World Journal of Radiology World J Radiol ISSN

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ISSN 1949-8470 (online)
World Journal of
Radiology
World J Radiol 2013 April 28; 5(4): 143-192
www.wjgnet.com
WJ R
World Journal of
Radiology
Editorial Board
2009-2013
The World Journal of Radiology Editorial Board consists of 319 members, representing a team of worldwide experts
in radiology. They are from 40 countries, including Australia (3), Austria (4), Belgium (5), Brazil (3), Canada (9),
Chile (1), China (25), Czech (1), Denmark (1), Egypt (4), Estonia (1), Finland (1), France (6), Germany (17), Greece
(8), Hungary (1), India (9), Iran (5), Ireland (1), Israel (4), Italy (28), Japan (14), Lebanon (1), Libya (1), Malaysia (2),
Mexico (1), Netherlands (4), New Zealand (1), Norway (1), Saudi Arabia (3), Serbia (1), Singapore (2), Slovakia (1),
South Korea (16), Spain (8), Switzerland (5), Thailand (1), Turkey (20), United Kingdom (16), and United States (82).
EDITOR-IN-CHIEF
Filippo Cademartiri, Monastier di Treviso
STRATEGY ASSOCIATE
EDITORS-IN-CHIEF
Ritesh Agarwal, Chandigarh
Kenneth Coenegrachts, Bruges
Mannudeep K Kalra, Boston
Meng Law, Lost Angeles
Ewald Moser, Vienna
Aytekin Oto, Chicago
AAK Abdel Razek, Mansoura
Àlex Rovira, Barcelona
Yi-Xiang Wang, Hong Kong
Hui-Xiong Xu, Guangzhou
GUEST EDITORIAL BOARD
MEMBERS
Wing P Chan, Taipei
Wen-Chen Huang, Taipei
Shi-Long Lian, Kaohsiung
Chao-Bao Luo, Taipei
Shu-Hang Ng, Taoyuan
Pao-Sheng Yen, Haulien
MEMBERS OF THE EDITORIAL
BOARD
Australia
Karol Miller, Perth
Tomas Kron, Melbourne
Zhonghua Sun, Perth
Siegfried Trattnig, Vienna
Belgium
Piet R Dirix, Leuven
Yicheng Ni, Leuven
Piet Vanhoenacker, Aalst
Jean-Louis Vincent, Brussels
Brazil
Emerson L Gasparetto, Rio de Janeiro
Edson Marchiori, Petrópolis
Wellington P Martins, São Paulo
Czech
Canada
Sriharsha Athreya, Hamilton
Mark Otto Baerlocher, Toronto
Martin Charron, Toronto
James Chow, Toronto
John Martin Kirby, Hamilton
Piyush Kumar, Edmonton
Catherine Limperpoulos, Quebec
Ernest K Osei, Kitchener
Weiguang Yao, Sudbury
Chile
Austria
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Vlastimil Válek, Brno
Denmark
Poul Erik Andersen, Odense
Egypt
Mohamed Abou El-Ghar, Mansoura
Mohamed Ragab Nouh, Alexandria
Ahmed A Shokeir, Mansoura
Masami Yamamoto, Santiago
Estonia
Tiina Talvik, Tartu
China
Herwig R Cerwenka, Graz
Daniela Prayer,Vienna
Shen Fu, Shanghai
Gang Jin, Beijing
Tak Yeung Leung, Hong Kong
Wen-Bin Li, Shanghai
Rico Liu, Hong Kong
Yi-Yao Liu, Chengdu
Wei Lu, Guangdong
Fu-Hua Peng, Guangzhou
Liang Wang, Wuhan
Li-Jun Wu, Hefei
Zhi-Gang Yang, Chengdu
Xiao-Ming Zhang, Nanchong
Chun-Jiu Zhong, Shanghai
Feng Chen, Nanjing
Ying-Sheng Cheng, Shanghai
Woei-Chyn Chu, Taipei
Guo-Guang Fan, Shenyang
Finland
Tove J Grönroos, Turku
January 28, 2013
France
Alain Chapel, Fontenay-Aux-Roses
Nathalie Lassau, Villejuif
Youlia M Kirova, Paris
Géraldine Le Duc, Grenoble Cedex
Laurent Pierot, Reims
Frank Pilleul, Lyon
Pascal Pommier, Lyon
Ireland
Joseph Simon Butler, Dublin
Israel
Amit Gefen, Tel Aviv
Eyal Sheiner, Be’er-Sheva
Jacob Sosna, Jerusalem
Simcha Yagel, Jerusalem
Greece
Panagiotis Antoniou, Alexandroupolis
George C Kagadis, Rion
Dimitris Karacostas, Thessaloniki
George Panayiotakis, Patras
Alexander D Rapidis, Athens
C Triantopoulou, Athens
Ioannis Tsalafoutas, Athens
Virginia Tsapaki, Anixi
Ioannis Valais, Athens
Hungary
Peter Laszlo Lakatos, Budapest
India
Anil Kumar Anand, New Delhi
Surendra Babu, Tamilnadu
Sandip Basu, Bombay
Kundan Singh Chufal, New Delhi
Shivanand Gamanagatti, New Delhi
Vimoj J Nair, Haryana
R Prabhakar, New Delhi
Sanjeeb Kumar Sahoo, Orissa
Iran
Vahid Reza Dabbagh Kakhki, Mashhad
Mehran Karimi, Shiraz
Farideh Nejat, Tehran
Alireza Shirazi, Tehran
Hadi Rokni Yazdi, Tehran
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Mexico
Heriberto Medina-Franco, Mexico City
Netherlands
Germany
Ambros J Beer, München
Thomas Deserno, Aachen
Frederik L Giesel, Heidelberg
Ulf Jensen, Kiel
Markus Sebastian Juchems, Ulm
Kai U Juergens, Bremen
Melanie Kettering, Jena
Jennifer Linn, Munich
Christian Lohrmann, Freiburg
David Maintz, Münster
Henrik J Michaely, Mannheim
Oliver Micke, Bielefeld
Thoralf Niendorf, Berlin-Buch
Silvia Obenauer, Duesseldorf
Steffen Rickes, Halberstadt
Lars V Baron von Engelhardt, Bochum
Goetz H Welsch, Erlangen
Malaysia
R Logeswaran, Cyberjaya
Kwan-Hoong Ng, Kuala Lumpur
Italy
Mohssen Ansarin, Milan
Stefano Arcangeli, Rome
Tommaso Bartalena, Imola
Sergio Casciaro, Lecce
Laura Crocetti, Pisa
Alberto Cuocolo, Napoli
Mirko D’Onofrio, Verona
Massimo Filippi, Milan
Claudio Fiorino, Milano
Alessandro Franchello, Turin
Roberto Grassi, Naples
Stefano Guerriero, Cagliari
Francesco Lassandro, Napoli
Nicola Limbucci, L'Aquila
Raffaele Lodi, Bologna
Francesca Maccioni, Rome
Laura Martincich, Candiolo
Mario Mascalchi, Florence
Roberto Miraglia, Palermo
Eugenio Picano, Pisa
Antonio Pinto, Naples
Stefania Romano, Naples
Luca Saba, Cagliari
Sergio Sartori, Ferrara
Mariano Scaglione, Castel Volturno
Lidia Strigari, Rome
Vincenzo Valentini, Rome
Jurgen J Fütterer, Nijmegen
Raffaella Rossin, Eindhoven
Paul E Sijens, Groningen
New Zealand
W Howell Round, Hamilton
Norway
Arne Sigmund Borthne, Lørenskog
Saudi Arabia
Mohammed Al-Omran, Riyadh
Ragab Hani Donkol, Abha
Volker Rudat, Al Khobar
Serbia
Djordjije Saranovic, Belgrade
Singapore
Uei Pua, Singapore
Lim CC Tchoyoson, Singapore
Japan
Shigeru Ehara, Morioka
Nobuyuki Hamada, Chiba
Takao Hiraki, Okayama
Akio Hiwatashi, Fukuoka
Masahiro Jinzaki, Tokyo
Hiroshi Matsuda, Saitama
Yasunori Minami, Osaka
Jun-Ichi Nishizawa, Tokyo
Tetsu Niwa, Yokohama
Kazushi Numata, Kanagawa
Kazuhiko Ogawa, Okinawa
Hitoshi Shibuya, Tokyo
Akira Uchino, Saitama
Haiquan Yang, Kanagawa
Lebanon
Aghiad Al-Kutoubi, Beirut
Libya
Anuj Mishra, Tripoli
II
Slovakia
František Dubecký, Bratislava
South Korea
Bo-Young Choe, Seoul
Joon Koo Han, Seoul
Seung Jae Huh, Seoul
Chan Kyo Kim, Seoul
Myeong-Jin Kim, Seoul
Seung Hyup Kim, Seoul
Kyoung Ho Lee, Gyeonggi-do
Won-Jin Moon, Seoul
Wazir Muhammad, Daegu
Jai Soung Park, Bucheon
Noh Hyuck Park, Kyunggi
Sang-Hyun Park, Daejeon
Joon Beom Seo, Seoul
Ji-Hoon Shin, Seoul
Jin-Suck Suh, Seoul
Hong-Gyun Wu, Seoul
January 28, 2013
Spain
Eduardo J Aguilar, Valencia
Miguel Alcaraz, Murcia
Juan Luis Alcazar, Pamplona
Gorka Bastarrika, Pamplona
Rafael Martínez-Monge, Pamplona
Alberto Muñoz, Madrid
Joan C Vilanova, Girona
Switzerland
Nicolau Beckmann, Basel
Silke Grabherr, Lausanne
Karl-Olof Lövblad, Geneva
Tilo Niemann, Basel
Martin A Walter, Basel
United Kingdom
K Faulkner, Wallsend
Peter Gaines, Sheffield
Balaji Ganeshan, Brighton
Nagy Habib, London
Alan Jackson, Manchester
Pradesh Kumar, Portsmouth
Tarik F Massoud, Cambridge
Igor Meglinski, Bedfordshire
Robert Morgan, London
Ian Negus, Bristol
Georgios A Plataniotis, Aberdeen
N J Raine-Fenning, Nottingham
Manuchehr Soleimani, Bath
MY Tseng, Nottingham
Edwin JR van Beek, Edinburgh
Feng Wu, Oxford
United States
Thailand
Sudsriluk Sampatchalit, Bangkok
Turkey
Olus Api, Istanbul
Kubilay Aydin, İstanbul
Işıl Bilgen, Izmir
Zulkif Bozgeyik, Elazig
Barbaros E Çil, Ankara
Gulgun Engin, Istanbul
M Fatih Evcimik, Malatya
Ahmet Kaan Gündüz, Ankara
Tayfun Hakan, Istanbul
Adnan Kabaalioglu, Antalya
Fehmi Kaçmaz, Ankara
Musturay Karcaaltincaba, Ankara
Osman Kizilkilic, Istanbul
Zafer Koc, Adana
Cem Onal, Adana
Yahya Paksoy, Konya
Bunyamin Sahin, Samsun
Ercument Unlu, Edirne
Ahmet Tuncay Turgut, Ankara
Ender Uysal, Istanbul
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Athanassios Argiris, Pittsburgh
Stephen R Baker, Newark
Lia Bartella, New York
Charles Bellows, New Orleans
Walter L Biffl, Denver
Homer S Black, Houston
Wessam Bou-Assaly, Ann Arbor
Owen Carmichael, Davis
Shelton D Caruthers, St Louis
Yuhchyau Chen, Rochester
Melvin E Clouse, Boston
Ezra Eddy Wyssam Cohen, Chicago
Aaron Cohen-Gadol, Indianapolis
Patrick M Colletti, Los Angeles
Kassa Darge, Philadelphia
Abhijit P Datir, Miami
Delia C DeBuc, Miami
Russell L Deter, Houston
Adam P Dicker, Phil
Khaled M Elsayes, Ann Arbor
Steven Feigenberg, Baltimore
Christopher G Filippi, Burlington
Victor Frenkel, Bethesda
Thomas J George Jr, Gainesville
Patrick K Ha, Baltimore
Robert I Haddad, Boston
Walter A Hall, Syracuse
Mary S Hammes, Chicago
III
John Hart Jr, Dallas
Randall T Higashida, San Francisco
Juebin Huang, Jackson
Andrei Iagaru, Stanford
Craig Johnson, Milwaukee
Ella F Jones, San Francisco
Csaba Juhasz, Detroit
Riyad Karmy-Jones, Vancouver
Daniel J Kelley, Madison
Amir Khan, Longview
Euishin Edmund Kim, Houston
Vikas Kundra, Houston
Kennith F Layton, Dallas
Rui Liao, Princeton
CM Charlie Ma, Philadelphia
Nina A Mayr, Columbus
Thomas J Meade, Evanston
Steven R Messé, Philadelphia
Nathan Olivier Mewton, Baltimore
Feroze B Mohamed, Philadelphia
Koenraad J Mortele, Boston
Mohan Natarajan, San Antonio
John L Nosher, New Brunswick
Chong-Xian Pan, Sacramento
Dipanjan Pan, St Louis
Martin R Prince, New York
Reza Rahbar, Boston
Carlos S Restrepo, San Antonio
Veronica Rooks, Honolulu
Maythem Saeed, San Francisco
Edgar A Samaniego, Palo Alto
Kohkan Shamsi, Doylestown
Jason P Sheehan, Charlottesville
William P Sheehan, Willmar
Charles Jeffrey Smith, Columbia
Monvadi B Srichai-Parsia, New York
Dan Stoianovici, Baltimore
Janio Szklaruk, Houston
Dian Wang, Milwaukee
Jian Z Wang, Columbus
Shougang Wang, Santa Clara
Wenbao Wang, New York
Aaron H Wolfson, Miami
Gayle E Woloschak, Chicago
Ying Xiao, Philadelphia
Juan Xu, Pittsburgh
Benjamin M Yeh, San Francisco
Terry T Yoshizumi, Durham
Jinxing Yu, Richmond
Jianhui Zhong, Rochester
January 28, 2013
WJ R
World Journal of
Radiology
Contents
MINI-REVIEWS
Monthly Volume 5 Number 4 April 28, 2013
143
Endovascular treatment of carotid cavernous sinus fistula: A systematic
review
Korkmazer B, Kocak B, Tureci E, Islak C, Kocer N, Kizilkilic O
ORIGINAL ARTICLE
156
Asymmetrically hypointense veins on T2*w imaging and susceptibilityweighted imaging in ischemic stroke
Jensen-Kondering U, Böhm R
BRIEF ARTICLE
166
Microstructural analysis of pineal volume using trueFISP imaging
Bumb JM, Brockmann MA, Groden C, Nolte I
173
Volumetric modulated arc radiotherapy for limited osteosclerotic myeloma
Robles A, Levy A, Moncharmont C, Farid L, Guy JB, Malkoun N, Cartier L, Chargari C,
Guichard I, Talabard JN, de Laroche G, Magné N
178
Role of color Doppler in differentiation of Graves' disease and thyroiditis in
thyrotoxicosis
Donkol RH, Nada AM, Boughattas S
CASE REPORT
184
MDCT of right aortic arch with aberrant left subclavian artery associated with
kommerell diverticulum and calcified ligamentum arteriosum
Kanza RE, Berube M, Michaud P
187
Thoracic epidural angiolipoma: A case report and review of the literature
Meng J, Du Y, Yang HF, Hu FB, Huang YY, Li B, Zee CS
WJR|www.wjgnet.com
April 28, 2013|Volume 5|Issue 4|
World Journal of Radiology
Contents
Volume 5 Number 4 April 28, 2013
APPENDIX
I-V
ABOUT COVER
Instructions to authors
Bumb JM, Brockmann MA, Groden C, Nolte I. Microstructural analysis of pineal
volume using trueFISP imaging.
World J Radiol 2013; 5(4): 166-172
http://www.wjgnet.com/1949-8470/full/v5/i4/166.htm
AIM AND SCOPE
World Journal of Radiology (World J Radiol, WJR, online ISSN 1949-8470, DOI: 10.4329) is
a peer-reviewed open access academic journal that aims to guide clinical practice and improve diagnostic and therapeutic skills of clinicians.
WJR covers topics concerning diagnostic radiology, radiation oncology, radiologic
physics, neuroradiology, nuclear radiology, pediatric radiology, vascular/interventional
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The current columns of WJR include editorial, frontier, diagnostic advances, therapeutics
advances, field of vision, mini-reviews, review, topic highlight, medical ethics, original
articles, case report, clinical case conference (clinicopathological conference), and autobiography.
We encourage authors to submit their manuscripts to WJR. We will give priority to
manuscripts that are supported by major national and international foundations and those
that are of great basic and clinical significance.
INDEXING/ABSTRACTING
World Journal of Radiology is now indexed in PubMed Central, PubMed, Digital Object Identifier, and Directory of Open Access Journals.
FLYLEAF
I-III
EDITORS FOR
THIS ISSUE
Responsible Assistant Editor: Shuai Ma
Responsible Electronic Editor: Li Xiong
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NAME OF JOURNAL
ISSN
LAUNCH DATE
December 31, 2009
FREQUENCY
Monthly
EDITOR-IN-CHIEF
Filippo Cademartiri, MD, PhD, FESC, FSCCT,
Professor, Cardio-Vascular Imaging Unit-Giovanni
XXIII Hospital, Via Giovanni XXIII, 7-31050-Monastier di Treviso (TV), Italy
EDITORIAL OFFICE
Jin-Lei Wang, Director
Xiu-Xia Song, Vice Director
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doi:10.4329/wjr.v5.i4.143
MINI-REVIEWS
Endovascular treatment of carotid cavernous sinus fistula:
A systematic review
Bora Korkmazer, Burak Kocak, Ercan Tureci, Civan Islak, Naci Kocer, Osman Kizilkilic
as the mainstay therapy for definitive treatment in
situations including clinical emergencies. Conservative
treatment, surgery and radiosurgery constitute other
management options for these lesions.
Bora Korkmazer, Burak Kocak, Civan Islak, Naci Kocer,
Osman Kizilkilic, Division of Neuroradiology, Department of
Radiology, Cerrahpasa School of Medicine, Istanbul University,
34098 Istanbul, Turkey
Ercan Tureci, Department of Anesthesiology and Reanimation,
Cerrahpasa School of Medicine, Istanbul University, 34098 Istanbul, Turkey
Author contributions: Kizilkilic O and Korkmazer B designed
the study; Korkmazer B and Kocak B conducted literature
research; Korkmazer B wrote the paper; Korkmazer B, Islak
C, Kizilkilic O, Kocer N, Kocak B, and Tureci E edited and revised the paper.
Correspondence to: Osman Kizilkilic, MD, Associated Professor, Division of Neuroradiology, Department of Radiology,
Cerrahpasa School of Medicine, Istanbul University, Osman Gazi
Mh., Paşa Sk, 34098 Istanbul, Turkey. [email protected]
Telephone: +90-212-4143000 Fax: +90-212-4143021
Received: November 30, 2012 Revised: January 30, 2013
Accepted: February 5, 2013
Published online: April 28, 2013
Key words: Cavernous sinus; Carotid cavernous sinus
fistula; Endovascular treatment
Core tip: Carotid cavernous sinus fistulas (CCFs) are
abnormal communications between the carotid arterial system and the cavernous sinus. The clinical presentation of CCFs, which is a direct consequence of
elevation in intracavernous pressure and revised flow
patterns, mostly comprises of ocular findings. Recent
advances in endovascular techniques have resulted in
several therapeutic modalities becoming available and
the endovascular approach has evolved as the primary
treatment option for the management of CCFs. This
review provides detailed information about classification, etiology, pathophysiology, clinical presentation,
diagnostic modalities, differential diagnosis, indications
for emergency treatment, post-treatment follow-up
and treatment modalities with emphasis on the endovascular approach in CCFs.
Abstract
Carotid cavernous sinus fistulas are abnormal communications between the carotid system and the
cavernous sinus. Several classification schemes have
described carotid cavernous sinus fistulas according to
etiology, hemodynamic features, or the angiographic
arterial architecture. Increased pressure within the
cavernous sinus appears to be the main factor in
pathophysiology. The clinical features are related to
size, exact location, and duration of the fistula, adequacy and route of venous drainage and the presence
of arterial/venous collaterals. Noninvasive imaging
(computed tomography, magnetic resonance, computed tomography angiography, magnetic resonance
angiography, Doppler) is often used in the initial workup of a possible carotid cavernous sinus fistulas. Cerebral angiography is the gold standard for the definitive
diagnosis, classification, and planning of treatment for
these lesions. The endovascular approach has evolved
WJR|www.wjgnet.com
Korkmazer B, Kocak B, Tureci E, Islak C, Kocer N, Kizilkilic
O. Endovascular treatment of carotid cavernous sinus fistula: A
systematic review. World J Radiol 2013; 5(4): 143-155 Available
from: URL: http://www.wjgnet.com/1949-8470/full/v5/i4/143.
htm DOI: http://dx.doi.org/10.4329/wjr.v5.i4.143
INTRODUCTION
Carotid cavernous sinus fistulas (CCFs) are abnormal
communications between the carotid arterial system and
the cavernous sinus. Recent advances in endovascular
143
Korkmazer B et al . Endovascular treatment of CCF
lead to direct CCFs [5,6]. Approximately 20% of type
A CCFs are not related to a history of trauma and regarded as spontaneous[7,8]. Spontaneous direct CCFs may
stem from any condition that predisposes the ICA wall
to weaken[4]. They are usually caused (formed) by the
rupture of either a cavernous segment aneurysm or a
weakened atherosclerotic artery[7,9]. Predisposing factors
associated with the development of spontaneous type A
CCFs are Ehlers-Danlos syndrome, fibromuscular dysplasia, and pseudoxanthoma elasticum[7,10,11]. Iatrogenic
alterations in flow dynamics and vascular pressure are
also suspected to contribute to spontaneous aneurysmal
rupture (following prior contralateral ICA occlusion)[1].
Most direct type A CCFs are high-flow shunts. Flow
rates in type A fistulas are variable and depend on the
size of the ostium and venous drainage. Type A fistulas
typically range from 1 to 5 mm in size (average = 3 mm),
typically small enough to be treated with detachable balloons with a mean volume of 0.28 L, equivalent to an
inflated balloon diameter of 7 to 9 mm[4,7,12,13].
Complete steal, which is defined as the complete absence of filling of the ICA above the fistula, occurs in 5%
of patients at diagnosis[7]. The complete steal phenomenon deserves enormous interest because it confirms that
the CCF is of high flow, that the rent is large, and that
the patient has an excellent collateral flow through the
circle of Willis if there are no contralateral deficits[11].
These lesions are usually unilateral although bilateral traumatic CCFs occur in approximately 1%-2% of
patients with traumatic CCFs[4]. These unusual bilateral
traumatic CCFs are generally associated with more severe head trauma, are more commonly fatal, and are
therefore less frequent[6]. Additionally, unilateral fistulas
may occur with bilateral or contralateral orbital symptoms, depending on the venous drainage route, via intercavernous communication[6,7,14]. Direct fistulae are less
likely to resolve spontaneously and may require intervention if symptomatic.
Indirect CCFs (types B, C and D) are also called dural fistulas and typically have low flow rates. The major
arterial supply to indirect fistulas arises from the internal
maxillary, middle meningeal, accessory meningeal and
ascending pharyngeal branches of the ECA, as well as
cavernous segment branches of the ICA[15].
Indirect CCFs tend to occur more frequently in postmenopausal women. The cause of these lesions is still
obscure, but infants presenting with dural fistulas in the
literature furnish some evidence to congenital origin[4,7,16].
Factors that may predispose patients to the development
of dural CCFs include hypertension, diabetes, pregnancy,
trauma and straining, atherosclerotic disease, cavernous
sinus thrombosis, sinusitis and collagen vascular disease. Trauma is less commonly associated with indirect
CCFs[1,5,7].
Traumatic indirect CCFs differ from the spontaneous
type because these lesions are usually single-hole fistulas
in which the accessory meningeal artery and middle meningeal artery are found to be the most common feeders[17].
techniques have resulted in several therapeutic modalities
becoming available and the endovascular approach has
evolved as the primary treatment option for the management of CCFs. This review provides an overview
of various treatment modalities with emphasis on the
endovascular approach. Furthermore, we will discuss the
classification, etiology, and clinical presentation including
pathophysiology and symptoms, diagnosis, indications
for emergency treatment and post-treatment follow-up
in CCFs.
CLASSIFICATION AND ETIOLOGY
Several classification schemes have categorized CCFs
according to etiology (traumatic or spontaneous), hemodynamic features (high versus low flow), or the angiographic arterial architecture (direct or indirect). The
angiographic classification defines the angioarchitecture
of the lesion on which a therapeutic strategy can be
planned. According to the angiographic findings, Barrow
et al[1] provided a detailed anatomical classification which
categorizes CCFs into four distinct types based on their
arterial supply. Type A fistulas are direct communications
between the internal carotid artery (ICA) and the cavernous sinus, usually associated with high flow rates. Indirect
fistulas (types B, C and D) are dural arteriovenous fistulas
fed by the meningeal arteries of the ICA, the external
carotid artery (ECA), or both. Type B fistulas have dural
ICA branches to the cavernous sinus, which are relatively
uncommon. Type C fistulas are supplied solely by the
dural branches of the ECA. The most prevalent form of
indirect CCF is the type D fistula that has dural ICA and
ECA branches to the cavernous sinus. Tomsick subclassified type D CCFs into type D1 or D2 depending on the
presence of a unilateral or bilateral arterial supply[2].
Traumatic CCFs often demonstrate a single direct
communication between the ICA and the cavernous
sinus and are almost always found to be type A direct
fistulas. However, spontaneous fistulas usually have multiple dural feeders and numerous microfistulas within the
cavernous sinus wall[3]. Spontaneous CCFs may fall into
any of the four angiographic categories defined by Barrow et al[1], because a type A shunt with high-flow characteristics can develop following spontaneous rupture of
an intracavernous ICA aneurysm.
Most direct CCFs occur at the proximal horizontal
intracavernous segment of the ICA in the vicinity of
the inferolateral trunk. With decreasing frequency, CCFs
are found to occur at the junction of the horizontal and
intracavernous ascending segments, posterior ascending
segment, junction of the anterior ascending and horizontal intracavernous segments, and the anterior ascending segment[4].
Traumatic disruption of the vessel wall is the most
common etiological factor for direct CCFs. Blunt and
penetrating head trauma as well as iatrogenic damage
(trans-sphenoidal surgery, glycerol rhizotomy, Fogarty
catheter manipulation for carotid angioplasty etc.) may
WJR|www.wjgnet.com
144
PATHOPHYSIOLOGY AND SYMPTOMS
Table 1 Carotid cavernous sinus fistula
The cavernous sinus normally receives drainage from
the superior and inferior ophthalmic veins as well as
superiorly from the sphenoparietal sinus, sylvian veins,
and cortical veins. The cavernous sinus drains posteriorly
through the inferior petrosal sinus (IPS) and superior
petrosal sinus to the jugular bulb, inferiorly through the
pterygoid plexus via emissary veins, and contralaterally
through the contralateral cavernous sinus[4,11].
A CCF allows highly pressurized arterial blood to
be transmitted directly into the cavernous sinus and
the draining veins, leading to venous hypertension. The
clinical presentation of CCF is a direct consequence of
elevation in intracavernous pressure and revised flow
patterns. The revised venous drainage of the CCFs may
head toward the ophthalmic venous system anteriorly;
the superior petrosal sinus, the IPS, or the basilar plexus
posteriorly; the sphenoparietal sinus laterally; the intercavernous sinus contralaterally; the pterygoid plexus via
the vein of the foramen rotundum and the vein of the
foramen ovale inferiorly. Most often, the direction of the
venous drainage is multidirectional[3,5].
The clinical features of CCFs are related to their size,
exact location, duration, adequacy and route of venous
drainage and the presence of arterial/venous collaterals[6].
The symptoms and signs that may be associated with
CCF are listed in Table 1.
The classic presentation for a direct, high-flow CCF is
the sudden development of Dandy’s triad: exophthalmos,
bruit, and conjunctival chemosis. Complete clinical triad
is not always found but most patients present with proptosis (90%), chemosis (90%), diplopia (50%), cephalic
bruit (25%), pain (25%), trigeminal nerve dysfunction, elevated intraocular pressure, and visual loss (up to 50%)[4].
Elevated pressure in veins draining the orbit may produce orbital venous congestion, transudation of interstitial fluid into the orbit with resultant proptosis, increased
intraocular pressure due to impaired drainage of the
aqueous humor, and secondary glaucoma. Elevated venous pressure and intraocular pressure can compromise
retinal perfusion and result in severely diminished visual
acuity[6]. Visual loss is one of the most worrying complications of CCFs and warrants immediate treatment.
Although minor deficits in visual acuity almost have complete resolution after closure of the fistula, severe visual
loss with loss of light perception rarely improves even if
the fistulous communication is obliterated[18]. Subconjuctival hemorrhages can be seen due to rupture of dilated
arterialized veins and, in addition, increased exposure
of the cornea may cause corneal damage. Intracranial
hemorrhage develops in 5% of patients, probably due
to revised venous drainage into the sphenoparietal sinus
with occlusion of other drainage pathways, resulting in
cerebral cortical venous hypertension[4,7].
External hemorrhage such as otorrhagia and epistaxis
can be seen in nearly 3% of cases in CCF[19]. Between 1%
Symptoms and signs
Exophthalmos, proptosis
Cephalic bruit
Conjunctival chemosis, ‘’red eye’’
Pain, headache
Trigeminal nerve dysfunction
Elevated intraocular pressure, secondary glaucoma
Diminished visual acuity, visual loss
Subconjunctival hemorrhages
Corneal damage
Intracranial hemorrhage
Otorrhagia
Epistaxis
Differential diagnosis
Vascular pathologies
Marginal sinus fistulas
(with a restriction of venous drainage via the jugular bulb)
Anomalous intracranial venous drainage
(sigmoid sinus hypoplasia/aplasia)
Cavernous sinus thrombosis
Intraorbital lesions
Fibrous dysplasia
Frontal sinus mucocele
Ocular neoplasms
Osteoma
Hemangioma
Inflammatory, allergic and infectious pathologies
Conjunctivitis
Endocrine pathologies
Thyroid ophthalmopathy
Indications for emergency treatment
Angiographic findings
Pseudoaneurysm
Large varix of the cavernous sinus
Venous drainage to cortical veins
Thrombosis of distant venous outflow pathways
Clinical signs and symptoms
Increased intracranial pressure
Rapidly progressive proptosis
Intracerebral, subarachnoid and external hemorrhage
Transient ischemic attack
Treatment modalities
Conservative management
(manual compression therapy and medical therapy)
Surgical management
Stereotactic radiosurgery
Endovascular management
Direct fistula
Transarterial treatment (preferred approach for direct CCF)
Detachable balloon occlusion
Transarterial coil and material embolization
Covered stent graft placement
(endovascular reconstruction of the parent artery)
Parent artery occlusion
Transvenous treatment
Transvenous detachable coil embolization
Liquid embolizing agents (n-BCA, Onyx)
Indirect fistula
Transvenous treatment (preferred approach for indirect CCF)
Transvenous detachable coil embolization
Liquid embolizing agents (n-BCA, Onyx)
Transarterial treatment
Transarterial coil and material embolization
CCF: Carotid cavernous sinus fistula; n-BCA: n-butyl 2-cyanoacrylate.
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and 2% of CCF cases manifest life-threatening massive
epistaxis caused by rupture of a pseudoaneurysmal cavernous sinus varix[4,7,20]. Most CCF cases that present with
epistaxis have a pseudoaneurysm or venous pouch that
entered the sphenoid sinus via a communication through
a basal skull fracture[19]. Bleeding from the veins draining
the ear canal can lead to otorrhagia[19].
Although the clinical manifestations may overlap,
indirect CCFs often do not demonstrate the classic triad
of symptoms. An ocular bruit may or may not be present with these lesions. The onset of symptoms of indirect CCFs is not as drastic as in direct CCFs. The symptoms and signs of indirect CCFs progress insidiously
and the majority of cases present with progressive glaucoma, proptosis or conjunctival injection (red eye)[4,7,15,21].
The natural evolution of indirect CCFs is variable
and the literature reports spontaneous resolution without treatment occurs in 10%-60% of cases, possibly due
to rethrombosis of the involved segment of the cavernous sinus[1,15]. Although these lesions have a tendency to
resolve spontaneously, patients suffering from progressive vision loss and intractable glaucoma require interventional therapy. Spontaneous thrombosis of traumatic
indirect fistulas is rare because of higher flow rates than
with the spontaneous type[17].
Exacerbation and remission of signs and symptoms
are the hallmark of dural CCFs, possibly due to cavernous sinus thromboses and rerouting of venous flow in
various directions[4]. Therefore any change in the symptoms must be followed up accurately because it may suggest alterations in venous drainage, possibly transitioning
to higher-risk patterns despite overt clinical improvement. The “white eye syndrome” defines the clinical
remission of ocular symptoms due to spontaneous occlusion of venous drainage pathways to the orbit and
potentially leaving only more dangerous venous drainage
routes[15].
pressures, cerebral edema and/or hemorrhage may be
encountered[4,5,7].
While CT angiography can be used as a first-line diagnostic tool in evaluating the presence of a CCF it has
some limitations. Despite its ability to reliably delineate
certain draining veins, CT angiography rarely depicts
small feeding arteries in dural CCFs or the exact site of
fistulous communication in direct CCFs. Moreover, this
technique cannot provide information about the bloodflow characteristics within fistulas[3].
Color Doppler imaging can assist in diagnosis and
follow-up of patients with CCFs. Increased velocity with
reversal of the direction of blood flow, arterial pulsations, and dilatation of SOV are characteristic findings[22].
Cerebral angiography is the gold standard for the
definitive diagnosis, classification, and planning of endovascular intervention in CCFs. The initial angiographic
evaluation can be used to obtain the following information: size and location of the fistula, differentiation of
direct from indirect lesions, presence of any associated
cavernous carotid aneurysm, presence of complete or
partial steal phenomena, assessment of the global cortical arterial circulation and collateral flow through the
circle of Willis, identification of high-risk features (e.g.,
cortical venous drainage, pseudoaneurysm, cavernous
sinus varix), venous drainage patterns, determination of
therapeutic route, associated vascular injuries (e.g., traumatic pseudoaneurysm, arterial dissection), identification
of any dangerous collateral pathways and evaluation of
carotid bifurcation before compression therapy[4-7,11,15].
In the evaluation of direct CCFs, identifying the exact location of fistulous communication in the cavernous
ICA can be challenging because of the high flow- related
washout of intra-arterial contrast and instantaneous opa
cification of the cavernous sinus. Angiographic highframe-rate imaging (> 5 frames/s) and rapid contrast
injection rates (7 or 8 mL/s) may assist in evaluating
the morphology of high-flow fistulas. High-flow CCFs
may be difficult to capture in digital subtraction angiography, even with selective high frame rates. Specific
maneuvers can be implemented to slow the fistula flow
and facilitate image capture. The Mehringer-Hieshima
maneuver consists of injecting the ipsilateral ICA and
manual compression of the ipsilateral common carotid
artery while filming at a slower frame rate. Use of this
maneuver slows the rate of opacification of the fistula
and thereby allows better delineation of the fistula site.
Another maneuver consists of using of a double-lumen
balloon catheter in the ipsilateral ICA with slow injection
of contrast at 1 mL/s at one or two frames per second.
Lastly, ipsilateral carotid compression during injection of
the vertebral artery, called the Heuber maneuver, opacifies the fistula through a patent posterior communicating
artery[4-7,11].
Tolerance for ICA occlusion should also be assessed
to identify the appropriate therapeutic choices before
embarking on a therapeutic intervention. Balloon test
occlusion is the currently accepted technique for evaluation. After confirmation of ICA occlusion, detailed
DIAGNOSTIC IMAGING AND
PRETHERAPEUTIC EVALUATION
Noninvasive imaging [computed tomography (CT), mag
netic resonance (MR), CT angiography, MR angiography,
Doppler] often is used in the initial work-up of a possible CCF. CT scan of the orbit usually demonstrates
proptosis of the affected globe, enlargement of the
extraocular muscles, dilatation and tortuosity of the superior ophthalmic vein (SOV), and enlargement of the
ipsilateral cavernous sinus. A noncontrast head CT scan
also allows for careful examination of possible cranial
injuries, such as bony fractures or intracranial hematomas. MR imaging findings in CCFs are similar to those
seen on CT with the addition of orbital edema and
abnormal flow voids in the affected cavernous sinus. In
the setting of a high-flow fistula and retrograde cortical
venous reflux, MR or CT studies may reveal dilatation of
leptomeningeal and cortical veins. In patients who have
cerebral venous congestion and elevated intracranial
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after the occlusion of venous outflow pathways[19].
Massive cortical venous drainage can eventually result
in hemorrhagic venous infarction and endovascular treatment should, therefore, be performed immediately[11].
Clinical signs and symptoms that are associated with
poor prognosis include increased intracranial pressure;
rapidly progressive proptosis, which may signify spontaneous thrombosis of venous outflow pathways to the
orbit; diminished visual acuity; hemorrhage (e.g., intracerebral, subarachnoid and external hemorrhage; otorrhagia or epistaxis); and transient ischemic attacks; which
may signify cerebral ischemia or impaired autoregulation
in cerebral perfusion, secondary to the chronic steal phenomenon caused by the fistulous communication. The
delineation of angiographic high-risk findings and recognition of the poor prognostic clinical features (Table 1)
should warrant emergent and aggressive interventional
treatment to improve outcome[4,15,19].
testing of mental status, speech, visual fields, facial
animation, and motor power in all four extremities are
performed. In the absence of significant deficit, the
patient is observed for 15-20 min and re-examined. If
the patient tolerates occlusion at normal blood pressure,
nitroprusside infusion is initiated and titrated to achieve
a mean arterial pressure two thirds of the patient’s baseline level. The patient is examined again and observed
for 15-20 min. Single proton emission computed tomography (SPECT) may be used to rule out significant asymmetry in perfusion during balloon test occlusion (BTO).
The SPECT evaluation can uncover the risk of suffering
a major stroke after permanent carotid occlusion even in
patients who seem to tolerate BTO during relative hypotensive challenge test[4].
Differential diagnosis
The differential diagnosis of CCF includes a wide spec
trum of pathologies (Table 1), so patients may be evaluated for endocrine, inflammatory, infectious and neoplastic etiologies before the presence of vascular pathology is
recognized, especially in the early phase of the disease.
Intraorbital lesions (osteoma, hemangioma, fibrous
dysplasia, frontal sinus mucocele, ocular neoplasms) may
cause ocular pain, exophthalmos, and ophthalmoplegia
although, bruits are not typically present[14].
Ocular findings of CCF may also mimic those associated with allergic/infectious conjunctivitis and thyroid
ophthalmopathy. However, ocular involvement in hyperthyroidism typically occurs bilaterally[14,15].
Imaging techniques (e.g., MR, CT) displaying prominent vessels within the orbit can lead the clinician to
consider vascular etiologies. Vascular pathologies that
can result in SOV dilatation include marginal sinus fistulas with a restriction or obstruction of venous drainage
via the jugular bulb[23], anomalous intracranial venous
drainage such as sigmoid sinus hypoplasia/aplasia[24], and
thrombosis of the cavernous sinus. Cerebral angiography must be performed to achieve a definitive diagnosis.
TREATMENT MODALITIES
The treatment modalities include conservative management, which consists of medical management and manual compression therapy; surgical management; stereotactic radiosurgery and endovascular repair via a transarterial
or transvenous route (Table 1).
Conservative management
A complete set of diagnostic angiographic evaluations is
required for choosing the appropriate treatment modality. While higher risk fistulas deserve the most aggressive
approach in order to eradicate the fistula, low-risk lesions with mild symptomatology may not require active
intervention and can be managed conservatively. Patients
with low-risk lesions can be given reassurance, educated
regarding potential changes in symptoms, and allowed
time for potential spontaneous closure of the fistula[11].
Spontaneous resolution of dural fistulas can occasionally occur within days to months after symptomatic presentation secondary to further thrombosis of the involved
segment of the cavernous sinus. Therefore, an accepted
practice is to treat the patient’s ocular symptoms medically with prism therapy or patching for diplopia, topical
β-adrenergic blockers and acetazolamide for elevated intraocular pressure, lubrication for proptosis-related keratopathy, and/or systemic corticosteroids if needed[7].
Furthermore, manual external carotid-jugular compression therapy may be initiated as a noninvasive treatment for indirect CCFs. The patient is instructed to
compress the carotid artery and jugular vein with the
contralateral hand for a period of 10 s while sitting or
lying down, four to six times each hour[7]. The aim of
the compression therapy is the transient reduction of arteriovenous shunting by decreasing arterial inflow while
simultaneously increasing the outlet venous pressure,
thereby promoting spontaneous thrombosis within the
fistula[25]. Use of the contralateral hand ensures that if
ischemia develops, the symptomatic arm will fall away
from the neck, thus allowing cortical revascularization
INDICATIONS FOR EMERGENCY
TREATMENT
Halbach et al[19] reviewed angiographic and clinical data
from 155 CCF patients to determine angiographic features associated with increased risk of morbidity and
mortality. These features comprise the presence of a
pseudoaneurysm, large varix of the cavernous sinus, venous drainage to cortical veins, and thrombosis of other
venous outflow pathways distant from the fistula.
Varix of the cavernous sinus and pseudoaneurysm
can both present with subarachnoid hemorrhage. Angiographic differentiation between a cavernous sinus varix
and a pseudoaneurysm may be difficult or impossible.
However, the clinical onset can be helpful to the differentiation process. The onset of the pseudoaneurysm is
usually coincidental with trauma, as opposed to the delayed onset of the cavernous sinus varix, which develops
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immediately[5]. Intermittent self-administered manual
carotid-jugular compression alone can result in a cure
in 30% of patients with spontaneous CCFs[7,26]. However, this treatment is usually ineffective in the high-flow
CCFs, which usually require endovascular intervention.
Cervical carotid bifurcation should be examined for
atherosclerotic changes using color Doppler or angiography before initiation of compression therapy[26]. Contraindications to manual carotid-jugular compression
are symptomatic bradycardia with carotid compression,
significant cortical venous drainage which may result in
venous infarction or hemorrhage during compression
therapy as well as clinical features that can signify difficulty in tolerating transient occlusion of ipsilateral ICA
such as atherosclerotic stenosis, ulceration of the carotid
artery, history of cerebral ischemia[5,7].
The possible adverse effects of carotid compression
may include hemodynamic or thromboembolic complications, vasovagal reactions, intracranial/retinal hemorrhage, clinical deterioration known as the “paradoxical
worsening phenomenon”, vertebral artery occlusion, brachial plexus/supraclavicular nerve injury and temporary
monocular blindness during carotid compression[26]. If
the decision not to treat a CCF interventionally is made,
the patient must be carefully followed for elevated intraocular pressure, progressive visual deterioration, neurological deficits and high-risk angiographic features[1,5,6].
fistulae inhibit the usage of radiosurgery as a first line
treatment[4].
Endovascular management
Recent advances in endovascular technology have made
available a number of different treatment options for
CCFs. As a result of these advances, the endovascular
approach has evolved as the primary treatment option
in clinical emergencies and following the failure of conservative therapy. Although the clinical manifestations
of direct and indirect fistulas may overlap, their natural
history and method of endovascular treatment are often
significantly different. The treatment choice is made according to the type, exact anatomy of the fistula, size
of the arterial defect, and operator/institutional preferences.
Direct fistulas occur from a tear in the cavernous
segment of the ICA or, less commonly, from the intracavernous rupture of an ICA aneurysm. The goal of
treatment in direct CCFs is to occlude the tear between
the ICA and the cavernous sinus while preserving the
patency of the ICA. This goal can be accomplished by
either transarterial obliteration of the fistula with a detachable balloon, transarterial or transvenous obliteration
of the ipsilateral cavernous sinus with coils or other embolic material, or deployment of a covered stent across
the fistula. Rarely, if the defect is large and cannot be
repaired, the ICA may need to be sacrificed or trapped[7].
Indirect fistulas consist of small dural arteriovenous
shunts between the meningeal branches of the ICA,
the ECA, or both, and the cavernous sinus. The goal
of treatment in this condition is to interrupt fistulous
communications and decrease pressure in the cavernous
sinus. This can be accomplished by occluding the arterial
branches supplying the fistula (transarterial embolization) or, more commonly, by occluding the cavernous
sinus that harbors the fistulous communications (transvenous embolization)[7]. The following sections provide
a brief overview of the various endovascular options for
the treatment of CCFs.
Surgical management
Early treatments for CCF consisted of various surgical
approaches such as ligation of the CCA, surgical trapping of the fistula, and surgical transvenous packing.
Although surgical management can be useful for both
direct and indirect CCFs, its role is limited because of
associated morbidity from cranial nerve deficits and residual fistulous communications. Indications for surgical
repair include compromised proximal arterial access that
prevents endovascular repair or causes it to fail. Surgical management remains a consideration for salvage of
failed endovascular treatments[4,7].
Complete angiographic documentation of the fistula
and BTO should be performed during preoperative evaluation. The appearance and condition of the superficial
temporal artery should also be noted because extracranial-to-intracranial bypass can be required to augment
blood flow when surgical sacrifice is unavoidable[4].
Endovascular repair: Direct CCFs
Detachable balloon occlusion: After Prolo and Hanberry described the use of a fixed balloon catheter to
block a CCF in 1971, Serbinenko et al[29] reported the first
case of successful embolization of a CCF from an endovascular approach using a detachable silicone balloon
with preservation of the ICA[13]. The use of detachable
balloon catheters has ushered a new age in the treatment
of type A direct CCFs. Transarterial balloon detachment
has been accepted as the endovascular treatment of
choice for direct CCFs since the 1980s.
The small-diameter vessels that often make up dural fistulas usually do not allow the introduction of a
balloon. However, the large carotid defect commonly
present in type A CCFs frequently permits transarterial
balloon occlusion of the fistula with preservation of the
ICA[1,4].
Radiosurgery
Stereotactic radiosurgery has emerged as an alternative treatment option and has been investigated for the
treatment of CCFs in several institutions. Gamma knife
radiosurgery can be used either alone or as an adjunct
therapy before/after endovascular intervention[27,28]. Although preliminary data show that radiosurgery is a safe
and effective alternative treatment for indirect CCFs,
the 22-mo average lag between treatment and complete
symptom relief is a significant drawback[21]. Furthermore, an inability to manage emergencies and traumatic
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A
B
C
Figure 1 A thirty one-year-old man who was diagnosed with carotid cavernous sinus fistula which developed secondary to a motor vehicle accident. A:
Digital subtraction angiogram view of left internal carotid artery (ICA) revealed laceration in the anterior loop and associated direct carotid cavernous sinus fistula; B:
Balloon detachment failed because of the site and small calibre of the fistula orifice. Coil embolization of the fistula was then performed with preservation of the ICA; C:
Post-procedural left ICA injection showed lack of residual filling, preservation of parent artery and detached coils at the site of fistula.
Coil and material embolization: Transarterial embolization with coils or other embolic material now is
the mainstay of endovascular treatment for high-flow
direct CCFs, given the limited availability of detachable balloons[7]. Transarterial CCF embolization can be
performed with the same technique as aneurysmal embolization. Embolization can be achieved with detachable platinum coils, silk and liquid embolic agents such
as n-butyl cyanoacrylate (n-BCA), and ethylene-vinyl
alcohol copolymer (EVOH)[5]. The standard transarterial
approach consists of placing a guiding catheter in the
cervical ICA. Next, a microcatheter is superselectively
advanced into the cavernous segment of the ICA and
through the tear into the cavernous sinus. Through this
microcatheter, embolic material is placed into the cavernous sinus[7].
Detachable platinum coils are preferred because of
their reliable and controlled deployment (Figure 1). The
coils can be adjusted easily or removed if the placement
is not optimal. Dense coil packing is performed using
the same principles as aneurysm coiling. Thrombogenic,
nonretrievable fibered microcoils can also be used but
these are associated with the risk of coil deposition into
the ICA if the microcatheter recoils into the parent
artery during placement[6]. The advantages of coil occlusion of CCFs, when compared with balloon embolization, include ease of access and availability of a variety
of sizes of the embolic device. Potential disadvantages
include slower gradual occlusion of the fistula, which increases procedure time, and the risk of incomplete fistula occlusion with loss of transarterial access; a loss which
would then require a second transvenous approach[4].
The transvenous approach is discussed more thoroughly
under the heading “transvenous embolization”.
Complications of transarterial coil embolization include thromboembolus, ICA compromise by protruding
coil mass, and ICA dissection[4]. For preventing the retrograde herniation of the embolic material into the parent
artery and distal intracranial circulation, the assistance
of a nondetachable balloon (balloon-assist technique)
or a porous stent may be preferred especially in the set-
The technique for detachable silicone balloon occlusion of a CCF involves transfemoral access to the proximal CCA with a 7-French guide catheter or long 6-French
sheath. Next, the uninflated balloon is advanced to the
distal end of the guide catheter; at this point, roadmap
imaging is used for further balloon positioning. The
balloon offers the advantage of being able to be flowdirected through the fistula and into the cavernous sinus.
The balloon is inflated to a volume larger than the orifice
of the fistula to prevent its retrograde prolapse into the
ICA and then is detached[7]. Following successful balloon
deployment, cerebral angiography is repeated to ensure
closure of the fistula and patency of the ICA. A single
silicone balloon is usually sufficient for most CCFs.
However, multiple balloons may be required in the setting of a large tear in the ICA.
The advantage of balloon occlusion of a CCF is
the ability to occlude the fistula rapidly with preservation of the ICA. However, technical difficulties can be
encountered. The size of the cavernous sinus and the
fistula may affect the success rate of detachable-balloon
embolization of a CCF. The cavernous sinus must be
large enough to accommodate the detachable balloon/
balloons for embolization. The size of the fistula must
be smaller than the inflated balloon, but large enough
to allow access for a deflated or partly inflated balloon.
However, the size of the fistula should not be too large,
because the embolization balloon may retract to the ICA
on inflation in the cavernous sinus[30]. To provide easier
navigation of the balloon into the cavernous sinus and
prevent protrusion of the inflated balloon through the
fistula site to narrow the adjacent ICA lumen, Teng et
al[30] developed a double-balloon technique.
Inadequate embolization may be seen due to early
balloon detachment, deflation or rupture by contact
with a bony fragment[4,5,7,31]. As a rare complication, the
balloon can migrate to the venous side of the treated fistula resulting ophthalmoplegic signs due to mechanical
compression of cranial nerves in close proximity to the
cavernous sinus[32,33].
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A
B
D
E
C
Figure 2 A fifty two-year-old woman who presented with galactorrhea due to hypophyseal adenoma underwent transsphenoidal surgery. During the operation internal carotid artery laceration and massive arterial hemorrhage occurred. A: T1 W C+ coronal magnetic resonance imaging view demonstrating hypointensity at
the left hypophyseal region which was consistent with hypophyseal adenoma; B: Immediate defect source analysis revealed a defect at the anteromedial wall of right
internal carotid artery (ICA) and associated carotid cavernous sinus fistula; C: Position of the stent-graft closing the orifice of the fistula; D: Postprocedural right ICA
injection demonstrating complete obliteration of the fistula and concentric luminal stenosis at the petrous segment associated with mechanic vasospasm secondary to
guide-wire and stent manipulation; E: Third month control angiography revealed regular parent artery contours, absence of recurrent fistula filling and intimal hyperplasia within the stent.
ting of a large tear in the ICA[4,5]. Stents also allow initial
reconstruction of the damaged segment of the ICA and
increase the ability to successfully treat fistulas without
parent artery sacrifice[34].
dovascular technique, their usage as a widely accepted
method in traumatic CCF is limited due to lack of configurations compatible with intracranial use and longterm safety data.
Covered stent graft placement: Recent advances in
endovascular techniques such as placement of polyfluorotetraethylene-covered stents have created alternatives
to ICA sacrifice in traumatic arterial damage, especially
in the setting of an unsuccessful balloon test occlusion
study. Covered stent grafts can be extremely useful for
the immediate obliteration of a direct CCF, while preserving ICA patency (Figure 2). Additionally, they may
decrease the risk of ischemic stroke by preserving the
involved artery while simultaneously sealing the site of
the fistula[5,7,35]. Covered stent grafts have the technical
disadvantage of limited longitudinal flexibility, making
it difficult to navigate them through the tortuosity of
the intracranial vasculature. Furthermore, the irritation
caused by the stiffness of covered stents may frequently
lead to periprocedural vasospasms, especially at the ends
of the stent (Figure 2). Intra-arterial nimodipine and
papaverine infusion can be used for the prevention and
resolution of these vasospasms[36,37].
The complications of this procedure include endoleak,
coverage of vital perforators, dissection and rupture[7,35].
Although covered stent grafts offer a promising en-
Parent artery occlusion: Arterial sacrifice may be required as a life-saving emergency treatment when endovascular occlusion of a direct CCF with preservation of
the ICA is not feasible due to extensive traumatic vesselwall damage, active hemorrhage or a rapidly expanding
hematoma of the soft tissues. Emergency surgical occlusion of ICA has been relegated to historical status with
the advance of therapeutic endovascular techniques,
which can be performed immediately after diagnostic
therapy under local anesthesia, thereby allowing monitorization of the neurological status[5,13,35].
If a decision to perform endovascular arterial sacrifice is made, assessment of the collateral flow and patient’s ability to tolerate ICA occlusion is paramount. In
cases of complete steal presenting without any ischemic
symptom, the quality of collateral flow through circle of
Willis is confirmed and a test occlusion may be unnecessary. If anterior and posterior communicating artery collaterals are found to be patent, the safety of parent artery occlusion is also high. Otherwise, balloon occlusion
test is recommended to ensure distal perfusion from
collateral circulation before permanent occlusion[4,7].
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A
B
C
D
E
F
Figure 3 A thirty one-year-old male patient with right ophthalmoplegia following head trauma was found to have a direct carotid cavernous sinus fistula. A,
B: Frontal (A) and lateral (B) digital subtraction angiogram views of right internal carotid artery (ICA) demonstrating laceration of ICA, pseudoaneurysm in the cavernous ICA and direct carotid cavernous sinus fistula; C: After considering the presence of the pseudoaneurysm, two detachable balloons were positioned to occlude the
parent artery; D: Right CCA digital subtraction angiogram after balloon occlusion of the ICA showing complete obliteration of the fistula; E, F: Posttreatment left ICA (E)
and left vertebral artery (F) injections demonstrating reconstruction of the right ICA area.
Endovascular repair: Indirect (type B, C, D) CCFs
Transvenous embolization: Although transvenous embolization is an alternative technique in direct CCFs that
cannot be treated by transarterial route, it is the preferred
treatment for indirect CCFs. For indirect CCFs, transvenous techniques have precedence over transarterial
methods because of their simplicity, lower ischemic risk,
higher success rates and capability to cure the fistula in a
single session. The aim of the transvenous approach is to
catheterize the abnormal cavernous sinus superselectively
and to occlude the fistula without rerouting venous drainage to cortical structures[4,5,7,21].
Navigation through the venous system and mechanical perforation are technical challenges in this procedure.
Furthermore, usage of the transvenous approach in the
acute fistula stages may be hazardous because the venous
walls have not undergone wall thickening via arterialization[5].
Current microcatheter technology permits access to
the cavernous sinus via multiple routes. The most commonly used venous pathway for cannulation of the cavernous sinuses is via the IPS. This transvenous route is
usually used from a posterior direction through the internal jugular vein and the IPS up to the pathologic shunts
of the cavernous sinus[5,7,15]. Anatomically, catheterization
of the cavernous sinus through the IPS is feasible in the
great majority (99%) of cases. However, accessibility of
the cavernous sinus through the IPS can become technically difficult as the disease progresses. Difficulties may
ICA occlusion can be performed with various endovascular techniques such as coil, balloon (Figure 3) and
vascular plug embolization. Occlusion of the ipsilateral
ICA is performed with coil embolization in a distal-toproximal approach to prevent the retrograde arterial filling of the fistula from the supraclinoid ICA[5,7]. Recently,
the Hydrocoil Embolization System (HES) has been introduced, which can achieve high rates of volumetric occlusion compared with that in platinum coils. The HES
device consists of a carrier platinum coil coupled with
an expandable hydrogel material that increases in volume
on contact with blood and facilitates vessel sacrifice, decreasing the procedure and fluoroscopy times. Hydrogelcoated detachable coils can be utilized to achieve rapid,
precise, targeted parent artery occlusion procedures,
even in short segments of vessel[7,37].
Fistula entrapment can be performed with the aid
of two ballons, which are positioned proximal and distal
to the fistula. If it is impossible to navigate either a balloon or a microcatheter beyond the fistula to allow distal
control, a microcatheter is navigated into the supraclinoid segment of the carotid artery via the anterior or
posterior communicating arteries with the aid of marked
retrograde flow to the fistula. Thereby, endovascular
trapping of the traumatic CCF can be performed by a
combination of proximal balloon occlusion and distal
trapping with coils[38,39]. Deployment of a vascular plug
is an alternative method but this device is limited to occlusions below the base of the skull because of the poor
navigability in the distal ICA[40].
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A
B
D
E
C
Figure 4 A forty-year-old woman with chemosis of the left eye and diplopia was found to have a dural carotid cavernous sinus fistula. A, B: Frontal (A) and
lateral (B) injections of the right common carotid artery demonstrating left dural carotid cavernous sinus fistula with antegrade drainage; C: Access to the fistula site
through the contralateral (right inferior petrous sinus) transvenous route and positioning of the microcatheter; D: Coil embolization within the microcather extending
into the venous compartment of the fistula; E: Posttreatment frontal digital subtraction angiogram view of right internal carotid artery demonstrating obliteration of the
fistula and lack of residual filling.
result from occlusion of the IPSs due to longstanding
venous hypertension, prior embolization, or both[18,41].
Because the drainage of the pons and brainstem may be
via the IPS, and any damage to these veins may result in
fatal venous thrombosis, the catheterization of the IPS
merits special attention[6].
Anterior approach through the SOV via the facial
vein provides a convenient alternative pathway for transvenous embolization of dural CCFs when cannulation
of the IPS is not successful, thereby increasing the technical success rate[18].
Less commonly used transvenous approaches are
through the lateral pterygoid plexus, superior petrosal
sinus, cortical veins, the inferior ophthalmic vein or the
contralateral IPS (Figure 4) or SOV with access into the
ipsilateral cavernous sinus through the circular sinus[5,7,15].
Alternatively, in extremely difficult cases of venous
occlusion, stenosis, or marked tortuosity, access to the
cavernous sinus can be provided by combined surgical
and endovascular approaches (Figure 5)[7].
Direct transorbital puncture or indirect puncture
through the superior or inferior ophthalmic vein allows
straightforward access to the cavernous sinus[42]. Surgical access also may be obtained into the SOV, superficial
middle cerebral vein, or sphenoparietal sinus leading to
the cavernous sinus. Quiñones et al[21] proposed surgical exposure of the SOV and retrograde venous catheterization in indirect CCF patients who present with
WJR|www.wjgnet.com
decreased visual acuity and predominant anterior venous
drainage. Surgical exposure permits direct visibility and
immobilization of the SOV, with less risk of rupture of
the arterialized vein than with direct puncture. This approach also allows immediate control of possible orbital
hemorrhage. The potential risks of the direct puncture
or surgical exposure are orbital hemorrhage, nerve damage and laceration of the ICA resulting in direct CCF,
globe puncture, and infection[21,42].
Sonographically guided direct percutaneous access
through the facial vein can be performed to eliminate
the risk of complications, such as intra- or retro-orbital
hemorrhage, cranial nerve damage, subarachnoid or intracranial hemorrhage, and arterial damage, which may
result from direct puncture of the SOV or the cavernous
sinus. Reduction in radiation exposure and ease of manual compression of the puncture site after the procedure
are additional advantages of this procedure although
the small diameter of the facial vein may cause technical
limitations[41]. Following successful catheterization of the
cavernous sinus, various embolic materials such as coils,
n-BCA, and EVOH, can be used either alone or in combination.
The advantages of coils include their radiopacity,
ease of use, and the ability to redeploy or remove the
devices if the initial placement is not optimal. However,
there may be difficulty in achieving adequate volumetric
packing or complete occlusion, especially in septated
152
A
B
D
E
C
Figure 5 In extremely difficult cases of venous occlusion, stenosis, or marked tortuosity, access to the cavernous sinus can be provided by combined
surgical and endovascular approaches. A, B: Left external carotid artery lateral (A) and left internal carotid artery lateral (B) digital subtraction angiogram views
of an uncovered dural carotid cavernous sinus fistula which has antegrade drainage; C: Posterior access to the fistula site was not feasible, so access was gained
through the superior ophthalmic vein following surgical angular vein cut-down; D: Coil detachment through a microcatheter into the fistula site; E: Posttreatment left
common carotid artery injection revealed lack of residual filling of the fistula.
necessary because of technical difficulties associated
with superselective distal access into small-sized arterial feeders. Additionally, potential complications (e.g.,
thromboembolic stroke, cranial nerve palsies) restrain
the choice of the transarterial approach as the mainstay
treatment of spontaneous indirect CCFs. Therefore,
transarterial embolization is typically used only to reduce
arterial inflow before transvenous occlusion for highflow indirect CCFs and as a viable alternative after failure of transvenous attempts[4,7].
The management strategy for traumatic indirect
CCFs differs from that for spontaneous indirect CCFs.
For traumatic lesions, transarterial embolization may
be preferred because the single arterial supply is large
enough to provide access to the feeder and cavernous
sinus by microcatheter. The transvenous approach is
reserved for cases in which failure or recurrence of the
fistula is observed and arterial access to the site of the
fistula is not feasible[17].
Transarterial techniques involve distal catheterization
of the small meningeal branches supplying the fistula.
Ideally, placement of the superselective microcatheter
is performed with the microcatheter tip as close as possible to the point of fistulous communication. Once a
satisfactory microcatheter position is achieved, liquid
embolic agents (n-BCA, EVOH) are injected under fluoroscopic control with the goal of occluding the fistulous
connections and penetrating the cavernous sinus. Al-
cavernous sinuses. Moreover, the reported rates of cranial nerve paresis are higher with coil embolization,
probably because of their mass effect[7]. Consequently,
transvenous liquid embolic agents are being used increasingly, either alone or in combination with platinum
coils. EVOH has the capability of mechanical occlusion
without vessel wall adhesion. Its nonadhesive nature decreases the risk of microcatheter retention and allows a
slow single injection of embolic agent with concomitant
angiogram checks. It must be remembered that EVOH
has a propensity for retrograde filling of arterial feeders
and must be used cautiously in order to prevent retrograde reflux into the ICA and ECA branches[7,43].
n-BCA has the advantages of rapid polymerization
and permanent occlusion of the injected feeders. However, in contrast to EVOH, catheter repositioning during
embolization and the reflux-hold-reinjection technique
cannot be performed in embolization with n-BCA. Prolonged injections are not possible and as they may risk
gluing the catheter because of the adhesive nature of
n-BCA[7,43]. The polymerization of n-BCA is accompanied by heat production, which may lead to a degree of
angionecrosis[6].
Transarterial embolization: Transarterial embolization
of indirect low-flow CCFs generally is cumbersome be
cause of the small size, complex anatomy, and multiplicity of arterial feeders. Multiple staged sessions may be
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153
though coils and particulate agents have been used, these
agents used alone cannot provide permanent occlusion
of the fistula[7].
2
POSTOPERATIVE IMAGING AND
FOLLOW-UP
3
While ocular symptoms resolve rapidly following successful treatment, patients may become transiently more
symptomatic due to propagation of thrombus throughout the cavernous sinus and extending into the SOV. This
clinical deterioration is called the “paradoxical worsening phenomenon” and can be observed in patients after
transarterial embolization, gamma knife radiosurgery or
conservative treatment. Although disconcerting to the patient, such symptoms usually resolve spontaneously over
time. A brief course of corticosteroids may help to reduce inflammation associated with sinus thrombosis[15,26].
Severe progression of the ocular manifestations in
the early postoperative period and recurrence of symptoms may suggest recurrent CCF. In cases where recurrent CCF is suspected, control cerebral angiography
should be performed and possible re-treatment should
be planned. After complete resolution of the ocular
manifestations, additional control imaging and follow-up
is not required.
In patients who were treated by the placement of a
covered stent, stent-graft patency should be followed
carefully as long-term safety data are lacking[35,44]. Longterm follow-up is necessary in CCF cases treated by
parent artery occlusion to monitor the possible development of hemodynamic aneurysm in the anterior communicating artery, due to increased flow and alteration in
hemodynamics.
Patients who have fistulas demonstrating cortical
venous rerouting or partially treated CCFs may show
clinical deterioration. In such cases, urgent examination
should be performed and treatment should be planned
if required. Acute onset of focal neurological deficit deserves immediate clinical evaluation and control imaging.
4
5
6
7
8
9
10
11
12
13
CONCLUSION
With advances in catheter design, embolic agents, and
fluoroscopic imaging equipment, interventional neuroendovascular techniques have become the preferred
treatment modality for carotid cavernous fistulas and
favorable long-term outcomes have been achieved. The
endovascular approach should be tailored to individual
cases according to the type, exact anatomy, and extent of
each fistula. With increasing knowledge about novitious
endovascular techniques, such as placement of covered
stent grafts, higher success rates can be achieved with
preservation of the ICA even in urgent cases.
14
15
16
17
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P- Reviewer Karmy-Jones R S- Editor Gou SX
L- Editor Hughed D E- Editor Xiong L
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WJ R
World Journal of
Radiology
[email protected]
doi:10.4329/wjr.v5.i4.156
ORIGINAL ARTICLE
Asymmetrically hypointense veins on T2*w imaging and
susceptibility-weighted imaging in ischemic stroke
Ulf Jensen-Kondering, Ruwen Böhm
vessel sign was 54% (range 32%-100%) for T2* (668
patients) and 81% (range 34%-100%) for SWI (334
patients). There was rare mentioning of interrater
agreement (6 publications, 210 patients) and reliability
(1 publication, 20 patients) but the numbers reported
ranged from good to excellent. In most publications (n
= 22) perfusion MRI was used as a validation method
(617 patients). More patients were scanned in the
subacute than in the acute phase (596 patients vs 320
patients). Clinical outcome was reported in 13 publications (521 patients) but was not consistent.
Ulf Jensen-Kondering, Institute of Neuroradiology, University
of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
Ruwen Böhm, Institute of Experimental and Clinical Pharmacology, University of Schleswig-Holstein, Campus Kiel, 24105
Kiel, Germany
Author contributions: Jensen-Kondering U and Böhm R performed the literature research, analyzed the data, and wrote and
revised the paper.
Correspondence to: Dr. Ulf Jensen-Kondering, MD, Institute
of Neuroradiology, University of Schleswig-Holstein, Campus
Kiel, Haus 41, Arnold-Heller-Str. 3, Haus 41, 24105 Kiel,
Germany. [email protected]
Telephone: +49-431-5974806 Fax: +49-431-5974913
Received: December 19, 2012 Revised: February 8, 2013
Accepted: March 6, 2013
CONCLUSION: The low presence of vessels signs on
T2*w imaging makes SWI much more promising. More
research is needed to obtain formal validation and
quantification.
Abstract
AIM: To review the literature on the assessment of venous vessels to estimate the penumbra on T2*w imaging and susceptibility-weighted imaging (SWI).
Key words: Acute ischemic stroke; Oxygen extraction
fraction; Susceptibility-weighted imaging; T2*; Penumbra
METHODS: Literature that reported on the assessment of penumbra by T2*w imaging or SWI and used
a validation method was included. PubMed and relevant stroke and magnetic resonance imaging (MRI)
related conference abstracts were searched. Abstracts
that had overlapping content with full text articles
were excluded. The retrieved literature was scanned
for further relevant references. Only clinical literature
published in English was considered, patients with
Moya-Moya syndrome were disregarded. Data is given
as cumulative absolute and relative values, ranges are
given where appropriate.
Core tip: Thrombolytic therapy with intravenous tissue
plasminogen activator is the only approved therapy for
acute ischemic stroke. The detection of hypointense
venous vessels with blood oxygenation level dependent
(BOLD) imaging to assess the amount of penumbral
tissue in acute ischemic stroke has emerged as a little
noticed alternative imaging technique. In the present
state the combined use of perfusion and BOLD imaging
would provide further complementary information to
help visualize and understand the role of the ischemic
penumbra.
RESULTS: Forty-three publications including 1145
patients could be identified. T2*w imaging was used
in 16 publications (627 patients), SWI in 26 publications (453 patients). Only one publication used both
(65 patients). The cumulative presence of hypointense
Jensen-Kondering U, Böhm R. Asymmetrically hypointense
veins on T2*w imaging and susceptibility-weighted imaging in
ischemic stroke. World J Radiol 2013; 5(4): 156-165 Available
from: URL: http://www.wjgnet.com/1949-8470/full/v5/i4/156.
htm DOI: http://dx.doi.org/10.4329/wjr.v5.i4.156
WJR|www.wjgnet.com
156
Jensen-Kondering U et al . Asymmetrically hypointense veins on T2* and SWI
Statistical analysis
Data is presented as cumulative absolute and relative
percentage values. Ranges are given where appropriate.
INTRODUCTION
Assessment of penumbral tissue is a key concept to iden
tify patients who may benefit from acute stroke therapy.
One has to keep in mind that the penumbra cannot be
regarded as a homogenous single entity but rather a gra
dient from ischemic core to normal tissue[1]. Therefore,
whatever imaging method is used for penumbra detec
tion, one or more arbitrary cut-off values need to be
chosen to segment the brain image into normal tissue
and ischemic core, with one or more penumbras in be
tween. Despite oxygen-15 positron emission tomography
(15O-PET) being the gold standard to define the penum
bra[2], its clinical use is very limited due to logistical and
practical reasons. As a substitute, magnetic resonance
imaging (MRI) with diffusion-weighted image (DWI)perfusion-weighted image (PWI) mismatch is com
monly used in the clinical work-up of stroke patients[3].
Although widely utilized, it has some methodological
limitations. The DWI lesion does not seem to represent
irreversibly damaged tissue[4], nor can PWI differentiate
between penumbra and benign oligemia[5]. Recently, the
use of blood oxygenation level dependent (BOLD) im
aging as an alternative to DWI-PWI mismatch has stirred
a lot of interest[6]. It is sensitive to an increased concen
tration of deoxyhemoglobin (DHb) and may therefore
be an indirect marker of oxygen metabolism. There are
two approaches to detect an increased oxygen extraction
fraction (OEF) using BOLD: assessment of tissue and
assessment of draining veins containing an increased
fraction of DHb.
As the latter has been described by several authors,
we will focus this review on the assessment of venous
vessels to estimate the amount of penumbral tissue. We
provide an overview on published data, take a glimpse at
experimental studies and critically appraise the method’s
clinical value and suggest future research.
RESULTS
Forty-three papers, conference abstracts and reports of
cases (partially from review articles) with a total of 1145
patients were identified[7-49]. For details of the reviewed
studies with relevant information, see Tables 1 and 2.
Sixteen publications (627 patients) were identified using
T2*w imaging (Table 1)[7-22]. SWI was used in 26 publica
tions (453 patients, Table 2)[23-48]. In one publication both
T2* and SWI was used (65 patients, Table 2)[49].
The cumulative presence of hypointense vessels was
54% (range 32%-100%) of 668 patients for T2* and 81%
(range 34%-100%) of 334 patients for SWI. However,
more single patient case reports were identified for SWI.
Inter-rater agreement was reported in six publications
(210 patients)[7,14,15,17,19,21] and ranged from good (κ =
0.7)[14] to excellent (intraclass correlation = 0.99)[17]. The
agreement between penumbra on T2*w imaging and dy
namic susceptibility contrast (DSC)-MRI was quantified
in one publication (20 patients)[17] and was 0.92 [time to
peak and relative cerebral blood flow (CBF)] to 0.96 (mean
transit time and relative cerebral blood volume).
In most publications perfusion MRI either utilizing
DSC-MRI (n = 17441 patients)[7,10-12,16,17,20,23,25,28,31-34,37,40,43] or
flow sensitive alternating inversion recovery (n = 4111 pa
tients)[14,15,19,38] combined with DWI/apparent diffusion co
efficient (ADC) was used for validation (perfusion method
not stated in one publication, 65 patients[49]). In three pub
lications one additional method was used [digital subtrac
tion angiography (DSA)[16], iodine-123 iodoamphetamine
single-photon emission computed tomography [20] or
magnetic resonance angiography (MRA)[43]]. Conventional
MRI (DWI/ADC, MRA, structural imaging) was used
in 14 publications (315 patients)[8,9,21,24,26,27,29,30,35,36,44,46,47], in
three publications[39,41,45] computed tomography or clinical
data were used as additional methods. Clinical informa
tion and unspecified imaging was used in one publication
(59 patients)[48]. One publication used clinical data alone
(30 patients)[48]. DSA alone was used in one publication (22
patients)[13]. In one case series gold standard 15O-PET was
used for validation (number of patients not stated)[18].
Time of onset ranged from 3 h to 7 d with more
publications reporting on the subacute (> 6 h, n = 15579
patients)[9,12,14,15,23,24,32,34,35,38,39,40,42,44,49] than the acute phase
(≤ 6 h, n = 11337 patients)[7,10,11,13,16,17,19,21,22,25,47]. In one
publication time from onset ranged from 3.5 to 8.5 h (49
patients)[41]. It was not provided in 16 publications (170
patients)[8,18,20,26-31,33,36,37,43,45,46,48].
Outcome was reported in 13 publications. In four
publications (185 patients)[10,19,21,39] no correlation with
clinical outcome was found. In four publications (107
patients)[11,13,16,22] a larger National Institute of Health
Stroke Score improvement was observed, while in an
other four publications a worse outcome was found (210
patients)[7,35,41,48]. In one publication there was a better
MATERIALS AND METHODS
Publications that reported on the assessment of the
penumbra in ischemic stroke by hypointense vessels
on T2*w imaging and/or SWI and performing at least
one validation method were included. Search terms in
PubMed were “T2*”, “GRE”, “SWI”, “susceptibility
weighted imaging”, “leptomeningeal vessels/veins”, “hy
pointense”, “stroke”. Full text articles and published ab
stracts from major stroke and MRI related conferences
(International Stroke Conference, European Stroke Conference,
World Stroke Congress, World Congress of Neurology, ISMRM,
ASNR, etc.) were included in this review. Only literature
published in English and dealing with human subjects
was included, patients with Moya-Moya syndrome were
disregarded. The reference section of retrieved publica
tions was manually searched for further relevant litera
ture. Abstracts with obviously overlapping content with
full text articles that were probably first presented as an
abstract and subsequently published as full text articles
were excluded.
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157
Table 1 Publications using T2*w sequences
Ref.
n
Field
strength
Hermier et al[7]
49
Liebeskind et al[8]
Liebeskind et al[9]
Occluded Time from
vessel
onset
Validation
method
Results
1.5 T
Anterior
circulation
6h
DWI;
DSC-MRI
91
83
NS
NS
MCA
MCA
MRA; DWI
MRA
Hermier et al[10]
48
1.5 T
NS
NS
Median
2d
6h
Seo et al[11]
20
3T
ICA, MCA
6h
Sohn et al[12]
86
NS
ICA, MCA
12 h
Ha et al[13]
22
3T
MCA
6h
Morita et al[14]
24
3T
ICA, MCA
12 h
Harada et al[15]
Ha et al[16]
24
35
3T
NS
NS
MCA
12 h
6h
Kaya et al[17]
20
3T
Large
arteries
3h
NS
(case
series)
33
2
1.5 T
NS
NS
AVV obvious in 8/49, moderate in 15/49 patients, inter- and intra-observer
reliability r > 0.9; Correlated with higher baseline NIHSS, larger DWI and
PWI lesions, worse outcome, intracranial haemorrhage and more severe
hemodynamic impairment
Hypointense vessels in or adjacent to the infarct in 40/91 patients
Unilateral hypointensity of the basal vein of Rosenthal was noted in 27/83
patients on the side of the occlusion
AVLV present in 17/48 patients, within TTP lesion, not concordant with DWI
lesion; No impact on clinical status and final stroke volume
HVS present in 13/20 patients. Patients with asymmetrical HVS had better
NIHSS improvement (8.1 ± 5.7 vs 2 ± 4.2)
Present in 59/86 patients; HypoTCV associated with large perfusion defect,
but low cholesterol and haemoglobin level may obscure its visibility
Present in 7/22 patients. Patients with HLV showed larger baseline NIHSS
(16.9 ± 3.4 vs 11.7 ± 5.3) and major improvement (≥ 8 points) was observed
more often. It corresponded with delayed venous wash-out on DSA
CVS present in all patients, BS present in 23/24 patients, good interobserver
agreement (κ = 0.7). Area defined by CVS/BS similar to hypoperfused area
κ for cortical and deep vessel signs 0.84 and 0.72, respectively
HLV present in 12/35 patients. Patients with HLV had larger NIHSS
improvement at 7 d (6.5 ± 4.6 d vs 0.5 ± 6.7 d) and bigger TTP-DWI mismatch.
HLV corresponded with delayed venous wash-out
Present in all patients. Very good correlation of RMHV with final infarct
(r = 0.91) and MTT/rCBV lesion (r = 0.96); very high interobserver correlation
(ICC = 0.99)
Enhanced venous contrast (hypointensity and enlargement of veins),
ipsilateral corresponding increased OEF
3T
3T
ICA, MCA
MCA
(stenosis)
3h
NS
Rosso et al[21]
60
3T
6h
Ryoo et al[22]
30
NS
Anterior
circulation
ICA, MCA
Kinoshita et al[18]
Harada et al[19]
Tada et al[20]
6h
DWI;
DSC-MRI
DSC-MRI;
DWI
DSC-MRI;
DWI
DSA
DWI;
FAIR
FAIR; DWI
DSC-MRI;
DWI; DSA
DWI;
DSC-MRI
15
O-PET
FAIR; DWI
DWI;
DSC-MRI;
123
I-IMP SPECT
DWI;
MRI
Clinical
IschV present in 79% (κ = 0.83); Not correlated with worse outcome
Area defined by ischemic signs was similar to area of hypoperfusion on MRI
and SPECT
VTV present in 58.3% (κ = 0.895), correlated with larger infarcts and
haemorrhage but not with baseline or follow-up NIHSS
GRE vein present in 15/30 patients. Early neurological improvement
(∆NIHSS ≥ 8 or NIHSS ≤ 2 at 24 h) more frequently observed with GRE vein
(8 patients vs 1 patients, P = 0.014)
NS: Not stated; ICA: Internal carotid artery; MCA: Middle cerebral artery; DWI: Diffusion-weighted image; DSC-MRI: Dynamic susceptibility-contrast
magnetic resonance imaging; MRA: Magnetic resonance angiography; AVV: Abnormal visibility of transcerebral veins; PWI: Perfusion-weighted image;
AVLV: Abnormal visualization of leptomeningeal vessels; TTP: Time to peak; CVS: Cerebral vasospasm; BS: Brush sign; HVS: Hyperintense vessel sign;
HLV: Hypointense leptomeningeal vessels; 15O-PET: Oxygen-15 positron emission tomography; CT: Computed tomography; HypoTCV: Hypointense
transcerebral or cortical veins; FAIR: Flow sensitive alternating inversion recovery; 123I-IMP SPECT: Iodine-123 iodoamphetamine single-photon emission
computed tomography; DSA: Digital subtraction angiography; NIHSS: National Institute of Health Stroke Score; RMHV: Region of multiple hypointense
vessels; MTT: Mean transit time; rCBV: Relative cerebral blood volume; ICC: Intraclass correlation; OEF: Oxygen extraction fraction; VTV: Visibility of the
transcerebral veins; GRE: Gradient-echo.
clinical outcome with normalized vessel appearance after
successful recanalization (19 patients)[47].
The occluded vessel was located in the anterior cir
culation in 33 publications (864 patients)[7-9,11-14,16,19,21,22,
24-40,44-47,49]
. It was not stated in seven publications (250 pa
tients)[10,15,18,23,41,42,48]. Other publications considered “large
arteries” (20 patients)[17], the basilar artery (1 patient)[47],
the posterior cerebral artery (1 patient)[46], TIA (9 pa
tients)[43] and critical MCA stenosis (2 patients)[20].
Field strength was 1.5 T in 10 publications (180 pa
tients)[7,10,18,23,25,26,31,37,40,46], 3 T in 11 publications (285 pa
tients)[11,13-15,17,19-21,28,38,39] and not stated in 22 publications
(662 patients)[8,9,12,16,22,24,27,29,30,32-36,41,42,43-45,48,49] while in one
publication (19 patients)[47] both field strengths were used
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but not identified for individual patients.
For detailed differences between T2*w imaging and
SWI see Table 3. A number of terms have been used to
describe the finding of hypointense venous vessels on
T2*w or SWI images: Abnormal visualisation of lepto
meningeal vessel, abnormal visualisation of transcere
bral veins, cortical vessel sign, veins on gradient echo,
hypointense leptomeningeal vessels, hypointense vessels,
hypointense vessel sign, hypointense transcerebral or cor
tical veins, ischemic vessel signs, increased vessel contrast,
multiple hypointense vessels and visibility of transcere
bral veins have been used almost synonymously. A “region
of multiple hypointense vessels” describes the area that
is bordered and thus defined by hypointense vessels. The
158
Table 2 Publications using susceptibility-weighted imaging and combining T2*w imaging and susceptibility-weighted imaging
Ref.
n
Field
strength
Ida[23]
Tong et al[24]
Mittal et al[25]
62
1
1
1.5 T
NS
1.5 T
Santhosh et al[26]
Tsui et al[27]
Christoforidis et al[28]
1
1
6
1.5 T
NS
3T
Hingwala et al[29]
Huisman et al[30]
Mittal et al[31]
1
1
2
NS
NS
1.5 T
Yen et al[32]
1
NS
Kesavadas et al[33]
2
NS
Park et al[34]
Lin et al[35]
Meoded et al[36]
82
53
2
NS
NS
NS
Gasparotti et al[37]
Yamashita et al[38]
1
30
1.5 T
3T
Huang et al[39]
44
3T
Kao et al[40]
Tsai et al[41]
15
49
1.5 T
NS
Meoded et al[42]
Park et al[43]
8
9
NS
NS
Fujioka et al[44]
Verschuuren et al[45]
Meoded et al[46]
1
1
1
NS
NS
1.5 T
Baik et al[47]
19
1.5 T
and
3T
Tsai[48]
59
NS
Sohn et al1[49]
65
NS
Occluded Time from
vessel
onset
NS
MCA
MCA
Validation
method
Results
24 h
3d
2h
DSC-MRI; DWI IVC were noted in 77.4%, agreement with perfusion defect in all patients
ADC
Prominent asymmetric medullary veins exceeding the area of the DWI lesion
DWI; DSC-MRI Prominently hypointense cortical veins exceeding the area of the DWI lesion,
similar to PWI lesion
MCA
NS
DWI
Prominent veins exceeding the area of the DWI lesion
MCA
NS
DWI
Prominent hypointense veins exceeding the area of the DWI lesion
MCA
NS
DSC-MRI; DWI MHV were noted within the MTT lesion while they absent within the DWI
lesion
MCA
NS
DWI
Prominent veins exceeding the area of the DWI lesion
MCA
NS
ADC/DWI
Prominent intramedullary veins exceeding the area of the DWI lesion
MCA
NS
ADC/DWI; Prominent hypointense veins exceeding the area of the DWI lesion, similar to
DSC-MRI
PWI lesion
MCA
4d
DWI; DSC-MRI Prominent venous hypointensities exceeding the area of the DWI lesion,
similar to PWI lesion
MCA
NS
DSC-MRI;
Prominent veins exceeding the area of the DWI lesion, similar to PWI lesion
ADC/DWI
ICA, MCA
3d
DSC-MRI; DWI MHV visible in 73/82 patients, excellent agreement with TTP maps
ICA, MCA
12 h
Traditional MRI Hypointense transmedullary veins predisposed to worse outcome (OR = 2.2)
MCA, ACA
NS
Conventional Prominent intramedullary veins were noted within the DWI lesion. In one
MRI; DWI
case prominent sulcal veins matched the area of infarct growth.
ICA
NS
DWI; DSC-MRI SWI lesion exceeded DWI lesion and matched MTT lesion
MCA
7d
DWI; FAIR
Increased venous contrast in 22/30 patients, area similar to hypoperfused
tissue
MCA
2d
DWI; MRA; CT Prominent veins present in 15/44 patients; Not correlated with haemorrhage
or outcome
MCA
18 h
DWI; DSC-MRI MTT-DWI and SWI-DWI mismatch similar to predict infarct growth
NS
3.5-8.5 h
MRI;
Presence of hypointense veins in all patients with worse outcome and
Clinical
haemorrhagic complications
NS
72 h
DWI
DWI > SWI mismatch found in 1/15 affected regions
TIA
NS
DWI; DSC-MRI; 4/9 patients with DWI negative TIA showed asymmetric hypointense vessels,
MRA
in accordance with perfusion deficit and stenosed/occluded vessel
ICA
10 h
MRI
SWI lesion exceeding DWI lesion matured into infarction
MCA, ACA
NS
ADC; CT
SWI lesion exceeding ADC lesion matured into infarction on CT
MCA, PCA
NS
T2; ADC
SWI lesion matches ADC lesion; Mismatch also noted, indicating critical
perfusion
ICA, MCA, Median
DWI
Prominent veins present in affected territory which disappeared
BA
2.5 h
after recanalization (10/10 patients); After recanalization within DWI
lesion: Equally prominent in 10/19 patients, small DWI lesions, good
clinical outcome (7 d NIHSS median 3.5, 90 d mRS median 0) indicating
normalisation; Less prominent in 5/19 patients, large DWI lesions, poor
clinical outcome (7 d NIHSS median 13, 90 d mRS median 4) indicating futile
reperfusion; Mixed in 4/19 patients, medium DWI lesions, relatively poor
outcome (7d NIHSS median 13, 90 d mRS median 2)
NS
NS
Imaging;
34 patients improved or stable (clinical, imaging), 25 worse; SWI correlated
Clinical
with poor prognosis
Anterior
12 h
Perfusion MRI Asymmetrical HVS in 98% (SWI) and 74% (T2*w)
circulation
1
Publication combining T2*w imaging and susceptibility-weighted imaging. NS: Not stated; ICA: Internal carotid artery; MCA: Middle cerebral artery;
ACA: Anterior cerebral artery; ADC: Apparent diffusion coefficient; BA: Basilar artery; FAIR: Flow sensitive alternating inversion recovery; MRA: Magnetic resonance angiography; CT: Computed tomography; PCA: Posterior cerebral artery; IVC: Increased vessel contrast; TIA: Transient ischemic attack;
DWI: Diffusion-weighted image; PWI: Perfusion-weighted image; MTT: Mean transit time; DSC-MRI: Dynamic susceptibility-contrast magnetic resonance
imaging; NIHSS: National Institute of Health Stroke Score; mRS: Modified ranking scal; SWI: Susceptibility-weighted imaging; HVS: Hypointense vessel
sign; MHV: Multiple hypointense vessels.
“brush sign” was described as a hypointense area along
the course of subependymal and medullary veins in deep
white matter.
ruption in the supply of oxygen through decreased CBF.
The threshold of 20 mL per 100 g/min is considered
the threshold for penumbra but this value is likely to
be time dependent[50]. The cerebral metabolism rate of
oxygen (CMRO2) in viable, i.e., penumbral tissue is still
at a near normal level (approximately 3.5 mL per 100
g/min) which causes the OEF to rise from its normal
range to its theoretical maximum of 100%[51]. As can be
DISCUSSION
Fundamentals of the penumbra and the BOLD-signal
The occlusion of a brain-supplying artery causes a dis
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159
an increased CBV (pooling of DHb) without concom
mitant change in overall flow or CMRO2 but may be
detected by perfusion MRI. The phenomenon of dark
ening veins was already observed in early experimental
stroke studies and was related to an increase in DHb[52].
Red blood cells carry haemoglobin which is present
as OHb and DHb. Other cellular components of blood
(leucocytes, platelets) do not contribute to oxygenation
related signal changes. OHb has four outer electrons
one of which is shared between the chelated hem iron
and oxygen which makes OHb diamagnetic. In DHb,
the four unpaired outer electrons are in a high-spin state
which gives it paramagnetic properties[53].
This makes DHb an endogenous contrast agent
which can be noninvasively imaged with appropriate MRI
techniques. DHb induces local magnetic field inhomoge
neity in vessels and surrounding tissue and causes faster
transverse relaxation decay. T2*w images pick up that
process which is translated into reduced T2* signal[54]. In
addition to faster transverse relaxation decay, a phase dis
persion is induced. This is exploited by SWI which com
bines both the magnitude and the phase information and
thus further enhances differences in susceptibility than
T2*w imaging alone. For an in-depth explanation of the
SWI technique and further clinical examples please refer
to the extensive reviews by Sehgal et al[55], Haacke et al[56]
and Tong et al[24].
Quantitative susceptibility mapping (QSM) is a devel
opment of SWI which utilizes the phase data. It requires
further postprocessing to obtain quantitative informa
tion on local susceptibility[57,58]. QSM may in the future
be able to quantify oxygen saturation and thus provide
fully quantitative and completely non-invasive informa
tion on oxygen metabolism.
The above stated pathophysiological considerations
suggest that veins that appear hypointense and more
pronounced in diameter may be used to assess oxygen
ation and in the face of acute ischemic stroke also may
detect metabolically active tissue.
Table 3 Comparison of publications using T2*w imaging and
susceptibility-weighted imaging n (%)
Number of publications
Presence of vessel signs
Interrater agreement
Reliability assessment
T2*w imaging
publications
(patients)
SWI
publications
(patients)
17 (692)1
54%
16 (668)
κ = 0.7 to > 0.9
and ICC = 0.99
6 (210)
r = 0.92-0.96
1 (20)
27 (518)1
81%
21 (334)
-
Occluded vessel
Anterior circulation
Large arteries
Critical MCA stenosis
TIA
BA
NS
Time from onset
≤6h
>6h
3.5-8.5 h
NS
Outcome
Worse outcome
Better NIHSS improvement
Better outcome with normalisation
No correlation
Validation method
DSC-MRI
FAIR
Conventional MRI
15
O-PET
DSA
Field strength
1.5 T
3T
NS
-
12 (598)1
1 (20)
1 (2)
3 (72)3
22 (331)1
1 (9)
1 (1)2
4 (178)
9 (317)
5 (282)
3 (93)3
2 (18)4
12 (364)1
1 (49)
13 (87)
1 (49)
4 (107)
3 (141)
3 (161)
1 (19)
1 (44)
7 (260)
3 (81)
3 (234)
1 (NS)
1 (22)
10 (181)
1 (30)
11 (242)
-
3 (97)
8 (205)
6 (390)1,3
7 (83)
3 (80)
17 (355)1,5
1
Including one publication using T2*w imaging and susceptibility-weighted imaging (SWI) (Sohn et al[49]), thus the total number of studies and
patients differs from the one stated in the main text; 2Including one patient
with occluded BA (Baik et al[47]); 3Number of subjects not stated (Kinoshita
et al[18]); 4Including 17 patients ≤ 6 h and 2 patients > 6 h (Baik et al[47]); 5Including those who used 1.5 T and 3 T (Baik et al[47]). NS: Not stated; ICA:
Internal carotid artery; MCA: Middle cerebral artery; BA: Basilar artery;
TIA: Transient ischemic attack; DSC-MRI: dynamic susceptibility-contrast
magnetic resonance imaging; FAIR: Flow sensitive alternating inversion
recovery; 15O-PET: Oxygen-15 positron emission tomography; DSA: Digital subtraction angiography; NIHSS: National Institute of Health Stroke
Score.
Intermethod and interrater reliability
The depiction of hypointense veins can provide an ap
proximation of the spatial extent of compromised oxygen
metabolism. Although it has been qualitatively assessed,
quantitative data is scarce. The published data however
suggest that an estimation of the affected area is pos
sible and reasonably reliable. The method does not deliver
quantitative information and is only an indirect indicator
of OEF. The main disadvantage is the fact that the exact
relationship between discernible hypointensity within the
vessels and increased OEF is unknown. Recently, SWI has
been indirectly validated against arterial spin labelling[59] and
has also been validated against 15O-PET in patients with
chronic cerebrovascular disease[60]. However, formal valida
tion is still missing and thus only subjective though repro
ducible[7,14,15,17,19,21] rater-dependent assessment is available.
seen in Equation 1 it is described as the ratio of CMRO2
and CBF multiplied with the oxygen content of blood
(CaO2).
OEF = CMRO2/(CBF × CaO2).
While the increased OEF can keep CMRO2 stable
over some time it causes the concentration of DHb to
increase as the oxygen is transferred from oxyhemoglo
bin (OHb) to tissue and DHb is generated (Figures 1 and
2). However, as the BOLD signal is a composite of CBF,
CMRO2 and cerebral blood volume (CBV) related signal
changes their individual contributions can be difficult to
establish. Dilatation of veins could thus in theory lead to
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T2* vs SWI
There is only one publication directly comparing SWI
160
A
OEF approximately 40%
CMRO2 approximately 3.5 mL per 100 g/min
CBF approximately 50 mL per 100 g/min
χDHb 0.4-0.5
Artery
Vein
Capillary network
B
OEF > 70%
CMRO2 approximately 3.5 mL per 100 g/min
CBF approximately 20 mL per 100 g/min
χDHb approximately 0.7-1
Clot in artery
Vein
Figure 1 Schematic drawing of brain supplying artery, capillary network and draining vein and the sequence of events leading to an increased visibility of
draining veins on T2*w imaging and susceptibility-weighted imaging during acute ischemic stroke. A: In the normal brain cerebral blood flow (CBF) is approximately 40 mL per 100 g/min to sustain normal brain function. Oxygen extraction fraction (OEF) and cerebral metabolism rate of oxygen (CMRO2) are in the range of
approximately 40%-50% and 3.5 mL per 100 g/min respectively. The fraction of deoxyhemoglobin (χDHb) provides the normal appearing venous vessels on T2*w and
susceptibility-weighted imaging; B: When the blood supply is interrupted CBF drops to approximately 20 mL per 100 g/min (penumbral threshold) or < 10 mL per 100
g/min (ischemic threshold). In penumbral tissue CMRO2 can be kept stable by an increase of OEF to > 70%. In effect, χDHb rises to its maximum (assuming optimal
arterial oxygenation) and draining veins may appear more pronounced and hypointense.
T2*w d0
MTT d0
ADC d0
T2*w d15
Figure 2 Image montage of magnetic resonance imaging findings in a 46-year-old woman with a right middle cerebral artery occlusion 321 min after
symptom onset and an National Institute of Health Stroke Score of 11 on admission. Note the subtle asymmetrically prominent veins (arrows) on T2*w imaging
(first row) within the mean transit time (MTT) lesion (second row) but outside the apparent diffusion coefficient (ADC) lesion (third row) on the day of admission (d0).
On follow-up imaging 15 d later (d15) vessel appearance has normalized (fourth row).
and T2*w imaging in the same set of patients [49]. As
expected, the sensitivity of T2*w imaging compared
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to SWI was significant (74% vs 98%). Accordingly, the
pooled presence of vessel signs on T2* compared to
161
SWI in the reviewed publications was considerably lower
(54% vs 81%). The low presence of vessel signs in T2*w
images is worrying and make SWI a much more suitable
candidate sequence.
SWI has long been hampered by long acquisition
times of about 10 min, making it unsuitable for acute
stroke studies due to extreme susceptibility to movement
artefacts. This is corroborated by the fact that only three
publications using SWI in the acute clinical setting could
be identified[25,41,47]. By the time of writing this article
however, scanning time has been reduced to about 3 min
for whole brain coverage, facilitating its usage in clinical
protocols. More publications and patients were included
using T2*w imaging. This is not completely surprising as
T2*w imaging is already incorporated in MRI stroke pro
tocols used in many institutions. However, their purpose
is currently the detection of haemorrhage[61] and screen
ing for blooming artefacts caused by thrombus in large
vessel occlusion[62]. Attractively, both T2* and SWI com
bine information on haemorrhage that would preclude
thrombolytic treatment, with information on penumbral
tissue. Additionally, there is no need for the application
of contrast agent in the light of potential albeit small
risks of anaphylactic reactions and nephrogenic systemic
fibrosis.
has provided very convincing results, validation with gold
standard PET or at least with complementary perfusion
MRI in the acute phase is still missing. Further studies
especially on SWI should be conducted since the data
already available seem to merit further evaluation of this
technique. A reliability assessment should be conducted
and, in particular the possibilities of SWI in the acute
clinical setting should be evaluated. It could prove use
ful in the non-acute setting or when no other imaging is
available or when functional assessment of stenosis or
occlusion is needed[65]. However, in the present state the
combined use of perfusion and BOLD imaging would
provide further complementary information to help visu
alize and understand the role of the ischemic penumbra.
ACKNOWLEDGMENTS
We would like to thank Harry Ingleby, PhD for editing
the manuscript.
COMMENTS
COMMENTS
Background
Thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rt-PA) is the only approved therapy for acute ischemic stroke. The target tissue for rt-PA therapy is the ischemic penumbra: electrically silent but viable and
salvagable tissue. If no penumbra is present a given patient will only be subjected to the risks of rt-PA treatment. Thus, an accurate estimation of penumbral
tissue to assess the risks and benefits of thrombolytic therapy is paramount.
Clinical outcome
The findings regarding clinical outcome are heteroge
neous. The reviewed publications either indicate larger
improvement measured on the National Institute of
Health Stroke Scale or worse outcomes. However, this
finding is not necessarily a contradiction. Larger volumes
of penumbral tissue may result in worse outcome if tis
sue at risk is not rescued by adequate therapy. The dif
ference is thus likely an effect of successful therapy and
not the volume of penumbral tissue itself.
Research frontiers
In recent years magnetic resonance imaging (MRI) using the diffusion- and
perfusion-weighted imaging mismatch concept was widely used to map the
ischemic penumbra. It defines the penumbra as the difference between tissue
that is terminally infarcted on diffusion weighted imaging and tissue that is undersupplied on perfusion MRI: the so-called mismatch. However, this concept
proved to be an oversimplification. That is why an imaging protocol that provides insight into oxygen metabolism is needed.
Innovations and breakthroughs
Recently, blood oxygenation level dependent (BOLD) imaging has become a
candidate sequence to map the ischemic penumbra. In short, it visualizes an
increased deoxyhemoglobin (DHb) concentration. An increased DHb concentration is the signature of tissue that displays an elevated oxygen extraction
fraction (OEF), a hallmark of the penumbra. Two approaches are generally
used: Direct assessment of penumbral tissue, definition of penumbral tissue by
draining veins. In this article the assessment of draining veins is reviewed.
Preclinical basic research
As stated before, there is not one penumbra but a 4-di
mensional gradient from necrosis to healthy tissue[1]. De
pending on the occluded vessel, duration of ischemia, the
tissue-specific vulnerability of certain areas of the brain,
dynamics of reperfusion damage, etc., various necrotic
and apoptotic pathways are activated. Recently, more
modes of cell death have been identified[63]. Putative neu
roprotective or neuroregenerative drugs will only work in
a small window of this 4-dimensional space. Therefore,
the need for MRI sequences that specifically visualize
certain aspects of infarction and good segmentation al
gorithms are needed, so the effects of the drugs can be
assessed correctly and not be masked by other processes
that take place during infarction. Very little preclinical
basic research[64] has been done so far on the imaging
method presented in this review.
In conclusion, the detection of hypointense venous
vessels with BOLD imaging to assess the amount of
penumbral tissue in acute ischemic stroke has emerged
as a little noticed alternative imaging technique. Although
the data seems very encouraging and indirect validation
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Applications
Asymmetrically hypointense draining veins on T2*w and even more on SWI
could serve as a surrogate marker for penumbral tissue. However, further validation and quantification is needed.
Terminology
Penumbra: Tissue that has become undersupplied and electrically silent by an
acute ischemic stroke. However, this tissue is still viable and can be salvaged
by therapy; OEF: The percentage of oxygen extracted from the bloodstream by
brain tissue. In normal tissue about 40%, elevated in penumbral tissue up to
100%; susceptibility weighted imaging: MRI sequence that combines the signal
from T2*w imaging with phase information and thus enhances the contrast.
BOLD imaging: Group of imaging methods that utilize the susceptibility difference between paramagnetic DHb and diamagnetic oxyhemoglobin. Any given
change in oxygenation status will alter the signal.
Peer review
This work represents a nice overview of what has been done in the field so far
and points out that consistent reporting is necessary. However, it also points out
that this is an important observation and should be more carefully studied as it
could have a significant impact on the diagnosis and treatment of patients.
162
3-Tesla MRI. ISMRM 17th Annual Meeting and Exhibition;
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L- Editor A E- Editor Xiong L
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WJ R
World Journal of
Radiology
[email protected]
doi:10.4329/wjr.v5.i4.166
BRIEF ARTICLE
Microstructural analysis of pineal volume using trueFISP
imaging
Jan M Bumb, Marc A Brockmann, Christoph Groden, Ingo Nolte
3
mm ), and the median parenchyma volume was 53.6
3
3
mm (71.9 ± 66.7 mm ). In cystic glands, the standard
deviation of the PGV was substantially higher than in
solid glands (98% vs 58% of the mean). PGV declined
with age (r = -0.130, P = 0.016).
Jan M Bumb, Department of Psychiatry and Psychotherapy,
Central Institute of Mental Health, Medical Faculty Mannheim,
Heidelberg University, 68167 Mannheim, Germany
Marc A Brockmann, Christoph Groden, Ingo Nolte, Department of Neuroradiology, University Hospital Mannheim, 68167
Mannheim, Germany
Marc A Brockmann, Department of Diagnostic and Interventional Neuroradiology, University Hospital of the RWTH Aachen,
52074 Aachen, Germany
Author contributions: Bumb JM and Nolte I performed the
majority of the experiments; Nolte I and Bumb JM designed the
study and wrote the manuscript; Brockmann MA and Groden C
edited the manuscript.
Correspondence to: Dr. Ingo Nolte, PD, Department of Neuroradiology, University Hospital Mannheim, Theodor-KutzerUfer 1-3, 68167 Mannheim,
Germany. [email protected]
Telephone: +49-621-3832443 Fax: +49-621-3832165
Received: December 5, 2012 Revised: January 11, 2013
CONCLUSION: The high interindividual volume variation is mainly related to cysts. Pineal parenchyma volume decreased slightly with age, whereas genderrelated effects appear to be negligible.
Key words: Pineal gland volume; Pineal cyst; Magnetic
resonance imaging; Etiology; Reference range
Bumb JM, Brockmann MA, Groden C, Nolte I. Microstructural
analysis of pineal volume using trueFISP imaging. World J
Radiol 2013; 5(4): 166-172 Available from: URL: http://www.
wjgnet.com/1949-8470/full/v5/i4/166.htm DOI: http://dx.doi.
org/10.4329/wjr.v5.i4.166
Abstract
AIM: To determine the spectrum of pineal microstructures (solid/cystic parts) in a large clinical population
using a high-resolution 3D-T2-weighted sequence.
INTRODUCTION
The enormous interindividual variation of the pineal
gland complicates radiological evaluations. Frequently,
cases with a presumably enlarged solid or cystic pineal
gland cannot be classified due to the lack of reliable data
for comparison. The differential diagnosis of pineal enlargements includes pineal neoplasms, such as pineocytoma, pinealoblastoma and germinoma.
For the definition of normal pineal volume and morphometry, cross-sectional imaging studies have not yet
provided sufficient data. A slice thickness of 4 mm to 10
mm is used for computed tomography, and most magnetic resonance imaging (MRI) suggest that this structure
has a mean size of 6-10 mm[1]. Recently, high-resolution
3D-MRI (1 mm isotropic voxel size or less) has been applied for the characterization of the pineal gland in more
METHODS: A total of 347 patients enrolled for cranial
magnetic resonance imaging were randomly included
in this study. Written informed consent was obtained
from all patients. The exclusion criteria were artifacts
or mass lesions prohibiting evaluation of the pineal
gland in any of the sequences. True-FISP-3D-imaging
(1.5-T, isotropic voxel 0.9 mm) was performed in 347
adults (55.4 ± 18.1 years). Pineal gland volume (PGV),
cystic volume, and parenchyma volume (cysts excluded) were measured manually.
RESULTS: Overall, 40.3% of pineal glands were cystic.
3
3
The median PGV was 54.6 mm (78.33 ± 89.0 mm ),
3
the median cystic volume was 5.4 mm (15.8 ± 37.2
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166
Bumb JM et al . Pineal volume and microstructure in trueFISP imaging
detail[2-5] and for 3D-volumetry of the pineal gland[5,6].
Bumb et al[6] measured pineal volume in a clinical pediatric population, whereas a study by Sun et al[5] included
young Chinese adults aged 20-30 years (n = 112) with
the intention of assisting in the early diagnosis of small
pineal lesions. The authors of that study concluded that
the exploration of a larger age range is required to define
the reference values of high resolution 3D-volumetry for
clinical evaluations. Therefore, the principal goal of our
study is to provide a reference range for pineal volume
(and the number and size of cystic changes) in a broader
clinical population ranging from young adulthood to old
age.
Moreover, prior histological and high-resolution MRI
studies have indicated that there is high interindividual
variability in the size of the pineal gland[4,7,8]. The extent
of this variability is unique among the organs of the
central nervous system. Although cysts are a common
finding in autoptic[7,8] and imaging studies[4], the degree to
which cysts and solid parenchyma contribute to this variability is not known.
Consequently, we used high-resolution 3D-MRI to
analyze in detail which morphological part of the pineal
gland (cystic or solid part) contributes to the high variability. As the underlying causes of the variability are not
well understood, we further investigated the effect of
age and gender on the volume and microstructure of the
pineal gland.
FISP images using the OsiriX volume quantification tool.
If cysts were detected in the trueFISP imaging, then the
total cyst volume (TCV) was also measured. Pineal parenchyma volume (PPV) was defined as PGV-TCV.
To determine the intrarater variability, the same evaluator assessed all datasets a second time with a time gap
of three weeks. To determine the interrater variability,
a second evaluator unaware of the results of the first
evaluation assessed ten randomly chosen datasets.
Ethical approval
The local ethics committee waived ethical approval of
this study.
For the statistical analysis, SPSS 18.0 (IBM, IL, United
States) was used. To determine intra- and interrater variability of the volume measurements, the Pearson correlation coefficient and the paired samples t test was used.
Student’s t test was used to detect gender differences in
PGV, PPV and TCV. The Pearson correlation coefficient
was computed for the relationship between age and PPV,
TCV, and number of cysts. For all tests, a significance
level of 0.05 was used. Descriptive values are given as the
mean ± SD if not otherwise specified.
RESULTS
Reliability of measurements
To assess intrarater variability, all 347 datasets were assessed twice by one evaluator with a time gap of three
weeks (PPV: mean of first assessment 71.9 ± 66.6 mm3,
mean of second assessment 72.3 ± 66.8 mm3). The Pearson correlation coefficient was 0.999 (P < 0.001). There
was no difference between the evaluations (P < 0.001).
To assess interrater variability, ten of the 347 datasets
were randomly chosen and assessed by a second evaluator. There was no difference between the two evaluators
for these ten datasets (P < 0.05). The Pearson correlation
coefficient between both evaluators was 0.829 (P = 0.003).
The coefficients indicate an adequately high reliability.
Population and MRI protocol
A total of 347 patients enrolled for cranial MRI were
randomly included in this study. Written informed consent was obtained from all patients. The exclusion criteria were artifacts or mass lesions prohibiting evaluation
of the pineal gland in any of the sequences.
MRI scans were performed using two 1.5-T scanners
(Siemens Sonata and Avanto, Siemens, Erlangen, Germany).
The MR sequences for all patients included transversal T1weighted spin echo (T1-SE, TR/TE 434/11), T2-weighted
turbo spin echo (T2-TSE, TR/TE 3900/101), fluid-attenuated inversion recovery (TR/TI/TE 9000/2500/89, all 24
slices, 5 mm slice thickness, 20% gap, field of view 205
mm × 230 mm, matrix 448 mm × 304 mm), and true
fast imaging with steady state precession (trueFISP, TR/
TE 7.1/3.5, field of view 178 mm × 220 mm, matrix
212 mm × 275 mm, 36 slices, slice thickness 800 μm). A
diagnosis for each patient was extracted from the medical records.
Population
The study population comprised 347 individuals (55.4 ±
18.1 years, range 19-94 years; 47.0% female and 53.0%
male). The diagnoses included intracranial neoplasm
[glioma (12.1%), meningioma (4.3%), metastasis (5.2%),
and other intracranial neoplasm (4.9%)], ischemia (25.4%),
hemorrhage (3.7%), inflammatory disease of the central
nervous system (3.5%), epilepsy (1.7%), hydrocephalus
(9.5%), other diagnosis (13.5%), and normal findings
(16.1%).
Figure 1 illustrates the smallest and largest solid pineal
gland as well as the largest monocystic gland. The mean
PGV, PPV and TCV values are shown in Table 1. Of the
347 pineal glands, 40.3% contained cysts. More than 10%
were multicystic (29.1% with one cyst, 9.5% with two
cysts, 1.2% with three cysts, 0.3% with four cysts and 0.3%
with five cysts).
Evaluation
All images were evaluated digitally using OsiriX software
(www.osirix-viewer.com). Two experienced neuroradiologists blinded to the clinical information evaluated the
images.
Pineal gland volume (PGV) was measured as describ
ed previously[4,9]. In brief, the contour of the pineal gland
was manually traced on transversal reconstructed true-
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Table 1 Morphometric characteristics of 347 pineal glands
Gender
Age (yr)
F/M
> 18
(n = 347)
PGV (mL)
Median
mean ± SD
PPV (mL)
Median
mean ± SD
TCV (mL)
Median
mean ± SD
Number of cysts
(in cystic glands)
Cystic glands
PPVsolid
Median
mean ± SD
F
> 18
(n = 163)
F
18-39
(n = 28)
F
40-59
(n = 63)
F
60-79
(n = 57)
F
> 80
(n = 15)
54.6
54.6
73.0
54.6
50.1
54.9
78.3 ± 89.0 82.0 ± 107.8 118.5 ± 191.7 78.8 ± 78.7 72.3 ± 88.9 64.3 ± 31.9
M
> 18
(n = 184)
M
18-39
(n = 41)
M
40-59
(n = 59)
M
60-79
(n = 79)
M
> 80
(n = 5)
54.6
77.8
58.0
51.3
75 ± 68.3 102.7 ± 99.9 56.2 ± 31.1 77.8 ± 65.5
27.2
26.1 ± 7.1
53.6
53.6
69.8
53.6
48.4
54.9
53.5
73.3
58.0
51.3
71.9 ± 66.7 74.0 ± 78.1 100.8 ± 133.4 72.1 ± 60.0 66.3 ± 66.5 61.4 ± 27.1 70.1 ± 55.0 92.3 ± 74.5 54.6 ± 28.0 72.9 ± 55.5
27.2
25.9 ± 6.9
5.4
5.3
15.8 ± 37.2 18.6 ± 46.7
1.3 ± 0.6
1.3 ± 0.6
40.3%
42.9%
42.7
42.1
46.6 ± 26.8 45.0 ± 23.0
6.3
30.9 ± 77.8
1.3 ± 0.4
57.1%
38.2
41.9 ± 22.0
6.3
4.7
15.6 ± 29.3 16.6 ± 40.7
1.4 ± 0.6
1.2 ± 0.5
42.9%
36.8%
3.2
7.3 ± 8.3
1.3 ± 0.5
40.0%
5.4
5.3
12.9 ± 24.3 20.2 ± 36.4
1.4 ± 0.7
1.2 ± 0.4
38.0%
51.2%
2.5
5.7 ± 7.4
1.5 ± 1.2
28.8%
8.4
1.0
12.3 ± 19.3 1.0 (n = 1)
1.4 ± 0.6
1 (n = 1)
39.2%
43.7
37.3
48.5
43.4
46.6
45.4
42.9
43.7 ± 19.0 45.4 ± 27.5 52.6 ± 20.9 47.9 ± 29.6 52.5 ± 29.2 47.7 ± 24.4 48.2 ± 34.4
20.0%
24.2
25.0 ± 7.7
F: Female; M: Male; PGV: Pineal gland volume; PPV: Pineal parenchyma volume; TCV: Total cyst volume.
A
B
AC
C
rd
3 V
Habenula
CP
QC
SP
10 mm
P
P
CP
SP
M
Figure 1 TrueFISP imaging of the pineal region illustrating the spectrum of pineal volumes and cysts. A, B: Solid glands. Smallest pineal parenchyma volume
(PPV), 5 mm3, the small pineal gland can hardly be demarcated from the habenula (A); largest PPV, 228 mm3 (B); C: Largest single cyst, 189 mm3. The pineal gland
was axially reformatted along its long axis. the cystic part (CP) of the pineal gland is larger than the solid part (SP) and accounts for most of the pineal volume. Upper
row: Axial reconstruction; Lower row: Sagittal reconstruction. 3rd V: Third ventricle; AC: Anterior commissure; M: Mesencephalon; P: Pineal gland; QC: Quadrigeminal
cistern.
Influence of gender
The differences in the median PGV, PPV, and TCV between females and males were subtle (Table 1). The median PGV was equivalent in females and males. The median
PPV was slightly higher in females, whereas the median
TCV was higher in males.
The mean PGV and PPV were slightly higher in females than in males, but the difference was far from significant (P = 0.464 and P = 0.586, respectively) (Table 1
and Figure 2A and B).
Females displayed almost 6% more cystic glands than
males. However, females had a smaller mean TCV, although this difference was not significant (Table 1 and
Figure 2C and D).
WJR|www.wjgnet.com
There was no difference with respect to the number
of cysts (P = 0.516) (Table 1).
In both females and males, PGV, PPV, and TCV had
high standard deviations (Table 1), indicating high interindividual variations.
To focus on the relationship between pineal parenchyma and gender, we factored out any possible effect
of the cysts and analyzed only the solid glands (PPVsolid
in Table 1). Interestingly, even in this case, the difference
between the sexes was still negligible.
Females: In women (n = 163), the mean PPV decreased
with age (Figure 2A) (r = -0.13, P = 0.097). Among the
cysts in females, TCV exhibited a weakly negative cor-
168
Y = 105.67 - 0.56X
800
R² = 0.02
B
800
Y = 94.67 - 0.45X
R² = 0.02
Pineal parenchyma (mm )
600
3
3
Pineal parenchyma (mm )
A
400
200
600
400
200
0
0
20
40
60
80
100
20
40
Age (yr)
300
Y = 30.56 - 0.22X
D
300
80
100
Y = 24.07 - 0.21X
R² = 0.03
3
Total cyst volume (mm )
R² = 0.01
3
Total cyst volume (mm )
C
60
Age (yr)
200
100
200
100
0
0
20
40
60
80
100
20
Age (yr)
40
60
80
100
Age (yr)
Figure 2 Regression diagram of pineal parenchyma and age. A, B: In both females (A) and males (B), the mean pineal parenchyma volume decreased slightly
with age; C, D: In both females (C) and males (D), the total cystic volume of the pineal gland decreased slightly with age. Dotted line: Linear regression and 95%
mean prediction interval.
slightly worse (R2 = 0.003, Y = 51.13 - 0.079X), which
highlights that the effect of age on the pineal volume is
minor.
relation with age (Figure 2C). TCV and number of cysts
showed no significant correlation with age (P = 0.455).
TCV showed a strong positive correlation with PPV (P
< 0.001, Pearson correlation coefficient 0.934).
Interindividual variation: Secondary to the solid or
cystic component?
The median and mean PGV, PPV, TCV, and the PPVcystic/solid values are shown in Table 1. The expected high
interindividual variability of PGV is reflected by a standard deviation of 114% of the mean PGV (PGV 78.3 ±
89.0 mm3).
To answer the question of whether the interindividual variation of the PGV is secondary to the solid or
cystic component, the standard deviations of the solid
and cystic glands were compared. The standard deviation of the PGVsolid was 58% of the mean (46.6 ± 26.8
mm3). This variation suggests that substantial variation is
secondary to the solid parenchyma. The standard deviation of PGVcystic was 98% of the mean (125.2 ± 122.2
mm3), emphasizing the high influence of the cystic component. Accordingly, TCV shows a high variation. Taken
together, the variation in the cystic component of the
pineal gland adds more to the variation than the solid
component.
Males: In men (n = 184), the mean PPV exhibited a weakly negative correlation with age (P = 0.044, r = -0.149)
(Table 1 and Figure 2B). Regarding cysts in males, TCV
showed a weakly negative correlation with age, although
this correlation was not significant (Figure 2D). The number of cysts showed no significant correlation with age (P
= 0.744, r = -0.024). Similar to women, TCV was strongly
correlated with PPV in men (P < 0.001, Pearson correlation coefficient 0.846).
Influence of age
PPV declined with age (r = -0.135, P = 0.012). PGV also
declined with age (r = -0.130, P = 0.016).
There were no significant correlations between age
and the number of pineal cysts (P = 0.242) and between
age and the TCV (P = 0.190).
To exclude a potential effect of the cysts on the volume measuring procedure, we analyzed the solid glands
separately (n = 207). Here, the correlation with age was
WJR|www.wjgnet.com
169
influence the sensitivity.
Theories concerning the pathogenesis of pineal cysts
include a dysontogenetic residual of the embryonic pineal diverticulum and a degeneration within a glial plaque
or within a cluster of pinealocytes[16,21-23].
A significant effect of the degenerative hypothesis
would entail more and possibly larger cysts with increasing age. We found no correlation either between age and
TCV or between age and the number of cysts. This result
is a strong argument against a significant influence of
age on most pineal cysts. The stable TCV and the stable
number of cysts support the assumption that the dysontogenetic mechanism is predominant for the formation
of pineal cysts.
Some authors suggest that pineal cysts are subject to
hormonal influence[16,24]. In our study, we analyzed the
prevalence, number of cysts, and cystic pineal volume
but did not find significant gender differences. Other
high-resolution MRI studies analyzing cyst prevalence reported that these values were slightly higher in females[2]
or that there was no difference between males and females[5]. Nevertheless, longitudinal studies are necessary
to fully answer this question with respect to hypothetical
volume changes during the menstrual cycle.
Phylogenetically, the pineal gland is a very old structure. It is present not only in almost all mammals but
also in a number of lizards, fishes, reptiles (but not in
crocodiles), birds, and even probably in certain dinosaurs
(brachiosaurus, among others)[25]. An interesting finding
is that across the different species, the volume appears to
be dependent on both the degree of latitude (the more
distant from the equator, the larger the volume) and
nocturnality and diurnality (e.g., a smaller volume in owls
and a larger volume in horses).
In humans, the variation in brain structures is relatively small; for example, the hippocampus volume of
young and healthy adults varies by approximately < 10%
of the mean (SD of the mean)[26]. In contrast, the pineal
weight has been reported to vary approximately 50% in
an autopsy study, with an estimated volume range from
20 to 330 mm3[7]. A study of young Chinese adults (20
to 30 years) reported a mean pineal volume of 95 ± 31
mm3[27]. Despite the observation that pineal cysts are very
common (13%-57% in high resolution 3D-imaging, depending on the sequence, resolution and minimal diameter[2,4-6]), until now, whether there is “true” variation in the
hormone-producing parenchyma or whether the cysts are
the cause of the high variability in humans was not clear.
To clarify whether the variation in PGV is secondary
to the cystic and/or solid compartments, we determined
that the volume variation in cystic glands was much higher (almost twice) than in purely solid glands (as a percent
of the mean). This finding is contrary to the study by
Sun et al[5], who reported higher variations in solid than
in “macrocystic” glands (standard deviation 29 mm3 vs
20 mm3). In this study, however, the small sample size of
the macrocystic group (n = 7) might explain the contraintuitive finding.
Although the high variation of cystic glands may not
DISCUSSION
The pineal gland is an important neuro-endocrine organ
located in the center of the brain. It is one of the circumventricular organs lacking a blood-brain barrier[10].
Its major function is circadian production of the hormone melatonin, the most important hormone in chronobiology[11].
The distinction between normal pineal tissue and a
small tumor can be problematic. In T1- and T2-weighted
imaging, the signal characteristics are similar[12,13]. As the
pineal gland lacks a blood-brain barrier, a distinction by
simple enhancement differences is not possible. Therefore, the establishment of normal reference values of
the pineal volume is important for their evaluation.
The development of new techniques has improved
the radiological precision of pineal imaging. Before the
introduction of high-resolution 3D-sequences, PGV
could only be estimated indirectly from two-dimensional
measurements. This estimation included the measurement of up to three diameters and a geometric model (for
example: globe). However, the shape of the pineal gland
is known to be highly variable[14], and consequently, there
is only a very weak correlation between the estimated
volume and the true volumetric value[5]. Until now, no
study has directly quantified volume in adults older than
thirty years. Two studies used direct volume quantification for pediatric patients[6] and for young male adults
up to 30 years of age[5]. For clinical practice, however, a
much broader age range is necessary[5].
For the first time, we present precise volumetric data
covering the whole spectrum of adulthood. For young
adults[5], a mean pineal volume of 94 mm³ was found. In
our study, the mean for this age group (18-39 years) was
higher (109 mm³). Although differences in the population
may play a role, the choice of the volumetric sequence
may also be influential [Sun et al[5] used non-isotropic
T1-weighted 3D-sequence (fast spoiled gradient echo)].
Because the contrast of a small structure surrounded
by the cerebrospinal fluid is obviously higher in heavily
T2-weighted imaging than in T1-weighted imaging, we
opted for the trueFISP sequence, an isotropic heavily T2weighted 3D-sequence. As a consequence, the observed
organ border volumes were more precise, the partial volume effects were minimized, and the volumes measured
were more valid.
Sequence choice was also the reason for the higher
prevalence of pineal cysts in our analysis. Pineal cysts
were detected in 40.3% of the participants in the present
study, which is in good agreement with histological studies reporting prevalences of 39.1%[7]. Similar prevalences
were reported for trueFISP imaging by Nolte et al[4] and
Bumb et al[6] (35.1% in adults and 57.4% in children). The
studies using T1-weighted 3D-sequences by Pu et al[2]
and Sun et al[5] found prevalences of only 25% and 23%,
respectively. Previous MRI studies using 2D-sequences
with a slice thickness of more than 3 mm reported substantially lower prevalences of 0.14%-4.3%[15-20]. Obviously, both the chosen sequence and the resolution may
WJR|www.wjgnet.com
170
a large population. These data can be used as reference values for radiological
comparison and reflect an enormous spectrum of morphological variability. The
results suggest that most of the high interindividual volume variation is secondary to cysts. Pineal parenchyma volume decreased slightly with age, whereas
gender-related effects appear to be negligible.
be surprising, the observation that the variation in the
solid glands was considerably high in both women and
men throughout the different age groups is important
for the evaluation of the pineal gland and has not been
reported so far.
Similar striking interindividual differences have been
reported for the production of melatonin[28-30]. In a pilot
study, Nolte et al[3] indicated that the production of melatonin was linked to the volume of the solid pineal tissue.
Interestingly, the high variability of the solid pineal volume reported here appears to mirror the highly varying
melatonin production in adults.
The reason for the high interindividual variability of
the pineal volume is not clear. By studying this variability
with respect to age, we found a weakly significant negative correlation (r = -0.130). In other words, only approximately 1.69% (R2) of the variance can be explained by
the influence of age, indicating that there is only a slight
decrease in the pineal volume with age. Whether genetic
factors are involved remains to be elucidated.
Herein, we report directly measured pineal volume
parameters in a large clinical population. The results can
be used as a reference for clinical research and radiological evaluations. The high interindividual variability of the
pineal volume is secondary mainly to the variability of
the cystic compartment and, to a lesser degree, to the solid compartment. Our study suggests that PPV and TCV
decrease slightly with age and that there is no substantial
effect of gender.
Terminology
The pineal gland is an endocrine gland localized in the diencephalon of the
human brain. Its major task is the synthesis and release of melatonin, a very
versatile hormone regulating many physiological body functions. The pineal
gland is localized at the dorsal wall of the third ventricle, in front of the superior
colliculi of the quadrigeminal plate and under the splenium of the corpus callosum. The habenulae connect the pineal gland to the thalamus.
Peer review
The authors reported their results of measured pineal volume parameters using
a high-resolution 3D-T2-weighted trueFISP-3D-imaging sequence. The study
is done in a large clinical population (347 adults). The conclusion is that most
of the high pineal volume variation is secondary to cysts. This group is a very
large population compared to that reported in literatures. Therefore, the results
are more convincing and provide useful reference for evaluation of the pineal
volume clinically.
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P- Reviewer Chen F S- Editor Gou SX
L- Editor Webster JR E- Editor Xiong L
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172
WJ R
World Journal of
Radiology
[email protected]
doi:10.4329/wjr.v5.i4.173
BRIEF ARTICLE
Volumetric modulated arc radiotherapy for limited
osteosclerotic myeloma
Aurélie Robles, Antonin Levy, Coralie Moncharmont, Lamine Farid, Jean-Baptiste Guy, Nadia Malkoun,
Lysian Cartier, Cyrus Chargari, Isabelle Guichard, Jean-Noël Talabard, Guy de Laroche, Nicolas Magné
RESULTS: VMAT improved dose homogeneity within
the target volume, as compared to 3D-RT (standard
deviations: 2.9 Gy and 1.6 Gy for 3D and VMAT, respectively). VMAT resulted in a better sparing of critical
organs. Dose delivered to 20% of organ volume (D20)
was reduced from 22 Gy (3D-RT) to 15 Gy (VMAT) for
small bowel, from 24 Gy (3D-RT) to 17 Gy (VMAT) for
bladder and from 47 Gy (3D-RT) to 3 Gy (VMAT) for
spinal cord. Volumes of critical organs that received at
least 20 Gy (V20) were decreased by the use of VMAT,
as compared to 3D-RT (V20 bladder: 10% vs 99%;
V20 small bowel: 6% vs 21%). One year after treatment completion, no tumor progression has been reported.
Aurélie Robles, Coralie Moncharmont, Lamine Farid, JeanBaptiste Guy, Nadia Malkoun, Lysian Cartier, Jean-Noël
Talabard, Guy de Laroche, Nicolas Magné, Department of
Radiotherapy, Institut de Cancérologie de la Loire, 42270 St
Priest en Jarez, France
Antonin Levy, Department of Radiation Oncology, Institut Gus
tave Roussy, Université Paris XI, 94800 Villejuif, France
Cyrus Chargari, Department of Radiation Oncology, Hôpital d’
Instruction des Armées du Val-de-Grâce, 75005 Paris, France
Isabelle Guichard, Department of Internal Medicine, CHU
Saint Etienne, 42000 Saint Etienne, France
Author contributions: Robles A provided data and wrote the
paper; Magné N and Levy A designed the study, analyzed data,
and wrote the paper; Moncharmont C, Farid L, Guy JB, Malk
oun N, Cartier L, Chargari C, Guichard I, Talabard JN and de
Laroche G reviewed the paper.
Correspondence to: Nicolas Magné, MD, PhD, Department
of Radiotherapy, Institut de Cancérologie de la Loire, 108 bis,
Avenue Albert Raimond, BP 60008, 42271 St Priest en Jarez
cedex, France. [email protected]
Telephone: +33-4-77917434 Fax: +33-4-77917197
Received: October 18, 2012 Revised: December 14, 2012
CONCLUSION: VMAT improved dose distribution as
compared to 3D-RT for limited osteosclerotic myeloma,
with better saving of critical organs.
Key words: Volumetric intensity-modulated arc radiotherapy; Conformal radiotherapy; Critical organs; Osteosclerotic myeloma; Polyneuropathy organomegaly endocrinopathy monoclonal gammopathy and skin change
syndrome
Abstract
AIM: To assess the feasibility of volumetric intensitymodulated arc radiotherapy (VMAT) in patients with
limited polyneuropathy, organomegaly, endocrinopathy,
monoclonal gammopathy, and skin changes syndrome.
Robles A, Levy A, Moncharmont C, Farid L, Guy JB, Malkoun
N, Cartier L, Chargari C, Guichard I, Talabard JN, de Laroche
G, Magné N. Volumetric modulated arc radiotherapy for limited
osteosclerotic myeloma. World J Radiol 2013; 5(4): 173-177
Available from: URL: http://www.wjgnet.com/1949-8470/full/
v5/i4/173.htm DOI: http://dx.doi.org/10.4329/wjr.v5.i4.173
METHODS: A 70-year-old male with histologically con
firmed osteosclerotic myeloma was treated in our department in July 2010 with VMAT. Fourty-six Gray in
23 fractions were given on three bone lesions. Doses
delivered to target volume and critical organs were
compared with a tridimensional conformal radiotherapy
(3D-RT) plan. Treatment was well tolerated without
any side effects.
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INTRODUCTION
Osteosclerotic myeloma (polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein, skin changes, PO-
173
Robles A et al . VMAT for limited osteosclerotic myeloma
raphy (CT) and 18F-fluorodeoxyglucose positron emission tomography-CT showed organomegaly, mediastinal
adenopathies and hypermetabolism of bone sclerotic lesions (T12, L5 vertebra and right ilium). Bone biopsy using immunohistochemical staining demonstrated clonal
lambda plasma cell infiltration. POEMS syndrome was
retained and this patient received T12 vertebra percutaneous cimentoplasty. Due to persistence of lower back
pain, he was referred to our department to receive radiation in July 2010.
EMS syndrome) is a rare paraneoplastic disease resulting
from a monoclonal plasma cell disorder[1,2]. Most frequent diagnostic criteria include polyneuropathy, monoclonal lambda plasma cell proliferative disorder, bone
lesions, elevated levels of vascular endothelial growth
factor (VEGF) and eventually association with Castleman disease (angiofollicular lymph node hyperplasia).
There are other clinical features, such as organomegaly
(hepato-splenomegaly, lymphadenopathy), endocrine
disorders, skin modifications, papilledema and high extravascular fluid accumulation leading to ascita or pleural
effusion [3]. Although POEMS’ pathogenesis remains
only partially understood, the overproduction of several
pro-inflammatory cytokines [higher levels of interleukine
(IL)-1, IL-6, tumor necrosis factor-α] and VEGF has
been frequently reported. Moreover, clinical manifestations of POEMS syndrome may be correlated with an
increased production of cytokines. Those could potentially be used as surrogate markers of disease activity[4,5].
There is no strong consensus on the appropriate
management of POEMS. Radiation therapy (RT) is generally employed for limited disease, and good response
to RT correlates with an increased survival[6]. On the
other hand, prognosis of POEMS is substantially better
than that of multiple myeloma and patients may be exposed to late toxicities of treatments[3]. The delivery of
RT in bone lesion is challenging because irradiated fields
may include sensitive critical organs. In the era of ballistic optimization, every effort should be made to further
improve the efficacy/toxicity ratio. Volumetric intensitymodulated arc radiotherapy (VMAT) is a new RT modality that allows for rapid delivery of highly consistent
dose distributions, critical organ sparing and it is currently used for various tumor localizations[7-12]. Herein,
we investigated the use of this new high-tech RT modality for a patient with three sclerotic bone lesions. A dosimetric comparison of a VMAT plan with a conventional
tridimensional conformal (3D) plan was performed to
evaluate the potential dosimetric benefit of VMAT in
sparing critical organs from detrimental irradiation.
Dosimetric study
Separate dosimetric analyses were performed for conformal 3D-RT and VMAT. The patient was scheduled
for CT treatment simulation one week prior to treatment. Planning target volume (PTV) was defined by the
tumoral growth volume, as shown on the CT, with a one
cm expansion in all dimensions. The dose to be delivered
was prescribed in terms of median dose to the PTVs
(three sclerotic lesions, two of the rachis and one of the
ilium) delivered with 2.0 Gy per fraction, once daily, 5
d per week, with a total dose of radiation 46 Gy in 23
fractions. PTV and critical organs (including kidneys,
femoral heads, spinal cord, bone marrow, and bladder)
were determined by the same physician. Optimization
was performed to spare normal tissues, including spinal
cord, bone marrow, kidneys and small bowel.
Treatment plans were created using Rapidarc Planning system software (Rapidarc, Varian Medical System,
Palo Alto, CA, United States). After a satisfactory dose
distribution was achieved, the plans were accepted and
treatment duration was determined. Plan acceptance criteria required that at least 95% of the dose covered 99%
of the PTV volume. Dose constraints to the organs at
risk were based on the Quantitative Analysis of Normal
Tissue Effects in the Clinic recommendations[13]. A second treatment plan was determined, with 3D conformal
system software (Eclipse, Varian; Varian Med Systems,
VA, United States). For this phase, a conformal RT technique was used, as routinely used at our Institute. After
the two plans were completed, we compared doses delivered to the critical organs, using the VMAT-based or the
3D conformal plan.
Patient characteristics
A 70-year-old man presented with lower back pain, equilibrium disorders, and a weight loss of 12 kg. He had a
past medical history of alcoholism, tobacco and high
blood pressure. Initial evaluation included complete history and physical examination, hematological and biochemical profiles, serum protein electrophoresis, bone
marrow biopsy and a radiographical skeletal survey.
Physical examination showed a symmetric sensorimotor neuropathy of the extremities, endocrine disorders
(hyperthyroidism and decrease of testosterone level) and
skin changes (melanoderma and hypertrichosis). Biological examinations revealed a plasma cell dyscrasia with an
IgA lambda monoclonal gammapathy and an increased
VEGF rate of 1275 pg/mL (normal < 5 pg/mL). A
myelogram was negative. Total body computed tomog-
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Ethical statement
The procedures followed were in accordance with the
ethical standards of the responsible committee on human experimentation (institutional or regional) and with
the Helsinki Declaration of 1975, as revised in 1983.
RESULTS
The patient was finally treated with VMAT. Tolerance
was excellent and no acute or late toxicities were observed. Clinical response consisted of a decreased of
the lower back pain following completion of RT. The
patient remains free from any tumor progression 18 mo
after treatment completion. In the latest evaluation, the
174
VEGF rate has halved (633 pg/mL) and radiological
controls showed a local tumoral regression.
Comparing VMAT and 3D-RT plans, 99% of the
target volume received 95% of prescribed dose with
either technique. However, dose homogeneity was improved for VMAT. For the doses delivered to the PTV,
standard deviations were 2.9 Gy and 1.6 Gy for 3D
and VMAT, respectively. VMAT resulted in substantial
critical organ sparing. Dose delivered to 20% of organ
volume (D20) was reduced from 22 Gy (3D-RT) to 15
Gy (VMAT) for small bowel, from 24 Gy (3D-RT) to 17
Gy (VMAT) for bladder and from 47 Gy (3D-RT) to 3
Gy (VMAT) for spinal cord. The volume that received
at least 20 Gy (V20) was lower with the use of VMAT
than with 3D-RT (V20 bladder: 10% vs 99%; V20 small
bowel: 6% vs 21%). Radiation doses delivered to critical
organs according conformal radiotherapy or VMAT are
reported in Table 1. Isodoses (Gy) and dose-volume histograms are presented for 3D-RT and VMAT plans in
Figures 1 and 2, respectively.
Table 1 Comparison between the treatment plans of critical
organs dose exposure
PTV (Gy)
Min
Max
mean ± SD
Kidney R (Gy)
D10
D20
D30
Dmax
Dmean
V10
V20
V30
Kidney L (Gy)
D10
D20
D30
Dmax
Dmean
V10
V20
V30
Small bowel (Gy)
D10
D20
D30
Dmax
Dmean
V10
V20
V30
Spinal cord (Gy)
D10
D20
D30
Dmax
Dmean
V10
V20
V30
Femoral head R (Gy) D10
D20
D30
Dmax
Dmean
V10
V20
V30
Femoral head L (Gy) D10
D20
D30
Dmax
Dmean
V10
V20
V30
Bladder (Gy)
D10
D20
D30
Dmax
Dmean
V10
V20
V30
3D-RT
VMAT
30.5
49.1
46.7 ± 2.9
16.2
14.4
13.1
39.6
7.9
46.7%
2.0%
0.1%
18.3
15.5
14.1
46.7
9.0
44.7%
7.5%
3.5%
25.8
21.6
12.4
46.8
9.6
40.6%
20.8%
2.6%
47.3
47.1
46.8
47.7
31.8
70.5%
67.9%
66.2%
27.2
25.8
21.5
30.2
11.6
38.8%
31.2%
0.02%
47.4
46.8
45.9
47.9
29.1
75.0%
64.0%
52.5%
25.6
24.4
24.1
45.0
24.3
100.0%
99.0%
5.3%
38.7
50.8
47.5 ± 1.6
18.7
14.2
11.1
38
7.5
33.9%
8.2%
0.7%
19.2
14.7
11.7
44.9
7.6
34.5%
8.7%
0.7%
18.1
15.3
13.2
43.1
8.8
43.6%
6.0%
0.2%
37.5
36.0
34.8
41.0
22.5
64.3%
59.7%
53.8%
5.5
4.4
3.2
7.8
2.3
0.0%
0.0%
0.0%
44.4
40.4
36.7
49.3
21.2
58.4%
48.2%
38.2%
19.8
16.7
14.2
36.2
12.5
59.0%
9.5%
0.4%
DISCUSSION
In our report, we describe the use of VMAT for localized POEMS syndrome. To our knowledge, there are no
previous reports of this technique in the medical literature for osteosclerotic myeloma. The course of POEMS
syndrome is frequently chronic and patients may survive
four times longer than in multiple myeloma. Dispenzieri
et al[3,6] reported a median overall survival of 165 mo
in their series of 99 patients. RT given in a dose of 40
to 50 Gy is a commonly accepted first-line treatment
for single or multiple osteosclerotic lesions. Indeed, the
benefit of radiation correlates with a drastic decrease
in symptoms and improvement in survival. However,
RT is also associated with acute and chronic toxicities
that might potentially affect the quality of life of longsurvivor patients. Although we did not have sufficient
follow-up to accurately evaluate local control or survival,
the risk of long-term severe morbidity increases as the
radiation doses delivered to critical organs increases.
Highly conformal RT allows efficient target coverage
and sparing of organs at risk, such as spinal cord, small
bowel or bladder. VMAT is a new form of intensity
modulated radiotherapy (IMRT) optimization combining one gantry rotation and variable dose-rate, variable
gantry speed and a dynamic multi-leaf collimator. It was
recently introduced in clinical practice for comparison
to conventional RT modalities in various malignancies,
including brain, prostate, head and neck, anal canal, and
cervix tumors[7-12]. Our report describes the potential
interest of VMAT for osteosclerotic myeloma for both
increasing dose homogeneity to the PTV and decreasing
the dose to the critical organs. Moreover, sparing of critical organs may allow patients that develop widespread
lesions or who did not respond to RT to receive further
systemic therapies in the future. Also, as in our case,
blood VEGF levels may be used as a surrogate marker
3D-RT: Conformational radiation therapy; VMAT: Volumetric intensitymodulated arc therapy; PTV: Planned target volume; Gy: Gray; D10, D20,
D30: Doses delivered to 10%, 20% and 30% of critical organs volumes, respectively; V10, V20, V30: Volumes of critical organs that received 10 Gy,
20 Gy and 30 Gy, respectively; R: Right; L: Left.
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175
Figure 1 Isodoses (Gray) according to treatment plan: volumetric intensity-modulated arc radiotherapy (right side) and conformal tridimensional radiotherapy (left side).
PTVs
L kidney
R kidney
Bladder
R femoral head
L femoral head
Small bowel
Spinal cord
Ratio of total structure volume (%)
100
90
80
70
60
50
40
30
20
10
0
0
10
20
30
40
50
Dose (Gy)
Figure 2 Dose volume histograms for the two treatment plans: Volumetric intensity-modulated arc radiotherapy (triangles) and tridimensional conformal
radiotherapy (squares). L: Left; R: Right; Gy: Gray; PTVs: Planning target volumes.
of disease after completion of RT, and then be useful in
deciding whether systemic therapy should be added[14].
VMAT does, however, have some limitations, principally a larger volume of normal tissues receiving low
doses irradiation. By using IMRT techniques, it was previously demonstrated that the volume exposed to low
doses was increased. This may be particularly important
for patients with long survival, where heterogeneous
low-dose volume may increase the incidence of second
malignancies[15]. Nevertheless, treatment duration and
monitor units are decreased with VMAT compared to
conventional IMRT, which can potentially affect the risk
of developing a second cancer[16]. Our study is the first
to report the possible use of arc-based RT for POEMS.
In other haematological malignancies, Chargari et al[17] reported the feasibility of helical tomotherapy in patients
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with paramedullar solitary plasmocytoma. In their experience, helical tomotherapy improved the dose homogeneity within the PTV and resulted in a more efficient
sparing of critical organs, when compared to 3D-RT.
Although improvement in normal tissue sparing and target coverage is suggested for tomotherapy compared to
conventional IMRT, other authors reported that VMAT
offered dosimetric qualities comparable to that of helical
tomotherapy[18,19].
In conclusion, VMAT allowed improved dose distribution in comparison to 3D-RT for limited osteosclerotic myeloma. In fact, VMAT achieved higher dose
homogeneity within the PTV and better saving of critical organs. The benefit of new highly conformal RT
techniques should be further examined in larger series
of patients.
176
COMMENTS
COMMENTS
8
Background
There is no strong consensus on the appropriate management of limited osteosclerotic myeloma. Radiation therapy (RT) is generally employed for limited
disease. The authors aimed to assess the feasibility of volumetric intensitymodulated arc radiotherapy (VMAT) in patients with limited polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin change
syndrome.
9
Research frontiers
VMAT is a new RT modality that allows rapid delivery of highly conformal dose
distributions, critical organs sparing and s currently used for various tumor
localizations. A dosimetric comparison of the VMAT plan with the conventional
tridimensional conformal (3D) plan was performed to assess the potential dosimetric benefit of VMAT in sparing critical organs from detrimental irradiation.
10
Applications
11
VMAT may provide a clinical and dosimetric benefit over 3D-RT techniques in
limited osteosclerotic myeloma.
Peer review
VMAT allowed improved dose distribution in comparison to 3D-RT for limited
osteosclerotic myeloma. Moreover, VMAT achieved higher dose homogeneity
within the planned target volume and better saving of critical organs. The benefit of new highly conformal RT techniques should be further examined in larger
series of patients.
12
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P- Reviewer Plataniotis E S- Editor Gou SX
L- Editor Hughes D E- Editor Xiong L
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177
WJ R
World Journal of
Radiology
[email protected]
doi:10.4329/wjr.v5.i4.178
BRIEF ARTICLE
Role of color Doppler in differentiation of Graves' disease
and thyroiditis in thyrotoxicosis
Ragab Hani Donkol, Aml Mohamed Nada, Sami Boughattas
18 cases with Graves’ disease and 8 cases with Hashimoto’s thyroiditis. All patients had suppressed thyrotropin. The diagnosis of Graves’ disease and Hashimoto’s
thyroiditis was supported by the clinical picture and follow up of patients.
Ragab Hani Donkol, Department of Radiology, Aseer Central
Hospital, Abha 61321, Saudi Arabia
Ragab Hani Donkol, Faculty of Medicine, Cairo University,
Cairo 12613, Egypt
Aml Mohamed Nada, Endocrine Unit, Department of Internal
Medicine, Faculty of Medicine, Mansoura University, Mansoura
35516, Egypt
Sami Boughattas, Department of Nuclear Medicine, Aseer
Central Hospital, Abha 61321, Saudi Arabia
Author contributions: Donkol RH designed the study, perform
ed Doppler studies, analyzed the data and wrote the manuscript;
Nada AM shared in manuscript writing, selection of cases, clini
cal and laboratory assessment and collection of data; Bougattas
S performed and interpreted radioactive thyroid scans.
Correspondence to: Ragab Hani Donkol, MD, Department of
Radiology, Assir Central Hospital, PO Box 34, Abha 61321,
Saudi Arabia. [email protected]
Telephone: +966-7-2291169 Fax: +966-3-8552244
Received: December 4, 2012 Revised: January 22, 2013
RESULTS: Peak systolic velocities of the inferior thyroid arteries were significantly higher in patients with
Graves’ disease than in patients with thyroiditis (P =
0.004 in the right inferior thyroid artery and P = 0.001
in left inferior thyroid artery). Color-flow Doppler ultrasonography parameters demonstrated a sensitivity
of 88.9% and a specificity of 87.5% in the differential
diagnosis of thyrotoxicosis.
CONCLUSION: Color Doppler flow of the inferior thyroid artery can be used in the differential diagnosis of
thyrotoxicosis, especially when there is a contraindication of thyroid scintigraphy by radioactive material in
some patients.
Abstract
Key words: Doppler; Thyrotoxicosis; Thyroid scintigraphy; Graves’ diseases; Thyroiditis
AIM: To evaluate the role of thyroid blood flow assessment by color-flow Doppler ultrasonography in the differential diagnosis of thyrotoxicosis and compare it to
technetium pertechnetate thyroid scanning.
Donkol RH, Nada AM, Boughattas S. Role of color Doppler in
differentiation of Graves’ disease and thyroiditis in thyrotoxico
sis. World J Radiol 2013; 5(4): 178-183 Available from: URL:
http://www.wjgnet.com/1949-8470/full/v5/i4/178.htm DOI:
http://dx.doi.org/10.4329/wjr.v5.i4.178
METHODS: Twenty-six patients with thyrotoxicosis
were included in the study. Clinical history was taken
and physical examination and thyroid function tests
were performed for all patients. Thyroid autoantibodies
were measured. The thyroid glands of all patients were
evaluated by gray scale ultrasonography for size, shape
and echotexture. Color-flow Doppler ultrasonography
of the thyroid tissue was performed and spectral flow
analysis of both inferior thyroid arteries was assessed.
Technetium99 pertechnetate scanning of the thyroid
gland was done for all patients. According to thyroid
scintigraphy, the patients were divided into two groups:
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INTRODUCTION
Thyrotoxicosis refers to the hypercatabolic state resulting
from elevated serum levels of thyroid hormone, mainly
free tetraiodothyronine (FT) 4 and/or triiodothyronine
FT3. Thyrotoxicosis is not synonymous with hyperthyroidism[1]. It may be caused either by hyperthyroidism or
178
Donkol HR et al . Color Doppler in thyrotoxicosis
by inflammation of the thyroid with release of stored
thyroid hormone but is not accelerated synthesis. It may
also be caused by ingestion of exogenous thyroid hormone. Graves’ disease causes hyperthyroidism with diffuse thyroid disease while thyrotoxicosis due to destructive thyroiditis includes various subsets like lymphocytic
thyroiditis, subacute thyroiditis and postpartum thyroiditis[2-5].
Differentiation between causes of thyrotoxicosis at
time of diagnosis, either hyperthyroidism due to Graves’
disease or destructive thyrotoxicosis due to thyroiditis,
is very important as management of each case is completely different. The absence of specific signs of Graves’
disease like ophthalmopathy, skin and nail changes may
make it difficult to distinguish it from thyroiditis, especially when the disease is mild or subclinical. Thyroid
scintigraphy by technetium99 (Tcm99) pertechnetate or
iodine 123 radioisotopes is used for this purpose. Measuring thyrotropin (TSH) receptor antibody levels can be
also used[6]. However, these methods are not usually available. Nuclear imaging is expensive and contraindicated
during pregnancy and lactation.
Thyroid hypoechogenicity at ultrasound is a characteristic of autoimmune thyroid diseases, with an overlap of this echographic pattern in patients affected by
Graves’ disease or Hashimoto’s thyroiditis. However, a
diffusely increased thyroid blood flow is pathognomonic
of untreated Graves’ disease and an abnormal color flow
Doppler (CFD) pattern identifies the majority of Graves’
patients with a normal thyroid ultrasound pattern. Thus,
CFD sonography may be useful in distinguishing patients
with Graves’ disease and Hashimoto’s thyroiditis with a
similar thyroid echographic pattern.
CFD ultrasonography is a useful, inexpensive, noninvasive and widely available method for measuring tissue
vascularization and blood flow. The evaluation can be
both qualitative (visual assessment of thyroid vascularity)
and quantitative (measuring peak systolic, end diastolic
and mean velocities in the inferior thyroid arteries). CFD
ultrasonography of the thyroid gland can provide valuable information about underlying thyroid functional
status and is useful in the differential diagnosis of thyrotoxicosis[7-10].
The aim of the study is to evaluate the efficiency of
CFD in differentiation of causes of thyrotoxicosis at
time of diagnosis, either hyperthyroidism due to Graves’
disease or destructive thyrotoxicosis due to thyroiditis,
and compare its sensitivity and specificity to technetium
thyroid scintigraphy to know if both investigations can
be used as alternatives in cases of thyrotoxicosis.
Exclusion criteria included toxic nodule, history of thyroid surgery, radioiodine therapy or radiation exposure to
neck. Patients whose goiter was multinodular or diffuse
were included in the study. Clinical history, including sex,
age, symptoms and signs, was performed. Serum levels
of TSH, free T3, free T4, antithyroid peroxidase and antithyroglobulin antibodies were measured in all patients.
Graves’ disease was diagnosed on the basis of clinical
parameters (marked weight loss, adrenergic symptoms,
goiter, skin and nail changes, eye signs) and high uptake
on Tcm99 thyroid scanning. Thyroiditis was diagnosed
on the basis of low Tcm99 uptake scan, the presence of
insignificant symptoms (no or minimal weight loss, occasional palpitations, absent eye signs with or without
goiter) or later development of hypothyroidism.
A radiologist with twenty years of experience in
sonography, who was blinded to the full clinical status,
performed all thyroid ultrasound examinations. A color
Doppler ultrasound scanner (iU22, Philips Ultrasound,
Bothell, WA, United States) equipped with a 3-9 MHz
broadband linear array transducer was used. The grey
scale ultrasound examinations of the thyroid gland were
performed regarding the size, shape and echotexture of
the gland, as well as the presence or absence of nodules
(Figure 1A). The color Doppler pattern of the glands
were studied (Figure 1B). Parameters for color Doppler are F. 6.6 MHz, G.76%, pulse-repetition frequency
(PRF) 2.1 KHz and wall filter (WF) was M. The Doppler
spectral analysis was of the right and left inferior thyroid
arteries in the transverse scanning, in which the vessels
crossed the common carotid arteries posteriorly, or in
the longitudinal scanning of the ascending parts of the
arteries, in which the vessels lie parallel to the common
carotid arteries (Figure 1C). Parameters for color Doppler are F. 6.6 MHz, G.64%, PRF 5.6 KHz and WF 50
Hz. The angle correction cursor was parallel to the direction of flow and the Doppler angle was kept at or below
60°. The peak systolic velocity, end diastolic velocity
and mean velocity were obtained. Peak systolic velocity
of the inferior thyroid artery of 40 cm/s is considered
significantly high and suggestive for Graves’ disease[11,12].
Another radiologist who was blinded to the clinical picture and ultrasound examination performed all isotopic
thyroid scans (Figure 2). A technetium pertechnetate scan
was done in all patients as the gold standard test for differentiation between both causes of thyrotoxicosis.
Frequency, arithmetic mean and standard deviation were
used to present the data. Student’s t test was used as a test
of significance at 5% level. Screening test evaluation was
carried out with positive/negative outcomes, sensitivity,
specificity, positive and negative predictive values and
likelihood ratios for positive and negative tests were calculated with the concomitant 95%CIs.
The McNemar test was applied to compare diagnostic performance of pulsed Doppler with the technetium
scan for discriminating between Grave’s disease and thy-
The Research and Ethics committee of our hospital approved the study and written informed consent was acquired from all patients. The study population consisted
of 26 patients presenting to the endocrine clinic with thyrotoxicosis during the period from January to July 2011.
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179
A
B
C
Rt lobe
Isthmus
IJV
CCA
Isthmus
ITA
CCA
Trachea
Trachea
Figure 1 Gray scale ultrasound, color Doppler, Doppler spectral analysis in patients with Graves’ disease. A: Gray scale ultrasound of the right lobe of the
thyroid gland in patients with Graves’ disease shows enlarged gland with smooth contour and heterogeneous echotexture; B: Color Doppler of the same patient shows
diffuse increase vascularity of the thyroid gland; C: Doppler spectral analysis of the right inferior thyroid artery of the same patients show elevated peak systolic velocity (V1 = 89.8 cm/s) and elevated end diastolic velocity (V2 = 44.9 cm/s). CCA: Common carotid artery; IJV: Internal jugular vein; IJV: Internal jugular vein.
R
Rt lobe
arteries, was significantly higher in patients with Graves’
disease than in patients with destructive thyroiditis (P =
0.004 in the right inferior thyroid artery and P = 0.001, in
the left inferior thyroid artery). End diastolic velocity was
significantly higher in Graves’ patients than in patients
with thyroiditis (P = 0.007, in the right inferior thyroid
artery and P = 0.001 in the left inferior thyroid artery).
Consequently, mean velocity in the inferior thyroid artery
was significantly higher in patients with Graves’ than in
patients with thyroiditis (Table 1).
Sixteen out of 18 patients diagnosed as Graves’ disease by Tcm99 scan had an inferior thyroid artery flow
velocity greater than 40 cm/s. Diagnosis of Graves’
disease in the remaining two patients was established by
increased uptake on the thyroid scan and clinical findings that favor Graves’ disease. Seven out of 8 patients
with destructive thyroiditis had an inferior thyroid artery
flow less than 40 cm/s. The last patient was diagnosed
as thyroiditis due to low Tcm99 uptake and by its clinical
picture and follow up of patients.
Comparing volume of the thyroid gland between both
groups revealed significantly larger volume in Graves’ patients than in patients with thyroiditis (P = 0.028) (Table 1).
CFD showed a sensitivity of 88.9% and a specificity
of 87.5%, positive predictive value of 94.1%, negative
predictive value of 77.8% and a diagnostic accuracy of
88.5% in the differential diagnosis of thyrotoxicosis compared to thyroid scanning by Tcm99 pertechnetate (Table
2). Also, the McNemar test result was significant (P =
0.453) and indicates that the two diagnostic tests (technetium scan and pulsed Doppler) are not significantly different with respect to sensitivity.
The power analysis and sample size calculation were
performed based on the equation for sample size for two
compared proportions with normal approximation to
the binomial distribution and b = 0.2, i.e., power = 0.8.
Applying the “Shapiro-Wilk test” assessed the normal
distribution of study variables and showed that most
variables proved to be normally distributed, (e.g., volume
of the thyroid gland P = 0.128, T3 serum level P = 0.076).
ROC analysis of the results showed that cut-off value of
Lt lobe
Isthmus
Tc99m pertechnetate thyroid
scintigraphy pin-hole collimator
Figure 2 Thyroid scintigraphy of the same patient showed enlarged both
lobes of the thyroid with diffuse increase uptake. R: Right; Tc99m: Technetium TC 99M pyrophosphate.
roiditis. The power analysis and sample size calculation
were performed based on the equation for sample size
for two compared proportions with normal approximation to the binomial distribution to determine the minimal required sample size. Applying the “Shapiro-Wilk
test” assessed the normal distribution of study variables.
Receiver operating characteristic (ROC) analysis of the
results was done to determine the appropriate cut-off
value of peak systolic velocity to differentiate Graves’ disease from thyroiditis.
RESULTS
All patients who participated in this study have suppressed TSH level (0.08-0.005 IU/L) with normal or high
free T4 and T3 levels. Thyroid scanning by Tcm99 was
done for all patients as the gold standard test for differentiation between Graves’ disease and thyroiditis. Supported
by the clinical picture of patients, eighteen patients had
Graves’ disease and eight patients had destructive thyrotoxicosis. No significant difference in age between both
groups (P = 0.565) was found.
Thyroid blood flow, as assessed by color flow imaging and Doppler spectral analysis of the inferior thyroid
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180
ROC curve
1.0
Table 1 Comparing parameters between hyperthyroidism and
thyroiditis
Age, yr (mean ± SD)
Thyroid volume (cm3)
RPSV (cm/s)
REDV (cm/s)
RMV (cm/s)
LPSV (cm/s)
LEDV (cm/s)
LMV (cm/s)
Graves
Thyroiditis
P value
31.1 ± 8.4
24.2 ± 10.1
50.4 ± 23.4
31.3 ± 16.6
68.9 ± 31.6
49 ± 25.7
29.6 ± 17.5
68.4 ± 35.2
33.1 ± 7.5
14.8 ± 7.54
21.7 ± 14.8
12.8 ± 9.4
30.6 ± 20.3
17.8 ± 6
10 ± 4.5
25.5 ± 8.3
0.565
0.028
0.004
0.007
0.004
0.001
0.001
0.001
Sensitivity
0.8
Parameter
0.6
0.4
0.2
0.0
RPSV: Right peak systolic velocity; REDV: Right end diastolic velocity;
RMV: Right man velocity; LPSV: Left peak systolic velocity; LEDV: Left
end diastolic velocity; LMV: Left mean velocity (t test).
Estimate
Sensitivity
Specificity
Positive predictive value
Negative predictive value
Diagnostic accuracy
Likelihood ratio of a positive test
Likelihood ratio of a negative test
Diagnostic odds
Cohen's kappa (unweighted)
88.9%
87.5%
94.1%
77.8%
88.5%
7.1
0.1
56
0.7
0.4
0.6
0.8
1.0
Figure 3 Receiver operating characteristic analysis of the results determined that 40 cm/s is the appropriate cut-off value of peak systolic velocity to differentiate Graves’ disease from thyroiditis. ROC: Receiver operating characteristic.
Lower-upper 95%CI
67.2-96.9
52.9-97.8
73.0-99
45.3-93.7
71-96
0.99-51.3
0.05-0.4
4.3-724.1
0.4-1.1
two types of thyrotoxicosis and thyroid blood flow was
evaluated by color Doppler as a parameter to differentiate the types of thyrotoxicosis and compare its sensitivity
and specificity to Tcm99 thyroid uptake.
Peak systolic, end diastolic and mean velocities of
inferior thyroid artery in patients with Graves’ disease
were significantly higher than patients with thyroiditis[14].
CFD ultrasonography in our study showed a sensitivity
of 88.9% with specificity of 87.5%. These results are
comparable to the results of a study carried out by Kurita
et al[15] on 75 patients with thyrotoxicosis, which demonstrated that CFD ultrasonography had a sensitivity of
84% and specificity of 90% in the differential diagnosis
of thyrotoxicosis.
On the other hand, Hari Kumar et al[16] in 2009 studied 65 patients with thyrotoxicosis. He found significantly
higher blood flow in inferior thyroid arteries in Graves’
disease than in destructive thyrotoxicosis. He also demonstrated that CFD ultrasonography had a sensitivity of
96% and a specificity of 95% in the differential diagnosis
of thyrotoxicosis.
Other forms of estimation of thyroid blood flow assessment, like thyroid blood flow area, vascularization index and high-resolution power Doppler, have been used
by investigators to provide better differentiation[17-19]. A
cut-off value of 40 cm/s was considered in differentiation between Graves’ diseases from thyroiditis based on a
review of relevant literature[16,20-23]. This cut-off was also
in agreement with obtained results from our own data, as
ROC curve of different values of sensitivity and specificity justifies this decision.
Referring to this study and similar various studies[24-30],
color Doppler ultrasonography of the thyroid gland is
considered to be one of the initial investigations that can
give great help in the differentiation of Graves’ disease
and Hashimoto’s thyroiditis. Color Doppler is a cheap
simple technique with no ionizing radiation exposure and
is cost effective in the diagnosis of thyrotoxicosis[31-35].
Inferior thyroid artery blood flow is a useful param-
40-cm/s peak systolic velocity was considered significant
to differentiate between Graves’ disease and thyroiditis
(Figure 3).
DISCUSSION
Clinical manifestations of thyrotoxicosis in cases of thyroiditis and early or mild Graves’ disease may be difficult
to differentiate. Although persistence of symptoms and
signs in Graves’ disease can distinguish it from thyroiditis,
it is very important to diagnose the disease early for the
proper management. Isotope uptake scan of the thyroid
is one of the definitive diagnostic tools, especially when
there is clinical confusion between the two conditions.
However, limited availability, high cost and contraindications to a radioisotope scan during pregnancy and lactation may restrict its application.
Although radioactive iodine is often useful in the
diagnosis and treatment of thyrotoxicosis, such tests cannot be performed in many patients because of recent use
of iodinated contrast for other diagnostic studies, such
as computed tomography (CT) scanning which interfere
with the accuracy of radioactive iodine tests. In their
study, Phillips et al[13] found that 45% of patients with
newly diagnosed thyrotoxicosis had received iodinated
contrast within 2 wk before endocrinology evaluation;
43% had received iodine for CT and the other 2% for
angiography.
In this study, Tcm99 pertechnetate was used as the
definitive radiological investigation to differentiate the
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0.2
1-Specificity
diagonal segments are produced by ties
Table 2 Sensitivity and specificity of color flow Doppler
Parameter
0.0
181
eter in the differential diagnosis of thyrotoxicosis. It has
a sensitivity of 88.9% with a specificity of 87.5% in the
differentiation between Graves’ disease and other forms
of autoimmune thyroiditis. It is an acceptable alternative
to radioisotope scans, especially when there is a contraindication to nuclear imaging of the thyroid. We recommend measurement of thyroid blood flow by Doppler as
an essential part of initial investigations of thyrotoxicosis.
4
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Maruta A, Ishigatsubo Y. [Thyrotoxicosis after cord blood
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6
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Vitti P, Rago T, Mazzeo S, Brogioni S, Lampis M, De Liperi
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A, Bartolozzi C, Pinchera A, Martino E. Thyroid blood flow
evaluation by color-flow Doppler sonography distinguishes
Graves' disease from Hashimoto's thyroiditis. J Endocrinol
Invest 1995; 18: 857-861 [PMID: 8778158]
11 Macedo TA, Chammas MC, Jorge PT, Pereira de Souza L,
Farage L, Pegoraro BL, Pessa SU, Cerri GG. Reference values for Doppler ultrasound parameters of the thyroid in a
healthy iodine-non-deficient population. Br J Radiol 2007; 80:
625-630 [PMID: 17681987]
12 Sponza M, Fabris B, Bertolotto M, Ricci C, Armini L. [Role
of Doppler color ultrasonography and of flowmetric analysis in the diagnosis and follow-up of Grave’s disease]. Radiol
Med 1997; 93: 405-409 [PMID: 9244919]
13 Phillips BD, Hennessey JV. Iodinated contrast prior to evaluation for thyrotoxicosis. J Hosp Med 2009; 4: 285-288 [PMID:
19263484]
14 Bogazzi F, Bartalena L, Brogioni S, Burelli A, Manetti L,
Tanda ML, Gasperi M, Martino E. Thyroid vascularity and
blood flow are not dependent on serum thyroid hormone
levels: studies in vivo by color flow doppler sonography.
Eur J Endocrinol 1999; 140: 452-456 [PMID: 10229913]
15 Kurita S, Sakurai M, Kita Y, Ota T, Ando H, Kaneko S, Takamura T. Measurement of thyroid blood flow area is useful
for diagnosing the cause of thyrotoxicosis. Thyroid 2005; 15:
1249-1252 [PMID: 16356088]
16 Hari Kumar KV, Pasupuleti V, Jayaraman M, Abhyuday V,
Rayudu B R, Modi KD. Role of thyroid Doppler in differential diagnosis of thyrotoxicosis. Endocr Pract 2009; 15: 6-9
[PMID: 19211390]
17 Arslan H, Unal O, Algün E, Harman M, Sakarya ME. Power
Doppler sonography in the diagnosis of Graves’ disease. Eur
J Ultrasound 2000; 11: 117-122 [DOI: 10.1016/S0929-8266(99)
00079-8]
18 Ralls PW, Mayekawa DS, Lee KP, Colletti PM, Radin DR,
Boswell WD, Halls JM. Color-flow Doppler sonography in
Graves disease: “thyroid inferno”. AJR Am J Roentgenol 1988;
150: 781-784 [PMID: 3279732]
19 Cappelli C, Pirola I, De Martino E, Agosti B, Delbarba A,
Castellano M, Rosei EA. The role of imaging in Graves’
disease: a cost-effectiveness analysis. Eur J Radiol 2008; 65:
99-103 [PMID: 17459638]
20 Levine RA. Doppler ultrasound. In: Baskin HJ, Duick DS,
Levine RA, editors. Thyroid ultrasound and ultrasound-guided FNA. 2nd ed. New York: Springer; 2008: 27-43 [DOI: 10.
1007/978-0-387-77634-7_3 ]
ACKNOWLEDGMENTS
The authors acknowledge the great help of the laboratory
team, radiology technicians, nursing staff and everybody
who participated in the collaboration of this research.
COMMENTS
COMMENTS
Background
Thyrotoxicosis may be caused either by hyperthyroidism of Graves’ disease
or be due to destructive thyroiditis. Differentiation between causes of thyrotoxicosis at time of diagnosis is very important as management of each one is
completely different. Thyroid scintigraphy is routinely used for this purpose but
it is expensive and uses ionizing radiation.
Research frontiers
Color flow Doppler (CFD) ultrasonography is a safe, inexpensive, non-invasive
and widely available method for measuring thyroid vascularization and blood
flow. It can provide valuable information to differentiate causes of thyrotoxicosis. In this study, the clinical, laboratory, thyroid scan and Doppler results of 26
patients with thyrotoxicosis are described and compared with the aim of evaluating the efficiency of CFD in the differentiation of causes of thyrotoxicosis and
comparing its sensitivity and specificity to thyroid scintigraphy.
This study highlighted the usefulness of color Doppler in differentiating between
the two common causes of thyrotoxicosis with a sensitivity of 88.9% and a
specificity of 87.5%. The authors emphasized that color Doppler is an acceptable alternative to radioisotope scans in the diagnosis of thyrotoxicosis.
Applications
Color Doppler flow of the inferior thyroid artery can be used in the differential
diagnosis of thyrotoxicosis, especially when there is contraindication of thyroid
scintigraphy by radioactive material in some patients.
Terminology
Thyrotoxicosis is a hypercatabolic state resulting from elevated serum levels of
thyroid hormone. Graves’ disease is a diffuse thyroid disease with hyperthyroidism due to accelerated synthesis of thyroid hormones. Hashimoto’s disease
is autoimmune inflammation of the thyroid with release of stored thyroid hormones.
Peer review
This is an interesting paper addressing the role of color/pulsed Doppler for the
differential diagnosis of thyrotoxicosis. This is a very careful and well thought
out study of an important clinical problem. The study design, methods and data
analysis are appropriate although the sample size is rather small and not well
described. The authors’ conclusions are supported by the data and the manuscript is very well written.
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P- Reviewers Juan A, Russell LD S- Editor Jiang L
L- Editor Roemmele A E- Editor Xiong L
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WJ R
World Journal of
Radiology
[email protected]
doi:10.4329/wjr.v5.i4.184
CASE REPORT
MDCT of right aortic arch with aberrant left subclavian
artery associated with kommerell diverticulum and calcified
ligamentum arteriosum
Rene Epunza Kanza, Michel Berube, Pierre Michaud
Rene Epunza Kanza, Michel Berube, Department of Radiology, Chicoutimi Hospital, Saguenay, Quebec G7H5H6, Canada
Rene Epunza Kanza, Department of Radiology, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec J1H5N4,
Canada
Pierre Michaud, Department of Surgery, Cardiothoracic Unit,
Chicoutimi Hospital, Saguenay, Quebec G7H5H6, Canada
Author contributions: Kanza RE performed the diagnosis and
wrote the manuscript; Berube M was involved in performing the
diagnosis and critically revised the manuscript; Michaud P was
involved in the patient care.
Correspondence to: Dr. Rene Epunza Kanza, MD, PhD, Clinical Assistant Professor, Department of Radiology, Chicoutimi
Hospital Affiliated with Sherbrooke University, 305 Rue SaintVallier, Saguenay, Quebec G7H5H6,
Canada. [email protected]
Telephone: +1-418-5411234 Fax: +1-418-5435104
Received: July 10, 2012
Revised: December 30, 2012
Accepted: January 31, 2013
with aberrant left subclavian artery associated with kommerell
diverticulum and calcified ligamentum arteriosum. World J
Radiol 2013; 5(4): 184-186 Available from: URL: http://www.
wjgnet.com/1949-8470/full/v5/i4/184.htm DOI: http://dx.doi.
org/10.4329/wjr.v5.i4.184
INTRODUCTION
Right aortic arch with aberrant origin of left subclavian
artery is rare congenital variation of the aortic arch and
its branches with a reported prevalence of 0.05%-1% in
the literature[1]. This anomaly is frequently an incidental
findings during autopsies series or angiographic studies because it is usually asymptomatic, but rarely may be
symptomatic especially when there is a partial or complete obstruction of the oesophagus and/or trachea.
With the recent development of newer non-invasive
imaging systems, the use computed tomography and magnetic resonance imaging (MRI) in daily practice has been
increase to diagnose and characterize anomalies of aortic
arch and its branches including vascular ring. Despite this,
the last part or the complete vascular ring which is made
by left-side ligamentum arteriosum is often not clearly
visualized pre-operatively.
We present multidetector row computed tomography
(MDCT)-angiographic findings of a case of right aortic
arch (RAA) with aberrant left subclavian artery (ALSA)
associated with Kommerell diverticulum and calcified
ligamentum arteriosum causing dysphagia lusoria. In
another patient, we emphasize the role that MDCT may
play to demonstrate calcified ligamentous arteriosum (LA).
Abstract
We present a case of the right aortic arch with kommerell diverticulum (KD) and aberrant left subclavian
artery in a symptomatic 50-year-old patient with a
calcification in the presumed attachment site of the
ligamentum arteriosum (LA) to the KD. In another
30-year-old male patient, the entire course of a calcified LA was demonstrated using multidetector row
computed tomography.
Key words: Multidetector row computed tomography;
Right aortic arch; Aberrant left subclavian artery; Kommerell diverticulum; Calcification of ligamentum arteriosum
CASE REPORT
Case 1
A 50-year-old man was referred to our department for
investigation of dysphagia.
Kanza RE, Berube M, Michaud P. MDCT of right aortic arch
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184
Kanza RE et al . MDCT-angiography of RAA and ALSA
Figure 1 Chest X-ray scan showing the right aortic knob and arch as well
as slight shift of the inferior trachea to the left (arrow).
Figure 2 Barium esophagogram showing the posterior compression of
the esophagus (arrow) in the oblique view.
The patient had a long history of arterial hypertension, type Ⅱ diabetes mellitus, and sleep apnea syndrome
and was newly diagnosed with ischemic cardiac disease.
A chest X-ray showed a right aortic knob and arch with
mild tracheal deviation to the left (Figure 1).
A barium esophagogram showed posterior compression of the esophagus (Figure 2).
MDCT-angiography was performed using a 16-slice
MDCT scanner (LightSpeed 16, GE Healthcare, WI, Milwaukee, United States). CT parameters included 2.5-mm
slice thickness, gantry rotation time 0.5 s, 120 Kvp and
300 mA. The scanning delay was determined with a bolus
tracking technique. The true CT study was obtained after
administration of 120 cc of contrast medium at the rate
of 4 cc/s. Multiplanar, maximum intensity projection and
three dimensional volume-rendered reformations were
obtained using a separate workstation (Voxar 3D in impax 6.3; Agfa).
MDCT-angiography demonstrated RAA with a kommerell diverticulum (KD) and an ALSA (Figure 3A and
B). Additionally, calcification was found in the presumed
site of the superior attachment of LA to the KD (Figure
3C).
Because of multiple comorbidities and relatively
non-disabling dysphagia, surgery was postponed and priority was given to thoroughly investigating the patient’s
cardiac disease and controlling all the comorbities before
safe surgery could be planned.
A
B
C
Case 2
A 30-year-old referred to our department for chest CT
following detection of 6 mm lung nodule in the right
lung base during abdominal CT performed for abdominal pain investigation. The chest CT shows calcification
of the entire course of the ligamentum arteriosum as an
incidental findings (Figure 4)
Figure 3 Multidetector computed tomography of the right aortic arch with
an aberrant left subclavian artery in a 50-year-old man with dysphagia.
Axial (A) and coronal (B) multiplanar reformatted and maximum intensity projection (C) images showing the kommerell diverticulum (white arrow). Note the
calcification in the presumed aortic insertion site of the ligamentum arteriosum
(black arrows).
WJR|www.wjgnet.com
DISCUSSION
Right aortic arch with aberrant origin of left subclavian
artery is one of the commonest mediastinal vascular
ring. This anomaly is often asymptomatic and most of
185
Kanza RE et al . MDCT-angiography of RAA and ALSA
A
B
C
Figure 4 Non-contrast computed tomography in another patient. A 30-year-old asymptomatic man. Axial (A), coronal (B) and sagittal (C), reformatted images
demonstrating the course of the calcified ligament arteriosum (arrows).
patient will remain symptom-free in their life time. Rarely patients may present symptoms in early life time or become symptomatic in young adulthood or later due the
compression of the oesophagus and/or trachea leading
to dysphagia and/or dyspnoea. Surgery may be required
if symptoms are moderate or severe. We present a new
case of RAA with ALSA and KD causing adult onset of
dysphagia lusoria. The diagnosis was suggested by the
chest X-ray and barium esophagram but confirmed by
MDCT-angiophaphy with better characterization of the
vascular ring.
This case illustrates the role of MDCT-angiography
in the diagnosis of RAA with KD and ALSA. This role
is quite similar with those of MRI. Although CT and
MRI are very useful for the diagnosis of a vascular ring
in routine clinical practice, the last part of the ring in
a complete vascular ring, which is made by the LA, is
often not clearly seen preoperatively, to guide surgical division. Several recent studies have shown that with modern imaging techniques, especially CT, the rate at which
LA calcification is being detected has increased, varying
from 11.2% to 48%[2,3]. Calcification usually occurs at the
aortic end of the LA - or at the KD near the take-off of
the ALSA; it may even show patterns, including curvilinear, clumped, punctuate or linear[3] (Figure 4).
In their recent article, Paparo et al[4] show that MRI
could be a powerful imaging tool for the diagnosis of
vascular rings and may be useful for demonstrating the
course of the LA. However, we believe in case of LA
calcification, MDCT may be superior to MRI. Further,
MDCT has the advantage of being fast and widely available, while MRI may not be suitable for patients with
claustrophobia, cardiac pacemakers, significant dyspnea,
or the need for sedation. The main drawback of CT
remains the radiation dose and the use of a contrast medium. In routine clinical practice, the choice of modality
may depend mainly on the patient’s age, type of surgery
(open vs endoscopic), and expertise at the institution
where the surgery is to be conducted.
REFERENCES
1
2
3
4
Cinà CS, Althani H, Pasenau J, Abouzahr L. Kommerell’s
diverticulum and right-sided aortic arch: a cohort study and
review of the literature. J Vasc Surg 2004; 39: 131-139 [PMID:
14718830 DOI: 10.1016/j.jvs.2003.07.021]
Hong GS, Goo HW, Song JW. Prevalence of ligamentum arteriosum calcification on multi-section spiral CT and digital
radiography. Int J Cardiovasc Imaging 2012; 28 Suppl 1: 61-67
[PMID: 22614938]
Wimpfheimer O, Haramati LB, Haramati N. Calcification of
the ligamentum arteriosum in adults: CT features. J Comput
Assist Tomogr 1996; 20: 34-37 [PMID: 8576478 DOI: 10.1097/
00004728-199601000-00007]
Paparo F, Bacigalupo L, Melani E, Rollandi GA, Caro GD.
Cardiac-MRI demonstration of the ligamentum arteriosum
in a case of right aortic arch with aberrant left subclavian
artery. World J Radiol 2012; 4: 231-235 [PMID: 22761985 DOI:
10.4329/wjr.v4.i5.231]
P- Reviewer Yazdi HR S- Editor Cheng JX
L- Editor A E- Editor Xiong L
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186
WJ R
World Journal of
Radiology
[email protected]
doi:10.4329/wjr.v5.i4.187
CASE REPORT
Thoracic epidural angiolipoma: A case report and review of
the literature
Jun Meng, Yong Du, Han-Feng Yang, Fu-Bi Hu, Ya-Yong Huang, Bing Li, Chi-Shing Zee
surgical specimen showed a typical angiolipoma. We
review the previously documented cases of spinal extradural angiolipomas performed with MRI.
Jun Meng, Yong Du, Han-Feng Yang, Fu-Bi Hu, Ya-Yong
Huang, Bing Li, Department of Radiology, Affiliated Hospital
of North Sichuan Medical College, Nanchong 637000, Sichuan
Province, China
Chi-Shing Zee, Department of Radiology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089,
United States
Author contributions: Meng J and Du Y contributed equally to
this work; Meng J, Du Y, Yang HF and Hu FB collected information about the patient; Meng J, Du Y, Yang HF and Zee CS
designed the research; Meng J, Du Y, Yang HF, Hu FB, Huang
YY and Li B collected the data; Meng J, Du Y, Yang HF and Hu
FB analyzed the data; Meng J and Du Y wrote the paper.
Correspondence to: Yong Du, MD, Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 63
Wenhua Road, Nanchong 637000, Sichuan Province,
China. [email protected]
Telephone: +86-817-3352006 Fax: +86-817-2262236
Received: November 6, 2012 Revised: December 18, 2012
Accepted: January 14, 2013
Key words: Angiolipoma; Spinal epidural tumor; Spinal
cord compression; Histopathology
Meng J, Du Y, Yang HF, Hu FB, Huang YY, Li B, Zee CS.
Thoracic epidural angiolipoma: A case report and review of the
literature. World J Radiol 2013; 5(4): 187-192 Available from:
URL: http://www.wjgnet.com/1949-8470/full/v5/i4/187.htm
DOI: http://dx.doi.org/10.4329/wjr.v5.i4.187
INTRODUCTION
Angiolipoma of the spine is a benign neoplasm consisting of mature fatty tissue and abnormal vascular elements, predominantly in middle-aged, female patients
and situated mainly in the mid-thoracic region. There
are only 142 cases with spinal extradural angiolipoma
reported to date[1]. They account for about 0.14%-1.2%
of all spinal axis tumors and 2%-3% of spinal epidural
tumors[2]. We report another case of spinal angiolipoma
in an elderly patient which showed a typical appearance
on magnetic resonance imaging (MRI). The pathology,
clinical features, diagnostic evaluation, and treatment of
spinal angiolipoma were reviewed.
Abstract
Angiolipoma of the spine is a benign neoplasm consisting of both mature fatty tissue and abnormal vascular
elements, and usually presents with a slow progressive
clinical course. Our patient presented with bilateral
lower extremity weakness and chest-back numbness.
Physical examination revealed adipose elements superficial hypesthesia below the T5 level and analgesia
below the T6 level. Magnetic resonance imaging (MRI)
scan showed an avidly and heterogeneously enhancing mass which was located in the posterior epidural
space. Compression of the thoracic cord by the fusiform mass was seen between T3-T4. During the operation, a flesh pink vascular mass (4.7 cm × 1.0 cm × 1.0
cm) with obscure margin and strong but pliable texture
was found in the posterior epidural space extending
from T3 to T4. There was no infiltration of the dura or
the adjacent bony spine. Histopathological study of the
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CASE REPORT
A 63-year-old man presented with a 1.0-year history of
bilateral lower extremities numbness and a 6-mo history
of difficulty in urination. Concurrently, he noticed bilateral lower extremity weakness and chest-back numbness
one month prior to admission. Physical examination
revealed a superficial hypesthesia below the T5 level and
187
Meng J et al . Thoracic epidural angiolipoma
A
B
C
D
E
Figure 1 Magnetic resonance imaging scan showed a fusiform posterior epidural mass compressing the thoracic cord over two vertebral body segments
between T3-T4. A: Sagittal T1 weighted magnetic resonance imaging (MRI) shows a posterior epidural mass with inhomogeneous isointensity constricting the spinal
cord (arrow); B: Sagittal T2 weighted MRI shows a fusiform mass with slightly inhomogeneous hyperintensity (arrow); C: Sagittal fat-saturated T2-weighted image
shows a hyperintense tumor (arrow); D: Post-contrast sagittal T1-weighted MRI with fat-saturation technique shows an inhomogeneously enhancing mass (arrow); E:
Post-contrast axial T1 weighted MRI show crack like low signal between spinal cord and the lesion, with compression and displacement of the spinal cord (arrow).
DISCUSSION
Pathology
Berenbruch et al[3] reported the first case of spinal angiolipoma (AGL) in 1890 in about a 16-year-old with numerous cutaneous lipomas, while the first pathological report
was made by Howard et al[4] in 1960. It is composed of
varying proportions of mature fat cells and abnormal
capillary, sinusoidal, venous or arterial vascular elements.
Subsequently, AGL has been further subdivided by Lin
et al[5] into two categories: noninfiltrating and infiltrating.
The former is encapsulated and well demarcated, not
inﬁltrating the dura or the vertebrae, often in the dorsal
aspect of the spinal canal. Whereas, the latter is very rare,
entirely or partially unencapsulated, situated in the anterior or anterolateral aspect of the spinal canal with illdefined margins and infiltrates the surrounding tissues.
Our case is type 1, unencapsulated, but not inﬁltrating
the dura or the vertebrae.
The origin and pathogenesis of AGLs is unknown.
Histologically, the lesion is mainly composed of mature fat cells and blood vessels. The fat composition is
similar to the general adipose tissue and the vascular
components consist of capillaries, sinusoids, thin-walled
blood vessels or thick-walled blood vessels with smooth
muscle and occasionally well-developed small arteries
can be seen. A diagnostic feature is the presence of fibrin thrombi in the lumen of capillaries. Degenerative
changes (i.e., myxoid change, hyalinization and fibrosis)
may be present in some longstanding cases[6]. Traditionally, AGL is considered a subtype of spinal lipomas, but
more recent clinicalpathological studies [7] considered
them as a specific entity different from pure lipomas because they were not associated with spinal dysraphism.
AGLs usually contain a much greater number of mature,
thick-walled vessels than liposarcomas[5]. Angiomyolipomas are a variant of angiolipoma characterized by
vascular smooth muscle proliferation extending into the
surrounding fat[8].
Figure 2 Histomicrograph of the surgical specimen shows typical angiolipoma. Composed of mature fat cells and abnormal vascular elements.
analgesia below the T6 level, varicose vein of the left lower limb, decreased muscle strength and increased muscle
tension, as well as hyperreflexia of the low extremities.
A MRI scan showed a fusiform posterior epidural
mass compressing the thoracic cord over two vertebral
body segments between T3-T4. The mass was inhomogeneous, isointense on T1-weighted images (Figure 1A),
slightly hyperintense on T2-weighted image (Figure 1B),
hyperintense on fat-saturated T2-weighted images (Figure
1C) and inhomogeneously enhanced on fat-saturated T1weighted image (Figure 1D). The lesion’s long axis paralleled the long axis of the spinal cord, tapering at both
ends. On the axial T1 weighted images, a crack like low
signal between spinal cord and the lesion (Figure 1E)
which is the typical appearance of the case can be seen.
A laminectomy with gross total resection of the lesion
was performed. During the operation, a flesh pink vascular mass with obscure margin and strong but pliable
texture was found in the posterior epidural space from
T3 to T4. There was no infiltration of the dura or the
vertebrae. Histopathological study of the surgical specimen showed a typical angiolipoma (Figure 2) composed
of mature fat cells and abnormal vascular elements.
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188
Clinical presentation
The clinical presentation of spinal AGLs is not different
from any other benign epidural tumor. We found that
the AGLs have been reported to occur predominantly
in women (female:male = 22:17; Table 1) and are more
common in the fifth decade[9]. In our review, age of presentation ranged from 4 to 81 years old, with mean age
at presentation of 46 years. The mode of onset may be
acute, subacute or chronic, may show radicular, paraplegic, progressive or remitting-relapsing clinical types. The
most common initial symptoms are back pain, lower
extremity numbness or paresthesias and leg weakness
(Table 1), and progressive neurological symptoms secondary to spinal cord compression may develop later on.
The symptoms usually evolve over a period of months
to years, but the progression can be accelerated by vascular steal phenomena, vascular engorgement, venous
stasis with thrombosis, bleeding into the tumor and rarely intratumoral abscess[10]. Bleeding is extremely rare in
angiolipomas. Akhaddar et al[10] reported a case presenting with spontaneous bleeding causing acute paraplegia.
Like other vascular lesions, onset or deterioration may
occur during pregnancy[11] or with weight gain. This was
not the case in our patient.
images. There is slightly heterogeneity which is consistent
with few vascular elements, less adipose elements of the
tumor. Gadolinium enhancement reflects the vascularity
of these tumors. In our case, the lesion was strongly enhanced after contrast injection.
Spinal hemangiomas also present as mixed signal
intensity lesions on MRI, although the hyperintensity
on T2-weighted images is more striking. Suppression of
high signal intensity on fat-saturated T1-weighted images
may be very useful for distinguishing between angiolipomas and melanomas or sub-acute hemorrhage. Most spinal angiolipomas show enhancement with contrast medium which better defines the borders of the tumor[30].
In our case the tumor has an obscure margin, while after
contrast injection its border becomes very clear. Contrast
enhancement allows for differential diagnosis between
spinal angiolipoma and extradural lipomatosis as the latter does not show contrast enhancement[31]. Unlike some
other vascular tumors (e.g., glomus jugulare tumors), angiolipomas do not typically contain vascular flow voids
on magnetic resonance images[32,33], there is only one
case containing vascular flow voids in the literature. This
is probably because of the preponderance of capillaries
and venous channels in angiolipomas, which distinguish
them from malformations with arteriovenous shunting
and from those lesions with predominantly arteriolar circulation both of which produce fast flow, seen on MRI
as flow-void phenomena. In our case, there is no flowvoid phenomena which is identical with those reported
in literature.
Diagnostic evaluation
The appearance of angiolipomas correlated well with
their histological composition, so the AGL is often
misdiagnosed. In the majority of cases, plain vertebral
radiography demonstrates normalities. If causing adjacent bone destruction, AGL must be differentiated from
epidural metastases. The metastasis is the most common malignancy of epidural space, which is typically an
irregular soft tissue mass with adjacent bone destruction.
Trabeculation of the affected vertebral body and erosion
of the pedicle may be identified in tumors infiltrating
bone[12,13]. Computed tomography (CT) usually demonstrates a hypodense lesion with fat density, provides information on the degree of bony involvement[7] and also
can demonstrate variable degree of enhancement after
contrast injection. However, CT may not be specific for
spinal epidural angiolipomas and could be misleading in
some cases[14].
MRI is the imaging modality of choice for detecting angiolipomas. MRI was performed in approximately
70 cases (since 1988), but there were only 39 cases
with adequate data (Table 1). The angiolipomas appear as an isointense or hyperintense extradural mass
on T1-weighted images, but occasionally a hypointense
mass[11,12,15,16] may be seen. The degree of central hypointensity on T1-weighted images is predictive of the
degree. On T2-weighted images, the tumors have variable signal intensity, with a predominance of hyperintensity[10,15,17-29]. Significant heterogeneity in the imaging
studies is attributed to the variable vascular and adipose
elements of the tumor[12]. In our case, the tumor is isointense with fewer areas of hypointensity on T1-weighted
images and hyperintense on fat-saturated T2-weighted
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Treatment
There is no clear consensus as to what combination of
therapy is optimal for spinal AGL. The biological behavior of the infiltrating and noninfiltrating AGL implicates
a different treatment approach [18]. To date, the main
treatment is total surgical resection. Most extradural noninfiltrative tumors are amenable to complete excision via
laminectomy. Total removal of infiltrating angiolipomas
that often involve the vertebral body has been recommended using the anterolateral approach and stabilization
of the affected vertebrae is desirable[9]. Extent of tumor
resection in infiltrative angiolipoma has been debated,
but most authors agree that risking neurological function
is not necessary with aggressive attempts to attain gross
total removal[9,17,34]. In spite of vascularization of the
tumor, profuse hemorrhage has rarely been reported[10].
Although complete removal of the lesion is not always
easily achievable, recurrence is exceptional[35]. In case of
recurring or infiltrative SALs, wider resection followed by
radiotherapy should be considered[17]. Most patients have
a good prognosis because the tumors are usually slow
growing and do not undergo malignant transformation.
In our case, the patient’s clinical symptoms improved
postoperatively. There are no signs of tumor recurrence
and no neurological deficit during the two year follow-up
period.
In conclusion, AGL is a rare but benign clinico-
189
Table 1 Reported cases of spinal extradural angiolipomas performed with magnetic resonance imaging
Ref.
Turgut et al[1]
Diyora et al[6]
Age (yr)
Sex
Clinical presentation (signs/duration)
MRI finding (T1/T2, post-contrast)
26
F
Acute onset of paraplegia, in week 31 of
T1 and T2: Hyperintense
Angiolipoma
M
pregnancy
Upper abdominal pain/6 mo, and lower limb
Isointense/hyperintense; enhancement
Angiolipoma
F
weakness/1 wk
Weakness, urinary incontinence,
Very hyperintense/nearly isointense
Angiolipoma
M
and constipation/5 mo
Sudden back pain, paresthesia and complete
Isointense/slightly hyperintense; no gadolinium
Angiolipoma
F
neurological palsy/a few-minutes period
Lower back pain/5 mo
enhancement
Low signal intensity/iso-or high signal intensity;
Angiolipoma
Lower back pain/3 yr
High signal intensity after gadolinium injection
Moderately hypointense/nearly isointense;
Angiolipoma
Paraparesis/2 yr
Slightly inhomogeneous enhancement
T1: Slightly hypointense; Inhomogeneous
Angiolipoma
Angiolipoma
Angiolipoma
20
Turgut et al[9]
54
Akhaddar et al[10]
Park et al[11]
47
74
Provenzale et al[12]
38
61
F
F
Pathological finding
Leu et al[15]
42
81
F
M
Midthoracic back pain/2 yr
Unstable gait, and lower limbs weakness/
enhancement
Iso-hypo-intense/nearly isointense
Inhomogeneous hypointensity/high signal intensity;
Yen et al[16]
Fourney et al[17]
71
46
M
F
2 wk
Acute paraparesis
Feet and legs numbness/4 yr
Strongly enhanced
T1: Homogeneously hyphointense
Homogeneously hyperintense/hyperintense;
Angiolipoma
Angiolipoma
Shibata et al[18]
Bouramas et al[19]
Boockvar et al[20]
38
27
34
F
F
F
Paraparesis/6 mo
Diminution sensation/2 mo
Interscapular back pain/5 mo
enhanced
T1 and T2: High-intensity signal
Heterogeneous signal intensity/high signal intensity
Hyperintense/hyperintense; Enhanced
Angiolipoma
Angiolipoma
Angiolipoma
Amlashi et al[21]
Garg et al[22]
36
12
M
F
Back pain, and both legs weakness
Paraparesis/the previous year
homogeneously
T1 and T2: Homogenous, hyperintense
Hyperintensity/hyperintensity; Heterogeneous
Angiolipoma
Angiolipoma
26
M
Paraparesis/3 mo
contrast enhancement
T1 and T2: Homogeneous high signal intensity;
Angiolipoma
M
contrast enhancement
Bowel and bladder impairment, paraparesis/the T1 and T2: Homogeneously hyperintense
Angiolipoma
F
previous year
Low back pain/10 yr
Isointense/hyperintense; Homogeneous and intense
Angiolipoma
Angiolipoma
Angiolipoma
28
do Souto et al[23]
46
Rabin et al[24]
Samdani et al[25]
47
49
M
F
Legs paresthesias/6 mo
Back pain, lower extremity weakness/
enhancement
T1 and T2: High signal
Intermediate-signal intensity/hyperintensity;
Dogan et al[26]
50
F
3 yr
Lumbosciatalgia/2 yr
homogenous contrast enhancement
Isointense/hyperintense; Homogeneous
Angiolipoma
Low back pain/8 mo
enhancement
Isointense/hyperintense; Homogeneous
Angiolipoma
Low back and leg pain/18 mo
enhancement
Iso-hyperintense/hyperintense;
Angiolipoma
Angiolipoma
Angiolipoma
36
Guzey et al[27]
41
M
F
Hungs et al[28]
Sankaran et al[29]
52
77
M
Thoracolumbar pain/1.5 yr
Paraparesis/48 h
homogeneously enhanced
T1: Hyperintense; Diffusely intense enhancement
Isointense/inhomogeneous hyperintensity;
Weill et al[33]
46
27
F
F
Paraparesis/1 yr
Right leg weak/several week
Inhomogeneous enhancement
Iso-hypointensities/mixed signal
Very-hyperintense/mixed-signal;
Angiolipoma
Angiolipoma
Gelabert-González
16
M
Low back pain/6 mo
Slightly inhomogeneous/heterogeneously
Angiolipoma
45
Both feet numbness, and leg weakness/
hypointense
T1 and T2: Moderately hyperintense relative to spinal
Angiolipoma
Sakaida et al[36]
Oge et al[37]
al-Anazi et al[38]
Gelabert-González
72
72
38
4
M
M
F
M
6 mo
Legs abnormal sensation/4 mo
Paraparesis/4 d
Both feet numbness, 8-mo pregnant housewife
Back pain, and both legs weakness/2 d
cord
T1: Hyperintense
T1: Hyperintense
T1: Mixed-intensity
Angiolipoma
Angiolipoma
Angiolipoma
Angiolipoma
et al[39]
Rocchi et al[40]
60
M
Lumbosciatalgia/2 yr
T1: Signal intensity similar to that of the
Angiolipoma
Angiolipoma
Angiolipoma
Angiolipoma
Angiolipoma
et al[34]
Chotai et al[41]
54
69
F
M
Lumbosciatalgia/12 mo
Back pain, paresthesias, and hypesthesia/
subcutaneous adipose tissue
Homogeneous contrast enhancement
T1: Slightly high intensity with areas of
Konya et al[42]
Current study
60
63
F
M
5 yr
Low back pain/6 mo
Lower extremities numbness/1 yr
hypointensity; Inhomogeneous enhancement
T1: Hyperintense; marked enhancement
Isointense/slightly hyperintense;
Obviously inhomogeneous enhancement
Age, sex, clinical presentation, magnetic resonance imaging findings, and pathological findings are shown for each case. Authors and year of publication
are shown for each case reported. F: Female; M: Male.
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190
pathological entity which is composed of fatty tissue
and vascular elements. It grows in a spindle shape along
the spinal canal, without associated malformations. The
postoperative outcome after surgical management of
this lesion is favorable. Accurate pre-operative diagnosis
is very important. MRI typically shows an iso- to hyperintense mass on T1 weighted images and hyperintense
mass without flow voids on T2 weighted images in the
posterior epidural space. Following intravenous injection
of contrast material, avid inhomogeneous enhancement
is seen.
17
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P- Reviewers Lokhande PV, Kasai Y S- Editor Song XX
L- Editor Roemmele A E- Editor Xiong L
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In press
3 Tian D, Araki H, Stahl E, Bergelson J, Kreitman M. Signature
of balancing selection in Arabidopsis. Proc Natl Acad Sci USA
2006; In press
Organization as author
4 Diabetes Prevention Program Research Group. Hypertension, insulin, and proinsulin in participants with impaired glucose tolerance. Hypertension 2002; 40: 679-686 [PMID: 12411462
DOI:10.1161/01.HYP.0000035706.28494.09]
Both personal authors and an organization as author
5 Vallancien G, Emberton M, Harving N, van Moorselaar RJ;
Alf-One Study Group. Sexual dysfunction in 1, 274 European men suffering from lower urinary tract symptoms. J Urol
2003; 169: 2257-2261 [PMID: 12771764 DOI:10.1097/01.ju.
0000067940.76090.73]
No author given
6 21st century heart solution may have a sting in the tail. BMJ
2002; 325: 184 [PMID: 12142303 DOI:10.1136/bmj.325.
7357.184]
Volume with supplement
7 Geraud G, Spierings EL, Keywood C. Tolerability and safety
of frovatriptan with short- and long-term use for treatment of
migraine and in comparison with sumatriptan. Headache 2002;
42 Suppl 2: S93-99 [PMID: 12028325 DOI:10.1046/j.15264610.42.s2.7.x]
Issue with no volume
8 Banit DM, Kaufer H, Hartford JM. Intraoperative frozen section analysis in revision total joint arthroplasty. Clin Orthop Relat
Res 2002; (401): 230-238 [PMID: 12151900 DOI:10.1097/0000
3086-200208000-00026]
No volume or issue
9 Outreach: Bringing HIV-positive individuals into care. HRSA
Careaction 2002; 1-6 [PMID: 12154804]
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Acknowledgments
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REFERENCES
Coding system
The author should number the references in Arabic numerals according to the citation order in the text. Put reference numbers in
square brackets in superscript at the end of citation content or after
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citation twice.
PMID and DOI
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PMID and DOI, which can be found at http://www.ncbi.nlm.nih.
gov/sites/entrez?db=pubmed and http://www.crossref.org/SimpleTextQuery/, respectively. The numbers will be used in E-version of
this journal.
Books
Personal author(s)
10 Sherlock S, Dooley J. Diseases of the liver and billiary system.
9th ed. Oxford: Blackwell Sci Pub, 1993: 258-296
Chapter in a book (list all authors)
11 Lam SK. Academic investigator’s perspectives of medical treatment for peptic ulcer. In: Swabb EA, Azabo S. Ulcer disease:
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1991: 431-450
Author(s) and editor(s)
12 Breedlove GK, Schorfheide AM. Adolescent pregnancy. 2nd
ed. Wieczorek RR, editor. White Plains (NY): March of Dimes
Education Services, 2001: 20-34
Conference proceedings
13 Harnden P, Joffe JK, Jones WG, editors. Germ cell tumours
V. Proceedings of the 5th Germ cell tumours Conference; 2001
Sep 13-15; Leeds, UK. New York: Springer, 2002: 30-56
Conference paper
14 Christensen S, Oppacher F. An analysis of Koza's computational effort statistic for genetic programming. In: Foster JA,
Lutton E, Miller J, Ryan C, Tettamanzi AG, editors. Genetic
programming. EuroGP 2002: Proceedings of the 5th European
Conference on Genetic Programming; 2002 Apr 3-5; Kinsdale,
Ireland. Berlin: Springer, 2002: 182-191
Electronic journal (list all authors)
15 Morse SS. Factors in the emergence of infectious diseases.
Emerg Infect Dis serial online, 1995-01-03, cited 1996-06-05;
1(1): 24 screens. Available from: URL: http://www.cdc.gov/
ncidod/eid/index.htm
Patent (list all authors)
16 Pagedas AC, inventor; Ancel Surgical R&D Inc., assignee.
Flexible endoscopic grasping and cutting device and positioning tool assembly. United States patent US 20020103498. 2002
Aug 1
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1 Jung EM, Clevert DA, Schreyer AG, Schmitt S, Rennert J,
Kubale R, Feuerbach S, Jung F. Evaluation of quantitative contrast harmonic imaging to assess malignancy of liver tumors:
A prospective controlled two-center study. World J Gastroenterol
2007; 13: 6356-6364 [PMID: 18081224 DOI: 10.3748/wjg.13.
6356]
Chinese journal article (list all authors and include the PMID where applicable)
2 Lin GZ, Wang XZ, Wang P, Lin J, Yang FD. Immunologic effect of Jianpi Yishen decoction in treatment of Pixu-diarrhoea.
Shijie Huaren Xiaohua Zazhi 1999; 7: 285-287
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