ISSN 1949-8470 (online) World Journal of Radiology World J Radiol 2013 April 28; 5(4): 143-192 www.wjgnet.com WJ R World Journal of Radiology Editorial Board 2009-2013 The World Journal of Radiology Editorial Board consists of 319 members, representing a team of worldwide experts in radiology. They are from 40 countries, including Australia (3), Austria (4), Belgium (5), Brazil (3), Canada (9), Chile (1), China (25), Czech (1), Denmark (1), Egypt (4), Estonia (1), Finland (1), France (6), Germany (17), Greece (8), Hungary (1), India (9), Iran (5), Ireland (1), Israel (4), Italy (28), Japan (14), Lebanon (1), Libya (1), Malaysia (2), Mexico (1), Netherlands (4), New Zealand (1), Norway (1), Saudi Arabia (3), Serbia (1), Singapore (2), Slovakia (1), South Korea (16), Spain (8), Switzerland (5), Thailand (1), Turkey (20), United Kingdom (16), and United States (82). EDITOR-IN-CHIEF Filippo Cademartiri, Monastier di Treviso STRATEGY ASSOCIATE EDITORS-IN-CHIEF Ritesh Agarwal, Chandigarh Kenneth Coenegrachts, Bruges Mannudeep K Kalra, Boston Meng Law, Lost Angeles Ewald Moser, Vienna Aytekin Oto, Chicago AAK Abdel Razek, Mansoura ГЂlex Rovira, Barcelona Yi-Xiang Wang, Hong Kong Hui-Xiong Xu, Guangzhou GUEST EDITORIAL BOARD MEMBERS Wing P Chan, Taipei Wen-Chen Huang, Taipei Shi-Long Lian, Kaohsiung Chao-Bao Luo, Taipei Shu-Hang Ng, Taoyuan Pao-Sheng Yen, Haulien MEMBERS OF THE EDITORIAL BOARD Australia Karol Miller, Perth Tomas Kron, Melbourne Zhonghua Sun, Perth Siegfried Trattnig, Vienna Belgium Piet R Dirix, Leuven Yicheng Ni, Leuven Piet Vanhoenacker, Aalst Jean-Louis Vincent, Brussels Brazil Emerson L Gasparetto, Rio de Janeiro Edson Marchiori, PetrГіpolis Wellington P Martins, SГЈo Paulo Czech Canada Sriharsha Athreya, Hamilton Mark Otto Baerlocher, Toronto Martin Charron, Toronto James Chow, Toronto John Martin Kirby, Hamilton Piyush Kumar, Edmonton Catherine Limperpoulos, Quebec Ernest K Osei, Kitchener Weiguang Yao, Sudbury Chile Austria WJR|www.wjgnet.com Vlastimil VГЎlek, Brno Denmark Poul Erik Andersen, Odense Egypt Mohamed Abou El-Ghar, Mansoura Mohamed Ragab Nouh, Alexandria Ahmed A Shokeir, Mansoura Masami Yamamoto, Santiago Estonia Tiina Talvik, Tartu China Herwig R Cerwenka, Graz Daniela Prayer,Vienna Shen Fu, Shanghai Gang Jin, Beijing Tak Yeung Leung, Hong Kong Wen-Bin Li, Shanghai Rico Liu, Hong Kong Yi-Yao Liu, Chengdu Wei Lu, Guangdong Fu-Hua Peng, Guangzhou Liang Wang, Wuhan Li-Jun Wu, Hefei Zhi-Gang Yang, Chengdu Xiao-Ming Zhang, Nanchong Chun-Jiu Zhong, Shanghai Feng Chen, Nanjing Ying-Sheng Cheng, Shanghai Woei-Chyn Chu, Taipei Guo-Guang Fan, Shenyang Finland Tove J GrГ¶nroos, Turku January 28, 2013 France Alain Chapel, Fontenay-Aux-Roses Nathalie Lassau, Villejuif Youlia M Kirova, Paris GГ©raldine Le Duc, Grenoble Cedex Laurent Pierot, Reims Frank Pilleul, Lyon Pascal Pommier, Lyon Ireland Joseph Simon Butler, Dublin Israel Amit Gefen, Tel Aviv Eyal Sheiner, BeвЂ™er-Sheva Jacob Sosna, Jerusalem Simcha Yagel, Jerusalem Greece Panagiotis Antoniou, Alexandroupolis George C Kagadis, Rion Dimitris Karacostas, Thessaloniki George Panayiotakis, Patras Alexander D Rapidis, Athens C Triantopoulou, Athens Ioannis Tsalafoutas, Athens Virginia Tsapaki, Anixi Ioannis Valais, Athens Hungary Peter Laszlo Lakatos, Budapest India Anil Kumar Anand, New Delhi Surendra Babu, Tamilnadu Sandip Basu, Bombay Kundan Singh Chufal, New Delhi Shivanand Gamanagatti, New Delhi Vimoj J Nair, Haryana R Prabhakar, New Delhi Sanjeeb Kumar Sahoo, Orissa Iran Vahid Reza Dabbagh Kakhki, Mashhad Mehran Karimi, Shiraz Farideh Nejat, Tehran Alireza Shirazi, Tehran Hadi Rokni Yazdi, Tehran WJR|www.wjgnet.com Mexico Heriberto Medina-Franco, Mexico City Netherlands Germany Ambros J Beer, MГјnchen Thomas Deserno, Aachen Frederik L Giesel, Heidelberg Ulf Jensen, Kiel Markus Sebastian Juchems, Ulm Kai U Juergens, Bremen Melanie Kettering, Jena Jennifer Linn, Munich Christian Lohrmann, Freiburg David Maintz, MГјnster Henrik J Michaely, Mannheim Oliver Micke, Bielefeld Thoralf Niendorf, Berlin-Buch Silvia Obenauer, Duesseldorf Steffen Rickes, Halberstadt Lars V Baron von Engelhardt, Bochum Goetz H Welsch, Erlangen Malaysia R Logeswaran, Cyberjaya Kwan-Hoong Ng, Kuala Lumpur Italy Mohssen Ansarin, Milan Stefano Arcangeli, Rome Tommaso Bartalena, Imola Sergio Casciaro, Lecce Laura Crocetti, Pisa Alberto Cuocolo, Napoli Mirko DвЂ™Onofrio, Verona Massimo Filippi, Milan Claudio Fiorino, Milano Alessandro Franchello, Turin Roberto Grassi, Naples Stefano Guerriero, Cagliari Francesco Lassandro, Napoli Nicola Limbucci, L'Aquila Raffaele Lodi, Bologna Francesca Maccioni, Rome Laura Martincich, Candiolo Mario Mascalchi, Florence Roberto Miraglia, Palermo Eugenio Picano, Pisa Antonio Pinto, Naples Stefania Romano, Naples Luca Saba, Cagliari Sergio Sartori, Ferrara Mariano Scaglione, Castel Volturno Lidia Strigari, Rome Vincenzo Valentini, Rome Jurgen J FГјtterer, Nijmegen Raffaella Rossin, Eindhoven Paul E Sijens, Groningen New Zealand W Howell Round, Hamilton Norway Arne Sigmund Borthne, LГёrenskog Saudi Arabia Mohammed Al-Omran, Riyadh Ragab Hani Donkol, Abha Volker Rudat, Al Khobar Serbia Djordjije Saranovic, Belgrade Singapore Uei Pua, Singapore Lim CC Tchoyoson, Singapore Japan Shigeru Ehara, Morioka Nobuyuki Hamada, Chiba Takao Hiraki, Okayama Akio Hiwatashi, Fukuoka Masahiro Jinzaki, Tokyo Hiroshi Matsuda, Saitama Yasunori Minami, Osaka Jun-Ichi Nishizawa, Tokyo Tetsu Niwa, Yokohama Kazushi Numata, Kanagawa Kazuhiko Ogawa, Okinawa Hitoshi Shibuya, Tokyo Akira Uchino, Saitama Haiquan Yang, Kanagawa Lebanon Aghiad Al-Kutoubi, Beirut Libya Anuj Mishra, Tripoli II Slovakia FrantiЕЎek DubeckГЅ, Bratislava South Korea Bo-Young Choe, Seoul Joon Koo Han, Seoul Seung Jae Huh, Seoul Chan Kyo Kim, Seoul Myeong-Jin Kim, Seoul Seung Hyup Kim, Seoul Kyoung Ho Lee, Gyeonggi-do Won-Jin Moon, Seoul Wazir Muhammad, Daegu Jai Soung Park, Bucheon Noh Hyuck Park, Kyunggi Sang-Hyun Park, Daejeon Joon Beom Seo, Seoul Ji-Hoon Shin, Seoul Jin-Suck Suh, Seoul Hong-Gyun Wu, Seoul January 28, 2013 Spain Eduardo J Aguilar, Valencia Miguel Alcaraz, Murcia Juan Luis Alcazar, Pamplona Gorka Bastarrika, Pamplona Rafael MartГnez-Monge, Pamplona Alberto MuГ±oz, Madrid Joan C Vilanova, Girona Switzerland Nicolau Beckmann, Basel Silke Grabherr, Lausanne Karl-Olof LГ¶vblad, Geneva Tilo Niemann, Basel Martin A Walter, Basel United Kingdom K Faulkner, Wallsend Peter Gaines, Sheffield Balaji Ganeshan, Brighton Nagy Habib, London Alan Jackson, Manchester Pradesh Kumar, Portsmouth Tarik F Massoud, Cambridge Igor Meglinski, Bedfordshire Robert Morgan, London Ian Negus, Bristol Georgios A Plataniotis, Aberdeen N J Raine-Fenning, Nottingham Manuchehr Soleimani, Bath MY Tseng, Nottingham Edwin JR van Beek, Edinburgh Feng Wu, Oxford United States Thailand Sudsriluk Sampatchalit, Bangkok Turkey Olus Api, Istanbul Kubilay Aydin, Д°stanbul IЕџД±l Bilgen, Izmir Zulkif Bozgeyik, Elazig Barbaros E Г‡il, Ankara Gulgun Engin, Istanbul M Fatih Evcimik, Malatya Ahmet Kaan GГјndГјz, Ankara Tayfun Hakan, Istanbul Adnan Kabaalioglu, Antalya Fehmi KaГ§maz, Ankara Musturay Karcaaltincaba, Ankara Osman Kizilkilic, Istanbul Zafer Koc, Adana Cem Onal, Adana Yahya Paksoy, Konya Bunyamin Sahin, Samsun Ercument Unlu, Edirne Ahmet Tuncay Turgut, Ankara Ender Uysal, Istanbul WJR|www.wjgnet.com Athanassios Argiris, Pittsburgh Stephen R Baker, Newark Lia Bartella, New York Charles Bellows, New Orleans Walter L Biffl, Denver Homer S Black, Houston Wessam Bou-Assaly, Ann Arbor Owen Carmichael, Davis Shelton D Caruthers, St Louis Yuhchyau Chen, Rochester Melvin E Clouse, Boston Ezra Eddy Wyssam Cohen, Chicago Aaron Cohen-Gadol, Indianapolis Patrick M Colletti, Los Angeles Kassa Darge, Philadelphia Abhijit P Datir, Miami Delia C DeBuc, Miami Russell L Deter, Houston Adam P Dicker, Phil Khaled M Elsayes, Ann Arbor Steven Feigenberg, Baltimore Christopher G Filippi, Burlington Victor Frenkel, Bethesda Thomas J George Jr, Gainesville Patrick K Ha, Baltimore Robert I Haddad, Boston Walter A Hall, Syracuse Mary S Hammes, Chicago III John Hart Jr, Dallas Randall T Higashida, San Francisco Juebin Huang, Jackson Andrei Iagaru, Stanford Craig Johnson, Milwaukee Ella F Jones, San Francisco Csaba Juhasz, Detroit Riyad Karmy-Jones, Vancouver Daniel J Kelley, Madison Amir Khan, Longview Euishin Edmund Kim, Houston Vikas Kundra, Houston Kennith F Layton, Dallas Rui Liao, Princeton CM Charlie Ma, Philadelphia Nina A Mayr, Columbus Thomas J Meade, Evanston Steven R MessГ©, Philadelphia Nathan Olivier Mewton, Baltimore Feroze B Mohamed, Philadelphia Koenraad J Mortele, Boston Mohan Natarajan, San Antonio John L Nosher, New Brunswick Chong-Xian Pan, Sacramento Dipanjan Pan, St Louis Martin R Prince, New York Reza Rahbar, Boston Carlos S Restrepo, San Antonio Veronica Rooks, Honolulu Maythem Saeed, San Francisco Edgar A Samaniego, Palo Alto Kohkan Shamsi, Doylestown Jason P Sheehan, Charlottesville William P Sheehan, Willmar Charles Jeffrey Smith, Columbia Monvadi B Srichai-Parsia, New York Dan Stoianovici, Baltimore Janio Szklaruk, Houston Dian Wang, Milwaukee Jian Z Wang, Columbus Shougang Wang, Santa Clara Wenbao Wang, New York Aaron H Wolfson, Miami Gayle E Woloschak, Chicago Ying Xiao, Philadelphia Juan Xu, Pittsburgh Benjamin M Yeh, San Francisco Terry T Yoshizumi, Durham Jinxing Yu, Richmond Jianhui Zhong, Rochester January 28, 2013 WJ R World Journal of Radiology Contents MINI-REVIEWS Monthly Volume 5 Number 4 April 28, 2013 143 Endovascular treatment of carotid cavernous sinus fistula: A systematic review Korkmazer B, Kocak B, Tureci E, Islak C, Kocer N, Kizilkilic O ORIGINAL ARTICLE 156 Asymmetrically hypointense veins on T2*w imaging and susceptibilityweighted imaging in ischemic stroke Jensen-Kondering U, BГ¶hm R BRIEF ARTICLE 166 Microstructural analysis of pineal volume using trueFISP imaging Bumb JM, Brockmann MA, Groden C, Nolte I 173 Volumetric modulated arc radiotherapy for limited osteosclerotic myeloma Robles A, Levy A, Moncharmont C, Farid L, Guy JB, Malkoun N, Cartier L, Chargari C, Guichard I, Talabard JN, de Laroche G, MagnГ© N 178 Role of color Doppler in differentiation of Graves' disease and thyroiditis in thyrotoxicosis Donkol RH, Nada AM, Boughattas S CASE REPORT 184 MDCT of right aortic arch with aberrant left subclavian artery associated with kommerell diverticulum and calcified ligamentum arteriosum Kanza RE, Berube M, Michaud P 187 Thoracic epidural angiolipoma: A case report and review of the literature Meng J, Du Y, Yang HF, Hu FB, Huang YY, Li B, Zee CS WJR|www.wjgnet.com April 28, 2013|Volume 5|Issue 4| World Journal of Radiology Contents Volume 5 Number 4 April 28, 2013 APPENDIX I-V ABOUT COVER Instructions to authors Bumb JM, Brockmann MA, Groden C, Nolte I. Microstructural analysis of pineal volume using trueFISP imaging. World J Radiol 2013; 5(4): 166-172 http://www.wjgnet.com/1949-8470/full/v5/i4/166.htm AIM AND SCOPE World Journal of Radiology (World J Radiol, WJR, online ISSN 1949-8470, DOI: 10.4329) is a peer-reviewed open access academic journal that aims to guide clinical practice and improve diagnostic and therapeutic skills of clinicians. WJR covers topics concerning diagnostic radiology, radiation oncology, radiologic physics, neuroradiology, nuclear radiology, pediatric radiology, vascular/interventional radiology, medical imaging achieved by various modalities and related methods analysis. The current columns of WJR include editorial, frontier, diagnostic advances, therapeutics advances, field of vision, mini-reviews, review, topic highlight, medical ethics, original articles, case report, clinical case conference (clinicopathological conference), and autobiography. We encourage authors to submit their manuscripts to WJR. We will give priority to manuscripts that are supported by major national and international foundations and those that are of great basic and clinical significance. INDEXING/ABSTRACTING World Journal of Radiology is now indexed in PubMed Central, PubMed, Digital Object Identifier, and Directory of Open Access Journals. FLYLEAF I-III EDITORS FOR THIS ISSUE вЂ„ Responsible Assistant Editor: Shuai Ma Responsible Electronic Editor: Li Xiong Proofing Editor-in-Chief: Lian-Sheng Ma NAME OF JOURNAL World Journal of Radiology ISSN ISSN 1949-8470 (online) LAUNCH DATE December 31, 2009 FREQUENCY Monthly EDITOR-IN-CHIEF Filippo Cademartiri, MD, PhD, FESC, FSCCT, Professor, Cardio-Vascular Imaging Unit-Giovanni XXIII Hospital, Via Giovanni XXIII, 7-31050-Monastier di Treviso (TV), Italy EDITORIAL OFFICE Jin-Lei Wang, Director Xiu-Xia Song, Vice Director WJR|www.wjgnet.com Editorial Board Responsible Science Editor: Xiu-Xia Song World Journal of Radiology Room 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, China Telephone: +86-10-85381891 Fax: +86-10-85381893 E-mail: wjr@wjgnet.com http://www.wjgnet.com COPYRIGHT В© 2013 Baishideng. Articles published by this OpenAccess journal are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. PUBLISHER Baishideng Publishing Group Co., Limited Flat C, 23/F., Lucky Plaza, 315-321 Lockhart Road, Wanchai, Hong Kong, China Fax: +852-31158812 Telephone: +852-58042046 E-mail: bpgoffice@wjgnet.com http://www.wjgnet.com SPECIAL STATEMENT All articles published in this journal represent the viewpoints of the authors except where indicated otherwise. PUBLICATION DATE April 28, 2013 ONLINE SUBMISSION http://www.wjgnet.com/esps/ II INSTRUCTIONS TO AUTHORS Full instructions are available online at http://www. wjgnet.com/1949-8470/g_info_20100316162358.htm. April 28, 2013|Volume 5|Issue 4| WJ R World Journal of Radiology World J Radiol 2013 April 28; 5(4): 143-155 ISSN 1949-8470 (online) В© 2013 Baishideng. All rights reserved. Online Submissions: http://www.wjgnet.com/esps/ wjr@wjgnet.com doi:10.4329/wjr.v5.i4.143 MINI-REVIEWS Endovascular treatment of carotid cavernous sinus fistula: A systematic review Bora Korkmazer, Burak Kocak, Ercan Tureci, Civan Islak, Naci Kocer, Osman Kizilkilic as the mainstay therapy for definitive treatment in situations including clinical emergencies. Conservative treatment, surgery and radiosurgery constitute other management options for these lesions. Bora Korkmazer, Burak Kocak, Civan Islak, Naci Kocer, Osman Kizilkilic, Division of Neuroradiology, Department of Radiology, Cerrahpasa School of Medicine, Istanbul University, 34098 Istanbul, Turkey Ercan Tureci, Department of Anesthesiology and Reanimation, Cerrahpasa School of Medicine, Istanbul University, 34098 Istanbul, Turkey Author contributions: Kizilkilic O and Korkmazer B designed the study; Korkmazer B and Kocak B conducted literature research; Korkmazer B wrote the paper; Korkmazer B, Islak C, Kizilkilic O, Kocer N, Kocak B, and Tureci E edited and revised the paper. Correspondence to: Osman Kizilkilic, MD, Associated Professor, Division of Neuroradiology, Department of Radiology, Cerrahpasa School of Medicine, Istanbul University, Osman Gazi Mh., PaЕџa Sk, 34098 Istanbul, Turkey. osmank@istanbul.edu.tr Telephone: +90-212-4143000 Fax: +90-212-4143021 Received: November 30, 2012 Revised: January 30, 2013 Accepted: February 5, 2013 Published online: April 28, 2013 В© 2013 Baishideng. All rights reserved. Key words: Cavernous sinus; Carotid cavernous sinus fistula; Endovascular treatment Core tip: Carotid cavernous sinus fistulas (CCFs) are abnormal communications between the carotid arterial system and the cavernous sinus. The clinical presentation of CCFs, which is a direct consequence of elevation in intracavernous pressure and revised flow patterns, mostly comprises of ocular findings. Recent advances in endovascular techniques have resulted in several therapeutic modalities becoming available and the endovascular approach has evolved as the primary treatment option for the management of CCFs. This review provides detailed information about classification, etiology, pathophysiology, clinical presentation, diagnostic modalities, differential diagnosis, indications for emergency treatment, post-treatment follow-up and treatment modalities with emphasis on the endovascular approach in CCFs. Abstract Carotid cavernous sinus fistulas are abnormal communications between the carotid system and the cavernous sinus. Several classification schemes have described carotid cavernous sinus fistulas according to etiology, hemodynamic features, or the angiographic arterial architecture. Increased pressure within the cavernous sinus appears to be the main factor in pathophysiology. The clinical features are related to size, exact location, and duration of the fistula, adequacy and route of venous drainage and the presence of arterial/venous collaterals. Noninvasive imaging (computed tomography, magnetic resonance, computed tomography angiography, magnetic resonance angiography, Doppler) is often used in the initial workup of a possible carotid cavernous sinus fistulas. Cerebral angiography is the gold standard for the definitive diagnosis, classification, and planning of treatment for these lesions. The endovascular approach has evolved WJR|www.wjgnet.com Korkmazer B, Kocak B, Tureci E, Islak C, Kocer N, Kizilkilic O. Endovascular treatment of carotid cavernous sinus fistula: A systematic review. World J Radiol 2013; 5(4): 143-155 Available from: URL: http://www.wjgnet.com/1949-8470/full/v5/i4/143. htm DOI: http://dx.doi.org/10.4329/wjr.v5.i4.143 INTRODUCTION Carotid cavernous sinus fistulas (CCFs) are abnormal communications between the carotid arterial system and the cavernous sinus. Recent advances in endovascular 143 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF lead to direct CCFs [5,6]. Approximately 20% of type A CCFs are not related to a history of trauma and regarded as spontaneous[7,8]. Spontaneous direct CCFs may stem from any condition that predisposes the ICA wall to weaken[4]. They are usually caused (formed) by the rupture of either a cavernous segment aneurysm or a weakened atherosclerotic artery[7,9]. Predisposing factors associated with the development of spontaneous type A CCFs are Ehlers-Danlos syndrome, fibromuscular dysplasia, and pseudoxanthoma elasticum[7,10,11]. Iatrogenic alterations in flow dynamics and vascular pressure are also suspected to contribute to spontaneous aneurysmal rupture (following prior contralateral ICA occlusion)[1]. Most direct type A CCFs are high-flow shunts. Flow rates in type A fistulas are variable and depend on the size of the ostium and venous drainage. Type A fistulas typically range from 1 to 5 mm in size (average = 3 mm), typically small enough to be treated with detachable balloons with a mean volume of 0.28 L, equivalent to an inflated balloon diameter of 7 to 9 mm[4,7,12,13]. Complete steal, which is defined as the complete absence of filling of the ICA above the fistula, occurs in 5% of patients at diagnosis[7]. The complete steal phenomenon deserves enormous interest because it confirms that the CCF is of high flow, that the rent is large, and that the patient has an excellent collateral flow through the circle of Willis if there are no contralateral deficits[11]. These lesions are usually unilateral although bilateral traumatic CCFs occur in approximately 1%-2% of patients with traumatic CCFs[4]. These unusual bilateral traumatic CCFs are generally associated with more severe head trauma, are more commonly fatal, and are therefore less frequent[6]. Additionally, unilateral fistulas may occur with bilateral or contralateral orbital symptoms, depending on the venous drainage route, via intercavernous communication[6,7,14]. Direct fistulae are less likely to resolve spontaneously and may require intervention if symptomatic. Indirect CCFs (types B, C and D) are also called dural fistulas and typically have low flow rates. The major arterial supply to indirect fistulas arises from the internal maxillary, middle meningeal, accessory meningeal and ascending pharyngeal branches of the ECA, as well as cavernous segment branches of the ICA[15]. Indirect CCFs tend to occur more frequently in postmenopausal women. The cause of these lesions is still obscure, but infants presenting with dural fistulas in the literature furnish some evidence to congenital origin[4,7,16]. Factors that may predispose patients to the development of dural CCFs include hypertension, diabetes, pregnancy, trauma and straining, atherosclerotic disease, cavernous sinus thrombosis, sinusitis and collagen vascular disease. Trauma is less commonly associated with indirect CCFs[1,5,7]. Traumatic indirect CCFs differ from the spontaneous type because these lesions are usually single-hole fistulas in which the accessory meningeal artery and middle meningeal artery are found to be the most common feeders[17]. techniques have resulted in several therapeutic modalities becoming available and the endovascular approach has evolved as the primary treatment option for the management of CCFs. This review provides an overview of various treatment modalities with emphasis on the endovascular approach. Furthermore, we will discuss the classification, etiology, and clinical presentation including pathophysiology and symptoms, diagnosis, indications for emergency treatment and post-treatment follow-up in CCFs. CLASSIFICATION AND ETIOLOGY Several classification schemes have categorized CCFs according to etiology (traumatic or spontaneous), hemodynamic features (high versus low flow), or the angiographic arterial architecture (direct or indirect). The angiographic classification defines the angioarchitecture of the lesion on which a therapeutic strategy can be planned. According to the angiographic findings, Barrow et al[1] provided a detailed anatomical classification which categorizes CCFs into four distinct types based on their arterial supply. Type A fistulas are direct communications between the internal carotid artery (ICA) and the cavernous sinus, usually associated with high flow rates. Indirect fistulas (types B, C and D) are dural arteriovenous fistulas fed by the meningeal arteries of the ICA, the external carotid artery (ECA), or both. Type B fistulas have dural ICA branches to the cavernous sinus, which are relatively uncommon. Type C fistulas are supplied solely by the dural branches of the ECA. The most prevalent form of indirect CCF is the type D fistula that has dural ICA and ECA branches to the cavernous sinus. Tomsick subclassified type D CCFs into type D1 or D2 depending on the presence of a unilateral or bilateral arterial supply[2]. Traumatic CCFs often demonstrate a single direct communication between the ICA and the cavernous sinus and are almost always found to be type A direct fistulas. However, spontaneous fistulas usually have multiple dural feeders and numerous microfistulas within the cavernous sinus wall[3]. Spontaneous CCFs may fall into any of the four angiographic categories defined by Barrow et al[1], because a type A shunt with high-flow characteristics can develop following spontaneous rupture of an intracavernous ICA aneurysm. Most direct CCFs occur at the proximal horizontal intracavernous segment of the ICA in the vicinity of the inferolateral trunk. With decreasing frequency, CCFs are found to occur at the junction of the horizontal and intracavernous ascending segments, posterior ascending segment, junction of the anterior ascending and horizontal intracavernous segments, and the anterior ascending segment[4]. Traumatic disruption of the vessel wall is the most common etiological factor for direct CCFs. Blunt and penetrating head trauma as well as iatrogenic damage (trans-sphenoidal surgery, glycerol rhizotomy, Fogarty catheter manipulation for carotid angioplasty etc.) may WJR|www.wjgnet.com 144 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF PATHOPHYSIOLOGY AND SYMPTOMS Table 1 Carotid cavernous sinus fistula The cavernous sinus normally receives drainage from the superior and inferior ophthalmic veins as well as superiorly from the sphenoparietal sinus, sylvian veins, and cortical veins. The cavernous sinus drains posteriorly through the inferior petrosal sinus (IPS) and superior petrosal sinus to the jugular bulb, inferiorly through the pterygoid plexus via emissary veins, and contralaterally through the contralateral cavernous sinus[4,11]. A CCF allows highly pressurized arterial blood to be transmitted directly into the cavernous sinus and the draining veins, leading to venous hypertension. The clinical presentation of CCF is a direct consequence of elevation in intracavernous pressure and revised flow patterns. The revised venous drainage of the CCFs may head toward the ophthalmic venous system anteriorly; the superior petrosal sinus, the IPS, or the basilar plexus posteriorly; the sphenoparietal sinus laterally; the intercavernous sinus contralaterally; the pterygoid plexus via the vein of the foramen rotundum and the vein of the foramen ovale inferiorly. Most often, the direction of the venous drainage is multidirectional[3,5]. The clinical features of CCFs are related to their size, exact location, duration, adequacy and route of venous drainage and the presence of arterial/venous collaterals[6]. The symptoms and signs that may be associated with CCF are listed in Table 1. The classic presentation for a direct, high-flow CCF is the sudden development of DandyвЂ™s triad: exophthalmos, bruit, and conjunctival chemosis. Complete clinical triad is not always found but most patients present with proptosis (90%), chemosis (90%), diplopia (50%), cephalic bruit (25%), pain (25%), trigeminal nerve dysfunction, elevated intraocular pressure, and visual loss (up to 50%)[4]. Elevated pressure in veins draining the orbit may produce orbital venous congestion, transudation of interstitial fluid into the orbit with resultant proptosis, increased intraocular pressure due to impaired drainage of the aqueous humor, and secondary glaucoma. Elevated venous pressure and intraocular pressure can compromise retinal perfusion and result in severely diminished visual acuity[6]. Visual loss is one of the most worrying complications of CCFs and warrants immediate treatment. Although minor deficits in visual acuity almost have complete resolution after closure of the fistula, severe visual loss with loss of light perception rarely improves even if the fistulous communication is obliterated[18]. Subconjuctival hemorrhages can be seen due to rupture of dilated arterialized veins and, in addition, increased exposure of the cornea may cause corneal damage. Intracranial hemorrhage develops in 5% of patients, probably due to revised venous drainage into the sphenoparietal sinus with occlusion of other drainage pathways, resulting in cerebral cortical venous hypertension[4,7]. External hemorrhage such as otorrhagia and epistaxis can be seen in nearly 3% of cases in CCF[19]. Between 1% Symptoms and signs Exophthalmos, proptosis Cephalic bruit Conjunctival chemosis, вЂ�вЂ™red eyeвЂ™вЂ™ Pain, headache Trigeminal nerve dysfunction Elevated intraocular pressure, secondary glaucoma Diminished visual acuity, visual loss Subconjunctival hemorrhages Corneal damage Intracranial hemorrhage Otorrhagia Epistaxis Differential diagnosis Vascular pathologies Marginal sinus fistulas (with a restriction of venous drainage via the jugular bulb) Anomalous intracranial venous drainage (sigmoid sinus hypoplasia/aplasia) Cavernous sinus thrombosis Intraorbital lesions Fibrous dysplasia Frontal sinus mucocele Ocular neoplasms Osteoma Hemangioma Inflammatory, allergic and infectious pathologies Conjunctivitis Endocrine pathologies Thyroid ophthalmopathy Indications for emergency treatment Angiographic findings Pseudoaneurysm Large varix of the cavernous sinus Venous drainage to cortical veins Thrombosis of distant venous outflow pathways Clinical signs and symptoms Increased intracranial pressure Rapidly progressive proptosis Intracerebral, subarachnoid and external hemorrhage Transient ischemic attack Treatment modalities Conservative management (manual compression therapy and medical therapy) Surgical management Stereotactic radiosurgery Endovascular management Direct fistula Transarterial treatment (preferred approach for direct CCF) Detachable balloon occlusion Transarterial coil and material embolization Covered stent graft placement (endovascular reconstruction of the parent artery) Parent artery occlusion Transvenous treatment Transvenous detachable coil embolization Liquid embolizing agents (n-BCA, Onyx) Indirect fistula Transvenous treatment (preferred approach for indirect CCF) Transvenous detachable coil embolization Liquid embolizing agents (n-BCA, Onyx) Transarterial treatment Transarterial coil and material embolization CCF: Carotid cavernous sinus fistula; n-BCA: n-butyl 2-cyanoacrylate. WJR|www.wjgnet.com 145 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF and 2% of CCF cases manifest life-threatening massive epistaxis caused by rupture of a pseudoaneurysmal cavernous sinus varix[4,7,20]. Most CCF cases that present with epistaxis have a pseudoaneurysm or venous pouch that entered the sphenoid sinus via a communication through a basal skull fracture[19]. Bleeding from the veins draining the ear canal can lead to otorrhagia[19]. Although the clinical manifestations may overlap, indirect CCFs often do not demonstrate the classic triad of symptoms. An ocular bruit may or may not be present with these lesions. The onset of symptoms of indirect CCFs is not as drastic as in direct CCFs. The symptoms and signs of indirect CCFs progress insidiously and the majority of cases present with progressive glaucoma, proptosis or conjunctival injection (red eye)[4,7,15,21]. The natural evolution of indirect CCFs is variable and the literature reports spontaneous resolution without treatment occurs in 10%-60% of cases, possibly due to rethrombosis of the involved segment of the cavernous sinus[1,15]. Although these lesions have a tendency to resolve spontaneously, patients suffering from progressive vision loss and intractable glaucoma require interventional therapy. Spontaneous thrombosis of traumatic indirect fistulas is rare because of higher flow rates than with the spontaneous type[17]. Exacerbation and remission of signs and symptoms are the hallmark of dural CCFs, possibly due to cavernous sinus thromboses and rerouting of venous flow in various directions[4]. Therefore any change in the symptoms must be followed up accurately because it may suggest alterations in venous drainage, possibly transitioning to higher-risk patterns despite overt clinical improvement. The вЂњwhite eye syndromeвЂќ defines the clinical remission of ocular symptoms due to spontaneous occlusion of venous drainage pathways to the orbit and potentially leaving only more dangerous venous drainage routes[15]. pressures, cerebral edema and/or hemorrhage may be encountered[4,5,7]. While CT angiography can be used as a first-line diagnostic tool in evaluating the presence of a CCF it has some limitations. Despite its ability to reliably delineate certain draining veins, CT angiography rarely depicts small feeding arteries in dural CCFs or the exact site of fistulous communication in direct CCFs. Moreover, this technique cannot provide information about the bloodflow characteristics within fistulas[3]. Color Doppler imaging can assist in diagnosis and follow-up of patients with CCFs. Increased velocity with reversal of the direction of blood flow, arterial pulsations, and dilatation of SOV are characteristic findings[22]. Cerebral angiography is the gold standard for the definitive diagnosis, classification, and planning of endovascular intervention in CCFs. The initial angiographic evaluation can be used to obtain the following information: size and location of the fistula, differentiation of direct from indirect lesions, presence of any associated cavernous carotid aneurysm, presence of complete or partial steal phenomena, assessment of the global cortical arterial circulation and collateral flow through the circle of Willis, identification of high-risk features (e.g., cortical venous drainage, pseudoaneurysm, cavernous sinus varix), venous drainage patterns, determination of therapeutic route, associated vascular injuries (e.g., traumatic pseudoaneurysm, arterial dissection), identification of any dangerous collateral pathways and evaluation of carotid bifurcation before compression therapy[4-7,11,15]. In the evaluation of direct CCFs, identifying the exact location of fistulous communication in the cavernous ICA can be challenging because of the high flow- related washout of intra-arterial contrast and instantaneous opaВ cification of the cavernous sinus. Angiographic highframe-rate imaging (> 5 frames/s) and rapid contrast injection rates (7 or 8 mL/s) may assist in evaluating the morphology of high-flow fistulas. High-flow CCFs may be difficult to capture in digital subtraction angiography, even with selective high frame rates. Specific maneuvers can be implemented to slow the fistula flow and facilitate image capture. The Mehringer-Hieshima maneuver consists of injecting the ipsilateral ICA and manual compression of the ipsilateral common carotid artery while filming at a slower frame rate. Use of this maneuver slows the rate of opacification of the fistula and thereby allows better delineation of the fistula site. Another maneuver consists of using of a double-lumen balloon catheter in the ipsilateral ICA with slow injection of contrast at 1 mL/s at one or two frames per second. Lastly, ipsilateral carotid compression during injection of the vertebral artery, called the Heuber maneuver, opacifies the fistula through a patent posterior communicating artery[4-7,11]. Tolerance for ICA occlusion should also be assessed to identify the appropriate therapeutic choices before embarking on a therapeutic intervention. Balloon test occlusion is the currently accepted technique for evaluation. After confirmation of ICA occlusion, detailed DIAGNOSTIC IMAGING AND PRETHERAPEUTIC EVALUATION Noninvasive imaging [computed tomography (CT), magВ netic resonance (MR), CT angiography, MR angiography, Doppler] often is used in the initial work-up of a possible CCF. CT scan of the orbit usually demonstrates proptosis of the affected globe, enlargement of the extraocular muscles, dilatation and tortuosity of the superior ophthalmic vein (SOV), and enlargement of the ipsilateral cavernous sinus. A noncontrast head CT scan also allows for careful examination of possible cranial injuries, such as bony fractures or intracranial hematomas. MR imaging findings in CCFs are similar to those seen on CT with the addition of orbital edema and abnormal flow voids in the affected cavernous sinus. In the setting of a high-flow fistula and retrograde cortical venous reflux, MR or CT studies may reveal dilatation of leptomeningeal and cortical veins. In patients who have cerebral venous congestion and elevated intracranial WJR|www.wjgnet.com 146 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF after the occlusion of venous outflow pathways[19]. Massive cortical venous drainage can eventually result in hemorrhagic venous infarction and endovascular treatment should, therefore, be performed immediately[11]. Clinical signs and symptoms that are associated with poor prognosis include increased intracranial pressure; rapidly progressive proptosis, which may signify spontaneous thrombosis of venous outflow pathways to the orbit; diminished visual acuity; hemorrhage (e.g., intracerebral, subarachnoid and external hemorrhage; otorrhagia or epistaxis); and transient ischemic attacks; which may signify cerebral ischemia or impaired autoregulation in cerebral perfusion, secondary to the chronic steal phenomenon caused by the fistulous communication. The delineation of angiographic high-risk findings and recognition of the poor prognostic clinical features (Table 1) should warrant emergent and aggressive interventional treatment to improve outcome[4,15,19]. testing of mental status, speech, visual fields, facial animation, and motor power in all four extremities are performed. In the absence of significant deficit, the patient is observed for 15-20 min and re-examined. If the patient tolerates occlusion at normal blood pressure, nitroprusside infusion is initiated and titrated to achieve a mean arterial pressure two thirds of the patientвЂ™s baseline level. The patient is examined again and observed for 15-20 min. Single proton emission computed tomography (SPECT) may be used to rule out significant asymmetry in perfusion during balloon test occlusion (BTO). The SPECT evaluation can uncover the risk of suffering a major stroke after permanent carotid occlusion even in patients who seem to tolerate BTO during relative hypotensive challenge test[4]. Differential diagnosis The differential diagnosis of CCF includes a wide specВ trum of pathologies (Table 1), so patients may be evaluated for endocrine, inflammatory, infectious and neoplastic etiologies before the presence of vascular pathology is recognized, especially in the early phase of the disease. Intraorbital lesions (osteoma, hemangioma, fibrous dysplasia, frontal sinus mucocele, ocular neoplasms) may cause ocular pain, exophthalmos, and ophthalmoplegia although, bruits are not typically present[14]. Ocular findings of CCF may also mimic those associated with allergic/infectious conjunctivitis and thyroid ophthalmopathy. However, ocular involvement in hyperthyroidism typically occurs bilaterally[14,15]. Imaging techniques (e.g., MR, CT) displaying prominent vessels within the orbit can lead the clinician to consider vascular etiologies. Vascular pathologies that can result in SOV dilatation include marginal sinus fistulas with a restriction or obstruction of venous drainage via the jugular bulb[23], anomalous intracranial venous drainage such as sigmoid sinus hypoplasia/aplasia[24], and thrombosis of the cavernous sinus. Cerebral angiography must be performed to achieve a definitive diagnosis. TREATMENT MODALITIES The treatment modalities include conservative management, which consists of medical management and manual compression therapy; surgical management; stereotactic radiosurgery and endovascular repair via a transarterial or transvenous route (Table 1). Conservative management A complete set of diagnostic angiographic evaluations is required for choosing the appropriate treatment modality. While higher risk fistulas deserve the most aggressive approach in order to eradicate the fistula, low-risk lesions with mild symptomatology may not require active intervention and can be managed conservatively. Patients with low-risk lesions can be given reassurance, educated regarding potential changes in symptoms, and allowed time for potential spontaneous closure of the fistula[11]. Spontaneous resolution of dural fistulas can occasionally occur within days to months after symptomatic presentation secondary to further thrombosis of the involved segment of the cavernous sinus. Therefore, an accepted practice is to treat the patientвЂ™s ocular symptoms medically with prism therapy or patching for diplopia, topical ОІ-adrenergic blockers and acetazolamide for elevated intraocular pressure, lubrication for proptosis-related keratopathy, and/or systemic corticosteroids if needed[7]. Furthermore, manual external carotid-jugular compression therapy may be initiated as a noninvasive treatment for indirect CCFs. The patient is instructed to compress the carotid artery and jugular vein with the contralateral hand for a period of 10 s while sitting or lying down, four to six times each hour[7]. The aim of the compression therapy is the transient reduction of arteriovenous shunting by decreasing arterial inflow while simultaneously increasing the outlet venous pressure, thereby promoting spontaneous thrombosis within the fistula[25]. Use of the contralateral hand ensures that if ischemia develops, the symptomatic arm will fall away from the neck, thus allowing cortical revascularization INDICATIONS FOR EMERGENCY TREATMENT Halbach et al[19] reviewed angiographic and clinical data from 155 CCF patients to determine angiographic features associated with increased risk of morbidity and mortality. These features comprise the presence of a pseudoaneurysm, large varix of the cavernous sinus, venous drainage to cortical veins, and thrombosis of other venous outflow pathways distant from the fistula. Varix of the cavernous sinus and pseudoaneurysm can both present with subarachnoid hemorrhage. Angiographic differentiation between a cavernous sinus varix and a pseudoaneurysm may be difficult or impossible. However, the clinical onset can be helpful to the differentiation process. The onset of the pseudoaneurysm is usually coincidental with trauma, as opposed to the delayed onset of the cavernous sinus varix, which develops WJR|www.wjgnet.com 147 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF immediately[5]. Intermittent self-administered manual carotid-jugular compression alone can result in a cure in 30% of patients with spontaneous CCFs[7,26]. However, this treatment is usually ineffective in the high-flow CCFs, which usually require endovascular intervention. Cervical carotid bifurcation should be examined for atherosclerotic changes using color Doppler or angiography before initiation of compression therapy[26]. Contraindications to manual carotid-jugular compression are symptomatic bradycardia with carotid compression, significant cortical venous drainage which may result in venous infarction or hemorrhage during compression therapy as well as clinical features that can signify difficulty in tolerating transient occlusion of ipsilateral ICA such as atherosclerotic stenosis, ulceration of the carotid artery, history of cerebral ischemia[5,7]. The possible adverse effects of carotid compression may include hemodynamic or thromboembolic complications, vasovagal reactions, intracranial/retinal hemorrhage, clinical deterioration known as the вЂњparadoxical worsening phenomenonвЂќ, vertebral artery occlusion, brachial plexus/supraclavicular nerve injury and temporary monocular blindness during carotid compression[26]. If the decision not to treat a CCF interventionally is made, the patient must be carefully followed for elevated intraocular pressure, progressive visual deterioration, neurological deficits and high-risk angiographic features[1,5,6]. fistulae inhibit the usage of radiosurgery as a first line treatment[4]. Endovascular management Recent advances in endovascular technology have made available a number of different treatment options for CCFs. As a result of these advances, the endovascular approach has evolved as the primary treatment option in clinical emergencies and following the failure of conservative therapy. Although the clinical manifestations of direct and indirect fistulas may overlap, their natural history and method of endovascular treatment are often significantly different. The treatment choice is made according to the type, exact anatomy of the fistula, size of the arterial defect, and operator/institutional preferences. Direct fistulas occur from a tear in the cavernous segment of the ICA or, less commonly, from the intracavernous rupture of an ICA aneurysm. The goal of treatment in direct CCFs is to occlude the tear between the ICA and the cavernous sinus while preserving the patency of the ICA. This goal can be accomplished by either transarterial obliteration of the fistula with a detachable balloon, transarterial or transvenous obliteration of the ipsilateral cavernous sinus with coils or other embolic material, or deployment of a covered stent across the fistula. Rarely, if the defect is large and cannot be repaired, the ICA may need to be sacrificed or trapped[7]. Indirect fistulas consist of small dural arteriovenous shunts between the meningeal branches of the ICA, the ECA, or both, and the cavernous sinus. The goal of treatment in this condition is to interrupt fistulous communications and decrease pressure in the cavernous sinus. This can be accomplished by occluding the arterial branches supplying the fistula (transarterial embolization) or, more commonly, by occluding the cavernous sinus that harbors the fistulous communications (transvenous embolization)[7]. The following sections provide a brief overview of the various endovascular options for the treatment of CCFs. Surgical management Early treatments for CCF consisted of various surgical approaches such as ligation of the CCA, surgical trapping of the fistula, and surgical transvenous packing. Although surgical management can be useful for both direct and indirect CCFs, its role is limited because of associated morbidity from cranial nerve deficits and residual fistulous communications. Indications for surgical repair include compromised proximal arterial access that prevents endovascular repair or causes it to fail. Surgical management remains a consideration for salvage of failed endovascular treatments[4,7]. Complete angiographic documentation of the fistula and BTO should be performed during preoperative evaluation. The appearance and condition of the superficial temporal artery should also be noted because extracranial-to-intracranial bypass can be required to augment blood flow when surgical sacrifice is unavoidable[4]. Endovascular repair: Direct CCFs Detachable balloon occlusion: After Prolo and Hanberry described the use of a fixed balloon catheter to block a CCF in 1971, Serbinenko et al[29] reported the first case of successful embolization of a CCF from an endovascular approach using a detachable silicone balloon with preservation of the ICA[13]. The use of detachable balloon catheters has ushered a new age in the treatment of type A direct CCFs. Transarterial balloon detachment has been accepted as the endovascular treatment of choice for direct CCFs since the 1980s. The small-diameter vessels that often make up dural fistulas usually do not allow the introduction of a balloon. However, the large carotid defect commonly present in type A CCFs frequently permits transarterial balloon occlusion of the fistula with preservation of the ICA[1,4]. Radiosurgery Stereotactic radiosurgery has emerged as an alternative treatment option and has been investigated for the treatment of CCFs in several institutions. Gamma knife radiosurgery can be used either alone or as an adjunct therapy before/after endovascular intervention[27,28]. Although preliminary data show that radiosurgery is a safe and effective alternative treatment for indirect CCFs, the 22-mo average lag between treatment and complete symptom relief is a significant drawback[21]. Furthermore, an inability to manage emergencies and traumatic WJR|www.wjgnet.com 148 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF A B C Figure 1 A thirty one-year-old man who was diagnosed with carotid cavernous sinus fistula which developed secondary to a motor vehicle accident. A: Digital subtraction angiogram view of left internal carotid artery (ICA) revealed laceration in the anterior loop and associated direct carotid cavernous sinus fistula; B: Balloon detachment failed because of the site and small calibre of the fistula orifice. Coil embolization of the fistula was then performed with preservation of the ICA; C: Post-procedural left ICA injection showed lack of residual filling, preservation of parent artery and detached coils at the site of fistula. Coil and material embolization: Transarterial embolization with coils or other embolic material now is the mainstay of endovascular treatment for high-flow direct CCFs, given the limited availability of detachable balloons[7]. Transarterial CCF embolization can be performed with the same technique as aneurysmal embolization. Embolization can be achieved with detachable platinum coils, silk and liquid embolic agents such as n-butyl cyanoacrylate (n-BCA), and ethylene-vinyl alcohol copolymer (EVOH)[5]. The standard transarterial approach consists of placing a guiding catheter in the cervical ICA. Next, a microcatheter is superselectively advanced into the cavernous segment of the ICA and through the tear into the cavernous sinus. Through this microcatheter, embolic material is placed into the cavernous sinus[7]. Detachable platinum coils are preferred because of their reliable and controlled deployment (Figure 1). The coils can be adjusted easily or removed if the placement is not optimal. Dense coil packing is performed using the same principles as aneurysm coiling. Thrombogenic, nonretrievable fibered microcoils can also be used but these are associated with the risk of coil deposition into the ICA if the microcatheter recoils into the parent artery during placement[6]. The advantages of coil occlusion of CCFs, when compared with balloon embolization, include ease of access and availability of a variety of sizes of the embolic device. Potential disadvantages include slower gradual occlusion of the fistula, which increases procedure time, and the risk of incomplete fistula occlusion with loss of transarterial access; a loss which would then require a second transvenous approach[4]. The transvenous approach is discussed more thoroughly under the heading вЂњtransvenous embolizationвЂќ. Complications of transarterial coil embolization include thromboembolus, ICA compromise by protruding coil mass, and ICA dissection[4]. For preventing the retrograde herniation of the embolic material into the parent artery and distal intracranial circulation, the assistance of a nondetachable balloon (balloon-assist technique) or a porous stent may be preferred especially in the set- The technique for detachable silicone balloon occlusion of a CCF involves transfemoral access to the proximal CCA with a 7-French guide catheter or long 6-French sheath. Next, the uninflated balloon is advanced to the distal end of the guide catheter; at this point, roadmap imaging is used for further balloon positioning. The balloon offers the advantage of being able to be flowdirected through the fistula and into the cavernous sinus. The balloon is inflated to a volume larger than the orifice of the fistula to prevent its retrograde prolapse into the ICA and then is detached[7]. Following successful balloon deployment, cerebral angiography is repeated to ensure closure of the fistula and patency of the ICA. A single silicone balloon is usually sufficient for most CCFs. However, multiple balloons may be required in the setting of a large tear in the ICA. The advantage of balloon occlusion of a CCF is the ability to occlude the fistula rapidly with preservation of the ICA. However, technical difficulties can be encountered. The size of the cavernous sinus and the fistula may affect the success rate of detachable-balloon embolization of a CCF. The cavernous sinus must be large enough to accommodate the detachable balloon/ balloons for embolization. The size of the fistula must be smaller than the inflated balloon, but large enough to allow access for a deflated or partly inflated balloon. However, the size of the fistula should not be too large, because the embolization balloon may retract to the ICA on inflation in the cavernous sinus[30]. To provide easier navigation of the balloon into the cavernous sinus and prevent protrusion of the inflated balloon through the fistula site to narrow the adjacent ICA lumen, Teng et al[30] developed a double-balloon technique. Inadequate embolization may be seen due to early balloon detachment, deflation or rupture by contact with a bony fragment[4,5,7,31]. As a rare complication, the balloon can migrate to the venous side of the treated fistula resulting ophthalmoplegic signs due to mechanical compression of cranial nerves in close proximity to the cavernous sinus[32,33]. WJR|www.wjgnet.com 149 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF A B D E C Figure 2 A fifty two-year-old woman who presented with galactorrhea due to hypophyseal adenoma underwent transsphenoidal surgery. During the operation internal carotid artery laceration and massive arterial hemorrhage occurred. A: T1 W C+ coronal magnetic resonance imaging view demonstrating hypointensity at the left hypophyseal region which was consistent with hypophyseal adenoma; B: Immediate defect source analysis revealed a defect at the anteromedial wall of right internal carotid artery (ICA) and associated carotid cavernous sinus fistula; C: Position of the stent-graft closing the orifice of the fistula; D: Postprocedural right ICA injection demonstrating complete obliteration of the fistula and concentric luminal stenosis at the petrous segment associated with mechanic vasospasm secondary to guide-wire and stent manipulation; E: Third month control angiography revealed regular parent artery contours, absence of recurrent fistula filling and intimal hyperplasia within the stent. ting of a large tear in the ICA[4,5]. Stents also allow initial reconstruction of the damaged segment of the ICA and increase the ability to successfully treat fistulas without parent artery sacrifice[34]. dovascular technique, their usage as a widely accepted method in traumatic CCF is limited due to lack of configurations compatible with intracranial use and longterm safety data. Covered stent graft placement: Recent advances in endovascular techniques such as placement of polyfluorotetraethylene-covered stents have created alternatives to ICA sacrifice in traumatic arterial damage, especially in the setting of an unsuccessful balloon test occlusion study. Covered stent grafts can be extremely useful for the immediate obliteration of a direct CCF, while preserving ICA patency (Figure 2). Additionally, they may decrease the risk of ischemic stroke by preserving the involved artery while simultaneously sealing the site of the fistula[5,7,35]. Covered stent grafts have the technical disadvantage of limited longitudinal flexibility, making it difficult to navigate them through the tortuosity of the intracranial vasculature. Furthermore, the irritation caused by the stiffness of covered stents may frequently lead to periprocedural vasospasms, especially at the ends of the stent (Figure 2). Intra-arterial nimodipine and papaverine infusion can be used for the prevention and resolution of these vasospasms[36,37]. The complications of this procedure include endoleak, coverage of vital perforators, dissection and rupture[7,35]. Although covered stent grafts offer a promising en- Parent artery occlusion: Arterial sacrifice may be required as a life-saving emergency treatment when endovascular occlusion of a direct CCF with preservation of the ICA is not feasible due to extensive traumatic vesselwall damage, active hemorrhage or a rapidly expanding hematoma of the soft tissues. Emergency surgical occlusion of ICA has been relegated to historical status with the advance of therapeutic endovascular techniques, which can be performed immediately after diagnostic therapy under local anesthesia, thereby allowing monitorization of the neurological status[5,13,35]. If a decision to perform endovascular arterial sacrifice is made, assessment of the collateral flow and patientвЂ™s ability to tolerate ICA occlusion is paramount. In cases of complete steal presenting without any ischemic symptom, the quality of collateral flow through circle of Willis is confirmed and a test occlusion may be unnecessary. If anterior and posterior communicating artery collaterals are found to be patent, the safety of parent artery occlusion is also high. Otherwise, balloon occlusion test is recommended to ensure distal perfusion from collateral circulation before permanent occlusion[4,7]. WJR|www.wjgnet.com 150 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF A B C D E F Figure 3 A thirty one-year-old male patient with right ophthalmoplegia following head trauma was found to have a direct carotid cavernous sinus fistula. A, B: Frontal (A) and lateral (B) digital subtraction angiogram views of right internal carotid artery (ICA) demonstrating laceration of ICA, pseudoaneurysm in the cavernous ICA and direct carotid cavernous sinus fistula; C: After considering the presence of the pseudoaneurysm, two detachable balloons were positioned to occlude the parent artery; D: Right CCA digital subtraction angiogram after balloon occlusion of the ICA showing complete obliteration of the fistula; E, F: Posttreatment left ICA (E) and left vertebral artery (F) injections demonstrating reconstruction of the right ICA area. Endovascular repair: Indirect (type B, C, D) CCFs Transvenous embolization: Although transvenous embolization is an alternative technique in direct CCFs that cannot be treated by transarterial route, it is the preferred treatment for indirect CCFs. For indirect CCFs, transvenous techniques have precedence over transarterial methods because of their simplicity, lower ischemic risk, higher success rates and capability to cure the fistula in a single session. The aim of the transvenous approach is to catheterize the abnormal cavernous sinus superselectively and to occlude the fistula without rerouting venous drainage to cortical structures[4,5,7,21]. Navigation through the venous system and mechanical perforation are technical challenges in this procedure. Furthermore, usage of the transvenous approach in the acute fistula stages may be hazardous because the venous walls have not undergone wall thickening via arterialization[5]. Current microcatheter technology permits access to the cavernous sinus via multiple routes. The most commonly used venous pathway for cannulation of the cavernous sinuses is via the IPS. This transvenous route is usually used from a posterior direction through the internal jugular vein and the IPS up to the pathologic shunts of the cavernous sinus[5,7,15]. Anatomically, catheterization of the cavernous sinus through the IPS is feasible in the great majority (99%) of cases. However, accessibility of the cavernous sinus through the IPS can become technically difficult as the disease progresses. Difficulties may ICA occlusion can be performed with various endovascular techniques such as coil, balloon (Figure 3) and vascular plug embolization. Occlusion of the ipsilateral ICA is performed with coil embolization in a distal-toproximal approach to prevent the retrograde arterial filling of the fistula from the supraclinoid ICA[5,7]. Recently, the Hydrocoil Embolization System (HES) has been introduced, which can achieve high rates of volumetric occlusion compared with that in platinum coils. The HES device consists of a carrier platinum coil coupled with an expandable hydrogel material that increases in volume on contact with blood and facilitates vessel sacrifice, decreasing the procedure and fluoroscopy times. Hydrogelcoated detachable coils can be utilized to achieve rapid, precise, targeted parent artery occlusion procedures, even in short segments of vessel[7,37]. Fistula entrapment can be performed with the aid of two ballons, which are positioned proximal and distal to the fistula. If it is impossible to navigate either a balloon or a microcatheter beyond the fistula to allow distal control, a microcatheter is navigated into the supraclinoid segment of the carotid artery via the anterior or posterior communicating arteries with the aid of marked retrograde flow to the fistula. Thereby, endovascular trapping of the traumatic CCF can be performed by a combination of proximal balloon occlusion and distal trapping with coils[38,39]. Deployment of a vascular plug is an alternative method but this device is limited to occlusions below the base of the skull because of the poor navigability in the distal ICA[40]. WJR|www.wjgnet.com 151 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF A B D E C Figure 4 A forty-year-old woman with chemosis of the left eye and diplopia was found to have a dural carotid cavernous sinus fistula. A, B: Frontal (A) and lateral (B) injections of the right common carotid artery demonstrating left dural carotid cavernous sinus fistula with antegrade drainage; C: Access to the fistula site through the contralateral (right inferior petrous sinus) transvenous route and positioning of the microcatheter; D: Coil embolization within the microcather extending into the venous compartment of the fistula; E: Posttreatment frontal digital subtraction angiogram view of right internal carotid artery demonstrating obliteration of the fistula and lack of residual filling. result from occlusion of the IPSs due to longstanding venous hypertension, prior embolization, or both[18,41]. Because the drainage of the pons and brainstem may be via the IPS, and any damage to these veins may result in fatal venous thrombosis, the catheterization of the IPS merits special attention[6]. Anterior approach through the SOV via the facial vein provides a convenient alternative pathway for transvenous embolization of dural CCFs when cannulation of the IPS is not successful, thereby increasing the technical success rate[18]. Less commonly used transvenous approaches are through the lateral pterygoid plexus, superior petrosal sinus, cortical veins, the inferior ophthalmic vein or the contralateral IPS (Figure 4) or SOV with access into the ipsilateral cavernous sinus through the circular sinus[5,7,15]. Alternatively, in extremely difficult cases of venous occlusion, stenosis, or marked tortuosity, access to the cavernous sinus can be provided by combined surgical and endovascular approaches (Figure 5)[7]. Direct transorbital puncture or indirect puncture through the superior or inferior ophthalmic vein allows straightforward access to the cavernous sinus[42]. Surgical access also may be obtained into the SOV, superficial middle cerebral vein, or sphenoparietal sinus leading to the cavernous sinus. QuiГ±ones et al[21] proposed surgical exposure of the SOV and retrograde venous catheterization in indirect CCF patients who present with WJR|www.wjgnet.com decreased visual acuity and predominant anterior venous drainage. Surgical exposure permits direct visibility and immobilization of the SOV, with less risk of rupture of the arterialized vein than with direct puncture. This approach also allows immediate control of possible orbital hemorrhage. The potential risks of the direct puncture or surgical exposure are orbital hemorrhage, nerve damage and laceration of the ICA resulting in direct CCF, globe puncture, and infection[21,42]. Sonographically guided direct percutaneous access through the facial vein can be performed to eliminate the risk of complications, such as intra- or retro-orbital hemorrhage, cranial nerve damage, subarachnoid or intracranial hemorrhage, and arterial damage, which may result from direct puncture of the SOV or the cavernous sinus. Reduction in radiation exposure and ease of manual compression of the puncture site after the procedure are additional advantages of this procedure although the small diameter of the facial vein may cause technical limitations[41]. Following successful catheterization of the cavernous sinus, various embolic materials such as coils, n-BCA, and EVOH, can be used either alone or in combination. The advantages of coils include their radiopacity, ease of use, and the ability to redeploy or remove the devices if the initial placement is not optimal. However, there may be difficulty in achieving adequate volumetric packing or complete occlusion, especially in septated 152 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF A B D E C Figure 5 In extremely difficult cases of venous occlusion, stenosis, or marked tortuosity, access to the cavernous sinus can be provided by combined surgical and endovascular approaches. A, B: Left external carotid artery lateral (A) and left internal carotid artery lateral (B) digital subtraction angiogram views of an uncovered dural carotid cavernous sinus fistula which has antegrade drainage; C: Posterior access to the fistula site was not feasible, so access was gained through the superior ophthalmic vein following surgical angular vein cut-down; D: Coil detachment through a microcatheter into the fistula site; E: Posttreatment left common carotid artery injection revealed lack of residual filling of the fistula. necessary because of technical difficulties associated with superselective distal access into small-sized arterial feeders. Additionally, potential complications (e.g., thromboembolic stroke, cranial nerve palsies) restrain the choice of the transarterial approach as the mainstay treatment of spontaneous indirect CCFs. Therefore, transarterial embolization is typically used only to reduce arterial inflow before transvenous occlusion for highflow indirect CCFs and as a viable alternative after failure of transvenous attempts[4,7]. The management strategy for traumatic indirect CCFs differs from that for spontaneous indirect CCFs. For traumatic lesions, transarterial embolization may be preferred because the single arterial supply is large enough to provide access to the feeder and cavernous sinus by microcatheter. The transvenous approach is reserved for cases in which failure or recurrence of the fistula is observed and arterial access to the site of the fistula is not feasible[17]. Transarterial techniques involve distal catheterization of the small meningeal branches supplying the fistula. Ideally, placement of the superselective microcatheter is performed with the microcatheter tip as close as possible to the point of fistulous communication. Once a satisfactory microcatheter position is achieved, liquid embolic agents (n-BCA, EVOH) are injected under fluoroscopic control with the goal of occluding the fistulous connections and penetrating the cavernous sinus. Al- cavernous sinuses. Moreover, the reported rates of cranial nerve paresis are higher with coil embolization, probably because of their mass effect[7]. Consequently, transvenous liquid embolic agents are being used increasingly, either alone or in combination with platinum coils. EVOH has the capability of mechanical occlusion without vessel wall adhesion. Its nonadhesive nature decreases the risk of microcatheter retention and allows a slow single injection of embolic agent with concomitant angiogram checks. It must be remembered that EVOH has a propensity for retrograde filling of arterial feeders and must be used cautiously in order to prevent retrograde reflux into the ICA and ECA branches[7,43]. n-BCA has the advantages of rapid polymerization and permanent occlusion of the injected feeders. However, in contrast to EVOH, catheter repositioning during embolization and the reflux-hold-reinjection technique cannot be performed in embolization with n-BCA. Prolonged injections are not possible and as they may risk gluing the catheter because of the adhesive nature of n-BCA[7,43]. The polymerization of n-BCA is accompanied by heat production, which may lead to a degree of angionecrosis[6]. Transarterial embolization: Transarterial embolization of indirect low-flow CCFs generally is cumbersome beВ cause of the small size, complex anatomy, and multiplicity of arterial feeders. Multiple staged sessions may be WJR|www.wjgnet.com 153 April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF though coils and particulate agents have been used, these agents used alone cannot provide permanent occlusion of the fistula[7]. 2 POSTOPERATIVE IMAGING AND FOLLOW-UP 3 While ocular symptoms resolve rapidly following successful treatment, patients may become transiently more symptomatic due to propagation of thrombus throughout the cavernous sinus and extending into the SOV. This clinical deterioration is called the вЂњparadoxical worsening phenomenonвЂќ and can be observed in patients after transarterial embolization, gamma knife radiosurgery or conservative treatment. Although disconcerting to the patient, such symptoms usually resolve spontaneously over time. A brief course of corticosteroids may help to reduce inflammation associated with sinus thrombosis[15,26]. Severe progression of the ocular manifestations in the early postoperative period and recurrence of symptoms may suggest recurrent CCF. In cases where recurrent CCF is suspected, control cerebral angiography should be performed and possible re-treatment should be planned. After complete resolution of the ocular manifestations, additional control imaging and follow-up is not required. In patients who were treated by the placement of a covered stent, stent-graft patency should be followed carefully as long-term safety data are lacking[35,44]. Longterm follow-up is necessary in CCF cases treated by parent artery occlusion to monitor the possible development of hemodynamic aneurysm in the anterior communicating artery, due to increased flow and alteration in hemodynamics. Patients who have fistulas demonstrating cortical venous rerouting or partially treated CCFs may show clinical deterioration. In such cases, urgent examination should be performed and treatment should be planned if required. Acute onset of focal neurological deficit deserves immediate clinical evaluation and control imaging. 4 5 6 7 8 9 10 11 12 13 CONCLUSION With advances in catheter design, embolic agents, and fluoroscopic imaging equipment, interventional neuroendovascular techniques have become the preferred treatment modality for carotid cavernous fistulas and favorable long-term outcomes have been achieved. The endovascular approach should be tailored to individual cases according to the type, exact anatomy, and extent of each fistula. With increasing knowledge about novitious endovascular techniques, such as placement of covered stent grafts, higher success rates can be achieved with preservation of the ICA even in urgent cases. 14 15 16 17 REFERENCES 1 Barrow DL, Spector RH, Braun IF, Landman JA, Tindall SC, WJR|www.wjgnet.com 154 Tindall GT. Classification and treatment of spontaneous carotid-cavernous sinus fistulas. 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Dural carotid cavernous fistula: definitive endovascular management and long-term follow-up. Am J Ophthalmol 2002; 134: 85-92 [PMID: 12095813 DOI: 10.1016/S0002-9394(02)01515-5] Pang D, Kerber C, Biglan AW, Ahn HS. External carotidcavernous fistula in infancy: case report and review of the literature. Neurosurgery 1981; 8: 212-218 [PMID: 7207787 DOI: 10.1227/00006123-198102000-00011] Luo CB, Teng MM, Chang FC, Chang CY. Traumatic indirect carotid cavernous fistulas: angioarchitectures and results of transarterial embolization by liquid adhesives in 11 patients. Surg Neurol 2009; 71: 216-222 [PMID: 18291502 DOI: 10.1016/ j.surneu.2007.09.032] April 28, 2013|Volume 5|Issue 4| Korkmazer B et al . Endovascular treatment of CCF 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Yu SC, Cheng HK, Wong GK, Chan CM, Cheung JY, Poon WS. Transvenous embolization of dural carotid-cavernous fistulae with transfacial catheterization through the superior ophthalmic vein. Neurosurgery 2007; 60: 1032-1037; discussion 1037-1038 [PMID: 17538376 DOI: 10.1227/01. NEU.0000255455.05355.31] Halbach VV, Hieshima GB, Higashida RT, Reicher M. Carotid cavernous fistulae: indications for urgent treatment. AJR Am J Roentgenol 1987; 149: 587-593 [PMID: 3497549] Tomsick TA. Type B,C, and D (dural) CCF: etiology, prevalence, and natural history. In: Tomsick TA, editor. Carotid cavernous sinus fistula. Cincinnati: Digital Education Publishing, 1997: 59-73 QuiГ±ones D, Duckwiler G, Gobin PY, Goldberg RA, ViГ±uela F. Embolization of dural cavernous fistulas via superior ophthalmic vein approach. AJNR Am J Neuroradiol 1997; 18: 921-928 [PMID: 9159371] Belden CJ, Abbitt PL, Beadles KA. Color Doppler US of the orbit. Radiographics 1995; 15: 589-608 [PMID: 7624565] Turner RD, Gonugunta V, Kelly ME, Masaryk TJ, Fiorella DJ. Marginal sinus arteriovenous fistulas mimicking carotid cavernous fistulas: diagnostic and therapeutic considerations. 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J Neurosurg 1996; 84: 804-809 [PMID: 8622154 DOI: 10.3171/jns.1996.84.5.0804] Koebbe CJ, Singhal D, Sheehan J, Flickinger JC, Horowitz M, Kondziolka D, Lunsford LD. Radiosurgery for dural arteriovenous fistulas. Surg Neurol 2005; 64: 392-38; discussion 392-38; [PMID: 16253680 DOI: 10.1016/j.surneu.2004.12.026] Serbinenko FA. Balloon catheterization and occlusion of major cerebral vessels. J Neurosurg 1974; 41: 125-145 [PMID: 4841872 DOI: 10.3171/jns.1974.41.2.0125] Teng MM, Chang CY, Chiang JH, Lirng JF, Luo CB, Chen SS, Chang FC, Guo WY. Double-balloon technique for embolization of carotid cavernous fistulas. AJNR Am J Neuroradiol 2000; 21: 1753-1756 [PMID: 11039361] Lasjaunias P, Berenstein A, Ter Brugge KG. Surgical neu- 32 33 34 35 36 37 38 39 40 41 42 43 44 roangiography. 2nd ed. Vol 2, Clinical and endovascular treatment. Berlin, Heidelberg: Springer-Verlag, 2004 Sencer S, Minareci O, Poyanli A. Management of a rare complication of endovascular treatment of direct carotid cavernous fistula. AJNR Am J Neuroradiol 1999; 20: 1465-1466 [PMID: 10512231] Klisch J, Schipper J, Husstedt H, Laszig R, Schumacher M. Transsphenoidal computer-navigation-assisted deflation of a balloon after endovascular occlusion of a direct carotid cavernous sinus fistula. AJNR Am J Neuroradiol 2001; 22: 537-540 [PMID: 11237982] MorГіn FE, Klucznik RP, Mawad ME, Strother CM. Endovascular treatment of high-flow carotid cavernous fistulas by stent-assisted coil placement. AJNR Am J Neuroradiol 2005; 26: 1399-1404 [PMID: 15956506] Kocer N, Kizilkilic O, Albayram S, Adaletli I, Kantarci F, Islak C. Treatment of iatrogenic internal carotid artery laceration and carotid cavernous fistula with endovascular stentgraft placement. AJNR Am J Neuroradiol 2002; 23: 442-446 [PMID: 11901015] Gomez F, Escobar W, Gomez AM, Gomez JF, Anaya CA. Treatment of carotid cavernous fistulas using covered stents: midterm results in seven patients. AJNR Am J Neuroradiol 2007; 28: 1762-1768 [PMID: 17885249 DOI: 10.3174/ajnr. A0636] Kallmes DF, Cloft HJ. The use of hydrocoil for parent artery occlusion. AJNR Am J Neuroradiol 2004; 25: 1409-1410 [PMID: 15466342] Uysal E, KizilkiliГ§ O, Ulusay M, Basak M. Endovascular trapping of direct carotid-cavernous fistula. J Clin Neurosci 2010; 17: 392-394 [PMID: 20074962 DOI: 10.1016/j.jocn.2009.06.020] Coley SC, Pandya H, Hodgson TJ, Jeffree MA, Deasy NP. Endovascular trapping of traumatic carotid-cavernous fistulae. AJNR Am J Neuroradiol 2003; 24: 1785-1788 [PMID: 14561603] Ross IB, Buciuc R. The vascular plug: a new device for parent artery occlusion. AJNR Am J Neuroradiol 2007; 28: 385-386 [PMID: 17297018] Berkmen T, Troffkin NA, Wakhloo AK. Transvenous sonographically guided percutaneous access for treatment of an indirect carotid cavernous fistula. AJNR Am J Neuroradiol 2003; 24: 1548-1551 [PMID: 13679268] White JB, Layton KF, Evans AJ, Tong FC, Jensen ME, Kallmes DF, Dion JE, Cloft HJ. Transorbital puncture for the treatment of cavernous sinus dural arteriovenous fistulas. AJNR Am J Neuroradiol 2007; 28: 1415-1417 [PMID: 17698555 DOI: 10.3174/ajnr.A0663] Suzuki S, Lee DW, Jahan R, Duckwiler GR, ViГ±uela F. Transvenous treatment of spontaneous dural carotid-cavernous fistulas using a combination of detachable coils and Onyx. AJNR Am J Neuroradiol 2006; 27: 1346-1349 [PMID: 16775294] Archondakis E, Pero G, Valvassori L, Boccardi E, Scialfa G. Angiographic follow-up of traumatic carotid cavernous fistulas treated with endovascular stent graft placement. AJNR Am J Neuroradiol 2007; 28: 342-347 [PMID: 17297009] P- Reviewer Karmy-Jones R S- Editor Gou SX L- Editor Hughed D E- Editor Xiong L WJR|www.wjgnet.com 155 April 28, 2013|Volume 5|Issue 4| WJ R World Journal of Radiology World J Radiol 2013 April 28; 5(4): 156-165 ISSN 1949-8470 (online) В© 2013 Baishideng. All rights reserved. Online Submissions: http://www.wjgnet.com/esps/ wjr@wjgnet.com doi:10.4329/wjr.v5.i4.156 ORIGINAL ARTICLE Asymmetrically hypointense veins on T2*w imaging and susceptibility-weighted imaging in ischemic stroke Ulf Jensen-Kondering, Ruwen BГ¶hm vessel sign was 54% (range 32%-100%) for T2* (668 patients) and 81% (range 34%-100%) for SWI (334 patients). There was rare mentioning of interrater agreement (6 publications, 210 patients) and reliability (1 publication, 20 patients) but the numbers reported ranged from good to excellent. In most publications (n = 22) perfusion MRI was used as a validation method (617 patients). More patients were scanned in the subacute than in the acute phase (596 patients vs 320 patients). Clinical outcome was reported in 13 publications (521 patients) but was not consistent. Ulf Jensen-Kondering, Institute of Neuroradiology, University of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany Ruwen BГ¶hm, Institute of Experimental and Clinical Pharmacology, University of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany Author contributions: Jensen-Kondering U and BГ¶hm R performed the literature research, analyzed the data, and wrote and revised the paper. Correspondence to: Dr. Ulf Jensen-Kondering, MD, Institute of Neuroradiology, University of Schleswig-Holstein, Campus Kiel, Haus 41, Arnold-Heller-Str. 3, Haus 41, 24105 Kiel, Germany. ulfrjensen@web.de Telephone: +49-431-5974806 Fax: +49-431-5974913 Received: December 19, 2012 Revised: February 8, 2013 Accepted: March 6, 2013 Published online: April 28, 2013 CONCLUSION: The low presence of vessels signs on T2*w imaging makes SWI much more promising. More research is needed to obtain formal validation and quantification. В© 2013 Baishideng. All rights reserved. Abstract AIM: To review the literature on the assessment of venous vessels to estimate the penumbra on T2*w imaging and susceptibility-weighted imaging (SWI). Key words: Acute ischemic stroke; Oxygen extraction fraction; Susceptibility-weighted imaging; T2*; Penumbra METHODS: Literature that reported on the assessment of penumbra by T2*w imaging or SWI and used a validation method was included. PubMed and relevant stroke and magnetic resonance imaging (MRI) related conference abstracts were searched. Abstracts that had overlapping content with full text articles were excluded. The retrieved literature was scanned for further relevant references. Only clinical literature published in English was considered, patients with Moya-Moya syndrome were disregarded. Data is given as cumulative absolute and relative values, ranges are given where appropriate. Core tip: Thrombolytic therapy with intravenous tissue plasminogen activator is the only approved therapy for acute ischemic stroke. The detection of hypointense venous vessels with blood oxygenation level dependent (BOLD) imaging to assess the amount of penumbral tissue in acute ischemic stroke has emerged as a little noticed alternative imaging technique. In the present state the combined use of perfusion and BOLD imaging would provide further complementary information to help visualize and understand the role of the ischemic penumbra. RESULTS: Forty-three publications including 1145 patients could be identified. T2*w imaging was used in 16 publications (627 patients), SWI in 26 publications (453 patients). Only one publication used both (65 patients). The cumulative presence of hypointense Jensen-Kondering U, BГ¶hm R. Asymmetrically hypointense veins on T2*w imaging and susceptibility-weighted imaging in ischemic stroke. World J Radiol 2013; 5(4): 156-165 Available from: URL: http://www.wjgnet.com/1949-8470/full/v5/i4/156. htm DOI: http://dx.doi.org/10.4329/wjr.v5.i4.156 WJR|www.wjgnet.com 156 April 28, 2013|Volume 5|Issue 4| Jensen-Kondering U et al . Asymmetrically hypointense veins on T2* and SWI Statistical analysis Data is presented as cumulative absolute and relative percentage values. Ranges are given where appropriate. INTRODUCTION Assessment of penumbral tissue is a key concept to idenВ tify patients who may benefit from acute stroke therapy. One has to keep in mind that the penumbra cannot be regarded as a homogenous single entity but rather a graВ dient from ischemic core to normal tissue[1]. Therefore, whatever imaging method is used for penumbra detecВ tion, one or more arbitrary cut-off values need to be chosen to segment the brain image into normal tissue and ischemic core, with one or more penumbras in beВ tween. Despite oxygen-15 positron emission tomography (15O-PET) being the gold standard to define the penumВ bra[2], its clinical use is very limited due to logistical and practical reasons. As a substitute, magnetic resonance imaging (MRI) with diffusion-weighted image (DWI)perfusion-weighted image (PWI) mismatch is comВ monly used in the clinical work-up of stroke patients[3]. Although widely utilized, it has some methodological limitations. The DWI lesion does not seem to represent irreversibly damaged tissue[4], nor can PWI differentiate between penumbra and benign oligemia[5]. Recently, the use of blood oxygenation level dependent (BOLD) imВ aging as an alternative to DWI-PWI mismatch has stirred a lot of interest[6]. It is sensitive to an increased concenВ tration of deoxyhemoglobin (DHb) and may therefore be an indirect marker of oxygen metabolism. There are two approaches to detect an increased oxygen extraction fraction (OEF) using BOLD: assessment of tissue and assessment of draining veins containing an increased fraction of DHb. As the latter has been described by several authors, we will focus this review on the assessment of venous vessels to estimate the amount of penumbral tissue. We provide an overview on published data, take a glimpse at experimental studies and critically appraise the methodвЂ™s clinical value and suggest future research. RESULTS Forty-three papers, conference abstracts and reports of cases (partially from review articles) with a total of 1145 patients were identified[7-49]. For details of the reviewed studies with relevant information, see Tables 1 and 2. Sixteen publications (627 patients) were identified using T2*w imaging (Table 1)[7-22]. SWI was used in 26 publicaВ tions (453 patients, Table 2)[23-48]. In one publication both T2* and SWI was used (65 patients, Table 2)[49]. The cumulative presence of hypointense vessels was 54% (range 32%-100%) of 668 patients for T2* and 81% (range 34%-100%) of 334 patients for SWI. However, more single patient case reports were identified for SWI. Inter-rater agreement was reported in six publications (210 patients)[7,14,15,17,19,21] and ranged from good (Оє = 0.7)[14] to excellent (intraclass correlation = 0.99)[17]. The agreement between penumbra on T2*w imaging and dyВ namic susceptibility contrast (DSC)-MRI was quantified in one publication (20 patients)[17] and was 0.92 [time to peak and relative cerebral blood flow (CBF)] to 0.96 (mean transit time and relative cerebral blood volume). In most publications perfusion MRI either utilizing DSC-MRI (n = 17441 patients)[7,10-12,16,17,20,23,25,28,31-34,37,40,43] or flow sensitive alternating inversion recovery (n = 4111 paВ tients)[14,15,19,38] combined with DWI/apparent diffusion coВ efficient (ADC) was used for validation (perfusion method not stated in one publication, 65 patients[49]). In three pubВ lications one additional method was used [digital subtracВ tion angiography (DSA)[16], iodine-123 iodoamphetamine single-photon emission computed tomography [20] or magnetic resonance angiography (MRA)[43]]. Conventional MRI (DWI/ADC, MRA, structural imaging) was used in 14 publications (315 patients)[8,9,21,24,26,27,29,30,35,36,44,46,47], in three publications[39,41,45] computed tomography or clinical data were used as additional methods. Clinical informaВ tion and unspecified imaging was used in one publication (59 patients)[48]. One publication used clinical data alone (30 patients)[48]. DSA alone was used in one publication (22 patients)[13]. In one case series gold standard 15O-PET was used for validation (number of patients not stated)[18]. Time of onset ranged from 3 h to 7 d with more publications reporting on the subacute (> 6 h, n = 15579 patients)[9,12,14,15,23,24,32,34,35,38,39,40,42,44,49] than the acute phase (в‰¤ 6 h, n = 11337 patients)[7,10,11,13,16,17,19,21,22,25,47]. In one publication time from onset ranged from 3.5 to 8.5 h (49 patients)[41]. It was not provided in 16 publications (170 patients)[8,18,20,26-31,33,36,37,43,45,46,48]. Outcome was reported in 13 publications. In four publications (185 patients)[10,19,21,39] no correlation with clinical outcome was found. In four publications (107 patients)[11,13,16,22] a larger National Institute of Health Stroke Score improvement was observed, while in anВ other four publications a worse outcome was found (210 patients)[7,35,41,48]. In one publication there was a better MATERIALS AND METHODS Publications that reported on the assessment of the penumbra in ischemic stroke by hypointense vessels on T2*w imaging and/or SWI and performing at least one validation method were included. Search terms in PubMed were вЂњT2*вЂќ, вЂњGREвЂќ, вЂњSWIвЂќ, вЂњsusceptibility weighted imagingвЂќ, вЂњleptomeningeal vessels/veinsвЂќ, вЂњhyВ pointenseвЂќ, вЂњstrokeвЂќ. Full text articles and published abВ stracts from major stroke and MRI related conferences (International Stroke Conference, European Stroke Conference, World Stroke Congress, World Congress of Neurology, ISMRM, ASNR, etc.) were included in this review. Only literature published in English and dealing with human subjects was included, patients with Moya-Moya syndrome were disregarded. The reference section of retrieved publicaВ tions was manually searched for further relevant literaВ ture. Abstracts with obviously overlapping content with full text articles that were probably first presented as an abstract and subsequently published as full text articles were excluded. WJR|www.wjgnet.com 157 April 28, 2013|Volume 5|Issue 4| Jensen-Kondering U et al . Asymmetrically hypointense veins on T2* and SWI Table 1 Publications using T2*w sequences Ref. n Field strength Hermier et al[7] 49 Liebeskind et al[8] Liebeskind et al[9] Occluded Time from vessel onset Validation method Results 1.5 T Anterior circulation 6h DWI; DSC-MRI 91 83 NS NS MCA MCA MRA; DWI MRA Hermier et al[10] 48 1.5 T NS NS Median 2d 6h Seo et al[11] 20 3T ICA, MCA 6h Sohn et al[12] 86 NS ICA, MCA 12 h Ha et al[13] 22 3T MCA 6h Morita et al[14] 24 3T ICA, MCA 12 h Harada et al[15] Ha et al[16] 24 35 3T NS NS MCA 12 h 6h Kaya et al[17] 20 3T Large arteries 3h NS (case series) 33 вЂ…вЂ…2 1.5 T NS NS AVV obvious in 8/49, moderate in 15/49 patients, inter- and intra-observer reliability r > 0.9; Correlated with higher baseline NIHSS, larger DWI and PWI lesions, worse outcome, intracranial haemorrhage and more severe hemodynamic impairment Hypointense vessels in or adjacent to the infarct in 40/91 patients Unilateral hypointensity of the basal vein of Rosenthal was noted in 27/83 patients on the side of the occlusion AVLV present in 17/48 patients, within TTP lesion, not concordant with DWI lesion; No impact on clinical status and final stroke volume HVS present in 13/20 patients. Patients with asymmetrical HVS had better NIHSS improvement (8.1 В± 5.7 vs 2 В± 4.2) Present in 59/86 patients; HypoTCV associated with large perfusion defect, but low cholesterol and haemoglobin level may obscure its visibility Present in 7/22 patients. Patients with HLV showed larger baseline NIHSS (16.9 В± 3.4 vs 11.7 В± 5.3) and major improvement (в‰Ґ 8 points) was observed more often. It corresponded with delayed venous wash-out on DSA CVS present in all patients, BS present in 23/24 patients, good interobserver agreement (Оє = 0.7). Area defined by CVS/BS similar to hypoperfused area Оє for cortical and deep vessel signs 0.84 and 0.72, respectively HLV present in 12/35 patients. Patients with HLV had larger NIHSS improvement at 7 d (6.5 В± 4.6 d vs 0.5 В± 6.7 d) and bigger TTP-DWI mismatch. HLV corresponded with delayed venous wash-out Present in all patients. Very good correlation of RMHV with final infarct (r = 0.91) and MTT/rCBV lesion (r = 0.96); very high interobserver correlation (ICC = 0.99) Enhanced venous contrast (hypointensity and enlargement of veins), ipsilateral corresponding increased OEF 3T 3T ICA, MCA MCA (stenosis) 3h NS Rosso et al[21] 60 3T 6h Ryoo et al[22] 30 NS Anterior circulation ICA, MCA Kinoshita et al[18] Harada et al[19] Tada et al[20] 6h DWI; DSC-MRI DSC-MRI; DWI DSC-MRI; DWI DSA DWI; FAIR FAIR; DWI DSC-MRI; DWI; DSA DWI; DSC-MRI 15 O-PET FAIR; DWI DWI; DSC-MRI; 123 I-IMP SPECT DWI; MRI Clinical IschV present in 79% (Оє = 0.83); Not correlated with worse outcome Area defined by ischemic signs was similar to area of hypoperfusion on MRI and SPECT VTV present in 58.3% (Оє = 0.895), correlated with larger infarcts and haemorrhage but not with baseline or follow-up NIHSS GRE vein present in 15/30 patients. Early neurological improvement (в€†NIHSS в‰Ґ 8 or NIHSS в‰¤ 2 at 24 h) more frequently observed with GRE vein (8 patients vs 1 patients, P = 0.014) NS: Not stated; ICA: Internal carotid artery; MCA: Middle cerebral artery; DWI: Diffusion-weighted image; DSC-MRI: Dynamic susceptibility-contrast magnetic resonance imaging; MRA: Magnetic resonance angiography; AVV: Abnormal visibility of transcerebral veins; PWI: Perfusion-weighted image; AVLV: Abnormal visualization of leptomeningeal vessels; TTP: Time to peak; CVS: Cerebral vasospasm; BS: Brush sign; HVS: Hyperintense vessel sign; HLV: Hypointense leptomeningeal vessels; 15O-PET: Oxygen-15 positron emission tomography; CT: Computed tomography; HypoTCV: Hypointense transcerebral or cortical veins; FAIR: Flow sensitive alternating inversion recovery; 123I-IMP SPECT: Iodine-123 iodoamphetamine single-photon emission computed tomography; DSA: Digital subtraction angiography; NIHSS: National Institute of Health Stroke Score; RMHV: Region of multiple hypointense vessels; MTT: Mean transit time; rCBV: Relative cerebral blood volume; ICC: Intraclass correlation; OEF: Oxygen extraction fraction; VTV: Visibility of the transcerebral veins; GRE: Gradient-echo. clinical outcome with normalized vessel appearance after successful recanalization (19 patients)[47]. The occluded vessel was located in the anterior cirВ culation in 33 publications (864 patients)[7-9,11-14,16,19,21,22, 24-40,44-47,49] . It was not stated in seven publications (250 paВ tients)[10,15,18,23,41,42,48]. Other publications considered вЂњlarge arteriesвЂќ (20 patients)[17], the basilar artery (1 patient)[47], the posterior cerebral artery (1 patient)[46], TIA (9 paВ tients)[43] and critical MCA stenosis (2 patients)[20]. Field strength was 1.5 T in 10 publications (180 paВ tients)[7,10,18,23,25,26,31,37,40,46], 3 T in 11 publications (285 paВ tients)[11,13-15,17,19-21,28,38,39] and not stated in 22 publications (662 patients)[8,9,12,16,22,24,27,29,30,32-36,41,42,43-45,48,49] while in one publication (19 patients)[47] both field strengths were used WJR|www.wjgnet.com but not identified for individual patients. For detailed differences between T2*w imaging and SWI see Table 3. A number of terms have been used to describe the finding of hypointense venous vessels on T2*w or SWI images: Abnormal visualisation of leptoВ meningeal vessel, abnormal visualisation of transcereВ bral veins, cortical vessel sign, veins on gradient echo, hypointense leptomeningeal vessels, hypointense vessels, hypointense vessel sign, hypointense transcerebral or corВ tical veins, ischemic vessel signs, increased vessel contrast, multiple hypointense vessels and visibility of transcereВ bral veins have been used almost synonymously. A вЂњregion of multiple hypointense vesselsвЂќ describes the area that is bordered and thus defined by hypointense vessels. The 158 April 28, 2013|Volume 5|Issue 4| Jensen-Kondering U et al . Asymmetrically hypointense veins on T2* and SWI Table 2 Publications using susceptibility-weighted imaging and combining T2*w imaging and susceptibility-weighted imaging Ref. n Field strength Ida[23] Tong et al[24] Mittal et al[25] 62 1 1 1.5 T NS 1.5 T Santhosh et al[26] Tsui et al[27] Christoforidis et al[28] 1 1 6 1.5 T NS 3T Hingwala et al[29] Huisman et al[30] Mittal et al[31] 1 1 2 NS NS 1.5 T Yen et al[32] 1 NS Kesavadas et al[33] 2 NS Park et al[34] Lin et al[35] Meoded et al[36] 82 53 2 NS NS NS Gasparotti et al[37] Yamashita et al[38] 1 30 1.5 T 3T Huang et al[39] 44 3T Kao et al[40] Tsai et al[41] 15 49 1.5 T NS Meoded et al[42] Park et al[43] 8 9 NS NS Fujioka et al[44] Verschuuren et al[45] Meoded et al[46] 1 1 1 NS NS 1.5 T Baik et al[47] 19 1.5 T and 3T Tsai[48] 59 NS Sohn et al1[49] 65 NS Occluded Time from vessel onset NS MCA MCA Validation method Results 24 h 3d 2h DSC-MRI; DWI IVC were noted in 77.4%, agreement with perfusion defect in all patients ADC Prominent asymmetric medullary veins exceeding the area of the DWI lesion DWI; DSC-MRI Prominently hypointense cortical veins exceeding the area of the DWI lesion, similar to PWI lesion MCA NS DWI Prominent veins exceeding the area of the DWI lesion MCA NS DWI Prominent hypointense veins exceeding the area of the DWI lesion MCA NS DSC-MRI; DWI MHV were noted within the MTT lesion while they absent within the DWI lesion MCA NS DWI Prominent veins exceeding the area of the DWI lesion MCA NS ADC/DWI Prominent intramedullary veins exceeding the area of the DWI lesion MCA NS ADC/DWI; Prominent hypointense veins exceeding the area of the DWI lesion, similar to DSC-MRI PWI lesion MCA 4d DWI; DSC-MRI Prominent venous hypointensities exceeding the area of the DWI lesion, similar to PWI lesion MCA NS DSC-MRI; Prominent veins exceeding the area of the DWI lesion, similar to PWI lesion ADC/DWI ICA, MCA 3d DSC-MRI; DWI MHV visible in 73/82 patients, excellent agreement with TTP maps ICA, MCA 12 h Traditional MRI Hypointense transmedullary veins predisposed to worse outcome (OR = 2.2) MCA, ACA NS Conventional Prominent intramedullary veins were noted within the DWI lesion. In one MRI; DWI case prominent sulcal veins matched the area of infarct growth. ICA NS DWI; DSC-MRI SWI lesion exceeded DWI lesion and matched MTT lesion MCA 7d DWI; FAIR Increased venous contrast in 22/30 patients, area similar to hypoperfused tissue MCA 2d DWI; MRA; CT Prominent veins present in 15/44 patients; Not correlated with haemorrhage or outcome MCA 18 h DWI; DSC-MRI MTT-DWI and SWI-DWI mismatch similar to predict infarct growth NS 3.5-8.5 h MRI; Presence of hypointense veins in all patients with worse outcome and Clinical haemorrhagic complications NS 72 h DWI DWI > SWI mismatch found in 1/15 affected regions TIA NS DWI; DSC-MRI; 4/9 patients with DWI negative TIA showed asymmetric hypointense vessels, MRA in accordance with perfusion deficit and stenosed/occluded vessel ICA 10 h MRI SWI lesion exceeding DWI lesion matured into infarction MCA, ACA NS ADC; CT SWI lesion exceeding ADC lesion matured into infarction on CT MCA, PCA NS T2; ADC SWI lesion matches ADC lesion; Mismatch also noted, indicating critical perfusion ICA, MCA, Median DWI Prominent veins present in affected territory which disappeared BA 2.5 h after recanalization (10/10 patients); After recanalization within DWI lesion: Equally prominent in 10/19 patients, small DWI lesions, good clinical outcome (7 d NIHSS median 3.5, 90 d mRS median 0) indicating normalisation; Less prominent in 5/19 patients, large DWI lesions, poor clinical outcome (7 d NIHSS median 13, 90 d mRS median 4) indicating futile reperfusion; Mixed in 4/19 patients, medium DWI lesions, relatively poor outcome (7d NIHSS median 13, 90 d mRS median 2) NS NS Imaging; 34 patients improved or stable (clinical, imaging), 25 worse; SWI correlated Clinical with poor prognosis Anterior 12 h Perfusion MRI Asymmetrical HVS in 98% (SWI) and 74% (T2*w) circulation 1 Publication combining T2*w imaging and susceptibility-weighted imaging. NS: Not stated; ICA: Internal carotid artery; MCA: Middle cerebral artery; ACA: Anterior cerebral artery; ADC: Apparent diffusion coefficient; BA: Basilar artery; FAIR: Flow sensitive alternating inversion recovery; MRA: Magnetic resonance angiography; CT: Computed tomography; PCA: Posterior cerebral artery; IVC: Increased vessel contrast; TIA: Transient ischemic attack; DWI: Diffusion-weighted image; PWI: Perfusion-weighted image; MTT: Mean transit time; DSC-MRI: Dynamic susceptibility-contrast magnetic resonance imaging; NIHSS: National Institute of Health Stroke Score; mRS: Modified ranking scal; SWI: Susceptibility-weighted imaging; HVS: Hypointense vessel sign; MHV: Multiple hypointense vessels. вЂњbrush signвЂќ was described as a hypointense area along the course of subependymal and medullary veins in deep white matter. ruption in the supply of oxygen through decreased CBF. The threshold of 20 mL per 100 g/min is considered the threshold for penumbra but this value is likely to be time dependent[50]. The cerebral metabolism rate of oxygen (CMRO2) in viable, i.e., penumbral tissue is still at a near normal level (approximately 3.5 mL per 100 g/min) which causes the OEF to rise from its normal range to its theoretical maximum of 100%[51]. As can be DISCUSSION Fundamentals of the penumbra and the BOLD-signal The occlusion of a brain-supplying artery causes a disВ WJR|www.wjgnet.com 159 April 28, 2013|Volume 5|Issue 4| Jensen-Kondering U et al . Asymmetrically hypointense veins on T2* and SWI an increased CBV (pooling of DHb) without concomВ mitant change in overall flow or CMRO2 but may be detected by perfusion MRI. The phenomenon of darkВ ening veins was already observed in early experimental stroke studies and was related to an increase in DHb[52]. Red blood cells carry haemoglobin which is present as OHb and DHb. Other cellular components of blood (leucocytes, platelets) do not contribute to oxygenation related signal changes. OHb has four outer electrons one of which is shared between the chelated hem iron and oxygen which makes OHb diamagnetic. In DHb, the four unpaired outer electrons are in a high-spin state which gives it paramagnetic properties[53]. This makes DHb an endogenous contrast agent which can be noninvasively imaged with appropriate MRI techniques. DHb induces local magnetic field inhomogeВ neity in vessels and surrounding tissue and causes faster transverse relaxation decay. T2*w images pick up that process which is translated into reduced T2* signal[54]. In addition to faster transverse relaxation decay, a phase disВ persion is induced. This is exploited by SWI which comВ bines both the magnitude and the phase information and thus further enhances differences in susceptibility than T2*w imaging alone. For an in-depth explanation of the SWI technique and further clinical examples please refer to the extensive reviews by Sehgal et al[55], Haacke et al[56] and Tong et al[24]. Quantitative susceptibility mapping (QSM) is a develВ opment of SWI which utilizes the phase data. It requires further postprocessing to obtain quantitative informaВ tion on local susceptibility[57,58]. QSM may in the future be able to quantify oxygen saturation and thus provide fully quantitative and completely non-invasive informaВ tion on oxygen metabolism. The above stated pathophysiological considerations suggest that veins that appear hypointense and more pronounced in diameter may be used to assess oxygenВ ation and in the face of acute ischemic stroke also may detect metabolically active tissue. Table 3 Comparison of publications using T2*w imaging and susceptibility-weighted imaging n (%) Number of publications Presence of vessel signs Interrater agreement Reliability assessment T2*w imaging publications (patients) SWI publications (patients) 17 (692)1 54% 16 (668) Оє = 0.7 to > 0.9 and ICC = 0.99 6 (210) r = 0.92-0.96 1 (20) 27 (518)1 81% 21 (334) - Occluded vessel Anterior circulation Large arteries Critical MCA stenosis TIA BA NS Time from onset в‰¤6h >6h 3.5-8.5 h NS Outcome Worse outcome Better NIHSS improvement Better outcome with normalisation No correlation Validation method DSC-MRI FAIR Conventional MRI 15 O-PET DSA Field strength 1.5 T 3T NS - 12 (598)1 1 (20) 1 (2) 3 (72)3 22 (331)1 1 (9) 1 (1)2 4 (178) 9 (317) 5 (282) 3 (93)3 2 (18)4 12 (364)1 1 (49) 13 (87) 1 (49) 4 (107) 3 (141) 3 (161) 1 (19) 1 (44) 7 (260) 3 (81) 3 (234) 1 (NS) 1 (22) 10 (181) 1 (30) 11 (242) - 3 (97) 8 (205) 6 (390)1,3 7 (83) 3 (80) 17 (355)1,5 1 Including one publication using T2*w imaging and susceptibility-weighted imaging (SWI) (Sohn et al[49]), thus the total number of studies and patients differs from the one stated in the main text; 2Including one patient with occluded BA (Baik et al[47]); 3Number of subjects not stated (Kinoshita et al[18]); 4Including 17 patients в‰¤ 6 h and 2 patients > 6 h (Baik et al[47]); 5Including those who used 1.5 T and 3 T (Baik et al[47]). NS: Not stated; ICA: Internal carotid artery; MCA: Middle cerebral artery; BA: Basilar artery; TIA: Transient ischemic attack; DSC-MRI: dynamic susceptibility-contrast magnetic resonance imaging; FAIR: Flow sensitive alternating inversion recovery; 15O-PET: Oxygen-15 positron emission tomography; DSA: Digital subtraction angiography; NIHSS: National Institute of Health Stroke Score. Intermethod and interrater reliability The depiction of hypointense veins can provide an apВ proximation of the spatial extent of compromised oxygen metabolism. Although it has been qualitatively assessed, quantitative data is scarce. The published data however suggest that an estimation of the affected area is posВ sible and reasonably reliable. The method does not deliver quantitative information and is only an indirect indicator of OEF. The main disadvantage is the fact that the exact relationship between discernible hypointensity within the vessels and increased OEF is unknown. Recently, SWI has been indirectly validated against arterial spin labelling[59] and has also been validated against 15O-PET in patients with chronic cerebrovascular disease[60]. However, formal validaВ tion is still missing and thus only subjective though reproВ ducible[7,14,15,17,19,21] rater-dependent assessment is available. seen in Equation 1 it is described as the ratio of CMRO2 and CBF multiplied with the oxygen content of blood (CaO2). OEF = CMRO2/(CBF Г— CaO2). While the increased OEF can keep CMRO2 stable over some time it causes the concentration of DHb to increase as the oxygen is transferred from oxyhemogloВ bin (OHb) to tissue and DHb is generated (Figures 1 and 2). However, as the BOLD signal is a composite of CBF, CMRO2 and cerebral blood volume (CBV) related signal changes their individual contributions can be difficult to establish. Dilatation of veins could thus in theory lead to WJR|www.wjgnet.com T2* vs SWI There is only one publication directly comparing SWI 160 April 28, 2013|Volume 5|Issue 4| Jensen-Kondering U et al . Asymmetrically hypointense veins on T2* and SWI A OEF approximately 40% CMRO2 approximately 3.5 mL per 100 g/min CBF approximately 50 mL per 100 g/min П‡DHb 0.4-0.5 Artery Vein Capillary network B OEF > 70% CMRO2 approximately 3.5 mL per 100 g/min CBF approximately 20 mL per 100 g/min П‡DHb approximately 0.7-1 Clot in artery Vein Figure 1 Schematic drawing of brain supplying artery, capillary network and draining vein and the sequence of events leading to an increased visibility of draining veins on T2*w imaging and susceptibility-weighted imaging during acute ischemic stroke. A: In the normal brain cerebral blood flow (CBF) is approximately 40 mL per 100 g/min to sustain normal brain function. Oxygen extraction fraction (OEF) and cerebral metabolism rate of oxygen (CMRO2) are in the range of approximately 40%-50% and 3.5 mL per 100 g/min respectively. The fraction of deoxyhemoglobin (П‡DHb) provides the normal appearing venous vessels on T2*w and susceptibility-weighted imaging; B: When the blood supply is interrupted CBF drops to approximately 20 mL per 100 g/min (penumbral threshold) or < 10 mL per 100 g/min (ischemic threshold). In penumbral tissue CMRO2 can be kept stable by an increase of OEF to > 70%. In effect, П‡DHb rises to its maximum (assuming optimal arterial oxygenation) and draining veins may appear more pronounced and hypointense. T2*w d0 MTT d0 ADC d0 T2*w d15 Figure 2 Image montage of magnetic resonance imaging findings in a 46-year-old woman with a right middle cerebral artery occlusion 321 min after symptom onset and an National Institute of Health Stroke Score of 11 on admission. Note the subtle asymmetrically prominent veins (arrows) on T2*w imaging (first row) within the mean transit time (MTT) lesion (second row) but outside the apparent diffusion coefficient (ADC) lesion (third row) on the day of admission (d0). On follow-up imaging 15 d later (d15) vessel appearance has normalized (fourth row). and T2*w imaging in the same set of patients [49]. As expected, the sensitivity of T2*w imaging compared WJR|www.wjgnet.com to SWI was significant (74% vs 98%). Accordingly, the pooled presence of vessel signs on T2* compared to 161 April 28, 2013|Volume 5|Issue 4| Jensen-Kondering U et al . Asymmetrically hypointense veins on T2* and SWI SWI in the reviewed publications was considerably lower (54% vs 81%). The low presence of vessel signs in T2*w images is worrying and make SWI a much more suitable candidate sequence. SWI has long been hampered by long acquisition times of about 10 min, making it unsuitable for acute stroke studies due to extreme susceptibility to movement artefacts. This is corroborated by the fact that only three publications using SWI in the acute clinical setting could be identified[25,41,47]. By the time of writing this article however, scanning time has been reduced to about 3 min for whole brain coverage, facilitating its usage in clinical protocols. More publications and patients were included using T2*w imaging. This is not completely surprising as T2*w imaging is already incorporated in MRI stroke proВ tocols used in many institutions. However, their purpose is currently the detection of haemorrhage[61] and screenВ ing for blooming artefacts caused by thrombus in large vessel occlusion[62]. Attractively, both T2* and SWI comВ bine information on haemorrhage that would preclude thrombolytic treatment, with information on penumbral tissue. Additionally, there is no need for the application of contrast agent in the light of potential albeit small risks of anaphylactic reactions and nephrogenic systemic fibrosis. has provided very convincing results, validation with gold standard PET or at least with complementary perfusion MRI in the acute phase is still missing. Further studies especially on SWI should be conducted since the data already available seem to merit further evaluation of this technique. A reliability assessment should be conducted and, in particular the possibilities of SWI in the acute clinical setting should be evaluated. It could prove useВ ful in the non-acute setting or when no other imaging is available or when functional assessment of stenosis or occlusion is needed[65]. However, in the present state the combined use of perfusion and BOLD imaging would provide further complementary information to help visuВ alize and understand the role of the ischemic penumbra. ACKNOWLEDGMENTS We would like to thank Harry Ingleby, PhD for editing the manuscript. COMMENTS COMMENTS Background Thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rt-PA) is the only approved therapy for acute ischemic stroke. The target tissue for rt-PA therapy is the ischemic penumbra: electrically silent but viable and salvagable tissue. If no penumbra is present a given patient will only be subjected to the risks of rt-PA treatment. Thus, an accurate estimation of penumbral tissue to assess the risks and benefits of thrombolytic therapy is paramount. Clinical outcome The findings regarding clinical outcome are heterogeВ neous. The reviewed publications either indicate larger improvement measured on the National Institute of Health Stroke Scale or worse outcomes. However, this finding is not necessarily a contradiction. Larger volumes of penumbral tissue may result in worse outcome if tisВ sue at risk is not rescued by adequate therapy. The difВ ference is thus likely an effect of successful therapy and not the volume of penumbral tissue itself. Research frontiers In recent years magnetic resonance imaging (MRI) using the diffusion- and perfusion-weighted imaging mismatch concept was widely used to map the ischemic penumbra. It defines the penumbra as the difference between tissue that is terminally infarcted on diffusion weighted imaging and tissue that is undersupplied on perfusion MRI: the so-called mismatch. However, this concept proved to be an oversimplification. That is why an imaging protocol that provides insight into oxygen metabolism is needed. Innovations and breakthroughs Recently, blood oxygenation level dependent (BOLD) imaging has become a candidate sequence to map the ischemic penumbra. In short, it visualizes an increased deoxyhemoglobin (DHb) concentration. An increased DHb concentration is the signature of tissue that displays an elevated oxygen extraction fraction (OEF), a hallmark of the penumbra. Two approaches are generally used: Direct assessment of penumbral tissue, definition of penumbral tissue by draining veins. In this article the assessment of draining veins is reviewed. Preclinical basic research As stated before, there is not one penumbra but a 4-diВ mensional gradient from necrosis to healthy tissue[1]. DeВ pending on the occluded vessel, duration of ischemia, the tissue-specific vulnerability of certain areas of the brain, dynamics of reperfusion damage, etc., various necrotic and apoptotic pathways are activated. Recently, more modes of cell death have been identified[63]. Putative neuВ roprotective or neuroregenerative drugs will only work in a small window of this 4-dimensional space. Therefore, the need for MRI sequences that specifically visualize certain aspects of infarction and good segmentation alВ gorithms are needed, so the effects of the drugs can be assessed correctly and not be masked by other processes that take place during infarction. Very little preclinical basic research[64] has been done so far on the imaging method presented in this review. In conclusion, the detection of hypointense venous vessels with BOLD imaging to assess the amount of penumbral tissue in acute ischemic stroke has emerged as a little noticed alternative imaging technique. Although the data seems very encouraging and indirect validation WJR|www.wjgnet.com Applications Asymmetrically hypointense draining veins on T2*w and even more on SWI could serve as a surrogate marker for penumbral tissue. However, further validation and quantification is needed. Terminology Penumbra: Tissue that has become undersupplied and electrically silent by an acute ischemic stroke. However, this tissue is still viable and can be salvaged by therapy; OEF: The percentage of oxygen extracted from the bloodstream by brain tissue. In normal tissue about 40%, elevated in penumbral tissue up to 100%; susceptibility weighted imaging: MRI sequence that combines the signal from T2*w imaging with phase information and thus enhances the contrast. BOLD imaging: Group of imaging methods that utilize the susceptibility difference between paramagnetic DHb and diamagnetic oxyhemoglobin. Any given change in oxygenation status will alter the signal. Peer review This work represents a nice overview of what has been done in the field so far and points out that consistent reporting is necessary. However, it also points out that this is an important observation and should be more carefully studied as it could have a significant impact on the diagnosis and treatment of patients. 162 April 28, 2013|Volume 5|Issue 4| Jensen-Kondering U et al . Asymmetrically hypointense veins on T2* and SWI 3-Tesla MRI. ISMRM 17th Annual Meeting and Exhibition; 2009 Apr 18-24; Honolulu, HI 16 Ha SY, Seo SH, Bang OY, Kim GM, Chung CS, Lee KH. Hypointense leptomeningeal vessels on T2*-weighted gradient echo imaging in acute ischemic stroke is correlated with isolated focal swelling on CT. 2009 International Stroke Conference; 2009 Feb 18-20; San Diego, CA. Stroke 2009; 40: e163 17 Kaya D, DinГ§er A, Yildiz ME, Cizmeli MO, Erzen C. Acute ischemic infarction defined by a region of multiple hypointense vessels on gradient-echo T2* MR imaging at 3T. AJNR Am J Neuroradiol 2009; 30: 1227-1232 [PMID: 19346312 DOI: 10.3174/ajnr.A1537] 18 Kinoshita T, Toyoshima H, Ibaraki M, Nakamura K, Shinohara Y, Kinoshita F. Susceptibility-weighted MR imaging findings associated with misery perfusion on 15O Positron emission tomography in patients with chronic cerebrovascular disease. 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Asymmetrically hypointense veins on T2* and SWI 31 Mittal P, Kalia V, Dua S. Pictorial essay: Susceptibility-weiВ ghted imaging in cerebral ischemia. Indian J Radiol Imaging 2010; 20: 250-253 [PMID: 21423897 DOI: 10.4103/0971-3026. 73530] 32 Yen JC, Lai YJ, Chan L. Middle cerebral artery susceptibility sign and venous prominence in acute ischemic stroke. Neurol India 2010; 58: 620-621 [PMID: 20739807 DOI: 10.4103/00283886.68672] 33 Kesavadas C, Thomas B, Pendharakar H, Sylaja PN. Susceptibility weighted imaging: does it give information similar to perfusion weighted imaging in acute stroke? J Neurol 2011; 258: 932-934 [PMID: 21116823 DOI: 10.1007/s00415010-5843-6] 34 Park KP, Lee W, Yang TI, Park MG, Oh SJ, Baik SK. Multiple hypointense vessels on susceptibility-weighted imaging represent diffusion-perfusion mismatch in acute ischemic stroke. 20th World Congress of Neurology; 2011 Nov 12-17; Marrakesh, Morocco 35 Lin C, Lai Y, Chen L, Guo W. Use of susceptibility-weighted imaging to predict the outcome of large vessel occlusion disease. ASNR 49th Annual Meeting; 2011 Jun 4-9; Seattle, WA 36 Meoded A, Poretti A, Chalian M, Tekes A, Huisman TAG. Susceptibility-weighted imaging: A potential noninvasive imaging tool for characterizing ischemic brain injury? ASNR 49th Annual Meeting; 2011 Jun 4-9; Seattle, WA 37 Gasparotti R, Pinelli L, Liserre R. New MR sequences in daily practice: susceptibility weighted imaging. A pictorial essay. Insights Imaging 2011; 2: 335-347 [PMID: 22347957 DOI: 10.1007/s13244-011-0086-3] 38 Yamashita E, Kanasaki Y, Fujii S, Tanaka T, Hirata Y, Ogawa T. Comparison of increased venous contrast in ischemic stroke using phase-sensitive MR imaging with perfusion changes on flow-sensitive alternating inversion recovery at 3 Tesla. Acta Radiol 2011; 52: 905-910 [PMID: 21844118 DOI: 10.1258/ar.2011.110159] 39 Huang P, Chen CH, Lin WC, Lin RT, Khor GT, Liu CK. Clinical applications of susceptibility weighted imaging in patients with major stroke. J Neurol 2012; 259: 1426-1432 [PMID: 22186853 DOI: 10.1007/s00415-011-6369-2] 40 Kao HW, Tsai FY, Hasso AN. Predicting stroke evolution: comparison of susceptibility-weighted MR imaging with MR perfusion. Eur Radiol 2012; 22: 1397-1403 [PMID: 22322311 DOI: 10.1007/s00330-012-2387-4] 41 Tsai FY, Kao HW, Chan W. Susceptibility-weighted (MR) imaging as prognostic indicator for patient selection with endovascular therapy of acute stroke. ASNR 50th Annual Meeting; 2012 Apr 21-26; New York, NY 42 Meoded A, Poretti A, Tekes A, Huisman TAGM. Evaluation of the ischemic penumbra with susceptibility-weighted imaging in children affected with arterial ischemic stroke. ASNR 50th Annual Meeting; 2012 Apr 21-26; New York, NY 43 Park KP, Lee WH, Park MG, Yang TI, Oh SJ, Baik SK. Susceptibility-weighted imaging in hemispheric transient ischemic attack with negative diffusion-weighted imaging. 21st European Stroke Conference; 2012 May 22-25; Lisbon, Portugal. Cerebrovasc Dis 2012; 33 (Suppl 2) 44 Fujioka M, Takahashi M, Tada Y, Asai H, Iwamura A, Ito S, Watanabe T, Kawai Y, Seki T, Fukushima H, Urizoni Y, Hata M, Akashi T, Taoka T, Okuchi K. вЂњDWI-SWIвЂќ mismatch may represent ischemic penumbra in acute stroke. 21st European Stroke Conference, 2012 May 22-25; Lisbon, Portugal. Cerebrovasc Dis 2012; 33 (Suppl 2) 45 Verschuuren S, Poretti A, Buerki S, Lequin MH, Huisman TA. Susceptibility-weighted imaging of the pediatric brain. AJR Am J Roentgenol 2012; 198: W440-W449 [PMID: 22528925 DOI: 10.2214/AJR.11.8049] 46 Meoded A, Poretti A, Northington FJ, Tekes A, Intrapiromkul J, Huisman TA. Susceptibility weighted imaging of the neonatal brain. Clin Radiol 2012; 67: 793-801 [PMID: 22341186 DOI: 10.1016/j.crad.2011.12.004] WJR|www.wjgnet.com 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 164 Baik SK, Choi W, Oh SJ, Park KP, Park MG, Yang TI, Jeong HW. Change in cortical vessel signs on susceptibility-weighted images after full recanalization in hyperacute ischemic stroke. Cerebrovasc Dis 2012; 34: 206-212 [PMID: 23006622 DOI: 10.1159/00034148] Tsai FY. Does mismatch of DWI and PWI mean penumbra with viable brain? 8th World Stroke Congress; 2012 Oct 10-13; Brasilia, Brazil Sohn C, Kim J, Chang H, Sohn S, Chung E. Value of susceptibility-weighted imaging in acute ischemic stroke with perfusion defect. ASNR 47th Annual Meeting; 2009 May 16-21; Vancouver, BC Baron JC. Mapping the ischaemic penumbra with PET: a new approach. Brain 2001; 124: 2-4 [PMID: 11133782 DOI: 10.1093/brain/124.1.2] Baron JC. Mapping the ischaemic penumbra with PET: implications for acute stroke treatment. Cerebrovasc Dis 1999; 9: 193-201 [PMID: 10393405 DOI: 10.1159/000015955] Meyer JS. Circulatory changes following occlusion of the middle cerebral artery and their relation to function. J Neurosurg 1958; 15: 653-673 [PMID: 13599056 DOI: 10.3171/ jns.1958.15.6.0653] Pauling L, Coryell CD. The Magnetic Properties and Structure of Hemoglobin, Oxyhemoglobin and Carbonmonoxyhemoglobin. Proc Natl Acad Sci USA 1936; 22: 210-216 [PMID: 16577697 DOI: 10.2307/86720] Chavhan GB, Babyn PS, Thomas B, Shroff MM, Haacke EM. Principles, techniques, and applications of T2*-based MR imaging and its special applications. Radiographics 2009; 29: 1433-1449 [PMID: 19755604 DOI: 10.1148/rg.295095034] Sehgal V, Delproposto Z, Haacke EM, Tong KA, Wycliffe N, Kido DK, Xu Y, Neelavalli J, Haddar D, Reichenbach JR. Clinical applications of neuroimaging with susceptibilityweighted imaging. J Magn Reson Imaging 2005; 22: 439-450 [PMID: 16163700 DOI: 10.1002/jmri.20404] Haacke EM, Mittal S, Wu Z, Neelavalli J, Cheng YC. Susceptibility-weighted imaging: technical aspects and clinical applications, part 1. AJNR Am J Neuroradiol 2009; 30: 19-30 [PMID: 19039041 DOI: 10.3174/ajnr.A1400] Haacke EM, Tang J, Neelavalli J, Cheng YC. Susceptibility mapping as a means to visualize veins and quantify oxygen saturation. J Magn Reson Imaging 2010; 32: 663-676 [PMID: 20815065 DOI: 10.1002/jmri.22276] Tang J, Liu S, Neelavalli J, Cheng YC, Buch S, Haacke EM. Improving susceptibility mapping using a threshold-based K-space/image domain iterative reconstruction approach. Magn Reson Med 2013; 69: 1396-1407 [PMID: 22736331 DOI: 10.1002/mrm.24384] Zaitsu Y, Kudo K, Terae S, Yazu R, Ishizaka K, Fujima N, Tha KK, Haacke EM, Sasaki M, Shirato H. Mapping of cerebral oxygen extraction fraction changes with susceptibilityweighted phase imaging. Radiology 2011; 261: 930-936 [PMID: 22031711 DOI: 10.1148/radiol.11102416] Kinoshita T, Kinoshita F, Shinohara Y. T2*-weighted gradient-echo type echo planar imaging in diagnosis of ischemic stroke. ASNR 48th Annual Meeting; 2010 May 15-20; Boston, MA Schellinger PD, Jansen O, Fiebach JB, Hacke W, Sartor K. A standardized MRI stroke protocol: comparison with CT in hyperacute intracerebral hemorrhage. Stroke 1999; 30: 765-768 [PMID: 10187876 DOI: 10.1161/01.STR.30.4.765] Cho KH, Kim JS, Kwon SU, Cho AH, Kang DW. Significance of susceptibility vessel sign on T2*-weighted gradient echo imaging for identification of stroke subtypes. Stroke 2005; 36: 2379-2383 [PMID: 16224077 DOI: 10.1161/01.STR.0000 185932.73486.7a] Galluzzi L, Kroemer G. Necroptosis: a specialized pathway of programmed necrosis. Cell 2008; 135: 1161-1163 [PMID: 19109884 DOI: 10.1016/j.cell.2008.12.004] Christoforidis GA, Yang M, Mohammad YM, Abduljalil April 28, 2013|Volume 5|Issue 4| Jensen-Kondering U et al . Asymmetrically hypointense veins on T2* and SWI A, Heverhagen JT, Chakeres DW, Knopp MV. Imaging of Microvascularity During Acute Ischemic Stroke with and without Intravascular Contrast Agent on High-Resolution Ultra-High Field MRI in a Rodent Model with Histopathologic Correlation. ASNR 42nd Annual Meeting; 2004 Jun 65 5-11; Seattle, WA Kesavadas C, Santhosh K, Thomas B. Susceptibility weighted imaging in cerebral hypoperfusion-can we predict increased oxygen extraction fraction? Neuroradiology 2010; 52: 1047-1054 [PMID: 20567811 DOI: 10.1007/s00234-010-0733-2] P- Reviewer Moser E S- Editor Gou SX L- Editor A E- Editor Xiong L WJR|www.wjgnet.com 165 April 28, 2013|Volume 5|Issue 4| WJ R World Journal of Radiology World J Radiol 2013 April 28; 5(4): 166-172 ISSN 1949-8470 (online) В© 2013 Baishideng. All rights reserved. Online Submissions: http://www.wjgnet.com/esps/ wjr@wjgnet.com doi:10.4329/wjr.v5.i4.166 BRIEF ARTICLE Microstructural analysis of pineal volume using trueFISP imaging Jan M Bumb, Marc A Brockmann, Christoph Groden, Ingo Nolte 3 mm ), and the median parenchyma volume was 53.6 3 3 mm (71.9 В± 66.7 mm ). In cystic glands, the standard deviation of the PGV was substantially higher than in solid glands (98% vs 58% of the mean). PGV declined with age (r = -0.130, P = 0.016). Jan M Bumb, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany Marc A Brockmann, Christoph Groden, Ingo Nolte, Department of Neuroradiology, University Hospital Mannheim, 68167 Mannheim, Germany Marc A Brockmann, Department of Diagnostic and Interventional Neuroradiology, University Hospital of the RWTH Aachen, 52074 Aachen, Germany Author contributions: Bumb JM and Nolte I performed the majority of the experiments; Nolte I and Bumb JM designed the study and wrote the manuscript; Brockmann MA and Groden C edited the manuscript. Correspondence to: Dr. Ingo Nolte, PD, Department of Neuroradiology, University Hospital Mannheim, Theodor-KutzerUfer 1-3, 68167 Mannheim, Germany. ingo.nolte@medma.uni-heidelberg.de Telephone: +49-621-3832443 Fax: +49-621-3832165 Received: December 5, 2012 Revised: January 11, 2013 Accepted: February 5, 2013 Published online: April 28, 2013 CONCLUSION: The high interindividual volume variation is mainly related to cysts. Pineal parenchyma volume decreased slightly with age, whereas genderrelated effects appear to be negligible. В© 2013 Baishideng. All rights reserved. Key words: Pineal gland volume; Pineal cyst; Magnetic resonance imaging; Etiology; Reference range Bumb JM, Brockmann MA, Groden C, Nolte I. Microstructural analysis of pineal volume using trueFISP imaging. World J Radiol 2013; 5(4): 166-172 Available from: URL: http://www. wjgnet.com/1949-8470/full/v5/i4/166.htm DOI: http://dx.doi. org/10.4329/wjr.v5.i4.166 Abstract AIM: To determine the spectrum of pineal microstructures (solid/cystic parts) in a large clinical population using a high-resolution 3D-T2-weighted sequence. INTRODUCTION The enormous interindividual variation of the pineal gland complicates radiological evaluations. Frequently, cases with a presumably enlarged solid or cystic pineal gland cannot be classified due to the lack of reliable data for comparison. The differential diagnosis of pineal enlargements includes pineal neoplasms, such as pineocytoma, pinealoblastoma and germinoma. For the definition of normal pineal volume and morphometry, cross-sectional imaging studies have not yet provided sufficient data. A slice thickness of 4 mm to 10 mm is used for computed tomography, and most magnetic resonance imaging (MRI) suggest that this structure has a mean size of 6-10 mm[1]. Recently, high-resolution 3D-MRI (1 mm isotropic voxel size or less) has been applied for the characterization of the pineal gland in more METHODS: A total of 347 patients enrolled for cranial magnetic resonance imaging were randomly included in this study. Written informed consent was obtained from all patients. The exclusion criteria were artifacts or mass lesions prohibiting evaluation of the pineal gland in any of the sequences. True-FISP-3D-imaging (1.5-T, isotropic voxel 0.9 mm) was performed in 347 adults (55.4 В± 18.1 years). Pineal gland volume (PGV), cystic volume, and parenchyma volume (cysts excluded) were measured manually. RESULTS: Overall, 40.3% of pineal glands were cystic. 3 3 The median PGV was 54.6 mm (78.33 В± 89.0 mm ), 3 the median cystic volume was 5.4 mm (15.8 В± 37.2 WJR|www.wjgnet.com 166 April 28, 2013|Volume 5|Issue 4| Bumb JM et al . Pineal volume and microstructure in trueFISP imaging detail[2-5] and for 3D-volumetry of the pineal gland[5,6]. Bumb et al[6] measured pineal volume in a clinical pediatric population, whereas a study by Sun et al[5] included young Chinese adults aged 20-30 years (n = 112) with the intention of assisting in the early diagnosis of small pineal lesions. The authors of that study concluded that the exploration of a larger age range is required to define the reference values of high resolution 3D-volumetry for clinical evaluations. Therefore, the principal goal of our study is to provide a reference range for pineal volume (and the number and size of cystic changes) in a broader clinical population ranging from young adulthood to old age. Moreover, prior histological and high-resolution MRI studies have indicated that there is high interindividual variability in the size of the pineal gland[4,7,8]. The extent of this variability is unique among the organs of the central nervous system. Although cysts are a common finding in autoptic[7,8] and imaging studies[4], the degree to which cysts and solid parenchyma contribute to this variability is not known. Consequently, we used high-resolution 3D-MRI to analyze in detail which morphological part of the pineal gland (cystic or solid part) contributes to the high variability. As the underlying causes of the variability are not well understood, we further investigated the effect of age and gender on the volume and microstructure of the pineal gland. FISP images using the OsiriX volume quantification tool. If cysts were detected in the trueFISP imaging, then the total cyst volume (TCV) was also measured. Pineal parenchyma volume (PPV) was defined as PGV-TCV. To determine the intrarater variability, the same evaluator assessed all datasets a second time with a time gap of three weeks. To determine the interrater variability, a second evaluator unaware of the results of the first evaluation assessed ten randomly chosen datasets. Ethical approval The local ethics committee waived ethical approval of this study. Statistical analysis For the statistical analysis, SPSS 18.0 (IBM, IL, United States) was used. To determine intra- and interrater variability of the volume measurements, the Pearson correlation coefficient and the paired samples t test was used. StudentвЂ™s t test was used to detect gender differences in PGV, PPV and TCV. The Pearson correlation coefficient was computed for the relationship between age and PPV, TCV, and number of cysts. For all tests, a significance level of 0.05 was used. Descriptive values are given as the mean В± SD if not otherwise specified. RESULTS Reliability of measurements To assess intrarater variability, all 347 datasets were assessed twice by one evaluator with a time gap of three weeks (PPV: mean of first assessment 71.9 В± 66.6 mm3, mean of second assessment 72.3 В± 66.8 mm3). The Pearson correlation coefficient was 0.999 (P < 0.001). There was no difference between the evaluations (P < 0.001). To assess interrater variability, ten of the 347 datasets were randomly chosen and assessed by a second evaluator. There was no difference between the two evaluators for these ten datasets (P < 0.05). The Pearson correlation coefficient between both evaluators was 0.829 (P = 0.003). The coefficients indicate an adequately high reliability. MATERIALS AND METHODS Population and MRI protocol A total of 347 patients enrolled for cranial MRI were randomly included in this study. Written informed consent was obtained from all patients. The exclusion criteria were artifacts or mass lesions prohibiting evaluation of the pineal gland in any of the sequences. MRI scans were performed using two 1.5-T scanners (Siemens Sonata and Avanto, Siemens, Erlangen, Germany). The MR sequences for all patients included transversal T1weighted spin echo (T1-SE, TR/TE 434/11), T2-weighted turbo spin echo (T2-TSE, TR/TE 3900/101), fluid-attenuated inversion recovery (TR/TI/TE 9000/2500/89, all 24 slices, 5 mm slice thickness, 20% gap, field of view 205 mm Г— 230 mm, matrix 448 mm Г— 304 mm), and true fast imaging with steady state precession (trueFISP, TR/ TE 7.1/3.5, field of view 178 mm Г— 220 mm, matrix 212 mm Г— 275 mm, 36 slices, slice thickness 800 Ојm). A diagnosis for each patient was extracted from the medical records. Population The study population comprised 347 individuals (55.4 В± 18.1 years, range 19-94 years; 47.0% female and 53.0% male). The diagnoses included intracranial neoplasm [glioma (12.1%), meningioma (4.3%), metastasis (5.2%), and other intracranial neoplasm (4.9%)], ischemia (25.4%), hemorrhage (3.7%), inflammatory disease of the central nervous system (3.5%), epilepsy (1.7%), hydrocephalus (9.5%), other diagnosis (13.5%), and normal findings (16.1%). Figure 1 illustrates the smallest and largest solid pineal gland as well as the largest monocystic gland. The mean PGV, PPV and TCV values are shown in Table 1. Of the 347 pineal glands, 40.3% contained cysts. More than 10% were multicystic (29.1% with one cyst, 9.5% with two cysts, 1.2% with three cysts, 0.3% with four cysts and 0.3% with five cysts). Evaluation All images were evaluated digitally using OsiriX software (www.osirix-viewer.com). Two experienced neuroradiologists blinded to the clinical information evaluated the images. Pineal gland volume (PGV) was measured as describВ ed previously[4,9]. In brief, the contour of the pineal gland was manually traced on transversal reconstructed true- WJR|www.wjgnet.com 167 April 28, 2013|Volume 5|Issue 4| Bumb JM et al . Pineal volume and microstructure in trueFISP imaging Table 1 Morphometric characteristics of 347 pineal glands Gender Age (yr) F/M > 18 (n = 347) PGV (mL) Median mean В± SD PPV (mL) Median mean В± SD TCV (mL) Median mean В± SD Number of cysts (in cystic glands) Cystic glands PPVsolid Median mean В± SD F > 18 (n = 163) F 18-39 (n = 28) F 40-59 (n = 63) F 60-79 (n = 57) F > 80 (n = 15) 54.6 54.6 73.0 54.6 50.1 54.9 78.3 В± 89.0 82.0 В± 107.8 118.5 В± 191.7 78.8 В± 78.7 72.3 В± 88.9 64.3 В± 31.9 M > 18 (n = 184) M 18-39 (n = 41) M 40-59 (n = 59) M 60-79 (n = 79) M > 80 (n = 5) 54.6 77.8 58.0 51.3 75 В± 68.3 102.7 В± 99.9 56.2 В± 31.1 77.8 В± 65.5 27.2 26.1 В± 7.1 53.6 53.6 69.8 53.6 48.4 54.9 53.5 73.3 58.0 51.3 71.9 В± 66.7 74.0 В± 78.1 100.8 В± 133.4 72.1 В± 60.0 66.3 В± 66.5 61.4 В± 27.1 70.1 В± 55.0 92.3 В± 74.5 54.6 В± 28.0 72.9 В± 55.5 27.2 25.9 В± 6.9 5.4 5.3 15.8 В± 37.2 18.6 В± 46.7 1.3 В± 0.6 1.3 В± 0.6 40.3% 42.9% 42.7 42.1 46.6 В± 26.8 45.0 В± 23.0 6.3 30.9 В± 77.8 1.3 В± 0.4 57.1% 38.2 41.9 В± 22.0 6.3 4.7 15.6 В± 29.3 16.6 В± 40.7 1.4 В± 0.6 1.2 В± 0.5 42.9% 36.8% 3.2 7.3 В± 8.3 1.3 В± 0.5 40.0% 5.4 5.3 12.9 В± 24.3 20.2 В± 36.4 1.4 В± 0.7 1.2 В± 0.4 38.0% 51.2% 2.5 5.7 В± 7.4 1.5 В± 1.2 28.8% 8.4 1.0 12.3 В± 19.3 1.0 (n = 1) 1.4 В± 0.6 1 (n = 1) 39.2% 43.7 37.3 48.5 43.4 46.6 45.4 42.9 43.7 В± 19.0 45.4 В± 27.5 52.6 В± 20.9 47.9 В± 29.6 52.5 В± 29.2 47.7 В± 24.4 48.2 В± 34.4 20.0% 24.2 25.0 В± 7.7 F: Female; M: Male; PGV: Pineal gland volume; PPV: Pineal parenchyma volume; TCV: Total cyst volume. A B AC C rd 3 V Habenula CP QC SP 10 mm P P CP SP M Figure 1 TrueFISP imaging of the pineal region illustrating the spectrum of pineal volumes and cysts. A, B: Solid glands. Smallest pineal parenchyma volume (PPV), 5 mm3, the small pineal gland can hardly be demarcated from the habenula (A); largest PPV, 228 mm3 (B); C: Largest single cyst, 189 mm3. The pineal gland was axially reformatted along its long axis. the cystic part (CP) of the pineal gland is larger than the solid part (SP) and accounts for most of the pineal volume. Upper row: Axial reconstruction; Lower row: Sagittal reconstruction. 3rd V: Third ventricle; AC: Anterior commissure; M: Mesencephalon; P: Pineal gland; QC: Quadrigeminal cistern. Influence of gender The differences in the median PGV, PPV, and TCV between females and males were subtle (Table 1). The median PGV was equivalent in females and males. The median PPV was slightly higher in females, whereas the median TCV was higher in males. The mean PGV and PPV were slightly higher in females than in males, but the difference was far from significant (P = 0.464 and P = 0.586, respectively) (Table 1 and Figure 2A and B). Females displayed almost 6% more cystic glands than males. However, females had a smaller mean TCV, although this difference was not significant (Table 1 and Figure 2C and D). WJR|www.wjgnet.com There was no difference with respect to the number of cysts (P = 0.516) (Table 1). In both females and males, PGV, PPV, and TCV had high standard deviations (Table 1), indicating high interindividual variations. To focus on the relationship between pineal parenchyma and gender, we factored out any possible effect of the cysts and analyzed only the solid glands (PPVsolid in Table 1). Interestingly, even in this case, the difference between the sexes was still negligible. Females: In women (n = 163), the mean PPV decreased with age (Figure 2A) (r = -0.13, P = 0.097). Among the cysts in females, TCV exhibited a weakly negative cor- 168 April 28, 2013|Volume 5|Issue 4| Bumb JM et al . Pineal volume and microstructure in trueFISP imaging Y = 105.67 - 0.56X 800 RВІ = 0.02 B 800 Y = 94.67 - 0.45X RВІ = 0.02 Pineal parenchyma (mm ) 600 3 3 Pineal parenchyma (mm ) A 400 200 600 400 200 0 0 20 40 60 80 100 20 40 Age (yr) 300 Y = 30.56 - 0.22X D 300 80 100 Y = 24.07 - 0.21X RВІ = 0.03 3 Total cyst volume (mm ) RВІ = 0.01 3 Total cyst volume (mm ) C 60 Age (yr) 200 100 200 100 0 0 20 40 60 80 100 20 Age (yr) 40 60 80 100 Age (yr) Figure 2 Regression diagram of pineal parenchyma and age. A, B: In both females (A) and males (B), the mean pineal parenchyma volume decreased slightly with age; C, D: In both females (C) and males (D), the total cystic volume of the pineal gland decreased slightly with age. Dotted line: Linear regression and 95% mean prediction interval. slightly worse (R2 = 0.003, Y = 51.13 - 0.079X), which highlights that the effect of age on the pineal volume is minor. relation with age (Figure 2C). TCV and number of cysts showed no significant correlation with age (P = 0.455). TCV showed a strong positive correlation with PPV (P < 0.001, Pearson correlation coefficient 0.934). Interindividual variation: Secondary to the solid or cystic component? The median and mean PGV, PPV, TCV, and the PPVcystic/solid values are shown in Table 1. The expected high interindividual variability of PGV is reflected by a standard deviation of 114% of the mean PGV (PGV 78.3 В± 89.0 mm3). To answer the question of whether the interindividual variation of the PGV is secondary to the solid or cystic component, the standard deviations of the solid and cystic glands were compared. The standard deviation of the PGVsolid was 58% of the mean (46.6 В± 26.8 mm3). This variation suggests that substantial variation is secondary to the solid parenchyma. The standard deviation of PGVcystic was 98% of the mean (125.2 В± 122.2 mm3), emphasizing the high influence of the cystic component. Accordingly, TCV shows a high variation. Taken together, the variation in the cystic component of the pineal gland adds more to the variation than the solid component. Males: In men (n = 184), the mean PPV exhibited a weakly negative correlation with age (P = 0.044, r = -0.149) (Table 1 and Figure 2B). Regarding cysts in males, TCV showed a weakly negative correlation with age, although this correlation was not significant (Figure 2D). The number of cysts showed no significant correlation with age (P = 0.744, r = -0.024). Similar to women, TCV was strongly correlated with PPV in men (P < 0.001, Pearson correlation coefficient 0.846). Influence of age PPV declined with age (r = -0.135, P = 0.012). PGV also declined with age (r = -0.130, P = 0.016). There were no significant correlations between age and the number of pineal cysts (P = 0.242) and between age and the TCV (P = 0.190). To exclude a potential effect of the cysts on the volume measuring procedure, we analyzed the solid glands separately (n = 207). Here, the correlation with age was WJR|www.wjgnet.com 169 April 28, 2013|Volume 5|Issue 4| Bumb JM et al . Pineal volume and microstructure in trueFISP imaging influence the sensitivity. Theories concerning the pathogenesis of pineal cysts include a dysontogenetic residual of the embryonic pineal diverticulum and a degeneration within a glial plaque or within a cluster of pinealocytes[16,21-23]. A significant effect of the degenerative hypothesis would entail more and possibly larger cysts with increasing age. We found no correlation either between age and TCV or between age and the number of cysts. This result is a strong argument against a significant influence of age on most pineal cysts. The stable TCV and the stable number of cysts support the assumption that the dysontogenetic mechanism is predominant for the formation of pineal cysts. Some authors suggest that pineal cysts are subject to hormonal influence[16,24]. In our study, we analyzed the prevalence, number of cysts, and cystic pineal volume but did not find significant gender differences. Other high-resolution MRI studies analyzing cyst prevalence reported that these values were slightly higher in females[2] or that there was no difference between males and females[5]. Nevertheless, longitudinal studies are necessary to fully answer this question with respect to hypothetical volume changes during the menstrual cycle. Phylogenetically, the pineal gland is a very old structure. It is present not only in almost all mammals but also in a number of lizards, fishes, reptiles (but not in crocodiles), birds, and even probably in certain dinosaurs (brachiosaurus, among others)[25]. An interesting finding is that across the different species, the volume appears to be dependent on both the degree of latitude (the more distant from the equator, the larger the volume) and nocturnality and diurnality (e.g., a smaller volume in owls and a larger volume in horses). In humans, the variation in brain structures is relatively small; for example, the hippocampus volume of young and healthy adults varies by approximately < 10% of the mean (SD of the mean)[26]. In contrast, the pineal weight has been reported to vary approximately 50% in an autopsy study, with an estimated volume range from 20 to 330 mm3[7]. A study of young Chinese adults (20 to 30 years) reported a mean pineal volume of 95 В± 31 mm3[27]. Despite the observation that pineal cysts are very common (13%-57% in high resolution 3D-imaging, depending on the sequence, resolution and minimal diameter[2,4-6]), until now, whether there is вЂњtrueвЂќ variation in the hormone-producing parenchyma or whether the cysts are the cause of the high variability in humans was not clear. To clarify whether the variation in PGV is secondary to the cystic and/or solid compartments, we determined that the volume variation in cystic glands was much higher (almost twice) than in purely solid glands (as a percent of the mean). This finding is contrary to the study by Sun et al[5], who reported higher variations in solid than in вЂњmacrocysticвЂќ glands (standard deviation 29 mm3 vs 20 mm3). In this study, however, the small sample size of the macrocystic group (n = 7) might explain the contraintuitive finding. Although the high variation of cystic glands may not DISCUSSION The pineal gland is an important neuro-endocrine organ located in the center of the brain. It is one of the circumventricular organs lacking a blood-brain barrier[10]. Its major function is circadian production of the hormone melatonin, the most important hormone in chronobiology[11]. The distinction between normal pineal tissue and a small tumor can be problematic. In T1- and T2-weighted imaging, the signal characteristics are similar[12,13]. As the pineal gland lacks a blood-brain barrier, a distinction by simple enhancement differences is not possible. Therefore, the establishment of normal reference values of the pineal volume is important for their evaluation. The development of new techniques has improved the radiological precision of pineal imaging. Before the introduction of high-resolution 3D-sequences, PGV could only be estimated indirectly from two-dimensional measurements. This estimation included the measurement of up to three diameters and a geometric model (for example: globe). However, the shape of the pineal gland is known to be highly variable[14], and consequently, there is only a very weak correlation between the estimated volume and the true volumetric value[5]. Until now, no study has directly quantified volume in adults older than thirty years. Two studies used direct volume quantification for pediatric patients[6] and for young male adults up to 30 years of age[5]. For clinical practice, however, a much broader age range is necessary[5]. For the first time, we present precise volumetric data covering the whole spectrum of adulthood. For young adults[5], a mean pineal volume of 94 mmВі was found. In our study, the mean for this age group (18-39 years) was higher (109 mmВі). Although differences in the population may play a role, the choice of the volumetric sequence may also be influential [Sun et al[5] used non-isotropic T1-weighted 3D-sequence (fast spoiled gradient echo)]. Because the contrast of a small structure surrounded by the cerebrospinal fluid is obviously higher in heavily T2-weighted imaging than in T1-weighted imaging, we opted for the trueFISP sequence, an isotropic heavily T2weighted 3D-sequence. As a consequence, the observed organ border volumes were more precise, the partial volume effects were minimized, and the volumes measured were more valid. Sequence choice was also the reason for the higher prevalence of pineal cysts in our analysis. Pineal cysts were detected in 40.3% of the participants in the present study, which is in good agreement with histological studies reporting prevalences of 39.1%[7]. Similar prevalences were reported for trueFISP imaging by Nolte et al[4] and Bumb et al[6] (35.1% in adults and 57.4% in children). The studies using T1-weighted 3D-sequences by Pu et al[2] and Sun et al[5] found prevalences of only 25% and 23%, respectively. Previous MRI studies using 2D-sequences with a slice thickness of more than 3 mm reported substantially lower prevalences of 0.14%-4.3%[15-20]. Obviously, both the chosen sequence and the resolution may WJR|www.wjgnet.com 170 April 28, 2013|Volume 5|Issue 4| Bumb JM et al . Pineal volume and microstructure in trueFISP imaging a large population. These data can be used as reference values for radiological comparison and reflect an enormous spectrum of morphological variability. The results suggest that most of the high interindividual volume variation is secondary to cysts. Pineal parenchyma volume decreased slightly with age, whereas gender-related effects appear to be negligible. be surprising, the observation that the variation in the solid glands was considerably high in both women and men throughout the different age groups is important for the evaluation of the pineal gland and has not been reported so far. Similar striking interindividual differences have been reported for the production of melatonin[28-30]. In a pilot study, Nolte et al[3] indicated that the production of melatonin was linked to the volume of the solid pineal tissue. Interestingly, the high variability of the solid pineal volume reported here appears to mirror the highly varying melatonin production in adults. The reason for the high interindividual variability of the pineal volume is not clear. By studying this variability with respect to age, we found a weakly significant negative correlation (r = -0.130). In other words, only approximately 1.69% (R2) of the variance can be explained by the influence of age, indicating that there is only a slight decrease in the pineal volume with age. Whether genetic factors are involved remains to be elucidated. Herein, we report directly measured pineal volume parameters in a large clinical population. The results can be used as a reference for clinical research and radiological evaluations. The high interindividual variability of the pineal volume is secondary mainly to the variability of the cystic compartment and, to a lesser degree, to the solid compartment. Our study suggests that PPV and TCV decrease slightly with age and that there is no substantial effect of gender. Terminology The pineal gland is an endocrine gland localized in the diencephalon of the human brain. Its major task is the synthesis and release of melatonin, a very versatile hormone regulating many physiological body functions. The pineal gland is localized at the dorsal wall of the third ventricle, in front of the superior colliculi of the quadrigeminal plate and under the splenium of the corpus callosum. The habenulae connect the pineal gland to the thalamus. Peer review The authors reported their results of measured pineal volume parameters using a high-resolution 3D-T2-weighted trueFISP-3D-imaging sequence. The study is done in a large clinical population (347 adults). The conclusion is that most of the high pineal volume variation is secondary to cysts. This group is a very large population compared to that reported in literatures. Therefore, the results are more convincing and provide useful reference for evaluation of the pineal volume clinically. REFERENCES 1 2 3 COMMENTS COMMENTS Background 4 The knowledge regarding pineal gland volume (PGV) and microstructure is fragmentary only. Cross-sectional imaging studies have not yet provided sufficient data on the definition of normal pineal volume and morphometry. Consequently, the enormous interindividual variation of the pineal gland frequently complicates the radiological evaluation in radiological practice. Especially, large solid or cystic pineal glands cannot be satisfactory classified. Therefore, their study was designed to determine and accurately describe the spectrum of pineal volume and microstructures (solid/cystic parts) in a large clinical population using a high-resolution 3D-T2-weighted sequence. 5 6 Research frontiers The development of new techniques has improved the radiological precision of pineal imaging. Up to now, PGV was estimated indirectly from two-dimensional measurements. These estimations were based on the measurement of up to three diameters and a geometric model (for example: globe). However, there is only a very weak correlation between the estimated volume and the true volumetric value. Furthermore, the relatively high slice thicknesses precluded an accurate measurement of the pineal volume. Therefore authors used a highresolution 3D-sequence to determine the pineal volume. 7 8 Innovations and breakthroughs For the first time, authors present precise volumetric data covering the whole spectrum of adulthood in a huge clinical sample. Previous studies were based on much smaller populations. Authors used the true fast imaging with steady state precession (trueFISP) sequence, an isotropic heavily T2-weighted 3Dsequence, because of the superior contrast for the definition of the small pineal gland against the cerebrospinal fluid in comparison to the frequently used 3DT1-weighted sequences. Thereby, the organ borders are more precisely delineated and partial volume effects are minimized, resulting in more valid volumes measurements. 9 10 Applications Authors obtained precise information about pineal volume and microstructure in WJR|www.wjgnet.com 171 Schmitz SA, Platzek I, Kunz D, Mahlberg R, Wolf KJ, Heidenreich JO. Computed tomography of the human pineal gland for study of the sleep-wake rhythm: reproducibility of a semi-quantitative approach. Acta Radiol 2006; 47: 865-871 [PMID: 17050369 DOI: 10.1080/02841850600827585] Pu Y, Mahankali S, Hou J, Li J, Lancaster JL, Gao JH, Appelbaum DE, Fox PT. High prevalence of pineal cysts in healthy adults demonstrated by high-resolution, noncontrast brain MR imaging. AJNR Am J Neuroradiol 2007; 28: 1706-1709 [PMID: 17885233 DOI: 10.3174/ajnr.A0656] Nolte I, LГјtkhoff AT, Stuck BA, Lemmer B, Schredl M, Findeisen P, Groden C. Pineal volume and circadian melatonin profile in healthy volunteers: an interdisciplinary approach. J Magn Reson Imaging 2009; 30: 499-505 [PMID: 19630077 DOI: 10.1002/jmri.21872] Nolte I, Brockmann MA, Gerigk L, Groden C, Scharf J. TrueFISP imaging of the pineal gland: more cysts and more abnormalities. Clin Neurol Neurosurg 2010; 112: 204-208 [PMID: 20034731 DOI: 10.1016/j.clineuro.2009.11.010] Sun B, Wang D, Tang Y, Fan L, Lin X, Yu T, Qi H, Li Z, Liu S. The pineal volume: a three-dimensional volumetric study in healthy young adults using 3.0 T MR data. Int J Dev Neurosci 2009; 27: 655-660 [PMID: 19665543 DOI: 10.1016/ j.ijdevneu.2009.08.002] Bumb JM, Brockmann MA, Groden C, Al-Zghloul M, NГ¶lte I. TrueFISP of the pediatric pineal gland: volumetric and microstructural analysis. Clin Neuroradiol 2012; 22: 69-77 [PMID: 22101692 DOI: 10.1007/s00062-011-0110-5] Hasegawa A, Ohtsubo K, Mori W. Pineal gland in old age; quantitative and qualitative morphological study of 168 human autopsy cases. Brain Res 1987; 409: 343-349 [PMID: 3580881 DOI: 10.1016/0006-8993(87)90720-7] Golan J, Torres K, StaЕ›kiewicz GJ, Opielak G, Maciejewski R. Morphometric parameters of the human pineal gland in relation to age, body weight and height. Folia Morphol (Warsz) 2002; 61: 111-113 [PMID: 12164049] Brzozowski T, Zwirska-Korczala K, Konturek PC, Konturek SJ, Sliwowski Z, Pawlik M, Kwiecien S, Drozdowicz D, Mazurkiewicz-Janik M, Bielanski W, Pawlik WW. Role of circadian rhythm and endogenous melatonin in pathogenesis of acute gastric bleeding erosions induced by stress. J Physiol Pharmacol 2007; 58 Suppl 6: 53-64 [PMID: 18212400] Duvernoy HM, Risold PY. The circumventricular organs: an atlas of comparative anatomy and vascularization. Brain Res Rev 2007; 56: 119-147 [PMID: 17659349 DOI: 10.1016/j.brain resrev.2007.06.002] April 28, 2013|Volume 5|Issue 4| Bumb JM et al . Pineal volume and microstructure in trueFISP imaging 11 Haus E. Chronobiology in the endocrine system. Adv Drug Deliv Rev 2007; 59: 985-1014 [PMID: 17804113 DOI: 10.1016/ j.addr.2007.01.001] 12 Hayakawa K, Konishi Y, Matsuda T, Kuriyama M, Konishi K, Yamashita K, Okumura R, Hamanaka D. Development and aging of brain midline structures: assessment with MR imaging. Radiology 1989; 172: 171-177 [PMID: 2740500] 13 Tien RD, Barkovich AJ, Edwards MS. MR imaging of pineal tumors. AJR Am J Roentgenol 1990; 155: 143-151 [PMID: 2162137] 14 Sener RN. The pineal gland: a comparative MR imaging study in children and adults with respect to normal anatomical variations and pineal cysts. Pediatr Radiol 1995; 25: 245-248 [PMID: 7567225 DOI: 10.1007/BF02011087] 15 Lum GB, Williams JP, Machen BC, Akkaraju V. Benign cystic pineal lesions by magnetic resonance imaging. J Comput Tomogr 1987; 11: 228-235 [PMID: 3608546 DOI: 10.1016/0149 -936X(87)90087-7] 16 Sawamura Y, Ikeda J, Ozawa M, Minoshima Y, Saito H, Abe H. Magnetic resonance images reveal a high incidence of asymptomatic pineal cysts in young women. Neurosurgery 1995; 37: 11-15; discussion 15-16 [PMID: 8587669 DOI: 10.1227/00006123-199507000-00002] 17 Petitcolin V, Garcier JM, Mohammedi R, Ravel A, Mofid R, Viallet JF, Vanneuville G, Boyer L. [Prevalence and morphology of pineal cysts discovered at pituitary MRI: review of 1844 examinations]. J Radiol 2002; 83: 141-145 [PMID: 11965161] 18 Mamourian A, Towfighi J. MR of pineal cysts. AJNR Am J Neuroradiol 1994; 15: 1796-1797 [PMID: 7847232] 19 Katzman GL, Dagher AP, Patronas NJ. Incidental findings on brain magnetic resonance imaging from 1000 asymptomatic volunteers. JAMA 1999; 282: 36-39 [PMID: 10404909 DOI: 10.1001/jama.282.1.36] 20 Caldas JG, Doyon D, Lederman H, Carlier R. [Magnetic resonance study of the pineal region. Normal pineal gland and simple cysts]. Arq Neuropsiquiatr 1998; 56: 237-244 [PMID: 21 22 23 24 25 26 27 28 29 30 9698734 DOI: 10.1590/S0004-282X1998000200012] Krabbe KH. Histologische und embryologische Untersuchungen Гјber die Zirbel-drГјse des Menschen. Anat Hefte 1916; 163: 187 Osborn AG, Preece MT. Intracranial cysts: radiologic-pathologic correlation and imaging approach. Radiology 2006; 239: 650-664 [PMID: 16714456 DOI: 10.1148/radiol.2393050823] Crosby EC, Humphrey T, Lauer EW, editors. Correlative Anatomy of the Nervous System. New York: MacMillan, 1962 Klein P, Rubinstein LJ. Benign symptomatic glial cysts of the pineal gland: a report of seven cases and review of the literature. J Neurol Neurosurg Psychiatry 1989; 52: 991-995 [PMID: 2677249 DOI: 10.1136/jnnp.52.8.991] Ralph CL. The pineal gland and geographical distribution of animals. Int J Biometeorol 1975; 19: 289-303 [PMID: 1232070 DOI: 10.1007/BF01451040] Lupien SJ, Evans A, Lord C, Miles J, Pruessner M, Pike B, Pruessner JC. Hippocampal volume is as variable in young as in older adults: implications for the notion of hippocampal atrophy in humans. Neuroimage 2007; 34: 479-485 [PMID: 17123834 DOI: 10.1016/j.neuroimage.2006.09.041] Agarwal M, Brahmanday G, Bajaj SK, Ravikrishnan KP, Wong CY. Revisiting the prognostic value of preoperative (18)F-fluoro-2-deoxyglucose ( (18)F-FDG) positron emission tomography (PET) in early-stage (I & amp; II) non-small cell lung cancers (NSCLC). Eur J Nucl Med Mol Imaging 2010; 37: 691-698 [PMID: 19915840 DOI: 10.1007/s00259-009-1291-x] Arendt J. Melatonin and human rhythms. Chronobiol Int 2006; 23: 21-37 [PMID: 16687277 DOI: 10.1080/074205205004 64361] Bergiannaki JD, Soldatos CR, Paparrigopoulos TJ, Syrengelas M, Stefanis CN. Low and high melatonin excretors among healthy individuals. J Pineal Res 1995; 18: 159-164 [PMID: 7562374 DOI: 10.1111/j.1600-079X.1995.tb00155.x] Touitou Y. Human aging and melatonin. Clinical relevance. Exp Gerontol 2001; 36: 1083-1100 [PMID: 11404053 DOI: 10.1016/S0531-5565(01)00120-6] P- Reviewer Chen F S- Editor Gou SX L- Editor Webster JR E- Editor Xiong L WJR|www.wjgnet.com 172 April 28, 2013|Volume 5|Issue 4| WJ R World Journal of Radiology World J Radiol 2013 April 28; 5(4): 173-177 ISSN 1949-8470 (online) В© 2013 Baishideng. All rights reserved. Online Submissions: http://www.wjgnet.com/esps/ wjr@wjgnet.com doi:10.4329/wjr.v5.i4.173 BRIEF ARTICLE Volumetric modulated arc radiotherapy for limited osteosclerotic myeloma AurГ©lie Robles, Antonin Levy, Coralie Moncharmont, Lamine Farid, Jean-Baptiste Guy, Nadia Malkoun, Lysian Cartier, Cyrus Chargari, Isabelle Guichard, Jean-NoГ«l Talabard, Guy de Laroche, Nicolas MagnГ© RESULTS: VMAT improved dose homogeneity within the target volume, as compared to 3D-RT (standard deviations: 2.9 Gy and 1.6 Gy for 3D and VMAT, respectively). VMAT resulted in a better sparing of critical organs. Dose delivered to 20% of organ volume (D20) was reduced from 22 Gy (3D-RT) to 15 Gy (VMAT) for small bowel, from 24 Gy (3D-RT) to 17 Gy (VMAT) for bladder and from 47 Gy (3D-RT) to 3 Gy (VMAT) for spinal cord. Volumes of critical organs that received at least 20 Gy (V20) were decreased by the use of VMAT, as compared to 3D-RT (V20 bladder: 10% vs 99%; V20 small bowel: 6% vs 21%). One year after treatment completion, no tumor progression has been reported. AurГ©lie Robles, Coralie Moncharmont, Lamine Farid, JeanBaptiste Guy, Nadia Malkoun, Lysian Cartier, Jean-NoГ«l Talabard, Guy de Laroche, Nicolas MagnГ©, Department of Radiotherapy, Institut de CancГ©rologie de la Loire, 42270 St Priest en Jarez, France Antonin Levy, Department of Radiation Oncology, Institut GusВ tave Roussy, UniversitГ© Paris XI, 94800 Villejuif, France Cyrus Chargari, Department of Radiation Oncology, HГґpital dвЂ™ Instruction des ArmГ©es du Val-de-GrГўce, 75005 Paris, France Isabelle Guichard, Department of Internal Medicine, CHU Saint Etienne, 42000 Saint Etienne, France Author contributions: Robles A provided data and wrote the paper; MagnГ© N and Levy A designed the study, analyzed data, and wrote the paper; Moncharmont C, Farid L, Guy JB, MalkВ oun N, Cartier L, Chargari C, Guichard I, Talabard JN and de Laroche G reviewed the paper. Correspondence to: Nicolas MagnГ©, MD, PhD, Department of Radiotherapy, Institut de CancГ©rologie de la Loire, 108 bis, Avenue Albert Raimond, BP 60008, 42271 St Priest en Jarez cedex, France. nicolas.magne@icloire.fr Telephone: +33-4-77917434 Fax: +33-4-77917197 Received: October 18, 2012 Revised: December 14, 2012 Accepted: February 5, 2013 Published online: April 28, 2013 CONCLUSION: VMAT improved dose distribution as compared to 3D-RT for limited osteosclerotic myeloma, with better saving of critical organs. В© 2013 Baishideng. All rights reserved. Key words: Volumetric intensity-modulated arc radiotherapy; Conformal radiotherapy; Critical organs; Osteosclerotic myeloma; Polyneuropathy organomegaly endocrinopathy monoclonal gammopathy and skin change syndrome Abstract AIM: To assess the feasibility of volumetric intensitymodulated arc radiotherapy (VMAT) in patients with limited polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome. Robles A, Levy A, Moncharmont C, Farid L, Guy JB, Malkoun N, Cartier L, Chargari C, Guichard I, Talabard JN, de Laroche G, MagnГ© N. Volumetric modulated arc radiotherapy for limited osteosclerotic myeloma. World J Radiol 2013; 5(4): 173-177 Available from: URL: http://www.wjgnet.com/1949-8470/full/ v5/i4/173.htm DOI: http://dx.doi.org/10.4329/wjr.v5.i4.173 METHODS: A 70-year-old male with histologically conВ firmed osteosclerotic myeloma was treated in our department in July 2010 with VMAT. Fourty-six Gray in 23 fractions were given on three bone lesions. Doses delivered to target volume and critical organs were compared with a tridimensional conformal radiotherapy (3D-RT) plan. Treatment was well tolerated without any side effects. WJR|www.wjgnet.com INTRODUCTION Osteosclerotic myeloma (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes, PO- 173 April 28, 2013|Volume 5|Issue 4| Robles A et al . VMAT for limited osteosclerotic myeloma raphy (CT) and 18F-fluorodeoxyglucose positron emission tomography-CT showed organomegaly, mediastinal adenopathies and hypermetabolism of bone sclerotic lesions (T12, L5 vertebra and right ilium). Bone biopsy using immunohistochemical staining demonstrated clonal lambda plasma cell infiltration. POEMS syndrome was retained and this patient received T12 vertebra percutaneous cimentoplasty. Due to persistence of lower back pain, he was referred to our department to receive radiation in July 2010. EMS syndrome) is a rare paraneoplastic disease resulting from a monoclonal plasma cell disorder[1,2]. Most frequent diagnostic criteria include polyneuropathy, monoclonal lambda plasma cell proliferative disorder, bone lesions, elevated levels of vascular endothelial growth factor (VEGF) and eventually association with Castleman disease (angiofollicular lymph node hyperplasia). There are other clinical features, such as organomegaly (hepato-splenomegaly, lymphadenopathy), endocrine disorders, skin modifications, papilledema and high extravascular fluid accumulation leading to ascita or pleural effusion [3]. Although POEMSвЂ™ pathogenesis remains only partially understood, the overproduction of several pro-inflammatory cytokines [higher levels of interleukine (IL)-1, IL-6, tumor necrosis factor-О±] and VEGF has been frequently reported. Moreover, clinical manifestations of POEMS syndrome may be correlated with an increased production of cytokines. Those could potentially be used as surrogate markers of disease activity[4,5]. There is no strong consensus on the appropriate management of POEMS. Radiation therapy (RT) is generally employed for limited disease, and good response to RT correlates with an increased survival[6]. On the other hand, prognosis of POEMS is substantially better than that of multiple myeloma and patients may be exposed to late toxicities of treatments[3]. The delivery of RT in bone lesion is challenging because irradiated fields may include sensitive critical organs. In the era of ballistic optimization, every effort should be made to further improve the efficacy/toxicity ratio. Volumetric intensitymodulated arc radiotherapy (VMAT) is a new RT modality that allows for rapid delivery of highly consistent dose distributions, critical organ sparing and it is currently used for various tumor localizations[7-12]. Herein, we investigated the use of this new high-tech RT modality for a patient with three sclerotic bone lesions. A dosimetric comparison of a VMAT plan with a conventional tridimensional conformal (3D) plan was performed to evaluate the potential dosimetric benefit of VMAT in sparing critical organs from detrimental irradiation. Dosimetric study Separate dosimetric analyses were performed for conformal 3D-RT and VMAT. The patient was scheduled for CT treatment simulation one week prior to treatment. Planning target volume (PTV) was defined by the tumoral growth volume, as shown on the CT, with a one cm expansion in all dimensions. The dose to be delivered was prescribed in terms of median dose to the PTVs (three sclerotic lesions, two of the rachis and one of the ilium) delivered with 2.0 Gy per fraction, once daily, 5 d per week, with a total dose of radiation 46 Gy in 23 fractions. PTV and critical organs (including kidneys, femoral heads, spinal cord, bone marrow, and bladder) were determined by the same physician. Optimization was performed to spare normal tissues, including spinal cord, bone marrow, kidneys and small bowel. Treatment plans were created using Rapidarc Planning system software (Rapidarc, Varian Medical System, Palo Alto, CA, United States). After a satisfactory dose distribution was achieved, the plans were accepted and treatment duration was determined. Plan acceptance criteria required that at least 95% of the dose covered 99% of the PTV volume. Dose constraints to the organs at risk were based on the Quantitative Analysis of Normal Tissue Effects in the Clinic recommendations[13]. A second treatment plan was determined, with 3D conformal system software (Eclipse, Varian; Varian Med Systems, VA, United States). For this phase, a conformal RT technique was used, as routinely used at our Institute. After the two plans were completed, we compared doses delivered to the critical organs, using the VMAT-based or the 3D conformal plan. MATERIALS AND METHODS Patient characteristics A 70-year-old man presented with lower back pain, equilibrium disorders, and a weight loss of 12 kg. He had a past medical history of alcoholism, tobacco and high blood pressure. Initial evaluation included complete history and physical examination, hematological and biochemical profiles, serum protein electrophoresis, bone marrow biopsy and a radiographical skeletal survey. Physical examination showed a symmetric sensorimotor neuropathy of the extremities, endocrine disorders (hyperthyroidism and decrease of testosterone level) and skin changes (melanoderma and hypertrichosis). Biological examinations revealed a plasma cell dyscrasia with an IgA lambda monoclonal gammapathy and an increased VEGF rate of 1275 pg/mL (normal < 5 pg/mL). A myelogram was negative. Total body computed tomog- WJR|www.wjgnet.com Ethical statement The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975, as revised in 1983. RESULTS The patient was finally treated with VMAT. Tolerance was excellent and no acute or late toxicities were observed. Clinical response consisted of a decreased of the lower back pain following completion of RT. The patient remains free from any tumor progression 18 mo after treatment completion. In the latest evaluation, the 174 April 28, 2013|Volume 5|Issue 4| Robles A et al . VMAT for limited osteosclerotic myeloma VEGF rate has halved (633 pg/mL) and radiological controls showed a local tumoral regression. Comparing VMAT and 3D-RT plans, 99% of the target volume received 95% of prescribed dose with either technique. However, dose homogeneity was improved for VMAT. For the doses delivered to the PTV, standard deviations were 2.9 Gy and 1.6 Gy for 3D and VMAT, respectively. VMAT resulted in substantial critical organ sparing. Dose delivered to 20% of organ volume (D20) was reduced from 22 Gy (3D-RT) to 15 Gy (VMAT) for small bowel, from 24 Gy (3D-RT) to 17 Gy (VMAT) for bladder and from 47 Gy (3D-RT) to 3 Gy (VMAT) for spinal cord. The volume that received at least 20 Gy (V20) was lower with the use of VMAT than with 3D-RT (V20 bladder: 10% vs 99%; V20 small bowel: 6% vs 21%). Radiation doses delivered to critical organs according conformal radiotherapy or VMAT are reported in Table 1. Isodoses (Gy) and dose-volume histograms are presented for 3D-RT and VMAT plans in Figures 1 and 2, respectively. Table 1 Comparison between the treatment plans of critical organs dose exposure PTV (Gy) Min Max mean В± SD Kidney R (Gy) D10 D20 D30 Dmax Dmean V10 V20 V30 Kidney L (Gy) D10 D20 D30 Dmax Dmean V10 V20 V30 Small bowel (Gy) D10 D20 D30 Dmax Dmean V10 V20 V30 Spinal cord (Gy) D10 D20 D30 Dmax Dmean V10 V20 V30 Femoral head R (Gy) D10 D20 D30 Dmax Dmean V10 V20 V30 Femoral head L (Gy) D10 D20 D30 Dmax Dmean V10 V20 V30 Bladder (Gy) D10 D20 D30 Dmax Dmean V10 V20 V30 3D-RT VMAT 30.5 49.1 46.7 В± 2.9 16.2 14.4 13.1 39.6 7.9 46.7% 2.0% 0.1% 18.3 15.5 14.1 46.7 9.0 44.7% 7.5% 3.5% 25.8 21.6 12.4 46.8 9.6 40.6% 20.8% 2.6% 47.3 47.1 46.8 47.7 31.8 70.5% 67.9% 66.2% 27.2 25.8 21.5 30.2 11.6 38.8% 31.2% 0.02% 47.4 46.8 45.9 47.9 29.1 75.0% 64.0% 52.5% 25.6 24.4 24.1 45.0 24.3 100.0% 99.0% 5.3% 38.7 50.8 47.5 В± 1.6 18.7 14.2 11.1 38 7.5 33.9% 8.2% 0.7% 19.2 14.7 11.7 44.9 7.6 34.5% 8.7% 0.7% 18.1 15.3 13.2 43.1 8.8 43.6% 6.0% 0.2% 37.5 36.0 34.8 41.0 22.5 64.3% 59.7% 53.8% 5.5 4.4 3.2 7.8 2.3 0.0% 0.0% 0.0% 44.4 40.4 36.7 49.3 21.2 58.4% 48.2% 38.2% 19.8 16.7 14.2 36.2 12.5 59.0% 9.5% 0.4% DISCUSSION In our report, we describe the use of VMAT for localized POEMS syndrome. To our knowledge, there are no previous reports of this technique in the medical literature for osteosclerotic myeloma. The course of POEMS syndrome is frequently chronic and patients may survive four times longer than in multiple myeloma. Dispenzieri et al[3,6] reported a median overall survival of 165 mo in their series of 99 patients. RT given in a dose of 40 to 50 Gy is a commonly accepted first-line treatment for single or multiple osteosclerotic lesions. Indeed, the benefit of radiation correlates with a drastic decrease in symptoms and improvement in survival. However, RT is also associated with acute and chronic toxicities that might potentially affect the quality of life of longsurvivor patients. Although we did not have sufficient follow-up to accurately evaluate local control or survival, the risk of long-term severe morbidity increases as the radiation doses delivered to critical organs increases. Highly conformal RT allows efficient target coverage and sparing of organs at risk, such as spinal cord, small bowel or bladder. VMAT is a new form of intensity modulated radiotherapy (IMRT) optimization combining one gantry rotation and variable dose-rate, variable gantry speed and a dynamic multi-leaf collimator. It was recently introduced in clinical practice for comparison to conventional RT modalities in various malignancies, including brain, prostate, head and neck, anal canal, and cervix tumors[7-12]. Our report describes the potential interest of VMAT for osteosclerotic myeloma for both increasing dose homogeneity to the PTV and decreasing the dose to the critical organs. Moreover, sparing of critical organs may allow patients that develop widespread lesions or who did not respond to RT to receive further systemic therapies in the future. Also, as in our case, blood VEGF levels may be used as a surrogate marker 3D-RT: Conformational radiation therapy; VMAT: Volumetric intensitymodulated arc therapy; PTV: Planned target volume; Gy: Gray; D10, D20, D30: Doses delivered to 10%, 20% and 30% of critical organs volumes, respectively; V10, V20, V30: Volumes of critical organs that received 10 Gy, 20 Gy and 30 Gy, respectively; R: Right; L: Left. WJR|www.wjgnet.com 175 April 28, 2013|Volume 5|Issue 4| Robles A et al . VMAT for limited osteosclerotic myeloma Figure 1 Isodoses (Gray) according to treatment plan: volumetric intensity-modulated arc radiotherapy (right side) and conformal tridimensional radiotherapy (left side). PTVs L kidney R kidney Bladder R femoral head L femoral head Small bowel Spinal cord Ratio of total structure volume (%) 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 Dose (Gy) Figure 2 Dose volume histograms for the two treatment plans: Volumetric intensity-modulated arc radiotherapy (triangles) and tridimensional conformal radiotherapy (squares). L: Left; R: Right; Gy: Gray; PTVs: Planning target volumes. of disease after completion of RT, and then be useful in deciding whether systemic therapy should be added[14]. VMAT does, however, have some limitations, principally a larger volume of normal tissues receiving low doses irradiation. By using IMRT techniques, it was previously demonstrated that the volume exposed to low doses was increased. This may be particularly important for patients with long survival, where heterogeneous low-dose volume may increase the incidence of second malignancies[15]. Nevertheless, treatment duration and monitor units are decreased with VMAT compared to conventional IMRT, which can potentially affect the risk of developing a second cancer[16]. Our study is the first to report the possible use of arc-based RT for POEMS. In other haematological malignancies, Chargari et al[17] reported the feasibility of helical tomotherapy in patients WJR|www.wjgnet.com with paramedullar solitary plasmocytoma. In their experience, helical tomotherapy improved the dose homogeneity within the PTV and resulted in a more efficient sparing of critical organs, when compared to 3D-RT. Although improvement in normal tissue sparing and target coverage is suggested for tomotherapy compared to conventional IMRT, other authors reported that VMAT offered dosimetric qualities comparable to that of helical tomotherapy[18,19]. In conclusion, VMAT allowed improved dose distribution in comparison to 3D-RT for limited osteosclerotic myeloma. In fact, VMAT achieved higher dose homogeneity within the PTV and better saving of critical organs. The benefit of new highly conformal RT techniques should be further examined in larger series of patients. 176 April 28, 2013|Volume 5|Issue 4| Robles A et al . VMAT for limited osteosclerotic myeloma COMMENTS COMMENTS 8 Background There is no strong consensus on the appropriate management of limited osteosclerotic myeloma. Radiation therapy (RT) is generally employed for limited disease. The authors aimed to assess the feasibility of volumetric intensitymodulated arc radiotherapy (VMAT) in patients with limited polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change syndrome. 9 Research frontiers VMAT is a new RT modality that allows rapid delivery of highly conformal dose distributions, critical organs sparing and s currently used for various tumor localizations. A dosimetric comparison of the VMAT plan with the conventional tridimensional conformal (3D) plan was performed to assess the potential dosimetric benefit of VMAT in sparing critical organs from detrimental irradiation. 10 Applications 11 VMAT may provide a clinical and dosimetric benefit over 3D-RT techniques in limited osteosclerotic myeloma. Peer review VMAT allowed improved dose distribution in comparison to 3D-RT for limited osteosclerotic myeloma. Moreover, VMAT achieved higher dose homogeneity within the planned target volume and better saving of critical organs. The benefit of new highly conformal RT techniques should be further examined in larger series of patients. 12 REFERENCES 1 2 3 4 5 6 7 13 Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Medicine (Baltimore) 1980; 59: 311-322 [PMID: 6248720] Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, Greipp PR, Witzig TE, Basu R, Suarez GA, Fonseca R, Lust JA, Gertz MA. POEMS syndrome: definitions and long-term outcome. Blood 2003; 101: 2496-2506 [PMID: 12456500] Dispenzieri A. POEMS syndrome. Blood Rev 2007; 21: 285-299 [PMID: 17850941] Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome. Lancet 1996; 347: 702 [PMID: 8596427] Gherardi RK, BГ©lec L, Soubrier M, Malapert D, Zuber M, Viard JP, Intrator L, Degos JD, Authier FJ. Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome. Blood 1996; 87: 1458-1465 [PMID: 8608236] Dispenzieri A, Moreno-Aspitia A, Suarez GA, Lacy MQ, Colon-Otero G, Tefferi A, Litzow MR, Roy V, Hogan WJ, Kyle RA, Gertz MA. Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood 2004; 104: 3400-3407 [PMID: 15280195] Clivio A, Fogliata A, Franzetti-Pellanda A, Nicolini G, Vanetti E, Wyttenbach R, Cozzi L. Volumetric-modulated arc radiotherapy for carcinomas of the anal canal: A treatment planning comparison with fixed field IMRT. Radiother Oncol 2009; 92: 14 15 16 17 18 19 118-124 [PMID: 19181409 DOI: 10.1016/j.radonc.2008.12.020] Cozzi L, Dinshaw KA, Shrivastava SK, Mahantshetty U, Engineer R, Deshpande DD, Jamema SV, Vanetti E, Clivio A, Nicolini G, Fogliata A. A treatment planning study comparing volumetric arc modulation with RapidArc and fixed field IMRT for cervix uteri radiotherapy. Radiother Oncol 2008; 89: 180-191 [PMID: 18692929 DOI: 10.1016/j.radonc.2008.06.013] Fogliata A, Clivio A, Nicolini G, Vanetti E, Cozzi L. Intensity modulation with photons for benign intracranial tumours: a planning comparison of volumetric single arc, helical arc and fixed gantry techniques. Radiother Oncol 2008; 89: 254-262 [PMID: 18760851 DOI: 10.1016/j.radonc.2008.07.021] Kjaer-Kristoffersen F, Ohlhues L, Medin J, Korreman S. RapidArc volumetric modulated therapy planning for prostate cancer patients. Acta Oncol 2009; 48: 227-232 [PMID: 18855157 DOI: 10.1080/02841860802266748] Lagerwaard FJ, Meijer OW, van der Hoorn EA, Verbakel WF, Slotman BJ, Senan S. Volumetric modulated arc radiotherapy for vestibular schwannomas. Int J Radiat Oncol Biol Phys 2009; 74: 610-615 [PMID: 19427560 DOI: 10.1016/j.ijrobp.2008.12. 076] Vanetti E, Clivio A, Nicolini G, Fogliata A, Ghosh-Laskar S, Agarwal JP, Upreti RR, Budrukkar A, Murthy V, Deshpande DD, Shrivastava SK, Dinshaw KA, Cozzi L. Volumetric modulated arc radiotherapy for carcinomas of the oro-pharynx, hypo-pharynx and larynx: a treatment planning comparison with fixed field IMRT. Radiother Oncol 2009; 92: 111-117 [PMID: 19157609 DOI: 10.1016/j.radonc.2008.12.008] Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, Bentzen SM, Nam J, Deasy JO. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 2010; 76: S10-S19 [PMID: 20171502 DOI: 10.1016/j.ijrobp.2009.07.1754] Dispenzieri A. POEMS syndrome: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol 2011; 86: 591-601 [PMID: 21681783 DOI: 10.1002/ajh.22050] Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006; 65: 1-7 [PMID: 16618572] Matuszak MM, Yan D, Grills I, Martinez A. Clinical applications of volumetric modulated arc therapy. Int J Radiat Oncol Biol Phys 2010; 77: 608-616 [PMID: 20100639 DOI: 10.1016/ j.ijrobp.2009.08.032] Chargari C, Kirova YM, Zefkili S, Caussa L, Amessis M, Dendale R, Campana F, Fourquet A. Solitary plasmocytoma: improvement in critical organs sparing by means of helical tomotherapy. Eur J Haematol 2009; 83: 66-71 [PMID: 19284417 DOI: 10.1111/j.1600-0609.2009.01251.x] Cao D, Holmes TW, Afghan MK, Shepard DM. Comparison of plan quality provided by intensity-modulated arc therapy and helical tomotherapy. Int J Radiat Oncol Biol Phys 2007; 69: 240-250 [PMID: 17707278] Davidson MT, Blake SJ, Batchelar DL, Cheung P, Mah K. Assessing the role of volumetric modulated arc therapy (VMAT) relative to IMRT and helical tomotherapy in the management of localized, locally advanced, and post-operative prostate cancer. Int J Radiat Oncol Biol Phys 2011; 80: 1550-1558 [PMID: 21543164 DOI: 10.1016/j.ijrobp.2010.10.024] P- Reviewer Plataniotis E S- Editor Gou SX L- Editor Hughes D E- Editor Xiong L WJR|www.wjgnet.com 177 April 28, 2013|Volume 5|Issue 4| WJ R World Journal of Radiology World J Radiol 2013 April 28; 5(4): 178-183 ISSN 1949-8470 (online) В© 2013 Baishideng. All rights reserved. Online Submissions: http://www.wjgnet.com/esps/ wjr@wjgnet.com doi:10.4329/wjr.v5.i4.178 BRIEF ARTICLE Role of color Doppler in differentiation of Graves' disease and thyroiditis in thyrotoxicosis Ragab Hani Donkol, Aml Mohamed Nada, Sami Boughattas 18 cases with GravesвЂ™ disease and 8 cases with HashimotoвЂ™s thyroiditis. All patients had suppressed thyrotropin. The diagnosis of GravesвЂ™ disease and HashimotoвЂ™s thyroiditis was supported by the clinical picture and follow up of patients. Ragab Hani Donkol, Department of Radiology, Aseer Central Hospital, Abha 61321, Saudi Arabia Ragab Hani Donkol, Faculty of Medicine, Cairo University, Cairo 12613, Egypt Aml Mohamed Nada, Endocrine Unit, Department of Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt Sami Boughattas, Department of Nuclear Medicine, Aseer Central Hospital, Abha 61321, Saudi Arabia Author contributions: Donkol RH designed the study, performВ ed Doppler studies, analyzed the data and wrote the manuscript; Nada AM shared in manuscript writing, selection of cases, cliniВ cal and laboratory assessment and collection of data; Bougattas S performed and interpreted radioactive thyroid scans. Correspondence to: Ragab Hani Donkol, MD, Department of Radiology, Assir Central Hospital, PO Box 34, Abha 61321, Saudi Arabia. ragabhani@hotmail.com Telephone: +966-7-2291169 Fax: +966-3-8552244 Received: December 4, 2012 Revised: January 22, 2013 Accepted: February 2, 2013 Published online: April 28, 2013 RESULTS: Peak systolic velocities of the inferior thyroid arteries were significantly higher in patients with GravesвЂ™ disease than in patients with thyroiditis (P = 0.004 in the right inferior thyroid artery and P = 0.001 in left inferior thyroid artery). Color-flow Doppler ultrasonography parameters demonstrated a sensitivity of 88.9% and a specificity of 87.5% in the differential diagnosis of thyrotoxicosis. CONCLUSION: Color Doppler flow of the inferior thyroid artery can be used in the differential diagnosis of thyrotoxicosis, especially when there is a contraindication of thyroid scintigraphy by radioactive material in some patients. В© 2013 Baishideng. All rights reserved. Abstract Key words: Doppler; Thyrotoxicosis; Thyroid scintigraphy; GravesвЂ™ diseases; Thyroiditis AIM: To evaluate the role of thyroid blood flow assessment by color-flow Doppler ultrasonography in the differential diagnosis of thyrotoxicosis and compare it to technetium pertechnetate thyroid scanning. Donkol RH, Nada AM, Boughattas S. Role of color Doppler in differentiation of GravesвЂ™ disease and thyroiditis in thyrotoxicoВ sis. World J Radiol 2013; 5(4): 178-183 Available from: URL: http://www.wjgnet.com/1949-8470/full/v5/i4/178.htm DOI: http://dx.doi.org/10.4329/wjr.v5.i4.178 METHODS: Twenty-six patients with thyrotoxicosis were included in the study. Clinical history was taken and physical examination and thyroid function tests were performed for all patients. Thyroid autoantibodies were measured. The thyroid glands of all patients were evaluated by gray scale ultrasonography for size, shape and echotexture. Color-flow Doppler ultrasonography of the thyroid tissue was performed and spectral flow analysis of both inferior thyroid arteries was assessed. Technetium99 pertechnetate scanning of the thyroid gland was done for all patients. According to thyroid scintigraphy, the patients were divided into two groups: WJR|www.wjgnet.com INTRODUCTION Thyrotoxicosis refers to the hypercatabolic state resulting from elevated serum levels of thyroid hormone, mainly free tetraiodothyronine (FT) 4 and/or triiodothyronine FT3. Thyrotoxicosis is not synonymous with hyperthyroidism[1]. It may be caused either by hyperthyroidism or 178 April 28, 2013|Volume 5|Issue 4| Donkol HR et al . Color Doppler in thyrotoxicosis by inflammation of the thyroid with release of stored thyroid hormone but is not accelerated synthesis. It may also be caused by ingestion of exogenous thyroid hormone. GravesвЂ™ disease causes hyperthyroidism with diffuse thyroid disease while thyrotoxicosis due to destructive thyroiditis includes various subsets like lymphocytic thyroiditis, subacute thyroiditis and postpartum thyroiditis[2-5]. Differentiation between causes of thyrotoxicosis at time of diagnosis, either hyperthyroidism due to GravesвЂ™ disease or destructive thyrotoxicosis due to thyroiditis, is very important as management of each case is completely different. The absence of specific signs of GravesвЂ™ disease like ophthalmopathy, skin and nail changes may make it difficult to distinguish it from thyroiditis, especially when the disease is mild or subclinical. Thyroid scintigraphy by technetium99 (Tcm99) pertechnetate or iodine 123 radioisotopes is used for this purpose. Measuring thyrotropin (TSH) receptor antibody levels can be also used[6]. However, these methods are not usually available. Nuclear imaging is expensive and contraindicated during pregnancy and lactation. Thyroid hypoechogenicity at ultrasound is a characteristic of autoimmune thyroid diseases, with an overlap of this echographic pattern in patients affected by GravesвЂ™ disease or HashimotoвЂ™s thyroiditis. However, a diffusely increased thyroid blood flow is pathognomonic of untreated GravesвЂ™ disease and an abnormal color flow Doppler (CFD) pattern identifies the majority of GravesвЂ™ patients with a normal thyroid ultrasound pattern. Thus, CFD sonography may be useful in distinguishing patients with GravesвЂ™ disease and HashimotoвЂ™s thyroiditis with a similar thyroid echographic pattern. CFD ultrasonography is a useful, inexpensive, noninvasive and widely available method for measuring tissue vascularization and blood flow. The evaluation can be both qualitative (visual assessment of thyroid vascularity) and quantitative (measuring peak systolic, end diastolic and mean velocities in the inferior thyroid arteries). CFD ultrasonography of the thyroid gland can provide valuable information about underlying thyroid functional status and is useful in the differential diagnosis of thyrotoxicosis[7-10]. The aim of the study is to evaluate the efficiency of CFD in differentiation of causes of thyrotoxicosis at time of diagnosis, either hyperthyroidism due to GravesвЂ™ disease or destructive thyrotoxicosis due to thyroiditis, and compare its sensitivity and specificity to technetium thyroid scintigraphy to know if both investigations can be used as alternatives in cases of thyrotoxicosis. Exclusion criteria included toxic nodule, history of thyroid surgery, radioiodine therapy or radiation exposure to neck. Patients whose goiter was multinodular or diffuse were included in the study. Clinical history, including sex, age, symptoms and signs, was performed. Serum levels of TSH, free T3, free T4, antithyroid peroxidase and antithyroglobulin antibodies were measured in all patients. GravesвЂ™ disease was diagnosed on the basis of clinical parameters (marked weight loss, adrenergic symptoms, goiter, skin and nail changes, eye signs) and high uptake on Tcm99 thyroid scanning. Thyroiditis was diagnosed on the basis of low Tcm99 uptake scan, the presence of insignificant symptoms (no or minimal weight loss, occasional palpitations, absent eye signs with or without goiter) or later development of hypothyroidism. A radiologist with twenty years of experience in sonography, who was blinded to the full clinical status, performed all thyroid ultrasound examinations. A color Doppler ultrasound scanner (iU22, Philips Ultrasound, Bothell, WA, United States) equipped with a 3-9 MHz broadband linear array transducer was used. The grey scale ultrasound examinations of the thyroid gland were performed regarding the size, shape and echotexture of the gland, as well as the presence or absence of nodules (Figure 1A). The color Doppler pattern of the glands were studied (Figure 1B). Parameters for color Doppler are F. 6.6 MHz, G.76%, pulse-repetition frequency (PRF) 2.1 KHz and wall filter (WF) was M. The Doppler spectral analysis was of the right and left inferior thyroid arteries in the transverse scanning, in which the vessels crossed the common carotid arteries posteriorly, or in the longitudinal scanning of the ascending parts of the arteries, in which the vessels lie parallel to the common carotid arteries (Figure 1C). Parameters for color Doppler are F. 6.6 MHz, G.64%, PRF 5.6 KHz and WF 50 Hz. The angle correction cursor was parallel to the direction of flow and the Doppler angle was kept at or below 60В°. The peak systolic velocity, end diastolic velocity and mean velocity were obtained. Peak systolic velocity of the inferior thyroid artery of 40 cm/s is considered significantly high and suggestive for GravesвЂ™ disease[11,12]. Another radiologist who was blinded to the clinical picture and ultrasound examination performed all isotopic thyroid scans (Figure 2). A technetium pertechnetate scan was done in all patients as the gold standard test for differentiation between both causes of thyrotoxicosis. Statistical analysis Frequency, arithmetic mean and standard deviation were used to present the data. StudentвЂ™s t test was used as a test of significance at 5% level. Screening test evaluation was carried out with positive/negative outcomes, sensitivity, specificity, positive and negative predictive values and likelihood ratios for positive and negative tests were calculated with the concomitant 95%CIs. The McNemar test was applied to compare diagnostic performance of pulsed Doppler with the technetium scan for discriminating between GraveвЂ™s disease and thy- MATERIALS AND METHODS The Research and Ethics committee of our hospital approved the study and written informed consent was acquired from all patients. The study population consisted of 26 patients presenting to the endocrine clinic with thyrotoxicosis during the period from January to July 2011. WJR|www.wjgnet.com 179 April 28, 2013|Volume 5|Issue 4| Donkol HR et al . Color Doppler in thyrotoxicosis A B C Rt lobe Isthmus IJV CCA Isthmus ITA CCA Trachea Trachea Figure 1 Gray scale ultrasound, color Doppler, Doppler spectral analysis in patients with GravesвЂ™ disease. A: Gray scale ultrasound of the right lobe of the thyroid gland in patients with GravesвЂ™ disease shows enlarged gland with smooth contour and heterogeneous echotexture; B: Color Doppler of the same patient shows diffuse increase vascularity of the thyroid gland; C: Doppler spectral analysis of the right inferior thyroid artery of the same patients show elevated peak systolic velocity (V1 = 89.8 cm/s) and elevated end diastolic velocity (V2 = 44.9 cm/s). CCA: Common carotid artery; IJV: Internal jugular vein; IJV: Internal jugular vein. R Rt lobe arteries, was significantly higher in patients with GravesвЂ™ disease than in patients with destructive thyroiditis (P = 0.004 in the right inferior thyroid artery and P = 0.001, in the left inferior thyroid artery). End diastolic velocity was significantly higher in GravesвЂ™ patients than in patients with thyroiditis (P = 0.007, in the right inferior thyroid artery and P = 0.001 in the left inferior thyroid artery). Consequently, mean velocity in the inferior thyroid artery was significantly higher in patients with GravesвЂ™ than in patients with thyroiditis (Table 1). Sixteen out of 18 patients diagnosed as GravesвЂ™ disease by Tcm99 scan had an inferior thyroid artery flow velocity greater than 40 cm/s. Diagnosis of GravesвЂ™ disease in the remaining two patients was established by increased uptake on the thyroid scan and clinical findings that favor GravesвЂ™ disease. Seven out of 8 patients with destructive thyroiditis had an inferior thyroid artery flow less than 40 cm/s. The last patient was diagnosed as thyroiditis due to low Tcm99 uptake and by its clinical picture and follow up of patients. Comparing volume of the thyroid gland between both groups revealed significantly larger volume in GravesвЂ™ patients than in patients with thyroiditis (P = 0.028) (Table 1). CFD showed a sensitivity of 88.9% and a specificity of 87.5%, positive predictive value of 94.1%, negative predictive value of 77.8% and a diagnostic accuracy of 88.5% in the differential diagnosis of thyrotoxicosis compared to thyroid scanning by Tcm99 pertechnetate (Table 2). Also, the McNemar test result was significant (P = 0.453) and indicates that the two diagnostic tests (technetium scan and pulsed Doppler) are not significantly different with respect to sensitivity. The power analysis and sample size calculation were performed based on the equation for sample size for two compared proportions with normal approximation to the binomial distribution and b = 0.2, i.e., power = 0.8. Applying the вЂњShapiro-Wilk testвЂќ assessed the normal distribution of study variables and showed that most variables proved to be normally distributed, (e.g., volume of the thyroid gland P = 0.128, T3 serum level P = 0.076). ROC analysis of the results showed that cut-off value of Lt lobe Isthmus Tc99m pertechnetate thyroid scintigraphy pin-hole collimator Figure 2 Thyroid scintigraphy of the same patient showed enlarged both lobes of the thyroid with diffuse increase uptake. R: Right; Tc99m: Technetium TC 99M pyrophosphate. roiditis. The power analysis and sample size calculation were performed based on the equation for sample size for two compared proportions with normal approximation to the binomial distribution to determine the minimal required sample size. Applying the вЂњShapiro-Wilk testвЂќ assessed the normal distribution of study variables. Receiver operating characteristic (ROC) analysis of the results was done to determine the appropriate cut-off value of peak systolic velocity to differentiate GravesвЂ™ disease from thyroiditis. RESULTS All patients who participated in this study have suppressed TSH level (0.08-0.005 IU/L) with normal or high free T4 and T3 levels. Thyroid scanning by Tcm99 was done for all patients as the gold standard test for differentiation between GravesвЂ™ disease and thyroiditis. Supported by the clinical picture of patients, eighteen patients had GravesвЂ™ disease and eight patients had destructive thyrotoxicosis. No significant difference in age between both groups (P = 0.565) was found. Thyroid blood flow, as assessed by color flow imaging and Doppler spectral analysis of the inferior thyroid WJR|www.wjgnet.com 180 April 28, 2013|Volume 5|Issue 4| Donkol HR et al . Color Doppler in thyrotoxicosis ROC curve 1.0 Table 1 Comparing parameters between hyperthyroidism and thyroiditis Age, yr (mean В± SD) Thyroid volume (cm3) RPSV (cm/s) REDV (cm/s) RMV (cm/s) LPSV (cm/s) LEDV (cm/s) LMV (cm/s) Graves Thyroiditis P value 31.1 В± 8.4 24.2 В± 10.1 50.4 В± 23.4 31.3 В± 16.6 68.9 В± 31.6 49 В± 25.7 29.6 В± 17.5 68.4 В± 35.2 33.1 В± 7.5 14.8 В± 7.54 21.7 В± 14.8 12.8 В± 9.4 30.6 В± 20.3 17.8 В± 6 10 В± 4.5 25.5 В± 8.3 0.565 0.028 0.004 0.007 0.004 0.001 0.001 0.001 Sensitivity 0.8 Parameter 0.6 0.4 0.2 0.0 RPSV: Right peak systolic velocity; REDV: Right end diastolic velocity; RMV: Right man velocity; LPSV: Left peak systolic velocity; LEDV: Left end diastolic velocity; LMV: Left mean velocity (t test). Estimate Sensitivity Specificity Positive predictive value Negative predictive value Diagnostic accuracy Likelihood ratio of a positive test Likelihood ratio of a negative test Diagnostic odds Cohen's kappa (unweighted) 88.9% 87.5% 94.1% 77.8% 88.5% 7.1 0.1 56 0.7 0.4 0.6 0.8 1.0 Figure 3 Receiver operating characteristic analysis of the results determined that 40 cm/s is the appropriate cut-off value of peak systolic velocity to differentiate GravesвЂ™ disease from thyroiditis. ROC: Receiver operating characteristic. Lower-upper 95%CI 67.2-96.9 52.9-97.8 73.0-99 45.3-93.7 71-96 0.99-51.3 0.05-0.4 4.3-724.1 0.4-1.1 two types of thyrotoxicosis and thyroid blood flow was evaluated by color Doppler as a parameter to differentiate the types of thyrotoxicosis and compare its sensitivity and specificity to Tcm99 thyroid uptake. Peak systolic, end diastolic and mean velocities of inferior thyroid artery in patients with GravesвЂ™ disease were significantly higher than patients with thyroiditis[14]. CFD ultrasonography in our study showed a sensitivity of 88.9% with specificity of 87.5%. These results are comparable to the results of a study carried out by Kurita et al[15] on 75 patients with thyrotoxicosis, which demonstrated that CFD ultrasonography had a sensitivity of 84% and specificity of 90% in the differential diagnosis of thyrotoxicosis. On the other hand, Hari Kumar et al[16] in 2009 studied 65 patients with thyrotoxicosis. He found significantly higher blood flow in inferior thyroid arteries in GravesвЂ™ disease than in destructive thyrotoxicosis. He also demonstrated that CFD ultrasonography had a sensitivity of 96% and a specificity of 95% in the differential diagnosis of thyrotoxicosis. Other forms of estimation of thyroid blood flow assessment, like thyroid blood flow area, vascularization index and high-resolution power Doppler, have been used by investigators to provide better differentiation[17-19]. A cut-off value of 40 cm/s was considered in differentiation between GravesвЂ™ diseases from thyroiditis based on a review of relevant literature[16,20-23]. This cut-off was also in agreement with obtained results from our own data, as ROC curve of different values of sensitivity and specificity justifies this decision. Referring to this study and similar various studies[24-30], color Doppler ultrasonography of the thyroid gland is considered to be one of the initial investigations that can give great help in the differentiation of GravesвЂ™ disease and HashimotoвЂ™s thyroiditis. Color Doppler is a cheap simple technique with no ionizing radiation exposure and is cost effective in the diagnosis of thyrotoxicosis[31-35]. Inferior thyroid artery blood flow is a useful param- 40-cm/s peak systolic velocity was considered significant to differentiate between GravesвЂ™ disease and thyroiditis (Figure 3). DISCUSSION Clinical manifestations of thyrotoxicosis in cases of thyroiditis and early or mild GravesвЂ™ disease may be difficult to differentiate. Although persistence of symptoms and signs in GravesвЂ™ disease can distinguish it from thyroiditis, it is very important to diagnose the disease early for the proper management. Isotope uptake scan of the thyroid is one of the definitive diagnostic tools, especially when there is clinical confusion between the two conditions. However, limited availability, high cost and contraindications to a radioisotope scan during pregnancy and lactation may restrict its application. Although radioactive iodine is often useful in the diagnosis and treatment of thyrotoxicosis, such tests cannot be performed in many patients because of recent use of iodinated contrast for other diagnostic studies, such as computed tomography (CT) scanning which interfere with the accuracy of radioactive iodine tests. In their study, Phillips et al[13] found that 45% of patients with newly diagnosed thyrotoxicosis had received iodinated contrast within 2 wk before endocrinology evaluation; 43% had received iodine for CT and the other 2% for angiography. In this study, Tcm99 pertechnetate was used as the definitive radiological investigation to differentiate the WJR|www.wjgnet.com 0.2 1-Specificity diagonal segments are produced by ties Table 2 Sensitivity and specificity of color flow Doppler Parameter 0.0 181 April 28, 2013|Volume 5|Issue 4| Donkol HR et al . Color Doppler in thyrotoxicosis eter in the differential diagnosis of thyrotoxicosis. It has a sensitivity of 88.9% with a specificity of 87.5% in the differentiation between GravesвЂ™ disease and other forms of autoimmune thyroiditis. It is an acceptable alternative to radioisotope scans, especially when there is a contraindication to nuclear imaging of the thyroid. We recommend measurement of thyroid blood flow by Doppler as an essential part of initial investigations of thyrotoxicosis. 4 Motohashi K, Sakai R, Hagihara M, Enaka M, Kanamori H, Maruta A, Ishigatsubo Y. [Thyrotoxicosis after cord blood transplantation for acute myelogenous leukemia]. Rinsho Ketsueki 2008; 49: 1631-1633 [PMID: 19110527] 5 Romero-RodrГguez N, Cabeza LetrГЎn ML, Villa Gil Ortega M, Ballesteros Pradas S. Thyrotoxicosis-induced vasospastic angina. Rev Esp Cardiol 2008; 61: 1355-1356 [DOI: 10.1016/ S0300-8932(08)75747-6] Amino N, Yabu Y, Miyai K. Differentiation of thyrotoxicosis 6 induced by thyroid destruction from GravesвЂ™disease. Lancet 1978; 2: 344-346 [DOI: 10.1016/S0140-6736(78)92943-4] Vitti P, Rago T, Mazzeo S, Brogioni S, Lampis M, De Liperi 7 A, Bartolozzi C, Pinchera A, Martino E. Thyroid blood flow evaluation by color-flow Doppler sonography distinguishes GravesвЂ™ disease from HashimotoвЂ™s thyroiditis. J Endocrinol Invest 1995; 18: 857-861 [PMID: 8778158] Ota H, Amino N, Morita S, Kobayashi K, Kubota S, Fukata 8 S, Kamiyama N, Miyauchi A. Quantitative measurement of thyroid blood flow for differentiation of painless thyroiditis from GravesвЂ™ disease. Clin Endocrinol (Oxf) 2007; 67: 41-45 [PMID: 17437515] ErdoДџan MF, Anil C, Cesur M, BaЕџkal N, ErdoДџan G. Color 9 flow Doppler sonography for the etiologic diagnosis of hyperthyroidism. Thyroid 2007; 17: 223-228 [PMID: 17381355] 10 Vitti P, Rago T, Mazzeo S, Brogioni S, Lampis M, De Liperi A, Bartolozzi C, Pinchera A, Martino E. Thyroid blood flow evaluation by color-flow Doppler sonography distinguishes Graves' disease from Hashimoto's thyroiditis. J Endocrinol Invest 1995; 18: 857-861 [PMID: 8778158] 11 Macedo TA, Chammas MC, Jorge PT, Pereira de Souza L, Farage L, Pegoraro BL, Pessa SU, Cerri GG. Reference values for Doppler ultrasound parameters of the thyroid in a healthy iodine-non-deficient population. Br J Radiol 2007; 80: 625-630 [PMID: 17681987] 12 Sponza M, Fabris B, Bertolotto M, Ricci C, Armini L. [Role of Doppler color ultrasonography and of flowmetric analysis in the diagnosis and follow-up of GraveвЂ™s disease]. Radiol Med 1997; 93: 405-409 [PMID: 9244919] 13 Phillips BD, Hennessey JV. Iodinated contrast prior to evaluation for thyrotoxicosis. J Hosp Med 2009; 4: 285-288 [PMID: 19263484] 14 Bogazzi F, Bartalena L, Brogioni S, Burelli A, Manetti L, Tanda ML, Gasperi M, Martino E. Thyroid vascularity and blood flow are not dependent on serum thyroid hormone levels: studies in vivo by color flow doppler sonography. Eur J Endocrinol 1999; 140: 452-456 [PMID: 10229913] 15 Kurita S, Sakurai M, Kita Y, Ota T, Ando H, Kaneko S, Takamura T. Measurement of thyroid blood flow area is useful for diagnosing the cause of thyrotoxicosis. Thyroid 2005; 15: 1249-1252 [PMID: 16356088] 16 Hari Kumar KV, Pasupuleti V, Jayaraman M, Abhyuday V, Rayudu B R, Modi KD. Role of thyroid Doppler in differential diagnosis of thyrotoxicosis. Endocr Pract 2009; 15: 6-9 [PMID: 19211390] 17 Arslan H, Unal O, AlgГјn E, Harman M, Sakarya ME. Power Doppler sonography in the diagnosis of GravesвЂ™ disease. Eur J Ultrasound 2000; 11: 117-122 [DOI: 10.1016/S0929-8266(99) 00079-8] 18 Ralls PW, Mayekawa DS, Lee KP, Colletti PM, Radin DR, Boswell WD, Halls JM. Color-flow Doppler sonography in Graves disease: вЂњthyroid infernoвЂќ. AJR Am J Roentgenol 1988; 150: 781-784 [PMID: 3279732] 19 Cappelli C, Pirola I, De Martino E, Agosti B, Delbarba A, Castellano M, Rosei EA. The role of imaging in GravesвЂ™ disease: a cost-effectiveness analysis. Eur J Radiol 2008; 65: 99-103 [PMID: 17459638] 20 Levine RA. Doppler ultrasound. In: Baskin HJ, Duick DS, Levine RA, editors. Thyroid ultrasound and ultrasound-guided FNA. 2nd ed. New York: Springer; 2008: 27-43 [DOI: 10. 1007/978-0-387-77634-7_3 ] ACKNOWLEDGMENTS The authors acknowledge the great help of the laboratory team, radiology technicians, nursing staff and everybody who participated in the collaboration of this research. COMMENTS COMMENTS Background Thyrotoxicosis may be caused either by hyperthyroidism of GravesвЂ™ disease or be due to destructive thyroiditis. Differentiation between causes of thyrotoxicosis at time of diagnosis is very important as management of each one is completely different. Thyroid scintigraphy is routinely used for this purpose but it is expensive and uses ionizing radiation. Research frontiers Color flow Doppler (CFD) ultrasonography is a safe, inexpensive, non-invasive and widely available method for measuring thyroid vascularization and blood flow. It can provide valuable information to differentiate causes of thyrotoxicosis. In this study, the clinical, laboratory, thyroid scan and Doppler results of 26 patients with thyrotoxicosis are described and compared with the aim of evaluating the efficiency of CFD in the differentiation of causes of thyrotoxicosis and comparing its sensitivity and specificity to thyroid scintigraphy. Innovations and breakthroughs This study highlighted the usefulness of color Doppler in differentiating between the two common causes of thyrotoxicosis with a sensitivity of 88.9% and a specificity of 87.5%. The authors emphasized that color Doppler is an acceptable alternative to radioisotope scans in the diagnosis of thyrotoxicosis. Applications Color Doppler flow of the inferior thyroid artery can be used in the differential diagnosis of thyrotoxicosis, especially when there is contraindication of thyroid scintigraphy by radioactive material in some patients. Terminology Thyrotoxicosis is a hypercatabolic state resulting from elevated serum levels of thyroid hormone. GravesвЂ™ disease is a diffuse thyroid disease with hyperthyroidism due to accelerated synthesis of thyroid hormones. HashimotoвЂ™s disease is autoimmune inflammation of the thyroid with release of stored thyroid hormones. Peer review This is an interesting paper addressing the role of color/pulsed Doppler for the differential diagnosis of thyrotoxicosis. This is a very careful and well thought out study of an important clinical problem. The study design, methods and data analysis are appropriate although the sample size is rather small and not well described. The authorsвЂ™ conclusions are supported by the data and the manuscript is very well written. REFERENCES 1 2 3 Kittisupamongkol W. Hyperthyroidism or thyrotoxicosis? (NOVEMBER 2008). Cleve Clin J Med 2009; 76: 152 [PMID: 19258460] De Waele S, Van den Bruel A, Selleslag D, Van Den Berghe I, Decallonne B. Acute thyrotoxicosis after SCT. Bone Marrow Transplant 2009; 43: 663-664 [PMID: 19011663] Kasagi K, Hattori H. A case of destructive thyrotoxicosis induced by neck trauma. Thyroid 2008; 18: 1333-1335 [PMID: 19067641] WJR|www.wjgnet.com 182 April 28, 2013|Volume 5|Issue 4| Donkol HR et al . Color Doppler in thyrotoxicosis 21 Tan GH, Gharib H, Reading CC. Solitary thyroid nodule. Comparison between palpation and ultrasonography. Arch Intern Med 1995; 155: 2418-2423 [PMID: 7503600] 22 Wiest PW, Hartshorne MF, Inskip PD, Crooks LA, Vela BS, Telepak RJ, Williamson MR, Blumhardt R, Bauman JM, Tekkel M. Thyroid palpation versus high-resolution thyroid ultrasonography in the detection of nodules. J Ultrasound Med 1998; 17: 487-496 [PMID: 9697951] 23 Gharib H, Papini E, Valcavi R, Baskin HJ, Crescenzi A, Dottorini ME, Duick DS, Guglielmi R, Hamilton CR, Zeiger MA, Zini M. American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 2006; 12: 63-102 [PMID: 16596732] 24 Bogazzi F, Vitti P. Could improved ultrasound and power Doppler replace thyroidal radioiodine uptake to assess thyroid disease? Nat Clin Pract Endocrinol Metab 2008; 4: 70-71 [PMID: 17984981] 25 Vlachopapadopoulou E, Thomas D, Karachaliou F, Chatzimarkou F, Memalai L, Vakaki M, Kaldrymides P, Michalacos S. Evolution of sonographic appearance of the thyroid gland in children with HashimotoвЂ™s thyroiditis. J Pediatr Endocrinol Metab 2009; 22: 339-344 [PMID: 19554808] 26 Eaton SE, Euinton HA, Newman CM, Weetman AP, Bennet WM. Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of colour-flow Doppler sonography. Clin Endocrinol (Oxf) 2002; 56: 33-38 [PMID: 11849244 DOI: 10.1046/j.0300-0664.2001.01457.x] 27 Macedo TA, Chammas MC, Jorge PT, Souza LP, Farage L, Watanabe T, Santos VA, Cerri GG. Differentiation between the two types of amiodarone-associated thyrotoxicosis using duplex and amplitude Doppler sonography. Acta Radiol 2007; 48: 412-421 [PMID: 17453522] 28 Saleh A, Furst G, Feldkamp J, Godehardt E, Grust A, Mod- der U. Estimation of antithyroid drug dose in Graves вЂ� disease: value of quantification of thyroid blood flow with color duplex sonography. Ultrasound Med Biol 2001; 27: 1137-1141 [DOI: 10.1016/S0301-5629(01)00410-0] 29 Wang CY, Chang TC. Thyroid Doppler ultrasonography and resistive index in the evaluation of the need for ablative or antithyroid drug therapy in GravesвЂ™ hyperthyroidism. J Formos Med Assoc 2001; 100: 753-757 [PMID: 11802534] 30 Nagasaki T, Inaba M, Kumeda Y, Fujiwara-Ueda M, Hiura Y, Nishizawa Y. Significance of thyroid blood flow as a predictor of methimazole sensitivity in untreated hyperthyroid patients with GravesвЂ™ disease. Biomed Pharmacother 2007; 61: 472-476 [PMID: 17420111] 31 Loy M, Perra E, Melis A, Cianchetti ME, Piga M, Serra A, Pinna G, Mariotti S. Color-flow Doppler sonography in the differential diagnosis and management of amiodaroneinduced thyrotoxicosis. Acta Radiol 2007; 48: 628-634 [PMID: 17611870] 32 Markovic V, Eterovic D. Thyroid echogenicity predicts outcome of radioiodine therapy in patients with GravesвЂ™ disease. J Clin Endocrinol Metab 2007; 92: 3547-3552 [PMID: 17609305] 33 Cohen O, Pinhas-Hamiel O, Sivan E, Dolitski M, Lipitz S, Achiron R. Serial in utero ultrasonographic measurements of the fetal thyroid: a new complementary tool in the management of maternal hyperthyroidism in pregnancy. Prenat Diagn 2003; 23: 740-742 [PMID: 12975785] 34 Cappelli C, Castellano M, Pirola I, Cumetti D, Agosti B, Gandossi E, Agabiti Rosei E. The predictive value of ultrasound findings in the management of thyroid nodules. QJM 2007; 100: 29-35 [PMID: 17178736] 35 Solivetti FM, Bacaro D, Cecconi P, Baldelli R, Marandino F. Small hyperechogenic nodules in thyroiditis: usefulness of cytological characterization. J Exp Clin Cancer Res 2004; 23: 433-435 [PMID: 15595632] P- Reviewers Juan A, Russell LD S- Editor Jiang L L- Editor Roemmele A E- Editor Xiong L WJR|www.wjgnet.com 183 April 28, 2013|Volume 5|Issue 4| WJ R World Journal of Radiology World J Radiol 2013 April 28; 5(4): 184-186 ISSN 1949-8470 (online) В© 2013 Baishideng. All rights reserved. Online Submissions: http://www.wjgnet.com/esps/ wjr@wjgnet.com doi:10.4329/wjr.v5.i4.184 CASE REPORT MDCT of right aortic arch with aberrant left subclavian artery associated with kommerell diverticulum and calcified ligamentum arteriosum Rene Epunza Kanza, Michel Berube, Pierre Michaud Rene Epunza Kanza, Michel Berube, Department of Radiology, Chicoutimi Hospital, Saguenay, Quebec G7H5H6, Canada Rene Epunza Kanza, Department of Radiology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec J1H5N4, Canada Pierre Michaud, Department of Surgery, Cardiothoracic Unit, Chicoutimi Hospital, Saguenay, Quebec G7H5H6, Canada Author contributions: Kanza RE performed the diagnosis and wrote the manuscript; Berube M was involved in performing the diagnosis and critically revised the manuscript; Michaud P was involved in the patient care. Correspondence to: Dr. Rene Epunza Kanza, MD, PhD, Clinical Assistant Professor, Department of Radiology, Chicoutimi Hospital Affiliated with Sherbrooke University, 305 Rue SaintVallier, Saguenay, Quebec G7H5H6, Canada. rn.kn.01@gmail.com Telephone: +1-418-5411234 Fax: +1-418-5435104 Received: July 10, 2012 Revised: December 30, 2012 Accepted: January 31, 2013 Published online: April 28, 2013 with aberrant left subclavian artery associated with kommerell diverticulum and calcified ligamentum arteriosum. World J Radiol 2013; 5(4): 184-186 Available from: URL: http://www. wjgnet.com/1949-8470/full/v5/i4/184.htm DOI: http://dx.doi. org/10.4329/wjr.v5.i4.184 INTRODUCTION Right aortic arch with aberrant origin of left subclavian artery is rare congenital variation of the aortic arch and its branches with a reported prevalence of 0.05%-1% in the literature[1]. This anomaly is frequently an incidental findings during autopsies series or angiographic studies because it is usually asymptomatic, but rarely may be symptomatic especially when there is a partial or complete obstruction of the oesophagus and/or trachea. With the recent development of newer non-invasive imaging systems, the use computed tomography and magnetic resonance imaging (MRI) in daily practice has been increase to diagnose and characterize anomalies of aortic arch and its branches including vascular ring. Despite this, the last part or the complete vascular ring which is made by left-side ligamentum arteriosum is often not clearly visualized pre-operatively. We present multidetector row computed tomography (MDCT)-angiographic findings of a case of right aortic arch (RAA) with aberrant left subclavian artery (ALSA) associated with Kommerell diverticulum and calcified ligamentum arteriosum causing dysphagia lusoria. In another patient, we emphasize the role that MDCT may play to demonstrate calcified ligamentous arteriosum (LA). Abstract We present a case of the right aortic arch with kommerell diverticulum (KD) and aberrant left subclavian artery in a symptomatic 50-year-old patient with a calcification in the presumed attachment site of the ligamentum arteriosum (LA) to the KD. In another 30-year-old male patient, the entire course of a calcified LA was demonstrated using multidetector row computed tomography. В© 2013 Baishideng. All rights reserved. Key words: Multidetector row computed tomography; Right aortic arch; Aberrant left subclavian artery; Kommerell diverticulum; Calcification of ligamentum arteriosum CASE REPORT Case 1 A 50-year-old man was referred to our department for investigation of dysphagia. Kanza RE, Berube M, Michaud P. MDCT of right aortic arch WJR|www.wjgnet.com 184 April 28, 2013|Volume 5|Issue 4| Kanza RE et al . MDCT-angiography of RAA and ALSA Figure 1 Chest X-ray scan showing the right aortic knob and arch as well as slight shift of the inferior trachea to the left (arrow). Figure 2 Barium esophagogram showing the posterior compression of the esophagus (arrow) in the oblique view. The patient had a long history of arterial hypertension, type в…Ў diabetes mellitus, and sleep apnea syndrome and was newly diagnosed with ischemic cardiac disease. A chest X-ray showed a right aortic knob and arch with mild tracheal deviation to the left (Figure 1). A barium esophagogram showed posterior compression of the esophagus (Figure 2). MDCT-angiography was performed using a 16-slice MDCT scanner (LightSpeed 16, GE Healthcare, WI, Milwaukee, United States). CT parameters included 2.5-mm slice thickness, gantry rotation time 0.5 s, 120 Kvp and 300 mA. The scanning delay was determined with a bolus tracking technique. The true CT study was obtained after administration of 120 cc of contrast medium at the rate of 4 cc/s. Multiplanar, maximum intensity projection and three dimensional volume-rendered reformations were obtained using a separate workstation (Voxar 3D in impax 6.3; Agfa). MDCT-angiography demonstrated RAA with a kommerell diverticulum (KD) and an ALSA (Figure 3A and B). Additionally, calcification was found in the presumed site of the superior attachment of LA to the KD (Figure 3C). Because of multiple comorbidities and relatively non-disabling dysphagia, surgery was postponed and priority was given to thoroughly investigating the patientвЂ™s cardiac disease and controlling all the comorbities before safe surgery could be planned. A B C Case 2 A 30-year-old referred to our department for chest CT following detection of 6 mm lung nodule in the right lung base during abdominal CT performed for abdominal pain investigation. The chest CT shows calcification of the entire course of the ligamentum arteriosum as an incidental findings (Figure 4) Figure 3 Multidetector computed tomography of the right aortic arch with an aberrant left subclavian artery in a 50-year-old man with dysphagia. Axial (A) and coronal (B) multiplanar reformatted and maximum intensity projection (C) images showing the kommerell diverticulum (white arrow). Note the calcification in the presumed aortic insertion site of the ligamentum arteriosum (black arrows). WJR|www.wjgnet.com DISCUSSION Right aortic arch with aberrant origin of left subclavian artery is one of the commonest mediastinal vascular ring. This anomaly is often asymptomatic and most of 185 April 28, 2013|Volume 5|Issue 4| Kanza RE et al . MDCT-angiography of RAA and ALSA A B C Figure 4 Non-contrast computed tomography in another patient. A 30-year-old asymptomatic man. Axial (A), coronal (B) and sagittal (C), reformatted images demonstrating the course of the calcified ligament arteriosum (arrows). patient will remain symptom-free in their life time. Rarely patients may present symptoms in early life time or become symptomatic in young adulthood or later due the compression of the oesophagus and/or trachea leading to dysphagia and/or dyspnoea. Surgery may be required if symptoms are moderate or severe. We present a new case of RAA with ALSA and KD causing adult onset of dysphagia lusoria. The diagnosis was suggested by the chest X-ray and barium esophagram but confirmed by MDCT-angiophaphy with better characterization of the vascular ring. This case illustrates the role of MDCT-angiography in the diagnosis of RAA with KD and ALSA. This role is quite similar with those of MRI. Although CT and MRI are very useful for the diagnosis of a vascular ring in routine clinical practice, the last part of the ring in a complete vascular ring, which is made by the LA, is often not clearly seen preoperatively, to guide surgical division. Several recent studies have shown that with modern imaging techniques, especially CT, the rate at which LA calcification is being detected has increased, varying from 11.2% to 48%[2,3]. Calcification usually occurs at the aortic end of the LA - or at the KD near the take-off of the ALSA; it may even show patterns, including curvilinear, clumped, punctuate or linear[3] (Figure 4). In their recent article, Paparo et al[4] show that MRI could be a powerful imaging tool for the diagnosis of vascular rings and may be useful for demonstrating the course of the LA. However, we believe in case of LA calcification, MDCT may be superior to MRI. Further, MDCT has the advantage of being fast and widely available, while MRI may not be suitable for patients with claustrophobia, cardiac pacemakers, significant dyspnea, or the need for sedation. The main drawback of CT remains the radiation dose and the use of a contrast medium. In routine clinical practice, the choice of modality may depend mainly on the patientвЂ™s age, type of surgery (open vs endoscopic), and expertise at the institution where the surgery is to be conducted. REFERENCES 1 2 3 4 CinГ CS, Althani H, Pasenau J, Abouzahr L. KommerellвЂ™s diverticulum and right-sided aortic arch: a cohort study and review of the literature. J Vasc Surg 2004; 39: 131-139 [PMID: 14718830 DOI: 10.1016/j.jvs.2003.07.021] Hong GS, Goo HW, Song JW. Prevalence of ligamentum arteriosum calcification on multi-section spiral CT and digital radiography. Int J Cardiovasc Imaging 2012; 28 Suppl 1: 61-67 [PMID: 22614938] Wimpfheimer O, Haramati LB, Haramati N. Calcification of the ligamentum arteriosum in adults: CT features. J Comput Assist Tomogr 1996; 20: 34-37 [PMID: 8576478 DOI: 10.1097/ 00004728-199601000-00007] Paparo F, Bacigalupo L, Melani E, Rollandi GA, Caro GD. Cardiac-MRI demonstration of the ligamentum arteriosum in a case of right aortic arch with aberrant left subclavian artery. World J Radiol 2012; 4: 231-235 [PMID: 22761985 DOI: 10.4329/wjr.v4.i5.231] P- Reviewer Yazdi HR S- Editor Cheng JX L- Editor A E- Editor Xiong L WJR|www.wjgnet.com 186 April 28, 2013|Volume 5|Issue 4| WJ R World Journal of Radiology World J Radiol 2013 April 28; 5(4): 187-192 ISSN 1949-8470 (online) В© 2013 Baishideng. All rights reserved. Online Submissions: http://www.wjgnet.com/esps/ wjr@wjgnet.com doi:10.4329/wjr.v5.i4.187 CASE REPORT Thoracic epidural angiolipoma: A case report and review of the literature Jun Meng, Yong Du, Han-Feng Yang, Fu-Bi Hu, Ya-Yong Huang, Bing Li, Chi-Shing Zee surgical specimen showed a typical angiolipoma. We review the previously documented cases of spinal extradural angiolipomas performed with MRI. Jun Meng, Yong Du, Han-Feng Yang, Fu-Bi Hu, Ya-Yong Huang, Bing Li, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan Province, China Chi-Shing Zee, Department of Radiology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, United States Author contributions: Meng J and Du Y contributed equally to this work; Meng J, Du Y, Yang HF and Hu FB collected information about the patient; Meng J, Du Y, Yang HF and Zee CS designed the research; Meng J, Du Y, Yang HF, Hu FB, Huang YY and Li B collected the data; Meng J, Du Y, Yang HF and Hu FB analyzed the data; Meng J and Du Y wrote the paper. Correspondence to: Yong Du, MD, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong 637000, Sichuan Province, China. yongdu2005@126.com Telephone: +86-817-3352006 Fax: +86-817-2262236 Received: November 6, 2012 Revised: December 18, 2012 Accepted: January 14, 2013 Published online: April 28, 2013 В© 2013 Baishideng. All rights reserved. Key words: Angiolipoma; Spinal epidural tumor; Spinal cord compression; Histopathology Meng J, Du Y, Yang HF, Hu FB, Huang YY, Li B, Zee CS. Thoracic epidural angiolipoma: A case report and review of the literature. World J Radiol 2013; 5(4): 187-192 Available from: URL: http://www.wjgnet.com/1949-8470/full/v5/i4/187.htm DOI: http://dx.doi.org/10.4329/wjr.v5.i4.187 INTRODUCTION Angiolipoma of the spine is a benign neoplasm consisting of mature fatty tissue and abnormal vascular elements, predominantly in middle-aged, female patients and situated mainly in the mid-thoracic region. There are only 142 cases with spinal extradural angiolipoma reported to date[1]. They account for about 0.14%-1.2% of all spinal axis tumors and 2%-3% of spinal epidural tumors[2]. We report another case of spinal angiolipoma in an elderly patient which showed a typical appearance on magnetic resonance imaging (MRI). The pathology, clinical features, diagnostic evaluation, and treatment of spinal angiolipoma were reviewed. Abstract Angiolipoma of the spine is a benign neoplasm consisting of both mature fatty tissue and abnormal vascular elements, and usually presents with a slow progressive clinical course. Our patient presented with bilateral lower extremity weakness and chest-back numbness. Physical examination revealed adipose elements superficial hypesthesia below the T5 level and analgesia below the T6 level. Magnetic resonance imaging (MRI) scan showed an avidly and heterogeneously enhancing mass which was located in the posterior epidural space. Compression of the thoracic cord by the fusiform mass was seen between T3-T4. During the operation, a flesh pink vascular mass (4.7 cm Г— 1.0 cm Г— 1.0 cm) with obscure margin and strong but pliable texture was found in the posterior epidural space extending from T3 to T4. There was no infiltration of the dura or the adjacent bony spine. Histopathological study of the WJR|www.wjgnet.com CASE REPORT A 63-year-old man presented with a 1.0-year history of bilateral lower extremities numbness and a 6-mo history of difficulty in urination. Concurrently, he noticed bilateral lower extremity weakness and chest-back numbness one month prior to admission. Physical examination revealed a superficial hypesthesia below the T5 level and 187 April 28, 2013|Volume 5|Issue 4| Meng J et al . Thoracic epidural angiolipoma A B C D E Figure 1 Magnetic resonance imaging scan showed a fusiform posterior epidural mass compressing the thoracic cord over two vertebral body segments between T3-T4. A: Sagittal T1 weighted magnetic resonance imaging (MRI) shows a posterior epidural mass with inhomogeneous isointensity constricting the spinal cord (arrow); B: Sagittal T2 weighted MRI shows a fusiform mass with slightly inhomogeneous hyperintensity (arrow); C: Sagittal fat-saturated T2-weighted image shows a hyperintense tumor (arrow); D: Post-contrast sagittal T1-weighted MRI with fat-saturation technique shows an inhomogeneously enhancing mass (arrow); E: Post-contrast axial T1 weighted MRI show crack like low signal between spinal cord and the lesion, with compression and displacement of the spinal cord (arrow). DISCUSSION Pathology Berenbruch et al[3] reported the first case of spinal angiolipoma (AGL) in 1890 in about a 16-year-old with numerous cutaneous lipomas, while the first pathological report was made by Howard et al[4] in 1960. It is composed of varying proportions of mature fat cells and abnormal capillary, sinusoidal, venous or arterial vascular elements. Subsequently, AGL has been further subdivided by Lin et al[5] into two categories: noninfiltrating and infiltrating. The former is encapsulated and well demarcated, not inп¬Ѓltrating the dura or the vertebrae, often in the dorsal aspect of the spinal canal. Whereas, the latter is very rare, entirely or partially unencapsulated, situated in the anterior or anterolateral aspect of the spinal canal with illdefined margins and infiltrates the surrounding tissues. Our case is type 1, unencapsulated, but not inп¬Ѓltrating the dura or the vertebrae. The origin and pathogenesis of AGLs is unknown. Histologically, the lesion is mainly composed of mature fat cells and blood vessels. The fat composition is similar to the general adipose tissue and the vascular components consist of capillaries, sinusoids, thin-walled blood vessels or thick-walled blood vessels with smooth muscle and occasionally well-developed small arteries can be seen. A diagnostic feature is the presence of fibrin thrombi in the lumen of capillaries. Degenerative changes (i.e., myxoid change, hyalinization and fibrosis) may be present in some longstanding cases[6]. Traditionally, AGL is considered a subtype of spinal lipomas, but more recent clinicalpathological studies [7] considered them as a specific entity different from pure lipomas because they were not associated with spinal dysraphism. AGLs usually contain a much greater number of mature, thick-walled vessels than liposarcomas[5]. Angiomyolipomas are a variant of angiolipoma characterized by vascular smooth muscle proliferation extending into the surrounding fat[8]. Figure 2 Histomicrograph of the surgical specimen shows typical angiolipoma. Composed of mature fat cells and abnormal vascular elements. analgesia below the T6 level, varicose vein of the left lower limb, decreased muscle strength and increased muscle tension, as well as hyperreflexia of the low extremities. A MRI scan showed a fusiform posterior epidural mass compressing the thoracic cord over two vertebral body segments between T3-T4. The mass was inhomogeneous, isointense on T1-weighted images (Figure 1A), slightly hyperintense on T2-weighted image (Figure 1B), hyperintense on fat-saturated T2-weighted images (Figure 1C) and inhomogeneously enhanced on fat-saturated T1weighted image (Figure 1D). The lesionвЂ™s long axis paralleled the long axis of the spinal cord, tapering at both ends. On the axial T1 weighted images, a crack like low signal between spinal cord and the lesion (Figure 1E) which is the typical appearance of the case can be seen. A laminectomy with gross total resection of the lesion was performed. During the operation, a flesh pink vascular mass with obscure margin and strong but pliable texture was found in the posterior epidural space from T3 to T4. There was no infiltration of the dura or the vertebrae. Histopathological study of the surgical specimen showed a typical angiolipoma (Figure 2) composed of mature fat cells and abnormal vascular elements. WJR|www.wjgnet.com 188 April 28, 2013|Volume 5|Issue 4| Meng J et al . Thoracic epidural angiolipoma Clinical presentation The clinical presentation of spinal AGLs is not different from any other benign epidural tumor. We found that the AGLs have been reported to occur predominantly in women (female:male = 22:17; Table 1) and are more common in the fifth decade[9]. In our review, age of presentation ranged from 4 to 81 years old, with mean age at presentation of 46 years. The mode of onset may be acute, subacute or chronic, may show radicular, paraplegic, progressive or remitting-relapsing clinical types. The most common initial symptoms are back pain, lower extremity numbness or paresthesias and leg weakness (Table 1), and progressive neurological symptoms secondary to spinal cord compression may develop later on. The symptoms usually evolve over a period of months to years, but the progression can be accelerated by vascular steal phenomena, vascular engorgement, venous stasis with thrombosis, bleeding into the tumor and rarely intratumoral abscess[10]. Bleeding is extremely rare in angiolipomas. Akhaddar et al[10] reported a case presenting with spontaneous bleeding causing acute paraplegia. Like other vascular lesions, onset or deterioration may occur during pregnancy[11] or with weight gain. This was not the case in our patient. images. There is slightly heterogeneity which is consistent with few vascular elements, less adipose elements of the tumor. Gadolinium enhancement reflects the vascularity of these tumors. In our case, the lesion was strongly enhanced after contrast injection. Spinal hemangiomas also present as mixed signal intensity lesions on MRI, although the hyperintensity on T2-weighted images is more striking. Suppression of high signal intensity on fat-saturated T1-weighted images may be very useful for distinguishing between angiolipomas and melanomas or sub-acute hemorrhage. Most spinal angiolipomas show enhancement with contrast medium which better defines the borders of the tumor[30]. In our case the tumor has an obscure margin, while after contrast injection its border becomes very clear. Contrast enhancement allows for differential diagnosis between spinal angiolipoma and extradural lipomatosis as the latter does not show contrast enhancement[31]. Unlike some other vascular tumors (e.g., glomus jugulare tumors), angiolipomas do not typically contain vascular flow voids on magnetic resonance images[32,33], there is only one case containing vascular flow voids in the literature. This is probably because of the preponderance of capillaries and venous channels in angiolipomas, which distinguish them from malformations with arteriovenous shunting and from those lesions with predominantly arteriolar circulation both of which produce fast flow, seen on MRI as flow-void phenomena. In our case, there is no flowvoid phenomena which is identical with those reported in literature. Diagnostic evaluation The appearance of angiolipomas correlated well with their histological composition, so the AGL is often misdiagnosed. In the majority of cases, plain vertebral radiography demonstrates normalities. If causing adjacent bone destruction, AGL must be differentiated from epidural metastases. The metastasis is the most common malignancy of epidural space, which is typically an irregular soft tissue mass with adjacent bone destruction. Trabeculation of the affected vertebral body and erosion of the pedicle may be identified in tumors infiltrating bone[12,13]. Computed tomography (CT) usually demonstrates a hypodense lesion with fat density, provides information on the degree of bony involvement[7] and also can demonstrate variable degree of enhancement after contrast injection. However, CT may not be specific for spinal epidural angiolipomas and could be misleading in some cases[14]. MRI is the imaging modality of choice for detecting angiolipomas. MRI was performed in approximately 70 cases (since 1988), but there were only 39 cases with adequate data (Table 1). The angiolipomas appear as an isointense or hyperintense extradural mass on T1-weighted images, but occasionally a hypointense mass[11,12,15,16] may be seen. The degree of central hypointensity on T1-weighted images is predictive of the degree. On T2-weighted images, the tumors have variable signal intensity, with a predominance of hyperintensity[10,15,17-29]. Significant heterogeneity in the imaging studies is attributed to the variable vascular and adipose elements of the tumor[12]. In our case, the tumor is isointense with fewer areas of hypointensity on T1-weighted images and hyperintense on fat-saturated T2-weighted WJR|www.wjgnet.com Treatment There is no clear consensus as to what combination of therapy is optimal for spinal AGL. The biological behavior of the infiltrating and noninfiltrating AGL implicates a different treatment approach [18]. To date, the main treatment is total surgical resection. Most extradural noninfiltrative tumors are amenable to complete excision via laminectomy. Total removal of infiltrating angiolipomas that often involve the vertebral body has been recommended using the anterolateral approach and stabilization of the affected vertebrae is desirable[9]. Extent of tumor resection in infiltrative angiolipoma has been debated, but most authors agree that risking neurological function is not necessary with aggressive attempts to attain gross total removal[9,17,34]. In spite of vascularization of the tumor, profuse hemorrhage has rarely been reported[10]. Although complete removal of the lesion is not always easily achievable, recurrence is exceptional[35]. In case of recurring or infiltrative SALs, wider resection followed by radiotherapy should be considered[17]. Most patients have a good prognosis because the tumors are usually slow growing and do not undergo malignant transformation. In our case, the patientвЂ™s clinical symptoms improved postoperatively. There are no signs of tumor recurrence and no neurological deficit during the two year follow-up period. In conclusion, AGL is a rare but benign clinico- 189 April 28, 2013|Volume 5|Issue 4| Meng J et al . Thoracic epidural angiolipoma Table 1 Reported cases of spinal extradural angiolipomas performed with magnetic resonance imaging Ref. Turgut et al[1] Diyora et al[6] Age (yr) Sex Clinical presentation (signs/duration) MRI finding (T1/T2, post-contrast) 26 F Acute onset of paraplegia, in week 31 of T1 and T2: Hyperintense Angiolipoma M pregnancy Upper abdominal pain/6 mo, and lower limb Isointense/hyperintense; enhancement Angiolipoma F weakness/1 wk Weakness, urinary incontinence, Very hyperintense/nearly isointense Angiolipoma M and constipation/5 mo Sudden back pain, paresthesia and complete Isointense/slightly hyperintense; no gadolinium Angiolipoma F neurological palsy/a few-minutes period Lower back pain/5 mo enhancement Low signal intensity/iso-or high signal intensity; Angiolipoma Lower back pain/3 yr High signal intensity after gadolinium injection Moderately hypointense/nearly isointense; Angiolipoma Paraparesis/2 yr Slightly inhomogeneous enhancement T1: Slightly hypointense; Inhomogeneous Angiolipoma Angiolipoma Angiolipoma 20 Turgut et al[9] 54 Akhaddar et al[10] Park et al[11] 47 74 Provenzale et al[12] 38 61 F F Pathological finding Leu et al[15] 42 81 F M Midthoracic back pain/2 yr Unstable gait, and lower limbs weakness/ enhancement Iso-hypo-intense/nearly isointense Inhomogeneous hypointensity/high signal intensity; Yen et al[16] Fourney et al[17] 71 46 M F 2 wk Acute paraparesis Feet and legs numbness/4 yr Strongly enhanced T1: Homogeneously hyphointense Homogeneously hyperintense/hyperintense; Angiolipoma Angiolipoma Shibata et al[18] Bouramas et al[19] Boockvar et al[20] 38 27 34 F F F Paraparesis/6 mo Diminution sensation/2 mo Interscapular back pain/5 mo enhanced T1 and T2: High-intensity signal Heterogeneous signal intensity/high signal intensity Hyperintense/hyperintense; Enhanced Angiolipoma Angiolipoma Angiolipoma Amlashi et al[21] Garg et al[22] 36 12 M F Back pain, and both legs weakness Paraparesis/the previous year homogeneously T1 and T2: Homogenous, hyperintense Hyperintensity/hyperintensity; Heterogeneous Angiolipoma Angiolipoma 26 M Paraparesis/3 mo contrast enhancement T1 and T2: Homogeneous high signal intensity; Angiolipoma M contrast enhancement Bowel and bladder impairment, paraparesis/the T1 and T2: Homogeneously hyperintense Angiolipoma F previous year Low back pain/10 yr Isointense/hyperintense; Homogeneous and intense Angiolipoma Angiolipoma Angiolipoma 28 do Souto et al[23] 46 Rabin et al[24] Samdani et al[25] 47 49 M F Legs paresthesias/6 mo Back pain, lower extremity weakness/ enhancement T1 and T2: High signal Intermediate-signal intensity/hyperintensity; Dogan et al[26] 50 F 3 yr Lumbosciatalgia/2 yr homogenous contrast enhancement Isointense/hyperintense; Homogeneous Angiolipoma Low back pain/8 mo enhancement Isointense/hyperintense; Homogeneous Angiolipoma Low back and leg pain/18 mo enhancement Iso-hyperintense/hyperintense; Angiolipoma Angiolipoma Angiolipoma 36 Guzey et al[27] 41 M F Hungs et al[28] Sankaran et al[29] 52 77 M Thoracolumbar pain/1.5 yr Paraparesis/48 h homogeneously enhanced T1: Hyperintense; Diffusely intense enhancement Isointense/inhomogeneous hyperintensity; Weill et al[33] 46 27 F F Paraparesis/1 yr Right leg weak/several week Inhomogeneous enhancement Iso-hypointensities/mixed signal Very-hyperintense/mixed-signal; Angiolipoma Angiolipoma Gelabert-GonzГЎlez 16 M Low back pain/6 mo Inhomogeneous enhancement Slightly inhomogeneous/heterogeneously Angiolipoma 45 Both feet numbness, and leg weakness/ hypointense T1 and T2: Moderately hyperintense relative to spinal Angiolipoma Sakaida et al[36] Oge et al[37] al-Anazi et al[38] Gelabert-GonzГЎlez 72 72 38 вЂ‰4 M M F M 6 mo Legs abnormal sensation/4 mo Paraparesis/4 d Both feet numbness, 8-mo pregnant housewife Back pain, and both legs weakness/2 d cord Inhomogeneous enhancement T1: Hyperintense T1: Hyperintense T1: Mixed-intensity Angiolipoma Angiolipoma Angiolipoma Angiolipoma et al[39] Rocchi et al[40] 60 M Lumbosciatalgia/2 yr T1: Signal intensity similar to that of the Angiolipoma Angiolipoma Angiolipoma Angiolipoma Angiolipoma et al[34] Chotai et al[41] 54 69 F M Lumbosciatalgia/12 mo Back pain, paresthesias, and hypesthesia/ subcutaneous adipose tissue Homogeneous contrast enhancement T1: Slightly high intensity with areas of Konya et al[42] Current study 60 63 F M 5 yr Low back pain/6 mo Lower extremities numbness/1 yr hypointensity; Inhomogeneous enhancement T1: Hyperintense; marked enhancement Isointense/slightly hyperintense; Obviously inhomogeneous enhancement Age, sex, clinical presentation, magnetic resonance imaging findings, and pathological findings are shown for each case. Authors and year of publication are shown for each case reported. F: Female; M: Male. WJR|www.wjgnet.com 190 April 28, 2013|Volume 5|Issue 4| Meng J et al . Thoracic epidural angiolipoma pathological entity which is composed of fatty tissue and vascular elements. It grows in a spindle shape along the spinal canal, without associated malformations. The postoperative outcome after surgical management of this lesion is favorable. Accurate pre-operative diagnosis is very important. MRI typically shows an iso- to hyperintense mass on T1 weighted images and hyperintense mass without flow voids on T2 weighted images in the posterior epidural space. Following intravenous injection of contrast material, avid inhomogeneous enhancement is seen. 17 REFERENCES 21 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 18 19 20 Turgut M. Thoracic epidural angiolipoma with extraspinal extension. Neurol India 2011; 59: 654; author reply 654-655 [PMID: 21891966 DOI: 10.4103/0028-3886.84370] Alter M. 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Spine J 2007; 7: 739-744 [PMID: 17998134 DOI: 10.1016/j.spinee.2006.08.014] Hungs M, ParГ© LS. Spinal angiolipoma: case report and literature review. J Spinal Cord Med 2008; 31: 315-318 [PMID: 18795485] Sankaran V, Carey M, Shad A. Traumatic bleeding of spinal angiolipoma presenting with subacute paraparesis--a case report and histopathological aspects. Br J Neurosurg 2010; 24: 714-715 [PMID: 20874452 DOI: 10.3109/02688697.2010.52 0760] Klisch J, Spreer J, Bloss HG, Baborie A, Hubbe U. Radiological and histological findings in spinal intramedullary angiolipoma. Neuroradiology 1999; 41: 584-587 [PMID: 10447570 DOI: 10.1007/s002340050811] OвЂ™Donovan NA, Naik K, Maloney WJ, Llewellyn CG. Spinal angiolipoma mimicking extradural lipomatosis. Can Assoc Radiol J 1996; 47: 51-53 [PMID: 8548470] Preul MC, Leblanc R, Tampieri D, Robitaille Y, Pokrupa R. Spinal angiolipomas. Report of three cases. J Neurosurg 1993; 78: 280-286 [PMID: 8421211 DOI: 10.3171/jns.1993.78.2.0280] Weill A, del Carpio-OвЂ™Donovan R, Tampieri D, Melanson D, Ethier R. Spinal angiolipomas: CT and MR aspects. J Comput Assist Tomogr 1991; 15: 83-85 [PMID: 1987206 DOI: 10.1097/ 00004728-199101000-00011] Gelabert-GonzГЎlez M, GarcГa-Allut A. Spinal extradural angiolipoma: report of two cases and review of the literature. Eur Spine J 2009; 18: 324-335 [PMID: 19127373 DOI: 10.1007/ s00586-008-0858-8] Ring D, Snyder B. Spinal canal compromise in Proteus syn- April 28, 2013|Volume 5|Issue 4| Meng J et al . Thoracic epidural angiolipoma 36 37 38 39 drome: case report and review of the literature. Am J Orthop (Belle Mead NJ) 1997; 26: 275-278 [PMID: 9113294] Sakaida H, Waga S, Kojima T, Kubo Y, Matsubara T, Yamamoto J. Thoracic spinal angiomyolipoma with extracanal extension to the thoracic cavity. A case report. Spine (Phila Pa 1976) 1998; 23: 391-394 [PMID: 9507632 DOI: 10.1097/0000763 2-199802010-00022] Oge HK, SГ¶ylemezoglu F, Rousan N, Ozcan OE. Spinal angiolipoma: case report and review of literature. J Spinal Disord 1999; 12: 353-356 [PMID: 10451053] al-Anazi A, Ammar A, Shannon P, al-Mulhim F. Spinal extradural angiolipoma. Br J Neurosurg 2000; 14: 471-472 [PMID: 11198773 DOI: 10.1080/02688690050175319] Gelabert-GonzГЎlez M, Agulleiro-DГaz J, Reyes-SantГas RM. 40 41 42 Spinal extradural angiolipoma, with a literature review. Childs Nerv Syst 2002; 18: 725-728 [PMID: 12483360 DOI: 10.1007/s00381-002-0653-5] Rocchi G, Caroli E, Frati A, Cimatti M, Savlati M. Lumbar spinal angiolipomas: report of two cases and review of the literature. Spinal Cord 2004; 42: 313-316 [PMID: 15123997 DOI: 10.1038/sj.sc.3101535] Chotai S, Hur JS, Moon HJ, Kwon TH, Park YK, Kim JH. Spinal angiolipoma--case report. Neurol Med Chir (Tokyo) 2011; 51: 539-542 [PMID: 21785253 DOI: 10.2176/nmc.51.539] Konya D, Ozgen S, Kurtkaya O, Pamir NM. Lumbar spinal angiolipoma: case report and review of the literature. Eur Spine J 2006; 15: 1025-1028 [PMID: 16172903 DOI: 10.1007/ s00586-005-1028-x] P- Reviewers Lokhande PV, Kasai Y S- Editor Song XX L- Editor Roemmele A E- Editor Xiong L WJR|www.wjgnet.com 192 April 28, 2013|Volume 5|Issue 4| WJ R World Journal of Radiology World J Radiol 2013 April 28; 5(4): I-V ISSN 1949-8470 (online) В© 2013 Baishideng. All rights reserved. Online Submissions: http://www.wjgnet.com/esps/ wjr@wjgnet.com www.wjgnet.com INSTRUCTIONS TO AUTHORS being published for no more than 2 years, reflecting cutting-edge trends in scientific research. Latest articles refer to the latest published high-quality papers that are included in PubMed, reflecting the latest research trends. 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The only register now available, to our knowledge, is http://www.clinicaltrials.gov sponsored by the United States National Library of Medicine and we encour- Conflict-of-interest statement In the interests of transparency and to help reviewers assess any potential bias, WJR requires authors of all papers to declare any competing commercial, personal, political, intellectual, or religious interests WJR|www.wjgnet.com II April 28, 2013|Volume 5|Issue 4| Instructions to authors age all potential contributors to register with it. However, in the case that other registers become available you will be duly notified. A letter of recommendation from each authorвЂ™s organization should be provided with the contributed article to ensure the privacy and secrecy of research is protected. Authors should retain one copy of the text, tables, photoВgraphs and illustrations because rejected manuscripts will not be returned to the author(s) and the editors will not be responsible for loss or damage to photographs and illustrations sustained during mailing. cine, Chief, Liver Center, Gastroenterology Division, University of California, Box 0538, San Francisco, CA 94143, United States. montgomery.bissell@ucsf.edu Telephone and fax: Telephone and fax should consist of +, country number, district number and telephone or fax number, e.g. Telephone: +86-10-85381891 Fax: +86-10-85381893 Peer reviewers: All articles received are subject to peer review. Normally, three experts are invited for each article. Decision on acceptance is made only when at least two experts recommend publication of an article. All peer-reviewers are acknowledged on Express Submission and Peer-review System website. 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Abstracts of original contributions should be structured into the following sections: AIM (no more than 20 words; Only the purpose of the study should be included. Please write the Aim in the form of вЂњTo investigate/study/вЂ¦вЂќ), METHODS (no less than 140 words for Original Articles; and no less than 80 words for Brief Articles), RESULTS (no less than 150 words for Original Articles and no less than 120 words for Brief Articles; You should present P values where appropriate and must provide relevant data to illustrate how they were obtained, e.g. 6.92 В± 3.86 vs 3.61 В± 1.67, P < 0.001), and CONCLUSION (no more than 26 words). MANUSCRIPT PREPARATION All contributions should be written in English. All articles must be submitted using word-processing software. All submissions must be typed in 1.5 line spacing and 12 pt. Book Antiqua with ample margins. Style should conform to our house format. Required information for each of the manuscript sections is as follows: Title page Title: Title should be less than 12 words. Key words Please list 5-10 key words, selected mainly from Index Medicus, which reflect the content of the study. Running title: A short running title of less than 6 words should be provided. Core tip Please write a summary of less than 100 words to outline the most innovative and important arguments and core contents in your paper to attract readers. Authorship: Authorship credit should be in accordance with the standard proposed by International Committee of Medical Journal Editors, based on (1) substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published. Authors should meet conditions 1, 2, and 3. Text For articles of these sections, original articles and brief articles, the main text should be structured into the following sections: INTRODUCTION, MATERIALS AND METHODS, RESULTS and DISCUSSION, and should include appropriate Figures and Tables. Data should be presented in the main text or in Figures and Tables, but not in both. The main text format of these sections, editorial, topic highlight, case report, letters to the editors, can be found at: http://www. wjgnet.com/1948-5204/g_info_list.htm. Institution: Author names should be given first, then the complete name of institution, city, province and postcode. For example, XuChen Zhang, Li-Xin Mei, Department of Pathology, Chengde Medical College, Chengde 067000, Hebei Province, China. One author may be represented from two institutions, for example, George Sgourakis, Department of General, Visceral, and Transplantation Surgery, Essen 45122, Germany; George Sgourakis, 2nd Surgical Department, Korgialenio-Benakio Red Cross Hospital, Athens 15451, Greece Illustrations Figures should be numbered as 1, 2, 3, etc., and mentioned clearly in the main text. Provide a brief title for each figure on a separate page. Detailed legends should not be provided under the figures. This part should be added into the text where the figures are applicable. Keeping all elements compiled is necessary in line-art image. Scale bars should be used rather than magnification factors, with the length of the bar defined in the legend rather than on the bar itself. File names should identify the figure and panel. Avoid layering type directly over shaded or textured areas. Please use uniform legends for the same subjects. For example: Figure 1 Pathological changes in atrophic gastritis after treatment. A: ...; B: ...; C: ...; D: ...; E: ...; F: ...; G: вЂ¦etc. It is our principle to publish high resolution-figures for the E-versions. Author contributions: The format of this section should be: Author contributions: Wang CL and Liang L contributed equally to this work; Wang CL, Liang L, Fu JF, Zou CC, Hong F and Wu XM designed the research; Wang CL, Zou CC, Hong F and Wu XM performed the research; Xue JZ and Lu JR contributed new reagents/analytic tools; Wang CL, Liang L and Fu JF analyzed the data; and Wang CL, Liang L and Fu JF wrote the paper. Supportive foundations: The complete name and number of supportive foundations should be provided, e.g. Supported by National Natural Science Foundation of China, No. 30224801 Tables Three-line tables should be numbered 1, 2, 3, etc., and mentioned clearly in the main text. Provide a brief title for each table. Detailed legends should not be included under tables, but rather added into the text where applicable. The information should complement, but not duplicate the text. Use one horizontal line under the title, a second under column heads, and a third below the Table, above any footnotes. Vertical and italic lines should be omitted. Correspondence to: Only one corresponding address should be provided. Author names should be given first, then author title, affiliation, the complete name of institution, city, postcode, province, country, and email. All the letters in the email should be in lower case. A space interval should be inserted between country name and email address. For example, Montgomery Bissell, MD, Professor of Medi- WJR|www.wjgnet.com III April 28, 2013|Volume 5|Issue 4| Instructions to authors In press 3 Tian D, Araki H, Stahl E, Bergelson J, Kreitman M. Signature of balancing selection in Arabidopsis. Proc Natl Acad Sci USA 2006; In press Organization as author 4 Diabetes Prevention Program Research Group. Hypertension, insulin, and proinsulin in participants with impaired glucose tolerance. Hypertension 2002; 40: 679-686 [PMID: 12411462 DOI:10.1161/01.HYP.0000035706.28494.09] Both personal authors and an organization as author 5 Vallancien G, Emberton M, Harving N, van Moorselaar RJ; Alf-One Study Group. Sexual dysfunction in 1, 274 European men suffering from lower urinary tract symptoms. J Urol 2003; 169: 2257-2261 [PMID: 12771764 DOI:10.1097/01.ju. 0000067940.76090.73] No author given 6 21st century heart solution may have a sting in the tail. BMJ 2002; 325: 184 [PMID: 12142303 DOI:10.1136/bmj.325. 7357.184] Volume with supplement 7 Geraud G, Spierings EL, Keywood C. Tolerability and safety of frovatriptan with short- and long-term use for treatment of migraine and in comparison with sumatriptan. Headache 2002; 42 Suppl 2: S93-99 [PMID: 12028325 DOI:10.1046/j.15264610.42.s2.7.x] Issue with no volume 8 Banit DM, Kaufer H, Hartford JM. Intraoperative frozen section analysis in revision total joint arthroplasty. Clin Orthop Relat Res 2002; (401): 230-238 [PMID: 12151900 DOI:10.1097/0000 3086-200208000-00026] No volume or issue 9 Outreach: Bringing HIV-positive individuals into care. HRSA Careaction 2002; 1-6 [PMID: 12154804] Notes in tables and illustrations Data that are not statistically significant should not be noted. aP < 0.05, b P < 0.01 should be noted (P > 0.05 should not be noted). If there are other series of P values, cP < 0.05 and dP < 0.01 are used. A third series of P values can be expressed as eP < 0.05 and fP < 0.01. Other notes in tables or under illustrations should be expressed as 1F, 2F, 3F; or sometimes as other symbols with a superscript (Arabic numerals) in the upper left corner. In a multi-curve illustration, each curve should be labeled with в—Џ, в—‹, в– , в–Ў, в–І, в–і, etc., in a certain sequence. Acknowledgments Brief acknowledgments of persons who have made genuine contributions to the manuscript and who endorse the data and conclusions should be included. Authors are responsible for obtaining written permission to use any copyrighted text and/or illustrations. REFERENCES Coding system The author should number the references in Arabic numerals according to the citation order in the text. Put reference numbers in square brackets in superscript at the end of citation content or after the cited authorвЂ™s name. For citation content which is part of the narration, the coding number and square brackets should be typeset normally. For example, вЂњCrohnвЂ™s disease (CD) is associated with increased intestinal permeability[1,2]вЂќ. If references are cited directly in the text, they should be put together within the text, for example, вЂњFrom references[19,22-24], we know that...вЂќ When the authors write the references, please ensure that the order in text is the same as in the references section, and also ensure the spelling accuracy of the first authorвЂ™s name. Do not list the same citation twice. PMID and DOI Pleased provide PubMed citation numbers to the reference list, e.g. PMID and DOI, which can be found at http://www.ncbi.nlm.nih. gov/sites/entrez?db=pubmed and http://www.crossref.org/SimpleTextQuery/, respectively. The numbers will be used in E-version of this journal. Books Personal author(s) 10 Sherlock S, Dooley J. Diseases of the liver and billiary system. 9th ed. Oxford: Blackwell Sci Pub, 1993: 258-296 Chapter in a book (list all authors) 11 Lam SK. Academic investigatorвЂ™s perspectives of medical treatment for peptic ulcer. In: Swabb EA, Azabo S. Ulcer disease: investigation and basis for therapy. New York: Marcel Dekker, 1991: 431-450 Author(s) and editor(s) 12 Breedlove GK, Schorfheide AM. Adolescent pregnancy. 2nd ed. Wieczorek RR, editor. White Plains (NY): March of Dimes Education Services, 2001: 20-34 Conference proceedings 13 Harnden P, Joffe JK, Jones WG, editors. Germ cell tumours V. Proceedings of the 5th Germ cell tumours Conference; 2001 Sep 13-15; Leeds, UK. New York: Springer, 2002: 30-56 Conference paper 14 Christensen S, Oppacher F. An analysis of Koza's computational effort statistic for genetic programming. In: Foster JA, Lutton E, Miller J, Ryan C, Tettamanzi AG, editors. Genetic programming. EuroGP 2002: Proceedings of the 5th European Conference on Genetic Programming; 2002 Apr 3-5; Kinsdale, Ireland. Berlin: Springer, 2002: 182-191 Electronic journal (list all authors) 15 Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis serial online, 1995-01-03, cited 1996-06-05; 1(1): 24 screens. Available from: URL: http://www.cdc.gov/ ncidod/eid/index.htm Patent (list all authors) 16 Pagedas AC, inventor; Ancel Surgical R&D Inc., assiВgnee. Flexible endoscopic grasping and cutting device and positioning tool assembly. United States patent US 20020103498. 2002 Aug 1 Style for journal references Authors: the name of the first author should be typed in bold-faced letters. The family name of all authors should be typed with the initial letter capitalized, followed by their abbreviated first and middle initials. (For example, Lian-Sheng Ma is abbreviated as Ma LS, Bo-Rong Pan as Pan BR). The title of the cited article and italicized journal title (journal title should be in its abbreviated form as shown in PubMed), publication date, volume number (in black), start page, and end page [PMID: 11819634 DOI: 10.3748/wjg.13.5396]. Style for book references Authors: the name of the first author should be typed in bold-faced letters. The surname of all authors should be typed with the initial letter capitalized, followed by their abbreviated middle and first initials. (For example, Lian-Sheng Ma is abbreviated as Ma LS, Bo-Rong Pan as Pan BR) Book title. Publication number. Publication place: Publication press, Year: start page and end page. Format Journals English journal article (list all authors and include the PMID where applicable) 1 Jung EM, Clevert DA, Schreyer AG, Schmitt S, Rennert J, Kubale R, Feuerbach S, Jung F. Evaluation of quantitative contrast harmonic imaging to assess malignancy of liver tumors: A prospective controlled two-center study. World J Gastroenterol 2007; 13: 6356-6364 [PMID: 18081224 DOI: 10.3748/wjg.13. 6356] Chinese journal article (list all authors and include the PMID where applicable) 2 Lin GZ, Wang XZ, Wang P, Lin J, Yang FD. Immunologic effect of Jianpi Yishen decoction in treatment of Pixu-diarrhoea. Shijie Huaren Xiaohua Zazhi 1999; 7: 285-287 WJR|www.wjgnet.com Statistical data Write as mean В± SD or mean В± SE. IV April 28, 2013|Volume 5|Issue 4| Instructions to authors Statistical expression Express t test as t (in italics), F test as F (in italics), chi square test as П‡2 (in Greek), related coefficient as r (in italics), degree of freedom as П… (in Greek), sample number as n (in italics), and probability as P (in italics). responses to the reviewers, and English language Grade B certificate (for non-native speakers of English), should be submitted to the online system via the link contained in the e-mail sent by the editor. If you have any questions about the revision, please send e-mail to esps@wjgnet.com. Units Use SI units. For example: body mass, m (B) = 78 kg; blood pressure, p (B) = 16.2/12.3 kPa; incubation time, t (incubation) = 96 h, blood glucose concentration, c (glucose) 6.4 В± 2.1 mmol/L; blood CEA mass concentration, p (CEA) = 8.6 24.5 mg/L; CO2 volume fraction, 50 mL/L CO2, not 5% CO2; likewise for 40 g/L formaldehyde, not 10% formalin; and mass fraction, 8 ng/g, etc. Arabic numerals such as 23, 243, 641 should be read 23вЂ‰243вЂ‰641. The format for how to accurately write common units and quantums can be found at: http://www.wjgnet.com/1948-5204/g_info_ 20100312183048.htm. Language evaluation The language of a manuscript will be graded before it is sent for revision. (1) Grade A: priority publishing; (2) Grade B: minor language polishing; (3) Grade C: a great deal of language polishing needed; and (4) Grade D: rejected. Revised articles should reach Grade A or B. Copyright assignment form Please download a Copyright assignment form from http://www. wjgnet.com/1948-5204/g_info_20100312182928.htm. Responses to reviewers Please revise your article according to the comments/suggestions provided by the reviewers. The format for responses to the reviewersвЂ™ comments can be found at: http://www.wjgnet.com/1948-5204/ g_info_20100312182841.htm. Abbreviations Standard abbreviations should be defined in the abstract and on first mention in the text. In general, terms should not be abbreviated unless they are used repeatedly and the abbreviation is helpful to the reader. Permissible abbreviations are listed in Units, Symbols and Abbreviations: A Guide for Biological and Medical Editors and Authors (Ed. Baron DN, 1988) published by The Royal Society of Medicine, London. Certain commonly used abbreviations, such as DNA, RNA, HIV, LD50, PCR, HBV, ECG, WBC, RBC, CT, ESR, CSF, IgG, ELISA, PBS, ATP, EDTA, mAb, can be used directly without further explanation. Proof of financial support For papers supported by a foundation, authors should provide a copy of the approval document and serial number of the foundation. Links to documents related to the manuscript WJR will be initiating a platform to promote dynamic interactions between the editors, peer reviewers, readers and authors. After a manuscript is published online, links to the PDF version of the submitted manuscript, the peer-reviewersвЂ™ report and the revised manuscript will be put on-line. Readers can make comments on the peer reviewerвЂ™s report, authorsвЂ™ responses to peer reviewers, and the revised manuscript. We hope that authors will benefit from this feedback and be able to revise the manuscript accordingly in a timely manner. Italics Quantities: t time or temperature, c concentration, A area, l length, m mass, V volume. Genotypes: gyrA, arg 1, c myc, c fos, etc. Restriction enzymes: EcoRI, HindI, BamHI, Kbo I, Kpn I, etc. Biology: H. pylori, E coli, etc. Examples for paper writing All types of articlesвЂ™ writing style and requirement will be found in the link: http://www.wjgnet.com/esps/NavigationInfo.aspx?id=15 Publication fee WJR is an international, peer-reviewed, OA online journal. Articles published by this journal are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium and format, provided the original work is properly cited. The use is nonвЂ‘commercial and is otherwise in compliance with the license. Authors of accepted articles must pay a publication fee. Publication fee: 600 USD per article. All invited articles are published free of charge. SUBMISSION OF THE REVISED MANUSCRIPTS AFTER ACCEPTED Authors must revise their manuscript carefully according to the revision policies of Baishideng Publishing Group Co., Limited. The revised version, along with the signed copyright transfer agreement, WJR|www.wjgnet.com April 28, 2013|Volume 5|Issue 4| Published by Baishideng Publishing Group Co., Limited Flat C, 23/F., Lucky Plaza, 315-321 Lockhart Road, Wan Chai, Hong Kong, China Fax: +852-31158812 Telephone: +852-58042046 E-mail: bpgoffice@wjgnet.com http://www.wjgnet.com Baishideng Publishing Group Co., Limited В© 2013 Baishideng. All rights reserved.