Marmara Medical Journal

Transkript

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
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:1988
2004 Yılından itibaren yanlızca elektronik olarak
yayınlanmaktadır
Yayın Dili: Türkçe, İngilizce
eISSN: 1309-9469
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: +90 0 216 4144734
Faks: +90 O 216 4144731
e-posta: [email protected]
Yayıncı
Plexus BilişimTeknolojileri A.Ş.
Tahran Caddesi. No:6/8, Kavaklıdere, Ankara
Tel: +90 0 312 4272608
Faks: +90 0312 4272602
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.
www.marmaramedicaljournal.org
Marmara Üniversitesi Tıp Fakültesi Dergisi
YAZARLARA BİLGİ
Marmara Medical Journal – Marmara
Üniversitesi Tıp Fakültesi Dergisine ilginize
teşekkür ederiz.
Derginin elektronik ortamdaki yayınına
erişim www.marmaramedicaljournal.org
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
http://marmaramedicaljournal.org/submit.
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
da
yayınlanmak
üzere
ya
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
(http://tdk.org.tr) 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.
(http://www. ulakbim.gov.tr /cabim/vt)
Makale içinde kullanılan kısaltmalar
Uluslararası kabul edilen şeklide olmalıdır
(http..//www.journals.tubitak.gov.tr/kitap/ma
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
(http://www.ncbi.nim.nih.gov/sites/entrez/qu
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, 1996.
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,
1995:465-78.
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; 1992:1561-5.
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.
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 27089
sayılı Resmi Gazete'de yayınlanan "Klinik
araştırmaları Hakkında Yönetmelik" ve daha
sonra yayınlanan 11 Mart 2010 tarihli resmi
gazete ve 25518 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:+90 0 216 4144734
Faks:+90 0 216 4144731
e-posta: [email protected]
İÇİNDEKİLER
Orjinal Araştırma
A LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM FOR THE TREATMENT
OF ABNORMAL UTERINE BLEEDING
Recep Yıldızhan, Begüm Pekin Yıldızhan, Ertan Adalı, Necdet Süer………………………………………53
A COMPARISON OF CONVENTIONAL EXTERNAL RADIOTHERAPY TECHNIQUE AND
CONFORMAL RADIOTHERAPY TECHNIQUE IN TERMS OF ACUTE TOXICITY WITH
REGARD TO HORMONAL TREATMENT
İlknur Çetin, Ufuk Abacıoğlu, Meriç Şengöz…………………………………………………..…………......58
THE EFFECT OF A LEVONORGESTREL-RELEASING INTRAUTERINE DEVICE ON
OVARIECTOMIZED RAT ENDOMETRIUM UNDER ESTROGEN REPLACEMENT
THERAPY
Murat Api, Feriha Ercan, Serap Arbak, Olus Api…………………………………………….……………...65
THE CONTRIBUTION OF HOME-FAMILY DISTRESS TO THE PRESENTATION
DIFFERENCE OF CHILDHOOD OBSESSIVE-COMPULSIVE DISORDER ACROSS HOME
AND SCHOOL SETTINGS
Osman Sabuncuoğlu, Meral Berkem…………………………………………………………………….……..73
Olgu Sunumu
MISPLACEMENT OF A NASOGASTRIC TUBE INTO THE POSTPNEUMONECTOMY
SPACE
Tümay Umuroğlu , İ. Varlık Doğan , Abdurrahman Yaycı………………………………….………………78
A FAMILY WITH A 17p: PERICENTRIC INVERSION: IMPLICATIONS FOR CARRIERS
Gülseren Bağcı, Özgül Alper, Anne Hagemeijer, Hasan Acar, Elizabeth M.E. Smit, Mine Üner
Güven Lüleci…………………………………………………………………………………………………...…81
COCHLEAR IMPLANTATION IN A PATIENT WITH LARGE VESTIBULAR AQUEDUCT
SYNDROME: A CASE REPORT
Ufuk Derinsu, Ayça Çiprut, Sezer Külekçi, Ferda Akdaş…………………………………………….……..84
CLINICAL AND ELECTRODIAGNOSTIC FOLLOW UP OF A CASE OF FOOD BORNE
BOTULISM
Nilgün Cengiz, Hande Türker, Meral Kiziltan…………….………………………………………………….89
Derleme
THE MANAGEMENT OF ELBOW FRACTURES IN CHILDREN
Bülent Erol, Murat Bezer, Gökhan Er, Mustafa Karahan, Osman Güven…………………………...…...93
ORIGINAL RESEARCH
A LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM FOR THE
TREATMENT OF ABNORMAL UTERINE BLEEDING
Recep Yıldızhan, Begüm Pekin Yıldızhan, Ertan Adalı, Necdet Süer
Department of Obstetrics and Gynaecology, SSK Göztepe Training and Research Hospital, Istanbul, Turkey
ABSTRACT
Objectives: To evaluate the efficacy and safety of an intrauterine system releasing 20µg levonorgestrel per 24 hours in the longterm treatment of heavy menstrual blood loss in women unrelated to intrauterine pathology.
Methods: Sixty parous women aged 35-48 years with recurrent menorrhagia participated in this study. Women were followed-up
for at least 12 months (12-16 months). The effect on menstrual blood loss was evaluated using a simple visual assessment technique. All
women to be included in the study were screened for their clinical suitability for intrauterine device insertion. An intrauterine device
releasing levonorgestrel 20 µg/day was inserted in each patient within 5 days of the start of menstrual flow. Women were followed-up at
1, 3, 6, 12 months following insertion of the intrauterine device, for clinical and transvaginal ultrasound examinations.
Results: One patient experienced intrauterine device expulsion 1 month after device insertion and one woman was lost to followup after achieving amenorrhea and expressing satisfaction. One year of follow-up has been completed for the remaining 58 women: 8
cases with amenorrhea, 12 with oligomenorrhea, 6 with spottings and 32 patients with regular flow, with a significant reduction in the
amount of menstrual blood loss. The levonorgestrel-releasing intrauterine system was well tolerated by all women involved in the study
and no systemic hormonal side effects were reported.
Conclusion: Our findings indicate that the levonorgestrel-releasing intrauterine system is effective in the significiant reduction of
the amount of menstrual blood loss in women with menorrhagia, even in the presence of adenomyosis, intramural and subserosal fibroids
and renders surgery unnecessary. In addition, the levonorgestrel-releasing intrauterine system showed a high contraceptive efficacy and a
good continuation rate for up to 1 year.
Keywords: Menorrhagia, Levonorgestrel-releasing intrauterine system, Contraception, Transvaginal ultrasound, Pipelle
endometrial biopsy
ŞİDDETLİ MENSTRUEL KANAMA TEDAVİSİNDE LEVONORGESTREL - SALINIMLI
İNTRAUTERİNE SİSTEMİN KULLANILMASI
ÖZET
Amaç: İntrauterin bir patolojiye bağlı olmayan şiddetli menstruel kanaması olan kadınlarda 20µg/gün levonorgestrel salınımlı
intrauterin sistemin etkinlik ve güvenilirliğinin değerlendirilmesidir.
Yöntem: Menoraji şikayeti olan ve daha önce doğum yapmış 35-48 yaşları arasında bulunan 60 kadın bu çalışmada yer
almıştır. Bu kadınlar en az 12 ay boyunca takip edilmiştir. Menstruel kan kaybının yaratmış olduğu etki, görsel değerlendirme tekniği
ile saptanmıştır. Çalışmaya katılan tüm kadınların, intrauterin araç uygulamaya uygun olup olmadığı araştırılmıştır. Tüm kadınlara
adetlerinin başlangıcından itibaren ilk 5 gün içinde 20µg/gün levonorgestrel salınımlı intrauterin araç uygulanmıştır. Her hasta,
uygulamayı takiben 1., 3., 6. ve 12. aylarda klinik ve ultrasonografik olarak takip edilmiştir.
Bulgular: Takip edilen hastalardan bir tanesinde uygulamadan 1 ay sonra intrauterin araç kendiliğinden çıkmıştır. Diğer bir
hastaya ise, amenore elde edilmesine ve hastanın yöntemden memnuniyetini ifade etmesine rağmen rutin takipler için
ulaşılamamıştır. Geriye kalan 58 hastada 1 yıllık rutin takipler tamamlanmıştır. Buna göre 8 hastada amenore, 12 hastada
oligomenore, 6 hastada lekelenme ve 32 hastada ise menstruel kan kaybında anlamlı bir azalma olmakla birlikte düzenli kanamaların
sürdüğü saptanmıştır. Çalışmada yer alan tüm hastalar tarafından levonorgestrel salınımlı intrauterin sistem iyi tolere edilebilmiş olup
sistemik hormonal yan etkiler izlenmemiştir.
Sonuç: Bulgularımız göstermiştir ki; levonorgestrel salınımlı intrauterin sistem, şiddetli menstruel kanama ile kaybedilen kan
miktarında belirgin oranda azalmaya neden olmuş ve hatta adenomyozis, intramural ve subseröz myom varlığında dahi cerrahiye
olan gereksinimi azaltmıştır. Bunların yanısıra, yüksek kontraseptif etkinliğe de sahiptir.
Anahtar Kelimeler: Menoraji, Levonorgestrel salınımlı intrauterin sistem, Kontrasepsiyon, transvajinal ultrasonografi,
pipelle endometrial biopsi.
Corresponding author:Recep Yıldızhan M.D.Cemil Topuzlu Cd.
103/15 34728 Caddebostan Istanbul, Turkey
Tel.:90 216 359 20 81 Fax:90 216 363 40 18
e-mail. [email protected]
Marmara Medical Journal 2004;17(2);53-57
53
Recep Yıldızhan, et al.
A levonorgestrel-releasıng intrauterine system for the treatment of abnormal uterine bleeding
study were screened for their clinical suitability
for IUD insertion and followed-up for 12 months
duration. Each woman underwent pelvic
examination, transvaginal ultrasound, pipelle
endometrial biopsy and Papanicolaou smear in the
2 months before entry into the study to evaluate
the uterine status. Four cases were diagnosed as
myoma uteri, single or multiple small intramural
and subserosal fibroids (<3 cm).There was no
evidence of submucosal fibroids. Eight women
were diagnosed at transvaginal ultrasound
(TVUS) as having adenomyosis. The remaining
48 women were diagnosed with dysfunctional
uterine bleeding.
INTRODUCTION
The levonorgestrel-releasing intrauterine system
(LNG-IUS) (Mirena, Schering) was originally
designed as a contraceptive method registered in
Europe, Latin America, U. S., and Canada 1. The
purpose was to improve the contraceptive efficacy
over that of inert intrauterine devices (IUDs) and
to reduce side effects. The effectiveness was
tested for up to 7 years in different settings, and
the cumulative pregnancy rate was from 0.0 to 0.5
in up to 7 years of use 2,3. The LNG-IUS is a
hormonal contraceptive, but its action is local to
the uterine cavity. Extensive studies of the LNGIUS revealed that its main mechanism of action
differs from that of inert IUDs. One of the main
characteristics of the LNG-IUS is to cause a
reduction in the amount of blood loss during each
menstrual period. Due to this characteristic, it has
been used as a medical treatment for women with
menorrhagia unrelated to intrauterine pathology 4.
Patients with the following were excluded:
congenital valvular heart disease, congenital
malformation of the vagina, cervix or uterus,
known or suspected uterine or cervical
malignancy; history of pelvic inflammatory
disease (PID), postpartum endometritis or history
of infected abortion. An IUD releasing 20 µg/day
of levonorgestrel was inserted in each patient
within 5 days of the start of menstrual flow. All
the women underwent clinical and transvaginal
ultrasound (TVUS) examinations at 1, 3, 6, and 12
months after IUD insertion. During follow-up,
women were interviewed about their bleeding
patterns and any side effects or adverse reactions.
At the final examination after 12 months, pipelle
endometrial biopsy was repeated to evaluate the
endometrial status. These specimens were fixed
and haematoxylin and eosin stained sections were
produced in a standard manner, and were assessed
by a consultant histopathologist of the hospital. In
this study, to discriminate between menorrhagia
and normal menstrual blood loss, a simple visual
assessment technique was used as described by
Gardner 6. The number of days of bleeding and
the maximum amount of bleeding during a 24hour period was scored by the following
definitions: spotting with a daily bleed score of 1
was defined as fresh blood seen on wiping but not
requiring sanitary protection; light loss with a
score of 2 was defined as small amount of blood
on any sanitary pad during that day; moderate loss
with a score of 3 was defined as moderate amount
of blood on any sanitary pad during that day; and
heavy loss with a score 4 was defined as soaking
of any sanitary pad with blood during that day.
We summed the maximum daily bleeding scores
for each of four 90-day intervals over the 12
months of follow-up to give total bleeding scores
for each of the intervals. Women returned these
An
intrauterine
system
that
releases
levonorgestrel, a potent 19-nortestosteron
derivative progestin, locally administered, has a
profound effect on the endometrium, which
becomes atrophic and inactive, although ovulation
is usually not supressed 5. Reduction or absence of
menstrual bleeding became a therapeutic effect in
women with abnormal uterine bleeding menometrorrhagia. An atrophic endometrial epithelium
was thought to account for this action. Today, the
LNG-IUS is the most effective medical therapy
for menorrhagia unrelated to intrauterine
pathology.
Intrauterine
administration
of
levonorgestrel has also been shown to be effective
in opposing the proliferative effect of oestrogen
on the endometrium during oestrogen replacement
therapy.
In this study, we evaluated the efficacy and
tolerability of treatment with a levonorgestrelreleasing intrauterine device in women affected by
abnormal uterine bleeding.
METHODS
This was a prospective study at the Department of
Obstetrics and Gynaecology, SSK Research and
Training
Hospital,
Istanbul-Turkey.
The
Institutional Review Board Approval was
obtained from the Ethical Committee of the
Hospital. All women voluntarily signed an
informed consent to the study. A total of 60
women aged 35 to 48 years (mean 42.36),
reported recurrent menorrhagia of at least 18
months duration. All women to be included in the
54
At the end of the trial, pipelle endometrial biopsy
showed pronounced progesteron influence with
decidua-like stroma in 39 samples, desquamated
endometrium in 12 samples, and no endometrium
in seven. Proliferation or atypia was not found in
any of the specimens. The mean endometrial
thickness was greater than 5mm in women at the
initial of the study. At the final screening there
was a significant decrease in mean endometrial
thickness less than 3mm which demonstrated an
extremely thin endometrium 12 months after IUD
insertion during the follow-up of our patients. The
mean cavity length, long diameter, and anteroposterior diameter were not significantly different
between the women at baseline, and over the 12
months of follow-up.
data at their three month and six month follow-up
appointment and at the end of the study period.
RESULTS
A total of 60 parous women, with a mean age of
42.36 years were recruited. Insertion of the LNGIUS was uneventful, and was performed in all
cases without anestesia and without particular
patient discomfort. No changes occurred during
the study period in body weight or blood pressure.
We found no abnormalities in the Papanicolaou
smears and noted no important side-effects or
adverse reactions such as headache, mood
changes, lower abdominal and back pain, nausea,
oedema or skin disorders.
In this study we used an (LNG-IUS) that contains
52 mg of levonorgestrel which is released at a rate
of 20 µg daily for 5 years. The system was
primarily designed for contraception but is now
widely used to decrease menstrual blood loss in
women with menorrhagia as well for endometrial
protection during oestrogen replacement therapy
7,8,
producing a very high local concentration in
the endometrial tissues with low-plasma
concentrations gained systemically 9. We have
shown that epithelial atrophy and stromal
decidualization
are
the
most
typical
morphological characteristics in the endometrium
during the use of LNG-IUS. Menstrual blood loss
is significantly decreased, and many women
treated with LNG-IUS have no menstrual bleeding
1 year after the insertion. At the beginning of the
trial period, there was simple hyperplasia in 33
patients, irregular proliferative endometrium in 18
patients, secretory endometrium in 9 patients.
DISCUSSION
Menorrhagia is defined as regular, prolonged and
excessive menstrual bleeding of more than 80 ml
from a secretory endometrium. When menstrual
blood loss exceeds 80ml, the incidence of anemia
increased significantly 10. Iron deficiency with
depletion of iron stores and or anemia predisposes
the women to ill health and disease.
The LNG-IUS was originally designed for
contraceptive use more than 20 years ago. The
purpose was to improve the contraceptive efficacy
over that of inert intrauterine devices and to
reduce side effects. Extensive studies following
the introduction of the LNG-IUS revealed that its
main mechanism of action differs from that of
inert IUDs. The LNG-IUS is a hormonal
contraceptive, but its action is local to the uterine
cavity. Levonorgestrel is a 19-nortestosterone
derivative which is much more potent than natural
progesterone and has major effects on the stromal
parts of the endometrium 11. Many women using
the LNG-IUS have ovulatory cycles 12 although
they may have menstrual irregularities during the
first few months of use.
One woman expelled the LNG-IUS 2 months after
insertion and she subsequently underwent
hysterectomy. The pathology confirmed the
diagnosis of uterine adenomyosis. One patient
was lost to follow-up after she became
amenorrheic and was satisfied with the treatment,
before the six month evaluation. The remaining 58
patients completed the study.
The effectiveness of the LNG-IUS to treat
menorrhagia may be caused by two actions. First
it causes strong decidualization and subsequent
marked atrophy of the endometrium 13,14. The
LNG-IUS also affects the vascular system in the
endometrium. The changes include thickening of
the arterial walls and supression of the spiral
arteries and capillary thrombosis 14. This probably
accounts for the marked reduction in menstrual
flow. Secondly, there is also direct action of the
hormone on endometrial tissues. The LNG-IUS
has been shown to cause down regulation of
oestrogen receptors (ER) in both glandular and
stromal endometrial tissues. This was evident at 1
Regarding the bleeding pattern in the first 3
months, spotting was by far the most frequent
menstrual
finding.
Spotting
decreased
progressively in subsequent months, but still
occurred occasionally in 6 patients at the end of
the study. Six months after LNG-IUS insertion,
amenorrhea was obtained in 8 patients and
oligomenorrhea in 12 patients and almost equal
throughout the observation period. Scanty regular
cycles were observed in the remaining 27 patients.
55
endometrium
therapy.
month postinsertion and persisted for up to 12
months after insertion 15. Lu reported that both
oestrogen and progesterone receptors decreased
significantly after 6-9 months of LNG-IUS use 16.
By down regulation ER in these foci, it may
prevent further stimulation by oestrogens, leading
to atrophy and shrinkage of endometrial tissues.
The marked efficacy of the LNG-IUS could result
from the fact that intrauterine LNG produced
endometrial LNG levels 1000 times greater than
serum concentrations 9. Thus, dose dependancy
effects on LNG could account for the difference
between intrauterine progesterone and other forms
of
progesterone
administration.
The
morphological changes in levonorgestrel-exposed
endometrium return to normal in most cases in the
menstrual cycle after removal of the system 12.
during
oestrogen
replacement
The LNG-IUS may constitute an innovative,
effective, safe and convenient alternative for local
delivery of a potent progestin in the long-term
therapy of recurrent menorrhagia.
The use of the LNG-IUS may thus represent a real
advance in the treatment of menorrhagia in
women who do not want children.
REFERENCES
1.
Hidalgo M, Bahamodes L, Perrotti M, Diaz J,
Dantes-Monteiro C, Petta C. Bleeding patterns
and clinical performance of the levonorgestrelreleasing intrauterine system (Mirena) up to two
years. Contraception 2002; 65: 129-132.
2. Faundes A, Alvarez F, Diaz J. A Latin American
experience with levonorgestrel IUD. Ann Med
1993; 25: 49-53.
3. Diaz J, Faundes A, Diaz M, Marchi N. Evaluation
of the clinical performance of a levonorgestrelreleasing IUD, up to seven years of use, in
Campinas, Brazil. Contraception 1996; 47: 169175.
4. Stewart A, Cummins C, Gold L, Jordan R, Philips
W. The effectiveness of the levonorgestrelreleasing intrauterine system in menorrhagia: a
systemic review. Br J Obstet Gynaecol 2001; 108:
74-86.
5. Crosignani PG, Vercellini P, Mosconi P, Oldani
S, Cortesi I, De Giorgi O. A levonorgestrel
releasing intrauterine device versus hysterescopic
endometrial resection in the treatment of
dysfunctional bleeding. Obstet Gynaecol 1997;
90: 257- 263.
6. Gardner F JE, Konje JC, Abrams KR, Brown L
JR, Khanna S, Al-Azzawi F, et al. Endometrial
protection from tamoxifen-stimulated changes by
a levonorgestrel-releasing intrauterine system:a
randomised controlled trial. The Lancet 2000;
356: 1711-1717.
7. Andersson K, Mattsson L-A, Rybo G, Stadberg E.
Intrauterine release of levonorgestrel- A new way
of adding progestogen in hormone replacement
therapy. Obstet Gynecol 1992; 79: 963-966.
8. Luukkainen T, Toivonen J. Levonorgestrelreleasing IUD as a method of contraception with
therapeutic properties. Contraception 1995; 52:
269-276.
9. Nilsson CG, Haukkamaa M, Vierola H,
Luukkainen T. issue concentrations of
levonorgestrel in women using levonorgestrelreleasing IUD. Clin Endocrinol 1982; 17: 529536.
10. Janssen CA, Scholten PC, Heintz APM.
Menorrhagia: a search for epidemiological risk
markers. Maturitas 1997; 28: 19-25.
11. Fedele L, Bianchi S, Raffaelli R, Portuese A,
Dorta M. Treatment of adenomyosis- associated
menorrhagia with a levonorgestrel-releasing
intrauterine device. Fertil Steril 1997; 68: 426429.
The LNG-IUS is associated with low risk of
infection, high continuation rate, and significant
reduction of menstrual bleeding 1-3,17. The only
reason for discontinuation in the group with heavy
menses before insertion of the device was
expulsion. The finding was also observed in our
trial in one woman who was inserted with LNGIUS as a treatment for heavy menorrhagia. The
bleeding amount dramatically decreased in 4
women with small fibroids after insertion, and
spotting frequency decreased in the same
proportion as amenorrhea increased after the sixth
month of observation. The effect may reflect the
strong endometrial suppression provoked by the
high levonorgestrel concentration in the uterine
cavity 18.
The LNG-IUS is a very useful, effective, nonsurgical and reversible treatment method of
menorrhagia in women harboring fibroids and
adenomyosis. In women with a normal uterus, the
success rate is close to 100%. In the presence of
small fibroids, however, the success rate is
satisfactory. This was also shown by other studies
conducted in women with fibroids and
adenomyosis 11,15,19.
In the present study, the reduction of
menstrual flow was impressive, and although
there was a high incidence of spotting and
oligomenorrhea, such menstrual anomalies
were well tolerated by our patients. In
addition, rapid recovery after discontinuation
of the treatment was shown. Today, the LNGIUS is the most effective medical therapy for
menorrhagia unrelated to intrauterine pathology.
Intrauterine administration of levonorgestrel has
also been shown to be effective in opposing the
proliferative effect of oestrogen on the
56
12. Nilsson CG, Lähteenmäki P, Luukkainen T.
Ovarian
function
in
amenorrheic
and
menstruating users of a levonorgestrel-releasing
intrauterine device. Fertil Steril 1984; 41: 52-55.
13. Sivin I, Stern J. Health during prolonged use of
levonorgestrel 20µg/d and the copper T cu 380
Ag intrauterine contraceptive devices: a
multicenter study. Fertil Steril 1994; 61: 70-73.
14. Zhu P, Luo HZ, Xu RH, et al. The effect of
intrauterine devices, the stainless steel ring,the
copper T 220, and releasing levonorgestrel, on the
bleeding profile and the morphological structure
of the human endometrium a comperative study
of three IUDs. A morphometric study of 96 cases.
Contraception 1989; 40: 425-438.
15. Fujimoto J, Hirose R, Ichigo S, et al. Expression
of progesterone receptor form A and B mRNAs in
uterine leiomyoma. Tumour Biol 1998; 19: 126131.
16. Lu SM. Effect of levonorgestrel intrauterine
device on human endometrial oestrogen and
progesterone receptors. Chung Hua Fu Chan Ko
Tsa Chih 1991; 26: 293-294, 323.
17. Barbosa I, Olsson SF, Odling V, Johansson E.
Ovarian function during use of a levonorgestrelreleasing IUD. Contraception 1990; 42: 51-66.
18. Pakarien P, Luukkainen T, Laine H, Lähteenmäki
P. The effect of local intrauterine levonorgestrel
administration on endometrial thickness and
uterine blood circulation.Hum reprod 1995; 10:
2390-2394.
19. Maruo T, Samoto T, Takeuchi S, Spitz I,
Johansson E. Usefulness of levonorgestrelreleasing IUD in the management of menorrhagic
women with uterine myoma and adenomyosis. In:
proceedings of the presantation held at the Xth
International Congress of the Society for the
Advancement
of
Contraception.
Manila,
Philippines, 1998.
57
ORIGINAL RESEARCH
A COMPARISON OF CONVENTIONAL EXTERNAL RADIOTHERAPY
TECHNIQUE AND CONFORMAL RADIOTHERAPY TECHNIQUE IN
TERMS OF ACUTE TOXICITY WITH REGARD TO HORMONAL
TREATMENT
İlknur Çetin, Ufuk Abacıoğlu, Meriç Şengöz
Department of Radiation Oncology, School of Medicine, Marmara University, Istanbul, Turkey
ABSTRACT
Objective: Comparing the application of conventional external radiotherapy technique (EBRT) and conformal radiotherapy
technique (CRT) in terms of acute side effects with respect to hormonotherapy (HT) in the primary treatment of prostate cancer.
Materials and Methods: Seventy-five patients diagnosed with localized prostate cancer were treated with primary radiotherapy
(RT) between March 1997 and July 2002, 47 with EBRT and 28 with CRT. 23 patients (31%) did not receive HT, 22 patients (29%)
received concomitant HT (CHT) and 30 patients (40%) received neoadjuvant HT (NAHT). The patients were observed for at least 3
months and the acute toxicity was evaluated by EORTC/RTOG (European Organization for Research and Treatment of Cancer /
Radiation Therapy Oncology Group) scale 1.
Results: There was no grade III-IV acute urinary and rectal toxicity. The percentage of grade I and II acute urinary toxicity was
determined as 30% and 23%, respectively in the EBRT group. The ratios were 61% and 18%, respectively in the CRT group (p=0.025).
Grade II urinary toxicities were 13% in patients who did not receive HT and who received NAHT, 41% in patients who received CHT
(p=0.02). Grade II rectal toxicities were 30% for EBRT and 7% for CRT group (p=0.022).
Conclusion: CRT caused a decrease in grade II rectal and urinary toxicity. Grade II acute urinary toxicities were observed more
frequently in the treatment of CHT than the NAHT.
Keywords: Acute toxicity,Cconventional-conformal radiotherapy, Prostate cancer
KONVANSİYONEL EKSTERNAL RADYOTERAPİ VE KONFORMAL
RADYOTERAPİ TEKNİKLERİNİN HORMONOTERAPİ DURUMUNA
GÖRE AKUT YAN ETKİLER AÇISINDAN KARŞILAŞTIRILMASI
ÖZET
Amaç : Prostat kanserinin primer tedavisinde konvansiyonel eksternal radyoterapi (EBRT) ile konformal radyoterapi teknik
(CRT)uygulamaların hormonoterapi (HT) durumuna göre akut yan etkiler açısından karşılaştırılması amaçlanmıştır.
Gereç ve Yöntem : Mart 1997- Temmuz 2002 tarihleri arasında lokalize prostat kanseri tanısı konmuş ve primer radyoterapi
uygulanmış 75 hastanın EBRT uygulanan 47 ve CRT uygulanan 28 hasta idi. Tüm hastalar için medyan yaş 72 (55-85), medyan
radyoterapi dozu 70 Gray (Gy) (63-76 Gy) olarak tespit edilmiştir. Hastaların 23’u (%31) hormonoterapi almamış , 22’si (%29) eş
zamanlı hormonoterapi almış ve 30’u (%40) neoadjuvan hormonoterapi almıştı. Hastaların en az 3 aylık takibi mevcut olup, görülen
akut yan etkiler EORTC/RTOG (European Organisation for Research and Treatment of Cancer / Radiation Therapy Oncology
Group) skalası kullanılarak değerlendirilmiştir 1 .
Bulgular: Grade I ve II akut üriner yan etkiler; konvansiyonel radyoterapi grubunda %30 ve %23 iken, konformal radyoterapi
grubunda %61 ve %18 oranında gözlenmiştir (p=0.025). Grade II üriner yan etkiler; HT almayanda ve neoadjuvan hormonoterapi
alanlarda %13 eş zamanlı hormonoterapi alan hastalarda %41 oranında saptanmıştır (p=0.02). Grade II rektal yan etkiler;
konvansiyonel radyoterapi grubunda %30, konformal radyoterapi grubunda %7 oranında tespit edilmiştir (p=0.022).
Sonuç : Konformal radyoterapi uygulaması ile grade II akut rektal ve üriner yan etkilerin azaldığı tespit edilmiştir. Eşzamanlı
hormonoterapi kullanımı ile grade II akut üriner yan etki neoadjuvan kullanıma göre daha sık gözlenmiştir.
Anahtar Kelimeler: Akut yan etkiler, Konvansiyonel, Konformal radyoterapi, Prostat kanseri
Corresponding author: İlknur Çetin, M.D
Department of Radiation Oncology, School of Medicine,
Marmara University Hospital, Tophanelioğlu Caddesi 13/15,
34660 Altunizade, İstanbul
E-mail: [email protected]
58
İlknur Çetin, et.al.
A comparison of Conventıonal External Radıotherapy Technique and Conformal Radiotherapy Technique in Terms of
Acute Toxıcity With Regard to Hormonal Treatment
Treatment was carried out by using Saturne 42
linear accelerator and 18 MV X-Ray.
Immobilization in the supine position was ensured
in the simulator for all patients. Axial BT images
with 0.5 cm thickness were taken with empty
rectum and full bladder in the same position. 10
mlt contrast were introduced to the urethra in
order to visualize the urethra and the apex of the
prostate. BT images were transferred to the
treatment planning system by the 'Dicom
Network' System.
INTRODUCTION
Radiation has been used in the curative treatment
of prostate cancer for approximately a hundredyears. With the technical improvements in
medicine, localized prostate cancer is now being
treated with EBRT. Such patients are usually old
and have comorbidities, so they have to be treated
effectively with the least side effects 1. The
radiation dose given in order to provide local
tumor control remains insufficient with the EBRT
technique used today 2. Toxicities increase when
the treatment dose increases. Thus, 3-dimensional
treatment planning and CRT has been widely
accepted in the treatment of prostate cancer. The
aim is to control the tumor by giving high doses
while protecting the surrounding normal tissues as
much as possible 3-7. Retrospective and
prospective studies indicate that CRT has fewer
side effects compared to standard technique with
the same dose 8-11. In addition, despite an increase
in the RT dose, tolerable side effects were
reported in some studies, regarding the conformal
treatment technique 12-14.
Using the conventional technique, PTV1 was
defined as small pelvis or prostate with seminal
vesicular and PTV2 was defined as the prostate
region. Standard lead blocks were used in the
areas. Patients were treated with the four-field box
technique (except for 3 patients with AP-PA fields
and 2 patients with 3 fields- AP and two lateral
opposing fields) to a dose range of 40-50 Gy. A
boost was given with the four-field box technique
to a total dose of 63-74 Gy.
In the CRT group, patients were treated with the
four field box technique (except one patient
treated with the 5 field technique) up to 40-50 Gy
and then boosted to a total of 66-76 Gy RT with
custom blocking to all fields. Median RT dose
was 70 Gy (63-76 Gy), 1.8-2 Gy/fraction/day, 5
fractions per week. Maximal Androgen Blockade
(MAD) (anti-androgen and LHRH analogue) was
started concomitant with RT or before (1-17
months) in the patients. Duration of MAD was
determined according to the risk group of the
patient. Acute side effects (during or 3 months
after primary RT) were evaluated by using the
EORTC/RTOG scale (Annex).
In this study, in the Marmara University Hospital
Radiation Oncology Department, the urinary rectal side effects observed during and after
treatment with EBRT and CRT were compared
with regard to the HT situation.
METHODS
Seventy-five patients with localized prostate
cancer treated in the Marmara University Hospital
Radiation Oncology Department between March
1997 and July 2002 were classified according to
1997 AJCC classification with thin injection
biopsy, Gleason score and/or BT accompanied
with rectal examination, and transrectal
ultrasonography (TRUSG) were taken before the
treatment 15. Metastatic disease was eliminated by
routine biochemical examination, whole body
bone scintigraphy, and radiological examinations
when required.
The relation between two different treatment
techniques and patient characteristics, the relation
between acute urinary and rectal side effects with
patient characteristics and treatment techniques
were evaluated by using Chi-square test or
Fisher's Exact Test in one variable analysis.
Relative ratio (odds ratio-OR) and results were
given in 95% confidence interval. The results
were accepted at the level of significance p≤0.05.
Statistical analysis was performed by the use of
the SPSS 10.0 package program.
Fourty-seven patients (62.6%) were treated with
EBRT, whereas 28 patients (37.3%) were treated
with CRT. Median age of patients was 72 (55-85),
median T phase was T2, median initial PSA
(Prostate-Specific Antigen) was 8ng/ml, median
RT dose was 70 Gy. 23 patients did not receive
HT, 22 patients were treated with CHT and 30
patients were treated with NAHT.
RESULTS
The distribution of urinary and rectal side effects
observed regarding two different treatment
techniques is shown in Table I.
Patient characteristics and treatment methods
together with distribution and significance of two
technical treatments are shown in Table I.
59
Table I: Patient Characteristics
EBRT (%)
CRT (%)
47 (62.6)
28 (37.2)
< 70
17 (36.1)
10 (35.7)
≥ 70
30 (63.8)
18 (64.2)
Number of Patients
P
Age
0.96
T stage
T1
12 (25.5)
4 (14.2)
T2
25 (53.1)
22 (78.5)
T3
9 (19.1)
2 (7.1)
T4
1 (2.1)
0.19
Initial PSA (ng/ml)
0-10
18 (38.2)
6 (21.4)
10-20
11 (23.4)
9 (32.1)
> 20
13 (27.6)
13 (46.4)
unknown
5 (10.6)
0.17
0.09
Known Disease
Hypertension
3 (6.3)
6 (21.4)
Heart Disease
-
4 (14.2)
Diabetes
4 (8.5)
2 (7.1)
Haemorrhoid
15 (31.9)
13 (46.4)
Pelvic Operation
2 (4.2)
3 (10.7)
TUR-P
2 (4.2)
-
Unknown
14 (29.7)
-
63-69 Gy
15 (%31.9)
5 (8.6)
70 Gy
22 (46.8)
20 (71.4)
71-76 Gy
10 (21.2)
3 (10.7)
18 (38.2)
5 (17.9)
NoneConcomitant
17 (36.1)
5 (17.9)
Neoadjuvant
12 (25.5)
18 (64.3)
Radiotherapy Dose
Hormonotherapy
60
0.11
0.004
There were no acute grade III and IV urinary
and rectal side effects in both groups. Grade II
urinary side effects were observed in 18% of
the patients after CRT, in 23% after EBRT
(p=0.025) (Fig. 1). The ratio of grade II side
effects in patients who received CHT, NAHT and
no HT was 41%, 13% and %13 respectively
(p=0.02) (Fig. 2).
Fig. 1. Distribution of acute GUS toxicity according to treatment technique
Fig. 2. Distribution of acute GUS toxicity according to hormonal treatment
Grade II rectal side effects were observed in
30% of the patients after CRT and 7% after
EBRT (p=0.022) (Fig. 3).
after treatment and characteristics related to
patients (age, diseases previously known,
operation
undergone
before)
and
characteristics related to treatment (RT dose)
(p>0.05).
No significant relationship was found
between urinary-rectal side effects observed
61
Fig. 3. Distribution of acuterectal toxicity according to treatment technique
DISCUSSION
Hanks and his colleagues found that the frequency
of grade II side effects was 34% in CRT and 57%
in EBRT (p<0.001). The frequency of grade II
side effects in the patients over age 65 decreased
in CRT (p<0.00001). With the use of CRT, grade
II side effects were observed less in patients with
early stage (T1-2) tumor (p<0.005). Conformal
technique and treatment volume were found as
independent significant indicators for grade II side
effects in multivariable analysis 8.
Koper and his colleagues compared the technical
applications of CRT and EBRT. They applied 66
Gy RT and found that CRT treatment caused less
grade II acute rectal side effects (16%-8%,
p<0.0001) 10.
Tait and his colleagues investigated CRT and
EBRT in terms of acute side effects in the
treatment of primary prostate cancer. A
questionnaire was given a week before, during
and after the treatment. It was determined that the
side effects increased during the treatment and
decreased after the treatment 16.
Nuyttens and his colleagues compared patients
who had CRT≤72 Gy and CRT≥76 Gy with
regard to acute and chronic complications. 10%18% grade II acute rectal side effects and 33%47% urinary side effects were observed. They
determined that acute rectal side effects depend on
dose, while acute and chronic urinary side effects
are independent from dose 19.
In the study of Pollack and his colleagues, 70 Gy
with EBRT and 78 Gy with CRT were applied.
Although RT dose was higher with CRT, no
significant difference regarding acute side effects
was found 11,17.
Odrazka and his colleagues applied 74 Gy CRT
and found a significant relationship between GUS
side effects and TUR applied before RT 20.
Vijayakumar and his colleagues applied EBRT
and CRT to patients with localized prostate
cancer. According to the outcome of weekly
gastrointestinal
(GIS)-genitourinary
(GUS)
toxicities evaluation during RT for three groups, it
was found that there was an increase in acute side
effects until 4-5 weeks, after that there was a
decrease or they remained at the same level 18.
Herold and his colleagues reported that diabetes
increased grade II GIS side effects and especially
GUS late side effects 21.
While apoptotic activity is 2%, this ratio increases
up to 10% with androgen blockade 22. Tumor
oxidation increases in relation with volume
decline and this leads to an increase in radiation
effectiveness. Target volume in NAHT decreases
in relation with the decrease in tumor size 23. In
randomized studies, the addition of neoadjuvant
androgen blockade caused an increase in survival,
local control and biochemical control 24,25. In the
Soffen and his colleagues reported urinary and
rectal side effects with a median dose of 68 Gy
RT with two different techniques in 46 patients.
Urinary side effects were observed in 80%-65%
of the patients and rectal side effects were
observed in 55%-42%. Acute side effects were
less in patients treated with CRT (p>0.05) 9.
62
EORTC 22863 study, age, surgery and RT dose
were found to be independent prognostic factors
in terms of acute side effects, yet no like effect of
HT was observed 26.
9.
Sanguinetti and his colleagues stated that NAHT
did not increase side effects, whereas adjuvant HT
increased rectal side effects 27.
10.
11.
In conclusion, no grade III-IV urinary and rectal
acute side effects were observed in both of the
techniques in this study. It was found that
application of CRT technique causes a reduction
in the frequency of grade II acute rectal and
urinary side effects. There was an increase in
grade II urinary side effects in patients treated
with CHT.
12.
13.
REFERENCES
14.
1.
2.
3.
4.
5.
6.
7.
8.
Cox JD, Stetz J, Pajak TF. Toxicity Criteria of the
Radiation Therapy Oncology Group (RTOG) and
the European Organization for Research and
Treatment of Cancer (EORTC). Int J Radiat Oncol
Biol Phys 1995; 31:1341-1346.
Zelefsky MJ, Leibel SA, Fuks Z. Conventional
external beam radiation therapy for prostate cancer:
Where do we go from here? Int J Radiat Oncol Biol
Phys 1993; 26:365-367.
Gallagher MJ, Brereton HD, Rostock RA, et al. A
prospective study of treatment techniques to
minimize the volume of pelvic small bowel with
reduction of acute and late effects associated with
pelvic irradiation. Int J Radiat Oncol Biol Phys
1986; 12:1565-1573.
Leibel SA, Zelefsky MJ, Kutcher GJ, et al. The
biological basis and clinical application of threedimensional conformal external beam radiation
therapy in carcinoma of the prostate. Semin Oncol
1994; 21:580.
Sandler HM, Perez-Tamayo C, Ten Haken RK, et
al. Dose escalation for stage C (T3) prostate cancer:
Minimal rectal toxicity observed using conformal
therapy. Radiother Oncol 1992; 23:53.
Sandler HM, McLaughlin PW, Ten Haken RK,
Addision H, Forman J, Lichter A. Three
dimensional conformal radiotherapy for the
treatment of prostate cancer: low risk of chronic
rectal morbidity observed in a large series of
patients. Int J Radiat Oncol Biol Phys 1995;
33:797-801.
Dale E, Olsen DR, Foss SD. Normal tissue
complication probabilities correlated with late
effects in the rectum after prostate conformal
radiotherapy. Int J Radiat Oncol Biol Phys 1999;
43:385-391.
Hanks GE, Schultheiss TE, Hunt MA, Epstein BE.
Factors influencing incidence of grade 2 morbidity
in conformal and standard radiation treatment of
prostate cancer. Int J Radiat Oncol Biol Phys 1995;
31:25-29.
15.
16.
17.
18.
19.
20.
21.
22.
23.
63
Soffen EM, Hanks GE, Hunt MA, Epsteın BE.
Conformal static field radiation therapy of early
prostate cancer versus non-conformal techniques: A
reduction in acute morbidity. Int J Radiat Oncol
Biol Phys 1992; 24:485-488.
Koper PC, Stroom JC, Van Putten WL, et al. Acute
morbidity reduction using 3DCRT for prostate
carcinoma: A randomized study. Int J Radiat Oncol
Biol Phys 1999; 43:727-734.
Pollack A, Zagars GK, Smith LG, et al. Preliminary
results of a randomized radiotherapy doseescalation study comparing 70 Gy with 78 Gy for
prostate cancer. J Clin Oncol 2000; 18:3904-3911.
Storey MR, Pollack A, Zagars G, Smith L, Antolak
J, Rosen I. Complications from radiotherapy dose
escalation in prostate cancer: Preliminary results of
a randomized trial. Int J Radiat Oncol Biol Phys
2000; 48:635-642.
Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose
escalation with three-dimensional conformal
radiation therapy affects the outcome in prostate
cancer. Int J Radiat Oncol Biol Phys 1998; 41:491500.
Storey MR, Pollack A, Zagars G, Smith L, Antolak
J, Rosen I. Complications from radiotherapy dose
escalation in prostate cancer: Preliminary results of
a randomized trial. Int J Radiat Oncol Biol Phys
2000; 48:635-642.
Fleming I, Cooper J, Henson D, et al. Prostate .In:
AJCC cancer staging manual. Philadelphia, New
York: Lippincott-Raven; 1997:219-224.
Tait DM, Nahum AE, Meyer LC, et al. Acute
toxicity in pelvic radiotherapy; a randomised trial
of conformal versus conventional treatment.
Radiother Oncol 1997; 42:121-36.
Pollack A, Zagars GK, Starkschall G, et al.
Conventional versus conformal radiotherapy for
prostate cancer: prelimary results of dosimetry and
acute toxicity. Int J Radiat Oncol Biol Phys 1996;
34:555-564.
Vijayakumar S, Awan A, Karrison T, et al. Acute
toxicity during external beam radiotherapy for
localized prostate cancer: comparison of different
techniques. Int J Radiat Oncol Biol Phys 1993;
25:359-371.
Nuyttens JJ, Milito S, Rust PF, Turrisi AT. Dosevolume relationship for acute side effects during
high dose conformal radiotherapy for prostate
cancer. Radiother Oncol 2002; 64:209-214.
Odrazka K, Vanasek J, Vaculikova M,, et al.
Conformal radiotherapy for prostate cancer-longer
duration of acute genitourinary toxicity in patients
with prior history of invasive urological procedure.
Acta Oncol 2001; 40:7810-7815.
Herold DM, Hanlon AL, Hanks GE. Diabetes
Mellitus: A predictor for late radiation morbidity.
Int J Radiat Oncol Biol Phys 1999; 43:475-479.
Lim Joon D, Hasegawa M,Wu CS, et al. Supraadditive apoptotic response in predominantly
quiescent prostate tumors when treated with
androjen-ablation and radiotherapy. Int J Radiat
Oncol Biol Phys 1996; 36:191.
Forman JD, Kumar R, Haas G, Montie J, Porter
AT, Mesina CF. Neoadjuvant hormonal downsizing
of localized carcinoma of prostate: effect on the
volume of normal tissue irradiation. CA Invest
1995; 13:132-133
24. Lawton CA, Winter K, Murray K, et al. Updated
results of the phase III radiation therapy oncology
group (RTOG) trial 85-31 evaluating the potential
benefit of androgen suppression following standard
radiation therapy for unfavorable prognosis
carcinoma of the prostate. Int J Radiat Oncol Biol
Phys 2001; 49;937-946.
25. Pilepich MV, Winter K, John MJ, et al. Phase III
radiation therapy oncology group (RTOG) trial 8610 of androgen deprivation adjuvant to definitive
radiotherapy in locally advanced carcinoma of the
prostate. Int J Radiat Oncol Biol Phys 2001;
50:1243-1252.
26. Zurlo A, Collete L, van Tienhoven G, Blank L, et
al, EORTC Radiotherapy and Genito-Urinary Tract
Cancer Group. Acute toxicity of conventional
radiation therapy for high-risk prostate cancer in
EORTC trial 22863. Eur Urol 2002; 42:125-132
27. Sanguineti G, Franzone P, Marcenaro M, Paoli G,
Orsatti M, Vitale V. Androgen deprivation impacts
late rectal toxicity after conformal radiotherapy.
Abstr 1328, 338a. ASCO Meeting 2000; 20-23.
64
ORIGINAL RESEARCH
THE EFFECT OF A LEVONORGESTREL-RELEASING INTRAUTERINE
DEVICE ON OVARIECTOMIZED RAT ENDOMETRIUM UNDER
ESTROGEN REPLACEMENT THERAPY
Murat Api1, Feriha Ercan2, Serap Arbak2, Olus Api3
1
Department of Obstetrics and Gynecology, Haseki Education and Research Hospital, Istanbul, Turkiye 2 Department of
Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkiye 3 Department of Obstetrics and
Gynecology, Kartal Education and Research Hospital, Istanbul, Turkiye
ABSTRACT
Objective: Our aim was to investigate the effects of levonorgestrel-releasing intrauterine system on the endometrium of
ovariectomized rats under estrogen replacement therapy.
Methods: Twenty-four Sprague-Dawley rats were divided into four groups and operated for the insertion of levonorgestrelreleasing (3 µg/day) or placebo-bearing intrauterine devices (IUD). Following the operation, the rats were randomly assigned to take
estrogen (0.01 mg. per kg. rats) or placebo replacement therapy for 30 days. Endometrial biopsies were collected at the end of the study
period. The sampled endometrial tissues have been analyzed for morphologic criteria under the light microscope. Group I was assigned
to take levonorgestrel-releasing IUD and systemic estrogen whereas Group II was assigned for levonorgestrel-releasing IUD and
systemic placebo and Group III for placebo-bearing IUD and systemic estrogen; finally Group IV was treated with placebo-bearing IUD
and systemic placebo.
Results: The endometrial morphology of Group I revealed inactive endometrium in 50%, edema in 33% and atrophy in 16%
whereas the endometrial morphology of Group II revealed inactive endometrium in 66%, and atrophy in 33%. The endometrial
morphology of Group III revealed epithelial hyperplasia in 66%, edema in 16% and myometrial hyperplasia in 16% while inactive
endometrium was identified in 16%, and atrophy in 83% of rats in Group IV.
Conclusion: Our results revealed that progestagen containing intrauterine systems are sufficient enough to protect the
endometrium from hyperplasia in rats under systemic estrogen replacement therapy. This is somehow encouraging data to support that
the endometrium of postmenopausal women under systemic estrogen can be sufficiently protected by an intrauterine gestagen-containing
device. The use of such an IUD will serve to protect them from the adverse effects of systemic gestagens.
Keywords: Rat endometrium, Levonorgestrel, Intrauterine device, Estrogen replacement therapy
ÖSTROJEN REPLASMAN TEDAVİSİ ALTINDAKİ OVARİEKTOMİZE SIÇANLARDA
LEVONORGESTREL-SALAN RAHİMİÇİ ARACIN ETKİLERİ
ÖZET
Amaç: Levonorgestrel salan rahimiçi sistemin, östrojen replasman tedavisi altındaki ovariektomize sıçanların endometriumu
üzerindeki etkilerini araştırmak.
Yöntem: Yirmidört adet Sprague-Dawley sıçanı 4 gruba bölünerek, levonorgestrel salan intrauterin sistemin (3 µg/day) ve
plasebo-içeren rahimiçi aracın (RİA) yerleştirilmesi için operasyona alındı. Operasyonu takiben, sıçanlar 30 gün süreyle östrojen
(0.01 mg./kg.) ve plasebo replasman tedavisi almak üzere gruplara randomize edildi. Çalışmanın sonunda deneklerden endometrial
örnekleme yapıldı. Alınan endometrial dokular morfolojik kriterler açısından incelenmek üzere ışık mikroskopisi ile incelendi. Grup
I levonorgestrel salan RİA ve sistemik östrojen alan, Grup II levonorgestrel salan RİA ve plasebo alan, Grup III plasebo içeren RİA
ve sistemik östrojen alan, Grup IV ise plasebo içeren RİA ve plasebo alan sıçanlar olarak belirlendi.
Bulgular: Grup I'e ait endometrial morfoloji %50'sinde aktif olmayan endometrium, %33'ünde ödem, %16'sında atrofi olarak
görülürken. Grup II'ye ait morfoloji %66'sında aktif olmayan endometrium, %33'ünde atrofi olarak saptandı. Grup III'te ise %
66'sında epitelyal hiperplazi, %16'sında ödem, %16'sında myometrial hiperplazi bulunurken, Grup IV’ ün. %83'ünde atrofi, %
16'sında ise aktif olmayan endometrium tespit edildi.
Sonuç: Sistemik östrojen replasman tedavisi altındaki sıçanların endometriumlarını hiperplaziden korumada, progestagen
içeren rahimiçi sistemin yeterli olduğu sonucuna ulaşılmıştır. Elde edilen veriler, sistemik östrojen alan postmenopozal kadınların
endometriumlarını korumada gestagen içerem rahimiçi aracın yeterli olabileceği yönünde cesaret vericidir. Bu tip RİA kullanımı ile
hastalar sistemik gestagenlerin istenmeyen etkilerinden korunmuş olacaklardır.
Anahtar Kelimeler: Sıçan endometriumu, levonorgestrel, intrauterin sistem, östrojen replasman tedavisi
Corresponding author: Murat API Acelya Sok. No: 12 / 2. Postal
code: 31865 Dragos/ Kartal/ İstanbul/ Türkiye Tel:( 0090 )
05424241807 ( 0090 ) 02163622280 E-mail: [email protected]
65
Murat Api, et al.
The Effect Of A Levonorgestrel-Releasing Intrauterine Device On Ovariectomized Rat Endometrium Under Estrogen
Replacement Therapy
ERT. The progesterons in use have variable
systemic adverse effects 5,6. In order to minimize
these adverse effects, the local use of gestagens by
the help of intrauterine device seems to be a
logical option. Nevertheless, the efficacy of this
route of administration is still under investigation.
For this purpose, the endometrial effects of
intrauterine use of levonorgestrel with systemic
estrogen therapy have been investigated at the
light microscopic levels.
INTRODUCTION
The intrauterine system (IUS) can be used to
supplement estrogen replacement therapy (ERT),
in which estrogen is used to relieve such
menopausal symptoms as hot flashes, sweating,
sleep disturbances and vaginal dryness. Estrogen
replacement therapy also helps to prevent
osteoporosis and cardiovascular disease.
However, ERT also stimulates the endometrium.
Adding a progestin at menopause, such as the
levonorgestrel in the IUS, counteracts endometrial
stimulation and helps protect against the
overgrowth of endometrial tissue, precancerous
endometrial changes and endometrial cancer 1,2.
MATERIALS AND METHODS
Animals
Twenty-four Spraque-Dawley rats ( mean weight:
240 gr.) were subdivided into four groups
containing six rats in each. The University Ethic
Commitee approved the trial to be performed
according to the rules of Strazburg declarations
(Marmara University Faculty of Medicine Ethic
Commitee No: 657/ 2). Table I shows the
distribution of rats according to their subdivisions.
The sustained release of low-dose levonorgestrel
directly into the uterus via the IUS may result in
more endometrial protection, less irregular
bleeding, and fewer systemic side effects than the
release of progestins via pills or implants 3,4.
Postmenopausal women should use progesteron in
order to protect their endometrium while taking
Table I: Distribution of the rats according to their subdivision
Groups
Intrauterine device
Therapy applied
Group I
Levonorgestrel (IUD)
Estrogen
Group II
Levonorgestrel (IUD)
Placebo (Olive oil)
Group III
Placebo silicon (IUA)
Estrogen
Group IV
Placebo silicon(IUA)
Placebo (Olive oil)
Calculation of rat dosages of estrogen and
progesteron-releasing intrauterine devices
Each flacon with a total volume of 1 ml. and
containing 0.738 mg estradiol benzoate and olive
oil vehicle was supplied by the company.
Organon® . Same volume of olive oil flacons
were used for placebo injections. As the estimated
ethinyl estradiol dosages used for hormone
replacement in the ovariectomized rats was
reported to be 0.01 mg. per kg. rats per day, the
equivalent estradiol benzoate dosage was
calculated by the usage of estradiol potency.
In the first group, an intrauterine device -releasing
levonorgestrel-(LNg-IUD) has been applied by
hysterotomy and estrogen replacement therapy
was given for a period of one month. In the
second group, an intrauterine device-releasing
levonorgestrel-was applied by hysterotomy and
placebo treatment was given for a period of one
month. In the third group, an intrauterine device releasing nothing- was applied by an operation
and estrogen replacement therapy was given for
one month. In the fourth group, an intrauterine
device -releasing nothing- was applied by an
operation and placebo treatment was given for one
month. At the end of one month, by a second
intervention, endometrial tissue samples were
collected for light and transmission electron
microscopic investigation and bones from the
right femurs were extracted for bone mineral
densitometric measurements. The revealed data
were statistically analysed.
From this point, it was estimated that 0.1 ml. of
daily estradiol benzoate intramuscular injections
was the appropriate dose for ovariectomized rats
with a mean weight of 240 grams.
The appropriate LNg-IUDs for rats have been
supplied by Lerias Pharmaceuticals, Huhtamaki,
Oy Turku, Finland, Norplant®. These IUDs for
human hormonal contraception contain 36 mg of
66
Murat Api, et al.
Replacement Therapy
levonorgestrel in each of 6 rods, 2.4 mm in
diameter in width and 3.4 cm in length. These
rods release 13.33 mcg/24 hour levonorgestrel for
the first 6-18 months in humans. It has been
calculated that one third of each rod can release a
sufficient amount of levonorgestrel for
ovariectomized rats (3 mcg/day) according to
relative dose equivalency of gestagens.
of chlorpromazine (0.15 mg/ 100gr. per rat ) and
ketamine ( 0.1 mg/ 100gr. per rat ) into the
peritoneal cavity.
The abdominal wall of the rats was depilated,
cleaned and a 2 cm. of vertical incision was made
for laparotomy. The rats were ovariectomized by
ligation and dissection of the utero-ovarian and
suspensory ligaments of the ovaries. Fig. 1 depicts
the operation applied to the rats internal genitalia (
Fig. 1 ).
The Operation procedures
Before surgery, the rats were weighed and
anesthesia was achieved by injections of a mixture
Fig. 1. The operation applied to the rats internal genitalia A: Normal anatomy of the rats. B: Ovariectomy and left uterine horn
incision site C: Intrauterine device and uterus ready for application D: The IUD has been applied and operation ended.
evaluation because of the limited numbers of
samples. Significance level was accepted at
p<0.05.
After the operation, the rats were injected with
placebo or estrogen, according to their groups, for
30 days and reoperated for endometrial sampling
from the left uterine horn.
RESULTS
Light microscopy
All morphologic findings under the light
microscopy in the endometrial samples of the
groups were been classified into five different
histopathological criteria according to a
veterinarian pathology specialist. Table II depicts
this distrubution among the groups.
The endometrial morphology of Group I revealed
inactive endometrium in 50%, edema in 33% and
atrophy in 16% whereas the endometrial
morphology of Group II revealed inactive
endometrium in 66%, and atrophy in 33%. The
endometrial morphology of Group III revealed
epithelial hyperplasia in 66%, edema in 16% and
myometrial hyperplasia in 16% while inactive
endometrium was identified in 16%, and atrophy
in 83% of rats in Group IV (Fig. 2).
For light microscopy, the endometrial specimens
were fixed in Bouin’s solution and embedded in
paraffin. The paraffin sections were cut at 5 µm
thickness and stained with hematoxylene and
eosin ( H&E ) for routine examination and
Masson’s Trichrome for fibrous tissue details.
Sections were examined with Olympus BH-2
photomicroscope.
Statistical analysis
Statistical evaluation was performed with
computer assisted SPSS version 11.5 (Statistical
Package for Social sciences) package programme.
The difference between the histopathologic
findings were computed by Fisher’s Exact test.
Non-parametric tests were used for statistical
67
Murat Api, et al.
Replacement Therapy
.
Fig. 2: The bar chart of histologic findings of the rats
Fig 2: The bar chart of histologic findings of the rats
Table II: The distribution of groups according to histologic findings. Among the histological findings there
were statistically significant difference established for epithelial hyperplasia (p=0.02) and atrophy (p=0.015)
findings. Other findings did not differ in each group (p>0.05).
Histology
Group
I
Inactive
Epithelial
Edema
endometrium hyperplasia
3 (50%)
2 (33%)
Atrophy
1 (16%)
Myometrial
hyperplasia
-
II
4 (66%)
-
-
2 (33%)
-
III
-
4 (66%)
1 (16%)
-
1
IV
1
-
-
5 (83%)
-
evaluated. The endometrium remained inactive in
50% of the this group and 33% of them featured
stromal edema (Fig. 3). This histologic result
seems to reflect the relative dominance of local
gestagenic effect of intrauterine device on the
endometrium. In 16% of this group atrophy was
revealed; which represents the local progestojenic
effect of intrauterine device was strong enough to
supress endometrium against the circulating level
of estrogen. There was a substantial reduction
(p<0.05) in both the atrophy and the proportion of
cells with epithelial hyperplasia in the first group.
The latter features are representitive for hormonal
abstinance or estrogenic dominance, respectively.
In the second group, a form of gestagenic
dominance was more prominent as the 66% of
Histologically, the cellular components of the
endometrium could be clearly subdivided into
glands and surrounding stroma cells comprising
the vasculature.
As ovariectomy was performed for all subjects,
the hormonal production from the gonads was
seized for the study period. It was clearly
demonstrated that atrophic changes occurred in
83% of the fourth group (Fig. 6) which was
revealed at the end of the study period. This
atrophic endometrial change was proportionally
more frequent than the other groups and this
difference was found to be statistically significant
(p<0.05). The first group has been served as a
sample group to answer the study question. So the
histologic findings of this group was extensively
68
Murat Api, et al.
Replacement Therapy
featured edema which has an unknown
significance at the rat endometrium but most
probably it should be related to steroidal
stimulation. The hyperplasia seen in the third
group (Fig. 5) was statistically more frequent than
the other groups (p<0.05).
inactive endometrium and 33% of atrophy were
demonstrated (Fig. 4). On the other hand in the
third group, the unopposed estrogen influenced
the endometrium and myometrium while 83% of
the subjects revealed some extent of adverse
events (66% epithelial hyperplasia and 16%
myometrial hyperplasia). Only 16% of this group
Fig. 3: Group I: Light micrographs indicate A-) inactive endometrium (→) H+EX 40; B) Mild stromal edema (→). Masson’s
Trichrome X40;
Fig. 4: Light micrographs of Group II: A) Inactive endometrium and thin epithelial cells with stromal atroply (→) H+E X 40
and B) Inactive endometrium with no glandular structure (→) Masson’s trichrome X 40;
Fig. 5: Light micrographs of Group III indicate A) epithelial hyperplasia (→) H+EX 40; B) myometrial hyperplasia (→)
Masson’s trichrome X 40
69
Murat Api, et al.
Replacement Therapy
Fig. 6: Light micrographs of Group IV indicate A) atrophic epithelial structure (→) and desquamation H+EX 40; B) inactive
endometrium (→) Masson’s trichrome X 40;
DISCUSSION
With a daily release rate of 20 µg. of
levonorgestrel for 5 years, LNg-IUD effectively
prevents the proliferative effect of estrogen on the
endometrium in humans. Its indication for use was
expanded to the treatment of menorrhagia and it
was reported to be a promising method for the
administration of gestagen in peri-menopausal
patients on oral estrogen replacement therapy 13,14.
The addition of a gestagen to estrogen
replacement therapy is necessary to protect the
endometrium against hyperplasia and to minimize
the risk of endometrial cancer. In order to
minimize the systemic adverse effects of
gestagens, they were administered in a sequential
fashion. The major disadvantage of such therapy
is cyclic menstrual bleeding which further
diminutes patients’ compliance for the estrogen
replacement therapy. This drawback can be
avoided by continuous gestagen administration
along with estrogen replacement which leads to
amenorrhea after initial periods of spotting 7. On
the other hand, the disadvantageous effect of
continuous administration of gestagen on lipid
metabolism may be even more pronounced than
that of progestogen administered cyclically.
This concept has gained support from the
observations that the continuous administration of
19-nortestosteron derivative has counteracted the
beneficial effect of estrogen on serum high
density lipoprotein (HDL) and cholesterol level 8,9
whereas the estrogen-induced reduction in total
cholesterol and low density lipoprotein (LDL)
cholesterol has remained unaffected by
continuous
administration
estrogen
and
progestin10,11.
Some amount of the levonorgestrel released from
the LNg-IUD is absorbed from the uterine cavity
into the systemic circulation, however its effect on
lipids and lipoproteins has been reported to be
insignificant 15.
The use of unopposed estrogens in women with
climacteric complaints increases the incidence of
endometrial hyperplasia and cancer 16,17. In our
first group of rats, no hyperplasia or cancer was
encountered. On the other hand, in the third group
treated with unopposed estrogen, keratinized
squamous metaplasia and myometrial hyperplasia
were seen more commonly. Even it is not
statistically significant, in the third group, one
case of glandular hyperplasia was detected as the
sole abnormal pathological finding. This finding
of glandular hyperplasia may reflect the
unopposed estrogenic effect on the rat uterus,
nevertheless, further studies with larger sample
sizes are needed to confirm these findings. In
2003, Philips et al evaluated the endometrial
effects of levonorgestrel releasing intrauterine
device in women of reproductive age and found
out that the effects were characteristic, relatively
constant and in keeping with the effects of both a
progestogenic compound and a mechanical
device. Morphological features found in most of
the endometria were decidualisation of stroma (72
One option for minimizing these possible
systemic effects of progestins while preventing
endometrial hyperplasia is to administer the
progestin locally in the uterine cavity. A
progesteron-releasing
intrauterine
device
developed for contraception may thus be a logical
alternative for gestagen administration along with
postmenopausal hormone replacement therapy 12.
70
Murat Api, et al.
Replacement Therapy
of 75 cases), atrophy of endometrial glands (65 of
75 cases), a surface papillary pattern (38 of 75
cases), and a stromal inflammatory cell infiltrate
(59 of 75 cases). Additional common histological
features were the presence of foci of stromal
myxoid change (29 of 75 cases) and stromal
haemosiderin pigment (24 of 75 cases). Reactive
atypia of surface glands, glandular metaplastic
changes, stromal necrosis, and stromal
calcifications were found in small numbers of
cases 18. In year 2002, Raudaskoski et al evaluated
the clinical and endometrial efficacy and lipid
response of two different doses of intrauterine
levonorgestrel assessed in comparison with
sequential oral medroxyprogesterone acetate in
postmenopausal women receiving continuous oral
E2-valerate 19. Endometrial hyperplasia was not
observed in any of the treatment groups during the
12-month study and they concluded that both 10
microg and 20 microg levonorgestrel systems
provided good endometrial protection in
postmenopausal women on estrogen replacement
therapy. Furthermore, Wildemeersch evaluated
the endometrial safety with a low-dose
intrauterine
levonorgestrel-releasing
system
(releasing 14 microg of LNG per day) after 3
years of estrogen substitution therapy 20. They
found out that the endometrial histology specimen
showed profound endometrial suppression with
glandular atrophy and stroma decidualization in
all women.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
Our animal data is in keeping with the above
mentioned human data and the results from this
study in a small group of rats are promising, since
it is important to study the rat endometrium at
light microscopic levels, providing pioneer data
for further investigations. To our knowledge, this
is the first such study in the literature.
9.
10.
As a result, light microscopical investigations both in animal and human models - suggest that it
is possible to supply a safe and beneficial
hormone replacement therapy to postmenopausal
non-hysterectomized women; taking systemic
estrogen replacement therapy by the use of locally
active levonorgestrel-releasing intrauterine device
in order to protect them from the systemic adverse
effects of gestagens and to supply the efficient and
safe protection in their endometrium.
11.
12.
13.
71
Wollter-Svensson LO, Stadberg E, Andersson K, et
al. Intrauterine administration of levonorgestrel 5
and 10 microg/24 hours in perimenopausal
hormone replacement therapy, a randomized
clinical study during one year. Acta Obstet Gynecol
Scand 1997; 76(5):449-54
Taddei GL, Bargelli G, Scarselli B, et al.
Precancerous lesions of the endometrium and
medical treatment. Eur J Contracept Reprod Health
Care 1997 ;2(4):239-41.
Suhonen SP, Holmström T, Allonen HO, et al.
Intrauterine and subdermal progestin administration
in postmenopausal hormone replacement therapy.
Fertil Steril 1995; 63(2):336-42
Suhonen SP, Allonen HO, Lähteenmäki P.
Sustained-release estradiol implants and a
levonorgestrel-releasing intrauterine device in
hormone replacement therapy. Am J Obstet
Gynecol 1995; 172(2 Pt 1):562-67.
Kim CJ,Jang HC, Cho DH, Min YK. Effects of
hormone replacement therapy on lipoprotein (a)
and lipids in postmenopausal women. Arterioscler
Thromb 1994; 14(2):275-81.
Kim CJ, Min YK, Ryu WS, Kwak JW, Ryoo UH.
Effect of hormone replacement therapy on
lipoprotein (a) and lipid levels in postmenopausal
women. Influence of various progestogens and
duration of therapy. Arch Intern Med 1996 12-26;
156(15):1693-700.
Staland B. Continious treatment with natural
estrogens and progestagens. A method to avoid
endometrial stimulation. Maturitas 1981; 3:145-56
Mattsson LA, Cullberg G, Samsioe G. A
continuous estrogen-progestogen regimen for
climacteric complaints effects on lipid and
lipoprotein metabolism. Acta Obstet Gynecol
Scand 1984; 63:673-7
Farish E, Fletcher CD, Dagen MM et al.
Lipoprotein and apolipoprotein levels in
postmenopausal women on continuous estrogenprogestogen therapy. Br J Obstet Gynecol 1989;
96:358-64.
Sporrong T, Hellgren M, Samsioe G, Mattsson LA.
Metabolic effects of continuous estradiol-progestin
therapy in postmenopausal women. Obstet Gynecol
1989; 73:754
Jensen J, Riis BJ, Strom V, Chiristiansen C.
Longterm and withdrawal effects of two different
estrogen-progestogens combination on lipid and
lipoprotein profiles in postmenopausal women.
Maturitas 1989; 11:117-28
Rybo G, Anderson K, Odlind V. Hormonal
intrauterine devices. Ann Med 1993;25:143-7
Andersson K, Rybo G. Levonorgestrel releasing
intrauterine device in the treatment of menorrhagia.
Br J Obstet Gynecol 1990; 97:690-4
Murat Api, et al.
Replacement Therapy
14. Andersson K, Mattsson LA, Rybo G, Stadberg E.
Intrauterine release of levonorgestrel- a new way of
adding progestogen in hormone replacement
therapy Obstet Gynecol 1992; 79:963-7.
15. Raudaskoski T, Tomas EI, Paakkari IA, Kauppila
AJ, Laatikainen TJ. Serum lipids and lipoproteins
in postmenopausal women receiving transdermal
estrogen in combination with levonorgestrel
relasing intrauterine device. Maturitas 1995; 22:4753.
16. Schiff I, Sala HK, Cramer D, Tulchinsky D, Ryan
KJ. Endometrial hyperplasia in women on cyclic or
continuous estrogen regimens. Fertil Steril 1982;
37:79-82.
17. Ziel HK, Finkle WD. Increased risk of endometrial
carcinoma among users of conjugated estrogens. N
Engl J Med 1975; 293:1167-70.
18. Phillips V, Graham CT, Manek S, McCluggage
WG. The effects of the levonorgestrel intrauterine
system (Mirena coil) on endometrial morphology. J
Clin Pathol. 2003; 56(4):305-7.
19. Raudaskoski T, Tapanainen J, Tomas E, Luotola H,
Pekonen F, Ronni-Sivula H, Timonen H, Riphagen
F, Laatikainen T. Intrauterine 10 microg and 20
microg levonorgestrel systems in postmenopausal
women receiving oral oestrogen replacement
therapy: clinical, endometrial and metabolic
response. BJOG. 2002; 109(2):136-44.
20. Wildemeersch D, Schacht E, Wildemeersch P,
Calleweart K, Pylyser K, De Wever N. Endometrial
safety with a low-dose intrauterine levonorgestrelreleasing system after 3 years of estrogen
substitution therapy. Maturitas. 2004; 48(1):65-70.
72
ORIGINAL RESEARCH
THE CONTRIBUTION OF HOME-FAMILY DISTRESS TO THE
PRESENTATION DIFFERENCE OF CHILDHOOD OBSESSIVECOMPULSIVE DISORDER ACROSS HOME AND SCHOOL SETTINGS
Osman Sabuncuoğlu, Meral Berkem
Department of Child Psychiatry, School of Medicine, Marmara University, Istanbul, Turkey
ABSTRACT
Objective: Further to our recent finding of presentation difference in the symptoms of childhood obsessive-compulsive disorder
across home and school settings, and that home is where symptoms predominate, we aimed to find out whether this phenomenon is
related to home-family distress.
Methods: After the application of CY-BOCS, CGI and a questionnaire consisted of items that served as a comparison of the
symptoms across home and school settings, family distress was rated on a 5-point scale (FDM) which reflected home stress factors such
as unemployment, parental conflict and care of elderly.
Results: Of the 20 children enrolled in the study, 70% were boys and 30% girls who had a mean age of 12.45 ± 3.36. Both CYBOCS and CGI-severity (home and school) scores did not differ significantly within themselves regarding caseness criteria of +3
cutscore on the FDM. Among the data obtained by CY-BOCS and CGI, only Compulsion Subscale of CY-BOCS revealed significant
correlation with FDM scores ( r = 0.510, p<0.05).
Conclusion: Preliminary data did not support any association between home-family distress and presentation difference. A larger
sample is needed to conclude on the contribution of home-family stress factors to the presentation difference in childhood obsessivecompulsive disorder.
Keywords: Obsessive-compulsive disorder, Child, Adolescent, Schools, Family
ÖZET
Amaç: Çocukluk çağı obsesif-kompulsif bozukluğunda, ev ortamında okul ortamına göre belirtilerin daha fazla dışavurulduğu
yönündeki son bulgumuzdan sonra bu sonucun ev-aile stresiyle ilişkili olup olmadığını araştırmayı amaçladık.
Yöntem: Yale-Brown Çocuklar İçin Obsesif-Kompulsif Sorulistesi (YBÇOKS), Klinik Global İzlenim Ölçeği (KGİÖ) ve evokul ortamları arasında belirtileri karşılaştırmaya yarayan sorulistesinin uygulanmasından sonra işsizlik, ebeveyn çatışması ve yaşlı
bakımı gibi nedenlerle yaşanan ev-aile stresi 5 bölümlük ölçek üzerinden puanlandı.
Bulgular: Çalışmaya alınan 20 çocuğun %70'i erkek, %30'u kız ve ortalama yaşı 12.45 ± 3.36 idi. Gerek YBÇOKS, gerek ev
ve okul için verilen KGİÖ-Hastalık Şiddeti puanları aile stresi için +3 olan olgusallık ölçütüne göre farklılık göstermedi. Yalnız
YBÇOKS Kompulsiyon altölçeği aile stres bulgularıyla anlamlı korelasyon gösterdi (r = 0.510, p<0.05).
Sonuç: On bulgular belirti dışavurumunda farklılık ile ev-aile stresi arasında bir ilişki olmadığını gösterdi. Çocukluk çağı
obsesif-kompulsif bozukluğunda ev-aile stresinin belirti dışavurumunda farklılığı nasıl etkilediğine karar vermek için daha geniş bir
örneklem incelenmelidir.
Anahtar Kelimeler: Obsesif kompulsif bozukluk, Çocuk, ergen, Okullar, Aile
presentation, treatment and course of the disorder.
Although information on childhood OCD still
accumulates,
various
phenomenological
dimensions await to be determined. The symptom
profile of children with OCD across home and
school settings is one of the topics which remain
unknown, unlike, for instance ADHD. Although
Rapoport notes that children with OCD may have
INTRODUCTION
Childhood obsessive-compulsive disorder (OCD)
is a chronic and underrecognized psychiatric
condition affecting 1% to 4% of children and
adolescents 1. The lifelong characteristic of OCD
necessitates in depth understanding of childhood
OCD in terms of age at onset, diagnosis, symptom
Corresponding author’s address: Dr. Osman Sabuncuoğlu Halk Cad.
Emin Ongan Sk. 11/ 7 80300 Üsküdar / Istanbul, Turkey Phone:
+90(542)4253397 +90(216)3271010-514 Fax:+90(216)3250323 Email: [email protected]
73
Osman Sabuncuoğlu, et al.
The contribution of home-family distress to the presentation difference of childhood obsessive-compulsive disorder across
home and school settings
by the interviewer. A Turkish version was used
for the present study 11.
a partial voluntarily control of symptoms in
public, there is no particular reference to any
study 2. On the other hand, DSM-IV criteria for
OCD merits the significant interference of
symptoms with school, social activities and
important relationships 3.
Recently we have described presentation
difference
phenomenon
characterized
by
significant difference in the presentation of
obsessive-compulsive disorder across home and
school settings 4. We found that home is where
symptoms predominate. Family setting is of
interest in numerous reports in relation to the
problem behavior of children. Early adverse
family circumstances and parenting characteristics
were found to have no contribution to the
prediction of later psychopathology once child
characteristics were accounted for 5. Contrary to
this finding, there are studies reporting direct
concurrent relations between home-family distress
and the problem behavior of children 6,7. Family
context in childhood OCD has also been
highlighted as a risk factor in the development and
maintenance of the disorder 8.
Clinical Global Impression (CGI) – Severity
Subscale 12: It is scored from 1 (no illness) to 7
(completely nonfunctional). The interviewer
determines the overall severity of the illness. In
the present study design, two ratings, one for the
school and one for the home setting were made
and compared.
Setting Specificity of OCD Symptoms In Children
Questionnaire: This questionnaire was prepared
by the research team and was based on the results
obtained on the CY-BOCS. The children and their
parents were questioned about the frequency of
symptoms across home and school settings with
particular reference to the CY-BOCS results.
Family Distress Measure (FDM): The clinician
rated the overall family distress on a 5-point scale
which reflected home stress factors such as
unemployment, parental conflict, illness and care
of elderly. This measure was introduced with a
perspective similar to CGI and +3 cutscore was
accepted as the level of clinical concern. Homefamily distress secondary to the child’s psychiatric
disorder was not taken into account.
As an implication of our previous research, we
aimed to determine whether presentation
difference phenomenon is related to the family
distress experienced at home.
SPSS 10.0 for Windows was used to analyze the
findings. T-test, Mann-Whitney U Test and
Correlational tests were required to analyse the
data.
MATERIALS AND METHODS
Twenty schoolchildren, aged 6 to 17 from our
OCD cohort, were enrolled in the study. Child
psychiatric diagnoses were based on the
Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV) criteria.
After the application of original measures on
admission, each case was assessed by the same
child psychiatrist (Dr. O. S.) in a following
session regarding home-family distress. Previous
progress records were used when necessary. Basic
informative data was gathered from the file
records of the children.
RESULTS
Of the total number of children, 70% were boys
and 30% girls with had a mean age of 12.45 ±
3.36.
The mean obsession and compulsion subscores
were 10.75 ± 4.05 and 10.55 ± 3.73 respectively,
both summing up a total score of 21.30 ± 6.77.
Table I displays the prevalence of obsessions and
compulsions experienced by the children in the
present sample. Ten (50%) of the subjects were
pure OCD whilst the remaining children had some
comorbid diagnoses. CGI-severity scores for both
home and school settings were 4.40 ± 0.88 and
2.20 ± 0.76 respectively, at a significant level of
difference (t=8.41, df=38, p<0.0001 and Levene’s
test revealing egual variances F= 1.59, p<0.05).
Child and parent estimated distribution of the
frequency of OCD symptoms according to the
Setting Specifcity Questionnaire is presented in
Fig. I.
Measures
Children’s Yale-Brown Obsessive Compulsive
Scale (CY-BOCS): This scale is a 10-item,
clinician rated, semi structured instrument
designed to rate the severity of obsessive and
compulsive symptoms in children, aged 6 to 17
years 9,10. Information obtained from the child and
parent which reflects the average course of
symptoms in the week prior to the study is rated
74
Table I : Prevalences of obsessions and compulsions on the CY-BOCS.
OBSESSIONS
n
%
Contamination
13
65
Aggressive
12
Sexual
COMPULSIONS
n
%
Washing/Cleaning
13
65
60
Checking
10
50
3
15
Repeating
12
60
Hoarding/Saving
0
0
Counting
0
0
Magical Thoughts/Superstitious
4
20
Ordering/Arranging
0
0
Somatic
3
15
Hoarding/Saving
3
15
Religious
2
10
Excessive Magical Games
1
5
Miscellaneous
0
0
Rituals Involving Others
1
5
Miscellaneous
7
35
Table II : The comparison of the CY-BOCS and CGI scores of the children with respect to low (n=14) and
high FDM (n=6) scores
CY-BOCS CY-BOCS CY-BOCS
CGI
CGI
COMP
OBS
TOTAL HOME SCHOOL
Mann-Whitney U
21,000
40,000
30,500
39,000
35,000
Wilcoxon W
126,000
145,000
135,500
60,000
140,000
-1,745
-,167
-,952
-,268
-,639
,081
,867
,341
,789
,523
a
a
a
a
,602a
Z
Asymp. Sig (2-tailed)
Exact Sig.[2*(1-tailed Sig.)]
,091
,904
,353
,841
a
. Not corrected for ties
Fig. 1: Child and parent estimated distribution of the frequency obsessive compulsive symptoms across settings.
Test. In comparison, no significant difference was
found between the dichotomised groups (Table
II).
Among the data obtained by CY-BOCS and CGI,
only Compulsion Subscale of CY-BOCS revealed
significant correlation with FDM scores (r =
0.510, P<0.05).
The mean family distress measure (FDM) score
was found to be 2.00 ± 1.12. According to +3
cutscore of FDM, 6 cases were identified. The
CY-BOCS and CGI scores of the children, each
dichotomised with respect to caseness criteria on
the FDM, were analysed using Mann-Whitney U
75
DISCUSSION
studied before
strategies.
Although distress experienced within the family
might have an additive impact on the childhood
OCD overall, it seems that the presentation
difference is not determined by this kind of
distress. Presentation difference is consistant in
the vast majority of enrolled children.
In conclusion, preliminary data showed no
association between home-family distress and
presentation difference. The study should be
replicated on a larger sample to conclude on the
contribution of home-family stress factors to that
phenomenon.
The positive correlation between the FDM and
CY-BOCS Compulsion Subscale is of interest. It
seems that, to some extent, the level of stress
experienced in the home environment is
associated
with
children’s
compulsions
experienced either at home or at school. What
should be kept in mind is that, although we found
significant presentation difference in the entire
sample, high FDM cases did not differ from the
low FDM cases in the variables studied. Thus, our
findings are in line with Mesman’s study 5.
developing
proper
treatment
REFERENCES
Carter AS, Pollock RA. Obsessive compulsive
disorder in childhood. Curr Opin Pediatr 2000;
12:325-330.
2. Rapoport JL, Swedo S, Leonard H. Obsessivecompulsive disorder. In: Rutter M, Taylor E,
Hersov L, eds. Child and Adolescent Psychiatry:
Modern Approaches. 3rd ed. London: Blackwell
Science, 1994: 441-454.
3. American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders, 4th ed
(DSM-IV), Washington DC: The American
Psychiatric Press, 1994.
4. Sabuncuoglu O, Berkem M. Çocukluk çağı obsesifkompulsif bozukluğunda ev ve okul ortamlarında
belirti profillerinin karşılaştırılması: bir ön çalışma.
14. Ulusal Çocuk ve Ergen Psikiyatrisi Kongresi,
Bursa, 2004.
5. Mesman J, Koot HM. Early preschool predictors of
preadolescent internalizing and externalizing DSMIV diagnoses. J Am Acad Child Adolesc Psychiatry
2001; 40:1029-1036.
6. Ackerman BP, Kogos J, Youngstrom E, Schoff K,
Izard C. Family instability and the problem
behaviors of children from economically
disadvantaged families. Dev Psychol 1999; 35:258268.
7. Gordis EB, Margolin G, John RS. Parents' hostility
in dyadic marital and triadic family settings and
children's behavior problems. J Consult Clin
Psychol 2001; 69:727-734.
8. Waters TL, Barrett PM. The role of the family in
childhood obsessive-compulsive disorder. Clin
Child Fam Psychol Rev 2000; 3:173-184.
9. Goodman WK, Price LH, Rasmussen SA, et al. The
Yale-Brown Obsessive Compulsive Scale. I.
Development, use, and reliability. Arch Gen
Psychiatry 1989; 46:1006-1011.
10. Goodman WK, Price LH, Rasmussen SA, et al. The
Yale-Brown Obsessive Compulsive Scale. II.
Validity. Arch Gen Psychiatry 1989;46:1012-1016.
11. Erkal AGY, Arman AR, Topçuoğlu V, Fişek G,
Yazgan MY. Çocuklar İçin Yale-Brown Obsesif
Kompulsif
Ölçeği
geçerlik
güvenirlik
değerlendirmesi. 12. Ulusal Çocuk ve Ergen
Psikiyatrisi Kongresi, İstanbul, 2002.
12. Guy W. Clinical Global Impressions: ECDEU
Assessment Manual for Pharmacology, revised
edition. Rockville, MD: National Institute of
Mental Health, Dept. of Health, Education and
Welfare Publication (ADM), 1976: 218-222.
1.
Interpersonal factors that might trigger OCD
symptoms within the family should be studied.
Early parental preoccupation and behavior
surrounding the birth of a family member
implicated in the possible evolutionary origins of
OCD may provide insight regarding the
presentation phenomenon 13. The contribution of
secondary family distress stemming from the
child’s OCD is worth investigating in further
studies.
Given these results, we can also hypothesize that
the distraction experienced in the school
environment may relieve the intrusive obsessions
and therefore lead to a better functioning at
school. In addition, certain forms of compulsions
might not be easily performed in the school
setting for practical reasons and due to anticipated
shame. If these factors predominate, any sort of
home-family distress is unlikely to contribute to
the presentation difference.
As this study was based on the self-reports of
children with the agreement of their parents,
secrecy was out of question in the studied sample.
In addition, the prevalence of obsession and
compulsion in our sample is similar to that of
previous findings in Turkey 14.
Therapeutic implications should be derived from
the presentation difference phenomenon as,
outlining the factors which relieve the symptoms
at school may be self-educative for a better
control over the symptoms experienced at home.
Interpersonal factors, such as the persistence of
early parental preoccupations should also be
76
13. Leckman JF, Mayes LC, Feldman R, Evans DW,
King RA, Cohen DJ. Early parental preoccupations
and behaviors and their possible relationship to the
symptoms of obsessive-compulsive disorder. Acta
Psychiatr Scand Suppl 1999; 396:1-26.
14. Diler RS, Avcı A, Tamam L, Toros F. Çocuk ve
ergenlerde
obsesif
kompulsif
bozukluk:
sosyodemografik, klinik özellikler ve eştanılar.
Türk Psikiyatri Dergisi 1999; 10: 294-304.
77
CASE REPORTS
MISPLACEMENT OF A NASOGASTRIC TUBE INTO THE
POSTPNEUMONECTOMY SPACE
Tümay Umuroğlu, İ. Varlık Doğan, Abdurrahman Yaycı
Department of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey
ABSTRACT
Nasogastric tubes cause complications related to traumatic insertion. We reported a case of misplacement of a nasogastric tube
into the postpneumonectomy space. A sixty-three-year old male patient was admitted to intensive care unit with the diagnosis of broncho
and esophagopleural fistula 3 months after a pneumonectomy. A nasogastric tube had to be inserted immediately for the maintenance
therapy of atrial fibrillation by the enteral route, by listening to the sound of air over the abdomen to minimize the risk of misplacement,
but gastroscopy revealed that it was in the postpneumonectomy space. We concluded that it is important to verify the exact place of a
nasogastric tube radiologically in patients with undiagnosed esophageal pathologies.
Keywords: Post-pneumonectomy, Nasogastric misplacement
NAZOGASTRİK SONDANIN POSTPNÖMONEKTOMİ ARALIĞINA
YANLIŞ YERLEŞİMİ
ÖZET
Nazogastrik sondaların travmatik olarak takılmaları sonrasında komplikasyonlar gelişebilmektedir. Burada postpnömonektomi
bölgesine yanlışlıkla yerleştirilen bir vakayı tartıştık. Hasta pnömonektomi operasyonu geçirdikten 3 ay sonra bronko ve özofageal
fistül tanısıyla yoğun bakım ünitesine kabul edildi. Atrial fibrilasyon tedavisinin idamesini sağlayabilmek amacıyla acil olarak
nazogastrik sonda takılması planlandı. Sondanın yanlış yere yönlenmesini önlemek amacıyla batın duvarından sonda ucundan verilen
hava sesi steteskop aracılığıyla dinlendi. Ancak daha sonra uygulanan gastroskopide nazogastrik sondanın postpnömonektomi
bölgesine ilerlemiş olduğu saptandı. Sonuç olarak, bilinmeyen özofageal patolojisi bulunan hastalarda, nazogastrik sondaların
yerlerinin doğruluğunun radyolojik olarak saptanmasının gerekli olduğu sonucuna vardık.
Anahtar Kelimeler: Postpnömonektomi, yanlış yerleşimli nazogastrik sonda
intensive care unit with hypotension (50/30
mmHg), hyperventilation (respiratory rate:
24/min),
tachycardia
(160/min)
and
hypothermia(35 C axillary). 10 months previously
he had been diagnosed with lung squamous cell
carcinoma and a right lower lobectomy was
performed. 7 months later, he underwent right
pneumonectomy for a recurrence. On admission,
his arterial blood gases, obtained while breathing
5L/min oxygen with a face mask,were as pH 7.40,
PaO2 67.2mmHg, PaCO2 38mmHg, HCO3
23.1mmol/L, BE –1.3 and SaO2 93%. The
electrocardiogram showed an atrial fibrillation
with a rate of 160/min. A chest radiograph
indicated fluid collection on the right side, clear
INTRODUCTION
Nasogastric tubes (NG) are commonly used for
stomach
lavage,
stomach
decompression,
administration of oral medications and enteral
nutrition in critically ill patients 1, however they
may lead to many complications such as
pulmonary or intracranial intubation, esophageal
perforation and pneumothorax 2-5. We report a
case of an unusual placement of a nasogastric tube
into the postpneumonectomy space in the absence
of trauma.
CASE REPORT
A 63-year-old man with hypertension and
coronary artery disease was admitted to the
Corresponding author: Tümay Umuroğlu Address: Kalfa Çeşme sok.
Validebag sitesi 7/ 5 Üsküdar- Istanbul / TURKEY 81020
Tel: +90 216 325 4356 Fax: +90 216 339 9989
e-mail address: tans6@ hotmail.com
78
Tümay Umuroğlu, et al.
Misplacement of a nasogastric tube into the postpneumonectomy space
left lung field and a normal-sized heart, consistent
with the diagnosis of bronchopleural fistula. A
fluid. After fluid resuscitation, 15µg/kg/min
dopamine hydrochloride infusion, piperacillin/
tazobactam
and
aminoglycoside
were
administered to the patient. Digitalization was
performed but a sinus rhythm was obtained only
after administration of 10mg metoprolol tartarate,
i.v. An echocardiogram showed normal left
ventricular function. The patient’s hypoxemia
improved after administration of 8L/min oxygen
with a face mask. Blood cultures obtained on
admission were positive for group F streptococcus
and thoracal drainage fluid culture was positive
for E. Coli. Antibiotic therapy was continued.
right chest tube was inserted for the drainage of
fistula was unsuccesful because of the fragile wall
of the esophagus. Gastrostomy was performed,
atrial fibrillation was controlled and he was
discharged on the 15thday after admission.
DISCUSSION
Gastrointestinal access for critically ill patients is
mandatory for administration of oral medications,
enteral nutrition, gastric decompression and
lavage 1. Nasogastric and nasoduodenal tube
placements are the most common preferred
accesses. Nasogastric tube placement is an easy
and simple method. Hearing the sound of air
injected into the tube over epigastrium and
demonstration of gastrointestinal contents in
syringe aspirate are methods to verify its place 6.
It does not require radiographic confirmation.
Nasoduodenal tube is made of radiopaque
material and has the advantage of radiologic
confirmation for proper placement but it is an
expensive and time consuming procedure 7.
Besides the incidence of tube displacement
increases with the use age of small-bore
nasoduodenal tubes 8,9. We used a large-bore
nasogastric tube in order to minimize this risk,
however, the defect on the esophageal wall was
big enough to cause misplacement.
On the 10th hour after admission, the patient’s
hemodynamic
status
improved,
dopamin
hydrochloride infusion was discontinued and he
was allowed to take oral nutrition. After 26 hours,
with a total oral intake of 3075cc, gastric contents
were observed in the thoracic drainage tube.
Esophagopleural fistula was suspected. Oral
nutrition was discontinued.
On the 3rd day after admission, the patient again
had atrial fibrillation with a rate of 156/min. 15mg
diltizem i.v. bolus followed by 10mg/h infusion
and magnesium replacement were ineffective.
Subsequent i.v. bolus of 10mg metoprolol
tartarate resolved atrial fibrillation and the heart
rate decreased to 80/min. Since administration of
a ß-blocker infusion is inappropriate for
maintenance therapy, a nasogastric tube had to be
inserted in order to give it enterally. A 16 French
polyvinylchloride nasogastric tube was inserted,
listening to the sound of air over the abdomen as
well as to the right hemithorax, keeping in mind
the possibility of tube misplacement into
postpneumonectomy space. Air was heard
strongly over the epigastrium but weakly over the
hemithorax and since drainage material from the
tube looked like a gastric juice, the tube was
accepted as properly placed. Metoprolol tartarate
50mg four times daily was started orally. The
patient again had tachycardic attacks only
resolved with the administration of propafenon
hydrochloride
150mg
i.v.
Propafenon
hydrochloride tablet 150mg three times daily was
administered from NG tube but tachycardial
episodes continued. Endoscopy revealed a 5x6 cm
fistula on the wall of the esophagus at 28thcm, a
tumor at 23rdcm from mouth, and it was observed
that the nasogastric tube was installed in
postpneumonectomy space through this fistula. It
was removed. The patient was accepted to be
inoperative. Application of a stent to esofageal
There are many complications related to
nasogastric placement, such as bleeding,
intracranial intubation, pneumothorax and
esophageal perforation 2-5. Review of the relevant
literature suggests that trauma is usually the
predisposing factor in such complications 5,10. In
our case report, we discussed an unusual
misplacement of a nasogastric tube to
postpneumonectomy space through a pathological
defect in the esophageal wall in the absence of
trauma. Although we knew that there was an
esophagopleural fistula, placement of a
nasogastric tube was vital for the administration
of oral medication for the maintenance treatment
of atrial fibrillation. To minimize the possibility of
inserting
the
nasogastric
tube
into
postpneumonectomy space, we listened to the
sound of air over the whole right hemithorax as
well as the epigastrium. Although the tube was
placed in postpneumonectomy space, the sound
was less pronounced over the right hemithorax
than over the upper abdomen. The reason for that
could be the thicker thoracic wall or the leak of air
from the thoracic drainage tube. The presence of
gastric juice in the nasogastric tube may be the
79
Tümay Umuroğlu, et al.
Misplacement of a nasogastric tube into the postpneumonectomy space
3.
Granier I, Leone M, Garcia E, Geissler A.
Nasogastric tube: intratracheal malposition and
entrapment in a bronchial suture. Ann Fr Anesth
Reanim 1998; 17:1232-1234
4. Kolbitsch C, Pomaroli A, Lorenz I, Gassner M,
Luger TJ. Pneumothorax following nasogastric
feeding tube insertion in a tracheostomized patient
after bilateral lung transplantation. Intensive Care
Med 1997; 23 440-442
5. Ferreras J, Junquera LM, Garcia-Consuegra L.
Intracranial placement of a nasogastric tube after
severe craniofacial trauma. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 2000; 90:564-566
6. Christen S, Hess T. Is a clinical positional control
for nasogastric tubes good enough? A prospective
study of 43 patients. Dtsch Med Wochenschr 1996;
121:1119-1122
7. Huerta G, Puri VK. Nasoenteric feeding tubes in
critically ill patients (fluoroscopy versus blind).
Nutrition 2000;16:264-267
8. Ibarra-Perez C. Lung perforation by a small-bore
enteral feeding tube. Rev Invest Clin 1992; 44:255258
9. Wendell GD, Lenchner GS, Promisloff RA.
Pneumothorax complicating small-bore feeding
tube placement. Arch Intern Med 1991; 151:599602
10. Fisman DN, Ward ME. Intrapleural placement of a
nasogastric tube: an unusual complication of
nasotracheal intubation. Can J Anaesth 1996;
43:1252-1256
result of the back flow of gastric contents into the
thoracal cavity through the fistula located very
close to the esophagogastric opening. It was not a
surprise that atrial fibrillation was uncontrollable,
despite many medical interventions as the drugs
administered were into the postpneumonectomy
space and had drained from the existant thoracic
tube without being absorbed.
It is suggested that in high risk patients a
nasogastric tube should only be inserted under
direct vision and a subsequent X-ray is mandatory
for confirming proper positioning 8.
Regarding our case report, we concluded that it is
important to verify the exact place of a nasogastric
tube either radiologically or fluoroscopically with
an injection of a contrast dye, in patients with
undiagnosed esophageal pathologies; or insertion
of radiopaque tubes may be an appropriate
approach to prevent the complications due to
misplacements.
REFERENCES
1.
2.
Rippe JM, Irwin RS, Alpert JS, Fink MP.
Gastroenterologic problems in the intensive care
unit. In: Clouse RE, editor. Intensive Care
Medicine. United States of America: Little, Brown
and Company, 1991: 903
Kuo YC, Wu CS. Spontaneous intramural
perforation of the esophagus: case report and
review of the literature. Endoscopy 1989; 21:153154
80
CASE REPORTS
A FAMILY WITH A 17p: PERICENTRIC INVERSION: IMPLICATIONS FOR
CARRIERS
Gülseren Bağcı1, Özgül Alper1, Anne Hagemeijer2, Hasan Acar3, Elizabeth M.E. Smit2,
Mine Üner4, Güven Lüleci1
1
Department of Medical Biology-Genetics, Faculty of Medicine, Akdeniz University, Antalya, Turkey 2Department of Cell
Biology and Genetics, Erasmus University, Rotterdam, Holland 3Department of Medical Biology and Genetics, Faculty of
Medicine, Selçuk University, Konya, Turkey 4Department of Obstetric and Gynecology, Faculty of Medicine, Akdeniz
University, Antalya, Turkey
ABSTRACT
Amniocentesis was performed at the 19th week of gestation because of advanced maternal age and a presumed risk of 1/14 for
Down syndrome as determined by the triple test. Chromosomal analysis of the fetus revealed a karyotype of 46,XX,inv(17)(p11.2;q25.1).
This chromosomal breakpoint can be associated with a microdeletion on chromosome 17 and be related with Smith-Magenis syndrome
and shown by cytogenetic observations. That is why, we have examined the fetus with the Smith-Magenis probe by the use of
fluorescence in situ hybridization (FISH) technique to identify the microdeletion of band p11.2 of chromosome 17. After it is confirmed
that the inverted chromosome is familial and no deletion has occurred, the pregnancy continued for a healthy carrier baby. These findings
have implications for prenatal counseling of carriers of pericentric inversions, who typically are considered to bear minimal reproductive
risk. This report shows that, FISH provides a reliable means for prenatal detection of the chromosome 17 rearrangements in this family.
Keywords: Chromosome 17, Pericentric inversion, Fluorescence in situ hybridization
17P PERİSENTRİK İNVERSİYONLU BİR AİLE: TAŞIYICILARA UYARILAR
ÖZET
İleri anne yaşı ve üçlü testte 1/14 risk ile Down sendromu düşünülen gebeliğe 19. haftasında amniyosentez uygulandı. Fetusun
kromozom analizi sonucu karyotipi 46,XX,inv (17) (p11.2;q25.1) olarak belirlendi. Sitogenetik olarak tespit edilen bu kromozomal kırık
noktası mikrodelesyon sendromu olan Smith-Magenis sendromu ile ilişkili olabileceği için, Smith Magenis probu kullanılarak FISH
yöntemi uygulandı.
Delesyon olmadığı ve familyal inversiyon 17 olduğu tesbit edilerek gebeliğe devam edildi ve sağlıklı bir bebek doğdu. Bu
bulguların ışığı altında, perisentrik inversiyon taşıyıcılarının prenatal genetik danışmasının önemli olabileceği dikkate alınmalıdır. Bu
makalede, FISH yönteminin prenatal olarak inversiyon sonucu kromozom 17'de oluşabilecek mikrodelesyon ve yeniden düzenlenmelerin
analizi açısından güvenilir olduğu vurgulanmaktadır.
Anahtar Kelimeler: Kromozom 17, Perisentrik inversiyon, Fluoresans in situ hibridizasyon
hybridization) technique is one of the higher
resolution molecular techniques for visualizing
chromosome regions which uses the DNA probes
labeled with fluorescent dyes to identify specific
chromosomal regions. The microdeletions can be
detected by the use of FISH analysis. These single
probes may also be used to determine the
breakpoints of the structural rearrangements 2.
INTRODUCTION
In general, chromosomal inversions, are not
infrequent, with an average incidence of 0.13 per
1000 liveborns 1. Usually, there is no phenotypic
effect in the majority of inversion carriers.
However, when an inversion disrupts a critical
gene, an associated disease phenotype can result 1.
Based on cytogenetic observations, several
microdeletion and contiguous gene-deletion
syndromes have been identified, as Prader-Willi,
Smith-Magenis. FISH (fluorescence in situ
Smith-Magenis syndrome (SMS) is a distinct and
clinically recognizable multiple congenital
anomaly (MCA) and mental retardation syndrome
Corresponding author: Gülseren Bağcı, Ph.D.,Department of Medical
Biology-Genetics, Akdeniz University, Faculty of Medicine 07070
Antalya, Turkey.e.mail address: [email protected]
81
Gülseren Bağcı, et al.
A family with a 17p: Perıcentric inversion: implications for carrıers
pericentric inversion of chromosome 17 and to
check whether there is a deletion of SmithMagenis region or not.
caused by an interstitial deletion of band p11.2
averaging of 4-5 Mb of chromosome 17 3,4. If this
region includes the breakpoint in carriers of
inversion is the same with microdeletion
syndromes, then the presence or absence at that
deletion can be tested in a cytogenetics laboratory
using FISH 5. Here, we present the identification
of a unusual inversion on chromosome 17 in a
family with a normal phenotype.
Cytogenetic and FISH Findings
Chromosome analysis by routine GTG-banding
on amniotic fluid cells, from the fetus, after the
birth from the peripheral lymphocytes revealed a
female karyotype (III-4) of 46,XX,inv(17)
(p11.2;q25.1). Family screening was performed to
determine whether this finding of pericentric
inversion of chromosome 17 was a familial or de
novo event in blood lymphocytes. In the pedigree
analysis, (Fig.1) cytogenetic results of the family
was as follows; I-1 and II-4 have a normal
chromosome 17 pattern, however, from I-2, II-3,
II-5 and III-3 exhibited the same structural
aberration, which was inv(17)(p11.2;q25.1) as
shown in Figure 2.
CASE REPORT
Amniocentesis and ultrasonography were
performed at the 19th week of gestation on a 38year-old woman referred to our clinic due to
advanced maternal age and high risk for Down
syndrome in triple test. Fetal ultrasonography
showed no significant fetal anomaly. The family
history was negative for various abnormalities.
The parents were not consanguineous and had a
healthy 13-year-old female child. Proband’s
family members were cytogenetically examined,
which is shown in the pedigree (Fig.1).
Fig. 1 : Pedigree showing the proband’s family
Fig. 2: GTG-banded chromosome 17 of the proband.
Cytogenetic and FISH Evaluation
The presence of pericentric inversion on
chromosome 17 is confirmed with the use of p53
and Miller-Dieker mix probes (Fig. 3a).
Metaphase and interphase FISH analysis with
Smith-Magenis probe (ONCOR) revealed that a
consistent signal was observed on both of the
normal and inverted chromosomes 17, indicating
no deletion (Fig. 3b). Thus, the pregnancy
continued and a 2850gr., 50cm. female with
normal phenotypic features was delivered at 39
weeks of gestation by cesarean section. The baby
was developmentally appropriate for age.
Amniotic fluid was cultured in Chang medium
(Irvine Scientific, USA) and peripheral blood
lymphocytes was grown for 72 hours in Mc Coy
5A medium (Gibco, England) supplemented with
10% FCS (Gibco, England). Metaphase
chromosomes were analyzed by the standard
methods. 6-8 and in situ hybridization (FISH)
technique 9,10. Metaphase spreads of fetus were
screened with the digoxigenin labeled p53 and
Miller Dieker mix probe and Smith-Magenis
probe (ONCOR) 9,10. Forty metaphases and 200
interphase nuclei were analyzed to confirm the
82
Gülseren Bağcı, et al.
A family with a 17p: Perıcentric inversion: implications for carrıers
in prenatal diagnosis. Recently, many reports
support the hypothesis that the 17p11.2 deletion
occurred as a result of a recombination between
the normal and the pericentric-inverted
chromosome 17 homologues of the carrier
individuals 11. In this regard, prenatal diagnosis is
suggested for carrier individuals in our case.
REFERENCES
1.
Samuel PY, Sanjay I, Bidichandia L, et al.
Molecular analysis of deletion (17)(p11.2;p11.2)in
a family segregating a 17p paracentric inversion:
implications for carriers of paracentric inversions.
Am J Hum Genet 1995; 60:1184-1193.
2. Ligon AH, Beaudet AL, Shaffer LG. Simultaneous
multilocus FISH analysis for detection of
microdeletions in the diagnostic evaluation of
developmental delay and mental retardation. Am J
Hum Genet 1997; 61:51-59.
3. Trask BJ, Mefford H, van den Engh G, et al.
Quantification by flow cytometry of chromosome
17 deletions in Smith-Magenis syndrome patients.
Hum Genet 1966; 98:710-718.
4. Seranski P, Heis NS, Dhorne-Pollet S, et al.
Transcription mapping in a medulloblastoma
breakpoint interval and Smith-Magenis syndrome
candidate
region:
identification
of
p53
transcriptional units and new candidate genes.
Genomics 1999; 56:1-11.
5. Seabright M. A rapid banding technique for human
chromosomes. Lancet 1971; 2:971-972.
6. Dutrillaux B, Viegas-Peguignot E. High resolution
R and G banding on the same preparation. Hum
Genet 1981; 57:93-95.
7. Sumner AT. A simple technique for human
demonstrating centromeric heterochromatin. Exp
Cell Res 1972; 75:304-306.
8. Acar H, Connor M J. Detection of trisomy 12 and
centromeric alteration in CLL by interphase and
metaphase FISH. Cancer Genet Cytogenet 1998;
100:148-151.
9. Acar H, Stewart J Boyd, Connor MJ. Identification
of variant translocations in chronic myeloid
leukemia by FISH. Cancer Genet Cytogenet 1997;
93:115-118.
10. Kuwano A, Ledbetter SA, Dobyns NB, Emanuel
BS, Ledbetter DH. Detection of deletions and
criptic translocations in Miller-Dieker syndrome by
in situ hybridization. Am J Hum Genet 1991;
49:707-714.
11. Juyal RC, Figuera LE, Hauge X, et al. Molecular
analysis of 17p11.2 deletions in 62 Smith-Magenis
syndrome patients. Am J Hum Genet 1996; 58:9981007.
Fig. 3a. FISH (a,c) and RBG (b,d) analysis of carrier
individuals. Arrows indicating the signal on 17p13.3 of
normal and on the long arm of inv (17) with the use ofp53
and Miller-Dieker mix probes.
Fig. 3b. FISH analysis of inv 17(p11.2:q25.1)
DISCUSSION
In our case, the breakpoints of pericentric
inversion of chromosome 17 lie to be at 17(p11.2;
q25.2) we used SMS probe in FISH procedure to
detect the submicroscopic deletions within this
band, which is thought to be associated with
Smith-Magenis syndrome. This strategy, using in
situ hybridization with cosmid or unique probes
mapping within the critical region, could be
applied to other microdeletion syndromes, in
addition to high-resolution cytogenetic studies.
Pericentric inversions frequently seen on
chromosomes 9, however, other chromosomes
have to be checked by the FISH method especially
83
CASE REPORT
COCHLEAR IMPLANTATION IN A PATIENT WITH LARGE VESTIBULAR
AQUEDUCT SYNDROME: A CASE REPORT
Ufuk Derinsu, Ayça Çiprut, Sezer Külekçi, Ferda Akdaş
Sub-department of Audiology, Department of Otorhinolaryngology, School of Medicine, Marmara University, Istanbul, Turkey
ABSTRACT
Large vestibular aqueduct syndrome (LVAS) is a distinct clinical entity characterized by fluctuative sensorineural hearing loss
associated with isolated enlargement of the vestibular aqueduct. In this report, we present our experience with cochlear implantation in a
patient with LVAS.
Keywords: Coclear implant, large vestibular aqueduct syndrome, enlarged vestibular aqueduct, hearing loss
GENİŞ VESTİBÜLER SENDROMLU HASTADA KOKLEAR
İMPLANTASYON
ÖZET
Geniş Vestibüler Kanal Sendromu, vestibüler kanalın genişlemesine bağlı olarak ortaya çıkan dalgalanmalı işitme kaybı ile
karakterize bir klinik olgudur. Bu çalışmada, koklear implantasyon yapılan LVAS'lı bir hastamızdan elde edilen bulgular
sunulmuştur.
Anahtar Kelimeler: Koklear implantasyon, Geniş Vestibüler Kanal Sendromu, İşitme kaybı
Hearing level may be from normal to profound
deafness. Only a few patients were reported to
have normal hearing with LVA 9.
INTRODUCTION
The association of congenital sensorineural
hearing loss with enlarged vestibular aqueducts
was initially determined from histopathologic
studies of inner ear malformations 1,2. The large
vestibular aqueduct syndrome (LVAS) was named
by Valvassori and Clemis in 1978, when they
described radiologic detection of this anomaly 3.
There is no treatment to prevent hearing loss in
patients with LVAS. Avoidance of head trauma is
important, and hearing aids are symptomatic
treatment 5,6,10.
The following case report describes a patient with
LVAS who received a cochlear implant. A review
of the patient’s audiological assessments before
and after the cochlear implantation will be
presented.
Vestibular aqueduct is defined as “large” if the
anteroposterior diameter is larger than 1.5mm. 4.
LVAS often associates with profound,
nonprogressive sensorineural hearing loss 5.
CASE REPORT
Sudden sensorineural hearing loss attacks and
fluctuative hearing loss have been reported in
some cases 5-7. The incidence of sudden hearing
loss was found to be rare in other reports 5,8.
Hearing loss is found to be generally
sensorineural but Jackler and De la Cruz found a
conductive component in 27% of the ears 8.
The patient is a 21-year-old female with LVAS.
The family suspected hearing loss at the age of 3,
she had an audiological evaluation elsewhere and
fitted a hearing aid on the left ear.
Corresponding author: Ufuk Derinsu Ph. D., Sub-department of
Audiology, Department of Otorhinolaryngology, School of Medicine,
Marmara University, Istanbul, Turkey
Tel: +90 216 327 10 10 / 245
+90 216 327 19 08
84
Ufuk Derinsu, et al.
Cochlear implantation in a patient with large vestibular aqueduct syndrome: a case report
She was a 9-year-old girl with normal speech
development when referred to our clinic. She was
the product of a full term pregnancy without any
complication. There is no consanguity between
the parents but there is a history of hearing loss.
Her sister also has hearing loss and benefits from
hearing aids.
The patient’s first audiological evaluation
demonstrated profound sensorineural hearing loss
in the right ear, and moderate to severe mixed
hearing loss in the left ear ( Fig. 1). Acoustic
immitancemetry indicated type A tympanograms
bilaterally (Fig. 2). Acoustic reflexes were present
only in the left ear contralaterally at the maximum
intensity levels at 500, 1000 and 2000 Hz.
Fig. 1: Audiogram in the first audiological evaluation
Fig. 2: Tympanogram in the first audiological evaluation
Three years later, her hearing in the left ear
progressed to severe then to profound, and the
hearing thresholds in the right ear improved (Fig.
3). A new hearing aid appropriate to her hearing
loss was recommended and scheduled for frequent
follow-ups. Two years later, although her hearing
85
thresholds did not change, significantly, her
speech discrimination score in the left ear
deteriorated to 12% from 68%. Fluctuations in
hearing were determined in both ears in the
following assessments.
Fig. 4, shows the final audiogram before the
implantation. The patient was evaluated for the
cochlear implantation at the age of 15 and found
to be a good candidate.
Fig. 3: Second audiogram obtained three years after the first audiological assessment
Fig. 4: The latest audiogram before cochlear implantation.
86
The otorhinological and neurological evaluations
were normal. Routine blood chemistries,
urinanalysis and complete metabolic work up
were also normal.
insertion of Nucleus 24M electrode array was
achieved. Electrically evoked stapedius reflexes
were recorded and electrically evoked compound
action potentials were reliably measured using
Neural Response Telemetry (NRT) software
intraoparatively.
A temporal bone high resolution computed
tomography (HRCT) scanning demonstrated
bilateral LVA. Her sister was assessed with
HRCT, because of the LVA diagnosis. She was
also diagnosed as LVA.
The postoperative performance is encouraging.
Her free field hearing thresholds with the cochlear
implant were found to be 35 to 45 dB HL from
250 to 8000 Hz ( Fig. 5)
Cochlear implantation to the right ear was
performed without any complication. Full
Fig. 5: Free field audiogram with cochlear implant.
Her speech performance after cochlear
implantation was evaluated with closed set three
syllable words and monosyllabic words and open
set three syllable words, monosyllabic words and
open set sentences. Table I illustrates the speech
perception test results of the patient with cochlear
implant.
The
improvement
in
speech
discrimination was significant. She continues to
use her hearing aid on the opposite ear because of
better sound lateralization.
Table I: Speech perception test results after implantation.
Speech test
6 months
1 year
2 years
Closed set 3 syllable words test
Closed set monosyllablic words test
Open set 3 syllabic words
Open set monosyllabic words
100%
82%
60%
56%
100%
98%
86%
60%
100%
98%
88%
76%
Open set sentences
72%
76%
80%
87
DISCUSSION
In LVAS, a conductive component has
occasionally been reported although hearing loss
is predominantly sensorineural 8,11,12. In our case,
although the patient has normal (type A)
tympanograms on both ears there was an
unexplained conductive component in the left ear.
According to Valvassori, the conductive
component is probably caused by a decreased
mobility of the stapes due to increased
perilymphatic or endolymphatic pressure 11. The
conductive component had disappeared in
subsequent audiograms.
4.
5.
6.
7.
8.
The hearing loss usually begins in early
childhood, often with an acute onset and
fluctuating or progressive in course in relation to
head trauma 8,5,10. In our case, the beginning age
of hearing loss is similar to most of the LVAS
cases in literature; there were fluctuations in the
hearing of both ears; but there was no significant
head trauma.
9.
10.
11.
12.
Cochlear implantation in patients with LVAS
have been reported since 1995 4,13,14. The
audiometric improvement is a common feature in
all of them. In this case, sound field warble tone
thresholds with the implant were within nearly
normal limits and the patient also displayed
valuable improvement in speech discrimination.
13.
14.
Patients with LVAS usually have an aquired
hearing loss, so they may be accepted as good
cochlear implant candidates when they can no
longer benefit from hearing aids.
REFERENCES
1.
2.
3.
Schuknecht HF. Mondini dysplasia: clinical and
pathological study. Ann Otol Rhinol Laryngol
Suppl., 1980; 89 (suppl 65):1-23.
Paparella MM. Mondini’s deafness: a review of
histopathology. Ann Otol Rhinol Laryngol Suppl
1980; 89 (suppl 67):1-10.
Valvassori GE, Clemis JD. The large vestibular
aqueduct syndrome. Laryngoscope 1978; 88:723728.
88
Harker LA, Vanderheiden S, Veazey D, et al.
Multichannel cochlear implantation in children
with large vestibular aqueduct syndrome. Ann Otol
Rhinol Laryngol 1999; 108:39-43.
Okumura T, Takahashi H, Honjo I, et al.
Sensorineural hearing loss in patients with large
vestibular aqueduct. Laryngoscope 1995; 105:289294.
Griffith AJ, Arts AH, Downs C, et al. Familial
large vestibular aqueduct syndrome. Laryngoscope
1996; 106:960-965.
Tong KA, Harnsberger HR, Dahlen RT, et al. AJR
1997; 168:1097-1101.
Jackler RK, De La Cruz A. The large vestibular
aqueduct syndrome. Laryngoscope 1989; 99:12381243.
Emmett JR. The large vestibular aqueduct
syndrome. Am J Otol 1995;387-415.
Nowak KC, Mesner AH. Isolated large vestibular
aqueduct syndrome in a family. Ann Otol Rhinol
Laryngol 2000; 109:40-44.
Abe S, Usami S, Shinkawa H. Three familial cases
of hearing loss associated with enlargement of the
vestibular aqueduct. Ann Otol Rhinol Laryngol
1997; 106:1063-1069.
Govaerts PJ, Casselman J, Daener K, et al.
Audiologic findings in large vestibular aqueduct
syndrome. Int J Pediatr Otorhinolaryngol 1999;
157-164.
Bent JP, Chute P, Parisier SC. Cochlear
implantation in children with enlarged vestibular
aqueducts. Laryngoscope 1999; 109:1019-102.
Bichey BG, Hoversland JM, Wyenne MK,
Miyamoto RT. Changes in quality of life and the
cost-utility associated with cochlear implantation in
patients with large vestibular aqueduct syndrome.
Otology&Neurotology 2002; 23:323-327.
CASE REPORT
CLINICAL AND ELECTRODIAGNOSTIC FOLLOW UP OF A CASE OF
FOOD BORNE BOTULISM
Nilgün Cengiz1, Hande Türker,1 Meral Kiziltan2
1
2
Department of Neurology, Ondokuzmayıs University School of Medicine, Samsun,Turkey
Department of Neurology, Istanbul University Cerrahpasa School of Medicine Istanbul, Turkey
ABSTRACT
In the following case report, we describe the follow up of electrodiagnostic studies together with the clinical pattern in a 40
year old woman diagnosed as botulinum intoxication caused by home-made canned green beans. She had dyplopia, blurred vision,
weakness and paresthesias in all four extremities, difficulty of swallowing and breathing and bifascial paralysis. Repetetive nerve
stimulation and blink reflex studies were performed during the follow up of the case. Serologic tests couldn’t be performed.
Antitoxin therapy was initialised immediately, recovery of symptoms began in about a month’s time and she was symptom free in
three months. Her electrodiagnostic tests also improved and were found to be normal. We believe that diagnosis of botulinum
intoxication on clinical grounds is far more important than it is supposed because electrodiagnosis may not be always very typical
and serologic tests may not be available. Therefore we believe that initialising the antitoxin therapy is life saving and should be
performed immediately, even if the diagnosis is mostly on clinical grounds.
Keywords: Botulinum intoxication, electrodiagnosis and botulinum intoxication
GIDA ALIMIYLA İLİŞKİLİ BOTULİNUM İNTOKSİKASYONLU BİR
OLGUNUN KİLİNİK VE ELEKTOFİZYOLOJİK İZLEMİ
ÖZET
Bu olgu sunumunda ev yapımı konserve tüketimi sonrasında clostridium botulinum intoksikasyonu gelişen 40 yaşındaki bir
bayan hastaya ait klinik ve elektrofizyolojik izlem rapor edilmektedir. Olguda diplopi, bulanık görme, güçsüzlük ve her dört
ekstremitede parestezilerin yanısıra yutma ve solunum güçlüğü ile bifasyal paralizi gelişmiştir. Olgunun izlemi sırasında ardışık sinir
uyarımı ve göz kırpma refleksi çalışmaları yapılmıştır. Serolojik testlerin yapılamadığı olguda, klinik tablo ve elektrofizyolojik
incelemelerle tanı konmuş ve derhal antitoksin tedavisi başlatılmıştır. Semptomlarda bir ay içinde düzelme başlamış, üç ayda
hastadaki semptomlar ortadan kalkmıştır. Elektrodiyagnostik izlemde de bulguların normale döndüğü izlenmiştir. Bu olguda
elektrodiyagnostik testler tipik sonuçlar göstermemiştir. Olgunun izlemiyle varılan kanı, botulinum intoksikasyonu tanısının daha çok
kliniğe dayandığı durumlarda bile, antitoksin tedavisine derhal başlamanın hayat kurtarıcı olduğu yönündedir.
Anahtar Kelime: Botulinum intoksikasyonu, elektrodiyagnoz ve botulinum intoksikasyonu
5)inadvertent botulism. A clinical pattern of
descending weakness is characteristic of all five
forms. Almost all human cases of botulism are
caused by one of three serotypes (A, B, or E).
Classic and wound botulism were the only two
forms known until the last quarter of this century.
Wound botulism was rare until the past decade. It
is caused by local production of toxin by
Clostridium botulinum after wound infection 3.
Although it is a rare variant of botulism, it is
increasingly being reported in drug users who
inject subcutaneously 4. Infant botulism, first
described in 1976, is now the most frequently
reported form especially in the USA. Food borne
INTRODUCTION
Botulism is a rare but serious and potentially
fatal ilness.The Botulinum intoxication is caused
by the exotoxin of Clostridium Botulinum which
has a generalised effect on the neuromuscular
junction involving both striated and smooth
muscles. Botulinum toxin causes its major effect
by blocking neuromuscular transmission in
autonomic and motor nerve terminals. The types
A,B and E account for human cases 1,2. Since the
discovery of the toxin about 100 years ago, five
clinical forms of botulism have been described: 1)
classic or foodborne botulism; 2) wound botulism;
3) infant botulism; 4) hidden botulism;
Corresponding author: Dr. Hande Türker, Ondokuzmayıs University,
School of Medicine, Department of Neurology, Samsun,Turkey
89
Hande Türker
Clinical and Electrodiagnostic Follow up of A Case of Food Borne Botulism
abolished and she had generalised hypotonia.
Nerve conduction studies of sensory nerves were
in normal limits whereas M amplitudes were quite
low in some of the motor nerves.
Electromyographic studies showed that there was
no voluntary motor activity in fascial muscles
while there was a decline in the recruitment
pattern of extremity muscles. In the repetetive
stimulation of the trapezius muscle which was
performed in the first week, all findings were in
normal limits (Stimulations were performed with
2Hz, 3Hz and 20 Hz frequencies). No blink reflex
was obtained in the first week. Regarding the
story, the neurological signs and electrodiagnostic
tests, a diagnosis of botulinum intoxication was
made and as the clinical signs were progressing
rapidly and in the descending fashion, antitoxin
therapy was initialised and the patient was given
A,B and E type antitoxin each given in 600 000
U/day, I.V and in slow infusion form.
botulism is the most severe and debilitating form,
caused by ingestion of the toxin 2. In our country
many of the reported cases are food borne and
mostly from home canned vegetables because
preparing such food is seen quite often in rural
areas of Turkey 2,5,6. Food-borne butulism may
manifest as an outbreak but there are also single
cases. Onset is within 12-36 hours after ingestion,
signs of gastroenteritis with diarrhea, nausea and
vomiting usually precede muscle weakness which
often is generalised.Ocular and bulbar signs such
as diplopia, ptosis, dysarthria and dysphagia are
common.
Weakness
decends
usually
symmetrically to involve muscles of the trunk,
respiratory system and limbs.Proximal muscles
and upper extremities are usually more prone to
involvement. Autonomic manifestations include
dry mouth, dilated, fixed or poorly reactive pupils,
blurred vision, constipation, ileus and urinary
retention 1,2,3. Identification of the toxin in the
patient’s serum confirms the diagnosis.
Electrodiagnosis is mostly helpful. Nerve
conduction studies show normal amplitude and
latency of sensory action potentials. A small
compound muscle action potential elicited by a
single shock further declines with repetetive
stimulation at a small rate. Repetetive stimulation
at 20-50 Hz is the most spesific test, showing an
incremental response in most patients 7. Single
fiber EMG has shown increased jitter and
blocking and some reduction in fiber density
8,9,10,11,12
. Spesific therapy is the antitoxin therapy
which should be administered early because it is
unlikely to be effective after 3 days of exposure.
In this condition only supportive therapy can be
applied 7.
Follow-up
A week after the antitoxin therapy, there
were no changes in the neurological examination
of the patient.The clinical improvement began
gradually after this first week and in her first
month’s check, her muscle strength was found to
be +4/5, her deep tendon reflexes came back and
she hadn’t ophthalmoplegia any more while light
reflex was intact in both eyes. Her clinical
improvement became more clear in the second
month’s control and her neurological exam was
found to be normal in the third month.
Electrodiagnostic tests were repeated in the
second week and in the third month. In the second
week, the repetetive nerve stimulation test showed
a mild decrement (10 Hz stimulation) while it was
normal in the third month (3 Hz stimulation)
(Fig.1-2 respectively). Blink reflex couldn’t be
obtained in the first two weeks whereas in the
third month its latency was in normal limits with a
slight reduction in the amplitude (Fig.3-4
respectively).
CASE PRESENTATION
A forty year old female patient who had
nausea and vomiting besides blurred vision and
generalised weakness of all four extremities was
admitted to the emergency room. Her complaints
had begun 2 days after she ate some of the home
canned green beans she had prepared before. The
day after the meal she had a fierce nausea and
vomiting and two days later she complained of
having blurred vision, diplopia, weakness and
paresthesias in all extremities, difficulty of
swallowing and breathing. She realised that she
couldn’t shut her eyes properly and that her fascial
muscles were weak. In neurological exam, she
had bilateral ptozis, bilateral total external
ophtalmoplegia, bilateral mydriasis and fascial
diplegia. She also had dysphonia and
dysphagia.She had quadriparesis involving all
extremities by 3/5. All deep tendon reflexes were
Figure I: Repetitive stimulation in the second week
90
Hande Türker
timing and severity of illness 8. Cox N. and Hinkle
R. reported that a high index of suspicion is
important for the diagnosis and prompt treatment
of infant botulism, because this disease can
quickly progress to respiratory failure 14. Unless
SFEMG is used electrodiagnostic studies may not
be helpful and diagnosis on clinical grounds is
more essential than it is believed to be, especially
in sporadic cases. Our patient happened to be one
of these. Signs of internal and external
ophthalmoplegia,
dry
mouth,
descending
paralysis, obstipation with weakness, absence of
fever and lucid sensorium as cardinal symptoms
should always bring botulism to mind 15. We
thought in the same way in our diagnostic
approach and made a clinical diagnosis firstly, the
electrodiagnostic tests supported our clinical
diagnosis partially (Findings of low amplitude
CMAPs in nerve conduction studies and finding
decremental response in the begining are helping
but foundation of no incremental response in
higher frequencies of stimulation is of no help).
The frequency of diagnostic findings in cases of
botulism intoxication seem to be quite different
from each other in case reports published so far.
Some of them claim that serology is more
important while the others stress the importance
of electrodiagnostic studies. In a presentation of a
case of two boys with symptoms of food borne
botulism , the diagnosis was made by serology
(mouse neutralization test), whereas the EMG
showed negative results 15. Graf WD. et
al.suggested that electrodiagnosis was not a
reliable tool as far as their 11-year review of
toxin-confirmed cases had reflected 16. In a report
of seven patients with foodborne botulism, the
clinical picture was characterized by mild
symptoms with a long latency of onset and by
involvement of cranial and upper limb muscles;
only one patient, a child, developed respiratory
failure. Spores of Clostridium botulinum were
found in stools in some but not all cases.
Conventional neurophysiological tests had low
sensitivity; abnormal findings were present only
in the patient with severe clinical involvement, in
whom compound muscle action potentials
(CMAPs) appeared to be reduced .Repetitive
nerve stimulation at a high rate showed
pseudofacilitation and not true posttetanic
facilitation, but single-fiber electromyography
(SFEMG) showed abnormalities of neuromuscular
transmission in every case 9. Clay SA. et al imply
that the EMG pattern of brief, small motor unit
potentials, in the context of the clinical syndrome
may be diagnostic for acute infantile cases 17,
almost alike our case. Graf WD. et al reported a
Figure II: Repetitive stimulation in the third month
Figure III-IV: Blink two weeks and third month respectively
DISCUSSION
Rapid diagnostic approach is very important
in life threatening diseases and botulinum
intoxication is one of these.The diagnosis is a
clinical one, confirmed by electrodiagnostic tests
and by testing stool for the organism, C.
botulinum, or its toxin in serum and feces 13.
Although serologic tests and electrodiagnosis are
important tools in making the diagnosis, serology
may be negative and electrodiagnostic results may
not always be typical. The principal
electrodiagnostic feature, an incremental response
on high rates of repetitive nerve stimulation, has
variable sensitivity and may not always be useful
as a diagnostic test given the vagaries of test
91
Hande Türker
3)
case where results of electrodiagnosis were
negative but enema effluent contained adequate
concentrations of organism and toxin to confirm
the diagnosis 16. L. Mulleague et al. wrote that the
diagnosis of botulism was based on clinical
findings, but EMG remained the most useful
discriminatory investigation. They also implied
that the diagnosis should be confirmed by toxin
bioassay, although occasional false-negatives can
occur 18. Early diagnosis and associated therapy
overcome the necessity of intubation and
prolonged intensive care 19. Although the
diagnostic approches may show slight variaties it
is certain that the important point is rapid
diagnosis and therapy in botulinum intoxication.
Our case confirms this very clearly. In this case
report we also underline the importance of clinical
and electrophysiological follow up in such
patients thus the clinical diagnosis is confirmed
and it is important supplying information of
prognosis and patterns of healing. We performed a
follow up of our patient up to 3 month’s time both
clinically and electrodiagnostically. Here we
performed a blink reflex study as well as the
repetetive test. Although we hadn’t had an
increment but a decrement pattern at the
beginning, our follow up study showed a normal
repetetive test finally and although the blink reflex
couldn’t be obtained at the beginning, the follow
up test showed a normal response. We also
followed up a pattern of healing which quite
overlapped the electrophysiological improvement.
We emphasize the importance of clinical
diagnosis and that making it rapidly is life saving.
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
14)
15)
16)
REFERENCES
1)
2)
Katirji B. Generalised disorders. In:Katirji B.,ed.
Electromyography in clinical practice. Mosby,
Inc.,1998:268-269.
Anlar O., Irmak H., Tombul T., Akdeniz H., Caksen H.,
Kose D., Ceylan A. Food-borne botulism cases in Van
region
in
eastern
Turkey:
importance
of
electromyography in the diagnosis. Electromyogr Clin
Neurophysiol. 2003 Sep;43(6):373-6.
17)
18)
19)
92
Cherington M.Clinical spectrum of botulism. Muscle
Nerve. 1998 Jun;21(6):701-10.
Rundervoort RS, van der Ven AJ, Vermeulen C., van
Oostenbrugge RJ.The clinical diagnosis 'wound
botulism' in an injecting drug addict.Ned Tijdschr
Geneeskd. 2003 Jan 18;147(3):1247. ed Ti
Ural AU, Avcu F., Sayar H., Beyan C., Kocabalkan F.
Botulism: a case report. Mikrobiyol Bul. 1992
Jan;26(1):70-6.
Onul M, Willke A. Food-borne botulism and its
epidemiological features as seen in our country during
the last few years. Mikrobiyol Bul. 1989 Oct;23(4):28491.
Jun
Kimura.
Botulism.
In:Jun
Kimura,ed.
Electrodiagnosis in diseases of nerve and muscle:
Principles and practice. Edition 3. New York:Oxford
University Press,Inc.,2001:764-767.
Chaudhry V., Crawford TO. Stimulation single fiber
EMG in infant botulism. Muscle Nerve. 1999
Dec;22(12):1698-703.
Padua L., Aprile I., Monaco ML, Fenicia L., Anniballi
F., Pauri F., et al. Neurophysiological assessment in the
diagnosis of botulism: usefulness of single-fiber EMG.
Muscle Nerve. 1999 Oct;22(10):1388-92.
Girlanda P., Dattola R., Messina C. Single fibre EMG in
6 cases of botulism. Acta Neurol Scand. 1983
Feb;67(2):118-23.
Keesey
JC.,
AAEE
Minimonograph
#33:
electrodiagnostic approach to defects of neuromuscular
transmission. Muscle Nerve. 1989 Aug;12(8):613-26.
Ehrenreich H., Garner CG., Witt TN. Complete bilateral
internal ophthalmoplegia as sole clinical sign of
botulism: Confirmation of diagnosis by single fibre
electromyography. Neurol. 1989 May;236(4):243-5.
McMaster P., Piper S., Schell D., Gillis J., Chong A. A
taste of honey. J Paediatr Child Health. 2000
Dec;36(6):596-7.
Cox N., Hinkle R. Infant botulism. Am Fam Physician.
2002 Apr 1;65(7):1388-92.
Golser A., Plochl E. Food-borne botulism in 2 brothers.
Padiatr Padol. 1992;27(1):21-4.
Graf WD, Hays RM, Astley SJ, Mendelman PM.
Electrodiagnosis reliability in the diagnosis of infant
botulism. J Pediatr. 1992 May;120(5):747-9.
Clay SA. et al, Ramseyer JC, Fishman LS, Sedgwick
RP. Acute infantile motor unit disorder. Infantile
botulism? Arch Neurol. 1977 Apr;34(4):236-43.
L. Mulleague, S., M. Bonner ,A. Samuel, P. Nichols, M.
Khan, S. Shaw et al.Wound botulism in drug addicts in
the United Kingdom. Anaesthesia Volume 56 Issue 2
Page 120 - February 2001.
Scheibe F, Hug B, Rossi M. Wound botulism after drug
injection. Dtsch Med Wochenschr. 2002 Feb
1;127(5):199-202.
REVIEW
THE MANAGEMENT OF ELBOW FRACTURES IN CHILDREN
Bülent Erol, Murat Bezer, Gökhan Er, Mustafa Karahan, Osman Güven
Department of Orthopaedics and Traumatology, School of Medicine, Marmara University, Istanbul, Turkey
ABSTRACT
Pediatric elbow fractures can be challenging to manage. Compression of the medial column in Gartland Type I and Type II
supracondylar fractures must be reduced to prevent varus deformity. Gartland Type III fractures may be stabilized with two lateral pins
or a medial lateral cross-pin technique. Non-displaced lateral condyle fractures require vigilant follow-up. Open reduction of displaced
lateral condyle fractures should avoid posterior dissection. T-condylar fractures in children rarely have the articular comminution found
in adults. Monteggia fractures in children can be managed well if recognized and treated promptly. Restoration of the ulnar length often
reduces the radial head. Angulated proximal radius fractures need to be reduced in order to restore the ability to supinate and pronate. It
is important to recognize and understand the diagnostic features of each type of fracture in order to determine the best course of
treatment.
Gartland described three stages of supracondylar
fractures of the humerus in children, based on the
degree of displacement: Type I, undisplaced;
Type II, minimally displaced; and Type III,
completely
displaced.
This
three-stage
classification with modifications is the one used
most commonly in recent pediatric fracture texts.
INTRODUCTION
Pediatric elbow fractures are different from many
other pediatric injuries. They are associated with a
relatively high rate of complications, and the
results of nonoperative management are not
always good. The child’s elbow is well
vascularized, and therefore fracture healing takes
place very quickly. Such a narrow window of
opportunity makes it imperative that the fracture
be properly managed very quickly. This paper
reviews some elbow fractures in children that are
particularly challenging to manage.
The diagnosis of an undisplaced supracondylar
fracture (Gartland Type I) is made on the basis of
the history of a fall in addition to local tenderness
in the supracondylar area. Radiographic
evaluation is not usually helpful. Type I fractures
often require no more than simple immobilization
for comfort and further protection. A simple longarm cast with the elbow at 90° of flexion and the
forearm in neutral is usually preferred. By three
weeks after injury, the pain and swelling have
usually subsided significantly and allow a
protected active range of motion.
Supracondylar Humerus Fracture
Supracondylar humerus fractures are the most
common elbow fractures in children, accounting
for 60-80% of pediatric elbow fractures 1. These
injuries are associated with a high rate of
complications and can be challenging to manage.
These fractures have been classified according to
both the direction and the degree of displacement.
Extension-type supracondylar humerus fractures
are overwhelmingly more common than flexiontype fractures (98% vs. 2%) 2. While
posteromedial fractures are more frequently
encountered than posterolateral fractures (75% vs.
25%) 1. However, posterolateral fractures are
more often associated with neurovascular injury.
Gartland Type II fractures (displaced with intact
posterior cortex) require closed reduction and
percutaneous fixation if a long-arm cast does not
adequately hold the reduction. Immobilization in a
long-arm cast can be discontinued after three
weeks.
In Gartland Type III fractures (totally displaced
with no cortical contact), the posterior cortex is
broken, resulting in proximal migration of the
distal fragment because of muscle activity
Corresponding author: Dr. Bülent Erol
Marmara Üniversitesi Hastanesi Ortopedi ve Travmatoloji Anabilim
Dalı Tophanelioğlu Cad., No:13/15, 81190 Altunizade/Istanbul
Tel: (216) 325 45 82
e-mail: [email protected]
93
Bülent Erol, et al.
The management of elbow fractures in children
technique to avoid nerve injury. A direct injury to
the ulnar nerve usually results in only
neuropraxia, and children ultimately experience
full recovery of the ulnar nerve function. Recent
studies have confirmed that two well-placed
lateral pins provide sufficient fixation in the vast
majority of cases 3,4. Should a third pin be
necessary to achieve adequate stability, a medial
pin can be placed through a mini-open approach.
The key to maintaining adequate stability with
two lateral pins is to assure that both pins have
good fixation of the distal fragment and engage
the medial cortex.
(Fig.1A-B). Displacement necessitates the
reestablishment of length and increases the chance
of interposed soft tissue. Displaced fractures are
the result of more severe injuries that produce
greater soft-tissue swelling, which in turn makes
the reduction and its maintenance more difficult.
Gartland Type III fractures are managed by closed
reduction with percutaneous fixation followed by
three weeks of immobilization in a long-arm cast.
The exact method of maintaining the reduction
has evolved over time. Medial and lateral crosspin technique was the gold standard, but it places
the ulnar nerve at risk. (Fig. 1C-D) Thus, some
surgeons advocate a mini-open pin placement
Fig. 1A-B-C-D: Preoperative antreoposterior (A) and lateral (B) plain radiographs of the elbow show an extension type suracondylar
humerus fracture (Grantland Type III). This fracture was managed by closed reduction and percutaneous pinnin, with medial and
lateral cross-pin technique (C-D).
an open reduction may be necessary for any
supracondylar humerus fracture, and, should it be
performed, may lead to some residual elbow
stiffness not found in children treated by closed
reduction.
An open reduction of a displaced supracondylar
humerus fracture may be necessary on rare
occasions. An anteromedial “hockey stick”
incision provides a good exposure, and fixation is
done percutaneously in the usual fashion. It is
important to inform the patient and the family that
94
has been described by Milch 1. The Milch Type I
fracture travels from the metaphysis of the distal
humerus through the distal lateral epiphysis and
through the trochleocapitellar groove. The Milch
Type II fracture travels from the distal lateral
humeral metaphysis above the epiphysis and exits
through the trochlea. Because the Milch Type II
transverses through the lateral aspect of the
trochlea, instability may ensue with posterolateral
radius and ulna subluxation.
Supracondylar humerus fractures can be
associated with a vascular injury (5-12%) 2,
particularly with posterolateral displacement of
the distal fragment, which would displace the
neurovascular
bundle
over
the
medial
metaphyseal spike. Management of a suspected
vascular injury can be challenging. A pulseless
but pink hand can be observed. Patients in this
group who underwent vascular intervention
developed re-occlusion of the brachial artery
without any sequelae, suggesting that careful
observation and vascular intervention had
equivalent outcomes 5. The presence of a pulseless
and white hand after reduction and pinning is a
clear indication for open exploration. The
anteromedial approach provides good exposure
for the vascular repair and an open reduction.
Non-displaced and minimally displaced fractures
of less than 2 mm may be immobilized in a longarm cast. In the first three weeks, good-quality
plain radiographs of the elbow (best taken with
the cast off) are obtained to make sure that the
reduction has been maintained. Techniques have
also been described for minimally displaced
fractures with closed reduction and percutaneous
pin fixation (with two divergent pins) in order to
maintain the alignment 7. Fractures displaced
more than 2 mm and with evidence of rotation are
treated with open reduction and internal fixation
followed by six weeks of immobilization. The
exposure interval is between the brachioradialis
and triceps. Posterior dissection is avoided to
preserve the vascular supply. The fracture
fragment is frequently much larger than it appears
on plain radiographs, because it has a large
cartilaginous portion.
Nerve injuries occur in 5-19% of elbow fractures
and are almost always neuropraxias. These may
take three-four months to resolve 2. The anterior
interosseous branch of the median nerve is the
most commonly involved nerve. A thorough
neurological examination should be performed
and documented for all elbow fractures pre- and
postoperatively.
Malunion is largely due to rotation and will result
in the classic cubitus varus deformity. Inadequate
correction of medial collapse can also lead to this
deformity.
A fully reduced fracture significantly diminishes
risks of nonunion. Nonunion is more frequent in
unstable fractures with significant displacement.
Proximal migration of the fracture fragment may
lead to valgus deformity with potential ensuing
tardy ulnar nerve palsy. Nonunion with
displacement most commonly leads to progressive
cubitus valgus deformity, which may be addressed
with an osteotomy and correction of any
translation of the radius and ulna.
Lateral Condyle Fractures
Fractures of the lateral condyle represent 15-17%
of pediatric elbow fractures 6. The orthopaedic
surgeon must be aware of the fracture patterns,
relevant anatomy including blood supply, risk of
nonunion, and the importance of postoperative
follow-up in order to assess potential deformity
and neurologic sequelae. The lateral condyle
functions as the origin of the extensor muscle
mass as well as the lateral collateral ligament
complex. Most fractures occur in patients with a
peak age of 5-7 years. The most common
mechanism of injury occurs when a varus force is
applied to the elbow, causing the extensor muscles
and lateral collateral ligaments to avulse the
lateral condyle. Appropriate management requires
an understanding of the mechanism of injury, as
well as an awareness of operative indications and
treatment methods to avoid complications.
Medial Epicondyle Fractures
Fractures of the medial epicondylar apophsysis in
children are, fortunately, one of the more benign
pediatric elbow injuries. However, the surgeon
must consider several important issues in order to
formulate a sound management plan and avoid
complications. Unlike many fractures of the
elbow, fractures of the medial epicondylar
apophysis do not involve the joint surface or
growth cartilage. The medial epicondyle is a
posteromedial structure that serves as the origin of
the flexor-pronator muscle mass as well as the
medial collateral ligamentous complex. About
80% of medial epicondyle fractures occur in boys
with a peak age in early adolescence. The
The diagnosis of a lateral condyle fracture can be
challenging because the fracture fragment is often
rotated. Therefore, obtaining an oblique view of
the elbow, in addition to the standard
anteroposterior and lateral, can be very helpful.
The most classical description of the fracture type
95
with open anatomic reduction and pin fixation.
The pins can be removed at about three weeks.
Early motion can be allowed even before the pins
are pulled. In older children with larger fracture
fragments, fixation with a single partially threaded
cannulated screw allows optimal stability and
motion within the first week 1.
mechanism of injury is typically an acute valgus
stress to the elbow, although chronic injuries can
occur in growing athletes. Successful management
of these injuries requires a heightened awareness
of the commonly associated injuries (i.e., elbow
dislocation
and
ulnar
neuropraxia),
an
understanding of the operative indications, risks
and benefits as supported in the literature, and the
avoidance of complications such as stiffness or
persistent stability.
Evaluation of a patient with a fracture of the
medial epicondylar apophysis requires a careful
history, physical examination and review of the
radiographs to determine the full extent of the
injury. In particular, radiographs should be studied
for evidence of an incarcerated medial epicondyle
fragment within the joint. Although incarcerated
fragments can occasionally be removed with
manipulation, surgical treatment is often
necessary. There is approximately 50% incidence
of associated elbow dislocations with medial
epicondyle fractures 8. If the history or
radiographs suggest that the elbow was or is
dislocated, greater soft tissue injury is likely to be
present, requiring increased need for early motion.
The physical examination should also include a
careful neurologic examination, particularly of the
ulnar nerve and median nerve. Any change in the
sensory or motor examination of the ulnar nerve
should be noted in the initial evaluation. If ulnar
nerve function is completely disrupted, operative
exploration is indicated.
Fig. 2: Anteroposterior plain radiograph of the elbow
demonstrates a displaced medial epicondyle fracture. This
fracture required surgical treatment.
Non-displaced fractures should be treated with
one-two weeks of cast or splint protection,
followed by patient-directed active range of
motion program. Results are usually excellent
with this treatment program. If the minimally
displaced fracture was associated with an elbow
dislocation, earlier motion may be warranted. In
general, re-dislocation is less of a risk than elbow
stiffness.
T-Condylar fractures
The T-condylar fracture of the distal humerus is a
very rare fracture of the elbow region in the
pediatric patient, accounting for less than 1% of
elbow fractures 1. As such, there is very little data
in the literature on the most reliable way to
achieve the best outcome. This injury typically
occurs in the adolescent near skeletal maturity,
usually from a direct blow to a flexed elbow. The
fracture line originates from the apex of the
trochlea and extends proximally. Successful
management
of
this
fracture
requires
understanding the intra-articular aspect of the
fracture and planning treatment based on the
skeletal maturity of the patient. This fracture
usually requires surgical management to restore
anatomic articular congruence. However, the joint
line often does not need to be directly visualized
because, unlike adult fractures, articular
comminution is rare.
There is an ongoing debate regarding the
operative management of displaced medial
epicondyle fractures. Although literature support
for non-operative management continues to exist,
it is generally the practice in most centers to treat
medial epicondyle fractures displaced more than 5
mm with internal fixation and an early motion
protocol (Fig. 2).
Operative management of medial epicondyle
fractures includes two fixation and two
positioning strategies. As a general rule, children
younger than 10 years old with small medial
epicondylar fragments can be satisfactorily treated
96
ulna and may fail to be recognized. A Bado Type
IV injury is characterized by a radial fracture in
conjunction with a radial head dislocation and an
ulnar fracture. The nature of the ulnar injury
dictates the management of the injury 11.
The T-condylar fractures can sometimes be
confused with other fractures, most commonly
extension-type supracondylar fractures. Therefore,
good-quality plain radiographs are key to the
proper diagnosis and treatment. The key to
differentiation from the other fractures is the
presence of vertical fracture line extending down
to the apex of the trochlea.
Approximately 8-17% of Monteggia fractures
have associated neurologic deficits, usually a
neurapraxia, involving most commonly the
posterior interosseous brach of the radial nerve.
Recovery of nerve function takes several days to
two months after injury 10,11.
Recent papers support the use of open reduction
and internal fixation as the best way to restore
anatomic articular congruence and to provide
enough fracture stability to start range of motion
exercises as early as two-four weeks after the
operation 9. The first goal is to achieve anatomic
alignment of the articular surface. The reduction is
held by a transverse screw through the center of
the axis of rotation. This part of the procedure
converts the fracture into a supracondylar fracture.
The next surgical goal is stabilization of the
supracondylar columns. In older patients near
skeletal maturity, reconstruction plates with screw
fixation placed at 90º to each other are
recommended. This provides a construct that is
stable for early range of motion exercises and
addresses the fact that this is essentially an adulttype fracture.
The goal of tratment is to correct the ulnar
deformity while restoring ulnar length and
realigning the radiocapitellar joint. Reduction of
the ulnar fracture often reduces the radial head. If
initial closed reduction fails (or for an unstable
fracture), the surgeon should proceed to
fluoroscopically aided operative reduction,
possibly with internal fixation. It is essential to
confirm maintenance of reduction. Minimal
internal fixation of the ulna with an
intramedullary Kirschner-wire may allow
reduction of the radial head. This method is
preferred over plate fixation 11.
Complications arise when there is a delay in
diagnosis of a Monteggia fracture or in case of a
re-fracture. If the time between injury and
diagnosis is prolonged, the patient may experience
limited elbow range of motion, arthrosis, or
additional nerve complications. These patients
may also present with a partially or fully healed
ulnar fracture with a radial head dislocation. In the
treatment of late Monteggia fracture, achieving
proper ulnar length and angulation is difficult, and
usually, an ulnar osteotomy followed by open
reduction of the radial head and reconstruction of
the annular ligament is required.
Monteggia Fractures
Monteggia fractures in children are easily
manageable if recognised and treated soon after
injury. Only about 1% of all forearm fractures in
children are classified as Monteggia fractures.
Three out of four of such cases occur in boys.
These fractures are characterized by dislocation of
the radial head accompanied by an associated
ulnar fracture, most often located in the proximal
third of the bone 10,11. These injuries are typically
sustained after a fall onto an outstretched hand
resulting in hyperextension or hyperpronation of
the elbow. Patients with Monteggia fractures
present with elbow or forearm pain accompanied
by tenderness localized over the radial head. The
most reliable method to recognize a Monteggia
fracture is to determine whether the axis of the
radius bisects the capitellum on every view 10-12.
Proximal Radius Fracture
Proximal radius fractures in children, unlike those
in adults, generally involve the metaphysis or the
physis, and not the radial head. These injuries
occur most commonly between ages 8 and 12, and
result from a fall onto an outstretched hand with a
valgus moment directed through the radius 13. One
should be aware of a Monteggia fracture (or
“Monteggia equivalents”) when recognizing the
proximal radius injury. The length and alignment
of the ulna should be compared to the other side,
when in doubt.
The Bado classification of Monteggia fractures
corresponds with the mechanism of injury and is
useful in determining the optimal treatment for
such injuries. Type I fractures are characterized by
anterior radial head dislocation, whereas Type II
fractures, which are rare in children, have
posterior dislocations. Type III fractures are
characterized by lateral radial head dislocation.
Lateral Monteggia injuries are usually associated
with a buckle-type or green-stick fracture of the
The goal of the treatment is to restore the ability
to supinate and pronate, usually 60º in either
direction. Displacement of the fracture fragment
97
results in a cam effect at the proximal radioulnar
joint, thereby interfering with normal motion.
REFERENCES
1.
Kasser JR, Beaty JH. Supracondylar fractures of
the distal humerus. In: Beaty JH, Kasser JR, eds.
Rockwood and Wilkins’ fractures in children. 5th
ed. Philadelphia: Lippincott Williams and Wilkins,
2001: 577-624
2. Otsuka NY, Kasser JR. Supracondylar fractures of
the humerus in children. J Am Acad Orthop Surg
1997; 5:19-26.
3. Skaggs DL, Hale JM, Bassett J, Kaminsky C, Kay
RM, Tolo VT. Operative treatment of
supracondylar fractures of the humerus in children.
The consequences of pin placement. J Bone Joint
Surg 2001; 83A:735-740.
4. Gordon JE, Patton CM, Luhmann SJ, Bassett GS,
Schoenecker PL. Fracture stability after pinning of
displaced supracondylar distal humerus fractures in
children. J Pediatr Orthop 2001; 21:313-318.
5. Sabharwal S, Tredwell SJ, Beauchamp RD,
Mackenzie WG, Jakubec DM, Cairns R, LeBlanc
JG. Management of pulseless pink hand in pediatric
supracondylar fractures of humerus. J Pediatr
Orthop 1997; 17:303-310.
6. Beaty J, Kasser JR. The elbow region: general
concepts in the pediatric patient. In: Kasser JR,
Beaty JH, eds. Rockwood and Wilkins’ fractures in
children. 5th ed. Philadelphia: Lippincott Williams
and Wilkins, 2001: 563-575.
7. Thomas DP, Howard AW, Cole WG, Hedden DM.
Three weeks of Kirschner wire fixation for
displaced lateral condylar fractures of the humerus
in children. J Pediatr Orthop 2001; 21:565-569.
8. Wilson NIL, Ingram R, Rymaszewski L, Miller JH.
Treatment of fractures of the medial epicondyle of
the humerus. Injury 1988; 19:342-344.
9. Re PR, Waters PM, Hresko T. T-condylar fractures
of the distal humerus in children and adolescents. J
Pediatr Orthop 1999; 19:313-318.
10. Kay RM, Skaggs DL. The pediatric Monteggia
fracture. Am J Orthop 1998;27: 606-609.
11. Ring D, Jupiter JB, Waters PM: Monteggia
fractures in children and adults. J Am Acad Orthop
Surg 1998; 6:215-224.
12. Papandrea R, Waters PM: Posttraumatic
reconstruction of the elbow in pediatric patients.
Clin Orthop 2000; 370:115-126.
13. Chambers HG. Fractures of the proximal radius and
ulna. In: Kasser JR, Beatty JH, editors. Rockwood
and Wilkins’ fractures in children. 5th ed.
Philadelphia: Lippincott Williams and Wilkins,
2001:483-528.
Patients with nondisplaced or minimally displaced
fractures with less than 30º of angulation do not
need to undergo reduction and can be treated in a
long-arm splint and with a range of motion
exercises 10-14 days after injury (Fig. 3).
Fractures with angulation from 30º up to 45º
should be treated with closed reduction. If closed
manipulation is unsuccessful in restoring 60º of
pronation and supination, a percutaneous
reduction can be performed with a Steinman pin
or a Kirshner-wire under fluoroscopic control. If
all above methods fail, open reduction can be
performed through the Kocher approach using the
interval between the anconeus and the extensor
carpi ulnaris. Once reduced, these fractures are
usually stable and do not require internal fixation.
After any sort of reduction, the elbow should be
immobilized in a posterior splint for two-three
weeks and then be started on a range of motion
program.
Fig. 3. Anteroposterior plain radiograph of the elbow
and proxima forearm shows a non-displaced, incomplete
fracture of the proxima radius (arrow). Also note a fracture
line in the proximal ulna. This patient had conservative
treatment.
98

Marmara Medical Journal

Transkript

Benzer belgeler

and et al., 2001 - ITU ESONET MARMARA DM Main Page

Pilotage and Tugboat Dues

Full Text

Medroxyprogesterone Acetate Plus Metformin to_Layout 1

A Case Report A Woman with Double Intra Uterine Device_Layout 1

clinical and electrodiagnostic follow up of a case of food borne