Skeletal Radiol DOI 10.1007/s00256-015-2135-3
REVIEW ARTICLE
Current knowledge and importance of dGEMRIC techniques in diagnosis of hip joint diseases Christoph Zilkens 1 & Carl Johann Tiderius 2 & Rüdiger Krauspe 1 & Bernd Bittersohl 1
Received: 20 December 2014 / Revised: 10 March 2015 / Accepted: 12 March 2015 # ISS 2015
Abstract Accurate assessment of early hip joint cartilage alterations may help optimize patient selection and followup of hip joint preservation surgery. Delayed gadoliniumenhanced magnetic resonance imaging of cartilage (dGEMRIC) is sensitive to the glycosaminoglycan content in cartilage that is lost early in the development of osteoarthritis (OA). Hence, the dGEMRIC technique holds promise for the development of new diagnostic and therapeutic procedures. However, because of the location of the hip joint deep within the body and due to the fairly thin cartilage layers that require high spatial resolution, the diagnosis of early hip joint cartilage alterations may be problematic. The purpose of this review is to outline the current status of dGEMRIC in the assessment of hip joint cartilage. A literature search was performed with PubMed, using the terms Bcartilage, osteoarthritis, hip joint, MRI, and dGEMRIC^, considering all levels of studies. This review revealed that dGEMRIC can be reliably used in the evaluation of early stage cartilage pathology in various hip joint disorders. Modifications in the technique, such as the operation of three-dimensional imaging and dGEMRIC after intra-articular contrast medium administration, have expanded the range of application. Notably, the studies differ considerably in patient selection and technical prerequisites. Furthermore, there is a need for multicenter prospective studies with the required technical conditions in place to establish outcome based dGEMRIC data to obtain, in
* Christoph Zilkens [email protected] 1
Medical Faculty, Department of Orthopedic Surgery, University of Düsseldorf, Moorenstr 5, 40225 Düsseldorf, Germany
2
Department of Orthopedic Surgery, Lund University Hospital, Lund, Sweden
conjunction with clinical data, reliable threshold values for normal and abnormal cartilage, and for hips that may benefit from conservative or surgical treatment. Keywords Magnetic resonance imaging . Cartilage . Osteoarthritis . Hip . dGEMRIC . Review
Introduction With advances in hip joint preservation surgery and improved understanding of hip joint abnormalities that cause instability (hip dysplasia), incongruence (femoroacetabular impingement, Legg–Calvé–Perthes disease) and eventually osteoarthritis (OA), it is important to adequately assess the cartilage status, particularly at the early stages of the disease [1]. Although conventional radiography remains the only validated technique to assess the progression in OA, its potential for diagnosing early cartilage changes or evaluating treatment success in the short-term follow-up is fairly limited. Magnetic resonance imaging (MRI) can provide a picture of the degree and extent of cartilage damage in the hip joint. However, the diagnosis of subtle cartilage matrix alterations such as collagen fiber network disorders, variations in water and glycosaminoglycan (GAG) content, which occur early in the course of OA, remains limited [2, 3]. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) is sensitive to the charge density of cartilage that is contributed to by the negatively charged GAG chains [4–11]. Because the GAG content decreases early over the course of cartilage degeneration, the dGEMRIC technique looks promising for the development of new diagnostic and therapeutic procedures. In the last decade, dGEMRIC has been recognized as a reliable tool for the assessment of cartilage status, particularly in the knee joint [1,
Skeletal Radiol
4–7, 12–27]. However, due to the location of the hip joint deep within the body and relatively thin cartilage layers requiring high spatial resolution to minimize in-plane and out-of-plane partial volume effects, the depiction of cartilage lesions may be challenging. The purpose of this review is to summarize the current status of dGEMRIC for the assessment of hip joint cartilage. A literature search was performed using PubMed using the terms Bcartilage, osteoarthritis, hip joint, MRI, and dGEMRIC^, considering all levels of studies. Technical considerations specific to dGEMRIC of the hip joint cartilage and current modifications of the technique, which may be applicable to many institutions for routine clinical practice, are presented.
dGEMRIC technique Briefly summarized, the dGEMRIC technique entails the administration of a negatively charged gadolinium-based contrast agent and the subsequent measurement of the T1 relaxation time (T1Gd, dGEMRIC index, T1Gd mapping). Because the contrast agent (1) infiltrates the cartilage tissue in an inverse relationship to the negatively charged GAG content and (2) reduces the T1 relaxation time within the infiltrated tissue, higher T1Gd values are seen in healthy cartilage whereas low T1Gd values are produced in degenerated, GAG-depleted cartilage (Fig. 1). Most dGEMRIC studies of hip cartilage have been obtained after the intravenously injected double negatively charged contrast agent (Gd-DTPA2−). However, recently the single negatively charged contrast agent (Gd-DOTA−) has been used both after intravenous administration [28] and after intra-articular contrast agent administration [29]. A significant correlation between iv-dGEMRIC and ia-dGEMRIC has been observed. However, the T1Gd values after ia contrast media application were lower than those after iv application.
Fig. 1 Healthy cartilage (a) and early cartilage degeneration (b). Before structural changes take place, the cartilages’ fixed charged density is reduced by degradation of the negatively charged glycosaminoglycans. After intravenous injection and systemic circulation, the negatively charged contrast agent penetrates into the cartilage in an inversely proportional manner to the negatively charged glycosaminoglycan content. According to the decrease of glycosaminoglycans in cartilage degeneration, more Gd-DTPA2− penetrates into the cartilage, which will cause a reduction of T1 relaxation time that can be measured in milliseconds
The recommended dose for dGEMRIC studies is 0.2 mM/kg body weight or twice the recommended clinical dose. In cross-sectional studies, where lean and obese individuals are compared, the BMI difference is a source of dosing error because the contrast medium distributes only in the extracellular water [30]. This can be compensated for by post-process T1Gd correction according to the formula described by Tiderius et al. [30]. To allow for appropriate gadolinium contrast agent penetration into cartilage, a certain time frame between the contrast agent administration and the T1Gd relaxation time measurement (Bdelayed^ gadolinium-enhanced MRI in cartilage) ranging from 15 to 120 min is required, which is dependent on the administration (intravenous versus intra-articular) and thickness of the cartilage (longer uptake times in knee joint cartilage) [6]. Regarding dGEMRIC in hip joint cartilage, a time frame of 30–90 min after intravenous application [6], or 15–30 min after intra-articular injection [31], should be considered. Notably, a recent study about asymptomatic individuals and patients with early hip OA related to hip joint dysplasia [26] revealed that the wash-in of Gd-DTPA2- into healthy hip joint cartilage after intravenous administration was similar to previously determined kinetics in femoral knee joint cartilage (maximum concentration after 90–120 min) [10, 32]. Notably, diseased cartilage presented with faster Gd-DTPA2- wash-in into the cartilage, indicating that T1Gd mapping at earlier time points (30–65 min), may increase the sensitivity to cartilage alterations [26]. There is a debate whether pre-contrast T1-mapping (T10), in addition to postcontrast T1-mapping (T1Gd) for dGEMRIC evaluation of OA changes in the hip joint is necessary, or if post-contrast evaluation (T1Gd) provides accurate information. According to Bittersohl et al., T1Gd assessment is sufficient for the clinical use of dGEMRIC and additional time-consuming T10 evaluation may not be necessary [14]. However, there are circumstances that may require the calculation of T10 for accurate GAG evaluation. This includes the follow-up of cartilage repair therapy where T10 values may differ significantly from those in normal hyaline cartilage, especially in the early stages post-surgery [33, 34]. The first T1 Gd images were obtained with a twodimensional (2D) T1-weighted inversion recovery (IR) sequence [10, 35]. Advantages of this technique are the widespread availability of the sequence and proper contrast properties. However, this 2D-based technique has limitations, including long acquisition times and the susceptibility for motion artifacts between acquisitions with different inversion times (TI) [36]. Current techniques, which are capable of generating entire 3D T1Gd data sets of the hip joint instead of just a selected cross section, as with 2D T1Gd mapping (Fig. 2), enable valid and reproducible cartilage assessments of both local or large cartilage changes, therefore improving diagnosis and follow-up [9, 34, 36–41]. Although the use of 3D
Skeletal Radiol
Fig. 2 Radial reformats of T1Gd maps and corresponding morphologic DESS images with an interval of 30° reaching from anterior to superior and then to posterior are derived by multi-planar reconstruction (MPR). For reproducibility reasons, and in order to ease intraoperative
comparison, we always begin anteriorly and use the seven reformats (anterior; anterosuperior; superoanterior; superior; superoposterior; posterosuperior; posterior) instead of clock-positions for both right and left hip joints
techniques in dGEMRIC is at an early stage, the results of validation studies comparing 3D dGEMRIC techniques with histology (Fig. 3) and conventional 2D techniques are promising [34, 36, 38, 42]. A reproducibility study demonstrated 3D dGEMRIC as a reliable instrument in the assessment of asymptomatic hip joint cartilage [13].
key role of dGEMRIC in hip dysplasia is its potential to detect early cartilage damage that is relevant for clinicians for decision-making with regards to timely intervention and treatment follow-up. Kim et al. obtained dGEMRIC images in patients with dysplastic hips (43 patients, 68 hips, mean age, 30 years, age range, 11–47 years), and compared the dGEMRIC index and joint space width with radiographic and clinical parameters [48]. The T1Gd values decreased concurrently with increasing severity of dysplasia and pain while the joint space width did not correlate with pain or the severity of hip dysplasia. Based upon the grade of dysplasia, the T1Gd values ranged from 550 ms (mild dysplasia) to 500 ms (moderate dysplasia) to 420 ms (severe dysplasia). For comparison, the T1Gd values in eight asymptomatic and morphologically normal hips (mean age, 37 years, age range, 20–48 years) on the contra-lateral side, were 570±90 ms. Jessel et al. studied anatomic and demographic factors associated with the early onset of OA in dysplastic hips by utilizing the dGEMRIC index (T1Gd) as a marker of the disease [49]. Hip OA was defined as a T1Gd value of
REVIEW ARTICLE
Current knowledge and importance of dGEMRIC techniques in diagnosis of hip joint diseases Christoph Zilkens 1 & Carl Johann Tiderius 2 & Rüdiger Krauspe 1 & Bernd Bittersohl 1
Received: 20 December 2014 / Revised: 10 March 2015 / Accepted: 12 March 2015 # ISS 2015
Abstract Accurate assessment of early hip joint cartilage alterations may help optimize patient selection and followup of hip joint preservation surgery. Delayed gadoliniumenhanced magnetic resonance imaging of cartilage (dGEMRIC) is sensitive to the glycosaminoglycan content in cartilage that is lost early in the development of osteoarthritis (OA). Hence, the dGEMRIC technique holds promise for the development of new diagnostic and therapeutic procedures. However, because of the location of the hip joint deep within the body and due to the fairly thin cartilage layers that require high spatial resolution, the diagnosis of early hip joint cartilage alterations may be problematic. The purpose of this review is to outline the current status of dGEMRIC in the assessment of hip joint cartilage. A literature search was performed with PubMed, using the terms Bcartilage, osteoarthritis, hip joint, MRI, and dGEMRIC^, considering all levels of studies. This review revealed that dGEMRIC can be reliably used in the evaluation of early stage cartilage pathology in various hip joint disorders. Modifications in the technique, such as the operation of three-dimensional imaging and dGEMRIC after intra-articular contrast medium administration, have expanded the range of application. Notably, the studies differ considerably in patient selection and technical prerequisites. Furthermore, there is a need for multicenter prospective studies with the required technical conditions in place to establish outcome based dGEMRIC data to obtain, in
* Christoph Zilkens [email protected] 1
Medical Faculty, Department of Orthopedic Surgery, University of Düsseldorf, Moorenstr 5, 40225 Düsseldorf, Germany
2
Department of Orthopedic Surgery, Lund University Hospital, Lund, Sweden
conjunction with clinical data, reliable threshold values for normal and abnormal cartilage, and for hips that may benefit from conservative or surgical treatment. Keywords Magnetic resonance imaging . Cartilage . Osteoarthritis . Hip . dGEMRIC . Review
Introduction With advances in hip joint preservation surgery and improved understanding of hip joint abnormalities that cause instability (hip dysplasia), incongruence (femoroacetabular impingement, Legg–Calvé–Perthes disease) and eventually osteoarthritis (OA), it is important to adequately assess the cartilage status, particularly at the early stages of the disease [1]. Although conventional radiography remains the only validated technique to assess the progression in OA, its potential for diagnosing early cartilage changes or evaluating treatment success in the short-term follow-up is fairly limited. Magnetic resonance imaging (MRI) can provide a picture of the degree and extent of cartilage damage in the hip joint. However, the diagnosis of subtle cartilage matrix alterations such as collagen fiber network disorders, variations in water and glycosaminoglycan (GAG) content, which occur early in the course of OA, remains limited [2, 3]. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) is sensitive to the charge density of cartilage that is contributed to by the negatively charged GAG chains [4–11]. Because the GAG content decreases early over the course of cartilage degeneration, the dGEMRIC technique looks promising for the development of new diagnostic and therapeutic procedures. In the last decade, dGEMRIC has been recognized as a reliable tool for the assessment of cartilage status, particularly in the knee joint [1,
Skeletal Radiol
4–7, 12–27]. However, due to the location of the hip joint deep within the body and relatively thin cartilage layers requiring high spatial resolution to minimize in-plane and out-of-plane partial volume effects, the depiction of cartilage lesions may be challenging. The purpose of this review is to summarize the current status of dGEMRIC for the assessment of hip joint cartilage. A literature search was performed using PubMed using the terms Bcartilage, osteoarthritis, hip joint, MRI, and dGEMRIC^, considering all levels of studies. Technical considerations specific to dGEMRIC of the hip joint cartilage and current modifications of the technique, which may be applicable to many institutions for routine clinical practice, are presented.
dGEMRIC technique Briefly summarized, the dGEMRIC technique entails the administration of a negatively charged gadolinium-based contrast agent and the subsequent measurement of the T1 relaxation time (T1Gd, dGEMRIC index, T1Gd mapping). Because the contrast agent (1) infiltrates the cartilage tissue in an inverse relationship to the negatively charged GAG content and (2) reduces the T1 relaxation time within the infiltrated tissue, higher T1Gd values are seen in healthy cartilage whereas low T1Gd values are produced in degenerated, GAG-depleted cartilage (Fig. 1). Most dGEMRIC studies of hip cartilage have been obtained after the intravenously injected double negatively charged contrast agent (Gd-DTPA2−). However, recently the single negatively charged contrast agent (Gd-DOTA−) has been used both after intravenous administration [28] and after intra-articular contrast agent administration [29]. A significant correlation between iv-dGEMRIC and ia-dGEMRIC has been observed. However, the T1Gd values after ia contrast media application were lower than those after iv application.
Fig. 1 Healthy cartilage (a) and early cartilage degeneration (b). Before structural changes take place, the cartilages’ fixed charged density is reduced by degradation of the negatively charged glycosaminoglycans. After intravenous injection and systemic circulation, the negatively charged contrast agent penetrates into the cartilage in an inversely proportional manner to the negatively charged glycosaminoglycan content. According to the decrease of glycosaminoglycans in cartilage degeneration, more Gd-DTPA2− penetrates into the cartilage, which will cause a reduction of T1 relaxation time that can be measured in milliseconds
The recommended dose for dGEMRIC studies is 0.2 mM/kg body weight or twice the recommended clinical dose. In cross-sectional studies, where lean and obese individuals are compared, the BMI difference is a source of dosing error because the contrast medium distributes only in the extracellular water [30]. This can be compensated for by post-process T1Gd correction according to the formula described by Tiderius et al. [30]. To allow for appropriate gadolinium contrast agent penetration into cartilage, a certain time frame between the contrast agent administration and the T1Gd relaxation time measurement (Bdelayed^ gadolinium-enhanced MRI in cartilage) ranging from 15 to 120 min is required, which is dependent on the administration (intravenous versus intra-articular) and thickness of the cartilage (longer uptake times in knee joint cartilage) [6]. Regarding dGEMRIC in hip joint cartilage, a time frame of 30–90 min after intravenous application [6], or 15–30 min after intra-articular injection [31], should be considered. Notably, a recent study about asymptomatic individuals and patients with early hip OA related to hip joint dysplasia [26] revealed that the wash-in of Gd-DTPA2- into healthy hip joint cartilage after intravenous administration was similar to previously determined kinetics in femoral knee joint cartilage (maximum concentration after 90–120 min) [10, 32]. Notably, diseased cartilage presented with faster Gd-DTPA2- wash-in into the cartilage, indicating that T1Gd mapping at earlier time points (30–65 min), may increase the sensitivity to cartilage alterations [26]. There is a debate whether pre-contrast T1-mapping (T10), in addition to postcontrast T1-mapping (T1Gd) for dGEMRIC evaluation of OA changes in the hip joint is necessary, or if post-contrast evaluation (T1Gd) provides accurate information. According to Bittersohl et al., T1Gd assessment is sufficient for the clinical use of dGEMRIC and additional time-consuming T10 evaluation may not be necessary [14]. However, there are circumstances that may require the calculation of T10 for accurate GAG evaluation. This includes the follow-up of cartilage repair therapy where T10 values may differ significantly from those in normal hyaline cartilage, especially in the early stages post-surgery [33, 34]. The first T1 Gd images were obtained with a twodimensional (2D) T1-weighted inversion recovery (IR) sequence [10, 35]. Advantages of this technique are the widespread availability of the sequence and proper contrast properties. However, this 2D-based technique has limitations, including long acquisition times and the susceptibility for motion artifacts between acquisitions with different inversion times (TI) [36]. Current techniques, which are capable of generating entire 3D T1Gd data sets of the hip joint instead of just a selected cross section, as with 2D T1Gd mapping (Fig. 2), enable valid and reproducible cartilage assessments of both local or large cartilage changes, therefore improving diagnosis and follow-up [9, 34, 36–41]. Although the use of 3D
Skeletal Radiol
Fig. 2 Radial reformats of T1Gd maps and corresponding morphologic DESS images with an interval of 30° reaching from anterior to superior and then to posterior are derived by multi-planar reconstruction (MPR). For reproducibility reasons, and in order to ease intraoperative
comparison, we always begin anteriorly and use the seven reformats (anterior; anterosuperior; superoanterior; superior; superoposterior; posterosuperior; posterior) instead of clock-positions for both right and left hip joints
techniques in dGEMRIC is at an early stage, the results of validation studies comparing 3D dGEMRIC techniques with histology (Fig. 3) and conventional 2D techniques are promising [34, 36, 38, 42]. A reproducibility study demonstrated 3D dGEMRIC as a reliable instrument in the assessment of asymptomatic hip joint cartilage [13].
key role of dGEMRIC in hip dysplasia is its potential to detect early cartilage damage that is relevant for clinicians for decision-making with regards to timely intervention and treatment follow-up. Kim et al. obtained dGEMRIC images in patients with dysplastic hips (43 patients, 68 hips, mean age, 30 years, age range, 11–47 years), and compared the dGEMRIC index and joint space width with radiographic and clinical parameters [48]. The T1Gd values decreased concurrently with increasing severity of dysplasia and pain while the joint space width did not correlate with pain or the severity of hip dysplasia. Based upon the grade of dysplasia, the T1Gd values ranged from 550 ms (mild dysplasia) to 500 ms (moderate dysplasia) to 420 ms (severe dysplasia). For comparison, the T1Gd values in eight asymptomatic and morphologically normal hips (mean age, 37 years, age range, 20–48 years) on the contra-lateral side, were 570±90 ms. Jessel et al. studied anatomic and demographic factors associated with the early onset of OA in dysplastic hips by utilizing the dGEMRIC index (T1Gd) as a marker of the disease [49]. Hip OA was defined as a T1Gd value of
