomy, performed on pediatric patients between 2009 and 2011 [30]. Previous studies on swallowed magnets have documented

Yuksel et al., Effects of neodymium magnets on health

life-threatening injuries including, fistula and perforation, particularly in children. In two separate studies comparing the number and size of magnets swallowed by children in 2002â&#x20AC;&#x201C;2009 and 2010â&#x20AC;&#x201C;2012, there was an increase in the number of cases involving more than one magnet and a decrease in the size of the magnet swallowed, but all cases required surgical intervention. This result was attributed to an increase in the availability of magnets to children in everyday life [31]. These findings suggest that the use of magnets rather than safety pins can be particularly harmful for children. North Atlantic American Society for Pediatric Gastroenterology, Hepatology, and Nutrition advocated for the ban on the sale of strong magnets including neodymium, but they stated in 2014 that these efforts were not effective enough. [32]. Magnet related injuries In a case report published in 2015 that led to the initiation of measures governing the use of magnets at the workplace, it was pointed out that a 52-year-old man was injured while trying to generate electricity for experimental purposes using a device containing neodymium magnets. The magnet crashed into pieces injuring his face. The report further discussed the difficulty of operating with strong magnets using traditional tools and the possible damages of uncontrolled movements caused by such tools. Accordingly, it was stated that there is also a need for medical equipment that are insensitive to magnetic effects [33]. Orientation of iron-containing nanoparticles by magnets and their use in pharmacotherapy Currently, magnetic iron oxide nanoparticles are used in several biomedical and neurobiological operations such as those performed for the monitoring and treatment of tumors. A study reported that the attachment of oxide nanoparticles to the astrocytic membrane and their entrance into the cells becomes easier by virtue of the magnetic field generated by neodymium magnets laid under the astrocyte cells in the brain [34]. Human stem cells in serum-free medium, to which an amount of magnetic nanoparticles containing iron (0.043 mg/ml) was added in a nontoxic level, were used along with neodymium magnets and observed on a daily basis. No effect on stem cell prepotency and proliferation was recorded was reported in this study [35]. In a study conducted on pigs in 2014, vascular stents

271

were rendered magnetic by means of neodymium magnets and, thus, ensured to hold to endothelium cells that were supported with iron particles. This may lead to an important development in stent-related procedures because the acceleration of endothelialization would reduce the risk of thrombosis [36]. An animal study published in 2012 had the orientation of stem cells containing iron particles to the targeted area in the retina again ensured with neodymium magnets. This appeared to be particularly important in the treatment of age-related macular degeneration and retinitis pigmentosa [37]. Nanoparticles loaded with cytotoxic chemotherapeutic agents can be oriented toward tumors. In tumor areas, capillary permeability increases and particles that cannot intercellularly travel elsewhere can pass into the tumor. This passage of nanoparticles can be reinforced through orientation by magnets [38]. In an experiment on aneurysm closure, magnets placed on the outer body of experimental rabbits were used to direct magnetic micro particles in the circulation toward the area for at least 30 minutes. Although aneurysmal recanalization was observed 12 weeks later during follow-up, this was an important study for possible new modalities in the treatment of aneurysms [39]. Another study conducted in 2014 showed that sperms exposed to magnetic field were more enduring [40]. Use of magnets in dentistry Magnets have also been used in orthodontic operations. The outward movement of the buried tooth root in cases of dental fracture can be achieved using magnets in 9â&#x20AC;&#x201C;12 weeks. The root reaching out can then be reformed by methods such as porcelain coating [41]. Neodymium magnets are used with coatings as they are not resistant to corrosion and gradual loss of strength [42]. Conclusion Electronic devices are being increasingly used in our lives. Fossil fuels are being replaced by renewable energies, a field that increasingly uses rare earth elements. These elements are used in electric cars and wind turbines. Although procurement challenges and high prices lead producers to seek alternatives, rare earth elements are still being used in numerous technology and Because of their demand, the health effects of these powerful magnets must be addressed along with their environmental impacts.

272

In this review, the history, definition, and properties of rare earth magnets were briefly explained. Additionally, basing on the results roughly examined from the studies carried out so far, we concluded that there are effects of magnets, especially neodymium magnets, on body systems, tissues, organs, diseases, and treatments. Although they have been used in various diagnostic devices in the health sector and as therapeutic tools, magnets are potentially harmful to the body and pose increased risk of accident. Despite insufficient studies conducted on the effects of neodymium magnets, they appear to have a great potential for both diagnostic and therapeutic procedures. 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., C.Y., N.A.Y.; Data collection &/or processing – S.A., C.Y., N.A.Y.; Analysis and/or interpretation – S.A., C.Y., N.A.Y.; Writing – S.A., C.Y., N.A.Y.; Critical review – S.A.

REFERENCES 1. Du X, Graedel TE. Global rare earth in-use stocks in NdFeB permanent magnets. J Ind Ecol 2011;15:836–43. 2. Colbert AP, Wahbeh H, Harling N, Connelly E, Schiffke HC, Forsten C, et al. Static magnetic field therapy: a critical review of treatment parameters. Evid Based Complement Alternat Med 2009;6:133–9. 3. Noar JH, Evans RD. Rare earth magnets in orthodontics: an overview. Br J Orthod 1999;26:29–37. 4. Tuncer C. Magnets and Applications in Orthodontics. GÜ Diş Hek Fak Derg 2006;23:131–5. 5. Ba X, Hadjiargyrou M, DiMasi E, Meng Y, Simon M, Tan Z, et al. The role of moderate static magnetic fields on biomineralization of osteoblasts on sulfonated polystyrene films. Biomaterials 2011;32:7831– 8. 6. Cunha C, Panseri S, Marcacci M, Tampieri A. Evaluation of the effects of a moderate intensity static magnetic field application on human osteoblast-like cells. Am J Biomed Eng 2012;2:263–8. 7. Mayrovitz HN, Groseclose EE. Effects of a static magnetic field of either polarity on skin microcirculation. Microvasc Res 2005;69:24–7. 8. Yan Y, Shen G, Xie K, Tang C, Wu X, Xu Q, et al. Wavelet analysis of acute effects of static magnetic field on resting skin blood flow at the nail wall in young men. Microvasc Res 2011;82:277–83. 9. Strieth S, Strelczyk D, Eichhorn ME, Dellian M, Luedemann S, Griebel J, et al. Static magnetic fields induce blood flow decrease and platelet adherence in tumor microvessels. Cancer Biol Ther 2008;7:814–9. 10. Morris CE, Skalak TC. Chronic static magnetic field exposure alters microvessel enlargement resulting from surgical intervention. J Appl Physiol (1985) 2007;103:629–36. 11. Wang SP, Yan XP, Xue F, Dong DH, Zhang XF, Ma F, et al. Fast magnetic reconstruction of the portal vein with allogeneic blood vessels in

North Clin Istanb canines. Hepatobiliary Pancreat Dis Int 2015;14:293–9. 12. Lee C, Choi EK, Kong HJ, Choy YB, Kim HC, Oh S. Generating radiofrequency ablation lesions using magnetically coupled bipolar catheters. Pacing Clin Electrophysiol 2011;34:934–8. 13. Oliviero A, Carrasco-López MC, Campolo M, Perez-Borrego YA, Soto-León V, Gonzalez-Rosa JJ, et al. Safety Study of Transcranial Static Magnetic Field Stimulation (tSMS) of the Human Cortex. Brain Stimul 2015;8:481–5. 14. Jin Y, Phillips B. A pilot study of the use of EEG-based synchronized Transcranial Magnetic Stimulation (sTMS) for treatment of Major Depression. BMC Psychiatry 2014;14:13. 15. Leuchter AF, Cook IA, Feifel D, Goethe JW, Husain M, Carpenter LL, et al. Efficacy and Safety of Low-field Synchronized Transcranial Magnetic Stimulation (sTMS) for Treatment of Major Depression. Brain Stimul 2015;8:787–94. 16. Barmettler A, Nissanka N, Rosenblatt MI, Rao R, Lipson D, Lelli GJ Jr. Magnetic systems for tarsorrhaphy. Ophthal Plast Reconstr Surg 2014;30:305–8. 17. Pinkerton JV, Stovall DW, Kightlinger RS. Advances in the treatment of menopausal symptoms. Womens Health (Lond) 2009;5:361–84. 18. Ciftci Z, Deniz M, Ciftci HG, Ozdemir DN, Isik A, Gultekin E. Magnetic Control of the Glottic Opening in an Ex Vivo Sheep Larynx Model: A Preliminary Study. J Voice 2016;30:621–5. 19. Leesungbok R, Ahn SJ, Lee SW, Park GH, Kang JS, Choi JJ. The Effects of a Static Magnetic Field on Bone Formation Around a Sandblasted, Large-Grit, Acid-Etched–Treated Titanium Implant. J Oral Implantol 2013;39:248–55. 20. Panseri S, Russo A, Sartori M, Giavaresi G, Sandri M, Fini M, et al. Modifying bone scaffold architecture in vivo with permanent magnets to facilitate fixation of magnetic scaffolds. Bone 2013;56:432–9. 21. Richmond SJ, Brown SR, Campion PD, Porter AJ, Moffett JA, Jackson DA, et al. Therapeutic effects of magnetic and copper bracelets in osteoarthritis: a randomised placebo-controlled crossover trial. Complement Ther Med 2009;17:249–56. 22. Greaves CJ, Harlow TN. Exploration of the validity of weak magnets as a suitable placebo in trials of magnetic therapy. Complement Ther Med 2008;16:177–80. 23. Colbert AP, Markov MS, Carlson N, Gregory WL, Carlson H, Elmer PJ. Static magnetic field therapy for carpal tunnel syndrome: a feasibility study. Arch Phys Med Rehabil 2010;91:1098–104. 24. Macfarlane GJ, Paudyal P, Doherty M, Ernst E, Lewith G, MacPherson H, et al; Arthritis Research UK Working Group on Complementary and Alternative Therapies for the Management of the Rheumatic Diseases. A systematic review of evidence for the effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatic diseases: rheumatoid arthritis. Rheumatology (Oxford) 2012;51:1707–13. 25. Macfarlane GJ, Paudyal P, Doherty M, Ernst E, Lewith G, MacPherson H, et al; Arthritis Research UK working group on Complementary and Alternative Therapies for Management of Rheumatic Diseases. A systematic review of evidence for the effectiveness of practitioner-based complementary and alternative therapies in the management of rheumatic diseases: osteoarthritis. Rheumatology (Oxford) 2012;51:2224–33. 26. Mikesky AE, Hayden MW. Effect of static magnetic therapy on recovery from delayed onset muscle soreness. Phys Ther Sport 2005;6:188–94. 27. Warnick P, Chopra SS, Raubach M, Kneif S, Hünerbein M. Intraoperative localization of occult colorectal tumors during laparoscopic surgery by magnetic ring markers-a pilot study. Int J Colorectal Dis

Yuksel et al., Effects of neodymium magnets on health

2013;28:795–800. 28. Jamshidi R, Stephenson JT, Clay JG, Pichakron KO, Harrison MR. Magnamosis: magnetic compression anastomosis with comparison to suture and staple techniques. J Pediatr Surg 2009;44:222–8. 29. Pichakron KO, Jelin EB, Hirose S, Curran PF, Jamshidi R, Stephenson JT, et al. Magnamosis II: Magnetic compression anastomosis for minimally invasive gastrojejunostomy and jejunojejunostomy. J Am Coll Surg 2011;212:42–9. 30. Padilla BE, Dominguez G, Millan C, Martinez-Ferro M. The use of magnets with single-site umbilical laparoscopic surgery. Semin Pediatr Surg 2011;20:224–31. 31. Strickland M, Rosenfield D, Fecteau A. Magnetic foreign body injuries: a large pediatric hospital experience. J Pediatr 2014;165:332–5. 32. Bousvaros A, Bonta C, Gilger M, Noel RA. Advocating for child health: how the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition took action against high-powered magnets. J Pediatr 2014;164:4–5.e1. 33. Aykan A, Güzey S, Avşar S, Öztürk S. Neodymium magnet injury causing nasal fracture: a case report. Ulus Travma Acil Cerrahi Derg 2015;21:231–4. 34. Lamkowsky MC, Geppert M, Schmidt MM, Dringen R. Magnetic field-induced acceleration of the accumulation of magnetic iron oxide nanoparticles by cultured brain astrocytes. J Biomed Mater Res A 2012;100:323–34.

273 35. Freitas ER, Santos RL, Lima EC, Guillo LA. Feeder-free culture of human embryonic stem cell line BG01V/hOG using magnetic fieldmagnetic nanoparticles system. Biomed Pharmacother 2013;67:17–21. 36. Uthamaraj S, Tefft BJ, Klabusay M, Hlinomaz O, Sandhu GS, Dragomir-Daescu D. Design and validation of a novel ferromagnetic bare metal stent capable of capturing and retaining endothelial cells. Ann Biomed Eng 2014;42:2416–24. 37. Yanai A, Häfeli UO, Metcalfe AL, Soema P, Addo L, Gregory-Evans CY, et al. Focused magnetic stem cell targeting to the retina using superparamagnetic iron oxide nanoparticles. Cell Transplant 2012;21:1137– 48. 38. Klostergaard J, Seeney CE. Magnetic nanovectors for drug delivery. Nanomedicine 2012;8 Suppl 1:S37–50. 39. Oechtering J, Kirkpatrick PJ, Ludolph AG, Hans FJ, Sellhaus B, Spiegelberg A, et al. Magnetic microparticles for endovascular aneurysm treatment: in vitro and in vivo experimental results. Neurosurgery 2011;68:1388–97. 40. Lee SH, Park CK. Effect of magnetized extender on sperm membrane integrity and development of oocytes in vitro fertilized with liquid storage boar semen. Anim Reprod Sci 2015;154:86–94. 41. Bondemark L, Kurol J, Hallonsten AL, Andreasen JO. Attractive magnets for orthodontic extrusion of crown-root fractured teeth. Am J Orthod Dentofacial Orthop 1997;112:187–93. 42. Yiu EY, Fang DT, Chu FC, Chow TW. Corrosion resistance of ironplatinum magnets. J Dent 2004;32:423–9.

Letter to the Editor

GENERAL SURGERY

North Clin Istanb 2018;5(3):274–276 doi: 10.14744/nci.2018.67625

The effects of neuromonitorization in thyroidectomies can be safely evaluated with the standardized technique Mert Tanal,

Mehmet Uludag

Department of General Surgery, University of Health Sciences, Istanbul Sisli Hamidiye Etfal Health Training and Research Hospital, Istanbul, Turkey

Cite this article as: Tanal M., Uludag M. The effects of neuromonitorization in thyroidectomies can be safely evaluated with the standardized technique. North Clin Istanb 2018;5(3):274–276.

To the Editor, We read the article written by Demiryas et al. [1] with interest, and we would like to offer some observations about the study based on the current literature. Though the purpose of the study was to determine the effect of intraoperative neuromonitoring (IONM) on thyroid surgery complications, the explanation of the IONM technique given in the Materials and Methods section was very limited. In addition, it would appear that only the recurrent laryngeal nerve (RLN) was stimulated and vagus nerve (VN) stimulation was not performed. The International Neural Monitoring Study Group published guidelines for RLN monitoring during thyroid surgery in 2011. The standardized technique includes VN stimulation both before thyroid dissection (V1) and after complete thyroidectomy (V2) [2]. V1 is used as a reference to verify the function of the IONM system and allows for subsequent dissection and RLN identification. V2 testing is the most appropriate technique to predict postoperative vocal cord function [2].

This protocol must be applied in order to optimize the prognostic value of IONM [2]. We suggest that because this standardized technique was not used, and because this study includes the data of patients from 2014 to 2016, the results regarding the effects of IONM might be misleading. Near-total thyroidectomies in which the RLN is partially visualized and total thyroidectomies in which the RLN is totally visualized were included in both groups. These two different techniques may lead to different RLN paralysis results. Complete dissection is greatly superior to simply localized or partial exposure of the nerve [3]. What were the vocal cord paralysis ratios of the near-total and total thyroidectomies? The preoperative diagnosis and hyperthyroidism ratios for the two groups were not provided. A high-risk thyroidectomy case, such as a substernal goiter, thyroid cancer, or Graves disease, may prolong the operation time. Without evaluating these factors, can the short duration of the operations in Group 1 only be attributed to IONM?

Received: September 07, 2018 Accepted: June 20, 2018 Online: September 14, 2018 Correspondence: Dr. Mert TANAL. Saglik Bilimleri Universitesi, Istanbul Sisli Hamidiye Etfal Egitim ve Arastirma Hastanesi, Genel Cerrahi Klinigi, Istanbul, Turkey. Tel: +90 212 373 50 00 e-mail: merttanal@yahoo.com © Copyright 2018 by Istanbul Provincial Directorate of Health - Available online at www.northclinist.com

Tanal et al., The effects of neuromonitorization in thyroidectomies can be safely evaluated with the standardized technique

The total hypocalcemia ratios were lower in the IONM group. Surgical factors, such as the extent of surgery, central node dissection, reoperation for bleeding, presence of Graves disease or thyroid cancer, operation for recurrent goiter, inadvertent parathyroid excision, and parathyroid autotransplantation may also affect the postoperative ratios of hypocalcemia [4]. Can a reduction in the rate of hypocalcemia be attributed to IONM without assessing these considerations? The conclusion of the article mentions that the authors’ research and similar studies in the literature did not reveal a benefit to IONM usage in terms of decreasing the rate of RLN injury. In the literature, the impact of IONM on RLN paralysis is still controversial. Nonetheless, in a recent meta-analysis of 34 comparative studies on this subject, it was determined that IONM significantly reduced total, temporary, and permanent RLN paralysis [5]. This study [1] is a retrospective study. Features such as the preoperative diagnosis, which can affect the results, were not evaluated and compared. The number of cases

275

was insufficient for a reliable assessment and the standard IONM technique was not implemented. Considering all of these limitations, the conclusions about IONM are questionable. REFERENCES 1. Demiryas S, Donmez T, Cekic E. Effect of nerve monitoring on complications of thyroid surgery. North Clin Istanb 2018;5:14–9. 2. Randolph GW, Dralle H; International Intraoperative Monitoring Study Group, Abdullah H, Barczynski M, Bellantone R, et al. Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement. Laryngoscope 2011;121 Suppl 1:S1–16. 3. Hermann M, Alk G, Roka R, Glaser K, Freissmuth M. Laryngeal recurrent nerve injury in surgery for benign thyroid diseases: effect of nerve dissection and impact of individual surgeon in more than 27,000 nerves at risk. Ann Surg 2002;235:261–8. 4. Lorente-Poch L, Sancho JJ, Muñoz-Nova JL, Sánchez-Velázquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surg 2015;4:82–90. 5. Bai B, Chen W. Protective Effects of Intraoperative Nerve Monitoring (IONM) for Recurrent Laryngeal Nerve Injury in Thyroidectomy: Meta-analysis. Sci Rep 2018;8:7761.

Author’s Reply

To the Editor, We are grateful for the interest of our colleagues in our article, “Effect of nerve monitoring on complications of thyroid surgery,” published in the Northern Clinics of Istanbul journal. However, we strongly believe that the stated aim and context of our article was not fully appreciated and that our clearly written purpose was not given enough attention. As we explained, it was a retrospective study of thyroid surgeries performed between 2014 and 2016 at a single center by a single surgeon. Our research was accepted for publication in 2017; therefore, data from the mentioned review article from 2018 was not available for consideration for this paper. Our study included a group of patients who had thyroidectomy indications and the operations were approved by an anesthesiology specialist at our state hospital. All of these patients were in a euthyroid state, and their postoperative primary pathological diagnoses were also

reported in our published paper. Preoperative diagnoses were disregarded in order to preserve the reliability and focus of our article, since there was no significant statistical correlation between the pathological primary diagnoses and the complications encountered. Interventions such as parathyroid surgery, retrosternal goiter surgery, preoperative planned oncological surgery, or neck dissection did not need to be mentioned because additional procedures were not performed at that time. The postoperative primary pathological diagnoses were reported; however, we did not mention each patient’s pathological diagnosis in greater detail in order to avoid adding unnecessary data. Furthermore, if the inclusion of the details mentioned above would have made an additional contribution to our paper, the editorial experts would certainly have urged us to do so during the meticulous evaluation period. As our colleagues will surely agree, when the text of an article is lengthened with nonessential information the reader may be distracted from the focus of article and the intended message may be lost.

276

In addition, we believe that mentioning the technical details of neuromonitorization, which is almost a ritual technique in endocrine surgery, would also have been extraneous and would not have served the concept of our article [1–3]. Developing new standards for the intraoperative neuromonitoring (IONM) technique was not the objective of this study and for this reason, superfluous, unnecessary technical details were not included. The data from patient files that really contribute to the aim of the study are what is appropriate in a retrospective paper. We object to the criticism that standard IONM was not implemented simply because the details of technical usage of the device were not mentioned. Finally, we wish to mention that the superiority of a study that included 191 surgeries performed by a single surgeon was completely ignored. We believe this experience with IONM contributed to the shorter operation time in the IONM group. It is accepted in endocrine surgery that the risks of recurrent laryngeal nerve (RLN) injury and hypocalcemia should be taken into account in near total thyroidectomies [4, 5]. The RLN is prone to damage and can easily be harmed during various intraoperative actions (e.g., cutting, clamping, stretching, compression, and heating) [6]. Cirocchi et al. [7] accepted near-total thyroidectomy as a total thyroidectomy in their study. We did not find any significant relationship between the surgical technique employed in our study and complication rates. As was clearly expressed in our paper, we found no meaningful data supporting a correlation between a decrease in RLN injuries and the use of IONM. We would like to emphasize once again here, as in our article, that we received no financial support during and/or after the study period. Furthermore, the research and results of this study presented no conflicts of interest. In terms of scientific paper writing technique, it is our opinion that the letter written by our colleagues seems to position itself as a post-review review, rather than a letter to the editor. It is important to remember that papers on retrospective research, despite all the limitations, are considered written products of general surgery. There are many retrospective studies in the literature from the field of endocrine surgery [5, 8, 9]. In addition, ethics policies in many hospitals of our country take the Helsinki Declaration into account, and due to widespread belief

North Clin Istanb

that prospective studies violate these terms, prospective studies are often not feasible. We would like to kindly remind you that the late Professor Doctor Sami Zan advised us: “Do not laugh at them. A doctor will not laugh, but smile!” Suleyman Demiryas,1

Turgut Donmez,2

Erdinc Cekic3

Department of General Surgery, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey

Department of General Surgery, Lutfiye Nuri Burat State Hospital, Istanbul, Turkey

Department of Otolaryngology Surgery, Lutfiye Nuri Burat State Hospital, Istanbul, Turkey

E-mail: suleyman.demiryas@istanbul.edu.tr doi: 10.14744/nci.2018.54775

REFERENCES 1. Wojtczak B, Sutkowski K, Kaliszewski K, Głód M, Barczyński M. Experience with intraoperative neuromonitoring of the recurrent laryngeal nerve improves surgical skills and outcomes of non-monitored thyroidectomy. Langenbecks Arch Surg 2017;402:709–17. 2. Dionigi G, Bacuzzi A, Barczynski M, Biondi A, Boni L, Chiang FY, et al. Implementation of systematic neuromonitoring training for thyroid surgery. Updates Surg 2011;63:201–7. 3. Randolph GW, Dralle H; International Intraoperative Monitoring Study Group, Abdullah H, Barczynski M, Bellantone R, et al. Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement. Laryngoscope 2011;121 Suppl 1:S1–16. 4. Sebastian M, Rudnicki J, Jakubaszko W, Zyśko D, Agrawal AK, Sebastian A. Clinical and biochemical factors affecting postoperative hypocalcemia after near-total thyroidectomy. Adv Clin Exp Med 2013;22:675–82. 5. Dinc T, Kayilioglu SI, Simsek B, Guldogan CE, Gulseren MO, Saylam B, et al. The evaluation of the complications observed in patients with bilateral total and bilateral near total thyroidectomy. Ann Ital Chir 2017;88:198–201. 6. Joliat GR, Guarnero V, Demartines N, Schweizer V, Matter M. Recurrent laryngeal nerve injury after thyroid and parathyroid surgery: Incidence and postoperative evolution assessment. Medicine (Baltimore) 2017;96:e6674. 7. Cirocchi R, Trastulli S, Randolph J, Guarino S, Di Rocco G, Arezzo A, et al. Total or near-total thyroidectomy versus subtotal thyroidectomy for multinodular non-toxic goitre in adults. sCochrane Database Syst Rev 2015:CD010370. 8. Frattini F, Mangano A, Boni L, Rausei S, Biondi A, Dionigi G. Intraoperative neuromonitoring for thyroid malignancy surgery: technical notes and results from a retrospective series. Updates Surg 2010;62:183–7. 9. Pisanu A, Porceddu G, Podda M, Cois A, Uccheddu A. Systematic review with meta-analysis of studies comparing intraoperative neuromonitoring of recurrent laryngeal nerves versus visualization alone during thyroidectomy. J Surg Res 2014;188:152–61.