Marmara Medical Journal Marmara Üniversitesi Tıp Fakültesi Dergisi

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2 Marmara Medical Journal Marmara Üniversitesi Tıp Fakültesi Dergisi Editör Prof. Dr. Mithat Erenus Koordinatörler Seza Arbay, MA Dr. Vera Bulgurlu Editörler Kurulu Prof. Dr. Mehmet Ağırbaşlı Prof. Dr. Serpil Bilsel Prof. Dr. Safiye Çavdar Prof. Dr. Tolga Dağlı Prof. Dr. Haner Direskeneli Prof. Dr. Kaya Emerk Prof. Dr. Mithat Erenus Prof. Dr. Zeynep Eti Prof. Dr. RainerVV. Guillery Prof. Dr. Oya Gürbüz Prof. Dr. Hande Harmancı Prof. Dr. Hızır Kurtel Prof. Dr. Ayşe Özer Prof. Dr. Tülin Tanrıdağ Prof. Dr. Tufan Tarcan Prof. Dr. Cihangir Tetik Prof. Dr. Ferruh Şimşek Prof. Dr. Dr. Ayşegül Yağcı Prof. Dr. Berrak Yeğen Doç. Dr. İpek Akman Doç. Dr. Gül Başaran Doç. Dr. Hasan Batırel Doç. Dr. Nural Bekiroğlu Doç. Dr. Şule Çetinel Doç. Dr. Mustafa Çetiner Doç. Dr. Arzu Denizbaşı Doç. Dr. Gazanfer Ekinci Doç. Dr. Dilek Gogas Doç. Dr. Sibel Kalaça Doç. Dr. Atila Karaalp Doç. Dr. Bülent Karadağ Doç. Dr. Handan Kaya Doç. Dr. Gürsu Kıyan Doç. Dr. Şule Yavuz Asist. Dr. Asım Cingi Asist. Dr. Arzu Uzuner

3 Marmara Medical Journal Marmara Üniversitesi T p Fakültesi Dergisi DERGİ HAKKINDA Marmara Medical Journal, Marmara Üniversitesi Tıp Fakültesi tarafından yayımlanan multidisipliner ulusal ve uluslararası tüm tıbbi kurum ve personele ulaşmayı hedefleyen bilimsel bir dergidir. Marmara Üniversitesi Tıp Fakültesi Dergisi, tıbbın her alanını içeren özgün klinik ve deneysel çalışmaları, ilginç olgu bildirimlerini, derlemeleri, davet edilmiş derlemeleri, Editöre mektupları, toplantı, haber ve duyuruları, klinik haberleri ve ilginç araştırmaların özetlerini, ayırıcı tanı, tanınız nedir başlıklı olgu sunumlarını,, ilginç, fotoğraflı soru-cevap yazıları (photo-quiz),toplantı, haber ve duyuruları, klinik haberleri ve tıp gündemini belirleyen güncel konuları yayınlar. Periyodu: Marmara Medical Journal -Marmara Üniversitesi Tıp Fakültesi Dergisi yılda 3 sayı olarak OCAK,MAYIS VE EKİM AYLARINDA yayınlanmaktadır. Yayına başlama tarihi: Yılından itibaren yanlızca elektronik olarak yayınlanmaktadır Yayın Dili: Türkçe, İngilizce eissn: Temel Hedef Kitlesi: Tıp alanında tüm branşlardaki hekimler, uzman ve öğretim üyeleri, tıp öğrencileri İndekslendiği dizinler: EMBASE - Excerpta Medica,TUBITAK - Türkiye Bilimsel ve Teknik Araştırma Kurumu, Türk Sağlık Bilimleri İndeksi, Turk Medline,Türkiye Makaleler Bibliyografyası,DOAJ (Directory of Open Access Journals) Makalelerin ortalama değerlendirme süresi: 8 haftadır Makale takibi -iletişim Seza Arbay Marmara Medical Journal (Marmara Üniversitesi Tıp Fakültesi Dergisi) Marmara Üniversitesi Tıp Fakültesi Dekanlığı, Tıbbiye cad No:.49 Haydarpaşa 34668, İSTANBUL Tel: Faks: +90 O e-posta: [email protected] Yayıncı Plexus BilişimTeknolojileri A.Ş. Tahran Caddesi. No:6/8, Kavaklıdere, Ankara Tel: Faks: Yayın Hakları: Marmara Medical Journal in basılı ve web ortamında yayınlanan yazı, resim, şekil, tablo ve uygulamalar yazılı izin alınmadan kısmen veya tamamen herhangi bir vasıtayla basılamaz. Bilimsel amaçlarla kaynak göstermek kaydıyla özetleme ve alıntı yapılabilir.

4 Marmara Medical Journal Marmara Üniversitesi Tıp Fakültesi Dergisi YAZARLARA BİLGİ Marmara Medical Journal Marmara Üniversitesi Tıp Fakültesi Dergisine ilginize teşekkür ederiz. Derginin elektronik ortamdaki yayınına erişim adresinden serbesttir. Marmara Medical Journal tıbbın klinik ve deneysel alanlarında özgün araştırmalar, olgu sunumları, derlemeler, davet edilmiş derlemeler, mektuplar, ilginç, fotoğraflı soru-cevap yazıları (photo-quiz), editöre mektup, toplantı, haber ve duyuruları, klinik haberleri ve ilginç araştırmaların özetlerini yayınlamaktadır. Yılda 3 sayı olarak Ocak, Mayıs ve Ekim aylarında yayınlanan Marmara Medical Journal hakemli ve multidisipliner bir dergidir.gönderilen yazılar Türkçe veya İngilizce olabilir. Değerlendirme süreci Dergiye gönderilen yazılar, ilk olarak dergi standartları açısından incelenir. Derginin istediği forma uymayan yazılar, daha ileri bir incelemeye gerek görülmeksizin yazarlarına iade edilir. Zaman ve emek kaybına yol açılmaması için, yazarlar dergi kurallarını dikkatli incelemeleri önerilir. Dergi kurallarına uygunluğuna karar verilen yazılar Editörler Kurulu tarafından incelenir ve en az biri başka kurumdan olmak üzere iki ya da daha fazla hakeme gönderilir. Editör, Kurulu yazıyı reddetme ya da yazara(lara) ek değişiklikler için gönderme veya yazarları bilgilendirerek kısaltma yapmak hakkına sahiptir. Yazarlardan istenen değişiklik ve düzeltmeler yapılana kadar, yazılar yayın programına alınmamaktadır. Marmara Medical Journal gönderilen yazıları sadece online olarak adresinden kabul etmektedir. Yazıların bilimsel sorumluluğu yazarlara aittir. Marmara Medical Journal yazıların bilimsel sorumluluğunu kabul etmez. Makale yayına kabul edildiği takdirde Yayın Hakkı Devir Formu imzalanıp dergiye iletilmelidir. Gönderilen yazıların dergide yayınlanabilmesi için daha önce başka bir bilimsel yayın organında yayınlanmamış olması gerekir. Daha önce sözlü ya da poster olarak sunulmuş çalışmalar, yazının başlık sayfasında tarihi ve yeri ile birlikte belirtilmelidir. Yayınlanması için başvuruda bulunulan makalelerin, adı geçen tüm yazarlar tarafından onaylanmış olması ve çalışmanın başka bir yerde yayınlanmamış olması ya da yayınlanmak üzere değerlendirmede olmaması gerekmektedir. Yazının son halinin bütün yazarlar tarafından onaylandığı ve çalışmanın yürtüldüğü kurum sorumluları tarafından onaylandığı belirtilmelidir.yazarlar tarafından imzalanarak onaylanan üst yazıda ayrıca tüm yazarların makale ile ilgili bilimsel katkı ve sorumlulukları yer almalı, çalışma ile ilgili herhangi bir mali ya da diğer çıkar çatışması var ise bildirilmelidir.( * ) ( * ) Orijinal araştırma makalesi veya vaka sunumu ile başvuran yazarlar için üst yazı örneği: "Marmara Medical Journal'de yayımlanmak üzere sunduğum (sunduğumuz) " -" başlıklı makale, çalışmanın yapıldığı laboratuvar/kurum yetkilileri tarafından onaylanmıştır. Bu çalışma daha önce başka bir dergide yayımlanmamıştır (400 sözcük ya da daha az özet şekli hariç) veya yayınlanmak üzere başka bir dergide değerlendirmede bulunmamaktadır. Yazıların hazırlanması Derginin yayın dili İngilizce veya Türkçe dir. Türkçe yazılarda Türk Dil Kurumu Türkçe Sözlüğü ( esas alınmalıdır. Anatomik terimlerin ve diğer tıp terimlerinin adları Latince olmalıdır. Gönderilen yazılar, yazım kuralları açısından Uluslararası Tıp Editörleri Komitesi tarafından hazırlanan Biomedikal Dergilere Gönderilen Makalelerde Bulunması Gereken Standartlar a ( Uniform Requirements For Manuscripts Submittted to Biomedical Journals ) uygun olarak hazırlanmalıdır. ( ulakbim.gov.tr /cabim/vt) Makale içinde kullanılan kısaltmalar Uluslararası kabul edilen şeklide olmalıdır (http..//

5 knasyaz/) kaynağına başvurulabilir. Birimler, Ağırlıklar ve Ölçüler 11. Genel Konferansı'nda kabul edildiği şekilde Uluslararası Sistem (SI) ile uyumlu olmalıdır. Makaleler Word, WordPerfect, EPS, LaTeX, text, Postscript veya RTF formatında hazırlanmalı, şekil ve fotoğraflar ayrı dosyalar halinde TIFF, GIF, JPG, BMP, Postscript, veya EPS formatında kabul edilmektedir. Yazı kategorileri Yazının gönderildiği metin dosyasının içinde sırasıyla, Türkçe başlık, özet, anahtar sözcükler, İngilizce başlık, özet, İngilizce anahtar sözcükler, makalenin metini, kaynaklar, her sayfaya bir tablo olmak üzere tablolar ve son sayfada şekillerin (varsa) alt yazıları şeklinde olmalıdır. Metin dosyanızın içinde, yazar isimleri ve kurumlara ait bilgi, makalede kullanılan şekil ve resimler olmamalıdır. Özgün Araştırma Makaleleri Türkçe ve İngilizce özetler yazı başlığı ile birlikte verilmelidir. (i)özetler: Amaç (Objectives), Gereç ve Yöntem (Materials and Methods) ya da Hastalar ve Yöntemler (Patients and Methods), Bulgular (Results) ve Sonuç (Conclusion) bölümlerine ayrılmalı ve 200 sözcüğü geçmemelidir. (ii) Anahtar Sözcükler Index Medicus Medical Subject Headings (MeSH) e uygun seçilmelidir. Yazının diğer bölümleri, (iii) Giriş, (iv) Gereç ve Yöntem / Hastalar ve Yöntemler, (v) Bulgular, (vi) Tartışma ve (vii) Kaynaklar'dır. Başlık sayfası dışında yazının hiçbir bölümünün ayrı sayfalarda başlatılması zorunluluğu yoktur. Maddi kaynak, çalışmayı destekleyen burslar, kuruluşlar, fonlar, metnin sonunda teşekkürler kısmında belirtilmelidir. Olgu sunumları İngilizce ve Türkçe özetleri kısa ve tek paragraflık olmalıdır. Olgu sunumu özetleri ağırlıklı olarak mutlaka olgu hakkında bilgileri içermektedir. Anahtar sözcüklerinden sonra giriş, olgu(lar) tartışma ve kaynaklar şeklinde düzenlenmelidir. Derleme yazıları İngilizce ve Türkçe başlık, İngilizce ve Türkçe özet ve İngilizce ve Türkçe anahtar kelimeler yer almalıdır. Kaynak sayısı 50 ile sınırlanması önerilmektedir. Kaynaklar Kaynaklar yazıda kullanılış sırasına göre numaralanmalıdır. Kaynaklarda verilen makale yazarlarının sayısı 6 dan fazla ise ilk 3 yazar belirtilmeli ve İngilizce kaynaklarda ilk 3 yazar isminden sonra et al., Türkçe kaynaklarda ise ilk 3 yazar isminden sonra ve ark. ibaresi kullanılmalıdır. Noktalamalara birden çok yazarlı bir çalışmayı tek yazar adıyla kısaltmamaya ve kaynak sayfalarının başlangıç ve bitimlerinin belirtilmesine dikkat edilmelidir. Kaynaklarda verilen dergi isimleri Index Medicus'a ( ery.fcgi?db=nlmcatalog) veya Ulakbim/Türk Tıp Dizini ne uygun olarak kısaltılmalıdır. Makale: Tuna H, Avcı Ş, Tükenmez Ö, Kokino S. İnmeli olguların sublukse omuzlarında kas-sinir elektrik uyarımının etkinliği. Trakya Univ Tıp Fak Derg 2005;22:70-5. Kitap: Norman IJ, Redfern SJ, (editors). Mental health care for elderly people. New York: Churchill Livingstone, Kitaptan Bölüm: Phillips SJ, Whisnant JP Hypertension and stroke. In: Laragh JH, Brenner BM, editors. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. New York: Raven Pres, 1995: Kaynak web sitesi ise: Kaynak makalerdeki gibi istenilen bilgiler verildikten sonra erişim olarak web sitesi adresi ve erişim tarihi bildirilmelidir. Kaynak internet ortamında basılan bir dergi ise: Kaynak makaledeki gibi istenilen bilgiler verildikten sonra erişim olarak URL adresi ve erişim tarihi verilmelidir. Kongre Bildirileri: Bengtsson S, Solheim BG. Enforcement of data protection, privacy and security in medical informatics. In: Lun KC, Degoulet P, Piemme TE, Rienhoff O, editors. MEDINFO 92. Proceedings of the 7th World Congress on Medical Informatics; 1992 Sep 6-10; Geneva, Switzerland. Amsterdam: North-Holland; 1992: Tablo, şekil, grafik ve fotoğraf Tablo, şekil grafik ve fotoğraflar yazının içine yerleştirilmiş halde gönderilmemeli. Tablolar, her sayfaya bir tablo olmak üzere yazının gönderildiği dosya içinde olmalı ancak yazıya ait şekil, grafik ve fotografların her biri ayrı bir imaj dosyası (jpeg yada gif) olarak gönderilmelidir.

6 Tablo başlıkları ve şekil altyazıları eksik bırakılmamalıdır. Şekillere ait açıklamalar yazının gönderildiği dosyanın en sonuna yazılmalıdır. Tablo, şekil ve grafiklerin numaralanarak yazı içinde yerleri belirtilmelidir. Tablolar yazı içindeki bilginin tekrarı olmamalıdır. Makale yazarlarının, makalede eğer daha önce yayınlanmış alıntı yazı, tablo, şekil, grafik, resim vb var ise yayın hakkı sahibi ve yazarlardan yazılı izin almaları ve makale üst yazısına ekleyerek dergiye ulaştırmaları gerekmektedir. Tablolar Metin içinde atıfta bulunulan sıraya göre romen rakkamı ile numaralanmalıdır. Her tablo ayrı bir sayfaya ve tablonun üst kısmına kısa ancak anlaşılır bir başlık verilerek hazırlanmalıdır. Başlık ve dipnot açıklayıcı olmalıdır. Sütun başlıkları kısa ve ölçüm değerleri parantez içinde verilmelidir. Bütün kısaltmalar ve semboller dipnotta açıklanmalıdır. Dipnotlarda şu semboller: ( ) ve P değerleri için ise *, **, *** kullanılmalıdır. SD veya SEM gibi istatistiksel değerler tablo veya şekildin altında not olarak belirtilmelidir. Grafik, fotoğraf ve çizimler ŞEKİL olarak adlandırılmalı, makalede geçtiği sıraya gore numaralanmalı ve açıklamaları şekil altına yazılmalıdır Şekil alt yazıları, ayrıca metinin son sayfasına da eklenmelidir. Büyütmeler, şekilde uzunluk birimi (bar çubuğu içinde) ile belirtilmelidir. Mikroskopik resimlerde büyütme oranı ve boyama tekniği açıklanmalıdır. Etik Marmara Medical Journal a yayınlanması amacı ile gönderilen yazılar Helsinki Bildirgesi, İyi Klinik Uygulamalar Kılavuzu,İyi Laboratuar Uygulamaları Kılavuzu esaslarına uymalıdır. Gerek insanlar gerekse hayvanlar açısından etik koşullara uygun olmayan yazılar yayınlanmak üzere kabul edilemez. Marmara Medical Journal, insanlar üzerinde yapılan araştırmaların önceden Araştırma Etik Kurulu tarafından onayının alınması şartını arar. Yazarlardan, yazının detaylarını ve tarihini bildirecek şekilde imzalı bir beyan ile başvurmaları istenir. Çalışmalar deney hayvanı kullanımını içeriyorsa, hayvan bakımı ve kullanımında yapılan işlemler yazı içinde kısaca tanımlanmalıdır. Deney hayvanlarında özel derişimlerde ilaç kullanıldıysa, yazar bu derişimin kullanılma mantığını belirtmelidir. İnsanlar üzerinde yapılan deneysel çalışmaların sonuçlarını bildiren yazılarda, Kurumsal Etik Kurul onayı alındığını ve bu çalışmanın yapıldığı gönüllü ya da hastalara uygulanacak prosedürlerin özelliği tümüyle kendilerine anlatıldıktan sonra, onaylarının alındığını gösterir cümleler yer almalıdır. Yazarlar, bu tür bir çalışma söz konusu olduğunda, uluslararası alanda kabul edilen kılavuzlara ve TC. Sağlık Bakanlığı tarafından getirilen ve 28 Aralık 2008 tarih ve sayılı Resmi Gazete'de yayınlanan "Klinik araştırmaları Hakkında Yönetmelik" ve daha sonra yayınlanan 11 Mart 2010 tarihli resmi gazete ve sayılı Klinik Araştırmalar Hakkında Yönetmelikte Değişiklik Yapıldığına Dair Yönetmelik hükümlerine uyulduğunu belirtmeli ve kurumdan aldıkları Etik Komitesi onayını göndermelidir. Hayvanlar üzerinde yapılan çalışmalar için de gereken izin alınmalı; yazıda deneklere ağrı, acı ve rahatsızlık verilmemesi için neler yapıldığı açık bir şekilde belirtilmelidir. Hasta kimliğini tanıtacak fotoğraf kullanıldığında, hastanın yazılı onayı gönderilmelidir. Yazı takip ve sorularınız için iletişim: Seza Arbay Marmara Universitesi Tıp Fakültesi Dekanlığı, Tıbbiye Caddesi, No: 49, Haydarpaşa 34668, İstanbul Tel: Faks: e-posta: [email protected]

7 İÇİNDEKİLER Orjinal Araştırma A LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM FOR THE TREATMENT OF ABNORMAL UTERINE BLEEDING Recep Yıldızhan, Begüm Pekin Yıldızhan, Ertan Adalı, Necdet Süer 53 A COMPARISON OF CONVENTIONAL EXTERNAL RADIOTHERAPY TECHNIQUE AND CONFORMAL RADIOTHERAPY TECHNIQUE IN TERMS OF ACUTE TOXICITY WITH REGARD TO HORMONAL TREATMENT İlknur Çetin, Ufuk Abacıoğlu, Meriç Şengöz THE EFFECT OF A LEVONORGESTREL-RELEASING INTRAUTERINE DEVICE ON OVARIECTOMIZED RAT ENDOMETRIUM UNDER ESTROGEN REPLACEMENT THERAPY Murat Api, Feriha Ercan, Serap Arbak, Olus Api THE CONTRIBUTION OF HOME-FAMILY DISTRESS TO THE PRESENTATION DIFFERENCE OF CHILDHOOD OBSESSIVE-COMPULSIVE DISORDER ACROSS HOME AND SCHOOL SETTINGS Osman Sabuncuoğlu, Meral Berkem...73 Olgu Sunumu MISPLACEMENT OF A NASOGASTRIC TUBE INTO THE POSTPNEUMONECTOMY SPACE Tümay Umuroğlu, İ. Varlık Doğan, Abdurrahman Yaycı. 78 A FAMILY WITH A 17p: PERICENTRIC INVERSION: IMPLICATIONS FOR CARRIERS Gülseren Bağcı, Özgül Alper, Anne Hagemeijer, Hasan Acar, Elizabeth M.E. Smit, Mine Üner Güven Lüleci COCHLEAR IMPLANTATION IN A PATIENT WITH LARGE VESTIBULAR AQUEDUCT SYNDROME: A CASE REPORT Ufuk Derinsu, Ayça Çiprut, Sezer Külekçi, Ferda Akdaş...84 CLINICAL AND ELECTRODIAGNOSTIC FOLLOW UP OF A CASE OF FOOD BORNE BOTULISM Nilgün Cengiz, Hande Türker, Meral Kiziltan..89 Derleme THE MANAGEMENT OF ELBOW FRACTURES IN CHILDREN Bülent Erol, Murat Bezer, Gökhan Er, Mustafa Karahan, Osman Güven

8 ORIGINAL RESEARCH A LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM FOR THE TREATMENT OF ABNORMAL UTERINE BLEEDING Recep Yıldızhan, Begüm Pekin Yıldızhan, Ertan Adalı, Necdet Süer Department of Obstetrics and Gynaecology, SSK Göztepe Training and Research Hospital, Istanbul, Turkey ABSTRACT Objectives: To evaluate the efficacy and safety of an intrauterine system releasing 20µg levonorgestrel per 24 hours in the longterm treatment of heavy menstrual blood loss in women unrelated to intrauterine pathology. Methods: Sixty parous women aged years with recurrent menorrhagia participated in this study. Women were followed-up for at least 12 months (12-16 months). The effect on menstrual blood loss was evaluated using a simple visual assessment technique. All women to be included in the study were screened for their clinical suitability for intrauterine device insertion. An intrauterine device releasing levonorgestrel 20 µg/day was inserted in each patient within 5 days of the start of menstrual flow. Women were followed-up at 1, 3, 6, 12 months following insertion of the intrauterine device, for clinical and transvaginal ultrasound examinations. Results: One patient experienced intrauterine device expulsion 1 month after device insertion and one woman was lost to followup after achieving amenorrhea and expressing satisfaction. One year of follow-up has been completed for the remaining 58 women: 8 cases with amenorrhea, 12 with oligomenorrhea, 6 with spottings and 32 patients with regular flow, with a significant reduction in the amount of menstrual blood loss. The levonorgestrel-releasing intrauterine system was well tolerated by all women involved in the study and no systemic hormonal side effects were reported. Conclusion: Our findings indicate that the levonorgestrel-releasing intrauterine system is effective in the significiant reduction of the amount of menstrual blood loss in women with menorrhagia, even in the presence of adenomyosis, intramural and subserosal fibroids and renders surgery unnecessary. In addition, the levonorgestrel-releasing intrauterine system showed a high contraceptive efficacy and a good continuation rate for up to 1 year. Keywords: Menorrhagia, Levonorgestrel-releasing intrauterine system, Contraception, Transvaginal ultrasound, Pipelle endometrial biopsy ŞİDDETLİ MENSTRUEL KANAMA TEDAVİSİNDE LEVONORGESTREL - SALINIMLI İNTRAUTERİNE SİSTEMİN KULLANILMASI ÖZET Amaç: İntrauterin bir patolojiye bağlı olmayan şiddetli menstruel kanaması olan kadınlarda 20µg/gün levonorgestrel salınımlı intrauterin sistemin etkinlik ve güvenilirliğinin değerlendirilmesidir. Yöntem: Menoraji şikayeti olan ve daha önce doğum yapmış yaşları arasında bulunan 60 kadın bu çalışmada yer almıştır. Bu kadınlar en az 12 ay boyunca takip edilmiştir. Menstruel kan kaybının yaratmış olduğu etki, görsel değerlendirme tekniği ile saptanmıştır. Çalışmaya katılan tüm kadınların, intrauterin araç uygulamaya uygun olup olmadığı araştırılmıştır. Tüm kadınlara adetlerinin başlangıcından itibaren ilk 5 gün içinde 20µg/gün levonorgestrel salınımlı intrauterin araç uygulanmıştır. Her hasta, uygulamayı takiben 1., 3., 6. ve 12. aylarda klinik ve ultrasonografik olarak takip edilmiştir. Bulgular: Takip edilen hastalardan bir tanesinde uygulamadan 1 ay sonra intrauterin araç kendiliğinden çıkmıştır. Diğer bir hastaya ise, amenore elde edilmesine ve hastanın yöntemden memnuniyetini ifade etmesine rağmen rutin takipler için ulaşılamamıştır. Geriye kalan 58 hastada 1 yıllık rutin takipler tamamlanmıştır. Buna göre 8 hastada amenore, 12 hastada oligomenore, 6 hastada lekelenme ve 32 hastada ise menstruel kan kaybında anlamlı bir azalma olmakla birlikte düzenli kanamaların sürdüğü saptanmıştır. Çalışmada yer alan tüm hastalar tarafından levonorgestrel salınımlı intrauterin sistem iyi tolere edilebilmiş olup sistemik hormonal yan etkiler izlenmemiştir. Sonuç: Bulgularımız göstermiştir ki; levonorgestrel salınımlı intrauterin sistem, şiddetli menstruel kanama ile kaybedilen kan miktarında belirgin oranda azalmaya neden olmuş ve hatta adenomyozis, intramural ve subseröz myom varlığında dahi cerrahiye olan gereksinimi azaltmıştır. Bunların yanısıra, yüksek kontraseptif etkinliğe de sahiptir. Anahtar Kelimeler: Menoraji, Levonorgestrel salınımlı intrauterin sistem, Kontrasepsiyon, transvajinal ultrasonografi, pipelle endometrial biopsi. Corresponding author:recep Yıldızhan M.D.Cemil Topuzlu Cd. Marmara Medical Journal 2004;17(2); / Caddebostan Istanbul, Turkey Tel.: Fax: [email protected] 53

9 Marmara Medical Journal 2004;17(2);53-57 Recep Yıldızhan, et al. A levonorgestrel-releasıng intrauterine system for the treatment of abnormal uterine bleeding INTRODUCTION The levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena, Schering) was originally designed as a contraceptive method registered in Europe, Latin America, U. S., and Canada 1. The purpose was to improve the contraceptive efficacy over that of inert intrauterine devices (IUDs) and to reduce side effects. The effectiveness was tested for up to 7 years in different settings, and the cumulative pregnancy rate was from 0.0 to 0.5 in up to 7 years of use 2,3. The LNG-IUS is a hormonal contraceptive, but its action is local to the uterine cavity. Extensive studies of the LNG- IUS revealed that its main mechanism of action differs from that of inert IUDs. One of the main characteristics of the LNG-IUS is to cause a reduction in the amount of blood loss during each menstrual period. Due to this characteristic, it has been used as a medical treatment for women with menorrhagia unrelated to intrauterine pathology 4. An intrauterine system that releases levonorgestrel, a potent 19-nortestosteron derivative progestin, locally administered, has a profound effect on the endometrium, which becomes atrophic and inactive, although ovulation is usually not supressed 5. Reduction or absence of menstrual bleeding became a therapeutic effect in women with abnormal uterine bleeding menometrorrhagia. An atrophic endometrial epithelium was thought to account for this action. Today, the LNG-IUS is the most effective medical therapy for menorrhagia unrelated to intrauterine pathology. Intrauterine administration of levonorgestrel has also been shown to be effective in opposing the proliferative effect of oestrogen on the endometrium during oestrogen replacement therapy. In this study, we evaluated the efficacy and tolerability of treatment with a levonorgestrelreleasing intrauterine device in women affected by abnormal uterine bleeding. METHODS This was a prospective study at the Department of Obstetrics and Gynaecology, SSK Research and Training Hospital, Istanbul-Turkey. The Institutional Review Board Approval was obtained from the Ethical Committee of the Hospital. All women voluntarily signed an informed consent to the study. A total of 60 women aged 35 to 48 years (mean 42.36), reported recurrent menorrhagia of at least 18 months duration. All women to be included in the study were screened for their clinical suitability for IUD insertion and followed-up for 12 months duration. Each woman underwent pelvic examination, transvaginal ultrasound, pipelle endometrial biopsy and Papanicolaou smear in the 2 months before entry into the study to evaluate the uterine status. Four cases were diagnosed as myoma uteri, single or multiple small intramural and subserosal fibroids (<3 cm).there was no evidence of submucosal fibroids. Eight women were diagnosed at transvaginal ultrasound (TVUS) as having adenomyosis. The remaining 48 women were diagnosed with dysfunctional uterine bleeding. Patients with the following were excluded: congenital valvular heart disease, congenital malformation of the vagina, cervix or uterus, known or suspected uterine or cervical malignancy; history of pelvic inflammatory disease (PID), postpartum endometritis or history of infected abortion. An IUD releasing 20 µg/day of levonorgestrel was inserted in each patient within 5 days of the start of menstrual flow. All the women underwent clinical and transvaginal ultrasound (TVUS) examinations at 1, 3, 6, and 12 months after IUD insertion. During follow-up, women were interviewed about their bleeding patterns and any side effects or adverse reactions. At the final examination after 12 months, pipelle endometrial biopsy was repeated to evaluate the endometrial status. These specimens were fixed and haematoxylin and eosin stained sections were produced in a standard manner, and were assessed by a consultant histopathologist of the hospital. In this study, to discriminate between menorrhagia and normal menstrual blood loss, a simple visual assessment technique was used as described by Gardner 6. The number of days of bleeding and the maximum amount of bleeding during a 24- hour period was scored by the following definitions: spotting with a daily bleed score of 1 was defined as fresh blood seen on wiping but not requiring sanitary protection; light loss with a score of 2 was defined as small amount of blood on any sanitary pad during that day; moderate loss with a score of 3 was defined as moderate amount of blood on any sanitary pad during that day; and heavy loss with a score 4 was defined as soaking of any sanitary pad with blood during that day. We summed the maximum daily bleeding scores for each of four 90-day intervals over the 12 months of follow-up to give total bleeding scores for each of the intervals. Women returned these 54

10 Marmara Medical Journal 2004;17(2);53-57 Recep Yıldızhan, et al. A levonorgestrel-releasıng intrauterine system for the treatment of abnormal uterine bleeding data at their three month and six month follow-up appointment and at the end of the study period. RESULTS A total of 60 parous women, with a mean age of years were recruited. Insertion of the LNG- IUS was uneventful, and was performed in all cases without anestesia and without particular patient discomfort. No changes occurred during the study period in body weight or blood pressure. We found no abnormalities in the Papanicolaou smears and noted no important side-effects or adverse reactions such as headache, mood changes, lower abdominal and back pain, nausea, oedema or skin disorders. In this study we used an (LNG-IUS) that contains 52 mg of levonorgestrel which is released at a rate of 20 µg daily for 5 years. The system was primarily designed for contraception but is now widely used to decrease menstrual blood loss in women with menorrhagia as well for endometrial protection during oestrogen replacement therapy 7,8, producing a very high local concentration in the endometrial tissues with low-plasma concentrations gained systemically 9. We have shown that epithelial atrophy and stromal decidualization are the most typical morphological characteristics in the endometrium during the use of LNG-IUS. Menstrual blood loss is significantly decreased, and many women treated with LNG-IUS have no menstrual bleeding 1 year after the insertion. At the beginning of the trial period, there was simple hyperplasia in 33 patients, irregular proliferative endometrium in 18 patients, secretory endometrium in 9 patients. One woman expelled the LNG-IUS 2 months after insertion and she subsequently underwent hysterectomy. The pathology confirmed the diagnosis of uterine adenomyosis. One patient was lost to follow-up after she became amenorrheic and was satisfied with the treatment, before the six month evaluation. The remaining 58 patients completed the study. Regarding the bleeding pattern in the first 3 months, spotting was by far the most frequent menstrual finding. Spotting decreased progressively in subsequent months, but still occurred occasionally in 6 patients at the end of the study. Six months after LNG-IUS insertion, amenorrhea was obtained in 8 patients and oligomenorrhea in 12 patients and almost equal throughout the observation period. Scanty regular cycles were observed in the remaining 27 patients. At the end of the trial, pipelle endometrial biopsy showed pronounced progesteron influence with decidua-like stroma in 39 samples, desquamated endometrium in 12 samples, and no endometrium in seven. Proliferation or atypia was not found in any of the specimens. The mean endometrial thickness was greater than 5mm in women at the initial of the study. At the final screening there was a significant decrease in mean endometrial thickness less than 3mm which demonstrated an extremely thin endometrium 12 months after IUD insertion during the follow-up of our patients. The mean cavity length, long diameter, and anteroposterior diameter were not significantly different between the women at baseline, and over the 12 months of follow-up. DISCUSSION Menorrhagia is defined as regular, prolonged and excessive menstrual bleeding of more than 80 ml from a secretory endometrium. When menstrual blood loss exceeds 80ml, the incidence of anemia increased significantly 10. Iron deficiency with depletion of iron stores and or anemia predisposes the women to ill health and disease. The LNG-IUS was originally designed for contraceptive use more than 20 years ago. The purpose was to improve the contraceptive efficacy over that of inert intrauterine devices and to reduce side effects. Extensive studies following the introduction of the LNG-IUS revealed that its main mechanism of action differs from that of inert IUDs. The LNG-IUS is a hormonal contraceptive, but its action is local to the uterine cavity. Levonorgestrel is a 19-nortestosterone derivative which is much more potent than natural progesterone and has major effects on the stromal parts of the endometrium 11. Many women using the LNG-IUS have ovulatory cycles 12 although they may have menstrual irregularities during the first few months of use. The effectiveness of the LNG-IUS to treat menorrhagia may be caused by two actions. First it causes strong decidualization and subsequent marked atrophy of the endometrium 13,14. The LNG-IUS also affects the vascular system in the endometrium. The changes include thickening of the arterial walls and supression of the spiral arteries and capillary thrombosis 14. This probably accounts for the marked reduction in menstrual flow. Secondly, there is also direct action of the hormone on endometrial tissues. The LNG-IUS has been shown to cause down regulation of oestrogen receptors (ER) in both glandular and stromal endometrial tissues. This was evident at 1 55

11 Marmara Medical Journal 2004;17(2);53-57 Recep Yıldızhan, et al. A levonorgestrel-releasıng intrauterine system for the treatment of abnormal uterine bleeding month postinsertion and persisted for up to 12 months after insertion 15. Lu reported that both oestrogen and progesterone receptors decreased significantly after 6-9 months of LNG-IUS use 16. By down regulation ER in these foci, it may prevent further stimulation by oestrogens, leading to atrophy and shrinkage of endometrial tissues. The marked efficacy of the LNG-IUS could result from the fact that intrauterine LNG produced endometrial LNG levels 1000 times greater than serum concentrations 9. Thus, dose dependancy effects on LNG could account for the difference between intrauterine progesterone and other forms of progesterone administration. The morphological changes in levonorgestrel-exposed endometrium return to normal in most cases in the menstrual cycle after removal of the system 12. The LNG-IUS is associated with low risk of infection, high continuation rate, and significant reduction of menstrual bleeding 1-3,17. The only reason for discontinuation in the group with heavy menses before insertion of the device was expulsion. The finding was also observed in our trial in one woman who was inserted with LNG- IUS as a treatment for heavy menorrhagia. The bleeding amount dramatically decreased in 4 women with small fibroids after insertion, and spotting frequency decreased in the same proportion as amenorrhea increased after the sixth month of observation. The effect may reflect the strong endometrial suppression provoked by the high levonorgestrel concentration in the uterine cavity 18. The LNG-IUS is a very useful, effective, nonsurgical and reversible treatment method of menorrhagia in women harboring fibroids and adenomyosis. In women with a normal uterus, the success rate is close to 100%. In the presence of small fibroids, however, the success rate is satisfactory. This was also shown by other studies conducted in women with fibroids and adenomyosis 11,15,19. In the present study, the reduction of menstrual flow was impressive, and although there was a high incidence of spotting and oligomenorrhea, such menstrual anomalies were well tolerated by our patients. In addition, rapid recovery after discontinuation of the treatment was shown. Today, the LNG- IUS is the most effective medical therapy for menorrhagia unrelated to intrauterine pathology. Intrauterine administration of levonorgestrel has also been shown to be effective in opposing the proliferative effect of oestrogen on the endometrium during oestrogen replacement therapy. The LNG-IUS may constitute an innovative, effective, safe and convenient alternative for local delivery of a potent progestin in the long-term therapy of recurrent menorrhagia. The use of the LNG-IUS may thus represent a real advance in the treatment of menorrhagia in women who do not want children. REFERENCES 1. Hidalgo M, Bahamodes L, Perrotti M, Diaz J, Dantes-Monteiro C, Petta C. Bleeding patterns and clinical performance of the levonorgestrelreleasing intrauterine system (Mirena) up to two years. Contraception 2002; 65: Faundes A, Alvarez F, Diaz J. A Latin American experience with levonorgestrel IUD. Ann Med 1993; 25: Diaz J, Faundes A, Diaz M, Marchi N. Evaluation of the clinical performance of a levonorgestrelreleasing IUD, up to seven years of use, in Campinas, Brazil. Contraception 1996; 47: Stewart A, Cummins C, Gold L, Jordan R, Philips W. The effectiveness of the levonorgestrelreleasing intrauterine system in menorrhagia: a systemic review. Br J Obstet Gynaecol 2001; 108: Crosignani PG, Vercellini P, Mosconi P, Oldani S, Cortesi I, De Giorgi O. A levonorgestrel releasing intrauterine device versus hysterescopic endometrial resection in the treatment of dysfunctional bleeding. Obstet Gynaecol 1997; 90: Gardner F JE, Konje JC, Abrams KR, Brown L JR, Khanna S, Al-Azzawi F, et al. Endometrial protection from tamoxifen-stimulated changes by a levonorgestrel-releasing intrauterine system:a randomised controlled trial. The Lancet 2000; 356: Andersson K, Mattsson L-A, Rybo G, Stadberg E. Intrauterine release of levonorgestrel- A new way of adding progestogen in hormone replacement therapy. Obstet Gynecol 1992; 79: Luukkainen T, Toivonen J. Levonorgestrelreleasing IUD as a method of contraception with therapeutic properties. Contraception 1995; 52: Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. issue concentrations of levonorgestrel in women using levonorgestrelreleasing IUD. Clin Endocrinol 1982; 17: Janssen CA, Scholten PC, Heintz APM. Menorrhagia: a search for epidemiological risk markers. Maturitas 1997; 28: Fedele L, Bianchi S, Raffaelli R, Portuese A, Dorta M. Treatment of adenomyosis- associated menorrhagia with a levonorgestrel-releasing intrauterine device. Fertil Steril 1997; 68:

12 Marmara Medical Journal 2004;17(2);53-57 Recep Yıldızhan, et al. A levonorgestrel-releasıng intrauterine system for the treatment of abnormal uterine bleeding 12. Nilsson CG, Lähteenmäki P, Luukkainen T. Ovarian function in amenorrheic and menstruating users of a levonorgestrel-releasing intrauterine device. Fertil Steril 1984; 41: Sivin I, Stern J. Health during prolonged use of levonorgestrel 20µg/d and the copper T cu 380 Ag intrauterine contraceptive devices: a multicenter study. Fertil Steril 1994; 61: Zhu P, Luo HZ, Xu RH, et al. The effect of intrauterine devices, the stainless steel ring,the copper T 220, and releasing levonorgestrel, on the bleeding profile and the morphological structure of the human endometrium a comperative study of three IUDs. A morphometric study of 96 cases. Contraception 1989; 40: Fujimoto J, Hirose R, Ichigo S, et al. Expression of progesterone receptor form A and B mrnas in uterine leiomyoma. Tumour Biol 1998; 19: Lu SM. Effect of levonorgestrel intrauterine device on human endometrial oestrogen and progesterone receptors. Chung Hua Fu Chan Ko Tsa Chih 1991; 26: , Barbosa I, Olsson SF, Odling V, Johansson E. Ovarian function during use of a levonorgestrelreleasing IUD. Contraception 1990; 42: Pakarien P, Luukkainen T, Laine H, Lähteenmäki P. The effect of local intrauterine levonorgestrel administration on endometrial thickness and uterine blood circulation.hum reprod 1995; 10: Maruo T, Samoto T, Takeuchi S, Spitz I, Johansson E. Usefulness of levonorgestrelreleasing IUD in the management of menorrhagic women with uterine myoma and adenomyosis. In: proceedings of the presantation held at the Xth International Congress of the Society for the Advancement of Contraception. Manila, Philippines,

13 ORIGINAL RESEARCH A COMPARISON OF CONVENTIONAL EXTERNAL RADIOTHERAPY TECHNIQUE AND CONFORMAL RADIOTHERAPY TECHNIQUE IN TERMS OF ACUTE TOXICITY WITH REGARD TO HORMONAL TREATMENT İlknur Çetin, Ufuk Abacıoğlu, Meriç Şengöz Department of Radiation Oncology, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Objective: Comparing the application of conventional external radiotherapy technique (EBRT) and conformal radiotherapy technique (CRT) in terms of acute side effects with respect to hormonotherapy (HT) in the primary treatment of prostate cancer. Materials and Methods: Seventy-five patients diagnosed with localized prostate cancer were treated with primary radiotherapy (RT) between March 1997 and July 2002, 47 with EBRT and 28 with CRT. 23 patients (31%) did not receive HT, 22 patients (29%) received concomitant HT (CHT) and 30 patients (40%) received neoadjuvant HT (NAHT). The patients were observed for at least 3 months and the acute toxicity was evaluated by EORTC/RTOG (European Organization for Research and Treatment of Cancer / Radiation Therapy Oncology Group) scale 1. Results: There was no grade III-IV acute urinary and rectal toxicity. The percentage of grade I and II acute urinary toxicity was determined as 30% and 23%, respectively in the EBRT group. The ratios were 61% and 18%, respectively in the CRT group (p=0.025). Grade II urinary toxicities were 13% in patients who did not receive HT and who received NAHT, 41% in patients who received CHT (p=0.02). Grade II rectal toxicities were 30% for EBRT and 7% for CRT group (p=0.022). Conclusion: CRT caused a decrease in grade II rectal and urinary toxicity. Grade II acute urinary toxicities were observed more frequently in the treatment of CHT than the NAHT. Keywords: Acute toxicity,cconventional-conformal radiotherapy, Prostate cancer KONVANSİYONEL EKSTERNAL RADYOTERAPİ VE KONFORMAL RADYOTERAPİ TEKNİKLERİNİN HORMONOTERAPİ DURUMUNA GÖRE AKUT YAN ETKİLER AÇISINDAN KARŞILAŞTIRILMASI ÖZET Amaç : Prostat kanserinin primer tedavisinde konvansiyonel eksternal radyoterapi (EBRT) ile konformal radyoterapi teknik (CRT)uygulamaların hormonoterapi (HT) durumuna göre akut yan etkiler açısından karşılaştırılması amaçlanmıştır. Gereç ve Yöntem : Mart Temmuz 2002 tarihleri arasında lokalize prostat kanseri tanısı konmuş ve primer radyoterapi uygulanmış 75 hastanın EBRT uygulanan 47 ve CRT uygulanan 28 hasta idi. Tüm hastalar için medyan yaş 72 (55-85), medyan radyoterapi dozu 70 Gray (Gy) (63-76 Gy) olarak tespit edilmiştir. Hastaların 23 u (%31) hormonoterapi almamış, 22 si (%29) eş zamanlı hormonoterapi almış ve 30 u (%40) neoadjuvan hormonoterapi almıştı. Hastaların en az 3 aylık takibi mevcut olup, görülen akut yan etkiler EORTC/RTOG (European Organisation for Research and Treatment of Cancer / Radiation Therapy Oncology Group) skalası kullanılarak değerlendirilmiştir 1. Bulgular: Grade I ve II akut üriner yan etkiler; konvansiyonel radyoterapi grubunda %30 ve %23 iken, konformal radyoterapi grubunda %61 ve %18 oranında gözlenmiştir (p=0.025). Grade II üriner yan etkiler; HT almayanda ve neoadjuvan hormonoterapi alanlarda %13 eş zamanlı hormonoterapi alan hastalarda %41 oranında saptanmıştır (p=0.02). Grade II rektal yan etkiler; konvansiyonel radyoterapi grubunda %30, konformal radyoterapi grubunda %7 oranında tespit edilmiştir (p=0.022). Sonuç : Konformal radyoterapi uygulaması ile grade II akut rektal ve üriner yan etkilerin azaldığı tespit edilmiştir. Eşzamanlı hormonoterapi kullanımı ile grade II akut üriner yan etki neoadjuvan kullanıma göre daha sık gözlenmiştir. Anahtar Kelimeler: Akut yan etkiler, Konvansiyonel, Konformal radyoterapi, Prostat kanseri Corresponding author: İlknur Çetin, M.D Department of Radiation Oncology, School of Medicine, Marmara University Hospital, Tophanelioğlu Caddesi 13/15, Altunizade, İstanbul [email protected] Marmara Medical Journal 2004;17(2);

14 Marmara Medical Journal 2004;17(2);58-64 İlknur Çetin, et.al. A comparison of Conventıonal External Radıotherapy Technique and Conformal Radiotherapy Technique in Terms of Acute Toxıcity With Regard to Hormonal Treatment INTRODUCTION Radiation has been used in the curative treatment of prostate cancer for approximately a hundredyears. With the technical improvements in medicine, localized prostate cancer is now being treated with EBRT. Such patients are usually old and have comorbidities, so they have to be treated effectively with the least side effects 1. The radiation dose given in order to provide local tumor control remains insufficient with the EBRT technique used today 2. Toxicities increase when the treatment dose increases. Thus, 3-dimensional treatment planning and CRT has been widely accepted in the treatment of prostate cancer. The aim is to control the tumor by giving high doses while protecting the surrounding normal tissues as much as possible 3-7. Retrospective and prospective studies indicate that CRT has fewer side effects compared to standard technique with the same dose In addition, despite an increase in the RT dose, tolerable side effects were reported in some studies, regarding the conformal treatment technique In this study, in the Marmara University Hospital Radiation Oncology Department, the urinary - rectal side effects observed during and after treatment with EBRT and CRT were compared with regard to the HT situation. METHODS Seventy-five patients with localized prostate cancer treated in the Marmara University Hospital Radiation Oncology Department between March 1997 and July 2002 were classified according to 1997 AJCC classification with thin injection biopsy, Gleason score and/or BT accompanied with rectal examination, and transrectal ultrasonography (TRUSG) were taken before the treatment 15. Metastatic disease was eliminated by routine biochemical examination, whole body bone scintigraphy, and radiological examinations when required. Fourty-seven patients (62.6%) were treated with EBRT, whereas 28 patients (37.3%) were treated with CRT. Median age of patients was 72 (55-85), median T phase was T2, median initial PSA (Prostate-Specific Antigen) was 8ng/ml, median RT dose was 70 Gy. 23 patients did not receive HT, 22 patients were treated with CHT and 30 patients were treated with NAHT. Patient characteristics and treatment methods together with distribution and significance of two technical treatments are shown in Table I. Treatment was carried out by using Saturne 42 linear accelerator and 18 MV X-Ray. Immobilization in the supine position was ensured in the simulator for all patients. Axial BT images with 0.5 cm thickness were taken with empty rectum and full bladder in the same position. 10 mlt contrast were introduced to the urethra in order to visualize the urethra and the apex of the prostate. BT images were transferred to the treatment planning system by the 'Dicom Network' System. Using the conventional technique, PTV1 was defined as small pelvis or prostate with seminal vesicular and PTV2 was defined as the prostate region. Standard lead blocks were used in the areas. Patients were treated with the four-field box technique (except for 3 patients with AP-PA fields and 2 patients with 3 fields- AP and two lateral opposing fields) to a dose range of Gy. A boost was given with the four-field box technique to a total dose of Gy. In the CRT group, patients were treated with the four field box technique (except one patient treated with the 5 field technique) up to Gy and then boosted to a total of Gy RT with custom blocking to all fields. Median RT dose was 70 Gy (63-76 Gy), Gy/fraction/day, 5 fractions per week. Maximal Androgen Blockade (MAD) (anti-androgen and LHRH analogue) was started concomitant with RT or before (1-17 months) in the patients. Duration of MAD was determined according to the risk group of the patient. Acute side effects (during or 3 months after primary RT) were evaluated by using the EORTC/RTOG scale (Annex). The relation between two different treatment techniques and patient characteristics, the relation between acute urinary and rectal side effects with patient characteristics and treatment techniques were evaluated by using Chi-square test or Fisher's Exact Test in one variable analysis. Relative ratio (odds ratio-or) and results were given in 95% confidence interval. The results were accepted at the level of significance p Statistical analysis was performed by the use of the SPSS 10.0 package program. RESULTS The distribution of urinary and rectal side effects observed regarding two different treatment techniques is shown in Table I. 59

15 Marmara Medical Journal 2004;17(2);58-64 İlknur Çetin, et.al. A comparison of Conventıonal External Radıotherapy Technique and Conformal Radiotherapy Technique in Terms of Acute Toxıcity With Regard to Hormonal Treatment Table I: Patient Characteristics EBRT (%) CRT (%) P Number of Patients 47 (62.6) 28 (37.2) Age < (36.1) 10 (35.7) (63.8) 18 (64.2) T stage T1 12 (25.5) 4 (14.2) T2 25 (53.1) 22 (78.5) 0.19 T3 9 (19.1) 2 (7.1) T4 1 (2.1) Initial PSA (ng/ml) (38.2) 6 (21.4) (23.4) 9 (32.1) 0.17 > (27.6) 13 (46.4) unknown 5 (10.6) Known Disease 0.09 Hypertension 3 (6.3) 6 (21.4) Heart Disease - 4 (14.2) Diabetes 4 (8.5) 2 (7.1) Haemorrhoid 15 (31.9) 13 (46.4) Pelvic Operation 2 (4.2) 3 (10.7) TUR-P 2 (4.2) - Unknown 14 (29.7) - Radiotherapy Dose Gy 70 Gy 15 (%31.9) 22 (46.8) 5 (8.6) 20 (71.4) Gy 10 (21.2) 3 (10.7) Hormonotherapy 18 (38.2) 5 (17.9) NoneConcomitant 17 (36.1) 5 (17.9) Neoadjuvant 12 (25.5) 18 (64.3) 60

16 Marmara Medical Journal 2004;17(2);58-64 İlknur Çetin, et.al. A comparison of Conventıonal External Radıotherapy Technique and Conformal Radiotherapy Technique in Terms of Acute Toxıcity With Regard to Hormonal Treatment There were no acute grade III and IV urinary and rectal side effects in both groups. Grade II urinary side effects were observed in 18% of the patients after CRT, in 23% after EBRT (p=0.025) (Fig. 1). The ratio of grade II side effects in patients who received CHT, NAHT and no HT was 41%, 13% and %13 respectively (p=0.02) (Fig. 2). Fig. 1. Distribution of acute GUS toxicity according to treatment technique Fig. 2. Distribution of acute GUS toxicity according to hormonal treatment Grade II rectal side effects were observed in 30% of the patients after CRT and 7% after EBRT (p=0.022) (Fig. 3). No significant relationship was found between urinary-rectal side effects observed after treatment and characteristics related to patients (age, diseases previously known, operation undergone before) and characteristics related to treatment (RT dose) (p>0.05). 61

17 Marmara Medical Journal 2004;17(2);58-64 İlknur Çetin, et.al. A comparison of Conventıonal External Radıotherapy Technique and Conformal Radiotherapy Technique in Terms of Acute Toxıcity With Regard to Hormonal Treatment Fig. 3. Distribution of acuterectal toxicity according to treatment technique DISCUSSION Koper and his colleagues compared the technical applications of CRT and EBRT. They applied 66 Gy RT and found that CRT treatment caused less grade II acute rectal side effects (16%-8%, p<0.0001) 10. Tait and his colleagues investigated CRT and EBRT in terms of acute side effects in the treatment of primary prostate cancer. A questionnaire was given a week before, during and after the treatment. It was determined that the side effects increased during the treatment and decreased after the treatment 16. In the study of Pollack and his colleagues, 70 Gy with EBRT and 78 Gy with CRT were applied. Although RT dose was higher with CRT, no significant difference regarding acute side effects was found 11,17. Vijayakumar and his colleagues applied EBRT and CRT to patients with localized prostate cancer. According to the outcome of weekly gastrointestinal (GIS)-genitourinary (GUS) toxicities evaluation during RT for three groups, it was found that there was an increase in acute side effects until 4-5 weeks, after that there was a decrease or they remained at the same level 18. Soffen and his colleagues reported urinary and rectal side effects with a median dose of 68 Gy RT with two different techniques in 46 patients. Urinary side effects were observed in 80%-65% of the patients and rectal side effects were observed in 55%-42%. Acute side effects were less in patients treated with CRT (p>0.05) 9. Hanks and his colleagues found that the frequency of grade II side effects was 34% in CRT and 57% in EBRT (p<0.001). The frequency of grade II side effects in the patients over age 65 decreased in CRT (p< ). With the use of CRT, grade II side effects were observed less in patients with early stage (T1-2) tumor (p<0.005). Conformal technique and treatment volume were found as independent significant indicators for grade II side effects in multivariable analysis 8. Nuyttens and his colleagues compared patients who had CRT 72 Gy and CRT 76 Gy with regard to acute and chronic complications. 10%- 18% grade II acute rectal side effects and 33%- 47% urinary side effects were observed. They determined that acute rectal side effects depend on dose, while acute and chronic urinary side effects are independent from dose 19. Odrazka and his colleagues applied 74 Gy CRT and found a significant relationship between GUS side effects and TUR applied before RT 20. Herold and his colleagues reported that diabetes increased grade II GIS side effects and especially GUS late side effects 21. While apoptotic activity is 2%, this ratio increases up to 10% with androgen blockade 22. Tumor oxidation increases in relation with volume decline and this leads to an increase in radiation effectiveness. Target volume in NAHT decreases in relation with the decrease in tumor size 23. In randomized studies, the addition of neoadjuvant androgen blockade caused an increase in survival, local control and biochemical control 24,25. In the 62

18 Marmara Medical Journal 2004;17(2);58-64 İlknur Çetin, et.al. A comparison of Conventıonal External Radıotherapy Technique and Conformal Radiotherapy Technique in Terms of Acute Toxıcity With Regard to Hormonal Treatment EORTC study, age, surgery and RT dose were found to be independent prognostic factors in terms of acute side effects, yet no like effect of HT was observed 26. Sanguinetti and his colleagues stated that NAHT did not increase side effects, whereas adjuvant HT increased rectal side effects 27. In conclusion, no grade III-IV urinary and rectal acute side effects were observed in both of the techniques in this study. It was found that application of CRT technique causes a reduction in the frequency of grade II acute rectal and urinary side effects. There was an increase in grade II urinary side effects in patients treated with CHT. REFERENCES 1. Cox JD, Stetz J, Pajak TF. Toxicity Criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995; 31: Zelefsky MJ, Leibel SA, Fuks Z. Conventional external beam radiation therapy for prostate cancer: Where do we go from here? Int J Radiat Oncol Biol Phys 1993; 26: Gallagher MJ, Brereton HD, Rostock RA, et al. A prospective study of treatment techniques to minimize the volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation. Int J Radiat Oncol Biol Phys 1986; 12: Leibel SA, Zelefsky MJ, Kutcher GJ, et al. The biological basis and clinical application of threedimensional conformal external beam radiation therapy in carcinoma of the prostate. Semin Oncol 1994; 21: Sandler HM, Perez-Tamayo C, Ten Haken RK, et al. Dose escalation for stage C (T3) prostate cancer: Minimal rectal toxicity observed using conformal therapy. 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Philadelphia, New York: Lippincott-Raven; 1997: Tait DM, Nahum AE, Meyer LC, et al. Acute toxicity in pelvic radiotherapy; a randomised trial of conformal versus conventional treatment. Radiother Oncol 1997; 42: Pollack A, Zagars GK, Starkschall G, et al. Conventional versus conformal radiotherapy for prostate cancer: prelimary results of dosimetry and acute toxicity. Int J Radiat Oncol Biol Phys 1996; 34: Vijayakumar S, Awan A, Karrison T, et al. Acute toxicity during external beam radiotherapy for localized prostate cancer: comparison of different techniques. Int J Radiat Oncol Biol Phys 1993; 25: Nuyttens JJ, Milito S, Rust PF, Turrisi AT. Dosevolume relationship for acute side effects during high dose conformal radiotherapy for prostate cancer. Radiother Oncol 2002; 64: Odrazka K, Vanasek J, Vaculikova M,, et al. Conformal radiotherapy for prostate cancer-longer duration of acute genitourinary toxicity in patients with prior history of invasive urological procedure. 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19 Marmara Medical Journal 2004;17(2);58-64 İlknur Çetin, et.al. A comparison of Conventıonal External Radıotherapy Technique and Conformal Radiotherapy Technique in Terms of Acute Toxıcity With Regard to Hormonal Treatment 24. Lawton CA, Winter K, Murray K, et al. Updated results of the phase III radiation therapy oncology group (RTOG) trial evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 49; Pilepich MV, Winter K, John MJ, et al. Phase III radiation therapy oncology group (RTOG) trial of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 50: Zurlo A, Collete L, van Tienhoven G, Blank L, et al, EORTC Radiotherapy and Genito-Urinary Tract Cancer Group. Acute toxicity of conventional radiation therapy for high-risk prostate cancer in EORTC trial Eur Urol 2002; 42: Sanguineti G, Franzone P, Marcenaro M, Paoli G, Orsatti M, Vitale V. Androgen deprivation impacts late rectal toxicity after conformal radiotherapy. Abstr 1328, 338a. ASCO Meeting 2000;

20 ORIGINAL RESEARCH THE EFFECT OF A LEVONORGESTREL-RELEASING INTRAUTERINE DEVICE ON OVARIECTOMIZED RAT ENDOMETRIUM UNDER ESTROGEN REPLACEMENT THERAPY Murat Api 1, Feriha Ercan 2, Serap Arbak 2, Olus Api 3 1 Department of Obstetrics and Gynecology, Haseki Education and Research Hospital, Istanbul, Turkiye 2 Department of Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkiye 3 Department of Obstetrics and Gynecology, Kartal Education and Research Hospital, Istanbul, Turkiye ABSTRACT Objective: Our aim was to investigate the effects of levonorgestrel-releasing intrauterine system on the endometrium of ovariectomized rats under estrogen replacement therapy. Methods: Twenty-four Sprague-Dawley rats were divided into four groups and operated for the insertion of levonorgestrelreleasing (3 µg/day) or placebo-bearing intrauterine devices (IUD). Following the operation, the rats were randomly assigned to take estrogen (0.01 mg. per kg. rats) or placebo replacement therapy for 30 days. Endometrial biopsies were collected at the end of the study period. The sampled endometrial tissues have been analyzed for morphologic criteria under the light microscope. Group I was assigned to take levonorgestrel-releasing IUD and systemic estrogen whereas Group II was assigned for levonorgestrel-releasing IUD and systemic placebo and Group III for placebo-bearing IUD and systemic estrogen; finally Group IV was treated with placebo-bearing IUD and systemic placebo. Results: The endometrial morphology of Group I revealed inactive endometrium in 50%, edema in 33% and atrophy in 16% whereas the endometrial morphology of Group II revealed inactive endometrium in 66%, and atrophy in 33%. The endometrial morphology of Group III revealed epithelial hyperplasia in 66%, edema in 16% and myometrial hyperplasia in 16% while inactive endometrium was identified in 16%, and atrophy in 83% of rats in Group IV. Conclusion: Our results revealed that progestagen containing intrauterine systems are sufficient enough to protect the endometrium from hyperplasia in rats under systemic estrogen replacement therapy. This is somehow encouraging data to support that the endometrium of postmenopausal women under systemic estrogen can be sufficiently protected by an intrauterine gestagen-containing device. The use of such an IUD will serve to protect them from the adverse effects of systemic gestagens. Keywords: Rat endometrium, Levonorgestrel, Intrauterine device, Estrogen replacement therapy ÖSTROJEN REPLASMAN TEDAVİSİ ALTINDAKİ OVARİEKTOMİZE SIÇANLARDA LEVONORGESTREL-SALAN RAHİMİÇİ ARACIN ETKİLERİ ÖZET Amaç: Levonorgestrel salan rahimiçi sistemin, östrojen replasman tedavisi altındaki ovariektomize sıçanların endometriumu üzerindeki etkilerini araştırmak. Yöntem: Yirmidört adet Sprague-Dawley sıçanı 4 gruba bölünerek, levonorgestrel salan intrauterin sistemin (3 µg/day) ve plasebo-içeren rahimiçi aracın (RİA) yerleştirilmesi için operasyona alındı. Operasyonu takiben, sıçanlar 30 gün süreyle östrojen (0.01 mg./kg.) ve plasebo replasman tedavisi almak üzere gruplara randomize edildi. Çalışmanın sonunda deneklerden endometrial örnekleme yapıldı. Alınan endometrial dokular morfolojik kriterler açısından incelenmek üzere ışık mikroskopisi ile incelendi. Grup I levonorgestrel salan RİA ve sistemik östrojen alan, Grup II levonorgestrel salan RİA ve plasebo alan, Grup III plasebo içeren RİA ve sistemik östrojen alan, Grup IV ise plasebo içeren RİA ve plasebo alan sıçanlar olarak belirlendi. Bulgular: Grup I'e ait endometrial morfoloji %50'sinde aktif olmayan endometrium, %33'ünde ödem, %16'sında atrofi olarak görülürken. Grup II'ye ait morfoloji %66'sında aktif olmayan endometrium, %33'ünde atrofi olarak saptandı. Grup III'te ise % 66'sında epitelyal hiperplazi, %16'sında ödem, %16'sında myometrial hiperplazi bulunurken, Grup IV ün. %83'ünde atrofi, % 16'sında ise aktif olmayan endometrium tespit edildi. Sonuç: Sistemik östrojen replasman tedavisi altındaki sıçanların endometriumlarını hiperplaziden korumada, progestagen içeren rahimiçi sistemin yeterli olduğu sonucuna ulaşılmıştır. Elde edilen veriler, sistemik östrojen alan postmenopozal kadınların endometriumlarını korumada gestagen içerem rahimiçi aracın yeterli olabileceği yönünde cesaret vericidir. Bu tip RİA kullanımı ile hastalar sistemik gestagenlerin istenmeyen etkilerinden korunmuş olacaklardır. Anahtar Kelimeler: Sıçan endometriumu, levonorgestrel, intrauterin sistem, östrojen replasman tedavisi Corresponding author: Murat API Acelya Sok. No: 12 / 2. Postal code: Dragos/ Kartal/ İstanbul/ Türkiye Tel:( 0090 ) ( 0090 ) [email protected] Marmara Medical Journal 2004;17(2);

21 Marmara Medical Journal 2004;17(2);65-72 Murat Api, et al. The Effect Of A Levonorgestrel-Releasing Intrauterine Device On Ovariectomized Rat Endometrium Under Estrogen Replacement Therapy INTRODUCTION The intrauterine system (IUS) can be used to supplement estrogen replacement therapy (ERT), in which estrogen is used to relieve such menopausal symptoms as hot flashes, sweating, sleep disturbances and vaginal dryness. Estrogen replacement therapy also helps to prevent osteoporosis and cardiovascular disease. However, ERT also stimulates the endometrium. Adding a progestin at menopause, such as the levonorgestrel in the IUS, counteracts endometrial stimulation and helps protect against the overgrowth of endometrial tissue, precancerous endometrial changes and endometrial cancer 1,2. The sustained release of low-dose levonorgestrel directly into the uterus via the IUS may result in more endometrial protection, less irregular bleeding, and fewer systemic side effects than the release of progestins via pills or implants 3,4. Postmenopausal women should use progesteron in order to protect their endometrium while taking ERT. The progesterons in use have variable systemic adverse effects 5,6. In order to minimize these adverse effects, the local use of gestagens by the help of intrauterine device seems to be a logical option. Nevertheless, the efficacy of this route of administration is still under investigation. For this purpose, the endometrial effects of intrauterine use of levonorgestrel with systemic estrogen therapy have been investigated at the light microscopic levels. MATERIALS AND METHODS Animals Twenty-four Spraque-Dawley rats ( mean weight: 240 gr.) were subdivided into four groups containing six rats in each. The University Ethic Commitee approved the trial to be performed according to the rules of Strazburg declarations (Marmara University Faculty of Medicine Ethic Commitee No: 657/ 2). Table I shows the distribution of rats according to their subdivisions. Table I: Distribution of the rats according to their subdivision Groups Intrauterine device Therapy applied Group I Levonorgestrel (IUD) Estrogen Group II Levonorgestrel (IUD) Placebo (Olive oil) Group III Placebo silicon (IUA) Estrogen Group IV Placebo silicon(iua) Placebo (Olive oil) In the first group, an intrauterine device -releasing levonorgestrel-(lng-iud) has been applied by hysterotomy and estrogen replacement therapy was given for a period of one month. In the second group, an intrauterine device-releasing levonorgestrel-was applied by hysterotomy and placebo treatment was given for a period of one month. In the third group, an intrauterine device - releasing nothing- was applied by an operation and estrogen replacement therapy was given for one month. In the fourth group, an intrauterine device -releasing nothing- was applied by an operation and placebo treatment was given for one month. At the end of one month, by a second intervention, endometrial tissue samples were collected for light and transmission electron microscopic investigation and bones from the right femurs were extracted for bone mineral densitometric measurements. The revealed data were statistically analysed. Calculation of rat dosages of estrogen and progesteron-releasing intrauterine devices Each flacon with a total volume of 1 ml. and containing mg estradiol benzoate and olive oil vehicle was supplied by the company. Organon. Same volume of olive oil flacons were used for placebo injections. As the estimated ethinyl estradiol dosages used for hormone replacement in the ovariectomized rats was reported to be 0.01 mg. per kg. rats per day, the equivalent estradiol benzoate dosage was calculated by the usage of estradiol potency. From this point, it was estimated that 0.1 ml. of daily estradiol benzoate intramuscular injections was the appropriate dose for ovariectomized rats with a mean weight of 240 grams. The appropriate LNg-IUDs for rats have been supplied by Lerias Pharmaceuticals, Huhtamaki, Oy Turku, Finland, Norplant. These IUDs for human hormonal contraception contain 36 mg of 66

22 Marmara Medical Journal 2004;17(2);65-72 Murat Api, et al. The Effect Of A Levonorgestrel-Releasing Intrauterine Device On Ovariectomized Rat Endometrium Under Estrogen Replacement Therapy levonorgestrel in each of 6 rods, 2.4 mm in diameter in width and 3.4 cm in length. These rods release mcg/24 hour levonorgestrel for the first 6-18 months in humans. It has been calculated that one third of each rod can release a sufficient amount of levonorgestrel for ovariectomized rats (3 mcg/day) according to relative dose equivalency of gestagens. The Operation procedures Before surgery, the rats were weighed and anesthesia was achieved by injections of a mixture of chlorpromazine (0.15 mg/ 100gr. per rat ) and ketamine ( 0.1 mg/ 100gr. per rat ) into the peritoneal cavity. The abdominal wall of the rats was depilated, cleaned and a 2 cm. of vertical incision was made for laparotomy. The rats were ovariectomized by ligation and dissection of the utero-ovarian and suspensory ligaments of the ovaries. Fig. 1 depicts the operation applied to the rats internal genitalia ( Fig. 1 ). Fig. 1. The operation applied to the rats internal genitalia A: Normal anatomy of the rats. B: Ovariectomy and left uterine horn incision site C: Intrauterine device and uterus ready for application D: The IUD has been applied and operation ended. After the operation, the rats were injected with placebo or estrogen, according to their groups, for 30 days and reoperated for endometrial sampling from the left uterine horn. Light microscopy For light microscopy, the endometrial specimens were fixed in Bouin s solution and embedded in paraffin. The paraffin sections were cut at 5 µm thickness and stained with hematoxylene and eosin ( H&E ) for routine examination and Masson s Trichrome for fibrous tissue details. Sections were examined with Olympus BH-2 photomicroscope. Statistical analysis Statistical evaluation was performed with computer assisted SPSS version 11.5 (Statistical Package for Social sciences) package programme. The difference between the histopathologic findings were computed by Fisher s Exact test. Non-parametric tests were used for statistical evaluation because of the limited numbers of samples. Significance level was accepted at p<0.05. RESULTS All morphologic findings under the light microscopy in the endometrial samples of the groups were been classified into five different histopathological criteria according to a veterinarian pathology specialist. Table II depicts this distrubution among the groups. The endometrial morphology of Group I revealed inactive endometrium in 50%, edema in 33% and atrophy in 16% whereas the endometrial morphology of Group II revealed inactive endometrium in 66%, and atrophy in 33%. The endometrial morphology of Group III revealed epithelial hyperplasia in 66%, edema in 16% and myometrial hyperplasia in 16% while inactive endometrium was identified in 16%, and atrophy in 83% of rats in Group IV (Fig. 2). 67

23 Marmara Medical Journal 2004;17(2);65-72 Murat Api, et al. The Effect Of A Levonorgestrel-Releasing Intrauterine Device On Ovariectomized Rat Endometrium Under Estrogen Replacement Therapy. Fig. 2: The bar chart of histologic findings of the rats Fig 2: The bar chart of histologic findings of the rats Table II: The distribution of groups according to histologic findings. Among the histological findings there were statistically significant difference established for epithelial hyperplasia (p=0.02) and atrophy (p=0.015) findings. Other findings did not differ in each group (p>0.05). Histology Group I II III IV Inactive endometrium Epithelial hyperplasia Edema Atrophy Myometrial hyperplasia 3 (50%) - 2 (33%) 1 (16%) - 4 (66%) (33%) (66%) 1 (16%) (83%) - Histologically, the cellular components of the endometrium could be clearly subdivided into glands and surrounding stroma cells comprising the vasculature. As ovariectomy was performed for all subjects, the hormonal production from the gonads was seized for the study period. It was clearly demonstrated that atrophic changes occurred in 83% of the fourth group (Fig. 6) which was revealed at the end of the study period. This atrophic endometrial change was proportionally more frequent than the other groups and this difference was found to be statistically significant (p<0.05). The first group has been served as a sample group to answer the study question. So the histologic findings of this group was extensively evaluated. The endometrium remained inactive in 50% of the this group and 33% of them featured stromal edema (Fig. 3). This histologic result seems to reflect the relative dominance of local gestagenic effect of intrauterine device on the endometrium. In 16% of this group atrophy was revealed; which represents the local progestojenic effect of intrauterine device was strong enough to supress endometrium against the circulating level of estrogen. There was a substantial reduction (p<0.05) in both the atrophy and the proportion of cells with epithelial hyperplasia in the first group. The latter features are representitive for hormonal abstinance or estrogenic dominance, respectively. In the second group, a form of gestagenic dominance was more prominent as the 66% of 68

24 Marmara Medical Journal 2004;17(2);65-72 Murat Api, et al. The Effect Of A Levonorgestrel-Releasing Intrauterine Device On Ovariectomized Rat Endometrium Under Estrogen Replacement Therapy inactive endometrium and 33% of atrophy were demonstrated (Fig. 4). On the other hand in the third group, the unopposed estrogen influenced the endometrium and myometrium while 83% of the subjects revealed some extent of adverse events (66% epithelial hyperplasia and 16% myometrial hyperplasia). Only 16% of this group featured edema which has an unknown significance at the rat endometrium but most probably it should be related to steroidal stimulation. The hyperplasia seen in the third group (Fig. 5) was statistically more frequent than the other groups (p<0.05). Fig. 3: Group I: Light micrographs indicate A-) inactive endometrium ( ) H+EX 40; B) Mild stromal edema ( ). Masson s Trichrome X40; Fig. 4: Light micrographs of Group II: A) Inactive endometrium and thin epithelial cells with stromal atroply ( ) H+E X 40 and B) Inactive endometrium with no glandular structure ( ) Masson s trichrome X 40; Fig. 5: Light micrographs of Group III indicate A) epithelial hyperplasia ( ) H+EX 40; B) myometrial hyperplasia ( ) Masson s trichrome X 40 69

25 Marmara Medical Journal 2004;17(2);65-72 Murat Api, et al. The Effect Of A Levonorgestrel-Releasing Intrauterine Device On Ovariectomized Rat Endometrium Under Estrogen Replacement Therapy Fig. 6: Light micrographs of Group IV indicate A) atrophic epithelial structure ( ) and desquamation H+EX 40; B) inactive endometrium ( ) Masson s trichrome X 40; DISCUSSION The addition of a gestagen to estrogen replacement therapy is necessary to protect the endometrium against hyperplasia and to minimize the risk of endometrial cancer. In order to minimize the systemic adverse effects of gestagens, they were administered in a sequential fashion. The major disadvantage of such therapy is cyclic menstrual bleeding which further diminutes patients compliance for the estrogen replacement therapy. This drawback can be avoided by continuous gestagen administration along with estrogen replacement which leads to amenorrhea after initial periods of spotting 7. On the other hand, the disadvantageous effect of continuous administration of gestagen on lipid metabolism may be even more pronounced than that of progestogen administered cyclically. This concept has gained support from the observations that the continuous administration of 19-nortestosteron derivative has counteracted the beneficial effect of estrogen on serum high density lipoprotein (HDL) and cholesterol level 8,9 whereas the estrogen-induced reduction in total cholesterol and low density lipoprotein (LDL) cholesterol has remained unaffected by continuous administration estrogen and progestin 10,11. One option for minimizing these possible systemic effects of progestins while preventing endometrial hyperplasia is to administer the progestin locally in the uterine cavity. A progesteron-releasing intrauterine device developed for contraception may thus be a logical alternative for gestagen administration along with postmenopausal hormone replacement therapy 12. With a daily release rate of 20 µg. of levonorgestrel for 5 years, LNg-IUD effectively prevents the proliferative effect of estrogen on the endometrium in humans. Its indication for use was expanded to the treatment of menorrhagia and it was reported to be a promising method for the administration of gestagen in peri-menopausal patients on oral estrogen replacement therapy 13,14. Some amount of the levonorgestrel released from the LNg-IUD is absorbed from the uterine cavity into the systemic circulation, however its effect on lipids and lipoproteins has been reported to be insignificant 15. The use of unopposed estrogens in women with climacteric complaints increases the incidence of endometrial hyperplasia and cancer 16,17. In our first group of rats, no hyperplasia or cancer was encountered. On the other hand, in the third group treated with unopposed estrogen, keratinized squamous metaplasia and myometrial hyperplasia were seen more commonly. Even it is not statistically significant, in the third group, one case of glandular hyperplasia was detected as the sole abnormal pathological finding. This finding of glandular hyperplasia may reflect the unopposed estrogenic effect on the rat uterus, nevertheless, further studies with larger sample sizes are needed to confirm these findings. In 2003, Philips et al evaluated the endometrial effects of levonorgestrel releasing intrauterine device in women of reproductive age and found out that the effects were characteristic, relatively constant and in keeping with the effects of both a progestogenic compound and a mechanical device. Morphological features found in most of the endometria were decidualisation of stroma (72 70

26 Marmara Medical Journal 2004;17(2);65-72 Murat Api, et al. The Effect Of A Levonorgestrel-Releasing Intrauterine Device On Ovariectomized Rat Endometrium Under Estrogen Replacement Therapy of 75 cases), atrophy of endometrial glands (65 of 75 cases), a surface papillary pattern (38 of 75 cases), and a stromal inflammatory cell infiltrate (59 of 75 cases). Additional common histological features were the presence of foci of stromal myxoid change (29 of 75 cases) and stromal haemosiderin pigment (24 of 75 cases). Reactive atypia of surface glands, glandular metaplastic changes, stromal necrosis, and stromal calcifications were found in small numbers of cases 18. In year 2002, Raudaskoski et al evaluated the clinical and endometrial efficacy and lipid response of two different doses of intrauterine levonorgestrel assessed in comparison with sequential oral medroxyprogesterone acetate in postmenopausal women receiving continuous oral E2-valerate 19. Endometrial hyperplasia was not observed in any of the treatment groups during the 12-month study and they concluded that both 10 microg and 20 microg levonorgestrel systems provided good endometrial protection in postmenopausal women on estrogen replacement therapy. Furthermore, Wildemeersch evaluated the endometrial safety with a low-dose intrauterine levonorgestrel-releasing system (releasing 14 microg of LNG per day) after 3 years of estrogen substitution therapy 20. They found out that the endometrial histology specimen showed profound endometrial suppression with glandular atrophy and stroma decidualization in all women. Our animal data is in keeping with the above mentioned human data and the results from this study in a small group of rats are promising, since it is important to study the rat endometrium at light microscopic levels, providing pioneer data for further investigations. To our knowledge, this is the first such study in the literature. As a result, light microscopical investigations - both in animal and human models - suggest that it is possible to supply a safe and beneficial hormone replacement therapy to postmenopausal non-hysterectomized women; taking systemic estrogen replacement therapy by the use of locally active levonorgestrel-releasing intrauterine device in order to protect them from the systemic adverse effects of gestagens and to supply the efficient and safe protection in their endometrium. REFERENCES 1. Wollter-Svensson LO, Stadberg E, Andersson K, et al. Intrauterine administration of levonorgestrel 5 and 10 microg/24 hours in perimenopausal hormone replacement therapy, a randomized clinical study during one year. Acta Obstet Gynecol Scand 1997; 76(5): Taddei GL, Bargelli G, Scarselli B, et al. Precancerous lesions of the endometrium and medical treatment. Eur J Contracept Reprod Health Care 1997 ;2(4): Suhonen SP, Holmström T, Allonen HO, et al. Intrauterine and subdermal progestin administration in postmenopausal hormone replacement therapy. Fertil Steril 1995; 63(2): Suhonen SP, Allonen HO, Lähteenmäki P. Sustained-release estradiol implants and a levonorgestrel-releasing intrauterine device in hormone replacement therapy. Am J Obstet Gynecol 1995; 172(2 Pt 1): Kim CJ,Jang HC, Cho DH, Min YK. Effects of hormone replacement therapy on lipoprotein (a) and lipids in postmenopausal women. Arterioscler Thromb 1994; 14(2): Kim CJ, Min YK, Ryu WS, Kwak JW, Ryoo UH. Effect of hormone replacement therapy on lipoprotein (a) and lipid levels in postmenopausal women. Influence of various progestogens and duration of therapy. Arch Intern Med ; 156(15): Staland B. Continious treatment with natural estrogens and progestagens. A method to avoid endometrial stimulation. Maturitas 1981; 3: Mattsson LA, Cullberg G, Samsioe G. A continuous estrogen-progestogen regimen for climacteric complaints effects on lipid and lipoprotein metabolism. Acta Obstet Gynecol Scand 1984; 63: Farish E, Fletcher CD, Dagen MM et al. Lipoprotein and apolipoprotein levels in postmenopausal women on continuous estrogenprogestogen therapy. Br J Obstet Gynecol 1989; 96: Sporrong T, Hellgren M, Samsioe G, Mattsson LA. Metabolic effects of continuous estradiol-progestin therapy in postmenopausal women. Obstet Gynecol 1989; 73: Jensen J, Riis BJ, Strom V, Chiristiansen C. Longterm and withdrawal effects of two different estrogen-progestogens combination on lipid and lipoprotein profiles in postmenopausal women. Maturitas 1989; 11: Rybo G, Anderson K, Odlind V. Hormonal intrauterine devices. Ann Med 1993;25: Andersson K, Rybo G. Levonorgestrel releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynecol 1990; 97:

27 Marmara Medical Journal 2004;17(2);65-72 Murat Api, et al. The Effect Of A Levonorgestrel-Releasing Intrauterine Device On Ovariectomized Rat Endometrium Under Estrogen Replacement Therapy 14. Andersson K, Mattsson LA, Rybo G, Stadberg E. Intrauterine release of levonorgestrel- a new way of adding progestogen in hormone replacement therapy Obstet Gynecol 1992; 79: Raudaskoski T, Tomas EI, Paakkari IA, Kauppila AJ, Laatikainen TJ. Serum lipids and lipoproteins in postmenopausal women receiving transdermal estrogen in combination with levonorgestrel relasing intrauterine device. Maturitas 1995; 22: Schiff I, Sala HK, Cramer D, Tulchinsky D, Ryan KJ. Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril 1982; 37: Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 1975; 293: Phillips V, Graham CT, Manek S, McCluggage WG. The effects of the levonorgestrel intrauterine system (Mirena coil) on endometrial morphology. J Clin Pathol. 2003; 56(4): Raudaskoski T, Tapanainen J, Tomas E, Luotola H, Pekonen F, Ronni-Sivula H, Timonen H, Riphagen F, Laatikainen T. Intrauterine 10 microg and 20 microg levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response. BJOG. 2002; 109(2): Wildemeersch D, Schacht E, Wildemeersch P, Calleweart K, Pylyser K, De Wever N. Endometrial safety with a low-dose intrauterine levonorgestrelreleasing system after 3 years of estrogen substitution therapy. Maturitas. 2004; 48(1):

28 ORIGINAL RESEARCH THE CONTRIBUTION OF HOME-FAMILY DISTRESS TO THE PRESENTATION DIFFERENCE OF CHILDHOOD OBSESSIVE- COMPULSIVE DISORDER ACROSS HOME AND SCHOOL SETTINGS Osman Sabuncuoğlu, Meral Berkem Department of Child Psychiatry, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Objective: Further to our recent finding of presentation difference in the symptoms of childhood obsessive-compulsive disorder across home and school settings, and that home is where symptoms predominate, we aimed to find out whether this phenomenon is related to home-family distress. Methods: After the application of CY-BOCS, CGI and a questionnaire consisted of items that served as a comparison of the symptoms across home and school settings, family distress was rated on a 5-point scale (FDM) which reflected home stress factors such as unemployment, parental conflict and care of elderly. Results: Of the 20 children enrolled in the study, 70% were boys and 30% girls who had a mean age of ± Both CY- BOCS and CGI-severity (home and school) scores did not differ significantly within themselves regarding caseness criteria of +3 cutscore on the FDM. Among the data obtained by CY-BOCS and CGI, only Compulsion Subscale of CY-BOCS revealed significant correlation with FDM scores ( r = 0.510, p<0.05). Conclusion: Preliminary data did not support any association between home-family distress and presentation difference. A larger sample is needed to conclude on the contribution of home-family stress factors to the presentation difference in childhood obsessivecompulsive disorder. Keywords: Obsessive-compulsive disorder, Child, Adolescent, Schools, Family ÖZET Amaç: Çocukluk çağı obsesif-kompulsif bozukluğunda, ev ortamında okul ortamına göre belirtilerin daha fazla dışavurulduğu yönündeki son bulgumuzdan sonra bu sonucun ev-aile stresiyle ilişkili olup olmadığını araştırmayı amaçladık. Yöntem: Yale-Brown Çocuklar İçin Obsesif-Kompulsif Sorulistesi (YBÇOKS), Klinik Global İzlenim Ölçeği (KGİÖ) ve evokul ortamları arasında belirtileri karşılaştırmaya yarayan sorulistesinin uygulanmasından sonra işsizlik, ebeveyn çatışması ve yaşlı bakımı gibi nedenlerle yaşanan ev-aile stresi 5 bölümlük ölçek üzerinden puanlandı. Bulgular: Çalışmaya alınan 20 çocuğun %70'i erkek, %30'u kız ve ortalama yaşı ± 3.36 idi. Gerek YBÇOKS, gerek ev ve okul için verilen KGİÖ-Hastalık Şiddeti puanları aile stresi için +3 olan olgusallık ölçütüne göre farklılık göstermedi. Yalnız YBÇOKS Kompulsiyon altölçeği aile stres bulgularıyla anlamlı korelasyon gösterdi (r = 0.510, p<0.05). Sonuç: On bulgular belirti dışavurumunda farklılık ile ev-aile stresi arasında bir ilişki olmadığını gösterdi. Çocukluk çağı obsesif-kompulsif bozukluğunda ev-aile stresinin belirti dışavurumunda farklılığı nasıl etkilediğine karar vermek için daha geniş bir örneklem incelenmelidir. Anahtar Kelimeler: Obsesif kompulsif bozukluk, Çocuk, ergen, Okullar, Aile INTRODUCTION Childhood obsessive-compulsive disorder (OCD) is a chronic and underrecognized psychiatric condition affecting 1% to 4% of children and adolescents 1. The lifelong characteristic of OCD necessitates in depth understanding of childhood OCD in terms of age at onset, diagnosis, symptom Corresponding author s address: Dr. Osman Sabuncuoğlu Halk Cad. Emin Ongan Sk. 11/ Üsküdar / Istanbul, Turkey Phone: +90(542) (216) Fax:+90(216) E- mail: [email protected] presentation, treatment and course of the disorder. Although information on childhood OCD still accumulates, various phenomenological dimensions await to be determined. The symptom profile of children with OCD across home and school settings is one of the topics which remain unknown, unlike, for instance ADHD. Although Rapoport notes that children with OCD may have Marmara Medical Journal 2004;17(2);

29 Marmara Medical Journal 2004;17(1);73-77 Osman Sabuncuoğlu, et al. The contribution of home-family distress to the presentation difference of childhood obsessive-compulsive disorder across home and school settings a partial voluntarily control of symptoms in public, there is no particular reference to any study 2. On the other hand, DSM-IV criteria for OCD merits the significant interference of symptoms with school, social activities and important relationships 3. Recently we have described presentation difference phenomenon characterized by significant difference in the presentation of obsessive-compulsive disorder across home and school settings 4. We found that home is where symptoms predominate. Family setting is of interest in numerous reports in relation to the problem behavior of children. Early adverse family circumstances and parenting characteristics were found to have no contribution to the prediction of later psychopathology once child characteristics were accounted for 5. Contrary to this finding, there are studies reporting direct concurrent relations between home-family distress and the problem behavior of children 6,7. Family context in childhood OCD has also been highlighted as a risk factor in the development and maintenance of the disorder 8. As an implication of our previous research, we aimed to determine whether presentation difference phenomenon is related to the family distress experienced at home. MATERIALS AND METHODS Twenty schoolchildren, aged 6 to 17 from our OCD cohort, were enrolled in the study. Child psychiatric diagnoses were based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. After the application of original measures on admission, each case was assessed by the same child psychiatrist (Dr. O. S.) in a following session regarding home-family distress. Previous progress records were used when necessary. Basic informative data was gathered from the file records of the children. Measures Children s Yale-Brown Obsessive Compulsive Scale (CY-BOCS): This scale is a 10-item, clinician rated, semi structured instrument designed to rate the severity of obsessive and compulsive symptoms in children, aged 6 to 17 years 9,10. Information obtained from the child and parent which reflects the average course of symptoms in the week prior to the study is rated by the interviewer. A Turkish version was used for the present study 11. Clinical Global Impression (CGI) Severity Subscale 12 : It is scored from 1 (no illness) to 7 (completely nonfunctional). The interviewer determines the overall severity of the illness. In the present study design, two ratings, one for the school and one for the home setting were made and compared. Setting Specificity of OCD Symptoms In Children Questionnaire: This questionnaire was prepared by the research team and was based on the results obtained on the CY-BOCS. The children and their parents were questioned about the frequency of symptoms across home and school settings with particular reference to the CY-BOCS results. Family Distress Measure (FDM): The clinician rated the overall family distress on a 5-point scale which reflected home stress factors such as unemployment, parental conflict, illness and care of elderly. This measure was introduced with a perspective similar to CGI and +3 cutscore was accepted as the level of clinical concern. Homefamily distress secondary to the child s psychiatric disorder was not taken into account. SPSS 10.0 for Windows was used to analyze the findings. T-test, Mann-Whitney U Test and Correlational tests were required to analyse the data. RESULTS Of the total number of children, 70% were boys and 30% girls with had a mean age of ± The mean obsession and compulsion subscores were ± 4.05 and ± 3.73 respectively, both summing up a total score of ± Table I displays the prevalence of obsessions and compulsions experienced by the children in the present sample. Ten (50%) of the subjects were pure OCD whilst the remaining children had some comorbid diagnoses. CGI-severity scores for both home and school settings were 4.40 ± 0.88 and 2.20 ± 0.76 respectively, at a significant level of difference (t=8.41, df=38, p< and Levene s test revealing egual variances F= 1.59, p<0.05). Child and parent estimated distribution of the frequency of OCD symptoms according to the Setting Specifcity Questionnaire is presented in Fig. I. 74

30 Marmara Medical Journal 2004;17(1);73-77 Osman Sabuncuoğlu, et al. The contribution of home-family distress to the presentation difference of childhood obsessive-compulsive disorder across home and school settings Table I : Prevalences of obsessions and compulsions on the CY-BOCS. OBSESSIONS n % COMPULSIONS n % Contamination Washing/Cleaning Aggressive Checking Sexual 3 15 Repeating Hoarding/Saving 0 0 Counting 0 0 Magical Thoughts/Superstitious 4 20 Ordering/Arranging 0 0 Somatic 3 15 Hoarding/Saving 3 15 Religious 2 10 Excessive Magical Games 1 5 Miscellaneous 0 0 Rituals Involving Others 1 5 Miscellaneous 7 35 Table II : The comparison of the CY-BOCS and CGI scores of the children with respect to low (n=14) and high FDM (n=6) scores CY-BOCS COMP CY-BOCS OBS CY-BOCS TOTAL CGI HOME CGI SCHOOL Mann-Whitney U 21,000 40,000 30,500 39,000 35,000 Wilcoxon W 126, , ,500 60, ,000 Z -1,745 -,167 -,952 -,268 -,639 Asymp. Sig (2-tailed),081,867,341,789,523 Exact Sig.[2*(1-tailed Sig.)],091 a,904 a,353 a,841 a,602 a a. Not corrected for ties Fig. 1: Child and parent estimated distribution of the frequency obsessive compulsive symptoms across settings. The mean family distress measure (FDM) score was found to be 2.00 ± According to +3 cutscore of FDM, 6 cases were identified. The CY-BOCS and CGI scores of the children, each dichotomised with respect to caseness criteria on the FDM, were analysed using Mann-Whitney U Test. In comparison, no significant difference was found between the dichotomised groups (Table II). Among the data obtained by CY-BOCS and CGI, only Compulsion Subscale of CY-BOCS revealed significant correlation with FDM scores (r = 0.510, P<0.05). 75

31 Marmara Medical Journal 2004;17(1);73-77 Osman Sabuncuoğlu, et al. The contribution of home-family distress to the presentation difference of childhood obsessive-compulsive disorder across home and school settings DISCUSSION Although distress experienced within the family might have an additive impact on the childhood OCD overall, it seems that the presentation difference is not determined by this kind of distress. Presentation difference is consistant in the vast majority of enrolled children. The positive correlation between the FDM and CY-BOCS Compulsion Subscale is of interest. It seems that, to some extent, the level of stress experienced in the home environment is associated with children s compulsions experienced either at home or at school. What should be kept in mind is that, although we found significant presentation difference in the entire sample, high FDM cases did not differ from the low FDM cases in the variables studied. Thus, our findings are in line with Mesman s study 5. Interpersonal factors that might trigger OCD symptoms within the family should be studied. Early parental preoccupation and behavior surrounding the birth of a family member implicated in the possible evolutionary origins of OCD may provide insight regarding the presentation phenomenon 13. The contribution of secondary family distress stemming from the child s OCD is worth investigating in further studies. Given these results, we can also hypothesize that the distraction experienced in the school environment may relieve the intrusive obsessions and therefore lead to a better functioning at school. In addition, certain forms of compulsions might not be easily performed in the school setting for practical reasons and due to anticipated shame. If these factors predominate, any sort of home-family distress is unlikely to contribute to the presentation difference. As this study was based on the self-reports of children with the agreement of their parents, secrecy was out of question in the studied sample. In addition, the prevalence of obsession and compulsion in our sample is similar to that of previous findings in Turkey 14. Therapeutic implications should be derived from the presentation difference phenomenon as, outlining the factors which relieve the symptoms at school may be self-educative for a better control over the symptoms experienced at home. Interpersonal factors, such as the persistence of early parental preoccupations should also be studied before developing proper treatment strategies. In conclusion, preliminary data showed no association between home-family distress and presentation difference. The study should be replicated on a larger sample to conclude on the contribution of home-family stress factors to that phenomenon. REFERENCES 1. Carter AS, Pollock RA. Obsessive compulsive disorder in childhood. Curr Opin Pediatr 2000; 12: Rapoport JL, Swedo S, Leonard H. Obsessivecompulsive disorder. In: Rutter M, Taylor E, Hersov L, eds. Child and Adolescent Psychiatry: Modern Approaches. 3rd ed. London: Blackwell Science, 1994: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV), Washington DC: The American Psychiatric Press, Sabuncuoglu O, Berkem M. Çocukluk çağı obsesifkompulsif bozukluğunda ev ve okul ortamlarında belirti profillerinin karşılaştırılması: bir ön çalışma. 14. Ulusal Çocuk ve Ergen Psikiyatrisi Kongresi, Bursa, Mesman J, Koot HM. Early preschool predictors of preadolescent internalizing and externalizing DSM- IV diagnoses. J Am Acad Child Adolesc Psychiatry 2001; 40: Ackerman BP, Kogos J, Youngstrom E, Schoff K, Izard C. Family instability and the problem behaviors of children from economically disadvantaged families. Dev Psychol 1999; 35: Gordis EB, Margolin G, John RS. Parents' hostility in dyadic marital and triadic family settings and children's behavior problems. J Consult Clin Psychol 2001; 69: Waters TL, Barrett PM. The role of the family in childhood obsessive-compulsive disorder. Clin Child Fam Psychol Rev 2000; 3: Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry 1989; 46: Goodman WK, Price LH, Rasmussen SA, et al. The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry 1989;46: Erkal AGY, Arman AR, Topçuoğlu V, Fişek G, Yazgan MY. Çocuklar İçin Yale-Brown Obsesif Kompulsif Ölçeği geçerlik güvenirlik değerlendirmesi. 12. Ulusal Çocuk ve Ergen Psikiyatrisi Kongresi, İstanbul, Guy W. Clinical Global Impressions: ECDEU Assessment Manual for Pharmacology, revised edition. Rockville, MD: National Institute of Mental Health, Dept. of Health, Education and Welfare Publication (ADM), 1976:

32 Marmara Medical Journal 2004;17(1);73-77 Osman Sabuncuoğlu, et al. The contribution of home-family distress to the presentation difference of childhood obsessive-compulsive disorder across home and school settings 13. Leckman JF, Mayes LC, Feldman R, Evans DW, King RA, Cohen DJ. Early parental preoccupations and behaviors and their possible relationship to the symptoms of obsessive-compulsive disorder. Acta Psychiatr Scand Suppl 1999; 396: Diler RS, Avcı A, Tamam L, Toros F. Çocuk ve ergenlerde obsesif kompulsif bozukluk: sosyodemografik, klinik özellikler ve eştanılar. Türk Psikiyatri Dergisi 1999; 10:

33 CASE REPORTS MISPLACEMENT OF A NASOGASTRIC TUBE INTO THE POSTPNEUMONECTOMY SPACE Tümay Umuroğlu, İ. Varlık Doğan, Abdurrahman Yaycı Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Nasogastric tubes cause complications related to traumatic insertion. We reported a case of misplacement of a nasogastric tube into the postpneumonectomy space. A sixty-three-year old male patient was admitted to intensive care unit with the diagnosis of broncho and esophagopleural fistula 3 months after a pneumonectomy. A nasogastric tube had to be inserted immediately for the maintenance therapy of atrial fibrillation by the enteral route, by listening to the sound of air over the abdomen to minimize the risk of misplacement, but gastroscopy revealed that it was in the postpneumonectomy space. We concluded that it is important to verify the exact place of a nasogastric tube radiologically in patients with undiagnosed esophageal pathologies. Keywords: Post-pneumonectomy, Nasogastric misplacement NAZOGASTRİK SONDANIN POSTPNÖMONEKTOMİ ARALIĞINA YANLIŞ YERLEŞİMİ ÖZET Nazogastrik sondaların travmatik olarak takılmaları sonrasında komplikasyonlar gelişebilmektedir. Burada postpnömonektomi bölgesine yanlışlıkla yerleştirilen bir vakayı tartıştık. Hasta pnömonektomi operasyonu geçirdikten 3 ay sonra bronko ve özofageal fistül tanısıyla yoğun bakım ünitesine kabul edildi. Atrial fibrilasyon tedavisinin idamesini sağlayabilmek amacıyla acil olarak nazogastrik sonda takılması planlandı. Sondanın yanlış yere yönlenmesini önlemek amacıyla batın duvarından sonda ucundan verilen hava sesi steteskop aracılığıyla dinlendi. Ancak daha sonra uygulanan gastroskopide nazogastrik sondanın postpnömonektomi bölgesine ilerlemiş olduğu saptandı. Sonuç olarak, bilinmeyen özofageal patolojisi bulunan hastalarda, nazogastrik sondaların yerlerinin doğruluğunun radyolojik olarak saptanmasının gerekli olduğu sonucuna vardık. Anahtar Kelimeler: Postpnömonektomi, yanlış yerleşimli nazogastrik sonda INTRODUCTION Nasogastric tubes (NG) are commonly used for stomach lavage, stomach decompression, administration of oral medications and enteral nutrition in critically ill patients 1, however they may lead to many complications such as pulmonary or intracranial intubation, esophageal perforation and pneumothorax 2-5. We report a case of an unusual placement of a nasogastric tube into the postpneumonectomy space in the absence of trauma. CASE REPORT A 63-year-old man with hypertension and coronary artery disease was admitted to the Corresponding author: Tümay Umuroğlu Address: Kalfa Çeşme sok. Validebag sitesi 7/ 5 Üsküdar- Istanbul / TURKEY Tel: Fax: address: tans6@ hotmail.com intensive care unit with hypotension (50/30 mmhg), hyperventilation (respiratory rate: 24/min), tachycardia (160/min) and hypothermia(35 C axillary). 10 months previously he had been diagnosed with lung squamous cell carcinoma and a right lower lobectomy was performed. 7 months later, he underwent right pneumonectomy for a recurrence. On admission, his arterial blood gases, obtained while breathing 5L/min oxygen with a face mask,were as ph 7.40, PaO2 67.2mmHg, PaCO2 38mmHg, HCO3 23.1mmol/L, BE 1.3 and SaO2 93%. The electrocardiogram showed an atrial fibrillation with a rate of 160/min. A chest radiograph indicated fluid collection on the right side, clear Marmara Medical Journal 2004;17(2);

34 Marmara Medical Journal 2004;17(21);78-80 Tümay Umuroğlu, et al. Misplacement of a nasogastric tube into the postpneumonectomy space left lung field and a normal-sized heart, consistent with the diagnosis of bronchopleural fistula. A fluid. After fluid resuscitation, 15µg/kg/min dopamine hydrochloride infusion, piperacillin/ tazobactam and aminoglycoside were administered to the patient. Digitalization was performed but a sinus rhythm was obtained only after administration of 10mg metoprolol tartarate, i.v. An echocardiogram showed normal left ventricular function. The patient s hypoxemia improved after administration of 8L/min oxygen with a face mask. Blood cultures obtained on admission were positive for group F streptococcus and thoracal drainage fluid culture was positive for E. Coli. Antibiotic therapy was continued. On the 10 th hour after admission, the patient s hemodynamic status improved, dopamin hydrochloride infusion was discontinued and he was allowed to take oral nutrition. After 26 hours, with a total oral intake of 3075cc, gastric contents were observed in the thoracic drainage tube. Esophagopleural fistula was suspected. Oral nutrition was discontinued. On the 3 rd day after admission, the patient again had atrial fibrillation with a rate of 156/min. 15mg diltizem i.v. bolus followed by 10mg/h infusion and magnesium replacement were ineffective. Subsequent i.v. bolus of 10mg metoprolol tartarate resolved atrial fibrillation and the heart rate decreased to 80/min. Since administration of a ß-blocker infusion is inappropriate for maintenance therapy, a nasogastric tube had to be inserted in order to give it enterally. A 16 French polyvinylchloride nasogastric tube was inserted, listening to the sound of air over the abdomen as well as to the right hemithorax, keeping in mind the possibility of tube misplacement into postpneumonectomy space. Air was heard strongly over the epigastrium but weakly over the hemithorax and since drainage material from the tube looked like a gastric juice, the tube was accepted as properly placed. Metoprolol tartarate 50mg four times daily was started orally. The patient again had tachycardic attacks only resolved with the administration of propafenon hydrochloride 150mg i.v. Propafenon hydrochloride tablet 150mg three times daily was administered from NG tube but tachycardial episodes continued. Endoscopy revealed a 5x6 cm fistula on the wall of the esophagus at 28 th cm, a tumor at 23 rd cm from mouth, and it was observed that the nasogastric tube was installed in postpneumonectomy space through this fistula. It was removed. The patient was accepted to be inoperative. Application of a stent to esofageal right chest tube was inserted for the drainage of fistula was unsuccesful because of the fragile wall of the esophagus. Gastrostomy was performed, atrial fibrillation was controlled and he was discharged on the 15 th day after admission. DISCUSSION Gastrointestinal access for critically ill patients is mandatory for administration of oral medications, enteral nutrition, gastric decompression and lavage 1. Nasogastric and nasoduodenal tube placements are the most common preferred accesses. Nasogastric tube placement is an easy and simple method. Hearing the sound of air injected into the tube over epigastrium and demonstration of gastrointestinal contents in syringe aspirate are methods to verify its place 6. It does not require radiographic confirmation. Nasoduodenal tube is made of radiopaque material and has the advantage of radiologic confirmation for proper placement but it is an expensive and time consuming procedure 7. Besides the incidence of tube displacement increases with the use age of small-bore nasoduodenal tubes 8,9. We used a large-bore nasogastric tube in order to minimize this risk, however, the defect on the esophageal wall was big enough to cause misplacement. There are many complications related to nasogastric placement, such as bleeding, intracranial intubation, pneumothorax and esophageal perforation 2-5. Review of the relevant literature suggests that trauma is usually the predisposing factor in such complications 5,10. In our case report, we discussed an unusual misplacement of a nasogastric tube to postpneumonectomy space through a pathological defect in the esophageal wall in the absence of trauma. Although we knew that there was an esophagopleural fistula, placement of a nasogastric tube was vital for the administration of oral medication for the maintenance treatment of atrial fibrillation. To minimize the possibility of inserting the nasogastric tube into postpneumonectomy space, we listened to the sound of air over the whole right hemithorax as well as the epigastrium. Although the tube was placed in postpneumonectomy space, the sound was less pronounced over the right hemithorax than over the upper abdomen. The reason for that could be the thicker thoracic wall or the leak of air from the thoracic drainage tube. The presence of gastric juice in the nasogastric tube may be the 79

35 Marmara Medical Journal 2004;17(21);78-80 Tümay Umuroğlu, et al. Misplacement of a nasogastric tube into the postpneumonectomy space result of the back flow of gastric contents into the thoracal cavity through the fistula located very close to the esophagogastric opening. It was not a surprise that atrial fibrillation was uncontrollable, despite many medical interventions as the drugs administered were into the postpneumonectomy space and had drained from the existant thoracic tube without being absorbed. It is suggested that in high risk patients a nasogastric tube should only be inserted under direct vision and a subsequent X-ray is mandatory for confirming proper positioning 8. Regarding our case report, we concluded that it is important to verify the exact place of a nasogastric tube either radiologically or fluoroscopically with an injection of a contrast dye, in patients with undiagnosed esophageal pathologies; or insertion of radiopaque tubes may be an appropriate approach to prevent the complications due to misplacements. REFERENCES 1. Rippe JM, Irwin RS, Alpert JS, Fink MP. Gastroenterologic problems in the intensive care unit. In: Clouse RE, editor. Intensive Care Medicine. United States of America: Little, Brown and Company, 1991: Kuo YC, Wu CS. Spontaneous intramural perforation of the esophagus: case report and review of the literature. Endoscopy 1989; 21: Granier I, Leone M, Garcia E, Geissler A. Nasogastric tube: intratracheal malposition and entrapment in a bronchial suture. Ann Fr Anesth Reanim 1998; 17: Kolbitsch C, Pomaroli A, Lorenz I, Gassner M, Luger TJ. Pneumothorax following nasogastric feeding tube insertion in a tracheostomized patient after bilateral lung transplantation. Intensive Care Med 1997; Ferreras J, Junquera LM, Garcia-Consuegra L. Intracranial placement of a nasogastric tube after severe craniofacial trauma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 90: Christen S, Hess T. Is a clinical positional control for nasogastric tubes good enough? A prospective study of 43 patients. Dtsch Med Wochenschr 1996; 121: Huerta G, Puri VK. Nasoenteric feeding tubes in critically ill patients (fluoroscopy versus blind). Nutrition 2000;16: Ibarra-Perez C. Lung perforation by a small-bore enteral feeding tube. Rev Invest Clin 1992; 44: Wendell GD, Lenchner GS, Promisloff RA. Pneumothorax complicating small-bore feeding tube placement. Arch Intern Med 1991; 151: Fisman DN, Ward ME. Intrapleural placement of a nasogastric tube: an unusual complication of nasotracheal intubation. Can J Anaesth 1996; 43:

36 CASE REPORTS A FAMILY WITH A 17p: PERICENTRIC INVERSION: IMPLICATIONS FOR CARRIERS Gülseren Bağcı 1, Özgül Alper 1, Anne Hagemeijer 2, Hasan Acar 3, Elizabeth M.E. Smit 2, Mine Üner 4, Güven Lüleci 1 1 Department of Medical Biology-Genetics, Faculty of Medicine, Akdeniz University, Antalya, Turkey 2 Department of Cell Biology and Genetics, Erasmus University, Rotterdam, Holland 3 Department of Medical Biology and Genetics, Faculty of Medicine, Selçuk University, Konya, Turkey 4 Department of Obstetric and Gynecology, Faculty of Medicine, Akdeniz University, Antalya, Turkey ABSTRACT Amniocentesis was performed at the 19 th week of gestation because of advanced maternal age and a presumed risk of 1/14 for Down syndrome as determined by the triple test. Chromosomal analysis of the fetus revealed a karyotype of 46,XX,inv(17)(p11.2;q25.1). This chromosomal breakpoint can be associated with a microdeletion on chromosome 17 and be related with Smith-Magenis syndrome and shown by cytogenetic observations. That is why, we have examined the fetus with the Smith-Magenis probe by the use of fluorescence in situ hybridization (FISH) technique to identify the microdeletion of band p11.2 of chromosome 17. After it is confirmed that the inverted chromosome is familial and no deletion has occurred, the pregnancy continued for a healthy carrier baby. These findings have implications for prenatal counseling of carriers of pericentric inversions, who typically are considered to bear minimal reproductive risk. This report shows that, FISH provides a reliable means for prenatal detection of the chromosome 17 rearrangements in this family. Keywords: Chromosome 17, Pericentric inversion, Fluorescence in situ hybridization 17P PERİSENTRİK İNVERSİYONLU BİR AİLE: TAŞIYICILARA UYARILAR ÖZET İleri anne yaşı ve üçlü testte 1/14 risk ile Down sendromu düşünülen gebeliğe 19. haftasında amniyosentez uygulandı. Fetusun kromozom analizi sonucu karyotipi 46,XX,inv (17) (p11.2;q25.1) olarak belirlendi. Sitogenetik olarak tespit edilen bu kromozomal kırık noktası mikrodelesyon sendromu olan Smith-Magenis sendromu ile ilişkili olabileceği için, Smith Magenis probu kullanılarak FISH yöntemi uygulandı. Delesyon olmadığı ve familyal inversiyon 17 olduğu tesbit edilerek gebeliğe devam edildi ve sağlıklı bir bebek doğdu. Bu bulguların ışığı altında, perisentrik inversiyon taşıyıcılarının prenatal genetik danışmasının önemli olabileceği dikkate alınmalıdır. Bu makalede, FISH yönteminin prenatal olarak inversiyon sonucu kromozom 17'de oluşabilecek mikrodelesyon ve yeniden düzenlenmelerin analizi açısından güvenilir olduğu vurgulanmaktadır. Anahtar Kelimeler: Kromozom 17, Perisentrik inversiyon, Fluoresans in situ hibridizasyon INTRODUCTION In general, chromosomal inversions, are not infrequent, with an average incidence of 0.13 per 1000 liveborns 1. Usually, there is no phenotypic effect in the majority of inversion carriers. However, when an inversion disrupts a critical gene, an associated disease phenotype can result 1. Based on cytogenetic observations, several microdeletion and contiguous gene-deletion syndromes have been identified, as Prader-Willi, Smith-Magenis. FISH (fluorescence in situ hybridization) technique is one of the higher resolution molecular techniques for visualizing chromosome regions which uses the DNA probes labeled with fluorescent dyes to identify specific chromosomal regions. The microdeletions can be detected by the use of FISH analysis. These single probes may also be used to determine the breakpoints of the structural rearrangements 2. Smith-Magenis syndrome (SMS) is a distinct and clinically recognizable multiple congenital anomaly (MCA) and mental retardation syndrome Corresponding author: Gülseren Bağcı, Ph.D.,Department of Medical Biology-Genetics, Akdeniz University, Faculty of Medicine Antalya, Turkey.e.mail address: [email protected] Marmara Medical Journal 2004;17(2);

37 Marmara Medical Journal 2004;17(2);81-83 Gülseren Bağcı, et al. A family with a 17p: Perıcentric inversion: implications for carrıers caused by an interstitial deletion of band p11.2 averaging of 4-5 Mb of chromosome 17 3,4. If this region includes the breakpoint in carriers of inversion is the same with microdeletion syndromes, then the presence or absence at that deletion can be tested in a cytogenetics laboratory using FISH 5. Here, we present the identification of a unusual inversion on chromosome 17 in a family with a normal phenotype. CASE REPORT Amniocentesis and ultrasonography were performed at the 19th week of gestation on a 38- year-old woman referred to our clinic due to advanced maternal age and high risk for Down syndrome in triple test. Fetal ultrasonography showed no significant fetal anomaly. The family history was negative for various abnormalities. The parents were not consanguineous and had a healthy 13-year-old female child. Proband s family members were cytogenetically examined, which is shown in the pedigree (Fig.1). pericentric inversion of chromosome 17 and to check whether there is a deletion of Smith- Magenis region or not. Cytogenetic and FISH Findings Chromosome analysis by routine GTG-banding on amniotic fluid cells, from the fetus, after the birth from the peripheral lymphocytes revealed a female karyotype (III-4) of 46,XX,inv(17) (p11.2;q25.1). Family screening was performed to determine whether this finding of pericentric inversion of chromosome 17 was a familial or de novo event in blood lymphocytes. In the pedigree analysis, (Fig.1) cytogenetic results of the family was as follows; I-1 and II-4 have a normal chromosome 17 pattern, however, from I-2, II-3, II-5 and III-3 exhibited the same structural aberration, which was inv(17)(p11.2;q25.1) as shown in Figure 2. Fig. 1 : Pedigree showing the proband s family Cytogenetic and FISH Evaluation Amniotic fluid was cultured in Chang medium (Irvine Scientific, USA) and peripheral blood lymphocytes was grown for 72 hours in Mc Coy 5A medium (Gibco, England) supplemented with 10% FCS (Gibco, England). Metaphase chromosomes were analyzed by the standard methods. 6-8 and in situ hybridization (FISH) technique 9,10. Metaphase spreads of fetus were screened with the digoxigenin labeled p53 and Miller Dieker mix probe and Smith-Magenis probe (ONCOR) 9,10. Forty metaphases and 200 interphase nuclei were analyzed to confirm the Fig. 2: GTG-banded chromosome 17 of the proband. The presence of pericentric inversion on chromosome 17 is confirmed with the use of p53 and Miller-Dieker mix probes (Fig. 3a). Metaphase and interphase FISH analysis with Smith-Magenis probe (ONCOR) revealed that a consistent signal was observed on both of the normal and inverted chromosomes 17, indicating no deletion (Fig. 3b). Thus, the pregnancy continued and a 2850gr., 50cm. female with normal phenotypic features was delivered at 39 weeks of gestation by cesarean section. The baby was developmentally appropriate for age. 82

38 Marmara Medical Journal 2004;17(2);81-83 Gülseren Bağcı, et al. A family with a 17p: Perıcentric inversion: implications for carrıers in prenatal diagnosis. Recently, many reports support the hypothesis that the 17p11.2 deletion occurred as a result of a recombination between the normal and the pericentric-inverted chromosome 17 homologues of the carrier individuals 11. In this regard, prenatal diagnosis is suggested for carrier individuals in our case. Fig. 3a. FISH (a,c) and RBG (b,d) analysis of carrier individuals. Arrows indicating the signal on 17p13.3 of normal and on the long arm of inv (17) with the use ofp53 and Miller-Dieker mix probes. Fig. 3b. FISH analysis of inv 17(p11.2:q25.1) DISCUSSION In our case, the breakpoints of pericentric inversion of chromosome 17 lie to be at 17(p11.2; q25.2) we used SMS probe in FISH procedure to detect the submicroscopic deletions within this band, which is thought to be associated with Smith-Magenis syndrome. This strategy, using in situ hybridization with cosmid or unique probes mapping within the critical region, could be applied to other microdeletion syndromes, in addition to high-resolution cytogenetic studies. Pericentric inversions frequently seen on chromosomes 9, however, other chromosomes have to be checked by the FISH method especially REFERENCES 1. Samuel PY, Sanjay I, Bidichandia L, et al. Molecular analysis of deletion (17)(p11.2;p11.2)in a family segregating a 17p paracentric inversion: implications for carriers of paracentric inversions. Am J Hum Genet 1995; 60: Ligon AH, Beaudet AL, Shaffer LG. Simultaneous multilocus FISH analysis for detection of microdeletions in the diagnostic evaluation of developmental delay and mental retardation. Am J Hum Genet 1997; 61: Trask BJ, Mefford H, van den Engh G, et al. Quantification by flow cytometry of chromosome 17 deletions in Smith-Magenis syndrome patients. Hum Genet 1966; 98: Seranski P, Heis NS, Dhorne-Pollet S, et al. Transcription mapping in a medulloblastoma breakpoint interval and Smith-Magenis syndrome candidate region: identification of p53 transcriptional units and new candidate genes. Genomics 1999; 56: Seabright M. A rapid banding technique for human chromosomes. Lancet 1971; 2: Dutrillaux B, Viegas-Peguignot E. High resolution R and G banding on the same preparation. Hum Genet 1981; 57: Sumner AT. A simple technique for human demonstrating centromeric heterochromatin. Exp Cell Res 1972; 75: Acar H, Connor M J. Detection of trisomy 12 and centromeric alteration in CLL by interphase and metaphase FISH. Cancer Genet Cytogenet 1998; 100: Acar H, Stewart J Boyd, Connor MJ. Identification of variant translocations in chronic myeloid leukemia by FISH. Cancer Genet Cytogenet 1997; 93: Kuwano A, Ledbetter SA, Dobyns NB, Emanuel BS, Ledbetter DH. Detection of deletions and criptic translocations in Miller-Dieker syndrome by in situ hybridization. Am J Hum Genet 1991; 49: Juyal RC, Figuera LE, Hauge X, et al. Molecular analysis of 17p11.2 deletions in 62 Smith-Magenis syndrome patients. Am J Hum Genet 1996; 58:

39 CASE REPORT COCHLEAR IMPLANTATION IN A PATIENT WITH LARGE VESTIBULAR AQUEDUCT SYNDROME: A CASE REPORT Ufuk Derinsu, Ayça Çiprut, Sezer Külekçi, Ferda Akdaş Sub-department of Audiology, Department of Otorhinolaryngology, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Large vestibular aqueduct syndrome (LVAS) is a distinct clinical entity characterized by fluctuative sensorineural hearing loss associated with isolated enlargement of the vestibular aqueduct. In this report, we present our experience with cochlear implantation in a patient with LVAS. Keywords: Coclear implant, large vestibular aqueduct syndrome, enlarged vestibular aqueduct, hearing loss GENİŞ VESTİBÜLER SENDROMLU HASTADA KOKLEAR İMPLANTASYON ÖZET Geniş Vestibüler Kanal Sendromu, vestibüler kanalın genişlemesine bağlı olarak ortaya çıkan dalgalanmalı işitme kaybı ile karakterize bir klinik olgudur. Bu çalışmada, koklear implantasyon yapılan LVAS'lı bir hastamızdan elde edilen bulgular sunulmuştur. Anahtar Kelimeler: Koklear implantasyon, Geniş Vestibüler Kanal Sendromu, İşitme kaybı INTRODUCTION The association of congenital sensorineural hearing loss with enlarged vestibular aqueducts was initially determined from histopathologic studies of inner ear malformations 1,2. The large vestibular aqueduct syndrome (LVAS) was named by Valvassori and Clemis in 1978, when they described radiologic detection of this anomaly 3. Vestibular aqueduct is defined as large if the anteroposterior diameter is larger than 1.5mm. 4. LVAS often associates with profound, nonprogressive sensorineural hearing loss 5. Sudden sensorineural hearing loss attacks and fluctuative hearing loss have been reported in some cases 5-7. The incidence of sudden hearing loss was found to be rare in other reports 5,8. Hearing loss is found to be generally sensorineural but Jackler and De la Cruz found a conductive component in 27% of the ears 8. Corresponding author: Ufuk Derinsu Ph. D., Sub-department of Audiology, Department of Otorhinolaryngology, School of Medicine, Marmara University, Istanbul, Turkey Tel: / [email protected] Hearing level may be from normal to profound deafness. Only a few patients were reported to have normal hearing with LVA 9. There is no treatment to prevent hearing loss in patients with LVAS. Avoidance of head trauma is important, and hearing aids are symptomatic treatment 5,6,10. The following case report describes a patient with LVAS who received a cochlear implant. A review of the patient s audiological assessments before and after the cochlear implantation will be presented. CASE REPORT The patient is a 21-year-old female with LVAS. The family suspected hearing loss at the age of 3, she had an audiological evaluation elsewhere and fitted a hearing aid on the left ear. Marmara Medical Journal 2004;17(2);

40 Marmara Medical Journal 2004;17(2);84-88 Ufuk Derinsu, et al. Cochlear implantation in a patient with large vestibular aqueduct syndrome: a case report She was a 9-year-old girl with normal speech development when referred to our clinic. She was the product of a full term pregnancy without any complication. There is no consanguity between the parents but there is a history of hearing loss. Her sister also has hearing loss and benefits from hearing aids. The patient s first audiological evaluation demonstrated profound sensorineural hearing loss in the right ear, and moderate to severe mixed hearing loss in the left ear ( Fig. 1). Acoustic immitancemetry indicated type A tympanograms bilaterally (Fig. 2). Acoustic reflexes were present only in the left ear contralaterally at the maximum intensity levels at 500, 1000 and 2000 Hz. Fig. 1: Audiogram in the first audiological evaluation Fig. 2: Tympanogram in the first audiological evaluation Three years later, her hearing in the left ear progressed to severe then to profound, and the hearing thresholds in the right ear improved (Fig. 3). A new hearing aid appropriate to her hearing loss was recommended and scheduled for frequent follow-ups. Two years later, although her hearing 85

41 Marmara Medical Journal 2004;17(2);84-88 Ufuk Derinsu, et al. Cochlear implantation in a patient with large vestibular aqueduct syndrome: a case report thresholds did not change, significantly, her speech discrimination score in the left ear deteriorated to 12% from 68%. Fluctuations in hearing were determined in both ears in the following assessments. Fig. 4, shows the final audiogram before the implantation. The patient was evaluated for the cochlear implantation at the age of 15 and found to be a good candidate. Fig. 3: Second audiogram obtained three years after the first audiological assessment Fig. 4: The latest audiogram before cochlear implantation. 86

42 Marmara Medical Journal 2004;17(2);84-88 Ufuk Derinsu, et al. Cochlear implantation in a patient with large vestibular aqueduct syndrome: a case report The otorhinological and neurological evaluations were normal. Routine blood chemistries, urinanalysis and complete metabolic work up were also normal. A temporal bone high resolution computed tomography (HRCT) scanning demonstrated bilateral LVA. Her sister was assessed with HRCT, because of the LVA diagnosis. She was also diagnosed as LVA. Cochlear implantation to the right ear was performed without any complication. Full insertion of Nucleus 24M electrode array was achieved. Electrically evoked stapedius reflexes were recorded and electrically evoked compound action potentials were reliably measured using Neural Response Telemetry (NRT) software intraoparatively. The postoperative performance is encouraging. Her free field hearing thresholds with the cochlear implant were found to be 35 to 45 db HL from 250 to 8000 Hz ( Fig. 5) Fig. 5: Free field audiogram with cochlear implant. Her speech performance after cochlear implantation was evaluated with closed set three syllable words and monosyllabic words and open set three syllable words, monosyllabic words and open set sentences. Table I illustrates the speech perception test results of the patient with cochlear implant. The improvement in speech discrimination was significant. She continues to use her hearing aid on the opposite ear because of better sound lateralization. Table I: Speech perception test results after implantation. Speech test 6 months 1 year 2 years Closed set 3 syllable words test 100% 100% 100% Closed set monosyllablic words test 82% 98% 98% Open set 3 syllabic words 60% 86% 88% Open set monosyllabic words 56% 60% 76% Open set sentences 72% 76% 80% 87

43 Marmara Medical Journal 2004;17(2);84-88 Ufuk Derinsu, et al. Cochlear implantation in a patient with large vestibular aqueduct syndrome: a case report DISCUSSION In LVAS, a conductive component has occasionally been reported although hearing loss is predominantly sensorineural 8,11,12. In our case, although the patient has normal (type A) tympanograms on both ears there was an unexplained conductive component in the left ear. According to Valvassori, the conductive component is probably caused by a decreased mobility of the stapes due to increased perilymphatic or endolymphatic pressure 11. The conductive component had disappeared in subsequent audiograms. The hearing loss usually begins in early childhood, often with an acute onset and fluctuating or progressive in course in relation to head trauma 8,5,10. In our case, the beginning age of hearing loss is similar to most of the LVAS cases in literature; there were fluctuations in the hearing of both ears; but there was no significant head trauma. Cochlear implantation in patients with LVAS have been reported since ,13,14. The audiometric improvement is a common feature in all of them. In this case, sound field warble tone thresholds with the implant were within nearly normal limits and the patient also displayed valuable improvement in speech discrimination. Patients with LVAS usually have an aquired hearing loss, so they may be accepted as good cochlear implant candidates when they can no longer benefit from hearing aids. 4. Harker LA, Vanderheiden S, Veazey D, et al. Multichannel cochlear implantation in children with large vestibular aqueduct syndrome. Ann Otol Rhinol Laryngol 1999; 108: Okumura T, Takahashi H, Honjo I, et al. Sensorineural hearing loss in patients with large vestibular aqueduct. Laryngoscope 1995; 105: Griffith AJ, Arts AH, Downs C, et al. Familial large vestibular aqueduct syndrome. Laryngoscope 1996; 106: Tong KA, Harnsberger HR, Dahlen RT, et al. AJR 1997; 168: Jackler RK, De La Cruz A. The large vestibular aqueduct syndrome. Laryngoscope 1989; 99: Emmett JR. The large vestibular aqueduct syndrome. Am J Otol 1995; Nowak KC, Mesner AH. Isolated large vestibular aqueduct syndrome in a family. Ann Otol Rhinol Laryngol 2000; 109: Abe S, Usami S, Shinkawa H. Three familial cases of hearing loss associated with enlargement of the vestibular aqueduct. Ann Otol Rhinol Laryngol 1997; 106: Govaerts PJ, Casselman J, Daener K, et al. Audiologic findings in large vestibular aqueduct syndrome. Int J Pediatr Otorhinolaryngol 1999; Bent JP, Chute P, Parisier SC. Cochlear implantation in children with enlarged vestibular aqueducts. Laryngoscope 1999; 109: Bichey BG, Hoversland JM, Wyenne MK, Miyamoto RT. Changes in quality of life and the cost-utility associated with cochlear implantation in patients with large vestibular aqueduct syndrome. Otology&Neurotology 2002; 23: REFERENCES 1. Schuknecht HF. Mondini dysplasia: clinical and pathological study. Ann Otol Rhinol Laryngol Suppl., 1980; 89 (suppl 65): Paparella MM. Mondini s deafness: a review of histopathology. Ann Otol Rhinol Laryngol Suppl 1980; 89 (suppl 67): Valvassori GE, Clemis JD. The large vestibular aqueduct syndrome. Laryngoscope 1978; 88:

44 CASE REPORT CLINICAL AND ELECTRODIAGNOSTIC FOLLOW UP OF A CASE OF FOOD BORNE BOTULISM Nilgün Cengiz 1, Hande Türker, 1 Meral Kiziltan 2 1 Department of Neurology, Ondokuzmayıs University School of Medicine, Samsun,Turkey 2 Department of Neurology, Istanbul University Cerrahpasa School of Medicine Istanbul, Turkey ABSTRACT In the following case report, we describe the follow up of electrodiagnostic studies together with the clinical pattern in a 40 year old woman diagnosed as botulinum intoxication caused by home-made canned green beans. She had dyplopia, blurred vision, weakness and paresthesias in all four extremities, difficulty of swallowing and breathing and bifascial paralysis. Repetetive nerve stimulation and blink reflex studies were performed during the follow up of the case. Serologic tests couldn t be performed. Antitoxin therapy was initialised immediately, recovery of symptoms began in about a month s time and she was symptom free in three months. Her electrodiagnostic tests also improved and were found to be normal. We believe that diagnosis of botulinum intoxication on clinical grounds is far more important than it is supposed because electrodiagnosis may not be always very typical and serologic tests may not be available. Therefore we believe that initialising the antitoxin therapy is life saving and should be performed immediately, even if the diagnosis is mostly on clinical grounds. Keywords: Botulinum intoxication, electrodiagnosis and botulinum intoxication GIDA ALIMIYLA İLİŞKİLİ BOTULİNUM İNTOKSİKASYONLU BİR OLGUNUN KİLİNİK VE ELEKTOFİZYOLOJİK İZLEMİ ÖZET Bu olgu sunumunda ev yapımı konserve tüketimi sonrasında clostridium botulinum intoksikasyonu gelişen 40 yaşındaki bir bayan hastaya ait klinik ve elektrofizyolojik izlem rapor edilmektedir. Olguda diplopi, bulanık görme, güçsüzlük ve her dört ekstremitede parestezilerin yanısıra yutma ve solunum güçlüğü ile bifasyal paralizi gelişmiştir. Olgunun izlemi sırasında ardışık sinir uyarımı ve göz kırpma refleksi çalışmaları yapılmıştır. Serolojik testlerin yapılamadığı olguda, klinik tablo ve elektrofizyolojik incelemelerle tanı konmuş ve derhal antitoksin tedavisi başlatılmıştır. Semptomlarda bir ay içinde düzelme başlamış, üç ayda hastadaki semptomlar ortadan kalkmıştır. Elektrodiyagnostik izlemde de bulguların normale döndüğü izlenmiştir. Bu olguda elektrodiyagnostik testler tipik sonuçlar göstermemiştir. Olgunun izlemiyle varılan kanı, botulinum intoksikasyonu tanısının daha çok kliniğe dayandığı durumlarda bile, antitoksin tedavisine derhal başlamanın hayat kurtarıcı olduğu yönündedir. Anahtar Kelime: Botulinum intoksikasyonu, elektrodiyagnoz ve botulinum intoksikasyonu INTRODUCTION Botulism is a rare but serious and potentially fatal ilness.the Botulinum intoxication is caused by the exotoxin of Clostridium Botulinum which has a generalised effect on the neuromuscular junction involving both striated and smooth muscles. Botulinum toxin causes its major effect by blocking neuromuscular transmission in autonomic and motor nerve terminals. The types A,B and E account for human cases 1,2. Since the discovery of the toxin about 100 years ago, five clinical forms of botulism have been described: 1) classic or foodborne botulism; 2) wound botulism; 3) infant botulism; 4) hidden botulism; Corresponding author: Dr. Hande Türker, Ondokuzmayıs University, School of Medicine, Department of Neurology, Samsun,Turkey [email protected] 5)inadvertent botulism. A clinical pattern of descending weakness is characteristic of all five forms. Almost all human cases of botulism are caused by one of three serotypes (A, B, or E). Classic and wound botulism were the only two forms known until the last quarter of this century. Wound botulism was rare until the past decade. It is caused by local production of toxin by Clostridium botulinum after wound infection 3. Although it is a rare variant of botulism, it is increasingly being reported in drug users who inject subcutaneously 4. Infant botulism, first described in 1976, is now the most frequently reported form especially in the USA. Food borne Marmara Medical Journal 2004;17(1);

45 Marmara Medical Journal 2004;17(1);89-92 Hande Türker Clinical and Electrodiagnostic Follow up of A Case of Food Borne Botulism botulism is the most severe and debilitating form, caused by ingestion of the toxin 2. In our country many of the reported cases are food borne and mostly from home canned vegetables because preparing such food is seen quite often in rural areas of Turkey 2,5,6. Food-borne butulism may manifest as an outbreak but there are also single cases. Onset is within hours after ingestion, signs of gastroenteritis with diarrhea, nausea and vomiting usually precede muscle weakness which often is generalised.ocular and bulbar signs such as diplopia, ptosis, dysarthria and dysphagia are common. Weakness decends usually symmetrically to involve muscles of the trunk, respiratory system and limbs.proximal muscles and upper extremities are usually more prone to involvement. Autonomic manifestations include dry mouth, dilated, fixed or poorly reactive pupils, blurred vision, constipation, ileus and urinary retention 1,2,3. Identification of the toxin in the patient s serum confirms the diagnosis. Electrodiagnosis is mostly helpful. Nerve conduction studies show normal amplitude and latency of sensory action potentials. A small compound muscle action potential elicited by a single shock further declines with repetetive stimulation at a small rate. Repetetive stimulation at Hz is the most spesific test, showing an incremental response in most patients 7. Single fiber EMG has shown increased jitter and blocking and some reduction in fiber density 8,9,10,11,12. Spesific therapy is the antitoxin therapy which should be administered early because it is unlikely to be effective after 3 days of exposure. In this condition only supportive therapy can be applied 7. CASE PRESENTATION A forty year old female patient who had nausea and vomiting besides blurred vision and generalised weakness of all four extremities was admitted to the emergency room. Her complaints had begun 2 days after she ate some of the home canned green beans she had prepared before. The day after the meal she had a fierce nausea and vomiting and two days later she complained of having blurred vision, diplopia, weakness and paresthesias in all extremities, difficulty of swallowing and breathing. She realised that she couldn t shut her eyes properly and that her fascial muscles were weak. In neurological exam, she had bilateral ptozis, bilateral total external ophtalmoplegia, bilateral mydriasis and fascial diplegia. She also had dysphonia and dysphagia.she had quadriparesis involving all extremities by 3/5. All deep tendon reflexes were abolished and she had generalised hypotonia. Nerve conduction studies of sensory nerves were in normal limits whereas M amplitudes were quite low in some of the motor nerves. Electromyographic studies showed that there was no voluntary motor activity in fascial muscles while there was a decline in the recruitment pattern of extremity muscles. In the repetetive stimulation of the trapezius muscle which was performed in the first week, all findings were in normal limits (Stimulations were performed with 2Hz, 3Hz and 20 Hz frequencies). No blink reflex was obtained in the first week. Regarding the story, the neurological signs and electrodiagnostic tests, a diagnosis of botulinum intoxication was made and as the clinical signs were progressing rapidly and in the descending fashion, antitoxin therapy was initialised and the patient was given A,B and E type antitoxin each given in U/day, I.V and in slow infusion form. Follow-up A week after the antitoxin therapy, there were no changes in the neurological examination of the patient.the clinical improvement began gradually after this first week and in her first month s check, her muscle strength was found to be +4/5, her deep tendon reflexes came back and she hadn t ophthalmoplegia any more while light reflex was intact in both eyes. Her clinical improvement became more clear in the second month s control and her neurological exam was found to be normal in the third month. Electrodiagnostic tests were repeated in the second week and in the third month. In the second week, the repetetive nerve stimulation test showed a mild decrement (10 Hz stimulation) while it was normal in the third month (3 Hz stimulation) (Fig.1-2 respectively). Blink reflex couldn t be obtained in the first two weeks whereas in the third month its latency was in normal limits with a slight reduction in the amplitude (Fig.3-4 respectively). Figure I: Repetitive stimulation in the second week 90

46 Marmara Medical Journal 2004;17(1);89-92 Hande Türker Clinical and Electrodiagnostic Follow up of A Case of Food Borne Botulism Figure II: Repetitive stimulation in the third month Figure III-IV: Blink two weeks and third month respectively DISCUSSION Rapid diagnostic approach is very important in life threatening diseases and botulinum intoxication is one of these.the diagnosis is a clinical one, confirmed by electrodiagnostic tests and by testing stool for the organism, C. botulinum, or its toxin in serum and feces 13. Although serologic tests and electrodiagnosis are important tools in making the diagnosis, serology may be negative and electrodiagnostic results may not always be typical. The principal electrodiagnostic feature, an incremental response on high rates of repetitive nerve stimulation, has variable sensitivity and may not always be useful as a diagnostic test given the vagaries of test timing and severity of illness 8. Cox N. and Hinkle R. reported that a high index of suspicion is important for the diagnosis and prompt treatment of infant botulism, because this disease can quickly progress to respiratory failure 14. Unless SFEMG is used electrodiagnostic studies may not be helpful and diagnosis on clinical grounds is more essential than it is believed to be, especially in sporadic cases. Our patient happened to be one of these. Signs of internal and external ophthalmoplegia, dry mouth, descending paralysis, obstipation with weakness, absence of fever and lucid sensorium as cardinal symptoms should always bring botulism to mind 15. We thought in the same way in our diagnostic approach and made a clinical diagnosis firstly, the electrodiagnostic tests supported our clinical diagnosis partially (Findings of low amplitude CMAPs in nerve conduction studies and finding decremental response in the begining are helping but foundation of no incremental response in higher frequencies of stimulation is of no help). The frequency of diagnostic findings in cases of botulism intoxication seem to be quite different from each other in case reports published so far. Some of them claim that serology is more important while the others stress the importance of electrodiagnostic studies. In a presentation of a case of two boys with symptoms of food borne botulism, the diagnosis was made by serology (mouse neutralization test), whereas the EMG showed negative results 15. Graf WD. et al.suggested that electrodiagnosis was not a reliable tool as far as their 11-year review of toxin-confirmed cases had reflected 16. In a report of seven patients with foodborne botulism, the clinical picture was characterized by mild symptoms with a long latency of onset and by involvement of cranial and upper limb muscles; only one patient, a child, developed respiratory failure. Spores of Clostridium botulinum were found in stools in some but not all cases. Conventional neurophysiological tests had low sensitivity; abnormal findings were present only in the patient with severe clinical involvement, in whom compound muscle action potentials (CMAPs) appeared to be reduced.repetitive nerve stimulation at a high rate showed pseudofacilitation and not true posttetanic facilitation, but single-fiber electromyography (SFEMG) showed abnormalities of neuromuscular transmission in every case 9. Clay SA. et al imply that the EMG pattern of brief, small motor unit potentials, in the context of the clinical syndrome may be diagnostic for acute infantile cases 17, almost alike our case. Graf WD. et al reported a 91

47 Marmara Medical Journal 2004;17(1);89-92 Hande Türker Clinical and Electrodiagnostic Follow up of A Case of Food Borne Botulism case where results of electrodiagnosis were negative but enema effluent contained adequate concentrations of organism and toxin to confirm the diagnosis 16. L. Mulleague et al. wrote that the diagnosis of botulism was based on clinical findings, but EMG remained the most useful discriminatory investigation. They also implied that the diagnosis should be confirmed by toxin bioassay, although occasional false-negatives can occur 18. Early diagnosis and associated therapy overcome the necessity of intubation and prolonged intensive care 19. Although the diagnostic approches may show slight variaties it is certain that the important point is rapid diagnosis and therapy in botulinum intoxication. Our case confirms this very clearly. In this case report we also underline the importance of clinical and electrophysiological follow up in such patients thus the clinical diagnosis is confirmed and it is important supplying information of prognosis and patterns of healing. We performed a follow up of our patient up to 3 month s time both clinically and electrodiagnostically. Here we performed a blink reflex study as well as the repetetive test. Although we hadn t had an increment but a decrement pattern at the beginning, our follow up study showed a normal repetetive test finally and although the blink reflex couldn t be obtained at the beginning, the follow up test showed a normal response. We also followed up a pattern of healing which quite overlapped the electrophysiological improvement. We emphasize the importance of clinical diagnosis and that making it rapidly is life saving. REFERENCES 1) Katirji B. Generalised disorders. In:Katirji B.,ed. Electromyography in clinical practice. Mosby, Inc.,1998: ) Anlar O., Irmak H., Tombul T., Akdeniz H., Caksen H., Kose D., Ceylan A. Food-borne botulism cases in Van region in eastern Turkey: importance of electromyography in the diagnosis. Electromyogr Clin Neurophysiol Sep;43(6): ) Cherington M.Clinical spectrum of botulism. Muscle Nerve Jun;21(6): ) Rundervoort RS, van der Ven AJ, Vermeulen C., van Oostenbrugge RJ.The clinical diagnosis 'wound botulism' in an injecting drug addict.ned Tijdschr Geneeskd Jan 18;147(3):1247. ed Ti 5) Ural AU, Avcu F., Sayar H., Beyan C., Kocabalkan F. Botulism: a case report. Mikrobiyol Bul Jan;26(1): ) Onul M, Willke A. Food-borne botulism and its epidemiological features as seen in our country during the last few years. Mikrobiyol Bul Oct;23(4): ) Jun Kimura. Botulism. In:Jun Kimura,ed. Electrodiagnosis in diseases of nerve and muscle: Principles and practice. Edition 3. New York:Oxford University Press,Inc.,2001: ) Chaudhry V., Crawford TO. Stimulation single fiber EMG in infant botulism. Muscle Nerve Dec;22(12): ) Padua L., Aprile I., Monaco ML, Fenicia L., Anniballi F., Pauri F., et al. Neurophysiological assessment in the diagnosis of botulism: usefulness of single-fiber EMG. Muscle Nerve Oct;22(10): ) Girlanda P., Dattola R., Messina C. Single fibre EMG in 6 cases of botulism. Acta Neurol Scand Feb;67(2): ) Keesey JC., AAEE Minimonograph #33: electrodiagnostic approach to defects of neuromuscular transmission. Muscle Nerve Aug;12(8): ) Ehrenreich H., Garner CG., Witt TN. Complete bilateral internal ophthalmoplegia as sole clinical sign of botulism: Confirmation of diagnosis by single fibre electromyography. Neurol May;236(4): ) McMaster P., Piper S., Schell D., Gillis J., Chong A. A taste of honey. J Paediatr Child Health Dec;36(6): ) Cox N., Hinkle R. Infant botulism. Am Fam Physician Apr 1;65(7): ) Golser A., Plochl E. Food-borne botulism in 2 brothers. Padiatr Padol. 1992;27(1): ) Graf WD, Hays RM, Astley SJ, Mendelman PM. Electrodiagnosis reliability in the diagnosis of infant botulism. J Pediatr May;120(5): ) Clay SA. et al, Ramseyer JC, Fishman LS, Sedgwick RP. Acute infantile motor unit disorder. Infantile botulism? Arch Neurol Apr;34(4): ) L. Mulleague, S., M. Bonner,A. Samuel, P. Nichols, M. Khan, S. Shaw et al.wound botulism in drug addicts in the United Kingdom. Anaesthesia Volume 56 Issue 2 Page February ) Scheibe F, Hug B, Rossi M. Wound botulism after drug injection. Dtsch Med Wochenschr Feb 1;127(5):

48 REVIEW THE MANAGEMENT OF ELBOW FRACTURES IN CHILDREN Bülent Erol, Murat Bezer, Gökhan Er, Mustafa Karahan, Osman Güven Department of Orthopaedics and Traumatology, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Pediatric elbow fractures can be challenging to manage. Compression of the medial column in Gartland Type I and Type II supracondylar fractures must be reduced to prevent varus deformity. Gartland Type III fractures may be stabilized with two lateral pins or a medial lateral cross-pin technique. Non-displaced lateral condyle fractures require vigilant follow-up. Open reduction of displaced lateral condyle fractures should avoid posterior dissection. T-condylar fractures in children rarely have the articular comminution found in adults. Monteggia fractures in children can be managed well if recognized and treated promptly. Restoration of the ulnar length often reduces the radial head. Angulated proximal radius fractures need to be reduced in order to restore the ability to supinate and pronate. It is important to recognize and understand the diagnostic features of each type of fracture in order to determine the best course of treatment. INTRODUCTION Pediatric elbow fractures are different from many other pediatric injuries. They are associated with a relatively high rate of complications, and the results of nonoperative management are not always good. The child s elbow is well vascularized, and therefore fracture healing takes place very quickly. Such a narrow window of opportunity makes it imperative that the fracture be properly managed very quickly. This paper reviews some elbow fractures in children that are particularly challenging to manage. Supracondylar Humerus Fracture Supracondylar humerus fractures are the most common elbow fractures in children, accounting for 60-80% of pediatric elbow fractures 1. These injuries are associated with a high rate of complications and can be challenging to manage. These fractures have been classified according to both the direction and the degree of displacement. Extension-type supracondylar humerus fractures are overwhelmingly more common than flexiontype fractures (98% vs. 2%) 2. While posteromedial fractures are more frequently encountered than posterolateral fractures (75% vs. 25%) 1. However, posterolateral fractures are more often associated with neurovascular injury. Corresponding author: Dr. Bülent Erol Marmara Üniversitesi Hastanesi Ortopedi ve Travmatoloji Anabilim Dalı Tophanelioğlu Cad., No:13/15, Altunizade/Istanbul Tel: (216) [email protected] Gartland described three stages of supracondylar fractures of the humerus in children, based on the degree of displacement: Type I, undisplaced; Type II, minimally displaced; and Type III, completely displaced. This three-stage classification with modifications is the one used most commonly in recent pediatric fracture texts. The diagnosis of an undisplaced supracondylar fracture (Gartland Type I) is made on the basis of the history of a fall in addition to local tenderness in the supracondylar area. Radiographic evaluation is not usually helpful. Type I fractures often require no more than simple immobilization for comfort and further protection. A simple longarm cast with the elbow at 90 of flexion and the forearm in neutral is usually preferred. By three weeks after injury, the pain and swelling have usually subsided significantly and allow a protected active range of motion. Gartland Type II fractures (displaced with intact posterior cortex) require closed reduction and percutaneous fixation if a long-arm cast does not adequately hold the reduction. Immobilization in a long-arm cast can be discontinued after three weeks. In Gartland Type III fractures (totally displaced with no cortical contact), the posterior cortex is broken, resulting in proximal migration of the distal fragment because of muscle activity Marmara Medical Journal 2004;17(2);

49 Marmara Medical Journal 2004;17(2);93-98 Bülent Erol, et al. The management of elbow fractures in children (Fig.1A-B). Displacement necessitates the reestablishment of length and increases the chance of interposed soft tissue. Displaced fractures are the result of more severe injuries that produce greater soft-tissue swelling, which in turn makes the reduction and its maintenance more difficult. Gartland Type III fractures are managed by closed reduction with percutaneous fixation followed by three weeks of immobilization in a long-arm cast. The exact method of maintaining the reduction has evolved over time. Medial and lateral crosspin technique was the gold standard, but it places the ulnar nerve at risk. (Fig. 1C-D) Thus, some surgeons advocate a mini-open pin placement technique to avoid nerve injury. A direct injury to the ulnar nerve usually results in only neuropraxia, and children ultimately experience full recovery of the ulnar nerve function. Recent studies have confirmed that two well-placed lateral pins provide sufficient fixation in the vast majority of cases 3,4. Should a third pin be necessary to achieve adequate stability, a medial pin can be placed through a mini-open approach. The key to maintaining adequate stability with two lateral pins is to assure that both pins have good fixation of the distal fragment and engage the medial cortex. Fig. 1A-B-C-D: Preoperative antreoposterior (A) and lateral (B) plain radiographs of the elbow show an extension type suracondylar humerus fracture (Grantland Type III). This fracture was managed by closed reduction and percutaneous pinnin, with medial and lateral cross-pin technique (C-D). An open reduction of a displaced supracondylar humerus fracture may be necessary on rare occasions. An anteromedial hockey stick incision provides a good exposure, and fixation is done percutaneously in the usual fashion. It is important to inform the patient and the family that an open reduction may be necessary for any supracondylar humerus fracture, and, should it be performed, may lead to some residual elbow stiffness not found in children treated by closed reduction. 94

50 Marmara Medical Journal 2004;17(2);93-98 Bülent Erol, et al. The management of elbow fractures in children Supracondylar humerus fractures can be associated with a vascular injury (5-12%) 2, particularly with posterolateral displacement of the distal fragment, which would displace the neurovascular bundle over the medial metaphyseal spike. Management of a suspected vascular injury can be challenging. A pulseless but pink hand can be observed. Patients in this group who underwent vascular intervention developed re-occlusion of the brachial artery without any sequelae, suggesting that careful observation and vascular intervention had equivalent outcomes 5. The presence of a pulseless and white hand after reduction and pinning is a clear indication for open exploration. The anteromedial approach provides good exposure for the vascular repair and an open reduction. Nerve injuries occur in 5-19% of elbow fractures and are almost always neuropraxias. These may take three-four months to resolve 2. The anterior interosseous branch of the median nerve is the most commonly involved nerve. A thorough neurological examination should be performed and documented for all elbow fractures pre- and postoperatively. Malunion is largely due to rotation and will result in the classic cubitus varus deformity. Inadequate correction of medial collapse can also lead to this deformity. Lateral Condyle Fractures Fractures of the lateral condyle represent 15-17% of pediatric elbow fractures 6. The orthopaedic surgeon must be aware of the fracture patterns, relevant anatomy including blood supply, risk of nonunion, and the importance of postoperative follow-up in order to assess potential deformity and neurologic sequelae. The lateral condyle functions as the origin of the extensor muscle mass as well as the lateral collateral ligament complex. Most fractures occur in patients with a peak age of 5-7 years. The most common mechanism of injury occurs when a varus force is applied to the elbow, causing the extensor muscles and lateral collateral ligaments to avulse the lateral condyle. Appropriate management requires an understanding of the mechanism of injury, as well as an awareness of operative indications and treatment methods to avoid complications. The diagnosis of a lateral condyle fracture can be challenging because the fracture fragment is often rotated. Therefore, obtaining an oblique view of the elbow, in addition to the standard anteroposterior and lateral, can be very helpful. The most classical description of the fracture type has been described by Milch 1. The Milch Type I fracture travels from the metaphysis of the distal humerus through the distal lateral epiphysis and through the trochleocapitellar groove. The Milch Type II fracture travels from the distal lateral humeral metaphysis above the epiphysis and exits through the trochlea. Because the Milch Type II transverses through the lateral aspect of the trochlea, instability may ensue with posterolateral radius and ulna subluxation. Non-displaced and minimally displaced fractures of less than 2 mm may be immobilized in a longarm cast. In the first three weeks, good-quality plain radiographs of the elbow (best taken with the cast off) are obtained to make sure that the reduction has been maintained. Techniques have also been described for minimally displaced fractures with closed reduction and percutaneous pin fixation (with two divergent pins) in order to maintain the alignment 7. Fractures displaced more than 2 mm and with evidence of rotation are treated with open reduction and internal fixation followed by six weeks of immobilization. The exposure interval is between the brachioradialis and triceps. Posterior dissection is avoided to preserve the vascular supply. The fracture fragment is frequently much larger than it appears on plain radiographs, because it has a large cartilaginous portion. A fully reduced fracture significantly diminishes risks of nonunion. Nonunion is more frequent in unstable fractures with significant displacement. Proximal migration of the fracture fragment may lead to valgus deformity with potential ensuing tardy ulnar nerve palsy. Nonunion with displacement most commonly leads to progressive cubitus valgus deformity, which may be addressed with an osteotomy and correction of any translation of the radius and ulna. Medial Epicondyle Fractures Fractures of the medial epicondylar apophsysis in children are, fortunately, one of the more benign pediatric elbow injuries. However, the surgeon must consider several important issues in order to formulate a sound management plan and avoid complications. Unlike many fractures of the elbow, fractures of the medial epicondylar apophysis do not involve the joint surface or growth cartilage. The medial epicondyle is a posteromedial structure that serves as the origin of the flexor-pronator muscle mass as well as the medial collateral ligamentous complex. About 80% of medial epicondyle fractures occur in boys with a peak age in early adolescence. The 95

51 Marmara Medical Journal 2004;17(2);93-98 Bülent Erol, et al. The management of elbow fractures in children mechanism of injury is typically an acute valgus stress to the elbow, although chronic injuries can occur in growing athletes. Successful management of these injuries requires a heightened awareness of the commonly associated injuries (i.e., elbow dislocation and ulnar neuropraxia), an understanding of the operative indications, risks and benefits as supported in the literature, and the avoidance of complications such as stiffness or persistent stability. Evaluation of a patient with a fracture of the medial epicondylar apophysis requires a careful history, physical examination and review of the radiographs to determine the full extent of the injury. In particular, radiographs should be studied for evidence of an incarcerated medial epicondyle fragment within the joint. Although incarcerated fragments can occasionally be removed with manipulation, surgical treatment is often necessary. There is approximately 50% incidence of associated elbow dislocations with medial epicondyle fractures 8. If the history or radiographs suggest that the elbow was or is dislocated, greater soft tissue injury is likely to be present, requiring increased need for early motion. The physical examination should also include a careful neurologic examination, particularly of the ulnar nerve and median nerve. Any change in the sensory or motor examination of the ulnar nerve should be noted in the initial evaluation. If ulnar nerve function is completely disrupted, operative exploration is indicated. Non-displaced fractures should be treated with one-two weeks of cast or splint protection, followed by patient-directed active range of motion program. Results are usually excellent with this treatment program. If the minimally displaced fracture was associated with an elbow dislocation, earlier motion may be warranted. In general, re-dislocation is less of a risk than elbow stiffness. There is an ongoing debate regarding the operative management of displaced medial epicondyle fractures. Although literature support for non-operative management continues to exist, it is generally the practice in most centers to treat medial epicondyle fractures displaced more than 5 mm with internal fixation and an early motion protocol (Fig. 2). Operative management of medial epicondyle fractures includes two fixation and two positioning strategies. As a general rule, children younger than 10 years old with small medial epicondylar fragments can be satisfactorily treated with open anatomic reduction and pin fixation. The pins can be removed at about three weeks. Early motion can be allowed even before the pins are pulled. In older children with larger fracture fragments, fixation with a single partially threaded cannulated screw allows optimal stability and motion within the first week 1. Fig. 2: Anteroposterior plain radiograph of the elbow demonstrates a displaced medial epicondyle fracture. This fracture required surgical treatment. T-Condylar fractures The T-condylar fracture of the distal humerus is a very rare fracture of the elbow region in the pediatric patient, accounting for less than 1% of elbow fractures 1. As such, there is very little data in the literature on the most reliable way to achieve the best outcome. This injury typically occurs in the adolescent near skeletal maturity, usually from a direct blow to a flexed elbow. The fracture line originates from the apex of the trochlea and extends proximally. Successful management of this fracture requires understanding the intra-articular aspect of the fracture and planning treatment based on the skeletal maturity of the patient. This fracture usually requires surgical management to restore anatomic articular congruence. However, the joint line often does not need to be directly visualized because, unlike adult fractures, articular comminution is rare. 96

52 Marmara Medical Journal 2004;17(2);93-98 Bülent Erol, et al. The management of elbow fractures in children The T-condylar fractures can sometimes be confused with other fractures, most commonly extension-type supracondylar fractures. Therefore, good-quality plain radiographs are key to the proper diagnosis and treatment. The key to differentiation from the other fractures is the presence of vertical fracture line extending down to the apex of the trochlea. Recent papers support the use of open reduction and internal fixation as the best way to restore anatomic articular congruence and to provide enough fracture stability to start range of motion exercises as early as two-four weeks after the operation 9. The first goal is to achieve anatomic alignment of the articular surface. The reduction is held by a transverse screw through the center of the axis of rotation. This part of the procedure converts the fracture into a supracondylar fracture. The next surgical goal is stabilization of the supracondylar columns. In older patients near skeletal maturity, reconstruction plates with screw fixation placed at 90º to each other are recommended. This provides a construct that is stable for early range of motion exercises and addresses the fact that this is essentially an adulttype fracture. Monteggia Fractures Monteggia fractures in children are easily manageable if recognised and treated soon after injury. Only about 1% of all forearm fractures in children are classified as Monteggia fractures. Three out of four of such cases occur in boys. These fractures are characterized by dislocation of the radial head accompanied by an associated ulnar fracture, most often located in the proximal third of the bone 10,11. These injuries are typically sustained after a fall onto an outstretched hand resulting in hyperextension or hyperpronation of the elbow. Patients with Monteggia fractures present with elbow or forearm pain accompanied by tenderness localized over the radial head. The most reliable method to recognize a Monteggia fracture is to determine whether the axis of the radius bisects the capitellum on every view The Bado classification of Monteggia fractures corresponds with the mechanism of injury and is useful in determining the optimal treatment for such injuries. Type I fractures are characterized by anterior radial head dislocation, whereas Type II fractures, which are rare in children, have posterior dislocations. Type III fractures are characterized by lateral radial head dislocation. Lateral Monteggia injuries are usually associated with a buckle-type or green-stick fracture of the ulna and may fail to be recognized. A Bado Type IV injury is characterized by a radial fracture in conjunction with a radial head dislocation and an ulnar fracture. The nature of the ulnar injury dictates the management of the injury 11. Approximately 8-17% of Monteggia fractures have associated neurologic deficits, usually a neurapraxia, involving most commonly the posterior interosseous brach of the radial nerve. Recovery of nerve function takes several days to two months after injury 10,11. The goal of tratment is to correct the ulnar deformity while restoring ulnar length and realigning the radiocapitellar joint. Reduction of the ulnar fracture often reduces the radial head. If initial closed reduction fails (or for an unstable fracture), the surgeon should proceed to fluoroscopically aided operative reduction, possibly with internal fixation. It is essential to confirm maintenance of reduction. Minimal internal fixation of the ulna with an intramedullary Kirschner-wire may allow reduction of the radial head. This method is preferred over plate fixation 11. Complications arise when there is a delay in diagnosis of a Monteggia fracture or in case of a re-fracture. If the time between injury and diagnosis is prolonged, the patient may experience limited elbow range of motion, arthrosis, or additional nerve complications. These patients may also present with a partially or fully healed ulnar fracture with a radial head dislocation. In the treatment of late Monteggia fracture, achieving proper ulnar length and angulation is difficult, and usually, an ulnar osteotomy followed by open reduction of the radial head and reconstruction of the annular ligament is required. Proximal Radius Fracture Proximal radius fractures in children, unlike those in adults, generally involve the metaphysis or the physis, and not the radial head. These injuries occur most commonly between ages 8 and 12, and result from a fall onto an outstretched hand with a valgus moment directed through the radius 13. One should be aware of a Monteggia fracture (or Monteggia equivalents ) when recognizing the proximal radius injury. The length and alignment of the ulna should be compared to the other side, when in doubt. The goal of the treatment is to restore the ability to supinate and pronate, usually 60º in either direction. Displacement of the fracture fragment 97

53 Marmara Medical Journal 2004;17(2);93-98 Bülent Erol, et al. The management of elbow fractures in children results in a cam effect at the proximal radioulnar joint, thereby interfering with normal motion. Patients with nondisplaced or minimally displaced fractures with less than 30º of angulation do not need to undergo reduction and can be treated in a long-arm splint and with a range of motion exercises days after injury (Fig. 3). Fractures with angulation from 30º up to 45º should be treated with closed reduction. If closed manipulation is unsuccessful in restoring 60º of pronation and supination, a percutaneous reduction can be performed with a Steinman pin or a Kirshner-wire under fluoroscopic control. If all above methods fail, open reduction can be performed through the Kocher approach using the interval between the anconeus and the extensor carpi ulnaris. Once reduced, these fractures are usually stable and do not require internal fixation. After any sort of reduction, the elbow should be immobilized in a posterior splint for two-three weeks and then be started on a range of motion program. Fig. 3. Anteroposterior plain radiograph of the elbow and proxima forearm shows a non-displaced, incomplete fracture of the proxima radius (arrow). Also note a fracture line in the proximal ulna. This patient had conservative treatment. REFERENCES 1. Kasser JR, Beaty JH. Supracondylar fractures of the distal humerus. In: Beaty JH, Kasser JR, eds. Rockwood and Wilkins fractures in children. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2001: Otsuka NY, Kasser JR. Supracondylar fractures of the humerus in children. J Am Acad Orthop Surg 1997; 5: Skaggs DL, Hale JM, Bassett J, Kaminsky C, Kay RM, Tolo VT. Operative treatment of supracondylar fractures of the humerus in children. The consequences of pin placement. J Bone Joint Surg 2001; 83A: Gordon JE, Patton CM, Luhmann SJ, Bassett GS, Schoenecker PL. Fracture stability after pinning of displaced supracondylar distal humerus fractures in children. J Pediatr Orthop 2001; 21: Sabharwal S, Tredwell SJ, Beauchamp RD, Mackenzie WG, Jakubec DM, Cairns R, LeBlanc JG. Management of pulseless pink hand in pediatric supracondylar fractures of humerus. J Pediatr Orthop 1997; 17: Beaty J, Kasser JR. The elbow region: general concepts in the pediatric patient. In: Kasser JR, Beaty JH, eds. Rockwood and Wilkins fractures in children. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2001: Thomas DP, Howard AW, Cole WG, Hedden DM. Three weeks of Kirschner wire fixation for displaced lateral condylar fractures of the humerus in children. J Pediatr Orthop 2001; 21: Wilson NIL, Ingram R, Rymaszewski L, Miller JH. Treatment of fractures of the medial epicondyle of the humerus. Injury 1988; 19: Re PR, Waters PM, Hresko T. T-condylar fractures of the distal humerus in children and adolescents. J Pediatr Orthop 1999; 19: Kay RM, Skaggs DL. The pediatric Monteggia fracture. Am J Orthop 1998;27: Ring D, Jupiter JB, Waters PM: Monteggia fractures in children and adults. J Am Acad Orthop Surg 1998; 6: Papandrea R, Waters PM: Posttraumatic reconstruction of the elbow in pediatric patients. Clin Orthop 2000; 370: Chambers HG. Fractures of the proximal radius and ulna. In: Kasser JR, Beatty JH, editors. Rockwood and Wilkins fractures in children. 5 th ed. Philadelphia: Lippincott Williams and Wilkins, 2001: