NCI / 2014 1

ISSN 2148 - 4902

NORTHERN CLINICS OF ISTANBUL • İSTANBUL KUZEY KLİNİKLERİ

Vol. 1 • No. 1 • Year 2014

Comparison of clinicopathological findings among patients whose mammography results were classified as category 4 subgroups of the BI-RADS

Is there a new finding added to the fibromyalgia syndrome?

Serum vitamin D levels in children with recurrent tonsillopharyngitis

Effects of smoking on healthy young men’s hematologic parameters Comparison of adefovir dipivoxil and pegylated interferon alpha-2a treatment in chronic hepatitis B patients

Efficacy of extracorporeal shock wave therapy in the treatment of lateral epicondylitis Our experiences with a single injection axillary block technique

Management of hematometrocolpos due to dysfunctional uterine bleeding following progestin use A trombosis story and PRES Disseminated lupus vulgaris Flexible flatfootness

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

Vıce Editors

Bekir Durmus, M.D.

Banu Mesci, M.D. Berna Terzioglu Bebitoglu, M.D. Ender Onur, M.D. Levent Doganay, M.D. Tunc Eren, M.D.

Editorial Board Abdullah Aydin, M.D. Ali Ihsan Dokucu, M.D. Ali Riza Odabas, M.D. Asiye Kanbay, M.D. Ates Kadioglu, M.D. Ayse Cikim Sertkaya, M.D. Aytekin Oguz, M.D. Ayten Kadanali, M.D. Bekir Atik, M.D. Birsen Yurugen, M.D. Canan Agalar, M.D. Didem Korular Tez, M.D. Dilaver Tas, M.D. Ebru Zemheri, M.D. Eren Gozke, M.D. Eren Ozek, M.D. Eyup Gumus, M.D. Fatma Eti Aslan, M.D. Ferruh Isman, M.D. Filiz Akyuz, M.D. Fugen Aker, M.D. Gozde Kir Cinar, M.D. Gulendam Kocak, M.D. H. Muammer Karakas, M.D. Hale Akbaylar, M.D. Haluk Vahaboglu, M.D. Hamit Okur, M.D. Haydar Sur, M.D. Hulya Apaydin, M.D.

Huseyin Bayramlar, M.D. Ibrahim Akalin, M.D. Ibrahim İkizceli, M.D. Ihsan Karaman, M.D. Kaya Saribeyoglu, M.D. Kemalettin Koltka, M.D. Lutfullah Orhan, M.D. Mehmet Ali Ozcan, M.D. Mehmet Doganay, M.D. Mehmet Eren, M.D. Mehmet Kanbay, M.D. Mehmet Tunca, M.D. Melek Gura, M.D. Murat Acar, M.D. Nilay Sahin, M.D. Nuran Komurcu, M.D. Onur S. Goksel, M.D. Ozge Ecmel Onur, M.D. Ozlem Guneysel, M.D. S. Tahir Eren, M.D. Sabahat Aksaray, M.D. Serhat Citak, M.D. Sevki Erdem, M.D. Sukran Kose, M.D. Tuba Yavuzsen, M.D. Umut Kefeli, M.D. Yasar Bukte, M.D. Yuksel Altintas, M.D.

NORTHERN CLINICS OF ISTANBUL İSTANBUL KUZEY KLİNİKLERİ YEAR 2014 VOLUME 1 NUMBER 1

p-ISSN 2148 - 4902

General Coordinators Neslihan Buyukmurat, M.D. Umut Elmas

Executive Office

Istanbul Anadolu Kuzey Kamu Hastaneler Birligi Genel Sekreterligi

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Phone: +90 216 578 78 00

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e-mail: bilgi@kuzeyklinikleri.com Ownership and Accountability for Contents on behalf of the Istanbul Northern Anatolian Association of Public Hospitals

Kemal Memisoglu, M.D. Publishing Manager

Bekir Durmus, M.D. Issued by the Istanbul Northern Anatolian Association of Public Hospitals

Publisher

Press

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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 ©2014 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

CONTENTS VI

INSTRUCTIONS FOR THE AUTHORS

IX

PREFACE

XI

EDITORIAL

ORIGINAL ARTICLES 1-5

Comparison of clinicopathological findings among patients whose mammography results were classified as category 4 subgroups of the BI-RADS

I. M. Leblebici, S. Bozkurt, T. T. Eren, I. A. Ozemir, J. Sagiroglu, O. Alimoglu

6-12

Is there a new finding added to the fibromyalgia syndrome?

B. Sarifakioglu, A. Yildirim Guzelant, S. Alpsoy, B. Topcu, C. Unsal, N. Sahin

13-18

Serum vitamin D levels in children with recurrent tonsillopharyngitis

A. Collak, A. Bozaykut, B. Demirel, R. G. Sezer, L. P. Seren, M. Dogru

19-25

Effects of smoking on healthy young men’s hematologic parameters

B. Inal, T. Hacibekiroglu, B. Cavus, Z. Musaoglu, H. Demir, B. Karadag

26-32

Comparison of adefovir dipivoxil and pegylated interferon alpha-2a treatment in chronic hepatitis B patients

P. Korkmaz, G. Usluer, I. Ozgunes, E. D. Kartal, N. Erben, S. N. Alpat

33-38

Efficacy of extracorporeal shock wave therapy in the treatment of lateral epicondylitis

K. Bayram, H. Yesil, E. Dogan

39-44

Our experiences with a single injection axillary block technique

Y. Yanli, M. Ozdemir, N. Bakan

CASE REPORTS 45-48

Management of hematometrocolpos due to dysfunctional uterine bleeding following progestin use: a case report

M. Bakacak, F. Avci, M. S. Bostanci, Z. Bakacak, S. Serin, O. Ercan, B. Kostu

49-52

A trombosis story and PRES

V. Kartal, Z. Zara, S. Yilmaz, A. Ayhan, A. Yoruk, C. Timur

53-56

Disseminated lupus vulgaris: a case report

B. Can, I. Zindanci, Z. Turkoglu, M. Kavala, V. Ulucay, F. Topaloglu Demir

REVIEW 57-63

Flexible flatfootness

A. Atik, S. Ozyurek

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. NCI printed three times a year.

Free full-text articles in English are available at (www.kuzeyklinikleri.com). The journal publishes researches, interesting case reports, letters to the editor, review articles, editorial comments, medical news, guidelines. The journal accepts manuscripts written in Turkish, and English. Opinions presented in published articles by no means represent the official endorsement of the Istanbul Northern Anatolian Association of Public Hospitals.

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Case Reports: NCI publishes reports on interesting, instructive or rarely seen cases.

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Articles in press: Roten L, Derval N, Sacher F, Pascale P, Wilton SB, Scherr D, et al.

Ajmaline attenuates electrocardiogram characteristics of inferolateral early repolarization. Heart Rhythm 2011 Sep 19 [E-pub ahead of print], doi:10.1016/j.hrthm.2011.09.013.

2. Book: Katz AM. Physiology of the heart. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2000.

3. 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.

4. 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.

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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

PREFACE

Dear readers, The most important basis of more quality and efficient service provision in the health sector which is one of the essential needs of society; is that to keep pace with developments in medical science on the scale of international standards and should be to get the researches as a source which consider these standards in medical education.

The medical science is a field of science which takes people at the center as existential need, open to change, develops by sharing. The societies which don’t follow the scientific developments can not adopt international standards as stay out of the change. Accordingly, the health care which should have quality and efficiency gradually declined to the point where it doesn’t meet requirements.

The main objective of medical journals is to meet the need of environment in which the findings and experiences of scientists and the medical studies for healthcare needs can be shared freely. In this regard, the better results are obtained in proportion as the wealth of scientific studies and resources, and the continuity is essential in line with the rapid growth and change of the world in medical education.

Nowadays, the existence of scientific publications have important values in many respects. The scientific values of individuals, institutions and countries can be measured in proportion as the obtained publications and citations, and the policies in this field can be determined. The medical science in this sense is used as an important international indicator, appeared in the development of the health service as the most decisive factor.

The Journal of Northern Clinics of Istanbul have initiated publishing life incorporated the Association of Public Hospital Northern Anatolian Region of Istanbul within the scope of all these structural and scientific studies in order to transfer the current developments in the health sciences and particularly medical field in our country and in the world, and contribute to medical research and medical literature of the world.

The Association of Public Hospital Northern Anatolian Region of Istanbul have 7 Training and Research Hospital within their 16 hospitals, therefore our Association has responsibility and has to exist in this scientific field.

I would like to thank especially, Deputy Undersecretary in Ministry of Health Dear Dr. Şuayip Birinci who does not grudge his valuable support and contribution from the project stage of this study, all people in the editorial board and all precious physicians who appears in our journal with their scientific articles.

I offer my love and respect with my wishes that our publication would be a quality scientific medical journal which appeals all the health world.

Assoc. Prof. Dr. Kemal MEMİŞOĞLU General Secretary

EDITORIAL Dear readers of Journal of Istanbul Northern Clinics, We, as the Association Public Hospital, Anatolian Northern Region of Istanbul, stand with first issue of Journal of Northern Clinics of Istanbul (NCI) which set a contribution to high-quality scientific publications in the medical field in our country as the first target.

Our country bears its name increasingly to high levels in the international arena with its works and innovations in the field of health. We have initiated publishing life as a team of Journal of NCI in order to make a grain of contribution to the success of our country in the scientific sense. We aim to place our journal whose medium of language is English in international indexes such as PubMed, Index Medicus, and Science Citation Index at an early date as soon as possible. In this manner, we are making an effort to present experiences and academic studies of our country in the field of health to the world.

We, as the Editorial Board of Journal of NCI, offer our most sincere gratitude to Deputy Undersecretary in Ministry of Health, Dr. Şuayip Birinci and our General Secretary, Assoc. Prof. Kemal Memişoğlu, who proposed that the promising potential of the Association Public Hospital, Anatolian Northern Region of Istanbul should be moved to a scientific field, and for this purpose, led to publish this journal, felt the same excitement with our team at each stage of forming the journal and deemed me worthy of the most honorable mission of the journal.

I would like to express my gratitude to the editors who are Assoc. Prof. Dr. Levent Doğanay, Assoc. Prof.

Banu Mesci, Dr. Tunç Eren; the publication coordinators who are Dr. Neslihan Büyükmurat and Umut Elmas for their selfless effort from the project stage to the day the journal was published, and also would like to share my happiness to be working with them. Lastly, I would like to thank Assoc .Prof. Ümit Başar Semiz who was with us in the first stages of the journal but left our team to continue his academic career at the university.

As the Editorial Board of Journal of NCI, we wish success and good health to all of our readers, our authors and our advisory board in their scientific lives, and also offer respect them with the wish that our journal would make a positive contribution to the health world.

In our first issue, we stand with 7 original researches, 3 case reports and 1 invited review.

The innovations in fibromyalgia syndrome, comparison of two different treatment options for patients with chronic hepatitis B, according to the results of mammography comparison of the clinicopathologic outcomes of patients, the effect of cigarette smoking on hematological parameters, the efficacy of extracorporeal shock wave therapy in the treatment of lateral epicondylitis, the effectiveness of a single injection axillary block techniques and the relation of serum vitamin D levels with frequency of permeation tonsillopharingitis are investigated and explicated in these unique and authentic studies.

We hope you would read with interest that the development of posterior reversible encephalopathy syndrome in a child with acute lymphocytic leukemia, case of generalized lupus vulgaris, development of hematocolpos in a patient who use progestin which we think are interesting in case reports.

We celebrate our authors who contributed to the formation of content of this very first issue, and thank our referees who allocated their valuable time for evaluation of the writings as the editorial team.

Hope to see you in the next issue.

Bekir Durmus, M.D. Editor-in-Chief

Orıgınal Article

GENERAL SURGERY

North Clin Istanbul 2014;1(1):1-5 doi: 10.14744/nci.2014.21931

Comparison of clinicopathological findings among patients whose mammography results were classified as category 4 subgroups of the BI-RADS Ihsan Metin Leblebici1, Suleyman Bozkurt2, Turgut Tunc Eren1, Ibrahim Ali Ozemir1, Julide Sagiroglu1, Orhan Alimoglu1 Department of General Surgery, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey

1

Department of General Surgery, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turkey

2

ABSTRACT OBJECTIVE: Our aim is to compare the mammographic, demographic and clinicopathological characteristics of patients whose mammographies were classified as subgroups of BI-RADS 4 category (Breast Imaging – Reporting and Data System).

METHODS: In total, 103 patients with mammography (Senographe 600t senix HF; General Electric, Moulineaux, France) results classified as BI-RADS 4 were included in the study. Demographic data (age, menopause, and family history) were recorded. All data were compared among BI-RADS 4 subgroups.

RESULTS: In all, 68.9% (71/103), 7.8% (8/103) and 23.3% (24/103) patients were in groups BI-RADS 4A, 4B and 4C, respectively. The incidence of malignancy was higher in Groups 4B and 4C than in Group 4A (p<0.05), but similar in Groups 4B and 4C (p>0.05). Mean age was lower in Group 4B than in Groups 4A and 4C (p<0.05). A positive family history was more common in Group 4A than in Group 4B (p=0.025). The frequency of menopausal patients was greater in Groups 4A and 4C than in Group 4B (p=0.021, and 0.003, respectively).

METHODS: The rate of malignancy was higher in Groups 4B, and 4C than in Group 4A. A positive family history was more common in Group 4A than in Group 4C. Groups 4A, and 4C patients tended to be older and were more likely to be menopausal than Group 4B patients.

Key words: BI-RADS 4, subcategories 4A, 4B and 4C, mammography

B

reast cancer is the most common type of cancer among women in our country and the second leading cause of cancer deaths, after lung cancer [1].

Mammography is a widely used imaging method to screen for breast cancer. Screening with newly developed mammography methods enables early diag-

Received: May 01, 2014 Accepted: May 21, 2014 Online: August 03, 2014 Correspondence: Ihsan Metin LEBLEBICI. Istanbul Medeniyet Universitesi, Goztepe Egitim ve Araştırma Hastanesi, Kadıkoy 34730 Istanbul, Turkey.

Tel: +90 216 - 566 66 00 e-mail: drleblebici@yahoo.com © Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

2

nosis, and may reduce death rates by 25% [2].

Breast Imaging - Reporting and Data System (BI-RADS) was developed in 1993 by The American College of Radiology (ACR) to improve communication between general surgeons, and radiologists, and to provide a common terminology among radiologists [3]. In BI-RADS, mammography results are classified into six categories on the basis of objective and standard criteria, and these categories are important to determine the necessity for biopsy in a patient with a breast lesion [3]. BI-RADS category 4 consists of mammograms that include suspected findings of malignancy, and 35% of such lesions require biopsy owing to the risk of malignancy [4]. Mammography findings belonging to BIRADS category 4 are subdivided as follows: mild suspicion of malignancy (4A), intermediate suspicion of malignancy (4B) and moderate concern, but not classic for malignancy (4C) [3]. However, these subcategories are based on the clinical experience of radiologists, and not on objective criteria. The determination of standard, objective criteria for dividing BI-RADS category 4 into subgroups would reduce the confusion in terminology among radiologists.

Furthermore, as the communication between radiologists becomes more standard, the frequency of unnecessary biopsies may decrease.

In an attempt to standardize the subclassification of BI-RADS category 4, this study aimed to determine the correlations between mammographic, pathological and clinical findings and BI-RADS 4 subcategories.

MATERIALS AND METHODS A total of 103 patients who were admitted to the hospital and underwent mammography (Senographe Senix 600t; General Electric, Moulineaux, France) with mammography results classified as BI-RADS category 4 were included in the study.

The criteria for indication of mammography were as follows: age above 40 years, positive family history, a symptomatic breast lesion and a palpable mass on physical examination. All patients were informed about the study, and informed consent was obtained. BI-RADS subgroup, age, family his-

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

tory and menopause data of the patients were recorded. Total of 103 patients underwent Tru-cut biopsies using a 14 G needle with (n=13, 12.6%) or without (n=90; 87.3%) mammographic guidance imaging guidance. Masses were completely excised under local or general anesthesia.

Statistical analysis was performed using Number Cruncher Statistical System (NCSS) 2007 and Power Analysis and Sample Size (Pass) 2008 statistical software (Utah, United States of America). One-way ANOVA was used to compare quantitative data, and the Tukey honestly significant difference test was used to detect between-group differences in descriptive data (mean and standard deviation, frequency, ratio, minimum, and maximum). The Fisher-Freeman-Halton test was used to compare quantitative data, and the Fisher exact test and Yates continuity correction test were used to detect intergroup differences. Significance was evaluated at p<0.01 and >0.05.

RESULTS The median age of the participants was 48.83 years (range, 38â&#x20AC;&#x201C;60 years). In all, patients were in BIRADS categories 4A (68.9%; 71/103), 4B (7.8%; 8/103), and 4C (23.3%; 24/103), respectively (Table 1). All patients underwent surgery, and malignant findings were detected in 16 (15.5%) patients.

The pathological diagnosis was invasive ductal carcinoma in all patients. Forty (38.8%) patients had a positive family history. Forty-five (43.7%) patients were post-menopausal.

The mean patient age significantly differed with the BI-RADS subcategory (p=0.001, Table 1). The mean age of the patients in Group 4B was significantly lower than that of the patients in Groups 4A and 4C. Furthermore, the mean age of the patients in Group 4C was higher than that of patients in Group 4A with a statistically insignificant intergroup difference close to the significance level, (p=0.070; p>0.05).

Pathological results also significantly differed with BI-RADS subcategory (p=0.001; Figure 1).

The percentage of patients with malignant disease was significantly higher in Groups 4B and 4C than

Leblebici et al., Category 4 subgroups of the BI-RADS

Table 1.

3

Assessment of descriptive characteristics of the patients according to BI-RADS subcategories

Age (years)

4A 4B 4C (n=71) (n=8) (n=24) Ap Mean±SD† Mean±SD† Mean±SD† 48.86±5.16 41.88±1.46 51.33±4.62 0.001**

Surgery

Family history

Menopause

BI-RADS subcategories

Benign Malignant No Yes No Yes

n (%)

n (%)

n (%)

67 (94.4%) 4 (5.6%) 39 (54.9%) 32 (45.1%) 41 (57.7%) 30 (42.3%)

4 (50.0%) 4 (50.0%) 4 (50.0%) 4 (50.0%) 8 (100%) 0 (0%)

16 (66.7%) 8 (33.3%) 20 (83.3%) 4 (16.7%) 9 (37.5%) 15 (62.5%)

B

p

0.001** 0.032* 0.004**

A: One-way ANOVA, B: Fisher-Freeman-Halton test; †SD: standard deviation. *p<0.05, **p<0.01.

in Group 4A (p<0.05). However, no significant difference was detected in the rate of malignancy between Groups 4B and 4C (p>0.05; Table 1).

The rate of positive family history significantly differed with BI-RADS subcategory (p=0.032).

According to paired comparisons done to determine the group causing the difference, the rate of a positive family history was significantly higher than that in Group 4C (p=0.025). A statistically significant difference was not detected between the other

DISCUSSION

100

Benign

90

Malignant

80 70 60 %

two groups (p>0.05).

The frequency of menopause also significantly differed among groups (p=0.004). According to paired comparisons done to determine the group causing the difference, the frequency of menopause was significantly greater in Groups 4A and 4C than in Group 4B (p=0.021 and p=0.003, respectively).

A statistically significant difference was not detected between the menopause rates in Groups 4A and 4C (p>0.05).

50 40 30 20 10 0 4A

4B

4C

Figure 1. Distribution of pathological results according to BI-RADS subcategories.

Among patients whose mammography findings are classified as BI-RADS category 4, the reported incidence of malignancy varies greatly (2%–95%) [5].

Malignancy or high-risk lesions are not present in many patients with BI-RADS category 4 mammograms. Therefore, this category has been divided into three subgroups based on the clinical experience of the radiologists, but standard and objective criteria have not been defined for subdividing BIRADS category 4. In 2006, Lazarus et al. compared differences in diagnoses among radiologists [6].

They found that the subdivision of BI-RADS category 4 was beneficial to determine indications for

4

biopsy, but recommended that definite criteria were required for the subcategorization.

Various differences arise in the interpretation of results [7]. The division of BI-RADS category 4 into subgroups 4A (mild suspicion), 4B (intermediate suspicion) and 4C (moderate concern) in terms of malignancy risk has not been approved by the FDA and MQSA [3]. A lesion must be suspected to be malignant to be classified as 4A. Similarly, suspicion must be intermediate to classify the lesion as 4B and severe for 4C. Many researchers have investigated the association between BI-RADS categories and pathological results. In 2004, Mendez et al. compared BI-RADS categories 3–5 and pathology results [8]; they found that the incidence of malignancy increased as the BI-RADS category increased. In their study, the incidence of malignancy among patients with mammography findings belonging to BI-RADS category 4 was 15%, which is similar to the result in our study (15.5%).

In 2013, Flowers et al. compared the biopsy results of 124 patients whose BI-RADS categories were 3–5 [5]. They found that the rate of malignancy among patients with BI-RADS categories 4A, 4B and 4C was 0%, 15% and 84%, respectively.

The corresponding rates in our study were 5.6%, 50% and 33.3%. They found that the malignancy rate increased as the BI-RADS subcategory became more severe. However, we found that although the rates of malignancy were higher in Groups 4B and 4C than in Group 4A, there was no significant difference in this incidence rate between Groups 4B and 4C. In addition, in a similar study conducted in 2012 by Yan et al., biopsy results did not significantly differ with BI-RADS subgroup [9]. Consistent with the findings of Flowers et al., Gweon et al. retrospectively evaluated patients who had undergone surgery owing to their biopsy results and found that the rate of malignancy increased as the BI-RADS category 4 subgroup grade increased [10].

In 2012, Chaiwerawattana et al. compared BIRADS 4 subgroups and attempted to detect differences between the subgroups in terms of survival rates [11]. They concluded that unnecessary biop-

North Clin Istanbul – NCI

sies could be avoided by good assessment of the subgroups.

In a 2013 study performed by Jales et al., 339 patients were evaluated by three experienced radiologists [12], who assessed the patients’ ultrasound data using BI-RADS criteria, and then compared the BI-RADS results with the pathology results.

The rate of malignancy in BI-RADS Groups 4A, 4B and 4C was 20%, 38% and 79%, respectively, according to the first radiologist. The corresponding rates as assessed by the other two radiologists were 17%, 40% and 85%, respectively. Considering the interobserver differences, the authors recommended that common diagnostic criteria be established to obtain consistent results. Torres et al. also made the same recommendation of objective diagnostic criteria for subgroup classification [13].

In an attempt to establish objective, standardized criteria, we analyzed the relationship between various clinical parameters, and BI-RADS 4 subgroups. We found that the rate of a positive family history was significantly greater in Group 4A than in Group 4C. In clinical practice, age, family history and parity of patients are recorded during mammography. We consider that mammographies evaluated in BI-RADS 3 category are evaluated as BI-RADS 4A in the presence of positive family history considering increased breast cancer risk.

No studies have yet investigated the relationship between BI-RADS 4 subgroups and patient age. In 2011, Fu et al. compared the ages of patients in BIRADS categories 3, 4 and 5 and found that age was significantly higher in Groups 4A and 4B [14]. In the present study, we found that mean patient age was significantly higher in Groups 4A and 4C than in Group 4B. We consider that this result is attributable to the patient distribution in our study.

Breast patterns were analyzed radiologically in many studies and allocated to subgroups according to BI-RADS criteria [15]. The relationship between BI-RADS 4 subgroups and menopause has not yet been investigated. In our study, we found that there were significantly more menopausal patients in Groups 4A and 4C than in Group 4B. This difference may be attributable to the higher mean

Leblebici et al., Category 4 subgroups of the BI-RADS

age of the patients in Groups 4A and 4C. Our study is limited by the small number of patients involved.

Therefore, the relationship between the above clinical parameters and BI-RADS 4 subgroups should be explored further in large-scale trials.

To the best of our knowledge this study is the first to investigate the relationship between clinicopathological variables and BI-RADS 4 subgroups.

The rate of malignancy was higher in Groups 4B and 4C than in Group 4A, but the rates in Groups 4B and 4C were similar. A positive family history was significantly more common in Group 4A than in Group 4C. Patients in Groups 4A and 4C tended to be older and more likely to be menopausal than those in Group 4B. Our findings should be confirmed in large-scale studies.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Andic S, Karayurt O. Determination of information and support needs of first degree relatives of women with breast cancer.

Asian Pac J Cancer Prev 2012;13:4491-9.

2. Berrington de Gonzalez A, Reeves G. Mammographic screening before age 50 years in the UK: comparison of the radiation risks with the mortality benefits. Br J Cancer 2005;93:590-6.

3. BI-RADS®–Mammography IV. Guidance Chapter. Available at: http://www.acr.org/~/media/ACR/Documents/PDF/QualitySafety/Resources/BIRADS/MammoGuidance.pdf. Accessed August 13, 2013.

4. Popiel M, Mroz-Klimas D, Kasprzak R, Furmanek M. Mammary carcinoma-current diagnostic methods and symptomatology in imaging studies. Pol J Radiol 2012;77:35-44.

5. Flowers CI, O’Donoghue C, Moore D, Goss A, Kim D, Kim JH,

5 et al. Reducing false-positive biopsies: a pilot study to reduce benign biopsy rates for BI-RADS 4A/B assessments through testing risk stratification and new thresholds for intervention. Breast Cancer Res Treat 2013;139:769-77.

6. Lazarus E, Mainiero MB, Schepps B, Koelliker SL, Livingston LS. BI-RADS lexicon for US and mammography: interobserver variability and positive predictive value. Radiology 2006;239:385-91.

7. Youk JH, Son EJ, Kim JA,Moon JH, Kim JM, Choi CH, Kim EK. Scoring system based on BI-RADS lexicon to predict probability of malignancy in suspicious microcalcifications. Ann Surg Oncol 2012;19:1491-8.

8. Mendez A, Cabanillas F, Echenique M, MalekSchamran K, Perez I, Ramos E. Mammographic features and correlation with biopsy findings using 11-gauge stereotactic vacuum-assisted breast biopsy (SVABB). Ann Oncol 2004;15:450-4.

9. Yan X, Stark A, Chitale D, Burke M, Zarbo R, Nathanson D, et al. Suspicious mammogram (BI-RADS 4) outcome and breast biopsy: Preliminary findings from a cohort of 6198 women. Clin Med Res 2012;10:147.

10. Gweon HM, Son EJ, Youk JH, Kim JA, Chung J. Value of the US BI-RADS final assessment following mastectomy: BI-RADS 4 and 5 lesions. Acta Radiol 2012;53:255-60.

11. Chaiwerawattana A, Thanasitthichai S, Boonlikit S, Apiwanich C, Worawattanakul S, Intakawin A, et al. Clinical outcome of breast cancer BI-RADS 4 lesions during 2003-2008 in the National Cancer Institute Thailand. Asian Pac J Cancer Prev 2012;13:4063-6.

12. Jales RM, Sarian LO, Torresan R, Marussi EF, Alvares BR, Derchain S. Simple rules for ultrasonographic subcategorization of BI-RADS-US 4 breast masses. Eur J Radiol 2013;82:1231-5.

13. Torres-Tabanera M, Cardenas-Rebollo JM, Villar-Castano P, Sanchez SM, Cobo J, Martos EE, et al. Analsis of the positive predictive value of the subcategories of BI-RADS 4 lesions: preliminary results in 880 lesions. Radiologia 2012;54:520-31.

14. FU CY, Hsu HH, Yu JC, Hsu GC, Hsu KF, Chan DC, et al.

Influence of age on PPV of sonographic BI-RADS categories 3, 4, and 5. Ultraschall Med 2011;32:8-13.

15. Spayne MC, Gard CC, Skelly J, Miglioretti DL, Vacek PM, Geller BM. Reproducibility of BI-RADS breast density measures among community radiologists: a prospective cohort study.

Breast J 2012;18:326-33.

Orıgınal Article

PTR

North Clin Istanbul 2014;1(1):6-12 doi: 10.14744/nci.2014.37450

Is there a new finding added to the fibromyalgia syndrome?

Banu Sarifakioglu1, Aliye Yildirim Guzelant1, Seref Alpsoy2, Birol Topcu3, Cuneyt Unsal4, Nilay Sahin5 Deparment of Physical Therapy and Rehabilitation, Namik Kemal University Faculty of Medicine, Tekirdag, Turkey;

1

Deparment of Cardiology, Namik Kemal University Faculty of Medicine, Tekirdag, Turkey;

2

Deparment of Biostatistics, Namik Kemal University Faculty of Medicine, Tekirdag, Turkey;

3

Department of Psychiatry, Namik Kemal University Faculty of Medicine, Tekirdag, Turkey;

4

Deparment of Physical Therapy and Rehabilitation, Balıkesir University Faculty of Medicine, Balikesir, Turkey

5

ABSTRACT OBJECTIVE: The aim of this study is to examine depression and anxiety related arrhytmia risk in fibromyalgia syndrome (FMS).

METHODS: Fifty-nine patients with the diagnosis of FMS and 20 control participants were included in the study.

Fibromyalgia Impact Questionnaire (FIQ), Visual Pain Scale (VPS) surveys were applied to determine the severity of the disease. Beck Anxiety (BAS) and Beck Depression scales (BDS) were applied to all participants. Electrocardiograms were obtained from all participants. P-wave dispersions (Pd) were estimated to determine the risk of the atrial arrhythmia, and QT wave dispersion (QTd) and corrected QT(QTdd) values were used to predict the risk of ventricular arrhythmia.

RESULTS: BAS and BDS results were significantly higher in the patient group compared to controls (p˂0001).

In the patient group, Pd was significantly longer (p=0.034). Other clinical, and demographic data did not differ significantly between groups.

CONCLUSION: In this study, the risk of arrhythmia in FMS was evaluated and increased Pd in patients with FMS compared to the control group was detected. This finding shows increased risk of atrial fibrilation (AF) in patients with FMS. If we consider that patients with fibromyalgia consist relatively of young patients together with the increased risk of AF with age, it is important to follow-up these patients in later ages for AF risk.

Key words: Anxiety, arrhythmia, depression, electrocardiogram, fibromyalgia

F

ibromyalgia syndrome (FMS) affects individual’s quality of life adversely, and it is characterized by widespread muscle pains [1]. It is more

frequently seen in female population, and its prevalence has been reported as 3-5 percent [1]. Its incidence increases with age, and peaks between 30,

Received: July 18, 2014 Accepted: September 01, 2014 Online: August 03, 2014 Correspondence: Nilay SAHIN. Balıkesir Universitesi Tıp Fakultesi, Fiziksel Tip ve Rehabilitasyon Anabilim Dalı, Balikesir, Turkey.

Tel: +90 266 - 612 14 00 e-mail: nilaysahin@gmail.com © Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

Sarifakioglu et al., Is there a new finding added to the fibromyalgia syndrome?

and 50 years of age [2]. Its etiopathogenesis is not clear-cut [3]. FMS patients also suffer from pains, sleep disorders, lassitude, and anxiety problems [4].

The disease has common characteristics with depression, and their clinical findings are alike. Some patients have both of these diagnoses. Besides antidepressants have a greater place in their treatment [5]. It has been asserted that psychogenic factors (depression, and anxiety) can be associated with cardiac pathologies which can increase disease recurrence, and mortality rates [6].

Autonomic nervous system which is a component of peripheral nervous system, is responsible for the regulation of vital parameters as blood pressure, heart rate, respiration, and body temperature [7]. In cases of stress, activation of sympathetic nervous system becomes more prominent, however long-lasting stress can not be tolerated which can increase the incidence of chronic diseases [7].

Chronic pain, and lassitude can accompany these diseases. As a consequence of all these factors, the assertion that excessive sympathetic activation can be a place in the pathogenesis of chronic pain, and lassitude has been more strongly emphasized [8]. In cases of sympathetic hyperactivation and/or parasympathetic dysfunction, the body can not tolerate excessive stress which can result in emergence of lassitude, rigidity, tender points, intolerance to exercise, and sleep disorders [7, 9]. In addition, it has been recognized that pathological changes in sympathetic/parasympathetic activities can induce various types of arrhytmias [10].

In the etiopathogenesis of FMS, dysfunction of autonomic nervous system (ANS) can play a role [11]. In FMS, both pathways (sympathetic, and parasympathetic) of autonomic nervous system are affected in various degrees [11]. As has been reported, blockage of stellar ganglion with administration of bupivacaine, resting pain, and the number of trigger points decreased [12]. Autonomic nervous system dysfunction accounts for accompanying sleep disorder, anxiety, Raynaud phenomenon, Sicca symptoms, and irritable colon [11].

The risk of atrial fibrillation (AF) due to activation of parasympathetic nervous system (PNS) is already known [13]. Similarly, sympathetic ner-

7

vous system (SNS) is thought to induce potential development of AF in some patients [13]. Still in a similar fashion, the association between ANS dysfunction with ventricular arrhytmias has been investigated. P-wave dispersion has been accepted as an indirect indicator of AF [13]. QT â&#x20AC;&#x201C;wave dispersion is also considered as an indirect indicator of ventricular arrhytmias [13].

In this study, we aimed to determine the levels of depression, and anxiety in patients with FMS, and investigate whether these psychopathologies increase the risk of atrial and/or ventricular arrhytmias.

MATERIALS AND METHODS The study was designed as a prospective, controlled clinical study. Female patients aged 20-55 years consulted to our outpatient clinics of physical therapy, and rehabilitation with the diagnosis of FMS based on 2010 FMS criteria were enrolled in our study [14]. Patients with an established diagnosis of cardiac pathology (arrhytmia, valvular disease, myocardial infarction, heart failure, and rheumatic heart disease), thyroid dysfunction, malignancies, renal disease, major depression, bipolar disorder, and users of some drugs (beta blockers, calcium channel blockers or antiarrhytmic drugs) were excluded from the study. Local ethics committee approval was obtained for this study.

Whole blood counts, sedimentation rate, Creactive protein values, kidney, and liver function tests, serum electrolyte, and TSH levels were analysed. Patients with electrolyte disorders, hypo/ hyperthyroidism were excluded from the study. Demographic data, number of tender points, Symptom Severity Scale (SSS), and Widespread Pain Index (WPI) scores which were included in 2010 diagnostic criteria were recorded.

Age-matched otherwise healthy female individuals who consulted to the PTR outpatient clinics with complaints of joint pain, without established diagnoses of FMS, depression/anxiety, cardiac, thyroid, and renal disease comprised the control group.

Clinical assessments Visual Pain Scale (VPS) was used to evaluate sever-

8

ity of pain which was rated on a scale of 10 points (0, no pain , and 10, intolerable pain). Fibromyalgia Impact Questionnaire (FIQ) whose validity, and reliability of its Turkish version were performed was used to assess disease severity of FMS [15]. This scale measures 10 separate items including physical function, feeling good, inability to go to work, pain, fatigueness, morning fatigueness, stiffness, anxiety, and depression. Excluding feeling good item , lower scores indicate improvement or lesser severity of the disease. FIQ questionnaire is completed by the patient. Maximum score of each subheading can only be 10 points. Thus total maximum score maounts to 100 points. An average FMS patient scores 50 points, and severely affected FMS patients generally get more than 70 points.

To determine the presence, and level of depressive mood of the patients, Beck’s Depression Scale (BDS) whose validity, and reliability of its Turkish version have been established was applied [16]. This scale consists a total of 21 items. Three points were assigned for the evaluation of each item. Maximum score is 63 points. Absence of depressive mood (013 pts), moderate (14-24 pts), and severe (>25 pts) depressive mood were evaluated as indicated.

In order to evaluate anxiety levels of the patients, Turkish version of the Beck’s Anxiety Scale (BAS) with established validity, and reliability was was used [17]. This scale consist of a total of 21 questions. Each question is rated on 3 points. Scores range between 0, and 63 points. Total number of points indicate severity of anxiety experienced by the patient.

Patients of the control group were also evaluated using BAS, and BDS scale scores, and ECG examinations.

Evaluation of risk of arrhytmia Patients evaluated in the PTR clinics were referred to the outpatient clinics of cardiology. Electrocardiograms (ECG) of the patients were obtained, and evaluated by the same physician (ŞA) blinded to the study population. Twelve –lead electrocardiograms were recorded at a velocity of ile 25 mm/sec on a scale of 1 mV/cm using Schiller-U2 ECG machine.

North Clin Istanbul – NCI

P waves, QT, and RR intervals were determined with standard measurement methods, and average of estimates from three ECG cycles was obtained.

In all calculations of ECG leads, the beginning of P wave from the isoelectric line was accepted as the onset of P wave. Its end point was considered as the beginning of the isolectric line.

QT complex was considered as the interval from the QRS complex up to the end of T wave.If the end point of the T wave is not clear-cut, then intersection point between descending arm of the T wave, and isoelectric line was accepted as the end point of T wave. Every maximum, and minimum values in 12-lead ECG were recorded to evaluate P-wave, and QT dispersion values. Briefly, P dispersion (Pd) can be indicated as the difference between maximum, and minimum P wave durations. For Pd, average duration of at least 3 P waves in each derivation was calculated. The longest (Pmax) and the shortest (Pmin) P waves were determined, and the difference between Pmax and Pmin was estimated, and defined as Pd in milliseconds.

Pd = Pmax - Pmin.

In 12-lead ECG, the difference between the longest, and the shortest QT intervals was called QT dispersion (QTd) which demonstrates increased ventricular repolarization. QTmax, and QTmin signify the longest, and the shortest QT intervals respectively. Since only QTd remains inadequate in the evaluation of ventricular arrhytmia, in lieu of QT intervals, corrected QT (QTdd) intervals were used.

Rate-corrected QT intervals in msec were estimated using Bazett formula. This conventional correction procedure aims to eliminate dependence of QT on heart rate.

QTd = QTmax-QTmin Bazett formula: QTdd= Qtd/√(RR) Statistical analysis Normality of distribution of each group was tested using Shapiro-Wilks test. Variables with normal were expressed as mean±standard deviation, and non-normal distribution as medians (minimummaximum), respectively. Comparisons of variables with normal, and non-normal distribution were

Sarifakioglu et al., Is there a new finding added to the fibromyalgia syndrome?

performed using independent samples-t test, and Mann-Whitney U-test, respectively. Correlations between variables were evaluated using Spearman’s correlation coefficient. Statistically, p<0.05 was considered to be significant.

RESULTS A total of 59 patients, and 20 control subjects were enrolled in the study. A statistically significant difference was not found between the patient, and the control groups as for body mass indexes (BMIs), and ages of the patients, however educational levels of both groups differed statistically significantly.

Educational level of the control group was relatively higher. Demographic data are summarized in Table 1.

VAS scores which indicate patient’s disease activity, in addition to number of tender points (TP), SSS, and WPI values are presented in Table 1. Patients’ BAS, and BDS scale scores were found to be statistically significantly higher when compared with those of the control group (Table 1).

Pmax and Pd values of the patients were significantly higher than those of the control group.

Table 1.

9

However, a significant difference was not detected between Pmin, QTd, and QTdd values.

Clinical scale scores, and EKG results are presented in Table 2.

Correlations between clinical scales, and ECG were examined, and positive correlations among FIQ, BAS, and BDS were detected (p<0.001, r=0.516; p<0.001, and r=0.485, respectively). BAS scores correlated significantly with the number of tender points (p=0.021, r=0.315). VAS scores were found to be significantly correlated with the number of tender points, SSS, and WPI scores. (p<0.001, r=0.710; p<0.001, r=0.544; p<0.001, r=0.724, respectively). While the number of tender points was positively correlated with SSS, WPI scores, Pmax and Pd values (p=0.003, r=0.400; p<0.001, r=0.567; p=0.004, r=0.390; p=0.032, r=0.293, respectively). SSS scores were significantly, and positively correlated with WPI, and Pmin (p<0.001, r=0.450; p=0.010, r=0.347, respectively).

DISCUSSION In this study, we evaluated whether risk of arrhytmia increases in FMS, and in FMS patients increased

Demographic data of the patient, and the control groups

Age (years) BKI (cm2/kg) Duration of education (years) Duration of symptoms (months) VAS Number of tender points SSS WPI FIQ BAS BDS

Patient group

Control group

p

Mean±SD Mean±SD 42.32±7.80 40.90±7.12 0.474 27.75±5.39 26.93±3.60 0.532 7.32±3.53 10.40±3.97 0.002 87.30±90.92 (3-360) 7.25±1.30 13.88±2.63 8.40±1.77 13.08±3.63 59.67±16.91 25.89±13.63 13.75±7.19 ˂0.001 29.42±12.96 13.95±7.17 ˂0.001

BKI: Body mass index; VAS: Visual analogue scale; SSS: Symptom severity scale; WPI: Widespread pain index; FIQ: Fibromialgia impact questionnaire; BAS: Beck’s anxiety scale; BDS: Beck’s depression scale.

10

North Clin Istanbul – NCI

Table 2. ECG data of the patient, and the control groups Variable Pmax (msec) Pmin (msn) Pd (msec) QTmax (msec) QTmin (msec) QTd (msec) QTcmax (msec) QTcmin (msec) QTcd (msec)

Patient group (n=59)

Control group (n=20)

p

110 (80-110) 60 (40-80) 45 (30-70) 360 (320-440) 340 (300-400) 40 (25-50) 412.04±28.39 372.12±24.91 43 (30-58)

100 (70-110) 60 (40-90) 39 (20-60) 400 (360-440) 360 (320-400) 40 (20-60) 417.89±22.85 375.06±25.49 43 (30-55)

0.015* 0.266 0.034* 0.079 0.164 0.315 0.429 0.665 0.593

Pd, P-wave dispersion; QTc: Corrected QT interval.

Pd values were detected in FMS patients when compared with the control group which demonstrates increased risk of arrhytmia in FMS patients relative to the control group. If we consider that FMS patients consist of relatively young patients, and increased risk of AF with advanced age, it is important to follow up these patients in their old age.

Neurohormonal factors, and autonomic dysfunction have been blamed in the etiopathogenesis of FMS [18]. In patients with FMS, it has been contemplated that together with autonomic activity, sustained, and variable heart rates also fluctuate [7].

With time fluctations in heart rates decrease, and autonomic system is dominated by the sympathetic system. Healthy adults respond in the same way, however this condition is not always as pronounced as in FMS patients [7]. It has been widely recognized that in FMS, sympathetic system is tonically active during the resting phase, but hyporeactive against physical stimuli [11]. If any other arrhytmogenic factor can not be identified, then autonomic dysfunction has been accepted as the cause of arrhytmias [18].

Many studies have investigated the correlations between FMS, and cardiac pathologies. Ablin et al. demonstrated the relationship between FMS, and coronary artery disease, and cardiac dysfunction in 43 patients with FMS [1]. Some authors reported increased mortality risk in FMS, but they couldn’t

reveal its etiopathogenesis [18]. In a study performed by Doğru et al. the investigators detected increased prevalence of supraventricular tachycardia in 50 patients with FMS relative to normal healthy individuals [18]. In this study, they revealed that all SVT attacks developed during the night hours.

They asserted that this phenomenon might be associated with increased sympathetic activity during night hours [18]. Increased risk of arrhytmia may be one of the probable etiological factors for this increased risk of arrhytmia.

P-wave dispersion is considered as a specific, and sensitive marker of AF [19]. Besides, it can reportedly be an indicator for paroxysmal atrial fibrillation [20]. Dilaveris et al. detected significantly higher levels of Pd when compared with the healthy group.

Still in the same study, the authors determined a Pd value of 40 msec is quiet sensitive (83%), and specific (85%) in the determination of AF risk with a 89% positive predictive value [21]. In another study, higher Pmax, and Pd values were detected in patients with PAF relative to the healthy control group [20].

Still, in our study, Pd value of the FMS group was determined as 45 msec which demonstrates that FMS patients are under the risk of AF, and PAF. In many studies performed, it has been found that anxiety detected in healthy individuals increased cardiac autonomic imbalance, and the risk of coronary artery disease [22]. It has been demon-

Sarifakioglu et al., Is there a new finding added to the fibromyalgia syndrome?

strated that increased QTd value is associated with increased sympathetic or decreased parasympathetic modulation. QTd value is also a significant marker of cardiovascular mortality [23]. In our study, severe degrees of anxiety were detected in the FSM group relative to the control group without any evidence of increased risk of VF or VT which might be related to the scarcity of our patient population.

Further studies with increased number of patients may demonstrate this correlation more clearly.

Autonomic nervous system innervates sinus, and atrioventricular nodes. Both of these nodes may be affected by autonomic stimuli. Both sympathetic, and parasympathetic stimuli can lead to the development of AF via different mechanisms [24]. If we consider the role of autonomic dysfunction in the etiopathogenesis of FMS, observance of arrhytmias in FMS should not be a surprisng finding. However this manifestation can be overlooked or neglected. Our study conveys importance, in that it revealed risk of AF in patients with FMS which was evidenced by the presence of Pd in these patients.

However this assertion should be clarified with further studies involving larger patient population.

Scarcity of our patient population, and evaluation of arrhytmias using only ECG are major limitations of our study. Studies to be conducted with a larger patient, and control groups will provide more precise data. Besides, with Holter recording of alterations in patients’ heart rhythms will enable us to obtain long-lasting information which will facilitate detection of arrhytmias.

In conclusion our study determined the presence of increased risk of atrial arrhytmia in FMS disease.

Atrial arrhytmias effect quality of life of the patients adversely, worsen preexisting disease, and also induce functional losses secondary to some ensuing complications. FMS patients should be followed up in consideration of this issue, and especially their risk for atrial fibrillation should be kept in mind.

Further studies should be conducted on this issue.

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.

11

REFERENCES 1. Ablin JN, Beilinson N, Aloush V, Elkayam O, Finkelstein A. Association between fibromyalgia and coronary heart disease and coronary catheterization. Clin Cardiol 2009;32:E7-11.

2. Wolfe F, Anderson J, Harkness D, Bennett RM, Caro XJ, Goldenberg DL, et al. A prospective, longitudinal, multicenter study of service utilization and costs in fibromyalgia. Arthritis Rheum 1997;40:1560-70.

3. Clauw DJ, Crofford LJ. Chronic widespread pain and fibromyalgia: what we know, and what we need to know. Best Pract Res Clin Rheumatol 2003;17:685-701.

4. Branco JC, Bannwarth B, Failde I, Abello Carbonell J, Blotman F, Spaeth M, et al. Prevalence of fibromyalgia: a survey in five European countries. Semin Arthritis Rheum 2010;39:448-53.

5. Hassett AL, Cone JD, Patella SJ, Sigal LH. The role of catastrophizing in the pain and depression of women with fibromyalgia syndrome. Arthritis Rheum 2000;43:2493-500.

6. Lespérance F, Frasure-Smith N, Talajic M, Bourassa MG. Fiveyear risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002;105:1049-53.

7. Meeus M, Goubert D, De Backer F, Struyf F, Hermans L, Coppieters I, et al. Heart rate variability in patients with fibromyalgia and patients with chronic fatigue syndrome: a systematic review.

Semin Arthritis Rheum 2013;43:279-87.

8. Martinez-Lavin M. Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia. Arthritis Res Ther 2007;9:216.

9. Furlan R, Colombo S, Perego F, Atzeni F, Diana A, Barbic F, et al. Abnormalities of cardiovascular neural control and reduced orthostatic tolerance in patients with primary fibromyalgia. J Rheumatol 2005;32:1787-93.

10. Aytemir K, Deniz A, Yavuz B, Ugur Demir A, Sahiner L, Ciftci O, et al. Increased myocardial vulnerability and autonomic nervous system imbalance in obstructive sleep apnea syndrome.

Respir Med 2007;101:1277-82.

11. Kulshreshtha P, Gupta R, Yadav RK, Bijlani RL, Deepak KK. A comprehensive study of autonomic dysfunction in the fibromyalgia patients. Clin Auton Res 2012;22:117-22.

12. Bengtsson A, Bengtsson M. Regional sympathetic blockade in primary fibromyalgia. Pain 1988;33:161-7.

13. Podrid PJ, Kowney PR. Cardaic arrhythmia, mechanisms, diagnosis & management. 2nd ed. Philadelphia: Lippincott Williams & Williams; 2001. p. 111-651.

14. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Häuser W, Katz RS, et al. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia. J Rheumatol 2011;38:1113-22.

15. Sarmer S, Ergin S, Yavuzer G. The validity and reliability of the Turkish version of the Fibromyalgia Impact Questionnaire.

Rheumatol Int 2000;20:9-12.

12 16. Hisli N. Beck Depresyon Envanterinin üniversite öğrencileri için geçerliği, güvenirliği. Psikoloji Dergisi 1989;7:3-13.

17. Ulusoy M, Sahin NH, Erkmen H. Turkish version of the Beck Anxiety Inventory: psychometric properties. Journal of Cognitive Psychotherapy 1998;1:163-72.

18. Dogru MT, Aydin G, Tosun A, Keleş I, Güneri M, Arslan A, et al. Correlations between autonomic dysfunction and circadian changes and arrhythmia prevalence in women with fibromyalgia syndrome. Anadolu Kardiyol Derg 2009;9:110-7.

19. Dilaveris PE, Gialafos JE. P-wave dispersion: a novel predictor of paroxysmal atrial fibrillation. Ann Noninvasive Electrocardiol 2001;6:159-65.

20. Aytemir K, Ozer N, Atalar E, Sade E, Aksöyek S, Ovünç K, et al. P wave dispersion on 12-lead electrocardiography in patients

North Clin Istanbul – NCI with paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 2000;23:1109-12.

21. Dilaveris PE, Gialafos EJ, Sideris SK, Theopistou AM, Andrikopoulos GK, Kyriakidis M, et al. Simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation. Am Heart J 1998;135:733-8.

22. Kawachi I, Colditz GA, Ascherio A, Rimm EB, Giovannucci E, Stampfer MJ, et al. Prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation 1994;89:1992-7.

23. Okin PM, Devereux RB, Howard BV, Fabsitz RR, Lee ET, Welty TK. Assessment of QT interval and QT dispersion for prediction of all-cause and cardiovascular mortality in American Indians: The Strong Heart Study. Circulation 2000;101:61-6.

24. Özin B. Otonom sinir sistemi ve aritmiler. Turk Kardiyol Dern Ars 1999;27:701-7.

Orıgınal Article

PEDIATRICS

North Clin Istanbul 2014;1(1):13-18 doi: 10.14744/nci.2014.76486

Serum vitamin D levels in children with recurrent tonsillopharyngitis Abdulhamit Collak1, Abdulkadir Bozaykut1, Bilge Demirel1, Rabia Gonul Sezer1, Lale Pulat Seren1, Mahmut Dogru2 Department of Pediatrics, Zeynep Kamil Maternity and Children’s Diseases Training and Research Hospital, Istanbul, Turkey;

1

Department of Pediatric Allergy and Immunology, Zeynep Kamil Maternity and Children’s Diseases Training and Research

2

Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: In this study, we aimed to compare vitamin D levels of children with recurrent tonsillopharingitis and healthy controls, and investigate the relationship between sociodemographic characteristics and serum vitamin D levels.

METHODS: Children with recurrent tonsillopharingitis and healthy controls aged between 2, and 12 years who consulted to the outpatient clinics of Zeynep Kamil Maternity and Children’s Diseases Training and Research Hospital from January to October 2012 were included in this study. Serum 25 (OH) vitamin D levels were studied by tandem mass spectroscopy (tandem ms) method. Risk factors which might be associated with vitamin D levels were questioned. Ethical aproval was obtained from the Ethics Committee of Zeynep Kamil Maternity and Children’s Diseases Training and Research Hospital and informed consent from the parents of the children.

RESULTS: A total of 147 children; 74 (50.3%) patients and 73 (49.7%) controls were included in our study. Age, gender and demographic characteristics did not differ significantly between the two groups. Vitamin D levels in patients with recurrent tonsillopharingitis and controls were 19.7±8.7 ng/ml and 23.6±9.2 ng/ml, respectively (p<0.01). Although duration of vitamin D usage was shorter in children with recurrent tonsillopharingitis, this difference was not statistically significant (p>0.05).

CONCLUSION: Vitamin D levels in children with ≥7 recurrent episodes of tonsillophargitis within the preceeding year were significantly lower compared to the control group. We believe that serum vitamin D levels should be checked in children with recurrent tonsillopharingitis and deficiencies should be treated.

Key words: 25-OH vitamin D, infection, recurrent tonsillopharyngitis, vitamin D

T

onsillopharyngitis is an important health problem in childhood because of potential development of its suppurative complications

(peritonsillary abscess, sinusitis, mastoiditis, otitis media, endocarditis, meningitis, and pneumonia) caused by group A beta- hemolytic streptococci,

Received: May 10, 2014 Accepted: July 02, 2014 Online: August 03, 2014 Correspondence: Rabia Gonul SEZER. Opr. Dr. Burhanettin Ustunel Cad. No: 10, Uskudar, Istanbul, Turkey.

Tel: +90 216 - 391 06 80 / 1161 e-mail: rabiagonul@hotmail.com © Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

14

and also non-suppurative complications, in addition to the difficulties in the identification of the etiological agent (bacterial vs viral). In the literature, recurrent tonsillopharyngitis is defined as 7 or more well-documented, clinically important, adequately treated episodes of tonsillopharyngitis in the preceeding year or 3 or more such episodes in each of the preceeding 3 years or 5 or more such episodes in the preceeding 2 years [1]. In the pediatric population tonsillopharyngitis is an important morbidity which adversely affects quality of life of the children, and parents because of its frequently recurrent symptoms, its treatment, and potential complications, and school absence it causes. In the United States of America in the year 1996 one of every 100 children had not reportedly attended their schools for a total of 152 days because of upper respiratory tract infections [2].

Comprehension of antiproliferative, prodifferentiative, proapoptotic, and immunomodulator functions of vitamin D whose deficiency was associated with only rickets for a long time has led to reconsideration of this vitamin regarding its newly discovered beneficial effects [3]. In studies performed, the role of vitamin D in decreasing the risks of many chronic diseases including prominently some types of cancer, followed by many autoimmune, infectious, and cardiovascular diseases are remarkable [4]. As revealed in many studies, vitamin D deficiency increases the risk of contracting many infectious [5].

Vitamin D deficiency is reportedly a risk factor for the development of tuberculosis, otitis media, upper respiratory tract, and gripal infections [6, 7, 8].

In this study, we aimed to compare vitamin D levels in children who had recurrent episodes of tonsillopharyngitis, and in healthy children, and investigate the correlation between sociodemographic characteristics, and vitamin D levels.

MATERIALS AND METHODS This prospective study included children aged between 2-12 years with recurrent tonsillopharingitis and their age-matched healthy controls who consulted to the outpatient clinics of Zeynep Kamil Maternity and Children’s Diseases Training and

North Clin Istanbul – NCI

Research Hospital from January to October 2012.

The number of episodes of infections were determined based on patients’ history of recurrent diagnoses of tonsillopharyngitis, hospital files, their prescriptions, and admission complaints. Demographic characteristics of the children, and their duration of vitamin D therapy during infancy were recorded.

Inclusion criteria for the study group were as follows: suffering from 7 or more well-documented, clinically important, and adequately treated episodes of tonsillopharyngitis in the preceeding year or 5 or more such episodes in each of the preceeding years or 3 or more such episodes in each of the 3 preceeding years. For the control group inclusion criteria were determined as experiencing less than 7 such episodes in the preceeding year, absence of any known chronic disease or any disease which might effect vitamin D metabolism or vitamin D therapy.

Blood samples were drawn from the children included in the study to analyze serum 25 (OH) D levels. Serum 25 (OH) vitamin D levels were analyzed using LC/MS/MS method which has been accepted as a reference method with higher sensitivity, and specificity. Waters® Micromass® Quattro Premier XE™ Tandem Quadrupole Mass Spectrometer was used for analyses.

Vitamin D deficiency, insufficiency, and adequacy were defined as the detection of vitamin D levels of <20 ng/ml, 20-32 ng/ml, and 32-100 ng/ml, respectively. Study population were divided into 3 groups based on the aforesaid vitamin D levels as groups with deficient, insufficient, and adequate vitamin D levels. Parameters as age, frequency of tonsillopharyngitis etc. were compared between groups.

SPSS (Statistical Package for Social Sciences 15; SPSS Inc., Chicago, IL, USA) program was used to evaluate study data. In intergroup comparisons for categorical variables chi-square, for comparisons of mean values between two or among three groups, Mann Whitney-U, and Kruskal-Wallis tests were used, respectively. The results were evaluated at accepted level of significance of p<0.05, and within 95% confidence limit.

The approval for the conduction of the study was obtained beforehand from The Ethics Com-

Collak et al., Serum vitamin D levels in children with recurrent tonsillopharyngitis

mittee of Zeynep Kamil Maternity, and Children’s Diseases Training and Research Hospital. Enlightened consent forms were signed by the parents who volunteered to participate in the study.

RESULTS A total of 147 children; 74 (50.3%) patients and 73 (49.7%) controls were included in the study. Age, gender and demographic characteristics did not differ significantly between the two groups. Vitamin D levels in patients with recurrent tonsillopharingitis and controls were 19.7±8.7 ng/ml and 23.6±9.2 ng/ml, respectively (p<0.01). Although duration of vitamin D usage was shorter in children with recur-

15

rent tonsillopharingitis, this difference was not statistically significant (p>0.05).

A total of 147 (girls, n=71; 48.3%) patients were included in the study. Study , and control groups consisted of 74 (50.3%) patients, and 73 (49.7%) healthy individuals, respectively. Study, and control groups were not significantly different as for age, gender, number of siblings, and duration of vitamin D use. In the recurrent tonsillopharyngitis group, vitamin D level was detected to be significantly lower when compared to the control group (p<0.01).

Duration of vitamin D use was shorter than the control group without any statistically significant difference between groups (p>0.05) (Table 1).

Table 1.

Comparison of vitamin D levels in patients suffered from frequent episodes of tonsillopharyngitis, and the control group

Control group

Study group

p

Mean SD1 Median Mean SD Median

Age (mos) Number of episodes of tonsillopharyngitis Vitamin D level (ng/ml) Duration of vitamin D therapy (mos)

65.72 2.54 23.62 9.91

28.11 1.55 9.22 5.81

60.00 2.00 23.00 12.00

67.36 8.42 19.73 9.38

29.75 1.55 8.77 6.29

60.00 8.00 18.00 12.00

0.782 0.0001 0.009 0.693

1SD: Standard deviation.

Table 2. Comparison of demographic characteristics of the patients based on vitamin D levels

Vitamin D deficiency <20 ng/ml

Vitamin D insufficiency 20-32 ng/ml

Vitamin D adequacy 32-100 ng/ml

p

n % Mean±SD n % Mean±SD n % Mean±SD

Patients 63 42.9 74 50.3 10 6.8 0.0001 Age (mos) 70.8±29.6 65.2±28.5 48.5±17.3 0.05 Gender (Female) 34 47.9 34 47.9 3 4.2 0.31 Episodes of 2URTI <7/yr 25 33.8 42 56.8 7 9.5 0.06 ≥7/yr 38 52.1 32 43.8 3 4.1 Levels of vitamin D (ng/ml) 13.8±4.15 25.4±3.36 43.2±10.11 0.0001 SD: Standard deviation; 2URTI: Upper respiratory tract infection.

16

Vitamin D level was deficient, insufficient, and adequate in 42.9 (n=63), 50.3 (n=74), and 6.8% (n=10) of the patients in the study population.

Although in patients with vitamin D deficiency, household members, and episodes of tonsillopharyngitis were more numerous, and the duration of vitamin D use was the shortest relative to the control group without any significant difference between groups as for demographic characteristics (p>0.05) (Table 2).

DISCUSSION Although our country takes advantage of the sunlight abundantly, vitamin D deficiency still continues to be an important health problem affecting pregnants, babies, and adolescents American Academy of Pediatrics recommends administration of 400 IU oral vitamin D supplementation beginning from the neonatal period, and continuing all along the infancy [9]. Although vitamin D supplementation program has been implemented in our country, especially in rural areas vitamin D deficiency is frequently encountered [10].

Detection of vitamin D receptors in many tissues of the body has led to the conduction of new studies on the functions, and correlations of vitamin D which plays an important role in the bone-mineral metabolism with various disease states [11].

Vitamin D exerts its effects through activation of vitamin D receptors which regulate transcriptions of target genes responsible for biological effects of its active form 1,25 (OH)2 D [12]. The presence of the receptor in immune system cells (dendritic cells, B-lymphocytes, T-lymphocytes, NK-cells, monocytes) has been demonstrated. Besides, genetic polymorphism in these cells which lead to modifications in the functions of immune cells has been indicated [13, 14, 15, 16]. Presence of vitamin D receptors in immune system cells, and various regulatory effects of these cells induced by stimulation of these receptors demonstrate the correlation between vitamin D, and especially with immune system of the upper respiratory tract [17].

Vitamin D has important roles in fighting against infectious agents, and in individuals with vitamin D

North Clin Istanbul – NCI

deficiency, increase in the predisposition, and frequency of especially respiratory tract infections has been demonstrated. In their case-controlled studies performed among Ethiopian children less than 5 years of age with rickets, Muhe et al.[18] reported an existence of a correlation between vitamin D deficiency, and development of pneumonia. Wayse et al.[19] reported that in India, subclinical vitamin D insufficiency in children less than 5 years of age is an important risk factor for the development of serious lower respiratory tract infection. In their series, Cannell et al.[20] indicated that the incidence of viral respiratory tract infection had increased in vitamin D insufficiency. Recurrent nature of acute tonsillopharyngitis has been reported in 10-15% of the pediatric cases [21, 22, 23]. Yildiz et al.[11] detected recurrent tonsillopharyngitis in 4.7% of the children referred to the polyclinics of general pediatrics In the literature, lower vitamin D levels were detected in children who had suffered from frequent episodes of tonsillopharyngitis [11, 24].

In our study, we detected lower vitamin D levels in children who suffered from frequent episodes of tonsillopharyngitis in consistent with the literature findings.

Yildiz et al.[11] reported that in patients with insufficient vitamin D levels, annual incidence rates of disease were markedly higher, and indicated that its incidence decreased directly proportional with increases in serum 25-(OH) vitamin D levels.

In the same study, despite serum vitamin D levels within normal limits in cases who had frequent episodes of tonsillopharyngitis, and in the control group, serum 25-(OH) vitamin D levels were significantly lower in the recurrent tonsillopharyngitis group (142.7±68.1 nmol/L) when compared with the control group (192.3±56.1 nmol/L).

In studies performed in adult patients similar outcomes have been found. Nseir et al.[25] detected significantly lower serum 25(OH) vitamin D levels in the group of patients who frequently suffered from group A beta-hemolytic streptococcal tonsillopharyngitis. Ginde et al.[26] detected the rate of URTI as 24, 20, and 17 % in patients with serum 25(OH) vitamin D levels of <10 ng/mL, 1030 ng/ml, and ≥30 ng/ml, respectively with statisti-

Collak et al., Serum vitamin D levels in children with recurrent tonsillopharyngitis

cally significant differences between groups. These outcomes demonstrate decrease in the frequency of tonsillopharyngitis in parallel with an increase in vitamin D levels.

However, some studies have demonstrated lack of any correlation between vitamin D levels, and frequent infections. In a study performed by Aydın et al.,[27] the authors couldn’t find a significant difference between patients who experienced frequent episodes of tonsillitis and tyhus underwent tonsellectomies and the control group regarding serum 25 (OH) vitamin D levels. Detection of similar serum vitamin D levels in both groups was interpreted as lack of any correlation between recurrent tonsillopharyngitis, and serum vitamin D levels.

Similarly, in other studies, various units of measurement, anmd cut-off values have been used for the definition of vitamin D deficiency. Since the definition of vitamin D deficiency has not been standardized, it is hardly possible to compare outcomes of our study with those of the others.

Serum 25 (OH) vitamin D levels less than 20 ng/ml (50 nmol/L) are defined as vitamin D deficiency, while serum vitamin D levels protective against infections, and those inducing immune system have not been clearly established yet [28, 29]. In our study, vitamin D levels were deficient, insufficient, and adequate in 42.9, 50.3, and 6.8% of the cases, respectively. The study population was divided into 3 groups as vitamin D deficient, insufficient, and adequate groups, and any significant difference was not detected between groups as for demographic characteristics, number of episodes of tonsillopharyngitis experienced, and duration of vitamin D use.

Vitamin D levels in children are influenced by maternal ,and environmental factors as daily diet, and sunlight [11, 27]. Protective role of vitamin D support against some diseases, predominantly upper, and lower respiratory tract infections in pregnancy, early childhood, and advanced age has been demonstrated [30, 31, 32]. However, controversial outcomes have been reported against protective role of vitamin D in upper respiratory tract infections [33, 34, 35]. Li-Ng et al. have demonstrated that daily 2000 IU vitamin D supplement for the

17

adults during winter months did not decrease the frequency, and severity of URTI [34]. Avenell et al. detected that administration of daily 800 IU vitamin D supplement decreased the incidence of infection at a rate of 10-15% without any statistically significant difference [35]. To reveal the correlation between vitamin D, and respiratory tract infection clearly, studies standardized according to seasons, dietary habits, the amount of sunlight exposure received by the countries, and regional clothing habits are needed.

One limitation of our study is that only a single measurement of vitamin D levels which show seasonal variations during the study period may not fully reflect vitamin D levels of the children.

In our country, vitamin D deficiency is an important public health problem which is often seen in pediatric cases with frequent tonsillopharyngitis.

We think that in children with frequent tonsillopharyngitis, as a result of treatment of deficiencies detected with measurement of serum vitamin D levels, frequency of diseases, and healthcare expenses will decrease.

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.

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3. Özkan B, Döneray H. D vitamininin iskelet sistemi dışı etkileri. Çocuk Sağlığı ve Hastalıkları Dergisi 2011;54:99-100.

4. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:26681.

5. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006;134:1129-40.

6. Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Endocrinol Metab Clin North Am

18 2010;39:365-79.

7. Walker VP, Modlin RL. The vitamin D connection to pediatric infections and immune function. Pediatr Res 2009;65:106R113R. 8. Hughes DA, Norton R. Vitamin D and respiratory health. Clin Exp Immunol 2009;158:20-5.

9. 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.

10. Hatun Ş, Bereket A, Çalıkoğlu AS, Özkan B. Günümüzde D vitamini yetersizliği ve nutrisyonel rikets. Çocuk Sağlığı ve Hastalıkları Dergisi 2003;46:224-41.

11. Yildiz I, Unuvar E, Zeybek U, Toptas B, Cacina C, Toprak S, et al. The role of vitamin D in children with recurrent tonsillopharyngitis. Ital J Pediatr 2012;38:25.

12. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 2005;289:F8-28.

13. Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 2001;15:2579-85.

14. Thien R, Baier K, Pietschmann P, Peterlik M, Willheim M. Interactions of 1 alpha,25-dihydroxyvitamin D3 with IL-12 and IL-4 on cytokine expression of human T lymphocytes. J Allergy Clin Immunol 2005;116:683-9.

15. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms.

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16. Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Endocrinol Metab Clin North Am 2010;39:365-79.

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18. Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet 1997;349:1801-4.

19. Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y. Eur J Clin Nutr 2004;58:563-7.

20. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006;134:1129-40.

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30. Boucher BJ, John WG, Noonan K. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;80:1666-7.

31. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.

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32. Nursyam EW, Amin Z, Rumende CM. The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med Indones 2006;38:3-5.

33. Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, Pihlajamäki H. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. J Infect Dis 2010;202:809-14.

34. Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, et al.

A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect 2009;137:1396-404.

35. Avenell A, Cook JA, Maclennan GS, Macpherson GC. Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). Age Ageing 2007;36:574-7.

Orıgınal Article

FAMILY MEDICINE

North Clin Istanbul 2014;1(1):19-25 doi: 10.14744/nci.2014.39974

Effects of smoking on healthy young men’s hematologic parameters Besime Inal1, Tuba Hacıbekiroglu2, Bilger Cavus3, Zeliha Musaoglu1, Hatice Demir4, Berrin Karadag5 Department of Family Medicine, Pinarhisar State Hospital, Kirklareli, Turkey;

1

Department of Hematology, Edirne State Hospital, Edirne, Turkey;

2

Department of Internal Medicine, Pinarhisar State Hospital, Kırklareli, Turkey;

3

Department of Biochemistry, Kirklareli State Hospital, Kirklareli; Turkey;

4

Department of Geriatrics, Acibadem University Faculty of Medicine, Istanbul, Turkey

5

ABSTRACT OBJECTIVE: Cigarette smoking carries higher risks for most of the chronic diseases. It also has chronic and acute effects over the hematologic system. This study explores the effects of cigarette smoking on some blood values of the healthy young male smokers.

METHODS: In this study, cigarette smoking and usage of substance, additional diseases, birth places, and education levels of 171 healthy male subjects between the ages of 20 and 30 years were investigated. Anthropometric measurements of the cases were obtained. The values of Thyroid function tests, vitamin B12, folic acid, ferritin, ferrous/ıron, total ıron binding capacity, leucocytes, platelet, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean platelet volume (MPV), HBs AG, Anti-HBs and Anti-HIV were evaluated. Groups of smokers and nonsmokers were compared. The group of smokers was also sorted into subgroups of “2 year-smokers”, “5 yearsmokers” and “10 year-smokers” according to their pack-years of smoking. The effects of pack-years of smoking over the blood values were also investigated.

RESULTS: The MCV values of the group of smokers were higher than the values of nonsmokers, which was statistically significant (p<0.05). As a result of the subgroup analyses of smokers, the white blood cell (WBC) counts of the individuals smoking for 5 or more years were significantly higher than those with a history of smoking less than 5 years, (p<0.05).

CONCLUSION: This study supports the idea that cigarette smoking and especially longer durations of smoking have adverse effects on the hematologic parameters.

Key words: Cigarette, hematologic parameters, young man

Received: August 06, 2014 Accepted: August 12, 2014 Online: August 03, 2014 Correspondence: Besime INAL. Ankara Sami Ulus Cocuk Hastanesi, Balgat Semt Poliklinigi, Ankara, Turkey.

Tel: +90 312 - 317 07 07 e-mail: besimeinal@gmail.com © Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

20

S

moking is the most important public health problem. Many studies performed have proved its deleterious effects on many organ systems mainly respiratory,and cardiovascular systems. With 6000 chemical substance it contains, it exerts pharmacological, mutagenic, cancerogenic, toxic, and inflammatory effects [1]. Nowadays, it is responsible in every six cases of death [2]. Cigarette contains carcinogens (polycyclic aromatic hydrocarbons etc.), irritant substances, nicotine, carbonmonoxide, and other gases. Cigarette smoke contains many oxidants, and free radicals which can harm lipids, proteins, DNA, carbohydrates, and other biomolecules [3]. The effects of smoking on various metabolic, and biological processes, hormone secretion, and hematopoietic system have been demonstrated. In many studies, among acute effects of smoking on hematological system, increase in WBC, eosinophil, and platelet (PLT) counts have been shown [1]. A correlation was established between smoking, and WBC counts. Relatively higher WBC counts were detected in smokers [4, 5, 6, 7, 8, 9, 10]. Smoking has been suggested to increase the levels of hematological parameters as hemoglobin (Hb) concentration, red blood cell (RBC), neutrophil, eosinophil, monocyte, and PLT counts. Smoking cessation studies have demonstrated that some of these changes are reversible, and transitory in case of cessation of smoking [11]. In our study, we investigated the effects of smoking, and especially duration of smoking in healthy young men on anthropometric measurements, thyroid function tests, vitamin B12, folic acid, ferritin, serum iron, total iron binding capacity (TIBC), whole blood counts, HBsAg, anti-HBs, anti-HCV, and anti-HIV values.

MATERIALS AND METHODS Our cross-sectional study was performed on healthy 171 male patients aged 20-30 years who consulted to Pınarhisar State Hospital between October 2012, and February 2013 for any indication. The first group consisted of smokers, and the second group of life-time nonsmokers. The cases who had acute infections, chronic diseases, acute bleeding episodes, cancer patients, and corticosteroid drug

North Clin Istanbul – NCI

users were not included in the study. From available recordings, patient’s age, measurements of body weight (kg), height (cm), waist circumference, and blood pressures were retrieved. Measurements of body weight, and height were made while barefooted patients were wearing light clothes. Body mass index (BMI) was calculated by dividing body weight (kg) by square meter of the height. Waist circumference was measured from the midpoint between the costal arch, and spina iliaca anterior superior.

Arterial blood pressure (ABP) was measured using mercury sphygomanometer. The cuff of the sphygomanometer was wrapped around the arm with its lower end 2.5-3 cm away from the cubital fossa.

Cuff was placed on the brachial artery. Information about educational level, smoking status, substance use, and existing disease was recorded after verbal approval of the patient.

Thyroid function tests (thyroid stimulating hormone: TSH, free T4: fT4, free T3: fT3), vitamin B12, ferritin, and folic acid were analyzed with electrochemiluminescence method using Roche cobas e 601 device. Normal ranges of some analytes set for this device were: TSH, 0.27-4.20 uIU/mL; fT4, 12-22 pmol/L; fT3, 3.1-6.8) pmol/L, vitamin B1, 156-698 pmol/L; ferritin 30-400 ng/mL, and folic acid, 4.6-34.8 ng/mL. Hepatitis B surface antigen (HBsAg), antibodies both to the surface antigen (anti-HBs), HCV (antiHCV), Anti -HIV tests were analyzed in Roche cobas e 411 device using an electrochemiluminescence method. Normal ranges of some analytes set for this device were: HbsAg, 0-1 S/CO, Anti Hbs negativity, 0-9.999 IU/L, Anti Hbs positivity, ≥10 IU/L; Anti HCV 0-1 S/CO; Anti –HIV, 0-1 S/CO. Iron, and iron binding capacity were tested in Roche cobas c 501 device using a colorimetric method. Normal ranges for iron, and iron binding capacity were accepted as 33-193 ug/dl, and 250450 ug/dl, respectively.

Hemoglobin, hematocrit, white blood cell, and platelet counts, mean erythrocyte, and platelet volumes were assessed in ABX Pentra DF device using electronic cell counter method. Normal ranges of some analytes accepted for this device were: he-

Inal et al., Effects of smoking on healthy young men’s hematologic parameters

moglobin 11-16.5 g/dL, hematocrit 34-48%, WBC 3.8-9.8 103/uL; platelets, 180-350 103/uL; MCV, 80-100 fL, and MPV 7.6-10.8 fL. Statistical analysis For descriptive analysis of data mean, standard deviation, ratio, and frequencies were used. Distribution of variables was controlled with KolmogorovSmirnov test. In the analysis of quantitative data Mann-Whitney-U test, and independent sampling test, and for qualitative data chi-square test, and if

21

not suitable Fisher’s exact test were used. In statistical analyses, SPSS 21.0 program was used.

RESULTS A total of 171 healthy male individuals aged 20-30 years were included in the study, and divided into smoker (n=101), and nonsmoker (n=70) groups.

Between smoker, and nonsmoker youngsters, a significant difference was not found as for age, body weight, waist circumference, ABP, and co-

Table 1.

Anthropometric measurements, educational level, blood pressure values, substance use, hepatitis markers, and presence of comorbities groups of smokers, and nonsmokers

Smokers

Nonsmokers

p

n % Mean±SD n % Mean±SD

Age (years) 21.96±2.34 21.55±2.20 0.182 BMI (kg/m2) 23.91±3.35 22.67±3.57 0.022 Waist circumference (cm) 85.44±7.81 84.43±7.99 0.412

Educational level

None

Primary

Secondary

Lycée

University Hypertension (ABP) mmHg

Yes No Substance use

Yes No Comorbidity Yes

No HBsAg (S/CO) None Present AntiHBs (S/CO)

None

Present

1 1.4

3 3.0

13 18.3 20 28.2 18 25.3 19 26.8

11 11.0 51 51.0 22 22.0 13 13.0

68 95.8 3 4.2

95 95.0 5 5.0

0.813

70 98.6 1 1.4

89 89.0 11 11.0

0.016

67 94.4 4 5.6

91 91.0 9 9.0

0.413

71 100 0 0

96 96.0 4 4.0

0.088

43 60.6 28 39.4

51 51.0 49 49.0

0.215

BMI: Body Mass İndex; Chi-square test/Independent samples t-test/Mann-Whitney U test.

0.033

22

North Clin Istanbul – NCI

morbidities (p>0.05), (Table 1). BMIs, and educational level (lycée or university) were significantly lower in smokers when compared with nonsmokers (p<0.05). Still substance use among smokers, was significantly higher when compared with nonsmokers. (p<0.05), (Table 1). Smoking had not any significant effect on HBsAg, antiHBs, TSH, fT4, fT3, vitamin B12, folic acid, PLT, Hb, Htc, MPV, ferritin, iron, and TIBC values, however MCV values of young smokers were observedly higher than those of the nonsmokers (p<0.05), (Table 2).

When group of smokers was classified based on duration of smoking of <2 (Group 1), and ≥2 (Group 2) years, age, height, body weight, waist circumference, BMI, educational level, substance use, ABP values, incidence of comorbidities, HBsAg, antiHBs, TSH, fT4, fT3, vitB12, folic acid, WBC, PLT, Hb, Htc, MCV, MPV, ferritin, iron, TBIC values did not differ between groups (p>0.05).

Age, height, body weight, waist circumference, BMI, educational level, substance use, ABP values, incidence of comorbidities, HBsAg, antiHBs, TSH, fT4, fT3, vitB12, folic acid, WBC, PLT, Hb,

Htc, MCV, MPV, ferritin,iron, TBIC values did not differ according to years of smoking for less or more than 5 years, respectively (p>0.05). While WBC values were found to be significantly higher in young male individuals with a smoking history of ≥5 years (p<0.05), (Table 3).

Any significant difference was not detected as for height, body weight, waist circumference, educational level, substance use, comorbidities, and ABP values between groups of individuals with a smoking history of <10, and >10 years, respectively (p>0.05). While WBC values were found to be significantly higher in young male individuals with a smoking history of more than 10 years (p<0.05).

DISCUSSION Smoking is known as a high risk factor for cardiovascular diseases, hypertension, inflammation, stroke, coagulopathies, and respiratory diseases [4, 5, 6, 7, 8, 9, 10]. Besides, as shown in various studies, smoking accelerates cancerogenesis in various organs as lungs, pancreas, kidney, and liver [5, 6,

Table 2. Whole blood cell counts, and hormonal values of the groups

TSH (uIU/mL) Ft4 (pmol/L) Ft3 (pmol/L) VitB12 (pmol/L) Folic acid (ng/mL) WBC (uL) PLT (uL) Hb (g/dL) Htc (%) MCV (fL) MPV (fL) Ferritin (ng/mL) Iron (ug/dl) TIBC (ug/dl)

Nonsmokers Smokers p Mean±SD 1.86±0.81 15.46±1.97 5.77±0.67 206.80±81.57 6.93±1.69 7.23±1.94 250.41±59.12 14.98±1.09 44.97±3.63 84.34±3.68 7.58±0.89 88.72±67.41 86.56±34.02 334.61±54.76

Independent samples t-test / Mann-Whitney U test.

Mean±SD 1.74±0.83 15.55±1.70 5.77±0.66 216.09±81.25 6.65±1.83 7.36±1.85 246.62±70.17 15.11±1.42 44.76±5.45 85.59±3.94 7.66±1.28 82.06±65.64 89.20±35.21 330.91±57.19

0.340 0.740 0.971 0.463 0.298 0.675 0.323 0.520 0.874 0.035 0.671 0.498 0.623 0.670

m m

m

Inal et al., Effects of smoking on healthy young men’s hematologic parameters

23

Table 3. Correlations between cigarette smoking for less or more than 5 years, and some hematological parameters

Smoking history ≤5 years

Mean±SD

TSH (uIU/mL) Ft4 (pmol/L) Ft3 (pmol/L) vitB12 (pmol/L) Folic acid (ng/mL) WBC (uL) PLT (uL) Hb (g/dL) Htc (%) MCV (fL) MPV (fL) Ferritin (ng/mL) Iron (ug/dl) TBIC (ug/dl)

1.65±0.87 15.77±1.84 5.71±0.67 207.55±81.30 6.35±1.49 6.98±1.55 249.38±75.08 15.18±1.42 45.19±3.57 85.61±4.21 7.61±0.81 78.14±76.69 85.79±40.33 332.14±53.82

Smoking history <5 years

p

Mean±SD 1.85±0.77 15.28±1.49 5.83±0.64 226.96±80.79 7.03±2.14 7.83±2.10 243.11±64.05 15.01±1.43 44.21±7.18 85.57±3.61 7.72±1.70 87.05±48.51 93.55±27.19 329.34±61.81

0.230 0.158 0.374 0.238 0.063 0.022 0.779 0.564 0.236 0.961 0.674 0.085 0.276 0.809

m m

m

Independent samples t-test/Mann-Whitney-U test.

12]. Effects of smoking on hemapoietic system have been also analyzed in many studies. In our study, we also investigated the impact of smoking on hematological parameters.

The mechanism of action of smoking on WBC is not clear-cut yet. In smokers, lymphocytosis is thought to be mainly associated with increase in Tcells [13]. Nicotine which is a component of cigarette smoke, stimulates cathecolamine release, and induces increase in cortisol levels. Increases in peripheral blood WBC counts, and alterations in WBC function can be the result of direct damage stemming from alterations in epithelial, and endothelial surfaces and/or cytokine levels (especially IL-6) caused by components of cigarette smoke [14]. In a study on the impact of smoking on hematological parameters, WBC, red blood cells, Hb, and Htc levels were found to be markedly increased, while MCV, and platelet counts were lower. These changes have been associated with atherosclerosis, polycythemia vera, chronic obstructive pulmonary disease, and cardiovascular diseases, and also higher risk of atherosclerosis, polycythemia, chronic obstructive pulmonary

disease, and cardiovascular disease in smokers has been revealed [15]. Kurtoğlu et al. detected that smoking significantly increased WBC, neutrophil, lymphocyte, monocyte, platelet counts, Hb, Hct, and RBC indexes in both genders [16]. Also some studies comparing smoker, and nonsmoker groups have demonstrated increases in Hb, Hct, RBC, MCV, WBC, neutrophil, lymphocyte, eosinophil, and monocyte counts in both groups [17, 18, 19, 20, 21, 22]. Similarly when smokers, and nonsmokers were compared, rates of MCV were found to be significantly higher in smokers in compliance with the literature. Zafar et al. investigated the impact of smoking on RBC, WBC, and Hb, and indicated increases in WBC counts, and decreases in RBC, and WBC counts in smokers. Linear regression model demonstrated a positive correlation between number of pack-years, and total WBC count, and the authors stressed the importance of these increments. Presence of a positive correlation has been revealed between pack-years of smoking, and WBC counts. Studies displayed sustained, and important increments in WBC counts in line with pack-years.

24

Even smoking 10 cigarettes a day led to important increase in WBC counts [23].

In our study, when we analyzed the impact of years of smoking on WBC counts, we detected significant increases in WBC counts in individuals with a smoking history of 5 or more years. However in individuals who used tobacco products for less than 5 years, we couldn’t detect any effect of smoking on WBC counts. Our study population consisted of healthy young adults without any chronic disease. We think that effects of smoking in individuals without any history of chronic disease can be seen at an earlier phase.

The harmful effects of smoking on hematological parametres improve with a little bit decrease in the daily number of cigarettes smoked. If chronic smokers quit smoking, then, as has been demonstrated in many studies, most of the parameters related to red, and white blood cells rapidly return to their normal values [24].

Even though place of smoking in social life has changed in recent years, it is prevalent among people of lower socioeconomic status as had been previously. Smoking age has decreased down to pediatric age qwing to social pressure, and popular culture [25]. Our study population consisted of youngsters aged 20-30 years. Our cases with a median age of 21, comprised most of our study population who had been using tobacco products for 5 years. Some of our patients started to use cigarettes while they were just a small child, and continued to use them for 15 years. Substance use was more frequent among smokers. Educational level of smokers (lycée, and high school) was significantly lower relative to nonsmokers which reveals the importance of education. Awareness should be raised in the community about smoking, and its harmful effects. With decrease in the prevalence of smoking, the incidence of chronic diseases whose treatment incur a great financial burden on public expenditures will drop significantly.

In conclusion, in our study, unfavourable effects of smoking on hematological parameters have been demonstrated, and correlation between pack-years, and these harmful effects have been determined.

North Clin Istanbul – NCI

Physicians who have an important role in the protection of public health, should inquire from their patients about their smoking history at every visit, and recommend smoking cessation. Even though public awareness about harmful effects of smoking has been raised considerably, still every effort should be made on this issue.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Öztuna F. Sigaranın hücresel etkileri. Akkciğer Arşivi 2004;2:111-6.

2. Kumar Cotran Robbins. Basic pathology. Çevikbaş U. 6. Baskı, Elma Basım; 2000.

3. Al-Azzawy LHA, Al-Qaicy AGS. A study about some physiological parameters in smokers. Ibn Al-Haitham J for Pure & Appl 2011;24. Available at http://www.iasj.net/ iasj?func=fulltext&aId=5108.

4. Abel GA, Hays JT, Decker PA, Croghan GA, Kuter DJ, Rigotti NA. Effects of biochemically confirmed smoking cessation on white blood cell count. Mayo Clin Proc 2005;80:1022-8.

5. Yarnell JW, Baker IA, Sweetnam PM, Bainton D, O’Brien JR, Whitehead PJ, et al. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell collaborative heart disease studies. Circulation 1991;83:836-44.

6. Carel RS, Eviatar J. Factors affecting leukocyte count in healthy adults. Prev Med 1985;14:607-19.

7. de Heens GL, Kikkert R, Aarden LA, van der Velden U, Loos BG. Effects of smoking on the ex vivo cytokine production in periodontitis. J Periodontal Res 2009;44:28-34.

8. Wannamethee SG, Lowe GD, Shaper AG, Rumley A, Lennon L, Whincup PH. Associations between cigarette smoking, pipe/ cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease. Eur Heart J 2005;26:1765-73.

9. Freedman DS, Flanders WD, Barboriak JJ, Malarcher AM, Gates L. Cigarette smoking and leukocyte subpopulations in men. Ann Epidemiol 1996;6:299-306.

10. Van Tiel E, Peeters PH, Smit HA, Nagelkerke NJ, Van Loon AJ, Grobbee DE, et al. Quitting smoking may restore hematological characteristics within five years. Ann Epidemiol 2002;12:37888.

11.

McKarns SC. Smoker-nonsmoker comparative study.

1992:3070.

12. Islam MM Amin MR, Begum S, Akther D, Rahman A. Total

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count of white blood cells in adult male smokers. J Bangladesh Soc Physiol 2007;2:49-53.

13. Silverman NA, Potvin C, Alexander JC Jr, Chretien PB. In vitro lymphocyte reactivity and T-cell levels in chronic cigarette smokers. Clin Exp Immunol 1975;22:285-92.

14. Smith MR, Kinmonth AL, Luben RN, Bingham S, Day NE, Wareham NJ, et al. Smoking status and differential white cell count in men and women in the EPIC-Norfolk population. Atherosclerosis 2003;169:331-7.

15. Asif M, Karim S, Umar Z, Malik A, Ismail T, Chaudhary A. Effect of cigarette smoking based on hematological parameters: comparison between male smokers and nonsmokers. Turkish Journal of Biochemistry-Turk J Biochem 2013;38:75-80.

16. Kurtuğlu E, Uğur A. Sigara kullanımının kan sayımı parametreleri üzerine etkileri. XXXIII. Ulusal Hematoloji Kongresi özet kitabı, Ankara: 2007:34.

17. Corre F, Lellouch J, Schwartz D. Smoking and leucocyte-counts.

Results of an epidemiological survey. Lancet 1971;2:632-4.

18. Helman N, Rubenstein LS. The effects of age, sex, and smoking on erythrocytes and leukocytes. Am J Clin Pathol 1975;63:3544.

19. Dodsworth H, Dean A, Broom G. Effects of smoking and the pill on the blood count. Br J Haematol 1981;49:484-8.

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20. Tollerud DJ, Clark JW, Brown LM, Neuland CY, Mann DL, Pankiw-Trost LK, et al. The effects of cigarette smoking on T cell subsets. A population-based survey of healthy caucasians.

Am Rev Respir Dis 1989;139:1446-51.

21. Yarnell JW, Sweetnam PM, Rogers S, Elwood PC, Bainton D, Baker IA, et al. Some long term effects of smoking on the haemostatic system: a report from the Caerphilly and Speedwell Collaborative Surveys. J Clin Pathol 1987;40:909-13.

22. Whitehead TP, Robinson D, Allaway SL, Hale AC. The effects of cigarette smoking and alcohol consumption on blood haemoglobin, erythrocytes and leucocytes: a dose related study on male subjects. Clin Lab Haematol 1995;17:131-8.

23. Zafar I, Mohammad KN, Nisar M, Rashida M, Shumaila B..

Effect of cigarette smoking on erythrocytes, leukocytes and haemoglobin. Journal of Medical Sciences 2003;3:245-50.

24. Bain BJ, Rothwell M, Feher MD, Robinson R, Brown J, Sever PS. Acute changes in haematological parameters on cessation of smoking. J R Soc Med 1992;85:80-2.

25. Önen ZP, Şen E, Eriş Gülbay B, Öztürk A, Akkoca Yıldız Ö, Acıcan T ve ark. Farklı tedavi yöntemlerinin sigara bırakma başarısı üzerine etkilerini değerlendirmek. Türk Toraks Derneği 11. Yıllık Kongresi, 23-27 Nisan 2008, Antalya: 2008. p. 337.

Orıgınal Article

INFECTIOUS DISEASES & MICROBIOLOGY

North Clin Istanbul 2014;1(1):26-32 doi: 10.14744/nci.2014.27247

Comparison of adefovir dipivoxil and pegylated interferon alpha-2a treatment in chronic hepatitis B patients Pinar Korkmaz1, Gaye Usluer2, Ilhan Ozgunes2, Elif Doyuk Kartal2, Nurettin Erben2, Saygin Nayman Alpat2 Department of Infectious Diseaes and Clinical Microbiology, Yunus Emre State Hospital, Eskisehir, Turkey;

1

Department of Infectious Diseaes and Clinical Microbiology, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey

2

ABSTRACT OBJECTIVE: In this study, we aimed to evaluate the efficacy of pegylated interferon alpha 2a and adefovir dipivoxil treatment in chronic hepatitis B patients.

METHODS: This study was performed on patients treated for chronic hepatitis B in the Infectious Disease Clinic of Eskişehir Osmangazi University between 01.09.2005 and 31.03.2008. A total of 30 patients aged between 18 and 65 years constituted the study group. One of patient groups received (10 HBeAg negative, 4 HBeAg positive) PEG-IFN alpha 2a at ¬a dose of 180 μg/once a week, whereas the other group (11 HBeAg negative, 5 HBeAg positive) received daily oral doses of 10 mg ADV. Treatment responses were evaluated at week 48.

RESULTS: Reductions in serum HBV DNA levels at the end of 48 weeks were 4.8 log10 copy/ml and 4.2 log10 copy/ml in HBeAg negative patients who received ADV or PEG-IFN alpha 2a, , respectively. Biochemical response rates were 60% and 91% in PEG-IFN alpha 2a and ADV groups, respectively. Among HBeAg positive patients, reductions in serum HBV DNA levels were 3. 2 log10 copy/ml and 4 log10 copy/ml in ADV and PEG-IFN alpha 2a groups, at week 48, respectively. Biochemical response rates were 50% and 40% in PEG-IFN alpha 2a and ADV groups, respectively. No significant difference was determined in biochemical and virological responses in HBeAg positive and negative patients between PEG-IFN alpha 2a and ADV groups, at week 48. When both treatment groups were evaluated for side effects, it was observed that side effects were significantly common in PEG-IFN alpha 2a group.

CONCLUSION: When we compared PEG-IFN alpha 2a and ADV treatment in both HBeAg positive and negative patients, biochemical and virological response at 48 weeks were similar.

Key words: Adefovir dipivoxil, chronic hepatitis B, pegylated interferon alpha 2a

Received: June 08, 2014 Accepted: August 07, 2014 Online: August 03, 2014 Correspondence: Pinar KORKMAZ. Uluonder Mahallesi, Salih Bozok Cad., No: 23, Tepebasi, Eskisehir 26200, Turkey.

Tel: +90 222 - 211 95 95 e-mail: drpinarkor@gmail.com © Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

Korkmaz et al., Adefovir dipivoxil and pegylated interferon alpha-2a treatmenthepatitis B patients

N

early 350 million people in the world have been estimated to contract chronic hepatitis B (CHB). Chronic hepatitis B patients have a higher risk of developing cirrhosis, hepatic failure, and hepatocellular carcinoma (HCC) [1]. Every year nearly one million people die from end-stage hepatic failure, and eventually 5-10% of them require liver transplantation [2]. Effective treatment modalities are needed to prevent progression of CHB to HCC, and death [3]. Therapeutic targets include suppression of the HBV replication, histopathological recovery of the liver, eradication of HBV, prevention of cirrhosis, and HCC, and prolongation of life span [4].

Currently, drugs used in the treatment of CHB are conventional interferon-alpha, pegylated interferon-alpha (PEG-IFN α-2a and α-2b), lamivudine, telbivudine, emtricitabine, entecavir, adefovir dipivoxil (ADV), and tenofovir [2].

Interferons (IFNs) have antiviral, antiproliferative, and immunomodulator effects. Because of short half-lives of classical interferons, fluctuations in blood levels of these drugs can be seen which decrease antiviral efficacy of them. Side effects are more frequently seen when conventional interferons reach to their peak serum levels. To preclude these disadvantages polyethylene glycol molecules were added to interferons, and pegylated interferons have been obtained. Thus, half-lives of interferons are prolonged, and once weekly doses have ensured sustained antiviral response [5, 6].

Non-interferon treatment alternatives of CHB include nucleotide analogues. Adefovir, is a prodrug of ADV. Adefovir is a acyclic nucleotide analogue of adenosine diphosphate [7]. Adefovir is phosporylated to its active metabolite adenosine diphosphate by cellular kinases. Following entry of adefovir diphosphate into viral DNA, it depletes DNA with resultant inhibition of HBV DNA polymerase. It is a weak inhibitor of human DNA polymerases [8].

This study was planned to compare therapeutic effectiveness of 48 weeks of ADV, and PEG-IFN α-2a therapies in CHB patients followed up in clinics of infectious diseases of our university hospital.

27

MATERIALS AND METHODS A total of 30 patients (HBeAg negative, n=21, and HbeAg positive, n=9) who were followed up in the Department of Infectious Diseases of our University hospital between 09.01. 2005, and 03.31. 2008 were included in the study. Approval of the Ethics Committee of our University was obtained. All patients were informed about the study, and they were enrolled in the study after receival of their written informed consent.

Inclusion criteria: • Male, and female patients aged between 18-65 years whose HbsAg positive status lasted for more than 6 months, • HBeAg-negative CHB patients with HBV DNA levels over 10 4 copies/ml, and elevated (1.3-10 ULN) or normal (0-40 IU/L) alanine aminotransferase (ALT) levels • HBeAg-positive CHB patients with HBV DNA values over 105 copies/ml together with elevated or normal ALT levels, • Previously untreated patients or those with posttreatment recurrences (cases who received last dose of treatment 6 months ago) Exclusion criteria: • Patients who received CHB treatment within the previous 6 months, those with hepatitis A, C or D or HIV co-infection, pregnancy, autoimmune disease, malignancy, decompensated liver disease, metabolic liver disease, severe psychiatric disease, serious cardiac, and pulmonary diseases, decreased Hb values (<12 g/ dl in female, and le <13 g/dl in male patients), lower neutrophil counts (<1500/mm3), and increased (>1.5 mg/dl) creatinine levels.

Patients who met inclusion criteria underwent liver biopsy, and patients with biopsy-proven chronic liver disease were divided into 2 groups.One of these groups received weekly subcutaneous doses of 180 µg PEG-IFN α-2a, while the other group was treated with daily oral doses of 10 mg ADV. Evaluation period was determined as 48 weeks. Patients who received pegylated interferon were monitored at the end of the first month of the treatment, and

28

North Clin Istanbul – NCI

then at 4-weekly intervals. In the ADV group, the first follow-up visit was performed at the end of the first month, then at 3-weekly intervals. Serum HBV DNA levels were measured using Corbett Real Time PCR method (viral load detection range of the device: 102-1011) Evaluation of the treatment modalities: Drop in serum HBV DNA levels down to undetectable levels at the end of 48. weeks as measured with PCR method was evaluated as virological response. However, regression of ALT levels down to normal limits was considered as biochemical response. In HBeAg-positive patients, clearance of HBeAg, and anti-Hbe positivity were evaluated as HBeAg seroconversion.

For statistical analysis, SPSS 13.0, and Sigmastat package programs were used.In statistical analysis, normality tests, frequency tables, T-test, Mann Whitney U-test, two way repeated measures ANOVA, and chi-square tests were used. P<0.05 was considered as the level of statistical significance.

RESULTS Study population consisted of 11 female (36.6%), and 19 male (63.4%) patients. Baseline characteristics of HBeAg-positive, and negative patients are seen in Table 1.

Table 1.

Any difference was not detected between groups of patients who received PEG-IFN α-2a or ADV as for reduction in HBV DNA values at the end of 12., 24., and 48. weeks (p>0.05) (Table 2). A significant difference was not detected among HBeAg –positive, and HbeAg-negative patients in the PEG-IFN α-2a and ADV groups with respect to biochemical, and virological response rates (p>0.05) (Table 3).

HBeAg negativity was achieved in one patient in both PEG-IFN α-2a, and ADV groups.

During the treatment process of the patients who received PEG-IFN α-2a, side effects such as fever, headache, dizziness, lassitude, myalgia, nausea, abdominal pain, dry mouth, nosebleed, pruritus, dry skin, and itching, reaction at the injection site, hair loss, weight loss, loss of appetite, irritability, and insomnia were seen. However, neutropenia, thrombocytopenia, and thyroid dysfunction were the most frequently detected biochemical abnormalities. Dose modifications were made in 42.8% of the patients who received PEG-IFN, and treatment of none of these patients was prematurely terminated because of development of side effects.

Emergence of neutropenia, and thrombocytopenia required dose reduction in 28.5, and 14.3% of the patients who received PEG-IFN, respectively.

(Table 4). However in the ADV treatment group, most frequently seen side effects were headache

Baseline characteristics of the patients

Characteristics

Age (years) Gender Female Male ALT* HBV DNA (log 10 copies/ml)* Fibrosis*

HBeAg (-)

HBeAg (+)

‡ PEG-IFN

ADV p alpha 2a

†

33.2±10.3

43.2±9.3

<0.05

PEG-IFN alpha 2a

28.7±9.9

ADV

p

30.6±5.9

>0.05

2 (20%) 5 (45.5%) >0.05 – 4 (80%) <0.05 8 (80%) 6 (54.5%) 4 (100%) 1 (20%) 126.70±177.24 89.18±77.73 >0.05 254.75±128.26 148.8±171.30 >0.05 5.36±0.72 6.39±1.67 >0.05 7.3±1.2 6.9±1.2 >0.05 1.50±0.85

2±1.09 >0.05 2.25±0.95

*Mean±SD; †PEG-IFN alpha 2a, pegylated interferon-alpha 2a; ‡ADV, adefovir dipivoxil.

1.80±1.3 >0.05

Korkmaz et al., Adefovir dipivoxil and pegylated interferon alpha-2a treatmenthepatitis B patients

29

Table 2. Mean HBV DNA values at certain time points of PEG-IFN alpha 2a, and ADV treatment in patients with HBeAg negative, and positive patients HBV DNA (10 log copies/ml) *

Onset of treatment 12. weeks 24. weeks 48. weeks

HBeAg (–)

HBeAg (+)

‡ PEG-IFN

ADV p alpha-2a

†

5.3±0.7 1.1±1.2 1.1±1.1 1.1±1.8

6.3±1.6 2.2±2.4 1.6±2.2 1.5±1.8

>0.05 >0.05 >0.05 >0.05

PEG-IFN alpha-2a

†

7.39±1.21 3.3±3.0 3.5±2.2 3.3±2.7

ADV p

†

6.9±1.2 5.1±2.7 4.2±3.9 3.7±3.4

>0.05 >0.05 >0.05 >0.05

*Mean±SD; †PEG-IFN alpha 2a, pegylated interferon-alpha 2a; ‡ADV, adefovir dipivoxil.

Table 3. Biochemical, and virological response rates (n, %) Characteristics

obtained with PEG-IFN α-2a, and ADV treatments

HBeAg (–)

†

Biochemical responses, n Virological responses, n

6 (60%) 9 (90%)

HBeAg (+)

‡ PEG-IFN

ADV p alpha-2a

10 (91%) 9 (82%)

>0.05 >0.05

PEG-IFN alpha-2a 2 (50%) 1 (25%)

ADV

p

2 (40%) 2 (40%)

>0.05 >0.05

*PEG-IFN alpha 2a, pegylated interferon-alpha 2a; †ADV, adefovir dipivoxil.

(n=3; 18.7%), abdominal pain (n=2; 12.5%), and dyspepsia (n=2; 12.5%). In none of the patients in the ADV group increase in serum creatinine values, and alterations in serum phosphorus levels were seen.

DISCUSSION Both PEG-IFN α-2a, and ADV are among recommended treatment modalities for CHB both in national, and international consensus reports [2, 4, 9, 10].

In the evaluation of treatment response in CHB, normalization of serum ALT levels, decrease in serum HBV DNA levels, loss of HbeAg in HbeAg positive patients, and improvement in histopathological markers of CHB are taken into consid-

eration. Endpoints for CHB are normalization of ALT, loss or seroconversion of HBV DNA in HBeAg positive patients, and improvement in histopathological markers of CHB [11, 12].

In the treatment, decrease in HBV DNA levels is important as for the suppression of viral replication. In HBeAg negative patients, Marcellin et al. detected a decrease of 4.1 log copies/ml in the level of HBV DNA, at the end of the treatment with PEG-IFN α-2a, while Hadziyannis et al. revealed a decrease of 3.91 log copies/ml in the level of HBV DNA following 48 weeks of treatment with ADV. [13, 14]. In our study, decreases in the mean HBV DNA values were detected at the end of 48 weeks in the group of patients who received PEG-IFN α-2a or ADV (at levels of 4.2, and 4.8 log copies/ml , respectively). A statistically significant difference was

30

North Clin Istanbul – NCI

Table 4. Mean HBV DNA values at certain time points of PEG-IFN alpha 2a, and ADV treatment in patients with HBeAg negative, and positive patients Side effect

n

%

Fever 13 92.9 Weight loss 13 92.9 Headache 10 71.4 Hair loss 9 64.3 lassitude 12 85.7 Muscle pain 12 85.7 Abdominal pain 4 28.6 Dry mouth 6 42.9

not found between both groups as for decreases in HBV DNA values at the end of 48 weeks (p>0.05).

Cooksley et al. and also Caruntu et al. detected decreases in post-treatment HBV DNA levels in HbeAg positive patients who received PEG-IFN α-2a (decreases of 3.5, and 3 log copies/ml, respectively [15, 16]. Marcellin et al. detected a decrease in HBV DNA levels at a rate of 3.5 log copies/ml, and Zeng et al. disclosed a drop of 4.2 log copies/ml in HBeAg positive patients who received ADV [17, 18]. In our patients who received PEG-IFN α-2a, HBV DNA levels decreased down to 4 log copies/ ml, while in the ADV group a decrease in HBV DNA levels was at a rate of 3.2 log copies/ml at the end of 48 weeks. A significant difference couldn’t be found between both groups as for decrease in HBV DNA values at the end of 48 weeks (p>0.05).

Marcellin et al. detected end-treatment virological response (HBV DNA <400 copies/ml) rates in HBeAg- negative patients who received PEGIFN α-2a (63%), PEG-IFN –LAM combination (87%) or LAM (73%), as indicated in parentheses [13]. Hadziyannis et al. reported median virological response rate of 51% in HBeAg negative patients under ADV treatment at the end of 48 weeks [14].

Virological response rates in patients who received PEG-IFN α-2a or ADV were 90, and 82 % at the end of 48 weeks, respectively. A significant differ-

Side effect

n

Dry skin. itching Nosebleed Injection site reaction Loss of appetite Thyroid dysfunction Neutropenia Thrombocytopenia Change in dosage, because of Leukopenia Thrombocytopenia

10 9 3 4 3 13 10 6 4 2

% 71.4 64.3 21.4 28.6 21.4 93 71.4 42.8 28.5 14.3

ence could not be found as for virological response rates as assessed at the end of 48 weeks (p>0.05).

Lau et al. had detected end-treatment virological response rates (HBV DNA <400 copies/ml) in HBeAg positive patients who received PEG-IFN α-2a (25%), pegylated interferon alpha-LAM combination (69%), and LAM (40%) as indicated in parentheses [3]. Cooksley et al. noted end-treatment virological response rate in the PEG-IFN α-2a group as 39 percent. While, Marcellin et al. revealed a 21% virological response rate in HBeAg positive patients who received ADV [15, 17]. In a study performed in our country, end-treatment virological response rate (HBV DNA <400 copies/ml) was detected as 33.3% in HBeAg positive patients who received PEG-IFN α-2a [19]. Virological response rates at the end of 48 weeks in our patients who received PEG-IFN α-2a or ADV were found to be 25, and 40%, respectively. A significant difference was not noted between both treatment groups as for virological response rates at the end of 48 weeks (p>0.05).

Another parametre indicative of treatment response, at the end of the treatment is normalization of ALT levels. Different ALT normalization rates were detected in HbeAg positive patients who received PEG-IFN α-2a (Lau et al., 41%) or ADV (Marcellin et al., 48%) [3, 17]. In our HBeAg posi-

Korkmaz et al., Adefovir dipivoxil and pegylated interferon alpha-2a treatmenthepatitis B patients

tive patients end-treatment ALT normalization rates were 40% in the ADV, and 50% in the PEGIFN α-2a groups. A significant intergroup difference could not be found as for mean ALT normalization rates at the end of 48 weeks (p>0.05).

Post-treatment ALT normalization rates were found to be 59%, and 77% in HBeAg negative patients treated with PEG-IFN α-2a (Marcellin et al.) or ADV (Hadziyannis et al.), respectively [13,14].

In a study performed in our country by Karabay et al., post-treatment biochemical response rate in HBeAg negative patients receiving PEG-IFN α-2a was detected to be 37.1 percent [20]. ALT normalization rates in our HBeAg negative patients receiving PEG-IFN α-2a or ADV were 60, and 91%, respectively. At the end of 48 weeks, both groups did not differ as for biochemical response rates (p>0.05).

Dogan et al. couldn’t detect HBeAg seroconversion at the end of 48 weeks in HBeAg positive patients who received PEG-IFN α-2a [19]. In our study, HBeAg negativity was achieved in one patient in both HBeAg treatment groups, without any significant intergroup difference (p>0.05). HBeAg seroconversion was not observed in both groups.

However because of scarcity of our patient population, larger scale studies should be performed for the evaluation of this issue.

Most frequently seen side effects in our PEGIFN α-2a group were fever, myalgia, lassitude, weight loss, skin itching, and dryness, nosebleed, headache, hair loss, and dry mouth, However in our ADV group mostly seen side effects were abdominal pain, headache, and dyspepsia. Our results related to side effects were in accordance with those of the other studies [13, 14, 15, 21, 22, 23, 24, 25]. Remarkably, greater number of side effects were seen in the PEG-IFN α-2a group relative to the ADV group.

In 42.8% of our patients who received PEGIFN α-2a, treatment dose was changed Most frequent causes of dose alterations were neutropenia, and thrombocytopenia. These results were in accordance with those of the other studies [5, 13]. In the PEG-IFN α-2a group dose alterations were re-

31

quired because of development of side effects, however in our ADV group dose modifications were not necessitated. In both groups, any condition which required discontinuation of treatment because of side effects was not encountered.

In conclusion, 48 weeks of PEG-IFN α-2a, and ADV treatments in both HBeAg positive, and negative patients are not superior to each other with respect to biochemical, and virological response rates. When these medications were evaluated as for side effects developing during treatments, PEGIFN α-2a therapy adversely effected quality of life of the patients more frequently. Evaluation of sustained viral response is important in the selection of treatment modality. Lack of any parametres which allow us to evaluate sustained viral, and histological response suggests the need for long-term studies which would evaluate therapeutic efficacy.

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.

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2. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-85.

3. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-95.

4. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661-2.

5. Keating GM. Peginterferon-alpha-2a (40 kD): A review of its use in chronic hepatitis B. Drugs 2009;69:2633-60.

6. Harris JM, Martin NE, Modi M. Pegylation: a novel process for modifying pharmacokinetics. Clin Pharmacokinet 2001;40:53951.

7. Kumar A, Dwivedi M, Misra SP, Narang S, Tiwari BK, Pandey R. Clinical profile, genotype and management updates of hepatitis B virus. Indian J Virol 2011;22:1-10.

8. Dando T, Plosker G. Adefovir dipivoxil: a review of its use in chronic hepatitis B. Drugs 2003;63:2215-34.

9. Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al. A treatment algorithm for the management of

32 chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008;6:1315-41; quiz 1286.

10. Hui AY, Chan HL, Cheung AY, Cooksley G, Sung JJ. Systematic review: treatment of chronic hepatitis B virus infection by pegylated interferon. Aliment Pharmacol Ther 2005;22:519-28.

11. Dienstag JL. Hepatitis B virus infection. N Engl J Med. 2008;359:1486-500.

12. Hadziyannis SJ. New developments in the treatment of chronic hepatitis B. Expert Opin Biol Ther. 2006;6:913-21.

13. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-17.

14. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003;348:800-7.

15. Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003;10:298-305.

16. Caruntu FA, Streinu-Cercel A, Gheorghe LS, Grigorescu M, Sporea I, Stanciu C, et al. Efficacy and safety of peginterferon alpha-2a (40KD) in HBeAg-positive chronic hepatitis B patients.

J Gastrointestin Liver Dis 2009;18:425-31.

17. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003;348:80816.

18. Zeng M, Mao Y, Yao G, Wang H, Hou J, Wang Y, et al. A

North Clin Istanbul – NCI double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B. Hepatology 2006;44:108-16.

19. Dogan UB, Golge N, Akin MS. The comparison of the efficacy of pegylated interferon α-2a and α-2b in chronic hepatitis B patients. Eur J Gastroenterol Hepatol 2013;25:1312-6.

20. Karabay O, Tuna N, Esen S; PEG-HBV Study Group. Comparative efficacy of pegylated interferons α-2a and 2b in the treatment of HBeAg-negative chronic hepatitis B infection. Eur J Gastroenterol Hepatol 2012;24:1296-301.

21. Tözün N, Sezgın O, Gülşen M, Kacar S, Yenıce N, Yilmaz Ş, et al. Safety of peginterferon alfa-2a (40KD) treatment in patients with chronic hepatitis B infection: an observational, multicenter, open label, non-interventional study in Turkish patients. Turk J Gastroenterol 2012;23:552-9.

22. Kartal ED, Alpat SN, Ozgunes I, Usluer G. Adverse effects of high-dose interferon-alpha-2a treatment for chronic hepatitis B. Adv Ther 2007;24:963-71.

23. Brunetto MR, Oliveri F, Coco B, Leandro G, Colombatto P, Gorin JM, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J Hepatol 2002;36:263-70.

24. Piccolo P, Lenci I, Demelia L, Bandiera F, Piras MR, Antonucci G, et al. A randomized controlled trial of pegylated interferonalpha2a plus adefovir dipivoxil for hepatitis B e antigen-negative chronic hepatitis B. Antivir Ther 2009;14:1165-74.

25. Sun J, Hou JL, Xie Q, Li XH, Zhang JM, Wang YM, et al. Randomised clinical trial: efficacy of peginterferon alfa-2a in HBeAg positive chronic hepatitis B patients with lamivudine resistance.

Aliment Pharmacol Ther 2011;34:424-31.

Orıgınal Article

PTR

North Clin Istanbul 2014;1(1):33-38 doi: 10.14744/nci.2014.77487

Efficacy of extracorporeal shock wave therapy in the treatment of lateral epicondylitis Korhan Bayram1, Hilal Yesil2, Erdal Dogan3 Department of Physical Medicine and Rehabilitation, Izmir Katip Celebi University Faculty of Medicine, Izmir, Turkey;

1

Department of Physical Medicine and Rehabilitation, Usak State Hospital, Usak, Turkey;

2

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

3

ABSTRACT OBJECTIVE: Lateral epicondylitis is one of the widely seen lesions of the arm characterized by pain localized over lateral epicondyle which is the insertion site of the wrist extensors, and extensor muscles of the forearm. It is easy to diagnose lateral epicondylitis but treatment involves some inherent drawbacks. Conservative management includes non-steroidal anti-inflammatory drugs, ultrasound therapy, steroid injections, functional bracing, laser therapy and extracorporeal shock wave therapy, however none of these modalities have been shown to be really effective based on evidence-based data. Our study is aimed to determine the efficacy of extracorporeal shock wave therapy (ESWT) therapy in the treatment of lateral epicondylitis.

METHODS: A total of 12 patients with the diagnosis of lateral epicondylitis were included in the study and 3 sessions of ESWT was applied (1 session per week). Maximum grip strength and pain scores were assessed before and at 1. month after the treatment. Spesific tests for lateral epicondylitis were utilized and Turkish version of the Patient Rated Tennis Elbow Evaluation (PRTEE-T) questionnaire was administered and data obtained were analyzed.

RESULTS: Visual analog scale (VAS) scores were significantly lower (p<0.05) and grip strength significantly increased (p<0.05) one month after ESWT treatment. Overall PRTEE-T survey scores decreased significantly at first month (p<0.001) after treatment. Patient’s and physician’s global self-assessment scores were significantly lower after treatment (p<0.05).

CONCLUSION: To conclude, ESWT utilization in conservative treatment of lateral epicondyilitis was found to be effective on reducing pain, and improving functional activities and quality of life.

Key words: Conservative treatment; ESWT; lateral epicondylitis.

L

ateral epicondylitis is one of the widely seen lesions of the arm characterized by pain localized over lateral epicondyle which is the insertion

site of the wrist extensors, and extensor muscles of the forearm [1]. Its prevalence in general population ranges between 1-3% which peaks between 40-50

Received: May 30, 2014 Accepted: June 16, 2014 Online: August 03, 2014 Correspondence: Hilal YESIL. Usak Devlet Hastanesi, Fiziksel Tip ve Rehabilitasyon Bolumu, Usak, Turkey.

Tel: +90 232 - 390 24 32 e-mail: dradanur@yahoo.com © Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

34

years of age [2, 3, 4]. It is seen more frequently in females, and more often affects the dominant hand [2, 3, 4]. Although its etiology is not known fully, reports indicate potential roles of aging, chemical, vascular, hormonal, and hereditary factors [5].

Lateral epicondylitis is frequently seen in individuals performing activities which repetitively strain extensor muscles of the wrist. It is characterized by pain, and decrease in grip strength which might manifest with resisted wrist extension, and extension of the middle finger accompanied with restriction of daily living activities [6]. Generally range of joint motion (ROM) is not affrected in lateral epicondylitis.

Increase in the severity of pain with palpation of the lateral epicondyle, and positivity of at least one of the tests which aggravate pain have diagnostic values [7]. A gold standard treatment modality for the management of lateral epicondylitis has not been found up to now owing to uncertainties in the etiology, and pathophysiology of the disease [8,9]. Basic principles of the treatment include pain relief, acceleration of the healing process, refraining from activities overloading arms, and patient’s return to daily living activities. Conservative treatment alternatives include medical treatment, resting, use of splint, and orthosis, application of ice, electrotherapy, massage, manipulation-mobilization, exrcise, and extracorporeal shock wave therapy (ESWT) [10, 11, 12].

Extracorporeal shock wave therapy has been reportedly successful in 48-73% of the cases with lateral epicondylitis who were refractoryother nonsurgical treatment alternatives [13]. Its noninvasive nature, and lower complication rates has increased its frequency of use. However, the mechanism of the symptomatic improvement achieved in lateral epicondylitis with shock waves, and its most effective curative doses have not been fully elucidated yet. This has been planned to determine the efficacy of shock wave therapy in patients with the diagnosis of lateral epicondylitis.

MATERIALS AND METHODS Our study was performed as a multi-centered prospective investigation aiming at determination of

North Clin Istanbul – NCI

efficacy of shock wave therapy in the treatment of the patients with the diagnosis of lateral epicondylitis. After approval of the local ethics committee was obtained, a total of 12 patients aged between 35-80 years with the diagnosis of lateral epicondylitis who had not previously received shock wave therapy were included in the study. Exclusion criteria of our study were: presence of a different or multiple elbow problems, cervical or other upper extremity pathology, history of elbow joint operation, rupture of the elbow tendon, neurological affection, limited ROM of the joint because of known history of humerus, radius or ulnar fracture, pregnancy, hemostatic disorder, tumor or local or systemic infection of the upper extremity, and implanted pacemaker. The diagnosis of lateral epicondylitis was based on detailed physical examination, feeling of pain on the lateral side of the elbow, tenderness on lateral epicondyle, and clinical tests indicative of lateral epicondylitis [14, 15].

Before initiating treatment, enlightened consent forms were obtained from the patients.

Treatment Demographic data, duration of the disease, laterality of complaints, and dominant sides of involvement were recorded, and then a total of 3 sessions of shock wave therapy at weekly intervals were delivered using vibrolith ortho tip ESWT (ELMED Turkey) equipment. At each session shock wave therapy was applied on painful point(s) (10 Hz, 1.9 bar, 2000 shocks), using a electric gun with a R10 applicator tip and a skin protective gel. The application was well tolerated by the patients, any adverse effect (edema, pain etc) was not observed during the therapy, and none of the patients discontinued the treatment.

Assessments Before the treatment, and at 1. month after the treatment using Jamar® dynamometer maximum grip strength, and with visual analog scale (VAS) levels of patients’ pain perception were evaluated.

Mean values of 3 recurrent measurements performed using Jamar dynamometer (which displays

Bayram et al., Efficacy of extracorporeal shock wave therapy in the treatment of lateral epicondylitis

grip force in pounds) while the patient was sitting erect, with his/her shoulder in adduction, elbow at 90o flexion, supported forearm at midrotation, and wrist in neutral position, were recorded. Pain levels felt by the patients during resting, under slight pressure on the epicondyle, and activity were evaluated on a 10 cm long-horizontal VAS scale. A 10 cm-long line was drawn, and the patients were requested to mark their perception level of pain on this line numbered from 0 to 10 at 1 cm intervals.

Then patient’s and the physician’s global assessment scores, and duration of paracetamol use by the patients were inquired, and recorded. Besides, tests specific to lateral epicondylitis (Maudsley’s, Mill’s, and Thomsen’s tests) were performed. For Thomsen’s test, the patients were seated on a chair with their elbows supported with a cushion placed on a table. Shoulder joint was kept in a slight degree of flexion, and elbow joint positioned in extension.

Forearm was placed in pronation, and wrist was flexed to nearly 30°. The patients were requested to extend their wrists, and asked them to resist the

Table 1.

35

forces exerted from the opposite direction. During this maneuver their feeling of pain was inquired.

If pain was elicited during this manipulation, then the result of this test was considered to be positive.

For Maudsley’s test , the patients were positioned as in Thomsen’s test., and requested to extend their middle fingers, Then the examiner pushed the 3. finger down, and asked the patient to resist. If this manoeuvre was painful then the test result was considered to be positive.

In Mill’s test, while the patient is seated on the chair, examiner standing behind the patient, positioned patient’s shoulder at 90° passive abduction, and elbow in extension, and with his/her free hand passively pronated and flexed patient’s wrist. The patient was questioned if this manoeuvre elicited pain (positive test result). Then Turkish version of the Patient Rated Tennis Elbow Evaluation Test (PRTEE-T) which contains subgroups of pain, special activities, and daily living activities especially constructed for patients with lateral epicondylitis was applied [16]. PRTEE-T questionnaire

Demographic, and clinical features of the patients n

%

Mean±SD

Age (years) 46.4±6.4 Gender Male 5 41.7 Female 7 58.3 Body mass index (kg/m2) 28.6±3.1 Occupation Housewife 5 41.7 Retired

4 33.3 Overuse of upper extremity

2 16.7 Other (phone operator) 1 8.3 Sportive activities/hobbies requiring overuse of hands 0 0 Duration of the disease (months) 3.5±3.2 Dominant hand Right 12 100 Left

0 0 Laterality of the painful side Right 10 83.3 Left 2 16.7

36

North Clin Istanbul – NCI

form consists of 15 items which makes us understand patient’s severity of pain, and amount of difficulties experienced because of his/her aching arm. It has two subscales specific to the patient as “Pain in the affected arm”, and “Function of the affected arm”. Total score is calculated by adding up pain and functional scores. Higher scores indicate increased pain, and functional disability (0= no disability).

Statistical evaluation For statistical analysis of data SPSS 14.01 program was used. In descriptive analysis, data were expressed as frequencies, ratios, and means, (±standard deviation). Differences between pre, and post-treatment values were evaluated using paired samples t test. P<0.05 was accepted as level of significance.

RESULTS Seven female (58.3%), and 5 (41.7%) male patients were included in the study. Mean age, and body

mass index of the patients were 46.4±6.4 years, and 28.6±3.1 kg/m2 (Table 1). Right hand dominancy was detected in all patients. Mean duration of the disease was 3.5±3.2 months. In 10 (83.3%) patients lateral epicondylitis of the right elbow was noted (Table 1).

VAS scores of the pain elicited with resting, compression, and activity significantly decreased at posttreatment 1. months when compared with pretreatment scores (p<0.05). As assessed with Jamar dynamometer, handgrip strength scores significantly increased at posttreatment 1. months relative to pretreatment values (p<0.05) (Table 2).

Total score of the PRTEE-T questionnaire demonstrated a significant drop at 1. months relative to pretreatment score (p<0.001). Patient’s and physician’s global posttreatment self-assessment scores also decreased significantly when compared with pretreatment values (p<0.05) (Table 2).

DISCUSSION Even though the diagnosis of lateral epicondylitis is

Table 2. Evaluation of pre-and post-treatment outcomes

Handgrip strength

Resting VAS

VAS with compression

VASb during activity

Patient’s global assessment

Physician’s global assessment

PRTEE (Total score)

pret postt pret postt pret postt pret postt pret postt pret postt pret postt

Mean±SD

1. month 1. month 1. month 1. month 1. month 1. month 1. month

42.92±22.51 58.75±21.23 2.67±2.01 1.17±1.27 8.42±0.90 3.92±2.68 8.00±0.96 4.92±1.92 4.33±2.53 2.92±1.44 3.58±0.79 2.08±0.51 91.50±11.24 55.83±11.69

t

p

3.506

0.005**

5.196

0.000***

5.817

0.000***

4.539

0.001**

2.376

0.037*

6.514

0.000***

12.340

0.000***

Pret: Pretreatment; Postt: Posttreatment; VAS: Visual analog scale; PRTEE: Patient Rated Tennis Elbow Evaluation. *Difference between pre-, and post-treatment values p<0.05, **Difference between pre-, and post-treatment values p<.,01, ***Difference between pre-, and post-treatment values p<0.001.

Bayram et al., Efficacy of extracorporeal shock wave therapy in the treatment of lateral epicondylitis

easily made, its treatment poses various difficulties.

Choice of treatment differs in individual patients, and depends on personal experience of the physicians. As conservative treatment modalities, nonsteroidal anti-inflammatory drugs, ultrasonographic applications, steroid injections, functional bracing, physical therapy, laser therapy, and shock wave therapy have been used, but currently none of them is really efficacious as assessed by evidence-based data [17,18].

In some studies performed, the effect of shock wave therapy in the treatment of lateral epicondylitis has been investigated, and success rates ranging between 68 and 91% have been reported [19]. However some studies have indicated that shock wave therapy has either no therapeutic effect or less effective than the placebo [20, 21]. However we think that shock wave therapy will have an ameliorating effect on pain which has an impact on both quality of life of the patients, and their functional status.

In our study, in the treatment of lateral epicondylitis, we observed short-term effectiveness of shock wave therapy on both subjective clinical parameters as VAS, patient’s, and physician’s global assessments scores, and PRTEE, and objective measurements as handgrip strength. However our study has limitations as scarce number of cases, and lack of a control group.

When we review the literature, in a pool analysis performed by Reza Nourbakhsh et al.[22] and Mehra et al.[23] concerning shock wave therapy, the authors reported 50% pain relief within 12 weeks of follow-up period with shock wave therapy. Spacca et al.[24] detected significant improvements with shock wave therapy in pain, and grip strength within 12 weeks of the follow-up period when compared with the placebo. Stillo Collins et al. found significant decrease in pain aggravating with activity using shock wave therapy during 8 weeks of the follow-up period.[25] The outcomes of all these studies demonstrate parallelism with ours, however follow-up periods of the studies indicating efficacy of shock wave therapy were generally shorter like ours. However in studies with longer follow-up periods the authors reported diverse outcomes. For example in high quality studies performed by Mehra et al.

37

(n=24) or Melikyan et al. (n=74), the authors indicated lack of any difference between shock wave therapy, and placebo during 1., 3., 6., and 12 months of the follow-up period [23, 25]. Again, in the year 2008, Staples et al. investigated short-, and longterm effectiveness of ultrasound-guided shock wave therapy on perception of pain, and functional status, and authors could obtain very few data supporting the use of shock wave therapy in the management of lateral epicondylitis [20]. Different outcomes retrieved with longer follow-up periods, suggest us possibly short-term effectiveness of the shock wave therapy. Regarding this issue, meta-analyses, and screening studies should be performed which will analyze studies with different follow-up periods.

Some studies compared shock wave therapy with other treatment modalities. For example in a randomized controlled trials performed with 93 patients, the authors indicated that when compared with the shock wave therapy group, pain scores significantly decreased favouring the injection group during 3 months of the follow-up period, but within 6 months the outcomes did not remain the same [26]. In a randomized controlled study performed more recently by Gündüz et al., shock wave therapy was compared with hot pack, ultrasound, and friction-massage therapies, and any significant intergroup difference was not reported as regarding pain scores, and grip strength [27]. When we reviewed the literature, we observed use of various rating scales, and methods of measurement.

Therefore, for healthy comparisons between shock wave therapy, and other modalities, survey studies, and meta-analyses should be performed on diverse studies using standardized assessment methods.

In addition to all of these abovementioned points, diverse outcomes can be obtained based on the dose delivered during the shock wave therapy, and the equipment used. For example in a systematic analysis published in 2007, it was reported that types of device (electromagnetic, radial), treatment doses, intensity, and number of shock waves delivered per unit time differed among studies. The authors also emphasized that in absolutely, and precisely indicated cases shock wave therapy can be effective, and be tried preoperatively in patients

38

refractory to other treatment modalities [28].

When we reviewed the literature we noted use of various measurement, and evaluation methods..

Use of various methods can yield controversial outcomes. Therefore we think that with randomizedcontrolled studies performed in the future with larger-scale patient population using standardized measurement, and assessment methods, the efficacy of shock wave therapy in the treatment of lateral epicondylitis can be better elucidated.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Stasinopoulos D, Johnson MI. Cyriax physiotherapy for tennis elbow/lateral epicondylitis. Br J Sports Med 2004;38:675-7.

2. Kamien M. A rational management of tennis elbow. Sports Med 1990;9:173-91.

3. Nirschl RP. The etiology and treatment of tennis elbow. J Sports Med 1974;2:308-23.

4. Meyer NJ, Walter F, Haines B, Orton D, Daley RA. Modeled evidence of force reduction at the extensor carpi radialis brevis origin with the forearm support band. J Hand Surg Am 2003;28:279-87.

5. Nirschl RP, Pettrone FA. Tennis elbow. The surgical treatment of lateral epicondylitis. J Bone Joint Surg Am 1979;61:832-9.

6. Nordin MFV. Basic biomechanics of the musculoskeletal system.

3rd ed. Lippincott Williams & Wilkins; 2001. p. 340-57.

7. Vicenzino B. Lateral epicondylalgia: a musculoskeletal physiotherapy perspective. Man Ther 2003;8:66-79.

8. Howitt SD. Lateral epicondylosis: a case study of conservative care utilizing ART and rehabilitation. J Can Chiropr Assoc 2006;50:182-9.

9. Labelle H, Guibert R, Joncas J, Newman N, Fallaha M, Rivard CH. Lack of scientific evidence for the treatment of lateral epicondylitis of the elbow. An attempted meta-analysis. J Bone Joint Surg Br 1992;74:646-51.

10. Sevier TL, Wilson JK. Treating lateral epicondylitis. Sports Med 1999;28:375-80.

11. Kochar MDA. Effectiveness of a specific physiotherapy regimen on patients with tennis elbow. Physiotherapy 2002;88:333-4.

12. Chan HL, Ng GY. Effect of counterforce forearm bracing on wrist extensor muscles performance. Am J Phys Med Rehabil 2003;82:290-5.

North Clin Istanbul – NCI 13. Ogden JA, Alvarez RG, Levitt R, Marlow M. Shock wave therapy (Orthotripsy) in musculoskeletal disorders. Clin Orthop Relat Res 2001;387:22-40.

14. Kalyon TA. Ultrason. In: Tuna N, editor. Elektroterapi. 2nd ed.

Istanbul: Nobel Tip Kitabevleri; 2001. p. 129-40.

15. Pienimäki T, Tarvainen T, Siira P, Malmivaara A, Vanharanta H. Associations between pain, grip strength, and manual tests in the treatment evaluation of chronic tennis elbow. Clin J Pain 2002;18:164-70.

16. Altan L, Ercan I, Konur S. Reliability and validity of Turkish version of the patient rated tennis elbow evaluation. Rheumatol Int 2010;30:1049-54.

17. Boyer MI, Hastings H 2nd. Lateral tennis elbow: “Is there any science out there?”. J Shoulder Elbow Surg 1999;8:481-91.

18. Theis C, Herber S, Meurer A, Lehr HA, Rompe JD. Evidencebased evaluation of present guidelines for the treatment of tennis elbow-a review. [Article in German] Zentralbl Chir 2004;129:252-60. [Abstract] 19. Wang CJ. Extracorporeal shockwave therapy in musculoskeletal disorders. J Orthop Surg Res 2012;7:11.

20. Staples MP, Forbes A, Ptasznik R, Gordon J, Buchbinder R. A randomized controlled trial of extracorporeal shock wave therapy for lateral epicondylitis (tennis elbow). J Rheumatol 2008;35:2038-46.

21. Buchbinder R, Green SE, Youd JM, Assendelft WJ, Barnsley L, Smidt N. Shock wave therapy for lateral elbow pain. Cochrane Database Syst Rev 2005;4:CD003524.

22. Reza Nourbakhsh M, Fearon FJ. An alternative approach to treating lateral epicondylitis. A randomized, placebo-controlled, double-blinded study. Clin Rehabil 2008;22:601-9.

23. Mehra A, Zaman T, Jenkin AI. The use of a mobile lithotripter in the treatment of tennis elbow and plantar fasciitis. Surgeon 2003;1:290-2.

24. Spacca G, Necozione S, Cacchio A. Radial shock wave therapy for lateral epicondylitis: a prospective randomised controlled single-blind study. Eura Medicophys 2005;41:17-25.

25. Collins EDH, Jafarnia KK. A clinical study of extracorporeal shock waves (ESW) for treatment of chronic lateral epicondylitis. Current Orthopaedic Practice 2011;22:185-92.

26. Crowther MA, Bannister GC, Huma H, Rooker GD. A prospective, randomised study to compare extracorporeal shockwave therapy and injection of steroid for the treatment of tennis elbow. J Bone Joint Surg Br 2002;84:678-9.

27. Gündüz R, Malas FÜ, Borman P, Kocaoğlu S, Özçakar L. Physical therapy, corticosteroid injection, and extracorporeal shock wave treatment in lateral epicondylitis. Clinical and ultrasonographical comparison. Clin Rheumatol 2012;31:807-12.

28. Rompe JD, Decking J, Schoellner C, Theis C. Repetitive lowenergy shock wave treatment for chronic lateral epicondylitis in tennis players. Am J Sports Med 2004;32:734-43.

Orıgınal Article

ANESTHESIOLOGY

North Clin Istanbul 2014;1(1):39-44 doi: 10.14744/nci.2014.02996

Our experiences with a single injection axillary block technique Yonca Yanli, Mehtap Ozdemir, Nurten Bakan Department of Anesthesiology and Reanimation, Umraniye Training and Research Hospital, Istanbul, Turkey

ABSTRACT OBJECTIVE: Axillary plexus block is one of the widely used technique for upper extremity surgery. In this study, we retrospectively evaluated the single injection axillary plexus block technique we used in our rutine anesthesia practice, between August 2010-March 2011.

METHODS: Medical records of ASA I-III, 40 17 female and 23 male patients who underwent single injection axillary block performed by neurostimulation technique in elective distal part of the arm, forearm and hand surgeries were evaluated, retrospectively. Axillary block was performed with a nerve stimulator, and a 22 G, 50 mm insolated needle. The needle was inserted immediately superior to axillary artery, advanced through the lateral border of the pectoralis major muscle and to the most proximal part of the axilla. The local anesthetic mixture (1% lidocaine 20 ml + 0.25% bupivacaine 15 ml) was injected to the place (point) where the distal motor responses of the median and ulnar nerves were elicited at the same time, before dropping the stimulation current down to 0.5 mA. In our study, demographic data, motor and sensory block times, the success rate and the complications of the block were evaluated.

RESULTS: The mean block performance time was 1.21±0.39 minutes in our 40 patients. The onset time of the motor block was 14.20±4.96 minutes and the sensory block was 17.19±2.71 minutes. The success rate of the block was 97.5 percent. No complication was found during 24 hours postoperatively. The sensory and motor functions returned properly in all patients.

CONCLUSION: In our study we found that the single injection axillary block tecnique was easy to perform with its higher success , and lower complication rates. Therefore we concluded that axillary block should be supported in appropriate cases.

Key words: Anesthetics, axillary nerve block, brachial plexus, local

P

eripheral nerve blocks are frequently used techniques in upper, and lower ekstremite surgery.

For upper extremity surgery, brachial plexus block is preferred due to its advantages as application with

ease with lower complication rates, and shorter hospital stay [1, 2, 3]. Various approaches can be used for brachial plexus block. Dependent on the surgical field, and individual experiences, choice of type of

Received: June 06, 2014 Accepted: July 08, 2014 Online: August 03, 2014 Correspondence: Yonca YANLI. Umraniye Egitim ve Arastirma Hastanesi, Anesteziyoloji ve Reanimasyon Klinigi, Istanbul, Turkey.

Tel: +90 216 - 632 18 18 e-mail: yoncayanli@yahoo.com © Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

40

North Clin Istanbul – NCI

the block varies [3, 4]. Axillary approach to brachial plexus provides adequate anesthesia in the surgeries performed on the distal arm, and hand. Besides, thanks to its ease of application, and reliability, its use is becoming more prevalent [2, 5, 6, 7].

For the determination of the location of brachial plexus, loss of resistance, transarterial injection, paresthesia, neurostimulation, and ultrasonographic techniques can be used [2, 4]. Thus brachial plexus can be blocked using single, double or multiple injections [2, 4, 5]. For a successful block local anesthetic solution should be injected into the nerve sheath, rather than directly into the nerve. In the axillary region, brachial plexus divides into median, radial, and ulnar nerves, However all of these nerves are contained in the same neurovascular sheath [2, 8].

In our study, we aimed to evaluate retrospectively axillary block method using neurostimulation method applied with a single dose of the anesthetic agent injected into the region where a combined distal motor response of median, and ulnar nerves is elicited.

MATERIALS AND METHODS After the informed consent of the patient was obtained, axillary block evaluations of 40 ASA I-III patients aged >17 years who had undergone surgi-

Figure 1. Injection site in axillary block.

cal interventions on the distal 1/3 of the arm, forearm, and hand in the operative room of the clinic of orthopedics, between August 2010, and March 2011 were analyzed retrospectively. We have detected that the patients with a body mass index of < 40 kg/m2 without any contraindication for regional anesthesia, neurological, and psychiatric disorder, bleeding diasthesis, and allergy to local anesthetics had received axillary block.

In the preoperative preparation room, in patients who will receive peripheral block, peripheral vascular access is opened using an 18-20 G catheter, and for premedication IV midazolam is administered at a dose of 0.03 mg/kg. In our axillary block applications, the arm to be intervened is brought into 90° abduction with the body, and elbow into 90° flexion. Following sterilization, and local anesthesia, axillary artery is palpated in the axillary fossa to the most proximal to the junction of pectoralis major, and coracobrachial muscles (Figure 1). Just over the axillary artery towards the direction of the brachial plexus using a peripheral nerve stimulator (Stimuplex HNS11; B.Braun Medikal, Germany) , and 50 mm 22 G insulated needle (Stimuplex, DB Braun Medikal) stimulation current at 1 mA with a frequency of 2 Hz is delivered for 0.1 ms to find the point where combined distal motor response of median, and ulnar nerves is elicited. On the point

Yanli et al., Our experiences with a single injection axillary block technique

where stimulation induced flexion of the index, and middle fingers (median nerve), and flexion of the fourth, and fifth digits together with adduction of the thumb (ulnar nerve), current intensity is reduced to 0.5 mA. This degree of motor response is considered to be adequate, and a local anesthetic mixture of 35 ml (1% lidocaine 20 ml + 0.25% bupivacaine 15 ml) is injected with aspirations at every 5 ml. At the start of the injection, abolishment of motor response following injection of 1 ml local anesthetic solution, and painless intraneural injection are considered as an evidence proving proper placement of the needle, and the rest of the local anesthetic solution is injected at a slower rate. After completion of the injection, the arm is brought to adduction, and arnmpit is compressed for 5 minutes.

The time elapsed from the insertion of the needle into the skin up to the completion of the injection is recorded as block performance time. Sensory block is evaluated at 5., 10., 15., 20., 25., and 30. minutes after completion of the procedure using a short-end needle at all areas innervated by all nerve groups, and recorded as onset time of the sensory block. At the same time points with the sensory block, motor block is evaluated (0=no block; 1=incomplete motor block; 2= complete motor block) The time to the first level is recorded as motor block onset time.

If the level of block is not adequate at areas innervated by the nerve groups in the patients brought into the operating room 30 minutes later or tourniquet pain occurs, IV fentanyl 1.5 µg/kg is administered, and if inadequate, additional sedation with 0.5-1 mg/kg IV propofol is performed. If pain persists despite these measures, then using a laryngeal mask general anesthesia is instituted. These events are recorded in anesthesia monitorization file of the patient. Self-satisfaction level of the patient from the anesthesia (good, moderate, bad, very bad) is inquired in the recovery room, after termination of the operation. Twenty-four hours later, before their discharge, the patients are questioned as for neurological complications.

In our study, data obtained were evaluated regarding block performance time, sensory, and motor block onset time, success rate, complications,

41

Table 1.

Demographic date, and types of the operations performed

n

Age (year) Height (cm) Body weight (kg) Female/Male 17/23 Types of operations Osteosynthesis 30 Ganglion cyst 3 Carpal tunnel syndrome 5 Foreign body 1 Lipoma extraction 1

Mean±SD 42.02±13.04 169.6±7.85 78.2±19.6

Data are shown as mean±standard deviation (SD) or number of patients (n).

Table 2. Block performance, and onset times (Mean±SD)

Block performance time (min) Motor block onset time (min) Sensory block onset time (min)

Mean±SD 1.21±0.39 14.20±4.96 17.19±2.71

requirement for an additional analgesic, and patient’s satisfaction. For statistical analysis, SPSS for Windows package program was used. Results were expressed as means plus standard deviation.

RESULTS Demographic data, and types of operations are shown in Table 1. In our case axillary block performance time was 1.21±0.39 min. Onset times of motor (14.20±4.96 min) ,and sensory block (17.19±2.71 min) were also determined (Table 2).

In 7 (17.5%) patients with inadequate analgesia, fentanyl had been used, and in cases with persistent pain (n=6; 15%), propofol was used to achieve additional analgesia. One patient (2.5%) whose ad-

42

ditional analgesia, and sedation were inadequate, was switched to general anesthesia. Patient satisfaction was rated as good (n=38; 95%), and moderate (n=2; 5%) None of our patientsâ&#x20AC;&#x2122; satisfaction levels was rated as bad, and very bad (Table 3). In 97.5% of the patients blocks had been achieved successfully with additional analgesics, and sedation without switching to general anesthesia.

Tourniquets had been applied intraoperatively in 32 out of 40 patients without inducing pain. Motor block level had been recorded as incomplete (n=39), and complete (n=1). In 3 patients during application of block, vascular punction had been required which had not interrupted the procedure. Any other complication had not developed. Since the patients had been in their wards during resolution of the block, block recovery time could not be evaluated.

Within the first 24 hours following application of block, any complication including hypotension, arrhytmias, nausea, paresthesia, and weakness had not occurred, and sensory, and motor functions of all patients had recovered without any problem.

DISCUSSION Axillary approach to the brachial plexus is a frequently used technique thanks to its easy applicability, close vicinity of the nerves to vascular structures, and lower complication rates [2, 3, 6]. Success in axillary block, depends on injection of the local anesthetic solution to the point nearest to the targeted nerve, concentration, and volume of the anesthetic solution used. Ease, and rapidity of application, and lower complication rates are targeted [7].

Our median block performance time was 1.21 minutes In publications on multiple injection techniques, block performance times for double, and triple-injection techniques have been reported as 5-6, and 8-13 minutes, respectively [6, 9, 10, 11, 12, 13, 14]. Single-injection technique can be evaluated as more advantageous relative to multiple injection techniques in that it has a shorter performance times, and its application is more comfortable both for the patient, and the physician.

In an arm at 90° abduction, median, and ulnar

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

Table 3. Number of

patients who received additional analgesics, and sedation, and those switched to general anesthesia

n

%

Additional analgesic Fentanyl Sedation General anesthesia Patient satisfaction Good Moderate Dissatisfied Extremely disssatisfied

7 17.5 6 15 1 2.5 38 95 2 5 0 0 0 0

superficial, radial, and musculocutaneous nerves moves into deeper structures [2, 15]. Most frequently, when compared with the axillary artery, median nerve is situated more laterally, and ulnar nerve is found at an anteromedial location. While radial nerve is adjacent to posterior aspect of the axillary artery. However various studies have demonstrated potential variations in their anatomical locations [1, 15, 16]. Retzl et al. performed ultrasound-guided studies with volunteers, and demonstrated that location of the nerves in the axillary region can be variable, and these nerves can leave the axillary sheath at the distal end of the pectoralis minor muscle [16]. Thus, they emphasized the need to perform the nerve block, as far as possible, from the most proximal part of the axillary region.

Combined use of short-, and long-acting anesthetic agents reportedly shortens block onset time [4]. In our applications, we also used short-, and long-acting anesthetic agents in combination, and injected anesthetic agent-as far as possible- into the most proximal part of the axillary region. With this approach, sensory block onset time was 17.18 minutes. In multiple injection techniques, sensory block onset times have been reported to vary between 15, and 18 minutes. [12, 14, 17]. This time interval appears to comply with our sensory block onset time we achieved with single-injection method In the axillary block technique, success rates changing between 60, and 100% have been reported [3, 4, 6, 10, 14,

Yanli et al., Our experiences with a single injection axillary block technique

18]. Many reports have indicated that neurovascular region septas within the axillary sheath prevented spread of the local analgesic agents which can cause induction of incomplete blocks [15, 19, 20]. However irrefutable data are lacking about the impact of septas on the spread of local anesthetic agents and whether they prevent distribution of local anesthetic agents or not [15, 21]. In fact, Partridge et al. injected methylene blue into the axillary sheath of cases with axillary septas, and demonstrated staining of all of medial, ulnar, and radial nerves. [21]. They indicated that owing to the communications between compartments amidst septas, multiple injections are unnecessary in order to achieve axillary block.

In their randomized studies, Liu et al. compared single, and double-injection methods using ultrasonographic guidance or nerve stimulator, and could not demonstrate any difference between groups as for block success rates [13]. They revealed that as determinative factors in the success rates of various nerve blocks, the injection point within the sheath of the brachial plexus, an the level of injection might be more important than the technique of multiple injections. They advocated that different rates of block quality, and success reported in their studies could be related to the site, and level of the injections.

In studies where local anesthetic agents more than 30 ml were used, better drug distribution in the axillary region with higher success rates have been demonstrated [22, 23]. Besides, as reported in the literature, local anesthetic agent applied lateral to the median nerve spreads along the axillary artery and easily blocks the musculocutaneous nerve [11, 13, 24]. Still in proportion with the time elapsed after the injection, due to the spread of local anesthetic agent within the axillary sheath, the quality of radial nerve block conceivably increases [11, 13].

Our single-injection block technique we applied in our procedures was very successful (97.5%). Our higher success rate can be attributed to our selection of injection site as the most proximal part of the axillary region, the level of the block, and the volume of injection solution used. We think that with this approach, nerves in the brachial plexus or those leaving the sheath of the plexus at the level of coracoid processus were blocked which increased

43

our success rates.

In conclusion, single –injection axillary block technique which is applied on the region where distal motor responses of median, and ulnar nerves to the neurostimulation (the region innervated both of these two terminal branches the brachial plexus) is elicited at the same time can be evaluated as a safe method in that it has a shorter block performance time with easily applied technique, lower complication, and higher success rate, and favourable patient satisfaction levels. Therefore we have concluded that axillary nerve block should be brought into agenda, and its use should be encouraged in suitable cases.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Orebaugh SL, Williams BA. Brachial plexus anatomy: normal and variant. ScientificWorldJournal 2009;9:300-12.

2. Satapathy AR, Coventry DM. Axillary brachial plexus block.

Anesthesiol Res Pract 2011;2011:173796.

3. Coventry DM, Barker KF, Thomson M. Comparison of two neurostimulation techniques for axillary brachial plexus blockade. Br J Anaesth 2001;86:80-3.

4. Neal JM, Gerancher JC, Hebl JR, Ilfeld BM, McCartney CJ, Franco CD, et al. Upper extremity regional anesthesia: essentials of our current understanding, 2008. Reg Anesth Pain Med 2009;34:134-70.

5. Conceição DB, Helayel PE, Oliveira Filho GR. A comparative study between ultrasound and neurostimulation guided axillary brachial plexus block. [Article in Portuguese] Rev Bras Anestesiol 2009;59:585-91. [Abstract] 6. Zencirci B. Comparision of nerve stimulator and ultrasonography as the techniques applied for brachial plexus anesthesia. Int Arch Med 2011;4:4.

7. Karaağaçlı MB, Yılmazlar A. Effects of different currents and local anaesthetic volumes in axillary block. Turk Anest Rean Der Dergisi 2005;33:151-7.

8. Sertöz N, Deniz MN, Bayraktaroğlu E, Ayanoğlu HÖ. Çoklu sinir uyarı yöntemi ile uygulanan aksiller brakial pleksus bloğonun geriye dönük değerlendirilmesi. Turk Anest Rean Der Dergisi 2010;38:254-61.

9. Koscielniak-Nielsen ZJ, Stens-Pedersen HL, Lippert FK. Readiness for surgery after axillary block: single or multiple injection techniques. Eur J Anaesthesiol 1997;14:164-71.

10. Handoll HH, Koscielniak-Nielsen ZJ. Single, double or mul-

44 tiple injection techniques for axillary brachial plexus block for hand, wrist or forearm surgery. Cochrane Database Syst Rev 2006;25:CD003842.

11. Sia S, Lepri A, Ponzecchi P. Axillary brachial plexus block using peripheral nerve stimulator: a comparison between double- and triple-injection techniques. Reg Anesth Pain Med 2001;26:499503.

12. Sia S, Bartoli M. Selective ulnar nerve localization is not essential for axillary brachial plexus block using a multiple nerve stimulation technique. Reg Anesth Pain Med 2001;26:12-6.

13. Liu FC, Liou JT, Tsai YF, Li AH, Day YY, Hui YL, et al. Efficacy of ultrasound-guided axillary brachial plexus block: a comparative study with nerve stimulator-guided method. Chang Gung Med J 2005;28:396-402.

14. Sia S, Bartoli M, Lepri A, Marchini O, Ponsecchi P. Multipleinjection axillary brachial plexus block: A comparison of two methods of nerve localization-nerve stimulation versus paresthesia. Anesth Analg 2000;91:647-51.

15. Klaastad Ø, Smedby O, Thompson GE, Tillung T, Hol PK, Røtnes JS, et al. Distribution of local anesthetic in axillary brachial plexus block: a clinical and magnetic resonance imaging study. Anesthesiology 2002;96:1315-24.

16. Retzl G, Kapral S, Greher M, Mauritz W. Ultrasonographic findings of the axillary part of the brachial plexus. Anesth Analg 2001;92:1271-5.

North Clin Istanbul – NCI 17. Casati A, Danelli G, Baciarello M, Corradi M, Leone S, Di Cianni S, et al. A prospective, randomized comparison between ultrasound and nerve stimulation guidance for multiple injection axillary brachial plexus block. Anesthesiology 2007;106:992-6.

18. Schroeder LE, Horlocker TT, Schroeder DR. The efficacy of axillary block for surgical procedures about the elbow. Anesth Analg 1996;83:747-51.

19. Thompson GE, Rorie DK. Functional anatomy of the brachial plexus sheaths. Anesthesiology 1983;59:117-22.

20. Ay S, Akinci M, Sayin M, Bektas U, Tekdemir I, Elhan A. The axillary sheath and single-injection axillary block. Clin Anat 2007;20:57-63.

21. Partridge BL, Katz J, Benirschke K. Functional anatomy of the brachial plexus sheath: implications for anesthesia. Anesthesiology 1987;66:743-7.

22. Rucci FS, Barbagli R, Pippa P, Boccaccini A. The optimal dose of local anaesthetic in the orthogonal two-needle technique. Extent of sensory block after the injection of 20, 30 and 40 mL of anaesthetic solution. Eur J Anaesthesiol 1997;14:281-6.

23. Vester-Andersen T, Christiansen C, Sørensen M, Kaalund-Jørgensen HO, Saugbjerg P, Schultz-Møller K. Perivascular axillary block II: influence of injected volume of local anaesthetic on neural blockade. Acta Anaesthesiol Scand 1983;27:95-8.

24. Yamamoto K, Tsubokawa T, Shibata K, Kobayashi T. Area of paresthesia as determinant of sensory block in axillary brachial plexus block. Reg Anesth 1995;20:493-7.

Case Report

OBSTETRICS & GYNECOLOGY

North Clin Istanbul 2014;1(1):45-48 doi: 10.14744/nci.2014.32932

Management of hematometrocolpos due to dysfunctional uterine bleeding following progestin use: a case report Murat Bakacak1, Fazil Avci1, Mehmet Suhha Bostanci2, Zeyneb Bakacak3, Salih Serin1, Onder Ercan1, Bulent Kostu1 Department of Obstetrics and Gynecology, Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey;

1

Department of Obstetrics and Gynecology, Sakarya University Training and Research Hospital, Sakarya, Turkey;

2

Private Caka Vatan Hospital, Kahramanmaras, Turkey

3

ABSTRACT Hematometrocolpos is accumulation of blood in the vagina and uterine cavity due to intra-uterine hemorrhage. A 20-year-old female presented to our clinic with massive menorrhagia at menarche after progestin usage.Hematometrocolpos was detected by transabdominal ultrasonography. She was pale because of heavy bleeding for 5 days and hemoglobin level was measured as 5.1 g/dl. Initial treatment was blood transfusion and medical drug therapy. After resolution of the hematometrocolpos was shown by transabdominal ultrasound 2 days later, the patient, who was stable, was discharged without complication. Obstruction of the female genital outflow tract is rarely seen. Hematocolpos has been reported in elderly women following vaginal occlusion due to radiotherapy, vaginal fibroma and labial synechiae causing infection or inflammatory conditions.The case is presented here because of the successful management of hematometrocolpos due to massive dysfunctional uterine bleeding in a young virgin patient.

Key words: Hematocolpos, pelvic mass, progestin

H

eavy menstrual bleeding (HMB) is a general problem with prevalence rates of more than 30% among adolescents who consult gynaecologists [1, 2, 3]. In a study of 153 girls aged 12-19 years with bleeding disorders, those who presented with HMB at menarche and those who required hospitalization were reported at rates of 90% and 12%,

respectively [3]. In addition, it is very important to understand the difference between non- life-threatening bleedings and those requiring emergent intervention [4]. Therefore, a careful anamnesis, and physical examination are essential for diagnosis and management. Uterine bleedings due to obstruction of the lower female genital tract cause proximal dil-

Received: May 26, 2014 Accepted: August 23, 2014 Online: August 03, 2014 Correspondence: Murat BAKACAK. Kahramanmaras Sutcu Imam Universitesi Tip Fakultesi, Kadin Hastal覺klar覺 ve Dogum Anabilim Dal覺, Kahramanmaras, Turkey.

Tel: +90 344 - 280 10 00 e-mail: muratbakacak46@gmail.com 穢 Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

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

46 B

A

Figure 1.

(A) Transabdominal sagital ultrasonographic view showing the markedly distended uterus. Heterogeneous structures the largest being 90 mm in diameter were seen in the uterine cavity. (B) Transabdominal sonographic view showing the markedly distended vagina measuring 88.9 mm x 39.2 mm (hematocolpos).

Heterogeneous structures the largest being 90 mm in diameter were seen in the vaginal cavity.

atation and the occurrence of hematocolpos, hematotrachelos or hematometra are the most common problems defined as congenital abnormalities [4, 5, 6]. Obstruction of the female genital outflow tract is rare [7, 8].

The case is presented here because of successful management of hematometrocolpos due to massive dysfunctional uterine bleeding in a young virgin patient.

CASE REPORT A 20-year-old virgin patient with an episode of massive menorrhagia at menarche was admitted to the Emergency Room (ER) of the Department of Obstetrics and Gynecology. Her medical history revealed that 15 days prior to the presentation at the Emergency Department, she had been prescribed a ten-day course of progestogen therapy on request to delay her menstrual cycle. She had no known bleeding disorders. Her gynecological history included menarche at 14 years of age. Her periods lasting for 6 to 7 days were normal and regular occurring at 25day intervals. On examination, she was afebrile with blood pressure of 70/40 mm Hg and pulse rate of 130 beats per minute. Her abdomen was soft, with moderate tenderness of the lower abdomen without rebound. Pelvic examination revealed an intact annular hymen. The hymenal opening was 7-8 mm in

diameter. Coagulated blood bulging outwards from the hymen opening was observed. A large hematometra and hematocolpos were detected by transabdominal ultrasound scanning. Transabdominal ultrasound depicted a distended uterus 90 mm in diameter (Figure 1a) which communicated with a markedly distended vagina (Figure 1b). Both ovaries were observedly normal. She had been bleeding heavily for 5 days causing a drop in hemoglobin level down to 5.1 gr/dl, while other laboratory test results were unremarkable. A pregnancy test was negative. She was initially treated with blood transfusion (Eight units of packed red blood cells and four units of packed fresh-frozen plasma were transfused) and hemostasis was achieved rapidly using high doses of combined oral contaceptive (ethinyl estradiol 0.02 mg, and gestodene 0.075 mg) twelve times a day, tranexamic acid 1000 mg q.i.d., and naproxen sodium 550 mg b.i.d. After one day, a chocolate-like fluid started to spill out from the vagina. A transabdominal ultrasound obtained 2 days later showed resolution of the hematometrocolpos.

The patient was discharged without complication.

DISCUSSION Congenital abnormalities resulting in hematometrocolpos include imperforate hymen, a complete transverse vaginal septum, vaginal and, rarely, cervical atresia [7, 8, 9]. Acquired obstruction of the

Bakacak et al., Management of hematometrocolpos

lower female genital tract is rare. These acquired problems are caused by iatrogenic interventional traumas to the uterine cervix such as cone biopsies, loop electrosurgical procedures, dilation and curettage, obstetric lacerations, cervical or endometrial carcinoma, and radiation therapy [9, 10, 11, 12, 13, 14]. Spontaneous obstruction is generally uncommon but has been reported recently [15]. Firstly, pregnancy and pregnancy-related complications need to be excluded from the patient’s medical history [1]. About one fifth of females presenting with heavy menstrual periods may have an underlying blood dyscrasia [2, 15, 16, 17]. HMB may be associated with a variety of endocrine disorders such as thyroid disease, adrenal problems and other medical problems such as hepatitis, chronic renal disease or diabetes mellitus. In addition, HMB episodes may occur because of disruptions or abnormalities of the coagulation cascade [1].

In the present case, sonographic findings demonstrated acquired obstruction of the lower female genital tract, specifically hematometra and hematocolpos. The intracavitary findings included different degrees of resolving hemorrhage, but a malignancy, although less likely, could not be ruled out. However, presenting symptoms of hematometra and hematocolpos without any evidence of primary and secondary amenorrhea were considered to be related to massive uterine bleeding following the use of progestin fifteen days previously. In the present case, it was thought that massive uterine bleeding could have caused an obstruction secondary to the clot formation. Narrow diameter of the hymenal opening may have facilitated this process. With medical therapy, the patient’s clinical symptoms improved, uterine and vaginal bleeding stopped and coagulated blood in the vagina dissolved and drained from the vagina.

As in the present case, abnormal uterine bleeding associated with the use of exogenous steroids, systemic or local agents is classified as “iatrogenic” according to the PALM-COEIN classification system [18].

There are some effective treatment methods for adolescents with HMB. Planning is very important in the treatment of both acute bleed and its maintenance therapy. It is generally recommended that adolescents with active HMB and hemoglobin of

47

less than 8 mg/dl should be admitted into ER during an acute bleed [5, 19].

Intravenous crystalloid for the replacement of the blood volume may be given to a patient with an acute HMB episode which is causing anemia [19].

A randomized controlled trial reported that in 72% of the patients given intravenous [4, 17] estrogen, bleeding was stopped after two doses (over 12 h) compared with 38% of controls given a placebo [20].

For adolescents already using combined oral contraceptives (COCs) and admitted with HMB despite treatment, transition to i.v. treatment or higher dose COC are appropriate methods [16]. There is not enough data as yet to recommend one specific type of COC over any other [21].

Antifibrinolytics have the effect of halting the lysis of clots occurring at the end of the clotting cascade thus improving the clotting process. Antifibrinolytics have been reported to decrease bleeding in about half of the women with HMB and can be administered in combination with contraceptive methods [20]. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also decrease HMB. Current studies have also shown that NSAIDs decrease menorrhagia in adolescents compared to placebo (600-1200 mg daily) [22].

Surgical management of adolescents with HMB is seldom necessary as more than 90% of them will respond to medical management [15].

The underlying etiology of the acquired obstructed cervix in the patient presented here is not as yet fully understood. Potential etiologies include progestin use, decreased uterine contractility triggered by high progestin levels, which might have prevented the effective removal of menstrual debris, and lastly, a possible partial obstruction causing massive uterine bleeding and drainage of bleeding around a solid obstruction. Decreased drainage of accumulated debris rather than acute hemorrhage may have caused hematometrocolpos.

Thus, the underlying etiology of the obstruction in this patient was uncertain, and this case denotes an unusual cause of acquired spontaneous hematometra and hematocolpos following progestin use.

Conclusion Adolescents often present at gynaecologists with

48

HMB, although HMB following the usage of contraceptive pills which may cause hematometrocolpos is rare. The diagnosis and treatment of this situation includes a careful physical, and ultrasonographic examinations, and laboratory tests to exclude other diagnoses such as bleeding disorders, anatomic and endocrine causes. Treatment methods include hormonal therapies, antifibrinolytics and nonsteroidal anti-inflammatory drugs, which are effective, welltolerated and safe. This case shows that a careful history and examination is very important in the recognition of a rarely seen life-threatening menorrhagic episodes arising from usage of progestin with the intention to delay the menstrual cycle.

Informed Consent: Written informed consent was obtained from the patient who participated in this study.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Benjamins LJ. Practice guideline: evaluation and management of abnormal vaginal bleeding in adolescents. J Pediatr Health Care 2009;23:189-93.

2. Jayasinghe Y, Moore P, Donath S, Campbell J, Monagle P, Grover S. Bleeding disorders in teenagers presenting with menorrhagia.

Aust N Z J Obstet Gynaecol 2005;45:439-43.

3. Chi C, Pollard D, Tuddenham EG, Kadir RA. Menorrhagia in adolescents with inherited bleeding disorders. J Pediatr Adolesc Gynecol 2010;23:215-22.

4. Tran AT, Arensman RM, Falterman KW. Diagnosis and management of hydrohematometrocolpos syndromes. Am J Dis Child 1987;141:632-4.

5. Ward A, Maher P. Haematocolpos--an unusual presentation. Br J Clin Pract 1979;33:83-4.

6. Pretorius DH, Dennis MA, Manco-Johnson ML, Gottesfeld KR. Ultrasound diagnosis of hematotrachelos: a case report. Am J Obstet Gynecol 1985;151:1080-2.

7. Sherer DM, Beyth Y. Ultrasonographic diagnosis and assisted surgical management of hematotrachelos and hematometra due to uterine cervical atresia with associated vaginal agenesis. J Ultrasound Med 1989;8:321-3.

8. Sanders RM, Nakajima ST. An unusual late presentation of im-

North Clin Istanbul â&#x20AC;&#x201C; NCI perforate hymen. Obstet Gynecol 1994;83:896-8.

9. Witt BR. Treatment of hematotrachelos after dilatation and curettage. A case report. J Reprod Med 1999;44:68-70.

10. Giannacopoulos K, Troukis E, Constandinou P, Rozis I, Kokonakis C, Giannikos L. Hematometra and extended vaginal haematoma after laser conization. A case report. Eur J Gynaecol Oncol 1998;19:569-70.

11. Scheerer LJ, Bartolucci L. Transvaginal sonography in the evaluation of hematometra. A report of two cases. J Reprod Med 1996;41:205-6.

12. Sherer DM, Khoury-Collado F, Hellmann M, Abdelmalek E, Kheyman M, Abulafia O. Transvaginal sonography of hematotrachelos and hematometra causing acute urinary retention after previous repair of intrapartum cervical lacerations. J Ultrasound Med 2006;25:269-71.

13. Pschera H, Kjaeldgaard A. Haematocervix after conization diagnosed by ultrasonography. Gynecol Obstet Invest 1990;29:30910.

14. Sherer DM, Eugene P, Gorelick C, Ramachandran S, Serur E, Kheyman M, et al. Acute spontaneous hematotrachelos following methotrexate treatment of a suspected tubal pregnancy. J Ultrasound Med 2006;25:1091-3.

15. Frishman GN. Evaluation and treatment of menorrhagia in an adolescent population. J Minim Invasive Gynecol 2008;15:6828.

16. James AH. Bleeding disorders in adolescents. Obstet Gynecol Clin North Am 2009;36:153-62.

17. Philipp CS, Faiz A, Dowling N, Dilley A, Michaels LA, Ayers C, et al. Age and the prevalence of bleeding disorders in women with menorrhagia. Obstet Gynecol 2005;105:61-6.

18. Munro MG, Critchley HO, Broder MS, Fraser IS; FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet 2011;113:3-13.

19. Wilkinson JP, Kadir RA. Management of abnormal uterine bleeding in adolescents. J Pediatr Adolesc Gynecol 2010;23(6 Suppl):22-30.

20. DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding--a double-blind randomized control study. Obstet Gynecol 1982;59:285-91.

21. Ahuja SP, Hertweck SP. Overview of bleeding disorders in adolescent females with menorrhagia. J Pediatr Adolesc Gynecol 2010;23(6 Suppl):15-21.

22. Pinto S, Costa J, Vaz Carneiro A, Fernandes R. Analysis of the Cochrane Review: Antibiotics for acute otitis media in children.

Cochrane Database Syst Rev. 2013;1:CD000219. [Article in Portuguese] Acta Med Port 2013;26:633-6. [Abstract]

Case Report

PEDIATRICS

North Clin Istanbul 2014;1(1):49-52 doi: 10.14744/nci.2014.25744

A trombosis story and PRES Vural Kartal1, Zeynep Zara1, Sema Yilmaz2, Aylin Ayhan2, Asim Yoruk2, Cetin Timur2 Department of Pediatrics, Istanbul Medeniyet Univesity, Goztepe Training and Research Hospital, Istanbul, Turkey;

1

Department of Pediatric Hematology and Oncology, Istanbul Medeniyet Univesity, Goztepe Training and Research

2

Hospital, Istanbul, Turkey

ABSTRACT Trombosis is seen in children with acute lymphoblastic leukemia during or after L-asparaginase treatment. Posterior reversible encephalopathy syndrome (PRES) is a complex syndrome characterized with sudden hypertension, headache, nausea, vomiting, alteration in the state of consciousness, vision defect and seizures. The cases related to this syndrome are reported after eclampsia, organ transplantation, immunsuppressive treatments, autoimmune diseases and chemotherapy, vasogenic edema occuring in the brain parencyhma constitues the basic pathophysiology. We present a case who developed seizures during treatment for B-cell acute lymphoblastic leukemia and diagnosed as posterior reversible encephalopathy.

Key words: Child, L-asparaginase, leukemia, PRES, thrombosis

D

evelopment of a thrombus is a multifactorial entity. In addition to hereditary disease, as a prerequisite, a serious disease (malignancy, infection, and nephrotic syndrome etc.), acquired inhibitor deficiencies or presence of extrinsic factors such as an indwelling catheter are required [1]. In children with cancer, evidences are accumulating suggesting a clinically significant prevalence of venous thrombotic events [2] Thrombus can be seen during, and after L-asparaginase treatment of children with acute lymphoblastic leukemia [3]. Activation of primary disease by means of procoagulant substances, deterioration of fibrinolytic anticoagulant pathway, chemotherapy, and prothrombotic risk factors play a role in thrombus formation. In the literature risk of thrombotic complication has been indicated as 1-37 % in the literature [4].

Posterior reversible encephalopathy syndrome (PRES) may manifest itself with clinical symptoms as headache, visual disturbances, paresis, vomiting, seizures, and impaired conscious. Hypertensive encephalopathy, eclampsia, organ transplantation, immunosuppressive treatments, autoimmune diseases, acute glomerulonephritis, chemotherapy, and shock can induce PRES. Vazsogenic cerebral edema is responsible for clinical symptoms [5]. Diagnosis is made based on clinical, and radiological findings.

On magnetic resonance images (MRI) typically, hyperintensity in parietooccipital regions consistent with diffuse edema is observed. With rapid diagnosis, and treatment, the patients recover within a few weeks [6]. In order to emphasize the importance of PRES We have presented a patient who developed thrombus, and PRES during treatment of acute

Received: June 09, 2014 Accepted: July 18, 2014 Online: August 03, 2014 Correspondence: Vural KARTAL. Doktor Erkin Caddesi, Istanbul Medeniyet Üniversitesi, Göztepe Egitim ve Arastirma Hastanesi, Cocuk Sagligi ve Hastaliklari Anabilim Dalı, Kadıkoy, Istanbul, Turkey.

Tel: +90 216 - 566 40 00 / 9393 e-mail: vuralkartal76@yahoo.com © Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

North Clin Istanbul – NCI

50

lymphoblastic leukemia whose clinical, and radiological findings improved following early diagnosis, and treatment.

CASE REPORT A swelling on the left arm of a 5-year-old girl diagnosed as common B ALL with a lower risk group who was hospitalized for an induction therapy (protocol#: ALL IC BFM-2009) attracted our attention. Her physical examination revealed an irritable patient with a moderate health state, open state of consciousness. Her vital findings were within normal limits. On the examination of her left arm, red-colored skin, diffuse edema (circumferences of the left, and right arms were 28 cm, and 17 cm, respectively), painful, and warm skin were observed. Doppler US of the left upper extremity was reported as “stagnation of venous blood flow at the

junction the left cephalic, and subclavian veins, and presence of a thrombus with a diameter of 7 mm.”

Her hematological, and biochemical examination results were within normal limits. However we had not necessary facilities to perform laboratory tests so as to reveal the etiological factors of thrombus.

Low-molecular weight heparin (LMWH) (enoxaparine sodium 100 U/kg/g, SC) was initiated as a thrombolytic treatment. At the same night the patient experienced tonic-clonic convulsions. Her convulsions were controlled with phenobarbital (15 mg/kg/g, IV). Cranial computed-tomograms obtained to reveal the cause of convulsions were unremarkable. On cranial magnetic resonance (MR) venograms, no-flow phenomenon was observed within the left transverse sinus (Figure 1a, arrow).

However diffusion MRI revealed the presence of blood flow inside the transverse sinuses without any thrombi. In fact contrast agent was not seen only on

A

B

C

D

Figure 1. Cerebral diffusion MRI. (A) MRI venography. Left transverse sinus blood flow is not observed (arrow). (B) Blood flow is seen inside transverse sinuses (arrows). (C) Hyperintense lesions in the occipital region.

(D) Normal cerebral MR images.

Kartal et al., A trombosis story and PRES

venograms obtained at that moment of observation.

(Figure 1b, arrows). During her monitorization, her cardiac apex beats per minute rised to 236 bpm which necessitated electrocardiographic (ECG) examination which was evaluated as supraventricular tachycardia. Adenosin at a dose of 0.05 mg/kg was administered, however heart rhythm did not normalize which necessitated a second dose with resultant normalization of the rhythm. Blood pressure remained at high levels (ABP, 145/110 mmHg), so antihypertensive treatment (amlodipine 5 mg/g, and metoprolol 1 mg/kg/g, oral) was initiated. Cranial MRI demonstrated bilateral, and symmetrical subcortical hyperintense lesions in occipital areas on T2-weighted, and flair images. Lesion were reported as unrelated to the metastases of the primary disease, but consistent with PRES (Figure 1c).

During monitorization of the patient, swelling on his left arm decreased in size, and serial Doppler US examinations revealed that thrombus remained in the same location but regressed The clinical status of the patient under antihypertensive treatment gradually improved, her blood pressure, and symptoms were kept under control. Control cranial MRI obtained three weeks later revealed disappearance of parenchymal lesions (Figure 1d). The patient is still under our follow-up protocol, and her chemotherapy still continues without any clinical complaints.

DISCUSSION Among thrombogenic factors in children, activation of coagulation mediated by procoagulant substances, deterioration of the fibrinolytic pathways, chemotherapy, and relevant prothrombotic risk factors can be enumerated. In a study by Celkan et al. [7] as predisposing factors, most frequently malignancies, and infections were detected. In another study, central venous catheterization was the most frequently seen factor [8]. In our patient a thrombus formation was detected on the junction between cephalic, and subclavian veins, and priorly central venous catheter was thought to be potentially responsible for thrombus formation.

In children most frequently seen malignancy associated with thrombus formation is acute lymphoblastic leukemia (ALL), and thrombus has been

51

detected in 5-40% of the cases with ALL. Bay et al. [9] detected thrombi in 1.1% of ALL patients.

Still in another study, the authors indicated that in pediatric cases with diagnosis of acute lymphoblastic leukemia, during induction chemotherapy, and especially during or after L-asparaginase therapy, thrombotic events could be seen [3]. In the present case, we thought that L-asparaginase might be responsible for thrombus formation. In another study, deep vein thrombosis was detected in 2 out of 10 cases diagnosed as ALL, and in one patient presence of a central catheter was reported [10]. Therefore, in the light of all thse results one can emphasize the potential role of L-asparaginase in thrombus formation in patients with ALL. In the diagnosis of deep vein thrombosis, as one of the noninvasive, cost-effective, easily applicable imaging modalities, color-Doppler US has been used.

Doppler US report of our case indicated presence of a thrombus on the junction of the left cephalic, and subclavian veins. In a study sensitivity, and specificity of color Doppler US was reported as 77.8, and 100% in the detection of both proximal, and distal vein thrombosis (DVT), respectively. Accordingly the authors stressed the importance of color Doppler US for the initial diagnosis of DVT [11].

Cerebral venous thrombosis can manifest itself with infection, dehidration, renal failure, trauma, malignancy, hematological disorders together with many risk factors. Our patient suffered from convulsive episodes which necessitated cranial MRI venography with the indication of suspect dural sinus thrombus. On cranial MRI venograms blood flow was not observed within the left transverse sinus. In another study, on cranial MR venograms, in a total of 16 patients, thrombi in only one (n=11; 68.8%) or multiple venous sinuses (n=5; 31.3%) were demonstrated [12]. However, interestingly in our case, diffusion MRI revealed presence of blood flow in transverse sinuses, and contrast agent was not seen momentarily on venograms which indicated lack of any thrombi. Management of venous thrombus involves anticoagulant, anticonvulsant, and supportive treatments. Besides, use of LMWH for ALL patients under L-asparaginase therapy is effective, and safe in the prevention of thromboembolism. Çalık et al. [13] used LMWH for the treatment of deep vein thrombosis with excellent response rates. We

52

also observed regression of thrombi with LMWH therapy.

Though pathophysiology of PRES has not been elucidated yet, currently, higher blood pressure, and arterial edema due to cerebral hyperperfusion secondary to impairment of cerebral autoregulation has been held responsible [2]. In a study, hypertension was indicated as the culprit etiological factor, in our case, hypertension which developed suddenly, but could be brought under control with treatment was observed. Clinically, convulsive episodes have been reported in cases with PRES secondary to brain edema. Only one of 2 cases with diagnosis of PRES, convulsions were reported in a study [14].

Similarly, we also observed tonic- clonic convulsions in our patient.

In PRES bilateral, and asymmetrical homogenous brain edema is detected in parietooccipital white matter on MRI, while asymmetrical locations have been also reported In 8 cases diagnosed as PRES, signal abnormalities were observed on the posterior, while in seven cases with PRES, on anterior circulatory structures [15]. Symmetrical, and bilateral hyperintense lesions were detected in the occipital regions which were reported to be consistent with PRES. In conclusion, we presented our case with diagnosis of PRES established by clinical, and radiological methods, and aimed to emphasize that in patients with sudden changes in the state of consciousness during chemotherapy, this syndrome which regresses completely with symptomatic treatment should be thought in the early stage of differential diagnosis.

Informed Consent: Written informed consent was obtained from the patient who participated in this study.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Tekşam M, Casey SO, Michel E, Truwit CL. Posterior reversibl

North Clin Istanbul – NCI ensefalopati sendromu: patofizyoloji ve ileri MRG teknikleri ile korelasyon. Tanısal ve Girişimsel Radyoloji Dergisi 2001;7:46472.

2. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol 2008;29:1043-9.

3. Caruso V, Iacoviello L, Di Castelnuovo A, Storti S, Mariani G, de Gaetano G, et al. Thrombotic complications in childhood acute lymphoblastic leukemia: a meta-analysis of 17 prospective studies comprising 1752 pediatric patients. Blood 2006;108:221622.

4. Athale UH, Chan AK. Thrombosis in children with acute lymphoblastic leukemia: part I. Epidemiology of thrombosis in children with acute lymphoblastic leukemia. Thromb Res 2003;111:125-31.

5. Demirtaş O, Gelal F, Vidinli BD, Demirtaş LO, Uluç E, Baloğlu A. Cranial MR imaging with clinical correlation in preeclampsia and eclampsia. Diagn Interv Radiol 2005;11:189-94.

6. Sharma A, Whitesell RT, Moran KJ. Imaging pattern of intracranial hemorrhage in the setting of posterior reversible encephalopathy syndrome. Neuroradiology 2010;52:855-63.

7. Celkan T, Apak H, Özkan A, Güven V, Erkan T, Çokuğraş FÇ, ve ark. Hastanede yatan çocuklarda saptanan tromboz etiyolojisi.

Türk Pediatri Arşivi 2004;39:65-70.

8. Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, et al. Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE. Blood 1994;83:1251-7.

9. Bay A, Öner AF, Cesur Y, Demir C, Mukul Y, Açıkgöz M. Çocukluk çağı akut lenfoblastik lösemi olgularında L-asparajinaz’a bağlı toksisite. Van Tıp Dergisi 2005;12:149-52.

10. Ranta S, Heyman MM, Jahnukainen K, Taskinen M, SaarinenPihkala UM, Frisk T, et al. Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis 2013;24:749-56.

11. Tiryaki Ş, Eğilmez H, Işık AO, Öztoprak İ, Arslan M. Alt ekstremite derin ven trombozu tanısında renkli Doppler ultrasonografi. C. Ü. Tıp Fakültesi Dergisi 2000;22:131-6.

12. Şenol MG, Toğrol E, Kaşıkçı T, Tekeli H, Özdağ F, Saraçoğlu M. Serebral Venöz Tromboz: 16 Olgunun İncelenmesi. Düzce Tıp Fakültesi Dergisi 2009;11:32-7.

13. Çalık M, Pişkin İE, Üstündağ G, Kardeş H. Derin ven trombozu ile başvuran bir akut miyeloid lösemi olgusu. Klinik ve Deneysel Arastırmalar Dergisi 2011;2:114-7.

14. Akgün N, Karaman M, Başyiğit S, Yılmaz H, Özcan AA. Posterior reversbl ensefalopati: 2 olgu sunumu. İstanbul Tıp Dergisi 2010;2:82-5.

15. Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 2008;29:447-55.

Case Report

DERMATOLOGY

North Clin Istanbul 2014;1(1):53-56 doi: 10.14744/nci.2014.98608

Disseminated lupus vulgaris: a case report Burce Can, Ilkin Zindanci, Zafer Turkoglu, Mukaddes Kavala, Vasfiye Ulucay, Filiz Topaloglu Demir Department of Dermatology, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey

ABSTRACT Lupus vulgaris is a secondary form of cutaneous tuberculosis which persists for years if not treated. The head and neck are the most commonly affected sites. While less frequently arms and legs, and rarely the trunk and the scalp are involved. Herein, we describe 73-year-old man with a 5-year history of slowly growing, atrophic, some eroded and ulcerated, red-brown plaques on his forehead, nose, cheeks, ear lobes, trunk and extremites. All of his disseminated lesions healed after antituberculosis therapy.

Key words: cutaneous tuberculosis, disseminated lupus vulgaris, lupus vulgaris

A

s a disease known for three thousand years, tuberculosis is most frequently seen in the developing countries. Cutaneous tuberculosis constitues less than 1% of all cases with tuberculosis.

Cutaneous tuberculosis emerges in different clinical forms dependent on many factors notably pathogenicity of the microorganism, route of entry of the infection, immune state of the host, and antimicrobial resistance. In women lupus vulgaris or scrofuloderma, and in men tuberculosis cutis verrucosa, and ulcerative tuberculosis are more frequently seen forms. Characteristic lesion of the lupus vulgaris is a red-brown papule with a soft consistency termed as lupoma frequently localized on head and neck region [1, 2, 3].

In this paper, a case with lupus vulgaris characterized by multiple atrophic and/or ulcerated plaques on the scalp, face, ears, anterior, and poste-

rior aspect of the trunk, upper, and lower extremities has been presented because of its rarely seen generalized form.

CASE REPORT A 73-year-old male patient consulted to our outpatient clinics with complaints of ever-increasing number of non-healing wounds with foul-smelling discharge. Skin wounds of the patient were firstly appeared on his hip five years ago, and became more numerous since then. Biopsy material obtained one year ago was evaluated as chronic granulomatous dermatitis. His personal medical history was unremarkable, while his two siblings died of tuberculosis, and his son was still receiving tuberculostatic therapy. On his dermatological examination, red-violet atrophic plaque lesions with

Received: May 29, 2014 Revised: July 20, 2014 Accepted: July 25, 2014 Online: August 03, 2014 Correspondence: Filiz TOPALOGLU DEMIR. Medeniyet Universitesi Goztepe Egitim ve Arastirma Hastanesi, Dermatoloji Klinigi, Istanbul, Turkey Tel: +90 216 - 566 66 00 e-mail: filizsvet@yahoo.com Š Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

54

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

Figure 1. Atrophic

plaque lesions with patchy areas of erosions and/or ulcerations localized on scalp, face, anterior, and posterior aspects of the trunk, extremities, and gluteal region.

irregular contours, and patchy areas of adhered yellow-brown crusts, and squamas localized on the frontal, parietal, temporal, and malar regions, nose, and left ear were observed. Seventeen- 18 plaqueshaped lesions measuring 2-15 cm in diameter with adhered brown crusts, and squamas, and also eroded areas 0.5 cm-2.0 cm in diameter localized as islets on the anterior, and posterior aspect of the trunk, also on both upper, and lower extremities were seen. In addition to eroded areas on similarly appearing plaque lesions localized on the gluteal region, an ulcerated lesion 4 cm in diameter, and

1-1.5 cm in depth striked our attention (Figure 1). Histopathological examination of the biopsy material revealed a large ulcerated area covered superficially with crusts, lymphocytic, and histiocytic infiltration, and giant cells within superficial, and middle layer of dermis, and granulomas more conspicuously on the periphery of the infiltrate (Figure 2).

Application of periodic acid-Shiff (PAS), and Erlich-Ziehl-Neelsen (EZN) staining couldnâ&#x20AC;&#x2122;t detect any specific infectious agent. Laboratory anal-

Can et al., Disseminated lupus vulgaris

yses revealed anemia, hypoproteinemia, increased CRP, and sedimentation rate. With these clinical, and histopathological findings, the diagnosis of

55

generalized lupus vulgaris was made. The patient with a 9 mm-PPD reaction size, but without systemic involvement received antituberculostatic treatment with 300 mg isonicotinic acid hydrazide, 600 mg rifampicin, 1500 mg ethambutol, and 3000 mg pyrazinamide for 2 months, then with 300 mg isonicotinic acid hydrazide, and 600 mg rifampicin for 4 months.At two months of the treatment, lesions regressed remarkably. At the end the sixth month all lesions healed with postinflammatory hyperpigmentation, hypopigmentation and/or atrophic scar (Figure 3).

DISCUSSION

Figure 2. Giant

cells, and lymphocytic, and histiocytic infiltration, and markedly conspicuous granulomas on the periphery of the infiltrate localized within the middermis (H&E x 40).

Lupus vulgaris is a cutaneous tuberculosis seen in individuals who previously encountered tuberculosis bacilli, and those with moderate, and higher tuberculin sensitivity. It can become manifest via endogenous (hematogenous, lymphogenous) or direct spread from a focus of tuberculosis infection, while it can develop as an exogenous infection on verrucous tuberculosis, scrofuloderma scar, and BCC vaccination site. Characteristic lesions of lupus vulgaris are red-brown plaques spreading to the periphery leaving a scar tissue in the middle through the process of healing. These plaques are formed by accumulation of papullonodular lesions which look like apple jelly on diascopic examination. New lesions develop on atrophic areas. Secondary to ulcerations, cicatrices, and complications emerging during the progression of the disease, lupus vulgaris can manifest in diverse clinical forms; 1) plaque or planar form, 2) ulcerative or mutilant form, 3) vegetant form, 4) tumor-like form and 5) papulonodular form [2, 3].

Although most frequently, head and neck region, and especially nose, cheeks, and earlobes are involved, less often, arms, and legs, and rarely trunk, and scalp can be affected. Oral, nasal, and conjunctival mucosa can be inflicted [2, 4, 5]. In our case, a widespread involvement all over body including scalp (excl. mocosal surfaces) was observed.

Typical histopathological findings of tuberculosis, are tubercles consisting of epitheloid histioFigure 3. At the end of the sixth month regression of all lesions was observed.

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cytes, and Langhans-type giant cells surrounded by lymphocytes, and monocytes. In the center of these granulomas, caseification necrosis is observed. Bacilli are very rarely seen in lesions, and they couldn’t be demonstrated in sections obtained. Mycobacterium tuberculosis can not be grown especially in cultures prepared from chronic lesions, and in patients with higher immunity [2, 3]. Polymerase chain reaction (PCR) is another diagnostic method which can identify Mycobacterium tuberculosis –specific DNA particles in samples. Diagnostic sensitivity of PCR in skin lesions changes between 53, and 77 percent [6, 7, 8]. Though for definitive diagnosis, identification of mycobacteria is required, it is not possible in most of the times. Diagnosis is usually made with clinicopathologtical correlation [3]. In our case, bacteria could not be identified in culture, and PCR analyses, and diagnosis was made based on clinical, and histopathological findings, and lesions healed with antituberculostatic drug therapy.

Our case is extremely important in that in the diagnosis of skin tuberculosis necessity of consideration of not only PCR, and culture outcomes, but also history, clinical, and histopathological findings especially in cases with lesions which persisted for years has been demonstrated.

Treatment of skin tuberculosis shows similarities with other organ tuberculosis in many aspects.

As is the case with our patient, following the treatment with isonicotinic acid hydrazide, rifampicin, ethambutol, and pyrazynamide lasting for 8 weeks, 16 weeks of treatment with isonicotinic acid hydrazide, and rifampicin is successful in most of the cases [2]. Since skin tuberculosis in undiagnosed cases, and inadequately treated patients leads a chronic course, within years it can result in severe tissue damage. Destruction of the nasal cartilage, ectropion, microstomy, keloid, lymphoedema, and functional disorders secondary to contractures are among sequelae that might become manifest years later in patients with lupus vulgaris. Besides, on the scars of lupus vulgaris prominently squamous cell

carcinoma, basal cell carcinoma or even sarcoma can develop [2, 3].

In conclusion, when we encounter long-lasting disseminated atrophic and/or ulcerated plaque-like lesions localized on the trunk, and extremities, we should investigate our patients, and their intimates as for tuberculosis infection, and consider lupus vulgaris in differential diagnosis.

Informed Consent: Written informed consent was obtained from the patient who participated in this study.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Tigoulet F, Fournier V, Caumes E. Clinical forms of the cutaneous tuberculosis. Bull Soc Pathol Exot 2003;96:362-7.

2. Yates VM, Rook GAW. Mycobacterial infections. In: Burns T, Breathnach S, Cox N, Griffiths C, editor. Rook’s Textbook of Dermatology. 7th ed. Turin: Blackwell Science; 2004. p. 281-39.

3. Tappeiner G, Wolff K. Tuberculosis and other mycobacterial infections. In: Freedberg IM, Eisen AZ, Wollf K, Austen KF, Goldsmith LA, Katz S, editor. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York: McGraw-Hill; 2003. p.

1933-49.

4. Sehgal VN. Cutaneous tuberculosis. Dermatol Clin 1994;12:645-53.

5. MacGgregor RR. Cutaneous tuberculosis. Clin Dermatol 1995;13:245-55.

6. Hsiao P-F, Tzen C-Y, Chen H-C, Su H-Y. Polymerase chain reaction based detection of Mycobacterium tuberculosis in tissues showing granulomatous inflammation without demonstrable acid-fast bacilli. Int J Dermatol 2003;42:281-6.

7. Degitz K, Steidl M, Neubert U, Plewig G, Volkenendt M. Detection of mycobacterial DNA in paraffin-embedded specimens of lupus vulgaris by polimerase chain reaction. Arch Dermatol Res 1993;285:168-70.

8. Margall N, Baselga E, Coll P, Barnadas MA, de Moragas JM, Prats G. Detection of Mycobacterium tuberculosis complex DNA by the polymerase chain reaction for rapid diagnosis of cutaneous tuberculosis. Br J Dermatol 1996;135:231-6.

REVIEW

ORTHOPEDICS & TRAUMATOLOGY

North Clin Istanbul 2014;1(1):57-63 doi: 10.14744/nci.2014.29292

Flexible flatfootness Aziz Atik1, Selahattin Ozyurek2 Department of Orthopedics and Tarumatology, Balikesir University Faculty of Medicine, Balikesir, Turkey;

1

Department of Orthopedics and Traumatology, Aksaz Military Hospital, Marmaris, Mugla, Turkey

2

ABSTRACT While being one of the most frequent parental complained deformities, flatfoot does not have a universally accepted description. The reasons of flexible flatfoot are still on debate, but they must be differentiated from rigid flatfoot which occurs secondary to other pathologies. These children are commonly brought up to a physician without any complaint. It should be kept in mind that the etiology may vary from general soft tissue laxities to intrinsic foot pathologies. Every flexible flatfoot does not require radiological examination or any treatment if there is no complaint. Otherwise further investigation and conservative or surgical treatment may necessitate.

Key words: Children; flatfoot; flexible; foot problem; pes planus.

T

hough the term flatfoot (pes planus) is generally defined as a condition which the longitudinal arch of the foot collapses, it has not a clinically or radiologically accepted universal definition. Flatfootness which we frequently encounter in routine outpatient practice will be more accurately seen as a result of laxity of ligaments of the foot. However each case of flatfootness is not similar to each other. Staheli divided flatfootness into 2 groups as physiological, and pathological flatfootness [1, 2, 3].

Within this context, flexible (flexible, physiological, and hypermobile) flatfootness should be differentiated from secondary ones which can develop as a consequence of other pathologies. In flexible flatfootness, medial longitudinal arch of the foot collapses in various degrees during weight-bearing (Figure 1). However during raising up one’s body

on tiptoe (tiptoe test) foot arch forms again (Figure 2). When weight-bearing forces on feet are relieved this arch can be observed. If the foot is not bearing any weight, still medial longitudinal arch is not seen, then it is called rigid (fixed) flatfootness. To differentiate between these two conditions easily, Jack’s test (great toe is dorisflexed as the plantar fascia tightens) can be used (Figure 3). In this review flexible flatfootness will be discussed.

Though actual incidence of flatfootness in children is not known, it is acknowledged that it is one of the most frequently seen deformites which cause parent’s complaints in the outpatient clinic of pediatrics. Still, the issue whether flexible flatfootness is a real deformity is debatable. For instance Staheli et al. [2] performed a study investigating the development of medial longitudinal arch of the sole, and re-

Received: May 29, 2014 Revised: July 18, 2014 Accepted: July 25, 2014 Online: August 03, 2014 Correspondence: Aziz ATIK. Balıkesir Universitesi Cagis Yerleskesi Tip Fakultesi, Ortopedi ve Travmatoloji Anabilim Dali, 10440 Balikesir, Turkey.

Tel: +90 216 - 566 66 00 e-mail: filizsvet@yahoo.com © Copyright 2014 by Istanbul Northern Anatolian Association of Public Hospitals - Available online at www.kuzeyklinikleri.com

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Figure 1. Collapse of the weight-bearing foot.

Figure 2. Tiptoe test.

is due to infantile adipose cushion formation localized on the medial part of the foot. Besides toddlers who start to walk can assume a flatfoot posture. In fact they try to walk with their feet resting entirely on the ground so as to maintain a balanced posture.

Consequently, they shift their weight-bearing axis to the first or second tarsometatarsal joint which may induce a flatfootness posture. In most of the children normal longitudinal arch develops at 3-5 years of age (Figure 4), and in only 4% of them flatfootness persists after 10 years of age.

Well, how is the situation in adults? In nearly 23% of the adult population collapse of the medial longitudinal arch of the foot can be seen [5]. However it is not an isolated entity, and in two thirds of the cases, subtalar complex, hyperflexible ankle joint, and in one-fourths contracture of the triceps surae muscle have been observed [5, 6]. Probably these combined pathologies cause patients’ complaints rather than collapse of the medial longitudinal arch per se.

Etiopathology Many theories have been generated related to the causes of flexible flatfootness, however precise etiology has not been elucidated yet. During routine outpatient practice, family history, and obesity are routinely inquired, while general theories are based

B

A

Figure 3. Dorsiflexion of the great toe test.

C

vealed that“ flatfootness is generally seen in infants, prevalently in children, and occasionally in adults”.

In their study, Wenger [4] et al. concluded that “flexible flatfootness is an unavoidable outcome of trying to walk on normal foot bones with loose ligaments.”

Apparently, most of the time flatfootness does not cause any problem.

Epidemiology In 90% of the children aged <2 years, an anatomic variation resembling flatfootness can be seen which

A

B

A-C: Medial longitudinal ark B-C: Lateral longitudinal ark A-B Anterior transvers ark

C

Figure 4. Schematic demonstration of the arches of the foot.

Atik et al., Flexible flatfootness

on structural bone deformities, muscular imbalance, and ligamentous laxity.

Foot bones supported with ligaments, tendons, and capsular structures form the normal medial longitudinal arch of the foot. Foot muscles do not maintain longitudinal arch. Electromyographic (EMG) studies have revealed that neither intrinsic, nor extrinsic muscles support, and maintain longitudinal arches at standing posture [7]. However during walking, and activities performed, both muscle groups maintain dynamic stabilization of the arch. In a study reinforcing this argument, Fiolkowski discovered the importance of intrinsic muscles of the foot in providing support for medial longitudinal arch [8]. In recent studies, flatfootness seen in posterior tibial tendon insufficiency which has been studied extensively, suggests the importance of this musculature. In their biomechanical study, Huang et al. indicated that plantar fascia is the most important anatomical structure contributing to the stability of the medial arch, followed by talonavicular, and spring ligaments [9].

In the normal weight-bearing pattern, lateral edge of the foot, the first, and the fifth metatarses come in contact with the ground. However, in flatfooted individuals valgus shift of the calcaneus occurs resulting in loss of support for talar head which assumes a more upright position. Normal arch is lost, the existing pattern shifts to the medial, and foot sole rests more heavily on the ground (Figure 5).

When the foot is in supination, bones of the mid-

Figure 5. Weight- shifting pattern.

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foot are locked, and lose much of their capacity to move. However joints of the pronated foot become more mobile. During weight-bearing, eversion of the heel, and abduction of the forefoot cause collapse of the midfoot, shortening of the longitudinal arch , and consequently talar head, and navicular tuberosity rest on the floor, and bears the whole weight.

With time Achilles tendon shortens, and everts the foot with potential worsening of the deformity, and development of tendon contracture. Many techniques have been used to identify, and define medial longitudinal arch of the foot including radiological imaging modalities, podoscopic systems which employ mirror to show the contact area beneath the foot, whole toeless footprint analysis, arch height, and foot plantar pressure measurements To obtain quantitative data, Clarke angle, Chippaux-Smirak index, Staheli arch index have been defined. Among them Chippaux-Smirak Index (CSI) [10, 11] has been reported to have a predictive value above 90 percent [12]. CSI is the ratio between he widest (segment a) and the narrowest (segment b) areas with borders passing through metatarsal heads as estimated from podographic measurements of footprints The classification of feet based on b/a ratio is as follows: b/a= 0, cavus foot; 0.01-0.29, normal foot; 0.30-0.39, intermediate foot; 0.40-0.44, collapsed foot, and , â&#x2030;Ľ0.45 flatfoot (Figure 6) [13].

Clinical evaluation Studies based on footprint analyses, and radiologi-

Figure 6. Chippaux-Smirak index: CSI = b/a.

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cal evaluations have shown that medial longitudinal arch of the feet continues to develop all along the first 10 years of life [2, 14, 15]. The suggestion that medial ligaments of the foot become harder ,and stronger with age which form the arch with time, reveals the futility of using corrective shoes and orthosis. Studies have shown that additional deformities do not develop in flatfooted individuals with aging [16]. Harris and Beath demonstrated that if not associated with comorbidities, collapsed longitudinal arch of the foot did not lead to persistent problems without adversely effrecting normal functions of the foot [5, 6].

Even some studies have reported that wearing shoes had harmful effects on the formation of longitudinal arch of the foot [17, 18]. The reason why Hippocrates had not mentioned about flatfootness can be explained by shoe-wearing habits of that time. Rao and Joseph evaluated footprints of 2300 children aged between 4, and 13 years, and indicated that in barefooted children normal medial longitudinal arch formed at a higher frequency, and stated that shoe-wearing habit might adversely effect the development of medial longitudinal arch [18]. Since modifications of shoe design, and sole insoles are ineffective in the treatment of flatfootness [19, 20], the main objective in the treatment of flatfootness should be to convince the patient’s relatives that this deformity will resolve with time, and use of orthosis is not necessary.

Physical examination: Generally, children without any complaints are brought to the medical centers by their families. Sometimes, standing for a long time may cause leg, and foot pains. Gait disorders are caused mainly by three factors: problems of stepping inward, and outward (increased femoral anteversion, tibial medial torsion, metatarsus adductus), O and X leg deformities, laming, and limping.

In the presence of contracture of the Achilles tendon, an induration along the Achilles tendon can be palpated while the ankle is in dorsiflexion, the knee in extension, and foot in inversion. The child can not walk on his/her heels when requested to do so. Characteristically on lateral radiograms obtained while the patients were pressing against the floor with their feet calcaneus equinus, and plantar flexion of the talus caused by retraction of the Achilles tendon can be seen.

North Clin Istanbul – NCI

On physical examination laxity of foot ligaments should be evaluated. In cases of general ligamentous laxity, child’s hyperextended thumb should touch his/her forearm, and hyperextended fingers can be brought parallel to the back of the hand. Besides genu, and cubital recurvatum should be present.

During tiptoe walking, inversion of the heel indicates importance of strengthening plantar, and invertor muscles, however this phenomenon has not been proved yet. If during raising up on tiptoe, inversion of the heel, and formation of a foot arch are not observed, then it is not a case of flexible flatfootness, and mainly the following abnormalities of rigid flatfoot deformity should be investigated: - Neurological, and myopathic disorders: disorders of muscular weakness (polyomyelitis, peripheral neuropathy); muscular weakness, and contracture of the Achilles tendon (Duchenne muscular dystrophy), calcaneus equinus deformity together with spasticity (cerebral palsy).

- Painful, and restricted hindfoot movements: tarsal coalition, inflammatory arthritis - Calcaneus equinus together with rocker-bottom deformity: congenital vertical talus - Pain elicited on pressing over navicular bone: accessory navicular bone or osteochondritis For the examination of the subtalar joint which is the most important joint in the inversion and eversion of the hindfoot, while the child was laid in the prone position, the knee is brought to 130° flexion, and the foot is held in dorsiflexion to restrict lateral movement of the tibiotalar joint, and evaluation of range of motion (ROM) of only subtalar joint is attempted. Restriction of subtalar joint ROM should suggest especially the presence of tarsal coalition.

Radiological investigations are not necessary for every flatfooted child.

In severe cases or in conditions were the family is dissatisfied, anteroposterior (AP) or lateral radiograms of the foot with the child standing on his/ her feet can be obtained. On AP radiograms talocalcaneal angle should range between 15°, and 35°.

An angle over 35° indicates hindfoot valgus. On lateral radiograms, talocalcaneal angle should vary between 25°, and 50° (Figure 7). Talar-first metatarsal angle (Meary’s angle) should not be present.

(Figure 8). Talonavicular coverage angle should not

Atik et al., Flexible flatfootness

Figure 7. Anterior and lateral talocalcaneal angle.

Figure 8. Normal, and deformed Meary angle.

exceed 7 degrees (Figure 9). On lateral radiograms of the patients standing on feet with shorter medial longitudinal arches, talus assumes a more vertical, while calcaneus, and metatarses take a more horizontal position. In cases requiring further examinations, on oblique radiograms or Harris radiograms (radiograms of the posterior aspect of the foot obtained from a 45° angle of projection) tarsal coalition, vertical talus, talipes calcaneovalgus, accessory navicular bone can be visualized.

Treatment Since flatfootness affects mostly our precious children, families with high levels of expectancy for cure most of the time do not satisfy with the treatment resulting in the application of miscellaneous, and extreme surgical, and non-surgical treatment alternatives probably not observed in any other pedal deformity.

There is no need to treat flatfootness in children without any complaint.

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Controlled studies have demonstrated that foot orthroses have no effect on the development of medial longitudinal arch of the foot [19, 20]. Interestingly these types of treatment only “cure” parents, rather than the patients.

Then, when, and what type of treatment are necessary? Flatfootness exercises are analyzed in two main headings: weight-bearing, and non-weightbearing exercises Exercises performed while seated are non-weight- bearing exercises which include rotating the feet, trying to grip the objects on the floor with foot, holding knees, and feet in extension, forcing the toes for abduction, and adduction, and crossing one foot over the other. Similarly, walking on tiptoes or on outside edge of the foot, standing on tiptoes on an elevated surface, walking with flexed feet are some of the weight-bearing exercises.

If contracture of the Achilles tendon is present, stretching exercises, and Thera-Band exercises should be performed by the parents or if compliant by the children themselves. If tendon stretching exercises are to be performed by the parents, then the method of holding the foot in supination should be taught to the parents so as to prevent forcing the forefoot to dorsiflexion relative to the midfoot. If heel valgus is very pronounced, and ligamentous laxity is present, then tiptoe walking, and gait exercises, and raising on tiptoes can be tried to strengthen tibialis

Figure 9. Normal, and deformed talonavicular grasping angle.

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posterior muscle. During these exercises, take care that feet of the patient are pacing parallel to each other. Firstly heel, then outer edge of the feet, and finally toes should come in contact with the floor..

During this heel-toe walking exercises, walking on the medial edge of the feet is not allowed, in addition balanced working of foot muscles is ensured.

In symptomatic patients with painful medial longitudinal arch, and night cramps in addition to stretching, and muscle strengthening exercises, orthosis, and arch support insoles, and inserts can be used. Use of arch support shoes manufactured for this purpose might resolve complaints.

In more persistent cases, use of more rigid orthoses such as UCBL [University of California Biomechanics Laboratory] or Helfet heel cups were found to be helpful in that they corrected talonaviculocuneiform axis, and increased calcaneal dorsiflexion with resultant alleviation of patientsâ&#x20AC;&#x2122; complaints [21, 22].

However, it should not be forgotten that permanent improvement in foot anatomy or mediallongitudinal arch could not be demonstrated with any modification of the shoe design or use of orthosis The most important comparative, and prospective study was published by Wenger [20]. Wenger divided children who were followed up with the indication of flatfootness into four groups as 1) control group without treatment under surveillance, users of 2) corrective orthopedic shoes 3) Helfet heel cups, and 4) UCBL orthoses. At the end of 3 years of follow-up period, any difference between radiologically, and clinically natural course group, and the other 3 groups was not detected [20].

Surgical treatment Patients whose complaints do not resolve, and couldnâ&#x20AC;&#x2122;t perform their daily activities because of their pain with resultant decline in their quality of life despite conservative treatments are candidates of surgical treatment. In 49-77% of the cases unsatisfactory long-term results have been reported after both soft tissue, and bone surgeries [23, 24]. Since joint fusion induces osteoarthritic changes in adjacent joints, joint separation procedures, extra-articular osteotomies, and soft tissue manipulation, and stretching should be preferably considered. To that end, silicon implantation [arthroereisis] has been

defined to prevent development of valgus tilting of the subtalar joint, however long-term outcomes are needed [25, 26]. In cases of Achilles tendon contracture, lengthening, and relaxation procedures should be absolutely performed.

Among conventional methods, subtalar arthrodesis which impairs kinematics of entire hindfoot, and consequently midfoot is not recommended.

Triple arthrodesis should be performed as a rescue procedure , if other surgical methods fail , currently, calcaneal osteotomy and lateral column lengthening using tricortical iliac graft appears to be an attractive surgical procedure. On the medial side, talonaviculocuneiform complex is elevated with its fascia, stretched, and suture-fixed (imbrication). However isolated imbrication is not recommended per se, and it should be performed in combination with lateral column lengthening or calcaneal sliding osteotomies. However, it should not be forgotten that during medial column shortening procedure, posterior tendon of the tibialis muscle should be also shortened so as to maintain its support to the medial column.

In conclusion: Flexible flatfootness in children has not a generally acceptable definition, and researches on its miscellaneous treatment alternatives have been continuing. Therefore, the best alternatives seem to involve letting the feet of these children alone, and raise awareness among families on this issue so as to refrain them from unnecessary applications.

Informed Consent: Written informed consent was obtained from the patient who participated in this study.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

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2. Staheli LT, Chew DE, Corbett M. The longitudinal arch. A survey of eight hundred and eighty-two feet in normal children and adults. J Bone Joint Surg Am 1987;69:426-8.

3. Kanatli U, Yetkin H, Bolukbasi S. Evaluation of the transverse metatarsal arch of the foot with gait analysis. Arch Orthop Trau-

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ma Surg 2003;123:148-50.

4. Wenger D. Flatfoot and children’s shoes. In: Wenger D, Rang M, ed. The art and practice of children’s orthopaedics. New York: Raven Press; 1993:77.

5. Harris RI, Beath T. Hypermobile flat-foot with short tendo achillis. J Bone Joint Surg Am 1948;30A:116-40.

6. Harris R, Beath T. Army foot survey: an investigation of foot ailments in Canadian soldiers, Ottawa: National Research Council of Canada; 1947:1.

7. Basmajian JV, Stecko G. The role of muscles in arch support of the foot. J Bone Joint Surg Am 1963;45:1184-90.

8. Cowan DN, Robinson JR, Jones BH, Polly DW Jr, Berrey BH. Consistency of visual assessments of arch height among clinicians. Foot Ankle Int 1994;15:213-7.

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10. Chippaux C. Elements d’Anthropologie. Le Phar: Marseille; 1947.

11. Smirak, J. “Prispeveck k problematice ploché nohy u skolni a pracijici miádeze.” Prague: SPN, 1960.

12. Chen KC, Yeh CJ, Kuo JF, Hsieh CL, Yang SF, Wang CH. Footprint analysis of flatfoot in preschool-aged children. Eur J Pediatr 2011;170:611-7.

13. Forriol F, Pascual J. Footprint analysis between three and seventeen years of age. Foot Ankle 1990;11:101-4.

14. MORLEY AJ. Knock-knee in children. Br Med J 1957;2:976-9.

15. Vanderwilde R, Staheli LT, Chew DE, Malagon V. Measurements on radiographs of the foot in normal infants and children.

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63 16. Rao UB, Joseph B. The influence of footwear on the prevalence of flat foot. A survey of 2300 children. J Bone Joint Surg Br 1992;74:525-7.

17. Sachithanandam V, Joseph B. The influence of footwear on the prevalence of flat foot. A survey of 1846 skeletally mature persons. J Bone Joint Surg Br 1995;77:254-7.

18. SIM-FOOK L, HODGSON AR. A comparison of foot forms among the non-shoe and shoe-wearing Chinese population. J Bone Joint Surg Am 1958;40-A:1058-62.

19. Gould N, Moreland M, Alvarez R, Trevino S, Fenwick J. Development of the child’s arch. Foot Ankle 1989;9:241-5.

20. Wenger DR, Mauldin D, Speck G, Morgan D, Lieber RL. Corrective shoes and inserts as treatment for flexible flatfoot in infants and children. J Bone Joint Surg Am 1989;71:800-10.

21. Bleck EE, Berzins UJ. Conservative management of pes valgus with plantar flexed talus, flexible. Clin Orthop Relat Res 1977;122:85-94.

22. Mereday C, Dolan CM, Lusskin R. Evaluation of the University of California Biomechanics Laboratory shoe insert in “flexible” pes planus. Clin Orthop Relat Res 1972;82:45-58.

23. Butte FL. Navicular-cuneiform arthrodesis for flat-foot and endresult study. J Bone Joint Surg 1937;19:496.

24. Crego CH Jr, Ford LT. An end-result of various operative procedures for correcting flat feet in children. J Bone Joint Surg Am 1952;34:183-95.

25. Addante JB, Chin MW, Loomis JC, Burleigh W, Lucarelli JE. Subtalar joint arthroereisis with SILASTIC silicone sphere: a retrospective study. J Foot Surg 1992;31:47-51.

26. Lanham RH Jr. Indications and complications of arthroereisis in hypermobile flatfoot. J Am Podiatry Assoc 1979;69:178-85.