ISSN (online) World Journal of Orthopedics World J Orthop 2015 August 18; 6(7): Published by Baishideng Publishing Group Inc

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1 ISSN (online) World Journal of Orthopedics World J Orthop 2015 August 18; 6(7): Published by Baishideng Publishing Group Inc

2 Editorial Board The World Journal of Orthopedics Editorial Board consists of 328 members, representing a team of worldwide experts in orthopedics. They are from 41 countries, including Australia (10), Austria (8), Bangladesh (1), Belgium (4), Brazil (10), Canada (4), Chile (1), China (29), Croatia (2), Cyprus (1), Denmark (2), Egypt (5), Finland (1), France (2), Germany (19), Greece (12), Hungary (1), India (17), Iran (4), Israel (6), Italy (21), Japan (14), Jordan (2), Malaysia (1), Netherlands (10), New Zealand (1), Poland (1), Saudi Arabia (2), Serbia (1), Singapore (4), Slovenia (2), South Korea (12), Spain (7), Sri Lanka (1), Sweden (8), Switzerland (4), Thailand (5), Turkey (11), United Arab Emirates (1), United Kingdom (16), and United States (65). EDITORS-IN-CHIEF Quanjun (Trey) Cui, Charlottesville Bao-Gan Peng, Beijing GUEST EDITORIAL BOARD MEMBERS Yuk-Kwan Chen, Kaohsiung Sheng-Mou Hou, Taipei Tsan-Wen Huang, Pu-Tz City Yen-Hsuan Jean, Pingtung Ko-Hsiu Lu, Tajchung Wei-Ren Su, Tainan Yih-Wen Tarng, Kaohsiung Kuo-Wei Wang, Kaohsiung James Cheng-Chung Wei, Taichung MEMBERS OF THE EDITORIAL BOARD Australia Nicky Bertollo, Sydney Stuart Adam Callary, Adelaide Changhai Ding, Hobart Herwig Drobetz, Mackay Melanie Jane Franklyn, Melbourne Laurent Frossard, Brisbane Pazit Levinger, Melbourne Munjed Al Muderis, Sydney Gordon L Slater, Sydney Lucian Bogdan Solomon, Adelaide Austria Christian Krasny, Vienna Florian M Kovar, Vienna Gerold Labek, Innsbruck Stefan Marlovits, Vienna Lukas Leopold Negrin, Himberg Reinhold Ortmaier, Salzburg Patrick Sadoghi, Graz Klemens Trieb, Wels Bangladesh Saidur Rahman Mashreky, Dhaka Belgium Olivier Bruyere, Liege Andre Farasyn, Ghent Tom Van Leemput, Zandhoven Geert Meermans, Berchem Brazil Rogerio Serpone Bueno, Sao Paulo Gustavo Constantino de Campos, Campinas Reginaldo K Fukuchi, Sao Paulo Tiago Lazzaretti Fernandes, Sao Paulo Mauro Cesar de Morais Filho, Sao Paulo Alexandre Leme Godoy-Santos, Sao Paulo Andrei Fernandes Joaquim, Campinas Daniel F Martins, Palhoca Leonardo Metsavaht, Rio de Janeiro Francis Trombini-Souza, Sao Paulo Canada Kivanc Atesok, Etobicoke Marwan El-Rich, Edmonton Richard Kremer, Montreal Neetu Rishiraj, Vancouver Chile Dante Parodi, Santiago China Wing-Hoi Cheung, Hong Kong Lin Guo, Chongqing Yong Qiang Hao, Shanghai Chen Jiao, Beijing Winson Chiu-Chun Lee, Hong Kong Jian-Min Li, Jinan Pauline Po Yee Lui, Hong Kong Dong-Yang Ma, Lanzhou Wei-Min Pan, Xi'an Kang-Lai Tang, Chongqing Defeng Wang, Hong Kong Yu Wang, Beijing Qing Xia, Shanghai Ya-Yi Xia, Lanzhou Xi-Jie Yu, Chengdu Xiao-Lei Zhang, Wenzhou Jian-Hua Zhao, Chongqing Jian-Ning Zhao, Nanjing Ping Zhen, Lanzhou Croatia Goran Bicanic, Zagreb Srecko Sabalic, Zagreb Cyprus Michalis Zenios, Limassol WJO I February 18, 2015

3 Denmark Lars C Borris, Arhus Morten Tange Kristensen, Hvidovre Egypt Barakat Sayed El-Alfy, Mansoura Khaled M Emara, Cairo Mohamed Mostafa Hosney El-Sayed, Tanta Mohammad Masoud, Assiut Elsayed Ibraheem Elsayed Massoud, Sohag Finland Hannu T Aro, Turku France Federico Canavese, Clermont Ferrand Hechmi Toumi, Orleans Hungary Andor Sebestyén, Pécs India Vikas Bachhal, Chandigarh Roopesh Kumar VR, Pondicherry Vikas Kulshrestha, Delhi Ashokkumar Navratnamal Johari, Mumbai Pramod V Lokhande, Pune Vivek Mahajan, New Delhi Karthik Selvaraj Murugappan, Coimbatore Satya Ranjan Patra, Bhubaneswar V Prakash, Anand Joshua Samuel Rajkumar, MPT, Bangalore Parag Sancheti, Pune Gaurav Sharma, Chandigarh Mohamed Shafi, Gangavalli Ajay Pal Singh, Punjab Sujit Kumar Tripathy, Bhubaneswar Raju Vaishya, New Delhi Divya Vohora, New Delhi Stefano Marco Paolo Rossi, Pavia Luigi Tarallo, Modena Japan Ukei Anazawa, Ichikawa Yoichi Aota, Yokohama Masahiro Hasegawa, Tsu City Takafumi Hiranaka, Takatsuki Eichi Itadera, Narita Hiroshi Kawaguchi, Tokyo Shigeru Kobayashi, Eiheiji Makoto Makishima, Itabashi-ku Kanji Mori, Otsu Tsuyoshi Ohishi, Hamamatsu Kazuya Oshima, Osaka Hirotaka Sano, Sendai Jun Takahashi, Matsumoto Kotaro Yamakado, Fukui Jordan Alia A Alghwiri, Amman Bashar Abuzayed, Irbid Germany Ahmet Ali Altintas, Koln Hagen Andruszkow, Aachen Mike H Baums, Wiesbaden Peter Bernstein, Dresden Bilal Farouk El-Zayat, Marburg Ahmad M Eweida, Ludwigshafen Chrisitan B Frank, Baden-Baden Michael Frink, Marburg Andreas B Imhoff, Munich Chlodwig Kirchhoff, Munich Matthias Knobe, Aachen Hans-Christoph Pape, Aachen Markus Peter Regauer, Munich Khaled Hamed Salem, Paderborn Frank M Schiedel, Muenster Volker Schoeffl, Bamberg Hagen Schmal, Freiburg Fritz Thorey, Heidelberg Tobias Topp, Berlin Greece Antonios Angoules, Athens Georgios I Drosos, Alexandroupolis Konstantinos Fousekis, Egio Michael Hantes, Larissa Marios G Lykissas, Athens George A Macheras, Athens Konstantinos N Malizos, Larissa Dimitrios Nikolopoulos, Athens Vassilis Paschalis, Trikala Dionysios J Papachristou, Patras Georgios Constantinos Papachristou, Athens Haris S Vasiliadis, Ioannina Iran MT Karimi, Isfahan Firooz Madadi, Tehran Mohammad Ali Mohseni-Bandpei, Tehran Amir Hossein Saveh, Tehran Israel Alexander Blankstein, Ramat HaSharon Itay Fenichel, Udim Youssef Maher Masharawi, Tel Aviv Nahum Rosenberg, Haifa Jona J Sela, Jerusalem Yehuda Ullmann, Haifa Italy Alessandro Aprato, Torino Andrea Angelini, Bologna Luigi Valentino Berra, Milano Matteo Cadossi, Bologna Lawrence Camarda, Palermo Giuseppe Maurizio Campo, Messina Andrea Camera, Pietra Ligure Stefano Carbone, Rome Patrizia D'Amelio, Torino Cesare Faldini, Bologna Olimpio Galasso, Catanzaro Umile Giuseppe Longo, Roma Alberto Grassi, Bologna Nicolò Martinelli, Milan Raffaele Mugnai, Modena Giuseppe Musumeci, Catania Roberto Postacchini, Rome Barbara Rossi, Rome Roberto Rossi, Torino Malaysia Arezoo Eshraghi, Kuala Lumpur Netherlands Michel Pieter Jozef van den Bekerom, Amsterdam Peter RG Brink, Maastricht Yvon Marielle den Hartog, Rotterdam Izaak Frederik Kodde, Amsterdam Jesse WP Kuiper, Alkmaar Tom M van Raaij, Groningen Hugo Christiaan van der Veen, Groningen Alexander TM van de Water, Enschede Walter van der Weegen, Geldrop Eline W Zwitser, Leiderdorp New Zealand Gary J Hooper, Christchurch Poland Agnieszka Tomaszewska, Gdańsk Saudi Arabia Ahmed Bakhsh, Al-Khobar Mohamed Zamzam, Riyadh Serbia Miroslav Ziva Milankov, Novi Sad WJO II February 18, 2015

4 Singapore Yee Han Dave Lee, Singapore Anselm Mak, Singapore Sean Ng, Singapore Ken Lee Puah, Singapore Slovenia Gregor Recnik, Maribor Matjaz Sajovic, Celje South Korea Yong Ahn, Seoul Seung-Hoon Baek, Daegu Chang-Ho Hwang, Ulsan Jin Ho Hwang, Seoul Jung-Taek Hwang, Chuncheon Tae-Young Kim, Anyang Sung-Uk Kuh, Seoul Haejung Lee, Busan Young-Kyun Lee, Seongnam Soon Hyuck Lee, Seoul Sang-Ki Lee, Daejeon Hee-Soo Seo, Seoul Spain Miguel Angel Ruiz Iban, Madrid Rafael Arriaza, La Coruna Enrique Guerado, Malaga Albert Isidro, Barcelona Sergio Hernandez-Sanchez, Sant Joan D'alacant Nuria Vilaboa, Madrid Rafael Villalba, Córdoba Sri Lanka Janaka Lenora, Galle Sweden Allan Abbott, Linkoping Paul W Ackermann, Enebyberg Johan von Heideken, Stockholm Karin Larsson, Gothenburg Anna Nordstrom, Umea Yan Li, Stockholm Jonas Ranstam, Lund Ola Rolfson, Gothenburg Switzerland Marco Barbero, Manno Dimitrios-Stergios Evangelopoulos, Bern Ladislav Mica, Zurich Michael Tobias Hirschmann, Bruderholz Thailand Sugalya Amatachaya, Maung Theerachai Apivatthakakul, Chiang Mai Wiroon Laupattarakasem, Mueang Boonsin Tangtrakulwanich, Hat Yai Tulyapruek Tawonsawatruk, Bangkok Turkey Tuncay Colak, Kocaeli Abdullah Demirtas, Istanbul Mehmet Erdil, Istanbul Kemal Gokkus, Antalya Alper Kaya, Istanbul Serdar Kahraman, Istanbul Ramazan Kahveci, Ankara Yavuz Kocabey, Kocaeli skemal Nas, Sakarya Salih Ozgocmen, Kayseri Namik Sahin, Bursa United Arab Emirates Ashraf Fathi Hefny, Al Ain United Kingdom Nawfal Al-Hadithy, London Sarah Cartmell, Manchester Nick Caplan, Newcastle upon Tyne Andrew Douglas Carrothers, Cambridge Efstathios Drampalos, Wigan Prithee Jettoo, Middlesbrough Saravana Vail Karuppiah, Nottingham Hammad Malik, Manchester Riazuddin Mohammed, Wigan Gohar Naqvi, Cambridge Christopher William Oliver, Edinburgh Philip Socrates Pastides, London Greg A Robertson, Edinburgh Adnan Saithna, Liverpool Praveen Sarda, Gillingham Deepak Gubbi Shivarathre, Liverpool United States Daniel Louis Aaron, Pawtucket Ashish Anand, Jackson Huston Davis Adkisson, St Louis Keith Baldwin, Philadelphia Adam Brufsky, Pittsburgh Ali Bydon, Baltimore Nicole J Chimera, Amherst Ock K Chun, Storrs Suresh Chinthakunta, Collegeville Alan H Daniels, Providence Nabanita S Datta, Detroit Deanna C Dye, Bozeman Scott Forsyth Dye, San Francisco Clark Dickin, Muncie Hossein Elgafy, Toledo Brandon J Erickson, Chicago Nathan Joseph Fanter, Hines Ashraf S Gorgey, Richmond Timothy August Hartshorn, Manhattan Beach John E Herzenberg, Baltimore Jake Paul Heiney, Toledo Matthew C Hoch, Norfolk Johanna Marie Hoch, Norfolk Mozammil Hussain, Chesterfield Pier Francesco Indelli, Albuquerque Michael Joseph, Storrs Srinath Kamineni, Lexington Eldin E Karaikovic, Evanston Jeffrey Bruce Knox, Honolulu Fatih Kucukdurmaz, Philadelphia Kevin Laudner, Normal KH Lee, Rockville Bingyun Li, Morgantown Xinning Li, Boston Zong-Ming Li, Cleveland Randall Loder, Indianapolis Mark Kevan Lyons, Phoenix Eleftherios A Makris, Davis Aditya Vikram Maheshwari, Brooklyn Paul David Metzger, North Chicago Subburaman Mohan, Loma Linda Arash Momeni, Palo Alto Freeman Miller, Wilmington Rahul Kumar Nath, Houston Ripul R Panchal, Sacramento Vinod Panchbhavi, Galveston Nikolaos K Paschos, Davis Ming Pei, Morgantown Shannon MBravo Petersen, Des Moines Matthew Robert Schmitz, Fort Sam Houston Bruce M Rothschild, Indiana Ran Schwarzkopf, Orange Jason Scott Scibek, Pittsburgh Shahin E Sheibani-Rad, Los Angeles Manish K Sethi, Nashville Vani Sabesan, Dearborn Kern Singh, Chicago William D Smith, Las Vegas Ettore Vulcano, Baltimore Ying-Chih Wang, Milwaukee Joshua T Weinhandl, Norfolk Charalampos Zalavras, Los Angeles Chunfeng Zhao, Rochester Nigel Zheng, Charlotte WJO III February 18, 2015

5 Contents Monthly Volume 6 Number 7 August 18, 2015 EDITORIAL 505 Arthroscopic approach to the posterior compartment of the knee using a posterior transseptal portal Ohishi T, Takahashi M, Suzuki D, Matsuyama Y ORIGINAL ARTICLE Retrospective Study 513 Cost analysis and outcomes of simple elbow dislocations Panteli M, Pountos I, Kanakaris NK, Tosounidis TH, Giannoudis PV Prospective Study 521 Can tranexamic acid change preoperative anemia management during total joint arthroplasty? Phan DL, Rinehart JB, Schwarzkopf R SYSTEMATIC REVIEWS 528 Persistent post-surgical pain and neuropathic pain after total knee replacement Drosos GI, Triantafilidou T, Ververidis A, Agelopoulou C, Vogiatzaki T, Kazakos K META-ANALYSIS 537 Predictors of spine deformity progression in adolescent idiopathic scoliosis: A systematic review with metaanalysis Noshchenko A, Hoffecker L, Lindley EM, Burger EL, Cain CMJ, Patel VV, Bradford AP CASE REPORT 559 Florid reactive periostitis ossificans of the humerus: Case report and differential diagnosis of periosteal lesions of long bones Soni A, Weil A, Wei S, Jaffe KA, Siegal GP WJO

6 Contents World Journal of Orthopedics Volume 6 Number 7 August 18, 2015 ABOUT COVER Editorial Board Member of World Journal of Orthopedics, Dionysios J Papachristou, MD, PhD, Associate Professor, Unit of Bone and Soft Tissue Studies, Department of Anatomy-Histology-Embryology, University of Patras, School of Medicine, Patras, Greece AIM AND SCOPE World Journal of Orthopedics (World J Orthop, WJO, online ISSN , DOI: ) is a peer-reviewed open access academic journal that aims to guide clinical practice and improve diagnostic and therapeutic skills of clinicians. WJO covers topics concerning arthroscopy, evidence-based medicine, epidemiology, nursing, sports medicine, therapy of bone and spinal diseases, bone trauma, osteoarthropathy, bone tumors and osteoporosis, minimally invasive therapy, diagnostic imaging. Priority publication will be given to articles concerning diagnosis and treatment of orthopedic diseases. The following aspects are covered: Clinical diagnosis, laboratory diagnosis, differential diagnosis, imaging tests, pathological diagnosis, molecular biological diagnosis, immunological diagnosis, genetic diagnosis, functional diagnostics, and physical diagnosis; and comprehensive therapy, drug therapy, surgical therapy, interventional treatment, minimally invasive therapy, and robot-assisted therapy. We encourage authors to submit their manuscripts to WJO. 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 Orthopedics is now indexed in PubMed Central, PubMed, Digital Object Identifier, and Directory of Open Access Journals. FLYLEAF I-III Editorial Board EDITORS FOR THIS ISSUE Responsible Assistant Editor: Xiang Li Responsible Electronic Editor: Xiao-Kang Jiao Proofing Editor-in-Chief: Lian-Sheng Ma Responsible Science Editor: Yue-Li Tian Proofing Editorial Office Director: Xiu-Xia Song NAME OF JOURNAL World Journal of Orthopedics ISSN ISSN (online) LAUNCH DATE November 18, 2010 FREQUENCY Monthly EDITORS-IN-CHIEF Quanjun (Trey) Cui, MD, Professor, Department of Orthopaedic Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, United States Bao-Gan Peng, MD, PhD, Professor, Department of Spinal Surgery, General Hospital of Armed Police Force, 69 Yongding Road, Beijing , China EDITORIAL OFFICE Jin-Lei Wang, Director Xiu-Xia Song, Vice Director World Journal of Orthopedics Room 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing , China Telephone: Fax: editorialoffice@wjgnet.com Help Desk: PUBLISHER Baishideng Publishing Group Inc 8226 Regency Drive, Pleasanton, CA 94588, USA Telephone: Fax: bpgoffice@wjgnet.com Help Desk: PUBLICATION DATE August 18, 2015 COPYRIGHT 2015 Baishideng Publishing Group Inc. Articles published by this Open-Access journal are distributed under the terms of the Creative Commons Attribution Noncommercial 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. SPECIAL STATEMENT All articles published in journals owned by the Baishideng Publishing Group (BPG) represent the views and opinions of their authors, and not the views, opinions or policies of the BPG, except where otherwise explicitly indicated. INSTRUCTIONS TO AUTHORS Full instructions are available online at wjgnet.com/ /g_info_ htm ONLINE SUBMISSION WJO II

7 Submit a Manuscript: Help Desk: DOI: /wjo.v6.i7.505 World J Orthop 2015 August 18; 6(7): ISSN (online) 2015 Baishideng Publishing Group Inc. All rights reserved. EDITORIAL Arthroscopic approach to the posterior compartment of the knee using a posterior transseptal portal Tsuyoshi Ohishi, Masaaki Takahashi, Daisuke Suzuki, Yukihiro Matsuyama Tsuyoshi Ohishi, Daisuke Suzuki, Department of Orthopedic Surgery, Enshu Hospital, Hamamatsu, Shizuoka , Japan Masaaki Takahashi, Joint Center, Jyuzen Memorial Hospital, Hamamatsu, Shizuoka , Japan Yukihiro Matsuyama, Department of Orthopedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka , Japan Author contributions: Ohishi T wrote the paper; Ohishi T and Suzuki D operated on patients; Takahashi M and Matsuyama Y reviewed the manuscript and provided useful comments. Conflict-of-interest statement: The authors declare no conflicting interests. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Correspondence to: Tsuyoshi Ohishi, MD, PhD, Department of Orthopedic Surgery, Enshu Hospital, Chuo, Naka-ku, Hamamatsu, Shizuoka , Japan. t-ohishi@ken.ja-shizuoka.or.jp Telephone: Fax: Received: April 13, 2015 Peer-review started: April 24, 2015 First decision: May 13, 2015 Revised: May 27, 2015 Accepted: June 18, 2015 Article in press: June 19, 2015 Published online: August 18, 2015 the knee is difficult when only two anterior portals are used for access because of the inaccessibility of the back of the knee. Since its introduction, the posterior transseptal portal has been widely employed to access lesions in the posterior compartment. However, special care should be taken to avoid neurovascular injuries around the posteromedial, posterolateral, and transseptal portals. Most importantly, popliteal vessel injury should be avoided when creating and using the transseptal portal during surgery. Purpose of the present study is to describe how to avoid the neurovascular injuries during establishing the posterior three portals and to introduce our safer technique to create the transseptal portal. To date, we have performed arthroscopic surgeries via the transseptal portal in the posterior compartments of 161 knees and have not encountered nerve or vascular injury. In our procedure, the posterior septum is perforated with a mm Kirschner wire that is protected by a sheath inserted from the posterolateral portal and monitored from the posteromedial portal to avoid popliteal vessel injury. Key words: Arthroscopic surgery; Knee; Posterolateral portal; Posteromedial portal; Transseptal portal The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Arthroscopic surgery in posterior compartment of the knee via the transseptal portal is less invasive to the patient compared to open surgery for access to the back of the knee. However, special care should be taken to avoid neurovascular injury when creating the three posterior portals. We have not encountered neurovascular injury with our procedure for creating a posterior transseptal portal in 161 treated knees, and conclude that it is safe and reliable. Abstract Arthroscopic surgery of the posterior compartment of Ohishi T, Takahashi M, Suzuki D, Matsuyama Y. Arthroscopic approach to the posterior compartment of the knee using a posterior transseptal portal. World J Orthop 2015; 6(7): Available from: URL: WJO 505

8 Ohishi T et al. Arthroscopic approach to the posterior compartment of the knee v6/i7/505.htm DOI: INTRODUCTION Prior to introduction of the posterior transseptal portal, arthroscopic surgery for lesions located in the posterior compartment of the knee was difficult because both the cruciate ligaments and curvature of the femoral condyles obstructed the advance of the arthroscope or other instruments to the back of the knee. Additionally, posterior lesions such as a posterior periphery or posterior horn of the medial meniscus might be missed when using an anterior approach alone [1,2]. Trans-notch views from anterior portals have allowed us to obtain clear views of the posterior compartment [1-3]. However, a particular blind zone on the medial meniscus that could not be viewed remained even with a 70-degree arthroscope [4,5]. The treatment of lesions located in the posterior compartment introduces further difficulty. The addition of posteromedial and posterolateral portals together with a 70-degree arthroscope facilitated treatment procedures for posterior lesions [2,6-9]. Nevertheless, the cruciate ligaments, femoral condyles, and prominence of the tibial spine limited the maneuverability of the arthroscope or other instruments advanced through the intercondylar notch from the anterior portals [1,3]. Ideally, either the posteromedial or posterolateral portal would be used as a viewing portal, while the other would be used as a working portal. However, the posterior compartment of the knee is divided into two compartments by a posterior septum comprising a thin synovial membrane between the posterior cruciate ligament (PCL) and the posterior capsule. In 1997, Kim first reported arthroscopic surgery in the posterior compartment of the knee through two posterior portals created after perforating the posterior septum [10]. Since then, many authors have demonstrated their techniques for transseptal portal creation [10-12]. However, important neurovascular or tendon structures lie just posterior to the posteromedial, posterolateral, and transseptal portals. Special care must be taken to avoid injuries to those structures [13,14]. To date, arthroscopic surgeries via transseptal portal have been employed more frequently along with broadening indications for arthroscopic surgery for posterior lesions of the knee, including synovectomy [15], meniscectomy [16], repair of the posterior horn of the medial meniscus [17-20], PCL reconstruction [21], PCL avulsion fracture fixation [22], loose body removal [23-26], cystic lesion removal [27-29], posterior capsular release [30], repair of posterior capsular tears [31], and synovectomy of a prosthetic knee [32]. We have also performed arthroscopic surgery via the transseptal portal to approach lesions located in the posterior compartment of the knee since In this paper, we present the techniques for creating posteromedial, posterolateral, and transseptal portals and for avoiding neurovascular injuries around the portal site reported by several authors as well as those performed at our institute. ANATOMY AND CLINICAL RELEVANCE The triangular posterior septum borders the dorsal aspect of the PCL anteriorly, femoral intercondylar notch superiorly, and posterior capsule posteriorly and divides the posterior compartment into the posteromedial and posterolateral compartments [11,12] (Figure 1). The septum comprises adipose tissue surrounded by a synovial membrane that contains blood vessels and nerve endings [33]. The medial genicular artery, which originates from the popliteal artery, enters the proximal portion of the septum, which accordingly features a richer vasculature than the distal portion. Mechanoreceptors are also abundant in the proximal septum [33]. Therefore, recommendations regarding limited resection or penetration of the septum indicate that this procedure should be performed at the distal portion, just behind the PCL, rather than at the proximal or femoral side to reduce bleeding while creating the transseptal portal. Immediately behind the septum, the popliteal artery lies outside of the posterior capsule [34-36]. The popliteal artery lies approximately 10 mm laterally to the septum [15,37]. Regarding the posteromedial portal, a sartorial branch of the saphenous nerve is located immediately inferoposteriorly to the portal site (Figure 2A). The common peroneal nerve and long head of the biceps femoris are immediately posterior to the posterolateral portal site, whereas the lateral collateral ligament and popliteal tendon are immediately anterior to this site [36,38-41] (Figure 2B). ESTABLISHMENT OF THE TRANSSEPTAL PORTAL In 1997, Kim first introduced an arthroscopic approach to lesions located in posterior compartment of the knee via the transseptal portal. According to Kim s technique, the posterior septum was perforated via the posteromedial portal using a blunt obturator with a sheath [10]. Ahn et al [11]. described a limited resection of the septum using a shaver introduced from the anteromedial portal through the intercondylar notch, which was viewed from the posteromedial portal. Louisia et al [12] penetrated the septum from the medial to lateral direction using a blunt obturator, which was followed by a skin incision to create a posterolateral portal. These authors demonstrated a back and forth technique in which each posterior portal is used alternately for the arthroscope and other instruments placed through the transseptal portal. Kim et al [15] penetrated the septum in the posterolateral to posteromedial direction to create a transseptal portal for complete synovectomy in a patient with rheumatoid arthritis. WJO 506

9 Ohishi T et al. Arthroscopic approach to the posterior compartment of the knee A B MGM MCL LCL BF LFC MFC * PT * HAM SN R_KNEE_CUR CPN R_KNEE_C//FC13 R_KNEE_CUR Figure 1 Axial image of double contrast arthrography of the knee. The white arrow indicates a posterior septum that borders the posterior cruciate ligament anteriorly and posterior capsule posteriorly. Note that posteromedial compartment is larger than posterolateral compartment. LFC: Lateral femoral condyle; MFC: Medial femoral condyle. RISKS INVOLVING NERVES AND VESSELS Special care should be taken to avoid popliteal neurovascular injuries during transseptal portal creation and subsequent arthroscopic surgery via this portal. The posterior compartment, which is enlarged upon knee flexion, is enlarged to an even greater extent during arthroscopic surgery under irrigation pressure [34]. The distances between the PCL and popliteal artery at different knee positions were measured in cadavers [34,35,38,41]. A flexion of 90 degrees resulted a greater distance (17-29 mm) between the PCL and popliteal artery than that observed at 30 degrees of flexion. As the popliteal neurovascular bundle lies laterally to the septum, posterolateral capsule injuries should be avoided during surgery [12,37]. Perforation of the septum in the posterolateral to the posteromedial direction, as described by Kim et al [15], is a safer technique. Arthroscopic procedures in the posteromedial compartment are easier than those in the posterolateral compartment because the former is 1.5 times larger and bulges a bit more posteriorly under irrigation pressure during surgery relative to the latter [15,37] (Figure 1). Fortunately, popliteal vessel injuries during arthroscopic surgery via the transseptal portal have not yet been reported in the literature. Care should be taken not only to avoid popliteal vessel injury when creating the transseptal portal, but also to avoid neurovascular injury when creating the posteromedial and posterolateral portals [35-38,40,41]. Oglivie-Harris et al [13] reported five complications related to the posteromedial portal that involved the saphenous nerve and vein. McGinnis et al [40] reported a so-called anatomical soft spot, which is surrounded by the posterior edge of the medial condyle of the femur, hamstrings, and medial tibial plateau, as a safe area in which to place the posteromedial portal. The posteromedial portal could be created more safely with the knee at a flexion of 90 degrees than in an extended Figure 2 Sagittal images of double contrast arthrography at the levels of the medial (A) and lateral (B) femoral condyle of the knee. Posteromedial (A) and posterolateral (B) sites are indicated by asterisks (*). The portal site is surrounded by important structures. MCL: Medial collateral ligament; MGM: Medial head of the gastrocnemius muscle; HAM: Hamstrings; SN: Saphenous nerve; LCL: Lateral collateral ligament; PT: Popliteus tendon; BF: Biceps femoris; CPN: Common peroneal nerve. position because the saphenous nerve and vessels move more posteriorly in the former position [36,38,41]. The mean distance between the posteromedial portal site and saphenous nerve is mm at a 90-degree flexion [36,38,41]. The distance between the posterolateral portal site and common peroneal nerve at a 90-degree knee flexion is relatively wide: 40 mm as reported by Pace et al [41], and 25.4 mm according to Ahn et al [21]. When creating a posterolateral portal, palpation of the fibular head as an identifiable landmark is recommended if the posterolateral capsule is not visible in the intercondylar posterior view [38]. However, excess knee flexion (e.g., > 120 ) is not acceptable because this reduces the distance between the common peroneal nerve and posterolateral portal to a greater extent [36]. OUR TECHNIQUE In our method, the patient is placed under spinal or general anesthesia and the knee is flexed beyond 90 degrees on the operating table using a footrest and lateral post. As a precaution, a tourniquet is applied but not inflated. No arthropump is used. The procedure begins with the creation of the posteromedial and posterolateral portals through the anterior two portals according to the approach reported by Schreiber [9], although our method uses a 30-degree rather than 70-degree arthroscope. The arthroscope is introduced into the posteromedial compartment through the intercondylar notch from the anterolateral portal. If osteophytes block the advance of the arthroscope through the intercondylar notch, knee extension facilitates the advance to the posteromedial compartment. A 23-gauge spinal needle is subsequently inserted just behind the posterior medial condyle and 5 mm above the tibial articular surface under guidance from a cutaneous trans-illumination arthroscopic light, as described by Schreiber [9] (Figure 3A). If a condition such as obesity prevents identification of the posterior WJO 507

10 Ohishi T et al. Arthroscopic approach to the posterior compartment of the knee arthroscope arthroscope PM portal PL portal A B MFC Popliteal vessels LFC Figure 3 Arthroscopic view of the posteromedial (A) and posterolateral (B) compartment through the intercondylar notch from the anterolateral (A) and anteromedial (B) portals. A 23-gauge spinal needle is inserted just posterior to the medial (A) and lateral (B) femoral condyle at 5 mm above the tibial articular surface. PM: Posteromedial; PL: Posterolateral; MFC: Medial femoral condyle; LFC: Lateral femoral condyle. (Permission for reproduction was obtained from Nankodo Co., Ltd.). edge of the medial femoral condyle, a 23-gauge spinal needle is first inserted to the medial aspect of the femoral condyle first, and the needle insertion site is then moved posteriorly to identify the posterior edge of the medial femoral condyle. The cutaneous transillumination arthroscopic guide helps to avoid injuries of the saphenous nerve and adjacent vein [9]. The entry point skin and capsule are incised with a No. 11 knife just anterior to and along with the 23-gauge needle. The posteromedial portal opening is subsequently maintained with a hemostat. Next, an arthroscope is introduced into the posterolateral compartment through the intercondylar notch from the anteromedial portal. A posterolateral portal is then created in the same manner as the posteromedial portal, using a 23-gauge spinal needle to determine the posterolateral portal site (Figure 3B). Palpation of the common peroneal nerve and fibular head may help to avoid common peroneal nerve injuries. Next, a switching rod with a sheath is inserted through the posterolateral portal to the septum. The camera head of the 30-degree arthroscope is turned to the septum so the operator can confirm that the tip of the rod is attached to the septum (Figure 4). The rod is then removed while the sheath is kept in place. The sheath is pushed into the septum, and the arthroscope is inserted into the posteromedial portal. While maintaining a view of the medial side of the septum using the arthroscope introduced through the posteromedial portal, 1.5-mm (Figure 5A) and 3.0-mm Kirschner wires (Figure 5B) are sequentially pushed to the septum from the posterolateral portal through the sheath while in close contact with the posterior femoral condyle, after which the septum is perforated. The sheath is expected to protect the posterolateral capsule. The Kirschner wires are pushed several times into the septum to enlarge the initial hole and allow the switching rod to pass easily through the septum (Figure 5C). The switching rod is then inserted from the posterolateral portal to the posteromedial portal via the transseptal portal. Once the transseptal portal has been created, the arthroscope and instruments can be easily interchanged through the two posterior portals using the posterior back and forth approach described by Louisia et al [12] (Figure 6). It is not necessary to remove the septum with a motorized shaver. OUR EXPERIENCE OF THR TECHNIQUE Using our procedure, we performed arthroscopic surgery for lesions in the posterior compartments of 161 knees between December 2006 and March 2015 (Figure 7). Some of these cases were reported elsewhere to demonstrate the use of the transseptal portal [42-47]. The arthroscopic procedures conducted using our WJO 508

11 Ohishi T et al. Arthroscopic approach to the posterior compartment of the knee arthroscope Septum Rod/sheath Rod/sheath PL portal Popliteal vessels Figure 4 Rod with a sheath is inserted from the posterolateral portal. The camera head of the 30-degree arthroscope is turned toward the septum so that the operator can confirm attachment of the tip of the rod to the septum (white star). PL: Posterolateral. (Permission for reproduction was obtained from Nankodo Co., Ltd.). A B C Septum 1.5-mm K-wire 3.0-mm K-wire 4.0-mm rod Arthroscope PM portal PL portal Popliteal vessels Figure 5 Arthroscopic views from the posteromedial portal. While maintaining a view of the medial side of the septum using an arthroscope introduced through the posteromedial portal, 1.5-mm (A) and 3.0-mm Kirschner wires (B) are pushed sequentially to the septum through the sheath from the posterolateral portal, finally, a 4.0-mm switching rod is passed through the septum (C). PM: Posteromedial; PL: Posterolateral. (Permission for reproduction was obtained from Nankodo Co., Ltd.). WJO 509

12 Ohishi T et al. Arthroscopic approach to the posterior compartment of the knee Table 1 List of procedures using our transseptal portal technique PL portal Instruments AM portal PM portal Arthroscope Procedure Synovectomy 57 Meniscal resection 20 Thermal shrinkage 1 Resection of PCL ganglion 1 Meniscal cyst decompression 1 Popliteal cyst decompression 53 Repair of PCL avulsion fracture 5 Free body resection 5 Repair of the posterior horn of the medial meniscus 5 PCL reconstruction 2 Probing only 11 n Figure 6 Image taken during an operation involving the posterior transseptal portal. One of the posterior two portals is used as a viewing portal; the other is used as a working portal. Anterior portals can be also used as working portals. PM: Posteromedial; PL: Posterolateral; AM: Anteromedial. A B MFC MFC Figure 7 Arthroscopic views of the posterior compartment of the knee in a patient with rheumatoid arthritis. The posteromedial compartment was filled with synovial villi prior to synovectomy. A shaver is introduced from the posterolateral portal through the transseptal portal (A). An arthroscopic view from the posterolateral portal through the transseptal portal after synovectomy (B). A radiofrequency device is introduced from the posteromedial portal. MFC: Medial femoral condyle. established transseptal portal technique are listed in Table 1. Postoperative complications were encountered in four knees (2.5%), including superficial infection of the posteromedial portal in two knees, subcutaneous hematoma in one knee, and deep infection of the posterolateral portal in one knee. Treatment for the latter case required open debridement of the affected knee. No PCL: Posterior cruciate ligament. popliteal neurovascular, peroneal nerve, or saphenous nerve injuries or postoperative deep vein thromboses occurred in any knee during these operations. ADVANTAGES OF OUR TECHNIQUE We have modified the procedures reported in previous papers [10-12,15] as follows. First, the knee is flexed beyond 90 degrees on the operating table, with a footrest placed at the heel, so that the popliteal vessels move posteriorly. Flexion beyond 90 is better achieved when the lower leg is not suspended from the side of the table. Moreover, the operator can work freely when the lower leg is on the operating table, as this provides more available space for working around the knee (Figure 6). Second, we perforated the septum while protecting the posterolateral capsule with a sheath to avoid popliteal vessel injury, as a popliteal neurovascular bundle is located just lateral to the septum (Figure 4). Finally, septum perforation using only a rod or blunt obturator might be difficult and could confer the risk of posterior rod or blunt obturator slippage, as the septum is very elastic and easily stretched. It is therefore safer to perforate the septum initially with a 1.5-mm Kirschner wire to determine the proper placement, followed by a 3.0 mm Kirschner wire to enlarge the hole and subsequent switching rod placement, rather than rod placement alone (Figure 5). However, the operator should ensure that the tip of the Kirschner wire is properly positioned just behind the PCL and is not directed towards the posterior capsule. It is essential that the operators use an arthroscope introduced through the opposite portal to maintain direct visibility of the tip of the Kirschner wire or the switching rod as it passes through the perforated septum. CONCLUSION An arthroscopic approach via a transseptal portal for posterior lesions of the knee confers several advantages upon patients and operators, including less invasive technique compared to the open surgery for access to WJO 510

13 Ohishi T et al. Arthroscopic approach to the posterior compartment of the knee the back of the knee. However, the risk of neurovascular injuries should be considered. It is important for operators to understand the anatomy around the posterior three portals. REFERENCES 1 Boytim MJ, Smith JP, Fischer DA, Quick DC. Arthroscopic posteromedial visualization of the knee. Clin Orthop Relat Res 1995; (310): [PMID: DOI: / ] 2 Gillquist J, Hagberg G, Oretorp N. Arthroscopic visualization of the posteromedial compartment of the knee joint. Orthop Clin North Am 1979; 10: [PMID: DOI: /BF ] 3 Lubowitz JH, Rossi MJ, Baker BS, Guttmann D. Arthroscopic visualization of the posterior compartments of the knee. Arthroscopy 2004; 20: [PMID: DOI: /S (04)00547-X] 4 Morin WD, Steadman JR. Arthroscopic assessment of the posterior compartments of the knee via the intercondylar notch: the arthroscopist s field of view. Arthroscopy 1993; 9: [PMID: DOI: /S (05) ] 5 Tolin BS, Sapega AA. 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14 Ohishi T et al. Arthroscopic approach to the posterior compartment of the knee Cohen M, Ingham SJ, Abdalla RJ. An anatomic study of the posterior septum of the knee. Arthroscopy 2012; 28: [PMID: DOI: /j.arthro ] 34 Ahn JH, Wang JH, Lee SH, Yoo JC, Jeon WJ. Increasing the distance between the posterior cruciate ligament and the popliteal neurovascular bundle by a limited posterior capsular release during arthroscopic transtibial posterior cruciate ligament reconstruction: a cadaveric angiographic study. Am J Sports Med 2007; 35: [PMID: DOI: / ] 35 Cosgarea AJ, Kramer DE, Bahk MS, Totty WG, Matava MJ. Proximity of the popliteal artery to the PCL during simulated knee arthroscopy: implications for establishing the posterior trans-septal portal. J Knee Surg 2006; 19: [PMID: ] 36 Makridis KG, Wajsfisz A, Agrawal N, Basdekis G, Djian P. Neurovascular anatomic relationships to arthroscopic posterior and transseptal portals in different knee positions. Am J Sports Med 2013; 41: [PMID: DOI: / ] 37 Kim SJ, Song HT, Moon HK, Chun YM, Chang WH. The safe establishment of a transseptal portal in the posterior knee. Knee Surg Sports Traumatol Arthrosc 2011; 19: [PMID: DOI: /s ] 38 Ahn JH, Lee SH, Jung HJ, Koo KH, Kim SH. The relationship of neural structures to arthroscopic posterior portals according to knee positioning. Knee Surg Sports Traumatol Arthrosc 2011; 19: [PMID: DOI: /s ] 39 Dickens JF, Kilcoyne K, Kluk M, Rue JP. The posterolateral corner: surgical approach and technique overview. J Knee Surg 2011; 24: [PMID: DOI: /s ] 40 McGinnis MD, Gonzalez R, Nyland J, Caborn DN. The posteromedial knee arthroscopy portal: a cadaveric study defining a safety zone for portal placement. Arthroscopy 2011; 27: [PMID: DOI: /j.arthro ] 41 Pace JL, Wahl CJ. Arthroscopy of the posterior knee compartments: neurovascular anatomic relationships during arthroscopic transverse capsulotomy. Arthroscopy 2010; 26: [PMID: DOI: /j.arthro ] 42 Ohishi T, Fujita T, Suzuki D, Yamamoto K, Ushirozako H, Matsuyama Y. Arthroscopic debridement of the posterior compartment of the knee after total knee arthroplasty. Case Rep Orthop 2014; 2014: [PMID: DOI: /2014/568417] 43 Ohishi T, Ichikawa T, Miyagi M, Irisawa H, Nagano A. Gouty synovitis of the knee with partial hypoxanthine-guanine phosphoribosyl transferase deficiency (Kelley-Seegmiller syndrome): A case report. J Rural Med 2009; 4: [DOI: /jrm.4.80] 44 Ohishi T, Suzuki D, Yamamoto K, Banno T, Shimizu Y, Ohmura A, Matsuyama Y. Meniscal pullout repair following meniscal ossicle resection: a case report. Knee 2013; 20: [PMID: DOI: /j.knee ] 45 Ohishi T, Takahashi M, Matsuyama Y. Osteochondritis dissecans with a large osteochondral free body in the posterolateral compartment of the knee: a case report. Knee 2014; 21: [PMID: DOI: /j.knee ] 46 Ohishi T, Takahashi M, Suzuki D, Fujita T, Yamamoto K, Ushirozako H, Banno T, Matsuyama Y. Treatment of popliteal cysts via arthroscopic enlargement of unidirectional valvular slits. Mod Rheumatol 2015; 1-7 [PMID: DOI: / ] 47 Ohishi T, Torikai E, Suzuki D, Banno T, Honda Y. Arthroscopic treatment of a medial meniscal cyst using a posterior trans-septal approach: a case report. Sports Med Arthrosc Rehabil Ther Technol 2010; 2: 25 [PMID: DOI: / ] P- Reviewer: Angoules A, Camera A, Robertson GA, von Heideken J S- Editor: Tian YL L- Editor: A E- Editor: Jiao XK WJO 512

15 Submit a Manuscript: Help Desk: DOI: /wjo.v6.i7.513 World J Orthop 2015 August 18; 6(7): ISSN (online) 2015 Baishideng Publishing Group Inc. All rights reserved. Retrospective Study ORIGINAL ARTICLE Cost analysis and outcomes of simple elbow dislocations Michalis Panteli, Ippokratis Pountos, Nikolaos K Kanakaris, Theodoros H Tosounidis, Peter V Giannoudis Michalis Panteli, Ippokratis Pountos, Peter V Giannoudis, Academic Department of Trauma and Orthopaedics, School of Medicine, University of Leeds, Clarendon Wing, Level A, Leeds LS1 3EX, United Kingdom Nikolaos K Kanakaris, Theodoros H Tosounidis, Leeds Teaching Hospitals, University of Leeds, Clarendon Wing, Level A, Leeds LS1 3EX, United Kingdom Author contributions: Panteli M, Kanakaris NK and Giannoudis PV designed the research; Panteli M, Pountos I and Tosounidis TH performed the research; Panteli M, Pountos I and Tosounidis TH analysed the data; Panteli M, Pountos I and Giannoudis PV wrote the paper. Institutional review board statement: Institutional board approval (Leeds Teaching Hospitals Institutional Review Board; ID3050; 23/11/2010) was obtained for this study. Informed consent statement: All involved subjects provided verbal informed consent prior to study enrolment. Data was anonymized and all study participants identifiable information was removed. Conflict-of-interest statement: The authors declare that they have no conflict of interest related to this study. Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at michalispanteli@gmail.com. Consent for identifiable data sharing was not obtained but the presented data are anonymized and risk of identification is low. No additional data are available. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Correspondence to: Michalis Panteli, MD, MRCS (Eng), Clinical Research Fellow, Honorary Lecturer, Academic Department of Trauma and Orthopaedics, School of Medicine, University of Leeds, Clarendon Wing, Level A, Great George Street, Leeds LS1 3EX, West Yorkshire, United Kingdom. michalispanteli@gmail.com Telephone: Fax: Received: March 2, 2015 Peer-review started: March 3, 2015 First decision: April 10, 2015 Revised: May 12, 2015 Accepted: June 1, 2015 Article in press: June 2, 2015 Published online: August 18, 2015 Abstract AIM: To evaluate the management, clinical outcome and cost implications of three different treatment regimes for simple elbow dislocations. METHODS: Following institutional board approval, we performed a retrospective review of all consecutive patients treated for simple elbow dislocations in a Level Ⅰ trauma centre between January 2008 and December Based on the length of elbow immobilisation (LOI), patients were divided in three groups (Group I, < 2 wk; Group Ⅱ, 2-3 wk; and Group Ⅲ, > 3 wk). Outcome was considered satisfactory when a patient could achieve a pain-free range of motion 100 (from 30 to 130 ). The associated direct medical costs for the treatment of each patient were then calculated and analysed. RESULTS: We identified 80 patients who met the inclusion criteria. Due to loss to follow up, 13 patients were excluded from further analysis, leaving 67 patients for the final analysis. The mean LOI was 14 d (median 15 d; range 3-43 d) with a mean duration of hospital engagement of 67 d (median 57 d; range d). Group Ⅲ (prolonged immobilisation) had a statistically significant worse outcome in comparison to Group Ⅰ and Ⅱ (P = 0.04 and P = 0.01 respectively); however, there was no significant difference in the outcome between groups Ⅰ and Ⅱ (P = 0.30). No statistically significant WJO 513

16 Panteli M et al. Cost analysis and outcomes of elbow dislocations difference in the direct medical costs between the groups was identified. CONCLUSION: The length of elbow immobilization doesn t influence the medical cost; however immobilisation longer than three weeks is associated with persistent stiffness and a less satisfactory clinical outcome. Key words: Elbow dislocations; Simple; Management; Outcome; Cost analysis The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Our study demonstrates that prolonged immobilisation following simple elbow dislocations may lead to detrimental effects. We therefore stress the need for increased vigilance to the duration of immobilisation and that every effort should be taken to ensure that without associated fractures, the elbow should not be immobilised for more than three weeks. In addition, our study supports that the direct medical cost from treating these injuries may be substantial regardless of the type of treatment, and this should be known both by commissioners and providers of health care. Panteli M, Pountos I, Kanakaris NK, Tosounidis TH, Giannoudis PV. Cost analysis and outcomes of simple elbow dislocations. World J Orthop 2015; 6(7): Available from: URL: DOI: with different protocols being suggested. These include surgical treatment with exploration and repair of the joint ligaments; non-surgical treatment with immobilisation of the elbow joint (varying from few days to more than 3 wk) [5,8-14] ; and non-surgical, functional treatment with just a short period of immobilisation of only a few days [5,9-13]. The primary functional outcome has been defined as achieving early active motion within the limits of pain with or without the use of a sling or a hinged brace [5,10]. Numerous complications of simple elbow dislocation have been described including neurovascular injury, joint instability, heterotopic ossification, occult distal radio-ulnar joint disruption and post-traumatic stiffness, most commonly defined as an arc of elbow motion less than 100 [3,5,15-18]. Biomechanical studies have shown that arcs of motion between 30 to 130 are required for most daily activities [19] and that a loss of 50 in the arc of motion, can cause up to an 80% loss of function [18]. Limited information is available with regards to the cost of the management of simple elbow dislocations. To the best of our knowledge, direct medical cost pertaining to National Health Service (NHS) including hospitalisation, imaging, outpatient follow-ups, need for physiotherapy and medication, have not been previously reported. We hypothesized that prolonged elbow immobilisation (longer than three weeks) yields inferior outcomes. Thereafter, the purpose of this study was to determine the optimal length of elbow immobilisation (LOI) following a simple elbow dislocation. Direct medical costs were also determined. INTRODUCTION Elbow dislocations represent the second most common dislocation in the adult population following shoulder dislocation, and the most common type of dislocation in the paediatric population [1]. In the United States population alone, the incidence of elbow dislocation has been reported as high as 5.21 per habitants, with males years of age, having the highest risk for dislocation [2]. Seventeen per cent of these dislocations are associated with fractures [3], with nearly half of them occurring in sports [2]. Falls represent the primary mechanism of injury being responsible for 56.5% of elbow dislocations overall [2]. The most commonly used classification system of elbow dislocation is based on the presence of concomitant fractures in the region. Simple dislocations are characterised by the absence of fractures (except from avulsion fractures) [4], whereas complex dislocations are those accompanied by fractures [5,6]. The terrible triad describes a complex posterior dislocation with an intraarticular fracture of the radial head and of the coronoid process [6]. Elbow dislocations are also defined by the direction and topography of the dislocated parts [7]. To date, there is no general consensus regarding the protocol of management of simple elbow dislocations MATERIALS AND METHODS Following institutional board approval (Leeds Teaching Hospitals Institutional Review Board; ID3050; 23/11/ 2010), we performed a retrospective review of all consecutive patients treated for elbow dislocations in a large United Kingdom Level Ⅰ trauma centre between January 2008 and December Inclusion criteria comprised of skeletally mature patients with clinically and/or radiologically confirmed acute simple elbow dislocations, having at least one year of follow-up. Simple dislocation were defined as dislocations that involved soft tissue disruption (Figure 1) [4]. Exclusion criteria included: associated fractures, with the exception of avulsion fractures ( complex elbow dislocations; Figure 2); open wounds requiring debridement in the operating room; and patients with inadequate followup, defined as patients not attending three consecutive appointments at the outpatients clinic, or being followed up by another institution. All patients were managed at the emergency department according to a standardised protocol. After a careful clinical and radiological evaluation, reduction was attempted under analgesia and conscious sedation or administration of Nitrous Oxide and Oxygen (Entonox ). If the dislocation was obvious and access to radiography WJO 514

17 Panteli M et al. Cost analysis and outcomes of elbow dislocations A B Figure 1 Simple elbow dislocation. A: Anteroposterior view; B: Lateral view. A L B Figure 2 Complex elbow dislocation. A: Anteroposterior view; B: Lateral view. was expected to significantly prolong time to reduction, reduction was performed before radiographs were obtained in order to relief the pressure to the soft tissues, thus reducing the risk of neurovascular injury. In case of failed closed reduction, the elbow was reduced in theatres under general anaesthetic. Once reduction was achieved, the stability of the joint and the neurovascular status were checked and documented, and the elbow was immobilised with a backslap and a collar and cuff. Finally, the patients were discharged and a followup appointment was arranged, or admitted where indicated. Further imaging [computed tomography (CT) and/or magnetic resonance imaging (MRI)], was performed only in patients with high clinical suspicion of occult fractures and/or complex injury patterns. Patient demographics including age, gender, mechanism of injury, side and type of dislocation [20], method of treatment, time to mobilisation, clinical outcome, complications, secondary procedures, outpatient reviews, need for physiotherapy and time of discharge from the clinic were recorded. The decision for the LOI and the need for formal physiotherapy were guided purely by the surgeon s preference and indirectly by the compliance of patients to attend their allocated appointments. Based on the LOI, patients were divided into three groups (Group Ⅰ, < 2 wk of immobilisation; Group Ⅱ, 2-3 wk of immobilisation; L and Group Ⅲ, > 3 wk of immobilisation). The major cause of the prolonged LOI of patients in Group Ⅲ was the lack of adherence to their scheduled outpatient trauma clinic appointments. The criteria for discharge from physiotherapy were the ability to perform daily living activities, an achievement of satisfactory arc of elbow motion (30 to 130 ), or the reach to a plateau in range of motion despite continuing physiotherapy and home exercises. In terms of the clinical outcome, a good/satisfactory result was defined as the achievement of a range of motion 100 (from 30 to 130 ) [19]. If a residual deficit in elbow motion was evident or if the patient reported any significant post-traumatic stiffness, outcome was considered poor/unsatisfactory and the patient was referred back to the treating surgeon. Cost estimation and analysis methods The associated direct medical costs for the treatment of each patient were calculated and analysed. The costs represent the actual treatment that each patient received, including admission costs where applicable, hospital stay, investigations, outpatient attendances and physiotherapy sessions. The cost of each individual entry was obtained from the appropriate department (Trauma and Orthopaedics finance department and inter-provider tariff list), (Table 1). Costs were given in GPB ( ). Statistical analysis This was undertaken using IBM SPSS Statistics version 22.0 software (SPSS inc., Chicago, IL). Continuous data were analysed for differences using a two-tailed independent samples t-test, whereas for parametric data a χ 2 was used to examine associations between variables. Yates correction was applied where appropriate and confidence intervals were calculated when necessary. A P-value < 0.05 was considered significant. RESULTS Eighty consecutive patients met the inclusion criteria and were included in the study. The mean age was years (median: 32 years; SD years). WJO 515

18 Panteli M et al. Cost analysis and outcomes of elbow dislocations Table 1 Costs of treatment, investigations and support services Category Item Cost ( ) Hospital Services A and E attendance leading to admission 95 A and E attendance not leading to admission 76 Minor Injuries leading to admission 34 Minor Injuries not leading to admission 42 Walk in centre leading to admission 31 Walk in centre not leading to admission 34 Theatre session (including recovery) 880 Hospitalisation/day Acute Care Adult wards admission per day 269 Follow-up Outpatient clinic (new) 116 Outpatient clinic (follow-up) 93 Support Services Physiotherapy/session in clinic 34 Radiology X-ray 59.5 Computed tomography scan 225 Magnetic resonance imagingscan 280 Radiographer per twenty minutes clinic visit (includes A and E) 13 Table 2 Demographic details of patients in each group Group Ⅰ Group Ⅱ Group Ⅲ No. of patients Age (yr) ± ± ± Median: 30 Median: 37 Median: 37 Male/female 18/8 17/10 8/6 Right/left 12/14 9/18 7/7 No. of patients admitted 5 (19%) 3 (11%) 3 (21%) LOS (h) ± ± ± Range: Range: Range: Patients referred to physiotherapy Patients seen by physiotherapy No. of physiotherapy sessions 2.43 ± ± ± 1.34 Median: 2 Median: 2 Median: 2 No. of clinic appointments 3.31 ± ± ± 1.48 Median: 3 Median: 3 Median: 3 Time of follow-up (d) ± ± ± Median: 53 Median: 58 Median: 62 Time to mobilisation (d) 5.82 ± ± ± 8.97 Median: 6 Median: 16 Median: 23 Good outcome 21 patients 23 patients 6 patients Admitted: Patients had an overnight stay in hospital. LOS: Length of stay; Follow-up: From time of injury to time of discharge or referral to upper limb specialist. Fifty-one patients in the cohort were male (63.8%), and 33 dislocations (41.3%) involved the right side. The most common mechanism of injury was fall to an outstretched hand from a standing height (30 patients, 37.5%), followed by sport related injuries (26 patients, 32.5%). Common sports associated with the elbow injuries sustained included: rugby (eight patients), football (six patients), skateboarding (three patients), biking and kickboxing (two patients respectively). The rest of the patients were involved in different sports (acrobatics, cricket, rollerblading, rounders and iceskating). Eighteen patients (22.5%) sustained their injuries following a fall from height, three patients (3.8%) were assaulted and three patients (3.8%) were involved in road traffic accidents. Posterior or posterior lateral dislocations were the most frequent presentations (63 patients, 78.8%). Medial or posterior medial dislocation was evident in six patients (7.5%), whereas lateral dislocation was diagnosed in three patients (3.8%). In eight patients (10.0%) the direction of dislocation was not documented due to the fact that the reduction of the dislocated joint was performed as an emergency procedure with no prereduction radiographic imaging being available. Thirteen patients had inadequate follow-up (16.3%) and were therefore excluded from the final analysis of the study, leaving 67 patients who formed the study cohort. Group Ⅰ consisted of 26 patients (median LOI 6 d; range 3-11 d), Group Ⅱ of 27 patients (median LOI 16 d; range d) and Group Ⅲ of 14 patients (median LOI 23 d; range d). The three groups were comparable in terms of age, gender, side, type of dislocation, need for hospital admission and length of follow-up. Table 2 summarises the demographic details WJO 516

19 Panteli M et al. Cost analysis and outcomes of elbow dislocations Table 3 Comparisons of the three groups Variable Group Ⅰ vs Group Ⅱ Group Ⅰ vs Group Ⅲ Group Ⅱ vs Group Ⅲ Test P 95%CI P 95%CI P 95%CI Gender χ 2 test Age t-test Side χ 2 test Admission χ 2 test Follow-up t-test Outcome χ 2 test Medical Costs t-test 1 Yates correction was employed. The results in bold indicate statistical significance (level of 0.05). LOI: Length of immobilisation. Table 4 Cost analysis per patient Group Ⅰ Group Ⅱ Group Ⅲ No. of X-rays 8.38 ± ± ± 4.58 Median: 7 Median: 6 Median: 7 CT scans 2 patients 1 patient 1 patient MRI scans 1 patient - - Need for theatre reduction 2 patients 2 patients - CT: Computed tomography; MRI: Magnetic resonance imaging. and the treatment course according to LOI. Four patients (6.0%) underwent a closed reduction of the dislocation under general anaesthesia (two from Group Ⅰ and two from Group Ⅱ). Ten patients (14.9%) were admitted for social reasons. No statistical significant difference was recorded regarding the length of follow-up in the three groups (Table 3). Patients from Group Ⅰ and Group Ⅱ had a significantly better outcome compared to Group Ⅲ, but we did not detect any difference between the first two groups (Table 3). No patient re-attended the emergency department of our institution with a recurrent dislocation within 12 mo from the initial injury. Patients in Group Ⅲ were more likely not to attend their scheduled physiotherapy appointments compared to Groups Ⅰ and Ⅱ (P = 0.23 and P = 0.02 respectively). Though, there was no difference in the number of patients referred to physiotherapy by the treading surgeon, or the number of physiotherapy sessions attended by the patients in all groups. With regards to the outcome, 17 patients (25.4%) were recorded as having an unsatisfactory outcome (Group Ⅰ: 5 patients; Group Ⅱ: 4 patients; Group Ⅲ: 8 patients). Two patients suffered from post-traumatic neurapraxia (median nerve: one patient in Group Ⅱ; ulnar nerve: one patient in Group Ⅰ), which has however improved during the follow-up period. The direct medical cost per patient according to treatment used was in Group Ⅰ 1184, in Group Ⅱ 1005, and in Group Ⅲ and The costs were then further broken down to the main components that contributed to the total cost (Tables 4 and 5). Analysis of the total costs per patient failed to indicate any statistically significant difference between the three groups. DISCUSSION There is insufficient evidence in the current literature from well-designed randomised controlled trials to determine the best method of treatment of simple elbow dislocations in adults. Historically, these were treated with prolonged casting followed up by physiotherapy [5]. It has also been suggested by several studies that the reduction should be followed-up by an up to 2-wk period of immobilisation [5,12]. Recent evidence however, supports the early active mobilisation within two weeks post-injury and as soon as pain allows [1,13,16,21]. The final functional outcomes obtained with early mobilisation are reported to be significantly better when compared to immobilisation [5,16,22,23]. The results of the present study are in agreement with the above findings. In particular, the final outcome of the patients managed with immobilisation not exceeding three weeks, was significantly better compared to the outcome of patients managed with prolonged immobilisation (more than three weeks). Of note is the observation that immobilisation for less that two weeks had the same outcome compared to immobilisation for 2-3 wk. The characteristics of the patients sustaining simple elbow dislocations were also found to be comparable to the international literature. Taylor et al [4] reported that more than 90% of simple elbow dislocations occur in a posterior or posterior lateral direction, compared to 87.5% in the herein study. Anakwe et al [24] suggested that the epidemiology of simple elbow dislocation is different between men and women, particularly with respect to the mechanism of injury, and that it correlated with patient s age. We have also found that the predominant gender in this group of injuries is young male patients, who are also more likely to have a sports related injury. Stoneback et al [2] separated sports activities by gender, reporting that males sustained elbow dislocations most often in association with football, wrestling, and basketball and females in gymnastics and skating activities. Even though an association between type of sports and gender was obvious with men being involved in sports such as rugby and football, the relatively small number of patients in our series did not allow us to draw any robust conclusions. WJO 517

20 Panteli M et al. Cost analysis and outcomes of elbow dislocations Table 5 Costs of treatment ( ) analysis per patient Treatment description Group Ⅰ Group Ⅱ Group Ⅲ Hospital ± ± ± Median: Median: Median: Radiology ± ± ± Median: Median: Median: Outpatients ± ± ± Median: Median: Median: Physiotherapy ± ± ± 8.97 Median: Median: Median: 0 Total cost of treatment ± ± ± Median: Median: Median: Hospital costs include emergency department s costs, admission costs and theatre costs. Any further costs after the patient s referral to an upper limb specialist were not included in the cost analysis. Previous research suggests that patients complete their recovery and return to normal activity by six months after such an injury [24]. We followed-up our patients for a longer period and advised them to contact the treating consultant in case of any concern. We therefore believe that the duration of follow-up in our study allowed us to assess accurately the final outcome in terms of range of motion of the affected elbow joint. The rates of residual pain and stiffness with early elbow motion have been reported to be 62% and 56% respectively, even though the functional outcome and patient reported satisfaction were favourable [23,24]. Residual pain restricting the function of the elbow did not seem to be of significant concern in our cohort, in contrast to significant stiffness limiting daily living activities that was reported as high as 25% [23,24]. Functional instability was less common involving four patients (6%) compared to 8% that was previously reported in the literature [24]. No re-dislocation or late instability was noted in the patients who were treated with early mobilisation. Similar studies in the literature agree with our findings and suggest that early mobilisation does not contribute to residual instability [5,12,13,20]. Other complications seen at the final follow-up included complaints of increasing pain during physical activities, which we believe could be related to the residual joint stiffness and stressing of the joint. None of our patients with a simple elbow dislocation was treated with an early surgical reconstruction. Noteworthy, the existing evidence does not suggest that surgical repair of elbow ligaments for simple elbow dislocation improves long-term function [4,20]. The current literature is limited in terms of the health economics of treating simple elbow dislocations. To the best of our knowledge there is only one study by Yang et al [3] reporting on the direct medical costs of these injuries. More specifically, the authors published a retrospective series of 428 simple and complex elbow dislocations treated in Taiwan, calculating the direct medical cost to be $504 per patient (included inpatient expenditure by admission and ambulatory care expenditure by visit) [3]. This is much lower compared to our estimated costs (average of 1088). We believe what accounts for this divergence are the different costs in a completely different national health care system, as well as the former timing at which these costs were obtained (between 2000 and 2005). Even though one would expect that the direct medical costs of patients with prolonged immobilisation are higher because of higher incidence of post-traumatic stiffness and associated complications [5,16,22,23], this was not observed in our cohort. Possible explanations of this finding may include: two patients in Group Ⅰ and two patients in Group Ⅱ required a reduction in theatre compared to none in Group Ⅲ, thus increasing the overall costs; patients in Group Ⅲ were more likely not to attend their physiotherapy sessions, therefore reducing their overall costs. At the same time, the relatively small number of patients included in our study increases the risk of a type Ⅱ error. Limitations of this study include its retrospective nature and the small number of subjects, meaning that there is a risk of a type Ⅱ statistical error. Yet, our findings are in line with the literature, thus providing sufficient evidence to support changes even with comparatively low numbers. Another limitation is the fact that elbow stiffness and loss of function was defined as an arc of elbow motion less than 100 [3,5,15-19]. Nevertheless, recent studies report that the functional elbow range of motion that is necessary for activities of daily living may actually be greater than this [25]. We also believe that this study could have been further enhanced by the collection of patient reported outcome measures, which probably reflects better on the loss of function from a patient s perspective. On the positive side, this study was performed in a level Ⅰ Trauma Centre, with no attempt for patient selection. Another improvement of the herein study was the inclusion of the associated costs for each group, a parameter that has not been previously adequately reported. This study clearly underlines the fact that prolonged immobilization adversely affects the clinical outcome following a simple elbow dislocation. Despite the limita- WJO 518

21 Panteli M et al. Cost analysis and outcomes of elbow dislocations tions and the retrospective nature of this study, the small number of patients included, and the 16.3% of lost to follow-up, we are confident that this cohort is representative of the actual clinical reality of a large United Kingdom hospital. In addition, this study depicts that the financial cost of treating elbow dislocations to the NHS may be substantial, regardless of the type of treatment. However, for the correct evaluation of each treatment modality a full prospective economic evaluation is desirable. This should include not only the direct medical and non-medical costs, but also the indirect costs associated with the duration of therapy, the final functional outcome, the loss of productivity and any disability payments of each patient [26]. The findings of our study stress the need for increased vigilance to the duration of immobilisation following simple elbow dislocations. Treating physicians (either orthopaedic surgeons or general practitioners) should be aware of the detrimental effects of prolonged immobilisation, and every effort should be taken to ensure that without associated fractures the elbow is not immobilised for more than three weeks. The direct medical cost from treating these injuries is substantial, and this should be known to both commissioners and providers of health care. ACKNOWLEDGMENTS The authors would like to recognize and thank Mr Morell D, for his assistance in the collection of data. COMMENTS Background Elbow dislocations represent the second most common dislocation in the adult population following shoulder dislocation, and the most common type of dislocation in the paediatric population. To date, there is no general consensus regarding the protocol of management of simple elbow dislocations with different protocols being suggested. In this study the authors determined the optimal length of elbow immobilisation following a simple elbow dislocation, along with their associated direct medical costs. Research frontiers The duration of immobilisation following simple elbow dislocations is directly associated to the final functional outcome. Treating physicians (either orthopaedic surgeons or general practitioners) should be aware of the optimal immobilisation period required and of the associated direct medical costs for treating these injuries. Innovations and breakthroughs This study clearly underlines the fact that immobilization longer than three weeks adversely affects the clinical outcome following a simple elbow dislocation. In addition, the financial cost of treating elbow dislocations to the NHS may be substantial, regardless of the type of treatment. Applications An increased vigilance to the duration of immobilisation is required when treating these injuries, ensuring that without associated fractures, the elbow should not be immobilised for more than three weeks. Additional prospective studies evaluating the direct medical and non-medical costs, as well as the indirect associated costs could shed more light to the optimal treatment method. Terminology Simple elbow dislocations include the dislocations that involve soft tissue disruption without any associated fractures, with the exception of avulsion fractures. Peer-review Very well done and useful study, which contributes to existing literature on this subject and clearly tells us that an unnecessary and prolonged immobilization is not only harmful to the patient but the hospital economics. REFERENCES 1 Kuhn MA, Ross G. Acute elbow dislocations. Orthop Clin North Am 2008; 39: , v [PMID: DOI: / j.ocl ] 2 Stoneback JW, Owens BD, Sykes J, Athwal GS, Pointer L, Wolf JM. Incidence of elbow dislocations in the United States population. J Bone Joint Surg Am 2012; 94: [PMID: DOI: /JBJS.J.01663] 3 Yang NP, Chen HC, Phan DV, Yu IL, Lee YH, Chan CL, Chou P, Renn JH. Epidemiological survey of orthopedic joint dislocations based on nationwide insurance data in Taiwan, BMC Musculoskelet Disord 2011; 12: 253 [PMID: DOI: / ] 4 Taylor F, Sims M, Theis JC, Herbison GP. Interventions for treating acute elbow dislocations in adults. Cochrane Database Syst Rev 2012; 4: CD [PMID: DOI: / CD pub2] 5 Maripuri SN, Debnath UK, Rao P, Mohanty K. Simple elbow dislocation among adults: a comparative study of two different methods of treatment. Injury 2007; 38: [PMID: DOI: /j.injury ] 6 Lee DH. Treatment options for complex elbow fracture dislocations. Injury 2001; 32 Suppl 4: SD41-SD69 [PMID: DOI: /S (01) ] 7 Rhyou IH, Kim YS. New mechanism of the posterior elbow dislocation. 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22 Panteli M et al. Cost analysis and outcomes of elbow dislocations dislocation of the elbow. J Bone Joint Surg Am 1984; 66: [PMID: ] 18 Charalambous CP, Morrey BF. Posttraumatic elbow stiffness. J Bone Joint Surg Am 2012; 94: [PMID: DOI: /JBJS.K.00711] 19 Morrey BF, Askew LJ, Chao EY. A biomechanical study of normal functional elbow motion. J Bone Joint Surg Am 1981; 63: [PMID: ] 20 de Haan J, Schep NW, Tuinebreijer WE, Patka P, den Hartog D. Simple elbow dislocations: a systematic review of the literature. Arch Orthop Trauma Surg 2010; 130: [PMID: DOI: /s ] 21 Ross G, McDevitt ER, Chronister R, Ove PN. Treatment of simple elbow dislocation using an immediate motion protocol. Am J Sports Med 1999; 27: [PMID: ] 22 de Haan J, Schep NW, Zengerink I, van Buijtenen J, Tuinebreijer WE, den Hartog D. Dislocation of the elbow: a retrospective multicentre study of 86 patients. Open Orthop J 2010; 4: [PMID: DOI: / ] 23 Kesmezacar H, Sarıkaya IA. The results of conservatively treated simple elbow dislocations. Acta Orthop Traumatol Turc 2010; 44: [PMID: DOI: /AOTT ] 24 Anakwe RE, Middleton SD, Jenkins PJ, McQueen MM, Court- Brown CM. Patient-reported outcomes after simple dislocation of the elbow. J Bone Joint Surg Am 2011; 93: [PMID: DOI: /JBJS.J.00860] 25 Sardelli M, Tashjian RZ, MacWilliams BA. Functional elbow range of motion for contemporary tasks. J Bone Joint Surg Am 2011; 93: [PMID: DOI: /JBJS.I.01633] 26 Bozic KJ, Rosenberg AG, Huckman RS, Herndon JH. Economic evaluation in orthopaedics. J Bone Joint Surg Am 2003; 85-A: [PMID: ] P- Reviewer: Erickson BJ, Garg B, Sano H, Vaishya R S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK WJO 520

23 Submit a Manuscript: Help Desk: DOI: /wjo.v6.i7.521 World J Orthop 2015 August 18; 6(7): ISSN (online) 2015 Baishideng Publishing Group Inc. All rights reserved. Prospective Study Can tranexamic acid change preoperative anemia management during total joint arthroplasty? ORIGINAL BRIEF ARTICLE Duy L Phan, Joseph B Rinehart, Ran Schwarzkopf Duy L Phan, Ran Schwarzkopf, Department of Orthopaedic Surgery, University of California, Irvine, CA 92868, United States Joseph B Rinehart, Department of Anesthesiology, University of California, Irvine, CA 92868, United States Author contributions: Phan DL performed the data collection, statistical analysis, and wrote the paper; Rinehart JB designed the research study and revised the paper; Schwarzkopf R designed the research study and revised the paper. Institutional review board statement: The study was reviewed and approved by the UCI Institutional Review Board. Clinical trial registration statement: Because all study participants received the same treatment, the project was not registered as a clinical trial. Informed consent statement: All study participants provided written consent prior to study enrollment. Conflict-of-interest statement: Dr. Duy Phan has no relevant disclosures to make in relation to the submitted study. Dr. Phan has not received research funding, speaker fees, consulting fees, or royalties from any organizations. Dr. Phan is an employee of the Department of Orthopaedic Surgery, University of California, Irvine. Dr. Phan does not own company stock or options. Dr. Phan does not own any patents. Dr. Phan is not on the editorial board of any journals. Dr. Phan is a not a board member of any societies. Data sharing statement: All technical data is available from the corresponding author at phandl@uci.edu. Consent was not obtained, but the presented data is anonymized and the risk of identification is low. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Correspondence to: Duy L Phan, MD, Department of Orthopaedic Surgery, University of California, 101 The City Drive South, Irvine, CA 92868, United States. phandl@uci.edu Telephone: Fax: Received: January 7, 2015 Peer-review started: January 7, 2015 First decision: February 7, 2015 Revised: February 24, 2015 Accepted: June 15, 2015 Article in press: June 16, 2015 Published online: August 18, 2015 Abstract AIM: To investigate the postoperative transfusion and complication rates of anemic and nonanemic total joint arthroplasty patients given tranexamic acid (TXA). METHODS: A cross-sectional prospective study was conducted of primary hip and knee arthroplasty cases performed from 11/2012 to 6/2014. Exclusion criteria included revision arthroplasty, bilateral arthroplasty, acute arthroplasty after fracture, and contraindication to TXA. Patients were screened prior to surgery, with anemia was defined as hemoglobin of less than 12 g/dl for females and of less than 13 g/dl for males. Patients were divided into four different groups, based on the type of arthroplasty (total hip or total knee) and hemoglobin status (anemic or nonanemic). Intraoperatively, all patients received 2 g of intravenous TXA during surgery. Postoperatively, allogeneic blood transfusion (ABT) was directed by both clinical symptoms WJO 521

24 Phan DL et al. Tranexamic acid and preoperative anemia and relative hemoglobin change. Complications were recorded within the first two weeks after surgery and included thromboembolism, infection, and wound breakdown. The differences in transfusion and complication rates, as well as the relative hemoglobin change, were compared between anemic and nonanemic groups. RESULTS: A total of 232 patients undergoing primary joint arthroplasty were included in the study. For the total hip arthroplasty cohort, 21% (18/84) of patients presented with preoperative anemia. Two patients in the anemic group and two patients in the nonanemic group needed ABTs; this was not significantly different (P = 0.20). One patient in the anemic group presented with a deep venous thromboembolism while no patients in the nonanemic group had an acute complication; this was not significantly different (P = 0.21). For nonanemic patients, the average change in hemoglobin was 2.73 ± 1.17 g/dl. For anemic patients, the average change in hemoglobin was 2.28 ± 0.96 g/dl. Between the two groups, the hemoglobin difference of 0.45 g/dl was not significant (P = 0.13). For the total knee arthroplasty cohort, 18% (26/148) of patients presented with preoperative anemia. No patients in either group required a blood transfusion or had an acute postoperative complication. For nonanemic patients, the average change in hemoglobin was 1.85 ± 0.79 g/dl. For anemic patients, the average change in hemoglobin was 1.09 ± 0.58 g/dl. Between the two groups, the hemoglobin difference of 0.76 g/dl was significant (P < 0.001). CONCLUSION: TXA administration results in low transfusion and complication rates and may be a useful adjunct for TJA patients with preoperative anemia. Key words: Total knee replacement; Tranexamic acid; Total hip replacement; Preoperative anemia The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Patients with preoperative anemia presenting for total joint arthroplasty (TJA) have an increased risk of requiring allogeneic blood transfusion (ABT). Current methods to increase preoperative hemoglobin is expensive, limited in efficacy, and have side effects. In this study, we found that intraoperative tranexamic acid (TXA) safely and effectively decreases blood loss and limits the rate of ABT after TJA for anemic patients. We recommend TXA for all patients without contraindications who have preoperative anemia. Phan DL, Rinehart JB, Schwarzkopf R. Can tranexamic acid change preoperative anemia management during total joint arthroplasty? World J Orthop 2015; 6(7): Available from: URL: htm DOI: INTRODUCTION Approximately 20% of patients presenting for total joint arthroplasty (TJA) have preoperative anemia and are at a relatively higher risk of needing allogeneic blood transfusion (ABT) [1-6]. This rate reflects the overall prevalence of anemia in the general elderly population, defined by the World Health Organization as hemoglobin (Hb) < 12 g/dl in females and < 13 g/dl in males, and can be contributed to by causes such as nutritional deficiency or chronic disease [7,8]. Preoperative and perioperative blood management is of considerable importance for these patients, especially given the influence of postoperative anemia on functional recovery, complications, and outcome [1,2]. Although there have been no large studies examining the effect of preoperative anemia on mortality after TJA, studies in the hip fracture [9,10], cardiac [11], vascular [12], and general surgery [13] patient populations have shown an increase in mortality rates. It is likely that there may be a similar effect with TJA. Multiple authors have proposed preoperative screening and treatment protocols to limit the potential for perioperative anemia [14-17]. General factors such as patient weight, comorbidities, and nutritional deficiencies should be addressed to optimize hematologic status [18]. Preoperative Hb should be routinely obtained and a thorough analysis performed for moderate to severe levels of anemia to determine the etiology of the disorder [18]. A preoperative Hb of 13 g/dl has historically been held as the gold standard to minimize the rate of symptomatic perioperative anemia [1]. Tranexamic acid (TXA) has gained popularity as an intraoperative adjunct to help decrease blood loss and perioperative anemia. TXA is a lysine analog that competitively inhibits the activation of plasminogen to plasmin, slowing the rate of fibrinolysis [19]. It can be applied intravenously or topically [20] has a short halflife, and preferentially affects fibrinolysis in the surgical field [21]. Although there have been sporadic case reports about side-effects, there have been no large-scale studies that show a significant increase in complications such as symptomatic thromboembolism [22-25]. When compared to other treatments, most specifically erythropoietin, TXA can be cost-effective [26]. The analog has been well documented as efficacious in orthognathic [27], cardiac [28], and spine [29] procedures. Multiple studies have shown a decrease in blood loss and ABT with TXA application for both primary and revision TJA [22-25,30,31]. The effect of TXA on patients presenting with preoperative anemia has been less well examined. The purpose of this study was to compare rates of transfusion and postoperative complications between anemic and nonanemic patients given TXA who underwent primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). Our hypothesis was that there would be no significant difference in the rates of trans WJO 522

25 Phan DL et al. Tranexamic acid and preoperative anemia Table 1 Patient demographics and outcome Anemic THA Nonanemic THA Anemic TKA Nonanemic TKA Number Gender (M/F) 10/8 33/33 10/16 48/74 Age 63.0 (± 15.6) 60.0 (± 13.8) 68.2 (± 8.6) 67.0 (± 10.2) Preoperative Hb (g/dl) (± 0.82) (± 0.92) (± 0.72) (± 0.94) Hospital day 1 Hb (g/dl) 9.17 (± 1.26) (± 1.35) (± 0.91) (± 1.09) Hb change (g/dl) 2.28 (± 0.96) 2.73 (± 1.17) 1.09 (± 0.58) (± 0.79) 1 Transfusions Complications Significant difference in hemoglobin change between anemic TKA and nonanemic TKA patients (P < 0.001). THA: Total hip arthroplasty; TKA: Total knee arthroplasty; Hb: Hemoglobin. fusion and complications for both groups of patients. If supported, this could lead to changes in preoperative management for anemic TJA patients. MATERIALS AND METHODS A prospective cross-sectional study was performed from 11/2012 to 6/2014 at a tertiary university academic institution. Patients undergoing elective primary THA or TKA by the lead author were eligible. Exclusion criteria included revision or bilateral TJA, TJA after hip fracture, or patients with contraindications towards receiving TXA. Preoperative Preoperative Hb was measured within 3 wk prior to surgery and patients were classified as anemic vs nonanemic based on World Health Organization guidelines (< 12 g/dl in females and < 13 g/dl in males). Patients were not prescribed supplemental treatment, such as iron supplementation or erythropoietin, and were advised to stop blood-thinning medications such aspirin or nonsteroidal anti-inflammatory medications 1 wk prior to surgery. Intraoperative All patients received two doses of intravenous TXA in the perioperative period: 1 g prior to incision and 1 g during wound closure. Spinal anesthesia was used for all eligible patients as determined by the anesthesia team; patients deemed ineligible received a general anesthetic with endotracheal tube. TKA patients were placed in the supine position, had a tourniquet applied prior to incision, and a standard parapatellar approach utilized to implant a cemented metal-on-polyetheylene system. THA patients were placed in the lateral decubitus position with a standard posterior approach utilized to implant a non-cemented metal or ceramic-onpolyethylene system. Fluid resuscitation and transfusion requirement was managed by the anesthesia team following standard guidelines. A cocktail for pain control, including 80 mcg clonidine, 30 mg ketorolac, 0.5 ml 1:1000 epinepherine, and ml 0.5% ropivicaine, combined with normal saline to a total volume of 100 ml, was injected into the joint capsule and surrounding tissues prior to final closure in both groups. Postoperative Patients were admitted to the Orthopaedics unit and followed a standardized postoperative protocol, including aggressive multimodal pain control with oral medications and physical therapy starting on the day of surgery. Coumadin and a sequential compression device were used to prevent thrombus formation. Hb was measured for all patients on the first postoperative day, as well as for the majority of patients on subsequent days as required. Transfusion was dictated by a significant decrease in Hb combined with clinical symptoms or changes in physiologic parameters. An absolute Hb threshold for transfusion was not used. Discharge was typically on the third postoperative day. Any postoperative complications up to the first postoperative visit, typically at two weeks, were recorded. Complications included superficial hematoma formation, deep joint effusion, wound breakdown, thromboembolism, and acute infection. Statistical analysis Patients were divided into one of four groups based on preoperative Hb and type of arthroplasty performed (nonanemic vs anemic, TKA vs THA). In each surgical group (TKA and THA), the nonanemic patients were used as controls and the anemic patients as the study groups. A two-sample T test was used to compare the average change in Hb between each of the groups (e.g., anemic TKA vs nonanemic TKA). A Fisher exact test was used to compare the rate of complications between each of the groups as well as the rate of transfusion between each of the groups. Significance was set at the P value of Statistical analysis was performed using Microsoft Excel (Microsoft, Richmond WA). RESULTS A total of 232 patients met inclusion criteria and were enrolled in the study (Table 1). THA Eighty-four patients had THA performed. Twentyone percent (18/84) of the patients presented with WJO 523

26 Phan DL et al. Tranexamic acid and preoperative anemia Hemoglobin level for THA patients Anemic Nonanemic Mean Hemoglobln (g/dl) Preoperative 1 2 Hospital day Figure 1 Hemoglobin levels in total hip arthroplasty using tranexamic acid. Boxplots showing median and interquartile ranges for hemoglobin levels in each group on each hospital day are shown. Both groups experienced a fall in hemoglobin following surgery and both groups had at least one patient who required transfusion on the first postoperative day. Despite the differences in starting hemoglobin, there was no significant difference between groups in rate of transfusion. THA: Total hip arthroplasty. preoperative anemia. For nonanemic patients, the average change in Hb from preoperative to the first postoperative day was 2.73 ± 1.17 g/dl. For anemic patients, the average change in Hb from preoperative to the first postoperative day was 2.28 ± 0.96 g/dl (Figure 1). Between the two groups, the Hb difference of 0.45 g/dl was not significant (P = 0.13). Two patients in the nonanemic group and two patients in the anemic group required ABT. There was no significant difference in the rate of ABT (P = 0.20). One patient in the anemic group presented with a deep venous thrombosis at the fourth postoperative day; there were no complications for patients in the nonanemic group. There was no significant difference in the rate of all immediate postoperative complications (P = 0.21). TKA One hundred and forty-eight patients had TKA performed. Eighteen percent (26/148) of the patients presented with preoperative anemia. For nonanemic patients, the average change in Hb from preoperative to the first postoperative day was 1.85 ± 0.79 g/dl. For anemic patients, the average change in Hb from preoperative to the first postoperative day was 1.09 ± 0.58 g/dl (Figure 2). Between the two groups, the Hb difference of 0.76 g/dl was significant (P < 0.001). No patients in either group required ABT. No patients in either group presented with complications within the first post-operative visit. DISCUSSION Current methods to increase Hb in patients with preoperative anemia have disadvantages. The results of iron supplementation are inconclusive, with studies showing diverging effects on preoperative Hb [6,32-34]. Common side effects such as constipation, and abdominal pain can lower the adherence rate [32]. Recombinant human erythropoietin has been shown to be efficacious [35-37], but is only available via an intravenous or subcutaneous route and is relatively expensive [14,38]. Preoperative autologous donation provides the patient a safe supply of blood [39] but physiologic compensation after donation may be inadequate [40] and a significant amount of donated blood is unused [1,40,41]. As such, the goal of this study was to determine if TXA would be useful as an alternative strategy for patients with preoperative anemia to limit the rate of blood loss and ABT. As expected from undergoing a TJA, all patients had a decrease in Hb at the first postoperative day. Anemic and nonanemic patients who underwent THA had a similar decrease in Hb, with anemic patients averaging only an additional 0.45 g/dl of blood loss. This supported the hypothesis that TXA would result in equivalent rates of blood loss, regardless of preoperative Hb levels. However, nonanemic patients who underwent TKA averaged a decrease in Hb that was significantly greater than that for anemic patients, at 0.76 g/dl; this was unexpected. It is not entirely clear what caused this difference in Hb change, but it may simply be that nonanemic patients lose more red cells per ml of blood lost than anemic patients (due to intraoperative fluid resuscitation), so for equivalent volumes lost between groups the nonanemic group would be expected to have lost more red cell mass overall and therefore experience a bigger drop in Hb. As all patients received fluids during the perioperative period according to strict guidelines following anesthesia protocol based on patient weight and hemodynamic status, it is unlikely that differences in fluid administration were contributive. WJO 524

27 Phan DL et al. Tranexamic acid and preoperative anemia Hemoglobin level for TKA patients Anemic Nonanemic Mean Hemoglobln (g/dl) Preoperative 1 2 Hospital day Figure 2 Hemoglobin levels in total knee arthroplasty using tranexamic acid. Boxplots showing median and interquartile ranges for hemoglobin levels in each group on each hospital day are shown. Both groups experienced a fall in hemoglobin following; in this case the nonanemic patients had a significant greater fall then the anemic patients at the first postoperative day (but still had a higher median hemoglobin). None of the patients in either group required transfusion. TKA: Total knee arthroplasty. Finally, only one patient, in the anemic THA group, had a postoperative complication, well within the normal occurrence rate reported for THA [42]. The thrombosis was treated with anticoagulation and did not result in symptomatic embolism. This low rate of complications reaffirms the safe use of TXA as seen in the current literature. There was no significant difference in the rate of ABT for anemic and nonanemic patients treated with TXA during THA, and none of the TKA patients required transfusion. This supports the hypothesis that use of TXA would result in equivalent rates of perioperative transfusion, regardless of preoperative blood levels. Given that patients with preoperative anemia generally require a higher rate of transfusion, the results suggest that TXA may actually decrease the rate of ABT for this patient population. The potential significance of this finding is two-fold. First, patients with a mild level of anemia may not require any preoperative or perioperative adjunct treatment aside from TXA, such as PO or Ⅳ iron supplementation or erythropoietin. Limiting the use of these treatments may decrease concerns about patient compliance and reduce overall surgical costs, as well as rare but real complications from the therapies themselves. In addition, the threshold to operate on patients may be lowered, increasing the availability of TJA for patients with anemia. For these patients, a preoperative course combining multiple treatment modalities in addition to perioperative TXA may be sufficient to minimize significant blood loss and ABT requirements. This study has several limitations. All procedures were performed by a single surgeon and thus operative blood loss may not be equivalent to that of other surgeons using alternative TJA techniques. Because the study highlighted the relative change (as opposed to absolute values) in Hb, the overall impact of this limitation should be small. In addition, the same approach and same implant system was used by the surgeon for the procedures, which limited variation in surgical technique. The study population was not large, which resulted in a low number of patients with anemia, and thus power could have been increased by enrolling additional patients. However, the percentage of patients presenting with preoperative anemia was equivalent to the rates seen in the existing literature, suggesting that the study population was a suitable representation of the patient population. As such, a formal power analysis was not performed. Another limitation was with regard to the rates of transfusion; with only four ABT s in the study it is possible that a much larger sample may have demonstrated differences, though even here the conclusion that TXA may allow safe TJA at lower Hb levels would not have changed. Finally, the decision for ABT was not dictated by a single factor, such as postoperative Hb. The current literature is increasingly supportive of using a restrictive transfusion threshold similar to that used in this study, but it is possible that other centers with more liberal transfusion practices may have different results. In this study, there was no significant difference in the rate of autologous blood transfusion and postoperative complications for anemic and nonanemic patients presenting for lower-extremity TJA when TXA was used. These results support the use of TXA as a safe and effective agent to limit perioperative blood transfusion in patients with preoperative anemia. Potentially, TXA may be used as the single treatment for patients with mild anemia, in place of preoperative methods such as iron supplementation WJO 525

28 Phan DL et al. Tranexamic acid and preoperative anemia and erythropoietin. TXA may also be helpful when combined with these adjuncts for patients with more severe anemia. Further investigations concerning TXA in patients with preoperative anemia are recommended. Topics to be considered, or are currently under examination, include comparing efficacy and analyzing costbenefit of TXA vs different preoperative treatments (e.g., iron supplementation, erythropoietin). These studies will ideally lead to a standardized and cohesive protocol for TJA patients with preoperative anemia. COMMENTS Background Total joint arthroplasty (TJA) of the hip and knee are successful surgeries that can dramatically reduce pain and increase function for patients with end-stage joint arthritis. However, despite changes in surgical approaches, techniques, and implants, intraoperative blood loss requiring blood transfusion is still prevalent, especially for patients presenting with anemia. Currently, the therapeutic options to treat preoperative anemia are limited and not commonly used. Research frontiers Tranexamic acid (TXA) has been highlighted in the last half-decade as a way to decrease intraoperative blood loss. Application during surgery, via intravenous or topical, has been shown to decrease the rate of blood transfusion in THA patients. TXA use has also expanded to other fields of orthopaedics, such as spine surgery. Innovations and breakthroughs To the authors knowledge, no previous study has closely examined TXA use on THA patients presenting with preoperative anemia. The current study is the first to directly compare blood loss, transfusion rate, and complication rate for anemic THA patients given TXA vs nonanemic controls. With the results shown, it may be possible to use TXA as the sole treatment for patients with mild anemia and as a adjunct with other treatment options for patients with severe anemia. Applications The current study shows the efficacy and safety of TXA use for THA patients presenting with preoperative anemia and suggests that routine use in anemic patients with no contraindications is warranted to limit the rate of blood transfusion. Terminology TXA - synthetic lysine analog that competitively inhibits the activation of plasminogen to plasmin. Anemia - Defined by the World Health Organization as hemoglobin < 12 g/dl in adult females and < 13 g/dl in adult males. Peer-review This is a manuscript which compares rates of transfusion and postoperative complications between anemic and nonanemic patients given TXA who underwent primary total hip arthroplasty and total knee arthroplasty. This is an interesting paper on a relevant issue. The paper is well written and well structured. REFERENCES 1 Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms RE, Welch RB. An analysis of blood management in patients having a total hip or knee arthroplasty. 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30 Submit a Manuscript: Help Desk: DOI: /wjo.v6.i7.528 World J Orthop 2015 August 18; 6(7): ISSN (online) 2015 Baishideng Publishing Group Inc. All rights reserved. SYSTEMATIC REVIEWS Persistent post-surgical pain and neuropathic pain after total knee replacement Georgios I Drosos, Triantafilia Triantafilidou, Athanasios Ververidis, Cristina Agelopoulou, Theodosia Vogiatzaki, Konstantinos Kazakos Georgios I Drosos, Triantafilia Triantafilidou, Athanasios Ververidis, Konstantinos Kazakos, Department of Orthopaedic Surgery, Medical School, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece Cristina Agelopoulou, Department of Neurology, Medical School, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece Theodosia Vogiatzaki, Department of Anaesthesia, Medical School, Democritus University of Thrace, University General Hospital of Alexandroupolis, Alexandroupolis, Greece Author contributions: Drosos GI, Triantafilidou T and Agelopoulou C contributed to conception and design of the study; Drosos GI, Triantafilidou T and Ververidis A contributed to acquisition; analysis and interpretation of data; Drosos GI, Triantafilidou T and Agelopoulou C contributed to drafting the article; Ververidis A, Vogiatzaki T and Kazakos K contributed to revising the article; all the authors read and approved the final manuscript. Conflict-of-interest statement: All the authors declare that there is no conflict of interest for this work. They have received no funds from any commercial party in relation to this work. Data sharing statement: It does not apply in this study. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Correspondence to: Georgios I Drosos, MD, PhD, Assistant Professor, Department of Orthopaedic Surgery, Medical School, Democritus University of Thrace, University General Hospital of Alexandroupolis, Dragana, Alexandroupolis, Greece. drosos@otenet.gr Telephone: Fax: Received: March 5, 2015 Peer-review started: March 8, 2015 First decision: April 10, 2015 Revised: May 16, 2015 Accepted: June 1, 2015 Article in press: June 2, 2015 Published online: August 18, 2015 Abstract AIM: To study the prevalence of persistent post-surgical pain (PPSP) and neuropathic pain (NP) after total knee replacement (TKR). METHODS: MEDLINE and Embase databases were searched for articles published until December 2014 in English language. Published articles were included if they referred to pain that lasts at least 3 mo after primary TKR for knee osteoarthritis, and measured pain with pain specific instruments. Studies that referred to pain caused by septic reasons and implant malalignment were excluded. Both prospective and retrospective studies were included and only 14 studies that match the inclusion criteria were selected for this review. RESULTS: The included studies were characterized by the heterogeneity on the scales used to measure pain and pre-operative factors related to PPSP and NP. The reported prevalence of PPSP and NP seems to be relatively high, but it varies among different studies. There is also evidence that the prevalence of post-surgical pain is related to the scale used for pain measurement. The prevalence of PPSP is ranging at 6 mo from 16% to 39% and at 12 mo from 13.1% to 23% and even 38% of the patients. The prevalence of NP at 6 mo post-operatively is ranging from 5.2% to WJO 528

31 Drosos GI et al. Persistent pain after TKR 13%. Pre-operative factors related to the development of PPSP also differ, including emotional functioning, such as depression and pain catastrophizing, number of comorbidities, pain problems elsewhere and operations in knees with early grade of osteoarthritis. CONCLUSION: No firm conclusions can be reached regarding the prevalence of PPSP and NP and the related factors due to the heterogeneity of the studies. Key words: Total knee replacement; Pain; Chronic pain; Neuropathic pain; Post-operative pain; Persistent postsurgical pain The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Persistent post-surgical pain (PPSP) is reported in a significant proportion of patients after total knee replacement. This proportion varies between the different studies and different factors have been implicated including the instrument used to measure pain. It is also obvious that in some of these patients the pain is neuropathic (NP) in origin or the NP pain coexists. Nevertheless, due to the heterogeneity of the studies, mainly on the scales used to assess pain and preoperative factors, we are unable to reach firm conclusions concerning the prevalence, and the risk factors of PPSP pain after total knee replacement. Additional studies focused on the prevalence and risk factors related to PPSP are needed. Drosos GI, Triantafilidou T, Ververidis A, Agelopoulou C, Vogiatzaki T, Kazakos K. Persistent post-surgical pain and neuropathic pain after total knee replacement. World J Orthop 2015; 6(7): Available from: URL: com/ /full/v6/i7/528.htm DOI: wjo.v6.i7.528 INTRODUCTION Total knee replacement (TKR) is a treatment of knee osteoarthritis to alleviate pain symptoms and improve mobility and physical functioning when other conservative treatments have failed [1-3]. It is a very common and successful procedure since 1970s for late stage osteoarthritis and there is a continuously increasing number in demand for primary TKR performed worldwide each year [4,5]. However, not all patients are satisfied after TKR. Pain after TKR is stronger determinant of satisfaction than function [6]. An unfavorable pain outcome was seen in at least 8.0% and up to 26.5% of patients [7] and contribute to functional disability after TKR [6,8-10]. Apart from the post-surgical pain that is a result of a specific cause, some patients suffer from a persistent post-surgical pain (PPSP) with no specific origin that represents an important cause for patients dissatisfaction. Although the cause of PPSP is not known, it seems that some of the patients with PPSP after TKR suffer from neuropathic pain (NP) [11]. The International Association for the Study of Pain (IASP) defines: (1) as PPSP the pain that is being developed after surgery and exists beyond the time for normal healing and is present for at least 3-6 mo [12] ; and (2) NP is also defined by the IASP as the pain caused by a lesion or a disease of the somatosensory nervous system (IASP website, org/) [13]. A wide variety of scores tools have been used in order to assess the outcome postoperatively. Almost all scores or instruments -either objective (clinicianbased) [14] or subjective (patient-reported) [15] or disease specific [3,16] - being used for the study of the outcome, function and satisfaction after TKR, include some kind of pain assessment [17]. However, a standard definition of pain severity at follow-up considered a difficult issue to be applied and the need to improve assessment and measurement of musculoskeletal pain in the clinical setting is recognized [18]. The purpose of this study is to present a review of the existing literature concerning the existence of PPSP and NP after TKR for at least 3 mo, including studies with main purpose the prevalence of the PPSP and NP after TKR using pain-specific instruments and not through other scores or instruments measuring functional outcome. MATERIALS AND METHODS Literature search MEDLINE and Embase databases were searched for articles published until December The keywords TKR, total knee arthroplasty, chronic postoperative pain, NP and synonyms were used to maximize the efficiency of the search. Both prospective and retrospective studies were included. Inclusion and exclusion criteria Published articles were included only if they referred to pain that lasts at least 3 mo after primary TKR and if the main reason of TKR was knee OA. Studies were excluded if they were abstracts, case studies, reviews, editorials and if they referred to pain caused by septic reasons and implant malalignment. Studies that assessed a mixed cohort of patients (e.g., knee and hip replacement patients) were included in the review and only data relevant to the TKR patients were extracted. Studies in other language than English were excluded. A total of 112 articles were found. Only 14 studies that match the inclusion criteria and measured pain with pain specific instruments were selected for this review. RESULTS PPSP after TKR (Table 1) Studies: We identified 5 prospective [19-23], and 3 retrospective [9,24,25] studies. Three of the studies found to have as primary aim the documentation of the existence and the prevalence of PPSP after TKR [19,20,25], while another WJO 529

32 Drosos GI et al. Persistent pain after TKR Table 1 Total knee replacement and chronic (persistent) post-surgical pain Ref. Design/patients Aim of the study Scores-scales Follow-up Pain Factors Brander et al [19] Prospective n = 116 Forsythe Prospective et al [20] n = 55 Ritter et al [24] Retrospective n = 7326 Wylde et al [9] Retrospective n = 632 Polkowski Prospective et al [23] n = 309 Noiseux et al [21] Prospective n = 215 Pérez-Prieto Prospective et al [22] n = 716 Depressed: n = 200 To describe the natural history of pain after TKR To identify factors predicting excessive postsurgical pain To document: the prospective pain experience following TKR To determine if: (1) comorbidities; (2) preoperative pain; or (3) preoperative pain catastrophizing scores are predictors of chronic pain after TKR To quantify the effect of sex on the clinical outcome and survivorship of a specific TKR (AGC, Biomet, Warsaw, Ind) To assess the (1) prevalence; (2) severity; (3) sensory qualities; and (4) postoperative determinants of persistent pain after primary THR and TKR To explore the relationship between early-grade preoperative OA with pain and dissatisfaction after TKR Τo discover whether any preoperative assessment could predict high pain scores and functional limitations postoperatively To evaluate quality of life, function, pain and satisfaction outcomes in patients, with and without depression, undergoing TKR VAS and other measures of patient health MPQ PCS KSS PS FS WOMAC Pain Scale SFMPQ pd-q Two-item Patient Health Questionnaire (PHQ-2) Group A: Pain after TKR Group B: Consecutive series of 100 TKR s performed the same period by the same surgeon Group C: Asymptomatic TKR Group D: Symptomatic TKR performed the same period Pain Intensity rating: NRS QST Anxiety Form of the State Trait Anxiety Inventory GDS PCS GDS KSS Medical Outcomes Study 36-Item Short Form Health (SF-36) MCS VAS Pre-op. Post-op.: (1) 1 mo; (2) 3 mo; (3) 6 mo; and (4) 12 mo Pre-op. Post-op.: (1) 3 mo; (2) 12 mo; and (3) 24 mo Clinical scores: Throughout 5 yr Survival data: Up to 17 yr Median: 41 mo Range: mo Pre-op.: 72.3% Post op.: (1) 44.4%; (2) 22.6%; (3) 18.4%; and (4) 13.1%, respectively Significant reduction only between preop and 3-mo post-op values. After 3-mo pain had reached a plateau Pain catastrophizing scores didn t show any significant differences Pain after TKR was less for men but there was no statistically significant difference between men and women Persistent post-surgical pain (PPSP): 44% Severe-extreme PPSP: 15% Constant PPSP: 5% Likely neuropathic pain: 6% 1-5 yr Early-grade OA pre-op: Group A: 49% Group B: 5% Group C: 6% Group D: 10%. Pre-op. Post-op.: 6 mo Moderate to severe pain At rest: Pre-op.: 17% Post-op.: 5% With range-of-motion: Pre-op.: 52% Post-op.: 16% 12 mo Depressed patients reported significant higher pain scores than non-depressed patients pre- and post-operatively Net changes (postoperative - preoperative): No significant difference Factors related with post-op pain at 12 mo (1) Pre-operative pain; and (2) Pre-operative depression and anxiety Predictive of chronic postoperative pain: (1) No. of comorbidities; and (2) Pre-operative pain catastrophizing scores Improvement after TKR is similar for men and women No significant difference in post-operative pain between men and women Significant and independent postoperative determinants of number of PPSP: (1) No. of pain problems elsewhere; and (2) The presence of major depression A high percentage of patients referred for unexplained pain after TKR had early-grade OA pre-operatively Significant predictors (for moderate or severe TKR pain with knee motion after 6 mo): (1) Severe preoperative knee pain with range-of motion; and (2) Anxiety Depression leads to (1) Poorer preoperative and postoperative scores in all but the mental domains; and (2) But similar net score changes (improvement) with a high rate of patient satisfaction WJO 530

33 Drosos GI et al. Persistent pain after TKR W-Dahl et al [25] Non-depressed: n = 516 retrospective To evaluate how the instruments used to measure pain affected the number of patients who reported no relief of pain or worse pain, and the relative effect of potential risk factors Osteoarthritis Outcome Score (KOOS) VAS EQ-5D Pre-operatively 1 year postoperatively No pain relief: 10.1% Only KOOS pain: 25% Only VAS knee pain: 52% Both: 23% The observed proportion of patients with unchanged or worse pain one year after TKR differed depending on the method of pain measurement used Risk factors for no pain relief are: (1) less pre-operative pain; and (2) higher degree of anxiety Charnley category C was a risk factor for unchanged or worse pain as measured by the VAS but not for the KOOS OA: Osteoarthritis; TKR: Total knee replacement; Pre-op: Preoperatively; Post-op: Postoperatively; PPSP: Persistent post-surgical pain; VAS: Visual Analogue Scale; EQ-5D: Euro-Qol 5 Dimension; MCS: Mental Composite Score; KSS: Knee Society Score; GDS: Geriatric Depression Scale; PCS: Pain Catastrophizing Scale; QST Quantitative Sensory Testing; NRS: Numerical Rating Scale; SFMPQ: Short-Form McGill Pain Questionnaire; pd-q: PainDETECT Questionnaire; WOMAC: Western Ontario and McMaster Universities Index of Osteoarthritis; FS: Function score; PS: Pain score; KSS: Knee Society knee score; MPQ: McGill Pain Questionnaire. one assessed PPSP retrospectively in patients after both TKR and THR [9]. Factors-variables related to PPSP: Multiple variables have been considered to play an important role at persistent postoperative pain. At times, different aspects of risk factors have been examined. In these studies, preoperative factors that were examined were comorbidities [20], preoperative pain [19,20] and pain catastrophizing scores [20,21]. But only one study found to quantify the effect of sex on postoperative pain outcomes [24] while another one assessed the relationship of PPSP and the Grade of knee osteoarthritis according to the scale of Kellgren and Lawrence [23]. Quality of life, pain and satisfaction were measured in depressed and non-depressed patients to identify differences that might exist in the scores [22]. Pain scales or scores: Pain intensity mainly was measured using validated patient reported measures of pain, the most common were the Visual Analogue Scale (VAS) [19,25] which is a well evaluated tool, the McGill pain questionnaire (MpQ) [9,20], the Knee Society Score [22,24] and the Numerical Rating Scale (NRS) [21]. To cover the influence of psychological factors on TKR outcomes Pain Catastrophizing Scale (PCS) was used to measure pain catastrophizing [20,21], while the Two-item Patient Health Questionnaire (PHQ-2) [9], Geriatric Depression Scale [21,22], Medical Outcomes Study 36-Item Short Form Health, Mental Composite Score [22] and Anxiety Form of the State Trait Anxiety Inventory (STAI) [21] were used to measure depression and anxiety. A recent study [25] evaluated the tools that used to measure pain intensity, Knee injury and Osteoarthritis Outcome Score (KOOS) and VAS and how they affect the pain outcomes. Pain assessment times and post-operative follow-up: At the most of the studies there was a continuous follow-up. Assessments took place preoperatively [19-21,25] and postoperatively at 1 mo [19], 3 mo [19,20], 6 mo [19,21], 12 mo [19,22,23,25] and up to 1 year postoperatively [19,22,23,25]. Prevalence of pain: A significant reduction of pain after TKR was observed between preoperative scores and postoperative scores; from 72% to 44% [19]. A further reduction was observed up to 3 mo postoperatively where pain reached a plateau [20]. At 6 mo post-operatively, pain at movements was found in 16% of patients [21] while pain at rest was significantly reduced in 5% of the patients. [21]. Others found PPSP in 18.4% of the patients at 6 mo [19]. PPSP has been reported at 1 year post-operatively in 13.1% of the patients [19] while in another study, 44% of the patients reported to had PPSP at a mean of 4 years after TKR [9]. Interestingly, in one study where the same patients were tested using two different scales at one year post-operatively, the prevalence of PPSP was different; in 25% of the patients using the KOOS and in 52% using the VAS [25]. Factors related to PPSP: Preoperative factors that affected pain scores were depression scores [9,19], affecting both preoperative and postoperative pain scores [22], early grade WJO 531

34 Drosos GI et al. Persistent pain after TKR of osteoarthritis [23], number of comorbidities [20] and pain problems elsewhere [9]. Gender didn t seemed to affect postoperative outcomes at all [24]. A high correlation was found between preoperative pain catastrophizing scores and the existence of PPSP and its intensity [20]. Which is in accordance with other reviews that is referred that patient s pain catastrophizing might play an important role in chronic pain intensity [26,27]. NP after TKR (Table 2) Studies: The existence and prevalence of NP have been reported by a small number of studies [9,28,29]. Three prospective studies [9,28,29] with the study population ranged from 77 to 120 patients, and 1 retrospective study [9] with a number of 632 patients were designed for this purpose. However, other studies that aimed to evaluate specific treatments for NP recorded its prevalence too [30]. Pain scales or scores: Scores, initially were used to establish the existence of pain in some of these studies. These scores were MpQ [9,28], VAS [29] and NRS [30]. Additionally, NP was assessed by paindetect Questionnaire (PD-Q) [9,29], Leeds Assessment of Neuropathic Symptoms and Signs scale [30] and MpQ [28]. The contribution of depression s and anxiety s presence and severity to the existence of NP were examined. PHQ-2 [9], Beck Depression Inventory (BDI) [28], the Hospital Anxiety and Depression score [29] and the STAI [28] were used for this purpose. Pain assessment times and post-operative followup: Pain assessment at these studies took place preoperatively [29,30] and postoperatively at 3-5 d [29], 6 wk [29], 1 mo [28], at 3, 6 and 9 mo [28-30] and up to 1 year postoperatively [9,29]. NP prevalence: A high correlation was found between VAS pain scores and NP at 3 mo, 1 year and 3 years post-op [29]. Six weeks postoperatively a peak at the graph was observed with 27% having possible and 8% of the patients having likely NP. At 3 mo that proportion reduced to 19% with possible and 4% with likely NP [29]. Buvanendran et al [30], identified a rate of NP of 5% at 6 mo postoperatively, while in another study [28] was found 13% of the patients having Complex Regional Pain Syndrome after TKR at both 3 and 6 mo. It is reported that at mean 4 years after TKR 6% of the patients have pain of likely neuropathic origin [9,29]. The use of perioperative pregabalin reduced the incidence of NP at 0%, while placebo pregabalin didn t seem to reduce NP [30]. Studies including TKR patients concerning the existence, prevalence and etiology of NP (Table 3) Studies: A retrospective study assessed the existence and the preoperative predictors of NP in 632 TKR patients and 662 THR patients [9], and two prospective studies in 100 TKR patients and 89 patients after breast surgery [31,32]. Another prospective study, also examined the relationship between postoperative trajectories and NP, in 112 TKR and UKR patients [33]. Pain scales or scores: Scores that used to assess NP were PD-Q [9] and Diagnosing Neuropathic 4 [31-33]. Shortform McGill Pain Questionnaire [9], NRS [31,33] and Brief Pain Inventory [32] were used to define the existence of pain postoperatively. Factors studied: Preoperative factors of NP that were examined were depression [9,31,32], anxiety [31,33], pain catastrophizing [31,33], cognitive and emotional functioning [32]. Depression was assessed with PHQ-2 [9] and 13-item BDI [31,32]. Spielberger STAI and PCS were used to assess anxiety and pain catastrophizing [31,33]. Cognitive functioning was assessed with Trail-Making Test A + B, Rey-Osterrieth Complex Figure-copy and immediate recall, Coping Strategies Questionnaire and Brief Version of the Survey of Pain Attitudes [32]. Pain assessment times and post-operative followup: Assessments took place preoperatively [9,31-33], 2 d postoperatively [31,32], at day 1 to 8 [33], 3 mo [31,33], 6 mo, 12 mo [32] and 3 to 4 years postoperatively [9]. Factors: Acute postoperative pain [31], cognitive functioning, pain coping [32], emotional functioning [9,32] and problems of pain elsewhere [9] found to be predictors of PPSP and NP. Prevalence: Seventy five percent of the patients seemed to have NP preoperatively, according to Attal et al [32], 2014, while in another study NP seemed to appear on 30.7% of the patients [31]. At 3 mo postoperatively, NP ranged between 11% [33] and 42.2% [31] of the patients. Six and 12 mo postoperatively patients with NP reduced at 32% and 26%, respectively [32]. At 3 to 4 years postoperatively only 6% of TKR patients had NP [9]. DISCUSSION The number of the 14 studies that used pain-specific instruments to measure pain after TKR is small and studies that approach and record NP after TKR are much less. According to these studies, a significant proportion of patients have persistent post-operative pain for years after TKR and part of these patients suffer from pain of neuropathic origin. Factors found to be related to persistent postoperative pain after TKR include emotional functioning such as depression and pain catastrophizing, number of comorbidities and pain problems elsewhere and operations in knees with early grade of osteoarthritis. Nevertheless, due to the heterogeneity of the studies, mainly on the scales used to assess pain and WJO 532

35 Drosos GI et al. Persistent pain after TKR Table 2 Total knee replacement and neuropathic pain Ref. Design No. of patients Aim of the study Scores-scales Follow-up Pain Factors Harden et al [28] Prospective 77 Preoperative emotional distress and pain intensity and would predict the occurrence of signs and symptoms of CRPS following TKR Buvanendran et al [30] Prospective Control: 120 Pregabalin: 120 To examine if perioperative treatment with pregabalin, would reduce the incidence of postsurgical NP Wylde et al [9] Retrospective 632 To assess: (1) prevalence; (2) severity; (3) sensory qualities; and (4) postoperative determinants of persistent pain after primary THR and TKR Phillips et al [29] Prospective 94 To record the prevalence of pain and NP To establish predictive factors that could be used to identify patients who were likely to have high levels of pain or NP CRPS: IASP criteria (signs/ symptoms) Beck Depression Inventory State Trait Anxiety Inventory McGill Pain Questionnaire- Short Form 11-point NRS LANS scale Osteoarthritis Outcome Score Physical function Short-form (KOOS-PS) WOMAC Pain Scale SF-MPQ PainDETECT Questionnaire Two-item PHQ-2 VAS HADS score pd-q score OKS Pre-op. Post-op.: (1) 1 mo; (2) 3 mo; and (3) 6 mo Pre-op. Post-op.: (1) 3 mo; and (2) 6 mo Median: 41 mo Range: mo Pre-op. Post-op.: (1) 3-5 d; (2) 6 wk; (3) 3 mo; (4) 6 mo; (5) 9 mo; (6) 1 yr; and (7) 46 mo 1 mo: 21.0% 3 mo: 13.0% 6 mo: 12.7% Study group: 0% Placebo group: (1) 3 mo: 8.7%; (2) 6 mo: 5.2% Persistent postsurgical pain (PPSP): 44% Severe-extreme PPSP: 15% Constant PPSP: 5% Likely NP: 6% VAS (value) Pre-op.: 5.8 Post-op.: (1) 3-5 d: 4.5; (2) 6 wk: 3.2; (3) 3 mo: 2.4; (4) 6 mo: 2.0; (5) 9 mo: 1.7; (6) 1 yr: 1.5; and (7) 46 mo: 2.0 Frequency (%) VAS moderate-severe/ paindetect possible -likely Pre-op.: 41-50/5-1 Post-op.: (1) 3-5 d: 47-19/5-3; (2) 6 wk: 39-9/27-8; (3) 3 mo: 21-10/19-4; (4) 6 mo: 16-6/17-3; (5) 9 mo: 16-4/13-6; (6) 1 yr: 14-3/9-2; and (7) 46 mo: 15-7/7-6 CRPS-like phenomena: (1) In a significant number of patients after TKR; and (2) No association with significantly greater complaints of postoperative pain Prediction by preoperative distress and pain: Modest utility Perioperative pregabalin administration reduces the incidence of chronic NP after TKR In the doses tested, it is associated with a higher risk of early postoperative sedation and confusion Significant and independent postoperative determinants of number of PPSP: (1) No. of pain problems elsewhere; and (2) The presence of major depression High correlation between the mean VAS scores for pain and the mean paindetect scores at 3 mo, 1 yr and 3 yr post-operatively No correlation between the pre-operative scores and any post-operative scores at any time point NP is an underestimated problem in patients after TKR CRPS: Complex regional pain syndrome; NP: Neuropathic pain; Pre-op: Preoperatively; Post-op: Postoperatively; LANS: Leeds Assessment of Neuropathic Symptoms and Signs; NRS: Numerical Rating Scale; WOMAC: Western Ontario and McMaster Universities Index of Osteoarthritis; SF-MPQ: Short-Form McGill Pain Questionnaire; PHQ-2: Patient Health Questionnaire; VAS: Visual Analogue Score; HADS: Hospital Anxiety and Depression; pd-q: PainDETECT; OKS: Oxford Knee score. WJO 533

36 Drosos GI et al. Persistent pain after TKR Table 3 Studies including total knee replacement patients concerning the prevalence and etiology of neuropathic pain Ref. Design No. of patients Aim of the study Scores-scales Follow-up Pain Factors Wylde et al [9] Retrospective 632 To assess: (1) prevalence; (2) severity; (3) sensory qualities; and (4) postoperative determinants of persistent pain after primary THR and TKR Masselin- Dubois et al [31] Lavand homme et al [33] Prospective TKR patients: 89 breast cancer surgery patients: 100 Prospective TKR and UKR patients: 120 To assess the BPI predictive value of: (1) Anxiety; (2) Depression; (3) Pain catastrophizing; and (4) Baseline pain intensity for chronic postsurgical pain. The existence of neuropathic pain To examine the relationship between postoperative pain trajectories and persistent pain, specifically neuropathic pain. Attal et al [32] Prospective TKR patients: 89 If: breast cancer (1) cognitive surgery patients: 100 functioning (2) emotional functioning and pain coping are predictors of persistent postsurgical pain and neuropathic pain Western Ontario and McMaster Universities Index of Osteoarthritis Pain Scale Short-Form McGill Pain Questionnaire PainDETECT Questionnaire Two-item Patient Health Questionnaire NRS Neuropathic Pain Diagnostic Questionnaire (DN4) Spielberger STAI 13-item BDI PCS Median: 41 mo Range: mo Pre-op. Post-op: (1) 2 d (2) 3 mo NRS Pre-op. Neuropathic Pain Post-op: Diagnostic Questionnaire (1) Day 1 (DN4) to day 8; PCS (2) 3 mo Spielberger STAI for Adults BPI Neuropathic Pain Diagnostic Questionnaire (DN4) TMT A TMT B ROCF-copy ROCF-immediate recall BDI Spielberger STAI CSQ Brief Version of the SOPA-B Pre-op: (1) 1 mo; and (2) 1 d Post-op: (1) 2 d; (2) 6 mo, 12 mo PPSP: 44% Severe-extreme PPSP: 15% Constant PPSP: 5% Likely NP: 6% Significant and independent postoperative determinants of number of PPSP: (1) No. of pain problems elsewhere; and (2) The presence of major depression TKR patients: Regardless the type of (1) Pre-op: 84% surgery, state anxiety, pain at least moderate catastrophizing (especially pain pain magnification) and acute postsurgical pain are predictive of (2) 2 d: 46.9%; and persistent post-surgical pain (3) 3 mo: 50.6% Acute post-surgical pain was Neuropathic pain also predictive of NP pain. TKR patients: Baseline pain intensity, trait (1) Pre-op: 30.7% anxiety and depression had no (2) 3 mo: 42.2% independent impact on postsurgical pain (considering low baseline scores for depression in this study) At 3 mo post-op: (1) 42% patients were pain free (2) 47% patients with persistent pain without NP pain; and (3) 11% patients with persistent pain involving neuropathic component Patients with neuropathic pain displayed higher pain scores, particularly during mobilization No differences found among pain trajectories for pain at rest TKR patients Cognitive functioning, (1) Pre-op: 84%; emotional functioning and pain (2) 6 mo: 39%; coping made an independent and contribution to the prevalence (3) 12 mo: 38% and severity of persistent postsurgical pain, as well as its Neuropathic pain TKR patients: neuropathic quality. Results (1) Pre-op: 75 at ROCF-copy and ROCFpatients; immediate recall test seemed (2) 6 mo: 32 to be predictors of pain with patients; and neuropathic nature (3) 12 mo: 26 patients PPSP: Persistent postsurgical pain; BPI: Brief Pain Inventory; NRS: Numerical Rating Scale; STAI: State-Trait Anxiety Inventory; PCS: Pain Catastrophizing Scale; BDI: Beck Depression Inventory; TMT A: Trail-Making Test A; ROCF-copy: Rey-Osterrieth Complex Figure-copy; ROCF-immediate recall: Rey- Osterrieth Complex Figure-immediate recall; CSQ: Coping Strategies Questionnaire; SOPA-B: Survey of Pain Attitudes. preoperative factors, we are unable to reach firm conclusions concerning the prevalence, and the risk factors of persistent post-operative pain after TKR. Additional studies focused on the prevalence and risk factors related to persistent postoperative pain are needed. COMMENTS Background Persistent-post-surgical pain of unknown origin and neuropathic pain (NP) is considered a major underestimated problem for patients and for clinicians too. There are several studies that measure pain with a wide variety of scores-tools. Research frontiers According to our acknowledgment this is the first review that analyses the prevalence of both persistent post-surgical pain (PPSP) and NP after total knee replacement (TKR), while pain is measured only with pain-specific instruments. Risk factors that might play an important role in the prediction and the prevalence of persistent postoperative pain were also analyzed. Innovations and breakthroughs PPSP measured by pain- specific instruments only by a few studies. From this review, it is obvious that post-surgical pain and NP exists in a significant WJO 534

37 Drosos GI et al. Persistent pain after TKR proportion of patients, for years after TKR. Risk factors that might affect its prevalence and its intensity, found to be emotional functioning, such as depression and pain catastrophizing, number of comorbidities and early grade of osteoarthritis. Application Although it became recognizable the existence and the prevalence of PPSP and NP after TKR, these studies did not lead us to firm conclusions. There was mainly heterogeneity on the scales used to measured pain. Thus, further studies concerning the prevalence of PPSP and NP and their risk factors are needed, with pain-specific instruments. Terminology PPSP is the pain that is being developed after surgery, exists beyond the time for normal healing and is present for at least 3-6 mo. NP is defined as the pain caused by a lesion or a disease of the somatosensory nervous system. Peer-review This is a nice review article concerning postoperative knee pain after total knee arthroplasty. 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38 Drosos GI et al. Persistent pain after TKR a prospective cohort study of the point prevalence of pain and neuropathic pain to a minimum three-year follow-up. Bone Joint J 2014; 96-B: [PMID: DOI: / x.96b ] 30 Buvanendran A, Kroin JS, Della Valle CJ, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial. Anesth Analg 2010; 110: [PMID: DOI: / ANE.0b013e3181c4273a] 31 Masselin-Dubois A, Attal N, Fletcher D, Jayr C, Albi A, Fermanian J, Bouhassira D, Baudic S. Are psychological predictors of chronic postsurgical pain dependent on the surgical model? A comparison of total knee arthroplasty and breast surgery for cancer. J Pain 2013; 14: [PMID: DOI: /j.jpain ] 32 Attal N, Masselin-Dubois A, Martinez V, Jayr C, Albi A, Fermanian J, Bouhassira D, Baudic S. Does cognitive functioning predict chronic pain? Results from a prospective surgical cohort. Brain 2014; 137: [PMID: DOI: /brain/awt354] 33 Lavand homme PM, Grosu I, France MN, Thienpont E. Pain trajectories identify patients at risk of persistent pain after knee arthroplasty: an observational study. Clin Orthop Relat Res 2014; 472: [PMID: DOI: /s ] P- Reviewer: Franklyn MJ, Hasegawa M, Huang TW, Sano H S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK WJO 536

39 Submit a Manuscript: Help Desk: DOI: /wjo.v6.i7.537 World J Orthop 2015 August 18; 6(7): ISSN (online) 2015 Baishideng Publishing Group Inc. All rights reserved. META-ANALYSIS Predictors of spine deformity progression in adolescent idiopathic scoliosis: A systematic review with meta-analysis Andriy Noshchenko, Lilian Hoffecker, Emily M Lindley, Evalina L Burger, Christopher MJ Cain, Vikas V Patel, Andrew P Bradford Andriy Noshchenko, Emily M Lindley, Evalina L Burger, Christopher MJ Cain, Vikas V Patel, Department of Orthopaedics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States Lilian Hoffecker, Health Sciences Library, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States Andrew P Bradford, Department of Orthopaedics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States Author contributions: Noshchenko A contributed to development of the study conception, design, and goals for electronic literature search, participation in analysis of the electronically revealed citations, and in selection of publications for systematic review, participation in the selected studies quality assessment, data extraction, meta-analysis of the extracted data, participation in the results interpretation and level of evidence assessment, writing of the manuscript draft; Hoffecker L contributed to development of the electronic literature search strategy, providing of the comprehensive electronic literature search and preliminary analysis of the results, in particular, removal of the duplicates, participation in the manuscript drafting; Lindley EM contributed to critical revision of the manuscript draft, creation of the final version of the manuscript; Burger EL contributed to analysis of the electronically revealed citations, selection of publications for systematic review, evaluation of the publications quality, control of the data extraction, interpretation of the analysis results, level of evidence and clinical applicability assessment, writing of the manuscript, approval of the final version to be published; Cain CMJ and Patel VV contributed to critical revision of the manuscript; Bradford AP contributed to participation in the study design development, analysis of the literature search results, contribution into the manuscript draft and final version writing. Conflict-of-interest statement: The manuscript presents results of original study that was performed as authors own initiative. The authors did not obtain any outside financial support from commercial or other organization to fulfil this research. Authors stated absence of any conflict of interest concerning current study. The obtained results can be used for grounding of research proposals in future. Data sharing statement: No additional data are available. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Correspondence to: Andriy Noshchenko, PhD, Department of Orthopaedics, University of Colorado Anschutz Medical Campus, E. 17 th Place, Mail Stop F432, Aurora, CO 80045, United States. andriy.noshchenko@ucdenver.edu Telephone: Fax: Received: February 7, 2015 Peer-review started: February 8, 2015 First decision: April 10, 2015 Revised: May 27, 2015 Accepted: June 9, 2015 Article in press: June 11, 2015 Published online: August 18, 2015 Abstract AIM: To evaluate published data on the predictors of progressive adolescent idiopathic scoliosis (AIS) in order to evaluate their efficacy and level of evidence. METHODS: Selection criteria: (1) study design: randomized controlled clinical trials, prospective cohort studies and case series, retrospective comparative and none comparative studies; (2) participants: adolescents with AIS aged from 10 to 20 years; and (3) treatment: observation, bracing, and other. Search method: Ovid MEDLINE, Embase, the Cochrane Library, PubMed WJO 537

40 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Description of the methods being investigated Currently, clinical criteria and features cannot adeand patent data bases. All years through August 2014 were included. Data were collected that showed an association between the studied characteristics and the progression of AIS or the severity of the spine deformity. Odds ratio (OR), sensitivity, specificity, positive and negative predictive values were also collected. A metaanalysis was performed to evaluate the pooled OR and predictive values, if more than 1 study presented a result. The GRADE approach was applied to evaluate the level of evidence. RESULTS: The review included 25 studies. All studies showed statistically significant or borderline association between severity or progression of AIS with the following characteristics: (1) An increase of the Cobb angle or axial rotation during brace treatment; (2) decrease of the rib-vertebral angle at the apical level of the convex side during brace treatment; (3) initial Cobb angle severity (> 25 o ); (4) osteopenia; (5) patient age < 13 years at diagnosis; (6) premenarche status; (7) skeletal immaturity; (8) thoracic deformity; (9) brain stem vestibular dysfunction; and (10) multiple indices combining radiographic, demographic, and physiologic characteristics. Single nucleotide polymorphisms of the following genes: (1) calmodulin 1; (2) estrogen receptor 1; (3) tryptophan hydroxylase 1; (3) insulin-like growth factor 1; (5) neurotrophin 3; (6) interleukin-17 receptor C; (7) melatonin receptor 1B, and (8) ScoliScore test. Other predictors included: (1) impairment of melatonin signaling in osteoblasts and peripheral blood mononuclear cells (PBMC); (2) G-protein signaling dysfunction in PBMC; and (3) the level of platelet calmodulin. However, predictive values of all these findings were limited, and the levels of evidence were low. The pooled result of brace treatment outcomes demonstrated that around 27% of patents with AIS experienced exacerbation of the spine deformity during or after brace treatment, and 15% required surgical correction. However, the level of evidence is also low due to the limitations of the included studies. CONCLUSION: This review did not reveal any methods for the prediction of progression in AIS that could be recommended for clinical use as diagnostic criteria. Key words: Orthopedics; Scoliosis; Adolescent idiopathic scoliosis; Spine deformity; Predictors The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: The systematic review with meta-analysis was performed for combining the published data on the predictors of progressive adolescent idiopathic scoliosis (AIS). Comprehensive literature search revealed 1391 citations, 25 of which were selected. All studies showed statistically significant or borderline association between severity or progression of AIS with the different characteristics such as: clinical, radiographic, physiologic, biochemical, genetic, and combinatorial. However, predictive values of all these findings were limited, and the levels of evidence were low. Current study did not reveal any methods for the prediction of progression in AIS that could be recommended for clinical use as diagnostic criteria. Noshchenko A, Hoffecker L, Lindley EM, Burger EL, Cain CMJ, Patel VV, Bradford AP. Predictors of spine deformity progression in adolescent idiopathic scoliosis: A systematic review with metaanalysis. World J Orthop 2015; 6(7): Available from: URL: DOI: INTRODUCTION Description of the problem Adolescent idiopathic scoliosis (AIS) is the most prevalent form of spinal deformity, accounting for 80% of pediatric scoliosis and impacts 2%-4% of children during their pubertal growth spurt [1,2]. The disease affects girls predominantly and is defined by a lateral spinal curvature with a rotational component, lacking a known neuromuscular cause or genetic origin, typically diagnosed between age 10 and 16, prior to skeletal maturity [3,4]. The total number of AIS patients in the United States is estimated at more than 4 million with approximately 1 million children exhibiting some degree of spinal deformity [1,5]. Progressive scoliosis may result in cosmetic deformity, back pain and functional deficits, psychological problems and impaired social interactions [6,7]. Severe cases are associated with cardiac dysfunction and pulmonary constraints [8-10]. Treatment of AIS is largely pragmatic and includes orthotic braces and physiotherapy, as well as surgical interventions to arrest curve progression, correct the deformity, and limit pain and functional deprivations [2,11]. Epidemiologic studies showed that among adolescents initially diagnosed with mild AIS, curve progression occurs in 10%-15%, while 22%-27% demonstrate spontaneous improvement [1,12-14]. A recent prospective multicenter randomized clinical trial has demonstrated that bracetreatment allows the prevention of severe deformity before maturity in 72% of adolescents with initial curvatures of degrees, while 28% experienced exacerbation of the curvature to more than 50 degrees necessitating surgical correction. In the observational group without brace treatment the rate of severe progression reached 52% [15]. Approximately surgeries to correct AIS spine deformities are performed annually in the United States [16]. The current standard of care suggests that spine deformities that exceed 45 degrees are an indication for surgical correction. Such deformities are typically associated with significant wedging of vertebral bodies and intervertebral discs requiring surgical intervention [11,14,17,18]. WJO 538

41 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis quately predict which children, diagnosed with mild disease, will undergo subsequent curve progression requiring intervention. Research findings during the last two decades suggest that the etiology of AIS is likely multifactorial [19]. Epidemiologic studies demonstrated that a single nucleotide polymorphism (SNP) at different chromosomal loci and possible susceptibility genes have an association with AIS with the following dysfunctions: connective tissue structural abnormalities [20-23], calcium and bone metabolism dysfunctions [24-26], and disorders in hormonal and growth factors signaling [27-30]. However, these studies indicate that AIS is a complex genetic disorder likely determined by different patterns of genes SNPs [19]. The functional role of these different genetic patterns in the pathogenesis and progression of AIS remains to be established. Axial Biotechnology has developed a ScoliScore test focused on identifying subjects with a low risk of curve progression in AIS, using a panel of 53 SNPs [31,32]. The prognostic test was validated retrospectively using AIS cases of known outcome [33], but its applicability to clinical practice remains to be proven [34]. Moreover, due to ethnic variations in the frequency of SNP markers, the test is only valid for white subjects and is not applicable to Hispanic, Asian or African American patients [33,35]. Some clinical and radiographic symptoms are associated with progression of spine deformity: thoracic and double or multiple thoracolumbar curves, occurrence of spine deformity prior to onset of menses, curve magnitude (Cobb angle 25 o ) at first presentation and delay in bone maturation [14,36-38]. Severe curves are also associated with wedging of an intervertebral disc and adjacent vertebrae body [11,14,17,39], and longitudinal overgrowth of vertebral bodies by endochondral ossification [40,41]. However, attempts to use these indices as prognostic indicators of curve progression showed low sensitivity (Sn) and specificity (Sp), with a high number of both false positive and false negative results [38]. Dysfunctional melatonin signaling was reported as a potentially informative index for prognosis of curve progression in scoliosis [16,42-44]. Calmodulin (CaM) has also been implicated in the pathogenesis of AIS [45-48]. However, the level of evidence in these studies was not defined, and the prognostic value and applicability of these characteristics, to clinical use, remain unclear. How these methods might work The ability to differentiate patients with a high risk of curve progression from those who do not have such risk or have high likelihood of spontaneous improvement at an early stage of their disease, could allow for optimal individualized treatment strategy, in particular, for less invasive surgical interventions in skeletally immature patients, reduced risk of complications and better treatment outcomes [2]. Theoretically, different clinical, radiographic and laboratory tests can be used for this purpose, if we can define the individual and/or combinatorial prognostic value of each index. The most valuable prognostic characteristics that have clinical implications are Sn, Sp and positive and negative predictive values. Why it is important to do this review Although AIS has been around for many years we have not advanced significantly in our ability to predict the outcome at first diagnosis. Despite contemporary methods, the follow up of AIS still consists of repeated visits with radiological imaging. Until the curve shows certain signs of progression we have no reliable method to predict the severity at the first presentation. Just because we can develop an index that shows a statistically significant difference between progressive and nonprogressive curves in AIS, it does not necessarily mean that this index has a high predictive value. Theoretically, to be helpful for making a rational evidence based decision for early preventive surgery, a predictor should have at least the following predictive values: Sn 95%; Sp 95%; positive predictive value (+PV) 95%; and negative predictive value (-PV) 95% and the corresponding odds ratio (OR) between progressive and non-progressive curves should exceed 100 with a P value The level of evidence should be strong or at least moderate allowing for the development of medical recommendations that can be applied in clinical practice. Previous reviews in this field were mainly narrative, and did not undertake an evaluation of predictive values or the evidence level of the reported findings [1,2,19,49-51]. One systematic review with metaanalysis, demonstrated that school screening tests have a low predictive value for spine deformity progression in scoliotic adolescents [52]. A comprehensive review is necessary to summarize the published data in this field, to define how strong is the evidence for selected risk factors for progression of spine deformity in AIS? and assess the applicability of the reported tests to clinical practice. Objectives The current review is focused on combining the published data, focusing on the predictors of progressive AIS, evaluation of their predictive values, and the level of evidence. MATERIALS AND METHODS Criteria for considering studies for this review Types of studies: Studies with the following design were included: randomized controlled trials (RCTs), prospective cohort studies, prospective case series, and retrospective comparative and non-comparative studies. Type of participants: (1) Human subjects; (2) Diagnosis: AIS, initial Cobb angle >10 degree; (3) Age: aged years; (4) Gender: female or male and female; (5) Progression of spine deformity; and (6) Follow-up: > 0.3 year. WJO 539

42 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Table 1 Ovid medline search strategy: Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE, Daily and Ovid OLDMEDLINE No. Search syntax 1 Adolescent idiopathic scoliosis.ab,ti. 2 (AIS and scoliosis).ab,ti. 3 Scoliosis/ and (exp adolescent/ or exp child/) 4 Or/1-3 5 Curve progression.ab,ti. 6 Disease susceptibility.ab,ti. 7 Prediction.ab,ti. 8 Disease progression.ab,ti. 9 Exp disease progression/ 10 Disease susceptibility/ 11 Predictive value of tests / 12 Exp decision support techniques/ 13 Or/ Scoliosis/ra 15 (Ogilvie JW or Ward K*).au. and scoliosis.ab,ti. 16 Scoliscore.mp. 17 Axial biotech.mp. 18 Moreau A*.au. and scoliosis.ab,ti and and Or/ (genetic adj2 test*).ab,ti. 23 Genetic predisposition.ab,ti. 24 Single nucleotide polymorphism.ab,ti. Or (SNP and polymorphism).ab,ti. 25 Genetic Testing/ 26 Exp genetic predisposition to disease/ 27 Polymorphism, single nucleotide/ 28 Or/ and or 29 Type of intervention: Observation, conservative treatment by bracing and/or physiotherapy, or surgery. Exclusion criteria: (1) Neuro-axial abnormalities; (2) Juvenile/infantile onset curves; (3) Neuromuscular disorders; (4) Kyphotic deformities (Scheuermann s); and (5) Other musculoskeletal disease leading to deformity. Type of outcome measure Primary outcomes: (1) Method(s) of progressive AIS prediction including the following predictive values: Sn (%); Sp (%); positive prediction value (%); negative prediction value (%); (2) Characteristics that describe correlation/association between the studied parameters and progressive AIS, or severity of spine deformity including: OR; rate ratio; rate or number of correct predictions; correlation coefficient, and P-value; and (3) Characteristics that describe the difference between progressive and none progressive cases, or severe and mild AIS cases including: mean; standard deviation; standard error of the mean; 95%CI; and corresponding P values. Secondary outcomes: (1) Fraction of AIS patients with curve progression after bracing; and (2) Fraction of AIS patients who required surgical correction during or after bracing. Search methods for identification of studies Electronic searches: Studies and relevant publications were identified using the both bibliographic and patent databases. The bibliographic resources included: Ovid MEDLINE (1946-current), Embase via Embase.com (1980-current), and the databases of the Cochrane Library via the Wiley platform, Database of Systematic Reviews, Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects, Methodology Register, and Technology Assessment Database. No year limits were applied, therefore the review included all years through August No language or types of publication limits were applied. The search strategies were based on the concepts of AIS, curve progression, prediction, disease progression, disease susceptibility, predictive value of tests, genetic testing, SNP, and genetic predisposition with multiple subject headings (MeSH and Emtree), and text words to describe each concept, (see Table 1 for the MEDLINE search strategy). From the total retrieval, we identified systematic reviews including meta-analyses and controlled trials. The patent search involved the online databases of the United States Patent and Trademark Office (AppFT and PatFT), the European Patent Office (Espacenet), the Japanese Patent Office (PAJ), and the World Intellectual Property Organization. English language textwords were used to search these databases: the terms scoliosis and AIS, combined with terms such as prediction, predisposition, progression, and markers (e.g., scoliosis AND predisposition). These searches were performed by a University of Colorado Health Sciences Library research Librarian (LH). Searching other resources: A manual search of reference lists of review articles and any revisions was also performed to identify studies potentially eligible for our review. Data collection and analysis Two reviewers (Burger EL, Noshchenko A) screened the titles, abstracts, and when necessary full texts, to determine potentially eligible studies. Full text reports of selected studies were then analyzed by the two reviewers (EB and AN). Disagreements regarding inclusion were resolved by discussion. Excluded studies were listed with the reason for exclusion. Data extraction and management: Data were extracted from the included studies by one reviewer (Noshchenko A) and checked by another (Burger EL). The following data were collected: (1) general information including: authors, title, publication status, year of publication, country, study design, sponsorship, and study objectives; (2) participants: inclusion and exclusion criteria (age, gender, type of spine deformity, WJO 540

43 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Risser sign, initial Cobb angle), number of participants in study groups, criteria of spine deformity progression; (3) trial characteristics: length of follow-up, dropout rate, randomization (if applicable), allocation concealment and blinding of assessors if applicable; (4) method of the spine deformity prediction, or differentiation between severe and mild deformities; and (5) characteristics of the prediction efficiency shown above. Assessment of risk of bias in included studies The risk of bias for each study included in the review was defined independently by two reviewers (Burger EL and Noshchenko A) taking into consideration the study design, and Cochrane Back Review Group recommendations for randomized clinical trials [53] modified for observational studies and goals of the current review [54]. Agreement between the two independent assessments was defined by Kappa test. Disagreements were resolved by discussion. Measures of studied effects OR, Sn, Sp, positive predictive values, and negative predictive values of studied characteristics were collected and analyzed. If authors of the selected studies did not calculate these parameters but presented primary data that allowed such calculations, we did that. If authors reported only mean values of studied characteristics in groups with progressive and none progressive AIS with corresponding indices of variability such as standard deviation, standard error of the mean, or 95% confident intervals with number of participants in each group, the data were binarized, assuming that distribution in each group was normal, Z-score probability was applied [55], and the average between means in studied groups was used as cut off value for both groups. Then, OR and predictive characteristics were approximated using a standard 2 2 table. Dealing with missing data Studies with a dropout rate of more than 30% as well as those that did not report this information were classified as having risk of attrition bias; this was taken into consideration during the level of evidence evaluation. Data synthesis A Meta-analysis was performed, if it was applicable. An inverse-variance method was used for combining the data across studies. Pooled OR and predictive characteristics with 95%CI were calculated. To summarize the data, a random-effect model was applied. The GRADE approach was used to evaluate the quality of the revealed evidence [53,56]. Grouping analysis was performed to assess the impact of potentially confounding factors and compare predictive values of different indices. The random effect modeling was applied in each group. Assessment of heterogeneity Statistical heterogeneity of the pooled data was defined by χ 2 test (P < 0.05 represented heterogeneity) and I 2 tests with the following interpretation of heterogeneity: less than 30% = low; 30% to 60% = moderate, greater than 60% = high [57]. Assessment of publication bias Funnel plots were used to evaluate the risk of publication bias [57]. Sn analysis Sn analysis was performed by extracting studies that showed results exceeding 95% confidence limits of the pooled result. Meta-analysis was performed by a qualified biostatistician (Noshchenko A) using special program: Comprehensive Meta Analysis Version (BIOSTAT, Englewood, NJ07631, United States; RESULTS Description of studies Electronic searches provided a total of 1391 citations and 21 were identified from other sources. After adjusting for duplicates, 1120 remained and were screened. Of these, 1054 were discarded because they did not meet the study criteria. The complete text of the remaining 66 publications was studied and 41 (Table 2) did not meet all of the inclusion criteria, leaving 25 studies that were included in the systematic review and meta-analysis, Figure 1. Included studies Twenty five studies selected for the review were published as full-text articles in English and were conducted in the following countries: the United States (4) [46,47,58,59] ; Canada (4) [16,44,60,61] ; Sweden (2) [62,63] ; Netherlands (1) [64] ; China (8) [65-72] ; Hong Kong (3) [73-75] ; Japan (1) [76] ; Singapore (1) [36] ; and South Korea (1) [77] ; Table 3. The search revealed no randomized controlled clinical trials meeting the inclusion criteria. Ten studies were nonrcts: 5 compared the treatment effect of bracing vs observation [46,47,60,63,74] ; 1 bracing with electrical stimulation vs observation [62] ; 2 studies examined differences between patients with severe AIS who underwent surgical correction and healthy controls [44,71] ; and 2 studies compared patients with different severity of spine deformity [58,61]. Eight retrospective case series studied the treatment effect of bracing [59,66,70,73,77], and 1 presented results of observation [75]. Three prospective case series reported the results of observation [16,36,65] ; and 3 case series did not specify the treatment of their participants [64,72,76]. Fourteen studies enrolled patients with thoracic or thoracolumbar spine deformities [44,46,47,62-67,69-71,73,77] ; 1 study enrolled patients with a genetic predisposition to AIS but without clinical scoliosis (Cobb angle < 10 o ) [16] ; and 10 studies did not specify the type of spine deformity in the enrolled patients [36,58-61,68,72,74-76]. WJO 541

44 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Table 2 Excluded publications No. Excluded publications 1 Buchan JG, Alvarado DM, Haller GE, Cruchaga C, Harms MB, Zhang T, Willing MC, Grange DK, Braverman AC, Miller NH, Morcuende JA, Tang NL, Lam TP, Ng BK, Cheng JC, Dobbs MB, Gurnett CA. Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. Hum Mol Genet 2014; 23: Danielsson AJ, Nachemson AL. Radiologic findings and curve progression 22 years after treatment for adolescent idiopathic scoliosis: comparison of brace and surgical treatment with matching control group of straight individuals. Spine (Phila Pa 1976) 2001; 26: Grauers A, Danielsson A, Karlsson M, Gerdhem P: Familial heredity of idiopathic scoliosis unrelated to age at diagnosis and prognosis. Eur Spine J 2012; 21: S314 4 Inoue M, Minami S, Nakata Y, Kitahara H, Otsuka Y, Isobe K, Takaso M, Tokunaga M, Nishikawa S, Maruta T, Moriya H. Association between estrogen receptor gene polymorphisms and curve severity of idiopathic scoliosis. Spine (Phila Pa 1976) 2002; 27: Lonstein JE, Carlson JM. The prediction of curve progression in untreated idiopathic scoliosis during growth. J Bone Joint Surg Am 1984; 66: Lowe TG, Burwell RG, Dangerfield PH. Platelet calmodulin levels in adolescent idiopathic scoliosis (AIS): can they predict curve progression and severity? Summary of an electronic focus group debate of the IBSE. Eur Spine J 2004; 13: Machida M, Dubousset J, Yamada T, Kimura J. Serum melatonin levels in adolescent idiopathic scoliosis prediction and prevention for curve progression--a prospective study. J Pineal Res 2009; 46: Miyake A, Kou I, Takahashi Y, Johnson TA, Ogura Y, Dai J, Qiu X, Takahashi A, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Kubo M, Tsunoda T, Watanabe K, Chiba K, Toyama Y, Qiu Y, Matsumoto M, Ikegawa S. Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3. PLoS One 2013; 8: e Nault ML, Mac-Thiong JM, Roy-Beaudry M, deguise J, Labelle H, Parent S. Three-dimensional spine parameters can differentiate between progressive and nonprogressive patients with AIS at the initial visit: a retrospective analysis. J Pediatr Orthop 2013; 33: Nault ML, Mac-Thiong JM, Roy-Beaudry M, Turgeon I, de Guise J, Labelle H, Parent S: Three-Dimensional Spinal Morphology can Differentiate Between Progressive and Non-Progressive Patients With Adolescent Idiopathic Scoliosis at the Initial Presentation. Spine (Phila Pa 1976) Ogilvie JW. Update on prognostic genetic testing in adolescent idiopathic scoliosis (AIS). J Pediatr Orthop 2011; 31: S46-S48 12 Ogura Y, Takahashi Y, Kou I, Nakajima M, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Yonezawa I, Tsuji T, Suzuki T, Sudo H, Kotani T, Watanabe K, Chiba K, Toyama Y, Matsumoto M, Ikegawa S. A replication study for association of 5 single nucleotide polymorphisms with curve progression of adolescent idiopathic scoliosis in Japanese patients. Spine (Phila Pa 1976) 2013; 38: Ogura Y, Takahashi Y, Kou I, Nakajima M, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Yonezawa I, Tsuji T, Suzuki T, Sudo H, Kotani T, Watanabe K, Chiba K, Toyama Y, Matsumoto M, Ikegawa S. A replication study for association of 53 single nucleotide polymorphisms in a scoliosis prognostic test with progression of adolescent idiopathic scoliosis in Japanese. Spine (Phila Pa 1976) 2013; 38: Patten SA, Moldovan F. Could genetic determinants of inner ear anomalies be a factor for the development of idiopathic scoliosis? Med Hypotheses 2011; 76: Peng Y, Liang G, Pei Y, Ye W, Liang A, Su P. Genomic polymorphisms of G-protein estrogen receptor 1 are associated with severity of adolescent idiopathic scoliosis. Int Orthop 2012; 36: Qiu XS, Tang NL, Yeung HY, Lee KM, Hung VW, Ng BK, Ma SL, Kwok RH, Qin L, Qiu Y, Cheng JC. Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 2007; 32: Qiu XS, Tang NL, Yeung HY, Qiu Y, Cheng JC. Genetic association study of growth hormone receptor and idiopathic scoliosis. Clin Orthop Relat Res 2007; 462: Roye BD, Wright ML, Williams BA, Matsumoto H, Corona J, Hyman JE, Roye DP, Vitale MG. Does ScoliScore provide more information than traditional clinical estimates of curve progression? Spine (Phila Pa 1976) 2012; 37: Sanders JO, Khoury JG, Kishan S, Browne RH, Mooney JF, Arnold KD, McConnell SJ, Bauman JA, Finegold DN. Predicting scoliosis progression from skeletal maturity: a simplified classification during adolescence. J Bone Joint Surg Am 2008; 90: Soucacos PN, Zacharis K, Gelalis J, Soultanis K, Kalos N, Beris A, Xenakis T, Johnson EO. Assessment of curve progression in idiopathic scoliosis. Eur Spine J 1998; 7: Soucacos PN, Zacharis K, Soultanis K, Gelalis J, Xenakis T, Beris AE. Risk factors for idiopathic scoliosis: review of a 6-year prospective study. Orthopedics 2000; 23: Stokes IA, Aronsson DD. Disc and vertebral wedging in patients with progressive scoliosis. J Spinal Disord 2001; 14: Sun X, Qiu Y, Zhu Z, Zhu F, Wang B, Yu Y, Qian B. Variations of the position of the cerebellar tonsil in idiopathic scoliotic adolescents with a cobb angle & gt; 40 degrees: a magnetic resonance imaging study. Spine (Phila Pa 1976) 2007; 32: Sun X, Zhu ZZ, Qiu Y, Wang B, Li WG, Zhu F, Yu Y, Qian BP, Ma WW. [The role of initial bone mineral status in predicting the early outcome of brace treatment in girls with adolescent idiopathic scoliosis]. Zhonghua Waike Zazhi 2008; 46: Takahashi Y, Kou I, Takahashi A, Johnson TA, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Tsuji T, Suzuki T, Sudo H, Kotani T, Watanabe K, Chiba K, Hosono N, Kamatani N, Tsunoda T, Toyama Y, Kubo M, Matsumoto M, Ikegawa S. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet 2011; 43: Takahashi Y, Matsumoto M, Karasugi T, Watanabe K, Chiba K, Kawakami N, Tsuji T, Uno K, Suzuki T, Ito M, Sudo H, Minami S, Kotani T, Kono K, Yanagida H, Taneichi H, Takahashi A, Toyama Y, Ikegawa S. Lack of association between adolescent idiopathic scoliosis and previously reported single nucleotide polymorphisms in MATN1, MTNR1B, TPH1, and IGF1 in a Japanese population. J Orthop Res 2011; 29: Takahashi Y, Matsumoto M, Karasugi T, Watanabe K, Chiba K, Kawakami N, Tsuji T, Uno K, Suzuki T, Ito M, Sudo H, Minami S, Kotani T, Kono K, Yanagida H, Taneichi H, Takahashi A, Toyama Y, Ikegawa S. Replication study of the association between adolescent idiopathic scoliosis and two estrogen receptor genes. J Orthop Res 2011; 29: Tang NL, Yeung HY, Hung VW, Di Liao C, Lam TP, Yeung HM, Lee KM, Ng BK, Cheng JC. Genetic epidemiology and heritability of AIS: A study of 415 Chinese female patients. J Orthop Res 2012; 30: Vijvermans V, Fabry G, Nijs J. Factors determining the final outcome of treatment of idiopathic scoliosis with the Boston brace: a longitudinal study. J Pediatr Orthop B 2004; 13: Wiley JW, Thomson JD, Mitchell TM, Smith BG, Banta JV. Effectiveness of the boston brace in treatment of large curves in adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 2000; 25: WJO 542

45 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis 31 Wise CA, Gao X, Shoemaker S, Gordon D, Herring JA. Understanding genetic factors in idiopathic scoliosis, a complex disease of childhood. Curr Genomics 2008; 9: Wu H, Ronsky JL, Cheriet F, Harder J, Küpper JC, Zernicke RF. Time series spinal radiographs as prognostic factors for scoliosis and progression of spinal deformities. Eur Spine J 2011; 20: Yamauchi Y, Yamaguchi T, Asaka Y. Prediction of curve progression in idiopathic scoliosis based on initial roentgenograms. A proposal of an equation. Spine (Phila Pa 1976) 1988; 13: Yang T, Jia Q, Guo H, Xu J, Bai Y, Yang K, Luo F, Zhang Z, Hou T. Epidemiological survey of idiopathic scoliosis and sequence alignment analysis of multiple candidate genes. Int Orthop 2012; 36: Yang T, Xu JZ, Jia QZ, Guo H, Luo F, Ye Q, Bai Y. [Comparative analysis of sequence alignment of SH3GL1 gene as a disease candidate gene of adolescent idiopathic scoliosis]. Zhonghua Waike Zazhi 2010; 48: Yang Y, Wu Z, Zhao T, Wang H, Zhao D, Zhang J, Wang Y, Ding Y, Qiu G. Adolescent idiopathic scoliosis and the single-nucleotide polymorphism of the growth hormone receptor and IGF-1 genes. Orthopedics 2009; 32: Ylikoski M. Spinal growth and progression of adolescent idiopathic scoliosis. Eur Spine J 1993; 1: Ylikoski M. Growth and progression of adolescent idiopathic scoliosis in girls. J Pediatr Orthop B 2005; 14: Yu Ws, Chan Ky, Yu FWP, Yeung Hy, Ng BKW, Lee Km, Lam Tp, Cheng JCY: Abnormal bone quality versus low bone mineral density in adolescent idiopathic scoliosis: a case-control study with in vivo high-resolution peripheral quantitative computed tomography. Spine Journal Zhang HQ, Lu SJ, Tang MX, Chen LQ, Liu SH, Guo CF, Wang XY, Chen J, Xie L. Association of estrogen receptor beta gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 2009; 34: Zhao D, Qiu GX, Wang YP, Zhang JG, Shen JX, Wu ZH, Wang H. Association of calmodulin1 gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Orthop Surg 2009; 1: Number of records identified through Ovid Medline, Embase and the Cochrane Library search: 1391 Number of additional records identified through patent data bases and other sources: 21 Number of records after duplicates removed: 1120 Number of records screened by title and abstract: 1120 Number of records excluded: 1054 Number of full-text articles assessed for eligibility: 66 Number of full-text articles excluded with reason not meeting all inclusion criteria: 41 Number of studies included in qualitative synthesis: 25 Number of studies included in qualitative synthesis (meta-analysis): 25 Figure 1 Flow diagram. All included studies enrolled participants with an age range from 10 to 20 years, 9 included female only [62,6 3,65-67,72,74-76], 13 included both sexes with a prevalence of females [16,36,44,46,47,58-60,64,68,70,71,77], and 3 did not report the gender of the participants [61,69,73]. The initial Cobb angle varied from 5 to 100 degrees (Table 3). The following criteria for progressive scoliosis were used: increase in the Cobb angle and/or vertebral rotation of more than 4 o -10 o during the observation period, 12 studies [16,47,60,62-65,69,73,74,77] ; Cobb angle exceeding 30 o, 3 studies [36,68,71] ; Cobb angle exceeding 40 o[58] or 45 o[59,61,67], 4 studies; a combination of different criteria including increase of Cobb angle and/or surgical correction, 3 studies [46,66,70] ; and 3 studies did not specify criteria for spine deformity progression [44,72,75]. The follow-up period was reported by 13 studies ranging from 3 mo to 22 WJO 543

46 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Table 3 Selected studies Ref. Study design Publication Spine deformity Age (mean/ range) Gender n Treatment Initial Cobb angle (degree) Follow-up Drop out Progression of deformity criteria Upadhyay et al [73] RCS Art. Thoracic, thoracolumbar, lumbar < 18 Risser sign 2 NS 85 Brace Until skeletal maturity or surgical tretment NS Cobb increasing 5 o, and/or vertebral rotation 5 o Peterson et al [62] PChS Art. Thoracic, thoracolumbar F (100%) 159 Observation (120) Electrical stimulation (39) Until skeletal maturity NS Cobb increasing 6 o Ajemba et al [60] RChS Art. NS 12.3 (10-15) F (87%) M (14%) 44 Observation (30) Brace (14) yr - skeletal maturity NS Cobb increasing 5 o 1 Cheung et al [64] PCS Art. Right thoracic F (87%) M (13%) 30 NS mo NS Cobb increasing >10 o 1 Danielsson PChS Art. Thoracic, et al [63] Thoracolumbar (skeletal) F (100%) 92 Observation Brace and electrical stimulation yr 14% Cobb increasing 6 o Kindsfater et al [46] RCS Art. Thoracic, thoracolumbar F (71%) M (29%) 17 Observation (7) Brace (10) 34 (15-90) < 1 yr NS Cobb > 30 o ; Increasing > 10 o /yr Analysis/ Method of prediction Indices used Comparative analysis of progress vs stable cases Predictor: Increase of Cobb angle and/or vertebral rotation 5 o at 1-2 mo follow-up during brace treatment Multiple logistic regression modeling 6 multiple support vector classifier models Multiple regression modeling, nomogram Predictors: (1) Risser sign (0-1); (2) Apical level (uperth12); (3) Imbalance (10 mm); and (4) Age Predictors: (1)16 Lenke Rad. Indices; (2)Wrist X-ray; (3) Age; (4) Sex; and (5) Growing index Predictor: (1) Spinal grows velocity ( 11 mm/yr); (2) Paraspinal EMG activity concave/convex 1.3 Rate comparison Predictor: Premenarche at inclusion vs menarche at inclusion Comparative analysis of progress vs stable cases Predictor: Level of platelet calmodulin (ng/μg of protein): progressive ; stable < 1.4 (P = 0.001) Prediction validity (progressive vs stable spine deformities) OR = (95%Cl: ) P < (1) Sensitivity: 39%; (2) Specificity: 98%; (3) +PV: 93%; and (4) -PV: 72% (1) Sensitivity: 81% 2 ; (2) Specificity: 81%; (3) +PV: 82%; and (4) -PV: 80% (1) Sensitivity: 67%-91% 2 ; (2) Specificity: 22%-67%; (3) +PV: 73%-86%; and (4) -PV: 43%-67% (1) Sensitivity: 69%-79% 2 ; (2) Specificity: 69%-79%; and (3) +PV: 60%-89% OR = (95%Cl: ) P = 0.05 (1) Sensitivity: 60%; (2) Specificity: 63%; (3) +PV: 53%; and (4) -PV: 70% OR = (95%Cl: ) P = (1) Sensitivity: 100%; (2) Specificity: 100%; (3) +PV: 100%; and (4) -PV: 100% WJO 544

47 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis 1 Lowe et al [47] PChS Art. King I-V Adolescents F (93%) M (7%) 55 Observation (28) Brace (17) Fusion(10) yr 9.80% Cobb increasing > 10 o /yr Comparative analysis of progress vs stable cases Predictor: Increasing of platelet calmodulin level during first year of observation Sun et al [67] RCS Art. Thoracic, thoracolumbar, lumbar F (100%) 142 Brace yr NS Cobb exceeding 45 o, surgical tretment Multiple logistic regression modeling Predictors: (1) Premenarche; (2) Curve > 30 o ; and (3) Risser sign: Sun et al [66] RCS Art. Thoracic, thoracolumbar Hung et al [65] PCS Art. Thoracic, thoracolumbar, lumbar Lam et al [74] PChS Art. NS F (100%) Chinese population Lee et al [68] RCS Art. NS F (82.3%) M (17.7%) F (100%) 68 Brace mo NS Cobb increasing > 6 o, or exceeding 45 o Comparative analysis of progress vs stable cases Predictors: (1) Premenarche; (2) Curve > 30 o ; (3) L2-L4 BMD < 0.76 g/cm 2 ; and (4) Thoracic curve Multiple Predictors: logistic (1) Age at diagnosis < 13 regression yr; modeling (2) Premenarche; (3) Risser sign: 0-1; (4) Curve pattern: thoracic or thoracolumbar; and (5) Initial Cobb angle > 30 o ; Osteopenia: decreased hip neck BMD at concave side > 10; Mean, 3.4 NS Cobb Multiple Predictors: Mean: 26 yr (St. D, increasing logistic (1)Age at diagnosis (St. D, 8.2 o ) 1.57 o ) > 6 o regression yr, modeling (2) Premenarche; (3) Initial Cobb angle > 25 o ; and (4) Ultrasound bone stiffness index (calcaneus) Z-score 0 Brace (331) NS NS Cobb > 30 o Risk assessment Predictor: Initial Cobb angle 26 o vs F (100%) 324 Observation yr NS Cobb increasing > 6 o, 294 Observation (192), Brace (102) o -10 o Tan et al [36] PCS Art. NS 7-14 F (84.9%) M (15.1%) 186 Observation Brace > yr 18% Cobb 30 o Risk assessment Predictor: Initial Cobb angle 25 o vs < 25 o OR = (95%Cl: ) P = 0.02 (1) Sensitivity: 69%; (2) Specificity: 83%; (3) +PV: 85%; and (4) -PV: 67% OR: P (1) Sensitivity 72%-89% 3 ; (2) Specificity 48%-77%; (3) +PV: 20%-33%; and (4) -PV: 94%- 97% OR: (0.001 > P < 0.072) (1) Sensitivity: 74.5%; (2) Specificity: 64.7% OR: (0.001 > P < 0.044) (1) Sensitivity: 76% (95%Cl: 69-83); (2) Specificity: 70% (95%Cl: 62-77) OR: ( > P < 0.2) (1) Sensitivity: 84.7%; (2) Specificity: 66.5% Hazard ratio, (95%Cl: ) OR = (95%Cl: ) P < (1) Sensitivity: 68% 3 ; (2) Specificity: 92%; (3) +PV: 68%; and (4) -PV: 92% WJO 545

48 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Modi et al [77] RCS Art. Thoracic, thoracolumbar F (84%) M (16%) Qiu et al [69] RCS Art. Thoracic, thoracolumbar Chinese population Xu et al [70] RCS Art. Thoracic, thoracolumbar, lumbar F (87%) M (13%) Yeung et al [75] RCS Art. NS F (100%) Chinese population 1 Ward et al [58] RChS Art. Severe: 8% Moderate/ mild: 92% 9-13 at diagnosis F (100%) F (100%) M (100%) 1 Bohl et al [59] RCS Art NS 10 F (81%) M (19%) 113 Brace Until skeletal maturity (Risser sign 4); average: 34 ± 13 mo NS Cobb increasing 5 o 120 Brace ± 0.35 yr NS Cobb increasing 5 o Comparative analysis of progress vs stable cases Comparative analysis of progress vs stable cases 312 Brace yr NS Cobb increasing 5 o and/or surgical correction Logistic regression modeling 340 Observation > 20 Until skeletal maturity, 16 years old or surgical intervention NS > 10 Till skeletal maturity or severe deformity NS NS Comparative analysis of Cobb angle in following genotypes of IGF1 SNP rs : TT; TC; and CC NS Severe: Cobb > 40 o Moderate: Cobb 25 o -40 o Multiple logistic regression modeling 16 Brace yr after brace discontinuation or skeletal maturity 36% Cobb > 45 o Comparative analysis: patients with Cobb > 45 o vs Cobb < 45 o logistic regression modeling Predictor: Rib-vertebral angle at convex side of the curve apex after brace treatment (< 65 o vs 65 o ) Predictor: NTF3 gene: rs , genotype GG vs AA Predictors: (1) ERα gene: rs , allele G; (2) TPH1 gene: rs , allele A; (3) Risser sign O-1; and (4) Curve 30 o Predictor: TT (mean Cobb, 38 ± 12.1, n = 169) vs CC (mean Cobb, 33 o ± 9.0, n = 33), P = 0.01 Cut-point: Cobb, 35.7 o Predictor: Scale (1-200 ) based on 53 SNP markers; cut point, 40: 1-40 ( 1% risk of progression) Predictor: Scale (1-200 ) based on 53 SNP markers and initial Cobb angle: cut-point, 160: (high risk of curve progression with Cobb > 45 o ) vs < 160 (low risk of curve progression with Cobb > 45 o ) OR = (95%Cl: ) P < (1) Sensitivity: 45%; (2) Specificity: 87%; (3) +PV: 69%; and (4) -PV: 71% OR = (95%Cl: ) P = 0.08 (1) Sensitivity: 43%; (2) Specificity: 82%; (3) +PV: 56%; and (4) -PV: 72% OR: > P < 0.1 (1) Sensitivity: 51%; (2) Specificity: 82%; and (3) Correct predictions: 75% OR = (95%Cl: ) P = 0.1 (1) Sensitivity: 88%; (2) Specificity: 22%; (3) +PV: 57%; and (4) -PV: 61% OR= (95%Cl: ) P < (1) Sensitivity: 91%; (2) Specificity: 63%; (3) +PV: 17%; and (4) -PV: 99% OR = (95%Cl: ) P = 0.05 (1) Sensitivity: 78%; (2) Specificity: 86%; (3) +PV: 88%; and (4) -PV: 75% WJO 546

49 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Zhao et al [71] RChS Art Double curves: thoracic, thoracolumbar or lumbar Cases (AIS): F (90%) M (10%) Controls: F (75%) M (25%) Chinese population Zhou et al [72] RCS Art. NS F (100%) Chinese population Surgical correction 241 NS Until skeletal maturity NS NS Cobb 30 o Comparative analysis of cases vs healthy controls 54% NS Comparative analysis of severe cases (mean Cobb, 36 o ± 13 o ) vs moderate cases (mean Cobb, 29 o Moreau et al [44] RChS Art. Thoracic, thoracolumbar, lumbar Akoume et al [16] PCS Art Asymptomatic subjects at-risk of AIS Cases (AIS): F (83%) M (17%) Controls: F (65%) M (35%) 5-15 F (65%) M (35%) Akoume et al [61] RChS Art NS NS NS Surgical correction ± 7.4 o ) NS NS NS Comparative analysis of AIS cases (mean Cobb, 54 o ± 14 o ) vs controls (non- idiopathic deformities) 31 Observation 10 2 yr NS Cobb > 10 o Comparative analysis of cases with developed AIS spine deformity (mean Cobb, > 10 o ) vs subjects at risk, but without deformity NS NS NS NS Cobb angle 45 o Cobb angle 10 o -44 o Comparative analysis of the G proteins functional status Predictors: (1) ER1 gene: rs , allele T; (2) CALM 1 gene: rs , allele T Predictor: Il-17RC gene: rs708567, genotype GG, Cut-point: Cobb angle, 32.5 o Predictor: low inhibition of forskolin stimulated camp by melatonin in osteoblasts vs significant inhibition of forskolin stimulated camp by melatonin in osteoblasts Predictor: peripheral blood mononuclear cells electrical impedance after melatonin or iodomelatonin administration: < 120 ohms vs 120 o homs Predictor: type of peripheral blood mononuclear cells G protein response to electrical stimulation: FG2 vs FG1 or FG3 OR: > P < 0.05 (1) Sensitivity: 28%-69%; (2) Specificity: 44%-82%; (3) +PV: 45%-51%; and (4) -PV: 63%-68% OR = (95%Cl: ) P = (1) Sensitivity: 94%; (2) Specificity: 17%; (3) +PV: 60%; and (4) -PV: 69% OR=3.9 3 (95%Cl: ) P = 0.3 (1) Sensitivity: 20%; (2) Specificity: 94%; (3) +PV: 89%; and (4) -PV: 33% OR = (95%Cl: ) P = 0.03 (1) Sensitivity: 33%; (2) Specificity: 100%; (3) +PV: 100%; and (4) -PV: 70% OR = (95%Cl: ) P < (1) Sensitivity: 26%; (2) Specificity: 88%; (3) +PV: 56%; and (4) -PV: 67% WJO 547

50 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Yamamoto et al [76] RCS Art. NS 9-15 F (100%) 28 Analysis of curve history yr NS Cobb increasing > 4 o Comparative analysis of progressive cases vs stable Predictor: Brain stem function, abnormal vestibular-eye test vs normal OR = (95%Cl: ) P = (1) Sensitivity: 91%; (2) Specificity: 71%; (3) +PV: 67%; and (4) -PV: 92% 1 Study used industrial or other sponsorship; 2 Predictive characteristics reported in the collected publication; 3 Predictive characteristics calculated by authors of current review using extracted results. PChS: Prospective cohort study; RChS: Retrospective cohort study; PCS: Prospective case series; RCS: Retrospective case series; +PV: Positive predictive value; -PV: Negative predictive value; NS: Not specified; EMG: Electromyography; SNP: Single nucleotide polymorphism; NTF3: Neurotropin-3; IGF1: Insulin-like growth factor 1; ERα: Estrogen receptor alpha; Il-17RC: Interleukin 17 receptor C; CALM1: Calmodulin1. years [16,36,46,47,63-67,69,70,74,76]. Eight studies declared that observation was performed until skeletal maturity of participants or surgical intervention [58-60,62,72,73,75,77]. Four studies did not report a follow-up period [44,61,68,71]. The dropout rate was reported by 3 prospective studies ranging from 9.8% to 18% [36,47,63], and by 2 retrospective studies as 36% [59] and 54% [72]. The following main characteristics were reported as having an association with progressive AIS or severe spine deformity: (1) radiographic: increasing of Cobb angle during bracing [73], rib-vertebral angle at the convex side of the curve apex after brace treatment [77], and initial Cobb angle [36,68] ; (2) physiologic: pre-menarche at inclusion [63], electrical activity of the paraspinal muscles (EMG) combined with spinal growth velocity [64], and brain stem dysfunction by vestibular test [76] ; (3) multiple characteristics based on combining different radiographic indices such as: Risser sign, wrist X-ray, apical level of deformity, imbalance, Cobb angle, type of spine deformity, and bone or vertebral mineral density; with physiologic: menarche status, growing index, spinal growth velocity; and demographic: age and gender characteristics [60,62,65-67,74] ; (4) SNPs of different genes [58,59,69-72,75] ; (5) intracellular melatonin signaling dysfunction [16,44] ; (6) Gi and Gs proteins functional status in peripheral blood mononuclear cells (PBMC) [61] ; and (7) levels of platelet CaM [46,47], Table 3. Risk of bias in included studies Two independent bias evaluations demonstrated good agreement (kappa coefficient, 0.85; standard error, 0.05; P = 0.71). Taking into consideration the observational design of the selected studies and revealed limitations, the general quality can be classified as moderate with a score range from 6 to 13 of 14 in 24 studies, and one study had low quality with a score of 2, (Table 4). Two studies did not clearly describe inclusion/exclusion criteria [47,61]. Seven studies failed to identify potential confounders, and did not take them into consideration as selection criteria [47,58,61,71,75-77]. Seventeen studies had retrospective or unclear design [16,44,46,58-61,66-73,75-77]. Three studies did not report on the gender of the participants [61,69,73]. Three studies did not specify criteria for curve progression [44,72,75]. Four studies did not describe the method for measurement of curve progression [47,59,61,76]. Four studies did not follow intention to treat analysis principles [36,47,68,76]. All selected studies did not declare that those who performed data analysis were blinded to the patients clinical outcome. Nine studies did not clearly report on the follow-up period [44,58,59,61,62,68,71,75,77]. Only 5 studies reported dropout rates: ranging from 9.8% to 18%, 3 studies [36,47,63] ; and exceeding 30% in two studies [59,72]. One study had some suggestion of selective outcome reporting [58]. Eleven studies did not take in to consideration the impact of gender during their analysis [16,44,47,61,64,68-71,73,77]. Seven studies used industrial or other financial support [47,58,59,61,63,64,66]. In summary, 80% of the included studies were at risk of selection bias, 100% at risk of detection bias, 24% at risk of performance bias, 60% at risk of reporting bias, and 80% at risk of attrition bias. Primary outcomes Radiographic characteristics: One retrospective study (n = 85) demonstrated that the increase in the Cobb angle and/or vertebral rotation 5 o at 1-2 mo follow-up during brace treatment was associated with further curve progression in skeletally immature patients [73]. In particular, 73% of such patients required surgical correction. Corresponding OR was 33.2 (95%Cl: ; P < 0.001); SN, 39%; SP, 98%; +PV, 93%; and -PV, 72%. Eight studies, 3 prospective [36,65,74] and 5 retrospective [66-68,70,73] reported an association between initial Cobb angle and progressive AIS in 3719 subjects. The criteria of progressive AIS were different: increasing of the Cobb angle more than 5 o or 6 o[65,73,74] ; Cobb angle exceeding 30 o[36,68] ; Cobb angle exceeding 45 o or surgical correction [67,70] ; WJO 548

51 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Table 4 Risk of bias assessment Ref. Questions for evaluation Score Upadhyay et al [73] Yes Yes Unsure No Yes Yes Yes Unsure Yes No Unsure Yes No Yes 8 Peterson et al [62] Yes Yes Yes Yes Yes Yes Yes Unsure No No Unsure Yes Yes Yes 10 Ajemba et al [60] Yes Yes No Yes Yes Yes Yes Unsure Yes No Unsure Yes Yes Yes 10 Cheung et al [64] Yes Yes Yes Yes Yes Yes Yes Unsure Yes No Unsure Yes No Yes 10 Danielsson et al [63] Yes Yes Yes Yes Yes Yes Yes Unsure Yes Yes Yes Yes Yes Yes 13 Kindsfater et al [46] Yes Yes No Yes Yes Yes Yes Unsure Yes No Unsure Yes Yes Yes 10 Lowe et al [47] No No Yes Yes Yes No No Unsure Yes Yes Yes Yes No No 7 Sun et al [67] Yes Yes No Yes Yes Yes Yes Unsure Yes No Unsure Yes Yes Yes 10 Sun et al [66] Yes Yes No Yes Yes Yes Yes Unsure Yes No Unsure Yes Yes Yes 10 Hung et al [65] Yes Yes Yes Yes Yes Yes Yes Unsure Yes No Unsure Yes Yes No 10 Lam et al [74] Yes Yes Yes Yes Yes Yes Yes Unsure Yes No Unsure Yes Yes Yes 11 Lee et al [68] Yes Yes No Yes Yes Yes No Unsure No No Unsure Yes No Yes 7 Tan et al [36] Yes Yes Yes Yes Yes Yes No Unsure Yes Yes Yes Yes Yes Yes 12 Modi et al [77] Yes No No Yes Yes Yes Yes Unsure No No Unsure Yes No No 6 Qiu et al [69] Yes Yes No No Yes Yes Yes Unsure Yes No Unsure Yes No No 7 Xu et al [70] Yes Yes No Yes Yes Yes Yes Unsure Yes No Unsure Yes No Yes 9 Ward et al [58] Yes No No Yes Yes Yes Yes Unsure No No Unsure No Yes Yes 7 Bohl et al [59] Yes Yes No Yes Yes No Yes Unsure No Yes No Yes Yes Yes 9 Zhao et al [71] Yes No Unsure Yes Yes Yes Yes Unsure No No Unsure Yes No Yes 7 Zhou et al [72] Yes Yes No Yes No Yes Yes Unsure Yes Yes No Yes Yes Yes 10 Moreau et al [44] Yes Yes No Yes No Yes Yes Unsure No No Unsure Yes No Yes 7 Akoume et al [16] Yes Yes No Yes Yes Yes Yes Unsure Yes No Unsure Yes No Yes 9 Akoume et al [61] No No No No Yes No Unsure Unsure No No Unsure Yes No No 2 Yamamoto et al [76] Yes No No Yes Yes No No Unsure Yes No Unsure Yes Yes No 6 Yeung et al [75] Yes No No Yes No Yes Yes Unsure No No Unsure Yes Yes Yes 7 Questions for evaluation: (1) Were inclusion/exclusion criteria clearly described? (2) Were confounding factors identified, and taken into consideration as selection criteria? (3) Was study prospective? (4) Were number/rate of male and female enrolled into the study reported? (5) Were criteria of curve progression clearly identified? (6) Was measurement of curve progression clearly described? (7) Were enrolled patients analyzed in the same treatment group (bracing, observation, physiotherapy) to which they were allocated? (8) Was statistician blind to the status of subjects enrolled into the study? (9) Was follow-up period clearly identified? (10) Was drop out rate reported? (11) Was drop out rate acceptable? (< 25%); (12) Are reports of the study free of suggestion of selective outcome reporting? (13) Was impact of gender taken into consideration during analysis? and (14) Was impact of confounding factors taken into consideration during analysis? and using of several criteria [66]. The following cut off values for the initial Cobb angle were applied: 25 o or 26 o, 3 studies [36,68,74] ; and 30 o, 5 studies [65-67,70,73]. All studies showed statistically significant (P < 0.02) associations between a higher initial Cobb angle and a risk of further severe spine deformity. The OR varied from 2.2 to 34.5, the pooled OR was 7.6 (95%Cl: ; P < 0.001; high heterogeneity, I 2 = 79.2%). The grouping analysis did not reveal significant differences between prospective and retrospective studies, or between studies using different cut off values. The pooled prognostic characteristics were low with a lack of statistical significance of +PV: Sn, 69% (95%Cl: 62%-74%; P < 0.001; high heterogeneity, I 2 = 89%); Sp, 73% (95%Cl: 65%-79%; P < 0.001; high heterogeneity, I 2 = 92%); +PV, 62% (95%Cl: 48%-74%; P = 0.096; high heterogeneity, I 2 = 97%); and -PV, 81% (95%Cl: 73%-87%; P < 0.001; high heterogeneity, I 2 = 94%). Four retrospective studies reported an association of curve pattern with progression of spine deformity in 607 AIS patients, in particular thoracic vs thoracolumbar, lumbar, or double [66,67,70,73]. Criteria for progression were Cobb angle increase > 5 o, exceeding 45 o, or surgical correction. All studies demonstrated that cases with thoracic curves showed a higher risk of progression than cases with other types of deformity. The OR ranged from 1.3 to Two studies showed a statistically significant association, P 0.03 [66,67], while 2 others were not significant, 0.1 > P < 0.3 [70,73]. The pooled OR was 2.3 (95%Cl: 1.2; 4.6; P = 0.017; moderate heterogeneity, I 2 = 59%). The pooled prognostic values were low with statistically insignificant Sn and +PV: Sn, 60% (95%Cl: 48%-72%; P = 0.098; high heterogeneity, I 2 = 87%); Sp, 59% (95%Cl: 52%-66%; P = 0.01, high heterogeneity, I 2 = 62%); +PV, 40% (95%Cl: 22%-60%; P = 0.30; high heterogeneity, I 2 = 91%); and -PV, 77% (95%Cl: 66%-86%; P < 0.001; high heterogeneity, I 2 = 85%). Four studies (1 prospective [65] and 3 retrospective [67,70,77] ) reported an association between skeletal maturity by Risser sign and progressive AIS in 1891 subjects. The Risser grade of 1 or 2 was used as a cut off. The criteria of progressive AIS were an increase of Cobb angle > 5 o, Cobb angle > 45 o or surgical correction. The OR ranged from 1.5 to 5.1. Three studies showed a statistically significant association between Risser grade 0-1 and progressive AIS (P 0.01) [65,67,70], while 1 study did not find a significant association of Risser grade 0-2 with progressive AIS (P = 0.3) [77]. The pooled OR was 2.8 (95%Cl: ; P < 0.001, moderate heterogeneity, I 2 = 50%). The WJO 549

52 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis pooled predictive characteristics were relatively low, in particular Sn and +PV showed lack of statistical significance: Sn, 64% (95%Cl: 43%-81%; P = 0.165; high heterogeneity, I 2 = 96%); Sp, 66% (95%Cl: 52%-77%; P = 0.018; high heterogeneity, I 2 = 92%); +PV, 43% (95%Cl: 22%-66%; P = 0.565; high heterogeneity, I 2 = 98%); and -PV, 82% (95%Cl: 60%-93%; P < 0.005; high heterogeneity, I 2 = 97%). One retrospective study (n = 113) revealed that a rib-vertebral angle of less than 65 o at the apical level of the convex side, after a few months of brace treatment, is associated with further curve progression in patients with initial Cobb angle of 40 o to 56 o[77]. The approximated OR was 5.6 (95%Cl: ; P < 0.001). The prognostic values were low: Sn, 45%; Sp, 87%; +PV, 69%; and -PV, 71%. Three studies, 2 prospective [65,74] and 1 retrospective [66], reported an association of osteopenia with progressive AIS in 686 subjects. The criteria of progression were an increase of Cobb angle > 6 o or exceeding 45 o in spite of brace treatment. Two studies used dual energy X-ray absorptiometry to define bone density: one in the femoral neck [65] and one in L2-L5 vertebrae [66]. One study used bone stiffness index by ultrasound in the calcaneus [74]. All 3 studies demonstrated a statistically significant association between markers of osteopenia and progression of spine deformity in AIS. The OR ranged from 2 to 11.3, P The pooled OR was 2.6 (95%Cl: ; P = 0.005; moderate heterogeneity, I 2 = 51%). The pooled prognostic values were low and highly heterogeneous, in particular, the pooled Sp was not statistically significant: Sn, 73.8 (95%Cl: 53.8%-87.2%; P = 0.021; I 2 = 96%); Sp, 62% (95%Cl: 47.4%-74.8%; P = 0.1; I 2 = 93%); +PV, 69% (95%Cl: 56%-78.3%; P = 0.004; I 2 = 90%); -PV, 68% (95%Cl: 55.9%-77.1%; P = 0.003; high heterogeneity, I 2 = 89%). Demographic and physiologic characteristics: Three studies (two prospective [65,74] and one retrospective [67] ) reported results with an association between the age at diagnosis of AIS with a progressive form of the disease in 760 girls. The criteria of progressive AIS were the following: increase of the Cobb angle > 6 o[65,74], and Cobb angle exceeding 45 o or surgical correction [67]. All 3 studies showed that patients < 13 years of age at diagnosis, had a higher risk of curve progression than those who were older, OR ranged from 2.1 to 3.1, P The pooled OR was 2.7 (95%Cl: ; P < 0.001; low heterogeneity, I 2 = 0%). The pooled prognostic values were low and heterogeneous with statistically insignificant Sp and positive prediction value: Sn, 66% (95%Cl: 45%-77%; P = 0.009; high heterogeneity, I 2 = 90%); Sp, 54% (95%Cl: 49%-59%; P = 0.077; moderate heterogeneity, I 2 = 43%); +PV, 45% (95%Cl: 24%-69%; P = 0.705; high heterogeneity, I 2 = 97%); -PV, 73%(95%Cl: 55%-86%; P = 0.013; high heterogeneity, I 2 = 95%). Six studies (3 prospective [63,65,74] and 3 retrospective [66,67,77] ) reported an association between premenarche status at diagnosis and progressive AIS in 980 girls. Five studies enrolled patients with Cobb angle < 40 o [63,65-67,74], and one with Cobb angle 40 o - 56 o[77]. Criteria for progression were different: increase of Cobb angle > 5 o, 4 studies [63,65,74,77] ; Cobb angle exceeding 45 o, 1 study [67] ; and both of these criteria, 1 study [66]. All studies showed that pre-menarche at diagnosis was associated with a higher risk of progressive AIS. The OR ranged from 1.5 to 11.5 and was statistically significant in studies that enrolled patients with Cobb angle < 40 o. The pooled OR was 4.0 (95%Cl: ; P < 0.001; high heterogeneity, I 2 = 64%). Grouping analysis confirmed that studies that enrolled patients with Cobb angle < 40 o, showed significantly (P = 0.023) higher association between pre-menarche status and curve progression than those that enrolled patients with more severe deformity. The pooled predictive values were low and heterogeneous with statistically insignificant positive predictive value: Sn, 60% (95%Cl: 50.7%-67.9%; P = 0.034; high heterogeneity, I 2 = 85%); Sp, 74.3% (95%Cl: 50.7%-67.9%; P = 0.001; high heterogeneity, I 2 = 93%); +PV, 52.3% (95%Cl: 37.8%-66.5%; P = 0.758; high heterogeneity, I 2 = 94%); -PV, 75% (95%Cl: 66.8%-81.5%; P < 0.001; high heterogeneity, I 2 = 89%). One retrospective study reported data showing a significant association between brain stem vestibular dysfunction and spine deformity progression (increase of Cobb angle > 4 o ), in a case series of 28 girls with AIS [76]. Initial Cobb angle ranged from 5 o to 59 o. The OR was 24 (95%Cl: ), P = 0.007; Sn, 91%; Sp, 71%; +PV, 67%; and -PV, 92%. Combining of radiographic, demographic and physiologic characteristics: Seven studies: 4 prospective [62,64,65,74], and 3 retrospective [60,66,67] applied multiple regressions modeling to combine selected radiographic, demographic, and physiological characteristics to generate an index with maximal prognostic value for progressive AIS. These studies enrolled 1057 participants. Five studies included patients with initially mild or moderate spine deformities with Cobb angle ranging from 10 o to 40 o[62,65-67,74] and two studies also included patients with a Cobb angle of > 45 o[60,64]. Criteria for AIS progression were: an increase in Cobb angle of more than 5 o -10 o, 5 studies [60,62,64,65,74] ; Cobb angle exceeding 45 o, one study [67] ; and both criteria, one study [66]. The following radiographic indices were used: skeletal maturity by Risser sign [62,65,67] or wrist X-ray [60] ; different characteristics of curve pattern [60,62,65,66] ; initial Cobb angle [65-67,74] ; imbalance [62] ; spine growth velocity [64] ; and osteopenia by different markers [65,66,74]. Demographic characteristics included age [60,62,65,74], and gender [60]. Physiologic indices included: menarche status [65-67,74] ; growth index [60] ; and asymmetry of the paraspinal muscles electrical activity by electromyography [64]. From 2 to 6 characteristics were combined to generate prognostic indices. All studies showed a high association of developed indices with the AIS progression. The WJO 550

53 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis OR ranged from 4.5 to 24.7 with P 0.1. The pooled OR was 9.6 (95%Cl: ; P < 0.001; moderate heterogeneity, I 2 = 34%). The funnel plot analysis revealed a small publication bias towards overestimation of this association. However, exclusion of two studies with the highest association (OR > 20) from the analysis decreased heterogeneity to low, without a significant change in the pooled OR, 7.2 (95%Cl: ; P < 0.001). The pooled prognostic values were moderate: Sn, 82.1% (95%Cl: 77.4%-86.2%; P < 0.001, high heterogeneity, I 2 = 66%); Sp, 71.1 (95%Cl: 66.9%-76.7%; P < 0.001; high heterogeneity, I 2 = 62%); + PV, 77.2% (95%Cl: 72.9%-81.1%; P < 0.001, moderate heterogeneity, I 2 = 52%); -PV, 81.9% (95%Cl: 74.5%-87.9%; P < 0.001; high heterogeneity, I 2 = 83.4%). SNP of different genes: One retrospective study reported a significant association between estrogen receptor (ER1) gene SNP at locus rs and progressive AIS with severe spine deformity (Cobb angle > 40 o ) and different curve patterns, P < 0.05 [71]. The result was obtained in the Chinese population by analysis of 67 AIS patients and 100 healthy controls. The approximated OR was 1.8 (95%Cl: ); Sn, 69%; Sp, 44%; +PV, 45%; -PV, 68%. Another retrospective study reported significant association between curve progression after brace treatment and estrogen receptor gene (ER1) SNP at locus rs , P < [70]. The result was obtained in 312 AIS patients of the Chinese population. The approximated OR was 2.7 (95%Cl: ); Sn, 27%; Sp, 87%; +PV, 44%; -PV, 76%. One retrospective study showed an association between different forms of progressive AIS and calmodulin 1 (CALM1) gene SNP at locus rs , P = [71]. The result was obtained in 67 AIS patients and 100 healthy controls (Chinese population). The approximated OR was 1.7 (95%Cl: ); Sn, 28%; Sp, 82%; +PV, 51%, -PV, 63%. One retrospective study reported an association between progressive AIS and tryptophan hydroxylase 1 (TPH1) gene SNP at locus rs , P = [70]. The result was obtained in 312 AIS patients treated by brace wearing (Chinese population). The approximated OR was 1.9 (95%Cl: ); Sn, 17%; Sp, 90%, +PV, 38%; -PV, 76% The same study reported an association between progressive AIS and SNP of melatonin receptor 1B gene (MTNR1B) at locus rs with borderline significance, P = The approximated OR was 1.5 (95%Cl: ); Sn, 72%; Sp, 37%, +PV, 29%; -PV, 79%. One retrospective study reported significant association between SNP in the neurotrophin 3 (NTF3) gene promoter at rs locus and curve severity in 362 AIS patients (Chinese population), P = [69]. In particular, patients with AA genotype demonstrated more successful brace treatment than those patients with GG genotype, P = 0.043, the OR was 3.3 (95%Cl: ); Sn, 56%; Sp, 72%; +PV43%; -PV, 82%. One retrospective study reported a significant association between the interleukin-17 receptor C (IL17RC) gene SNP at rs locus and curve severity in 529 Chinese girls with AIS [72]. In particular, skeletally mature patients with GG genotype (n = 215) showed a higher mean Cobb angle (36.0 o ± 13.1 o ) than those patients with AG genotype (n = 26; mean Cobb angle, 28.9 o ± 7.4 o ), P = The approximated OR with Cobb angle cut off 32.5 o was 3.4 (95%Cl: ); Sn, 94%; Sp, 17%; +PV, 60%; -PV, 69%. One retrospective study showed an association between the Insulin-like growth factor 1 (IGF1) gene SNP at rs locus and curve severity in AIS girls with Cobb angle > 20 o (Chinese population) [75]. In particular, patients with TT genotype (n = 169) had mean Cobb angle (38.1 o ± 12.1 o ) higher than those who had TC (n = 138; mean Cobb angle, 35.6 o ± 12.0 o ) or CC (n = 33; mean Cobb angle, 33.3 ± 9.0 o ) genotypes. The approximated OR (TT vs CC, with Cobb angle cut off 35.6 o ) was 2.1 (95%Cl: ; P = 0.1); Sn, 88%; Sp, 22%; +PV, 57%; -PV61%. Two retrospective studies reported an association of a multiple index developed by combining 53 different gene SNPs and initial Cobb angle (ScoliScore test) with non-progressive or progressive AIS [58,59]. OR between the selected SNPs and different forms of the AIS ranged from 0.26 to 1.94 suggesting low association [58]. However, the developed multiple index had a positive correlation with severity of spine deformity ranging from 0 to 200. In particular, one study presented results obtained in 697 Caucasian AIS patients with Cobb angle > 10 o[58]. It was shown that the index value of < 41 is associated with a small spine deformity. Correspondingly, the index values ranged from 40 to 200 showed significant association with severe spine deformity (Cobb angle > 40 o ): OR, 16.8 (95%Cl: ; P < 0.001). However, Sp and positive prediction value of this test were low: Sn, 91%; Sp, 63%; +PV, 17%; -PV, 99%. The second study demonstrated that the index values > 160 associated with severe spine deformity (Cobb angle > 45 o ) in 16 AIS patients with initial Cobb angle 20 o : OR, 21.0 (95%Cl: : P = 0.05); Sn, 78%; Sp, 86%; +PV, 88%; -PV, 75% [59]. The pooled OR was relatively high: 17.2 (95%Cl: ); P < 0.001; low heterogeneity, I 2 = 0%). However, the pooled prognostic characteristics were moderate and highly heterogeneous with statistically insignificant Sp and positive predictive value: Sn, 87.3% (95%Cl: 71.8%-94.9%; P < 0.001; high heterogeneity, I 2 = 79%); Sp, 73.2% (95%Cl: 44.8%-90.2%; P = 0.101; high heterogeneity, I 2 = 70%); +PV, 53.4% (95%Cl: 3.3%-97.4%; P = 0.940; high heterogeneity, I 2 = 96%); -PV, 94.6% (95%Cl: 36.4%-99.8%; P = 0.1; high heterogeneity, I 2 = 97%). Melatonin signaling: Two studies 1 prospective [16] and 1 retrospective [44] reported an association of AIS spine deformity with changes in intracellular melatonin signaling [16,44]. One study demonstrated that a reduced inhibition of forskolin stimulated camp by melatonin WJO 551

54 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis in osteoblasts, harvested during surgery, was more typical in patients with severe AIS (41 cases who underwent surgical correction) compared to patients with other types of scoliosis, or non-scoliotic controls (n = 17) [44]. The approximated OR was 3.9 (95%Cl: ; P = 0.3) with the corresponding prognostic characteristics: Sn, 20%; Sp, 94%; +PV, 89%; -PV, 33%. A second study showed that electrical impedance of PBMC < 120 ohms after melatonin or iodomelatonin administration associated with progression of the initially small spine deformity with Cobb angle < 10 o to clinically significant deformities with Cobb angle > 10 o in children genetically predisposed to AIS (n = 31), P = 0.03 [16]. The approximated OR was 18.5 (95%Cl: ), corresponding predictive values: Sn, 33%; Sp, 100%; +PV, 100%; -PV, 70%. The pooled OR was 6.5 (95%Cl: ; P = 0.037; low heterogeneity, I 2 = 0), corresponding predictive values showed low Sn, but relatively high Sp and positive predictive value: Sn, 25.4% (95%Cl: 15%-39.8%; P = 0.001; moderate heterogeneity, I 2 = 44%); Sp, 94.9% (95%Cl: 87.2%-98.1%; P < 0.001; low heterogeneity, I 2 = 0%); +PV, 93.5% (95%Cl: 70%-98.9%; P = 0.004; moderate heterogeneity, I 2 = 47.6%); -PV, 51.1% (95%Cl: 18.6%-82.8%; P = 0.954; high heterogeneity, I 2 = 90.4%. Gi and Gs proteins functional status in PBMC: One retrospective study reported that Gi and Gs proteins functional status in PBMC, defined by cellular dielectric spectroscopy, allowed classification of AIS patients into three functional groups (FG1, FG2, and FG3) according to the profile of imbalance between the responses to Gi and Gs stimulation. Activation of Gs, by isoproterenol, predominated in FG1, while FG3 was characterized by Gi dominant, somatostatin, responses [61]. It was suggested that FG2 group, which exhibited balanced responses to Gs and Gi, had significantly higher risk of severe spine deformity (Cobb angle 45 o ) than FG1 or FG3 groups. In particular, among 162 patients with a Cobb angle of 45 o, 56% related to the FG2 group, 31% to the FG3 group, and 13% to the FG1 group; while among 794 patients with Cobb angle ranging from 10 o to 44 o the distribution was different: the FG2 group, 33%; the FG3 group, 39%; and the FG1, 28%. Corresponding OR (FG2 vs FG3 + FG1) was 2.6 (95%Cl: ; P < 0.001) with relatively low prognostic values: Sn, 26%; Sp, 88%; +PV, 56%; -PV, 67%. Platelet CaM: Two studies (1 retrospective [46] and 1 prospective [47] ) studied the level of platelet CaM in AIS with different progression and healthy controls. The retrospective study reported that platelet CaM defined by radioimmune analysis and measured as nanograms of CaM per microgram of protein (ng/μg protein) was more than twice higher in patients with AIS (n = 17) than in healthy controls (n = 10), but this difference was not statistically significant by the standard student s t-test (P > 0.05) [46]. However, all 5 patients with progressive scoliosis (increase of Cobb angle > 10 o during observation) had levels of platelet CaM ranging from 1.46 to ng/μg protein, while 12 patients with stable deformities had platelet CaM from 0.09 to 1.16 ng/μg protein. Theoretically it means that there could be a strong association between the level of platelet CaM and progressive AIS by χ 2 -test (P = 0.007) with high predictive values; Sn, 100%; Sp, 100%; +PV, 100%; -PV, 100%. The prospective study used enzyme-linked immunosorbent analysis developed for the study to evaluate the platelet CaM level in 55 AIS patients [47]. The authors noted a high variability of the platelet CaM levels making results of quantitative statistical analysis not significant. However, it was revealed that among patients without treatment (observational group; n = 28) the progressive AIS cases (increase of Cobb angle 10 o per year of observation) were associated with an increase of platelet CaM levels during the first year of observation, while in patients with stable curvatures such increases were not observed: OR, 11 (95%Cl: ; P = 0.02); Sn, 69; Sp, 83; +PV, 85; -PV, 67. Combining the results of these two studies showed significant association between platelet CaM levels, and progressive AIS: the pooled OR was 32.6 (95%Cl: ; P = 0.022; n = 45; moderate heterogeneity, I 2 = 50%); the pooled predictive values showed moderate level: Sn, 86% (95%Cl: 31%-99%; P = 0.17; high heterogeneity, I 2 = 71%); Sp, 89% (95%Cl: 60%-98%; P = 0.015; moderate heterogeneity, I 2 = 40%); +PV, 90% (95%Cl: 66%-98%; P = 0.005; low heterogeneity, I 2 = 29%); -PV, 86% (95%Cl: 29%-99%; P = 0.194; high heterogeneity, I 2 = 73%). Secondary outcomes Eight studies (1 prospective [63], and 7 retrospective [46,66,67,69,70,73,77] ) reported on the number/rate of AIS patients who experienced progression of spine deformity in spite of brace treatment, in 907 participants. The initial Cobb angle exceeded 15 o in all 8 studies. Criteria for curve progression were different: increasing of the initial Cobb angle with more than 5 o or 6 o during or after treatment, 4 studies [63,70,73,77] ; Cobb angle exceeding 45 o, 2 studies [67,69] ; and using of a few criteria, 2 studies [46,66]. The rate of progressive cases ranged from 19% to 39% with P 0.05 in all studies. The pooled rate was 26.9% (95%Cl: 22.9%-31.2%; P < 0.001; moderate heterogeneity, I 2 = 42%). Group analysis did not reveal a significant difference between prospective and retrospective studies. Four studies: 1 prospective [63] and 3 retrospective [66,67,70] reported the number/rate of AIS patients requiring surgical correction, due to progression of spine deformity, during or after brace treatment in 579 AIS patients. The initial Cobb angle ranged from 20 o to 45 o. Rates of surgical treatment ranged from 10.5% to 19.2% with P < in all studies. The pooled rate was 15% (95%Cl: 11.0%-41.6%; P < 0.001; moderate heterogeneity, I 2 = 41%). WJO 552

55 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis Table 5 Summary table of meta-analysis of association between studied characteristics and progressive adolescent idiopathic scoliosis Studied characteristics Study Participants Heterogeneity Summary statistics P value Level of evidence (n ) (n ) I 2 (%) Level Pooled odds ratio 95% confident limits (GRADE) Lower Upper Age (< 13 yr) Moderate Low Osteopenia Moderate Low Brain stem dysfunction 1 28 NA NA Very low Multiple indices Moderate < Low Curve pattern Moderate Low Curve progression during bracing 1 85 NA NA Very low Initial Cobb angle High < Low Melatonin signaling Low Low Platelet calmodulin Moderate Low Premenarche High < Low Rib-vertebral angle NA NA < Very low Skeletal immaturity Moderate < Low SNP CALM NA NA Very low SNP ER High Low SNP IGF NA NA Very low SNP IL17RC NA NA Very low SNP NTF NA NA Very low SNP TPH NA NA Very low SNPs(53), ScoliScore test Low < Low Gi proteins functional status NA NA < Very low 1 Multiple indices included combinatorial radiographic, demographic, and physiologic characteristics. NA: Not available; SNP: Single nucleotide polymorphism; CALM1: Calmodulin 1; ER1: Estrogen receptor 1; IGF1: Insulin-like growth factor 1; IL17RC: Interleukin-17 receptor C; NTF3: Neurotrophin 3; TPH1: Tryptophan hydroxylase 1. DISCUSSION In the present review, we have systematically collected and analyzed the available evidence from published data evaluating the predictive values of various characteristics and parameters for the prediction of severe spine deformity in AIS. The prediction values of various indices were collected from published data, if necessary, additional calculation were performed. Methods of metaanalysis were applied, to summarize results of different publications. This was an independent study, performed without industrial or commercial support. Summary of main results Twenty five observational clinical studies were included in the current review. One retrospective study demonstrated that the increase of spine deformity with more than 5 o (Cobb angle and/or vertebral rotation) at 1-2 mo follow-up after starting brace treatment had a significant association with risk of further curve progression and requirement for surgical correction [73]. However, despite a high association (Table 5) the prognostic values of this index were limited. The level of evidence is very low because only one retrospective study reported this finding [53]. It was shown by one retrospective study that a ribvertebral angle of less than 65 o, at the apical level of convex side after a few months of brace treatment, had a significant association with the risk of further curve progression (Table 5) [77]. The predictive values of this index were low. The level of evidence is very low due to the same reason. Eight studies (3 prospective and 5 retrospective) showed that severity of the initial spine deformity (Cobb angle more than 25 o -30 o ) demonstrated significant association with a risk of further curve progression [36,65-68,70,73,74]. The pooled OR was relatively high (Table 5), nonetheless prognostic values were low. The level of evidence is low due to the high heterogeneity of the pooled results and limitations of the included studies (Tables 3 and 4). Four retrospective studies examined spinal curve patterns and found that thoracic deformities had a significantly higher risk of progression than thoracolumbar, lumbar or double curvatures (Table 5) [66,67,70,73]. However, prognostic values of this index were low. The level of evidence is low due to high heterogeneity of the pooled results and the limitations of the included studies (Tables 3 and 4). Four studies (1 prospective and 3 retrospective) showed that skeletally immature patients (based on radiographic criteria), had significantly higher risks of curve progression than those who were skeletally mature (Table 5) [65,67,70,77]. However, the pooled predictive values were low. The level of evidence is also low due to the high heterogeneity of the pooled results and limitations of the included studies (Tables 3 and 4). Three studies (2 prospective and 1 retrospective) have found that osteopenia, defined by radiographic or ultrasound methods, is significantly associated with progressive spine deformity in AIS (Table 5) [65,66,74]. However, the predictive values were low. The high heterogeneity of the pooled results and limitations of the included studies suggested a low level of evidence (Tables 3 and 4). WJO 553

56 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis One prospective cohort study has reported that 3-dimensional morphological parameters of spine at the first visit significantly differed in patients with progressive and non-progressive AIS [78]. However, reported data did not allow evaluation of the predictive values of these characteristics, therefore these results were not included in our review. Three retrospective studies showed that patients age < 13 years old at diagnosis have a significant associated risk for spine deformity progression (Table 5), but with low predictive values [65,67,74].The level of evidence is low due to the lack of significance and the high heterogeneity of the pooled prognostic values and the limitations of the included studies (Tables 3 and 4). Six studies 3 prospective [63,65,74] and 3 retrospective [66,67,77] showed that the premenarche status at diagnosis had a significant association with risk of curve progression, particularly in girls with mild and moderate spine deformity (Table 5). However, this index showed low predictive values. The level of evidence is low due to the lack of significance and high heterogeneity of the pooled prognostic values, and limitations of the included studies (Tables 3 and 4). It was demonstrated by one retrospective study that brain stem vestibular dysfunction had a significant association with progressive AIS (Tale 5) with moderate Sn, but low Sp and positive predictive value [76]. This finding has very low level of evidence. Seven studies (4 prospective [62,64,65,74] and 3 retrospective [60,66,67] ) showed that use of multiple indices, based on a combination of radiographic, bone densitometry, demographic and physiologic characteristics, demonstrates a significant association with progressive AIS (Table 5). However, the prognostic values of these combinatorial indices did not exceed moderate level. The level of evidence is low due to the limitations of the included studies (Tables 3 and 4), high heterogeneity of the pooled prognostic values, and the risk of the publication bias. SNPs of the following genes have been reported as having significant association with progressive AIS: CALM1 [71] ; ER1 [70,71] ; TPH1 [70] ; IGF1 [75] ; NTF3 [69] ; IL17RC [72] ; and MTNR1B [70]. However, the levels of association were relatively low (Table 5) with small predictive capacity. All these findings have very low level of evidence due to the limitations of the studies design (Tables 3 and 4) and that fact that only one study reported each finding. Of note, results concerning association between SNPs and AIS have low replicability in different populations [19,49]. It was also reported that rare variants in fibrilin-1 and fibrilin-2 genes [79], and rs on chromosome 17q24.3 [80] have significant association with severity of spine deformity in AIS. These studies did not match the inclusion criteria of our review, and thus were not included in the detailed analysis. However, the level of revealed associations was not high (OR: ) corresponding with low prognostic values. Retrospective design of these studies and other limitations suggest a low level of evidence. It has been reported by two retrospective, industry sponsored studies that a complex index based on 53 SNPs and initial Cobb angle (ScoliScore test) had significant association with progressive or stable AIS [58,59]. The pooled OR was relatively high (Table 5); but the pooled predictive characteristics ranged between low and moderate level with limited statistical significance. To note, these predictive values are similar to those obtained by other complex indices which included initial Cobb angle as an input parameter (Table 5). The level of evidence is low due to the limitations in the studies design (Tables 3 and 4), and the high heterogeneity of the pooled prognostic values. Of note, replicability of this method was low in the Japanese population [35]. The results of two studies, 1 retrospective [44] and 1 prospective [16], from the same group of researchers suggested a significant association between impairment of melatonin signaling and development of AIS (Table 5). That fact that this defect was revealed in cells of different tissues (osteoblasts and blood mononuclear cells), means that the defect is likely systemic, and thus can impact the functionality of different systems in the body. Potential physiological and biochemical mechanisms of this association have been discussed elsewhere [19,50]. The pooled prognostic values showed relatively high Sp and positive predictive value, but low Sn, and negative predictive value. Of note, the design of these studies does not allow evaluation of the predictive values of the melatonin signaling impairment as a predictor of severe spine deformity in AIS. The level of evidence is low due to the small number of studied cases and the limitations in the studies design (Tables 3 and 4). One retrospective study from the same research group reported a significant association between the functional status of Gi and Gs proteins in PBMC and severity of spine deformity in idiopathic scoliosis [61]. In spite of this significant association (Table 5) the results suggested low predictive capacity. Thus, G-proteins dysfunction is likely involved in the pathogenesis of idiopathic scoliosis, corresponding with melatonin signaling impairment, but this index cannot currently be used as diagnostic criteria for treatment strategy selection. The level of evidence is very low due to the limitations the presented results (Table 2) and the fact that only one study reported this finding. Combining the results of two studies 1 retrospective [46] and 1 prospective [47] suggested that platelet CaM levels also have a significant association with progressive AIS (Table 5) [46,47]. Potential mechanisms of this association have been discussed elsewhere [19]. The pooled prognostic values were moderate. The level of evidence is low due to the small number of studied cases and the limitations of the studies reported this finding (Tables 3 and 4). The pooled results of 8 studies suggested that around 27% of the AIS patients with initial Cobb angle exceeding 15 degrees had exacerbation of the spine WJO 554

57 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis deformity in spite of brace treatment [46,63,66,67,69,70,73,77], and pooled results of 4 studies demonstrated that 15% of patients treated by bracing required surgical correction [63,66,67,70]. However, the level of evidence is low due to the limitations of the studies presented these findings (Tables 3 and 4). Strength and weakness of the review To our knowledge this is first systematic review, with a meta-analysis, focused on summarizing the published results and analyzing the reported predictive values of different characteristics in progressive AIS, the risk of severe spine deformity during and after brace treatment, and in particular, the risk of requiring surgical correction. The review was conducted independent of industry following contemporary requirements for systematic reviews and meta-analysis of studies that evaluate diagnostic methods and health care interventions [81,82]. Comprehensive searches were performed to identify relevant studies. Unfortunately, no randomized controlled clinical trials met the inclusion criteria. Therefore, we had to include nonrandomized studies, while taking into consideration the risk of corresponding biases [56]. The results of the meta-analysis are limited by the quality of the studies identified in the review. In spite of a comprehensive search, studies relevant to the review may have been missed, which should be regarded as a potential limitation. Unfortunately, studies included in the review used different criteria for the progression of AIS, making the results of the meta-analysis less certain. In particular, such criteria as Cobb angle exceeding 45 o an important potential indication for preventive surgical treatment, was used by only 4 of 25 studies. OR and predictive values were approximated based on the assumption that the studied indices were normally distributed. This is a potential source of inaccuracy, as in reality, all parameters may not exhibit a normal distribution. However, we think that this potential error was accounted for by considering 95%CI and thus did not significantly affect the results. Overall, the presented findings have low or very low level of evidence due to the limitations typical of observational studies; high heterogeneity and lack of significance of the some pooled results suggesting inconsistency, and due to the fact that some findings were reported by only one study suggesting imprecision and have yet to be validated or reproduced [53]. Implication for practice The current review did not reveal any methods for the prediction of severe spine deformity progression in AIS that could be recommended as diagnostic criteria for selection of treatment strategy, in particular, preventive surgical intervention. Implication for research The current review revealed a paucity of high quality studies such as: randomized controlled clinical trials or prospective cohort studies focused on evaluation or development of diagnostic criteria, which would allow selection of patients, with a high risk of severe spine deformity, for preventive surgical intervention at the earlier stage of the AIS. Further research is needed in this field. Such studies should incorporate multiple criteria and integrate different characteristics linked with potential pathogenetic mechanisms, taking into consideration the contemporary concept of the multifactorial etiology of AIS. COMMENTS Background Adolescent idiopathic scoliosis (AIS) is the most prevalent form of spinal deformity, accounting for 80% of pediatric scoliosis and impacts 2%-4% of children during their pubertal growth spurt. The disease affects girls predominantly and diagnosed between age 10 and 16, prior to skeletal maturity. Severe spine deformity occurs in 10%-15%, while 22%-27% demonstrates spontaneous improvement. Medical care depends on the curve progression including observation, none surgical treatment, and surgical correction. Accurate prediction of the spine deformity progression at first patient s visit would significantly improve selection of treatment strategy making it more efficient. Research frontiers Over the past 3 decades different indices were reported as having significant association with progression or severity of spine deformity including demographic, radiographic, physiologic, biochemical, genetic, and their combinations. However, published data concerning prognostic value of these findings and their level of evidence have not been systematically collected and evaluated yet. Innovations and breakthroughs Current publication is first systematic review with meta-analysis which summarize published data concerning predictive value and level of evidence of different findings that were presented as predictors of progressive or severe spine deformity in AIS. It was shown that all published predictors have low level of evidence and limited predictive capability. The current review did not reveal any methods for the prediction of severe spine deformity progression that could be recommended as diagnostic criteria for selection of treatment strategy, in particular, preventive surgical intervention. Applications The study results suggest that further high quality researches are needed in this field. Terminology Meta-analysis is a statistical methodology that allows pooling together results of different studies. Low level of evidence means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Peer-review The authors present a highly interesting and diligently performed, important meta-analysis aiming at the identification of factors predicting progression of scoliosis in idiopathic adolescent cases. The review apparently includes all relevant studies published in the field, it represents a detailed, open and rigorous analysis, and finally draws conclusions demonstrating all results in the appropriate level of evidence. REFERENCES 1 Reamy BV, Slakey JB. Adolescent idiopathic scoliosis: review and current concepts. Am Fam Physician 2001; 64: [PMID: WJO 555

58 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis ] 2 Weinstein SL, Dolan LA, Cheng JC, Danielsson A, Morcuende JA. Adolescent idiopathic scoliosis. Lancet 2008; 371: [PMID: DOI: /S (08) ] 3 Grivas TB, Vasiliadis E, Malakasis M, Mouzakis V, Segos D. Intervertebral disc biomechanics in the pathogenesis of idiopathic scoliosis. Stud Health Technol Inform 2006; 123: [PMID: ] 4 Wong HK, Hui JH, Rajan U, Chia HP. Idiopathic scoliosis in Singapore schoolchildren: a prevalence study 15 years into the screening program. Spine (Phila Pa 1976) 2005; 30: [PMID: ] 5 CensusScope. [accessed 2015 Apr]. Available from: URL: Ylikoski M. Growth and progression of adolescent idiopathic scoliosis in girls. J Pediatr Orthop B 2005; 14: [PMID: ] 7 Bengtsson G, Fällström K, Jansson B, Nachemson A. A psychological and psychiatric investigation of the adjustment of female scoliosis patients. Acta Psychiatr Scand 1974; 50: [PMID: ] 8 Liu L, Xiu P, Li Q, Song Y, Chen R, Zhou C. 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60 Noshchenko A et al. Predictors of progressive adolescent idiopathic scoliosis 67 Sun X, Wang B, Qiu Y, Zhu ZZ, Zhu F, Yu Y, Qian BP, Ma WW, Liu Z, Mao SH. Outcomes and predictors of brace treatment for girls with adolescent idiopathic scoliosis. Orthop Surg 2010; 2: [PMID: DOI: /j x] 68 Lee CF, Fong DY, Cheung KM, Cheng JC, Ng BK, Lam TP, Yip PS, Luk KD. A new risk classification rule for curve progression in adolescent idiopathic scoliosis. Spine J 2012; 12: [PMID: DOI: /j.spinee ] 69 Qiu Y, Mao SH, Qian BP, Jiang J, Qiu XS, Zhao Q, Liu Z. A promoter polymorphism of neurotrophin 3 gene is associated with curve severity and bracing effectiveness in adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 2012; 37: [PMID: DOI: /BRS.0b013e31823e5890] 70 Xu L, Qiu X, Sun X, Mao S, Liu Z, Qiao J, Qiu Y. Potential genetic markers predicting the outcome of brace treatment in patients with adolescent idiopathic scoliosis. Eur Spine J 2011; 20: [PMID: DOI: /s ] 71 Zhao D, Qiu GX, Wang YP, Zhang JG, Shen JX, Wu ZH. Association between adolescent idiopathic scoliosis with double curve and polymorphisms of calmodulin1 gene/estrogen receptor-α gene. Orthop Surg 2009; 1: [PMID: DOI: /j x] 72 Zhou S, Qiu XS, Zhu ZZ, Wu WF, Liu Z, Qiu Y. A singlenucleotide polymorphism rs in the IL-17RC gene is associated with a susceptibility to and the curve severity of adolescent idiopathic scoliosis in a Chinese Han population: a casecontrol study. BMC Musculoskelet Disord 2012; 13: 181 [PMID: DOI: / ] 73 Upadhyay SS, Nelson IW, Ho EK, Hsu LC, Leong JC. New prognostic factors to predict the final outcome of brace treatment in adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 1995; 20: [PMID: ] 74 Lam TP, Hung VW, Yeung HY, Chu WC, Ng BK, Lee KM, Qin L, Cheng JC. Quantitative ultrasound for predicting curve progression in adolescent idiopathic scoliosis: a prospective cohort study of 294 cases followed-up beyond skeletal maturity. Ultrasound Med Biol 2013; 39: [PMID: DOI: /j.ultrasmedbio ] 75 Yeung HY, Tang NL, Lee KM, Ng BK, Hung VW, Kwok R, Guo X, Qin L, Cheng JC. Genetic association study of insulin-like growth factor-i (IGF-I) gene with curve severity and osteopenia in adolescent idiopathic scoliosis. Stud Health Technol Inform 2006; 123: [PMID: ] 76 Yamamoto H, Tani T, MacEwen GD, Herman R. An evaluation of brainstem function as a prognostication of early idiopathic scoliosis. J Pediatr Orthop 1982; 2: [PMID: ] 77 Modi HN, Suh SW, Song HR, Yang JH, Ting C, Hazra S. Drooping of apical convex rib-vertebral angle in adolescent idiopathic scoliosis of more than 40 degrees: a prognostic factor for progression. J Spinal Disord Tech 2009; 22: [PMID: DOI: /BSD.0b013e a8a] 78 Nault ML, Mac-Thiong JM, Roy-Beaudry M, Turgeon I, de Guise J, Labelle H, Parent S. Three-Dimensional Spinal Morphology can Differentiate Between Progressive and Non-Progressive Patients With Adolescent Idiopathic Scoliosis at the Initial Presentation. Spine (Phila Pa 1976) 2014 [PMID: DOI: / BRS ] 79 Buchan JG, Alvarado DM, Haller GE, Cruchaga C, Harms MB, Zhang T, Willing MC, Grange DK, Braverman AC, Miller NH, Morcuende JA, Tang NL, Lam TP, Ng BK, Cheng JC, Dobbs MB, Gurnett CA. Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. Hum Mol Genet 2014; 23: [PMID: DOI: /hmg/ddu224] 80 Miyake A, Kou I, Takahashi Y, Johnson TA, Ogura Y, Dai J, Qiu X, Takahashi A, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Kubo M, Tsunoda T, Watanabe K, Chiba K, Toyama Y, Qiu Y, Matsumoto M, Ikegawa S. Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3. PLoS One 2013; 8: e72802 [PMID: DOI: /journal.pone ] 81 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009; 151: W65-W94 [PMID: ] 82 Norvell DC, Dettori JR, Fehlings MG, Fourney DR, Chapman JR. Methodology for the systematic reviews on an evidence-based approach for the management of chronic low back pain. Spine (Phila Pa 1976) 2011; 36: S10-S18 [PMID: DOI: / BRS.0b013e31822ef8ee] P- Reviewer: Classen CF, Hussain M, Spiegel DA S- Editor: Ji FF L- Editor: A E- Editor: Jiao XK WJO 558

61 Submit a Manuscript: Help Desk: DOI: /wjo.v6.i7.559 World J Orthop 2015 August 18; 6(7): ISSN (online) 2015 Baishideng Publishing Group Inc. All rights reserved. CASE REPORT Florid reactive periostitis ossificans of the humerus: Case report and differential diagnosis of periosteal lesions of long bones Abha Soni, Alec Weil, Shi Wei, Kenneth A Jaffe, Gene P Siegal Abha Soni, Shi Wei, Gene P Siegal, R.W. Mowry, Endowed Professor of Pathology, the Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL 35249, United States Alec Weil, Kenneth A Jaffe, Alabama Orthopaedic Center, Birmingham, AL 35209, United States Author contributions: All authors contributed to the acquisition of data, writing, and revision of this manuscript. Supported by The University of Alabama at Birmingham, Alabama and The Orthopaedic Center, Birmingham, AL, United States. Institutional review board statement: This case report was exempt from the Institutional Review Board standards at The University of Alabama at Birmingham. Informed consent statement: The patient involved in this study gave her written informed consent authorizing use and disclosure of her protected health information. Conflict-of-interest statement: All the authors have no conflicts of interest to declare. Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: licenses/by-nc/4.0/ Correspondence to: Gene P Siegal, MD, PhD, R.W. Mowry, Endowed Professor of Pathology, the Division of Anatomic Pathology, University of Alabama at Birmingham, HSB149K, th Street South, Birmingham, AL 35249, United States. gsiegal@uab.edu Telephone: Fax: Received: February 28, 2015 Peer-review started: March 2, 2015 First decision: May 14, 2015 Revised: June 6, 2015 Accepted: June 18, 2015 Article in press: June 19, 2015 Published online: August 18, 2015 Abstract A case of florid reactive periostitis ossificans (RPO) arising in a long bone is presented. This is a rare bone proliferation with a pronounced periosteal reaction. Less than 100 cases have been described in the literature with far fewer outside the bones of the hand, feet, fingers, and toes. Although the etiology is unknown, a relationship to preceding trauma is suggested. The imaging and histologic features show an overlap with other bone lesions including bizarre parosteal osteochondromatous proliferation, subungual exostosis, and malignant surface tumors of bone and cartilage which include, periosteal and parosteal osteosarcoma. It is important to recognize the clinical presentation and diagnostic features of RPO as a benign entity so that it is not mistaken for a more aggressive neoplasm. We present a case of a right distal humeral lesion that on histopathological review revealed florid RPO. This diagnosis was not suspected on imaging studies, but was made on open biopsy of the mass. The patient remains disease free, years postoperatively. In addition to presenting this unique case report, we review the pertinent literature, and offer a differential diagnosis and treatment strategy for its management. Key words: Bizarre parosteal osteochondromatous proliferation (Nora s lesion); Reactive tumor-like lesions of long bones; Florid reactive periostitis ossificans; Periosteal and parosteal osteosarcomas WJO 559

62 Soni A et al. Reactive periostitis ossificans of the humerus The Author(s) Published by Baishideng Publishing Group Inc. All rights reserved. Core tip: Florid reactive periostitis ossificans (RPO) is a rare benign entity that is classically localized to the phalanges of the distal extremities. This lesion is often clinicoradiologically and histologically confused for malignant entities, like osteosarcoma and chondrosarcoma. We report a rare presentation of this lesion arising from the posterior aspect of the right elbow in a 38-yearold woman, diagnosed on biopsy. Recognizing the key similarities and differences between florid RPO, and other similar appearing disorders discussed in this paper, can prevent the pitfall of misdiagnosis and unnecessary aggressive surgery. Soni A, Weil A, Wei S, Jaffe KA, Siegal GP. Florid reactive periostitis ossificans of the humerus: Case report and differential diagnosis of periosteal lesions of long bones. World J Orthop 2015; 6(7): Available from: URL: wjgnet.com/ /full/v6/i7/559.htm DOI: org/ /wjo.v6.i7.559 INTRODUCTION Reactive or reparative lesions of bone, which historically have been related to trauma, include subungual exostosis, giant cell reparative granuloma, florid reactive periostitis, and bizarre parosteal osteochondromatous proliferation (BPOP) [1]. Spjut and Dorfman [2] first identified reactive periostitis in 1981 within small tubular bones (phalanges, metacarpals, metatarsals) of the hands and feet. Typically florid reactive periostitis occurs in adolescent or young adults and presents as a small area of painful swelling and erythema over the affected bone [3,4]. As noted, these tumors typically occur in the bones of the hands and feet, but they may also present in long bones of the axial skeleton, as in our case [3-5] ; when they occur in the phalanges, they are clinically reassuring, because such lesions are more likely to be benign than malignant (21:1) [4,5]. Regardless, it is important to recognize them so that they are not misdiagnosed. In this case report, we present an unusual presentation of this lesion, discuss its clinical, radiologic, and histologic appearance, review the pertinent literature, and offer a differential diagnosis and treatment strategy for its management. CASE REPORT A 38-year-old woman presented with a 2-mo interval of throbbing pain in her right elbow, which was aggravated by bending and lifting. The first time the patient noticed pain was soon after completing a half marathon where she carried her phone in her right hand. On physical examination she was found to have moderate swelling in the posterior aspect of her elbow along with a mild effusion and significant tenderness in the posteriorlateral compartment. Conventional radiographs revealed an irregular mass posterior to the distal humerus just superior to the olecranon fossa (Figure 1). Magnetic resonance imaging showed extensive edema in the distal triceps muscle adjacent to the mass. A CT scan showed diffuse calcifications within the mass. No bony destruction was seen (Figure 2). At this point the differential diagnosis included atypical myositis ossificans or a neoplastic process. A repeat CT after 11 wk showed a 2.0 cm 1.9 cm osseous excrescence arising from the posterior distal humeral metaphysis (Figure 3). The differential considerations broadened to include BPOP, a low-grade parosteal osteosarcoma, or less likely a periosteal chondroma. An open biopsy was performed through a posterior excision. Operative findings revealed pallor of the anterior deep triceps and significant edema of the distal triceps. The specimen was removed piece-meal. The gross appearance was of loosely adherent tan-gray fibrous tissue. The distal portion of humerus showed focal necrosis and hemorrhage. Based on this appearance, an infectious etiology was considered and a fragment of the lesion was submitted for aerobic, anaerobic, mycobacterial, and fungal cultures. Histologic examination revealed mixed bland spindle cells adjacent to osteoblastic proliferation with reactive (woven) new bone formation (Figure 4). Zonation was seen suggestive of myositis ossificans (heterotopic ossification). Osteomyelitis was ruled out because of a lack of a significant inflammatory infiltrate. Osteosarcoma was ruled out because of lack of cellular atypia or tumor osteoid. There were no cytomorphologic features of a parosteal (low grade) osteosarcoma. After surgery, her elbow motion improved from 30-degree flexion to full flexion and full forearm rotation over several weeks. The wrist and hand motion were judged to be normal with normal neuromuscular function. Neither recurrent heterotopic bone nor osteoblastic proliferation of the posterior humerus was seen radiographically. She was discharged home on a supportive Dynasplint with follow up on an outpatient basis. DISCUSSION Florid reactive periostitis is a benign bone lesion characterized by an aggressive periosteal reaction and soft-tissue inflammation [2,3]. This rare tumor has been identified by various names such as, pseudomalignant osseous tumor of the soft tissue, fasciitis ossificans, parosteal fasciitis and benign fibro-osseous pseudotumor [6]. For classification purposes this diagnosis is often grouped with either pseudomalignant osseous tumors of the soft tissue or myositis ossificans. Due to its mild course, it is generally managed by observation after initial biopsy, but rarely it can be locally aggressive and recurrent [7]. The imaging and histologic features of this benign bone lesion, show an overlap with other WJO 560

63 Soni A et al. Reactive periostitis ossificans of the humerus A R Figure 1 Conventional radiograph at two months from onset revealing an irregular mass posterior to the distal humerus superior to the olecranon fossa. B A B Figure 3 Computed tomography scan 11 wk after the initial imaging showing a 2.0 cm 1.9 cm osseous excrescence arising from the posterior distal humeral metaphysis. Figure 2 Sagittal (A) and axial (B) views demonstrating fine calcifications within the mass; no boney destruction was seen. A bone lesions including BPOP, subungual exostosis, osteomyelitis, myositis ossificans, and malignant surface tumors of bone and cartilage which include, conventional, periosteal and parosteal osteosarcoma. Like florid reactive periostitis, BPOP (also known as Nora s lesion) is also a rare entity that is grossly described as an exophytic outgrowth of the cortical surface of the phalanges of the hands and feet [6,8]. It is composed of a disorganized mixture of bone, cartilage, and fibrous tissue and the upper extremities are four B times more affected than the lower extremities [8-10]. This lesion can present itself at any age, but individuals in their 20's and 30's are higher at risk [10-12]. It is sometimes mistaken for a malignant process due to its high rate of recurrence, proliferative nature, and atypical microscopic appearance [12]. However, unlike osteosarcoma, on imaging BPOP lacks cortical flaring and communication with the underlying medullary canal [12-15]. On histology, the exophytic bone mass has a characteristic dark blue tinctorial quality, especially at the interface with the cartilage. The intertrabecular spaces contain proliferating spindle cells that lack cytological atypia. Figure 4 Histologically the lesion was composed of woven bone in The cartilaginous component is hypercellular and contains irregular groups of binucleated and bizarre the background of mildly cellular bland spindle cells [haematoxylin and eosin, original magnification x 40 (A), and 100 (B)]. chondrocytes. Although double-nucleated chondrocytes are common, hyperchromasia and cytological atypia are typically not present [13,16]. WJO 561

64 Soni A et al. Reactive periostitis ossificans of the humerus Another benign lesion that occurs in relation to the long bones (and shows overlapping radiologic and histologic findings with reactive periostitis) is myositis ossificans traumatica [17]. This lesion most commonly occurs in the muscles of the arms or in the quadriceps following covert or overt trauma [17]. On imaging, soft tissue calcifications are visible within 2 6 wk of the inciting incident. Peripheral ossification is the characteristic feature noted on CT [17,18]. This lesion is generally not biopsied as it rapidly resolves, but if clinical and imaging studies are inconclusive, an open biopsy may be indicated. There are three phases of myositis ossificans: acute (fibroblastic zone), subacute (osteoblastic zone), and late (calcified zone). Detection of this zonal phenomenon on histology is diagnostic of myositis ossificans [17,18]. Chronic osteomyelitis may also be in the differential diagnosis. This diagnosis is made radiologically by the presence of an osteolytic center with a ring of sclerosis on conventional imaging [19]. Additionally, a culture of the biopsy tissue is needed to support the diagnosis and identify the specific pathogen. Histology often only shows sclerotic bone with chronic inflammatory cells [20]. Due to its infectious etiology, treatment involves surgical debridement and prolonged antibiotic therapy. Furthermore, subungual exostoses can also mimic florid reactive periostitis. These are bony projections that protrude from the dorsal aspect of the distal phalanx [21]. The reason it occurs on the dorsal aspect is thought due to the fact that the periosteum is relatively loose dorsally, but very tightly adherent on its volar aspect [22]. Due to its location, this lesion may lead to the destruction of the nail bed causing considerable pain or discomfort. There is a reproducible translocation [t(x; 6) (q13; q22)] associated with this diagnosis and thus, it may be considered a true neoplasm. Surgical excision is the mainstay of therapy. Lastly, malignant osteoblastic tumors including parosteal, periosteal, and conventional osteosarcoma are considered in the differential diagnosis. These tumors are most prevalent in children and young adults [23,24]. They are localized at the end of long bones. Most often they affect the proximal end of the tibia or humerus, or the distal end of the femur. Of the three types, parosteal osteosarcoma has the best prognosis, followed by periosteal and then conventional. Periosteal osteosarcoma is the most uncommon among the three types [25]. This lesion most commonly appears in the diaphysis or metadiaphysis of the tibia and femur. Grossly, the tumor may form a cavity deep in the cortex with radiating striations that may break into the medullary cavity as the disease progresses. Histologically, there is a prominent cartilaginous component to this tumor with a small amount of osteoid production. Treatment depends on grade. Low-grade lesions may be treated with wide surgical excision alone, while higher-grade lesions may require chemotherapy in addition to surgery [25]. Parosteal osteosarcoma is the most frequently occurring osteosarcoma and thus it is crucial to diagnostically separate this entity from reactive periostitis. Seventy percent of the time, it arises in the metaphysis of the posterior aspect of the distal femur and less frequently involves the proximal tibia and humerus. It is composed of a dense osteoid component that extends from the outer cortex via a narrow zone [26,27]. Histologically, it exhibits an extensive boney matrix with a hypocellular stroma and mild to minimal fibroblastic cellular atypia. Radiologically, it takes the appearance of a firm, lobulated cauliflower-like, lesion encircling the bone. A thin radiolucent line delineating the tumor from the cortex, known as the string sign, is seen radiologically in 30% of cases. Treatment for parosteal osteosarcomas usually involves surgical resection without neoadjuvant chemotherapy, as these tumors are commonly lowgrade in nature [26,27]. Conventional osteosarcoma can usually be easily separated from reactive periostitis. Histologically, these tumor cells are very pleomorphic with numerous atypical mitoses that are entrapped in the osteoid matrix. Complete radical surgical en bloc resection with chemotherapy is the treatment of choice for conventional osteosarcoma [25]. It can be appreciated from the above differentials that the diagnosis of florid reactive periostitis is often challenging. Therefore, a careful assessment of clinical history, radiology, and pathology are helpful in reaching an accurate diagnosis. Although rare, this entity should be considered in the differential diagnosis of any osteogenic growth in long bones. Being aware of the above differentials can assist in separating this benign entity from its malignant mimickers. Once the malignant and infectious imitators of this lesion are ruled out, treatment can be discussed. When presenting early, this process can be treated conservatively with rest and nonsteroidal anti-inflammatory medication. When presenting late, with an aggressive nature and/or with recurrence, wide local resection is considered treatment of choice. COMMENTS Case characteristics A 38-year-old woman with no significant medical history presented with a 2-mo history of throbbing pain in her right elbow, which was aggravated by bending and lifting. Clinical diagnosis Moderate swelling in the posterior aspect of her elbow along with a mild effusion and significant tenderness in the posterior-lateral compartment. Differential diagnosis Atypical myositis ossificans, bizarre parosteal osteochondromatous proliferation, low-grade parosteal osteosarcoma, periosteal chondroma or chondrosarcoma. Laboratory diagnosis All labs were within normal limits. Imaging diagnosis CT showed a 2.0 cm 1.9 cm osseous excrescence arising from the posterior distal humeral metaphysis. Pathological diagnosis Florid-reactive periostitis ossificans. WJO 562

65 Soni A et al. Reactive periostitis ossificans of the humerus Treatment Complete surgical excision of lesion. Related reports Reactive periostitis ossificans is a benign entity that classically present in the hands/feet, very rarely it has been reported in long bones with an etiology related to trauma. This entity is commonly confused for a neoplastic process due to its unusual location and can at times even histologically mimic sarcoma. Term explanation Benign parosteal osteochondromatous proliferations (BPOP) is a rare cartilaginous neoplasm that like reactive periostitis ossisficans (RPO) presents in the hands/feet. BPOP is known to be locally aggressive and requires extensive surgical resection. Experiences and lessons This is entity is commonly confused for a neoplastic process due to its unusual location and can at times even histologically mimic sarcoma. Recognizing this as a diagnostic pitfall can prevent misdiagnosis and eliminate the need for aggressive surgical treatment. 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