Page 1

ISSN 2148 - 4902

NORTHERN CLINICS OF ISTANBUL • İSTANBUL KUZEY KLİNİKLERİ

Vol. 3 • No. 1 • Year 2016

Blink reflex in migraine headache • Factors affecting postoperative hypocalcemia after thyroid surgery: Importance of incidental parathyroidectomy • Relationship between

newborn craniotabes and vitamin D status • Rehabilitation after successful finger replantation • Stent versus bypass: The reasons and risk factors for early readmission to hospital after myocardial

revascularization • The use of complementary medicine in patients with diabetes • Is triglyceride/HDL ratio a reliable screening test for assessment of atherosclerotic risk in patients with chronic

inflammatory disease? • Relationship between size of varices and platelet count/spleen size ratio in cirrhotic patients • Comparison of mirtazapine, gabapentin and ondansetron to prevent intrathecal

morphine-induced pruritus • Acute appendicitis in pregnancy: Case series and review • A patient presenting with acute heart failure: A dilemma of diagnosis • Pleomorphic adenoma of the larynx • Fahr’s

INDEXED IN TUBITAK TR INDEX, EBSCO, CINAHL AND TURKIYE CITATION INDEX.

syndrome presenting with epileptic seizure: Two case reports • A rare cause of intestinal obstruction in a newborn: Congenital band compression • A brief summary of clinical types of psoriasis


NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ Editor-in-Chief

Vıce Editors

Bekir Durmus, M.D.

Berna Terzioglu Bebitoglu, M.D. Levent Doganay, M.D. Tunc Eren, M.D. Yavuz Bastug, M.D. Arzu Tatlipinar, M.D. Derya Buyukkayhan, M.D.

Scientıfıc Commıttee Abdullah Aydin, M.D.

Eren Ozek, M.D.

Kemal Memisoglu, M.D.

Recep Alp, M.D.

Adem Ozkan, M.D.

Eyup Gumus, M.D.

Kemal Nas, M.D.

Remzi Cevik, M.D.

Afitap Icagasioglu, M.D.*

Fahri Ovali, M.D.

Kemalettin Koltka, M.D.

S. Tahir Eren, M.D.

Ahmet Gocmen, M.D.

Fatih Goktay, M.D.

Leyla Karadeniz Bilgin, M.D.

Sabahat Aksaray, M.D.

Alaattin Ozturk, M.D.

Fatih Saygili, M.D.

Lutfullah Orhan, M.D.

Sait Naderi, M.D.

Ali Ihsan Dokucu, M.D.

Fatma Eti Aslan, M.D.

Mahmut Durmuş, M.D.

Salih Boluk, M.D.*

Ali Ozdemir, M.D.

Ferruh Isman, M.D.

Mehmet Ali Ozcan, M.D.

Salih Cetinkursun, M.D.*

Ali Riza Cenk Celebi, M.D.

Filiz Akyuz, M.D.

Mehmet Doganay, M.D.

Sarenur Gokben, M.D.

Ali Riza Odabas, M.D.

Filiz Topaloglu Demir, M.D.

Mehmet Eren, M.D.

Sahin Senay, M.D.*

Asiye Kanbay, M.D.

Fugen Aker, M.D.

Mehmet Kanbay, M.D.

Selcuk Mistik, M.D.

Atakan Yesil, M.D.*

Fusun Mayda Domac, M.D.

Mehmet Selcuki, M.D.

Serhat Citak, M.D.

Ateş Kadioglu, M.D.

Gizem Dinler Doganay, M.D.

Mehmet Tayyar, M.D.

Seyhan Hidiroglu, M.D.

Atilla Polat, M.D.

Gozde Kir Cinar, M.D.

Mehmet Tunca, M.D.

Seyhun Kurşat, M.D.

Ayhan Verit, M.D.

Gulbahar Sarac, M.D.*

Melek Celik, M.D.

Sibel Dogan, M.D.

Aysel Milanlioglu, M.D.*

Gulendam Kocak, M.D.

Melek Gura, M.D.

Selami Sozubir, M.D.*

Ayse Cikim Sertkaya, M.D.

Gulnur Tokuc, M.D.

Melih Atahan Guven, M.D.

Sema Yilmaz, M.D.*

Ayse Serap Karadag, M.D.

H. Muammer Karakas, M.D.

Metin Akbulut, M.D.*

Sevki Erdem, M.D.

Aysegul Gunduz, M.D.*

Hakan Erdogan, M.D.

Metin Kapan, M.D.

Soner Sanioglu, M.D.*

Aytekin Guven, M.D.*

Hale Akbaylar, M.D.

Mine Hekimgil, M.D.*

Sukran Kose, M.D.

Aytekin Oguz, M.D.

Haluk Vahaboglu, M.D.

Muhammed Fatih Onsuz, M.D. Tamer Okay, M.D.

Ayten Kadanali, M.D.

Hamit Okur, M.D.

Muhammet Tekin, M.D.

Baris Onder Pamuk, M.D.*

H. Isin Ozisik Karaman, M.D.* Murat Acar, M.D.

Tayfun Kirazli, M.D.

Bekir Atik, M.D.

Hasan Bombaci, M.D.

Murat Muhcu, M.D.

Tongabay Cumurcu, M.D.

Beyhan Cengiz Ozyurt, M.D.

Hasan Borekci, M.D.

Mustafa Aldemir, M.D.*

Tolga Baglan, M.D.*

Birsen Yurugen, M.D.

Haydar Sur, M.D.

Mustafa Caliskan, M.D.

Tolga Canbak, M.D.*

Canan Agalar, M.D.

Hilmi Ciftci, M.D.

Mustafa Girgin, M.D.*

Tuba Tulay Koca, M.D.*

Cevdet Ugur Kocogullari, M.D. Hulya Apaydin, M.D.

Nelgin Gerenli, M.D.*

Tuba Yavuzsen, M.D.

Derya Buyukkayhan, M.D.

Huseyin Bayramlar, M.D.

Nezih Ozkan, M.D.

Turhan Caskurlu, M.D.

Destina Yalcin, M.D.

Ibrahim Akalin, M.D.

Nihat Aksakal, M.D.*

Turkan Kudsioglu, M.D.*

Didem Akcali, M.D.

Ibrahim Ali Ozemir, M.D.

Nilay Sahin, M.D.

Umut Kefeli, M.D.

Didem Korular Tez, M.D.

Ibrahim Ikizceli, M.D.

Nuri Aydin, M.D.

Veli Citisli, M.D.*

Dilaver Tas, M.D.

Ihsan Karaman, M.D.

Nusret Acikgoz, M.D.*

Volkan Ince, M.D.

Duygu Geler Kulcu, M.D.*

Ihsan Metin Leblebici, M.D.*

Onur S. Goksel, M.D.

Yasar Bukte, M.D.

Ebru Zemheri, M.D.

Ilknur Aktas, M.D.

Orhan Alimoglu, M.D.

Yesim Tuncok, M.D.

Emek Kocaturk Goncu, M.D.

Ismail Islek, M.D.

O. Emek Kocaturk Goncu, M.D. Yurdanur Kilinc, M.D.

Emin Evren Ozcan, M.D.

Kadriye Avci, M.D.

Ozge Ecmel Onur, M.D.

Yuksel Altintas, M.D.

Emine Samdanci, M.D.

Kamil Ozdil, M.D.*

Ozlem Baysal, M.D.

Yuksel Ersoy, M.D.

Ercan Madenci, M.D.

Kaya Saribeyoglu, M.D.

Ozlem Guneysel, M.D.

Eren Gozke, M.D.

Kazim Capaci, M.D.

Ozlem Tanriover, M.D.

Tarik Sapci, M.D.

*For the first issue of NCI.


NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ YEAR 2016 VOLUME 3 NUMBER 1

p-ISSN 2148 - 4902

Ownership and Accountability for Contents on behalf of the Istanbul Northern Anatolian Association of Public Hospitals

Kemal Memisoglu, M.D.

Publicatıon Manager

Bekir Durmus, M.D.

Publicatıon Coordinators

Neslihan Buyukmurat, M.D.

Umut Elmas

Executive Office Istanbul Anadolu Kuzey Kamu Hastaneler Birligi Genel Sekreterligi E5 Karayolu Uzeri, 34752 Atasehir, Istanbul, Turkey Phone: +90 216 578 78 00 Fax: +90 216 577 40 48 http://www.kuzeyklinikleri.com e-mail: bilgi@kuzeyklinikleri.com Issued by the Istanbul Northern Anatolian Association of Public Hospitals Indexed in TUBITAK TR Index, EBSCO, CINAHL, Turkiye Citation Index.

Publisher

Press

KARE PUBLISHING Altayceşme Mah., Samanyolu Sok., Mecit Varli Apt., No: 19/6, 34843 Maltepe, Istanbul, Turkey Tel: +90 216 550 61 11 Fax: +90 216 550 61 12 http://www.kareyayincilik.com e-mail: kare@kareyayincilik.com

DESIGN

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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

Press date: June 2016 Circulation: 1000 Type of publication: Periodical

English Editing by

Gurkan Kazanci, M.D. PhD. Kazanci English Editing, and Medical Translation Office kazanci.g@gmail.com

Northern Clinics of Istanbul (NCI) is a peer-reviewed journal published triannually by the Istanbul Northern Anatolian Association of Public Hospitals. Materials published in the Journal is covered by copyright ©2016 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


CONTENTS Vol. 3 • No. 1 • Year 2016

ORIGINAL ARTICLES

CASE SERIES C A S E REPORTS

INVITED REVIEW

VI

INSTRUCTIONS FOR THE AUTHORS

IX

EDITORIAL

1–8

Blink reflex in migraine headache Z. Unal, F. Mayda Domac, E. Boylu, A. Kocer, T. Tanridag, O Us

9–14

Factors affecting postoperative hypocalcemia after thyroid surgery: Importance of incidental parathyroidectomy I. A. Ozemir, M. Z. Buldanli, O. Yener, M. Leblebici, T. Eren, H. Baysal, O. Alimoglu

15-21

Relationship between newborn craniotabes and vitamin D status M. Ercan, M. Ozcetin, M. Karaci, G. Ozgurhan, A. Yasar, B. Guven

22-26

Rehabilitation after successful finger replantation M. Ugurlar, F. Kabakas, H. Purisa, I. Sezer, P. Celikdelen, I. B. Ozcelik

27-33

Stent versus bypass: The reasons and risk factors for early readmission to hospital after myocardial revascularization M. Sargin, M. A. Tatlisu, M. Tasdemir Mete, N. Selcuk, S. Bayer, S. Akansel, S. Aykut Aka, M. Eren

34–38

The use of complementary medicine in patients with diabetes M. Ilhan, B. Demir, S. Yüksel, S. Aydın Çataklı, R. S. Yıldız, O. Karaman, E. Taşan

39–45

Is triglyceride/HDL ratio a reliable screening test for assessment of atherosclerotic risk in patients with chronic inflammatory disease? N. Keles, F. Aksu, G. Aciksari, Y. Yilmaz, K. Demircioglu, O. Kostek, M. E. Cekin, M. Kalcik, M. Caliskan

46-52

Relationship between size of varices and platelet count/spleen size ratio in cirrhotic patients K. Ozdil, O. Ozturk, E. S. Calık, E. S. Akbas, E. Kanat, Z. Calıskan, H. Demirdag, R. Kahraman, A. Bulur, N. Mutlu Bilgic, L. Doganay, H. M. Sokmen

53–59

Comparison of mirtazapine, gabapentin and ondansetron to prevent intrathecal morphine-induced pruritus A. Akhan, F. D. Subasi, G. Bosna, O. Ekinci, H. Pamuk, S. Batan, R. Y. Ateser, G. Turan

60–63

Acute appendicitis in pregnancy: Case series and review B. Burcu, O. Ekinci, T. Atak, K. Orhun, T. T. Eren, O. Alimoglu

64–66

A patient presenting with acute heart failure: A dilemma of diagnosis A. Kaya, B. A. Aydin, A. Oz, E. Bozbeyoglu, M. Eren

67–70

Pleomorphic adenoma of the larynx M. Doğan Altunpulluk, M. H. Karabulut, G. Kır, Ş. Şahin

71-74

Fahr’s syndrome presenting with epileptic seizure: Two case reports N. Ongun, E. Degirmenci, C. Erdogan

75-78

A rare cause of intestinal obstruction in a newborn: Congenital band compression E. Aydin

79–82

A brief summary of clinical types of psoriasis G. Sarac, T. T. Koca, T. Baglan


INSTRUCTIONS FOR THE AUTHORS Northern Clinics of Istanbul

- NCI is a peer-reviewed, open-access, international journal published by the Istanbul Northern Anatolian Association of Public Hospitals (INAAPH). The NCI is printed 3 times a year. Free full-text articles in English are available at www. kuzeyklinikleri.com. The NCI is indexed in the Turkey Citation Index (Türkiye Atıf Dizini). 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 INAAPH. 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-of-the 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 comments, 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 resources, (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 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


INSTRUCTIONS FOR THE AUTHORS 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 should be provided.

or

institution

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 [Epub 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. 88107. 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. 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


INSTRUCTIONS FOR THE AUTHORS 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 above-mentioned 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 declaration 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. REVIEW OF 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 begin until a document with the signed approval of all authors has been received. During typesetting and other preparation of the manuscript for pub-

lication, 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 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. ADDRESS OF CORRESPONDENCE Istanbul Anadolu Kuzey Kamu Hastaneler Birligi Genel Sekreterligi, E5 Karayolu Uzeri 34752 Atasehir, Istanbul, Turkey Tel: 0216 578 78 00 - 0216 578 78 50 Fax: 0216 577 40 48 E-mail: bilgi@kuzeyklinikleri.com


EDITORIAL

Dear readers of Northern Clinics of Istanbul, I am very pleased to present the first issue of NCI for 2016. I would like to express my sincere thanks to our authors, to the reviewers who evaluated our manuscripts, and to you, the readers, for showing interest in our journal. With your support, we are achieving greater success with every day. NCI is now part of the Scientific and Technological Research Council of Turkey (TÜBİTAK) Turkish Academic Network and Information Centre (ULAKBİM) Turkish Medical Index Database. In addition, our application to join the PubMed Central index has been accepted. As of now, our journal is indexed in 2 national (TÜBİTAK ULAKBİM and Citation Index of Turkey) and 4 international indices. (EBSCO, Cumulative Index to Nursing and Allied Health Literature [CINAHL], and Index Copernicus [IC]). This issue of our journal contains 9 original research articles, 5 case reports, and 1 review article. The original research articles explore topics including treatment of diabetes with complimentary medicine, craniotabes and vitamin D, the relationship between the size of varices and platelet count/ spleen size ratio in cirrhotic patients, postoperative hypocalcemia after thyroid surgery, blink reflex in migraine headaches, use of triglyceride/HDL ratio to assess atherosclerotic risk in patients with chronic inflammatory diseases, rehabilitation after finger replantation, preventing intrathecal morphine-induced pruritus, and a comparison of stent versus bypass after myocardial revascularization. We have very interesting case reports that discuss acute appendicitis in pregnancy, congenital band compression in a newborn, pleomorphic adenoma of the larynx, Fahr’s syndrome presenting with epileptic seizure, and a challenging case of aortic dissection. Finally, in this issue we also have a review article concerning clinical types of psoriasis. We congratulate the authors who contributed their work to the contents of this issue, and we are very grateful to the reviewers and the editorial board of the journal for giving their valuable time to the evaluation of the manuscripts. See you in the next issue, Bekir Durmus, Assoc. Prof. M.D.

Editor-in-Chief


Orıgınal Article

NEUROLOGY

North Clin Istanbul 2016;3(1):1-8 doi: 10.14744/nci.2016.30301

Blink reflex in migraine headache Zeynep Unal,1 Fusun Mayda Domac,2 Ece Boylu,3 Abdulkadir Kocer,4 Tulin Tanridag,5 Onder Us5 Neurology Department, Manisa State Hospital for Mental Health and Neurological Disorders, Manisa, Turkey

1

Neurology Department, Erenköy Training and Research Hospital for Psychiatric and Neurological Disorders, Istanbul, Turkey

2

Neurology Department, Gelişim University, Istanbul, Turkey

3

Neurology Department, Medeniyet University Göztepe Training and Research Hospital, Istanbul, Turkey

4

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

5

ABSTRACT OBJECTIVE: Activation of trigeminovascular system is thought to play an important role in migraine pathogenesis. Blink reflex (BR) test is an easy method to study the trigeminal system. Latencies recorded in BR test were evaluated to examine neurophysiological changes that occur in migraine patients. METHODS: A total of 40 patients diagnosed with migraine (9 with aura and 31 without aura) according to the International Headache Society (IHS) International Classification of Headache Disorders, 2nd edition, and 30 healthy control subjects were assessed using BR test. Supraorbital nerve was stimulated on each side, and unilateral early component (R1), and bilateral late component (R2) latencies were evaluated. RESULTS: Significantly longer latency values were recorded on both right and left sides (RR1 and LR1) as well as both ipsilateral and contralateral R2 on the left side (LR2i and LR2c) in the migraine group compared to the control group. Longer RR1 and LR1 latencies were found in patients with migraine who had an attack at the time of study (p<0.01). There was no statistically significant correlation between the location of pain and latencies in the interictal period (p>0.05). But significantly longer R1 and R2i latencies were found at the symptomatic side of patients examined during the headache attack (p=0.037 and p=0.028 respectively). There was no statistically significant correlation between the recorded latencies and gender, attack duration, attack frequency and migraine type (p>0.05). CONCLUSION: Results of BR test in the present study are thought to point to a dysfunction in brainstem and trigeminovascular connections of patients with migraine headache and support the trigeminovascular theory of migraine. Keywords: Blink reflex; headache; migraine.

Received: March 16, 2015 Accepted: April 11, 2016 Online: April 26, 2016 Correspondence: Dr. Fusun Mayda Domac. Erenköy Ruh ve Sinir Hastalıkları EAH, Noroloji Klinigi, Sinan Ercan Cad. No:29, Kozyatagi, Istanbul, Turkey Tel: +90 216 302 59 59 / 422 e-mail: fusundomac@yahoo.com.tr © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


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A

s a result of previous studies, theories related to pathophysiology of migraine have become more complex and concentrated on neuronal dysfunction [1]. Important roles played by neurogenic inflammation of meningeal vessels combined with activation of trigeminovascular system, and sensitization of trigeminal nuclei in the brainstem have been demonstrated [2-4]. Sensitization of trigeminovascular system has been thought to be responsible for pain felt during initial phase of migraine, and evidence concerning its potential subclinical continuation during interictal phase is available [1,57]. Cutaneous allodynia occurring during migraine attacks has been associated with sensitization of central trigeminal nuclei [2,8]. Association between impairment of central inhibitor mechanisms and sensitization processes developed during and following migraine attacks has been emphasized [8,9]. Chronic pain has also been thought to stem from derangement of inhibitory control mechanisms [9]. Neurophysiological tests, such as transcranial magnetic stimulation, evoked potentials, event-related endogenous potentials, autonomic tests, and blink reflex (BR) have become important tools in the investigation of cerebral excitability, nociceptive systems, central, and peripheral mechanisms in primary headaches [1,10-14]. BR is a noninvasive test to obtain information about peripheral and central neurologic functions and thus far it has been used in the investigation of pathophysiology of various types of headaches [11-15]. Early component of BR (R1) is transmitted via pontine pathway, and it is recorded only by unilateral stimulation. Late component (R2) is a polysynaptic response passing through lateral reticular formation, and is recorded bilaterally [16]. R2 reflects excitability of interneurons in the brainstem, and its synaptic transmission function at this level [17]. Central sensitization of neurons in the spinal trigeminal nuclei induces depolarization of cutaneous trigeminal axons with resultant alterations in R2 responses [9]. In studies of BR, R1 and R2, latency measurements have yielded different data in cases of migraine headache. The aim of this study was to investigate whether latency values from BR test performed on patients with migraine headache differ

North Clin Istanbul â&#x20AC;&#x201C; NCI

from those of the control group, and to analyze the role of trigeminovascular system in the pathogenesis of migraine. MATERIALS AND METHODS A total of 27 female and 13 male patients diagnosed as having migraine, with or without aura, based on International Classification of Headache Disorders, 2nd edition, criteria published by International Headache Society (IHS) were included in the study. Control group consisted of 30 age-matched (20 female, and 10 male) subjects without any known present or past systemic or neurological disease. Detailed neurological examinations were performed on all participants. Tests to be performed were thoroughly explained to study participants, and consent was obtained. Approval of the study was obtained from the ethics committee of Marmara University Faculty of Medicine. Migraine patient data on gender, type of migraine (with or without aura), time interval between examination and onset of attack (during, within or 72 hours after onset of the attack), frequency and location of attack were recorded. Patients who had received prophylactic treatment within the previous 3 months, in whom there was presence of disease that might affect electrophysiological examination or involving trigeminal or facial nerve, or in whom a structural lesion was detected on cranial images, had headaches other than migraine, or aged younger than 18 or older than 60 years were excluded from the study. Blink Reflex (BR) BR was measured using 4-channel Medelec electromyography (EMG) device (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) in the Marmara University Department of Neurology electrophysiology laboratory. The examinations were performed at normal room temperature in a noiseless laboratory with patients lying on examination table in supine position with eyes closed. Silver-coated electrodes were used for testing: Active electrodes were placed bilaterally on m.orbicularis oris, and


Unal et al., Blink reflex in migraine headache

reference electrodes were placed on nasal wings. Ground electrode was placed between the stimulator and active electrode. Right and left supraorbital nerves were stimulated successively over the supraorbital foramen. Stimuli were applied for 0.2 milliseconds with 30-second intervals. Responses were elicited 5 times, consecutively from both sides: early component (R1), late component ipsilateral (R2i) and late component contrlateral (R2c). Latency of reflex responses was measured from shortest initial deflection. Average values of R1, R2, and R2c latencies were calculated. Latency values recorded in patients with migraine and in the control group were compared. Correlations between gender of patients, location and frequency of pain, and latency values were assessed. Statistical Analysis SPSS software (version 13.0; SPSS Inc., Chicago, IL, USA) was used to evaluate data obtained from patient and control groups. Normality of distribution was tested using Kolmogorov-Smirnov test. Descriptive statistics (mean, standard deviation) were gathered for all groups. Student’s-t test was used to compare the 2 groups and chi-square test

3

was used to evaluate categorical variables. For the comparison of more than 2 groups, one-way analysis of variance (ANOVA) test was used. Results were evaluated as statistically significant at a level of p<0.05. RESULTS Mean age of patients with migraine headache was 37.36±9.67 (19-50) years. Control group consisted of healthy volunteers with a mean age of 36.5±11.68 (20-51) years. Migraine headache group comprised 28 (70%) female and 12 (30%) male patients, while the control group consisted of 20 (66.7%) women and 10 (33.3%) men. Nine patients (22.5%) met criteria of migraine with aura; 31 (77.5%) were diagnosed as having migraine without aura. More than 4 attacks per month were experienced by 27 patients (67.5%), while 13 patients (32.5%) experienced fewer. Migraine headache was felt on the right by 17 participants (42.5%), on the left by 14 (35%), and on both sides by 9 study participants (22.5%) (Table 1). A total of 12 (30%) patients were examined during migraine headache attack. Fourteen patients (35%) had experienced their last attack within the

Table 1. Demographic characteristics of migraine and control groups

Migraine group

Number of study participants Age (years)

Control group

40

30

37.36±9.67

36.5±11.68

Gender

Female, n (%)

28 (70)

20 (66.7)

Male, n (%)

12 (30)

10 (33.3)

Frequency of attacks

<4/month

13 (32.5)

≥4/month

27 (67.5)

Location

Unilateral

31 (77.5)

Bilateral

9 (22.5)

Type of migraine

With aura

9 (22.5)

Without aura

31 (77.5)


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North Clin Istanbul – NCI

Table 2. Comparison of latency values obtained in migraine and control groups on eye blink reflex test Latency

Migraine group

Control group

Mean±SD

Mean±SD

p

R1 latency (ms)

Right

11.07±1.42

10.27±1.61

0.004*

Left

11.66±1.3

9.85±1.25

0.000*

R2 latency (ms)

Right R2i

28.84±3.65

27.82±3.16

0.136

Right R2c

29.02±3.26

28.09±3.17

0.291

Left R2i

30.21±3.23

27.73±2.89

0.018*

Left R2c

30.45±2.80

27.55±3.02

0.001*

R1: Early component; R2i: Ipsilateral late component; R2c: Contralateral late component; SD: Standard deviation; *Statistically significant values.

previous 3 days, and it was significantly longer ago for the remaining 14 (35%). In the patient group, right and left R1 latency values (0.000 and 0.004, respectively) were found to be significantly longer than the control group. R2i and R2c latency values after stimulation to right side were compared with those of the control group and no significant intergroup difference was found; however, R2i and R2c latency values after stimulation to left side (0.018 and 0.001, respectively) were also significantly longer than those of the control group (Table 2).

R1, R2i, and R2c latency values after right- and left-side stimulation did not have a statistically significant difference between types of migraine (p>0.05) (Table 3). Patients were divided into 3 groups based on time of the attack. LR1 latency values obtained from patients during headache attack were significantly longer than those recorded within or more than 72 hours after attack (p=0.042 and p=0.034, respectively). RR1 latency values measured during attack were longer relative to other groups without any statistically significant intergroup difference (Table 4).

Table 3. Comparison of latency values obtained on eye blink reflex test in patient groups with migraine Latency

Migraine with aura

Migraine without aura

Mean±SD

Mean±SD

p

R1 latency (ms)

Right

11.01±1.5

11.09±1.43

0.646

Left

10.98±1.4

11.12±1.43

0.252

R2 latency (ms)

Right R2i

28.37±2.61

28.98±3.95

0.687

Right R2c

29.1±3.28

29±3.32

0.291

Left R2i

29.85±2.53

30.32±3.46

0.159

Left R2c

30.17±3.05

30.23±2.75

0.389

R1: Early component; R2i: Ipsilateral late component; R2c: Contralateral late component; SD: Standard deviation.


Unal et al., Blink reflex in migraine headache

5

Table 4. Comparison of latency values obtained on eye blink reflex test according to time elapsed between onset of examination and last attack Right R1

Ictal

The last 3 days

The last >3 days

p

11.62±1.5

10.96±1.45

10.89±1.42

0.157

28.24±2.67

29.11±4.22

29.18±3.68

0.626

28.74±3.09

28.68±3.6

30.22±3.3

0.318

12.44±0.69

10.91±1.44

10.59±1.24

0.042*

31.04±1.61

29.04±3.76

28.05±2.66

0.034*

29.6±2.66

30.08±2.9

30.44±2.65

0.237

Latency (ms) Right R2i Latency (ms) Right R2c Latency (ms) Left R1 Latency (ms) Left R2i Latency (ms) Left R2c

Latency (ms) R1: Early component; R2i: Ipsilateral late component; R2c: Contralateral late component; *Statistically significant values.

No statistically significant correlation was found between patient gender, frequency of attacks, or time of onset and latency values (p>0.05) (Tables 4,5,6). In the patient group, R1 and R2i latency values recorded during ictal (headache attack) phase from symptomatic and intact side were found to be statistically significantly correlated (p=0.037, and p=0.028, respectively), while prolongation of laten-

cy values of the intact side recorded during interictal phase were independent from symptomatic side. DISCUSSION Various functional imaging studies have shown that during migraine headache attack, brainstem is activated and abnormalities are seen in ascending

Table 5. Comparison of latency values obtained on the eye blink reflex test in male and female patients

Female Male p

(n=28)

(n=12)

10.98±1.36

11.26±2.02

0.316

28.95±3.76

28.7±3.03

0.944

Right R1 Latency (ms) Right R2i

Latency (ms) Right R2c

30.3±4.52

29.88±3.17

0.485

10.99±1.41

11.12±1.48

0.543

30.06±3.27

30.6±3.1

0.445

30.25±2.77

30.26±2.93

0.244

Latency (ms) Left R1 Latency (ms) Left R2i Latency (ms) Left R2c Latency (ms) R1: Early component; R2i: Ipsilateral late component; R2c: Contralateral late component.


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North Clin Istanbul – NCI

Table 6. Comparison of latency values obtained on eye blink reflex test according to frequency of migraine attacks Frequency of attacks Right R1

<4/month

>4/month

p

11.27±1.38

10.81±1.41

0.388

28.69±3.48

29.03±4.1

0.803

29.38±3.49

28.56±3.01

0.504

11.27±1.44

10.89±1.39

0.476

29.63±3.28

30.65±3.23

0.402

30.04±2.95

30.76±2.73

0.496

Latency (ms) Right R2i Latency (ms) Right R2c Latency (ms) Left R1 Latency (ms) Left R2i Latency (ms) Left R2c Latency (ms) R1: Early component; R2i: Ipsilateral late component; R2c: Contralateral late component.

and descending nociceptive pathways during ictal and interictal phases [18,19]. Trigeminal system provides sensory innervation of extracranial and intracranial arteries, as well as afferent fibers of nociceptive transmission. The contribution of trigeminovascular system to pathogenesis of migraine has been detected in experimental animal and human studies [6,7]. In BR studies performed in cases of migraine, data measuring R1 and R2 latencies have demonstrated differences. It has been thought that this discrepancy was related to different methods used, diversities in patients selected, and latency recording time (ictal/interictal) [20]. Aktekin et al. conducted BR tests on migraine patients during interictal phase using standard methods and compared measurements of R1 and R2 latencies, R2 amplitudes, and area with those of control group without finding any significant intergroup difference. They stated that these findings can be considered evidence that migraine-specific trigeminal dysfunction is a transient condition [21,22]. In healthy control participants, headache was induced with electrical stimulation and the effects of central inhibition mechanisms on experimental migraine model were investigated. BR tests were performed before, during and after experimentally triggered headache. It was found that R2 sup-

pressed after pain induced by electrical stimulation normalized during pain-free phases. The authors claimed that the obtained findings demonstrated that inhibition in migraine was not impaired [23]. Sand et al. compared patients who experience migraine-type headaches with control group during interictal phase, and stated that R2 amplitude values were not different [24]. Similar results have also been obtained in other studies [25-28]. In a study by Bank et al., R1 latency values elicited by supraorbital stimulation did not differ significantly from those of the control group, while significantly longer R2 latencies were found in the patient group. However, they did not indicate whether or not this study was performed during patient migraine attack or not. They stated that these findings could be presented as objective evidence of the involvement of trigeminal afferents and/or polysynaptic pathways in the brainstem of patients with migraine headache [29]. In the present study, right- and left-sided R1, as well as R2i and R2c latency values were compared with those of the control group, and significantly longer latencies were detected in the patient group, supporting role of trigeminovascular system in migraine. R2 was prolonged compared to responses during migraine attack, pain-free phases or controls


Unal et al., Blink reflex in migraine headache

[12,25]. This condition is thought to emerge as a response to sensitization of cutaneous nociceptive afferent arch or neurons in the trigeminal nucleus [12]. Yet these findings may be useful to better understanding of the role of trigeminal complex in pathophysiology of headache, follow-up of patients during migraine episodes or evaluation of treatment response [30]. A limitation of the present study is that amplitudes of early and late components elicited during BR test were not investigated or evaluated. When compared with those of the control group, significantly prolonged latency values of early and late components recorded during both ictal (headache attack) and interictal phases suggest that trigeminovascular dysfunction in patients with migraine headache is not a transient phenomenon. Predominant prolongation of latency during ictal phase implies that the brain is passing through different excitability phases and increased sensitization of trigeminal neurons during migraine attack. The association between location of pain and recorded side of BR has been investigated in various studies. In studies performed during pain-free period, no correlation between location of pain and recorded side was found. [2,25,31]. Despite abnormal responses elicited when stimulation was delivered from both sides, lack of any correlation on the painful side has been thought to be related to widespread suppression of the R2 interneurons at a bulbopontine level [25]. However, prolonged late component latency on the involved side in the BR test, and increase in the area of R3, which uses the same pathways as R2, have been more frequently detected with statistical significance during ictal phase [2,25,26]. In the present study, a statistically significant correlation was found between symptomatic side and R1 and R2i latency values during ictal phase. This finding is thought to reflect sensitization of trigeminal nucleus of the symptomatic side during ictal phase. In conclusion, the results obtained in BR test demonstrated presence of dysfunctional connections between brainstem and trigeminovascular system in patients with migraine headache and support trigeminovascular hypothesis in migraine.

7 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 - Z.Ü., T.T., Ö.U; Design - Z.Ü., F.M.D., E.B., T.T., Ö.U; Supervision - Z.Ü., F.M.D., A.K., E.B., T.T., Ö.U; Materials - Z.Ü., F.M.D., E.B., A.K., T.T., Ö.U; Data collection and/or processing - Z.Ü., F.M.D., E.B., A.K., ; Analysis and/or interpretation - Z.Ü., F.M.D., A.K.; Literature search - Z.Ü., F.M.D., E.B., A.K.; Writing - Z.Ü., F.M.D.; Critical review - Z.Ü., F.M.D., T.T., Ö.U.

REFERENCES 1. Aguggia M. Allodynia and migraine. Neurol Sci 2012;33:9-11. 2. De Marinis M, Pujia A, Colaizzo E, Accornero N. The blink reflex in chronic migraine. Clin Neurophysiol 2007;118:457-63. 3. Dodick D, Silberstein S. Central sensitization theory of migraine: clinical implications. Headache 2006;46:182-91. 4. Bolay H, Reuter U, Dunn A, Huang Z, Boas D, Moskowitz A. İntrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nature Medicine 2002;8:136-42. 6. Moskowitz MA. The neurobiology of vascular head pain Ann Neurol 1984;16:157-68. 7. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993;33:48-56. 8. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol 2000;47:614–24. 9. Ellrich J, Andersen OK, Messlinger K, Arendt-Nielsen L. Convergence of meningeal and facial afferents onto trigeminal brainstem neurons: an electrophysiological study in rat and man. Pain 1999; 82:229–37. 10. Magis D, Ambrossini A, Bendtsen L, Ertas M, Kaube H, Schoene J. Eurohead Project. Evaluation and proposal for optimalization of neurophysiological tests in migraine: part 1-electrophysiological tests. Cephalalgia 2007;27:1323-38. 11. Yıldırım G, Sayın R, Cögen EE, Odabas FO, Tombul T. Randomised, controlled blink reflex in patients with migraine and tension type headache. J Pak Med Assoc 2011;61:978-82. 12. Miskov S. Neurophysiological methods in headache diagnosis. Acta Med Croatica 2008;62:189-96. 13. Zduńska A, Cegielska J, Kochanowski J. Variability of the blink reflex in patients with migraine. Neurol Neurochir Pol 2013;47:352-6. 14. Magis D, Vigano A, Sava S, d’Elia TS, Schoenen J, Coppola G. Pearls and pitfalls: electrophysiology for primary headaches. Cephalalgia 2013;33:526-39. 15. Sohn JH, Choi HC, Kim CH. Differences between episodic and chronic tension-type headaches in nociceptive-specific trigeminal pathways. Cephalalgia 2013;33:330-9. 16. Shahani BT, Young RR. Human orbicularis oculi reflexes. Neu-


8 rology 1972;22:149-54. 17. Nardone R, Tezzon F. Brainstem reflexes in migraine patients. In: Clarke LB, editor. Migraine disorders research trends. New York: Nova Science Publishers; 2007. p. 183-208. 18. Bahra A, Matharu MS, Buchel C, Frackowiak RS, Goadsby PJ. Brainstem activation specific to migraine headache. Lancet 2001;357:1016-18. 19. Weiller C, May A, Limmroth V, et al.: Brainstem activation in spontaneous human migraine attacks. Nat Med 1995;1:658. 20. Schoenen J. Neurophysiological features of the migrainous brain. Neurol Sci 2006;27:77-81. 21. Brooks JB, Fragoso YD. The blink reflex test does not show abnormalities in a large group ofpatients with chronic migraine. Arq Neuropsiquiatr 2013;71:862-5. 22. Aktekin B, Yaltkaya K, Özkaynak S, Oğuz Y. Recovery cycle of the blink reflex and exteroceptive supression of temporalis muscle activity in migraine and tension type headache. Headache 2001;41:142-9. 23. Drummond PD. The effect of trigeminal nociceptive stimulation on blink reflexes and pain evoked by stimulation of the supraorbital nerve. Cephalalgia 2003;23:534–40. 24. Sand T, Zwart JA. The blink reflex in chronic tension-type

North Clin Istanbul – NCI headache, migraine and cervicogenic headache. Cephalalgia 1994;14:447–50. 25. Avramidis TG, Podikoglou DG, Anastasopoulos IE, Koutroumanidis MA, Papadimitriou AL. Blink reflex in migraine and tension-type headache. Headache 1998;38:69 l-6. 26. De Tommaso M, Guido M, Libro G, Sciruicchio V, Puca F. The three responses of the blink reflex in adult and juvenile migraine. Acta Neurol Belg 2000;100:96–102. 27. Kaube H, Katsarava Z, Przywara S, Drepper J, Ellrich J, Diener HC. Acute migraine headache : Possible sensitization of neurons in the spinal trigeminal nucleus? Neurology 2002;58:1234-8. 28. Sandrini G, Proietti Cecchini A, Milanov I, Tassorelli C, Buzzi MG, Nappi G. Electrophysiological evidence for trigeminal neuron sensitization in patients with migraine. Neurosci Lett 2002;317:135–8. 29. Bank J, Bense E, Kiraly C. The blink reflex in migraine. Cephalalgia 1992;12:289-92. 30. Valls-Sole J. Neurophysiological assessment of trigeminal nerve reflexes in disorders of central and peripheral nervous system. Clin Neurophysiol 2005;116:2255-65. 31. Shibata K, Yamane K, Iwata M. Change of excitability in brainstem and cortical visual processing in migraine exhibiting allodynia. Headache 2006;46:1535-44.


Orıgınal Article

Internal medicine

North Clin Istanbul 2016;3(1):9–14 doi: 10.14744/nci.2016.48802

Factors affecting postoperative hypocalcemia after thyroid surgery: Importance of incidental parathyroidectomy Ibrahim Ali Ozemir, Mehmet Zeki Buldanli, Oktay Yener, Metin Leblebici, Tunc Eren, Hakan Baysal, Orhan Alimoglu Department of General Surgery, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: The present study evaluated effects of incidental parathyroidectomy, surgical technique, and presence of thyroiditis or hyperthyroidism on occurrence of postoperative persistent or transient hypocalcemia. METHODS: Patients who underwent thyroidectomy at İstanbul Medeniyet University between 2013 and 2015 were included in the study. Patient information, postoperative serum calcium levels, and pathology reports were investigated retrospectively. Group 1 was made up of patients who were found to have hypocalcemia (calcium ≤8.5 mg/dL) according to postoperative serum level and normocalcemic patients were placed in Group 2. Groups were compared statistically in terms of rate of incidental parathyroidectomy, surgical technique, and presence of thyroiditis or hyperthyroidism. RESULTS: Mean age was 49.8±12.8 years (range: 20-88). A total of 417 patients were included in the study, 74 (17.7%) were male and 343 (82.3%) were female. Group 1 consisted of 205 (49.2%) patients who had hypocalcemia according to postoperative serum level, and remaining 212 (50.8%) patients were placed in Group 2. In Group 1, 38 (18.5%) patients had incidental parathyroidectomy, and with only 18 (8.5%) patients in Group 2, a statistically significant relationship was found between incidental parathyroidectomy and hypocalcemia (p=0.003). There was no statistically significant difference in terms of presence of thyroiditis or hyperthyroidism between groups. There was statistically significant decrease in postoperative hypocalcemia rate in patients with lobectomy compared to patients with bilateral total thyroidectomy or central neck dissection (p<0.01). CONCLUSION: Risk of postoperative hypocalcemia may be reduced with lobectomy for selected patients. In addition, delicate dissection during thyroidectomy is important in order to protect parathyroid glands and prevent hypocalcemia. Keywords: Hypocalcemia; incidental parathyroidectomy; thyroidectomy.

Received: February 29, 2016 Accepted: March 15, 2016 Online: April 07, 2016 Correspondence: Dr. Ibrahim Ali OZEMIR. Kucuksu Mah., Asma Sok., Eston Kandilli Evleri Sitesi, A12 Blok, D: 8, Kandilli, Uskudar Istanbul, Turkey. Tel: +90 505 803 21 25 e-mail: draliozemir@hotmail.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


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T

hyroid surgery is accepted as a safe operation, and now has lower morbidity and satisfactory postoperative outcomes resulting in a shorter hospital stay. It is even performed as day surgery. [1, 2] Thyroidectomy is a widely performed operation in the practice of general surgery and has a complication rate lower than 5%. Most frequently, postoperative hypocalcemia has been observed. Based on literature reviews, temporary, and permanent hypocalcemia are seen in 1.6–50%, and 1.5–4% of cases, respectively [3, 4]. Since postoperative hypocalcemia requires calcium replacement and monitoring of serum calcium levels, it leads to prolongation of hospital stay and ensuing increase in hospital expenditures [3]. Trauma to 1 or more parathyroid glands or vasculature during thyroidectomy, or incidental removal of parathyroid gland with the specimen may lead to development of postoperative hypocalcemia. Etiological considerations include postoperative alkalosis-induced hypocalcemia resulting from hyperventilation triggered by postoperative pain, and dilutional hypocalcemia [5]. Incidental rate of parathyroid organs in thyroidectomy specimens have been reported to range between 6.4–31% [6, 7]. In this study, factors related to the patient as well as surgical methods have been analyzed in the development of postoperative hypocalcemia, and importance and outcomes of incidental parathyroidectomy have been evaluated. MATERIALS AND METHODS Patients with various indications who had undergone thyroidectomy in general surgery clinic of Istanbul Medeniyet University between January 2013 and January 2015 were included in the study. Patients who had undergone combined thyroidectomy-parathyroidectomy operation with indication of primary hyperparathyroidism were excluded. Demographic data; preoperative serum T3 hormone, T4 hormone, thyroid-stimulating hormone (TSH), anti-thyroid peroxidase antibody (anti-TPO), and anti-thyroglobulin values; diagnoses; surgical notes; histopathology reports; and postoperative 24-hour serum calcium levels were recorded and evaluated

North Clin Istanbul – NCI

retrospectively. Patients with postoperative calcium levels of ≤8.5 mg/dL were considered hypocalcemic (Group 1). The patients in Group 1 were divided into subgroups of manifest hypocalcemia (serum calcium <8.0 mg/dL) and mild hypocalcemia (serum calcium 8.1–8.5 mg/dL). Presence of hyperthyroidism was determined based on results of the preoperative thyroid function tests, while presence of thyroiditis was assessed based on histopathology reports and preoperative antibody levels. Surgical methods used were compared between groups and statistically evaluated for rate of incidental parathyroiditis. This study was realized in compliance with World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Approval of the ethics committee, and informed written consent of patients was obtained. Statistical analysis Statistical analysis of data was performed using SPSS software (version 20.0; SPSS Inc., Chicago, IL, USA). Pearson’s chi-squared test or Fisher’s exact test was used to compare qualitative nonparametric variables, and for comparison of 3 or more than 3 independent variables, one-way analysis of variance (ANOVA) test was used. To compare quantitative data, Mann-Whitney U test was used. Level of statistical significance was determined at p<0.05. RESULTS A total of 417 patients who had undergone thyroidectomy due to various indications were included in the study. Study population consisted of 74 (17.7%) male and 343 (82.3%) female patients with an overall mean age of 49.8±12.8 (range: 20–88 years). At postoperative 24 hours, 205 (49.2%) patients with serum calcium levels of ≤8.5 mg/dL were accepted as hypocalcemic, and classified as Group 1. The remaining 212 patients with serum calcium levels of >8.5 mg/dL were considered normocalcemic and placed in Group 2. Mean age of patients in Group 1 was 50.2±13.1 years, and in Group 2 it was 49.3±12.7 years. No intergroup difference was found with respect to patient age (p>0.05). In


Ozemir et al., Factors affecting postoperative hypocalcemia after thyroid surgery

Group 1, there were 64 (31.2%) patients with thyroiditis and 44 (21.5%) with hyperthyroidism; in Group 2, there were 58 (27.4%) with thyroiditis and 41 (19.3%) with hyperthyroidism. No statistically significant intergroup difference was found with respect to the presence of thyroiditis or hyperthyroidism (Table 1). Incidental parathyroidectomy was noted in a total of 56 (13.4%) patients: 38 (18.5%) in Group 1, and 18 (8.5%) cases of incidental parathyroidectomy were found in Group 2. A statistically significant correlation was not found between incidental parathyroidectomy and development of postoperative hypocalcemia (p=0.003). Patients were divided into subgroups according to the number of incidentally excised parathyroid glands. No statistically significant difference was found between development of hypocalcemia and excision of 1 or 2 parathyroid glands (Table 1). Patients in Groups 1 and 2 were also divided into 4 subgroups based on type of operation performed: lobectomy, bilateral total thyroidectomy, recurrent thyroidectomy, and central dissection. A statistically significant difference was detected between the 2 groups as far as surgery performed. Post hoc analysis revealed a significant difference between patients who had under-

11

gone central dissection and lobectomy regarding development of postoperative hypocalcemia (Table 1). In 102 (49.3%) patients in Group 1, serum calcium levels of between 8.1–8.5mg/dL comprised subgroup of mild hypocalcemia, while 104 (50.7%) patients with calcium levels of ≤8.0 mg/dL constituted subgroup of manifest hypocalcemia. Presence of thyroiditis, hyperthyroidism and rate of incidental parathyroidectomy between these 2 subgroups were not statistically significantly different (Table 2). When type of operation performed was compared, statistically significant increase in development of manifest hypocalcemia was seen in patients who underwent central dissection compared to lobectomy. Six (1.4%) hypocalcemic patients receiving calcium and vitamin D replacement therapy at 1 year into follow-up period were considered to have permanent hypocalcemia. Three (50%) had undergone central dissection, and a significant correlation was detected between central dissection and permanent hypocalcemia (Table 3). Discussion Thyroid diseases have an important place among

Table 1. Comparison of development of hypocalcemia and incidental parathyroidectomy, presence of thyroiditis, hyperthyroidism, type of surgery performed in patient groups with and without hypocalcemia

Group 1 (n=205) n

%

Group 2 (n=212) n

%

Total (n=417) n

p

%

Thyroiditisα 64 31.2 58 27.4 122 29.3 NS. Hyperthyroidism α 44 21.5 41 19.3 85 20.4 NS α Incidental parathyroidectomy (+) 38 18.5 18 8.5 56 13.4 0.003* 1 parathyroid glandα 30 14.6 16 7.5 46 11 NS 2 parathyroid glandγ 8 3.9 2 1 10 2.4 NS Type of operationβ <0.001* α Lobectomy 26 12.7 56 26.4 82 19.7 <0.001* α Bilateral total thyroidectomy 144 70.2 140 66 284 68.1 NS Secondary thyroidectomyα 13 6.3 9 4.2 22 5.3 NS Central dissectionα 22 10.7 7 3.3 29 6.9 0.002* α: Pearson’s chi-squared test; β: One-way analysis of variance (ANOVA) test; γ: Fisher’s exact test; *: Level of statistical significance: p<0.01 ; NS: Not significant.


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Table 2. In subgroups of mild and manifest hypocalcemia, comparison of incidental parathyroidectomy, presence of thyroiditis, hyperthyroidism, and type of surgery performed

Mild hypocalcemia (8.1–8.5 mg/dL) (n=101) n

%

Manifest hypocalcemia (≤8.0 mg/dL) (n=104) n

p

%

Thyroiditisα 29 31.5 35 32.5 NS α 44 21.5 41 19.3 NS Hyperthyroidism Incidental parathyroidectomy (+)α 15 14.9 23 22.1 NS 1 parathyroid glandα 14 13.9 16 15.4 NS 2 parathyroid glandγ 1 1 7 6.7 NS β Type of operation <0.001* α Lobectomy 20 19.8 6 5.8 <0.001* α Bilateral total thyroidectomy 67 66.3 77 74.1 NS Secondary thyroidectomyα 9 8.9 4 3.8 NS Central dissectionα 5 5 17 16.3 <0.05** α: Pearson’s chi-squared test; β: One way analysis of variance (ANOVA) test; γ: Fisher’s exact test; *: Level of statistical significance: p<0.01; **: Level of statistical significance: p<0.05; NS: Not significant.

Table 3. At postoperative one year check, comparison of normocalcemic patients with six patients who were receiving treatment for permanent hypocalcemia

Normocalcemia (n=411) n

%

Permanent Hipocalcemia (n=6) n

p

%

Thyroiditisα 119 28.9 3 50 NS 84 20.4 1 16.7 NS Hyperthyroidismα Incidental parathyroidectomy (+)α 53 12.9 3 50 NS 1 parathyroid glandα 44 10.7 2 33.3 NS 2 parathyroid glandγ 9 2.2 1 16.7 NS Type of operationβ – Lobectomyα 20 19.8 – – – Bilateral total thyroidectomyα 67 66.3 3 50 NS α Secondary thyroidectomy 9 8.9 – – – Central dissectionα 3 5 3 50 <0.001* γ: Fisher’s exact test; *: Level of statistical significance p<0.01; **: Level of statistical significance p<0.05; NS: Not significant.

endocrine disorders, and thyroid gland surgery is the most frequently performed endocrine surgery [8]. Thyroidectomy is now performed by experienced endocrine surgeons and morbidity rates are lower. The most frequently seen complication following thyroidectomy is temporary or permanent

hypocalcemia, which can impair quality of life [5] and prolong hospital stay. In the literature, both temporary and permanent hypocalcemia have been reported in 1.6–50% and 1.5–4% of cases, respectively [3, 4]. The most important factors influencing postoperative development of hypocalcemia


Ozemir et al., Factors affecting postoperative hypocalcemia after thyroid surgery

include, intraoperative trauma to parathyroid gland or its vasculature, inability to identify parathyroid gland during operation, incidental parathyroidectomy, and experience of the surgeon [5, 9, 10, 11]. Variations in the number and anatomical location of parathyroid glands increase risk of incidental parathyroidectomy [12]. In studies, rates of incidental parathyroidectomy were reported to range between 6.4–19.7% [6, 13]. Thyroid surgeries of the present study were performed by experienced surgeons who do at least 50 thyroidectomies a year, and incidental parathyroidectomy rate is estimated at 13.4%, within the rates cited in the literature. In a study performed by Özoğul et al., it was reported that the risk of incidental parathyroidectomy and related postoperative hypocalcemia was higher in thyroidectomies performed because of presence of malignancy and in patients who had undergone neck dissection in compliance with oncological principles [3, 7]. In the same study, a statistically significant correlation was detected between incidental parathyroidectomy, and hypocalcemia. In studies performed by Bergenfelz et al. [10], authors reported that this correlation was independent of extent of thyroidectomy and neck dissection. It has also been indicated that routine use of autotransplantation will be useful in postoperative examination of the specimen and identification of parathyroid gland [14]. Sasson et al. [15] detected a significant correlation between incidental parathyroidectomy and postoperative hypocalcemia. In the present study, statistically significant higher incidence of hypocalcemia was found in groups of patients who had undergone central dissection and incidental parathyroidectomy. In studies performed on parathyroid gland damage and incidental parathyroidectomy, authors have reported correlations between onset and longevity of hypocalcemic symptoms and the number of extracted and damaged parathyroid glands [16, 17]. However in the present study, a statistically significant difference was not found in incidence of hypocalcemia between patients in whom 1 or 2 parathyroid glands were extirpated. In the literature, contrary opinions have been asserted about correlations between development of postoperative hypocalcemia and patient age. In

13

some studies, advanced age group [18], and in other studies younger age group [11] were found to be at risk. In a review of 2576 patients performed by Edafe et al., no difference in development of hypocalcemia based on age [19]. The present study also found no significant intergroup difference with regard to age of patients. In patients with hyperthyroidism, difficulties encountered during surgery because of complex vascularity of thyroid gland have also been evaluated as a risk factor for development of hypocalcemia. Zambudio et al. [20] found presence of hyperthyroidism to be an independent risk factor for development of hypocalcemia. Contradictory publications are found in the literature [3]. In the present study, no correlation was seen between hyperthyroidism and risk of hypocalcemia. Various studies have found a number of factors that increase risk of permanent hypocalcemia including, extent of surgical resection, total parathyroidectomy, recurrent goiter, secondary surgeries, identification of fewer than 2 parathyroid glands, incidental parathyroidectomy, and surgical inexperience [21, 22, 23, 24]. Unless surgeons have ample experience with parathyroid glands and vascularization can be preserved using capsular dissection, routine exploration of all 4 parathyroid glands is not recommended [5, 25, 26, 27]. It has been noted that in 83% of cases, parathyroid glands with impaired nutrient supply or autotransplanted dissected glands with intact capsules retained their biochemical activity [28]. In conclusion, this study has shown that incidental parathyroidectomy, bilateral thyroidectomy, and central dissection significantly increase the risk of developing postoperative hypocalcemia. Intraoperative identification of parathyroid glands is recommended. Any part removed should be analyzed to reveal incidental parathyroidectomy, and autotransplantation should be performed when needed to decrease risk of postoperative hypocalcemia. Similarly, in indicated cases, limited surgery, preferably lobectomy, and meticulous dissection in patients with more extensive surgery will decrease rates of incidental parathyroidectomy and development of postoperative hypocalcemia.


14 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 – İ.A.Ö; Design – İ.A.Ö; Supervision – İ.A.Ö, T.E.; Materials – M.Z.B., O.Y., M.L.; Data collection and/or processing – M.Z.B., O.Y., M.L.; Analysis and/ or interpretation – İ.A.Ö, T.E., H.B., O.A.; Literature search – Writing – İ.A.Ö, T.E.; Critical review – İ.A.Ö, T.E., O.A.

REFERENCES 1. Koyuncu A, Dökmetas HS, Turan M, Aydin C, Karadayi K, Budak E, et al. Comparison of different thyroidectomy techniques for benign thyroid disease. Endocr J 2003;50:723–7. 2. Sun GH, DeMonner MM. Epidemiological and economic trends in impatient and outpatient thyroidectomy in the United States, 1996-2006. Thyroid 2013;23:727-33. 3. Noureldine SI, Genther DJ, Lopez M, Agrawal N, Tufano RP. Early Predictors of Hypocalcemia After Total Thyroidectomy: An Analysis of 304 Patients Using a Short-Stay Monitoring Protocol, JAMA Otolaryngol Head Neck Surg 2014;140:1006-13. 4. Pattou F, Combermale F, Fabre S, Carnaille B, Decoulx M, Wemeau JL, et al. Hypocalcemia following thyroid surgery: incidence and prediction of outcome. World J Surg 1998;22:718– 24. 5. Uludağ M. Tiroid ve paratiroid cerrahisi sonrası hipokalsemi ve tedavisi. ŞEEAH Tıp Bülteni 2014;48:161-75. 6. Erbil Y, Barbaros U, Ozbey N, Aral F, Ozarmağan S. Risk factors of incidental parathyroidectomy after thyroidectomy for benign thyroid disorders. Int J Surg 2009;7:58–61. 7. Özoğul B, Akçay MN, Kısaoğlu A, Atamanalp SŞ, Öztürk G, Aydınlı B. Incidental parathyroidectomy during thyroid surgery: risk factors, incidence, and outcomes. Turk J Med Sci 2014;44:84-8. 8. Baldassarre RL, Chang DC, Brumund KT, Bouvet M. Predictors of hypocalcemia after thyroidectomy: results from the nationwide inpatient sample. ISRN Surg 2012;2012:838614. 9. Campos NS, Cardoso LP, Tanios RT, Oliveira BC, Guimarães AV, Dedivitis RA, Marcopito LF. Risk factors for incidental parathyroidectomy during thyroidectomy. Braz J Otorhinolaryngol 2012;78:57–61. 10. Bergenfelz A, Jansson S, Kristoffersson A, Mårtensson H, Reihnér E, Wallin G, et al. Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg 2008;393:667-73. 11. Lang BH, Yih PC, Ng KK. A prospective evaluation of quick intraoperative parathyroid hormone assay at the time of skin closure in predicting clinically relevant hypocalcemia after thyroidectomy. World J Surg 2012;36:1300–6. 12. Abboud B. Topographic anatomy and arterial vascularization of the parathyroid glands: practical application. Presse Med 1996;25:1156–61. 13. Sakorafas GH, Stafyla V, Bramis C, Kotsifopoulos N, Kolettis

North Clin Istanbul – NCI T, Kassaras G. Incidental parathyroidectomy during thyroid surgery: an underappreciated complication of thyroidectomy. World J Surg 2005;29:1539–43. 14. Olson JA Jr, DeBenedetti MK, Baumann DS, Wells SA Jr. Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up. Ann Surg 1996;223:472–8. 15. Sasson AR, Pingpank JF Jr, Wetherington RW, Hanlon AL, Ridge JA. Incidental parathyroidectomy during thyroid surgery does not cause transient symptomatic hypocalcemia. Arch Otolaryngol Head Neck Surg 2001;127:304–8. 16. Asari R, Passler C, Kaczirek K, Scheuba C, Niederle B. Hypoparathyroidism after total thyroidectomy. Arch Surg 2008;143:132–7. 17. Spiliotis J, Vaxevanidou A, Sergouniotis F, Tsiveriotis K, Datsis A, Rogdakis A, Kekelos S. Risk factors and consequences of incidental parathyroidectomy during thyroidectomy. Am Surg 2010;76:436–41. 18. Kamer E, Unalp HR, Erbil Y, Akguner T, Issever H, Tarcan E. Early prediction of hypocalcemia after thyroidectomy by parathormone measurement in surgical site irrigation fluid. Int J Surg 2009;7:466–71. 19. Edafe O, Antakia R, Laskar N, Uttley L, Balasubramanian SP. Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg 2014;101:307–20. 20. Zambudio Ar, Rodriguez J, Riquelme J, Soria T, Canteras M, Parilla P. Prospective study of postoperative complications after total thyroidectomy for multinodular gaiters by surgeons with experience in endocrine surgery. Ann Syrg 2004;240:18-25. 21. Karamanakos SN, Markou KB, Panagopoulos K, Karavias D, Vagianos CE, Scopa CD, et al. Complications and risk factors related to the extent of surgery in thyroidectomy. Results from 2,043 procedures. Hormones (Athens) 2010;9:318-25. 22. Paek SY, Lee YM, Min SY, Kim SW, Chung KW, Youn YK. Risk factors of hypoparathyroidism following total thyroidectomy for thyroid cancer. Worl J Surg 2013;37:94-101. 23. Thomusch O, Machens A, Sekulla C, Ukkat J, Brauckhoff M, Dralle H. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 2003;133:180-5. 24. Burge MR, Zeise TM, Johnsen MW, Conway MJ, Qualls CR. Risks of complication following thyroidectomy. J Gen Intern Med 1998;13:24-31. 25. Yetkin E, Makay Ö. Tiroidektomi komplikasyonları: Genel bakış. In: İşgör A, Uludağ M, editör. Tiroid. 1. Baskı. İstanbul: Nobel Tıp Kitabevleri; 2013. s. 941-54. 26. Delbridge L, Reeve TS, Khadra M, Poole AG. Total thyroidectomy: the technique of capsular dissection. Aust N Z J Surg 1992;62:96-9. 27. Sheahan P, Mehanna R, Basheeth N, Murphy MS. Is systematic identification of all four parathyroid glands necessary during total thyroidectomy?: a prospective study. Laryngoscope 2013;123:2324-8. 28. Sierra M, Herrera MF, Herrero B, Jiménez F, Sepúlveda J, Lozano RR, et al. Prospective biochemical and scintigraphic evaluation of autografted normal parathyroid glands in patients undergoing thyroid operations. Surgery 1998;124:1005-10.


Orıgınal Article

PEDIATRICS

North Clin Istanbul 2016;3(1):15-21 doi: 10.14744/nci.2016.48403

Relationship between newborn craniotabes and vitamin D status Makbule Ercan,1 Mustafa Ozcetin,2 Mehmet Karaci,3 Gamze Ozgurhan,2 Adem Yasar,3 Berrak Guven4 Faculty of Medicine, Department of Pediatrics, Bulent Ecevit University, Zonguldak, Turkey

1

Children’s Health and Diseases Clinic, Dr. Lutfi Kirdar Kartal Training and Research Hospital, Istanbul, Turkey

2

Children’s Health and Diseases Clinic, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey

3

Faculty of Medicine, Department of Biochemistry, Bulent Ecevit University, Zonguldak, Turkey

4

ABSTRACT OBJECTIVE: In recent studies, vitamin D deficiency during pregnancy and early infancy has been reported to predispose children to many chronic diseases, except those of the skeletal system. The aim of this study was to investigate whether craniotabes in otherwise healthy newborns is physiological, its relationship to vitamin D deficiency and whether or not it requires treatment. METHODS: A total of 150 healthy newborns with a weight of over 2000 g were included. Newborns were divided into two groups during postnatal discharge (1-3.’s day): those with and without craniotabes. The 25-hydroxy (OH) vitamin D levels of the newborns’ mothers were measured, and all infants were re-evaluated for craniotabes, as well as tested to determine levels of serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH) and 25(OH) vitamin D, urine calcium and creatinine. RESULTS: Craniotabes was present in 45 (30%) of newborns enrolled in the study. Craniotabes of the newborns born during the winter months was significantly higher. PTH level was significantly higher in 1-month-old newborns with craniotabes than those without craniotabes. No relationship was observed between diet and craniotabes, but in exclusively breastfed infants, vitamin D level was statistically significantly lower. No statistically significant difference was found in the occurrence of craniotabes in newborns with or without vitamin D support. CONCLUSION: The relationship between newborn craniotabes and maternal vitamin D deficiency is not clear. However, the present study illustrates that maternal vitamin D deficiency is still a major problem. Therefore, measures to prevent maternal vitamin D deficiency should be strengthened. Keywords: Craniotabes; newborn; vitamin D deficiency.

C

raniotabes is the softening of the bones of the skull and is known to be associated with many diseases such as rickets, hypervitaminosis, osteo-

genesis imperfecta, hydrocephalus and congenital syphilis. Craniotabes in otherwise normal newborns has largely been regarded as a physiological condi-

Received: December 14, 2015 Accepted: February 05, 2016 Online: May 02, 2016 Correspondence: Dr. Mehmet KARACI. Fatih Sultan Mehmet Egitim ve Arastirma Hastanesi Cocuk Sagligi ve Hastaliklari Klinigi, Istanbul, Turkey. Tel: +90 216 - 578 30 00 e-mail: mkaraci@gmail.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


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tion that does not require treatment. It is found in up to 30% of healthy neonates, and usually heals within 2-3 months [1, 2]. Craniotabes is thought to be due to minor changes in calcium metabolism and the physiological compaction of premature engagement of the head [1]. Unlike classical vitamins, vitamin D is synthesized in the body and termed a hormone. In recent studies, vitamin D deficiency during pregnancy and early infancy has been reported to predispose children to many chronic diseases, except those of skeletal system [3, 4]. For this reason, requiring normal vitamin D values has gained more importance [5, 6]. In studies conducted in Turkey, maternal vitamin D deficiency is reported to be 80% [7]. Intrauterine exposure to temporary vitamin D deficiency during infancy or childhood creates an increased risk for type 1 diabetes mellitus, asthma, lower respiratory tract infections and even schizophrenia [4, 8-10]. If craniotabes in normal neonates reflects vitamin D deficiency in utero, and if the condition persists in infancy, it may lead to a variety of health problems later in life. Accordingly, treatment with vitamin D would be appropriate in those newborns [11]. The aim of this study was to investigate whether craniotabes in otherwise healthy newborns is physiological, its relationship to vitamin D deficiency and whether or not it requires treatment. MATERIALS AND METHODS The study consisted of 150 neonates born at term between April 2012 and April 2013 in Bulent Ecevit University Medical Faculty Hospital and was conducted prospectively. It included 150 healthy, term infants with a body weight of more than 2000 g. No sex discrimination was made. Infants whose families declined to sign a written consent agreement, and those with acute illness, major congenital anomalies, abnormal calcium metabolism or liver disease were excluded. Newborns included in the study were examined by one physician for craniotabes (first and third day) on discharge and divided into two groups: those with craniotabes (study group) and without craniotabes (control group). Presence of soft bones,

North Clin Istanbul – NCI

inward collapse when pressure was applied to parieto-occipital region with the index and middle fingers of both hands and typically snapping back when pressure was relieved was considered to constitute craniotabes. Serum 25-hydroxy (OH) vitamin D levels were measured in all mothers of participating infants. The same physician repeated the physical examination of all the newborns when they were 1 month old to evaluate the presence of craniotabes and levels of serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH), 25 (OH) vitamin D, urinary calcium and creatinine. Epidemiological data was gathered, including, date of birth; birth weight; gestational week; gender; maternal age; number of pregnancies; number of children; mother’s education level; mother’s occupation; mother’s clothing style; daily, weekly and monthly average duration of exposure to the sun; cigarette usage; place of residence (rural/urban), calcium and vitamin D supplementation during pregnancy; nutritional status of baby up to 1 month of age; vitamin D supplementation in infancy and if provided, date initiated. Infants who were breastfed but received more than 40 mL per day formula were considered to be mixed-fed. The information obtained was examined for relationship to craniotabes. The study was approved by the Ethics Committee of Bulent Ecevit University School of Medicine and written informed consent was obtained from parents. Data were evaluated using SPSS software (version 13.0; SPSS Inc., Chicago, IL, USA). Numerical variables were presented as mean, standard deviation, median, minimum and maximum values; categorical variables were shown with frequencies and percentages. All comparisons in statistical analysis with p-value of <0.05 were considered statistically significant. RESULTS The study included 150 neonates born at term between April 2012 - April 2013 in Bulent Ecevit


Ercan et al., Relationship between newborn craniotabes and vitamin D status

17

Table 1. Gestational ages, birth seasons, birth weights of newborns Season Craniotabes (n)

Gestational Age (days)

With (45) 268.87±7.51 Without (105) 271.43±8.21 p 0.091

University Medical Faculty Hospital. Of the total, 79 were female (52.6%) and 71 were male (47.4%). Craniotabes was detected in 45 (30%) of the newborns enrolled in the study and the sex ratio of participants with and without craniotabes was similar. Neonates with and without craniotabes were compared in terms of gestational age and birth weight. No statistically significant relationship was detected between craniotabes and weeks of gestation, but in newborns with low birth weight, the incidence of craniotabes was found to be significantly higher (p=0.002). All of the patients with cranio-

Birth Weight (g)

Summer n (%)

Winter n (%)

3027.44±486.11 (2100-3940) 3317.38±460.43 (2400-4740) 0.002*

0 (0)

45 (45,9)

46 (100)

53 (54,1)

<0,001*

tabes were born in the fall and winter months with poor sunlight (Table 1). The incidence of craniotabes was significantly higher in infants born during the winter months (p<0.001). There was no statistically significant relationship between education, profession, the family residence, clothing styles and craniotabes (Table 2). Mothers’ use of cigarettes did not increase the incidence of craniotabes statistically, but detection of craniotabes in 50% of infants whose mothers smoke and only in 27.9% of infants of non-smoking mothers suggests that smoking may increase the risk of craniotabes.

Table 2. Relationship between craniotabes and some perinatal maternal factors Mother’s

With Craniotabes

n

Education

%

Without Craniotabes n

%

Total

p

Primary school 26 27.1 70 High school 13 37.1 22 University 6 31.6 13

72.9 96 62.9 35 0.539 68.4 19

Profession

Housewife 35 28.9 86 Worker 5 38.5 8 Officer 5 31.3 11

71.1 121 61.5 13 0.778 68.8 16

Clothes

Modern 17 30.9 38 Traditional 28 29.5 67

69.1 55 0.351 70.5 95

Family residence Smoking status

Urban Rural

32 30.5 73 13 28.9 32

Smoker 7 Non-smoker 38

50 7 27.9 98

69.5 105 0.254 71.1 45 50 14 0.123 72.1 136


18

North Clin Istanbul – NCI

Table 3. 25-hydroxy (OH) vitamin D level and duration of calcium (Ca)-vitamin D intake of mother Craniotabes

Duration of Ca-Vit D suplementation of mother (months)

25 (OH) vitamin D level of mother (ng/mL)

With 4.52±2.15 (1-9) 22.7± 6.8 (4.9-36.3) Without 4.35± 1.8 (1-9) 22± 5.9 (8.2-35.9) P 0.843 0.410

Mothers were evaluated in terms of receiving calcium and vitamin D supplementation during pregnancy. Groups were defined as receiving either calcium or vitamin D, receiving both, and receiving neither in terms of likelihood of craniotabes; no statistically significant difference was detected between the groups. Additionally, craniotabes incidence and calcium and vitamin D supplementation period of mothers and maternal 25 (OH) vitamin D levels were compared. There was no statistically significant difference (Table 3). However, serum 25 (OH) vitamin D levels <10 ng/mL were detected in 6.6% of mothers of neonates with craniotabes, while serum 25 (OH) vitamin D levels <10 ng/mL were detected in 0.95% of mothers of neonates without craniotabes. Vitamin D deficiency was observed in 96% of mothers while 90% of neonates had normal (>20ng/ml) vitamin D levels. No statistically significant relationship was detected between craniotabes

and daily, weekly and monthly sunshine exposure. All neonates were examined at the newborn clinic at 1 month of age. Of 45 newborns that initially had craniotabes (68.8%), it was still present in 31 at 1 month of age. No statistically significant relationship was found between gender and persistent craniotabes. Although no significant difference was observed between gestational age and persistent craniotabes, more low birth weight newborns had craniotabes than newborns with normal birth weight. Those with craniotabes had 2899.5±448.3 g average birth weight, while the average birth weight was 3316.6±458.2 g for newborns without craniotabes (p<0.001). Mothers who received calcium and vitamin D supplementation and those who did not were compared, and there was no statistically significant difference between the two groups in terms of average maternal 25 (OH) vitamin D level and serum Ca,

Table 4. Relationship between craniotabes seen soon after birth and Ca, P, ALP, PTH, 25(OH) vitamin D, urine Ca/ creatinine levels of newborns Craniotabes With Without p

Newborns at 1 month Serum Ca Serum P ALP PTH 25(OH) vitamin D mg/dL mg/dL U/L pg/mL ng/mL 10.40±0.42 (9.6-11.5) 10.5±0.35 (9.8-11.4) 0.053

6.60±0.56 (5-7.4) 6.50±0.54 (4.6-7.7) 0.176

312.8±64.5 (156-466) 337.2±109 (140-712) 0.387

39.8±21.9 (3-92) 32.6±17.9 (3-100) 0.03*

Ca: calcium; P: phosphorus; ALP: alkaline phosphatase; PTH: parathyroid hormone; OH: hydroxy.

31.7±12.5 (11.6-83) 30.2±8.5 (10.5-65.5) 0.499

UrineCa/Cr 0.61±0.42 (0.1-1.82) 0.58±0.33 (0.04-2.23) 0.972


Ercan et al., Relationship between newborn craniotabes and vitamin D status

P, ALP, PTH, 25 (OH) vitamin D, and urine calcium/creatinine levels of newborns at 1 month of age. Newborns who had craniotabes and were exclusively breastfed had significantly higher serum PTH levels than those without craniotabes (p=0.03). Between the two groups, there was no significant correlation in terms of 25 (OH) vitamin D levels of mothers and newborns (Table 4). Of the 150 newborns in the study, 86 (57.3%) were breastfed, 4 (2.7%) were formula-fed and 60 (40%) were both breastfed and formula-fed. When the relationship between feeding patterns and craniotabes persisting at 1 month of age was evaluated, no statistically significant difference was found. Infants who were exclusively breastfed had an average of 27.5±7.5 ng/mL 25 (OH) vitamin D level, whereas formula and mixed-fed infants had an average of 34.8±10.9 ng/ml 25 (OH) vitamin D level (p<0.0001, Figure 1). Four newborns (2.7%) had vitamin D deficiency (<15 ng/mL), 11 (7.3%) had vitamin D insufficiency (15-20 ng/mL), and 135 (90%) of all newborns had vitamin D levels within normal limits (>20 ng/ml). According to maternal vitamin D levels, 103 of 150 mothers (68.7%) had vitamin D deficiency (<25 ng/mL), 41 of them (27.3%) had vitamin D insufficiency (25-32 ng/ 25 (OH) Vitamin D ng/ml

50 45 40 35 30 25 20 15 10 5 0 Breast milk

Formula/mixed

Figure 1. Dietary patterns of newborns and Vitamin D levels.

19

mL). Only 6 of those (4%) had vitamin D levels within normal limits (>32 ng/mL). No statistically significant relationship was found between vitamin D levels of mothers and presence of craniotabes at discharge or at 1 month of age. Analysis revealed that 95.3% of the newborns had 400 IU of vitamin D supplementation. No statistically significant relationship was found between the incidence of craniotabes and vitamin D supplementation. DISCUSSION Vitamin D is a fat-soluble vitamin; however, it is produced in tissue and released into the bloodstream. It acts on other tissue with “feedback” mechanisms and is considered a steroid hormone rather than a vitamin [12, 13]. Craniotabes is detected in 30% of healthy newborns and usually disappears in 2-3 months [1, 2]. A study in Japan suggested that physiological craniotabes frequency in newborn infants might be a result of in utero exposure to vitamin D deficiency [11]. Craniotabes was detected in 22% of neonates in that study, and 27% still had craniotabes at 1 month of age. In the present study, 30% of newborns had craniotabes, and 68.8% of those had persistent craniotabes at 1 month of age. Although no statistically significant relationship was found in terms of frequency of craniotabes among mothers who smoke cigarettes, 50% of smokers’ infants had craniotabes whereas this was true for only 27.9% of non-smokers’ infants. Recently, many studies conducted in various countries have found that 25 (OH) vitamin D levels in mothers who give birth in the summer and autumn months were higher than in those who give birth in the winter and spring months [14-17]. In one study, 25 (OH) vitamin D levels were found to be higher in patients diagnosed with nutritional rickets during summer months than those diagnosed during winter months [18]. In the present study, craniotabes was significantly higher in neonates born during the winter months. But no statistically significant difference was found in terms of 25 (OH) vitamin D levels of neonates born in summer or winter months and their mothers. Recent studies have also found that adminis-


20

tration of 800-1600 IU/day of vitamin D during pregnancy was insufficient for normal serum 25OH vitamin D levels [19, 20]. In a study with broad participation, 25 (OH) vitamin D level was found to be higher in mothers given vitamin D supplementation during pregnancy and in their infants at sixth postnatal day [21]. In the present study, only 3 mothers (2%) were given 1200 IU of vitamin D supplementation. Infants with and without craniotabes were evaluated according to their mothers’ calcium and vitamin D supplement intake during pregnancy and duration of supplementation. There were no statistically significant differences between the two groups. In conclusion, despite a program launched in 2011 in Turkey, pregnant women still do not receive adequate vitamin D supplementation. All physicians dealing with the issue in the country have a big responsibility in this respect. Breast milk is poor in vitamin D, containing about 10 to 60 U/L [22]. A study compared infants fed breast milk and fed vitamin D-fortified formula in addition to breast milk and found, similar to the present study, serum 25-OH vitamin D levels were higher in formula-fed [23] infants. There was no statistically significant difference between infants with or without craniotabes in terms of their feeding patterns and vitamin D supplementation status. In the present study, vitamin D status in children was evaluated according to proposals of American Pediatric Endocrine Association [24]. In only 2.7% of newborns were 25 (OH) vitamin D levels <15ng/mL. All of those were breastfed and 50% did not have vitamin D supplementation. Vitamin D levels (>20 ng/mL) were adequate in 90% of the newborns. This indicates that a free vitamin D support program for newborns started in 2005 by the Ministry of Health in Turkey is being implemented effectively and that 400 IU of vitamin D is sufficient for newborns [25]. In the present study, no statistically significant difference was observed between the two groups in terms of craniotabes detected at 1 month of age and serum Ca, P, ALP, 25 (OH) vitamin D, PTH levels and spot urine calcium/ creatinine levels. The vitamin D support program has also had a positive effect on incidence of rickets, which has decreased noticeably [18].

North Clin Istanbul – NCI

Recently, reports in different countries have been published about frequent vitamin D deficiency in women of childbearing age, pregnant and nursing mothers and significant risks of this situation for mothers and babies [26-28]. In studies conducted in Turkey, vitamin D levels of mothers are quite low, as were the levels in the present study [15, 29, 30]. The present analysis indicated median maternal vitamin D levels did not differ significantly between the two groups, but 6.6% of the mothers of infants with craniotabes had 25 (OH) vitamin D levels <10 ng/mL; only 0.95% of mothers of infants without craniotabes had 25 (OH) vitamin D level <10 ng/mL (8.2 ng/mL). Only 6 of the mothers had vitamin D levels in normal range (>32 ng/mL). This suggests that in Turkey, pregnant women do not get appropriate supplementation of vitamin D. As a result of this study, although we cannot identify a clear relationship between neonatal craniotabes and maternal vitamin D deficiency, we suggest that more extensive studies be conducted focusing on the subject. Maternal vitamin D deficiency is still a major issue in Turkey. The authors suggest that at least 1600-2000 IU of vitamin D supplementation per day should be included in antenatal care for pregnant women. 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 - M.E., M.K.; Design - M.E., M.K., M.Ö.; Supervision - G.Ö.; Funding - A.Y., G.Ö.; Materials - M.E., M.K., M.Ö.; Data collection and/or processing - M.E., M.K.; Analysis and/or interpretation - M.K., B.G.; Literature search - M.E., M.K.; Writing - M.K., M.E.; Critical review - B.G., A.Y.

REFERENCES 1. Fox GN, Maier MK. Neonatal craniotabes. Am Fam Physician 1984;30:149–51. 2. Otto FM, Hesse V. Craniotabes, craniomalacia (Wieland) and active ricketts in infants. [Article in German] Kinderarztl Prax 1990;58:179–83. [Abstract] 3. Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia 1999;42:51–4. 4. Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM.


Ercan et al., Relationship between newborn craniotabes and vitamin D status

Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500–3. 5. Ward LM. Vitamin D deficiency in the 21st century: a persistent problem among Canadian infants and mothers. CMAJ 2005;172:769–70. 6. American Academy of Pediatrics. Clinical Report: Prevention of Rickets and Vitamin D Deficiency: New Guidelines for Vitamin D. Pediatrics 2003;111:908–11. 7. Pehlivan I, Hatun S, Aydoğan M, Babaoğlu K, Gökalp AS. Maternal vitamin D deficiency and vitamin D supplementation in healthy infants. Turk J Pediatr 2003;45:315–20. 8. Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, et al. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 2006;367:36–43. 9. Camargo Jr CA, Rifas-Shiman SL, Litonjua AA, Edwards JWR, Weiss ST, Gold DR, et al. Prospective study of maternal intake of vitamin D during pregnancy and risk of wheezing illness in children at age 2 years. J Allergy Clin Immunol 2006;117(3):721–2. 10. Najada AS, Habashneh MS, Khader M. The frequency of nutritional rickets among hospitalized infants and its relation to respiratory diseases. J Trop Pediatr 2004;50:364–8. 11. Yorifuji J, Yorifuji T, Tachibana K, Nagai S, Kawai M, Momoi T, et al. Craniotabes in normal newborns: the earliest sign of subclinical vitamin D deficiency. J Clin Endocrinol Metab 2008;93:1784–8. 12. Şimşek E, Kocabay K. Calcium, phosphorus and magnesium homeostasis. Türkiye Klinikleri J Pediatr 2002;11:211–20. 13. Güven A, Ecevit A, Tarcan A, Tarcan A, Özbek N. Cord blood vitamin D levels. Çocuk Sağ Hast Derg 2011;54:55–61. 14. Sachan A, Gupta R, Das V, Agarwal A, Awasthi PK, Bhatia V. High prevalence of vitamin D deficiency among pregnant women and their newborns in northern India. Am J Clin Nutr 2005;81:1060–4. 15. Bodnar LM, Simhan HN, Powers RW, Frank MP, Cooperstein E, Roberts JM. High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates. J Nutr 2007;137:447–52. 16. Hollis BW, Pittard WB 3rd. Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences. J Clin Endocrinol Metab 1984;59:652–7. 17. Nicolaidou P, Hatzistamatiou Z, Papadopoulou A, Kaleyias J, Floropoulou E, Lagona E, et al. Low vitamin D status in mother-

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newborn pairs in Greece. Calcif Tissue Int 2006;78:337–42. 18. Ozkan B, Doneray H, Karacan M, Vançelik S, Yildirim ZK, Ozkan A, et al. Prevalence of vitamin D deficiency rickets in the eastern part of Turkey. Eur J Pediatr 2009;168:95–100. 19. Mulligan ML, Felton SK, Riek AE, Bernal-Mizrachi C. Implications of vitamin D deficiency in pregnancy and lactation. Am J Obstet Gynecol 2010;202:429.e1–9. 20. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911–30. 21. Cockburn F, Belton NR, Purvis RJ, Giles MM, Brown JK, Turner TL, et al. Maternal vitamin D intake and mineral metabolism in mothers and their newborn infants. Br Med J 1980;281:11–4. 22. Henderson A. Vitamin D and the breastfed infant. J Obstet Gynecol Neonatal Nurs 2005;34:367–72. 23. Greer FR. Vitamin D deficiency--it’s more than rickets. J Pediatr 2003;143:422–3. 24. Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M; Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics 2008;122:398–417. 25. Hatun S, Bereket A, Ozkan B, Coşkun T, Köse R, Calýkoğlu AS. Free vitamin D supplementation for every infant in Turkey. Arch Dis Child 2007;92:373–4. 26. Gannagé-Yared MH, Chemali R, Yaacoub N, Halaby G. Hypovitaminosis D in a sunny country: relation to lifestyle and bone markers. J Bone Miner Res 2000;15:1856–62. 27. Ghannam NN, Hammami MM, Bakheet SM, Khan BA. Bone mineral density of the spine and femur in healthy Saudi females: relation to vitamin D status, pregnancy, and lactation. Calcif Tissue Int 1999;65:23–8. 28. Mishal AA. Effects of different dress styles on vitamin D levels in healthy young Jordanian women. Osteoporos Int 2001;12:931– 5. 29. Andiran N, Yordam N, Ozön A. Risk factors for vitamin D deficiency in breast-fed newborns and their mothers. Nutrition. 2002;18:47–50. 30. Ergür AT, Berberoğlu M, Atasay B, Şıklar Z, Bilir P, Arsan S, et al. Vitamin D deficiency in Turkish mothers and their neonates and in women of reproductive age. J Clin Res Pediatr Endocrinol 2009;1:266–9.


Orıgınal Article

Physical Medicine and Rehabilitation

North Clin Istanbul 2016;3(1):22-6 doi: 10.14744/nci.2016.19870

Rehabilitation after successful finger replantation Meric Ugurlar,1 Fatih Kabakas,2 Husrev Purisa,2 Ilker Sezer,2 Pınar Celikdelen,2 Ismail Bulent Ozcelik2 Department of Orthopedics and Traumatology, Sişli Hamidiye Etfal Education and Research Hospital, Istanbul, Turkey

1

IST-EL Hand Surgery, Microsurgery and Rehabilitation Group, Istanbul, Turkey

2

ABSTRACT OBJECTIVE: The aim of the present study was to assess results of rehabilitation of patients after finger replantation. METHODS: The study examined 160 fingers amputated and replanted at various levels between 2000 and 2013 at the clinic. Mean patient age was 29.4 years. Mean follow-up time was 23 months. Rehabilitation of fingers began between postoperative fourth and eighth week and continued until the 24th week. Range of motion of affected hand, return to daily activities, aesthetic appearance, and patient satisfaction were assessed according to Tamai criteria. RESULTS: Functional results according to Tamai criteria were perfect in 36 patients, good in 54 patients, average in 27 patients, and poor in 18 patients. CONCLUSION: Post-operative rehabilitation of replanted fingers should begin as soon as possible. During the rehabilitation period, physiotherapist, surgeon, and patient must work in close cooperation. Functional results of patients who adjust to the rehabilitation program, home practice, and splint usage are better. Keywords: Finger; rehabilitation; replantation.

F

inger amputations cause emotional and social trauma to patients in addition to physical trauma. Although there are individual differences, the primary goal for most patients is to regain use of their fingers and return to their lives [1]. Finger replantation requires a difficult and complex rehabilitation program, but results are highly satisfactory in the long term.

This study assessed rehabilitation results of 160 fingers replanted at different levels on 135 patients. MATERIALS AND METHODS Between 2000 and 2013, 135 patients had a total of 160 fingers that had been amputated at different levels successfully replanted at the clinic. The study

Received: March 07, 2016 Accepted: May 04, 2016 Online: May 24, 2016 Correspondence: Dr. Meric UGURLAR. Sisli Hamidiye Etfal Egitim ve Arastirma Hastanesi, Halaskargazi Cad. Etfal Sok., Istanbul, Turkey. Tel: +90 216 373 50 00 e-mail: mugurlar@yahoo.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


Ugurlar et al., Rehabilitation after successful finger replantation

group consisted of 95 male patients and 40 female patients. Mean age of patients was 29.4 (range: 6-57) years. The injuries occurred in the right hand of 84 patients (62.2%) and the left hand of 51 patients (37.8%). Replantation was performed on 17 thumbs (12.6%), 32 index fingers (23.7%), 42 middle fingers (31.1%), 30 ring fingers (22.2%), and 14 little fingers (10.4%) (Table 1). More than one finger was replanted in 11 patients (2 fingers amputated at the same level in 5 patients, and 3 fingers amputated at the same level in 6 patients). Replantation levels were grouped according to Tamai classification [1]. A total of 45 reattachments were categorized as being in zone I, 32 in zone II, 37 in zone III, 31 in zone IV, and 15 in zone V (Table 1). Rehabilitation began in the postoperative fourth to eighth week and continued until the 24th week. All patients used splints supporting the wrist in the neutral position, metacarpophalangeal joints in 60-degree flexion, and interphalangeal joints in extension. Internal bone fixators were removed after sixth week and mobilization was initiated according to status of bone fusion. Rehabilitation of all patients began was started in first postoperative week with edema control and by splinting wrist and fingers in functional position. For patientsâ&#x20AC;&#x2122; comfort, and because of the advantage of controlling flexion contractures that might develop in the fingers, generally volar splints were preferred. To avoid possible complications such as pseudoarthrosis, exercise programs for replanted fingers were not initiated during early postoperative period. However, physical therapy support is necessary in this process to position the hand, control edema, and maintain range of motion (ROM) of unaffected

23

fingers. Massage was used before exercise to soften scar tissue at surgical area and to control edema in the fingers during rehabilitation process. Exercise programs arranged as block exercises targeting active, active-assistive, passive, isolated interphalangeal joint motions; strengthening exercises; and light functional activities, such as writing and holding small objects, were initiated after eighth week. Number and level of difficulty of the activities was increased according to patient tolerance in the succeeding weeks. Muscle stimulators were used in order to preserve ROM obtained after exercise and to increase tendon strength. Rehabilitation program of patients differed after th 10 to 12th week according to the level of replantation. Active rehabilitation program of patients was completed at 10 to 12 weeks for replantations of distal interphalangeal joint and fingertips located more distally. Active rehabilitation process was longer for digital replantations located at proximal part of distal interphalangeal joint. Follow-up of patients continued intermittently until postoperative sixth month and secondary surgical interventions were planned according to functional gains. Secondary reconstruction was performed in two patients and tenolysis was performed in one patient who had undergone finger replantation at medium level of proximal phalanx. Results were evaluated according to Tamai criteria, including assessment of joint ROM, sensation assessment, subjective assessments, aesthetic appearance, and satisfaction of the patient, and were scored on a 100-point scale [1]. In the assessment of joint ROM, total active ROM of the fingers was measured using standard

Table 1. Affected fingers and zones Affected finger Affected zone

Thumb

Index

Middle finger

Ring finger

Little finger

17 32 42 30 14 Zone I

Zone II

Zone III

Zone IV

Zone V

15 32 37 31 15


24

goniometric measurements defined by American Association of Orthopaedic Surgeons (AAOS) [2]. Measurements of joint ROM correspond to a value of 20 points in the calculation of functional level according to Tamai criteria, and each replanted finger was assessed separately. In thumb replantations, patient success in opposition motion, percentage of total active motion loss in the thumb, and degree of total active joint motion in the other fingers were evaluated. Twenty different daily life activities were assessed on a 20-point scale. The last step in the evaluation was the satisfaction of the patient. They were asked about their professional status and if they were obliged to change jobs, in addition to how happy they were with their replanted fingers. During evaluation of subjective symptoms, complaints such as pain and cold intolerance were evaluated where present. Deformities such as atrophy, scarring, color change, angulation, mallet finger, etc. were assessed with regard to aesthetic appearance. If present, the severity of these problems and how they limited functional use of the finger was considered in the scoring [3]. Postoperative sensation was evaluated using Semmes-Weinstein monofilament (SWM) and two-point discrimination (2-PD) tests. SWM test values used for interpretation were: green filament, size 2.83 (normal); blue filament, size 3.61 (diminished light touch); purple filament, size 4.31 (diminished protective sensation); red filament, size 6.65 (loss of protective sensation)[4]. A 2-PD score of 6 mm or less was excellent, 7-15 mm was good, and 16 mm or greater was defined as poor [5]. Superficial touch-deep pressure perception in fingers was evaluated using monofilament test and the fine tactile discrimination sensation important in daily life activities was evaluated using static and dynamic 2-PD tests. Sensory rehabilitation was initiated after postoperative sixth week. Treatment modalities such as whirlpool, paraffin, ultrasound, electrotherapy, and various dynamic and static splints were also used in addition to therapeutic exercises. Patients were also

North Clin Istanbul â&#x20AC;&#x201C; NCI

informed regarding keeping the hand elevated, protecting it from cold, and avoiding substances such as nicotine and caffeine that could disturb replanted finger blood circulation [6]. RESULTS Mean follow-up time of patients was 23 (range: 12-62) months. During treatment, goniometric, dynamometric, sensory, and functional assessments were performed at periodic intervals and treatment programs were designed according to test results. Additionally, it was observed that assessments performed during treatment contributed significantly to increased patient motivation and participation. SWM test results were green in 52 fingers (32.5%), blue in 59 fingers (36.9%), purple in 38 fingers (23.7%), and red in 11 fingers (6.8%). Mean static 2-PD test of patients was determined to be 6.9 (range: 3-11) mm and mean dynamic 2-PD test result was 4.5 (range: 3-6) mm. At the end of the follow-up period, there was chronic pain complaint in 3 patients. Although cold intolerance was seen almost in all patients in the postoperative first year, it was observed that in all but 5 patients the cold intolerance complaint regressed in subsequent years. There was atrophy in 8 patients, and significant atrophy affecting aesthetic appearance was present in 3. Two patients had scar tissue that led to proximal interphalangeal joint contracture. Three patients had mallet finger formation. During assessment of patient satisfaction, it was observed that the most important factor affecting patient expectations and results was the occupation of the patient. Patients in occupational groups such as laborer and farmer stated that they were very happy with the result, while patients from occupational groups such as jeweler, musician, and others using fine motor skills stated that they were less happy with the result. However, generally the satisfaction level of patients was greater than expected. All patients stated that they were happy with their replanted fingers. Functional results according to Tamai criteria


Ugurlar et al., Rehabilitation after successful finger replantation

[1] were excellent in 36 (26.7%) patients, good in 54 (40%) patients, average in 27 (20%) patients, and poor in 18 (13.3%) patients. It was observed that sensation, motion, and function results in distal finger replantations were better than those at the level of middle phalanx and proximal phalanx. Although level and type of injury are important factors affecting functional results, patient continuation of rehabilitation and participation in treatment is the most important factor [7]. Discussion Finger amputation is an emotionally and physically traumatic injury. Typically, regaining use of their fingers and returning to their lives is the patientâ&#x20AC;&#x2122;s greatest concern [8]. There are several alternatives available for treatment of distal amputations. Following procedures such as primary stump repair, local flap, free flap, neurovascular island flap, skin graft, etc., problems like pain, hypersensitivity, numbness, and cold sensitivity can occur, in addition to impaired aesthetic appearance. Most importantly, though the affected area is small in size, disturbance of body wholeness affects patients negatively. While the technique is difficult for surgeons, replantation is the preferred treatment modality for patients with zone I and zone II amputations. Replantation is also targeted in amputations of fingers in zones III, IV, and V; however, insufficient flexion in the replantation and flexion contracture in distal interphalangeal (DIP) joint are frequently encountered problems. To increase functional use of the hand in cases that cannot be controlled with early rehabilitation and splinting, secondary reconstructions like flexor tenolysis, and DIP joint arthrodesis may be recommended. Secondary reconstructions were performed as part of the current study and it was observed that recovery of finger and functional use of the hand increased in both patients. The study also determined that functional levels of replanted fingers were very similar in patients with multiple finger replantation. Longterm results are very satisfactory, even for patients for whom sufficient joint motion cannot be provided after finger replantation and rehabilitation.

25

Rehabilitation should be initiated as soon as possible after surgery and the patient, physician, and physiotherapist should work in collaboration [9]. It should be noted that exercises performed in early postoperative period without sufficient bone healing can cause undesired results like pseudoarthrosis. However, the difficulty of controlling problems like tendon cohesion and joint contracture in patients initiating a physical therapy program later must also be taken into consideration. It was observed that secondary reconstructions were not required in the long term for patients kept stable and given limited physical therapy treatment beginning from the postoperative first week and initiating further physical therapy after the start of bone healing. Secondary reconstruction was required in only 7 of 135 patients in the present study. The importance of exercises performed, physical therapy modalities used and splints applied during the rehabilitation process should be explained in detail to patients and they should be asked to actively participate in therapy. It was observed that patients who initiated rehabilitation quickly and who had good participation in treatment found relief from the period of depression experienced after the accident and surgery. In finger replantations, if a deliberate and serious rehabilitation program is not undertaken, it is difficult to achieve the desired functional level despite surgical success. Physical, psychological, and social conditions, such as age and mental status of the patient, should be considered when establishing the rehabilitation program and determining the best follow-up program the patient can maintain given these conditions. As in all rehabilitation programs, the aim in finger rehabilitation is to increase quality of life of the patient in daily life and in work life [10]. Although finger replantations require a difficult and complex rehabilitation program due to anatomical structure, the results can be highly satisfactory in the long term. In the present study it was observed that patients with good treatment compliance, who performed home exercise program regularly, and used splint correctly and with appropriate frequency, had better functional outcomes [11].


26 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 - M.U.; Design - P.Ç.; Supervision - F.K.; Funding - P.Ç.; Materials - P.Ç.; Data collection and/or processing - H.P.; Analysis and/or interpretation - İ.S.; Literature search - M.U.; Writing - M.U.; Critical review - İ.B.Ö.

REFERENCES 1. Tamai S. Twenty years’ experience of limb replantation – review of 293 upper ext gremity replants. J Hand Surg Am 1982;7:54956. 2. Cambridge CA. Range of motion measurements in the hand. In: Hunter J, Schneider LH, Mackin EJ, Callahan AD, editors. Rehabilitation of the Hand Surgery and Therapy. 3rd ed. St Louis: Mosby; 1990. p.82-92. 3. Matsuzaki H, Yoshizu T, Maki Y, Tsubokawa N. Functional and cosmetic results of fingertip replantation: anastomosing only the digital artery. Ann Plast Surg 2004;53:353-9.

North Clin Istanbul – NCI 4. Semmes J, Weinstein S, Ghent L, Teber HL. Somatosensory changes after penetrating brain wounds in man. Cambridge, Massachusets, Harvard University Press; 1960. p.91. 5. Weber RA, Breindenbach WC, Brown RE, Jabaley ME, Mas DP. A randomized prospective study of polyglycolic acid conduits for digital nerve reconstruction in humans. Plast Reconstr Surg 2000;106:1036-45. 6. Papanastasiou S. Rehabilitation of the replanted upper extremity. Plast Reconstr Surg 2002;109:978-81. 7. Ross DC, Manktelow RT, Wells MT, Boyd JB. Tendon function after replantation: prognostic factors and strategies to enhange total active motion. Ann Plast Surg 2003;51:141-6. 8. Sagiv P, Shabat S, Mann M, Ashur H, Nyska M. Rehabilitation process and functional results of patient with amputated fingers. Plast Reconstr Surg 2002;110:497-503. 9. Silverman PMN, Vilette-Green W, Petrilli J. Early protective motion in digital revascularization and replantation. J Hand Ther 1989;2:84-101. 10. Kader PB. Therapist’s management of the replanted hand. Hand Clin 1986;2:179-91. 11. Scheker LR, Hodges A. Brace and rehabilitation after rehabilitation and revascularization. Hand Clin 2001;17:473-80.


Orıgınal Article

cardıovasculAr surgery

North Clin Istanbul 2016;3(1):27-33 doi: 10.14744/nci.2016.43434

Stent versus bypass: The reasons and risk factors for early readmission to hospital after myocardial revascularization Murat Sargin,1 Mustafa Adem Tatlisu,2 Muge Tasdemir Mete,1 Nehir Selcuk,1 Sevinc Bayer,1 Serdar Akansel,1 Serap Aykut Aka,1 Mehmet Eren2 Siyami Ersek Thoracic and Cardiovascular Surgery Center Cardiovascular Surgery Clinic, Istanbul, Turkey

1

Siyami Ersek Thoracic and Cardiovascular Surgery Center Cardiology Clinic, Istanbul, Turkey

2

ABSTRACT OBJECTIVE: Though 30-day rates of readmission for coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) remain high, readmission rates and associated risk factors have not been well examined. The purpose of the present study was to determine the risk factors for and rates of readmission and to compare two revascularization methods on that basis. METHODS: The study included 2664 consecutive patients who underwent coronary revascularization either with CABG surgery or PCI. The study was performed retrospectively and a wide variety of risk factors related to readmission were selected for analysis, including demographic data, preoperative risk factors and postoperative complications. RESULTS: From the CABG group (Group 1, n=1103), 18.3% were readmitted, as were 15.2% of the PCI group (Group 2, n=1561). In multivariate analysis, age, gender, left ventricular ejection fraction (LVEF), chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), length of stay (>10 days), body mass index (BMI), and creatinine level on admission were associated with early readmission for group 1 (Table 3). In group 2, age, gender, LVEF, DM, length of stay (>10 days), and creatinine level on admission were associated with early readmission. CONCLUSION: When two methods of revascularization were compared, rates of readmission were found to be similar. Patients with cited risk factors are prone to readmission in the first 30 days, so extra precautions should be taken at discharge. Neither method can be concluded to be superior with regard to readmission rates. Keywords: Aorta-coronary bypass; percutaneous coronary intervention; readmission.

Received: March 14, 2016 Accepted: May 04, 2016 Online: May 15, 2016 Correspondence: Dr. Murat Sargin. Tibbiye Caddesi, 34000 Uskudar, Istanbul, Turkey Tel: +90 216 337 99 20 e-mail: muratsargin@gmail.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


28

T

he incidence of coronary artery disease has increased, yet despite new effective medical therapies, new drug-eluted stents, and novel surgical techniques developed, the early period following revascularization after discharge is prone to many problems. Risk factors for morbidity and mortality related to coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) have been extensively studied. The 30-day rate of readmission for both revascularization methods remains high, despite decreases in mortality [1, 2, 3]. However, readmission rates and associated risk factors have not been well examined. In particular, the two methods have not been compared with respect to early readmission. The primary objective of the present study was to determine the risk factors for and rates of readmission in the first 30 days after surgical or percutaneous revascularization. The secondary goal was to use the data to compare the two surgical methods. MATERIALS AND METHODS The study included 2664 consecutive patients with coronary artery disease who underwent revascularization at the hospital either with CABG surgery or PCI between January 1 and September 1, 2013. The study was performed retrospectively and approved by the scientific board of the hospital. Of these patients, 1561 had PCI, and 1103 had CABG surgery. The patients included underwent only either CABG or PCI. Patients who died while in hospital and surviving patients who had not been discharged by postoperative day 30 were excluded. Patients who received concomitant surgeries or procedures were also excluded. In this study cohort, the goal was to identify patients who were readmitted within 30 days after discharge for a variety of complications of CABG surgery or PCI and to compare them to patients who were not readmitted within 30 days of discharge. A wide variety of potential risk factors related to readmission within 30 days, such as demographic data, preoperative risk factors and postoperative complications were selected for analysis, in addition to other variables. These included demographic data such as age and gender,

North Clin Istanbul â&#x20AC;&#x201C; NCI

comorbidities (diabetes mellitus [DM], chronic obstructive pulmonary disease [COPD]), previous revascularization (PCI or CABG), length of hospital stay (1-10 days, more than 10 days) postoperative complications such as bleeding revision, intra-aortic balloon pump requirement, major complications such as sepsis, gastrointestinal bleeding, renal failure, or respiratory failure. The rates of readmission, hospitalization and risk factors were analyzed. Statistical analysis All statistical analyses were performed using SPSS software (version 21.0; SPSS Inc., Chicago, IL, USA) and p value<0.05 was considered statistically significant. Categorical variables are expressed as n (%), and continuous variables are expressed as mean+SD. Forward stepwise multivariate logistic regression models were created to identify the independent predictors of 30-day readmission to emergency room (ER) after myocardial revascularization. Variables with p value<0.05 in univariate analysis were included in the multivariate model. To estimate the impact of demographic, clinical and angiographic variables on occurrence of any cause for ER services, we performed multiple logistic regression analysis, including all variables with a univariate relationship (p<0.10). RESULTS The study included 2664 consecutive patients with coronary artery disease undergoing coronary revascularization, and these patients were divided into two groups: CABG group (Group 1, n=1103) and PCI group (Group 2, n=1561). A total of 440 (16.5%) of 2664 patients were readmitted within 30 days of discharge following revascularization. Of the CABG group, 18.3% (n=202) were readmitted, as were 15.2% (n=238) of the PCI group. The number of patients and their baseline demographic and clinical data are presented in Figure 1 and Table 1. Cardiac care prompted the readmission of 33.6% (n=148), while 66.4% (n=292) of patients were admitted for non-cardiac reasons (diabetes-associated problems, respiratory infections, non-specific). The most frequent 6 reasons for readmission


Sargin et al., Stent versus bypass

29

Number of patients

Total Patients

2500

Total Readmitted

2000

CABG

1500

Readmitted CABG

1000

PCI

500

Readmitted PCI

Re a

I

Re a

dm

dm

itt ed

itt ed

PC

PC I

CA BG

BG CA

itt ed

dm

Re a

To ta l

To ta l

Pa tie n

ts

0

Figure 1. Number of patients retrospectively studied in the analysis.

CABG: Coronary artery bypass graft surgery; PCI: Percutaneous coronary intervention.

for whole patient group were dysrhythmia (15.7%), nonspecific causes (15.1%), heart failure (10.2%), respiratory problems (9.8%), infection (7.2%), and vascular access site complications (6.8%). Principal reasons for readmission for Group 1 and Group 2 are presented in Table 2.

Of the readmissions, 15.38% of CABG group (n=32) and 17.2% of PCI group (n=41) were rehospitalized. The rehospitalization rate for the whole cohort was 2.7%; that is, 2.9% of all CABG patients and 2.6% of all PCI patients. The approach to treatment of complications was standard hospital

Table 1. Comparison of demographic and clinical features of patients in Group 1 and in Group 2 at presentation (n=2664) Variables

Group 1 (n=1103)

Group 2 (n=1561)

p

65.1±10.6

56.5±10.6

0.03

Male

609 (55.3%)

914 (58.6%)

0.21

Hypertension

756 (68.5%)

566 (36.2%)

0.02

DM

286 (25.9%)

276 (17.7%)

0.18

COPD

203 (18.4%)

217 (13.9%)

0.22

Hyperlipidemia

330 (29.9%)

374 (23.9%)

0.35

LDL-cholesterol (mg/dL)

111.2±32.2

120.1±33.1

0.06

History of smoking

551 (49.9%)

858 (54.9%)

0.23

Previous revascularization

117 (10.6 %)

219 (14.02%)

0.04

Age (years)

EF (%) (on readmission)

37.5±10.5

47.6±8.6

0.01

Creatinine (mg/dL) (on readmission)

1.34±1.02

0.88±0.25

0.01

BMI>30

91 (8.3%)

Length of stay>10 days

103 (9.3%)

96 (6.14%)

0.07

BMI: Body mass index; COPD: Chronic obstructive pulmonary disease; DM: Diabetes mellitus; EF: Ejection fraction. * Parametric variables are reported in mean±SD or median (interquantile range); categorical variables are reported in number (percentage). Hypertension: Patients using medication for hypertension; DM: Patients using oral antidiabetics or insulin; Smoking: Declaration of smoking, regardless of packs/years; COPD: Use of COPD medications before or after revascularization.


30

North Clin Istanbul â&#x20AC;&#x201C; NCI

Table 2. Principal causes of readmission for both Group 1 and Group 2 Principal Diagnosis

Group 1 (%)

Group 2 (%)

Cardiac

33.1

34.3

Myocardial infarction/Ischemia

2.9

3.3

Angina pain/Chest pain

3.8

4.2

Heart failure

8.9

9.4

Dysrhythmia

13.2

17.4

Postcardiotomy syndrome

4.3

-

Non-Cardiac

66.9

Incisional infections

16.9

Respiratory

14.5 10.2

Renal

2.3 3.4

Vascular access site complication

65.7 -

-

Other

12.3

19.8 23.1

Nonspecific

13.4

16.7

%100

%100

BMI: Body mass index; COPD: Chronic obstructive pulmonary disease; DM: Diabetes mellitus; EF: Ejection fraction.

policy for surgical and cardiology teams. Reasons for rehospitalization in the CABG group were primarily deep sternal infection, myocardial ischemia/ infarction, and pleural effusion. For the PCI group,

rehospitalization was mainly the result of myocardial ischemia/infarction, arrhythmia, and vascular access site complications. Eight (1.8% of readmissions) of the readmitted patients underwent coro-

Table 3. Univariate and multivariate analysis of the predictors for early readmission in Group 1 population

Univariate Analysis

Multivariate Analysis *

OR (95% CI)

p

OR (95% CI)

p

Age

1.5 (1.33-1.65)

Female gender

1.3 (1.26-1.45)

0.01

1.18 (1.0-1.32)

0.02

0.01

1.22 (1.12-1.32)

Smoking

0.01

1.56 (0.6-4.7)

0.34

-

-

Left ventricular EF

0.03

0.7 (0.58-1.02)

0.01

0.82 (0.61-0.99)

Hypertension

1.8 (0.9-4.1)

0.22

-

-

DM

1.9 (1.53-2.2)

0.01

1.4 (1.3-1.66)

0.02

COPD

1.3 (1.08-1.54)

0.01

1.09 (0.96-1.28)

0.04

Creatinine

1.42 (1.3-1.68)

0.01

1.16 (0.92.-1.32)

0.03

BMI

1.5 (1.1-1.78)

0.01

1.18 (0.92-1.34)

0.03

Previous revascularization

1.8 (1.2-3.4)

0.03

1.22 (0.9-2.34)

0.12

Length of stay (>10 days)

1.9 (1.43-2.7)

0.01

1.3 (0.96-1.41)

0.02

BMI: Body mass index; CI: Confidence interval; COPD: Chronic obstructive pulmonary disease; DM: Diabetes mellitus; EF: Ejection fraction; OR: Odds ratio. *Variables with a p value<0.05 in univariate analysis were included in the multivariate model. â&#x20AC; Each parameter was studied separately using multiple regression analysis. BMI: Body mass index; COPD: Chronic obstructive pulmonary disease; DM: Diabetes mellitus; EF: Ejection fraction.


Sargin et al., Stent versus bypass

31

Table 4. Univariate and multivariate analysis of the predictors for early readmission in Group 2 population

Univariate Analysis

Multivariate Analysis *

OR (95% CI)

p

OR (95% CI)

p

1.1 (1.03-1.15)

0.01

1.085 (1.042-1.132)

0.01

1.6 (1.3-1.7)

0.01

1.2 (1.08-1.34)

0.04

Smoking

1.6 (0.82-4.94)

0.19

Left ventricular EF

0.91 (0.88-0.94)

0.01

0.95 (0.91-0.99)

0.01

Hypertension

1.64 (0.81-3.32)

0.16

DM

1.64 (1.43-1.72)

0.01

1.34 (1.24-1.46)

0.01

1.1 (0.9-1.58)

0.02

1.01 (0.6-1.36)

0.12

Creatinine

1.59 (1.32-1.74)

0.01

1.26 (1.13-1.42)

0.01

Hemoglobin

0.7 (0.32-2.92)

0.21

Previous revascularization

1.6 (1.1-4.62)

0.04

1.1 (0.92-2.6)

0.16

Length of stay (>10 days)

1.8 (1.62-2.3)

0.01

1.2 (0.9-1.43)

0.03

Age Female gender

COPD

CI: Confidence interval COPD: Chronic obstructive pulmonary disease; DM: Diabetes mellitus; EF: Ejection fraction; OR: Odds ratio. *Variables with a p value <0.05 in univariate analysis were included in the multivariate model. †Each parameter was studied separately using multiple regression analysis.

nary angiography. Three of the readmitted patients had another PCI, and 4 patients died (2 CABG, 2 PCI). The univariate and multivariate logistic regression analysis for predictors of early readmission in both Group 1 and Group 2 are presented in Table 3 and Table 4, respectively. Variables with p val-

ue<0.05 in univariate analysis were included in the multivariate model. In multivariate analysis, age, gender, LVEF, COPD, DM, length of stay (>10 days), BMI, and creatinine level on admission (p<0.05 for each parameter) were associated with early readmission for Group 1 (Table 3). In Group 2, age, gender, LVEF,

20 18 16 14 12 Group I

10

Group II

8 6 4 2 0

Days 2

6

11

16

Figure 2. Days/number of readmissions.

21

26


32

DM, length of stay (>10 days), and creatinine level on admission (p<0.05 for each parameter) were associated with early readmission (Table 4). DISCUSSION Although long-term results of revascularization methods have been extensively studied, knowledge of early readmission rates and causes is still limited [1-4]. The main objectives of the present study were to document the extent of 30-day readmissions after CABG surgery and PCI, to identify reasons for those readmissions, and to determine independent predictors of readmission for patients who underwent PCI and CABG surgery. The study results indicated that 16.5% of all patients, 18.3% of CABG group, and 15.2% of PCI group were readmitted within 30 days. The need for cardiac care led to readmission within 30 days of 6.1% of CABG patients and 5.3% of PCI patients. The findings were fairly similar to those of other studies. Hannan et al. studied 33936 patients who underwent CABG surgery and found that the most common reasons for readmission were post-operative infection (16.9%), heart failure (12.8%), and “other complications of surgical and medical care” (9.8%). Increased age, female sex, higher BMI, presence of more than 1 comorbidity, use of saphenous vein grafts, and longer lengths of stay were all associated with higher rates of readmission. The correlation between risk-adjusted 30-day readmission rate of hospitals and risk-adjusted in-hospital/30-day mortality rate was 0.32 (p=0.047). The range in the readmission rate across hospitals was 8.3% to 21.1% [5,6]. In another study, Hannan et al. retrospectively analyzed 30-day readmissions after PCI using statewide PCI registry to identify 40093 New York State patients who underwent PCI. A total of 15.6% of all PCI patients were readmitted within 30 days, and most common reasons for readmission were chronic ischemic heart disease (22.5%), chest pain (10.8%), and heart failure (8.2%). A total of 2015 patients (32.2% of readmissions) underwent a repeat PCI. Age over 65, female gender, low ejection fraction (EF), COPD, DM, renal failure, and

North Clin Istanbul – NCI

longer stay in hospital after PCI were found to be risk factors [7]. Khawaja et al. reported in a study of 30-day readmission rates after PCI (15498) that overall, 9.4% of PCI patients (n=1459) were readmitted, and 0.68% (n= 106) died within 30 days after discharge. After multivariate analysis, female sex, education level below high school, unstable angina, cerebrovascular accident or transient ischemic attack, moderate to severe renal disease, COPD, peptic ulcer disease, metastatic cancer, and a length of stay of more than 3 days were associated with an increased risk of 30-day readmission after PCI. Thirty-day readmission after PCI was associated with a higher risk of 1-year mortality (adjusted hazard ratio, 1.38; 95% confidence interval, 1.08-1.75; p=.009) [8]. In the present study, BMI data for the CABG group were determined to be a risk factor for readmission, usually related to incisional infection. For the PCI group, BMI data were not available for all patients; therefore, it was not included in the analysis. DM, female gender, increased age, congestive heart failure, increased creatinine level on admission, and longer lengths of stay were defined as risk factors for readmission after PCI. Gender has become an important consideration in revascularization. Female patients are known to have greater rates of morbidity and mortality [14]. Some studies have shown that women were readmitted more than twice as often as men within 30 days of CABG surgery [4-7,9,10]. The results of the present study also indicate that significantly more women were readmitted to hospital than men. DM is a comorbidity that almost all studies define as a risk factor for any cardiac event [4-8,11]. Similarly, we found diabetes to be a risk factor for readmission. Diabetic female patients, regardless of which procedure was performed, were readmitted to the hospital more than any other patient group. The secondary outcome of the study was a comparison of the two groups of revascularization patients in terms of readmission. Diabetes, female gender, obesity and older age were found to be risk factors for readmission for patients of both procedures. In the CABG group, females, diabetics and


Sargin et al., Stent versus bypass

obese patients were readmitted to ER primarily due to infections; however, in the PCI group, the reasons were mostly non-cardiac. Multiple comorbidities, low EF, and emergency revascularization were other common risk factors for cardiac readmissions. Effects of cardiopulmonary bypass, general anesthesia and sternotomy may be primary causes of problems that lead to readmission. Similarity of risk factors for readmission in PCI and CABG groups is evidence that the surgery itself is not the only cause. Subgroups according to age (30-50 years, 5070 years, over 70 years) were analyzed. In the PCI group, readmission was more frequent in 30-50 age group. Multivariate analysis did not reveal younger age as a risk factor for readmission. Identification of younger age as a risk factor for the PCI group needs further analysis. In our young PCI patient cohort, the most frequent reason for readmission was chest pain without electrocardiography findings. These patients were mostly diabetic. History of smoking and dyslipidemia were higher in these patients and they were often multivessel atherosclerotic patients. We believe these patients had widespread atherosclerosis aside from target vessel PCI, and these patients were more prone to be readmitted to ER for cardiac reasons. The distrıbution of number of patients who were readmitted in first 30 days is shown in Figure 2. Readmission rates were higher in the first 10 days than for the remainder of the 30-day period. This finding was similar to those in literature [4-8,11]. CONCLUSION Readmission to hospital in the first 30 days after discharge is a common problem. Although we identified a number of important predictors for readmission, many variables associated with readmission remain unexplained. Future research will be needed to better understand why many patients require readmission after revascularization. When two methods of revascularization were compared, rates of readmission were found to be similar between groups. Neither method can be concluded to be superior with regard to readmission rates.

33 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 - M.S., M.A.T.; Design M.S., M.A.T.; Supervision - S.A.A., M.E.; Materials - M.S., M.A.T, M.E.T.; Data collection and processing - N.S., S.B., S.A.; Analysis and interpretation - M.S., M.A.T., M.E.T., N.S.; Literature Search - S.B., S.A.; Writing - M.S., M.A.T.; Critical Review S.A.A., M.E.

REFERENCES 1. Stanton BA, Jenkins CD, Goldstein RL, Vander Salm TJ, Klein MD, Aucoin RA. Hospital readmissions among survivors six months after myocardial revascularization. JAMA 1985;253:3568–73. 2. Kiefe C. Predicting rehospitalization after bypass surgery: can we do it? Should we care? Med Care 1999;37:621–4. 3. Stewart RD, Campos CT, Jennings B, Lollis SS, Levitsky S, Lahey SJ. Predictors of 30-day hospital readmission after coronary artery bypass. Ann Thorac Surg 2000;70:169–74. 4. Curtis JP, Schreiner G, Wang Y, Chen J, Spertus JA, Rumsfeld JS, et al. All-cause readmission and repeat revascularization after percutaneous coronary intervention in a cohort of medicare patients. J Am Coll Cardiol 2009;54:903–7. 5. Hannan EL, Racz MJ, Walford G, Ryan TJ, Isom OW, Bennett E, et al. Predictors of readmission for complications of coronary artery bypass graft surgery. JAMA 2003;290:773–80. 6. Hannan EL, Zhong Y, Lahey SJ, Culliford AT, Gold JP, Smith CR, et al. 30-day readmissions after coronary artery bypass graft surgery in New York State. JACC Cardiovasc Interv 2011;4:569–76. 7. Hannan EL, Zhong Y, Krumholz H, Walford G, Holmes DR Jr, Stamato NJ, et al. 30-day readmission for patients undergoing percutaneous coronary interventions in New York state. JACC Cardiovasc Interv 2011;4:1335–42. 8. Khawaja FJ, Shah ND, Lennon RJ, Slusser JP, Alkatib AA, Rihal CS, et al. Factors associated with 30-day readmission rates after percutaneous coronary intervention. Arch Intern Med 2012;172:112–7. 9. Jennings DL, Petricca JC, Yageman LA, O’Dell K, Kalus JS. Predictors of rehospitalization after acute coronary syndromes. Am J Health Syst Pharm 2006;63:367–72. 10. Steuer J, Blomqvist P, Granath F, Rydh B, Ekbom A, de Faire U, et al. Hospital readmission after coronary artery bypass grafting: are women doing worse? Ann Thorac Surg 2002;73:1380–6. 11. Harjai KJ, Singh M, Boura J. Early readmissions after percutaneous coronary intervention in a rural tertiary care center (from the Guthrie Health Off-label Stent [GHOST] Registry). Am J Cardiol 2012;110:491–7.


Orıgınal Article

ENDOCRINOLOGY

North Clin Istanbul 2016;3(1):34–8 doi: 10.14744/nci.2016.63825

The use of complementary medicine in patients with diabetes Muzaffer Ilhan,1 Büşra Demir,2 Sena Yüksel,2 Serra Aydın Çataklı,2 Rabia Sevda Yıldız,3 Ozcan Karaman,4 Ertuğrul Taşan4 Department of Endocrinology and Metabolism, Ümraniye Training and Research Hospital, Istanbul, Turkey

1

Student, Bezmialem Foundation University Faculty of Medicine, Istanbul, Turkey

2

Department of Internal Medicine, Bezmialem Foundation University, Istanbul, Turkey

3

Department of Endocrinology and Metabolism, Bezmialem Foundation University, Istanbul, Turkey

4

ABSTRACT OBJECTIVE: Diabetes mellitus (DM) is a growing health problem with serious complications. The chronic and progressive nature of the disease often leads patients to use complementary and integrative medicine. The present study aimed to investigate the frequency of use of alternative medicine by patients with DM and the products used. METHODS: Between September 2014 and May 2015, 301 patients with DM were selected from Bezmialem Foundation University Hospital Diabetes Clinic to participate in the study. RESULTS: The results of the study indicate that 81 (26.9%) patients had tried alternative medicine, and 50 (16.6%) patients continued to use some form of alternative medicine product. A total of 43 (14.3%) patients used such products every day and 24 (8%) patients had used alternative medicine products for up to 6 months. Glycated hemoglobin (HbA1c) levels were significantly decreased in patients using alternative medicine products compared to the remainder of patients in the study (p=0.017). No other significant difference was found between the two groups. It was observed that among patients using alternative medicine products, only 10 (12%) had informed their physicians. CONCLUSION: This study indicated that patients with diabetes are very likely to use alternative medicine products. Additional studies are needed to further determine the efficacy of these products. Patients as well as health providers must be educated about complementary medicine and alternative products. Keywords: Complimentary medicine; diabetes mellitus; regulation of glucose.

D

iabetes Mellitus (DM) is a critically significant disease and its global prevalence is increasing. Its outcomes have a serious effect on patient quality of life, and costs associated with DM also have

an important impact on national budgets. According to 2015 World Health Organization (WHO) data, a total of 150 million patients have been diagnosed with DM worldwide, and this figure is likely

Received: January 19, 2016 Accepted: February 04, 2016 Online: May 16, 2016 Correspondence: Dr. Muzaffer ILHAN. Umraniye Egitim Arastirma Hastanesi Endokrinoloji ve Metabolizma Hastaliklari, Istanbul, Turkey. Tel: +90 216 632 18 18 e-mail: muzoilhan@yahoo.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


Ilhan et al., The use of complementary medicine in patients with diabetes

to double by 2025, attributed largely to factors such as population increase, aging of population, unhealthy dietary habits, and sedentary lifestyles.[1] According to data published by Turkish Diabetes Epidemiology Study (TURDEP-II), the incidence of diabetes among adult population of Turkey has reached 13.7%.[2] The increase in the number of patients diagnosed with DM, and the chronic, progressive nature of the disease means that more patients are seeking out alternative products in addition to clinical medical therapy. Many studies have been performed in Turkey on use of complementary medicine; however, only a limited number of studies have been conducted about its use in patients with DM. [36] The aim of the present study was to investigate the frequency of use of alternative methods and the products used. MATERIALS AND METHODS Between September 2014 and May 2015, patients from Bezmialem Faculty of Medicine Diabetes Outpatient Clinic whose follow-up care was conducted only at Bezmialem Foundation University Hospital were asked to answer a survey about the use of alternative medicine supplements. Patients were asked to provide demographic data, information regarding

35

complications secondary to diabetes, available treatments, and any use of alternative medicine products. Participants who responded affirmatively regarding alternative medicine were then asked to indicate the duration of this therapy, where they learned about the product(s), where they obtained the item(s), and whether or not they had informed their physician about use of the product(s). Patient clinical information was collected from patient medical files, including glycated hemoglobin (HbA1c) values and diabetic complications. Patients who had sought treatment at the outpatient clinic for the first time or whose follow-up examinations were not performed at Bezmialem Foundation University Hospital were excluded from the study. This study was approved by Bezmialem Foundation University Hospital Ethics Committee. Signed written informed consent forms were obtained from all patients before initiation of the survey. SPSS software (version 20.0; SPSS Inc., Chicago, IL, USA) was used for statistical calculations. Studentâ&#x20AC;&#x2122;s t-test was used for intergroup comparisons of variable means with normal distribution, and Mann-Whitney U test was used for variables with non-normal distribution. Nonparametric variables were compared using chi-square test. P <0.05 was the limit for statistical significance.

Table 1. Demographic characteristics of the study participants Parameters

Number of patients n

Parameters

%

Gender Female, n (%) 214 (71.1) Male, n (%) 87 (28.9) Marital status Married 267 (88.7) Single 34 (11.3) Monthly income <1500 TL 219 (72.8) 1500-3000 TL 64 (21.3) >3000 TL 18 (5,9)

Education level Illiterate Primary school Secondary school LycĂŠe University Profession Housewife Retired Other

Number of patients n

%

44 175 36 29 17

(14.7) (58.1) (11.9) (9.7) (5.6)

188 52 60

(62.5) (17.3) (20,2)


36

North Clin Istanbul â&#x20AC;&#x201C; NCI

RESULTS Demographic characteristics of the 301 diabetic patients included in this study are provided in Table 1. Patients were taking oral antidiabetic drugs plus insulin (n=143; 47.5%), just oral antidiabetics (n=101; 33.6%), or just insulin therapy (n=56; 18.6%). Some patients discontinued treatment within 1-6 months. Of the total, 81 (26.9%) study participants had tried alternative medicine products, and 50 (16.6%) were continuing to use these treatment methods. The most preferred alternative products in order of decreasing frequency were nigella sativa (black seed), cinnamon, various herbal teas, olive leaf, herbal mixtures with unknown content purchased from an herbalist, lemon, green lentils, flaxseed, yogurt, parsley juice, hibiscus, fruits, and herbs (Table 3). Patients cited the presumptive hypoglycemic, weight loss, and mood-enhancing effects of the products as basis for use. Lack of beneficial effect, difficulty procuring the items, dramatic decrease in blood sugar levels, and unpleasant taste were among various adverse effects reported as cause for discontinuing use. Patients were most often first introduced to the products by close friends or through media. The majority of participants (n=43; 14.3%) who used alternative products were doing so every day or had consumed them for a period of 1-6 months

(n=24; 8%). Forty study participants indicated that they liked alternative medicine products because they observed blood sugar lowering effects. Only 4 (1.3%) patients discontinued antidiabetic drugs prescribed by physician while using alternative therapies. The recommendations of family members and/or friends influenced 27 (9%) patients to begin consuming alternative medicine products, and television and radio programs led 19 (6.3%) patients to use the alternative treatments. However, only 10 participants informed their physician about the dietary supplements they elected to use. The present study revealed significantly lower levels of HbA1c in patients who used alternative medicine products compared to those who did not (p=0.017). Unmarried individuals with higher income levels used the products more frequently (Table 2). Study data did not yield a statistically significant correlation between the use of alternative medicine products and other parameters. Discussion Many patients are choosing to use alternative medicine, and inevitably this interest has an effect on theoretical and clinical applications of medicine. The global rate of diabetic patients using alternative medicine products varies from 17-72.8 %.[7-

Table 2. Comparison of users and non-users of alternative medicine Gender (male-female), n (%) Median age (years) Median age of diabetics (years) Glycated hemoglobin (HbA1c) (%) Marital status (married-single) Retinopathic patients, n (%) Patients with bypass stent, n (%) Nephropathic patients, n (%) Neuropathic patients, n (%) Patients with diabetic foot, n (%)

Users (n=81) 19 (23.5)-62 (76.5) 56.09 13 7.72 66 (81.5)-15 (18.5) 18 (22.2) 12 (5.5) 15 (18.5) 33 (40.7) 8 (9.9)

Non-users p (n=220)

68 (30.9)-152 (69.1) 56.29 11.8 8.33 201 (91.4)-19 (8.6) 60 (27.2) 39 (17.7) 28 (12.7) 100 (45.5%) 10 (4.5)

0.206 0.885 0.311 0.017 0.016 0.375 0.550 0.203 0.465 0.101


Ilhan et al., The use of complementary medicine in patients with diabetes

Table 3. Alternative medicine products used by patients (n=81) Product

n

Nigella sativa/Black seed Cinnamon Herbal tea Olive leaf Herbal medicine mixture purchased from an herbalist Other

19 23.4 18 22.2 18 22.2 15 18.5 6 5

%

7.4 6.2

9] Analysis of current trends indicates that Momordica charantia (bitter gourd) and cinnamon are used most frequently worldwide, but there is a broad spectrum of herbal products in use that varies greatly between countries.[10,11] In Turkey, 41% of diabetic patients choose to use alternative medicine therapies. In the past, thyme, pomegranate, stinging nettle, and rosehip were preferred; [8] however, in the present study, 26.9 % of participants most often used cinnamon and nigella sativa. Female gender, high income, monthly blood glucose tests, birthplace, education level, and living with immediate family are common demographic characteristics of patients who have a preference for alternative medicine products, according to international data. [7,8] Although a significant correlation was not found between education level and use of these products, the majority of patients in the present study (58%) were primary school graduates, with a few (n= 17; 5.6%) high school graduates. Additional studies with a different population group are recommended. Criteria such as gender, average age of the patients, and average age at onset of diabetes, and education level do not seem to be relevant to use of alternative medicine, nor did present or past history of retinopathy, nephropathy, diabetic foot or cardiac disease create significant difference. This suggests that progression, severity of the disease, and complications developed are not meaningful factors in patientsâ&#x20AC;&#x2122; choice to use alternative medicine products. Another notable outcome concerns sources of patient information. Patients primarily learned

37

about alternative treatments from television and radio, their family and friends, and the newspaper, demonstrating that they are open to external influence, they trust non-scientific sources, and make decisions about their health based on the recommendations of laymen who are not knowledgeable about acute or chronic effects of DM. The Ministry of Health, media organs, and nongovernmental organizations have a tremendous responsibility in this regard. For example, only experts in their fields should give medical information on TV programs, and programs not relying on scientific sources should be prohibited in order to protect the health of patients and ensure that they make rational choices. Efforts should be made to raise awareness about the risks associated with uninformed and potentially misleading recommendations from members of patientâ&#x20AC;&#x2122;s family and social circle. Requirements of the disease differ among individuals, and the course of the disease demonstrates individual variation. Products recommended by family and friends may not have the same effect on different individuals. Another significant outcome of the study is that only 10 (12%) patients informed their physicians about the use of alternative medicine products. This finding reveals weakness in patient-physician rapport. Patients reported shyness, fear of the physician, physician indifference, and disregard for or lack of knowledge about side effects as reasons for not informing their physicians about use of the products. It is thought that lack of good communication and the fact that diabetes requires lifelong treatment and has no possibility of complete cure leads many patients to try easily applied treatment modalities with uncertain outcomes. Worldwide, patients with DM have been inclined to use alternative medicinal products. As a result of this trend, the effects of alternative products on diabetes should be further investigated. Some studies have suggested that alternative medicine products can decrease blood sugar levels of diabetic patients. [12] The effectiveness of alternative medicine products is beyond the scope of this study; however, when we evaluated levels of HbA1c as criteria of effectiveness of alternative treatments for diabetes,


38

lower HbA1c values were found in patients who used alternative medicine products. This outcome may indicate that patients who used alternative medicine products are more attentive to blood glucose regulation. In the present study, 81 patients used alternative medicine products. The most common choice, used by 19 patients, was nigella sativa. For better evaluation of alternative medicine products, prospective randomized studies should be performed with a larger number of patients comparing users and non-users of each product. The results of the present study indicated that patients did not cease to use clinically prescribed drugs, adopting a complementary approach, and that users of alternative medicine products frequently discontinued use of the products in the event of any adverse effect or lack of beneficial effect, suggesting that patients still ultimately trust their physicians and clinical medicine more than alternative medicine. Life-long treatment of DM is a challenge for patients. Living with the disease of diabetes, compliance with dietary therapy, performing regular blood glucose tests, and the compulsory, regular use of antidiabetic drugs can be very demanding. Patients often seek a quick cure, leading many to try alternative medicine. More detailed studies should be conducted on the effects and potential role of alternative medicine therapies in the context of diabetes regulation and treatment. 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 - M.İ., Ö.K.; Design Materials - B.D., S.Y., S.A.Ç., R.S.Y.; Data collection and/or processing - B.D., S.Y., S.A.Ç., R.S.Y.; Analysis and/or interpreta-

North Clin Istanbul – NCI tion - M.İ., Ö.K., E.T.; Literature search - Writing - M.İ.; Critical review - Ö.K., E.T.

REFERENCES 1. WHO Media Centre. http://www.who.int/mediacentre/factsheets/fs138/en. 2. Satman I, Omer B, Tutuncu Y, Kalaca S, Gedik S, Dinccag N, et al. Twelve-year trends in the prevalence and risk factors of diabetes and prediabetes in Turkish adults. Eur J Epidemiol 2013;28:169–80. 3. Ozkol H, Tuluce Y, Dilsiz N, Koyuncu I. Therapeutic potential of some plant extracts used in Turkish traditional medicine on streptozocin-induced type 1 diabetes mellitus in rats. J Membr Biol 2013;246:47–55. 4. Arıkan D, Sívríkaya SK, Olgun N. Complementary alternative medicine use in children with type 1 diabetes mellitus in Erzurum, Turkey. J Clin Nurs 2009;18:2136–44. 5. Parildar H, Serter R, Yesilada E. Diabetes mellitus and phytotherapy in Turkey. J Pak Med Assoc 2011;61:1116–20. 6. Ceylan-Isik AF, Fliethman RM, Wold LE, Ren J. Herbal and traditional Chinese medicine for the treatment of cardiovascular complications in diabetes mellitus. Curr Diabetes Rev 2008;4:320–8. 7. Chang HY, Wallis M, Tiralongo E. Use of complementary and alternative medicine among people living with diabetes: literature review. J Adv Nurs 2007;58:307–19. 8. Ceylan S, Azal O, Taşlipinar A, Türker T, Açikel CH, Gulec M. Complementary and alternative medicine use among Turkish diabetes patients. Complement Ther Med 2009;17:78–83. 9. Haliloğlu B, Işgüven P, Yıldız M, Arslanoğlu I, Ergüven M. Complementary and alternative medicine in children with type 1 diabetes mellitus. J Clin Res Pediatr Endocrinol 2011;3:139–43. 10. Ching SM, Zakaria ZA, Paimin F, Jalalian M. Complementary alternative medicine use among patients with type 2 diabetes mellitus in the primary care setting: a cross-sectional study in Malaysia. BMC Complement Altern Med 2013;13:148. 11. Manya K, Champion B, Dunning T. The use of complementary and alternative medicine among people living with diabetes in Sydney. BMC Complement Altern Med 2012;12:2. 12. Pandey A, Tripathi P, Pandey R, Srivatava R, Goswami S. Alternative therapies useful in the management of diabetes: A systematic review. J Pharm Bioallied Sci 2011;3:504–12.


Orıgınal Article

Cardiology

North Clin Istanbul 2016;3(1):39–45 doi: 10.14744/nci.2016.52824

Is triglyceride/HDL ratio a reliable screening test for assessment of atherosclerotic risk in patients with chronic inflammatory disease? Nursen Keles,1 Feyza Aksu,1 Gonul Aciksari,1 Yusuf Yilmaz,1 Kenan Demircioglu,1 Osman Kostek,2 Muhammed Esad Cekin,1 Macit Kalcik,3 Mustafa Caliskan1 Department of Cardiology, Goztepe Training and Research Hospital, Istanbul Medeniyet University, Istanbul, Turkey

1

Department of Internal Medicine, Goztepe Training and Research Hospital, Istanbul Medeniyet University, Istanbul, Turkey

2

Department of Cardiology, Iskilip Atif Hoca State Hospital, Corum, Turkey

3

ABSTRACT OBJECTIVE: The term chronic inflammatory disease (CID) refers to a category of inflammatory diseases that includes Ankylosing spondylitis (AS) and familial Mediterranean fever (FMF). The incidence of adverse cardiovascular events is greater among patients with CID, though they may not have conventional atherosclerotic risk factors. Endothelial dysfunction is one of the underlying fundamental mechanisms that trigger development of atherosclerotic alterations in arteries, and flow-mediated dilatation (FMD) is a noninvasive method to determine endothelial dysfunction. Recent studies have shown a relationship between high triglyceride high-density lipoprotein cholesterol (TG/HDL-C) ratio and coronary atherosclerosis. Many studies have demonstrated that patients with CID have lower FMD values compared to healthy population, indicating endothelial dysfunction. However TG/HDL ratio and its relationship to FMD in patients with CID has not been investigated. The present study investigated whether TG/ HDL ratio in CID patients differs from that of healthy population, and its relationship to FMD in patients with CID. METHODS: A total of 58 patients with CID and a group of 58 healthy volunteer individuals were enrolled in the study. FMD measurements were taken with high resolution ultrasound (US), and TG/HDL ratios were calculated. RESULTS: Patients with CID had significantly higher TG/HDL-C ratio (2.5 [2.2–2.8] vs 2.3 [2.1–2.5]; p=0.03) and lower FMD values (5.2 [4.2–6.3] vs 6.7 [6.3–9.7]; p<0.001), compared to healthy group, and a negative correlation was found between FMD levels and TG/HDL ratio of the study population. CONCLUSION: Higher TG/HDL ratio and lower FMD values found in CID patients may reflect increased atherosclerotic risk. Keywords: Chronic inflammatory disease; flow-mediated dilatation; triglyceride/high-density lipoprotein-cholesterol ratio.

Received: March 25, 2016 Accepted: April 26, 2016 Online: May 25, 2016 Correspondence: Dr. Nursen KeleS. Istanbul Medeniyet Universitesi, Goztepe Egitim ve Arastirma Hastanesi, Kardiyoloji Klinigi, Istanbul, Turkey. Tel: +90 216 - 566 40 00 e-mail: drnursenkeles@yahoo.com.tr © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


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T

he term chronic inflammatory disease (CID) refers to a category of diseases, including Ankylosing spondylitis (AS) and familial Mediterranean fever (FMF). Although they may not have traditional risk factors of atherosclerosis, incidence of cardiovascular events is increased in this group of patients [1]. Harmful effects of chronic inflammation on vascular system play a fundamental role in the increase of cardiovascular events in patients with CID. Both experimental and clinical studies have demonstrated the role of inflammation on the development of atherosclerosis, having found it to be associated with all stages and acute complications of atherosclerosis [2, 3]. In the development of vascular pathology that triggers atherosclerosis, active inflammatory processes involving leucocytes and soluble substances play important roles [4]. Endothelial dysfunction is the basic mechanism that triggers development of atherosclerotic changes, and flow-mediated dilatation (FMD) in brachial artery is a noninvasive method to determine endothelial dysfunction [5]. Many clinical studies have demonstrated significant decreases in FMD, indicating endothelial dysfunction, in patients with CID relative to normal population, and derangement in FMD has been identified as predictor of atherosclerosis [6]. Recently, use of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio has been recommended as a simple method to determine insulin resistance and cardiometabolic risk in healthy individuals [7, 8, 9, 10, 11]. A case-control study revealed that higher TG/HDL-C ratio can strongly predict risk of myocardial infarction [12]. The reliability of TG/HDL-C ratio in prediction of risk of atherosclerosis in patients with CID has not been investigated thus far. In this study, we tested whether TG/HDL-C ratio is increased in patients with CID relative to healthy population, and examined the relationship between FMD, an indicator of endothelial functions of arteries, and TG/HDL-C ratio. Based on the relationship between TG/HDL-C ratio and FMD, another objective of the study was to test whether combined use of these two markers would be a stronger predictor of atherosclerotic risk.

North Clin Istanbul â&#x20AC;&#x201C; NCI

MATERIALS AND METHODS Study population A total of 58 CID patients, consisting of both AS and FMD patients, and a group of 58 healthy volunteers were included in the study. All participants were evaluated for major cardiovascular risk factors such as diabetes mellitus (DM), history of coronary artery disease (CAD), and use of cigarettes or alcohol. Exclusion criteria were history of stroke; congestive heart failure (CHF); CAD; hypertension; obstructive sleep apnea (OSA); impaired glucose tolerance; familial dyslipidemia; hepatic, henolytic, and renal diseases; excess alcohol intake (>120g/d); morbid obesity (body mass index [BMI]>35 kg/m2); and vasoactive drug users. Patients with Q wave, left bundle block, ST segment, and T wave changes specific to myocardial ischemia on electrocardiogram (ECG) were also excluded. The study was conducted in compliance with the World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Approval of the ethics committee was granted, and written informed consent was obtained from all study participants. Biochemical analysis Study groups were advised to abstain from intense physical activity and alcohol intake for 3 days before biochemical analysis. Venous blood samples were drawn from each participant after 24 hours of fasting to measure biochemical parameters. For the measurement of serum glucose, spectrophotometry was performed using Aeroset automated analyzer (Abbott Laboratories, Abbott Park, IL, USA). Total serum cholesterol, HDL-C, and lowdensity lipoprotein cholesterol (LDL-C) levels were measured using enzymatic methods. Plasma highsensitivity-C-reactive protein (hs-CRP) levels were calculated using enzyme-linked immunosorbent assay (ELISA) test. Echocardiographic study All echocardiographic measurements were made using a GE Vivid 7 cardiac ultrasound (US) machine


Keles et al., Triglyceride/HDL ratio and chronic inflammatory diseases

(GE Healthcare, Horton, Norway). Standard pulse wave, tissue Doppler, M-mode, and 2-D echocardiographic measurements were recorded [8]. Measurements of left ventricular end diastolic diameter (LVEDD) and left ventricular end systolic diameter (LVESD, interventricular septal (IVS), and posterior wall (PD) thickness were performed using Mmode modality from parasternal long-axis view. E wave and E wave deceleration time (DT), and early (E) and late (L) diastolic peak flow velocities were retrieved from transmitral Doppler images. All tissue Doppler measurements were made from apical 4-chamber view with 5 mm-sample volume positioned lateral to the edge of mitral annulus [13]. During Doppler screening, 5–10 cycles with flow velocity of 100 mm/sec were recorded. Tissue Doppler measurements included myocardial early (E’), and atrial (A’) peak velocities (m/sec). Doppler US measurements were recorded during normal respiration. For the evaluation of LV diastolic function, E/A, E/E’, and E’/A’ values were calculated. Average of 3 measurements of diastolic parameters made during 3 successive cycles was computed. Measurements were performed by a researcher blind to patient data and analyzed by two researchers who were also blind to the study results.

41

Vascular evaluation FMD of brachial artery was evaluated with measurement of response to transient ischemia using highresolution ultrasonography [14]. Measurements were made while all participants were in supine position and rested for 10 minutes. Right arm of participants was free and brought to extension. FMD measurements of brachial artery were made 2–5 cm above antecubital fossa. Entire length of brachial artery was scanned using GE Vivid 7 17–5 MHz linear array transducer. B-mode and pulse Doppler spectral curves were recorded. Basal diameter of brachial artery was measured, and cuff of sphygmomanometer was wrapped proximal to artery visualized on forearm. Pressure cuff of sphygmomanometer was inflated to 30 mm Hg above systolic blood pressure of the patient and left in place for 5 minutes before being deflated. The maximum diameter of brachial artery was measured in this manner 6 times. All measurements were made at onset of end-diastolic R wave on ECG. FMD percentages of maximum diameter of brachial artery during hyperemia triggered by basal and transient ischemia were estimated based on the formula FMD=(maximum brachial artery diameter-basal brachial artery diameter/basal brachial artery diameter)x100.

Table 1. Comparison of demographic characteristics and biochemical parameters of study groups Age, years Gender, F/M SBP, mmHg DBP, mmHg BMI, kg/m2 FBG mg/dL hs-CRP LDL-C, mg/dL HDL-C, mg/dL Triglyceride, mg/dL TG/HDL-C

CID Group (n=58)

Control Group (n=58)

p

37 (31–47) 19/39 120 (110–125) 80 (75–81) 25.8±3.9 94 (90–97) 4.8 (1.8–12.0) 111±28 53 (45–55) 124 (117–145) 2.5 (2.2–2.8)

39 (37–41) 25/33 120 (110–130) 80 (76–80) 26.9±2.3 90 (87–96) 1.3 (0.8–2.2) 112±30 53 (49–55) 121 (110–132) 2.3 (2.1–2.5)

0.16 0.34 0.50 0.72 0.07 0.08 <0.001 0.85 0.72 0.06 0.03

BMI: Body mass index; DBP: Diastolic blood pressure; FBG: Fasting blood glucose; HDL-C: High-density lipoprotein cholesterol; hsCRP: High-sensitivity C-reactive protein; LDL-C: Low-density lipoprotein cholesterol; SBP: Systolic blood pressure; TG: Triglyceride.


42

p=0.03

4.0 3.5

TG/HDL-C

Statistical analysis Statistical analysis was performed using SPSS software (version 16.0; SPSS Inc., Chicago, IL, USA). Normality of distribution of variables was evaluated using Shapiro-Wilk test. Descriptive statistics were expressed as medians (25–75 percentiles) for continuous variables and frequencies, and as percentages for categorical variables. In intergroup comparisons of continuous variables, Mann-Whitney U test was used, and for categorical variables chi-square test was used. Correlation coefficient and its significance were calculated using Spearman’s rank correlation test, and p<0.05 was accepted as the level of significance.

North Clin Istanbul – NCI

3.0 2.5 2.0 1.5

Control

CID

Figure 1. Comparison of TG/HDL-C ratio between study groups.

RESULTS

Biochemical evaluation Hs-CRP levels of CID patients were significantly higher (4.8 [1.8–12.0] vs 1.3 [0.8–2.2]; p<0.001) (Table 1). TG/HDL-C levels of the patients with CID were significantly higher when compared to control group (2.5 [2.2–2.8] vs 2.3 [2.1–2.5]; p=0.03) (Figure 1). Echocardiographic examination LVEDD, LVESD, ejection fraction (EF), thickness of IVS, and PD were similar between groups (Table 2). E/E’ ratios of patients with CID were lower when compared to control group with a p-value close to level of significance (3.8±0.9 vs 4.2±1.1; p=0.06) (Table 2). Vascular evaluation FMD values of the patients with CID were significantly lower when compared to CID patients (5.2 [4.2–6.3] vs 6.7 [6.3–9.7]; p<0.001) (Figure 2). In addition, negative correlation was detected between elevated TG/HDL-C ratio and FMD values (Figure 3).

p<0.001 12.5

FMD

10.0 7.5 5.0 2.5

Control

CID

Figure 2. Comparison of FMD values of study groups. r=-0.267 p=0.005 12.5 10.5

FMD

Study population Median age of the patient (CID) and control group was 37 (31–47) and 39 (37–41) years, respectively, without any intergroup difference. Systolic and diastolic blood pressure and body mass indices of groups did not differ significantly (Table 1).

7.5 5.0 2.5 1.5

2.0

2.5

3.0

3.5

4.0

TG/HDL-C

Figure 3. Correlation curve for comparison between TG/HDL-C ratio and FMD values of study population.


Keles et al., Triglyceride/HDL ratio and chronic inflammatory diseases

43

Table 2. Comparison of echocardiographic parameters and FMD values of study groups E, m/s A, m/s E/A DT, msec IVRT, msec E’, m/s A’, m/s E’/A’ E/E’ LVEDD mm LVESD mm IVS, mm PD, mm EF % FMD %

CID Group (n=58)

Control Group (n=58)

p

0.77±0.17 0.66±0.12 1.18±0.28 197 (177–221) 109±17 0.21±0.06 0.16±0.04 1.31±0.42 3.8±0.9 46 (42–49) 29 (27–32) 9 (9–10) 9 (8–9) 68 (65–70) 5.2 (4.2–6.3)

0.76±0.16 0.62±0.13 1.25±0.28 189 (177–201) 106±19 0.19±0.04 0.14±0.03 1.35±0.31 4.2±1.1 45 (42–48) 29 (27–30) 10 (9–11) 9 (8–10) 67 (65–70) 6.7 (6.3–9.7)

0.68 0.07 0.15 0.06 0.62 0.05 <0.001 0.57 0.06 0.57 0.98 0.12 0.13 0.35 <0.001

A: Atrial; DT: Deceleration time; E: Early; EF: Ejection fraction, FMD: Flow-mediated dilatation; IVRT: Isovolumic relaxation time; IVS: Interventricular septum; LVEDD: Left ventricular end-diastolic diameter; LVESD: Left ventricular end-systolic diameter; PPD: Posterior wall.

DISCUSSION Studies have demonstrated that inflammation plays a fundamental role at all stages of atherosclerosis from beginning through development of thrombotic complications [2, 3]. FMF is an autoinflammatory disease caused by mutation of FMF gene, and is characterized by periodic hyperfebrile episodes and polyserositis. Asymptomatic periods exist between episodes of FMF, but during these intervals subclinical inflammation continues and it has been established that in cases of chronic inflammatory disease such as FMF, risk of atherosclerosis remains [15, 16]. Anxylosing spondylitis is a prototype of spondyloarthropathies, and in these patients 1.5–2-fold increase in mortality rates is seen due to cardiovascular complications compared to overall population. As is the case with other chronic inflammatory rheumatologic diseases, accelerated atherosclerotic processes are responsible for increase in cardiovascular mortal-

ity. Inflammation plays a fundamental role in accelerated atherogenesis in this patient group [17, 18, 19, 20, 21]. In spondyloarthropathic patients with chronic inflammatory polyarthritis, a significant correlation was observed between levels of C-reactive protein, erythrocyte sedimentation rate, and presence of endothelial dysfunction [2]. This observation reveals the role of inflammation in development of atherosclerosis in spondyloarthropathies. Endothelial dysfunction was determined with a noninvasive method, while response of brachial artery diameter to reactive hyperemia was measured with the aid of high-resolution US device. Reactive hyperemia induces increase in blood flow, wall strain, nitric oxide release, and FMD. FMD can be measured as an index of vasomotor function [22, 23]. Close relationship between forearm and coronary arteries reflects systemic nature of atherosclerosis [24]. Çalışkan et al. revealed presence of endothelial dysfunction in patients with FMF [25]. Akdoğan et al. detected significantly lower FMD in


44

FMF patients compared to healthy population [26]. Bodnár et al. demonstrated presence of endothelial dysfunction in patients with AS based on significant decrease in FMD values compared to healthy population [27], and Sarı et al. found significantly lower FMD values in AS patients when compared to healthy population [28]. In the present study, FMD values in a group of CID patients consisting of cases of AS, and FMF, were compared to those of healthy population and, similar to previous studies, significantly lower FMD levels were detected in the CID patient group. FMD indirectly demonstrates endothelial dysfunction of coronary arteries, and TG/HDL-C ratio is an easily calculated and reproducible predictor of atherosclerosis in daily practice [29]. Close relationship between TG/HDL-C ratio and insulin resistance has been noted [30]. In addition, TG/HDLC has been demonstrated to be a strong predictor independent of important prognostic variables, including total mortality, incidence of coronary artery disease, cardiovascular mortality, age, cigarette use, hypertension, and diabetes [31, 32, 33, 34]. Acay et al. detected significantly higher TG/ HDL-C ratio in patients with FMF versus healthy population [35]. However, the correlation between TG/HDL-C ratio and endothelial dysfunction in CID cases has not been fully clarified. In this study, correlation between TG/HDL-C ratio, defined as an atherogenic index, and FMD was investigated. In parallel with findings in previous studies, this study found TG/HDL-C ratio in patients with CID was significantly higher when compared to control group. A negative correlation was detected between FMD and TG/HDL-C ratio. The findings of this study indicate that in patients with CID, increased TG/HDL-C ratio is correlated with decreased FMD value, an indicator of endothelial dysfunction that is precursor of atherosclerosis. Thus, higher TG/HDL-C ratio was found to be associated with presence of endothelial dysfunction and atherogenesis. In conclusion, this study determined that TG/HDL-C ratio in CID patients may be used as an easily evaluated, reliable predictor of atherosclerosis.

North Clin Istanbul – NCI Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Consept - N.K., M.C.; Design N.K., M.C., F.A., G.A., Y.Y.; Supervision - N.K., M.C.; Funding - N.K., M.C., Materials - N.K., M.C.; Data Collection and processing - N.K., M.C., F.A., G.A., Y.Y.; Analysis and interpretation N.K., M.C., K.D., O.K., M.E.C, M.K.; Literature search N.K., M.C., K.D., O.K., M.E.C., M.K.; Writing - N.K., M.C., K.D., O.K., M.E.C., M.K.; Critical review - N.K., M.C., K.D., O.K., M.E.C., M.K.

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13. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997;30:474–80. 14. Harris LM, Faggioli GL, Shah R, Koerner N, Lillis L, Dandona P, et al. Vascular reactivity in patients with peripheral vascular disease. Am J Cardiol 1995;76:207–12. 15. Drenth JP, van der Meer JW. Hereditary periodic fever. N Engl J Med 2001;345:1748–57. 16. Holmes AH, Booth DR, Hawkins PN. Familial Mediterranean fever gene. N Engl J Med 1998;338:992–3. 17. Lehtinen K. Mortality and causes of death in 398 patients admitted to hospital with ankylosing spondylitis. Ann Rheum Dis 1993;52:174–6. 18. Li R, Cai J, Tegeler C, Sorlie P, Metcalf PA, Heiss G. Reproducibility of extracranial carotid atherosclerotic lesions assessed by B-mode ultrasound: the Atherosclerosis Risk in Communities Study. Ultrasound Med Biol 1996;22:791–9. 19. Mathieu S, Joly H, Baron G, Tournadre A, Dubost JJ, Ristori JM, et al. Trend towards increased arterial stiffness or intima-media thickness in ankylosing spondylitis patients without clinically evident cardiovascular disease. Rheumatology (Oxford) 2008;47:1203–7. 20. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006;296:1633–44. 21. Peters MJ, van der Horst-Bruinsma IE, Dijkmans BA, Nurmohamed MT. Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis. Semin Arthritis Rheum 2004;34:585–92. 22. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–5. 23. Sorensen KE, Celermajer DS, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Thomas O, et al. Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility. Br Heart J 1995;74:247–53. 24. Keles N, Caliskan M, Dogan B, Keles NN, Kalcik M, Aksu F, et al. Low Serum Level of Klotho Is an Early Predictor of Atherosclerosis.

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Tohoku J Exp Med 2015;237:17–23. 25. Caliskan M, Gullu H, Yilmaz S, Erdogan D, Unler GK, Ciftci O, et al. Impaired coronary microvascular function in familial Mediterranean fever. Atherosclerosis 2007;195:161–7. 26. Akdogan A, Calguneri M, Yavuz B, Arslan EB, Kalyoncu U, Sahiner L, et al. Are familial Mediterranean fever (FMF) patients at increased risk for atherosclerosis? Impaired endothelial function and increased intima media thickness are found in FMF. J Am Coll Cardiol 2006;48:2351–3. 27. Bodnár N, Kerekes G, Seres I, Paragh G, Kappelmayer J, Némethné ZG, et al. Assessment of subclinical vascular disease associated with ankylosing spondylitis. J Rheumatol 2011;38:723–9. 28. Sari I, Okan T, Akar S, Cece H, Altay C, Secil M, et al. Impaired endothelial function in patients with ankylosing spondylitis. Rheumatology (Oxford) 2006;45:283–6. 29. Sonmez A, Yilmaz MI, Saglam M, Unal HU, Gok M, Cetinkaya H, et al. The role of plasma triglyceride/high-density lipoprotein cholesterol ratio to predict cardiovascular outcomes in chronic kidney disease. Lipids Health Dis 2015;14:29. 30. González-Chávez A, Simental-Mendía LE, Elizondo-Argueta S. Elevated triglycerides/HDL-cholesterol ratio associated with insulin resistance. Cir Cir 2011;79:126–31. 31. Bittner V, Johnson BD, Zineh I, Rogers WJ, Vido D, Marroquin OC, et al. The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: a report from the Women’s Ischemia Syndrome Evaluation (WISE). Am Heart J 2009;157:548–55. 32. Drexel H, Aczel S, Marte T, Benzer W, Langer P, Moll W, et al. Is atherosclerosis in diabetes and impaired fasting glucose driven by elevated LDL cholesterol or by decreased HDL cholesterol? Diabetes Care 2005;28:101–7. 33. Shishehbor MH, Hoogwerf BJ, Lauer MS. Association of triglyceride-to-HDL cholesterol ratio with heart rate recovery. Diabetes Care 2004;27:936–41. 34. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Low triglycerideshigh high-density lipoprotein cholesterol and risk of ischemic heart disease. Arch Intern Med 2001;161:361–6. 35. Acay A, Ulu MS, Ahsen A, Ozkececi G, Demir K, Ozuguz U, et al. Atherogenic index as a predictor of atherosclerosis in subjects with familial Mediterranean fever. Medicina (Kaunas) 2014;50:329–33.


Orıgınal Article

GASTROENTEROLOGY

North Clin Istanbul 2016;3(1):46-52 doi: 10.14744/nci.2016.60362

Relationship between size of varices and platelet count/spleen size ratio in cirrhotic patients Kamil Ozdil,1 Oguzhan Ozturk,1 Ecem Sevim Calık,2 Eyup Sami Akbas,2 Evren Kanat,1 Zuhal Calıskan,1 Hakan Demirdag,1 Resul Kahraman,1 Atilla Bulur,1 Nermin Mutlu Bilgic,1 Levent Doganay,1 Hacı Mehmet Sokmen1 Gastroenterology Clinic, Umraniye Training and Research Hospital, Istanbul, Turkey

1

Internal Medicine Clinic, Umraniye Training and Research Hospital, Istanbul, Turkey

2

ABSTRACT OBJECTIVE: This study investigated the relationship between size of gastroesophageal varices and platelet count/spleen diameter ratio in cirrhotic patients. METHODS: The present study included 186 cirrhotic patients in whom gastroesophageal varices were seen during upper gastrointestinal system endoscopy. Clinical features, laboratory parameters, upper gastrointestinal system endoscopy, and abdominal ultrasonographic findings of patients were evaluated retrospectively. Platelet count/spleen diameter ratio (P/S) was calculated by dividing number of platelets in complete blood count (CBC) to largest diameter of spleen. Varices were classified as small, medium, or large, and patients were separated into two groups for comparison: those with small varices and those with medium or large varices. Of the total, 66.7 % of the patients were men (n=124) and 33.3% were women (n=62). Esophageal varices were found in 82.7% and gastric varices were found in 17.3%. RESULTS: Patients with large esophageal varices were found to have significantly lower P/S compared to patients with small esophageal varices (p=0.04). In receiver operating characteristic (ROC) curve analysis, P/S and large varices correlated with 82% sensitivity and 79% positive predictive value. However, no statistically significant correlation between size of varices and P/S was found in patients with gastric varices (p=0.78). CONCLUSION: In patients with esophageal varices, P/S was found to be correlated with large varices with 82% sensitivity. However, this ratio did not predict large varices in patients with gastric varices. Prospective and randomized clinical researches are needed to clarify our findings. Keywords: Cirrhosis; esophageal varices; gastric varices; platelet count; spleen diameter.

Received: January 02, 2016 Accepted: January 20, 2016 Online: June 07, 2016 Correspondence: Dr. Oguzhan OZTURK. Umraniye Egitim ve Arastirma Hastanesi, Gastroenteroloji Klinigi, Istanbul, Turkey. Tel: +90 216 632 18 18 e-mail: droguzozturk@hotmail.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


Ozdil et al., Relationship between size of varices and platelet count/spleen size ratio in cirrhotic patients

P

ortal hypertension is a pathological condition that onsets with abnormal increase (>5mm hemoglobin [Hg]) in hepatic venous pressure gradient and causes dilatation of portosystemic collaterals [1]. Portal hypertension manifests itself most frequently as a complication of hepatic cirrhosis, and subsequently leads to development of esophagogastric varices. The incidence of gastroesophageal varices in cirrhotic patients ranges between 50-66% and life-threatening variceal bleeding can develop in 30-40% of patients with varices [1,2]. Therefore detection and treatment of varices at an early stage is vital. Incidence of variceal bleeding varies between 5-15%. Most often it is esophageal varices that bleed; however, gastric varices are responsible for 10-36% of bleeding episodes. Studies have demonstrated that incidence of recurrent bleeding episodes and risk of mortality observed in cases with gastric variceal bleeding are higher when compared to esophageal varices [3-6]. The best method to detect varices in cirrhotic patients is endoscopic evaluation of upper gastrointestinal system, and if not contraindicated, it should be performed for every patient with diagnosis of cirrhosis [7]. However lack of necessary equipment for endoscopic screening, patient intolerance, and/or contraindication for endoscopy may delay detection of varices. In cases where endoscopy cannot be performed, various noninvasive methods have been developed to predict presence of varices. Therefore, correlation between various hematological parameters, imaging modalities, and endoscopic findings have been evaluated. Among these noninvasive methods, one of the most important is platelet count/spleen diameter ratio (P/S). It has been demonstrated in studies of cirrhotic patients that diagnostic sensitivity of P/S for large varices approaches as much as 90% [8]. The present study investigated the relationship between size of varices and P/S ratio. MATERIALS AND METHODS A total of 186 patients diagnosed with cirrhosis and gastroesophageal varices treated at Ă&#x153;mraniye Training and Research Hospital between 2009 and

47

2013 were included in the study. Patient data were evaluated retrospectively. Diagnosis of cirrhosis was made using data obtained from clinical, laboratory examinations and/ or liver biopsy results. Cirrhotic patients who had undergone endoscopic examination at least once were included in the study. Laboratory tests were performed concomitantly with endoscopy, or 1 month before or after biopsy procedure. Only the most current endoscopic examination was taken into consideration for patients who had undergone multiple endoscopies. Demographic, clinical, and laboratory findings of patients were compared with endoscopic findings. Disease stage of patients was determined according to the Child-Pugh scoring system based on prothrombin time (PT), albumin, bilirubin values, and presence of encephalopathy or ascites. Patients were classified into Child A (5-6 points), B (7-9 points), and C (10-15 points) groups [9]. From automatically measured patient whole blood counts, the number of platelets in 1 cubic mm was determined. Platelet counts were divided by ultrasonographically measured maximum spleen diameter to calculate platelet counts/spleen diameter ratios (P/S) [10]. Endoscopically detected esophageal varices were classified as small (minimum elevation from the esophageal mucosa), moderate (tortuous varices occupying less than one-third of lumen), and large (tortuous varices occupying greater than one-third of lumen) [3]. Since treatment guidelines recommend primary prophylaxis for moderate and large varices, these two categories were combined to form a single group. Thus, varices were evaluated based on two groups: small and medium or large. Evaluation of gastric varices according to their location was made according to the classification system proposed by Sarin et al. Gastric varices were classified as gastroesophageal varices (GOV), and isolated esophageal varices (IGV). GOV are subdivided into GOV1, GOV at the level of small curvature, and GOV2, GOV at the level of the greater curvature. IGV located in the fundus are classified as IGV1, and those located in other regions of the


48

North Clin Istanbul â&#x20AC;&#x201C; NCI

stomach are defined as IGV2 [11]. Gastric varices were also classified as small (<5 mm), moderate (510 mm), and large (>10 mm) [12]. Patients experiencing active variceal bleeding, those with a history of transjugular intrahepatic portosystemic shunt (TIPS) procedure, shunt surgery, and patients who had undergone band ligation, sclerotherapy, or variceal occlusion therapy

were excluded from the study. Approval for the study was obtained from the ethics committee of Ă&#x153;mraniye Training and Research Hospital. Statistical Analysis SPSS software (version 22.0; SPSS Inc., Chicago, IL, USA) was used for statistical analysis of the

Table 1. Comparison of patient characteristics according to variceal groups

Patients with

GOV1

GOV2

IGV1

Total all types

esophageal

(n=15)

(n=13)

(n=4)

of gastric varices

varices

(GOV1+

(n=154)

GOV2+

IGV1)

(n=32)

n (%)

n (%)

n (%)

n (%)

n (%)

p

p

1

2

Gender

Male

97 (63)

13 (86.6)

11 (84.6)

3 (75)

27 (84.4)

Female

57 (37)

2 (13.4)

2 (15.4)

1 (25)

5 (15.6)

0.130

a

0.033*

b

Etiology

HBV

47 (30.5)

3 (20)

4 (30.8)

3 (75)

10 (31.2)

HCV

26 (16.9)

3 (20)

3 (23.1)

0 (0)

6 (18.8)

Ethanol

11 (7.1)

1 (6.6)

3 (23.1)

0 (0)

4 (12.5)

Cryptogenic

46 (29.9)

6 (40)

2 (15.3)

1 (25)

9 (28.1)

NASH

13 (8.4)

1 (6.6)

0 (0)

0 (0)

1 (3.1)

Autoimmune

5 (3.3)

0 (0)

0 (0)

0 (0)

0 (0)

Other

6 (3.9)

1 (6.6)

1(7.7)

0 (0)

2 (6.3)

Absent

125 (81.2)

13 (86.6)

10 (76.9)

2 (50)

25 (78.1)

Present

29 (18.8)

2 (13.4)

3 (23.1)

2 (50)

7 (21.9) 17 (53.1)

a

0.789

a

0.757

0.427

b

HCC a

0.947

Child-Pugh

A

45 (29.2)

8 (53.3)

8 (61.5)

1 (25)

B

67 (43.5)

7 (46.7)

1 (7.7)

1 (25)

a a 0.021* 0.033* 9 (28.1)

C

42 (27.3)

0 (0)

4 (30.8)

2 (50)

6 (18.8)

Size of varices

Small

42 (27.3)

4 (26.7)

6 (46.2)

3 (75)

13 (40.6)

Moderate

67 (43.5)

10 (66.7)

3 (23.1)

0 (0)

13 (40.6)

Large

45 (29.2)

1 (6.7)

4 (30.8)

1 (25)

6 (18.8)

a

0.067

0.258

b

1p value obtained by separate evaluation of all variceal groups, 2p value for comparison between patients with esophageal and gastric varices (GOV1 + GOV2 + IGV1); aChi-square test; bcontinuity correction; Child-Pugh classification: A: 5-6 pts B: 7-9 pts C: 10-15 pts.; *p<0.05. GOV: Gastroesophageal varices; GOV1: Esophageal varices extending to cardia or lesser curve; GOV2: Esophageal and fundal varices; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; IGV: Isolated gastric varices; IGV1: IGV located in the fundus; IGV2: IGV located elsewhere in stomach; NASH: Non-alcoholic steatohepatitis.


Ozdil et al., Relationship between size of varices and platelet count/spleen size ratio in cirrhotic patients

data obtained from the study. Fitness of the parameters to normal distribution was evaluated using Shapiro-Wilk test. In addition to descriptive statistical methods (mean, standard deviation), in the comparison of quantitative data from more than two groups regarding parameters with nonnormal distribution, Kruskal-Wallis test was used. For intergroup comparisons of parameters with normal and nonnormal distribution, Student’s-t test, and Mann-Whitney U test were used, respectively. Chisquare test and Yates’ correction for continuity were also used to compare quantitative data. Optimal models were selected based on receiver operating characteristic (ROC) curve analysis. In the calculation of sensitivity and specificity, diagnostic screening tests were used. Level of statistical significance was accepted as p<0.05. RESULTS The study was performed on 186 patients with a mean age of 59.51±12.75 years (range 16-86

49

years). Study population consisted of 124 (66.7%) male and 62 female (33.3%) patients. Demographic characteristics of patients are provided in Table 1. Patients had esophageal (n=154; 82.7%) and gastric varices (n=32; 17.3%) Distribution of patients among subgroups of gastric varices were as follows: GOV1: n=15, 46.8%; GOV2: n=13, 40.6%; IGV1: n=4, 12.6%. No instance of IGV2 was found. Female patients made up a greater percentage among those with esophageal varices (37%) than all types of gastric varices (15.6%) (p=0.033). Patients were evaluated as four distinct groups (esophageal varices, GOV1, GOV2, and IGV1), and no significant difference between groups was found with respect to etiology of cirrhosis, hepatocellular carcinoma (HCC), or Child-Pugh classification (p>0.05). Nor was a significant intergroup difference found for the same parameters when the patients were evaluated in two groups: those with esophageal varices or all types of gastric varices (GOV1 + GOV2 + IGV1) (Table 1).

Table 2. Comparison between hematologic parameters and platelet count/spleen diameter ratios in variceal groups Esophageal

GOV1

GOV2

IGV1

Total gastric varices

varices

(n:15)

(n:13)

(n:4)

(n:32)

P

P

1a

2b

(n:154) Age

59.19±13.44

59.53±8.69

61±9.59

66.75±3.86

61.03±8.74

a

T/D

788.81±462.73

601.29±307.21

838.79±707.97

869.73±761.48

723.13±539.54

a

117195.39±64326.69

94273.33±43149.15

117366.67±80383.03

122750±85425.89

106887.1±62224.96

a

6218.62±3607.01

4386±1618.55

5688.33±2467.62

7780±3022.63

5328.06±2380.36

a

3.75±0.82

3.77±0.5

3.92±1

3.94±1.26

3.85±0.80

a

11.14±2.44

11.07±2.16

10.64±2.65

11.88±3.5

11.00±2.48

a

9.39±1.62

8.6±1.27

9.22±1.11

9.38±1.28

8.94±1.22

a

Platelets

0.492

b

0.513

c

0.216

0.334

0.557

c

0.222

0.113

c

0.292

0.847

b

0.834

b

0.332

b

(K/mm ) 3

Leukocyte (K/mm3) Erythrocyte

0.526

(million/µL) Hemoglobin

0.785

(gr/dl) Mpv

0.147

p<0.05

*

p value obtained by separate evaluation of all variceal groups, 2p value for comparison between esophageal and total gastric varices (esophageal varices,

1

GOV1 + GOV2 + IGV1); a: Kruskal- Wallis test b: Student’s t-test; c: Mann-Whitney U test. GOV: Gastroesophageal varices; GOV1: Esophageal varices extending to cardia or lesser curve; GOV2: Esophageal and fundal varices; IGV: Isolated gastric varices; IGV1: IGV located in the fundus; IGV2: IGV located elsewhere in stomach; Mpv: Mean platelet volume; Plt: platelet; WBC: white blood cell count.


50

North Clin Istanbul – NCI

100

Duyarlılık

80

60

40

20

0 0

20

40

60

80

100

Özgüllük

Figure 1. Correlation between platelet count/spleen diameter ratio and size of varices.

Comparison of groups of varices based on P/S did not yield a significant difference; therefore, a significant correlation was not found between P/S and location of varices (Table 2). Correlation between size of varices and P/S was investigated. Mean P/S ratios were 742.16±450.59

in large (medium-large) varices, and 917.41±477.51 in small varices. Mean P/S ratio was significantly lower in large varices group (p=0.04, Table 3). ROC curve analysis determined P/S limit of 1057. P/S ratios below this value had 82% sensitivity, 40% specificity, 79% positive, and 45% negative predictive values (Figure 1). P/S ratio was not significantly different between large and small gastric varices (p>0.05). Esophageal varices were compared to all types of gastric varices with regard to stage of cirrhosis (based on Child-Pugh classification), and significant intergroup difference was detected (p=0.033). Patients with Child-Pugh Stage A cirrhosis were significantly more numerous (53.1%) in all cases with gastric varices relative to the group with esophageal varices (29.2 %) (p=0.016). However, among Child B and Child C patient groups, the number of patients with esophageal varices did not differ significantly from those with gastric varices (p>0.05). DISCUSSION One of the most important complications of cirrhosis is variceal bleeding. Guidelines published by the Baveno VI Consensus Workshop and The American Association for the Study of Liver Dis-

Table 3. Comparison of grade of esophageal varices, platelet count/spleen diameter ratio and hematological parameters

Patients with small varices

Patients with large varices

(n=42)

(n=112)

917.41±477.51

742.16±450.59

0.040*

130119.05±72581.34

112260.91±60513.32

0.181

6090±3579.83

6267.73±3632.43

0.974

3.87±0.88

3.7±0.8

0.205

Hgb (gr/dL)

11.75±2.4

10.9±2.42

0.060

Mpv

8.96±1.26

.56±1.71

0.125

Plt/spleen Plt (K/mm3) WBC (K/mm3) RBC (106 /µL)

Mann-Whitney U test; * p<0.05. Hgb: Hemoglobin value; Mpv: Mean platelet volume; Plt: platelet; RBC: Red blood cell count; WBC: white blood cell count.


Ozdil et al., Relationship between size of varices and platelet count/spleen size ratio in cirrhotic patients

ease (AASLD) recommend screening for the presence of varices in all cirrhotic patients using upper gastrointestinal system endoscopy, and application of prophylaxis is advised in patients with a risk of bleeding [3, 13]. However, in cases where endoscopic procedures could not be performed or were postponed because of difficulties inherent to endoscopic examination (i.e., experienced team and cost), and various patient-related factors (i.e., state of health, fear of procedure), diagnosis and treatment may be delayed. Therefore, noninvasive methods have been developed to predict the presence and size of varices. In a study by Gue et al., correlation between size of varices and lower platelet and leukocyte counts was demonstrated [14]. Similarly, studies conducted in cirrhotic patients have demonstrated that decrease in platelet count and supranormal diameter of spleen are independent risk factors in determination of large esophageal varices [15, 16]. In recent years, P/S has been added to these noninvasive parameters. In studies of Mexican cirrhotic patients, González-Ojeda et al. demonstrated that P/S could predict presence of varices with 84% sensitivity and 70% specificity [17]. Sarangapani et al. reported that platelet count/spleen diameter ratio could predict large esophageal varices with higher sensitivity and specificity [18]. Meta-analysis performed by Ying et al. consisting of 20 studies and a total of 3063 patients evaluated the performance of platelet count/spleen diameter ratio in the prediction of esophageal varices, and the authors demonstrated that the noninvasive method can predict esophageal varices with 92% sensitivity [19]. In the present study, P/S predicted size of the varices with 82% sensitivity and 79% positive predictive value. According to this outcome, in the follow-up of cirrhotic patients with varices who cannot tolerate and/or do not consent to endoscopic examination, P/S ratio can be a useful noninvasive method to evaluate size of varices. In various studies, Child-Pugh scores have been demonstrated to be an important prognostic criterion in the prediction of survival of cirrhotic patients as well as bleeding risk of preexisting varices [9,20,21]. Similarly, some studies have demonstrated close association between Child-Pugh scores and

51

recurrent bleeding risk of variceal bleeds that ceased spontaneously or as a result of treatment [22, 23]. Distribution of patients according to groups based on Child-Pugh stages revealed that cirrhotic patients in Child A stage were more numerous in all groups with gastric varices. For patients with gastric varices, diagnosis at Child A stage can contribute favorably to prognosis, improve hemostatic control, and decrease recurrence rates. This outcome may be important for patients with gastric varices in Turkish population. Large-scale prospective studies to support our findings are needed. Retrospective design of the present study is a limitation. Prospective studies should be conducted for better evaluation and follow-up of patients with varices. Limited number of patients and conducting the study in a certain region of Turkey are further limitations that may not reflect the present condition throughout the country. Multi-centered studies will yield more reliable data. In conclusion, this study demonstrated that P/S ratio could predict presence of large varices with a high sensitivity in patients with esophageal varices. Therefore, in the follow-up of varices in cirrhotic patients with esophageal varices not amenable to endoscopy, P/S ratio can be used as a noninvasive parameter. Child A stage cirrhosis was more frequently detected in patients with gastric varices, which may be important for prognosis. Large-scale prospective studies are needed. 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 - K.Ö., O.Ö.; Design K.Ö., O.Ö.; Materials - K.Ö., O.Ö.; Data collection and/or processing - E.S.Ç, E.S.A, E.K., H.D., Z.Ç., R.K.; Analysis and/or interpretation - K.Ö.; Literature search - Writing - O.Ö., R.K. Critical review - O.Ö.

REFERENCES 1. Miyaaki H, Ichikawa T, Taura N, Miuma S, Isomoto H, Nakao K. Endoscopic management of esophagogastric varices in Japan. Ann Transl Med 2014;2:42 2. Moodley J, Lopez R, Carey W. Compliance with practice guidelines and risk of a first esophageal variceal hemorrhage in pa-


52 tients with cirrhosis. Clin Gastroenterol Hepatol 2010;8:703-8. 3. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and varicealhemorrhage in cirrhosis. Hepatology 2007;46:922-38. 4. Qureshi W, Adler DG, Davila R, Egan J, Hirota W, Leighton J, et al. ASGE Guideline: the role of endoscopy in the management of variceal hemorrhage, updated July 2005. Gastrointest Endosc 2005;62:651-5. 5. de Franchis R. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010;53:762-8. 6. Sarin SK, Kumar A. Endoscopic Treatment of Gastric Varices. Clin Liver Dis. 2014;18:809-27. 7. de Franchis R. Updating consensus in portal hypertension: Report of the Baveno III consensus workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000;33:846-52. 8. Giannini EG, Zaman A, Kreil A, Floreani A, Dulbecco P, Testa E, et al. Platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results of a multicenter, prospective, validation study. Am J Gastroenterol 2006;101:2511-9. 9. Child CG, Turcotte JG. Surgery and portal hypertension. In: Child CG, editor. The liver and portal hypertension. Philadelphia: Saunders; 1964. p. 50–64. 10. Lamb PM, Lund A, Kanagasabay RR, Martin A, Webb JA, Reznek RH. Spleen size: how well do linear ultrasound measurements correlate with three-dimensional CT volume assessments? Br J Radiol 2002;75:573-7. 11. Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a longterm follow-up study in 568 portal hypertension patients. Hepatology 1992;16:1343-49. 12. Triantafyllou M, Stanley AJ. Update on gastric varices. World J Gastrointest Endosc 2014;6:168-75. 13. de Franchis R; Baveno VI Faculty. Expanding consensus in por-

North Clin Istanbul – NCI tal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743-52. 14. Gue CS, Yap CK, Ng HS. The correlation between cytopenia and esophageal varices in patients with liver cirrhosis. Med J Malaysia 2004;59:604-8. 15. Madhotra R, Mulcahy HE, Willner I, Reuben A. Prediction of esophageal varices in patients with cirrhosis. J Clin Gastroenterol 2002;34:81-5. 16. Sharma SK, Aggarwal R. Prediction of large esophageal varices in patients withcirrhosis of the liver using clinical, laboratory and imaging parameters. J Gastroenterol Hepatol 2007;22:1909-15. 17. González-Ojeda A, Cervantes-Guevara G, Chávez-Sánchez M, Dávalos-Cobián C, Ornelas-Cázares S, Macías-Amezcua MD, et al. Platelet count/spleen diameter ratio to predict esophageal varices in Mexican patients with hepatic cirrhosis. World J Gastroenterol 2014;20:2079-84. 18. Sarangapani A, Shanmugam C, Kalyanasundaram M, Rangachari B, Thangavelu P,Subbarayan JK. Noninvasive prediction of large esophageal varices in chronic liver disease patients. Saudi J Gastroenterol 2010;16:38-42. 19. Ying L, Lin X, Xie ZL, Hu YP, Shi KQ. Performance of platelet count/spleen diameter ratio for diagnosis of esophageal varices in cirrhosis: a meta-analysis. Dig Dis Sci 2012;57:1672-81. 20. North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988;319:983-9. 21. Park EJ, Jang JY, Lee JE, Jeong SW, Lee SH, Kim SG, et al. The risk factors for bleeding of fundal varices in patients with liver cirrhosis. Gut Liver 2013;7:704-11. 22. Jun CH, Kim KR, Yoon JH, Koh HR, Choi WS, Cho KM, et al. Clinical outcomes of gastric variceal obliteration using N-butyl2-cyanoacrylate in patients with acute gastric variceal hemorrhage. Korean J Intern Med 2014;29:437-44. 23. Jensen DM. Endoscopic screening for varices in cirrhosis: findings, implications, and outcomes. Gastroenterology 2002;122:1620-30.


Orıgınal Article

Anesthesiology and Reanimation

North Clin Istanbul 2016;3(1):53–9 doi: 10.14744/nci.2016.38233

Comparison of mirtazapine, gabapentin and ondansetron to prevent intrathecal morphine-induced pruritus Ayse Akhan,1 Ferhunde Dilek Subasi,2 Gulsen Bosna,2 Osman Ekinci,2 Hakan Pamuk,2 Siddika Batan,2 Rezzan Yagmur Ateser,2 Gulden Turan2 Department of Anesthesiology and Reanimation, Karabük Training and Research Hospital, Karabük, Turkey

1

Department of Anesthesiology and Reanimation, Haydarpasa Numune Training and Research Hospital, Uskudar, Istanbul, Turkey

2

ABSTRACT OBJECTIVE: Antagonism of the central nervous system inhibitor neurotransmitter gamma-Aminobutyric acid (GABA) or serotonergic system activation is an important factor in the pathogenesis of intrathecal morphine-induced pruritus. This study tested the hypothesis that preoperative use of ondansetron, gabapentin or mirtazapine can prevent morphine-induced pruritus. METHODS: We randomly allocated 80 patients of American Society of Anesthesiology (ASA) classification I and II physical status who were to undergo unilateral inguinal hernia or pilonidal sinus operations under spinal anesthesia into 4 equal groups. The first 3 groups received oral doses of 30 mg mirtazapine, 8 mg ondansetron, and 1200 mg gabapentin at 2 hours, 10 minutes, and 1 hour before surgery, respectively, and the fourth group was given a placebo. All patients received intrathecal injection of 15 mg of 0.5% hyperbaric bupivacaine and 0.2 mg morphine. Pruritus was evaluated at 0, 3, 6, 9, 12, and 24 hours after intrathecal morphine administration, and details of presence, onset time, duration, localization, and severity of pruritus were recorded. RESULTS: Incidence of pruritus was significantly more frequent in the placebo group compared to ondansetron, gabapentin, and mirtazapine groups (70%, 55%, 35%, and 35%, respectively). In general, onset of pruritus was between 2 and 6 hours after intrathecal morphine injection; however, onset in the gabapentin group (mean±SD: 4.75±2.7 hours; p=0.019) was delayed compared to other groups. It was observed that pruritus persisted relatively longer in the ondansetron and placebo groups (mean±SD: 6±3.08; 5.82±2.96 hours, respectively; p=0.047). No statistical determination was made regarding location of pruritus. Severity of pruritus was greater in the placebo group (p=0.0001). Necessity for antipruritic treatment was not statistically significantly different between groups. CONCLUSION: Incidence and severity of intrathecal morphine-induced pruritus decreased with use of each of all 3 drugs compared to placebo. Keywords: Gabapentin; intrathecal; mirtazapine; morphine; ondansetron; pruritus.

Received: October 28, 2015 Accepted: May 17, 2016 Online: June 10, 2016 Correspondence: Dr. Rezzan Yagmur AteSer. Haydarpasa Numune Egitim ve Arastirma Hastanesi, Istanbul, Turkey. Tel: +90 216 - 3360363 e-mail: rezzanyagmur@hotmail.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


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North Clin Istanbul – NCI

I

During preoperative visit, all patients were informed about the procedure and their written consent was obtained. Patients for whom regional anesthesia was contraindicated; those who declined to undergo the procedure; individuals allergic to drugs used; patients with any systemic disease that causes itching; patients with history of locomotor diseases or postoperative nausea and vomiting; those suffering from preoperative pruritus; cases treated with opioids or antiemetics; mentally retarded persons; and antidepressant, antipsychotic, and antiepileptic drug users were not included in the study. In addition, patients in whom dural puncture could not be achieved, and those using opioids perioperatively as pain relievers were excluded from the study. None of the patients received premedication. Patients were randomized equally into groups of 20 subjects. As prophylaxis, Group 1 received oral dose 8 mg ondansetron 10 minutes before the operation, and Group 2 was given oral dose 1200 mg gabapentin 1 hour preoperatively. Group 3 received oral dose 30 mg mirtazapine 2 hours before surgery, and Group 4 was given sugar pills as placebo 10 minutes before the operation. Venous access was provided using a 20-gauge cannula 30 minutes preoperatively, and patients were hydrated with 500 ml 0.9% NaCl intravenous (IV) infusion. Patients were monitored, and noninvasive measurements of systolic arterial pressure (SAP), mean arterial pressure (MAP), heart rate (HR), and blood oxygen saturation (SpO2) level were taken. Patients were seated, and site of the spinal anesthesia was disinfected with sterile solution. L3-4 or L4-5 intervertebral space was located and 26-gauge spinal needle was inserted through midline approach to enter subarachnoidal space. After clear drainage of cerebral spinal fluid (CSF) was observed, spinal anesthesia was applied using 0.5% hyperbaric bupivacaine 15 mg (3 mL), and 0.2 mg (0.1 mL) morphine. Patients were placed in supine position and head was elevated 30 degrees. Level of sensory block was evaluated using pinprick test for dermatome level, and grade of motor block was assessed using Bromage Scale: 0=lack of paralysis, the patient is able to freely move hip, feet, knee, and ankle; 1=patient is able to move knee, and feet, but

ntrathecal use of morphine provides intense, prolonged analgesic effect, and it is frequently used in the relief of postoperative pain [1]. However, the side effects of opioids, which can affect patient comfort and safety, restrict the therapeutic effects. Itching is the most frequently seen side effect of intrathecal morphine, with an incidence ranging 62–94% [2, 3]. Itching continues to be a challenging and problematic issue that is difficult for anesthetists to treat [4, 5]. Pharmacological agents, such as antihistamines, 5-HT3 (serotonin) receptor antagonists, opioid antagonists, opioid agonist-antagonists, propofol, and non-steroidal anti-inflammatory drugs (NSAID) have been used to fight this challenging side effect [1, 6]. Interaction between intrathecal morphine and 5-hydroxytryptamine subtype 3 (5-HT3), which affects the central nervous system (CNS), is thought to play a role in the pathogenesis of itching [5]. Therefore, ondansetron, as a 5-HT3 receptor antagonist, and mirtazapine, a presynaptic α-2 antagonist that increases central serotoninergic effect by blocking 5-HT2 and 5-HT3 receptors, may be effective in controlling itching. Though its mechanism has not been explained, itching may be associated with opioids that behave as antagonists to central inhibitor neurotransmitters (GABA and glycine) [7]. The anticonvulsant agent gabapentin, which is a structural analogue of GABA, may be effective in the management of itching. To this end, the present prospective, randomized, placebo-controlled study was conducted to determine the efficacy of ondansetron, gabapentin, and mirtazapine in the prevention of the itching that frequently develops after spinal anesthesia using bupivacaine and morphine on patients undergoing unilateral inguinal hernia or pilonidal sinus surgery, and to assess the superiority of one drug over another. MATERIALS AND METHODS The present study was performed on a total of 80 patients with American Society of Anesthesiology (ASA) classification I and II physical status aged 18–65 years who underwent unilateral inguinal hernia or pilonidal sinus surgery. Approval was obtained from the ethics committee of Istanbul University Faculty of Medicine.


Akhan et al., Comparison of mirtazapine, gabapentin and ondansetron to prevent intrathecal morphine-induced pruritus

cannot elevate straight leg; 2=patient cannot bend knee, can only move feet; 3=complete paralysis. At the time of surgical team incision, patients were given midazolam (Demizolam®) at a dose of 0.05 mg/kg. Degree of sedation was evaluated using Ramsay scale: 1=patient is agitated and restless; 2=patient is cooperative, oriented, and tranquil; 3=patient is sleeping, but responds to verbal stimuli; 4=patient is sleeping, moderate response to painful stimuli; 5=patient is sleeping, slow response to painful stimuli; 6=patient is sleeping, lack of any response to painful stimuli. SAP and MAP levels below 80 and 60 mmHg, respectively, were accepted as hypotension. In the event of persistent hypotension, IV fluid replacement, then 5–10 mg IV ephedrine was administered. Heart rate below 50 bpm was considered bradycardia and treated with 0.5 mg IV atropine. In addition, it was predetermined that midazolam would be re-instituted during operation if needed to maintain Ramsay score between 2–4 points and that oxygen support via facemask would be kept ready in case of need. At postoperative 0, 3, 6, 9, 12, and 24 hours, patients were questioned about the presence of itching, and if present, further questioned about time of onset, duration, location, and severity (none, mild, moderate or severe). If itching was severe, then 10 mg IV diphendydramine was administered, followed by an opioid antagonist, if necessary. At the

same time intervals, patients were questioned about severity of pain using visual analogue scale (VAS) in which 0 indicated patient was asymptomatic and 10 represented the most severe pain. Intramuscular diclofenac sodium at a dose of 75 mg was administered when VAS score was >5. At the same time intervals, inquiries were also made about presence of nausea or vomiting (absent, mild, moderate or severe). In case of severe nausea or vomiting, metoclopramide (10 mg IV) was administered. Other side effects related to intrathecal morphine application, including urinary retention, constipation, and respiratory depression, were also evaluated. While evaluating study data, for statistical analysis Number Cruncher Statistical System software (2007 package; NCSS, LLC; Kaysville, Utah, USA) was used. In addition to descriptive statistical methods (mean, standard deviation), in repetitive measurements of multiple groups, Friedman test was used, and for comparisons between groups, Kruskal-Wallis test was used. Subgroups were compared employing Dunn’s multiple comparison test, and for qualitative data, chi-square and McNemar’s tests were used. Results were evaluated at a level of p<0.05. RESULTS None of the eligible patients was excluded from the study for any reason; a total of 80 patients were al-

Table 1. Comparison of demographic data of the patient groups

Group 1 (n=20)

55

Group 2 (n=20)

Group 3 (n=20)

Age (years) 41.6±10.92 41.4±10 41.75±9.94 Gender (M/F) 16/4 15/5 16/4 Height (cm) 174±6.97 171.9±6.27 173.95±6.64 Body weight (kg) 76.95±7.91 76.65±6.83 76.4±7.98 Operative time (min) 62±11.85 60.25±11.64 61.25±7.41 Type of surgery (n; %) İnguinal hernia repair 13; 53.84% 12; 60% 12; 60% Pilonidal sinus excision 7; 46.16% 8; 40% 8; 40%

Group 4 (n=20) 41.55±9.84 17/3 173.15±6.64 78.45±8.09 61.25±9.72 12; 60% 8; 40%


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North Clin Istanbul â&#x20AC;&#x201C; NCI

Table 2. Comparison of incidence of itching in patient groups

Group 1 n

Group 2

%

n

Group 3

%

n

Group 4

%

n

p

%

0 hr 1 5 0 0 1 5 3 15 3 hr 7 35 4 20 7 35 14 70 6 hr 11 55 7 35 4 20 14 70 9 hr 5 25 7 35 2 10 7 35 12 hr 1 5 3 15 0 0 3 15 24 hr 0 0 0 0 0 0 0 0

located equally into 4 groups that were compared based on demographic data. No significant difference was seen between groups with regard to age, gender, body weight, operative time, and type of surgery (p>0.05) (Table 1). During 24 hours of follow-up, a statistically significant difference was observed between incidence of itching at postoperative 3 and 6 hours (p=0.01 and p=.008, respectively). At these time points, incidence of itching was higher in Group 4 compared to Groups 1, 2, and 3. However at other time points, a significant difference was not detected among the 4 groups (Table 2). A statistically significant difference was observed between onset and duration of itching in all patient groups. In Group 2, onset of itching was statistically significantly delayed compared to Group 3 and Group 4 (p=0.019). Duration of hr

Group 1

Group 2

Group 3

Group 4

6

4 3 2 1 0

itching in Group 1 and Group 4 was found to be statistically significantly longer versus Groups 2 and 3 (p=0.047) (Figure 1). Itching was observed on face, trunk, lower, and upper extremities, and no significant intergroup difference was detected with regard to location of itching. In Group 4, severity of itching observed at postoperative third and sixth hours was higher relative to other groups. (p=0.006, and p=0.009, respectively). However, a significant difference was not found between groups as for necessity of treatment for itching (Figure 2). In Group 4, mean VAS scores detected at postoperative hour 4 and 9 were higher compared to other groups. However, need for pain treatment did not differ among groups. No difference in presence of adverse effects of opioids, such as nausea, vomiting, and urinary retention was observed. While no Was treatment of itching required?

%

16 14 12 10 8 6 4 2

5

0 Onset time of itching

Duration of itching

Figure 1. Comparison of patient groups regarding onset time and duration of itching.

=0.256 =0.01 =0.008 =0.228 =0.238

Group 1

0

Group 2

Group 3

3 6 9 Postoperative time intervals (hrs)

Group 4

12

Figure 2. Comparison of the patient groups regarding treatment of itching.


Akhan et al., Comparison of mirtazapine, gabapentin and ondansetron to prevent intrathecal morphine-induced pruritus

difference was detected between intraoperative sedation doses, mean Ramsay score at post treatment 60 minutes in Group 2 was found to be statistically significantly higher when compared to mean values of Groups 1, 3, and 4 (p=0.004). Ramsay sedation scores did not exceed 5 points in any of the patients, nor was respiratory depression seen in any patient. DISCUSSION Intrathecal morphine is an attractive alternative in the management of postoperative pain in that it provides intense and long-term analgesia without motor block and marked central system depression [1]. Itching is the most frequently seen side effect of intrathecal opioids, with a reported incidence of 62–94% [2, 3, 4, 5, 6, 7, 8]. Numerous theories have been proposed to explain the mechanism of itching caused by intrathecal opioids, however underlying etiology is still unknown. This unwanted side effect can be very disturbing to the patient, patient may be resistant to traditional antipruritic treatments, itching may adversely affect patient satisfaction, and may hinder postoperative management of pain. In the present study evaluating itching related to the use of intrathecal morphine, itching of relatively higher incidence (70%) and severity was observed in the placebo group. In all groups, itching was generally observed to begin between postoperative hours 2 and 6; in the gabapentin group, time of onset was greater than in other groups (6±3.08 hours vs 5.82±2.96 hours). Scratch marks were observed on face, trunk, upper, and lower extremities; however, in none of these locations was the itching statistically significantly more frequent. Excluding the mirtazapine group, in all other groups itching was more severe at 3, 6, and 9 hours post surgery. Treatment for itching was required in 1 ondansetron, 2 mirtazapine, and 3 placebo users, while none of the patients in the gabapentin group required antipruritic treatment. Yet a significant difference in need for treatment was not observed between groups. Sheen et al. administered prophylactic treatment with 1200 mg oral gabapentin or placebo to prevent itching developed after orthopedic surgery of lower extremities in 2 groups of 43 patients who had re-

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ceived 0.2 mg intrathecal morphine, and they found higher incidence rates of itching in placebo group when compared with gabapentin group (77.5% vs 47.5%) [9]. Similar to the present study, itching manifested later in the gabapentin group relative to the placebo group (gabapentin: 6.2±1.8 hours). In the current study location sites of itching did not differ between groups; however, in the Sheen et al. study, itching was most frequently (68%) observed in the trigeminal region. In addition, in the present study, antipruritic treatment was not required in the gabapentin group; however, 3% of patients in the gabapentin group in their study required antipruritic treatment. In another study, Sheen et al. compared prophylactic use of mirtazapine with placebo on 110 patients, and observed higher incidence of itching in the placebo group (52% and 75%, respectively). Duration of itching was not different between groups, but onset of itching was delayed with mirtazapine premedication (3.2±7.2 hours) [10]. In the current study, time to onset of itching did not differ between mirtazapine and placebo groups, but onset of itching was delayed in the gabapentin group (4.75±2.7 hours). Though itching was more frequently localized on face, in the mirtazapine group, itching was most frequently localized on the trunk. The face was also the most common location for itching in the placebo group. Itching was more severe in the placebo group, and 19% of the patients required treatment. In the mirtazapine group, only 4 patients needed treatment. In the current study, treatment was required for 10% of the patients in the mirtazapine group, and 15% in the placebo group, without any significant intergroup difference in the severity of itching. Koju et al. used prophylactic doses of 4 mg IV ondansetron, and also 4 mL physiologic saline as placebo in 50 patients who were to undergo cesarean section in order to prevent itching caused by intrathecal morphine, and observed itching 16–88% more frequently in the placebo group. Ondansetron also demonstrated effectiveness reducing postoperative nausea and vomiting, two side effects that were seen more frequently in the placebo group (8% and 56%, respectively) [11]. In another study investigat-


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ing intrathecal morphine-induced itching, Kung et al. prophylactically used 8 mg IV ondansetron during umbilical cord clamping or postoperatively in the postanesthesia recovery room as a therapeutic dose in 82 patients who had undergone cesarean section, while the placebo group received only physiologic saline. When compared to the placebo group, prophylactic or therapeutic use of ondansetron did not decrease severity of itching at all [12]. In the present study, decrease in the severity of itching at third and sixth hours after administration of ondansetron was observed, but without any significant difference when compared to placebo group. In a prospective randomized, double-blind placebo-controlled study performed by Chiravanich et al. on 180 cases of orthopedic surgery using intrathecal 0.5% isobaric bupivacaine and 0.2 mg morphine, the authors compared preoperative prophylactic use of 600 mg oral gabapentin and placebo in the prevention of itching induced by intrathecal morphine [13]. They observed only 21.4â&#x20AC;&#x201C;41.7% decrease in the severity of itching at postoperative 4 hours without serious drop in the degree of itching with gabapentin [14]. In the current study, gabapentin decreased severity of itching at postoperative 3 and 6 hours, without a significant difference compared to placebo group. Szarvas et al. compared higher doses of intrathecal morphine (dose of 0.01 mg/kg up to 0.7 mg) with ondansetron and placebo in the prevention of postoperative itching, and apart from abovementioned studies, superiority of ondansetron over placebo was not reported [1]. Yazigi et al. combined highly lipophilic sufentanyl (2.5 mcg) to intrathecal 0.1 mg morphine, and compared this combination with 8 mg ondansetron and placebo, and couldnâ&#x20AC;&#x2122;t observe any difference between groups in prevention of postoperative itching [15]. This finding was explained by preferential binding of sufentanyl to serotonin receptors in the spinal cord relative to ondansetron because of its rapid onset of action. Pirat et al. compared ondansetron and placebo in young male patients, and Somrat Charuluxananan et al. compared nalbufin, ondansetron, and placebo in 240 women who had undergone cesarean section. As in the present study, a significant difference was

North Clin Istanbul â&#x20AC;&#x201C; NCI

not detected between groups regarding postoperative nausea and vomiting [16, 5]. The effect of morphine on the chemoemetic trigger zone in the area postrema is dependent on size of dose, and Yazigi et al. found ondansetron to be superior to placebo in the prevention of nausea and vomiting with smaller dose of morphine [15]. A significant intergroup difference was not detected with respect to pain score, urinary retention, gastrointestinal side effects or sedation. Respiratory depression was not seen in any patient. In a study performed by Chinachoti et al. on patients receiving intrathecal morphine, as in the Sheen et al. study where mirtazapine and placebo were compared, mirtazapine provided significantly higher (50%) levels of sedation when compared with the placebo [10, 14]. The present study had some limitations. The perception of itching manifests with individual variation; however, efforts were made to evaluate and measure its effects with care. Second, use of prophylactic drugs with similar taste and appearance in all groups may be preferable. In addition, precise appropriate doses to prevent itching were unknown. Finally, antipruritic drugs used in the clinic for prophylaxis had different degrees of effectiveness. Lack of statistical difference was attributed to small number of patients in population group; therefore, studies with larger patient series will be more appropriate. In conclusion, the present study compared antipruritic effectiveness of prophylactic oral dose of 8 mg ondansetron, 1200 mg gabapentin, 30 mg mirtazapine, and sugar pills given as oral placebo administered to a total of 80 patients allocated equally into 4 groups before application of intrathecal 15 mg (3 mL) 0.5% hyperbaric bupivacaine plus 0.2 mg (0.1 mL) morphine for spinal anesthesia for unilateral hernia repair or pilonidal sinus surgery. All 3 drugs decreased incidence, duration, and severity of itching when compared with placebo. No intergroup difference was observed with regard to requirement for antipruritic treatment. The authors recommend studies with larger patient series to further examine this subject. Conflict of Interest: None declared.


Akhan et al., Comparison of mirtazapine, gabapentin and ondansetron to prevent intrathecal morphine-induced pruritus

Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept - A.A.; Design - F.D.S.; Supervision - O.E.; Materials - A.A.; Data collection and/or processing - S.B., H.P., G.B., G.T.; Analysis and/or interpretation - A.A., F.D.S., Literature search - A.A., R.Y.A.; Writing - A.A., R.Y.A.; Critical review - O.E.

REFERENCES 1. Szarvas S, Harmon D, Murphy D. Neuraxial opioid-induced pruritus: a review. J Clin Anesth 2003;15:234–9. 2. Carr D, Cousins M. Spinal route of analgesia, opioids and future options. In: Bridenbaugh P, editor. Neural blockade in clinical anesthesia and management of pain. 3rd ed. Philadelphia: LippincottRaven; 1998. p. 115–83. 3. Charuluxananan S, Somboonviboon W, Kyokong O, Nimcharoendee K. Ondansetron for treatment of intrathecal morphine-induced pruritus after cesarean delivery. Reg Anesth Pain Med 2000;25:535– 9. 4. Szarvas S, Chellapuri RS, Harmon DC, Owens J, Murphy D, Shorten GD. A comparison of dexamethasone, ondansetron, and dexamethasone plus ondansetron as prophylactic antiemetic and antipruritic therapy in patients receiving intrathecal morphine for major orthopedic surgery. Anesth Analg 2003;97:259–63. 5. Charuluxananan S, Kyokong O, Somboonviboon W, Narasethakamol A, Promlok P. Nalbuphine versus ondansetron for prevention of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg 2003;96:1789–93. 6. Yeh HM, Chen LK, Lin CJ, Chan WH, Chen YP, Lin CS, et al. Prophylactic intravenous ondansetron reduces the incidence of intrathecal morphine-induced pruritus in patients undergoing cesarean delivery. Anesth Analg 2000;91:172–5.

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7. Gürkan Y, Toker K. Prophylactic ondansetron reduces the incidence of intrathecal fentanyl-induced pruritus. Anesth Analg 2002;95:1763–6. 8. Korhonen AM, Valanne JV, Jokela RM, Ravaska P, Korttila K. Ondansetron does not prevent pruritus induced by low-dose intrathecal fentanyl. Acta Anaesthesiol Scand 2003;47:1292–7. 9. Sheen MJ, Ho ST, Lee CH, Tsung YC, Chang FL. Preoperative gabapentin prevents intrathecal morphine-induced pruritus after orthopedic surgery. Anesth Analg 2008;106:1868–72. 10. Sheen MJ, Ho ST, Lee CH, Tsung YC, Chang FL, Huang ST. Prophylactic mirtazapine reduces intrathecal morphine-induced pruritus. Br J Anaesth 2008;101:711–5. 11. Koju RB, Gurung BS, Dongol Y. Prophylactic administration of ondansetron in prevention of intrathecal morphine-induced pruritus and post-operative nausea and vomiting in patients undergoing caesarean section. BMC Anesthesiol 2015;15:18. 12. Kung AT, Yang X, Li Y, Vasudevan A, Pratt S, Hess P. Prevention versus treatment of intrathecal morphine-induced pruritus with ondansetron. Int J Obstet Anesth 2014;23:222–6. 13. Chiravanich W, Oofuvong M, Kovitwanawong N. Single dose of gabapentin for prophylaxis intrathecal morphine-induced pruritus in orthopedic surgery: a randomized controlled trial. J Med Assoc Thai 2012;95:186–90. 14. Chinachoti T, Nilrat P, Samarnpiboonphol P. Nausea, vomiting and pruritus induced by intrathecal morphine. J Med Assoc Thai 2013;96:589–94. 15. Yazigi A, Chalhoub V, Madi-Jebara S, Haddad F, Hayek G. Prophylactic ondansetron is effective in the treatment of nausea and vomiting but not on pruritus after cesarean delivery with intrathecal sufentanil-morphine. J Clin Anesth 2002;14:183–6. 16. Pirat A, Tuncay SF, Torgay A, Candan S, Arslan G. Ondansetron, orally disintegrating tablets versus intravenous injection for prevention of intrathecal morphine-induced nausea, vomiting, and pruritus in young males. Anesth Analg 2005;101:1330–6.


Case Series

General Surgery

North Clin Istanbul 2016;3(1):60–3 doi: 10.14744/nci.2015.96530

Acute appendicitis in pregnancy: Case series and review Busra Burcu1, Ozgur Ekinci1, Tuba Atak2, Kivilcim Orhun1, Turgut Tunc Eren1, Orhan Alimoglu1 Department of General Surgery, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey

1

Department of General Surgery, Bursa Cekirge State Hospital, Bursa, Turkey

2

ABSTRACT OBJECTIVE: Acute appendicitis is one of the most common acute surgical pathology we encountered. In this study we investigated our pregnant cases of appendicitis, and reviewed literature. METHODS: A total of 21 pregnant women who underwent appendectomy with the initial diagnosis of acute appendicitis in Istanbul Medeniyet University Clinics of General Surgery between January 2012, and December 2014 were retrospectively analyzed. The patients’s ages, trimesters, complaints, abdominal examination, laboratory, and ultrasonographic findings, surgical techniques, complications and hospital stay were noted. RESULTS: The patients were in their first (n=12; 57.1%), second (n=5; 23.8%), and third trimesters (n=4; 19.0%) of their pregnancies Median age was 23.9 years. All of the patients had abdominal pain. Median value of WBC count was 13.297/mm³. Ultrasound was positive in 12 patients (57.1%). In 14 (66.6%) patients McBurney incision, and in 6 (28.6%) cases right paramedian incision were used. One patient (4.8%) underwent laparoscopic appendectomy. Nineteen cases were acute appendicitis (90.5%), and two cases were perforated appendicitis (9.5%). Average hospital stay was 3.8 days. Two cases with perforated acute appendicitis developed wound infection and treated conservatively. There were no fetomaternal mortality. CONCLUSION: Physiologically anatomic and biochemical changes occurring during pregnancy can delay the diagnosis of acute appendicitis threaten the lives of both the mother and the fetus Therefore, rapid diagnosis and appropriate treatment convey importance. Key words: Acute appendicitis; appendectomy; fetus; laparoscopic appendectomy; pregnancy.

T

he most frequently seen pathology in pregnancy which requires emergency surgery apart from obstetrical indications is suspect appendicitis [1]. We can encounter appendicitis in all three tri-

mesters. Compared with the healthy pregnants, they harbour increased risks of premature birth, miscarriage, and cesarean section [2]. Complaints physiologically related to pregnancy, changing physical

Received: March 21, 2015 Accepted: June 06, 2015 Online: October 04, 2015 Correspondence: Dr. Busra Burcu. Istanbul Medeniyet Univeristesi, Goztepe Egitim ve Arastirma Hastanesi, Genel Cerrahi Anabilim Dali, Istanbul, Turkey. Tel: +90 216 - 570 91 85 e-mail: b_kargo_b@hotmail.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


Burcu et al., Acute appendicitis in pregnancy

examination findings, ineffective use of radiological methods can delay the diagnosis. Delayed cases confront us with higher rates of perforation. Rapid diagnosis, and surgery is a must for decreasing complication rates. In the past open appendectomy was performed beyond dispute, while in recent years laparoscopy is an alternative with accepted safety. In this paper we aimed to investigate our pregnant patients operated with the diagnosis of appendicitis in our clinic. MATERIALS AND METHODS A total of 21 pregnant women who underwent appendectomy with the initial diagnosis of acute appendicitis in Istanbul Medeniyet University Clinics of General Surgery between January 2012, and December 2014 were retrospectively analyzed. Data about patients’ ages, gestational weeks, complaints, physical examination findings, leukocyte counts, blood biochemistry, complete urinalysis, ultrasonographic findings, the surgical technique applied, type of surgical incision, postoperative complications, and duration of hospitalization were recorded. All patients received single prophylactic doses of ampicillin-sulbactam 1 gr. In two cases with surgical field infection, antibiotherapy was completed to seven days. Any tocolytic agent was not used in any patient. Results Median age of the patients was 23.9 years. At admission, the cases were in their first (n=12; 57.1%), second (n=5; 23.8%), and third trimesters (n=4; 19.0%) of their pregnancies. Median gestational week was 20.4 weeks. The patients were pregnant for the first (n=11;52.4%), second (n=5; 19.0%), third (n=4; 23.8%), and fifth (n=1; 4.8%) time. Their medical past was unremarkable excluding one patient with MTHFR (methylene tetrahydrofolate reductase) gene mutation, and abortion. All patients consulted with admission complaints of abdominal pain. On physical examination abdominal guarding (n=5; 23.8%) or rebound tenderness together with abdominal guarding (n=16; 76.2%) were observed. In one patient (4.8%) widespread abdominal tenderness was detected. At admission the patients complaints were loss of appetite (19.1%), nausea

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(52.3%), and vomiting (14.2%). Median WBC count was 13.297/mm³ (range, 9.200–18.500/ mm3). Complete urinalysis was unremarkable in only three patients (14.3%). While bacterial positivity (n=9; 42.9%), leucocyte esterase positivity (n=4; 19.0%), epithelial cells (n=4; 19.0%), and glucosuria (n=1; 4.8%) were detected in indicated number of patients. Biochemical parametres were within normal limits in 17 (81.0%) patients. While increased LDH levels (n=2; 9.5%), and hyperglycemia (n=2; 9.5%) were also detected. On abdominal ultrasound findings compatible with acute appendicitis were detected in 12 (57.1%) patients. In only one patient (4.8%). magnetic resonance imaging was used which demonstrated findings consistent with appendicitis. One patient underwent spinal anesthesia, and 20 patients received general anesthesia. Any complication was not detected in the patient (4.8%) who received spinal anesthesia. In 14 (66.6%) patients McBurney incision, and in 6 (28.6%) cases right paramedian incision were used. One patient (4.8%) underwent laparoscopic appendectomy. During the postoperative period, none of the patients received any tocolytic agent. Histopathological evaluation of all the (100%) cases were compatible with acute appendicitis. Negative appendectomy was not detected. Median hospital stay was 3.8 days (range: 2–8 days). During postoperative period surgical site infection was developed in two (9.5%) patients. Two cases with perforrated appendicitis which contained abscess material. In both cases preoperative white blood cell counts were higher than 16.000/mm3 which was compatible with the literature findings. Medical history of the patient who underwent laparoscopic appendectomy was unremarkable. Preoperative white blood cell count was 12.050/mm3. On histopathological examination phlegmonous appendicitis was detected. Postoperative period was uneventful, and the patients were discharged within 4 days. Fetomaternal mortality was not detected. Discussion The most frequently nonobstetrical indication of emergency surgery is acute appendicitis. It is seen nearly one out of 1700 pregnants [3]. As a result of changing physiological, and anatomical parameters, its diagnosis is delayed with resultant maternofetal risks.


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Twenty-five to thirty percent of pregnants who undergo surgical treatment with the presumed indication of acute abdomen are eventually diagnosed as acute appendicitis [4]. However, the incidence of acute appendicitis is similar to that seen in normal population [5]. It is seen most frequently during the second decade of life [6]. In many studies, its occurence is frequently reported during the 2. trimester. Kim et al. indicated that it is more frequenly seen in the first trimester, while according to Cho et al. it is more often observed during the 3. trimester. Finally Lee et al. reported that any difference between trimesters as for incidence rates was not seen [6]. In our daily practice we observed acute appendicitis more frequently during the second trimester. In a study encompasing 908 pregnant women, increased fetal risks have been reported for pregnants with acute appendicitis relative to those healthy ones. These risks include SGA (small for gestational age: babies whose birth weight lies below the 10th percentile for that gestational age), lowbirth weight), preterm labour, and major congenital anomalies). Congenital anomalies were only seen in pregnants during their first trimester. However SGA, and LBW have been found to be associated with increased infant mortality [3]. Fetal mortality is 1.5% in the presence of uncomplicated appendicitis, while it increases to 37% in cases with perforation [1]. In general population incidence of perforation is 19%, while it can increase up to 43 percent [2]. Delay for more than 24 hours increases the risk of perforation for more than 66 percent [1]. Enlarging uterus prevents movement of omentum towards the area of inflammation which may be considered as the causative factor for perforation. [7]. Early diagnosis, and surgical intervention will decrease mortality rate [8]. It should not be forgotten that there is no difference between negative laparotomy, and appendectomy performed during the early stage of pregnancy as for preterm labour [4]. In this study, negative appendectomy was not detected, and preterm labour and /or mortality were/was not detected in all cases including those with perforation. In acute appendicitis, typically pain starting from the periumbilical area and settling in the lower right quadrant is pathognomic. During pregnancy, conventional signs, and symptoms of appendicitis may not be seen. In 1932 Baer et al. demonstrated

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upward displacement of appendix following 3. gestational week [9]. This shift in the position of appendix may relieve irritation of parietal peritoneum. The pain may settle in the right middle or upper quadrant. Although guarding, and rebound tenderness are seen in 70% of the patients, they are not sine qua non findings in the pregnant women due to relaxation of abdominal muscles [7]. Alvarado scoring system or like can not be used in pregnants. Physiologically nausea, vomiting, and loss of appetite can be seen in pregnant women. Abdominal tenderness is the most frequently seen, and the most reliable diagnostic sign [6]. In this study, most frequently, complaints of abdominal pain were detected. Although nausea, and loss of appetite were anticipated findings, they were not seen at a higher rate. Contrary to the literature findings, on physical examination we mostly encountered abdominal guarding. Leucocytosis is harmful during pregnancy. In normal pregnancy white blood cell count is around 12.000 /mm3 which increases in number as the pregnancy progresses. It may also increase up to 30.000 mm3 during delivery. Kim et al. indicated that WBC count higher than 16.000 /mm3 should raise the suspicion of perforation [6]. However, increase in the number of neutrophil counts, and its shift to left aid in diagnosis [4]. In our cases median WBC count was 13.297/mm3. In perforated cases it was higher than 16.000 /mm3 as indicated before. Owing to its easy applicability, and reproducibility, ultrasound is an indispensable diagnostic tool. Inability to compress uterus because of enlarging uterus, obesity, intestinal gas, and its operator dependency are disadvantages of US. It has a 36â&#x20AC;&#x201C;100% sensitivity, and 33â&#x20AC;&#x201C;99% specificity [1]. Magnetic resonance imaging (MRI) which can be used safely in pregnants has a higher sensitivity, and specificity. In many studies, it has been reported that MR which can visualize appendix has a 100% negative predictive value [1]. In an article which investigated diagnostic accuracy of MRI, rates of negative appendectomy, and perforation were indicated as 0, and 8%, respectively [3]. In cases where US does not yield net results, MR is a gold standard [10]. Computed-tomography strikingly protect normal population from undergoing negative appendectomies. In a study encompassing pregnants com-


Burcu et al., Acute appendicitis in pregnancy

bined use of US, and CT resulted in minimal rates of negative appendectomy [3]. However radiation exposure carries risk for fetus, and it can be used in selected patients [11]. We observed that US aided in diagnosis in 57.1% of the cases. MR was used in only one case, and it yielded accurate results In suspect cases we think that use of MR will increase the rate of accurate diagnosis, and decrease the incidence of perforation. Recurrence rate of appendicitis treated with medical therapy is 30 percent [3]. Limited number of pregnant cases have been conservatively observed as reported in the literature. This approach has been seen to increase maternal morbidity, and fetal loss [2]. Conventional or laparoscopic appendectomy is applied. In the past debates about laparoscopy were entertained. Recent reports have indicated that it does not increase the risk for preterm labour, miscarriage, maternal complications when compared with conventional appendectomy [5]. Laparoscopic appendectomy has many advantages in addition to decreasing wound site infections which encounter us more frequently [6]. Intraabdominal access using Hasson technique, and laparoscopic procedure under 10–12 mm Hg insufflation pressure provided that it lasts less than 30 minutes are among recommended techniques. In this study we performed laparoscopic appendectomy on only one patient, and observed that it did not increase complication rates, and hospitalization period. We think that surgeons experienced in laparoscopy should not refrain from performing laparoscopy with the intention to be more careful in pregnant patients, and it will be a standard procedure with time. Besides, its safety of use in all three trimesters has been acknowledged [3]. In conclusion, absence of typical signs, and symptoms of appendicitis, and clinicians ‘ predisposition to conservative approach can cause delay in treatment. To curtail perforation, and increased complications, abdominal pain in pregnants should be carefully investigated. With its cost-effectiveness, and easy applicability, US is the primary imaging modality. In cases of inadequacy, MR is the predominant radiological technique. If diagnosis of acute appendicitis is made, emergency surgi-

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cal treatment is rapidly applied. Laparoscopy has some advantages as decreased postoperative pain, and wound infection. It also allows the chance of diagnosis without increasing the rate of complications. 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.B.; Design - Ö.E.; Supervision - O.A.; Funding - T.A.; Materials - T.T.E., K.O.; Data Collection - B.B., K.O.; Analysis - Ö.E.; Literature search - B.B., T.A.; Writing - B.B., T.A.; Critical review - O.A., T.T.E.

REFERENCES 1. Thompson MM, Kudla AU, Chisholm CB. Appendicitis during pregnancy with a normal MRI. West J Emerg Med 2014;15:652–4. 2. Cheng HT, Wang YC, Lo HC, Su LT, Soh KS, Tzeng CW, et al. Laparoscopic appendectomy versus open appendectomy in pregnancy: a population-based analysis of maternal outcome. Surg Endosc 2015;29:1394–9. 3. Flexer SM, Tabib N, Peter MB. Suspected appendicitis in pregnancy. Surgeon 2014;12:82–6. 4. Gezginç K, Korkmaz T. The Causes and Treatment of Nonobstetric Acute Abdomen in Pregnancy. Selçuk Medical Journal 2013;29:192–9. 5. Chung JC, Cho GS, Shin EJ, Kim HC, Song OP. Clinical outcomes compared between laparoscopic and open appendectomy in pregnant women. Can J Surg 2013;56:341–6. 6. Jung SJ, Lee do K, Kim JH, Kong PS, Kim KH, Bae SW. Appendicitis during Pregnancy: The Clinical Experience of a Secondary Hospital. J Korean Soc Coloproctol 2012;28:152–9. 7. Çil AP, Dağ ZÖ, Pekcan MK, Akarsu M. Acute appendicitis mimicking labor. Kırıkkale University Faculty of Medicine Journal 2012;14. 8. Eryilmaz R, Sahin M, Baş G, Alimoglu O, Kaya B. Acute appendicitis during pregnancy. Dig Surg 2002;19:40–4. 9. Baer JL, Reis RA, Arens RA. Appendicitis in pregnancy. J Am Med Assoc 1932;98:1359–64. 10. Dietrich A, Nicolas M, Iniesta J, Smith DE. Empyema and lung abscess as complication of a perforated appendicitis in a pregnant woman. Int J Surg Case Rep 2012;3:622–4. 11. Yağcı MA, Sezer A, Hatipoğlu AR, Coşkun İ, Hoşcoşkun Z. Acute appendicitis in pregnancy. Dicle Medical Journal 2010;37:134–9.


CASE REPORT

cardıology

North Clin Istanbul 2016;3(1):64–6 doi: 10.14744/nci.2015.10337

A patient presenting with acute heart failure: A dilemma of diagnosis Adnan Kaya, Berat Arikan Aydin, Ahmet Oz, Emrah Bozbeyoglu, Mehmet Eren Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Center, Istanbul, Turkey

ABSTRACT Acute dyspnea is a major complaint of patients admitted to cardiology and emergency departments (ED). Acute dyspnea can be life-threatening, and is seen in cases of asthma, pulmonary embolism, acute heart failure and myocardial infarction. The present case is that of a 32-year-old man admitted to the ED with orthopnea position and agitation. Physical examination, electrocardiogram (ECG), transthoracic echocardiogram (TTE), contrastenhanced computed tomography (CECT) of thorax and coronary angiography (CAG) helped to rule out chest disease pathologies such as pneuomo-thorax, pulmonary embolism and coronary artery disease, but were not enough to make an appropriate diagnosis in this case. Because of high pretest probability of aortic dissection, transesophageal echocardiography (TEE) was performed and a diagnosis of Stanford type A dissection closing left main coronary artery (LMCA) ostia from beat to beat was made. Keywords: CT angiography; misdiagnosis; transesophageal echocardiography; type A aortic dissection.

D

yspnea, or breathing difficulty, is one of the cardinal symptoms of cardiac and pulmonary diseases [1]. Most ED dyspnea attack admissions are due to systolic or diastolic heart failure. The specific reason for the sudden onset of dyspnea must be determined and appropriate treatment according to the etiology started as soon as possible. Aortic dissection is rare, and presentation of aortic dissection with dyspnea is even more infrequent. Aortic dissection is a life-threatening cardiovascular disorder in which the inner layer of aorta has ruptured, and for which early diagnosis is crucial for definitive surgical management and patient survival. As the

aorta is the main supplier of blood to organs and all of the body, a tear in the inner layer of the aorta causes false lumen to form, which could block the flow of blood through the true lumen and prevent distal organ perfusion. Primary symptom of dissection is an abrupt, tearing-like chest pain that radiates to thorax and abdomen. Dyspnea, pain in arms, weakness, and loss of consciousness are other symptoms. There are two classification systems for aortic dissection: Stanford type A refers to dissections occurring in the ascending aorta, while Stanford type B means dissections occurring in the descending aorta. The De Bakey classification uses De Bakey I

Received: 25.01.2015 Accepted: 19.08.2015 Online: 04.04.2016 Correspondence: Dr. Adnan KAYA. Suruc Devlet Hastanasi, Kardiyoloji Poliklinigi, 63800 Sanlıurfa, Istanbul, Turkey Tel: +90 262 648 19 83 e-mail: adnankaya@gmail.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


Kaya et al., A patient presenting with acute heart failure

for a dissection that starts from ascending aorta and includes the arc and descending aorta, De Bakey II is a dissection in the ascending aorta and the arc, and De Bakey III dissections involve the descending aorta. Computed tomographic (CT) angiography has very high sensitivity and specificity for diagnosing acute aortic dissection. Patients with vascular Ehlers-Danlos syndrome, Marfan syndrome, bicuspid aortic valve and Loeys-Dietz syndrome are known to have a greater risk of aortic dissection. The present case is that of a 32-year-old man admitted to the hospital with pulmonary edema and aortic dissection. CASE REPORT A 32-year male patient presented to the ED with severe dyspnea and agitation at 2:00 a.m. The patient was placed in orthopnea position and oxygen was administered. Blood pressure was 165/50 mmHg, heart rate was 113 bpm, body temperature was 36.5 °C, 25 breaths of respiratory rate per minute and oxygen saturation with pulse oximetry was 78% with nasal cannula. Physical examination revealed rales as far as upper zones of both of lungs and at base of heart, and a diastolic grade 2/6 murmur of aortic regurgitation was heard. There was no pulse deficit of peripheral pulses. Medical history included hypertension treated with angiotensin receptor blocker (ARB) and smoking habit. No recorded pulmonary disease, coronary artery disease or valvular disease was present. Electrocardiography (ECG) showed sinus tachycardia with T-wave inversion in leads DI and VL. The working diagnosis was pulmonary edema, and use of bronchodilator inhaler was initiated, as well as intravenous nitrates and intravenous diuretic therapy. While taking arterial blood gas sample, patientâ&#x20AC;&#x2122;s condition deteriorated and abdominal respiration pattern became obvious. Elective tracheal intubation of patient was performed, and patient was admitted to coronary intensive care unit (CICU) with pulmonary edema and possible acute valvular insufficiency. Transthoracic echocardiogram (TTE) showed mild to moderate aortic regurgitation with 3.3 cm of sinus of Valsalva. No sign of flap in ascending aorta was present. There

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was no pericardial effusion. Systolic function of ventricle was normal and left ventricular (LV) cavity widened to 5.1 cm at end-diastolic volume. Arterial blood gas before intubation showed hypoxia with 76% arterial oxygen saturation and hypocarbia with metabolic acidosis of 7.13 Ph. Contrast-enhanced computed tomography (CECT) of thorax was used to refine the diagnosis. As a team, the cardiologist, the cardiovascular surgeon, and the radiologist checked the computed tomography (CT) images. Sinus of Valsalva was 3.5 cm and no flap was found in ascending or descending aortas. Pulmonary embolism was also ruled out with CT scan. As lab test results showed coronary ischemia with positive troponin I levels (1.016 ng/dL), it was decided that a diagnostic coronary angiography (CAG) would be performed. In the catheterization laboratory, intubation of right coronary artery (RCA) and left main coronary artery (LMCA) was difficult, and the test required 1 hour to complete. Surprisingly, the CAG revealed normal coronary arteries. Pulmonary embolism and coronary artery disease as cause of acute dyspnea were ruled out, but the cause of dissection of aorta was still unclear because of possibility of a false negative CT scan. Transesophageal echocardiography (TEE) was selected as the next diagnostic tool due to high pretest probability of aortic dissection. TEE showed a Stanford type A dissection flap closing LMCA ostia from beat to beat and compromising the aortic valve with moderate aortic regurgitation. Determining the appropriate diagnosis for acute heart failure was very challenging, but at 6.00 a.m., surgery to correct a Stanford type A dissection localized in the valve and coronary ostia was performed. Upon further careful review of CT scan images, a very tiny flap was observed at the ostium of LMCA (Figure 1). DISCUSSION Acute aortic dissection is a life-threatening medical emergency that can quickly lead to death. Incidence is estimated to be 3 in a 1000 cases according to International Registry of Aortic Dissection (IRAD). If left untreated, 33% of individuals will die within 24 hours of presentation, and 50% die in


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Figure 1. Transverse cut view of contrast enhenced enhanced computed tomography shows a tiny flap at the ostium of LMCA that was initially misdiagnosed.

the initial 48 hours [2]. Although diagnostic tests have improved, the condition remains undiagnosed in about half of patients because of variable symptoms and negative laboratory tests. After first admission tests of physical examination, vital signs, and electrocardiogram (ECG); the most frequently performed tests to diagnose aortic dissection are CT, TEE and magnetic resonance imaging (MRI). A recent meta-analysis by Shiga et al. [3] reviewed published studies of diagnosis of aortic dissection by TEE, helical CT and MRI showed that these tests have equal and reliable diagnostic value. TEE had 99% sensitivity and 95% specificity, helical CT had 100% sensitivity and 98% specificity, and MRI had 98% sensitivity and 98% specificity [4, 5]. In the present case, first admission physical examination and laboratory tests were supportive of aortic dissection. After a misdiagnosis was made by the radiologist, the cardiologist, and the surgeon based on CT of chest, CAG was performed to clarify coronary ischemia, which is contraindicated in aortic dissection. Correct diagnosis of aortic dissection was made with TEE, and the patient was taken to surgery. Further examination of CT scan images then revealed a tiny flap at the ostium of LMCA (Figure 1). Aortic dissection may occur in a small part of aorta and not be seen in CT scan or labora-

tory test results. If suspicion of aortic dissection is high, diagnosis can be made with TTE and TEE in intensive care units (ICUs). Dyspnea is the major symptom of acute heart failure and an etiologic assessment must be made for every patient who presents with acute dyspnea. In the present case, aortic dissection compromised aortic valve and coronary ostium, increasing left ventricle end-diastolic pressure, which led to pulmonary edema and acute dyspnea. In episodes of acute dyspnea, aortic dissection must be kept in mind as a differential diagnosis. Though a diagnostic tool like CT scan may have 100% sensitivity and 98% specificity, it may also contribute to a misdiagnosed aortic dissection. If high pretest probability is present and CT scan does not support the diagnosis, TEE and MRI may be used next to determine the correct diagnosis. 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.K., A.O., B.A.A., M.E., E.B.; Design - Supervision - Funding - Materials - M.E., E.B., B.A.A., A.O.; Analysis and/or interpretation – A.K., A.O.; Literature search - M.E., E.B.; Writing - Critical review - A.K.

REFERENCES 1. Topol EJ, Califf RM. Textbook of cardiovascular medicine. Lippincott 2007. 2. Williams & Wilkins.pg-189. 3. Wiesenfarth JM. Dissection, Aorta. Emedicine 2005. 4. Shiga T, Wajima Z, Apfel CC, Inoue T, Ohe Y. Diagnostic accuracy of transesophageal echocardiography, helical computed tomography, and magnetic resonance imaging for suspected thoracic aortic dissection: systematic review and meta-analysis. Arch Intern Med 2006;166:1350–6. 5. Nienaber CA, Fattori R, Lund G, Dieckmann C, Wolf W, von Kodolitsch Y, et al. Nonsurgical reconstruction of thoracic aortic dissection by stent-graft placement. N Engl J Med 1999;340:1539–45. 6. Fleming C, Whitlock EP, Beil TL, Lederle FA. Screening for abdominal aortic aneurysm: a best-evidence systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2005;142:203–11.


CASE REPORT

pathology

North Clin Istanbul 2016;3(1):67–70 doi: 10.14744/nci.2015.47965

Pleomorphic adenoma of the larynx Meryem Doğan Altunpulluk,1 Murat Hakan Karabulut,1 Gözde Kır,1 Şamil Şahin2 Department of Pathology, Umraniye Education and Research Hospital, Istanbul, Turkey

1

Department of Otolaryngology Umraniye Education and Research Hospital, Istanbul, Turkey

2

ABSTRACT Pleomorphic adenoma (PA) is the most common benign neoplasm of the salivary glands. It usually occurs in major salivary glands, such as the parotid and submandibular glands. Occasionally, however, it occurs in the larynx. These lesions generally present as a slow-growing, painless mass. Malignant transformation is very rare, but it increases with time. The present report is the case of a 59-year-old male who presented with a complaint of hoarseness. Right vertical partial hemilaryngectomy revealed an intact, mucosa-covered, fleshy 2×1.5×1 cm mass in the supraglottic area of the larynx. Lesion had histological characteristics of a PA, and this was confirmed by immunohistochemical expression of cytokeratin, S100 protein, Glial fibrillary acidic protein (GFAP) and vimentin. Their histopathological identification is, however, not always straightforward; immunohistochemistry can contribute significantly to formulation of a definitive diagnosis and to the realization of appropriate follow-up. Keywords: Immunohistochemistry; larynx; pleomorphic adenoma.

P

leomorphic adenoma (PA) is the most common salivary gland tumor and accounts for 60% of all salivary gland neoplasms [1]. About 80% of PAs arise in the parotid gland, 10% in the submandibular gland, and 10% in the minor salivary glands of the oral cavity, paranasal sinuses, and upper respiratory and alimentary tract [2]. Histologically, these tumors are encapsulated and consist of epithelial (or myoepithelial) and stromal elements. Epithelial component may form a variety of structures, including tubules, ductules, or trabeculae, and the stromal component may also consist of a variety of forms, including mucoid,

myxoid, cartilaginous, and osseous elements. PAs may also occur at other sites, including the breast and skin (chondroid syringoma). It is rarely found in the larynx [3]. This report presents a case of PA in the larynx with characteristic pathologic and clinical findings as a reminder of a common benign neoplasm occurring with rare locality. CASE REPORT A male patient aged 59 had a history of hoarseness. A right vertical hemilaryngectomy was performed. Tum or consisted of a firm, well-circumscribed,

Received: January 30, 2015 Accepted: June 15, 2016 Online: April 04, 2016 Correspondence: Dr. Meryem Dogan Altunpulluk. Umraniye Egitim ve Arastirma Hastanesi, Istanbul, Turkey Tel: +90 216 632 18 18 e-mail: dr.meryem@yahoo.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


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A

A

B

B

C

Figure 2. Immunohistochemistry

Figure 1. (A-B) Hematoxylin and eosin (H&E) stained section showing sheets of myoepithelial cells and ductular structures lined with epithelial cells set in chondromyxoid stroma (H&E, A: ×40; B: ×100). (C) Adjacent to the lesion, normal laryngeal cartilage can be seen (H&E, ×100).

indicates that the myoepithelial cells cytoplasm is focally positive for S100 protein (A) and glial fibrillary acidic protein (GFAP) (B) (A: ×100; B: ×100).

ovoid piece of soft pink tissue measuring 2×1.5×1 cm in the supraglottic area of the larynx. Histologically, the mass showed a fibrous and chondromyxoid stroma containing epithelial and myoepithelial cells. Epithelial component consisted of relatively uniform-appearing cells arranged in tubules and small, nested aggregates (Figure 1). Results of immunohistochemical staining were consistent with PA. The epithelial component showed positivity for cytokeratin. Myoepithelial component was positive for p63, S100 protein (Figure 2A), and glial fibrillary acidic protein (GFAP) (Figure 2B); and focally positive smooth muscle actin (SMA).


Dogan Altunpulluk et al., Pleomorphic adenoma of the larynx

DISCUSSION PA is a commonly diagnosed benign tumor in the salivary glands that may also occur in a variety of other sites; however, it is rarely seen in the larynx. The diagnosis of PA is simple, but when it grows in an unusual site like the larynx, it can be mistaken for a malignant neoplasm. PAs are usually slow-growing, solitary, painless tumors. Histopathological confirmation is mandatory for these tumors. Pleomorphic adenomas are characterized by epithelial tissue mixed with tissues of myxoid, mucoid or chondroid appearance. Histologically, pleomorphic adenoma of the larynx may resemble aggressive epithelial tumors because of the high cellularity and lack of a stromal component. Importantly, this feature is not in keeping with that of major salivary glands, which demonstrate relatively reduced myoepithelial cellularity. Occasionally, pleomorphic adenomas are composed almost entirely of epithelial cells with few or no stromata. This can lead to misdiagnosis as carcinoma [4]. Immunohistochemically, the inner ductal cells are positive for cytokeratin. Myoepithelial cells are variably positive for S100 protein, SMA, GFAP, calponin, and CD10 [5]. Although PA is a benign tumor, it can cause problems in clinical management due to its tendency to recur and risk of malignant transformation. Histological features indicative of malignant transformation include cytological atypia, increased mitotic figures, satellite tumor nodules, tumor necrosis, and infiltrative margins7. PAs have tendency to recur when not widely excised, particularly if they are predominantly mucoid [6], and have variability in the thickness of the capsule and the tumor invading the capsule [7]. In addition, due to low biological requirements, the neoplastic cells can survive when spilt into the operative sites [5]. PAs should be differentially diagnosed from other tumors such as carcinoma ex pleomorphic adenoma, adenoid cystic carcinoma, basal cell carcinoma, basal cell adenoma, myoepithelioma, polymorphous low-grade adenocarcinoma, angiofibroma, hamartoma, epidermoid cyst, hemangioma, vascular malformations, nasopharyngeal carcinoma, and nonepithelial tumors.

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Carcinoma ex pleomorphic adenoma exhibits extensively infiltrative malignancy with necrosis, perineurial invasion, frequent mitotic figures, marked nuclear atypia. Adenoid cystic carcinoma usually shows cribriform, solid or tubular pattern similar to cylindromas of the skin. It is composed of small, bland myoepithelial cells with scant cytoplasm and dark, compact, angular nuclei that surround pseudoglandular spaces with periodic-acid Schiff (PAS)-positive excess basement membrane material and mucin. Peripheral perineurial invasion and small, true, glandular lumina are sometimes seen, but no squamous differentiation, and extensive necrosis is usually absent. Adenoid cystic carcinoma has high proliferative index, high p53 immunoreactivity, and intense staining for B-cell lymphoma 2 (BCL 2), but negative reactivity for glial fibrillary acidic protein. In contrast, pleomorphic adenoma is not invasive, shows no perineurial invasion and has squamous metaplasia and mesenchyme-like areas. Characteristically, pleomorphic adenoma has strong glial fibrillary acidic protein in the myxochondromatous areas [8]. Basal cell carcinoma is a lowgrade malignancy similar to basal cell adenoma. It is an infiltrative tumor with perineurial invasion and vascular invasion as well as variable cytologic atypia and mitotic activity. It is composed of solid, trabecular, tubular or membranous patterns, but no myxoid matrix or cartilagenous areas. Basal cell adenoma is composed of basaloid cells sharply delineated from the stroma by basement membrane. Polymorphous low-grade adenocarcinoma is usually a nonencapsulated tumor with diverse (polymorphous) growth patterns, infiltrative borders, perineurial invasion and tumor necrosis is rare [9,10]. Differential diagnosis of PA consists of myoepithelioma, a benign epithelial salivary gland tumor, and presence of plasmacytoid or spindled myoepithelial cells. Additionally, basal cell adenoma may also be involved in the differential diagnosis [11]. To conclude, pleomorphic adenoma of the larynx is a rare neoplasm and therefore its diagnosis requires a high index of suspicion. Complete wide surgical excision is the treatment of choice. Recurrence many years after surgical excision as well as malignant transformation should be a concern and


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therefore long-term follow-up is necessary. 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 - M.D.A; Design M.D.A; Data collection and/or processing - M.H.K.; Analysis and/or interpretation - M.D.A; Literature search - M.D.A.; Writing - M.D.A; Critical review - G.K., M.H.K.

REFERENCES 1. Spiro RH. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 1986;8:177–84. 2. Eveson JW, Cawson RA. Salivary gland tumours. A review of 2410 cases with particular reference to histological types, site, age and sex distribution. J Pathol 1985;146:51–8. 3. Ordóñez NG, Manning JT, Luna MA. Mixed tumor of the vulva: a report of two cases probably arising in Bartholin’s gland. Cancer 1981;48:181–6. 4. Compagno J, Wong RT. Intranasal mixed tumors (pleomorphic adenomas): a clinicopathologic study of 40 cases. Am J Clin Pathol 1977;68:213–8. 5. Eveson JW, Kusafuka K, Stenman G, Nagao T. Pleomorphic

North Clin Istanbul – NCI adenoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. Pathology & Genetics, Head and Neck Tumours. 1st ed. Lyon: IARC Press; 2005. p. 254–9. 6. Renehan A, Gleave EN, Hancock BD, Smith P, McGurk M. Long-term follow-up of over 1000 patients with salivary gland tumours treated in a single centre. Br J Surg 1996;83:1750–4. 7. Henriksson G, Westrin KM, Carlsöö B, Silfverswärd C. Recurrent primary pleomorphic adenomas of salivary gland origin: intrasurgical rupture, histopathologic features, and pseudopodia. Cancer 1998;82:617–20. 8. Cerulli G, Renzi G, Perugini M, Becelli R. Differential diagnosis between adenoid cystic carcinoma and pleomorphic adenoma of the minor salivary glands of palate. J Craniofac Surg 2004;15:1056–60. 9. van Heerden WF, Raubenheimer EJ. Intraoral salivary gland neoplasms: a retrospective study of seventy cases in an African population. Oral Surg Oral Med Oral Pathol 1991;71:579–82. 10. Harada H. Histomorphological investigation regarding to malignant transformation of pleomorphic adenoma (so-called malignant mixed tumor) of the salivary gland origin: special reference to carcinosarcoma. Kurume Med J 2000;47:307–23. 11. Torske K. Benign neoplasms of the salivary glands. In: Thompson LDR, Goldblum JR. eds. Head and Neck Pathology (Foundations of Diagnostic Pathology). 1st ed. Philadelphia, PA: Elsevier’s Health Sciences, Churchill Livingstone 2006:295–320.


CASE REPORT

neurology

North Clin Istanbul 2016;3(1):71-4 doi: 10.14744/nci.2015.47966

Fahr’s syndrome presenting with epileptic seizure: Two case reports Nedim Ongun,1 Eylem Degirmenci,2 Cagdas Erdogan2 Department of Neurology, Denizli State Hospital, Denizli, Turkey

1

Department of Neurology, Pamukkale University Hospital, Denizli, Turkey

2

ABSTRACT Fahr’s syndrome is a neuropsychiatric syndrome characterized by symmetrical and bilateral intracerebral calcifications located in the basal ganglia and usually associated with a phosphorus and calcium metabolism disorder. Clinical manifestations of Fahr’s syndrome vary; it may start at different ages and have a variety of presentations. This article discusses rare presentation of Fahr’s syndrome with epileptic seizure. These cases are important because they appear to be the first cases in the literature of Fahr’s syndrome presenting with generalized tonic clonic seizure. Keywords: Epilepsy; Fahr’s syndrome; intracerebral calcification.

E

xtensive cerebral calcification may occur idiopathically as Fahr’s syndrome, or may arise from secondary metabolic disorders, such as hypoparathyroidism. Fahr’s syndrome is a neuropsychiatric syndrome characterized by symmetrical and bilateral intracerebral calcifications located in the basal ganglia and usually associated with a phosphorus and calcium metabolism disorder. Fahr’s syndrome or Striato-pallido-dentate calcification (SPDC) is a well-defined entity with familial or sporadic presentation and approximately two-thirds of patients are symptomatic. It may clinically present with an array of movement disorders, dementia, epileptic seizures, various degrees of neuropsychological impairment and behavioral disturbances [1].

The present report is of rare presentation of epileptic seizure in 2 patients with Fahr’s syndrome. CASE REPORT Case 1– A 52-year-old male was examined in the clinic on first generalized tonic clonic seizure. His neurological examination was normal. He was hospitalized and evaluated for differential diagnosis of epileptic seizure. Blood tests were normal, except decreased levels of parathormone (6.46 pg/ mL [Range: 15-65 pg/mL] and calcium (5.7 mg/ dL [Range: 8.6-10.2 mg/dL]). Medical history included subtotal thyroidectomy 20 years prior. He was not taking any medication, and there was no

Received: July 26, 2014 Accepted: June 18, 2015 Online: May 01, 2016 Correspondence: Dr. Nedim ONGUN. Denizli Devlet Hastanesi Noroloji Klinigi Denizli, Turkey. Tel: +90 258 263 93 11 e-mail: nedimongun15@yahoo.com © Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


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North Clin Istanbul â&#x20AC;&#x201C; NCI

bilateral calcification of basal ganglia (Figure 1). His electroencephalographic (EEG) examination was normal. It was his first and last seizure. Clinical evaluation was acute symptomatic seizure. No antiepileptic treatment was recommended and underlying situation was medicated by endocrinologists.

Figure 1. Brain computerized tomography: Extensive, bilateral calcification of basal ganglia. family history of dementia, movement disorder or other neurological illness. His brain computerized tomography (CT) scans demonstrated extensive,

Case 2â&#x20AC;&#x201C; A 56-year-old male who had his first epileptic seizure, a generalized tonic clonic motor seizure, was referred to the hospital. Blood tests were in normal range, except decreased vitamin D level (12 ug/L [Range: 20-120 ug/L]). There was no patient medical history or family history of neurological illness. His CT scans demonstrated bilateral calcification of basal ganglia and cerebellum (Figure 2). His EEG examination showed left frontal epileptiform activity. Though it was patientâ&#x20AC;&#x2122;s first seizure, sodium valproat was prescribed for 6 months in addition to vitamin D replacement treatment because of the EEG abnormality and no further seizure was seen after treatment.

Figure 2. Brain computerized tomography: Bilateral calcification of basal ganglia and cerebellum.


Ongun et al., Fahr’s syndrome presenting with epileptic seizure

Discussion In the literature, varying manifestations of Fahr’s syndrome are described as memory disturbance, hallucination, delusions, personality change, and depression [2]; motor and phonic tics, stereotyped behaviors [3]; and extrapyramidal signs, such as Parkinsonism and paroxysmal nonkinesigenic dyskinesia [4]. Hoque et al. [5] described a case of Fahr’s disease that presented with complex partial seizure and behavioral abnormalities. Several families with basal ganglia calcification, representing a heterogeneous group of disorders with variable inheritance, have been described [6]. Fahr’s syndrome is typically inherited. In Case 1, the cause of the intracranial calcification is abnormal calcium metabolism due to iatrogenic hypoparathyroidism. This case is a typical example of secondary Fahr’s syndrome. However, no phosphorus or calcium metabolism disorder, with the exception of decreased vitamin D level, was found in Case 2. Since just decreased vitamin D level could not be the cause of intracerebral calcification, Case 2 was diagnosed as primary Fahr’s syndrome. It was notable that no family history of neurological disease or psychiatric, demential or extrapiramidal signs were found in neurological examination of Case 2. It is possible that others with Fahr’s syndrome in this patient’s family are asymptomatic. The cause of seizure in Case 1 seems to be hypocalcaemia due to iatrogenic hypoparathyroidism. In addition, another theory of pathogenesis in these patients may be a dysfunction of cortico-basal connections and their interhemispheric relationship. In Case 2, no pathological cause was found for acute symptomatic seizure. The term “Fahr’s disease” has been used to describe a characteristic pathological pattern of nonarteriosclerotic vascular calcification of the striopallidodentate system bilaterally, with variable deposition of ferro-calcareous concretions in cortical sulci, thalamus, cerebral white matter, and cerebellum [7]. It is a misnomer, as Fahr’s original case was a rare example of hypoparathyroidism associated with calcification in the media of larger vessels in the cerebral white matter, without basal

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ganglia calcification. Basal ganglia calcification may be categorized as idiopathic versus symptomatic (especially of parathyroid insufficiency), or sporadic versus familial. Prevalence of certain common neurological disorders, including dementia, stroke, and epilepsy, is similar in patients with incidentally discovered basal ganglia calcification and in agematched controls [8]. However, the relative prevalence of extrapyramidal disorders is contentious. Forty-two patients with incidentally discovered radiological basal ganglia calcification in the series of Harrington et al. [9], and 33 cases reported by Vles et al. [10], had no clinical evidence of basal ganglia disorder. Murphy [11] found basal ganglia calcification in 53 of 7081 consecutive CT scans. In patients over 50 years of age, it was associated with clinical signs of basal ganglia dysfunction (Parkinsonism) in only 3 patients. In a series of 42 cases of basal ganglia calcification revealed on CT (performed for “various reasons”), Puvanendran et al. [12] found a single patient with Parkinsonism (right-sided tremor and rigidity) associated with dementia. Most of reported families with basal ganglia calcification do not display clinical evidence of basal ganglia disease. The clinical feature of epileptic seizure in present cases was not typical for basal ganglia calcifications, whereas radiological appearances were those of Fahr’s syndrome. In conclusion, Fahr’s syndrome clinical manifestations can vary. It may begin at different ages and have a variety of presentations. The present cases are important because it would appear that there is no case in the literature of Fahr’s disease presenting with generalized tonic clonic seizure. The seizures in such patients may be due to calcium metabolism abnormities and/or dysfunction of cortico-basal connections and their interhemispheric relationship. 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: Data collection and/or processing - N.O.; Interpretation - E.D., C.E.; Literature search - N.O.; Writing - N.O.; Critical review - C.E.


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REFERENCES 1. Ashtari F, Fatehi F. Fahr’s disease: variable presentations in a family. Neurol Sci 2010;31:665–7. 2. Modrego PJ, Mojonero J, Serrano M, Fayed N. Fahr’s syndrome presenting with pure and progressive presenile dementia. Neurol Sci 2005;26:367–9. 3. Kummer A, de Castro M, Caramelli P, Cardoso F, Teixeira AL. Severe behavioral changes in a patient with Fahr’s disease. Arq Neuropsiquiatr 2006;64:645–9. 4. Oliveira JR, Spiteri E, Sobrido MJ, Hopfer S, Klepper J, Voit T, et al. Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease). Neurology 2004;63:2165–7. 5. Hoque MA, Siddiqui MR, Arafat Y, Khan SU, Rahman KM, Mondol BA, Mohammad QD. Fahr’s disease: a very rare cause of epilepsy. Mymensingh Med J 2010;19:27-9. 6. Manyam BV, Walters AS, Narla KR. Bilateral striopallidodentate calcinosis: clinical characteristics of patients seen in a regis-

North Clin Istanbul – NCI try. Mov Disord 2001;16:258–64. 7. Klein C, Vieregge P. Fahr’s disease: far from a disease. Mov Disord 1998;13:620–1. 8. Forstl H, Krumm B, Eden S, Kohlmeyer K. Neurological disorders in 166 patients with basal ganglia calcification: a statistical evaluation. J Neurol 1992;239:36–8. 9. Harrington MG, MacPherson P, McIntosh WB, Allam B, Bone I. The significance of the incidental finding of basal ganglia calcification on computed tomography. J Neurol Neurosurg Psychiatry 1981;44:1168–70. 10. Vles JSH, Lodder J, Van der Lugi PJM. Clinical significance of basal ganglia calcifications detected by CT (a retrospective study of 33 cases). Clin Neurol Neurosurg 1981;83:253–6. 11. Murphy MJ. Clinical correlations of CT scan-detected calcifications of the basal ganglia. Ann Neurol 1979;6:507–11. 12. Puvanendran K, Low CH, Boey HK, Tan KP. Basal ganglia calcification on computer tomographic scan: a clinical and radiological correlation. Acta Neurol Scand 1982;66:309–15.


CASE REPORT

neurology

North Clin Istanbul 2016;3(1):75-8 doi: 10.14744/nci.2015.26349

A rare cause of intestinal obstruction in a newborn: Congenital band compression Emrah Aydin Bahcelievler State Hospital, Istanbul, Turkey

ABSTRACT Congenital band compression syndrome should be considered in cases diagnosed prenatally or postnatally as intestinal obstruction. Presently described is a report of newborn admitted to hospital with abdominal distension and bilious vomiting. A suspected intestinal obstruction had been diagnosed in prenatal examination. Surgery revealed congenital band compressing ileal segments and preventing transmission of intestinal content. Band was successfully removed and intestinal integrity is intact. Keywords: Congenital band compression; intestinal obstruction; newborn.

C

ongenital band compression is one cause of intestinal obstruction. It is a pathology usually encountered during childhood. Preoperative diagnosis is challenging [1]. Bands are considered remnants of fetal vessels and ventral mesenterium that are ordinarily resorbed [1]. The present case is a report of a patient with congenital simple band compression. Due to suspicion of intestinal obstruction observed prenatally, and because of inability to demonstrate intestinal continuum during postnatal period, surgery was performed. CASE REPORT A newborn girl with birth weight of 2440 gr who was born via vaginal route to a healthy, gravida 1, para 1 mother at 37 weeksâ&#x20AC;&#x2122; gestation was admitted

to clinic with vomiting and abdominal distension. On physical examination, metallic bowel sounds were heard, abdominal distension was observed, and patient had not yet defecated. Bilious discharge was detected emerging from nasogastric tube. Rectal irrigation did not elicit a defecation response. Blood gas and biochemical values were within normal limits. Upright, plain abdominal radiographs revealed small air-fluid levels and passage of gas to distal area (Figure 1). Whole abdominal ultrasound did not reveal any intra-abdominal mass lesion. Radiographs obtained after rectal administration of contrast material showed unused large bowel (Figure 2). Radiograms obtained following oral intake of contrast material showed no passage of contrast material beyond ileal level, prompting decision to perform surgery. Surgical exploration disclosed con-

Received: 30.01.2015 Accepted: 15.06.2015 Online: 07.05.2016 Correspondence: Dr. Emrah AYDIN. Kocasinan Merkez Mah., Karadeniz Cad., No:48 Bahcelievler, Istanbul Turkey. Tel: +90 212 496 70 00 e-mail: dremrahaydin@yahoo.com Š Copyright 2015 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


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North Clin Istanbul â&#x20AC;&#x201C; NCI

Figure 1. Upright, plain abdominal radiograph. genital band compression on ileal loops (Figure 3). Intestinal integrity and passage were intact and not disrupted by excision of band. No remnant of omphalomesenteric canal was found. On postoperative

Figure 3. Band compression.

Figure 2. Barium enema radiograph. forth day, patient was fed through nasogastric tube. On postoperative sixth day, patient was fed wholly through oral route. Patient was discharged on postoperative 10th day with oral intake and spontane-


Aydin, A rare cause of intestinal obstruction in a newborn

ous defecation. Patient follow-up continued and revealed no medical problem. DISCUSSION During neonatal period, intestinal obstruction requires emergency surgery. Causes of intestinal obstruction include duodenal, jejunal, ileal, and colonic atresia; volvulus; annular pancreas; or congenital bands. Cases other than congenital bands can be diagnosed during prenatal period, and pathologies secondary to congenital bands manifest themselves thereafter. Congenital bands can be in the form of omphalodiverticular, omphalomesenteric or mesodiverticular bands; simple bands with unknown origin have been also reported [2,6]. In the literature, 2 patients with congenital bands diagnosed at 8 days and 3 weeks of age, respectively, have been reported [7,8]. Both cases presented at hospital with vomiting and abdominal distension after they had been sent home following birth, and band compression due to Meckel diverticulum was found. In the present case, patient with suspected intestinal obstruction was examined, and surgery was performed with the same diagnosis. Unlike the literature, no remnant of omphalomesenteric canal was found; however, a band extending from mesenteric towards antimesenteric aspect of the ileum was seen. In the literature, vascular problems and band compression have been reported as possible causes of intestinal atresia [9]. In 1922, Davis and Poynter suggested that intestinal atresia stem from an intrauterine problem [10]. In 1955, Louw and Bernard asserted that occlusion of mesenteric vessels can result in atresia, and Nixon and Tawes reported cases of atresia that occurred following cases of volvulus [10]. Many theories have been proposed, but as yet none can be proven. Since congenital band compression resulted in symptoms during prenatal period in the present case, it may shed light on pathophysiology of intestinal atresia. Development of band compression during last stages of pregnancy may explain why intestinal atresia did not occur in this case. Some authors prefer minimally invasive approaches for patients with intestinal obstruction

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during childhood [8,11]. In those instances, pathology was related to Meckel diverticulum, and delayed referral was the issue. In the present case, patient was very young, initial diagnosis was made during prenatal period, and inability to demonstrate continuum of intestinal passage suggested atresia, leading to decision for open surgery. During neonatal period, though it may be rare, surgery based on indication of intestinal obstruction may reveal simple congenital band compression rather than atresia. It is treated by excising the band, and examining entire intestinal loop for concomitant presence of atresia. 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 - E.A.; Design - E.A.; Supervision - E.A.; Funding - E.A.; Materials - E.A.; Data collection and/or processing - E.A.; Analysis and/or interpretation - E.A.; Literature search - E.A.; Writing - E.A.; Critical review - E.A.

REFERENCES 1. Akgur FM, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Anomalous congenital bands causing intestinal obstruction in children. J Pediatr Surg 1992;27:471–3. 2. Maeda A, Yokoi S, Kunou T, Tsuboi S, Niinomi N, Horisawa M, et al. Intestinal obstruction in the terminal ileum caused by an anomalous congenital vascular band between the mesoappendix and the mesentery: report of a case. Surg Today 2004;34:793–5. 3. Adedeji OA, McAdam WA. Small bowel obstruction due to encapsulation and abnormal artery. Postgrad Med J 1994;70:132– 3. 4. Fujimoto T, Segawa O, Lane GJ, Esaki S, Miyano T. Laparoscopic surgery in newborn infants. Surg Endosc 1999;13:773-7. 5. Goyal MK, Bellah RD. Neonatal small bowel obstruction due to Meckel diverticulitis: Diagnosis by ultrasonography. J Ultrasound Med 1993;12:119-22. 6. 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. 7. Loh AHP, Prasad STR, Chew SH. Neonatal intestinal volvulus due to a persistent right vitelline artery. Pediatr Surg Int 2007;23:373–6. 8. Kandpal DK, Siddharth S, Balan S, Chowdhary SK. Intestinal obstruction in a premature baby: Endoscopic diagnosis and management by minimal access surgery. J Indian Assoc Pediatr Surg 2013;18:118-20.


78 9. Nayci A, Avlan D, Polat A, Aksoyek S. Ileal atresia associated with a congenital vascular band anomaly: observations on pathogenesis. Pediatr Surg Int 2003;19:742â&#x20AC;&#x201C;3. 10. Frischer JS, Azizkhan RG. Jejunoileal atresia and stenosis. In:

North Clin Istanbul â&#x20AC;&#x201C; NCI Coran AG, editors. Pediatric surgery. 2012; p. 1059-1071. 11. Li B, Chen WB, Wang SQ, Liu SL, Li L. Laparoscopy-assisted surgery for neonatal intestinal atresia and stenosis: A report of 35 cases. Pediatr Surg Int 2012;28:1225-8.


Invited Review

Dermatology

North Clin Istanbul 2016;3(1):79â&#x20AC;&#x201C;82 doi: 10.14744/nci.2016.16023

A brief summary of clinical types of psoriasis Gulbahar Sarac,1 Tuba Tulay Koca,2 Tolga Baglan3 Department of Dermatology, Malatya State Hospital, Malatya, Turkey

1

Department of Physical Medicine and Rehabilitation, Malatya State Hospital, Malatya, Turkey

2

Department of Cytopathology, Ankara Numune Research and Training Hospital, Ankara, Turkey

3

ABSTRACT Psoriasis is a chronic inflammatory dermatosis that is thought to onset as a result of T lymphocyte-mediated immunological response. Disease may manifest itself in different modalities with regard to clinical features and severity. Clinical type of psoriasis is an important element in determining the therapy regimen. This article reviews clinical types of psoriasis. Keywords: Clinic; psoriasis; therapy.

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rom clinical perspective, psoriasis can be seen as a wide spectrum of various skin manifestations At any given time, various forms can be present in an individual at the same time. All of the lesions have common characteristics, including erythema, thickening, and squamae. Although size of lesion can vary from a pinhead up to a diameter of 20 cm, borders of lesions are usually round, oval or polycyclic. Although it can affect any region, knees, elbows, lumbosacral region, scalp, and genital area are most frequently involved [1]. Psoriasis is clinically classified in 2 groups: pustular and non-pustular lesions. 1) Non-pustular psoriasis Psoriasis vulgaris (early and late onset) Guttate psoriasis Erythrodermic psoriasis

Palmoplantar psoriasis Psoriatic arthritis (PsA) Inverse psoriasis 2) Pustular psoriasis Generalized pustular psoriasis (von Zumbusch type) Impetigo herpetiformis Localized pustular psoriasis - Palmoplantar pustular psoriasis (Barber type) -Acrodermatitis continua of Hallopeau Psoriasis vulgaris The most frequently seen clinical form of psoriasis, Psoriasis vulgaris, constitutes nearly 90% of cases. Clinically it is observed as erythematous plaques with sharp boundaries and covered with pearles-

Received: November 27, 2015 Accepted: January 08, 2016 Online: June 14, 2016 Correspondence: Dr. Tuba Tulay Koca. Malatya Sehir Devlet Hastanesi, Beydagi Kampusu, Fiziksel Tip ve Rehabilitasyon Klinigi, Malatya, Turkey. Tel: +90 416 - 228 28 00 e-mail: tuba_baglan@yahoo.com Š Copyright 2016 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com


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cent squamae. Lesions demonstrate symmetric distribution, and they are most frequently localized on knees, elbows, scalp, and sacral region. Predilection for these lesions may be a result of traumatic incident [2, 3]. If the surface of psoriatic plaque is scraped with a blunt scalpel, squamae fall off as layers of white lamellae that exhibit coherence after removal, much like candle wax. This desquamation is sometimes referred to as “wax spot phenomenon.” It is a sign of parakeratotic hyperkeratosis. If psoriatic plaque is scraped further, a wet layer adhered to the lesion can be revealed. This is the last layer of the dermal papillae of the epidermis, and it is a pathognomonic sign of psoriasis, known as “last membrane phenomenon.” Further scraping of the plaque reveals erythematous background and bleeding foci with appearance of small red pinpoints known as “Auspitz sign,’’ signifying papillomatosis on tips of dermal papillae. Around healed psoriatic plaques, a hypopigmented macular ring can be observed, which is called “Woronoff ring” [2, 3, 4]. The pathogenesis of this ring has not been fully clarified; however, it is thought to be related to decreasing levels of prostaglandin in healing lesions [5]. Guttate psoriasis This type of psoriasis is frequently seen in children and young adults. Lesions onset suddenly with an appearance like small droplets, and less frequently as squamous psoriatic papules, generally manifesting after streptococcal infections. This form of psoriasis is most frequently associated with HLACw6 gene. Often antistreptolysin titers are elevated. With regression of the infection, lesions generally disappear spontaneously. Lesions are generally seen on the trunk, proximal part of extremities, face, and scalp. They generally regress within 3–4 months. Sometimes lesions enlarge and take the shape of psoriatic plaque [6]. Erythrodermic psoriasis Psoriatic lesions affect nearly 80% of the body surface in this generalized form of psoriasis. Predominantly erythematous lesions are seen, typical papules and plaques lose their characteristic features. Desquamation is not so distinct. In patients with erythrodermic psoriasis, hypothermia due to wide-

North Clin Istanbul – NCI

spread vasodilatation can be seen. Desquamation may also lead to protein loss and related systemic problems, such as edema of the lower extremities, and cardiac, hepatic, and renal failure, can occur. In addition, protective barrier of the skin is impaired, leading to potential development of systemic reactions. Most frequently, it develops as a complication of psoriasis vulgaris, or it can onset independently as erythrodermic psoriasis. Nail disorders may be very dramatic. Dermatopathic lymphadenopathy and severe pruritus may be observed. In a case of erythroderma, presence of small areas of intact skin should be evaluated for psoriatic erythroderma or ptyriasis rubra pilaris (PRP) erythroderma. There is no specific laboratory finding. There is substantial risk of cardiovascular shock or septic shock; therefore, these findings should be followed closely. It is a severe, potentially fatal, and treatment-resistant clinical picture [2, 3, 7]. Palmoplantar psoriasis Usually this type of psoriasis symmetrically involves palms of the hands and soles of the feet, and thenar regions are more frequently affected than hypothenar regions. Erythema is not always found, but when it exists it appears as a pinkish-yellow lesion. Squamae are the predominant lesions. Thick squamae may give appearance of keratoderma [8]. Phenomena are negative [7]. Psoriatic arthritis (PsA) General prevalence of PsA ranges between 0.02– 0.1%, while its prevalence varies between 5.4–7% among psoriatic patients. In cases with severe skin involvement, and particularly pustular psoriasis, prevalence of PsA rises to 30–40%. Uncomplicated psoriasis usually onsets in second or third decade of life, while prevalence of PsA increases at third decade. Average male:female ratio is 1:1 in PsA. In 75% of patients with PsA, psoriasis onsets before appearance of arthritic symptoms, while in 15% of cases, skin lesions are seen concurrently with arthritis. In 10% of patients, arthritis manifests before emergence of skin lesions [9]. In 80% of patients with arthropatic psoriasis, nail involvement is seen [10]. PsA can be seen in different clinical forms. Most often used are the classification criteria developed by Moll and Wright describing 5 subgroups [9]:


Sarac, A brief summary of clinical types of psoriasis

1) Classical PsA: It affects distal interphalangeal joints of the hands and feet and has an incidence of nearly 10%. Nail involvement is usually seen. 2) Asymmetric oligoarticular arthritis: It is the most characteristic form of joint involvement. In addition to major joints, such as knee joints, distal and proximal interphalangeal, metacarpophalangeal, and metatarsophalangeal joints are asymmetrically affected. It is seen in 11% of cases. It may lead to dactyly. 3) Symmetric poliarticular form: It resembles rheumatoid arthritis (RA). When compared to RA, distal interphalangeal joints are more frequently involved, and a tendency to bone ankylosis is observed in joints. In various studies, incidence has been demonstrated to range between 15–61%. 4) Arthritis mutilans: It is characterized by progressive osteolysis of phalangeal and metacarpal bones. It is frequently associated with sacroiliitis. This definition is generally used for hands; however, feet can also see similar involvement. 5) Spondylitic form: Isolated spondylitis is rarely seen (2–4%). Generally, it is associated with peripheral arthritis. This form resembles ankylosing spondylitis, and symmetric or asymmetric sacroiliac joint involvement is seen. Due to less severe joint ankylosis, it has a better prognosis than ankylosing spondylitis [9, 10, 11]. Inverse psoriasis Psoriasis that is localized in skinfolds is termed flexural or inverse psoriasis. Squamous lesions do not form due to friction and moisture in skin folds. Lesions manifest as bright red, symmetric, infiltrative, fissured plaques with distinct contours [7]. Fissured plaques with sharp contours are diagnostic for this form of psoriasis. It is more frequently seen in obese individuals, and there is tendency to develop seborrheic lesions. This form is generally more resistant to classical treatments [7]. Generalized pustular psoriasis This is a rarely seen form of psoriasis that progresses with pustules. It is most frequently seen in young individuals. It can develop independently or as a complication of psoriasis vulgaris, such as secondary to abrupt withdrawal of systemic steroid treat-

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ment, intervening triggering factors, hypocalcemia, or irritant treatment. It onsets suddenly on an erythematous background in association with general symptoms, such as high fever, lassitude, and polyarthralgia. Increase in sedimentation rate, leukocytosis, lymphopenia, and negative nitrogen balance can be seen. Pustules dry within a few days, followed by eruption of new pustules. Peripustular erythema has tendency to disseminate, and thus it can result in erythrodermia. It should be promptly treated. If disseminated form is not treated, acute phase may lead to a fatal course [7, 8, 11]. Impetigo herpetiformis This is a rarely seen type of psoriasis, also known as generalized pustular psoriasis of pregnancy. It is characterized by erythrematous lesions covered with pustules, which start and radiate from flexural regions and have tendency to agglomerate. It may gain vegetative character at skin folds. During its course, involvement of mucous membranes, and onycholysis secondary to subungual pustules can be seen. Lesions itch or cause burning sensation and have a foul odor. In addition to deterioration of general health, symptoms of lassitude, fever, shivering, nausea, and vomiting may be present. [2, 7]. It is generally seen in association with hypocalcemia. It may be seen in the last trimester of pregnancy or during puerperal period. Frequently it recurs during subsequent pregnancies [2, 7]. Localized pustular psoriasis Palmoplantar pustulosis is divided into 2 forms: Barber’s pustular psoriasis and acrodermatitis continua of Hallopeau [7]. 1) Pustular psoriasis of the Barber type: It is a chronic, recurrent form more frequently seen in women and those with a family history of palmoplantar pustulosis. Clinically, it is observed as 2–4 mm-sized pustules localized on palmoplantar region, and especially erythematous thenar and hypothenar regions. While its etiology is not precisely known, underlying contact sensitivity is remarkable. Smoking, tonsillitis, humidity, and high temperature may activate the disease [12]. 2) Acrodermatitis continua (Hallopeau disease): It is a proximally progressive skin disorder char-


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acterized by sterile pustular eruptions involving fingers and toes, and leading to loss of nails and distal phalanges in severe cases. Pustules become joined, resulting in small, polycyclic, purulent, fluid-filled vesicles. Presence of a variant of psoriasis is still debatable [12]. Conclusion Psoriasis manifests itself on a wide clinical spectrum. Studies performed have demonstrated that clinical type is not a determinative factor of severity or course of the disease; however, clinical type is an important element in the determination of treatment protocol [13, 14]. Conflict of Interest: None declared. Financial Disclosure: The authors declared that this study has received no financial support. Authorship contributions: Concept - G.S., Design - G.S., T.T.K.; Supervision - G.S., T.T.K., T.B.; Materials - G.S.; Data collection and/or processing - G.S.; Analysis and/or interpretation - T.B.; Literature search - T.T.K., T.B.; Writing - G.S.; Critical review - T.T.K.

REFERENCES 1. Sarıcaoğlu H, Başkan EB, editörler. Papüloskuamöz ve eritematöz

dermatozlar. İstanbul: Nobel Tıp; 2012. s. 115-48. 2. Gudjonsson JE, Elder JT. Psoriasis. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, editors. Fitzpatrick’s Dermatology in General Medicine. New York: McGraw Hill; 2008. p. 169-94. 3. Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC. Dermatology. 2nd ed. Berlin: Springer-Verlag; 2000. p. 585-607. 4. Christophers E. Psoriasis-epidemiology and clinical spectrum. Clin Exp Dermatol 2001;26:314–20. 5. Van de Kerkhof PC. The Woronoff zone surrounding the psoriatic plaque. Br J Dermatol 1998;139:167. 6. Van De Kerkhof PCM. Papulosquamous and Eczematous dermatoses: Psoriasis. In: Dermatology. Bolognıa JL, Jorizzo JL, Rapini RP, editors. Edinburg: Mosby; 2003. p.125-49. 7. Gülekon A. Psöriasis ve benzeri dermatozlar. In: Tüzün Y, Gürer MA, Serveroğlu S, Sungur O, Aksungur LA, editörler. Dermatoloji. 3. baskı. İstanbul: Nobel Tıp; 2008. p.745-60 8. Bowcock AM, Barker JN. Genetics of psoriasis: the potential impact on new therapies. J Am Acad Dermatol 2003;49(2 Suppl):1–6. 9. Erdem H. Psöriatikartritin klinik özellikleri. Romatizma 2000;15:31-8. 10. Yazıcı CA. Treatment of Nail Psoriasis. Turkiye Klinikleri J Dermatol-Special Topics 2008;1:31–7. 11. Habif T. ClinicalDermatology. 4rd ed. Mosby: 2004. pp. 209-40. 12. Sarıfakıoğlu E. Pustular diseases of the hand. Yeni Tıp Dergisi 2010;27:138,41. 13. Kalaycıyan A, Tüzün Y. Clınical characteristics of psoriasis. Turk Klin J Dermatol 2003;13:154–9. 14. Limaye K. Psoriasis: an overview and update. Nurse Pract 2015;40:23–6.

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