Direct Comparison of Intra-articular Versus Intravenous Delayed Gadolinium-Enhanced MRI of Hip Joint Cartilage

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1 JOURNAL OF MAGNETIC RESONANCE IMAGING 39: (2014) Original Research Direct Comparison of Intra-articular Versus Intravenous Delayed Gadolinium-Enhanced MRI of Hip Joint Cartilage Christoph Zilkens, MD, 1 * Falk Miese, MD, 2 Young-Jo Kim, MD, PhD, 3 Marcus J ager, MD, 4 Tallal C. Mamisch, MD, 3 Harish Hosalkar, MD, 5 Gerald Antoch, MD, 2 Rüdiger Krauspe, MD, 1 and Bernd Bittersohl, MD 1 Purpose: To investigate the potential of delayed gadolinium-enhanced magnetic resonance imaging in cartilage (dgemric) after intra-articular (ia) contrast agent administration at 3 Tesla (T), a paired study comparing intravenous (iv) dgemric (standard) with ia-dgemric was performed. Materials and Methods: Thirty-five symptomatic patients with suspected cartilage damage underwent ia- and ivdgemric. MRI was performed with a 3T system wherein the interval between both measurements was 2 weeks. For iv-dgemric, FDA approved Gd-DOTA was injected intravenously 45 min before the MRI scan. For ia-dgemric, ml of a 2 mm solution of Gd- DOTA was injected under fluoroscopic guidance 30 min before the MRI scan. Results: Both ia- and iv-dgemric demonstrated the typical T1 Gd pattern in hip joint cartilage with increasing values toward the superior regions in acetabular cartilage reflecting the higher glycosaminoglycan (GAG) content in the main weight-bearing area. Correlation analysis revealed a moderate correlation between both techniques (r ¼ 0.439, P-value < 0.001), whereas the T1 Gd values for iv-dgemric were significantly higher than those for iadgemric. This corresponds with the Bland-Altman plot analysis, which revealed a systemic bias (higher T1 Gd values after iv gadolinium application) of 70 ms. Conclusion: Ia-dGEMRIC was able to reveal the characteristic T1 Gd pattern in hip joint cartilage confirming the 1 Univ Dusseldorf, Medical Faculty, Department of Orthopedic Surgery, D Dusseldorf, Germany. 2 Univ Dusseldorf, Medical Faculty, Department of Diagnostic and Interventional Radiology, D Dusseldorf, Germany. 3 Department of Orthopedic Surgery, The Children s Hospital Boston, Boston, Massachusetts USA. 4 Univ of Essen, Medical Faculty, Department of Orthopedic Surgery, D Essen, Germany. 5 Department of Orthopedic Surgery, Radys Childrens Hospital San Diego, USA. Contract grant sponsor: German Osteoarthritis Aid (Deutsche Arthrose-Hilfe e.v.); Contract grant number: P216-A *Address reprint requests to: C.Z., Univ Dusseldorf, Medical Faculty, Department of Orthopedic Surgery, Moorenstr. 5, Düsseldorf, Germany. christoph.zilkens@med.uni.duesseldorf.de Received January 9, 2012; Accepted February 5, DOI /jmri View this article online at wileyonlinelibrary.com. sensitivity of ia-dgemric for GAG. In addition, there was a significant correlation between iv-dgemric and iadgemric. However, the T1 Gd values after ia contrast media application were significantly lower than those after iv application that has to be considered for future studies. Key Words: dgemric; cartilage; hip joint; 3T; osteoarthritis J. Magn. Reson. Imaging 2014;39: VC 2013 Wiley Periodicals, Inc. THE UNDERSTANDING OF abnormal hip morphology such as symptomatic femoroacetabular impingement (FAI) as a causative factor of premature hip osteoarthritis (OA) (1 4) has improved. Advanced treatment modalities including open surgical hip dislocation (2) or hip arthroscopy (5) are used to address these deformities in an effort to halt or potentially reverse joint damage in early stages. Precise diagnosis of cartilage and labral damage is crucial when considering therapeutic strategies. MR arthrography (MRA) after intra-articular (ia) injection of a gadolinium-containing contrast agent has emerged as the standard method for a precise evaluation of labrum and cartilage (6 9). Delayed gadolinium-enhanced MRI in cartilage (dgemric) is a valid technique to assess cartilage quality in vivo (10 17) and has widely been used in clinical studies for the assessment of hip joint cartilage (18 30). Therefore, in prearthritic hip joint deformities, the dgemric technique may potentially be used to monitor therapeutic or preventive treatment strategies. The loss of glycosaminoglycans (GAG) is an early and potentially reversible event in the process of OA (31,32). The dgemric index (T1 Gd relaxation time in ms) reflects the uptake of negatively charged gadolinium-containing contrast agent into cartilage. The uptake of gadolinium is reciprocally proportional to the GAG content within cartilage. Because gadolinium induces T1 relaxation, higher T1 Gd values will be VC 2013 Wiley Periodicals, Inc. 94

2 Comparison of iv-dgemric Versus ia-dgemric 95 measured in healthy cartilage in contrast to decreased T1 Gd values in degenerated cartilage (14). For the standard dgemric technique, the iv-administration of a gadolinium-containing contrast agent is necessary. Bittersohl et al (33) have previously reported on the potential of combining the benefits of MRA with the dgemric technique. However, this study was limited to a 1.5 Tesla (T) system and the distinction between femoral and acetabular cartilage was not feasible. Furthermore, this study was conducted with two separate study groups; thus, iv-dgemric and ia-dgem- RIC could not be compared directly in the same set of patients. The purpose of this present study was, therefore, to directly compare ia- with iv-dgemric in the assessment of hip joint cartilage quality at 3T in the same set of patients. We hypothesized that ia-dgemric is a potential alternative for biochemical hip joint cartilage assessment yielding comparable results as the standard iv-dgemric technique. METHODS The study met the regulations of the local ethic committee, and all subjects provided a written informed consent before the study. Study Population The study group consisted of 35 adult patients who were referred to our clinic with hip pain due to various underlying clinically and radiographically confirmed hip joint deformities. These deformities included: camor pincer FAI (31 patients), residual hip dysplasia (three patients), and coxa magna secondary to Legg-Calve- Perthes disease (one patient). The mean age was years (range: years). Exclusion critearia were: age below 18 years; contraindications for MRI/ MRA; radiographically evident OA exceeding T onnis grade 1; allergies to contrast agent; renal disorders or any abnormal values in the routine blood exam including blood cell count, C-reactive protein, and creatinine. There were 14 males and 21 females with involvement of 24 right hips and 11 left hips. Of these, 13 hips demonstrated no radiographic signs of OA while 22 hips revealed T onnis grade 1 changes. MRI Both iv-dgemric and ia-dgemric were performed with a 3T system (Magnetom Trio, Siemens Medical Solutions, Erlangen, Germany) and a body-matrix phased-array coil, whereas the subjects were examined in supine position. For iv-dgemric, FDA approved Gd-DOTA (0.4 ml/kg, 0.2 mmol Gd/kg, Dotarem VR, Guerbet GmbH, Sulzbach, Germany) was injected intravenously 45 min before the dgemric scan. Patients were asked to walk between the contrast agent administration and the MRI scan (15). Table 1 Imaging Parameters of the 3D DESS and 3D VIBE Sequence for Morphological Assessment and T1 Gd Mapping* 3D DESS 3D VIBE TR (repition time, ms) TE (echo time, ms) FA (flip angle, ) 25 5,26 NEX (number of excitations) 1 1 FOV (Field of view, mm 2 ) Slice thickness (mm) In-plane resolution (mm) 0.6 x x 0.6 Slice gap (mm) Bandwith (Hz / Pixel) TA (aquisition time, min) *Note the isotropic resolution of 0.6 mm 3 for sufficient distinction between acetabular and femoral cartilage. For ia-dgemric, ml of a 2 mm solution of Gd-DOTA (1.88 mg/ml, Artirem VR, Guerbet GmbH, Sulzbach, Germany) was injected under fluoroscopic guidance and strict sterile precautions 30 min before MRI (33). In contrast to the iv-dgemric approach, patients were asked not to walk between contrast agent administration and MRI to prevent contrast medium escape through the joint capsule (34). In every patient, iv-mri was performed first, followed by ia- MRI. The mean interval between both measurements was approxiamtely 17 days (range: 6 64 days) (15,35). The MRI protocol for both iv-mri and ia-mri were similar and included a three-dimensional (3D) doubleecho steady state (DESS) sequence with water-excitation for morphological cartilage assessment, a B1 prescan for field-inhomogeneity correction (36), and a dual-flip angle (FA) 3D gradient echo (GRE) sequence with volumetric interpolated breathhold examination (VIBE) for T1 Gd assessment. T1 Gd maps were derived by an inline processing package (SyngoMapIt, Siemens Medical Solutions, Erlangen, Germany), which uses a nonlinear least square fitting routine. Geometric imaging paramters were similar for both DESS and T1 Gd imaging. Further details on the imaging paramters are provided in Table 1. Image Analyses The 3D data sets of DESS and VIBE, which included the inline 3D T1 Gd maps, were transferred to an external workstation (Leonardo, Siemens Medical Solutions, Erlangen, Germany) to perform further processing. In accordance with previously published hip joint evaluation approaches (37), seven radial reformats that were concentric within the center of the femoral head and perpendicular to the acetabulum were derived from the 3D data sets by using multi-planar reconstruction (MPR). Therefore, a reference plane through the center of the femoral head and perpendicular to the femoral neck axis in both the coronal and sagittal plane was defined. Seven radial DESS and T1 GD map reformats 30 apart were then created on this reference image. Subsequently, hip joint cartilage was analyzed in seven regions: (i) anterior, (ii) antero-

3 96 Zilkens et al. Figure 1. Four regions of interest (ROIs) were analyzed within each radial slice (b): (i) peripheral acetabular cartilage, (ii) central acetabular cartilage, (iii) peripheral femoral cartilage, and (iv) central femoral cartilage. In these regions, T1 Gd values were obtained by using ROI analysis. The corresponding DESS reformats (a) served as anatomical reference for the correct placement of the ROIs. superior, (iii) supero-anterior, (iv) superior, (v) superoposterior, (vi) postero-superior, and (vii) posterior. Four regions of interest (ROIs) were analyzed within each radial reformat: (i) peripheral acetabular cartilage, (ii) central acetabular cartilage, (iii) peripheral femoral cartilage, and (iv) central femoral cartilage. In these regions, T1 Gd values were obtained by using ROI analysis. During this process, all iv and ia reformats (DESS images and T1 Gd maps) were analyzed simultaneously, side by side, in which the corresponding DESS reformats served as anatomic reference for the correct placement of the ROI squares within cartilage bounds (Fig. 1). All primary T1 Gd measurements were performed by one observer who has special expertise in biochemically sensitive MRI. For reliability assessment, T1 Gd measurements were repeated by the first observer and by a second observer (orthopedic consultant) in 10 randomly selected hip joints (70 reformats, 140 acetabular ROIs, 140 femoral ROIs). Statistical Analyses SPSS software (Version 20.0; SPSS, Inc., Chicago, IL) was used for all statistical analyses. Mean T1 Gd values, standard deviation (SD), and value range were recorded. Distribution histograms and the Shapiro- Wilk test revealed a nonparametric T1 Gd distribution in various regions. Therefore, nonparametric (distribution-free) tests were used in this study. The correlation between the iv-dgemric and ia-dgemric T1 Gd measures was assessed by Spearman s rank-order correlation analysis. The Wilcoxon signed-rank test was used to identify statistically significant differences between T1 Gd values obtained with iv-dgemric and those obtained with ia-dgemric. Confidence intervals of 95% were measured for all assessments with P values of <0.05 being considered as statistically significant. Bland-Altman analyses (38) were performed to identify trends and the average difference (systemic bias) between the two measurements. Intra-observer and interobserver agreement were evaluated by intra-class correlation (ICC) analyses (pair-wise correlation, absolute agreement). RESULTS A total of 980 ROIs including 490 ROIs on the acetabular and 490 ROIs on the femoral site were assessed. Of these, 32 ROIs on the acetabular and 25 ROIs on the femoral site were excluded due to severe cartilage loss or MR artifacts, leaving 458 ROIs (acetabulum) and 465 ROIs (femur) for iv and ia dgemric assessment. The mean size of the ROIs was cm 2 (range: cm 2 ). Acetabular and femoral cartilage were distinguishable in both iv-dgemric and iadgemric maps, whereas the separation between both articulating surfaces was more apparent with the latter technique due to contrast medium filling of the intra-articular space. T1 Gd mapping with both iv-dgemric and ia-dgem- RIC revealed the typical T1 Gd pattern demonstrating a T1 Gd increase toward the superior regions in acetabular cartilage consistent with a higher GAG content in the weight-bearing area of the acetabululm. In contrast, no T1 Gd pattern could be revealed within femoral cartilage (Fig. 2). Spearman s rank correlation analysis revealed a fairly positive correlation between the iv-dgemric and ia-dgemric T1 Gd measures (correlation coefficient ¼ 0.439, P-value < 0.001). The T1 Gd values for iv-dgemric were significantly higher than those obtained with ia-dgemric (Table 2). This corresponds with the Bland-Altman plot analyses, which revealed a systemic bias (higher T1 Gd values after iv gadolinium application) of 68 ms for acetabular cartilage assessment and 79 ms for femoral cartilage assessment. The scatter around the bias line raised with increasing mean T1 Gd values (T1 Gd iv þ T1 Gd ia / 2), indicating a high T1 Gd variablitiy

4 Comparison of iv-dgemric Versus ia-dgemric 97 Figure 2. Radial reconstruction allows for the assessment of T1 Gd value distribution throughout the hip joint. Note: a ¼ anterior; a-s ¼ antero-superior; s-a ¼ supero-anterior; s ¼ superior; s-p ¼ supero-posterior; p-s ¼ postero-superior; p ¼ posterior. Ia-dGEMRIC revealed significantly lower T1 Gd times than iv-dgemric. On the acetabular site, both iv- and iadgemric demonstrate the same typical pattern with T1 Gd elevation superiorly and supero-posteriorly, in keeping with a higher glycosaminoglycan (GAG) content in the main weight-bearing area of the acetabulum. In contrast, on the femoral site, there is no such pattern. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] between both dgemric techniques. Of note, there was a slight trend of higher ia T1 Gd values as the mean T1 Gd values (T1 Gd iv þ T1 Gd ia / 2) exceeded 600 ms (Fig. 3). High intra- and interobserver agreements were observed for both iv-dgemric (ICC values: and 0.951, P < 0.001) and ia-dgemric (ICC values: and 0.984, P < Table 2 T1 Gd Values Obtained With iv-dgemric Were Significantly Higher Than Those Obtained With ia-dgemric N T1 Gd iv (95% CI) (ms) T1 Gd ia (95% CI) (ms) P values Peripheral Acetabular ( ) ( ) < Femoral ( ) ( ) < Central Acetabular ( ) ( ) < Femoral ( ) ( ) < CI ¼ confidence intervals.

5 98 Zilkens et al. Figure 3. Bland-Altman plots of T1 Gd values measured using the iv-dgemric versus the ia-dgemric technique demonstrating the higher T1 values measured using the ivdgemric than those measured with the ia-dgemric technique. There is a slight trend of higher T1 values in contrast to the mean values using the ia technique in T1 Gd values above 600 ms. DISCUSSION Magnetic resonance arthrography (MRA) after ia contrast agent application is a potential method of evaluating hip joint labrum and cartilage (6 9) (Fig. 4). The dgemric technique is used to depict cartilage quality in vivo. The aim of this study was to investigate the potential of combining the benefits of MRA with biochemically sensitive imaging. Therefore, a comparison of ia versus iv contrast agent administration for dgemric in the assessment of hip joint cartilage was performed. We hypothesized that ia-dgemric is comparable to the standard iv-dgemric technique. The feasibility of ia-dgemric compared with ivdgemric has been reported previously (33): contrast agent infiltration into the cartilage was assessed sequentially and significant differences were noted between the T1 values measured precontrast (T1 0 ) and the T1 values measured 15 min postcontrast (T1 Gd ) in different grades of cartilage degeneration. After 45 min, the T1 Gd values increased, indicating a washout of the contrast agent from the cartilage. Furthermore, there was a significant change in the T1 Gd values with varying extent of cartilage damage (0 to 0.75 cm to < 0.75 cm) demonstrating the ability of T1 Gd to depict different severities of cartilage damage after ia-gd-dtpa 2 injection. Similar results were noted by the same study group by comparing ivdgemric with ia-dgemric at 1.5T (34): In this study, 53 patients with symptomatic FAI were randomly recruited for either ia- or iv- dgemric: 26 patients underwent iv-dgemric while 27 patients underwent ia-dgemric. In both groups, similar differences of T1 Gd times were noted between various grades of cartilage degeneration. The authors concluded that the information obtained by the ia-technique was similar to the information obtained by ivdgemric and that the ia-technique could be a potential alternative when the iv-administration of contrast agent is not suitable for different reasons, including patients with renal dysfunction. However, these studies had limitations at 1.5T with the resolution-associated inability to differentiate acetabular cartilage from femoral cartilage. ROI analyses in these reports alluded to acetabular and femoral cartilage as one entity in which inclusion of gadolinium-containing joint fluid mapping reduces the T1 Gd value. Notably, when mapping acetabular and femoral cartilage as one entity, inclusion of joint fluid will increase with proceeding cartilage degeneration and cartilage thinning generating further underestimation of the T1 Gd measures. In addition, this previously reported study included two separate study groups and, thus, iv-dgemric and ia-dgemric could not be compared directly in the same set of patients. Therefore, there was a need to further elaborate on the methodology of performing T1 Gd mapping after ia contrast agent administration (ia-dgemric). The present study confirmed the potential of iadgemric to assess hip joint cartilage. The typical pattern of T1 Gd distribution was found to be identical in both groups. Similar to the iv-dgemric technique, ia-dgemric was able to depict the typical pattern of the GAG distribution in acetabular cartilage with higher T1 Gd times in the superior regions. This pattern in both the central and peripheral areas was not found in femoral cartilage. A similar cartilage T1 Gd distribution pattern was described in a previous study using radial T1 Gd reformats (39). This study reports on the 3D T1 Gd patterns in 10 volunteers and in 26 symptomatic FAI patients with different types of FAI (cam, pincer, and mixed type). It was noted that FAI patients had significantly lower T1 Gd values compared with volunteers in all areas of the hip joint. The distribution of the T1 Gd values was in accordance with the specific FAI damage pattern: cam-patients had a significant T1 Gd decrease anterosuperiorly, whereas pincer patients had lower T1 Gd values circumferentially. In most previous studies using dgemric, the differentiation between acetabular and femoral cartilage has not been performed due to insufficient image resolution. However, in ia- and iv-dgemric, acetabular

6 Comparison of iv-dgemric Versus ia-dgemric 99 Figure 4. The MR arthrogram (MRA) after ia contrast agent application (b) demonstrates the vantage of clear cartilage and labrum assessment over MRI with iv contrast agent application (a). The corresponding T1 Gd maps after iv- (c) and ia- (d) contrast agent administration of the same patient demonstrate significantly different contrast agent uptake and dispersion. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] and femoral cartilage separation is crucial in the evaluation of T1 Gd times. ROIs that do not evaluate acetabular and femoral cartilage separately may erroneously measure effusion and/or contrast agent leading to incorrect T1 Gd values (Fig. 5). With advances in imaging techniques, adequate image resolution will be mandatory in the future for the separate assessment of acetabular and femoral cartilage. In this study, a 3D GRE sequence combined with a 3T MRI system allowed for high-resolution imaging and distinguishing between acetabular and femoral cartilage throughout the hip joint. This dual-flip angle GRE technique (as an alternative to the inversion recovery [IR] method for T1 mapping) has been previously validated for the hip joint in phantom and in vivo studies (40,41). However, in particular at high field strengths (3T and higher), B 1 field-inhomogeneity may provoke T1 inaccuracy especially at higher T1 values (36). Therefore, as performed in this study, B 1 field inhomogeneity correction should be implemented. Several gadolinium-based contrast agents are available for contrast-enhanced MRI while the double

7 100 Zilkens et al. Figure 5. Region of interest (ROI) placement without distinction between acetabular and femoral cartilage demonstrates the susceptibility to commit the mistake of inadvertently measuring contrast agent instead of cartilage. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] negatively charged contrast agent gadolinium dimeglumine (GdDTPA 2 ) was used in most previously reported dgemric studies (23,42 48). To better incorporate the dgemric technique into clinical routine, we used the single negatively charged contrast agent Dotarem VR (the arthrography-specific contrast agent Artirem VR is a diluted form of Dotarem VR ), which is the standard gadolinium-based contrast agent in many departments because it has been proven to be very stable with regard to its chelate compound and unlikely to cause nephrogenic systemic fibrosis (NSF) (49). There is increasing evidence on characterising differences considering efficacy and safety of these agents that may be relevant in clinical routine. However, the purpose of the present study was not to outline the complex pharmacokinetics of different contrast agents after different modes of application but to directly compare two clinically used MRI methods in the same set of patients. We hypothesized that the single negatively charged contrast agent Dotarem VR is a potential alternative to the double negatively charged contrast agent GdDTPA 2 for visualization and estimation of the GAG content within cartilage by means of T1 Gd mapping. The results of our study suggest that dgemric imaging is feasible using a single negatively charged contrast agent such as Dotarem VR. Notably, the T1 Gd times after ia application were significantly lower than those after iv application. This is in keeping with the Bland-Altman plot demonstrating a systematic bias (higher T1 Gd values after iv gadolinium application) of approximately 70 ms. The differences between both measures (iv T1 Gd versus ia T1 Gd ) became more variable as the mean T1 Gd values (T1 Gd iv þ T1 Gd ia / 2) increased. Beyond T1 Gd ¼ 600 ms, a slight trend of higher ia T1 Gd values was noted. However, there was a high variablitly in these measures above 600 ms and the number of T1 Gd values > 600 ms was low. Therefore, a conclusion on wether ia dgemric over-estimates high values cannot be drawn. This study has limitations. First, our study population was heterogeneous including symptomatic patients with various types of FAI, hip dysplasia and coxa magna as a sequel of LCPD. As such, a final conclusion on the typical T1 Gd pattern, which may be specific for a pathological hip condition, cannot be derived from this study. Second, ROI analyses acquire only mean values that represent the entire encircled area. Therefore, focal but significant changes may have been underestimated. Third, although anatomical landmarks served as guidance for reformatting the radial planes by means of MPR, it is possible that corresponding ROIs were slightly different either due to potential mismatch in plane orientation or inequality in ROI placement. Finally, this study included patients only with likely decreased T1 Gd values due to cartilage damage. It also lacks a diagnostic gold standard such as histological evaluation or intra-operative assessment. As a consequence, no reference values in particular for the ia-dgemric technique could be worked out from this study. In conclusion, our results demonstrate that iadgemric could be a good alternative to dgemric with iv-contrast application. It would combine the benefits of an arthrography including capsule distention and delineation of intra-articular structures with sophisticated biochemical analysis of hip joint cartilage. Thereby, even distinct lesions within the cartilage may be identified. However, MRA by itself does not guarantee an accurate hip joint assessment. Instead, image quality and reliable hip joint

8 Comparison of iv-dgemric Versus ia-dgemric 101 evaluation are equally affected by pulse sequence parameter, coil selection, and section planning. Moreover, the intra-articular technique is certainly more invasive and uncomfortable for the patient. It necessitates a stringent sterile environment, and carriages, although extremely rare, the risk of joint infection. Of note, the T1 Gd values after ia contrast media application were significantly lower than those after iv application, which has to be considered for future studies. Contrast agents with a single negative charge might be used leading to a broader clinical application of the dgemric technique. ACKNOWLEDGMENT This study was funded by a research grant of the German Osteoarthritis Aid (Deutsche Arthrose-Hilfe e.v.). REFERENCES 1. Ito K, Minka MA Jr, Leunig M, Werlen S, Ganz R. Femoroacetabular impingement and the cam-effect. A MRI-based quantitative anatomical study of the femoral head-neck offset. 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