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 SERUM ALPHA FETOPROTEIN LEVELS IN HEALTHY FULL-TERM NEONATES AND INFANTS Funda Çorapçıoğlu, Gülcan Türker, Ayşen Aydoğan, Nazan Sarper, Can Duman, A. Engin Arısoy.. 1 EARLY POSTOPERATIVE RESULTS OF THE SUBEPITHELIAL DISSECTION TECHNIQUE IN THE TREATMENT OF PTERYGIUM Ahmet F. Nohutçu, Susanne Öner...8 THE EFFECT OF CHANGE OF STIMULATION FREQUENCIES ON LATENCIES, PEAK AMPLITUDES AND CENTRAL CONDUCTION TIME IN MEDIAN SOMATOSENSORY EVOKED POTENTIALS OF NORMAL SUBJECTS Hande Türker, Önder Us, Gülseren Akyüz, Tülin Tanrıdağ...14 THE COMBINATION OF NORMAL SALINE AND LACTATED RINGER'S SOLUTION FOR LARGE INTRAVASCULAR VOLUME INFUSION Zeynep Eti, Arzu Takıl, Tümay Umuroğlu, Pınar Irmak, F.Yılmaz Göğüş..22 Olgu Sunumu DELAYED INTRACEREBRAL HEMORRHAGE AFTER VENTRICULOPERITONEAL SHUNTING Selçuk Peker, Koray Özduman, Serdar Özgen, M.Necmettin Pamir 28 BILATERAL ELASTOFIBROMA DORSI: A RARE SOFT TISSUE TUMOR Mehmet Oğuzhan Özyurtkan, Sevgi Güler, Bedrettin Yıldızeli, Hasan F.Batırel, Mustafa Yüksel. 32 A MALE (15;15) ROBERTSONIAN TRANSLOCATION CASE WITH 11 PREVIOUS CONSECUTIVE RECURRENT SPONTANEOUS ABORTIONS Anıl Biricik, Ilter Guney, Hakan Berkil, Moncef Benkhalifa, Semra Kahraman...35 INVASIVE MICROPAPILLARY CARCINOMA OF THE BREAST: CASE REPORT Handan Kaya, Ahmet Midi, Bahadır Güllüoğlu, Erkin Arıbal..39 METASTATIC DUCTAL ADENOCARCINOMA OF THE PROSTATE: REPORT of A CASE WITH FINE NEEDLE ASPIRATION BIOPSY FINDINGS and HISTOLOGIC CORRELATION Mine G.Güllüoğlu, Işın Kılıcaslan, Dilek Yılmazbayhan, Veli Uysal...42 Derleme ADOLESCENT DEPRESSION: PROGRESS AND FUTURE CHALLENGES IN PREVENTION-CONTROL ACTIVITIES Pınar Ay, Dilşad Save

8 ORIGINAL RESEARCH SERUM ALPHA FETOPROTEIN LEVELS IN HEALTHY FULL-TERM NEONATES AND INFANTS Funda Çorapçıoğlu 1, Gülcan Türker 2, Ayşen Aydoğan 3, Nazan Sarper 4, Can Duman 5, A. Engin Arısoy 2 1 Department of Pediatric Oncology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey 2 Department of Neonatology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey 3 Department of Pediatrics, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey 4 Department of Pediatric Hematology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey 5 Department of Biochemistry, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey ABSTRACT Objective: Alpha fetoprotein (AFP) is an important tumor marker in childhood. However, AFP levels remain high during the first few months of life, making clinical interpretation difficult in this period. The aim of the present study is to determine normal AFP levels in healthy full-term neonates and infants followed-up at Kocaeli University Hospital, Department of Pediatrics. Materials and Methods: Healthy full-term neonates born in Kocaeli University Hospital and <12 month-old infants attending the well baby outpatient clinic were enrolled in the study. Blood samples were drawn from the umbilical cord vein at delivery or peripheral vein after delivery. Serum AFP concentration was determined by solid phase, two-site chemiluminescent immunometric commercial diagnostic assay. Results: Ninety-four neonates with a gestational age of weeks and <12 month-old infants (48 male, 46 female) were enrolled. Mean AFP level of cord blood samples was ± ( ) ng/ml. Serum AFP levels of all 94 babies had a significant negative correlation with the postnatal age (r=-0.877, p<0.001). Results of regression analyses did not support a significant sex dependency (r= -.096, p=0.35). Conclusion: Normal range of AFP in healthy full-term neonates and infants is very wide. Pediatric oncologists must consider moderately high values carefully in the follow-up period and if the decrease in the follow-up measurement is slower than the expected half-life for that age, the probability of an AFP-producing tumor could be high. This approach would prevent unnecessary interventions depending on false positive AFP results. Keywords: Alpha fetoprotein, Normal range, Newborns, Infants SAĞLIKLI TERM YENİDOĞAN VE İNFANTLARDA SERUM ALFA FETOPROTEİN DÜZEYLERİ ÖZET Amaç: Alfa fetoprotein (AFP) çocukluk çağında önemli bir tümör belirleyicisidir. Bununla birlikte yaşamın ilk birkaç ayında AFP düzeyinin yüksek kalması bu periyodda klinik yorumu zorlaştırmaktadır. Bu çalışmanın amacı Kocaeli Üniversitesi Hastane, Pediatri Bölümü nde izlenen sağlıklı term yenidoğan ve infantlarda serum AFP düzeylerinin belirlenmesidir. Materyal ve Metod: Kocaeli Üniversitesinde doğan sağlıklı term yenidoğanlar ve sağlam çocuk polikliniğine başvuran sağliklı <12 aylık infantlar çalışmaya alındı. Kord veninden (doğumda) veya periferik venlerden kan örnekleri alındı. Serum AFP konsantrasyonu solid faz, ikili-bölümlü kemilüminesen immünometrik tanısal yöntemle değerlendirildi. Bulgular: Doksan dört örnek (48 erkek, 46 kız) değerlendirildi. Kord kanı ortalama AFP düzeyi ± ( )ng/ml bulundu.doksan dört bebekte serum AFP düzeyi ile postnatal yaş arasında anlamlı negatif korelasyon saptandı (r= , p<0.001).regresyon analizinde, cinsiyete bağlı farklılık gösterilemedi (r= -.096, p=0.35). Sonuç: Sağlıklı yenidoğan ve infantlarda AFP normal sınırları çok geniştir. Pediartik onkolog orta derecede yüksek AFP değerlerini dikkat ile değerlendirmeli ve izlemde AFP düzeyindeki düşme, yaş için uygun yarılamna süresinden yavaş ise AFP üreten tümör olasılığının yüksek olabileceği düşünülmelidir. Bu yaklaşım, yanlış pozitif AFP sonuçlarına bağlı gereksiz girişimleri önleyecektir. Anahtar Kelimeler: Alfa fetoprotein, Normal sınır,yenidoğan, İnfant Corresponding author: Funda Çorapçıoğlu, MD. Cumhuriyet Mah. Mısır Sok EKAS yapı koop. B blok, Kat:1, Da:1 IZMIT-KOCAELİ / Turkey Tel. :+90 (262) (1605)Fax :+90 (262) [email protected] Marmara Medical Journal 2004;17(1);1-7 1

9 Marmara Medical Journal 2004;17(1);1-7 Funda Çorapçıoğlu, et al. Serum Alpha Fetoprotein Levels in Healthy Full-Term Neonates and Infants INTRODUCTION Alpha fetoprotein (AFP) is one of the important tumor markers in pediatric oncology 1. AFP secretion is characteristic for malignant germ cell tumor with yolk sac component and hepatoblastoma in childhood 2. As a tumor marker AFP has an important role in initial diagnostic evaluation, and follow-up during therapy, but the physiologically elevated AFP levels in infancy or in benign conditions, such as hepatic diseases or hereditary disorders, must also be considered in the differential diagnosis 2. AFP levels remain high during the first few months of life, thus making clinical interpretation difficult in this early period and normal variations in AFP levels were found to be extremely large in early postnatal life 2-6. Very few and incomplete data regarding the determination of reference values for AFP in healthy newborn are available 4. Postnatal serum AFP levels are age dependent and gradually decline as the infant matures 6. Sex and racerelated differences in serum AFP levels, especially in early postnatal life, have been conflicting and the cause for these controversies remain obscure 3,7,8. The aim of the present study is to determine normal AFP levels in healthy fullterm neonates and infants who attended Kocaeli University Hospital, Department of Pediatrics. METHODS Healthy full-term neonates born in Kocaeli University Hospital and <12 month-old infants attending the well baby outpatient clinic were enrolled in the study after parental consent. The study respected the guidelines of the Helsinki declaration concerning medical research in humans and received local Ethics Committee approval. Gestational age was calculated by the mother s last menstrual period, by fetal ultrasonic evaluation and by new Ballard scoring system 9. Babies who had an appropriate birth weight for their gestational age were included in the study. Exclusion criteria were: prematurity (<37 gestational weeks), small or large for gestational age, hyperbilirubinemia, hepatobiliary disease or abnormal liver function profile results, positive hepatitis-b surface antigen, respiratory distress, respiratory or cardiac disease, severe infection and congenital malformations, and history of high maternal serum AFP during pregnancy follow-up. Blood samples were drawn from the umbilical cord vein at delivery or peripheral vein after delivery. Residual serum from the venous umbilical cord or peripheral blood samples collected for routine biochemical analyses essential to patient care was used for estimation of AFP. Repeated venopunctures were avoided. Serum AFP concentration was determined by solid phase, two-site chemiluminescent immunometric commercial diagnostic assay developed for the Immulite automated immunoassay system (Diagnostic Products Corporation, Los Angeles, CA, USA) 10,11. Whitin-run coefficient variation was 6.3% at a mean AFP concentration of 0.80U/ml and 2.4% at a mean concentration of 182U/ml. The assay requires 10µL of serum. Proper dilution was required due to much higher serum AFP concentrations compared to adult samples. Results were reported in ng/ml. One international unit (1IU) of AFP of the standard preparation of the World Health Organisation (72/225) was equivalent to 1.21ng in our method. Patient characteristics were summarized using descriptive statistics; mean±sd was used for the expression of continuous variables. Chi-square test or Fisher s exact test was used to evaluate the differences among the cathegorical variables. Kruskal Wallis test was used for continous variables. Spearman correlation, linear regression and exponential regression analyses were used to assess the relation between postnatal age and AFP level. Statistical significance was determined at p<0.05. RESULTS Six samples were excluded from our study due to congenital anomalies and respiratory disease. Ninety-four neonates (48 male, 46 female) with an appropriate birth weight for their gestational age and infants (<12 month-old) were enrolled. All subjects were delivered vaginally or with cesearian section without any significant perinatal complication. No babies had a diabetic mother or abnormal maternal plasma AFP level that was evaluated during rutin pregnancy follow-up. Eighty-nine babies were singletons, two babies were from twin pregnancies and another 3 were triplets. In the first step of statistical evaluation, we evaluated AFP levels of cord blood samples taken at delivery from 35 babies. Demographic data of 35 newborns with gestational ages between weeks is shown in Table I. Mean AFP level of 35 cord blood samples was ± ( ) ng/ml. Mean cord blood AFP levels of full-term newborns with regard to gestational age and sex are shown in Table II. 2

10 Marmara Medical Journal 2004;17(1);1-7 Funda Çorapçıoğlu, et al. Serum Alpha Fetoprotein Levels in Healthy Full-Term Neonates and Infants Gestational age Table I: Demographic characteristics of full-term newborns All newborns (38-40 weeks) 38 weeks 39 weeks 40 weeks p Number Male/Female 14/21 6/6 7/10 1/ Birth weight (g) (range) 3193±327 ( ) 3318±388 ( ) 3081±293 ( ) 3258±188 ( ) Table II: The concentration of AFP* in the cord blood of full-term newborns partitioned by gestational age and sex Gestation (week) AFP(ng/ml) mean±sd (range) ± ( ) ± ( ) ± ( ) AFP(ng/ml) mean±sd(range) Male ( ) ± ( ) AFP(ng/ml) mean±sd(range) Female ± ( ) ± ( ) ± ( ) p *single values demonstrate median level or patient s AFP level when there is only one patient in the subgroup. Peripheral venous blood was collected from 59 newborns or infants with postnatal age of days (median 7 days). In the second step of statistical evaluation, we evaluated AFP levels of all newborns and infants (35 cord blood samples and 59 peripheral blood samples; total 94 samples). Serum AFP levels of study group partitioned by age groups and sex, is shown in Table III. No statistically significant difference was found between sex and postnatal age groups (p=0.817, 0.924, respectively). Postnatal age Table III: Serum AFP* levels of infants partitioned by age groups and sex No. (M/F) 0-1 month 56 (27/29) 2 months 7 (4/3) 3-6 months 6 (3/3) 7 months 11 (6/5) 8-9 months 8 (4/4) months 6 (3/3) AFP (ng/ml) mean±sd (range) ± ( ) ( ) 84 (27-788) 39 ( ) 22 ( ) 18 (6-590) AFP(ng/ml) mean±sd (range) Male ( ) 1.328±623 ( ) 105 (27-397) 32±17 (13-64) 23±21 (7-53) 18 (17-590) AFP(ng/ml) mean±sd (range) Female ± ( ) 4279 ( ) 64 (27-788) 96 ( ) 47 ( ) 14 (6-560) p *single values demonstrate median level or patient s AFP level when there is only one patient in the subgroup

11 Marmara Medical Journal 2004;17(1);1-7 Funda Çorapçıoğlu, et al. Serum Alpha Fetoprotein Levels in Healthy Full-Term Neonates and Infants Serum AFP levels of all 94 babies (newborns and infants) had a significant negative correlation with postnatal age (r=-0.877, p<0.001). Results of linear regression analyses demonstrated a significant negative correlation between plasma AFP concentrations and postnatal age (Table IV and Fig. 1). Linear regression analyses did not support a significant sex dependency (r= , p=0.35). Table IV: Least squares regression of plasma AFP (ng/ml) concentration by infant age (day) n Correlation coefficient All infants (y=afp; x=age) Linear regression (y=a+bx) y= x r 2 95% CI P value Fig. 1: Normal ranges of serum AFP in early infancy 4

12 Marmara Medical Journal 2004;17(1);1-7 Funda Çorapçıoğlu, et al. Serum Alpha Fetoprotein Levels in Healthy Full-Term Neonates and Infants DISCUSSION AFP is an oncofetal protein with molecular weight of 68,000 Da 2. AFP is produced in the developing fetus in equal amounts by the yolk sac and the fetal liver 7. Because the human yolk sac involutes at the 9 th week, the fetal liver and to lesser extent, the gastrointestinal tract is responsible for most of the AFP production during fetal development 12. During early pregnancy AFP is the predominant serum protein, showing maximum fetal serum levels of 3-4g/L in the 12 th week of pregnancy. As AFP crosses the placenta it can be measured in the serum of the pregnant women 2. The synthesis of AFP does not cease entirely at term, but a small amount of AFP is continuously synthesized until 8 months of age. The infant plasma concentration falls exponentially from a mean of U/ml to a typical adult concentration of less than 10 U/ml at 6 to 8 months of age 1,7. The explanation for the observation of AFP synthesis not ceaseing entirely at term may be the presence of fetal hepatocytes, that sustain transient production of AFP during the early postnatal period, although they decrease in number 7. The value of serum AFP for detection and/or differentiation of a great number of infantile diseases is well established, especially for germ cell tumor with yolk sac component and hepatoblastoma, and benign liver disorders 2,12. But serum AFP levels are high in normal fetuses and children in early infancy, making the interpretation of AFP levels very difficult at this age group 1. Abnormal concentrations of AFP in biologic fluids during embryonic and fetal development have been found to be associated with congenital malformations and hereditary disorders Reference values for AFP in healthy full-term newborns at birth are not well-defined 4. The postnatal serum AFP levels are age-dependent and gradually decline as the infant matures 1,3,5,6. Low birth weight infants have a clearly greater mean concentration of AFP than other newborns 5. When the low birth weight group was partitioned into two subgroups to distinguish small for gestastional age from premature infants, a distinctively high mean was found for both groups 5. On the other hand, birth weight itself has been correlated with gestational age 6. Since the estimation of gestational age without sonography can be highly subjective, Mizejewski GJ, et al. 5 suggested that birth weight is the parameter of choice upon which to measure postnatal AFP blood concentrations. In the present study, we excluded infants with birth weight inappropriate for gestationel age to eliminate any factor that may cause a change in serum AFP concentration. In our study fetal sonography is a routine examination for the determination of gestational age and it is also confirmed by the mother s estimated date of her last menstrual period and physical examination of the neonatologyst by the new Ballard scoring system. Bellini C, et al. 4 examined AFP levels in 150 healthy newborns and preterms within the postnatal 24 hours. All babies included in their study were of appropriate birth weight. They found a significant correlation between AFP values and both birth weight and gestational age. In their study mean AFP values in male and female newborns were 151±61mg/L and 150±59mg/L, respectively. These were higher than our AFP values as a result of presence of premature babies in their study group. Blohm ME, et al. 19, found that, at birth mean serum AFP levels were 41,687 ng/ml in 256 term babies. We found higher mean AFP values ( ng/ml) in a similar group with a wide range ( ). Our mean values in newborns and infants are similar to Wu JT, et al. 20 but show wider AFP ranges in all postnatal age groups. In most infants, serum AFP levels decrease to normal adult levels within the first 8-10 months, but in a significant proportion of children AFP levels do not normalize until the end of the 2nd year of life 19,21. Our study group was limited to 12 month-old infants. Some babies had normal adult values even in the 7 th month but this study is inefficient to make a conclusion about the age for AFP decrease to normal adult values. Findings of sex-related differences in serum AFP levels, especially in early postnatal life, have been conflicting, and the cause of these controversies remain obscure 3,7. The levels of fetal AFP at parturition are found to be significantly higher in the male infants 8,22. In a study fetal AFP serum concentration was found higher in boys than girls and this sex related difference remained during the first week of life 22. Lee PI, et al. 3 investigated the normal developmental pattern of serum AFP level. Their results support the presence of a sexrelated difference in AFP levels during early postnatal life. Higher AFP levels are noted for newborn boys during the first 2 postnatal weeks. In newborn girls, the mean serum AFP level decreased rapidly from postnatal day 1 to 2 and remained relatively constant thereafter until 7 days of age. It is hard to explain the different 5

13 Marmara Medical Journal 2004;17(1);1-7 Funda Çorapçıoğlu, et al. Serum Alpha Fetoprotein Levels in Healthy Full-Term Neonates and Infants developmental patterns of AFP in male and female neonates. It may also be that the biodynamics of AFP is influenced by such sexdetermined factors as hormones. Sex related difference diminish with increasing age 3. However, Bellini C, et al. 4 found that there was no significant difference between AFP values in males vs. females in 150 healthy newborns and preterms 4. In the present study AFP values were not statisticaly different in males and females except values of the 7 th month which were higher in females. We showed with exponential and linear regression analyses that a significant sex dependency does not exist in AFP values of 0-12 month-old infants. But we cannot make a final conclusion with this small group of infants and such a wide variation of AFP levels. Observation on the relationship between race and AFP levels has been inconsistent. In fact, maternal serum AFP values have been shown to be higher in blacks and Orientals than in Caucasians 3. Maternal serum AFP concentrations are affected by a number of variables including ethnicity 23,24. However, there is no evidence about ethnical differences in infant serum AFP levels 3. More studies are necessary to explain wide variations in ethnicity. In conclusion, we showed that the normal range of AFP in healthy infants who were followed-up in our center is very wide and pediatric oncologists must consider moderately high values carefully and if the decrease in the follow-up measurement is slower than the expected half-life for that age, the probability of an AFP-producing tumor could be high. This approach would prevent unnecessary interventions depending on false positive AFP results. REFERENCES 1. Ohama K, Nagase H, Ogino K, et al. Alphafetoprotein (AFP) levels in normal children. Eur J Pediatr Surg 1997; 7: Schneider DT, Calaminus G. Diagnostic value of alpha1-fetoprotein and beta-human chorionic gonadotropin in infancy and childhood. Pediatr Hematol Oncol 2002; 18: Lee PI, Chang MH, Chen DS, Lee CY. Serum a- fetoprotein levels in normal infants: a reappraisal of regression analysis and sex difference. J Pediatr Gastroenterol Nutr 1989; 8: Bellini C, Wanda B, Parodi E, Sera G. Serum a- fetoprotein in newborns. Clin Chem 1998; 44: Mizejewski GJ, Bellisario R, Carter TP. Birth weight and alpha-fetoprotein in the newborn. Pediatrics 1984; 73: Mizejewski GJ, Carter TP, Beblowski DW, Bellisario R. Measurement of serum alphafetoprotein in early infancy: utilization of dried blood specimens. Pediatr Res 1983; 17: Blair JI, Carachi R, Gupta R, Sim FG, McAllister EJ, Weston R. Plasma a fetoprotein reference ranges in infancy: effect of prematurity. Arch Dis Child 1987; 62: Obiekwe BC, Malek N, Kitau MJ, Chard T. Maternal and fetal alphafetoprotein (AFP) levels at term. Relation to sex, weight and gestation of infant. Acta Obstet Gynecol Scand 1985; 64: Ballard JL, Khoury JC, Wedig K, Wang L, Eilers- Walsman BL, Lipp R. New Ballard Score, expanded to include extremely premature infants. J Pediatr 1991; 119: Mutlu N, Turkeri L, Emerk K. Analytic and clinical evaluation of new urinary tumor marker: bladder tumor fibronectin in diagnosis and follow-up of bladder cancer. Clin Chem Lab Med 2003; 41: Correale M, Pagliarulo A, Donatuti G, et al. Preliminary clinical evaluation of free/total PSA ratio by the IMMULITE system. Int J Biol Markers 1996; 11: Mizejewski GJ. Levels of alpha-fetoprotein during pregnancy and early infancy in normal and disease states. Obstet Gynecol Surv 2003; 58: Everman DB, Shuman C, Dzolganovski B, O Riordan MA, Weksberg R, Robin NH. Serum a- fetoprotein levels in Beckwith-Wiedemann syndrome. J Pediatr 2000; 137: Pitkanen S, Salo MK, Kuusela P, Holmberg C, Simell O, Heikinheimo M. Serum levels of oncofetal markers CA 125, CA 19-9, a-fetoprotein in children with hereditary tyrosinemia type I. Pediatr Res 1994; 35: Mengreli C, Sarafidou E, Petmezaki S, Pantelakis S. a-fetoprotein in congenital hypothyroidism. Biol Neonate 1990; 58: van Rijin M, van der Schouw YT, Hagenaars AM, Visser GH, Christiaens GC. Adverse obstetric outcome in low- and high- risk pregnancies: predictive value of maternal serum screening. Obstet Gynecol 1999; 94: Zarzour SJ, Gabert HA, Diket AL, St Amant M, Miller JM Jr. Abnormal maternal serum alpha fetoprotein and pregnancy outcome. J Matern Fetal Med 1998; 7: Hogge WA, Thiagarajah S, Ferguson JE 2nd, Schnatterly PT, Harbert GM JR. The role of ultrasonography and amniocentesis in the evaluation of pregnancies at risk for neural tube defects. Am J Obstet Gynecol 1989; 161: Blohm ME, Vesterling-Horner D, Calaminus G, Gobel U. Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. 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14 Marmara Medical Journal 2004;17(1);1-7 Funda Çorapçıoğlu, et al. Serum Alpha Fetoprotein Levels in Healthy Full-Term Neonates and Infants pediatric malignant tumors. Pediatr Surg Int 1997; 12: Caballero G, Vekemans M, Lopez del Campo JG, Robyn C. Serum alpha-fetoprotein in adults, in women during pregnancy, in children at birth and during the first week of life: a sex difference. Amer J Obstet Gynecol 1997; 127: Nuttal KL, Lenke RR, Ashwood ER. Maternal serum alpha-fetoprotein and altitude. Med Hypotheses 2000; 54: Hsieh TT, Hung TH, Hsu JJ, Shau WY, Su CW, Hsieh FJ. Prediction of adverse perinatal outcome by maternal serum screening for Down syndrome in an Asian population. Obstet Gynecol 1997; 89:

15 ORIGINAL RESEARCH EARLY POSTOPERATIVE RESULTS OF THE SUBEPITHELIAL DISSECTION TECHNIQUE IN THE TREATMENT OF PTERYGIUM Ahmet F. Nohutçu, Susanne Öner Haydarpaşa Numune Hospital for Education and Research, Ophthalmology Clinic-1, Istanbul, Turkey ABSTRACT Objective: Pterygium is a fibrovascular connective tissue proliferation extending on the cornea in the interpalpebral space. To relieve the symptoms and signs of pterygium, numerous surgical approaches have been developed. The aim of this study was to investigate the short-term results of the subepithelial dissection technique (D Ombrain s Technique) in regard to best-corrected visual acuity (BCVA) and computerized corneal topography (CCT) results. Methods: Eighteen eyes of 15 patients presenting at our clinic have been prospectively investigated and followed for a duration of 1 month. Pre- and postoperatively, a complete ophthalmologic examination and CCT were performed. Statistics were performed using the Wilcoxon s rank sum test, with the level of significance set at p<0.05. Results: The study included 14 primary and 4 secondary pterygia. Preoperatively mean BCVA was 0.61, and CCT showed a mean astigmatism of 2.60 D. These values were 0.82 (p<0.05) and 1.22 D (p<0.05), respectively, at 1 month. There were no serious intra- or postoperative complications observed. Conclusion: We consider the subepithelial dissection technique in the treatment of pterygium as an effective and safe method in the short-term. Keywords: Pterygium, Bare sclera technique, Computerized cornea topography PTERYGİUM TEDAVİSİNDE SUBEPİTELYAL DİSEKSİYON YÖNTEMİNİN KISA DÖNEM SONUÇLARI ÖZET Amaç: Pterygium interpalpebral alanda korneanın üzerine yürüyen fibrovasküler bağ dokusu proliferayonudur. Pterygiumun belirti ve bulgularını ortadan kaldırmak için çeşitli cerrahi yöntemler geliştirilmiştir. Bu çalışmanın amacı, subepitelyal diseksiyon yönteminin (D Ombrain in yöntemi) kısa dönem sonuçlarını, en iyi düzeltilmiş görme keskinliği (EİDGK) ve bilgisayarlı kornea topografisi (BKT) açısından, incelemek idi. Yöntem: Kliniğimize başvuran 15 hastanın 18 gözü prospektif olarak incelendi ve 1 ay süre ile takip edildi. Ameliyat önce ve sonrası kapsamlı göz muayenesi ve BKT yapıldı. İstatistikler için Wilcoxon un eşleştirilmiş iki örnek testi kullanıldı ve p<0.05 değerler anlamlı olarak değerlendirildi. Bulgular: Çalışmada 14 primer ve 4 sekonder pterygium incelendi. Ameliyat öncesi ortalama EİDGK 0.61 ve BKT de ortalama astigmatizma 2.60 D idi. Bir ay sonra bu değerler sırasıyla 0.82 (p<0.05) ve 1.22 D (p<0.05) idi. Ameliyat sırasında ya da sonrasında ciddi komplikasyon görülmedi. Sonuç: Pterygiumun tedavisinde subepitelyal diseksiyon yöntemi kısa dönemde etkili ve güvenli bir yöntem olarak değerlendirildi. Anahtar Kelimeler: Pterygium, Çıplak sklera yöntemi, Bilgisayarlı kornea topografisi. INTRODUCTION Pterygium is a benign fibrovascular proliferation that develops from the conjunctiva and invades the cornea 1,2. Symptoms of this disorder include foreign body sensation, photophobia, a decrease in visual acuity due to invasion of the optic axis, induced corneal astigmatism and tear film Corresponding author: Susanne Öner, M.D Osmangazi Sok. No. 11/5, Üsküdar, İstanbul Tel: [email protected] abnormalities, ocular motility disorders, and cosmetic disturbance 3-5. Treatment of pterygium is surgical. The postoperative recurrence rate of pterygium is reported as 0-88 % Numerous surgical techniques, including radiation therapy, the use of thiotepa and mitomycin C, conjunctival and amniotic membrane grafts, and lamellar Marmara Medical Journal 2004;17(1);8-13 8

16 Marmara Medical Journal 2004;17(1);8-13 Ahmet Nohutçu, et al. Early postoperative results of the subepithelıal dissection technique in the treatment of pterygium keratoplasty have been developed to decrease the recurrence rate 1,7-14. However, higher serious intra- and postoperative complication rates are reported with these methods 10, Although the etiology of pterygium is still unclear, ultraviolet radiation and damage of the limbal stem cells has been proposed 18,19. In concordance with this theory we performed subepithelial dissection 20, (D Ombrain s Technique) a bare sclera technique involving excision of the subepithelial tissue as much as possible, and investigated the short-term results in regard to best-corrected visual acuity (BCVA), and pterygium-induced corneal astigmatism as measured by computerized cornea topography (CCT). With CCT, pterygiuminduced astigmatism shows higher values compared to measurements with keratometry 21. This is especially valuable for early surgical intervention in small pterygia 22,23. There is no other study using D Ombrain s Technique and comparing these parameters. METHODS Eighteen eyes of fifteen subsequent patients, presenting at the Ophthalmology Clinic-1 of Haydarpaşa Numune Hospital between September 2002 and March 2003, were prospectively investigated in the study. Indications for operation were symptoms of disturbed vision, foreign body sensation, lacrimation or cosmetic disturbance in pterygia >1mm. Preoperatively, a complete anamnesis and ophthalmologic examination, including BCVA, keratometry, biomicroscopy of the anterior segment with measurement of the horizontal and vertical extentions of the pterygium on the corneal surface, applanation tonometry, fundoscopy, ocular motility tests, and CCT (Technomed) were performed. Of the 15 patients enrolled in the study, 7 were women, and 8 were men.three patients were operated on both eyes. From the 18 cases 14 were primary, and 4 were secondary pterygia. Pterygia were present for a period of a mean of 7.1 years (1-40 years). The symptom most often reported was disturbance of visual acuity. Other symptoms were foreign body sensation, hyperemia, photophobia and epiphora, itching, ocular pain, and growing of the pterygium. Ten patients reported more than one symptom. The pterygia had a mean horizontal extention of 2.6 mm ( mm) on the cornea. Applanation tonometry was in normal range for all eyes, including those with preexisting glaucoma. Mean BCVA was 0.61 ( ). Mean corneal astigmatism as measured by CCT was 2.6 D ( ); 14 eyes had with-the-rule astigmatism, 2 had oblique astigmatism, and 2 had irregular corneal astigmatism. There was no patient with diplopia or ocular motility disturbance. Preparations for operation included treatment of the periocular skin and the conjunctiva with povidon-iodine and sterile draping. After instillation of proparacaine hydrochlorid 0.5% drops, the body of the pterygium was infiltrated with 0.5 ml of 2% lidocaine hydrochloride. D Ombraine s Technique was performed according to the explanations of Buratto 24 ; the conjunctiva was incised with Westcott scissors at a distance of 0.5 mm on either edge of the pterygium to reach the semilunar folds, and the pterygium tissue was dissected from the sclera. Subsequently, a preincision was performed in clear cornea in front of the hood of the pterygium, and the apex of the pterygium was scraped from the cornea, leaving a smooth surface. The apex of the pterygium was removed, and the pterygium tissue dissected from the overlying conjunctiva up to the semilunar fold and excised. In some cases light cauterization was performed for hemorrhage disturbing the visibility of the operation field. A small portion of conjunctiva close to the limbus was excised, and the remainder of the conjunctiva was distended on the sclera and sutured on either side with 8/0 silk, leaving 3 mm of bare sclera. The steps of pterygium excision with subepithelial dissection are shown in Figs The eye was bandaged with antibiotic ointment. Routine postoperative treatment included ciprofloxacine 0.3% drops four times a day for 1 week, fluorometholon 0.1% drops four times a day for 1 week, tapered over the 2 nd week, and preservativefree artificial tears, until a smooth ocular surface was observed. 9

17 Marmara Medical Journal 2004;17(1);8-13 Ahmet Nohutçu, et al. Early postoperative results of the subepithelıal dissection technique in the treatment of pterygium Fig. 1: Preoperative pterygium Fig. 2: Intraoperative view after excision of the pterygium apex Fig. 3: Subepithelial dissection of the pterygium tissue. Fig. 4: Excision of the subepithelial pterygium tissue Fig. 5: Placement of conjunctival sutures Fig. 6: Postoperative view of excised pterygium Postoperative examinations were performed on day 1, after 1 week and every following week during the first month. On the last examination, patients symptoms were recorded, and a complete ophthalmic examination including BCVA, keratometry, biomicroscopy of the anterior segment, applanation tonometry, ocular motility testing and CCT was performed. For statistical analysis the Wilcoxon s rank sum test was used, and the significance level set at p<0.05. RESULTS There were no intraoperative complications observed. In the immediate postoperative period, symptoms were slight ocular pain, and epiphora in 4 patients. Eleven patients had slight conjunctival hyperemia, chemosis, and/or watery discharge. Additionaly, one patient showed reaction to the sutures, which responded to medical therapy. At the end of the 1 st month, there was minimal conjunctival hyperemia in 5 cases. Two patients reported slight pain, one patient foreign body sensation, and one patient redness of the eye. At 1 month postoperatively, mean BCVA was 0.82 ( ). This increase in BVCA compared to the preoperative value was statistically significant (p<0.05). With pterygia extending 2.5 mm horizontally on the cornea (n=9), mean preoperative BCVA was 0.67, and mean postoperative BCVA was 0.83 (p<0.05). These values were 0.56 and 0.80, respectively, for pterygia extending more than 2.5 mm on the cornea (p<0.05). Table I shows the pre- and postoperative BCVA of all patients for pterygia with an extention of 2.5 mm and >2.5 mm on the cornea. 10

18 Marmara Medical Journal 2004;17(1);8-13 Ahmet Nohutçu, et al. Early postoperative results of the subepithelıal dissection technique in the treatment of pterygium The increase in BCVA was higher for pterygia extending more than 2.5 mm on the cornea. In 2 patients postoperative BCVA had decreased compared to the preoperative value. At 1 month postoperatively mean corneal astigmatism was 1.22 D ( ). With pterygia extending 2.5 mm horizontally on the corneal surface, mean preoperative corneal astigmatism was 1.25 D, and mean postoperative astigmatism was 1.04 D (pii shows the pre- and postoperative corneal astigmatism of all patients for pterygia with an extention of 2.5 mm and >2.5 mm on the cornea. The decrease in corneal astigmatism was higher for pterygia extending more than 2.5 mm horizontally on the cornea. Postoperatively, eleven eyes had with-the-rule astigmatism, five had oblique astigmatism, and two had against-the-rule astigmatism. There was a significant residual astigmatism (>1 D) in 9 eyes postoperatively; but with adequate correction, these eyes achieved better BCVA compared to the preoperative value. The mean central corneal refractive power was D preoperatively, and D postoperatively (p>0.05). There were no significant elevations in intraocular pressure (IOP) or pterygium recurrence observed in the 1 month period. Table I: Pre- and postoperative best-corrected visual acuity for patients with astigmatism 2.5 mm and >2.5 mm. Patients Preoperative BCVA Postoperative BCVA Pterygium 2.5 mm Pterygium >2.5 mm Table II: Pre- and postoperative astigmatism (Diopters) for patients with astigmatism 2.5 mm and >2.5 mm Patient Preoperative astigmatism (D) Postoperative astigmatism (D) Pterygium 2.5 mm Pterygium >2.5 mm

19 Marmara Medical Journal 2004;17(1);8-13 Ahmet Nohutçu, et al. Early postoperative results of the subepithelıal dissection technique in the treatment of pterygium DISCUSSION Pterygium is a mostly nasaly located degenerative lesion, with a higher prevalance in hot, sunny climates 25. The etiology of this disorder remains unclear. In accordance with the theory of stem cell mutation by ultraviolet radiation, with subsequent extention on the cornea; we performed subepithelial dissection (D Ombrain s Technique) 20 with resection of the complete pterygium tissue until the semilunar fold, and directed our investigations on the effect of pterygium excision on BCVA and corneal astigmatism as measured by CCT in the shortterm. We did not experience any serious intra- or postoperative complication with this method. There is a higher risk of intraoperative hemorrhage with this technique, requiring a good assistance. All intraoperative hemorrhages stopped after light cauterization or closure of the wound. With taking care of the medial rectus muscle, especially in recurrent cases, we did not observe any damage to this muscle. We did not observe any serious postoperative complication in this study. Nevertheless, early postoperative complications requiring further intervention, like conjunctival granuloma, anterior uveitis, elevated IOP, scleral thinning and corneal perforation, have been reported before with bare sclera excision of pterygium 8,26, and careful postoperative follow-up is mandatory in all cases. The only sign at postoperative 1 month was slight conjunctival hyperemia in 4 eyes. Due to the use of fluorometholone 0.1%, we did not observe any elevation of IOP in the 1 month period; this corticosteroid decreases inflammation of the ocular surface without penetrating the cornea 27. In accordance with the literature 5,28-30, most of the eyes in this study had with-the-rule regular astigmatism preoperatively. This has been related to the observation that pterygia press against and flatten the cornea, thus increasing the horizontal diameter of curvature 28. In our study, mean corneal astigmatism decreased from 2.6 D preoperatively to 1.22 D postoperatively. Preoperative astigmatism of D decreasing to a mean of D after pterygium surgery 22,31,32 has been reported before. In this study pterygia with a horizontal extention on the cornea of 2.5 mm induced less astigmatism (1.25 D) than pterygia >2.5 mm (3.94 D). Similarly, Hansen et al. 28 found an average astigmatism of 1.97 D with pterygia with a horizontal extention of 3 mm, and of 1.11 D with smaller pterygia. Avisar et al 29 found induced astigmatism of 1.0 D in 16,2% of cases with an extention of the pterygium on the cornea for up to 1.0 mm, in 45.5%, if the pterygium extended for mm on the cornea, and in 100% if the extention on the cornea was mm. In our study corneal astigmatism induced by larger pterygia decreased significantly more postoperatively. This is in accordance with the literature 22,31-34, Lindsay et al. 30 observed a decrease of astigmatism of 7.00 D after surgery on a pterygium extending for 4 mm on the cornea. Concommitant with the decrease in corneal astigmatism, BCVA in this study increased significantly from a mean value of 0.61 preoperatively to a mean value of 0.82 postoperatively. Similarly, Lindsay et al. 30 report an increase of BCVA from 6/9.5 pre- to 6/6 postoperatively. As in our study, this increase in postoperative BCVA has been reported to be higher in pterygia >2.5 mm compared to pterygia 2.5 mm 21. The decrease in postoperative BCVA in 2 eyes in this study, both with preexisting glaucoma, was attributed to ongoing glaucomatous damage, because there was no intra- or postoperative complication observed. Limitations of this study are the fact that not all operations have been performed by one surgeon, although under the supervision of one surgeon, and the short follow-up period in regard to pterygium recurrence. All the patient in this study are being followed for long-term results. We conclude that pterygium excision with subepithelial dissection and removal of the complete pterygium tissue is safe intra- and postoperatively, and effective in terms of early postoperative increase in BCVA, decrease of pterygium-induced corneal astigmatism, and cosmetic appearance. REFERENCES 1. Durukan A, Doğan H. Pterjium eksizyonundan sonra mitomisin-c uygulama sonuçları. MN Oftalmoloji 1998; 5: Buratto L, Phillips RL, Carito G. Part A. Chapter 1. Introduction. In: Buratto L, Phillips RL, Carito G, eds. Pterygium Surgery. Thorofare, NJ: SLACK Inc., 2000: Buratto L, Phillips RL, Carito G. Part A. Chapter 9. Symptoms. In: Buratto L, Phillips RL, Carito G, eds. Pterygium Surgery. Thorofare, NJ: SLACK Inc., 2000:

20 Marmara Medical Journal 2004;17(1);8-13 Ahmet Nohutçu, et al. Early postoperative results of the subepithelıal dissection technique in the treatment of pterygium 4. Oldenburg JB, Garbus J, McDonnel JM, McDonnel PJ. Conjunctival pterygia: mechanism of corneal topografic changes. Cornea 1990; 9: Lin A, Stern G. Correlation between pterygium size and induced corneal astigmatism. Cornea 1998; 17: Tan DT, Chee SP, Dear KB, Lim AS. Effect of pterygium morphology on pterygium recurrence in a controlled trial comparing conjunctival autografting with bare sclera excision. Arch Ophthalmol 1997; 115: Mastropasqua L, Carpineto P, Ciancaglini M, Gallenga PE. Long term results of intraoperative mitomycin C in the treatment of recurrent pterygium. Br J Ophthalmol 1996; 80: Atmaca P, Bekir NA, B ¹lb ¹l M. Pterijium cerrahisinde farklı tekniklerin karşılaştırılması. T Klin Oftalmoloji 2002; 11: Chen PP, Ariyasu RG, Kaza V, Labree LD, McDonnell PJ. A randomized trial comparing mitomycin C and conjunctival autograft after excision of primary pterygium. Am J Ophthalmol 1995; 120: Ma DHK, See LC, Liau SB, Tsai RJF. Amniotic membrane graft for primary pterygium: comparison with conjunctival autograft and topical mitomycin C treatment. Br J Ophthalmol 2000; 84: MacKenzie FD, Hirst LW, Kynaston B, Bain C. Recurrence rate and complications after beta irradiation for pterygia. Ophthalmology 1991; 98: Olander K, Halk KG, Halk GM. Management of pterygia: should thiotepa be used? Ann Ophthalmol 1978; 10: Starck T, Kenyon KR, Serrano F. Conjunctival autograft for primary and recurrent pterygia: surgical technique and problem management. Cornea 1991; 10: Buratto L, Phillips RL, Carito G. Part A. Chapter 14. Lamellar keratoplasty in pterygium surgery. In: Buratto L, Phillips RL, Carito G, eds. Pterygium Surgery. Thorofare, NJ:SLACK Inc., 2000: Rubinfeld RS, Pfister RR, Stein RM, et al.. Serious complications of topical mitomycin CC after pterygium surgery. Ophthalmology 1992; 99: Moriarty AP, Crawford GJ, McAllister JL, Constable IJ. Severe corneoscleral infection. A complication of beta irradiation scleral necrosis following pterygium excision. Arch Ophthalmol 1993; 111: Hsiao CH, Chen JJY, Huang SCM, Ma HK, Chen PYF, Tsai RJF. Intrascleral dissemination of infectious scleritis following pterygium excision. Br J Ophthalmol 1998; 82: Dushku N, John MK, Schultz GS, Reid TW. Pterygia pathogenesis: corneal invasion by matrix metalloproteinase expressing altered limbal epithelial basal cells. Arch Ophthalmol 2001; 119: Barraquer RI. Part B. Chapter 1. Personal Approach to Pterygium. In: Buratto L, Phillips RL, Carito G, eds. Pterygium Surgery. Thorofare, NJ: SLACK Inc. 2000: D Ombrain A. The surgical treatment of pterygium. Br J Ophthalmol 1948; 32: Seitz B, Gutay A, Kuchle M, Kus MM, Langenbucher A. Impact of pterygium size on corneal topography and visual acuity - a prospective clinical cross-sectional study. Klin Monatsbl Augenheilkd 2001; 218: Tomidokoro A, Miyata K, Sakaguchi Y, Samejima T, Tokunaga T, Oshika T. Effects of pterygium on corneal spherical power and astigmatism. Ophthalmology 2000; 107: Stern GA, Lin A. Effect of pterygium excision on induced corneal topografic abnormalities. Cornea 1998; 17: Buratto L, Phillips RL, Carito G. Part A. Chapter 17. Technique for excision of the pterygium without scleral cover. In: Buratto L, Phillips RL, Carito G, eds. Pterygium Surgery.Thorofare, NJ: SLACK Inc., 2000: Buratto L, Phillips RL, Carito G. Part A. Chapter 3-5. Epidemiology. Etiology. Histology. In: Buratto L, Phillips RL, Carito G, eds. Pterygium Surgery. Thorofare, NJ: SLACK Inc., 2000: Kır E, Denizli L, Özkan SB, Dayanır V. Açık sklera yöntemi ile pterijium cerrahisinde erken postoperatif komplikasyonlar. T Oft Gaz 2002; 32: Ermiş SS, İnan ÜU, Öztürk F. İltihabi pterijium ve pinguekulit tedavisinde topikal indometazin ve florometolonun karşılaştırılması. T Klin Oftalmoloji 2002; 11: Hansen A, Norn M. Astigmatism and surface phenomena in pterygium. Acta Ophthalmol 1980; 58: Avisar R, Loya N, Yassur Y, Weinberger D. Pterygium Cinduced corneal astigmatism. Isr Med Assoc J 2000; 2: Lindsay RG, Sullivan L. Pterygium-induced corneal astigmatism. Clin Exp Optom 2001; 84: Cinal A, Yasar T, Demirok A, Topuz H. The effect of pterygium surgery on corneal topography. Ophthalmic Surg Lasers 2001; 32: Soriano JM, Janknecht P, Witschel H. Effect of pterygium operation on preoperative astigmatism. Prospective study. Ophthalmologe 1993; 90: Tomidokoro A, Oshika T, Amano S, Eguchi K, Eguchi S. Quantitative analysis of regular and irregular astigmatism induced by pterygium. Cornea 1999; 18: Fong KS, Balakrishnan V, Chee SP, Tan DT. Refractive change following pterygium surgery. CLAO J 1998; 24:

21 ORIGINAL RESEARCH THE EFFECT OF CHANGE OF STIMULATION FREQUENCIES ON LATENCIES, PEAK AMPLITUDES AND CENTRAL CONDUCTION TIME IN MEDIAN SOMATOSENSORY EVOKED POTENTIALS OF NORMAL SUBJECTS Hande Türker 1, Önder Us 2, Gülseren Akyüz 3, Tülin Tanrıdağ 2 1 Department of Neurology, School of Medicine, Ondokuzmayıs University, Samsun, Turkey 2 Department of Neurology, School of Medicine, Marmara University, Istanbul, Turkey 3 Department of Physical Medicine and Rehabilitation, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Objective: The nature of somatosensory evoked potential (SEP) studies of normal subjects is obviously much different from the patients. In this study our aim was to find out the effects of the change of stimulus frequencies on absolute latencies, amplitudes and central conduction time in median SEPs of normal subjects. Methods: Normal values of somatosensory evoked potentials were obtained from 30 healthy subjects (14 women and 16 men). Nerve conduction studies of each of the subjects were performed before the SEP study in order to eliminate the subclinical peripheral nerve pathologies. Results: We found that the values of N11 peak, N13 peak, N20 peak, N11-13 complex onset and N20 onset latencies and N11-13 complex amplitudes of normal subjects were affected by changes of stimulus frequencies. As the stimulation frequency increased, the latencies showed statistically significant increases while the amplitude of N11-13 complex showed a statistically very significant decrease. On the other hand, the values of peak and onset central conduction times and the amplitude of N20 did not show any statistically significant changes from each other as the stimulation frequencies increased. Conclusion: It is our belief that the studies on stimulus frequency changes in SEPs may play a role as a guide for SEP studies with different patient groups and have an impact in the physiological dynamics of SEPs. Keywords: Somatosensory evoked potentials, Median SEP, Central conduction time NORMAL KİŞİLERDE MEDYAN SOMATOSENSORİYEL UYANDIRILMIŞ POTANSİYELLERİN KAYDI SIRASINDA UYARIM FREKANSI DEĞİŞİKLİKLERİNİN LATANS, AMPLİTÜD VE SANTRAL İLETİM ZAMANINA ETKİLERİ ÖZET Amaç: Normal kişilerde medyan somatosensoriyel uyandırılmış potansiyellerin (SUP) kaydı sırasında uyarım frekansı değişikliklerinin, mutlak latanslar, amplitüd ve santral iletim zamanına etkilerinin araştırılması. Metod: Medyan somatosensoriyel uyandırılmış potansiyel kayıtları 14 ü kadın, 16 sı erkek; 30 sağlıklı bireyde yapılmıştır. Subklinik periferik sinir patolojilerini ekarte etmek için SUP kaydı öncesinde her normal bireye sinir iletim testleri yapılmıştır. Uyarım frekansı 2, 4, 6 ve 9 Hz olacak şekilde değiştirilmek suretiyle mutlak latans, amplitüd ve santral iletim zamanı parametrelerindeki değişiklikler saptanmıştır. Bulgular: N11 pik, N13 pik, N20 pik ve N11-13 kompleksi başlangıç latansları ile N20 başlangıç latansı ve N11-13 kompleksinin amplitüdü uyarım frekansı değişikliklerinden etkilenmişlerdir. Uyarım frekansı artışı ile latanslarda istatistiksel olarak anlamlı bir gecikme izlenirken; N11-13 kompleksinin amplitüdü, istatistiksel olarak anlamlı şekilde düşüş göstermiştir. Ancak pik ve başlangıç santral iletim zamanları ile N20 amplitüdünde istatistiksel olarak anlamlı değişimler izlenmemiştir. Sonuç: Normallerde somatosensoriyel uyandırılmış potansiyellerin kaydında uyarım frekansı değişikliklerine ilişkin çalışmalar, farklı hasta guruplarındaki çalışmalar için bir rehber niteliği taşırken, SUP un fizyolojik dinamiklerinin anlaşılmasında etkili olabilir. Anahtar kelimeler: Somatosensoriyel uyandırılmış potansiyeller, Medyan SUP, Santral iletim zamanı. INTRODUCTION Although the effects of frequency changes on somatosensory evoked potential (SEP) responses have been studied since the 1970 s, the results show many differences in various study groups. It Corresponding author: Hande Turker, M.D. Ondokuzmayıs University, School of Medicine, Department of Neurology Kurupelit Samsun / Turkey E- mail: [email protected] Tel Fax: may be very important to find out the differences of effects of stimulation frequencies in normal subjects and patient groups in electrophysiological diagnosis. The studies on SEP recordings in normal subjects make a good basis for SEP Marmara Medical Journal 2004;17(1);

22 Marmara Medical Journal 2004;17(1);14-21 Hande Turker, et al. The Effect of Change of Stimulation Frequencies on Latencies, Peak Amplitudes and Central Conduction Time in Median Somatosensory Evoked Potentials of Normal Subjects studies for patient groups because the increase of stimulation frequencies affect absolute latencies, amplitudes and central conduction time in different ways in various groups of patients. Studies on stimulus frequency changes in SEPs in the normal group may help explaining the physiological dynamics of SEPs. METHODS Normal values of somatosensory evoked potentials were obtained from 30 healthy subjects (14 women and 16 men). Their mean age was ± 12.9 years (range from 12 to 56). Before the study, the procedure was explained thoroughly to the subjects and each of them signed an informed consent. The study protocol was also approved by the ethic committee. Nerve conduction studies of each of the subjects were performed before the SEP study in order to eliminate the subclinical peripheral nerve pathologies. Method of median SEP study In this study, we used Medelec/Teca Sapphire II F04 / 00. Active and reference points are shown in Table I. Table I: Active and reference points of median SEP study Channel Active Reference 1 ( Erb Channel ) Ipsilateral Erb Contralateral Erb 2 ( Cervical channel ) Spinal process of fifth cervical vertebra 3 ( Scalp channel ) Five centimetres behind the point which is 7 centimetres lateral of CZ Supraglottal region Fz The stimulation was made upon the median nerve on the wrist with surface electrodes and the ground was put on the ipsilateral arm. Silver electrodes were used for recordings. High and low frequency filters were 20Hz and 2kHz respectively, sweep speed was 50msec/div, sensitivity was 20microvolts. Stimulation frequency was 2/sec in four of the subjects, in 6 of them it was 2/sec, 4/sec, 6/sec and in 20 of them it was 2/sec, 4/sec, 6/sec and 9/sec. This difference occurred because ten of the subjects could not tolerate higher stimulation frequencies. Stimulus duration was 0.1 msec and the intensity stimulus was adjusted according to the minimal contraction in thenar muscles. The recordings of stimuli were superposed. Besides the absolute latencies of N9 obtained from the Erb channel, N11-N13 complex obtained from the spinal channel and N20 obtained from the scalp channel, the amplitudes of these potentials and the interpeak latencies which are listed as follows were taken together to form the statistical results : 1) N13-N20 interpeak latency (peak central conduction time ) 2) The difference between onset latencies of N11- N13 complex and N20 onset ( onset central conduction time) SPSS (Statistical package for social sciences) for Windows 7.0 and 10 programs were used while obtaining the results and besides mean values and standard deviations, student s test was performed. RESULTS The parameters, which were studied statistically, were as follows: 1) N9 peak latency 2) N11 peak latency 3) N13 peak latency 4) N20 peak latency 5) N11-N13 complex onset latency 6) N20 onset latency 7) Peak central conduction time 8) Onset central conduction time 9) N11-13 complex amplitude (peak) 10)N20 amplitude (peak)mean values and standard deviations of every parameter were calculated and every parameter in different stimulation frequencies (2/sec, 4/sec, 6/sec, 9/sec) was compared statistically to the others. The statistical comparison of N9 peak latencies obtained with different stimulation frequencies in the normal group did not show any statistical differences (p>0.05). 15

23 Marmara Medical Journal 2004;17(1);14-21 Hande Turker, et al. The Effect of Change of Stimulation Frequencies on Latencies, Peak Amplitudes and Central Conduction Time in Median Somatosensory Evoked Potentials of Normal Subjects Table II: The statistical comparison of N9 peak latencies obtained with different stimulation frequencies in the normal group 1.frequency Mean±2.SD N9 Peak (msec) 2.frequency Mean±2.SD t+ p N9 Peak (2/s 4/s) 9.09± ± N9 Peak (2/s 6/s) 9.09± ± N9 Peak (2/s 9/s) 8.93± ± N9 Peak (4/s 6/s) 9.12± ± N9 Peak (4/s 9/s) 8.97± ± N9 Peak (6/s 9/s) 8.98± ± t test of the difference between two Table III: The statistical comparison of N11 peak latencies obtained with different stimulation frequencies in the normal group N11 Peak (msec) 1.frequency Mean±2.SD 2.frequency Mean±2.SD N11 Peak (2/s 4/s) (n=14) 10.75± ± N11 Peak (2/s 6/s) (n=15) 10.79± ± * N11 Peak (2/s 9/s) (n=12) 10.46± ± N11 Peak (4/s 6/s) (n=12) 10.90± ± N11 Peak (4/s 9/s) (n=9) 10.62± ± N11 Peak (6/s 9/s) (n=11) 10.62± ± * p< t test of the difference between two t + p In the statistical comparison of the values of N11 peak latency, values obtained with 6/sec stimulation frequency were significantly higher than the values obtained with 2/sec stimulation frequency (p< 0.05). Table IV: The statistical comparison of N13 peak latencies obtained with different stimulation frequencies in the normal group 1.frequency Mean±2.SD N13 Peak (msec) 2.frequency Mean±2.SD N13 Peak (2/s 4/s) (n=21) 12.24± ± N13 Peak (2/s 6/s) (n=21) 12.24± ± N13 Peak (2/s 9/s) (n=15) 11.93± ± ** N13 Peak (4/s 6/s) (n=21) 12.41± ± N13 Peak (4/s 9/s) (n=15) 12.13± ± * N13 Peak (6/s 9/s) (n=15) 12.22± ± **p<0.01 *p<0.05 t + p 16

24 Marmara Medical Journal 2004;17(1);14-21 Hande Turker, et al. The Effect of Change of Stimulation Frequencies on Latencies, Peak Amplitudes and Central Conduction Time in Median Somatosensory Evoked Potentials of Normal Subjects In the statistical comparison of the values of N13 peak latency, values obtained with 9/sec stimulation frequency were significantly higher than the values obtained with 2/sec stimulation frequency (p< 0.01) which were also significantly higher than the values obtained with 4/sec stimulation frequency (p< 0.05). Table V: The statistical comparison of N20 peak latencies obtained with different stimulation frequencies in the normal group 1.frequency Mean±2.SD N20 Peak (msec) 2.frequency Mean±2. SD t + p N20 Peak (2/s 4/s) (n=21) 18.03± ± ** N20 Peak (2/s 6/s) (n=21) 18.03± ± ** N20 Peak (2/s 9/s) (n=15) 17.72± ± ** N20 Peak (4/s 6/s) (n=21) 18.30± ± N20 Peak (4/s 9/s) (n=15) 18.05± ± N20 Peak (6/s 9/s) (n=15) 18.08± ± **p<0. 01 *p< t test of the difference between two In the statistical comparison of the values of N20 peak latency, values obtained with 4/sec 6/sec and 9/sec stimulation frequencies were significantly higher than the values obtained with 2/sec stimulation frequency (p<0.01). Table VI: The statistical comparison of N11-13 complex onset latencies obtained with different stimulation frequencies in the normal group N11-13 Onset (msec) 1.frequency Mean±2.SD 2.frequency Mean±2.SD N onset (2/s 4/s) (n=21) 2.51± ± N onset (2/s 6/s) (n=21) 2.51± ± * N onset (2/s 9/s) (n=15) 2.33± ± * N onset (4/s 6/s) (n=21) 2.59± ± N onset (4/s 9/s) (n=15) 2.51± ± N onset (6/s 9/s) (n=15) 2.46± ± *p< t test of the difference between two t + p In the statistical comparison of the values of N11-13 onset latency, values obtained with 6/sec and 9/sec stimulation frequencies were significantly higher than the values obtained with 2/sec stimulation frequency (p< 0.05). 17

25 Marmara Medical Journal 2004;17(1);14-21 Hande Turker, et al. The Effect of Change of Stimulation Frequencies on Latencies, Peak Amplitudes and Central Conduction Time in Median Somatosensory Evoked Potentials of Normal Subjects Table VII: The statistical comparison of N20 onset latencies obtained with different stimulation frequencies in the normal group 1.frequency Mean±2.SD N20 Onset (msec) 2.frequency Mean±2.SD N20 Onset (2/s 4/s) (n=21) 15.28± ± * N20 Onset (2/s 6/s) (n=21) 15.28± ± ** N20 Onset (2/s 9/s) (n=15) 14.88± ± ** N20 Onset (4/s 6/s) (n=21) 15.48± ± N20 Onset (4/s 9/s) (n=15) 15.11± ± N20 Onset (6/s 9/s) (n=15) 15.32± ± **p<0. 01 *p< t test of the difference between two t + p In the statistical comparison of the values of N20 onset latency, values obtained with 6/sec and 9/sec stimulation frequencies were significantly higher than the values obtained with 2/sec stimulation frequency (p<0.01) while 4/sec values were significantly higher than the values obtained with 2/sec stimulation frequency (p<0.05). Table VIII: The statistical comparison of Peak CCT obtained with different stimulation frequencies in the normal group 1.frequency Mean±2.SD Peak CCT (msec) 2.frequency Mean±2.SD t + p Peak CCT (2/s-4/s) (n=21) 5.78± ± Peak CCT (2/s-6/s) (n=21) 5.78± ± Peak CCT (2/s-9/s) (n=15) 5.77± ± Peak CCT (4/s-6/s) (n=21) 5.89± ± Peak CCT (4/s-9/s) (n=15) 5.92± ± Peak CCT (6/s-9/s) (n=15) 5.86± ± t test of the difference between two The statistical comparison of peak CCT obtained with different stimulation frequencies in the normal group did not show any statistical differences (p>0.05). 18

26 Marmara Medical Journal 2004;17(1);14-21 Hande Turker, et al. The Effect of Change of Stimulation Frequencies on Latencies, Peak Amplitudes and Central Conduction Time in Median Somatosensory Evoked Potentials of Normal Subjects Table IX: The statistical comparison of onset CCT obtained with different stimulation frequencies in the normal group 1.frequency Mean±2.SD Onset CCT (msec) 2.frequency Mean±2.SD Onset CCT (2/s-4/s) (n=21) 5.53± ± Onset CCT (2/s-6/s) (n=21) 5.53± ± Onset CCT (2/s-9/s) (n=15) 5.31± ± Onset CCT (4/s-6/s) (n=21) 5.65± ± Onset CCT (4/s-9/s) (n=15) 5.48± ± Onset CCT (6/s-9/s) (n=15) 5.56± ± t test of the difference between two t + p The statistical comparison of onset CCT obtained with different stimulation frequencies in the normal group did not show any statistical differences (p >0.05). Table X: The statistical comparison of N11-13 amplitude obtained with different stimulation frequencies in the normal group N amplitude(µv) Mean ± 2SD Frequency ± 1.78 Frequency ± 2.22 Frequency ± 1.04 Frequency ± 1.62 ** p<0. 01 Frequency 2-4 p Frequency 2-6 p Frequency 2-9 p Frequency 4-6 p Frequency 4-9 p Frequency 6-9 p ** In the statistical comparison of the values of N11-13 amplitude, values obtained with 6/sec frequencies were significantly lower than the values obtained with 2/sec stimulation frequency (p<0.01). Table XI: The statistical comparison of N20 amplitude obtained with different stimulation frequencies in the normal group N 20 amplitude(µv) Mean ± 2SD Frequency 2-4 p Frequency 2-6 p Frequency 2-9 p Frequency 4-6 p Frequency 4-9 p Frequency 6-9 p Frequency ± 1.12 Frequency ± 1.52 Frequency ± 1.20 Frequency ±

27 Marmara Medical Journal 2004;17(1);14-21 Hande Turker, et al. The Effect of Change of Stimulation Frequencies on Latencies, Peak Amplitudes and Central Conduction Time in Median Somatosensory Evoked Potentials of Normal Subjects The statistical comparison of N20 amplitude obtained with different stimulation frequencies in the normal group did not show any statistical differences (p>0.05). DISCUSSION In this study our aim was to find out the effects of the change of stimulus frequencies on absolute latencies, peak amplitudes and central conduction times in median SEPs of normal subjects in our laboratory. We found that the peak latencies of N11, N13, N20 and onset latencies of N11-13 complex and N20 as well as N11-13 complex amplitudes of normal subjects were affected by changes of stimulus frequencies. As the stimulation frequency increased, the latencies showed statistically significant increases while the amplitude of N11-13 complex showed a statistically very significant decrease. On the other hand, the values of peak and onset central conduction times and the amplitude of N20 did not show any significant changes from each other as the stimulation frequencies increased. The effects of frequency changes on SEP responses have been studied since 1970 s. In 1976 Pimmel et al. studied the effects of stimulation characteristics and level of anaesthesia on SEP responses in Rhesus monkeys and found that although the latencies did not show any changes, the amplitudes were affected by stimulus intensity, duration and stimulus frequency 1. Manzano et al. reported in one of their studies that, increasing the stimulation frequency did not change the peak central conduction time in normals whereas absolute peak and onset latencies increased 2. Somatosensory evoked potentials were obtained by electrical stimulation of the median nerve in 10 normal subjects at 3 and 30 Hz. At the higher rate of stimulation, a reduction was observed in amplitudes and prolongation of latencies of the N9, N/P13 and N20 components as well as the increase of the interpeak latency N9-N/P13. A significant increase between the onsets of the N11 and N20 components was also seen; however, no significant increase of the N/P13-N20 interpeak latency was observed. Their analysis suggested that an important reason for this last finding was related to the fact that in some cases different fast frequency components (FFC) determined the N20 peak in the different situations 2. Delberghe et al. and Huttunen et al. also studied the effects of stimulation frequency changes on spinal and cortical potentials of SEP 3,4. They assessed the influence of the stimulus frequency on short-latency SEPs recorded over the parietal and frontal scalp of 26 subjects to median nerve stimulation and 16 subjects to digital nerve stimulation. When the stimulus frequency was increased from 1.6Hz to 5.7Hz, the amplitude of N13 potential decreased as the stimulation frequency increased while there was no change in the amplitude of N20 3.We also found the same results in our study. Huttunen et al. reported the influence of varying stimulus repetition rate from 0.5 to 5 Hz on cortical SEPs up to 60-msec latency after right median nerve stimulation, separately analyzed at frontal (F3), central (C3) and parietal (P3) electrodes 4. The amplitudes of early frontal P20 and N25, central P14 and N18, and parietal N20 did not change with stimulation rate. Later deflections were significantly modified when their amplitudes were determined with respect to the baseline 4. Larrea et al. found a significant decrease in the amplitude of N20 but they did not report any changes of absolute latencies 5. They performed topographic mapping of somatosensory responses to median nerve stimulation delivered at 2, 5 and 10Hz. Parietal N20 was significantly attenuated in 10Hz somatosensory evoked potentials (SEPs), while central P22 diminished between 2 and 5 Hz, remaining stable thereafter. The single component most affected by increasing stimulus rate was N30, which abated by more than 50% in 10 Hz SEPs, as compared with basal responses. They concluded that there was no single "optimal" stimulation rate for SEP recordings and that a combination of different frequencies of stimulation should enhance the diagnostic utility of this technique 5. Abbruzzese et al. 6 studied the effects of changing the stimulus presentation rate on early parietal (N20-P25) and frontal (P22-N30) somatosensory potentials, evoked by median nerve stimulation in 15 normal subjects. Stimuli were presented at 0.1, 0.4, 1.0, 4.0 and 10/sec. Only minor latency changes, mainly for the frontal P22 component, were observed when the stimulus rate was increased up to 10/sec: while the frontal P22-N30 complex was more rapidly and severely reduced in amplitude than the parietal N20-P25 complex. In their opinion, the differential effects of stimulus presentation rate on early frontal and parietal SEPs supported the hypothesis of separate neural generators and suggested that the choice of the stimulation frequency may be critical for the interpretation of diagnostic SEP studies 6. Pelosi et al. 7.found that the increase in stimulation frequency did not 20

28 Marmara Medical Journal 2004;17(1);14-21 Hande Turker, et al. The Effect of Change of Stimulation Frequencies on Latencies, Peak Amplitudes and Central Conduction Time in Median Somatosensory Evoked Potentials of Normal Subjects affect the spinal responses but it caused a decrease of amplitude in cortical responses of SEP. The effect of variation in the stimulus frequency on spinal and cortical somatosensory evoked potentials to common peroneal nerve stimulation at the knee (CPN-K) and tibial nerve stimulation at the ankle (TN-A) were studied in 11 healthy subjects. Six stimulus frequencies, 0.7, 1.5, 3.0, 5.0, 7.0 and 10.0 Hz, were used in random order. With increasing stimulus rate spinal responses remained unchanged. By contrast, early cortical responses became significantly reduced in amplitude or undetectable for stimulation frequencies above 3.0 Hz for the CPN-K and 5.0 Hz for the TN-A. In 2 subjects the configuration and the latency of CPN-K SSEPs were affected by stimulus frequency. Similar changes were not observed in TN-A SSEPs 7. In our study we observed changes of amplitude and latency in different parameters with different stimulation frequencies. However, we did not find any change in peak and onset central conduction times. This last finding was not assessed in the studies mentioned above. It is important because it can be used with different patient groups where central conduction time is expected to rise. The reason for differences of effects of stimulation frequencies on different SEP parameters of normal subjects was not understood very clearly and is still debated. We believe that studies on SEP recordings in normal subjects make a good basis for SEP studies for patient groups. We think that results may be different for various groups of patients and thus we can use this point for various groups of patients where we expect central conduction time changes. Increasing stimulus frequency may be practical in routine SEP studies for obtaining reliable results in various patient groups suspected of having central conduction time changes. As far as other studies are concerned, it is quite clear that the amount of increase in stimulus frequency affects the results and this is most significant in the changes of the amplitudes. We believe this is what leads to different results in different studies. It is also our belief that the studies on stimulus frequency changes in SEPs in the normal group may be of great help in understanding the physiological dynamics of SEPs. REFERENCES 1. Pimmel RL, Hung N, Bresnahan J. Effects of anesthesia level and stimulus characteristics on the amplitude and latency of the somatosensory evoked response in monkeys. J Neurosci Res 1976; 2: Manzano GM, De Navarro JM, Nobrega JA. Short latency median nerve somatosensory evoked potential (SEP): Increase in stimulation frequency from 3 to 30 Hz. Electroenceph Clin Neurophysiol 1995; 96: Delberghe X, Mavroudakis N, Zegers de Beyl D, Bruriko E. The effect of stimulus frequency on post and precentral short latency somatosensory evoked potentials (SEP). Electroenceph Clin Neurophysiol 1990; 77: Huttunen J, Homberg V. Influence of stimulus repetition rate on cortical somatosensory potentials evoked by median nerve stimulation:implication for generation mechanisms. J Neurol Sci 1991; 105: Larrea GL, Bastuji H, Mauguiere F. Unmasking of cortical SEP components by changes in stimulus rate : A topographic study. Electroenceph Clin Neurophysiol 1992; 84: Abbruzzese G, Dall'Agata D, Morena M. Selective effects of repetition rate on frontal and parietal somatosensory evoked potentials (SEPs). Electroenceph Clin Neurophysiol Suppl 1990; 41: Pelosi L, Balbi P, Caruso G. The effect of stimulus frequency on spinal and scalp somatosensory evoked potentials to stimulation of nerves in the lower limb. Electroenceph Clin Neurophysiol 1990; 41(Suppl.):

29 ORIGINAL RESEARCH THE COMBINATION OF NORMAL SALINE AND LACTATED RINGER'S SOLUTION FOR LARGE INTRAVASCULAR VOLUME INFUSION Zeynep Eti, Arzu Takıl, Tümay Umuroğlu, Pınar Irmak, F.Yılmaz Göğüş Department of Anesthesiology, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Objective: The aim of this study was to evaluate the perioperative effects of large intravascular volume infusion of both normal saline (NS) and lactated Ringer's (LR) solution on electrolytes and acid base balance. Materials and Methods: In 20 patients, aged between years, undergoing major spine surgery, ASA I-II NS and LR solutions were infused at the rate of 20 ml.kg -1.h -1 peroperatively and 2.5 ml.kg -1.h -1 postoperatively by switching between the two solutions every other liter. Mean arterial pressure, heart rate, oxygen saturation, end-tidal carbondioxide pressure, central venous pressure, esophageal temperature were recorded every 15 minutes and crystalloid infusion volumes, urinary output, blood loss, and blood transfusion volumes were recorded hourly peroperatively. Electrolytes (Na +,K +,Cl - ) and arterial blood gases were measured preoperatively, every hour peroperatively and at the 1 st, 2 nd, 4 th, 6 th, 8 th, 12 th, 16 th, 20 th and 24 th hours postoperatively. Results: Arterial ph, HCO 3 and base excess values decreased and serum Cl- values increased significantly peroperatively. Arterial CO2 pressure increased significantly at peroperative 6 th h (p0.05). Conclusion: The combination of NS and LR solutions causes not only hyperchloremic acidosis peroperatively but also a mixed acidosis postoperatively. Keywords: Normal saline, Lactated Ringer's solution, Hyperchloremic acidosis YÜKSEK VOLÜMDE % 0.9 SERUM FİZYOLOJİK VE LAKTATLI RINGER SOLÜSYONLARININ BİRLİKTE KULLANIMI ÖZET Amaç: Yüksek volümde % 0.9 serum fizyolojik (SF) ile hiperkloremik metabolik asidoz ve hipernatremi, ringer laktat (RL) infüzyonu ile de postoperatif asidoz ve hafif hiponatremi geliştiği gösterilmiştir. Bu çalışmada, major vertebra cerrahisinde, yüksek volümde SF ve RL solüsyonlarının birlikte kullanımının elektrolit ve asit baz dengesi üzerine etkilerinin belirlenmesi amaçlanmıştır. Gereç ve Yöntem: Elektif vertebra cerrahisi geçirecek, ASA I-II, yaş arasında 20 hasta çalışmaya alındı. 5 mg/kg tiyopental ve 0.1 mg/kg vekuronyum bromid ile indüksiyon sonrası anestezi idamesi % 70 N 2 O içinde oksijen ve 2 MAC sevofluran ile sağlandı. Tüm hastalara SF ve RL her 1 litrede değiştirilerek peroperatif dönemde 20 ml/kg/s, postoperative dönemde 2.5 ml/kg/s hızla verildi. Tüm hastalarda ortalama arter basıncı, kalp atım hızı, SpO 2, ETCO 2, CVP, vücut sıcaklığı, idrar miktarı, kristalloid miktarı, kan kaybı ve kan transfüzyon miktarları 30 dakika ara ile kayıt edildi. Preop, perop 1 saat ara ile ve postop 0, 1, 2, 4, 6, 6, 12, 16, 20 ve 24.saatlerde arteryel kan gaz ve elektrolit değerleri (Na +, K +, Cl - ) ölçüldü. Elde edilen veriler tek yönlü ANOVA ve Tukey- Kramer testleri ile istatistiksel olarak karşılaştırıldı (p<0.05). Bulgular: Arteryel ph, HCO 3 - ve baz fazlalığı değerlerinde peroperatif belirgin azalma ve serum klor değerlerinde belirgin artış saptandı. Serum sodyum ve potasyum değerlerinde değişiklik saptanmadı. Arteryel pco 2 değerleri intraoperatif 6.saatte belirgin artış gösterdi. Hemodinamik parametreler, PaO 2, SpO 2, SaO 2, ETCO 2, CVP, kan kaybı, kan transfüzyonu ve hemoglobin konsantrasyonları açısından istatistiksel fark saptanmadı. Sonuç: Yüksek volümde SF ve RL solüsyonlarının birlikte kullanımı hiperkloremik metabolik asidoz gelişimini engelleyememesinin yanı sıra karbondioksit değerlerinde artış ile asidozun artmasına neden olmaktadır. Major cerrahi girişimlerde, yüksek volümde SF ve RL solüsyonlarının birlikte kullanımının sadece SF veya RL kullanımına göre bir üstünlük sağlamadığı sonucuna varılmıştır. Anahtar Kelimeler: Serum fizyolojik, Laktatlı Ringer Solüsyonu, Hiperkloremik asidoz Corresponding author: Zeynep Eti MD, Marmara University Hospital, Department of Anesthesiology Tophanelioğlu cad. No: 13-15, Altunizade, IstanbulTelephone: Fax: [email protected] Marmara Medical Journal 2004;17(1);

30 Marmara Medical Journal 2004;17(1);22-27 Zeynep Eti, et al, The combination of normal saline and lactated ringer's solution for large intravascular volume infusion INTRODUCTION Beyond all technological developments in anesthesiology, perioperative fluid management during surgery is a major problem. Crystalloids are the main and the first step fluids to supply hemodynamic stability for normovolemia when large fluid and blood loss occur during major surgery 1. Normal saline (NS) and lactated Ringer's (LR) solutions are the most commonly used crystalloids because of their similarity with human plasma. However, published data showed that hyperchloremic metabolic acidosis occurs in the course of large NS infusion 1-7. In our previous study comparing the effects of large volume infusion of NS and LR, we concluded that although LR infusion did not cause hyperchloremic metabolic acidosis as did NS, it did lead to postoperative respiratory acidosis and mild hyponatremia. As none of these solutions seemed to be the ideal choice to supply hemodynamic stability during major surgery, we hypothesized that a combination of the two (switching between the two solutions every other liter) may be a better alternative. The aim of this study was to evaluate the effects of the combination of NS and LR solutions on acid base balance and electrolytes during major spine surgery by switching between the two solutions every other liter. METHODS After Institutional Ethics Committee approval and the patients' written consent, were obtained 20 patients, ASA physical status I and II, aged between yrs, undergoing elective major spine surgery (Cotrel Dubousset posterior spinal instrumentation) were enrolled in the study. The patients were premedicated with atropine 0.5 mg and midazolam 0.07 mg/kg IM preoperatively. General anesthesia was induced with thiopental sodium at the rate of 5mg/kg and vecuronium bromide 0.1 mg/kg IV. After endotracheal intubation, anesthesia was maintained with oxygen in 70% nitrous oxide and 1.5%-2% sevoflurane. The patients were ventilated mechanically to maintain PaCO2 as close as possible to 40 mmhg. The combination of NS and LR solutions were infused 20 ml.kg -1.h -1 intraoperatively and 2.5 ml.kg -1.h -1 for postoperative 24 hours by switching between the two solutions every other liter. Patients with over 20% blood loss were given blood transfusions. 500 ml of colloid solution (Gelofusine) was administered for the first 500 ml blood loss. Intraoperative monitoring included continuous monitoring of mean arterial pressure, heart rate, oxygen saturation, endtidal carbondioxide pressure, central venous pressure and esophageal temperature in all patients. The values were recorded every 15 minutes. Crystalloid infusion volumes, urinary output, blood loss, and blood transfusion volumes were recorded hourly. Electrolytes (Na +,K +,Cl - ) and arterial blood gases were measured preoperatively, every hour peroperatively and at the 1 st,2 nd,4 th,6 th,8 th,12 th,16 th,20 th and 24 th hours postoperatively. Serum albumin and total protein concentrations were measured and anion gaps (Na-[Cl+HCO3]) were calculated preoperatively and at the end of the surgery. IV patient-controlled analgesia with morphine was administered to all patients. All measured data were compared with two-way repeated measures of analyses of variance and post-hoc testing was performed by the Tukey-Kramer test statistically. Student's t test was performed for unpaired data and a p<0.05 was considered significant. RESULTS In Table I demographic data of the patient characteristics and duration of the surgery and in Table II the NS and LR infusion volumes, urinary output, total blood loss and blood transfusion volumes were presented. There was no significant difference between the infusion volumes of NS and LR (p>0.05). 23

31 Marmara Medical Journal 2004;17(1);22-27 Zeynep Eti, et al, The combination of normal saline and lactated ringer's solution for large intravascular volume infusion Table I: Demographic characteristics and duration of surgery Age (year) 47 ± 20 (20-70) Body weight (kg) 61 ± 13 (41-80) Duration of surgery (min) 326 ± 70 ( ) ASA classification 1.4 ± 0.5 (I and II) Values are mean ± SD (ranges) Table II: Intraoperative crystalloid volume, blood loss and blood transfusion volume, urinary output Normal saline solution (ml) 2843 ± 913 ( ) Lactated Ringer s solution (ml) 2575 ± 914 ( ) Blood loss (ml) 2286 ± 1091 ( ) Blood transfusion volume (ml) 1854 ± 697 ( ) Urinary output (ml) 494 ± 381 ( ) Values are mean ± SD (ranges) Serum sodium concentrations did not change significantly intraoperatively and postoperatively (Table III). Serum chloride concentrations increased significantly at the 4 th hour intraoperatively and persisted until the 6 th hour postoperatively (Table III). Serum potassium concentrations decreased significantly during the first two hours intraoperatively (Table III). Table III: Serum sodium, chloride and potassium concentration SODIUM CHLORIDE POTASSIUM (meq/l) (meq/l) (meq/l) Preoperative 140±2 108±5 4.4±0.4 Intraoperative 1 141±2 113±4 3.7± ±2 115±4 3.8±0.4* 3 141±3 116±4 4.0± ±3 120±8 4.0± ±3 121±9 3.8± ±2 120±6 4.7±1.2 Postoperative 1 141±3 119±8 4.0± ±3 117±8* 4.0± ±3 117±8* 4.0± ±3 116±6 4.0± ±4 115±7 4.0± ±3 113±6 4.0± ±3 113±7 3.8± ±4 110±4 3.8± ±6 110±5 3.8±0.3 Values are mean ± SD *P<0.05 and ** P<0.01 compared with preoperative values 24

32 Marmara Medical Journal 2004;17(1);22-27 Zeynep Eti, et al, The combination of normal saline and lactated ringer's solution for large intravascular volume infusion Arterial ph values decreased significantly at the 3 rd hour intraoperatively and persisted until the 16 th hour postoperatively (Table IV). Bicarbonate concentrations decreased significantly at the 1 st hour intraoperatively and returned to preoperative values at the 8 th hour postoperatively (Table IV). Base excess values decreased significantly at the 2 nd hour intraoperatively and persisted until the 12 th hour postoperatively (Table IV). Table IV: pha values, bicarbonate concentration and base deficit values pha Bicarbonate (meq/l) Base deficit Preoperative 7.40± ± ±1.3 Intraoperative ± ±1.5** -3.1± ± ±1.0** -3.6±1.3* ± ±1.6# -5.1±1.8** ±0.03** 19.7±1.4# -5.8±1.5** ±0.04** 19.4±2.1# -6.3±2.4# ±0.05** 20.5±0.8** -6.2±0.5# Postoperative ±0.06# 20.1±1.9# -6.4±2.6# ±0.06# 20.7±2.0* -5.8±2.9# ±0.06# 21.3±2.0* -4.9±2.6** ±0.05# 21.6±1.6* -4.3±2.0** ±0.04# 22.1± ±2.0* ±0.05** 22.2± ± ± ± ± ± ± ± ± ± ±1.6 Values are mean±sd p<0.05, p<0.01 and # p<0.001 compared with preoperative values Arterial PCO 2 values increased significantly at the 6 th hour intraoperatively and returned to preoperative values at the 12 th hour postoperatively. Arterial PO 2 and SO 2 values increased significantly at the 1 st hour intraoperatively and persisted until the 16 th hour postoperatively (Tablo V). 25

33 Marmara Medical Journal 2004;17(1);22-27 Zeynep Eti, et al, The combination of normal saline and lactated ringer's solution for large intravascular volume infusion Table V: PaCO 2,PaO 2 and SaO 2 values (mmhg) (mean±sd) PaCO 2 PaO 2 SaO 2 Preoperative 37.5± ± ±1.9 Intraoperative ± ±30.1# 99.3±0.4# ± ± ±0.7# ± ± ± ± ± ± ± ± ± ±6.4* 152.7± ±0.7 Postoperative ±4.2* 145.3± ± ±4.0* 146.6± ± ±4.2* 153.9± ± ±3.9* 160.7± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±1.4 Values are mean±sd p<0.05, p<0.01 and # p<0.001 compared with preoperative values Albumin concentration (from 4.06±0.57 to 2.42±0.57 g/dl) and anion gap (from 7.4±4.0 to (3.7±5.7 meq/l) decreased significantly at the end of surgery (p<0.001). No significant differences were observed in hemodynamic parameters (mean arterial pressure, heart rate), end-tidal carbon dioxide pressure, central venous pressure, body temperature and hemoglobin concentration. DISCUSSION The main result of this study was that the combination of large intravascular volume infusions of NS and LR changing the two solutions every other liter caused hyperchloremic metabolic acidosis intraoperatively as well as mixed acidosis postoperatively. Hyperchloremic metabolic acidosis developing after large intravascular volumes of NS has been described in many clinical studies 1-7. However the etiology and clinical relevance of this acidosis remain controversial. Some investigators called this dilutional acidosis suggesting that the mechanism was a dilutional reduction of plasma bicarbonate concentration whereas others explained it by the Steward model, emphasizing the importance of hyperchloremia resulting in a reduction of the strong ion difference (SID). In our previous study comparing the effects of large 26

34 Marmara Medical Journal 2004;17(1);22-27 Zeynep Eti, et al, The combination of normal saline and lactated ringer's solution for large intravascular volume infusion volume infusion of NS and LR, we concluded that although large volume infusion of LR did not cause hyperchloremic metabolic acidosis as NS did, it led to postoperative respiratory acidosis and we suggested that the combination of NS and LR may be a better strategy as the removal of lactate as a bicarbonate precursor from the circulation would increase the SID and reduce acidosis 2. Also the metabolic acidosis caused by NS could stimulate ventilation and compensate the carbondioxide load. However, in this study we found that the combination of NS and LR caused an increase in serum chloride concentration and a decrease in bicarbonate concentration, resulting in intraoperative hyperchloremic metabolic acidosis. The addition of LR infusion did not prevent metabolic acidosis but it led to an increase in arterial carbondioxide pressure, resulting in a postoperative mixed acidosis. Although the mean postoperative arterial carbondioxide pressures were not higher than 45 mmhg in our patients, in four patients the values were found to be higher than 50 mmhg. One of the main differences in our two studies is that at the end of surgery there was a significant decrease in albumin concentration and anion gap in this study. The decrease in anion gap resulting from increased chloride and decreased bicarbonate concentration supports hyperchloremia as the main mechanism of metabolic acidosis. According to the Steward model, the major determinant of hydrogen concentration in the body is the SID and a significant hyperchloremia decreasing SID is associated with a metabolic acidosis 6. Also Figge et al 8 demonstrated that a reduction in serum albumin of 1 g/dl reduced the anion gap by 2.5 meq/l. It is obvious that acute dilutional hypoalbuminemia accompanied with rapid crystalloid infusion also reduced the anion gap 3. Besides, in vitro data showed a linear correlation between albumin and bicarbonate concentration 9. According to this information, the mechanism of metabolic acidosis associated with large intravascular infusion of NS can be explained by hyperchloremia but also the decrease in bicarbonate concentration. As a result we conclude that using 20 ml.kg -1.h -1 infusion of NS and LR in combination changing the solutions every other liter, causes hyperchloremic metabolic acidosis peroperatively and a mixed type acidosis (metabolic and respiratory) postoperatively after major spine surgery. We do not recommend using crystalloids instead of NS alone in a combination during major surgery. REFERENCES 1. Boldt J. New light on intravascular volume replacement regimens: What did we learn from the past three years? Anesth Analg 2003; 97: Takıl A, Eti Z, Irmak P, et al. Early postoperative respiratory acidosis after large intravascular volume infusion of lactated Ringer's solution during major spine surgery. Anesth Analg 2002; 95: Scheingraber S, Rehm M, Schmisch C, et al. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology 1999; 90: Blanloeil Y, Roze B, Rigal JC, et al. Hyperchloremic acidosis during plasma replacement. Ann Fr Anesth Reanim 2002; 21: Waters JH, Miller LR, Clack S, et al. Cause of metabolic acidosis in prolonged surgery. Crit Care Med 1999; 27: Rehm M, Conzen PF, Peter K, et al. The Stewart model. Modern approach to the interpretation of the acid-base metabolism. Anaesthesist 2004; 53: Miller LR, Waters JH, Provost C. Mechanism of hyperchloremic metabolic acidosis. Anesthesiology 1996; 84: Figge J, Jabor A, Kazda A, et al. Anion gap and hypoalbuminemia. Crit Care Med 1998; 26: Rossing TH, Maffeo N, Fencl V. Acid-base effects of altering plasma protein concentration in human blood in vitro. J Appl Physiol 1986; 61:

35 CASE REPORT DELAYED INTRACEREBRAL HEMORRHAGE AFTER VENTRICULOPERITONEAL SHUNTING Selçuk Peker, Koray Özduman, Serdar Özgen, M.Necmettin Pamir Marmara University Department of Neurosurgery, Marmara University Neurological Sciences Institute, Istanbul, Turkey ABSTRACT Delayed intracerebral hemorrhage after ventriculoperitoneal shunt insertion is a rare complication. Here in we report the case of an 83-year-old female patient with a left posterior cerebral artery aneurysm and hydrocephalus. A hemorrhage at site of insertion was diagnosed on the postoperative day 4 after ventriculoperitoneal shunt insertion. The causative factor in our patient was probably the disruption of an intracerebral vessel by the ventricular catheter which was initially tamponaded by the intraparenchymal pressure, but later became manifest as the shunt became functional. Keywords: Intracerebral hemorrhage, Shunt complication, Ventriculoperitoneal shunt VENTRİKÜLOPERİTONEAL ŞANT TAKILMASINI TAKİBEN GEÇ DÖNEMDE GELİŞEN İNTRASEREBRAL HEMATOM ÖZET Ventriküloperitoneal şant takılmasını takiben geç dönemde intraserebral hematom gelişmesi oldukça nadir görülür. Bu yazıda sol posterior serebral arter anevrizması ve hidrosefalisi olan 83 yaşında bir bayan hastada, şant takılmasını takiben 4. günde ortaya çıkan intraserebral hematom komplikasyonu bildirilmektedir. Bu olguda kanamanın nedeninin şant kateterinin arteriosklerotik damar duvarını zedelemesi ve buna bağlı damar duvarındaki harabiyet olduğu düşünülmüştür. Anahtar Kelimeler: İntraserebral kanama, Şant komplikasyonu, Ventriküloperitoneal şant INTRODUCTION Ventriculoperitoneal shunt placement is a routine procedure in daily neurosurgical activity. It is usually a simple and straightforward procedure. Intracranial hemorrhage is very rare after shunt insertion. The literature data shows that most of the cases had early hemorrhages soon after the surgery, but late or delayed intracerebral hemorrhages are very rare. We report an unusual case with delayed intracerebral hematoma after a shunting procedure. Literature is reviewed and the causative factors are discussed. Corresponding author: Dr.Selcuk Peker P.K Kadıköy Istanbul, Turkey Tel: Fax: [email protected] 28 CASE REPORT An 83-year-old woman presented with one-yearhistory of dizziness. On admission, she had headache and nausea with a blood pressure of 170/80 mmhg. Neurological examination revealed slight ataxia. A CT scan of the head with and without contrast demonstrated enlarged lateral and third ventricles and a left-sided hyperdense, slightly calcified 1.5x2 cm mass at the tentorial notch (Fig. 1). MR angiogram showed that this was a left posterior cerebral artery saccular aneurysm (Fig. 2). Marmara Medical Journal 2004;17(1);28-31

36 Marmara Medical Journal 2004;17(1);28-31 Selçuk Peker, et al. Delayed intracerebral hemorrhage after ventriculoperitoneal shunting Fig 1: Contrast enhanced CT scan shows t: calcified round mass at the tentorial edge. Fig 2: MR Angiogram reveals a left PCA aneurysm Endovascular interventional treatment of this vascular pathology was denied by the patient and her family. A new CT examination on the 2nd day showed increased hydrocephalus. Ventriculoperitoneal shunting was performed on same day without complication. The ventricular catheter was inserted in to the frontal horn through a right frontal burrhole. The cerebrospinal fluid was clear with a pressure of 220 mmh 2 O. The catheter was connected to a medium pressure valve. A control CT was performed immediately after the surgery and no hemorrhage was seen (Fig. 3). The tip of the ventricular catheter was in appropriate place. Postoperatively the patient was also well initially. On postoperative day 4, she developed a generalized seizure and decreased conscious level. A CT scan showed intracerebral hemorrhage around the ventricular catheter and mild intraventricular hemorrhage (Fig. 4). Her blood pressure was stable at 160/80mmHg. After the incident the tests for coagulation defects were repeated and no abnormality was found. Her clinical condition got worse over the following days. She eventually developed aspiration pneumonia and expired on the postoperative 18 th day. Fig 3: CT in the postoperative early period Fig 4: CT in the postoperative fourth day. Blood is visualized around ventricular catheter 29

37 Marmara Medical Journal 2004;17(1);28-31 Selçuk Peker, et al. Delayed intracerebral hemorrhage after ventriculoperitoneal shunting DISCUSSION Ventricular shunting operations are among the most frequently performed neurosurgical procedures 1. Obstruction or blockage of the ventricular and abdominal ends of the tubing and infection are the most common complications 2. Small hemorrhages in the ventricles, in the subependymal area and around the ventricular catheters are relatively frequently seen 3. The reason for these early hemorrhages is almost always trauma of the catheter insertion 1-6. A late or delayed hemorrhage at the site of the ventricular catheter is very rare. There are only some case reports in the literature 1-6. As an early complication, Udvarhelyi et al. 7 first reported two cases with intracerebral hemorrhage after ventriculoperitoneal shunt insertion. Sayers 8 reported six cases of intracerebral hemorrhage among 1390 shunted cases. Matsumura et al 6 reported the first case with CT pictures of delayed intracerebral hemorrhage after shunting. In our institution all patients with ventricular shunt insertions, undergo a control CT scan few hours after the of surgery. We had some patients with small hemorrhages around the catheter or in the ventricles, but none of them presented any clinical significance. We had only one patient with delayed intracerebral hemorrhage. There are some possible mechanisms for intracerebral hemorrhages after shunt insertion; a bleeding disorder, antiaggregant or anticoagulant therapy, surgery induced disseminated intravascular coagulation, disruption of an intracerebral vessel by the catheter, hemorrhage into an intracerebral tumor, hemorrhage from a vascular malformation or spontaneous vascular rupture secondary to progressive degenerative vascular changes 1-6. In the preoperative period all the laboratory tests were performed to discover any coagulation defects. The medications such as warfarin Na or acetylsalicylic acid were discontinued one week before the surgery. Because of these reasons it is very unlikely for these factors to be a causative factor. Disseminated intravascular coagulation (DIC) has been described after head trauma, operation for brain tumor and after ventriculoperitoneal shunt insertion 1. The proposed mechanism for DICinduced hemorrhage in these instances is release of brain thromboplastin as well as other substances found in the choroid plexus and meninges that act like plasminogen activators 1. Hemorrhage into a cerebral tumor or hemorrhage due to a vascular malformation can also be seen in shunted patients. However, none of these seemed to be the causative factor in our patient. The disruption of an intracerebral vessel by the catheter or spontaneous vascular rupture secondary to progressive degenerative vascular changes appears to be the most likely mechanisms. 1 Snow reported a case of idiopathic hydrocephalus with delayed hemorrhage. The hemorrhage was found at the catheter insertion site on the postoperative 5 th day. The author concluded that the normal pulsations of the cerebrospinal fluid transmitted to the ventricular catheter may have helped the catheter to erode a blood vessel with subsequent intracerebral hemorrhage. This mechanism may have been the reason in our patient too. Savitz 2 reported five patients with delayed hemorrhages and he suspected of the same mechanism. 5 Mascalchi reported a patient who had a hemorrhage 14 days after the shunt insertion. As a causative factor, changes in the intracranial and interstitial pressures heading to parenchymal or intravascular pressure changes in a hypertensive patient were suggested. Yet if this mechanism was operational, hemorrhage could have occurred in any part in the brain. Indeed in most of the patients delayed intracerebral hemorrhages were seen around the ventricular catheter. Bavbek and Göksel 3 reported a patient which has been shunted after posterior fossa tumor surgery. Their patient had multiple hematomas on the postoperative 18 th day. These authors suspected from the decompressive surgeries and prolonged increased intracranial pressure in their patient. 9 Woollam and Millen showed that in nontraumatic conditions, the hypoxia of the endothelial cells may lead to perivascular hemorrhage. At the insertion site, the traumatic edema of the cerebral tissue may cause this hypoxia. We conclude that the mechanism of bleeding in our patient might be the disruption and irritation of the arteriosclerotic small diameter arteries of the brain near the catheter. The disruption was probably initially tamponaded by the high intraparenchymal pressure. 30

38 Marmara Medical Journal 2004;17(1);28-31 Selçuk Peker, et al. Delayed intracerebral hemorrhage after ventriculoperitoneal shunting Delayed intracerebral hemorrhage after ventricular shunting is rare. The mechanism is not clear, but the surgeon must be aware of this complication. REFERENCES 1. Snow RB, Zimmerman RD, Devinsky O. Delayed intracerebral hemorrhage after ventriculoperitoneal shunting. Neurosurgery 1986; 19: Savitz MH, Bobroff LM. Low incidence of delayed intracerebral hemorrhage secondary to ventriculoperitoneal shunt insertion. J Neurosurg 1999; 91: Bavbek M, Göksel M. Multiple delayed intracerebral hematoma after ventriculoperitoneal shunting. Turk Norosirurji Dergisi (in Turkish) 1997; 7: Kubokura T, Nishimura T, Koyama S. Delayed intracerebral hemorrhage following VP shunt operation. No Shinkei Geka 1988; 16(5 suppl): Mascalchi M. Delayed intracerebral hemorrhage after CSF shunt for communicating normalpressure hydrocephalus. Case report. Ital J Neurol Sci 1991; 12: Matsumura A, Shinohara A, Munekata K, Maki Y. Delayed intracerebral hemorrhage after ventriculoperitoneal shunt. Surg Neurol 1985; 24: Udvarhelyi GB, Wood JH, James AE, Bartelt D. Results and complications in 55 shunted patients with normal pressure hydrocephalus. Surg Neurol 1975; 3: Sayers MP. Shunt complications. Clin Neurosurg 1976; 23: Woollam DH, Millen JW. Vascular tissue in the central nervous system. In: Mickler J, editor. Pathology of the central nervous system, Vol. 1. New York: McGraw-Hill 1968:

39 CASE REPORT BILATERAL ELASTOFIBROMA DORSI: A RARE SOFT TISSUE TUMOR Mehmet Oğuzhan Özyurtkan, Sevgi Güler, Bedrettin Yıldızeli, Hasan F.Batırel, Mustafa Yüksel Department of Thoracic Surger, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Elastofibroma, a rare, noncapsulated benign lesion usually arising beneath the rhomboid major and latissimus dorsi muscles subjacent to the inferior angle of the scapula. Recognition of the lesion is important as the differential diagnosis includes other benign and also malignant tumors. A 71- year-old woman was presented with a three year history of mild back pain and bilateral infrascapular swellings. Thorax computed tomography (CT) revealed two poorly circumscribed, heterogenous masses bilaterally located at the infrascapular areas, and magnetic resonance imaging (MRI) confirmed the bilateral involvement. Both masses were excised and diagnosed as elastofibroma. Lesions located deep beneath the inferior tip of the scapula should arouse suspicion of an elastofibroma. Keywords: Elastofibroma, Soft tissue tumors, Surgery BİLATERAL ELASTOFİBROMA DORSİ: NADİR GÜRÜLEN YUMUŞAK DOKU TÜMÖRÜ ÖZET Elastofibroma, genelde skapulanın alt ucuna yakın ve rhomboid ile latissimus dorsi kaslarının altında yerleşen nadir, kapsülsüz benign bir lezyondur. Lezyonun bilinmesi, diğer malin ve benign lezyonlar arasında ayırıcı tanıda yer alması açısından önemlidir. Yazıda üç yıldır hafif şiddetli sırt ağrısı ve bilateral infraskapular şişliği olan 71 yaşındaki bayan hasta sunulmuştur. Lezyonların bilgisayarlı toraks tomografisi ve magnetik rezonans görüntülenmesinde bilateral ve sınırları tam düzgün olmayan heterojen kitleler şeklinde oldukları görülmüştür. Cerrahi olarak eksize edilen lezyonların patolojik tanısı elastofibroma dorsi şeklindedir. Skapulanın alt ucunda, kas tabakalarının altında yerleşen lezyonlarla karşılaşıldığında elastofibroma akla gelmelidir. Anahtar kelimeler: Elastofibroma, Yumuşak doku tümörleri, Cerrahi INTRODUCTION Elastofibroma, a rare, noncapsulated benign entity, first described by Jarvi and Saxen in 1961, is characterized by the proliferation of fibrous tissue with elastin and occurs most often in the infrascapular area of elderly women 1. This lesion usually arises beneath the rhomboid major and latissimus dorsi muscles subjacent to the inferior angle of the scapula, and it adheres densely to muscle, periosteum of ribs, and scapula like a malignant lesion 2. It often presents as a nontender mobile mass 3. Recognition of the lesion is important as the differential diagnosis includes other benign and also malignant tumors 4. Corresponding author: Mustafa Yüksel, MD, Marmara Üniversitesi Hastanesi Göğüs Cerrahisi Aanabilim Dalı PK Acıbadem, İstanbul, Türkiye. Telefon: , Faks: , [email protected] Marmara Medical Journal 2004;17(1);

40 Marmara Medical Journal 2004;17(1);32-34 Mehmet Oğuzhan Özyurtkan, et al. Bilateral elastafibroma dorsi: A rare soft tissue tumor We herein report a case of a 71-year-old woman with bilaterally located elastofibroma dorsi, presenting with mild pain and a clicking or catching sensation with the arm motion. CASE REPORT A 71-year-old woman was admitted to our hospital with a three year history of mild back pain. The pain was described as a dull ache of gradual onset, around the infrascapular area bilaterally, which was worse on movement of the arm. Over the last two years, she has noticed two infrascapular swellings which would appear and disappear with movement of the arms. She had no other medical history except for a history of diabetes mellitus and hyperlipidemia, both under control with adequate medications. Physical examination revealed two palpable masses, measuring about 6x6cm on the left, and 5x4 cm on the right, located at the both infrascapular areas. There was a full range of movement of both shoulders with no neurological signs. Pain was reproduced mostly around the left shoulder when the arm was circumducted. Initial investigations showed a normal full blood count, bone profile, and inflammatory markers. Chest roentgenogram presumed an extrathoracic mass and CT revealed two poorly circumscribed, heterogenous masses bilaterally located at the infrascapular areas (Fig.1, and Fig.2). MRI confirmed the bilateral involvement of the infrascapular soft tissue tumor (Fig.3, and Fig.4). The signal intensity in both lesions were similar to that of skeletal muscle interlaced with strands of fat. Fig 1: CT scan of the patient. Uncapsulated soft tissue seen beneath left latissmus dorsi muscle (arrow) Fig 3: MRI of the patient. Mass on the left posterolateral chest wall with marked signal enhancement after contrast injection (arrow) Fig 2: Ct scan of the patient. Arrow indicates a soft tissue density at the right infrascapular area. Fig 4: MRI of the patient. Another mass on the right side of the chest wall, containing both fibrous and fatty tissue (arrow) 33

41 Marmara Medical Journal 2004;17(1);32-34 Mehmet Oğuzhan Özyurtkan, et al. Bilateral elastafibroma dorsi: A rare soft tissue tumor The surgical approach included bilateral posterolateral incisions made over the lesion with the arms positioned to expose the mass under general anesthesia. A firm, rubbery, nonencapsulated, malignant tumor-like lesion measuring 8x7x4 cm was observed under the left latissimus dorsi muscle. The tumor was not attached to the periosteum of the underlying ribs, but was densely adherent to the striated muscle. Frozen section of the incisional biopsy disclosed a benign tumor rich from collagen fibers. Then, the mass on the right, measuring 6x6x3 cm, sharing similar features like the left one, was excised with sharp and blunt dissection. On histologic examination with hematoxylen-eosin staining, the tumors showed eosinophilic collagen and elastic fibers with aggregates of mature fat cells. Both masses were diagnosed as elastofibroma. The postoperative course of the patient was uneventful. She was discharged on the third postoperative day and remained well and diseasefree two years after surgery. DISCUSSION Elastofibroma is a rare benign tumor of the connective tissue first described by Jarvi and Saxen 1. It occurs mostly in patients over 50 years old 2-4. Women are more commonly affected, and the back is the most frequent site 2-5. The lesion is usually located in the lower subscapular region, deep in the rhomboid and latissimus dorsi muscles, where it may be firmly attached to the chest wall 2. Elastofibroma dorsi is usually unilateral, and bilateral involvement occurs in only 10% of patients 2,4. Clinically, over 50% of the patients are asymptomatic and may present with a painless swelling, while fever is present with pain in 10%. 4 The origin of these lesions is not yet clear. It is considered to be a benign tumor in which elastic fibers had formed by abnormal elastogenesis 1, or a true dysplasia of the elastic tissue with excessive formation of elastic material by fibroblasts 6. There is no correlation with repetitive trauma and genetic theory in the development of elastofibroma dorsi 7. A multifactorial etiology may be more explanatory for elastofibroma 3. MRI is the best non-invasive technique and most useful for diagnosis 4. On CT and MRI examinations, elastofibroma dorsi is a noncapsulated mass, with variably-defined borders, showing an heterogenous soft-tissue attenuation, mostly similar to the skeletal muscles, with linear interlaced low density streaks suggesting mature fat 5. Surgical excision is recommended when it causes functional disability, compression sypmtoms, an asymmetric outline of the chest wall, or when it is more than 5 cm in diameter 2,5,8. Marginal excision carries a very low risk of recurrence 9. In conclusion, elastofibroma dorsi is a rare, illdefined, pseudotumoral lesion of the soft tissues. Lesions located deep beneath the inferior tip of the scapula should arouse suspicion of an elastofibroma. Making a differential diagnosis radiographically from other tumors of the soft tissues is possible with CT and MRI. Marginal excision carries a very low risk of local recurrence. REFERENCES 1. Jarvi OH, Saxen AE. Elastofibroma dorsi. Acta Pathol Microbiol Scand 1961; 144(Suppl 51): Briccoli A, Casadei R, Di Renzo M, Favale L, Bacchini P, Bertoni F. Elastofibroma dorsi. Surg Today 2000; 30: Kara M, Dikmen E, Kara SA, Atasoy P. Bilateral elastofibroma dorsi: proper positioning for an acuute diagnosis. Eur J Cardiothorac Surg 2002; 22: Pyne D, Mootoo R, Bhanji A. Elastofibroma dorsi. Ann Rheum Dis 2002; 61: Soler R, Requejo I, Pombo F, Sáez A. Elastofibroma dorsi: MR and CT findings. Eur J Radiol 1998; 27: Winkelmann PK, Sams WM. Elastofibroma. Report of case with special histochemical and electronmicroscopic studies. Cancer 1963; 23: Stemmermann GN, Stout AP. Elastofibroma dorsi. Am J Clin Pathol 1968; 21: Giebel GD, Bierhoff E, Vogel J. Elastofibroma and preelastofibroma a biopsy and autopsy study. Eur J Surg Oncol 1996; 22: Nagamine N, Nohara Y, Ito E. Elastofibroma in Okinawa. A clinicopathologic study of 170 cases. Cancer 1982; 50:

42 CASE REPORTS A MALE (15;15) ROBERTSONIAN TRANSLOCATION CASE WITH 11 PREVIOUS CONSECUTIVE RECURRENT SPONTANEOUS ABORTIONS Anıl Biricik 1, Ilter Guney 2, Hakan Berkil 1, Moncef Benkhalifa 1,3, Semra Kahraman 1 1 Istanbul Memorial Hospital, ART and Genetics Unit, Istanbul, Turkey 2 Department of Medical Biology, School of Medicine, Marmara University, Istanbul, Turkey 3 Advanced Technology Laboratories, Paris, France ABSTRACT Robertsonian translocation is one of the major chromosomal re-arrangements and constitutes 18% of all genetic abnormalities with an incidence of 1/1000 in the general population. Re-arrangements between homologous chromosomes are very rare and mainly manifest as monosomic or trisomic offspring. A couple was referred to our center with a history of eleven consecutive spontaneous abortions. The father was diagnosed as having 15;15 Robertsonian translocation. Fluorescence in situ hybridization analysis (FISH) was applied on sperm cells and resulted in only nullisomy and disomy for chromosome 15 that leads to monosomy or trisomy 15 in case fertilization occurs. Therefore the couple was counselled extensively on the risk of a future pregnancy. Furthermore they were informed that they would not benefit from preimplantation genetic diagnosis and sperm donation and adoption could be the only solution. Keywords: Homologous Robertsonian translocation, Recurrent abortion, Sperm FISH ARD ARDA 11 DÜŞÜKLÜ ÇİFTTE, ( 15; 15 ) ROBERTSONIAN TRANSLOKASYON TAŞIYICISI BABA ÖZET Robertsonian translokasyon önemli kromozomal düzensizliklerden biridir ve toplumda 1/1000 sıklıkla tüm genetik anomalilerin %18 ini oluşturur. Homolog kromozomlar arasındaki yeniden düzenlenmeler çok nadirdir ve kendini özellikle monozomik veya trizomik çocuklarla gösterir. Ard arda onbir düşük nedeniyle merkezimize yollanan bir çiftte, baba 15;15 Robertsonian translokasyon taşıyıcısı çıkmıştır. Sperm hücrelerine flöresan in situ hibridizasyon (FISH) analizi yapılmış ve fertilizasyonun oluşması durumunda monozomi veya trizomi 15 e yol açan, sadece kromozom 15 nullizomi ve dizomisi bulunmuştur. Bu nedenle çifte gelecek bir hamilelikteki risk yönünden danışma verilmiştir. Ayrıca çift, preimplantasyon genetik tanının yararlı olmayacağı ve sperm donasyonu ve evlat edinmenin tek çözüm olabileceği konusunda bilgilendirilmiştir. Anahtar Kelimeler: Homolog Robertsonian translokasyon, Ard arda düşük, Sperm FISH INTRODUCTION Robertsonian translocations are recognized to be the most common structural chromosomal abnormalities in the population with an incidence of 1.23/1000 live births 1. These chromosomal translocations are mainly observed in group D chromosomes including 13, 14, 15, and group G including 21 and 22. The D/D translocation is the most frequent type, including a high predominance of 13;14 translocation 2. In Robertsonian translocations, the pericentric regions of two acrocentric chromosomes fuse to form a single or two centromeres. The resulting balanced karyotype has only 45 chromosomes Corresponding author: Anıl Biricik, Istanbul Memorial Hospital, ART and Genetics Unit, Piyalepasa Bulvari, Okmeydanı, Istanbul / TURKEY Telephone: Fax: [email protected] including the translocated one, which is a result of a fusion of the long arms of two chromosomes. Malsegregation of Robertsonian translocation, results in trisomy or monosomy of complete chromosomes 3. In this study, we report a couple with a male 15q;15q Robertsonian translocation, the couple had 11 recurrent spontaneous abortions and one perinatal death. This homologous male 15q;15q translocation is in analogy of 13q;13q 4,5 6-8 and 21q;21q translocations and mainly originated de novo without any chance of having a normal offspring. Male gamete segregation would give a nullisomic or disomic sperm for chromosome 15 and produce monosomic or Marmara Medical Journal 2004;17(1);

43 Marmara Medical Journal 2004;17(1);35-38 Anıl Biricik, et al. A male (15;15) Robertsonıan translocation case with 11 previous consecutive recurrent spontaneous abortions trisomic embryos after fertilization. The effect of the marker chromosome on repeated abortions and the place of preimplantation genetics and genetic counselling are discussed in this study. CASE REPORT A couple both 41 years of age was referred to our in vitro fertilization (IVF) center due to the history of repeated spontaneous abortions. The mother had twelve pregnancies, eleven of which ended in spontaneous abortions during the first trimester and one live born male infant died after six hours. The infant weighed 2400 g and had right hemiplegia; unfortunately, no genetic investigation and autopsy were performed. Chromosome Analysis For karyotype analysis, 2 ml peripheral blood was sampled from both partners in 5 ml lithium heparinized tubes. A blood sample of 0,5 ml was added to 5 ml HAM S F-10 medium (Biochrom, Germany) which contains 0,8 ml Fetal Bovine Serum Albumin (Sigma, USA), 0,04 ml L- Glutamin, 0,04 ml Penicillin-Streptomycine and 0,1 ml Phytohemagglutinin was added. During 72 hours incubation at 37 ºC, 50 µl ethidium bromide was added at 68 th hour and 100 µl colcemide (0,05 mg/ml) added 3 hours later to harvest the cells at early metaphase and the cells were prepared for GTG banding (Giemsa Trypsin G-banding). Sperm Parameters The sperm analysis showed normal sperm parameters with 52x10 6 sperm cells/ml, a progressive total motility of 67% and a normal morphology in 8%. Sperm Preparation and Fluorescence in situ hybridization analysis (FISH) Semen specimens for sperm FISH analysis were allowed to liquefy at 37 ºC under 5% CO 2 and evaluated within 30 min of collection. Specimens were analyzed for sperm concentration, percentage of motile spermatozoa forward progressive motility and morphological analysis (according to Kruger s strict criteria) using a Papanicolau stain (Spermac, Fertipro, Beernum, Belgium). Following analysis, the semen specimens were mixed with sperm rinse (Vitrolife Mölndalsvagen, Sweden) and concentrated by centrifugation (Labofuge 400, Heraeus, Germany) under 3000 rpm for 10 min. After centrifugation, supernatant was discarded. Precipitated pellet was mixed with 0,2ml sperm rinse. The sperm cells were fixed in methanol:acetic acid (2:1) for FISH analysis. Sperm slides were washed with 2xSSC 15 min and the sperm heads were decondensed by using 1M Tris ph: 9,5, which contains 25 mm dithiothreitol (DTT), for 1 min. Washing steps were performed again with 2xSSC and PBS for 5 min respectively. After the washing with different alcohol concentrations, FISH was performed using the standard protocol 9 and employing a hybridization mixture containing CEP 11 alpha satellite probe in spectrum green (D11Z1; Vysis, Inc., USA) and telomeric 15q probe in spectrum orange (D15S396; Vysis Inc., USA). The slides were observed under a fluorescence microscope (Olympus Optical Co.; Japan) with the appropriate filters to visualize the fluorochromes and by using a computerized image capturing system (Isis in situ imaging system, Version 3.4.0; MetaSystems GmbH, Germany). Chromosome analysis revealed male 45,XY,der(15;15)(q10;q10) (Fig. 1) and normal female 46,XX karyotypes. The FISH analysis of the sperm sample using the centromeric probe of chromosome 11 for an internal control and telomeric probes for chromosome 15 demonstrate 50% of nullisomy and 50% of disomy 15 in the ejaculate. Translocated disomic sperm cells were observed with two telomeric signals for chromosome 15 and one centromeric signal for chromosome 11 while the nullisomic ones contained only one centromeric signal for chromosome 11 (Fig. 2). Fig. 1: Robertsonian translocation 15;15 36

44 Marmara Medical Journal 2004;17(1);35-38 Anıl Biricik, et al. A male (15;15) Robertsonıan translocation case with 11 previous consecutive recurrent spontaneous abortions Fig. 2a: Disomic sperm cells for chromosome 15 (D15S396, spectrum orange; D11Z1, spectrum green) 2b: Nullisomic sperm cells for chromosome 15 (D15S396, spectrum orange; D11Z1, spectrum green) DISCUSSION This paper demonstrates that Robertsonian translocation did not affect the sperm production and sperm parameters. Nullisomy or disomy of chromosome 15 did not affect the fertilization capacity of this sperm, because the couple declared 12 pregnancies in the past. By performing sperm FISH, we confirmed that this male would produce only monosomic or trisomic offspring of chromosome 15 and therefore there was no reason for the couple to refer to preimplantation genetic diagnosis since a trial of a natural conception would be fruitless. In general non homologous Robertsonian translocations are higher in infertile men and they are associated with infertility 10. The translocation between the D/D group is the most frequent one and studies of both spontaneous abortions and live births indicate a high predominance of 13;14 translocation. Translocations of Dq;Dq were about six times more frequent than Dq;Gqs 11. Meiotic segregation in Robertsonian translocation carriers can produce similar numbers of chromosomally normal and balanced gametes 12. However, another study indicates that this ratio is different at 14;21 translocation carriers and the incidence of the normal gametes is higher than the balanced ones 13. This particular case of 15;15 Robertsonian translocation is very rarely seen in the postnatal or prenatal period and it is associated with infertility like in all Robertsonian translocations. However, it did not affect the fertility of the father in our case. Although it was not possible to analyze the parents of the translocation carrier, normal phenotype of the patient suggested a de novo mutation at the post zygotic stage via fusing two homologous chromosomes to form a monocentric balanced translocation 15. Couples carrying balanced re-arrangements with severe segregation and suffering embryo blockage, implantation failure or abortions are referred to assisted reproduction technology. When assisted reproduction is pursued, preimplantation genetic diagnosis (PGD) is an option that permits the embryo selection to increase the implantation rate and avoids the risk of spontaneous abortion. Robertsonian translocation carriers in non homologous chromosomes have the ability to produce normal gametes and to have an unaffected child 21. However, it is not possible to have an unaffected child in cases with Robertsonian translocations in homologous chromosomes as there is no chance to produce normal or balanced gametes 22. Translocation formation prevents the normal segregation of chromosome 15 at meiosis during spermatogenesis. The segregation results in the formation of disomic or nullisomic gametes and this phenomenon leads to offspring with abnormal karyotypes, either monosomy 15 or trisomy 15. Sperm FISH analysis accurately describes the proportion of normal sperm in male patients with chromosome abnormalities. This analysis also predicts the meiotic behaviour of such anomalies and may also serve to compare abnormalities in different patients. For this particular case, sperm FISH analysis revealed disomic and nullisomic sperm cells which lead to the formation of aneuploid zygotes. Probably, abnormal paternal gametes were responsible for the majority of recurrent abortions. This is a very important point about recurrent abortions as parents should be firstly investigated by chromosome analysis in order to rule out a possible balanced translocation. 37

45 Marmara Medical Journal 2004;17(1);35-38 Anıl Biricik, et al. A male (15;15) Robertsonıan translocation case with 11 previous consecutive recurrent spontaneous abortions Theoretically, there are two possible ways that will permit the achievement of live births in this case. One of them is the fertilization of a disomic sperm cell which is carrying translocated chromosome 15 with a nullisomic oocyte. This is theoretically not acceptable due to the low possibility of formation of the nullisomic oocytes during oogenesis. The zygote resulted from this fertilization will receive both chromosomes 15 from the father and this will result in uniparental disomy. Absence of maternal loci on chromosome 15 causes Angelman syndrome recognized with the hallmarks of severe mental retardation, absent speech, jerky gait, inappropriate outbursts of laughter, microcephaly, flat occiput, wide mouth with protuberant tongue and prognathism. On the other hand, fertilization of a nullisomic sperm cell with a normal monosomic oocyte results a monosomic zygote for chromosome 15. If chromosome 15 undergoes duplication, it causes maternal uniparental disomy and Prader-Willi syndrome which is characterized by severe neonatal hypotonia, hypogonadism, mild to moderate retardation and onset of obesity after approximately two years of age. In this case, preimplantation genetic diagnosis would not give any benefit to the problem and the only option was to recommend sperm donation or adoption. ACKNOWLEDGEMENTS We would like to thank Sevim Balci for her scientific support, to Semra Sertyel, Nihal Oncu and Sevil Unal for their technical assistance. REFERENCES 1. Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13 year incidence studty in Arhus, Denmark. Hum Genet 1991; 87: Jacobs PA. Mutation rates of structural chromosome rearrangements in man. Am J Hum Genet 1981; 33: Pellestor F. Analysis of meiotic segregation in a man heterozygous for a 13;15 Robertsonian translocation and a review of the literature. Hum Genet 1990; 85: Shaffer LG, MCKaskill C, Han JY. Molecular characterization of de novo secondry 13. Am J Hum Genet 1994; 55: Veld PA, Weber RF, Los FJ, et al. Two cases of Robertsonian translocations in oligoozospermic males and their consequences for pregnancies induced by intracytoplamic sperm injection. Hum Reprod 1997; 12: Shaffer LG, Jackson-Cook CK, Meyer JM, Brown JA, Spence JE. A molecular genetic approach to the identification of isochromosomes of chromosome 21. Hum Genet 1991; 4: Shaffer LG, McCaskill C, Haller V, Brown JA, Jackson-Cook CK. Further characterization of 19 cases of rea(21q21q) and delineation as isochromosomes or Robertsonian translocations in Down syndrome. Am J Med Genet 1993; 8: Robinson WP, Bernasconi F, Basaran S, et al. A somatic origin of homologous Robertsonian translocations and isochromosomes. Am J Hum Genet 1994; 54: Preimplantation Diagnosis of Genetic Diseases: In: Verlinsky Y, Kuliev A, eds A New Technique for Assisted Reproduction. New York: Wiley-Liss, 1994: Guichaoua MR, Quack B, Speed RM, Noel B, Chandley AC, Luciani JM. Infertility in human males with autosomal translocations: meiotic study of a 14;22 Robertsonian translocation. Hum Genet 1990; 86: Gilgenkrantz S. Robertsonian translocations and abnormal phenotypes. Ann Genet 1989; 32,1: Escurado T, Lee M, Carrel D, Blanco J, Munne S. Analysis of chromosome abnormalities in sperm and embryos from two 45,XY,t(13;14)(q10;q10) carriers. Prenat Diagn 2000 ;20: Balkan W, Martin RH. Segregation of chromosomes into the spermatozoa of a man heterozygous for a 14;21 Robertsonian translocation. Am J Med Genet 1983; 16: Neri G, Ricci R, Pelino A, Bova R, Tedeschi B, Serra A. A boy with ring chromosome 15 derived from a t(15q;15q) Robertsonian translocation in the mother: cytogenetic and biochemical findings. Am J Med Genet 1983; 14: Wolff DJ, Schwartz S. Characterization of Robertsonian translocations by using fluorescence in situ hybridization. Am J Hum Genet 1992; 50: Freeman SB, May KM, Pettay D, Fernhoff PM, Hassold TJ. Paternal uniparental disomy in a child with a balanced 15;15 translocation and Angelman syndrome. Am J Med Genet 1993; 45: Ramsden S, Gaunt L, Seres-Santamaria A, Clayton- Smith J. A case of Angelman syndrome arising as a result of a de novo Robertsonian translocation. Acta Genet Med Gemellol 1996; 45: Tonk V, Schultz RA, Christian SL, Kubota T, Ledbetter DH, Wilson GN. Robertsonian (15q;15q) translocation in a child with Angelman syndrome: evidence of uniparental disomy. Am J Med Genet 1996; 66: Abrams DJ, Aronoff AR, Ann Berend S, Roa BB, Shaffer LG, Geier MR. Prenatal diagnosis of a homologous Robertsonian translocation involving chromosome 15. Prenat Diagn 2001; 21: Cheung SW, Shaffer LG, Richards CS, Page SL, Riconda DL. Prenatal diagnosis of a fetus with a homologous Robertsonian translocation of chromosomes 15. Am J Med Genet 1997; 72: Gualandi F, Sensi A, Trabanelli C, Falciano F, Bonfatti A, Calzolari E. Prenatal UPD testing survey in Robertsonian translocations. Prenat Diagn 2000; 20: Ercis M, Balci S. Can a parent with balanced Robertsonian translocation t(21q;21q) have a non- Down s offspring? Lancet 1999; 353:

46 CASE REPORT INVASIVE MICROPAPILLARY CARCINOMA OF THE BREAST: CASE REPORT Handan Kaya 1, Ahmet Midi 1, Bahadır Güllüoğlu 2, Erkin Arıbal 2 1 Department of Pathology, Marmara University Hospital, Istanbul 2 Department of Radiology, Marmara University Hospital, Istanbul ABSTRACT Invasive micropapillary carcinoma (IMPC) is a recently reported entity that is a histological variant of breast cancer with a poor prognosis. The tumor is best characterized by a nested pattern of eosinophilic tumor cells aranged in a solid, morular, tubular pattern. The tumor cells have intermediate to high grade nuclei and individual groups have a clear space separating them from the surrounding stroma. We report one case of pure IMPC of the breast Keywords: Breast, carcinoma, Micropapillary carcinoma, Pathology MEME İNVAZİF MİKROPAPİLLER KARSİNOMU: OLGU SUNUMU ÖZET İnvazif mikropapiller karsinom (IMPC) son yıllarda tanımlanmış meme kanserlerinin kötü prognoza sahip özel bir histolojik tipidir. Tümör yuvalar, solid, morular ve tubuler patern gösteren eozinofilik hücrelerle karakterizedir. Tümör hücre gruplarının nukleusları orta, yüksek dereceli nukleusa sahip çevre stromadan belirgin bir boşlukla ayrılırlar. Memenin saf IMPC olgusu sunulmuştur. Anahtar Kelimeler: Meme karsinomu, Mikropapiller karsinom INTRODUCTION Invasive micropapillary carcinoma (IMPC) of the breast has been recently described as a poorly recognized aggressive and a rare variant (<3%) of infiltrating ductal carcinoma. It is definitively associated with lymphatic invasion and a high incidence of nodal metastases 1,2. CASE REPORT A 70 year old woman presented with a lesion on the right breast that has been first noted four months ago. Physical examination revealed a discrete mass in central location of the right breast. Mammography showed a high density mass of 3 cm in diameter with spicular borders which caused slight skin retraction. Ultrasound(US) examination showed a mass of 2.5x 2 mm in size with ill defined margins with a marked posterior acustic shadow. The US and mammography findings were typical for a malign lesion. Following the fine needle aspiration biopsy of the mass which has reported as positive carcinoma, the patient underwent a right modified radical mastectomy with axillary dissection. On gross examination, the specimen measured 30cmx25cmx5cm with 27cmx12cm epidermis and nipple. On the cut surface of the breast there was a 2.5cmx2cm ill-circumscribed tumoral lesion with extensive fibrosis that was 3 cm distance to nipple. On low power microscopic examination, the tumor was constituted of abundant invasive epithelial nest, cohesive tumor cell clusters within clear spaces and the stroma surrounding the clear spaces had a fine reticular to colageneus structure (Fig. 1). The cell clusters mainly had round pattern while some of them had serrated peripheral borders. There was not desmoplasia around epithelial cell nests but micropapillary type of ductal carcinoma insitu area was present. Corresponding author: Handan KAYA, M.D Marmara University Hospital, Department of Pathology 81190, Altunizade Istanbul TURKEY Tel-Fax : [email protected] Marmara Medical Journal 2004;17(1);

47 Marmara Medical Journal 2004;17(1);39-41 Handan Kaya, et al. Invasıve Mıcropapıllary Carcınoma Of The Breast: Case Report Fig. 1: Cohesive tumor cell clusters within clear spaces and the stroma surrounding the clear spaces had a fine collagenous structure (H&EX40) On high power microscopic examination, the epithelial cells were cuboidal to columnar with variable amounts of cytoplasm that range from finely granular to densely eosinophilic (Fig. 2). Fig. 2: Cuboidal to columnar epithelial cells with variable amounts of cytoplasm that range from finely granular to densely eosinophilic (H&EX20) Fig. 3: Oestrogen receptor immunoexpression (X20) Myoepithelial cells were not identifiable at the periphery of cell clusters. Histological grading and mitotic index were fairly high and pleomorphism, multinucleated giant cells were present. The only metastatic lymph node was sentinal lymph node one out of 13 lymph nodes which were found in level I-II of axillary dissection. The metastatic lymph node was sharing the same morphology with the tumor. Immunohistochemistry for oestrogen receptor (ER) (Fig. 3) and progestrone receptor (PR), c- erbb-2 was performed. Both ER and PR immunoexpressions were positive in 70% of the tumor cells. c-erbb-2 was (+++) positive in cytoplasmic membrane of the tumor cells. DISCUSSION Invasive micropapillary carcinoma (IMPC) of the breast has been recently described as a poorly recognized aggressive and a rare variant 1,2. Invasive papillary cancers were first described by Fisher et al, who recognised several subtypes in their review of 1603 patients tumors from the National Surgical Adjuvant Breast Project (protocol 4) 3. The patterns that termed exfoliative was thought clinically poor prognosis. In 1993 Siriaunkgu and Tavassoli from the Armed Forces Institute of Pathology described the first series of this tumor which they called as invasive micropapillary carcinoma 4. They noted that this pattern is a different entity from metastatic papillary carcinoma and tubular carcinoma 4. The tumor is best characterized by a nested pattern of eosinophilic tumor cells arranged in a solid, morular and tubular pattern. The tumor cells have intermediate to high grade nuclei and individual groups have a clear space separating them from the surrounding stroma. These spaces are not lined by endothelial cells and this is most likely shrinkage artifact 4-6. In the frozen sections of our case there was not any clear spaces around the tumor nests and this finding is consistent with the shrinkage artifact due to the formalin fixation procedure. The intraductal component that accompanies these tumors often has a micropapillary pattern in which intermediate to high grade nuclei and necrosis typically present. It has been further defined by electron microscopic analyses, which showed microvilli on the external surfaces of cell clusters 1. Our case also had intraductal carcinoma with micropapillary pattern beside the invasive tumor nests. 40

48 Marmara Medical Journal 2004;17(1);39-41 Handan Kaya, et al. Invasıve Mıcropapıllary Carcınoma Of The Breast: Case Report IMPC has a high percentage of oestrogen receptor (ER) and progesterone receptor (PR) positivity (90% and 70%) and nearly doubles the expected percentage of HER-2/neu positivity (60%) 2,6,7. ER positivity has traditionally been associated with better differentiated tumors would appear to be an exception to these general rules. Expression of acid mucins and surface linear staining with epithelial membrane antigen (EMA) antibody was also described. The clinical significance and role of prognostic markers in IMPC are not fully described. It has been shown that prognostic factors in IMPC of the breast are the grade and extensive lymphatic invasion 2. Other factors such as ER and PR states, HER- 2/neu protein overexpression and p53 deletions have also been studied. It appears that the presence or absence of these markers in IMPC generally mimic that of the usual breast cancer in terms of predicting patient prognosis 2,8,9. It has also been found that pure IMC histology was associated with high-grade histology, metastases to regional lenf nodes, a high mitotic index and c- erbb-2 immunopositivity 9,10. In this case c-erbb- 2 immunoexpression was positive in 20% of the tumor cells. Survival rates were similar to those of other patients with equivalent numbers of lymph node metastases 9. In terms of the differential diagnosis of IMPC of the breast, other primary breast tumors, such as the rare invasive papillary carcinoma and colloidal carcinoma, must be considered. Invasive papillary carcinoma is of histologically a distinguishable from invasive micropapillary by its lack of clear spaces surrounding tumor clusters, truly papillary architectures and typically low nuclear grade 6. The distinction from pure colloid carcinoma is especially relevant because mucin secretion is an occasional, albeit usually minor, feature of IMPC of the breast. The large extracellular mucin pools of colloid carcinoma are infrequent in IMPC 6. Metastatic tumors especially ovarian serous papillary adenocarcinoma, micropapillary variant of transitional cell carcinoma of the bladder must also be considered in the differential diagnosis 8. Both of these tumors may exactly mimic the histological appearance of primary IMPC of the breast. A thorough and accurate clinical history and the presence of associated DCIS will aid in the correct diagnosis of primary IMPC of the breast. The observation of a papillary pattern in intramammary lymphatic tumor emboli or lymph node metastases should prompt a search for even a small amount of IMPC differentiation in the primary tumor. Identification of this entity as a distinct variant of breast cancer seems prudent because of the IMPC is predilection for lymphatic and lymph node spread. REFERENCES 1. Luna-More S, Gonzalez B, Acedo C, et al. Invasive micropapillary carcinoma of the breast:a new special type of invasive mammary carcinoma. Pathol Res Pract 1994; 190: Luna-More S, de los Santos F, Breton JJ, et al. Estrogen and progesterone receptors, c-erbb-2, p53 and Bcl-2 in thirty tree invasive micropapillary breast carcinoma. Pathol Res Pract 1996; 192: Fisher ER, Costantino J, Fisher B, et al. Pathologic finding from the National Surgical Adjuvant Breast and Bowel Project Investigators. Cancer 1993; 71: Siriaunkgul S, Tavassoli FA. Invasive micropapillary carcinoma of the breast. Mod Pathol 1993; 6: Petersen JL. Breast carcinomas with an un expected inside autgrowth pattern. Rotation of polarisation associated with angioinvasion. Pathol Res Pract 1993 (abstr): 189: Walsh MM, Ira J. Bleiweiss. Invasive micropapillary carcinoma of the breast: Eighty cases of an underrecognized entity. Hum Pathol 2001; 32: Gong Y, Sun X, Huo L, Wiley EL, Rao MS. Expression of cell adhesion molecules, CD44s and e-cadherin, and microvessel density in invasive micropapillary carcinoma of the breast. Histopathol 2005; 46: Amin MB, Ro JY, El-Sharkawy T, et al. Micropapillary variant of transitional cell carcinoma of the urinary bladder. Am J Surg Pathol 1994; 18: Paterakos M, Watkin WG, Edgerton SM,.Moore, Thor AD. Invasive micropapillary carcinoma of the breast: A prognostic study. Hum Pathol 1999; 30: Pettinato G, Manivel CJ, Panico L, Sparano L, Petrella G. Invasive micropapillary carcinoma of the breast: clinicopathologic study of 62 cases of a poorly recognized variant with highly aggressive behavior. Am J Clin Pathol 2004; 121:

49 CASE REPORTS METASTATIC DUCTAL ADENOCARCINOMA OF THE PROSTATE: REPORT of a CASE WITH FINE NEEDLE ASPIRATION BIOPSY FINDINGS and HISTOLOGIC CORRELATION Mine G.Güllüoğlu 1, Işın Kılıcaslan 2, Dilek Yılmazbayhan 1, Veli Uysal 2 1 Department of Pathology, Cytopathology Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey 2 Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey ABSTRACT Prostatic ductal adenocarcinoma is a rare neoplasm that arises from the prostatic urethra and large periurethral prostatic ducts. We described the cytologic features of a cribriform type of prostatic ductal adenocarcinoma in the transthoracic fine needle aspiration material of the pulmonary metastatic lesions in a 74-year-old patient with a previous diagnosis of cribriform type ductal adenocarcinoma in the prostate of which the histologic features were descibed also in the present case report. In the microscopic examination of the aspirate, three-dimentional groups of small cells displaying cribriform features and peripheral palisading cells were observed on a necrotic background. These cells had hyperchromatic round to oval nuclei with clumped chromatin, small inconspicious nucleoli and scant cytoplasm. Positive PSA immunocytochemical staining confirmed the prostatic origin. The present case is the first cribriform type of prostatic ductal adenocarcinoma described with its cytological features. In this case report, we aim to present the cytologic and histologic features of a metastatic prostatic ductal adenocarcinoma with special emphasis on its cytopathological features. Keywords: Prostate, Fine needle aspiration, Pulmonary metastasis, Ductal adenocarcinoma PROSTATİK DUKTAL ADENOKARSİNOM METASTAZI: VAKA SUNUMU; İNCE İĞNE ASPİRASYON BULGULARI VE HİSTOLOJİK KORELASYONU ÖZET Prostatik duktal adenokarsinom, prostatik üretradan ve geniş periüretral prostatik duktuslardan köken alan ender bir neoplazidir. Bu vaka sunumunda, daha önceden kribriform tipte prostatik duktal adenokarsinom tanısı almış olan 74 yaşındaki hastada akciğerdeki metastatik lezyonların transtorasik ince iğne aspirasyon biyopsisinde izlenen sitolojik özellikleri tanımlanmaktadır. Aspiratın mikroskopik incelemesinde, nekrotik zeminde küçük hücrelerden oluşan kribriform özelliklere sahip, yer yer periferik palisadlanma gösteren üç boyutlu gruplar izlenmekteydi. Grupları oluşturan oval-yuvarlak şekilli hücreler kaba kromatine, küçük belirgin olmayan nükleole ve dar sitoplazmaya sahip hücrelerdi. Hücrelerin prostatik kökeni immunsitokimyasal PSA pozitifliği ile gösterildi. Vakamız sitolojik özellikleri ile tanımlanan ilk kribriform tipte prostatik duktal karsinom olarak sunulmaktadır. Bu vaka sunumunda, bir metastatik prostatik duktal adenokarsinomun histopatolojik ve sitopatolojik özelliklerini sunmayı amaçladık. Anahtar Kelimeler: Prostat, İnce iğne aspirasyonu, Pulmoner metastaz, Duktal adenokarsinom INTRODUCTION Prostatic ductal adenocarcinoma is a rare neoplasm that arises from the prostatic urethra and large periurethral prostatic ducts 1. It accounts for 0.2%-0.8% of prostatic adenocarcinomas and less than 100 cases were reported 1,2. Even though the existence of this lesion as a separate entity from Corresponding author s address:mine G.Güllüoğlu, M.D. Istanbul University, Istanbul Faculty of Medicine, Department of Pathology, Cytopathology Unit Temel Tip Bilimleri Binası, Millet Cad. Capa, Topkapı, Istanbul TURKEYTel: Fax: mggulluistanbul.edu.tr typical prostatic acinar adenocarcinoma has been debated 3, its histopathologic features are unique. Only three cases exist in the literature with cytopathological features 4-6. In this case report, we aim to present the cytologic and histologic features of a metastatic prostatic ductal adenocarcinoma with a special emphasis on its cytopathological features. Marmara Medical Journal 2004;17(1);

50 Marmara Medical Journal 2004;17(1);42-46 Mine Güllüoğlu, et al. Metastatic Ductal Adenocarcinoma Of The Prostate: Report Of A Case With Fine Needle Aspiration Biopsy Findings And Histologic Correlation CASE REPORT A seventy four-year-old man was admitted to the hospital with obstructive symptoms of the lower urinary tract. The serum prostate specific antigen (PSA) level was 5,2 ng/ml (normal level:0-4 ng/ml). It was detected that there was a neoplastic lesion within the prostate gland and it filled the urethra. A transurethral resection (TUR) was done and a neoplastic lesion in the periurethral region of the prostate gland was resected. In the microscopic examination of the TUR material of the tumor, among the areas of classical prostatic acinar adenocarcinoma, we observed an adenocarcinoma composed of tumor cell groups displaying solid and cribriform growth pattern with necrosis of comedo type (Figs. 1a,b,c). Peripheral palisading were noted in some groups (Figs. 1b,c). The cells generally were small and uniform with hyperchromatic round to oval nuclei and scant cytoplasm. Pleomorphic cells and a few mitotic figures (3/10 HPF) were also observed. In the immunohistochemical examination, these cells showed focal PSA and PAP immunoreactivity (Fig. 1d) whereas the areas of classical acinar adenocarcinoma were diffusely immunopositive. Cytokeratin 7, cytokeratin 20 and neuroendocrine markers (neuron specific enolase, chromogranin, synaptophysin) were found to be negative in these cells. Accordingly, the lesion was diagnosed as prostatic ductal adenocarcinoma coexistent with classical acinar carcinoma (Gleason pattern 3, pattern score 3+3=6). Fig. 1: a: Areas of ductal adenocarcinoma with comedo necrosis (left upper) (H&E, 125x). b. Comedo necrosis and focal cribriform architecture and (H&E, 125x). c. Palisading cells at the periphery of the islands of tumoral cells (arrows) and cribriform areas H&E, 310x). d. Postive cytoplasmic immunoreactivity with antipsa antibody (PSA & Mayer hematoxylin, 500x). Four months later, a penile periurethral mass was resected and a neoplastic lesion of the same histologic appearence with the prostatic ductal adenocarcinoma areas in the TUR material were detected in the microscopic examination. Six months after the TUR was performed, the patient was admitted to the hospital with multiple masses in the lungs and a transthoracic fine needle aspiration (FNA) biopsy was performed. 43

51 Marmara Medical Journal 2004;17(1);42-46 Mine Güllüoğlu, et al. Metastatic Ductal Adenocarcinoma Of The Prostate: Report Of A Case With Fine Needle Aspiration Biopsy Findings And Histologic Correlation In the cytopathological examination of the aspirate it was detected that these pulmonary lesions were neoplastic. In the alcohol-fixed, Papanicolaou stained slides prepared from the aspirate, groups of small cells having hyperchromatic round to oval nuclei with clumped chromatin, small inconspicuous nucleoli and scant cytoplasm were observed on a necrotic background (Figs. 2a-d). These cells formed three dimentional groups displaying peripheral palisading cells (Fig. 2c). A few spindle cells (Fig. 2d), pleomorphic cells and mitotic figures were also observed. Positive immunocytochemical staining with PSA confirmed the prostatic origin. Figure 2: Groups of small cells with round-oval nuclei, clumped chromatin, inconspicuous nucleoli and scant cytoplasm. Cribriform structures (2b-arrows) and peripheral palisading (2d-arrow) are observed (Papanicolaou stain, original magnifications; 2a- 310x, 2b,c,d-500x) After primary pulmonary adenocarcinoma, small cell carcinoma and metastatic prostatic acinar adenocarcinoma were considered in the differential diagnosis, the pulmonary lesions were diagnosed as metastatic prostatic ductal adenocarcinoma. DISCUSSION The first description of prostatic ductal adenocarcinoma as a distinct pathologic entity dates back to 1967 and Melicow and Pachter who called it endometrioid carcinoma 7. Morphologically, it is characterized by tall columnar pseudostratified cells forming complex papillary and cribriform structures. Two architectural patterns designated as type A and type B have been described 2 : type A, the papillary pattern in which tumor shows papillary and tubulopapillary growth, and type B in which tumor appears solid and cribriform with or without comedonecrosis 1,2,8. The tumor in the present case is a good example of type B pattern with its cribriform structures and comedo necrosis in the large tumor cell groups. Typical prostatic acinar adenocarcinoma usually coexists with this lesion 1,8 as in the present case. Copland et al. reported that prostatic ductal adenocarcinoma was the second most common type of prostatic adenocarcinoma in their series of 44

52 Marmara Medical Journal 2004;17(1);42-46 Mine Güllüoğlu, et al. Metastatic Ductal Adenocarcinoma Of The Prostate: Report Of A Case With Fine Needle Aspiration Biopsy Findings And Histologic Correlation prostatic adenocarcinoma with lung metastasis, 9 although this tumor accounts for less than 1% among all prostatic adenocarcinomas 1,2. The observation that this tumor overrepresented metastatically indicates its more aggressive nature than that of classical prostatic adenocarcinoma. Urothelial cell carcinoma is one of the lesions which should be considered in the differential diagnosis of such tumors 1. Urothelial cell carcinoma involving prostatic ducts and acini can mimic prostatic ductal adenocarcinoma because it can present as a neoplasm with a large ductal pattern 2. In the present case, the cribriform structures, necrosis, negative cytokeratin 7 and cytokeratin 20 immunohistochemistry results and positive immunoreactivity for PSA in the neoplastic cell groups were not consistent with urothelial cell carcinoma 1. Colonic adenocarcinoma was also considered in the differential diagnosis because of the presence of cribriform structures and peripheral palisading within the tumor. Cytokeratin 20 immunonegativity was not consistent with colonic adenocarcinoma and positive immunohistochemical staining with PSA confirmed the prostatic origin. Prostatic adenocarcinoma of the classical type was also taken into consideration in the differential diagnosis because of the results of immunohistochemical studies, but the histomorphological features of the tumor were not consistent with classical prostatic adenocarcinoma. In the differential diagnosis of the pulmonary lesions, pulmonary adenocarcinoma, small cell carcinoma and metastasis of classical prostatic adenocarcinoma have been taken into consideration. As we confirmed the prostatic origin of these cells by positive PSA immunocytochemistry, the differential diagnosis of only acinar type prostatic adenocarcinoma will be discussed here with cytomorphological features. The patient had a coexistent typical prostatic acinar adenocarcinoma (Gleason pattern 3, pattern scor 3+3=6) apart from the ductal adenocarcinoma. In the cytologic examination of the transthoracic FNA material, three dimentional cell groups with peripheral palisading and cribriform structures were observed, instead of acinar and/or rosette-like structures which are typical cytologic features of classical acinar prostatic adenocarcinoma 10. Necrosis which was a major finding in the cytologic examination of the aspirate is generally a feature of high grade prostatic tumors 1. However, the presence of large nucleoli and pleomorphism which we did not observe in the present case was the two striking features of poorly differentiated acinar type prostatic adenocarcinoma 10. Apart from that, necrosis was not a feature of acinar adenocarcinoma which had the pattern score of 3+3=6, but it was of ductal adenocarcinoma. As a result, the cytologic features were not consistent with classical acinar adenocarcinoma of the prostate. The cytologic features of prostatic ductal adenocarcinoma have been described in only three cases previously 4-6. They were prostatic ductal adenocarcinoma cases of type A tumors with papillary growth pattern. The authors described papillary groups composed of cells with hyperchromatic nuclei and prominent nucleoli. Masood et al 4 also described cells with grooved nuclei which constituted the 10% of the tumor cells in the aspirate.. We did not observe any tumor cells having this feature. Our case is the first type B, cribriform type prostatic ductal adenocarcinoma described with its cytological features in FNA. Even though it has been debated whether this lesion is a separate entity from classical prostatic adenocarcinoma 3, like its histopathological features, its cytopathological features are distinct and should be described because of this neoplasm s more aggressive behavior than the classical prostatic adenocarcinoma 1. ACKNOWLEDGMENTS: A part of this work was presented at the XXIVth International Congress of the International Academy of Pathology, 5-10 October 2002, Amsterdam, The Netherlands. REFERENCES 1. Bostwick DG. Neoplasms of the Prostate. In: Bostwick DG, Eble JN, eds. Urologic Surgical Pathology. St.Louis, Missouri: Mosby-Yearbook Inc.; 1997: Randolph TL, Amin MB, Ro JY, Ayala AG. Histologic variant of adenocarcinoma and other carcinoma of prostate: Pathologic criteria and clinacal significance. Mod Pathol 1997; 10: Bock BJ, Bostwick DG. Does prostatic adenocarcinoma exist? Am J Surg Pathol 1999; 23: Masood S, Swartz DA, Meneses M, Hardy NH, Prempree T. Fine needle aspiration cytology of 45

53 Marmara Medical Journal 2004;17(1);42-46 Mine Güllüoğlu, et al. Metastatic Ductal Adenocarcinoma Of The Prostate: Report Of A Case With Fine Needle Aspiration Biopsy Findings And Histologic Correlation papillary endometrioid carcinoma of the prostate. Acta Cytol 1991; 35: Howell LP, Teplitz RL. Papillary carcinoma of prostatic ductal origin: a cytologic case report with immunohistochemical and quantitative DNA correlation. Diagn Cytopathol 1989; 5: Epstein NA. Primary papillary carcinoma of the prostate: report of a histopathologic, cytologic and electron microscopic study on one case. Acta Cytol 1977; 21: Melicow MM, Pachter MR. Endometrioid adenocarcinoma of the prostatic utricle (uterus masculinus). Cancer 1967; 20: Oxley JD, Abbot CD, Gillat DA, MacIver AG. Ductal carcinomas of the prostate: a clinicopathological and immunohistochemical study. Br J Urol 1998; 81: Copeland JN, Amin MB, Humphrey PA, Tamboli P, Ro JY, Gal AA. The morphologic and histologic features overlapping with other pulmonary neoplasms. Am J Clin Pathol 2002; 117: Geisinger KR, Raab SS, Stanley MW, Silverman JF, Abati A. Pelvis and Scrotal Contents. In: Modern Cytopathology. Philadelphia: Churchill Livingstone, 2004:

54 REVIEW ADOLESCENT DEPRESSION: PROGRESS AND FUTURE CHALLENGES IN PREVENTION-CONTROL ACTIVITIES Pınar Ay, Dilşad Save Department of Public Health, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT It is accepted that depression during adolescence is a highly prevalent yet mostly an under recognized mental health problem. Studies carried out in diverse cultures report prevalence rates ranging from 1% to 50% for adolescent depression. Presence of depression during adolescence, effects the development negatively and creates a tendency towards high-risk behaviors as alcohol, tobacco use and substance abuse. Current research points out that although there is a biological tendency for the development of adolescent depression, psychological and social factors also play an important role. Therefore intervention programs, focusing on particularly psychosocial factors, gain attention for the prevention and control of adolescent depression. The findings from school based studies which aim to prevent adolescent depression through utilizing cognitive behavioral techniques are promising. This paper discusses the burden and the factors influencing the development of depression during adolescence, as well as the objectives, methods, findings and the effectiveness of prevention programs which focus on psychosocial factors. ERGENLERDE DEPRESYON: ÖNLEME VE KONTROL STRATEJİLERİNDEKİ GELİŞMELER VE GELECEĞE YÖNELİK HEDEFLER ÖZET Depresyon, ergenlik çağında oldukça sık görülebilmesine karşın çoğu zaman olması gerektiğinden daha az tanı koyulan bir sağlık sorunudur. Çeşitli toplumlarda yapılan çalışmalar, ergenlerde depresyon prevalansının %1 ile %50 arasında değişebildiğini ortaya koymaktadır. Bu çağda gelişen depresyon, ergenin gelişimini olumsuz yönde etkilemekte ve intihar, alkol, sigara veya madde kullanımı gibi riskli davranışlara eğilim yaratmaktadır. Araştırmalar, ergenlerde depresyon gelişiminde biyolojik yatkınlığın yanı sıra, sosyal ve psikolojik faktörlerin de önemli rol oynadığını göstermektedir. Bu nedenle, depresyonun önlenmesi ve kontrolünde özellikle psikososyal faktörlere odaklı müdahale çalışmaları önem kazanmaktadır. Okullarda yürütülen ve bilişsel-davranışçı teknikleri temel alan depresyon önleme programlarının sonuçları olumlu olarak değerlendirilmektedir. Bu yazıda, ergenlerdeki depresyon yükü, depresyon gelişimini etkileyen faktörler ve psikososyal faktörlere odaklı depresyon önleme programlarının amaçları, uygulama yöntemleri, sonuçları ve uygulanabilirlikleri tartışılmaktadır. INTRODUCTION There is a growing concern regarding adolescent depression since it is highly prevalent yet mostly an under recognized mental health problem. Nevertheless, the intervention programs that aim to prevent and control adolescent depression yield promising results. Since some of the determinants of adolescent depression are modifiable, it is important to develop and discuss policies focusing on prevention and control activities. World Health Organization reports that depression is the fourth leading cause to the global burden of disease worldwide 1. Although today we know that depression affects all age groups, for many years it was considered to be rare before adulthood since children were considered to lack the mature psychological and cognitive structure necessary to experience these problems 2. The main belief was that mood disturbance was a normative and self-limiting aspect of child and Corresponding author:pınar Ay Marmara Medical Journal 2004;17(1);47-52 Department of Public Health, School of Medicine, Marmara University Tıbbiye Cad. No:49, 34716, Haydarpasa Istanbul, Turkey. Tel: Fax: [email protected] 47

55 Marmara Medical Journal 2004;17(1);47-52 Pınar Ay, et al. Adolescent depression: Progress and future challenges in prevention-control activities adolescent development. Moreover, the diagnosis of depression for these adolescents present a less differentiated clinical picture compared to adults. And because children and adolescents do not seek for help for their emotional problems, neither parents nor teachers recognize emotional problems effectively 3. Yet, current epidemiological research points out that depression before adulthood, although under recognized, is a common health problem and should be addressed as a priority issue 2,4-11. Several studies point out that depression and even depressive symptoms during adolescence have serious consequences both at the individual and the community level. Presence of depressive symptoms during adolescence is related with high-risk behaviors as tobacco use, substance abuse or suicidal ideation Patten et al. 14 noted that among adolescents who had depressive symptoms at baseline, more than one third reported the persistence of symptoms within the past 12 months. The same study determined that if depressive symptoms persisted, the risk for secondary problems as drug or alcohol abuse and suicidal attempts increased 14. Even sub threshold depression or the presence of depressive symptoms is reported to be a risk factor for subsequent depression episodes for both genders 12,15. And because of the continuity between child or adolescent depression with that of adulthood, it is important to focus on prevention and control activities at younger ages. The magnitude of the problem Epidemiological studies evaluating the burden of depression among adolescents report different prevalence rates ranging from 1% to 50% 4. The discrepancies are not surprising since the data collection tool as well as the time, the setting of the surveys and the age group considered have an important impact on the prevalence detected. Nevertheless, almost all the researches carried out in diverse cultures point that adolescent depression is prevalent. A survey carried out among a representative sample of adolescents in US determined that lifetime prevalence of major and minor depression as 15.3% and 9.9%, respectively 5. The 30-day period prevalence for major and minor depression was determined as 5.8% and 2.1% in the same study 5. A school-based survey in Sweden revealed that, among the age group, the 1- year prevalence of major depression was 5.8% and the lifetime prevalence was 11.4% 6. Again a school-based survey encompassing the ages of year olds determined a prevalence rate of 16.9% in China 16. The rates can be higher among the adolescents who attend to health units. A study carried out among adolescents who attended to primary care units in Brazil revealed a prevalence rate of 26.5% 7. There are also three studies reporting prevalence rates from Turkey. In a school-based survey carried out in one of the provinces of Turkey, it was revealed that the prevalence of depression was 12.5% in the age group Another school-based survey determined a higher prevalence rate because the latter study was carried out in a region, which was affected by a devastating earthquake. Three and a half years after the earthquake, the depression prevalence was determined as 30.8% among adolescents 9. In another research carried out among high school students in a socio economically disadvantaged region of Istanbul, the prevalence was determined as 30.3% 10. Basically, studies evaluate the presence of depression through two approaches 4. The first one is by utilizing screening tests, which use the self-reported symptom scales as most of the above examples. And the second approach for determining prevalence is by using diagnostic interviews. Studies using diagnostic interviews reported relatively lower rates compared to studies using self-report scales. It was proposed that the gap between the prevalence rates might result from an artifact due to adolescents over reporting of their symptoms. But most probably a considerable high proportion of adolescents suffer from sub threshold depression 4. It is important to note that an increasing trend in the rates is observed among different cohorts throughout the years. With the epidemiological transition, the burden of depression among communities had been growing. It is proposed that as the communities evolve from modernization to post modernization many changes take place within the society and many persons experience psychological distress while trying to adapt to the changing social norms. This social transition is considered to move from collectivity to individualism thus weakening the individual s bond to life leading to helplessness and hopelessness 17. This fact is argued as the one of the main reasons leading to the increase in depression and thus suicidal rates 17. Research showed that after the 2 nd World War, lifetime prevalence of depression had increased with each birth cohort 18. A survey carried out among 48

56 Marmara Medical Journal 2004;17(1);47-52 Pınar Ay, et al. Adolescent depression: Progress and future challenges in prevention-control activities adolescents in US determined that higher prevalence as well as early onset of the disorder was observed among the younger cohort 5. And WHO estimates that depression will be the second leading cause of disability by 2020 worldwide 1. Determinants of adolescent depression Research points out to a number of risks as well as protective factors that influence the mental well being of adolescents 3. Any intervention program interventions Table I: Selected researches that focus on the school-based depression prevention interventions Author, publication year Target population Intervention Results Clarke, 2001 (41) At-risk offspring (aged years) of adults treated for depression in a health CBT delivered by clinical psychologists maintenance organization years). Harnett, 2004 (44) Students aged 12 to 16 years Cognitive behavioral strategies and exercises delivered by teachers Clarke, 1995 (46) Adolescents with elevated but subdiagnostic levels of selfreported depressive symptomatology CBT delivered trough specially trained school psychologists and counselors Kerfoot, 2004 (47) Depressed adolescents CBT delivered by social workers Gillham 1995 (48) 5 th and 6 th grade adolescents CBT delivered by clinical psychologists Seligman 2001 (49) First year university students at risk CBT delivered by clinical psychologists Shochet 2001 (50) Adolescents years old CBT delivered by clinical psychologists Puskar, 2003 (51) Adolescents at least 13 years of age living in a rural region CBT delivered by master s level nurses with psychiatric mental health experience The incidence of major depression in the intervention group was a third of that in the control group (9.3% vs 28.8% over two No benefit A significant 12-month advantage for the prevention program, with affective disorder total incidence rates of 14.5% for the active intervention, versus 25.7% for the control condition. Adolescents who had therapy from trained social workers had a similar level of depression post treatment (mean depression score 17.5) to those who did not have such therapy (mean depression score 16.7). On average children in the intervention group reported fewer depressive symptoms on average. Also the intervention group was only half as likely as the control group to report symptoms in the moderate to severe range The intervention group had fewer episodes of generalized anxiety disorder, showed a trend toward fewer depressive episodes. The intervention group had also fewer moderate depressive episodes but not severe depressive episodes. Intervention groups showed a significantly greater decrease in depressive symptoms 10 months later compared with the control group Intervention group showed improvement in depressive symptoms and certain coping skills as well as the use of cognitive problem solving coping strategies aiming to prevent and control mental health disorders should focus on reducing the risk while promoting the preventive factors. Biological factors Gender is one of the factors, which influences the rate of depression and depressed mood during adolescence. In early adolescence there is an increase in the rate of depression among girls but not the boys 6,11,19-22 although there are some studies controversial 23. The developmental events are considered to increase the vulnerability of the female gender 22,24. Also an environment that fosters negativity and rumination is thought to be important 24. Genetic tendency to depression is one of the known risk factors although environmental influence is sometimes hard to distinguish 4,25,26. Early puberty was also shown to increase the vulnerability to adolescent depression 11,27,28. It was argued that this is because of major hormonal changes 29 or stressful effect of deviation from normality. Nevertheless, pubertal development 49

57 Marmara Medical Journal 2004;17(1);47-52 Pınar Ay, et al. Adolescent depression: Progress and future challenges in prevention-control activities involves biological, psychological and social changes that all may contribute to mental health problems. And girls were more influenced than boys 30. Obesity and depression are interrelated 31. It is not clear whether obesity or depression come first since one of the expressions for depression is weight gaining or losing. Negative childhood experiences are considered to reinforce the development of both disorders and their cooccurrence 31. Body perception among youngsters is regarded as important especially for girls, many mental health problems disorders were found more prevalent than boys and perception of overweight was shown to be an important factor A study carried out among Chinese adolescents had indicated that perceived overweight was related to depression and anxiety for both genders. Also perceived overweight groups were exposed to a higher degree of social isolation 34. Psychological and Social Factors Cognitive factors were seen important for adolescent depression. Among those who have ability to learn from experiences, good selfesteem, high level of problem solving ability and social skills experienced depression less 3,15,35. There are number of studies examining relationship between family environment and adolescent psychological background. Intact families were usually reported to be protective. Inconsistent care-giving, family conflict, poor family discipline, poor family management, death of a family member are associated with depression. Family attachment, opportunities for positive involvement in family, rewards for involvement in family are regarded as protective factors 15,24,30,35,36 Academic failure in school, failure of schools to provide an appropriate environment to support attendance and learning, inadequate/inappropriate provision of education may also contribute to presence of depression among adolescents 3,15,30. Opportunities for involvement in school life, positive reinforcement from academic achievement may be favored factors for good mental health 3. Perceived lack of social support, perceived discrimination and marginilazation, lack of cultural identity, experience of war and exposure to violence, transitions (urbanizations) are regarded as risk factors as a reflection of negative outcomes of modernization 3,11, Number of friends is also associated with depression. Those who have more friends are found to have less depressive symptoms 10,30. Research on prevention and control activities WHO puts forward main reasons for developing effective interventions targeting children and adolescents. Implementing intervention activities focusing on prevention and screening programs for adolescence will be important in reducing the long term impairment in adulthood and solve the problems at the stage that it is most likely to appear. Effective interventions will also be important in reducing the health costs at the community and the individual level 3. Research puts forward promising results for depression prevention programs for adolescents who are at risk for depression. Intervention trials are based on cognitive behavioral therapy (CBT) since on the individual bases the efficiency of CBT is proven to be effective for adolescent depression. Studies using cognitive programs basically utilize two different approaches in delivering the interventions. The first one is through trained psychologists and the second one is by means of teachers or social workers. A considerable improvement is achieved in depression prevention when cognitive therapy is delivered by trained psychologists. An outstanding example is conducted by Clarke et al. A randomized controlled trial utilized cognitive therapy prevention program targeted the offspring of depressive parents. Participants were adolescents with depressive symptoms who did not meet the diagnostic criteria for depression. This study determined the effectiveness of cognitive therapy; it revealed a cumulative major depression incidence during a median of 15 months of follow of 9.3% and 28.8% in experiment and control groups, respectively 41. A placebo-controlled trial in New Zealand evaluated the effectiveness of a school based depression prevention program. The intervention was based on a manual based program, which was derived from cognitive behavioral therapy. Immediately after the program a significant clinical benefit with an absolute risk reduction of 3% and with a number needed to treat for shortterm benefit of 33 was achieved 42. The research points out that the intensive interventions utilizing CBT delivered by trained mental health professionals are shown to be efficient, but the activities delivered by teachers or social workers mostly showed no benefit. It is 50

58 Marmara Medical Journal 2004;17(1);47-52 Pınar Ay, et al. Adolescent depression: Progress and future challenges in prevention-control activities clear that under real world conditions it is not possible to carry out prevention and control activities through psychologists. So the question that needs to be addressed is that the effectiveness of the interventions rather then their efficiency 43. The interventions are efficient in other words they are successful under ideal laboratory conditions. But will they be effective when delivered as a community based program in the real world? And will they be cost effective? 43. A recently published study addressed the abovementioned question. This study evaluated the effectiveness of a depression prevention program under real-world conditions in schools. The program was implemented through the existing school personnel. Although the program did not demonstrate a beneficial effect for the students, the knowledge, the confidence as well as the quality of program implementation was acceptable. It was important that the personnel did not consider the program difficult to implement 44. Authors discuss that there was a high level of variability between students within classes, which made it difficult to detect differences between classes that could be attributed to facilitator variables 44. Some approaches are suggested in order to overcome the availability of trained staff who is capable to deliver CBT. An internet-based CBT program and a computerized carton-based program are examples of such approaches. Internet based programs in some cultures can REFERENCES 1. World Health Organization. The World Health Report 2001: New Understanding, New Hope. Geneva, WHO, Son SE, Kirchner JT. Depression in Children and Adolescents. Am Fam Physician 2000; 62: World Health Organization. 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