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 ACUTE PAIN SERVICE ORGANIZATION Zeynep Eti, Tümay Umuroğlu, Emel YahĢi, Rüya Göz, F. Yılmaz GöğüĢ... 1 PROTECTIVE EFFECTS OF 2-MERCAPTOETHANE SULFONATE (MESNA) ON PROTAMINE SULFATE INDUCED BLADDER DAMAGE Beyhan Sağlam, Esra Cikler, Ali Zeybek, ġule Çetinel, Feriha Ercan, Göksel ġener...6 DOES THE FREQUENCY OF SELF MONITORING OF BLOOD GLUCOSE INFLUENCE GLYCEMIC CONTROL IN TYPE 2 DIABETIC PATIENTS? Hasan Aydın, Oğuzhan Deyneli, Dilek Yavuz, Özlem Tarçın, Sema Akalın...13 EVALUATION OF THE PREVALENCE AND BEHAVIOURS OF THE EX-SMOKER UNIVERSITY STUDENTS RuhuĢen Kutlu, Kamile MARAKOĞLU Olgu Sunumu STIFF PERSON SYNDROME WITH ATYPICAL FEATURES AND A FAVOURABLE OUTCOME WITH STEROIDS Hande Türker, Nilgün Cengiz, Levent Güngör, Musa Onar.. 24 PATHOLOGICAL LAUGHING FOLLOWING PONTINE INFARCTION DUE TO BASILAR ARTERY STENOSIS NeĢe Tuncer, Nazire AfĢar, Tülin Tanrıdağ, Önder Us A CONGENITAL AQUADUCTUS CEREBRI STENOSIS CASE Ali Zeybek, Mahmut BeĢer PEROPERATIVE DIAGNOSIS OF RHABDOMYOLYSIS Binnaz Ay, Ġ. Varlık Doğan, Tümay Umuroğlu, F. Yılmaz GöğüĢ.35 ENDOSCOPIC REMOVAL OF FRONTOETHMOID OSTEOMA: A CASE REPORT Murat Sarı, Tekin Bağlam, Zahide Mine Yazıcı, Cüneyd Üneri Derleme AGING AND THE EYE Sumru Onal, Tayfun Bavbek

8 ORIGINAL RESEARCH ACUTE PAIN SERVICE ORGANIZATION Zeynep Eti, Tümay Umuroğlu, Emel Yahşi, Rüya Göz, F. Yılmaz Göğüş Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, İstanbul, Turkey ABSTRACT Objective: The aim of this retrospective study was to evaluate the organization of acute pain service of Marmara University Hospital, and the efficacy, side effects and complications of the analgesic methods used between september Materials and Methods: Data sheets of the postoperative pain survey of 3190 patients treated by the acute pain service were examined retrospectively between September 2003 and Analgesic methods used and complications related to them, numeric rating scale (NRS) scores, TORDA scores and patient s satisfaction were recorded. Results: The incidence of additional analgesic requirement (NRS>3) in epidural intermittent group were higher than the other groups (p<0.05). The incidence of nausea and vomiting were higher in intravenous patient controlled analgesia and epidural patient controlled methods compared to other groups. Pruritis was less prominent in parenteral intermittent group compared to other groups. 98 % of the patients were satisfied with the analgesic method performed. Conclusion: Acute pain service organization provides maximum satisfaction either in patients treated with invasive methods such as regional blocks or in patients treated with simple and noninvasive methods such as the administration of parenteral / oral nonsteroidal anti inflammatory agents and opioids. Keywords: Analgesia: postoperative. Anesthetic techniques: epidural. Pain: acute pain service AKUT AĞRI SERVİSİ ORGANİZASYONU Amaç: Bu retrospektif çalışmada, Marmara Üniversitesi Hastanesi Akut Ağrı Servisi organizasyonunun ve Eylül tarihleri arasında uygulanmış olan analjezik metodların etkinlik, yan etki ve komplikasyonlarının değerlendirilmesi amaçlanmıştır. Yöntem: Eylül 2003 ve 2004 tarihleri arasında akut ağrı servisi tarafından tedavi edilen 3190 hastanın postoperatif ağrı formları retrospektif olarak incelenmiştir. Uygulanan analjezik metodlar ve bu metodlara bağlı gelişen komplikasyonlar, nümerik derecelendirme skalası (NRS) skorları, TORDA skorları (açık hali söylenmeli) ve hastaların memnuniyetleri kaydedilmiştir. Bulgular: Aralıklı epidural grubundaki hastaların ek analjezik gereksinimleri (NRS>3) diğer gruplardaki hastalardan belirgin yüksek bulunmuştur (p<0.05). İntravenöz ve epidural hasta kontrollü analjezi metodlarında bulantı kusma insidansı diğer gruplara göre belirgin yüksek bulunmuştur. Kaşıntı insidansı, aralıklı parenteral grubunda diğer gruplar ile karşılaştırıldığında belirgin azalmıştır. Hastaların % 98 i kendilerine uygulanan analjezi metodundan memnuniyet bildirmişlerdir. Sonuç: Akut ağrı servisi organizasyonu; etkin postoperatif ağrı tedavisi yapılabilmesinin, özellikle bölgesel bloklar gibi ciddi yan etki ve komplikasyonları olan yöntemlerin güvenli uygulanabilmesinin yanısıra en sık kullanılan ve en basit yöntem olan aralıklı NSAI+opioid uygulamasında bile yüksek oranda hasta memnuniyeti sağlanabilmesinin gerek ve yeter şartıdır. Anahtar Kelimeler: Analjezi: postoperatif. Anestetik teknikler: epidural. Ağrı: akut ağrı servisi INTRODUCTION Management of perioperative analgesia is required for humanitarian reasons as well as for decreasing postoperative morbidity and mortality 1-5. Many patients undergoing surgery are still suffering from pain postoperatively, despite the development of new analgesic agents and techniques 6. The reason for this fact usually depends on the disorganizations, discoordinations and lack of pharmacological knowledge of medical practitioners in providing adequate analgesia during the postoperative period 6. Acute pain treatment is said to be effective if it decreases postoperative morbidity such as respiratory complications or myocardial infarction, and length of hospital stay and if it provides optimal comfort and prevents complications related to the treatment 1-5. Acute Corresponding author Tümay Umuroğlu Department of Anesthesiology and Reanimation, Marmara University Hospital, Altunizade, İstanbul, Turkey tans6@ hotmail.com Marmara Medical Journal 2005;18(1);1-5 1

9 Marmara Medical Journal 2005;18(1);1-5 Zeynep Eti, et al. Acute Pain Service Organization pain service organization has been developed for the effective control of acute postoperative pain 5,7. Its existence depends upon the ongoing training of medical staffs in methods of postoperative pain management, research and application of new analgesic methods. Anesthesiologists are skilled in the systemic administration of analgesics and are more experienced in the application of regional techniques perioperatively, because they are more familiar with the pharmacology of analgesics and the anatomy of the pain patways. Therefore the members of acute pain service should always be anesthesiologists 7-8. In our hospital, acute pain service has been organized in September 2003 by the Anesthesiology Department. The aim of this retrospective study was to evaluate the organization of acute pain service of Marmara University Hospital and the efficacy, side effects and complications of the analgesic methods used between September METHODS The data sheets of the postoperative pain survey of 3190 patients who were treated by the acute pain service between September 2003 and 2004 were examined retrospectively. Demographic characteristics, type of surgery, comorbid diseases, analgesic method used, complications related to the analgesic methods, hemodynamic parameters, respiratory rate, NRS (numeric rating scale) scores at rest, TORDA scores (0= no pain with coughing; 1= pain with coughing but no pain with deep inspiration; 2= pain with deep inspiration but no pain in rest; 3= pain in rest), sedation scores, side effects such as nausea, vomiting, pruritis, urinary retention, headache, and patient s satisfaction were recorded. Data are expressed as percentage. Statistical significance was checked by setting the level of significance at p< Data collected were analyzed with Fisher s exact test for detection of significant differences between groups. RESULTS Acute pain service team consists of an associate professor, a resident standing in the recovery room, a resident assigned to the service for 2- month and an anesthesiology technician assigned to the service for 1-month rotations (Fig. 1). The entire team makes clinical rounds on each patient who has received any of the postoperative analgesia methods, twice a day, each morning and each afternoon. After the admission of the patient to the ward, clinical rounds are repeated in every two hours during the first 8 hours and in every 4 hours thereafter. During these rounds, numeric rating scale scores of the patients and TORDA scores with coughing and activity, side effects and patient s satisfaction scores, sensorial and motor blocks are evaluated and recorded. The site of insertion of each catheter is inspected. These recordings are made by the anesthesiologist on call during the off work hours. The written analgesic treatment protocol has been defined according to the type of surgery and comorbidity of the patient. The surgical disciplines have been informed about the protocols. Fig. 1: Acute pain service team 2

10 Marmara Medical Journal 2005;18(1);1-5 Zeynep Eti, et al. Acute Pain Service Organization Postoperative analgesia begins in the recovery room. The type and dose of analgesic which is planned to be administered, are written to the analgesia sheet of the patient; and the first analgesic dose is administered in the recovery room. When the patient s NRS score is less than 3, he or she is referred to the ward. Postoperative pain management is done by one of the following methods: 1 Systemic administration of opioids with constant intervals 2 Intrathecal or epidural opioids and/or local anesthetics as needed 3 Intravenous or epidural patient controlled analgesia (PCA). Every patient in each method receives intravenous, thereafter oral non-steroidal anti inflammatory agents and/or oral paracetamol. 52 % of the 3190 patients were male and 48 % were female % of the patients were less than 10 years old, 76.1 % were between years old and 7.6 % were greater than 75 years old ( the youngest patient was 10 months old and the oldest patient was 88 years old). The percentage of patients treated by the acute pain service at each surgical department were expressed in Table I. The characteristics of the analgesic methods used were expressed in Table II. The need for additional analgesic was decribed as NRS > 3. The overall incidence of NRS > 3 was 7.8 % in all analgesic methods. Side effects of the analgesic methods were expressed in Table III. Three patients who had epidural anesthesia had accidentally dural puncture, 11 had a disconnection of the filter from the epidural catheter, 2 had catheter dislodgement and 6 patients had insufficient analgesia. In the latter, intravenous patient controlled analgesia was performed. 98 % of the patients were satisfied with the analgesic method performed. Table I: The percentages of patients involved in the surgical departments Surgical Departments % General surgery 22 Urology 18 Orthopedic Surgery 16 Ear-Nose-Throat Surgery 15 Plastic Surgery 8 Gynecology 7 Neurosurgery 6 Pediatric Surgery 5 Thoracic Surgery 3 Table II: The characteristics of the analgesic methods Intravenous PCA Epidural PCA Epidural intermitten Parenteral intermitten Caudal t 149 (6) t 1477 (59) Patient s number (n) (%) (14.4) (7) Follow-up time (hrs) TORDA > 1 (n) (%) (53.5)** (25) (75)* (23) NRS > 3 (n) (%) (14.5) (6.2) (63.8) # (7.3) * p < 0.05, compared to all groups. ** p < 0.05,compared to epidural PCA, parenteral intermittent, caudal and intrathecal opioid # p< 0.05, compared to other groups. 205 (8.2) Intrathecal opioid (25) 20 (10) 170 (6.8) 48 (28) 23 (13.5) 3

11 Marmara Medical Journal 2005;18(1);1-5 Zeynep Eti, et al. Acute Pain Service Organization Intravenous PCA Table III: Side effects (%) Epidural PCA Epidural intermittent Parenteral intermittent Intrathecal opioid Nausea vomiting 28* 27.5* Pruritis 13.4** 18** ** Sedation Parestesia Urinary retention *** Headache * p < 0.05, compared to epidural intermittent, parenteral intermittent, intrathecal opioid ** p < 0.05, compared to parenteral intermittent *** p < 0.05, compared to other groups DISCUSSION The results of this study reveals that acute pain service organization is indispensible for the effective control of acute postoperative pain control. Acute pain service organization provides maximum satisfaction either in patients treated with invasive methods such as regional blocks or in patients treated with simple and noninvasive methods such as the administration of parenteral / oral non-steroidal anti inflammatory agents and opioids. In spite of increasing interest and publications in the understanding of mechanism and management of chronic pain, ineffective management of postoperative analgesia is still a great problem in Turkey as well as in other countries of the world 9. The first acute pain services have been organized in 1985, in the United States and in Germany 7,10,11. Neverthless, despite 20 years passed, it is not easy to realize that many centers do not still have their own acute pain services and that many patients all over the world still receive inadequate postoperative analgesia. The reason for this problem seems to be multifactorial. First of all, close postoperative follow-up of the patient s pain scores and side effects related to the analgesic method used, requires appropriate education, time, effort, increased specialist supervisor and specially dedicated medical staff 6. Secondly, nurses or doctors involving in the postoperative pain management should not be resistant to changes in this field and should not be in a tendency to underestimate patient s pain. We found that the overall incidence of the need for additional analgesic described as NRS > 3 was 7.8 % comparable to 10.9 % in the published datas 12. Regarding the analgesic methods used, only the incidence of moderatesevere pain is very high in the intermittent epidural analgesia method when compared with that in the literature. In intermittent epidural analgesia method, epidural injection is done upon the patient s request when he or she perceives pain. This easily explains why this group of patients has high NRS scores. Undoubtly, continous epidural technique will be more satisfactory, however the cost and the incidence of side effects will also increase. The patient satisfaction was very high in our study, even in the intermittent epidural analgesia group in which the patients NRS scores were high. In the literature, it is suggested that patient satisfaction is equally expressed in the opioid based intravenous PCA method as in the local anesthesia based epidural method, although epidural analgesia is associated with increased analgesic efficacy This finding means that satisfaction depends more on the length of time spent with the patient rather than the analgesic efficacy. In our study, side effects related to the analgesic methods used were few. The analgesic methods used are invasive and sophisticated methods and they require close monitorization. The low incidence of the side effects is related to careful and frequent follow-up of the patient s analgesic status by the acute pain service members. So, we can conclude that one of the advantages of this service is that it favors the use of sophisticated analgesic methods during surgery continuing on the wards and it decreases the use of expensive monitorization techniques in the sake of frequent visits on the wards, including the physical and neurological examinations. 4

12 Marmara Medical Journal 2005;18(1);1-5 Zeynep Eti, et al. Acute Pain Service Organization There are few centers that have organized acute pain service in Turkey. The organization of this service in our hospital is nearly new and it will be reasonable for us to investigate and make publications during the coming years, whether this organization is going to improve postoperative pain relief, patient satisfaction, and decrease side effects related to the analgesic methods, morbidity, hospital stay and cost issues. REFERENCES 1. Ballantyne JC, Carr DB, deferranti S, et al. The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. Anesth Analg 1998; 86: Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomized trials. BMJ 2000; 321: Kehlet H, Holte K. Effects of postoperative analgesia on surgical outcome. Br J Anaesth 2001; 87: Beattie WS, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial infarction: a metaanalysis. Anesth Analg 2001; 93: Werner MU, SØholm L, RotbØll-Nielsen P, et al. Does an acute pain service improve postoperative outcome? Anesth Analg 2002; 95: Frenette L. The acute pain service. Critical Care Clinics 1999; 15: Ready B, Oden R, Chadwick H, et al. Development of an anesthesiology-based postoperative pain management sevice. Anesthesiology 1988; 68: Miaskowski C, Crews J, Ready LB, et al. Anesthesiabased pain services improve the quality of postoperative pain management. Pain 1999; 80: Varrasi G, Donatelli F, Marinangeli F, et al. Organization of an acute pain service and pain management. In General considerations for regional anesthesia. 10. Petrakis JK. Acute pain services in a community hospital. Clin J Pain 1989; 5 (Suppl 1): S Maier C, Kibbel K, Mercker S, et al. Postoperative pain therapy at general nursing stations: an analysis of eight year s experience at an anesthesiological acute pain service. Anaesthesist 1994; 43: Dolin SJ, Cashman JN, Bland JM. Effectiveness of acute postoperative pain management: I. Evidence from published data. British Journal of Anaesthesia 2002; 89: Capdevilla X, Barthelet Y, Biboulet P, et al. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology 1999; 91: Liu SS, Carpenter RL, Mackey DC, et al. Effects of postoperative analgesic technique on rate of recovery after colon surgery. Anesthesiology 1995; 83: Mann C, Pouzeratte Y, Boccara G, et al. Comparison of intravenous or epidural patient- controlled analgesia in the elderly after major abdominal surgery. Anesthesiology 2000; 92:

13 ORIGINAL RESEARCH PROTECTIVE EFFECTS OF 2-MERCAPTOETHANE SULFONATE (MESNA) ON PROTAMINE SULFATE INDUCED BLADDER DAMAGE Beyhan Sağlam 1, Esra Cikler 1, Ali Zeybek 2, Şule Çetinel 1, Feriha Ercan 1, Göksel Şener 3 1 Department of Histology and Embryology, School of Medicine, Marmara University, İstanbul, Turkey 2 Department of Anatomy, School of Medicine, Kocaeli University, Kocaeli, Turkey 3 Department of Pharmacology, School of Pharmacy, Marmara University, İstanbul, Turkey ABSTRACT Objective: This morphological and biochemical study aims to investigate the putative protective effects of 2-mercaptoethane sulfonate (MESNA) on protamine sulfate (PS) induced bladder injury. Material and methods: Wistar albino female rats were catheterized and intravesically infused with phosphate buffered solution-pbs (control group) or PS (PS group) dissolved in PBS. In the PS + MESNA group after the PS instillation MESNA (50 mg/kg) was injected intraperitoneally for three days. Bladder morphology was investigated by light and scanning electron microscopy. Tissue samples were also obtained to determine bladder malondialdehyde and glutathione levels. Results: In the PS group ulcerated areas, an irregular mucus layer, inflammatory cell infiltration, increased number of mast cells were observed. In the PS + MESNA group a relatively normal urothelial topography, glycosaminoglycan layer and decreased number of mucosal mast cells and inflammatory cells were observed. Increased malondialdehyde levels as a result of PS induction lead us to propose that free radicals may have a critical role in this injury. The decrease in malondialdehyde and increase in glutathione levels in the PS + MESNA group was in accordance with morphological findings. Conclusion: Based on the results, MESNA treatment significantly prevented PS induced degenerative changes in the bladder Keywords: MESNA, Protamine sulfate, Urinary bladdder 2-MERCAPTOETAN SÜLFONAT (MESNA) IN, PROTAMİN SÜLFATIN TETİKLEDİĞİ MESANE HASARI ÜZERİNDEKİ KORUYUCU ETKİLERİ ÖZET Amaç: Bu morfolojik ve biyokimyasal çalışmanın amacı 2-mercaptoetan sulfonat (MESNA) ın protamin sülfat (PS) ın tetiklediği mesane hasarı üzerindeki koruyucu etkilerinin araştırılmasıdır. Gereç ve Yöntem: Wistar albino dişi sıçanlar kateterize edilerek mesane içine fosfat tamponu (kontrol grubu) ya da fosfat tamponu içinde çözünmüş PS (PS grubu) infüze edildi. PS + MESNA grubundaki sıçanlara PS verilmesinden sonra, 3 gün boyunca, 50 mg/kg MESNA i.p. olarak enjekte edildi. Mesane morfolojleri ışık ve taramalı elektron mikroskopi düzeylerinde incelendi; ayrıca dokudaki malondialdehit ve glutatyon düzeylerine de bakıldı. Bulgular: PS grubunda ülserli alanlar, düzensiz mukus tabakası, inflamatuvar hücre infiltrasyonu ve mast hücre sayısında artış gözlendi. PS + MESNA grubunda PS grubuna oranla, normal ürotel görüntüsü ve glikozaminoglikan tabakası ile inflamatuvar hücrelerin ve mukozal mast hücrelerinin sayısında azalma izlendi. PS nin tetiklemesi ile oluşan hasarda önemli rol oynayabilecek olan serbest radikallerin ortaya çıkması sonucunda malondialdehit düzeyi artmış glutatyon düzeyi ise düşmüş bulundu. PS + MESNA grubunda morfolojik bulgularla uyumlu olarak, malondialdehit düzeyi önemli derecede düşmüş, glutatyon düzeyi ise artmıştır. Sonuç: Bu bulgular, mesane mukozasında PS ın tetiklediği morfolojik hasar ve biyokimyasal değişikliklerin MESNA tedavisi ile önemli düzeyde önlenebileceğini göstermektedir. Keywords: MESNA, Protamin sülfat, Mesane INTRODUCTION Protamine sulfate (PS) is an arginine-rich protein with a molecular weight of It has strong alkali and polycationic components 1. When protamine is added to heparin in vitro, stable deposits occur between the two components because of ionic influence. After it was shown Corresponding author: Şule Çetinel, M.D., Department of Histology and Embryology, School of Medicine, Marmara University, Tıbbiye Cad. No: 49, Haydarpaşa, İstanbul, Turkey. [email protected] that protamine sulfate neutralizes heparin in vivo, it was used to aid recovery from the anticoagulant effect of heparin 1. PS changes the permeability of different types of epithelium based on its concentration in the environment. Later, other effects of protamine sulfate were observed 2,3, including its effects on permeability of the Marmara Medical Journal 2005;18(1);6-12 6

14 Marmara Medical Journal 2005;18(1);6-12 Şule Çetinel, et al. Protective Effects of 2-Mercaptoethane Sulfonate (Mesna) on Protamine Sulfate Induced Bladder Damage endothelium and the types of epithelium 2-4. PS and urea given intravesically cause de-epithelization of the epithelial tissue. This procedure is now used as an in situ treatment for bladder carcinoma 5. Interstitial cystitis (IC) is a sterile bladder condition that occurs almost exclusively in women (90%). This disease is characterized by urinary frequency, urgency, burning and suprapubic pain. 6. Among the proposed theories are infection 7 autoimmunity 8 the presence of toxic substances in the urine 9 and psychiatric causes 10. The morphological criteria for research into IC were established by The National Institute of Health (NIH), and the National Institute of Arthritis, Digestive, Diabetic and Kidney Diseases (NIDDKD). Mononuclear inflammation, mucosal hemorrhage, and deficiencies in the mucous layer of the bladder, epithelial disruption and increased mast cells in the urothelium are the criteria included Mercaptoethane sulfonate (MESNA) is a synthetic small molecule that has the potential to scavenge reactive oxygen metabolites (ROM) by virtue of its sulfhydryl group. 11. MESNA was proven to be effective as an antioxidant drug in various in vivo and in vitro models 12. MESNA binds acrolein within the urinary tract and detoxifies it; the resulting inert the other does not induce damage to the urothelium 13,14. It is widely used as a systemic protective agent against the toxicity of chemotherapy and is primarily used to reduce hemorrhagic cystitis induced by cyclophosphamide 15. Although MESNA has been widely used as an agent against cyclophosphamide-induced cystitis, significant hemorrhagic cystitis, defined as an episode of symptomatic (burning, frequency, and dysuria), microscopic, or macroscopic hematuria has been encountered clinically 16. In addition, MESNA was shown to inhibit the development of bladder tumor in rats 17 and by increasing the kidney levels of free thiol levels it was shown to prevent renal oxidative damage in rats treated with ferric nitrilotriacetate 18. Owing to its direct suppressive effect on the production of hydrogen peroxide, thiol-containing MESNA may be considered as an antioxidant drug to limit the toxic effects of free radicals produced by all kinds of oxidative injuries. In the present study, the putative protective effect of MESNA against PS-induced urinary bladder damage was examined using morphological techniques such as light and scanning microscopy, and biochemical approaches such as measurement of urinary bladder malondialdehyde (MDA) and glutathione (GSH) levels. METHODS Animals: Wistar albino adult female rats weighing g. were used in this study. They were housed individually in light and temperature controlled rooms on a 12/12 light-dark cycle. They had free access to standard pellet laboratory chow and water. Experimental group: Three groups of 6 rats each were used, including the control, PS and PS + MESNA groups. Bladder injury was induced with grade x PS (Sigma Chemical Co., St. Louis, Missouri) applied intravesically by a PE50 catheter at a dose of 5 mg/ml twice in 24 hours (protamine sulfate group). Each time 0.2 ml solution was instilled to the bladder. In the PS + MESNA group 2 hours after the second PS dose, 150 mg/kg MESNA was injected intraperitoneally twice daily for 3 days (PS + MESNA group). In the control group only phosphate buffered solution was instilled twice daily. All instillations were performed with the animal under light anesthesia. Bladder samples were removed after the experiments and processed for morphological and biochemical investigations. Microscopic Preparation: For light microscopy, urinary bladder samples were fixed in 10% formaldehyde and processed routinely.. Tissue sections (5 µm) were stained with hematoxylin and eosin (H&E) for general morphology and with 0,5% acidified toluidine blue (ph 2,5) for mast cells. Stained sections were examined under an Olympus BX51 photomicroscope. For scanning electron microscopy the samples were fixed in 4% phosphate buffered gluteraldehyde (0.13 M and PH 7,4) for 4 hours, postfixed with 1% OsO4 for one hour, and processed routinely for scanning electron microscopic investigation. These samples were observed under Jeol JSM scanning electron microscope (SEM). Malondialdehyde and Glutathione Assays: Tissue samples were homogenized with ice-cold trichloracetic acid (1 g tissue plus 10 ml 10% TCA) in an Ultra Turrax tissue homogenizer. The MDA levels were assayed for products of lipid peroxidation by monitoring thiobarbituric acid reactive substance formation as described previously 19. Lipid peroxidation was expressed in 7

15 Marmara Medical Journal 2005;18(1);6-12 Şule Çetinel, et al. Protective Effects of 2-Mercaptoethane Sulfonate (Mesna) on Protamine Sulfate Induced Bladder Damage terms of MDA equivalents using an extinction coefficient of 1.56 x 10 5 M 1 cm 1 and results are expressed as nmol MDA/g tissue. Glutathione was determined by a spectrophotometric method based on the use of Ellman s reagent 20. Briefly, after centrifugation at 3000 rev./min for 10 min, 0.5 ml of supernatant was added to 2 ml of 0.3 mol/l Na 2 HPO 4.2H 2 O solution. A 0.2 ml solution of dithiobisnitrobenzoate (0.4 mg/ml 1% sodium citrate) was added and the absorbance at 412 nm was measured immediately after mixing. Glutathione levels were calculated using an extinction coefficient of M 1 cm 1. Results are expressed in mol GSH/g tissue. Mast Cell Counts: Paraffine sections stained with toluidine blue were used for both granulated and degranulated mast cell counting. Ten areas in each sample were selected and mast cells containing metachromatic granules were counted separately at 400x magnification in the mucosa by one or more observers and the observers were blind to the group from which each sample was obtained. An eye-piece graticule ( mm 2 ) was used in order to avoid overlapping of counting areas. Areas selected in each region were surveyed for mast cells and the mast cell density was then expressed as cell number per unit area. Statistical analysis: Statistical analysis was carried out using GraphPad Prism 3.0 (GraphPad Software, San Diego; CA; USA). All data were expressed as means ± SEM. Groups of MDA and GSH data were compared with an analysis of variance (ANOVA) followed by Tukey s multiple comparison tests. Mann Whitney U nonparametric test was used to evaluate mast cells. Values of p<0.05 were regarded as significant. RESULTS In the control group, normal mucosa and overlying mucus layer (Fig. 1a), a small number of mast cells (Fig. 1b) was observed in the bladder wall at the light microscopy level. Regular mucosal topography (Fig. 1c) was observed at SEM level. In the PS group, loss of urothelial cells, focal decrease of the cell layer of urothelium and irregularity of mucus layer, severe inflammatory cell infiltration (Fig. 2a) and increased number of both granulated and degranulated mast cells (Fig. 2b) were observed with the light microscope. Detachment and loss of urothelial cells and local ulcerated areas were the dominant features at SEM level (Fig. 2c). Fig 1: Control group: a) Urothelial mucosa with regular mucus layer and epithelial cells H-E X 200. b) A small number of mast cells (->) in mucosa, toluidine blue staining, X400. c) Luminal surface of the bladder with mucosal folding, mucous covered areas and polygonal shaped apical cells (*), scale bar: 10µm. Fig 2: PS group: a) Degeneration of the urothelial layer and local ulceration areas (->) with severe accumulation of neutrophils (>), H-E staining, X 200, inset X400. b) Increased number of mast cells, in mucosa, toluidine blue staining, X400. c) Ulcerations in most of the urothelium with mucus and epithelial cell loss (*), scale bar: 10µm. 8

16 Marmara Medical Journal 2005;18(1);6-12 Şule Çetinel, et al. Protective Effects of 2-Mercaptoethane Sulfonate (Mesna) on Protamine Sulfate Induced Bladder Damage In the PS + MESNA group, the urothelium retained its integrity. A decrease in the density of inflammatory (Fig. 3a) and mast cell (Fig. 3b) population was evident when compared to the PS group at light microscopic level. SEM observations showed regeneration of luminal mucosa (Fig. 3c) but local degenerated sites were still present. The number of granulated and degranulated mast cells per square millimeter in the mucosa of bladder stained with toluidine blue was counted. According to the statistical analysis there was a significant increase in both the granulated (p<0.01) and degranulated (p<0.01) mast cell number in the protamine sulfate group when compared with the control and protamine sulfate plus MESNA group. MESNA treatment reduced the number of both granulated and degranulated mast cell in mucosa of PS- induced urinary bladder ( Fig. 4). Protamine sulfate induction caused a prominent increase in MDA levels (22.5 ± 2.1 nmol/g) an end product of lipid peroxidation, compared to the control group (11.3 ± 1.2 nmol/g, p<0.01). Bladder tissues in the PS + MESNA group responded to MESNA treatment with a decrease in MDA levels (11.9 ± 1.2 nmol/g, p<0.01, Fig. 5a) and this response was statistically significant (p<0.01). The decrease in bladder GSH levels in the protamine sulfate group (0.51 ± 0.1 µmol/g) was also significant when compared to the control group (1.7 ± 0.3 µmol/g, p<0.01) and increased by MESNA treatment (1.6 ±0.1 µmol/g, p<0.05, Fig. 5b). Fig 3: PS + MESNA group: a) Regeneration of urothelium (->) in most areas and decrease in number of inflammatory cells (>) in mucosa, H-E staining, X 200, inset X400. b) Decreased number of mast cells in mucosa, toluidine blue staining, X400. c) Healing of the urothelial mucosa (*) and mucus layer, scale bar: 10µm. Fig 4: Number of mast cells per mm 2 in control, PS and PS+MESNA groups. **p<0.01: compared to control group; ++p<0.01 compared to PS group. 9

17 Marmara Medical Journal 2005;18(1);6-12 Şule Çetinel, et al. Protective Effects of 2-Mercaptoethane Sulfonate (Mesna) on Protamine Sulfate Induced Bladder Damage Fig 5: Urinary bladder a) malondialdehyde (MDA) and b) glutathione (GSH) levels of the control, protamine sulphate (PS), and MESNA-treated-PS (PS+MESNA) groups. **p<0.01 compared to control; ++ p<0.01 compared to PS group. DISCUSSION The results of the present study demonstrate that MESNA has protective effects on PS-induced urinary bladder damage. The degenerative morphological and biochemical changes of the urinary bladder are reversed by MESNA treatment. As the oxidative injury on cellular structures is reduced by MESNA, intracellular antioxidant GSH, which is otherwise oxidized during the process of inactivating free radicals, is not changed. Bladder urothelium integrity relies primarily on its surface glycosaminoglycans (GAG) and the structure of cell-cell contacts to maintain its permeability 21. Sulfated polysaccharides have a higher affinity for quaternary amines than for water on the bladder surface and they inactivate native bladder polysaccharide 21. Experimental studies showed that when the electron negative surface polysaccharide is neutralized by the polycation of PS, the epithelium leaks urea, calcium, and water 22. These deleterious effects of PS were reversed by subsequent intravesical treatment of GAG (heparin) 23. Many studies have shown that protamine increases the permeability of different types of epithelium 24,25. Generally defects or any changes in the GAG layer of the urothelium have an initiating role in interstitial cystitis 21. In the current study we observed focal loss of the urothelial layer, and loss and irregularity of the GAG layer in most areas, similar to the study of Parsons et al. 24,22. Scanning electron microscopy observations in patients with IC showed a decrease in the mucous layer, degeneration of cell junctions and increase in the number of microvilli 25. Our light and scanning electron microscopy observations on PS administration showed a decrease in the mucous layer, dilatation of the superficial cells and ulcerated areas at the apical surface. It has been shown that MESNA is rapidly oxidized to the MESNA disulfide form (DIMESNA) in plasma, and DIMESNA is then reduced to MESNA, an active thiol form, by cytosolic enzymes in renal tubular epithelia. When MESNA is administered at high doses, the autooxidation process will be saturated and a higher plasma concentration of free MESNA will be presented to the renal tubules. Following absorption by the tubular cells, this substance will supply free thiol groups, which will continue the detoxification of toxic oxygen metabolites 26. Thus, the protective effect of MESNA on the urinary bladder, as observed in the present study, may be attributed to its thiol-supplying action. In an in vitro study, it was shown that hyperthermiainduced cytotoxicity in Chinese hamster ovary cells was reduced and intracellular glutathione levels were increased by MESNA pretreatment 27. MESNA is primarily used as a chemoprotector agent to reduce hemorrhagic cystitis induced by oxazaphosphorine (e.g. cyclophosphamide and ifosfamide) 28. Methotrexate-induced cytotoxicity was also limited with MESNA by inhibiting excessive hydrogen peroxide production during chemotherapy 11. Lipid peroxidation, mediated by free oxygen radicals, is believed to be an important cause of destruction and damage to cell membranes, since polyunsaturated fatty acids of the cellular membranes are degraded by this process with consequent disruption of membrane integrity. Membrane peroxidation can lead to changes in membrane fluidity and permeability and also to 10

18 Marmara Medical Journal 2005;18(1);6-12 Şule Çetinel, et al. Protective Effects of 2-Mercaptoethane Sulfonate (Mesna) on Protamine Sulfate Induced Bladder Damage enhanced rates of protein degradation, and these will eventually lead to cell lysis 29. In the present study, the level of MDA, an end product of lipid peroxidation, is significantly increased in the PSinduced urinary bladder. Our results demonstrate that MESNA inhibits MDA elevation significantly and reverses it to control levels. Thus MESNA could be protective against PS- induced oxidative urinary bladder damage by preserving the cellular integrity. Glutathione, a key antioxidant, is an important constituent of intracellular protective mechanisms against various noxious stimuli, including oxidative stress. On the other hand, reduced glutathione, which constitutes the main component of endogenous non-protein sulfhydryl pool, is known to be a major low molecular weight scavenger of free radicals in the cytoplasm 30. These data are in accordance with the findings of a recent study which demonstrated that MESNA treatment caused marked reductions in tissue lipid peroxidation levels and normalized glutathione activities in ischemia-reperfusison induced renal damage 31 and cyclophosphamide and ifosphamide-induced urinary bladder damage 32. Observations suggest that ROMs play a role in the recruitment of neutrophils into postischemic tissue, but activated neutrophils are also a potential source of ROMs 33,34. In this study, as expected, PS induction caused a neutrophil infiltration and mast cell activation and furthermore this increased infiltration and activation was inhibited by MESNA treatment. This might also result in reduced lipid peroxidation and thus, less accumulation of MDA, since activation of neutrophils might lead to the generation of more oxygen reactive metabolites. Mast cell recruitment is the result of the inflammation present in the inflamed bladder tissue 35. Besides the inflammatory cells mast cells contribute the inflammation via the agents in their granules such as histamine, heparin, tyrptase, etc. This study showed PS induction leads to an increase in both granulated and degranulated mast cells. In the MESNA treated group after PS induction, there is a reduction in both granulated and degranulated mast cells which points that MESNA reducing the inflammation via the inhibition of lipid peroxidation also leads to a reduction in the number of both granulated and degranulated mast cells. In conclusion, in view of previous observations and our data, with potent free radical scavenger and antioxidant properties, MESNA seems to be a promising agent for protecting tissues from oxidative damage and preventing organ dysfunction due to PS induction and can be used as a therapeutic agent in inflammatory urinary bladder diseases such as interstitial cystitis. REFERENCES 1. Horrow JC. Protamine a review of its toxicity. Anesth Analg 1985;64: Peterson MW, Gruenhaupt D. Protamine interaction with the epithelial cell surface. J Appl Physiol 1992;72: Quinton PM, Philpott CW. A role for anionic sites in epithelial architecture. J Cell Biol 1973;56: Tzan CJ, Berg J, Lewis SA. Effect of protamine sulfate on the permeability properties of the mammalian bladder. J Membrane Biol 1993;133: Niku DS, Stein PC, Scherz HC, Parsons CL. A new method for cytodestruction of bladder epithelium using protamine sulfate and urea. J Urol 1994;152: Johansson SL, Fall M. Pathology of interstitial cystitis. Urol Clin North Am 1994; 21: Fall M, Johansson SL, Vahlne A. A clinicopathological and virological study of interstitial cystitis. J Urol 1985;133: Sant GR. Diagnosis of interstitial cystitis. A clinical, endoscopic and pathologic approach. In: Hanno PM, Staskan DR, Krane RJ, Wein AJ..Interstitial Cystitis. London.: Springer. 1990: Fowler JE, Jr Lynes WL, Lau JLT, Ghosh L, Mounzer A. Interstitial cystitis is associated with intraurethelial Tamm-Horsfall protein. J Urol 1988;140: Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, J Urol 1988;140 : Gressier B, Lebegue S, Brunet C, et al: Pro-oxidant properties of methotrexate: evaluation and prevention by anti-oxidant drug. Pharmazie 1994;49: Gressier B, Lebegue N, Brunet C, et al. Scavenging of reactive oxygen species by letosteine, a molecule with two blocked-sh groups. omparison with free SH drugs. Pharm World Sci 1995;17: Goren MP, McKenna LM, Goodman TL. Combined intravenous and oral mesna in outpatients treated with ifosfamide. Cancer Chemother Pharmacol 2003; 40: Kurovski V, Wagner T. Urinary excretion of ifosfamide, 4-hydroxyfosfamide, 3- and 2-dechloroethylifosfamide, mesna, and dimesna in patients on fractionated intravenous ifosfamide and concomitant mesna therapy. Cancer Chemother Pharmacol 1997;39: Berrigan MJ, Marinello AJ, Pavelic Z, Williams CJ, Struck RF, Gurtoo HL.Protective role of thiols in cyclophosphamide-induced urotoxicity and depression of hepatic drug metabolism. Cancer Res 1982;42:

19 Marmara Medical Journal 2005;18(1);6-12 Şule Çetinel, et al. Protective Effects of 2-Mercaptoethane Sulfonate (Mesna) on Protamine Sulfate Induced Bladder Damage 16. West NJ. Prevention and treatment of hemorrhagic cystitis. Pharmacother 1997; 17: Nishikawa A, Morse MA, Chung FL. Inhibitory effects of 2-mercaptoethane sulfonate and 6-phenylhexyl isothiocyanate on urinary bladder tumorigenesis in rats induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. Cancer Lett 2003;193: Umemura T, Hasegawa R, Sai-Kato K, et al. Prevention by 2-mercaptoethane sulfonate and N-acetylcysteine of renal oxidative damage in rats treated with ferric nitrilotriacetate. Jpn J Cancer Res 1996;87: Beuge JA, Aust SD. Microsomal lipid peroxidation. Method Enzymol 1978;52: Beutler E. Glutathione in red blood cell metabolism. A manual of Biochemical Methods. Published by Grune and Stratton. New York, 1975: Lilly JD, Parsons L. Bladder surface glycosaminoglycans. Is a human epithelial permeability barrier?. Surg. Gynecol Obstet 1990;171: Parsons CL, Lilly JD, Stein P. Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J Urol 1991;145: Parsons CL, Housley T, Schmidt JD, Lebow D. Treatment of interstitial cystitis with intravesical heparin. Br J Urol 1994;73: Parsons CL, Boychuk D, Jones S, Hurst R, Callahan H. Bladder surface glycosaminoglycans: An epithelial permeability barrier. J Urol 1990;143: Anderström CRK, Fall M, Johansson SL. Scanning electron microscopic findings in interstitial cystitis. Br J Urol 1989;63: Skinner R, Sharkey IM., Pearson ADJ, Craft AW. Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol 1993;11: Lord-Fontaine S, Averill DA. Enhancement of cytotoxicity of hydrogen peroxide by hyperthermia in Chinese hamster ovary cells: role of antioxidant defenses. Arch Biochem Biophys 1999;363: Souid AK, Fahey RC, Aktas MK, et al. Blood thiols following amifostine and mesna infusions, a pediatric oncology group study. Drug Metab Dispos 2001;29: Garcia JJ, Reiter RJ, Guerrero JM, Escames G, Yu BP, Oh CS, Munoz-Hoyos A. Melatonin prevents changes in microsomal membrane fluidity during induced lipid peroxidation. FEBS Lett 1997:408: Ross D. Glutathione, free radicals and chemotherapeutic agents. Mechanisms of free-radical induced toxicity and glutathione-dependent protection. Pharmacol Ther 1988;37: Kabasakal L, Sehirli AO, Cetinel S, Cikler E, Gedik N, Sener G. Mesna (2-mercaptoethane sulfonate) prevents ischemia/reperfusion induced renal oxidative damage in rats. Life Sci 2004,Sep 24;75: Vieira MM, Macedo FY, Filho JN, et al.. Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamideinduced hemorrhagic cystitis in rats. Phytother Res 2004 Feb;18: Granger DN, Korthuis RJ. Physiological mechanisms of postischemic tissue injury. Annu Rev Physiol. 1995;57: Zimmerman BJ, Grisham MB, Granger DN: Role of oxidants in ischemia-reperfusion induced granulocyte infiltration. Am J Physiol 1990;258:G185 G Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 2001;57 (suppl.6a):

20 ORIGINAL RESEARCH DOES THE FREQUENCY OF THE SELF -MONITORING OF BLOOD GLUCOSE INFLUENCE GLYCEMIC CONTROL IN TYPE 2 DIABETIC PATIENTS? Hasan Aydın, Oğuzhan Deyneli, Dilek Yavuz, Özlem Tarçın, Sema Akalın Department of Endocrinology and Metabolism, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Objective: The aim of this study was to evaluate the effects of different intervals of the self-monitoring of blood glucose (SMBG) on glycemic control in a selected type 2 diabetic population. Methods: Type 2 diabetic patients with disease duration >1 year who were on insulin treatment for at least 6 months and were already applying SMBG were included in the study. A total of 118 patients were enrolled and classified into groups based on SMBG frequencies as once in a week, once in two weeks, once in a month and not at all. At the end of the 12 weeks glycemic control was assessed with measured blood glucose and A1c levels. Results: After 3 months of monitorization, A1c levels significantly decreased in group 1 (p<0.005) and group 2 patients (p<0.05) and no change or even an increase was observed in other groups. Reported hypoglycemic events were rare in all patients. Conclusion: SMBG is important for the achievement of glycemic goals and simplifying SMBG may help to overcome problems of compliance and cost. Keywords: Self monitoring of blood glucose, Type 2 diabetes mellitus, Glycemic control TİP 2 DİYABETİK HASTALARDA KENDİ KENDİNE KAN GLUKOZ İZLEM SIKLIĞI GLİSEMİK KONTROLÜ ETKİLER Mİ? ÖZET Amaç: Kendi kendine kan şekeri ölçümü insülinle tedavi edilen tüm diyabetik hastalar için önerilmektedir. Her ne kadar tip 1 diyabetik hastalar için standart takip programları belirlenmiş ise de tip 2 diyabetik hastalar için standart bir kan glukoz takip programı yoktur. Bu çalışmanın amacı tip 2 diyabetik hastalarda kendi kendine kan glukoz ölçüm sıklığının glisemik kontrol üzerine olan etkilerini değerlendirmektir. Yöntem: Bu çalışmaya kendi kendine kan şekeri ölçümü yapan insülin kullanan tip 2 diyabetik 118 hasta dahil edilmiştir. Hastalar kan şekeri ölçüm sıklıklarına göre haftada bir (n=49), onbeş günde bir (n=33), ayda bir (n=14) ve hiç ölçüm yapmayan (n=22) olarak gruplara ayrılmıştır. Hastalara ölçüm tekniği konusunda eğitim verildikten sonra kan şekeri ölçümlerini yaparak insülin dozlarını ayarlamaları istenmiştir. Hiç kan şekeri ölçümü yapmayan hastalardan 3 aylık dönemlerde açlık ve tokluk kan şekeri ölçümleri istenmiştir. 3 aylık takip dönemi sonunda hastalar kan şekerleri ve A1c düzeylerindeki değişim açısından tekrar değerlendirilmiştir. Bulgular: Hastaların demografik özellikleri, kullanmakta oldukları insülin tipleri ve dozları açısından farklı olmadığı görülmüştür. Bazal A1c düzeyleri tüm grıuplarda benzer bulunmuştur. Kendi kendine kan şekeri ölçümü yapan hastaların komplikasyon oranları daha düşüktür. Haftada bir ve onbeş günde bir kendi kendine kan şekeri ölçümü yapan hastaların 3. ay sonunda A1c düzeylerinde anlamlı bir düzelme görülürken (p<0,001 ve p=0,017) ayda bir ölçüm yapan ve hiç ölçüm yapmayan grupların A1c düzeylerinde değişim olmamıştır. Sonuç: İnsülin kullanan tip 2 diyabetik hastalarda kendi kendine kan glukoz ölçüm sıklığı arttıkça glisemik kontrol daha iyi sağlanabilmektedir. Anahtar kelimeler: Kendi kendine kan şekeri ölçümü, Tip 2 diabetes mellitus INTRODUCTION The American Diabetes Association (ADA) recommends the self -monitoring of blood glucose (SMBG) for all type 1 and type 2 diabetic patients treated with insulin 1. SMBG improves the efficacy of treatment and provides better glycemic targets. SMBG also prevents hypoglycemic episodes and enables a better adjustment of medications in a Corresponding author: Hasan Aydın, M.D. Department of Endocrinology and Metabolism, School of Medicine, Marmara University Hospital, Altunizade, Istanbul, Turkey. [email protected] better way. SMBG has been applied with different measuring intervals and different timings 2,3. It is evident that SMBG provides better glycemic control compared to patients not measuring their blood glucose 4. Furthermore, increasing sampling frequency increases the likelihood of better A1c levels 5,6. On the other hand, only 39.1% of insulin-treated type Marmara Medical Journal 2005;18(1);

21 Marmara Medical Journal 2005;18(1);13-16 Hasan Aydın, et al. Does The Frequency of Self Monitoring of Blood Glucose Influence Glycemic Control In Type 2 Diabetic Patients? 2 diabetic patients perform SMBG daily and 10% measure blood glucose two or more times per day 7. This shows that there is an important compliance problem. Although ADA reinforces more efforts for appropriate use of SMBG, a change in strategy is needed to increase compliance. Data from most studies are based on daily SMBG in both type 1 and type 2 diabetic patients but the consequences of increasing the measuring intervals of SMBG is not known. The aim of this study is to evaluate the effects of different intervals of SMBG on glycemic control in a selected type 2 diabetic population. METHODS The study was designed as open and prospective trial with a follow-up period of 12 weeks. Subjects were recruited from the outpatient endocrinology clinic of Marmara University Hospital. The recruitment of patients was completed in three months. Type 2 diabetic patients with a disease duration >1 year who were on insulin treatment for at least 6 months and were already applying SMBG were included in the study. Patients who were unable to continue SMBG for any reason or who were on oral antidiabetic medications were excluded. Pregnant or lactating women, patients with any chronic illness, drug or alcohol abuse were also not included. The use of drugs interfering with glucose metabolism such as glucocorticoids was also a reason for exclusion. Patients were asked not to change their dietary habits during the study period. The study was approved by the Ethics Committee of Marmara University Medical School and written informed consent was given by all subjects participating in the study. A total of 118 patients were enrolled between November 2003 and January A one week run-in period was used for the education of patients in the use of blood glucose meters (Medisense Optium Sensor-Abbott Laboratories). Patients were instructed to measure their blood glucose as often as they could. They were then classified into groups based on SMBG frequencies as once a week, once in two weeks, once a month and not at all. They were requested to measure blood glucose four times a day, before each main meal and at bed time without changing meal intervals. Obtained values were recorded in a diary. Patients were seen every four weeks. At each visit, patients were checked for the correct use of blood glucose meters and the self regulation of blood glucose was discussed. Height, weight, body mass index were recorded at the beginning of the study and at each visit. A1c levels were tested at the beginning and at the end of 12 weeks. Data were analyzed using a SPSS program (version 11.0). Comparisons between groups were done using Mann-Whitney test. A p value less than 0.05 was considered significant. The results were expressed as mean±sd. RESULTS Patients measuring their blood glucose once in a week constitute group I, once in two weeks group II, once in a month group III, not at all group IV, respectively. The demographic characteristics of the study groups are shown in Table I. Mean age of the subjects in all groups was above 60 years. Patients in group 2 were younger than patients in group 4 (64±9 vs 70±10 years, p<0.05). Sixty one percent of the patients (n=72) were women. Disease duration in group 3 was longer than others (p<0.05). Mean duration of insulin use and mean insulin doses were similar. Microvascular complications were significantly less in group II patients and were found to be increased significantly in patients who did not monitor their blood glucose (p<0,001). Table1: Demographic characteristics of study patients Group 1 Group II Group III Group IV Age (years) 64±9 62±10 66±10 70±10 Sex (M/F) 36/13 12/21 9/5 15/7 Disease duration (years) 13±7 9±6 15±7 10±7 Duration of insulin use (years) 4±3 4±3 5±4 4±3 Mean insulin dose (U/day) 43±23 44±23 49±20 48±20 Rate of complications (%) Retinopathy Nephropathy Neuropathy *p<0.05, p< GroupI patients measuring blood glucose once in a week, Group II once in two weeks, Group III once in a month, Group IV not at all. 14

22 Marmara Medical Journal 2005;18(1);13-16 Hasan Aydın, et al. Does The Frequency of Self Monitoring of Blood Glucose Influence Glycemic Control In Type 2 Diabetic Patients? Table II: Change in glycemic parameters during study Group I Group II Group III Group IV Rate of hypoglycemia (%) Basal 12* Week 12 2* A1c (%) Basal 7.3± ± ± ±1.1 Week ± ± ± ±1.6 P<0.005, p<0.05, Group I patients measuring blood glucose once in a week, Group II once in two weeks, Group III once in a month, Group IV not at all. Baseline A1c levels were above 7% in all groups, without a significant difference between groups. After 3 months of monitorization, A1c levels significantly decreased in group 1 (p<0.005) and group 2 patients (p<0.05) and no change or increase was observed in other groups. Changes in A1c levels were similar in group I and II (Table II). The reduction in A1c levels was more prominent in women than in men (p<0.05). A1c levels improved as patients education status increased (p<0.05). Patients who had had at least one microvascular complication had A1c levels higher than those who did not (p<0.05). On the other hand, A1c levels were improved by frequent monitorization even in these complicated patients (p<0.05). Reported hypoglycemic events were rare in all patients and were almost equal in each group. A significant decrease was observed in hypoglycemic episodes in group I (Table II). DISCUSSION The results of this study confirm the importance of SMBG in insulin-treated type 2 diabetic patients. Glycemic control improves as frequency of monitorization increases. These results are in accordance with previous studies 2,3. SMBG is recommended for all type 1 and insulin using type 2 diabetic patients in the ADA annual revisions. It is stated that SMBG should be an integral component of diabetes therapy and should be included in the management plans 1. Most of the major clinical trials point out that tightness of glycemic control plays a central role in the prevention of both microvascular and macrovascular complications in type 1 and type 2 diabetes mellitus 8,9. Most of these trials include and recommend SMBG as part of the treatment plan. Besides providing tight glycemic control, SMBG also allows patients to self monitor their response to treatment. Being a part of treatment can increase the compliance of patients. In addition, SMBG may help to prevent hypoglycemic episodes and allows management of treatment plans. The frequency and timing of SMBG change with the needs of the patients to achieve glycemic targets. ADA recommends 3 or more blood glucose measurements per day for type 1 and gestational diabetic patients 1. There is no optimal frequency of SMBG in type 2 diabetic patients. It is recommended that SMBG should be frequent enough to facilitate the achievement of appropriate glycemic control and prevent hypoglycemia 1. Most of the studies done with type 2 diabetic patients demonstrate that SMBG provides better achievement of glycemic targets. These studies suggest that the frequency of SMBG should be at least once daily and indicate that better glycemic control is achieved as the frequency of measurements increases. There is no data on the effect of less frequent measurements on glycemic control. This is the first study investigating the outcome of various sampling intervals and showing that sampling once in one or two weeks improves glycemic control in a short period of time. The results of this study are important and should be carefully interpreted. It does not deny the importance of more frequent monitorization. SMBG with more frequent intervals provide a better control but increasing the frequency may lead to poor compliance. Only 10% of patients do the samplings two or more times per day irrespective of glycemic status 7. In our study, compliance was 100%. Another important problem is acquirement of test strips. Only 20% of type 1 diabetics and 17% of insulin treated type 2 diabetic patients obtain enough test strips to measure their blood glucose 3. This may be an important issue when state insurance reimburses only one test strip per day for insulin dependant type 2 diabetic patients. Considering the problem of compliance, measurement of blood glucose at least once in two weeks with four measurements per day would be a relevant message of this study. Limitations of this study are brief study duration, small sample size and having no group performing daily SMBG. Furthermore the results 15

23 Marmara Medical Journal 2005;18(1);13-16 Hasan Aydın, et al. Does The Frequency of Self Monitoring of Blood Glucose Influence Glycemic Control In Type 2 Diabetic Patients? cannot be extrapolated for a longer term. This study should be verified with future studies that take into account these limitations. In conclusion, SMBG is important for the achievement of glycemic goals and this can be attained by measuring blood glucose at least once in two weeks, with four measurements done on each day. Since poor compliance and failure to reimburse test strips may be an obstacle in reaching glycemic targets, simplifying SMBG should be an important and prior issue for physicians. REFERENCES 1. American Diabetes Association Position Statement: Standarts of Medical Care in Diabetes. Diabetes Care 2004;27 (Suppl 1): S Harris MI. Frequency of blood glucose monitoring in relation to glycemic control in patients with type 2 diabetes. Diabetes Care 2001; 24: Evans JMM, Newton RW, Ruta DA, MacDonald TM, Stevenson RJ, Morris AD. Frequency of blood glucose monitoring in relation to glycemic control: observational study with diabetes database. BMJ 1999; 319: Schiel R, Müller UA, Rauchfub J, Sprott H, Müller R. Blood-glucose self-monitoring in insulin treated type 2 diabetes mellitus: a cross-sectional study with an intervention group. Diabetes Metab 1999; 25: Murata GH, Shah JH, Hoffman RM, et al. Intensified blood glucose monitoring improves glycemic control in stable, insulin treated veterans with type 2 diabetes. The Diabetes Outcomes in Veterans Study. Diabetes Care 2003; 26: Hoffman RM, Shah JH, Wendel CS, et al. Evaluating once- and twice-daily self-monitored blood glucose testing strategies for stable insulin-treated patients with type 2 diabetes: The Diabetes Outcomes in Veterans Study. Diabetes Care 2002; 25: Harris MI. Health care and health status and outcomes for patients with type 2 diabetes. Diabetes Care 2000;23: Stratton IM, Adler AI, Neil HA, et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: The Diabetes Control and Complication Trial Research Group: the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:

24 ORIGINAL RESEARCH EVALUATION OF THE PREVALENCE AND BEHAVIOURS OF THE EX-SMOKER UNIVERSITY STUDENTS Ruhuşen Kutlu, Kamile Marakoğlu Department of Family Medicine, Meram School of Medicine, Selçuk University, Konya, Turkey ABSTRACT Objective: To evaluate the prevalence, knowledge, and attitudes of ex-smokers at the university in Konya. Methods: This study consisted of 613 ex-smoker university students. The participants were selected by multiphase sampling from 17 different faculties. Data were obtained via questionnaire technique by interviewing. The Chi-square test was used for statistical analysis. Result: In the majority of ex-smokers (98 %), the initiation age of smoking was under 21 years % of ex-smokers had had the knowledge of the harmful effects of smoking before. The most effective way of smoking-cessation was sudden quitting (55.7 %). Conclusion: Cigarette smoking is an important public health problem in Turkey. An effective and comprehensive-national tobacco control program is urgently needed. Keywords: Smoking-cessation, University students, Socio-demographic characteristics SİGARA BIRAKAN ÜNİVERSİTE ÖĞRENCİLERİNDE SİGARA BIRAKMA SIKLIĞI VE DAVRANIŞ ÖZELLİKLERİNİN DEĞERLENDİRİLMESİ ÖZET Amaç: Bu çalışmada Konya da üniversite öğrencilerinde sigara bırakma sıklığı ve davranışlarının değerlendirilmesi amaçlandı. Yöntem: Bu çalışmada 613 sigarayı bırakan üniversite öğrencisi yer almıştır. Katılanlar 17 farklı fakülteden çok aşamalı örneklem yoluyla seçilmiştir. Veriler yüzyüze görüşülerek uygulanan anket yoluyla elde edilmiştir. İstatistiksel analiz için ki-kare testi kullanılmıştır. Bulgular: Sigarayı bırakanların çoğunluğu (%98) sigaraya 21 yaş altında başlamıştı ve %70 i sigaranın zararlı etkileri hakkında bilgiye sahipti. Sigara bırakmada en etkin yol olarak aniden bırakma tespit edildi (%55.7). Sonuç: Türkiye de sigara içme alışkanlığı önemli bir halk sağlığı problemidir. Etkili ve kapsamlı bir ulusal sigara control programına acilen ihtiyaç vardır. Anahtar Kelimeler: Sigara bırakma, Üniversite öğrencileri, Sosyodemografik veriler INTRODUCTION Cigarette smoking is the most important avoidable cause of morbidity and premature death in the developed world 1,2. The harmful effects of smoking on health are now well known 3,4. Such effects include the direct action of cigarettes on the respiratory tract, causing emphysema, bronchopneumonia, bronchitis and cancer of the lung, as well as more indirect action on other organs such as the heart, pancreas, bladder, stomach, uterus etc 5,6. It is therefore important to determine why people begin smoking, because most smokers start smoking soon after starting secondary and high school. Adolescent smoking is thus a communicable disorder, and may be preventable by measures that reduce exposure to other smokers 1,7-9. Having close friends who smoked and being encouraged by close friends to smoke were strong risk factors for smoking 7,10,11. The most effective programs start from the principle that youth have to learn skills to resist pro-smoking pressure from peers, family, media, and advertising 12,13. Anti-smoking school education can postpone smoking initiation for years. One possible measure to reduce the percentage of youth smokers is introducing an age limit for tobacco sales. This has been adopted by many countries, most setting the age limit at 18 years of age 12. Corresponding author: Ruhuşen Kutlu Selçuk Universitesi MeramTıp Fakültesi Aile Hekimligi AD Konya, Turkıye [email protected] Marmara Medical Journal 2005;18(1);

25 Marmara Medical Journal 2005;18(1);17-23 Ruhuşen Kutlu, et al. The Evaluation of The Prevalence and Behaviours of The Ex-Smoker University Students Nicotine, a key ingredient in tobacco products, is an addictive drug. The difficulties in smoking cessation are suggested to be related to nicotine 14. Addiction to nicotine involves the interaction of psychological, physical, behavioral, and social factors 3,4,15. Current health education activities against smoking should be continued and extended to the young population to further reduce the prevalence of smoking and its health consequences If a smoker has been thinking about giving up, advice from health care professionals can encourage him to stop 4,19. The WHO has estimated that the number of deaths each year from smoking-attributable disease will increase to 10 million within the next 30 years or so, of which 70 % will occur in developing countries Prevention and treatment of tobacco use have been targeted by the WHO as a priority in developing countries. However, such efforts are difficult because tobacco companies have applied active marketing and economic pressure to these countries, which are enticed by increased revenues provided by tobacco use 23. Thus tobacco consumption is decreasing by 1 % per year in industrialized nations and increasing by about 2% per year in developing countries 24. Cigarette smoking not only increases risk of death among older adults but also affects quality of life and physical functioning 25. Smoking cessation at any age reduces the overall risk of death 26. Smoking cessation also decreases the risk of developing lung and other cancers 27. Psychological and behavioral factors affecting success in quitting smoking must be established. 23. Health promotion at schools was considered very important because people usually start smoking before the age of 20. Therefore, focusing attention on smoking cessation among university students is an immediate and urgent priority for public health professionals 26,28. METHODS This study was performed with using multiphase sampling among 4504 university students who were selected from 17 faculties of Selçuk University in academic year. In this period, students were having education in the university. In this study, we only selected faculties which had students. Vocational high schools were not included. We used multiphase sampling. Participants were first divided into faculties, after that classes and then gender. We randomly selected from every strata by using 10% sampling. Consequently we reached 4504 students. Data were obtained via the questionnaire form by interviewing. First, the student s smoking status was defined as neversmoker, ever-smoker, and ex-smoker. Secondly, ex-smoker students were selected. This study consisted of 613 ex-smoker university students. Ever- smokers were defined as those who had smoked 100 cigarettes and now smoked either every day (i.e., daily smokers) or some days (i.e., some-day smokers). Ex- smokers had smoked at least 100 cigarettes in their lives but did not currently smoke. The minimum quitting period for the ex-smokers was accepted as 6 months. Neversmokers were defined as those who had never smoked. This special questionnaire included 44 items and contained the students socio-demographic characteristics, opinions related to smoking cessation, the status of smoking in family, and the effects of TV programmes on smoking cessation. Participants answered questions on the following factors. Socio-demographic characteristics: gender, marital status, age, faculty, class, place of living, place of residence, participation in sport activities, the use of another addictive substance, Family characteristics: father s occupation, mother s occupation, father s and mother s educational level, the status of smoking in family. Opinions related to smoking cessation: the reason for smoking cessation, the effect of TV programmes on smoking cessation, the method of smoking cessation, effectiveness of TV programmes related to the harmful effects of smoking, reactions to TV programmes related to smoking. Smoking-related habits before quitting smoking: the initiation age of smoking, duration of smoking, the reason to start smoking, believing the hazards of smoking, being influenced by advertisements related with smoking. Data Analysis The data were entered into a personal computer using the SPSS statistical package. Chi-square and analysis of variance were used to test for baseline differences in demographic and smoking-history variables. Statistical significance was defined as p< RESULTS This study was performed by using multiphase sampling according to faculties, classes and 18

26 Marmara Medical Journal 2005;18(1);17-23 Ruhuşen Kutlu, et al. The Evaluation of The Prevalence and Behaviours of The Ex-Smoker University Students gender by using 10% sampling among 4504 university students. The student s smoking status was defined as never-smoker, ever-smoker, and ex-smoker. Of the students in this study, 36 % (n=1621) were ever-smokers, 13.6 % (n=613) were ex-smokers, 50.4 % (n=2270) were never smokers. For this study, ex-smokers were separated. Table I: Socio-demographic characteristics Of the students in this study 33.1% (n=203) were female, 66.9% (n=410) were male, 92.3% (n=566) were single, and 7.7% (n=47) were married. The age interval of participants was years. The majority of students (90.2%) were not using another addictive substance. The sociodemographic characteristics of the study subjects are shown in Table I. In this study, the mothers educational levels were intermediate and low (92.3 %). Smoking prevalence of fathers was 38.3%. 72.9% of family members were smoking (only father, only mother, brothers, or both parents). The most important reason for smoking-cessation was knowledge of the harmful effects of smoking (51.1%). In the majority of participants (40.6 %), there was a negative opinion that TV programs on smoking-cessation were ineffective. The best way of smoking-cessation was sudden quitting (55.7 %). The majority of participants (56.7 %) had believed that effective TV programmes related to the harmful effects of smoking were lacking. Approximately 88.8% of ex-smokers watched TV programmes related to smoking. Table II shows opinions related with smoking cessation. We found that 3 % of the ex-smokers began smoking before 9 years of age, 17 % of this group began smoking at years of age. In the majority of ex-smokers (78.1 %) the initiation age of smoking was between years. The most important reason to start smoking was social factors (environment, friend groups, etc) (39.1 %). Later, distress and anxiety were found (30.5 %). More than 70.7 percent of ex-smokers were aware of the hazards of smoking. The majority of ex - smokers (65.4 %) did not want their children to smoke. Smoking-related habits before quitting smoking are shown in Table III. Differences of some parameters between smokers and exsmokers are shown in Table IV. 19

27 Marmara Medical Journal 2005;18(1);17-23 Ruhuşen Kutlu, et al. The Evaluation of The Prevalence and Behaviours of The Ex-Smoker University Students Table II: Opinions related with smoking Table III: Smoking-related habits before quitting smoking cessation Table IV: Differences between ever-smokers and ex-smokers at different parameters 20

28 Marmara Medical Journal 2005;18(1);17-23 Ruhuşen Kutlu, et al. The Evaluation of The Prevalence and Behaviours of The Ex-Smoker University Students DISCUSSION Adolescent smoking is a communicable disorder, and may be preventable by various measures 1,7. Smoking prevalence among adolescents has increased recently 29. Recent research has shown that children aged years are susceptible to smoking 12. Adolescents are most likely exposed to the effects of both pro- and anti-tobacco advertising simultaneously 30. The results in table 1 show the influence of family on current smoking status. According to our data, the risk was highest when the father was a smoker. Unfortunately, the mass media has not been used adequately in Turkey to combat smoking. In the last census, the total population was 67 million in Turkey. The Turkish population is predominantly young; with 40.6 million above 15 years of age. Turkish laws are inadequately enforced to combat smoking. There is a light legislation against tobacco, including a ban on many forms of advertising, restrictions on smoking in many public places, prohibition to buy cigarette for those aged under 18. Therefore, smoking rates in adolescents have continued to rise in recent years 31. Alikasifoğlu et al. also reported that the prevalence of smoking among Turkish high school students gradually increased. A significant increase was observed in cigarette experimentation rate across grades for both female and male students. Twenty- three percent of the students reported that they were current users 32. In this study, although the prevalence of exsmokers was 13.6%, the prevalence of eversmokers was 36 %.This high ratio was similar to other studies. Recent data from the 1997 Youth Risk Behavior Survey suggest that youth smoking rates are increasing. The prevalence of smoking among high school seniors increased from 27.5% in 1991 to 36.4% in 1997 in USA 33,34. Scientific data demonstrate that tobacco use is the leading preventable cause of death and illness. Smoking is a known cause of cancer, heart disease, stroke, and chronic obstructive pulmonary disease. The prevalence of eversmokers among Turkish adolescents was higher than in the USA, European and other developed countries. Despite the tobacco companies aggressive expansion of its markets in Asia, Turkey, Middle East, and other developing countries, a small group of students had succeeded in stopping smoking. In this paper, we found that the prevalence of ex-smokers was 13.6%. The Saudi Smoking Control Charitable Society reported that the smoking cessation rate was 13% 20. This rate was 24.8% in USA 35. There was a significant difference. This may be attributed to the more effective smoking cessation protocols, educational programmes at schools, anti-tobacco advertising, and strict laws banning tobacco use. Presently, tobacco use is the single, most important health disorder in Turkey. Thus, urgent effective cessation programmes must be established. Having close friends and family members who smoked were strong factors for smoking 7,32. We found that the risk was highest when the father was a smoker. Parental smoking may cause children to view smoking as an acceptable adult behavior engaged in by those they most admire 33. In this paper, the smoking prevalence of fathers was 38.3 %. Unfortunately, 72.9 % of family members were smokers (only father, only mother, brothers, or both parents). Because of this high smoking ratio of family members, a wide health educational programme for everybody must be arranged. Adolescents often follow the health advice of their doctors rather than of their parents or other adults 33. Both doctors and teachers can play an important role in preventing tobacco use among children by adopting and modelling effective prevention strategies. Young smokers listed 3 factors that would motivate them to try to stop smoking: 1-the tobacco-related death or illness of a close relative, 2-a request from their boyfriend or girlfriend, 3-advice from their doctor 36 We found that the most important reason for smoking cessation was knowledge of the harmful effects of smoking (51.1 %). The second reason was the health problems (13.9%). These findings showed that health education, positive motivation, and effective cessation programmes offered by health services could play an important role in quitting smoking. The majority of participants (40.6%) thoughtthat TV programmes on smoking-cessation were ineffective and insufficient. As much as possible, a measure s effectiveness is quantified in terms of declines in tobacco consumption and smoking prevalence among youth (12). Unfortunately, everybody is free to buy cigarettes in our country. When we retrospectively examined the former lifestyle of ex-smokers, the initiation age of 21

29 Marmara Medical Journal 2005;18(1);17-23 Ruhuşen Kutlu, et al. The Evaluation of The Prevalence and Behaviours of The Ex-Smoker University Students smoking was under 21 years (98%). The most important reason for starting smoking was social factors (environment, friend groups, etc.) This rate was 39.1%. The second major reason was distress and anxiety (30.5%). The majority of ex-smokers (70.7%) have believed in the hazards of smoking. This belief positively influenced them to stop smoking. Research and theory must be directed towards understanding why some individuals smoke and others do not 37,38. Further research on the etiology of smoking in young people must be performed. Approximately 53.6% of the ex-smokers were influenced by commercials related with smoking. Fortunately, 65.4% of the ex-smokers do not want their children to smoke. Thus, the concept of a tobacco-free society must be promoted through involvement in anti-tobacco activities and educational projects in local communities, organizations and educational institutions. We found that men were more susceptible than women to both smoking and quitting smoking. This finding was in accordance with other studies 20,39. Although the causes are multifactorial, age, gender, having classmates, parents and teachers who smoked were very important 19. The decision to stop smoking can be a long process which is established on behavioral change model. Smoking cessation is a dynamic process that occurs before; during and after the person quit 9. There was a meaningful relation between smoking and alcohol use in our study. Among the exsmokers, the rate of alcohol use was significantly lower than among the ever-smokers (p=0.001). In the faculties of social sciences, the rate of quitting smoking was significantly higher than in the others (p=0.000). Tot et al., also reported that cigarette smoking was associated with alcohol use 10. Because of the rules in dormitories, residence at a dormitory was significantly more effective for quitting smoking (p=0.000). CONCLUSION The results of this study should help the development of anti-smoking policies in Turkey. A comprehensive strategy for smoking control must be established and adopted from other developing countries. Research teams should include representatives from a broad spectrum of disciplines, particularly educators and programme providers. The results of this multidisciplinary study, and the information gathered will be useful in the identification of high risk groups and the design of interventions. Norms for not smoking, a comprehensive strategy and environmental incentives must be supported through multiple channels in the community. 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31 CASE REPORT STIFF PERSON SYNDROME WITH ATYPICAL FEATURES AND A FAVOURABLE OUTCOME WITH STEROIDS Hande Türker, Nilgün Cengiz, Levent Güngör, Musa Onar Department of Neurology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey ABSTRACT Stiff Person Syndrome (SPS) is a rare and disabling disorder characterised by continuous motor unit activity causing severe rigidity and episodic spasms in axial and limb muscles. It deteriorates the quality of life and causes a serious burden in the patient s life. Here we describe a male patient with stiff person syndrome having atypical features like pyramidal signs and generalised convulsions. Benzodiazepines, baclofen and IVIG did not alter the clinical status whereas oral methylprednisone had a dramatic effect and resulted in a favourable outcome. Keywords: Stiff person syndrome, Stiff man syndrome, Stiff person syndrome and steroids ATİPİK BULGULARI OLAN STIFF PERSON SENDROMLU BİR OLGUDA KORTİKOSTEROİDE DRAMATİK YANIT ÖZET Stiff Person Sendromu (SPS), seyrek rastlanan, gövde ve ekstremite kaslarında rijidite ve epizodik spazmlarla hastanın yaşam kalitesini oldukça bozan, devamlı motor ünite aktivitesi ile karakterli bir tablodur. Burada stiff person sendromunun tipik özellikleriyle birlikte jeneralize nöbetler ve piramidal bulgular gibi atipik öğelerin de rastlandığı 40 yaşındaki bir erkek olguda altı aylık izlem bildirilmektedir. Nörolojik muayenesinde bilateral biseps reflekslerinin aktivitesinde artış ve taban cildi refleksinin iki yanlı ekstansör oluşu gibi piramidal bulgular izlenen hastanın kranyal MR, servikal MR ve EEG si normal bulunmuştur. Özellikle alt ekstremitelerindeki tonus artışı ön planda olan hastanın EMG sinde, quadriseps femoris kas grubunda şiddetli, biceps femoris, gastrokinemus ve lomber paraspinal kas grubunda hafif ve bilateral trapez kas grubunda orta derecede devamlı motor ünite aktivitesi saptanmıştır. Baklofen, benzodiazepin ve IVIG tedavisine yanıt vermeyen hastada metil prednizolon tedavisine oldukça dramatik bir yanıt izlenmiş ve hasta kortikoterapi başlanmasını izleyerek bir hafta içinde mobilize hale gelmiştir. Elektrofizyolojik izlemde de yukarıda belirtilen kas gruplarında, devamlı motor ünite aktivitesinin belirgin ölçüde gerilediği izlenmiştir. Altı aylık izlemde oral steroide devam eden hastanın klinik tablosundaki iyilik hali devam etmiş, sürdürülen elektrofizyolojik izleminde sadece trapez ve biseps femoris kas gruplarında minimal düzeyde devamlı motor ünite aktivitesinin varlığı gösterilmiştir. Anahtar kelimeler: Stiff person sendromu, Stiff-man sendromu, Stiff person sendromu ve steroidler INTRODUCTION Stiff person syndrome (SPS) was first described by Moersch and Woltman in The authors named the syndrome as Stiff-man syndrome and reported 14 patients with progressive muscular rigidity and spasms 1. In 1967 Gordon, et al. described the clinical and electrophysiological diagnostic criteria of the disease 1,2. There are several conditions with clinical features resembling SPS with demonstrable central nervous system pathology reported in the literature as atypical cases of this disorder 1. Here we report a patient diagnosed as SPS with atypical features such as pyramidal signs in his neurological examination besides generalised tonic clonic seizures. Imaging studies and EEG were normal and the patient responded well to steroids both clinically and electrophysiologically. CASE REPORT A forty year old male patient with complaints of difficulty of swallowing, generalised muscle spasms and generalised seizures was admitted to our clinic. His complaints began 3 months before his admission. He had severe difficulty in swallowing both liquids and solid foods. The seizures were generalized and tonic and lasted for Corresponding author: Hande Türker Department of Neurology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey [email protected] Marmara Medical Journal 2005;18(1);

32 Marmara Medical Journal 2005;18(1);24-27 Hande Türker, et al. Stiff Person Syndrome With Atypical Features and A Favourable Outcome With Steroids 10 minutes. Apart from the seizures he also had episodic spasms that affected both his axial and limb muscles and they occurred very frequently. The patient reported that he could not walk because of his stiffness and had become bedridden with involuntary spasms lasting all day long. He also reported an aura like feeling preceding the spasmodic attacks. He had lost weight and realized that his limb muscles were wasting. He reported a sequela of poliomyelitis affecting his left lower extremity. Cranial nerves were intact. Cervical, thoracal, abdominal and limb muscles had increased tonus. The tonus increase was especially very prominent in the lower extremities. Muscle strength in the left lower extremity was 3/5 both in the proximal and distal muscles (according to MCR scale). All other extremity muscle groups were normal in muscle strength. Deep tendon reflexes except biceps were normal. Biceps reflexes had increased activity bilaterally. Plantar reflexes were both extensor. Cerebellar tests and examination of sense were normal. There was not any syphincter disorder. Electromyography (EMG) was performed and nerve conduction studies were normal while there was a continuous motor unit activity of both agonist and antagonist muscles at the same time. The clinical symptoms along with the continuous motor unit activity of both agonist and antagonist muscles were thought to be consistent with stiff person syndrome. Anti glutamic acid decarboxylase (anti GAD) antibodies were detected in serum but could not be found. During his stay in the hospital the patient did not have any convulsions. His EEG was normal. In order to investigate neoplasia that can be seen with stiff person syndrome, tumor markers were studied and the tests were negative. Abdominal ultrasound and thorax CT were also normal. As there were signs of pyramidal involvement in the neurological examination, cranial and cervical MRI were performed. The cranial MRI showed nonspesific gliotic lesions and the cervical MRI was normal. In EMG the degree of continuous muscle activity in both of the trapezius muscles was moderate. Left biceps femoris, right rectus abdominis, right lumbar paraspinals, left gastrocinemius, left tibialis anterior and right rectus femoris muscles showed a milder degree of continuous motor unit activity while the activity was very prominent in the right vastus medialis muscle (Fig 1 and Fig 2). Baclofen and benzodiazepines did not alter the clinical status so IVIG (Intravenous immune globulin) therapy (0.4/g/kg/day for 5 days) was initiated. IVIG therapy was not sucsessful, either. It was decided to begin methyl prednisone therapy and the patient gave a favourable response to a therapy of 40mg/day oral methyl prednisone. EMG was performed again after the first week of the therapy and the continuous motor unit activity of the muscle groups that was recorded before, had decreased significantly (Fig 1). The patient became mobilised in about a week s time and the hypertonicity of the muscles decreased. It was decided to continue the therapy with 50 mg oral methyl prednisone per day and the patient was discharged to continue the follow up in the outpatient program. After a month the neurological examination and EMG were reviewed. Most of the patient s complaints ceased and he could walk without help. The EMG recordings showed that the continuous motor unit activity had disappeared in most muscle groups, but there was still some activity in both of the trapezius muscles. DISCUSSION According to the criteria of diagnosis of stiff person syndrome established by Gordon, et al., normal motor and sensory examinations are the rule 2. Our patient had pyramidal signs in both lower extremities. In order to investigate the origin of the pyramidal signs, we performed MRI but both cranial and cervical MRI were normal. Another atypical feature was his generalised seizures. Although we had not witnessed them, we had to take the information seriously because doctors had observed his fits and had put down notes in his file during his stay in the previous hospital he had visited. The presence of anti GAD antibodies is well reported in stiff person syndrome but most reports say that the level of the enzyme does not correlate directly with the severity of the disease or the outcome. The techal synthesis of antigad antibodies is specific for SPS 3. We could only investigate serum antigad Ab in our patient and we could not perform the test for techal antibodies. It is not a must for every SPS patient to have antibodies and Rakocevic,. et al. reported that anti GAD antibody titers in serum and CSF do not correlate with disease severity or duration 4. 25

33 Marmara Medical Journal 2005;18(1);24-27 Hande Türker, et al. Stiff Person Syndrome With Atypical Features and A Favourable Outcome With Steroids Fig. 1: Recordings of continuous motor unit activity from various muscle groups before and after one week of steroid therapy, from left to right: First raw: Left: Left tapezius recording before steroid therapy Right: Left tapezius recording after steroid therapy Second raw: Left: Right tapezius recording before steroid therapy Right: Right tapezius recording after steroid therapy Third raw: Left: Right biceps femoris recording before steroid therapy Right: Right biceps femoris recording after steroid therapy Fourth raw: Left: Left gastrocinemus recording before steroid therapy Right: Left gastrocinemus recording after steroid therapy Fifth raw: Left: Right vastus medialis recording before steroid therapy Right: Right vastus medialis recording after steroid therapy Sixth raw: Left: Left tibialis anterior recording before steroid therapy Right: Left tibialis anterior recording after steroid therapy Seventh raw: Left: Right rectus femoris recording after steroid therapy Right: Right rectus femoris recording before steroid therapy Fig. 2: Recordings of left biceps femoris, left rectus abdominis and right lumbar paraspinal muscles (from left to right) after one week of steroid treatment. The continuous motor unit activity is very mild After a month it was not seen any more. 26

34 Marmara Medical Journal 2005;18(1);24-27 Hande Türker, et al. Stiff Person Syndrome With Atypical Features and A Favourable Outcome With Steroids Stiff person syndrome is reported to be associated with type 1 diabetes mellitus, autoimmune diseases and some types of cancer. Our patient had epilepsy besides SPS but not type 1 DM or malignancy. Epilepsy is less reported when compared with the other diseases appearing with SPS. Martinelli et al. reported a case of SPS associated with nocturnal myoclonus and epilepsy 5. Another case of SPS reported with epilepsy had also type 1 diabetes mellitus 6. According to Barker, et al., the response to diazepam and baclofen is only partial with half of the patients becoming wheelchair bound. The role of immunosupressive therapy is currently unknown. The disease lasts many years and may be due to a spinal interneuronitis although this remains speculative 7. There are case reports expressing favourable outcome with IVIG 8-12 but studies with large numbers of patients are still lacking. In a recent review by Murinson BB, it was stated that IVIG is effective in the treatment of SPS while diazepam remains useful in managing the symptoms 13.There are also a few reports in the literature referring to therapy with plasma exchange (PE) and steroids. In a report of two patients with SPS it was concluded that autoantibody negative cases were less likely to respond to PE 14. In another report of two patients with SPS, by Piccolo, et al., ACTH infusion produced an immediate clinical relief of muscle contracture and cramps, with parallel marked reduction of the EMG pattern of continuous motor unit activity in agonist and antagonist muscles. Apart from this effect, a more delayed response to oral prednisone was observed in both cases. These data lead the authors to consider a possible dysimmune pathogenesis of some cases with the stiff-man syndrome 15. Our patient produced a good response to steroids and the clinical and neurophysiological findings improved quite rapidly. Our report therefore bares similarity to the report of Piccolo et al. We believe that studies of large numbers of patients are needed to find out the role of immune mediated therapies in SPS which can also enlighten the pathogenesis of this rare syndrome. REFERENCES 1. Gershanik OS. Stiff-person syndrome. In: Watts R, Koller W, eds. Movement Disorders: Neurologic Principles and Practice. St. Louis: McGraw-Hill, 1997: Gordon EE, Januszko DM, Kaufman L. A critical survey of stiff-man syndrome. Am J Med 1967;42: Arimura K. Isaacs syndrome, stiff person syndrome and Satayoshi disease: pathomechanisms and treatment. Rinsho Shinkeigaku 2004; 44: Rakocevic G, Raju R, Dalakas MC. Antiglutamic acid decarboxylase antibodies in the serum and cerebrospinal fluid of patients with stiff-person syndrome: Correlation with clinical severity. Arch Neurol 2004;61(6): Martinelli P, Pazzaglia P, Montagna P. et al. Stiffman syndrome associated with nocturnal myoclonus and epilepsy. J Neurol Neurosurg Psychiatry 1978;41: Solimena M, Folli F, Denis-Donini S, et al. Antibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy and type 1 diabetes mellitus. N Engl J Med 1988;318: Barker RA, Revesz T, Thom M, Marsden CD, Brown P. Review of 23 patients affected by the stiff man syndrome: Clinical subdivision into stiff trunk (man) syndrome, stiff limb sndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry (kısaltması mı?) 1998;65: Khanlou H, Eiger G. Long term remission of refractory stiff-man syndrome after treatment with intravenous immunoglobulin. Mayo Clin Proc 1999; 74: Barker RA, Marsden CD. Successful treatment of stiff man syndrome with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 1997;62: Amato AA, Cornman EW, Kissel JT. Treatment of stiff-man syndrome with intravenous immunoglobulin. Neurology 1994;44: Karlson EW, Sudarsky L, Ruderman E, Pierson S, Scott M, Helfgott SM. Treatment of stiff-man syndrome with intravenous immunoglobulin. Arthritis Rheum 1994;37: Sevrin C, Moulin T, Tatu L, Monnier G, Rumbach L, Sevrin P. Stiff-man syndrome treated with intravenous immunoglobulins. Rev Neurol 1998;154: Murinson BB. Stiff person syndrome. Neurologist 2004;10: Shariatmadar S, Noto A. Plasma exchange in stiffman syndrome. Ther Apher 2001;5: Piccolo G, Cosi V, Zandrini C, Moglia A. Steroid responsive and dependent stiff-man syndrome: A clinical and electrophysiological study of two cases. Ital J Neurol Sci 1988;9:

35 ORIGINAL RESEARCH PATHOLOGICAL LAUGHING FOLLOWING PONTINE INFARCTION DUE TO BASILAR ARTERY STENOSIS ABSTRACT Neşe Tuncer, Nazire Afşar, Tülin Tanrıdağ, Önder Us Marmara University School of Medicine, Neurology, Istanbul, Türkiye Pathological laughing-(pl) is a situation defined by uncontrollable episodes of laughter without motivating stimulus or appropriate emotional expression. Pathological laughing has been described with cerebrovascular disorders. A 60-year-old man was admitted to the hospital with a right conjugated gaze paresis, left facial hemiparesis, nineth and tenth cranial nerve paresis, absent gag reflexes mild right sided hemiparesis.-cranial MR angiography revealed giant dolichoectatic basilar artery and with severe stenosis at the mid portion of the basilar artery. Six months later he presented with pathological laughing. However, the exact mechanism of pathological laughing is unclear and disturbances in the coordination and modulatory functions of cerebellum and cerebro-pontocerebellar pathways might strongly explain the nature of this phenomenon. Keywords: Pathological laughing, Basilar artery stenosis, Cerebro-ponto cerebellar pathways ÖZET BAZİLER ARTER TROMBOZUNA BAĞLI PONS İNFARKTI SONRASI GELİŞEN PATOLOJİK GÜLME OLGUSU Patolojik gülme, uygun duygu durumu veya uyaran olmaksızın ortaya çıkan ve kontrol edilemeyen gülme ataklarıdır. Serebrovasküler hastalıklarda ortaya çıkabilen bir durumdur. 60 yaşında erkek hasta sağa konjuge bakış parezisi, sol fasyal parezi, 9 ve 10. cranial sinir parezisi ve sağ hemiparezi bulguları ile başvurdu. Kranial MR anjiografide dolikoektatik baziler arter ve midbaziler stenoz saptandı. Hastanın izleminin altıncı ayında patolojik gülme tablosu gelişti. Patolojik gülmenin mekanizmaları tam olarak bilinmese de serebellum ve serebropontoserebellar yolakların düzenleyici fonksiyonları bu fenomeni açıklamada yeni bir alternatif görüş oluşturmaktadır. Anahtar Kelimeler: Patolojik gülme, Baziler arter trombozu, Serebropontoserebellar yollar INTRODUCTION Pathological laughing (PL) is a situation defined by uncontrollable episodes of laughter without motivating stimulus or appropriate emotional expression. Pathological laughing is distinguishable from mood disorders because laughter is not associated with feelings of happiness. The PL is a symptom of gelastic epilepsy, pseudobulbar palsy and the tumors of cerebellopontine angle 1-6. Pathological laughing has also been described with cerebrovascular disorders which affect internal capsule, thalamus, cerebral peduncles and basis pontis 7-9. We report of a case presenting with pathological laughing following pontine infarction due to basilar artery thrombosis. CASE PRESENTATION A 60-year-old, right handed man was admitted to the emergency room complaining of vertigo, recurrent nausea and vomiting, slurred speech and disphagia. His symptoms first began with slurred speech. Ten hours after the onset of slurred speech, his symptoms progressed and the patient developed dysphagia, dysphonia and right sided motor weakness. Past medical history was significant for hypertension and uncontrolled diabetes mellitus type II and hyperlidemia. He had no personal history of neurological or psychiatric disease. On admission he was conscious but drowsy and presented with a right conjugated gaze paresis, left facial hemiparesis, nineth and tenth cranial nerve Corresponding author: Neşe Tuncer, M.D. Department of Neurology, School of Medicine, Marmara University Hospital, Altunizade, İstanbul, Turkey E- mail: [email protected] Marmara Medical Journal 2005;18(1);

36 Marmara Medical Journal 2005;18(1);28-31 Neşe Tuncer, et al. Pathological Laughing Following Pontine Infarction Due To Basilar Artery Stenosis paresis, absent gag reflexes mild right sided hemiparesis involving the arm and the leg with a bilateral brisk tendon reflexes and extensor plantar responses. Moreover, his examination revealed limb ataxia of both the upper and lower extremities, with trunckal and gait ataxia toward the right side. A non-enhanced CT scan, performed in the first hour of admission was within normal limits whereas cranial MR angiography revealed giant dolichoectatic basilar artery and with severe stenosis at the mid portion of the basilar artery (Figs 1,2). His hemiparesis deteriorated progressively and intravenous heparin (1000IU/h) was started the following day. A cranial MRI repeated 2 days after the first symptoms revealed a left midpontine large infarct (Fig 3). His dysphagia, right sided hemiparesis, and ataxia deteriorated for 48 hours and then gradually improved. Three month later he was able to walk alone and returned to work. Fig 3: T2-weighted axial cranial MRI demonstrated a left mid-pontin large infarct Fig 1: Cranial MRA showed a giant dolichoectatic basilar artery with severe stenosis at the mid portion. Fig 2: T1-weighted axial cranial MRI demonstrated a large, fusiform dilated basilar artery compressing the brainstem. The patient was diagnosed to have progressive basilar artery thrombosis and he was treated with intravenous 0.9mg/kg tissue plasminogen activator(t-pa) followed by aspirin (300mg/day). Six months later he presented to the neurology out-patient clinic complaining of unwilling laughter. He started to experience frequent episodes of inappropriate and involuntary laughing, triggered by talking -,-unaccompanied by mood elevation. He did not understand what was happening and was puzzled by it. He did not feel happiness during laughing attacks and could not control the paroxysms. The episodes did not have an apparent motivating stimulus for that emotional outburst. The patient was director in a large company and felt deeply embarrassed by the attacks particularly when occuring during professional activities. These attacks usually persisted for 30-seconds to 1 minute. His personal and social behaviour was appropriate except for the attacks of laughter and he had normal cognitive functions. The Beck Depression Inventory revealed mild depressive symptoms. Episodes of laughter, during which he was unable to control the tone of his voice and his breathing were observed during examination. Fluoxetine hydrochloride 10mg/day was started but the attacks were not controlled and the therapy was switched to paroxetine (20mg/day). Although the attacks did not resolve completely, severity of the symptom improved significantly. 29

37 Marmara Medical Journal 2005;18(1);28-31 Neşe Tuncer, et al. Pathological Laughing Following Pontine Infarction Due To Basilar Artery Stenosis DISCUSSION Normal laughing is a complex motor action in which the facial and respiratory muscles are involved, and accompanied by mood elevation. Pathological laughing (PL) may be defined as uncontrollable, inappropriate, exaggerated laughing which is not related with a real emotional condition. Although the pathogenesis of pathological laughing is not clear yet, there are some speculative explanations. Wilson suggested that PL is the result of damaged voluntary inhibition of laughing and crying center (medullary effector center) located in the upper brainstem and defined this situation as a release phenomenon 10. This center is also controlled involuntarily by higher centers of the cerebral cortex and the limbic system. The medullary effector center can also control faciorespiratory functions during laughing and crying. According to Wilson s theory the location of this subcortical center must be above the faciorespiratory nuclei in upper pons or midbrain. On the other hand, Davison et al., reported that the hypothalamus is the primary center for laughing and crying, which is itself under the control of the inhibitory influences of the cortex 11. More recently, Arroya et al., reported that the main regulatory center for emotional responses may be located in the cingulate gyrus and the basal temporal cortex 2. However, these tempting speculations have been questioned by Parvizi et al., who presented an alternative hypothesis depending on Damasio s functional and neuroanotomical researches 12,13. They suggested that after the triggering stimuli is perceived, the ventromedial prefrontal cortex, anterior cingulate and amygdala are activated, in turn stimulating the effector sites as hypothalamus, periaqueductal grey mater, the cranial nerve nuclei and premotor regions. They postulated that the cerebellum plays an important role for adjusting laughing and crying behaviours12. The reason for this hypothesis is that the projections received by the cerebellum from telencephalic structures can convey social and cognitive stimuli, thus allowing the performed task to take into account such contexts. The cerebellum is capable of coordinating the complex facial, laryngopharyngeal and diaphragmatic rhythmic movements via the projections from the cerebellum to the brainstem and telencephalic structures. As a result Parvazi et al., believe that the occurence of pathological laughing and crying should be the consequence of distrupted cerebroponto cerebellar pathways. Pathological laughing generally occurs following cerebrovascular lesions involving the descending corticobulbar pathways, especially with bilateral lesions at the level of the internal capsule, basis pontis and cerebral peduncles 9,14,15. Kim describes 13 patients with pathological laughing following cerebrovascular accident having mostly striatocapsular (- basal ganglia and subcortical white matter) infarction9. Pontine lesions are the second most common ones and such patients have been previously reported16. Our patient is the second one in the literature presenting with pontine infarction due to basilar artery thrombosis. Tei et al., have reported a patient who presented with hemiparesis accompanied by pathological laughing due to pontine infarction with basilar artery thrombosis 17. Like the latter, pathological laughing can herald a brainstem stroke, called fou rire prodromique by Fere and can be the transient18. However, the immediate occurrence of pathological laughing after ischemic vascular lesions is rare and as it generally occurs after a period of time up to 1 year following stroke. Our patient started to experience episodes of inappropriate laughing six months ago following a cerebrovascular accident. Although the reason for the latent period between the onset of stroke and the occurrence of pathological laughing is still unclear, Kim hypothesized that recovery of the cortical dysfunction takes time and hyperexcitability can be seen in this period 9. However, the exact mechanism of pathological laughing is unknown and the role of coordination and modulatory functions of cerebellum and cerebro-pontocerebellar pathways, as hypothesized by Parvizi et al., might be a strong alternative mechanism to explain the nature of this phenomenon. The other question is why this phenomenon is not encountered in all patients with the same lesion localization and if there are some individual differences between patients. Further neuroanatomical and neurophysiological studies are necessary to investigate pathogenetic mechanisms of post-stroke pathological laughing. REFERENCES 1. Poeck K. Pathological laughing and crying, In: Vinken PJ, Bruyn GW, Klawans HV, eds. Handbook of Clinical Neurology. 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38 Marmara Medical Journal 2005;18(1);28-31 Neşe Tuncer, et al. Pathological Laughing Following Pontine Infarction Due To Basilar Artery Stenosis pathological laughter: JAMA 1976;235: Bhatjiwale MG, Nadkarni TD, Desai KI, Goel A. Pathological laughter as a presenting symptom of massive trigeminal neuromas: report of four cases. Neurosurgery 2000;47: Shafgat S, Elkind MSV, Chiocca EA, Takeoka M, Koroshetz WJ. Petroclival menengioma presenting with involuntary laughter. Neurology 1998;50: Derex L,Ostrowsky K, Nighoghossian N, Trouillas P. Severe pathological crying after left anterior choroidal artery infarct. Stroke 1997;28: Lago A. Fou rire prodromique and ischemic stroke. Stroke 1998;29: Kim JS. Pathological laughter after unilateral stroke. J Neurological Science 1997; 148: Wilson SAK:Some problems in neurology.ii. Pathological laughing and crying. J NeurolPsychopathol 1924;ıv: Davison C, Kelman H ET AL. Pathological laughing and crying. Arch Neurol. Psychiatry 1939;42: Parvizi J, Anderson SW, Martin C, Damasio H, Damasio AR. Pathological laughter and crying. Brain 2001, 124, Damasio AR, Grabowski TJ, Bechara A, Damasio H, Ponto LLB,Parvazi J et al. Distinctive patterns of subcortical and cortical brain activity during the feeling of self-generated emotions. Nat Neurosci 2000;3: Ceccaldi M, Poncent M, Milandre L, Rouyer C. Temporary forced laughter after unilateral strokes. Eur Neurol. 1994;34: Poeck K. Pathological laughing and crying, In Vinken PJ, Bruyn GW, Klawans HV (eds) Handbook of Clinical Neurology, Elsevier, Amsterdam, pp Robinson RG, Parikh RM, Lipsey JR, Starkstein SE, Price TR. Pathological laughter and crying following stroke: Validation of measurement scale and double blind treatment study. Am J. Psychiatry 1993;132: Helgason CM, Wilbur AC. Basilary branch pontine infarction with prominent sensory signs. Stroke 1991;22: Sakamoto Y, Tei H. Pontine infarction due to basilar artery stenosis presenting as pathological laughter. Neuroradiology 1997;39: Fere C. Le fou rire prodromique. Rev Neurol (Paris) 1903;11:

39 VAKA SUNUMU KONJENİTAL AKUADUKTUS SEREBRİ STENOZU OLGUSU Ali Zeybek 1, Mahmut Beşer 2 1 Anatomi Anabilim Dalı, Tıp Fakültesi, Kocaeli üniversitesi, Kocaeli, Türkiye 2 Radyodiagnostik Bölümü, Sağlık Bakanlığı Taksim Eğitim ve Araştırma Hastanesi, İstanbul, Türkiye ÖZET Konjenital akuaduktus serebri stenozu 1000 doğumda 0,5-1 görülür. Sıklıkla da (% 20-43) konjenital hidrosefaliye neden olur. Erkeklerde iki kat fazla görülür. Etiyolojisinde; postinflamatuar, gelişimsel ve neoplastik nedenler yer almaktadır. Olgumuz 23 yaşında erkek hasta olup başağrısı nedeniyle kliniğe başvurmuştu. Kraniyal magnetik rezonans (MR) ile sagittal ve axial planda görüntüler alındı ve sagittal planda aquaduktal BOS dinamiği analizi amaçlı fonksiyonel MR incelemesi yapıldı. Hastamızda, triventriküler (ventriculus lateralis ler ve ventriculus tertius) hidrosefali vardı. Aquaductus cerebri de colliculus inferior proksimalinde belirgin ciddi bir dilatasyona karşılık ventriculus quartus un tamamen normal boyutlarda olması colliculus inferior düzeyindeki stenozu düşündürdü. Ayrıca corpus callosum da yaylanma izlendi. Sagittal planda kalitatif BOS akım analizine yönelik gerçekleştirilen fonksiyonel MR incelemesinde, aquaductus cerebri de akıma bağlı sinyal kaybı gözlenmedi ve nabız ile uyumlu ventriküler dilatasyonların azaldığı izlendi. Anahtar Kelimeler: Akuaduktus serebri, Stenoz, Hidrosefali A CONGENITAL AQUADUCTUS CEREBRI STENOSIS CASE ABSTRACT The frequency of the congenital aquaductus cerebri is about over 1000 births. It frequently causes congenital hydrocephalus (20-43 %), and appears among men two times more than women. In its ethyology, there are postinflammatic-developmentalneoplatic causes. Our case study was about a 23- year-old male patient demanded for the medical treatment because of his headache. He was examined by MR for having certain pictures both in the sagittal and axial plane and by functional MR for the analysis of aquaductal CSF dynamic in the sagittal plane.-our patient had a triventricular hydrocephaly (right and left ventriculus lateralis, and ventriculus tertius). The ventriculus quartus with normal size reminded us of the stenosis at the colliculus inferior level even we observed a serious apparent dilatation in aquaductus cerebri at the colliculus inferior proximal level. In addition, an arch was observed in the form of corpus callosum. In the functional MR scanning, which provides the analysis of the qualitative CSF flow, in the sagittal plane, we did not observe the loss of signal with respect to the flow in aquaductus cerebri. However, we observed a decrease in ventricular dilatations suited to pulse. Keywords: Aquaductus cerebri, Stenosis, Hydrocephaly GİRİŞ Aquaductus cerebri hamileliğin 6.-haftasında gelişir ve komşu büyüyen mezensefalik yapıların basıncına bağlı olarak doğuma kadar hacmi azalır. Colliculus superior veya sulcus intercollicularis seviyesinde akuadukt hacminde fokal bir azalma olması durumuna aquaduktus serebri stenozu denilmektedir (normal değerler mm 2 ) 1. Aquaduktus serebri stenozuna neden olan durumlar iki ana başlıkda toplanabilir. Birincisi konjenital stenoz olup, ikincisi edinsel nedenlerdir. Edinsel nedenler arasında post infeksiyöz, post hemorajik, gliosis, tümorler ve seyrek olarak da venöz angioma gibi vasküler malformasyonlar sayılabilir 2,3 Aquaduktal stenoz ve hidrosefali görülen olgularda major olarak X e bağlı ve daha seyrek olarak da otozomal resesif geçiş bilinmektedir 4. Konjenital akuaduktus serebri stenozunun görülme sıklığı; 1000 doğumda 0,5-1 olup sıklıkla da (% 20-43) konjenital hidrosefaliye neden olur. Erkeklerde iki kat fazla görülür. Mortalite %11-30 arasındadır 1. OLGU SUNUMU Olgumuz 23 yaşında erkek hasta olup başağrısı nedeniyle kliniğe başvurmuştu. İnceleme için uygun olan kraniyal magnetik rezonans (MR) ile sagittal ve aksiyel planda görüntüler alındı ve sagittal planda aquaduktal BOS dinamiği analizi amaçlı fonksiyonel MR incelemesi yapıldı. Philips Gyroscan 1,5 Tesla cihazı kullanıldı. İletişim Bilgileri: Ali Zeybek Anatomi Anabilim Dalı, Tıp Fakültesi, Kocaeli Üniversitesi, Kocaeli, Türkiye. [email protected] Marmara Medical Journal 2005;18(1);

40 Marmara Medical Journal 2005;18(1);32-34 Ali Zeybek, et al. A Congenital Aquaductus Cerebri Stenosis Case İnceleme neticesinde hastamızda, triventriküler (ventriculus lateralis ler ve ventriculus tertius) hidrosefali saptandı. Aquaductus cerebri de colliculus inferior proksimal inde belirgin ciddi bir dilatasyona karşılık ventriculus quartus un tamamen normal boyutlarda olduğu izlendi. Bu da colliculus inferior düzeyinde stenozu düşündürdü. Ayrıca corpus callosum da yaylanma izlenmekte idi (Resim 1A, 1B). Resim 1a: T1 ağırlıklı sagittal spin eko kesit (orta hat) : Aquaductus cerebri de colliculus inferior proximalinde belirgin dilatasyon ( beyaz düz ok ), ventriculus quartus normal boyutlarda ( kıvrımlı beyaz ok ) ve 3. ventrikülde dilatasyon ( beyaz ok başı ). TARTIŞMA Aquaduktus serebri stenozunun etiyolojisinde ilk sırada postinflamatuar (%50) nedenler; Perinatal enfeksiyonlara sekonder; toxoplasmosis, CMV, sifiliz, kabakulak, influenza virus veya intrakraniyal hemoroji-aquadukt çevresindeki epandimal hücrelerde destrüksüyon gelmektedir. İkinci sırada ise gelişimsel neden; Aquaduktal çatallanma / daralma ve üçüncü olarak da neoplastik nedenler (seyrek); pinealoma, meningioma, tectal astrocytoma sayılmaktadır. Vaskuler malformasyonlar da yine seyrek olarak aquaduktus serebri stenozuna neden olmaktadır 1,2. Bizim olgumuzda enfeksiyon öyküsü yoktu ve gelişimsel neden olduğu düşünüldü. Erkeklerde kadınlara göre iki kat fazla görülüyordu ve bizim olgumuzda erkekdi. Birlikte olabileceği durumlar arasında diğer konjenital anomaliler (%16) özellikle de başparmak deformiteleri görülebiliyorsa da hastamızda bulunmuyordu 1,5. Olgumuzdaki triventriküler hidrosefali varlığı, aquaductus cerebri de colliculus inferior proksimalinde belirgin ciddi bir dilatasyon olması, ventriculus quartus un tamamen normal boyutlarda olması, colliculus inferior düzeyindeki stenoz varlığı ve corpus callosum da yaylanma, incelme olması literatür ile uyumlu idi 1,5. Literatürde konjenital akuadukt stenozu ile birlikte posthemorajik hidrosefali, periakuaduktal tümör ve sisterna quadrigeminale de küçük lipom gibi tümörler görülebilse de olgumuzda yoktu 6,7,8. Sonuçda fetal ultrasonografi ile inceleme yapılarak konjenital akuadukt stenozunun prenatal tanısının konulması, gebeliğin sürdürülüp sürdürülmemesi kararı açısından terapatik ve etik olarak önem taşımaktadır 9. REFERANSLAR Resim 1b: T2 ağırlıklı aksiyal turbo spin eko kesit (bazal ganglion seviyesi) : Lateral ventrikülde dilatasyon (ventrikülomegali ) ( siyah düz ok ). Sagittal planda, kalitatif BOS akım analizine yönelik olarak gerçekleştirilen fonksiyonel MR incelemesinde aquaductus cerebri de akıma bağlı sinyal kaybı gözlenmedi ve nabız ile uyumlu ventriküler dilatasyonların azaldığı izlendi. 1. Dahnert W: Radiology Review Manual. Williams Wilkins Company Baltimore, Third Edition, 1996; Sato S, Sonoda Y, Kuroki R, Kayama T. A rare case of aqueductal stenosis due to venous angioma. No To Shinkei Dec;56(12): Marcorelles P, Fallet-Bianco C, Oury JF, van Wallenghem E, Parent P, Labadie G, Lagarde N, Laquerriere A. Fetal aqueductal glioneuronal hamartoma: a clinicopathological and physiopathological study of three cases. Clin Neuropathol Jul-Aug;24(4): Hamada H, Watanabe H, Sugimoto M, Yamada N, Kubo T. Autosomal recessive hydrocephalus due to congenital stenosis of the aqueduct of sylvius. Prenat Diagn Nov; 19(11):

41 Marmara Medical Journal 2005;18(1);32-34 Ali Zeybek, et al. A Congenital Aquaductus Cerebri Stenosis Case 5. Moore KL, Persaud TVN: The Developing Human: Clinically Oriented Embryology. W.B. Saunders Company Philadelphia, 6.th Edition, 1998; Takashima S, Fukumizu M. Pathology of congenital aqueductal stenosis and posthemorrhagic hydrocephalus. No To Hattatsu May;26(3): Steinbok P, Boyd MC. Periaqueductal tumor as a cause of late-onset aqueductal stenosis. Childs Nerv Syst. 1987;3(3): Kawamata T, Aoki N, Sakai T, Takakura K. Congenital triventricular hydrocephalus associated with a small lipoma in the quadrigeminal plate cistern. Childs Nerv Syst Feb;11(2): Vanlieferinghen P, Chazal J, Francannet C, Malpuech G, Storme B. Congenital stenosis of the aqueduct of Sylvius transmitted in an autosomal recessive mode (5 cases in 2 families.) J Genet Hum Aug;35(4):

42 CASE REPORT ABSTRACT PEROPERATIVE DIAGNOSIS OF RHABDOMYOLYSIS Binnaz Ay, İ. Varlık Doğan, Tümay Umuroğlu, F. Yılmaz Göğüş Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey Crush syndrome or traumatic rhabdomyolysis constitutes the systemic changes seen after crush injury. The pressure causes necrosis of muscle, and during revascularisation diffusion of calcium, sodium and water into the muscle cells is seen, together with loss of potassium, phosphate, lactic acid, myoglobin and creatinine kinase. Untreated these changes can lead to: hyperkalemia, acidosis, acute renal failure and hypovolemic shock. This case report describes a patient developing rhabdomyolysis following fracture of femur. It was diagnosed and treated early during the course of anesthesia. Keywords: Crush injury, Rhabdomyolysis ÖZET RABDOMİYOLİZİN PEROPERATİF TANISI Crush sendromu veya travmatik rabdomiyoliz crush hasarı sonrası görülen sistemik değişiklikleri içerir. Basınç ve travmanın neden olduğu kas nekrozu ve revaskülarizasyon sırasında kalsiyum, sodyum ve su hücre içine girerken, potasyum, fosfat, laktik asit, miyoglobin ve kreatin kinaz hücre içinden hücre dışına çıkar. Tedavi edilmediği takdirde bu olaylar hiperkalemi, asidoz, akut böbrek yetmezliği ve hipovolemik şoka neden olur. Bu olgu sunumu femur fraktürü sonrası rabdomiyoliz gelişen bir hastayı anlatmaktadır. Peroperatif erken dönemde teşhis edilmiş ve tedavi başlanmıştır. Anahtar Kelimeler: Ezik yaralanmaları, Rabdomiyaliz INTRODUCTION Rhabdomyolysis is a potentially life-threatening syndrome resulting from the breakdown of skeletal muscle fibers with leakage of muscle contents into the circulation. The most common causes of traumatic origin are chrush injury, overexertion, seizures, and electric shock. Nontraumatic causes are myopathies, alcohol abuse, certain drugs and toxic substances 1. Here we report a patient who developed rhabdomyolysis following fracture of the femur after a car accident. CASE REPORT A 66-yr-old man (weight 90 kg, height 180 cm) was scheduled for popliteal exploration and external-internal fixation of the fractured femur. His past medical history was unremarkable. The patient was struck by a car and was admitted to a Corresponding author: İ. Varlık Doğan Ataköy 5. kısım E2-3 blok C kapı No:55 Bakırköy Istanbul, Turkey [email protected] Tel: nearby hospital where he had undergone explorative laparotomy. The lacerations in the jejunum and sigmoid colon were repaired and then the patient was transferred to our hospital. Any information regarding fluid replacement and the vital signs during the previous surgery could not be obtained. Chest radiography revealed fracture of the eleventh rib and contusion of the left upper lobe. Pulses from the left popliteal, dorsalis pedis, and tibialis posterior arteries were not detected. Computed tomography showed linear fracture at the base of the anterior fossa without any sign of epidural / subdural or intracerebral hematoma. All preanesthetic laboratory results and blood gas analysis were within normal limits except lactate dehydrogenase (LDH) (981; normal range U/L) (Table I). Anaesthesia was induced with thiopental, 5 mg/kg IV and fentanyl, 3µg/kg IV. Endotracheal intubation was facilitated with vecuronium Marmara Medical Journal 2005;18(1);

43 Marmara Medical Journal 2005;18(1);35-38 Binnaz Ay, et al. Peroperative Diagnosis of Rhabdomyolysis bromide, 0.1 mg/kg IV. Anaesthesia was maintained with 1 MAC sevoflurane and 66 % nitrous oxide in oxygen. Monitoring included direct arterial blood pressure, central venous pressure (CVP), end-tidal carbondioxide, esophageal temperature, and urinary output. At the third hour of anesthesia laboratory values from arterial blood were as follows: hemoglobin 8.8 g/dl, normal platelet count, pha,7.22; Paco 2, 45.7; Pao 2, 136.3; HCO3, 18.6; base excess, Despite hydration with colloids and cristalloids the patient remained hypotensive throughout the surgery ( 90/60 mmhg), CVP was 3 mmhg and the heart rate was between 90-95/min. Urine output at the time was 200 ml (0.5 ml/kg/h). Due to ongoing hypotension and metabolic acidosis blood electrolytes were checked and were as follows: Na, 143 meq/l; K, 6.6 meq/l; bloodurea nitrogen (BUN), 32 mg/dl; creatinine, 1.42 mg/dl. There was no sign of hyperkalemia on the electrocardiography. course of the operation. After an uneventful surgery and anesthesia, patient was transferred to the intensive care unit (ICU) where his lungs were mechanically ventilated. Upon admission to the ICU,blood-gas analysis revealed severe metabolic acidosis (pha, 7.05; Paco2, 47.2; Pao 2, 169; HCO 3, 12.8; base excess, ).Intravenous bolus and infusion of sodium bicarbonate were administered (total dose of 250 meq). Oliguria developed and renal function continued to deteriorate (Table I). Dopamine, furosemide, and mannitol infusions were administered to maintain urine output. On the fourth postoperative day, venovenous hemodialysis was performed. He died of circulatory insuffiency on the sixth postoperative day. DISCUSSION Extensive skeletal muscle injury, whether caused by mechanical crush or by extreme physical Table I: Laboratory Results Laboratory tests Normal range Preop Perop PD-0 PD-1 PD- 2 PD- 3 PD- 4 PD- 6 Na (meq/l) K (meq/l) BUN (mg/ml) Cr (mg/ml) LDH (U/L) AST (U/L) ALT (U/L) Aldolase (U/L) Ca (mg/dl) CPK U Urine Output _ Urine Myoglobin ng/ml Urine ph Urine Density Urine Bilirubine Neg Neg Neg Neg PD-0: postoperative day 0; Na: sodium; K: potassium; BUN: blood-urea nitrogen; Cr: creatinine; LDH: lactate dehydrogenase; AST: aspartate transaminase; ALT: alanine transminase; Ca: calcium; CPK: creatinine phosphokinase. Neg: negative Because of suspected rhabdomyolysis, forced diuresis was induced with mannitol 20% (40 g) and, 20 mg furosemide intravenously. Hyperkalemia was treated with 10% dextrose with insulin. At the end of surgery estimated blood loss was 3300 ml and urine output 600 ml (1 ml/kg/h) ml of whole blood, 3000 ml isotonic saline and 1000 ml gelatin were administered during the exertion, is incompatible with life, unless treated early and vigorously. The immediate cause of morbidity is leakiness of the sarcolemmal membrane to cardiotoxic or nephrotoxic cations and metabolites ( potassium, phosphate, lactic acid, creatine kinase, myoglobin and urate) of the sarcoplasma, and rapid massive uptake by the muscles of extracellular fluid, sodium, and calcium, leading to profound hypovolemic and 36

44 Marmara Medical Journal 2005;18(1);35-38 Binnaz Ay, et al. Peroperative Diagnosis of Rhabdomyolysis hypocalcemic shock. Rhabdomyolysis occurs frequently but is usually asymptomatic (laboratory abnormalities only). However, in more severe cases, severe electrolyte disorders and acute renal failure may (ARF) occur, leading to lifethreatening conditions. Rhabdomyolysis develop in any situation where energy demands in muscle exceed the available energy supply 2. Multiple complications can occur and are classified as early or late. Early complications include severe hyperkalemia that causes cardiac arrhythmia and arrest. The most serious late complication is ARF, which occurs in approximately 15 percent of patients with the syndrome. Patients who survive the early stage of hyperkalemia and arterial hypotension are susceptible to myoglobinuric ARF which is due to the combination of renal vasoconstriction, nephrotoxicity, and tubular obstruction by myoglobin plugs and urate 3,4. Myoglobinuric renal failure accounts for 2-5 % of all cases of ARF in the ICU. It should be considered a possible cause in all cases of ARF of uncertain etiology. If the serum content of sarcoplasmic enzymes is very high (creatine kinase values to units) myoglobinuria must be the cause 5.-Crush injuries resulting in traumatic rhabdomyolysis are an important cause of ARF. Ischemia reperfusion is the main mechanism of muscle injury. Intravascular volume depletion and renal hypoperfusion, combined myoglobinuria, result in renal dysfunction. In our case underlying cause of severe rhabdomyolysis was crush injury and ischemia by vascular obstruction which contributed to the development of ARF with concomitant volume depletion and hypotension 6. In a recent study de Meijer et al evaluated the risk factors for the development of ARF and demonstrated that in patients with severe rhabdomyolysis the level of serum creatine kinase levels predicted the development of ARF 7. Management includes immediate intravenous volume replacement followed by mannitolalkaline diuresis. The alkali regimen ameliorates the acidosis associated with shock and the hyperkalemia, and protects against the nephrotoxicity of myoglobin and urate by alkalinization of the urine 8. In the present case, anesthesia was commenced with a standart approach. The patient was diagnosed having an open femur fracture of which an external and internal fixation of the bone together with arterial anastomosis was planned. The time past after the accident to the second operation was twenty-four hours. At the third hour of anesthesia the result of blood gas analysis revealed metabolic acidosis together with increased level of preoperative LDH we correlated with nothing but rhabdomyolysis. Blood chemistry showed that he was hyperkalemic at that time (6.6 mg/dl) without any electrocardiographic changes. Test result for blood in urine was negative. Urine output was 200 ml at the third hour. After then treatment initiated immediately, aiming at a rapid correction of the extracellular volume with crystalloids, colloids and blood products. Hyperkalemia was treated accordingly. Mannitol and furosemide were employed to promote renal tubular flow, flush myoglobin plugs, and to enhance urinary elimination of nephrotoxic metabolites. In our case, despite early diagnosis and vigorous treatment, the patient died of circulatory insuffiency on the sixth postoperative day. Since physiologic amputation is a treatment option that halts myonecrosis, prevents myoglobinuria, and lessens the risk of associated acute renal failure 9, we speculate that he could have benefited the procedure. The reason we report this case is that anaesthesiologists who do not deal with trauma cases on daily bases would easily skip the diagnosis. Besides, patient s preoperative history and clinical picture did not direct us toward the possibility of rhabdomyolysis. It was the first case in our institute of rhabdomyolysis detected after a fracture of femur. Metabolic acidosis detected after a coincidental blood-gas analysis was the harbinger of rhabdomyolysis. We tried to rule out the possible causes which might have led to metabolic acidosis in this patient. Rightafter we checked the serum potassium level. Increased potassium level together with metabolic acidosis detected peroperatively and the preoperative increased LDH rendered us to the diagnosis of rhabdomyolysis. Furthermore this case demonstrates the importance of a careful and continous monitoring in traumatized patients. We would like to emphasize that fracture of the long bones and pelvic fractures may lead to crush injuries (rhabdomyolysis) although skeletal muscle injury seems to be minimal clinically. Early recognition of rhabdomyolysis and prompt management of complications are crucial to a successful outcome. If the patient continues to deteriorate physiologic amputation should be considered. 37

45 Marmara Medical Journal 2005;18(1);35-38 Binnaz Ay, et al. Peroperative Diagnosis of Rhabdomyolysis REFERENCES 1. Gehr TWB, Schoolwerth AC. Adult acute and chronic renal failure. In: Grenvik A, Ayres SM, Holbrook SM, Shoemaker WC, eds. Textbook of Critical Care. Philadelphia: WB Saunders, 2000: Polderman KH. Acute renal failure and rhabdomyolysis. Int J Artif Organs 2004; 27: Abassi ZA, Hoffman A, Better OS. Acute renal failure complicating muscle crush injury. Semin Neprol 1998; 18: Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician 2002; 65: Rawland LP. Diseases of muscle and neuromuscular junction. In: Wyngaarden JB, Smith LH, eds. Cecil Textbook of Medicine. Philadelphia: WB Saunders, 1985: Malinoski DJ, Slater MS, Mullins RJ. Crush injury and rhabdomyolysis. Crit Care Clin 2004; 20: De Meijer AR, Fikkers BG, de Keijzer MH, van Engelen BG, Drenth JP. Serum creatine kinase as predictor of clinical course in rhabdomyolysis: 5 year intensive care survey. Intensive Care Med 2003; 29: Better OS, Stein JH. Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med 1990: 322: Winburn GB, Hawkins ML, Wood MC. Physiologic amputation prevents myoglobinuria from lower extremity myonecrosis. South Med J 1993: 86:

46 CASE REPORT ENDOSCOPIC REMOVAL OF FRONTOETHMOID OSTEOMA: A CASE REPORT Murat Sarı, Tekin Bağlam, Zahide Mine Yazıcı, Cüneyd Üneri Department of Otorhinolaryngology, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Osteoma is the most common benign tumor of the nose and paranasal sinuses. Most commonly seen in the frontal sinus, it is less common in the ethmoid and maxillary sinuses. This tumor may be discovered incidentally on radiographs, or may grow enough to produce symptoms. Rarely, complications occur at its location near the orbit and anterior skull base. We present a case of frontoethmoid osteoma treated by endoscopic resection, and we emphasise the advantages of this minimally invasive method compared with traditional methods. Keywords: Osteoma, Frontoethmoid region, Endoscopic approach ÖZET FRONTOETMOİD OSTEOMANIN ENDOSKOPİK YAKLAŞIMLA ÇIKARILMASI Osteoma burun ve paranasal sinüslerin sık görülen benign tümörüdür. Sıklıkla frontal sinüste, daha nadir olarak etmoid ve maksiler sinüslerde görülür. Bu tümör radyografilerde rastlantısal olarak tespit edilebildiği gibi semptom oluşturacak kadar büyüyebilir ve nadiren orbita ve ön kafa kaidesine yakınlığı nedeniyle komplikasyonlara neden olabilir. Endoskopik rezeksiyon yöntemi ile tedavi edilen bir frontoetmoid osteoma olgusunu sunduk ve bu minimal invazif tekniğin geleneksel yöntemlere göre belirgin avantajlarını vurguladık. Anahtar Kelimeler: Osteoma, Frontoetmoid bölge, Endoskopik yaklaşım INTRODUCTION Paranasal sinus osteoma is a slow-growing, benign, encapsulated bony tumor that may be commonly asymptomatic, being detected incidentially in 1 % of plain sinus radiographs or in 3 % of sinus computerized tomographic scans 1-3. The true incidence of these tumors is unclear, since they are frequently asymptomatic and diagnosed incidentally 4. Osteomas usually present between the fifth and sixth decades of life. There is a slight male predominance, with ratios varying from 1.3:1 to 3:1 5. The greater preponderance of sinus osteomas in men is attributed to men s greater exposure to trauma and the large size of their sinuses 6. Paranasal sinus osteomas may sometimes be a component of Gardner s syndrome, an autosomal dominant disease, characterized by intestinal poliposis and bone and skin lesions 7. There are several theories regarding the origin of osteomas. The embryological theory postulates that osteomas arise at the junction of the embryonic cartilagenous ethmoid and membranous frontal bones. But we know that Corresponding author: Murat Sarı Department of Otorhinolaryngology, School of Medicine, Marmara University Hospital, Tophanelioğlu Caddesi, No/13/15,Altunizade 81190, İstanbul, Turkey. muratsarı@hotmail.com Tel: Fax: many osteomas arise at sites distant from this junction 8. Sinusitis has been suspected in the etiology of osteoma formation, but the incidence of osteoma and infection do not correlate 5,9. Trauma is an another factor blaimed in the formation of osteomas. However, many patients lack a history of trauma 8. Two different histopathologic types of osteoma have been described. Firstly, the ivory osteoma, composed of dense bone with only a minimal amount of fibrous tissue and secondly, the osteoma spongiosum, containing mature cancellous bone. Occasionally, a third variety called mixed osteoma contains features of both two 4,8,10. Although plain films play a role in the diagnosis of paranasal sinus osteomas, they do not give sufficient information. Computed tomography (CT) scan is the suggested method for determining the regional anatomy and the extent of the lesion. One should consider other fibroosseous lesions of the paranasal sinuses in the differential diagnosis. These lesions include fibrous osteoma, fibrous displasia, and ossifying fibroma 11. Marmara Medical Journal 2005;18(1);

47 Marmara Medical Journal 2005;18(1);39-42 Murat Sarı, et al. Endoscopic Removal of Frontoethmoid Osteoma: A Case Report CASE REPORT A 28-year-old female patient presented with a 1- year history of left-sided facial and frontal pain. There was no history of trauma, nasal surgery, or major paranasal sinus infection. Nasal endoscopy revealed nothing abnormal. The remainder of the head and neck examination was unremarkable. Subsequent computed tomography (CT) scan of the paranasal sinuses revealed an extremely dense lesion located in the left frontoethmoid region (Fig.1). Both anterior and posterior ethmoid cells were affected by the lesion. There was no significant secondary sinusitis. The lesion extended to orbita and skull base without invading them. These findings strongly suggested an osteoma. The patient consented to endoscopic removal of the mass. The possibility of intraoperative need for an open approach was also discussed with the patient. Fig. 2: Macroscopic appearance of the frontoethmoid osteoma after resection (2,5x2x2 cm) The patient s postoperative course was uneventful. She was discharged on the first postoperative day. The nasal packing was removed on the third postoperative day. The patient subsequently made a complete and uneventful recovery. Histologic examination after decalcification showed typical benign osteoma. Postoperatively, control CT scanning showed no residual disease. (Fig.3). Fig. 1: Preoperatif coronal computed tomography scan showing an osseous mass in the left frontoethmoid region The operation was performed under general anesthesia using endotracheal intubation. The patient is placed in the supine position with the head slightly elevated and turned towards the surgeon. The face was disinfected properly. Pledgets soaked with 1:1000 epinephrine were applied to the middle meatal area. Ten minutes after application, the pledgets were removed. The middle turbinate was subluxed medially to allow adequate visualization of the middle meatus. After uncinectomy, ethmoid bulla was opened and the whitish osteoma appeared. The osteoma was completely mobilized using a freer elevator. The middle turbinate was partially resected and then the mass was removed with a forceps. A gross specimen is shown in Fig 2. After control of minor hemorrhage, the area was inspected and there was no CSF leakage. Merocel packing was applied. Fig. 3: Postoperatif coronal computed tomography 6 months after surgery revealed no residual tumor DISCUSSION The clinical presentation of paranasal osteomas covers a broad spectrum. Most of the paranasal sinus osteomas are asymptomatic due to their slow growth rate. When they produce symptoms, headache or facial pain localized over the area of osteoma is the most common one 12. Other symptoms include facial deformity, anosmia, 40

48 Marmara Medical Journal 2005;18(1);39-42 Murat Sarı, et al. Endoscopic Removal of Frontoethmoid Osteoma: A Case Report rhinorrhea or secondary sinusitis 2. They may also produce orbital or intracranial complications when they extend beyond the confines of the sinuses. Orbital symptoms include diplopia, proptosis, exophtalmus, and vision changes 7,12,13. Neurologic complications such as subdural abscess, meningitis, and intracranial pneumotocele are also reported 10, Symptoms are generally related to the location, size and growth rate of the osteoma. It is generally agreed that asymptomatic osteomas without intracranial, or orbital extension, or cosmetic deformity require no treatment 6,10. These should be followed up with serial radiographs to determine any change in size. Surgical removal for osteomas enlarging rapidly, extending beyond the confines of the sinus, filling more than 50 % of the volume of frontal sinus is suggested by Savic and Djeric in They also recommend removal of osteomas associated with unexplained headache, recurrent sinusitis, ocular symptoms, central nervous system symptoms, and those that are located near the frontal sinus ostium or those causing cosmetic deformity 1. Unlike others, sphenoid osteomas should be removed immediately, as their slow progressive growth can cause loss of vision due to compression of visual pathways 6. External surgical procedures have been the method of choice in the treatment of paranasal sinus osteomas 18. Various surgical approaches for osteomas have been described, including osteoplastic flap technique, lateral rhinotomy, and direct anterior surgical approach. Although all these techniques are effective in certain conditions, they bear some disadvantages like permanent scar formation, blood loss, mucocele formation, and paresthesias 8,19. Recently, endonasal endoscopic sinus surgery offers a minimally invasive alternative in the treatment of paranasal sinus osteomas. Lesions limited to sinuses without evidence of orbital or intracranial extension, are suitable for this treatment. The endoscopic approach offers marked advantages over the traditional open techniques. These are, excellent cosmetic results without any external incision, shorter duration of operative time, and early discharge from hospital. It also allows closer and more direct visualization during operation 2. Normal sinonasal functioning can be expected after the initial period of healing. In this case, our patient was appropriately treated by endonasal endoscopic technique without any complication, and was spared more agressive open procedures. The cosmetic result was also more appealing, with no external incision present. The hospital stay was shorter, and the postoperative care was similar to that of any other patient undergoing endoscopic sinus surgery. We present a case of frontoethmoid osteoma successfully managed by endoscopic sinus techniques, and describe the marked advantages of this technique compared with traditional methods in selected cases. We believe that endoscopic approach in the treatment of paranasal sinus osteoma is a viable technique in the absence of significant orbital extension or skull base invasion. Although it is a safe technique, meticulous care and patience is necessary to prevent potential complications such as cerebrospinal fluid leakege and loss of vision. REFERENCES 1. Savic DL, Djeric DR. Indications for surgical treatment of osteomas of the frontal and ethmoid sinuses. Clin Otolaryngol 1990;15: Huang HM, Liu CH, Lin KN, Chen HAT. Giant ethmoid osteoma with orbital extension, a nasoendoscopic approach using an intranasal drill. Laryngoscope 2001;- 111: Brunori A, Bruni P, Delitala A, Greco R, Chiappetta F. Frontoethmoid osteoma complicated by intracranial mucocele and hypertensive pneumocephalus: case report. Neurosurgery 1995;36: Ataman M, Ayas K, Gürsel B. Giant osteoma of the frontal sinus. Rhinology 1993;31: Menezes CO, Davidson TM. Endoscopic resection of a sphenoid osteoma. Ear Nose Throat J 1994;73: Mansour AM, Salti H, Uwaydat S, Dakroub R, Bashshouur Z. Ethmoid sinus osteoma presenting as epiphora and orbital cellulitis: case report and literature review. Surv Ophthalmol 1999;43: Hehar SS, Jones NS. Fronto-ethmoid osteoma: the place of surgery. J Laryngol Otol 1997;-111: Seiden AM, El Hefny YI. Endoscopic trephenation for the removal of frontal sinus osteoma. Otolaryngol Head Neck Surg 1995;112: Smith ME, Calcaterra TC. Frontal sinus osteoma Ann Otol Rhinol Laryngol 1989;98: Al-Sebei K, Desrosiers M. Bifrontal endoscopic resection of frontal sinus osteoma. Laryngoscope 1998;108: Margo CE, Weiss A, Habal MB. Psammomatoid ossifying fibroma. Arch Ophthalmol 1986;104: Atallah N, Jay MM. Osteomas of the paranasal sinuses. J Laryngol Otol 1981;95: Koivunen P, Lopponen H, Fros AP, Jokinen K. The growth rate of osteomas of the paranasal sinuses. Clin Otolaryngol 1997;22: Shady JA, Bland LI, Kazee AM, Pilcher WH. Osteoma of the frontoethmoidal sinus with secondary brain abscess and intracranial mucocele: case report. Neurosurgery 1994;-34: Koyuncu M, Belet U, Sesen T, Tanyeri Y, Simsek M. Huge osteoma of the frontoethmoidal sinus with secondary brain abscess. Auris Nasus Larynx 2000; 27:

49 Marmara Medical Journal 2005;18(1);39-42 Murat Sarı, et al. Endoscopic Removal of Frontoethmoid Osteoma: A Case Report 16. Shick B, Steigerwald C, el Rahman el Tahan A, Draf W. The role of endonasal surgery in the management of frontoethmoidal osteomas. Rhinology 2001; 39: Schwartz MS, Crockett DM. Managemant of a large frontoethmoid osteoma with sinus cranialization and cranial bone graft reconstruction. Int J Pediatr Otorhinolaryngol 1990; 20: Önerci M, Hosal S, Korkmaz H. Nasal osteoma: a case report. J Oral Maxillofac Surg 1993;51: Akmansu H, Eryilmaz A, Dagli M, Korkmaz H. Endoscopic removal of paranasal sinus osteoma: A case report. J Oral Maxillofac Surg 2002;60:

50 REVIEW AGING AND THE EYE Sumru Onal, Tayfun Bavbek Department of Ophthalmology,School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Aging is a fundamental biologic phenomenon that occurs even in the absence of disease, each cell having a genetically programmed lifespan. Tissues that do not undergo mitotic division to replace this cell fallout, such as the central nervous system and the retina, have a high incidence of aging manifestations, particularly after 75 years of age. As the lens ages, it increases in weight and thickness and decreases in accommodative power. No method to halt the formation of age-related macular degeneration and/or senile cataract has been shown to be effective. Nevertheless, advances in the treatment of age-related macular degeneration and advances in surgical removal of cataracts have made treatment very effective. Three major topics related to aging and the eye that will be discussed here are presbyopia, age-related macular degeneration and senile cataract. Keywords: Aging, Eye, Presbyopia, Age-related macular degeneration, Cataract YAŞLANMA VE GÖZ ÖZET Yaşlanma hastalık olmaksızın da gelişen temel biyolojik bir fenomen olup, her bir hücrenin genetik olarak planlanmış bir ömrü vardır. Santral sinir sistemi ve retina gibi hücre kaybını mitoz ile bölünerek yerine koyamayan dokularda özellikle 75 yaş üstünde yaşlanma belirtileri sıklığı daha fazladır. İlerleyen yaş ile birlikte lens ağırlığı ve kalınlığında artış ve akomodasyon gücünde azalma görülür. Yaşa bağlı makula dejenerasyonu ve/veya senil kataraktın gelişiminin önlenmesinde hiçbir yöntemin etkinliği gösterilememiştir. Ancak yaşa bağlı makula dejenerasyonu tedavisinde ve kataraktın cerrahi tedavisinde meydana gelen gelişmeler bu iki oküler hastalığın tedavini etkin hale getirmiştir. Burada yaşlanma ve göz başlığı altında presbiyopi, yaşa bağlı makula dejenerasyonu ve senil katarakt başlıkları incelenmiştir. Anahtar Kelimeler: Yaşlanma, Göz, Presbiyopi, Yaşa bağlı makula dejenerasyonu, Katarakt INTRODUCTION Changes in the visual function with aging go beyond the need for eyeglass prescription. Frequently the physiological ocular changes that accompany aging interact with environmental or disease factors to cause visual impairment. Especially two eye diseases have high prevalence in the elderly: macular degeneration and cataract. In addition, the effects of systemic disease on the eye can cause visual impairment. Visual impairment is the most common sensory problem faced by the elderly. Prevalence data accumulated from the National Health Interview study revealed that 12.8% of the elderly reported some visual problems, and this number increased to over 25% for those aged 85 years and older, 12% of whom were legally blind 1. Perhaps the most common problem with aging and visual acuity is refraction. Almost 95% of those surveyed over age 65 years either wore glasses or reported needing glasses or some form of corrective lenses to improve visual acuity. However, only 45% of those over age 85 years reported that their glasses corrected all of their visual problems 1. The aging process itself has a number of effects on the eye, some of which have variable effects on vision. Physiological changes in the aging eye are: decreased tear viscosity, increased eyelid laxity, decreased color sensitivity, decreased light sensitivity and impaired lens accommodation 2. The almost universal impairment in the accommodation capability of older persons is caused primarily by an increase in the density and inelasticity of the lens. Decreased contrast sensitivity and increased susceptibility to glare also occur frequently and impair reading, driving, and detailed near vision. Color vision is generally Corresponding author: Sumru Onal Altunizade Mah. Okulcikmazi Sok. No: 11/ Üsküdar İstanbul [email protected] Marmara Medical Journal 2005;18(1);

51 Marmara Medical Journal 2005;18(1);43-52 Sumru Onal, et al. Aging and The Eye well preserved, although the progressive yellowing of the lens over time may interfere with blue-green vision. Because of the progressive narrowing of the pupil s diameter and reduced translucency of the lens with advancing age the quantity of light striking the retina also decreases. Interaction of such normal aging changes with medication effects or with ocular manifestations of systemic illness may also result in a decrease in visual function 3. Presbyopia Presbyopia is a normal part of the aging process and leads to a decrease in accommodation associated with loss of elasticity of the lens and lens capsule. Accommodative ability decreases with age. While a great deal of variability occurs in the normal level of accommodation, a general rule is that 6 diopters (D) of accommodation should be present at 40 years of age, 4D at 44 years of age, and 3D at 48 years of age. For each 4-year period under 40 years of age, 1D should be added; for each 4-year period over 48 years of age, 0.5D should be subtracted. This rule is suggested by Milder and Rubin 4. Treatment of presbyopia involves the use of plus lenses for near work. Several methods can be used to determine the proper add. The correction of emetropia and the use of trial frames to determine the proper add yields the best results. Other options for correction of presbyopia include the use of bifocal contact lenses 5. Age-related Macular Degeneration Age-related macular degeneration (AMD) is not only the leading cause of legal blindness in patients aged 65 or over, 6 but also is now the overall cause of blindness in the Western world. It is estimated that in the United States people aged 75 and over will develop AMD over any 5-year period, 7 and the incidence continues to rise as a result of the increasing percentage of elderly persons and the improved management of other eye diseases. Senile macular degeneration was first reported as a clinical entity in 1885 by Otto Haab, who described a variety of pigmentary and atrophic changes in the macular region, causing progressive impairment of central vision in patients over the age of Subsequent observers referred to the different fundus manifestations of the disease as separate entities, resulting in a variety of descriptive eponyms. A major step toward a better understanding of the disease was taken when Gass clarified that drusen, senile macular degeneration, and senile disciform macular degeneration represented a single disease 9. In recent years it has been proposed that the disease should be termed age-related maculopathy (ARM), early and late forms, with the term agerelated macular degeneration AMD being reserved for the late forms and encompassing dry AMD (geographic atrophy) and wet (exudative, or neovascular ) AMD 10,11. Early ARM represents those changes predisposing to AMD. The International Epidemiological Age-related Maculopathy Study Group defined early ARM as a degenerative disorder in persons 50 years of age 10. Normal aging results in a spectrum of changes in the macula, many clinically undetected, that effect the outer retina, retinal pigment epithelium (RPE), Bruch s membrane, and choriocapillaries. Photoreceptors are reduced in density and distribution. Ultrastructural aging changes in the RPE include loss of melanin granules, formation of lipofuscin granules, and accumulation of residual bodies. Basal laminar deposits which are long-spacing collagen collecting between the plasma membrane of the RPE cells and the inner aspect of the basement membrane of the RPE accumulate. Lastly, progressive involutional changes occur in the choriocapillaries 12. Age-related Maculopathy: Nonneovascular Age- Related Macular Degeneration and the evolution of Geographic Atrophy: Onset of ARM may present clinical features in the absence of drusen often characterized by diffuse mottling of small pigment clumps or as a microreticular pattern of small lines, more obvious on fluorescein angiography. Drusen Donders described drusen in Drusen are deposits of extracellular material lying between RPE and the inner collagenous zone of the Bruch s membrane. Generally, classifications based on features of drusen morphology that are evident clinically are favored (Table I) 12. Several population based surveys have found that drusen are present in more than 95% of people, with small hard drusen being most common in all age groups 11, All types of drusen can undergo calcification, thus giving the druse a glistening appearance. Calcification of soft drusen usually precedes drusen regression and the development of RPE atrophy. 44

52 Marmara Medical Journal 2005;18(1);43-52 Sumru Onal, et al. Aging and The Eye Table I: Clinicopathologic Classification of Drusen Type of Druse Clinical Description Histologic Decription Small, Hard (hyalinized) Yellow, well-demarcated boundaries; usually <63 µm diameter; can be evident in the second decade of life; tend to hyperfluoresce on fluorescein angiography Hyalinized material containing membrane-bound bodies external to the RPE basement membrane; can exist in the absence of basal laminar deposits Soft (pseudosoft), clusterderived Yellowish with indistinct margins along some portions of the druse s perimeter; usually occur after age 55 years; variable staining on fluorescein angiography; can regress, leading to atrophy Fused hard drusen cluster in which the amorphous internal rim of the druse is interrupted, forming globular or finely granular material True soft Granular Fluid (Serous) Yellowish with indistinct margins; smaller than soft clusterderived drusen; confined to the macula; precursor to choroidal neovascularization About 250 µm diameter; yellow, solid appearance, their confluence resulting in crescentic sinuous shapes Soft, confluent drusen >500 µm diameter; may have pooled serous fluid in the lipoidal debris; further confluence leads to larger soft fluid drusen that resemble serous pigment epithelial detachments Associated with accumulation of membranous debris external to the RPE basement membrane; consists of focal accentuation of basal laminar deposits, focal accentuation of basal linear deposits, or localized accumulation of basal linear deposits Coarsely granular structure consisting of membrane-bound globules of amorphous material, small membrane fragments and cellular debris Membranous (accumulation of basal linear deposits) Paler and shallower than the yellow granular drusen; usually <250 µm diameter; on fluorescein angiography they fluoresce later and less brightly than small, hard drusen Reticular (pseudodrusen) Regressing (fading) Yellowish interlacing network about 250 µm diameter; first appear in the superior outer macula; resembles soft confluent drusen, but is flat and lie deep to drusen; delayed choroidal perfusion on fluorescein angiography; carries a very high risk for choroidal neovascularization All drusen types may disappear in time; does not signify a return to normal state; fluorescein angiography generally shows increased transmission of fluorescence where drusen have faded Uncertain; the pattern has been suggested to result from fibrous placement of the middle layer of the choroid Both RPE and photoreceptors over regressing drusen disappear, leaving a thick layer of late-type amorphous basal laminar deposit over the apex 45

53 Marmara Medical Journal 2005;18(1);43-52 Sumru Onal, et al. Aging and The Eye On fluorescein angiography soft drusen fill more slowly and are not as brightly fluorescent as hard drusen, but they remain fluorescent for a longer period 16. On indocyanine green angiography (ICG) hard drusen become hyperfluorescent 2 to 3 minutes after dye administration, and this persists throughout the middle and late phases. Soft drusen are either hypofluorescent throughout the angiogram or remain undetectable 17. The cumulative incidence of late ARM in patients with bilateral drusen has been reported in two prospective studies. Among patients attending the ophthalmology clinic in England the 3-year cumulative incidence of late ARM and of exudative AMD alone were, respectively, 23.5% and 18%, one significant risk factor being degree of confluence of drusen within 1600 µm of the center of the fovea 18. In the Beaver Dam study of persons with signs of early ARM in both eyes at baseline, the respective figures at 5 years were 11% and 7.1% 7. In patients who have developed choroidal neovascularization (CNV) in the first eye, the presence of five or more drusen, or one or more large drusen, were two factors associated independently with an increased risk of developing CNV within 5 years in the second eye 19. Another prospective study followed 101 patients with unilateral exudative AMD and drusen only in the fellow eye for up to 9 years. Yearly incidence rates for the development of CNV or geographic atrophy in the fellow were between 5% and 14%. The risk of CNV peaked at 4 years and decreased thereafter. The risk of CNV in patients with ARM was heralded by an increase in the number, size and confluence of drusen. The risk eventually declines and is followed by later increased risk of geographic atrophy 20. This risk is also reflected in pathologic specimens, in which active subretinal new vessels are more likely to be associated with soft membranous-type drusen. Geographic Atrophy Geographic atrophy (GA) is the end result of atrophic AMD and is currently defined as any sharply delineated round or oval area of hypopigmentation or apparent absence of RPE, in which choroidal vessels are more visible than surrounding areas and which must be at least 175 µm in diameter 10. However since such small area could result from regression of a single druse, other dimensions proposed have been wider, varying from 200 µm, 21 to 500 µm, 22 to 700 µm, 14 to 1mm 23. If a larger size is chosen, it has greater prognostic significance, especially if the atrophy has already entered the fovea, because CNV then is less likely to develop or, if it should occur, is more likely to be muted. The evolution of GA can be drusen-unrelated, drusen-related, or following pigment epithelial detachments 24. Among patients with early ARM the 5-year incidence of pure GA atrophy has been found to be 4.6% 7. Once GA has commenced, the factors that influence the rate and direction of further spread are the number, distribution, and regression of drusen and the extent of incipient atrophy (RPE thinning). When this extends to the central fovea, visual acuity can be expected to drop more rapidly. In general, the percentage of foveal involvement increases rapidly at first, slowing once all the area of incipient atrophy has become involved. Histological studies have shown that eyes with geographic atrophy may also contain small inactive CNV and that CNV is more frequently bilateral than clinical impressions suggest 25,26. Neovascular (Exudative) Age-related Macular Degeneration: AMD is the major cause of severe visual loss in older adults 11,15, Most AMD patients have macular drusen or retinal pigment epithelial abnormalities or both 32. However, approximately 10% of AMD patients manifest the neovascular form of the disease 33. Neovascular AMD includes CNV and associated manifestations such as retinal pigment epithelial detachment, retinal pigment epithelial tears, fibrovascular disciform scarring, and vitreous hemorrhage 32. The prevalence of AMD-associated vision loss in at least one eye increases with age 11,14,15,27,28,30,31,34,35. AMD was the leading cause of blindness in white (prevalence, 2.7 per 1000) but not black subjects randomly selected in the Baltimore Eye survey. In this study, AMD resulting in blindness affected 3% of all white subjects 80 years of age or older 31. Risk factors implicated in clinical and laboratory studies include drusen, visible (but not ultraviolet) injury, micronutrient deficiency, cigarette smoking, family history (genetic predisposition), and cardiovascular risk factors (including systemic hypertension) 36,37. 46

54 Marmara Medical Journal 2005;18(1);43-52 Sumru Onal, et al. Aging and The Eye Choroidal neovascularization CNV appears as a neovascular sprout growing under or through the RPE through breaks in Bruch s membrane 25. Blurred vision and distortion, especially distorted near vision, are the symptoms most patients with CNV notice first 32,38. Patients may also complain of decreased vision, micropsia, metamorphopsia, or a scotoma 38. Visual acuity, although frequently decreased, may not always be affected. Functional vision generally declines in accordance with Snellen visual acuity 39. In some patients with AMD, CNV may appear as a gray-green elevation of tissue deep to the retina with overlying detachment of the neurosensory retina. The gray-green color may arise from hyperplastic RPE in response to the CNV 40. However, it is not always present in older individuals with AMD. Often, the presence of blood or lipid or a sensory retinal detachment in an elderly patient with vision loss indicates the presence of CNV. Retinal Pigment Epithelial Detachments (PED) Retinal PED appear clinically as sharply demarcated, dome shaped elevations of RPE. They usually transilluminate if they are filled with serous fluid only. Although an overlying sensory retinal detachment may be a clue to the presence of CNV beneath a PED, sometimes a shallow neurosensory detachment may occur as a result of breakdown of the physiologic RPE pump or from disruption of the tight junctions between adjacent RPE cells in the absence of CNV 41. The presence of a PED may or may not be a feature of CNV. The fluorescein angiographic pattern can differentiate a drusenoid PED, which does not have CNV, from a fibrovascular PED, which is a form of occult CNV, as well as from serous PED, which may or may not overlie an area with CNV 42,43. Several clinical signs suggest the presence of CNV underlying an PED, including overlying sensory retinal detachment and lipid, blood, and chorioretinal folds radiating from the PED 32. When confined to the sub-rpe space, the blood may appear as a discretely elevated, green or dark red mound. The hemorrhage can dissect through the RPE into the subretinal sensory retinal space or into the retina. Rarely, blood may pass through the retina into the vitreous cavity, causing extensive vitreous hemorrhage. Disciform Scars Histologically, CNV usually is accompanied by fibrous tissue, even when no fibrous tissue is readily apparent on initial presentation 44. This fibrous tissue may be accompanied by CNV (fibrovascular tissue) or not (fibroglial tissue) 44. The fibrous tissue complex may be beneath the PRE (usually proliferating within the inner aspect of an abnormally thickened Bruch s membrane) or between the RPE and the photoreceptors 45. Often, over time, the plane of the RPE is destroyed by the fibrovascular or fibroglial tissue, so the location of the CNV with respect to RPE can no longer be identified readily. When the fibrous tissue becomes apparent clinically, the CNV and fibrous tissue complex may be termed a disciform scar. Classification of CNV using Fluorescein Angiography Whenever one suspects CNV for which treatment might be indicated, stereoscopic fluorescein angiography should be performed promptly. Fluorescein angiography frequently allows one to determine the pattern (classic or occult), boundaries (well defined or poorly defined), and location of the neovascular lesion with respect to the foveal avascular zone (FAZ) 46. Classic CNV appears as a well-demarcated area of uniform hyperfluorescence surrounded by a hypofluorescent margin in the early phase frames of the angiogram, with fluorescein leakage that obscures the boundaries of the lesion through the mid- and late-phase frames. Occult CNV is divided into two types. Type I is characterized by a fibrovascular RPE detachment that appears as stippled hyperfluorescence with irregular elevation of this fluorescence at the level of RPE, usually within 1-2 minutes of fluorescein injection. The boundaries are often poorly defined or difficult to demarcate and there is fluorescein leakage in the late phase frames of the angiogram. Type II has poorly demarcated boundaries with fluorescein leakage from an undetermined source at the level of RPE in the late phase frames of the angiogram, which do not correspond to classic CNV or fibrovascular PED in the early- or midphases 46. Lesion composition is assessed using the fluorescein angiography and the classification is defined by the proportion of the lesion that is classic CNV. Predominantly classic lesions are defined as those in which the classic component comprises 50% or more of the entire lesion. Lesions in which the classic component comprises less than 50% of the entire lesion area are defined as minimally classic and those with no evidence of classic CNV are defined no classic 46. The terms well defined (well demarcated) and poorly defined (poorly or ill demarcated) refer to a description of 47

55 Marmara Medical Journal 2005;18(1);43-52 Sumru Onal, et al. Aging and The Eye the boundaries of the lesion. In a well-defined lesion, the entire boundary for 360 degrees is well demarcated. If the entire boundary is not well demarcated for 360 degrees, then the lesion is poorly defined. These terms describe lesion boundaries for a lesion that may be composed of classic CNV, or occult CNV, or both. When lesions have well-defined boundaries, the CNV lesion can be classified according to the location of the most posterior boundary with respect to the center of the FAZ on the fluorescein angiogram. CNV lesions located more than 200 µm from the FAZ center are termed extrafoveal; those between 1 and 199 µm from the center are juxtafoveal; CNV lesions extending under the center of the FAZ are termed subfoveal. In contrast to other pathologic conditions predisposing to CNV in eyes with AMD, CNV presents more commonly under the FAZ center 46. Treatment Laser photocoagulation has been shown to be beneficial only for well-defined lesions. If the entire boundary of the lesion is not well defined, then the treating ophthalmologist can not determine where to apply laser photocoagulation with certainty in order to cover the lesion its entirety; undertreatment or overtreatment will occur likely. Failure to cover the entire lesion increases the likelihood of recurrent CNV and, for extrafoveal and juxtafoveal lesions, additional visual acuity loss 47,49,50. Overtreatment likely will destroy retinal tissue and corresponding function that was not overlying CNV unnecessarily 49. The decision for laser photocoagulation should be made considering the size of the CNV and the initial visual acuity. Specifically, the smaller the lesion and the better the visual acuity at the time of treatment, the greater will be the benefit. Laser treatment may not be indicated in three common presentations: if only occult CNV is noted in a subfoveal lesion; if the boundaries of the entire neovascular lesion are not well demarcated; and if a subfoveal lesion is large (>3.5 MPS disc diameter). A patient undergoing treatment for an extrafoveal or juxtafoveal lesion should understand that this therapy will not improve existing vision and will induce a permanent scotoma 46. The choice of wavelength for photocoagulation (green or red) appears to have no effect on the treatment benefit. The risk of recurrence appears greatest in the following situations: when the fellow eye has evidence of active CNV or scarring; when treatment fails to cover the neovascular lesion in its entirety; and when photocoagulation is not as intense as a moderately white treatment intensity standard 46. Photodynamic therapy (PDT) involves the use of an intravenously injected photosensitizing drug combined with a low-intensity laser light to cause damage of choroidal neovascular tissue selectively through a photochemical reaction by the light-activated drug that appears to result in direct cellular injury, including damage to vascular endothelial cells and vessel thrombosis 51,52. It has been shown that PDT with verteporfin (Visudyne) can safely reduce the risk of moderate and severe vision loss in patients with subfoveal lesions that are predominantly classic CNV secondary to AMD. While this benefit seemed to be even greater in the absence of occult CNV, the effect may be related to the smaller lesions and worse visual acuity associated with predominantly classic lesions without occult CNV and not solely to the lesion composition itself 53. Additionally, lesion size in the TAP Investigation and VIP Trial was also an important predictor of the magnitude of treatment benefit with verteporfin therapy in occult with no classic and minimally classic lesion compositions 54. Potential future treatments for CNV in AMD are submacular surgery, radiation therapy and pharmacologic therapy with angiogenesis inhibitors 46. Senile Cataract Cataract, an opacity of the lens that impairs vision, is the most common cause of visual loss in humans. Any opacity in the lens or its capsule whether congenital or acquired is known as cataract 55. Throughout the world the elderly population is increasing. For the period the projected increase in the elderly population for the developed world is 186%, while in developing countries the projected increase is 356%. On this basis, the World Health Organization estimates that 54 million blind people aged 60 years or more will occur by the year Based on morphology cataract can be classified as capsular, subcapsular, cortical, supranuclear, nuclear, lamellar and sutural cataract. Cataracts have also been classified according to developmental stage. These are: immature, intumescent, mature, hypermature and Morgagnian cataract. Etiological classification is ideally considered as the most widely accepted classification of cataract. Various types of 48

56 Marmara Medical Journal 2005;18(1);43-52 Sumru Onal, et al. Aging and The Eye cataracts under this classification are congenital, developmental, senile, metabolic, traumatic, toxic and secondary cataract and cataracts associated with systemic diseases 57. The most common type of cataract encountered is senile or age-related cataract. It is an affection of advanced life and is essentially an aging process. Sometimes there appears to be a familial tendency for cataract in which case the condition may develop at an earlier age in successive generations and phenomenon is known as anticipation and as a rule is usually bilateral but develops earlier in one eye than the other. Usually some degree of cataract is present after the age of 50 years and it equally affects both sexes. Although the precise etiopathogenesis is not clear, yet the various factors involved in senile cataractogenesis are hereditary factors, cigarette smoking, alcohol use, ultraviolet irradiation, dietary factors, and severe dehydration Senile cataract is of various types and occurs in subcapsular, cortical and nuclear regions of the lens. The locations of the predominant senile cataract have been shown to be cortical in 70%, nuclear in 25%, and subcapsular in 5% of cases 57. Subcapsular Senile Cataract (Cupuliform Cataract) These cataracts may be anterior or posterior and are seen as brown granules and cysts in the shape of a shallow cup in the subcapsular region. The anterior subcapsular cataract lies directly under the lens capsule and is associated with fibrous metaplasia of the anterior epithelium of the lens. The posterior subcapsular cataract lies just in front of the posterior capsule and is associated with posterior migration of epithelial cells of the lens. These cataracts usually develop in 60 to 80 yearold age group, but may be present in an inherited form at an earlier age. Patients with posterior subcapsular cataract specifically get troubled by bright sun light and headlights of incoming vehicles 57,62. Cortical Senile Cataract (Cuneiform or Soft Cataract) Cortical senile cataract is the most common form of senile cataract. This type of cataract is characterized by opacities in cortical fibers and appears to be due to an accumulation of globules and vacuoles between adjacent fibers. There is hydration due to accumulation of water droplets between the fibers followed by changes in the colloid system within the fibers. The lens proteins are first denaturated and then are coagulated forming opacity. Ultimately the whole lens becomes opaque and assumes a pearly white appearance. The appearance of cuneiform cataract with its vacuoles, radial spoke like separation of lens fibers and wedge-shaped water clefts and shield-like configuration is characteristic. Cuneiform opacities represent areas in which lens fiber membranes get damaged allowing sodium influx and osmotic inhibition of water. Increased membrane permeability and inactivation of active transport process in these areas leads to loss of potassium, gluthatione, soluble protein and inositol. These biochemical changes eventually lead to precipitation, opacification and aggregation of lens proteins. If the whole cortex is opacified such a cataract is known as mature cataract 57,62. Nuclear Senile Cataract In this type of senile cataract the nucleus gradually becomes opaque and cortex being clear. Increased optical density of the nucleus occurs normally with aging but it may be stimulated to excess with the formation of brown nucleus (brunescent cataract) or even a black nucleus (cataracta nigra) and is usually bilateral. Dehydration and compaction of nucleus are associated with the process of nuclear sclerosis. The sclerotic process renders the lens inelastic and hard and decreases its ability to accommodate. At first a certain degree of myopia is induced. These changes start centrally and speed towards periphery. This type of cataract does not develop into hypermature stage. The progress of cataract is slow and myopic eyes are more prone to develop this type of cataract. Biochemical changes in nuclear senile cataract include an increase in the concentrations of protein, corresponding decrease in the degree of hydration, marked increase in sodium level along with decrease in potassium concentration. These changes are associated with accumulation of yellow-brown pigment urochrome which may represent an oxidation product of amino acids or lipids. Nuclear sclerosis begins between 50 to 60 years of age and progresses very slowly unless accelerated by the superimposition of subcapsular cataract 57,62. Treatment Treatment of cataract essentially consists of its surgical removal. The indications for a particular lens surgery technique to be used may be determined by several factors. Different conditions or pathological states of the eye and the lens may dictate the use of one technique over another. In different countries, the availability of 49

57 Marmara Medical Journal 2005;18(1);43-52 Sumru Onal, et al. Aging and The Eye equipment and the level of training of the surgeon may be factors that dictate the technique. Intracapsular Cataract Extraction Intracapsular Cataract Extraction (ICCE) is an old traditional method of cataract removal. In ICCE the entire lens is removed with cryoprobe or capsule forceps. This method has not been the procedure of choice in industrialized nations since the development of modern extracapsular techniques in the late 1970 s, primarily because of lower rates of postoperative posterior segment complications as hemorrhage, vitreous loss, retinal detachment, and cystoid macular edema. Posterior chamber intraocular lens (IOL) implantation is impossible as the posterior capsule is absent due to total removal of the lens and its capsule 57,63. Extracapsular Cataract Extraction Extracapsular Cataract Extraction (ECCE) became popular in the 1980 s. The lens is removed without disturbing the integrity of the posterior capsule and anterior vitreous face. ECCE involves the excision of a portion of anterior capsule and nucleus expression through incision and aspiration of the residual equatorial cortex. The posterior capsule is left undisturbed and serves as resting site for the posterior chamber IOL implants 63. Postoperative posterior capsule opacification (PCO) may occur in a significant number of cases. PCO can be managed using neodymium-yttriumaluminum-garnet (Nd:YAG) laser capsulotomy 57. Phacoemulsification Kelman devised this technique about 25 years ago It differs from ECCE in that corneoscleral incisions required are very small (3.0 mm), central continuous curvilinear capsulorrhexis of about 4-5 mm is preferred over other methods of anterior capsulotomy, the use of foldable IOLs and in that the nucleus is emulsified and aspirated in the posterior chamber by the phacoemulsifier which acts through a titanium needle in an longitudinal axis at an ultrasonic speed of 400,000 times a second. Smaller incisions, more rapid wound healing, short convalescence and early stabilization of refractive error with less astigmatism are major advantages 63. New and future technologies are phaconit, laser cataract surgery using Nd:YAG or Er:YAG laser systems, laser phaconit and focused electromagnetic field technology REFERENCES 1. Kovar MG. Aging in the eighties, Preliminary data from the supplement on aging to the National Health Interview Survey, United States, Jan-June 11984, Advance data from vital and health statistics, No 115, DHHS Publication No (PHS) , Hyattsville, Md, 1986, Public health service. 2. Adams AJ, Wong LS, Wong L, Gould B. Visual acuity changes with age: some new perspectives. Am J Optom Physiol Ophthalmol 1988; 65: Heath JM, Hoepner JA. Vision. In: Ham RJ, Sloane PD eds. Primary care geriatrics. A case-based approach. St Louis, Missouri: Mosby, 1997: Milder b, Rubin ML. Accommodation. In: The fine art of prescribing glasses without making a spectacle of yourself. Gainesville: Triad Scientific Publishers. 1978: Donahue SP. Loss of accommodation and presbyopia. In: Yanoff M, Duker JS, eds. Ophthalmology. St Louis, Missouri: Mosby, 1999: Ferris, FL III. Senile macular degeneration: review of epidemiologic features, Am J Epidemiol 1983; 118: Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1997; 104: Haab O. Erkrankungen der Macula Lutea, Centralblat Augenheilkd 1885; 9: (Cited by Duke-Elder, S: System ofophthalmology, vol 9, London, 1966, Kimpton.) 9. Gass JDM. Pathogenesis of disciform detachment of the neuroepithelium (parts I and III). Am J Ophthalmol 1967; 63: Bird AC, Bressler NB, Bressler SB, et al. The International ARM Epidemiological Study Group: An international c1assification and grading system for age-related maculopathy and age related macular degeneration. Surv Ophthalmol 1995; 39: Klein R, Klein BEK, and Linton KLP. Prevalence of age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology 1992; 99: Abdelsalam A, Del Priore L, and Zarbin MA. Drusen in age-related macular degeneration: Pathogenesis, natural course, and laser photocoagulation-induced regression. Surv Ophthalmol 1999; 44: Donders FC. Beitrage zur pathologischen Anatomie des Auges. Arch Ophthalmol 1854; 1: Bressler NM, Bressler SB, West SK, Fine SL, and Taylor HR. The grading and prevalence of macular degeneration in Chesapeake Bay watermen. Arch Ophthalmol 1989; 107: Vingerling JR, Dielemans I, Hofman A. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995; 102: Barondes M, Pauleikhoff D, Chisholm IC, Minassian D, and Bird AC. Bilaterality of drusen. Br J Ophthalmol 1990; 74:

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