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1 This copy is for personal use only. To order printed copies, contact Original Research n Pediatric Imaging Pediatric Brain: Repeated Exposure to Linear Gadolinium-based Contrast Material Is Associated with Increased Signal Intensity at Unenhanced T1- weighted MR Imaging 1 Thomas F. Flood, MD, PhD Nicholas V. Stence, MD John A. Maloney, MD David M. Mirsky, MD 1 From the Department of Radiology, University of Colorado, Aurora, Colo (T.F.F.); and Department of Radiology, University of Colorado Children s Hospital, E 16th Ave, Box B125, Aurora, CO (N.V.S., J.A.M., D.M.M.). Received February 19, 2016; revision requested March 30; revision received April 15; accepted May 10; final version accepted May 24. Address correspondence to D.M.M. ( David.Mirsky@childrenscolorado.org). q RSNA, 2016 Purpose: Materials and Methods: Results: Conclusion: To determine whether repeated exposure of the pediatric brain to a linear gadolinium-based contrast agent (GBCA) is associated with an increase in signal intensity (SI) relative to that in GBCA-naive control subjects at unenhanced T1- weighted magnetic resonance (MR) imaging. This single-center, retrospective study was approved by the institutional review board and compliant with HIPAA. The authors evaluated 46 pediatric patients who had undergone at least three GBCA-enhanced MR examinations (30 patients for two-group analysis and 16 for pre- and post-gbca exposure comparisons) and 57 age-matched GBCA-naive control subjects. The SI in the globus pallidus, thalamus, dentate nucleus, and pons was measured at unenhanced T1-weighted MR imaging. Globus pallidus thalamus and dentate nucleus pons SI ratios were calculated and compared between groups and relative to total cumulative gadolinium dose, age, sex, and number of and mean time between GBCA-enhanced examinations. Analysis included the Wilcoxon signed rank test, Wilcoxon rank sum test, and Spearman correlation coefficient. Patients who underwent multiple GBCA-enhanced examinations had increased SI ratios within the dentate nucleus (mean SI ratio 6 standard error of the mean for two-group comparison: for GBCA-naive group and for GBCA-exposed group [P,.001]; mean SI ratio for pre- and post-gbca comparison: for pre-gbca group and for post-gbca group [P,.001]) but not the globus pallidus (mean SI ratio for two-group comparison: for GBCAnaive group and for GBCA-exposed group [P =.21]; mean SI ratio for pre- and post-gbca comparison: for pre-gbca group and for post-gbca group [P =.12]). There was a significant correlation between dentate nucleus SI and total cumulative gadolinium dose (r = 0.4; 95% confidence interval [CI]: 0.03, 0.67; P =.03), but not between dentate nucleus SI and patient age (r = 0.23; 95% CI: 20.15, 0.56; P =.22), sex (mean SI ratio: for boys and for girls; P =.88), number of contrast-enhanced examinations (r = 0.13; 95% CI: 20.25, 0.48; P =.49), or time between contrast-enhanced examinations (r = 20.06; 95% CI: 20.42, 0.32; P =.75). SI in the pediatric brain increases on unenhanced T1-weighted MR images with repeated exposure to a linear GBCA. q RSNA, radiology.rsna.org n Radiology: Volume 282: Number 1 January 2017

2 Gadolinium-based contrast agents (GBCAs) have been used to enhance magnetic resonance (MR) examinations since the 1980s (1 5). Although GBCAs are generally considered well tolerated and safe, there are major safety concerns, including nephrogenic systemic fibrosis and severe allergies to contrast material, both of which are rare (6,7). A potential new safety concern has been suggested in multiple recent studies in adults (8 12). Those studies demonstrated increased brain intraparenchymal signal intensity on unenhanced T1-weighted MR images with repeated exposure to multiple linear and macrocyclic GBCAs. Postmortem brain analyses have confirmed that the increased signal intensity is secondary to intracranial gadolinium deposition (12 14). To our knowledge, no published reports have demonstrated clinical harm from intracranial gadolinium deposition; however, free gadolinium is toxic and subcutaneous deposition is associated with nephrogenic systemic fibrosis. Therefore, clinicians, radiologists, and patients remain concerned about potential long-term detrimental effects (4,6). Except for two pediatric case reports (15,16), it is not known how repeated exposure to linear GBCAs affects the pediatric brain. Confirmation of findings in the adult literature, which Advances in Knowledge nn The signal intensity in the pediatric dentate nucleus increases on unenhanced T1-weighted MR images with repeated exposure to a linear gadolinium-based contrast agent (GBCA) (P,.001 at two-group analysis; P,.001 at pre- and post-gbca analysis). nn There is a statistically significant correlation between dentate nucleus signal intensity and cumulative gadolinium dose (P,.03) but not between dentate nucleus signal intensity and age, sex, total number of contrastenhanced examinations, or mean time between contrast-enhanced examinations (P =.22,.88,.49, and.75, respectively). demonstrates intraparenchymal brain deposition of specific GBCAs, within pediatric patients is important given their potential for many GBCA examinations over a lifetime and the unknown clinical consequences of intracranial gadolinium deposition. Therefore, to address this question, we conducted a controlled pediatric study to determine whether repeated exposure to a linear GBCA is associated with an increase in signal intensity in the pediatric brain relative to that of GBCA-naive control subjects at unenhanced T1-weighted MR imaging. Materials and Methods Participants This single-center, retrospective study was approved by the institutional review board and compliant with the Health Insurance Portability and Accountability Act. The requirement to obtain informed consent was waived. Pediatric patients who underwent multiple brain MR examinations with a linear GBCA were consecutively sampled from our institution s electronic database and assessed according to inclusion and exclusion criteria, as described below, with reference to the patient s electronic medical record. This review resulted in the final patient population used for analysis: Thirty patients were included in the two-group comparison and 16 were included in the pre- and post-gbca analysis. Patients were included if they were pediatric patients (age.31 days and,18 years) at our institution and had undergone at least three contrast material enhanced brain MR examinations with a linear GBCA (gadopentetate dimeglumine [Magnevist; Berlex, Wayne, NJ]) between November 11, 2005, and July 21, 2013, with documentation of normal MR brain findings on the most recent MR brain report (see Table for the initial indication for repeated contrast-enhanced MR brain examinations). Patients without axial unenhanced T1-weighted MR images, those with substantial artifacts on the MR images, those who did not undergo a three-dimensional magnetization-prepared rapid gradient-echo sequence (MPRAGE) at the last brain MR examination (two-group comparison only), those without matching pre- and post-gbca exposure image acquisition sequences (two-dimensional spin-echo or three-dimensional MPRAGE sequences; pre- and post-gbca comparison only), those who received a contrast agent other than gadopentetate dimeglumine, and those with a history of brain radiation, neurofibromatosis type I, or impaired renal function were excluded. For the two-group comparison, one patient was excluded because axial T1-weighted MR images were not obtained, 13 patients were excluded because three-dimensional gradient-echo images were not obtained, and three patients were excluded because they had a history of brain radiation. For the preand post-gbca comparison, one patient was excluded because axial T1-weighted MR images were not obtained and 30 patients were excluded because they did not undergo matching image acquisition sequences before and after contrast material exposure between the first and last MR examinations. GBCA-naive control subjects with a normal result at brain MR imaging were consecutively selected from our institution s electronic database during the same period such that three patients were selected for analysis per patient year of life (age,1 year to 18 years; Published online before print /radiol Content code: Radiology 2017; 282: Abbreviations: CI = confidence interval GBCA = gadolinium-based contrast agent MPRAGE = magnetization-prepared rapid gradient-echo sequences Author contributions: Guarantors of integrity of entire study, all authors; study concepts/study design or data acquisition or data analysis/ interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, all authors; clinical studies, all authors; statistical analysis, T.F.F., D.M.M.; and manuscript editing, all authors Conflicts of interest are listed at the end of this article. 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3 Summary of Group Characteristics Characteristic one patient was 19 years of age). Inclusion criteria included a normal result at brain MR imaging performed at our institution. Exclusion criteria were as noted for patients exposed to contrast material, except that any patient with a history of GBCA exposure was eliminated from analysis (n = 0). The number of MR examinations per patient was not limited in the control group. For the two-group comparison, the mean age of the GBCA-naive control subjects was matched to that of the patients exposed to GBCA. Imaging Protocol All brain MR examinations were performed with a 1.5-T whole-body MR Two-Group Comparison GBCA-exposed Patients (n = 30) GBCA-naive Control Subjects (n = 57) Pre- and Post-GBCA Comparison (n = 16) Age Mean (y) Range 69 d to 18 y 60 d to 19 y 310 d to 18 y Sex M F Mean no. of contrast-enhanced MR examinations Mean interval between contrast-enhanced examinations (d) Mean accumulated gadolinium dose (g) Initial MR findings necessitating follow-up Extracranial neoplasm Pituitary abnormality Transient parenchymal enhancement Orbit/optic nerve abnormality Mild volume loss Perimesencephalic lipoma Cavernous sinus cyst Clival mass Sinus disease Choroid plexus abnormality Unilateral temporalis muscle abnormality No. of subjects with unenhanced T1-weighted images MPRAGE sequence Spin-echo sequence Matched pre- and postcontrast MR sequences 16 Note. Except where indicated, data are numbers of subjects. imaging system within our institution (Avanto; Siemens Medical Systems, Erlangen, Germany). All examinations included an unenhanced axial T1-weighted spin-echo sequence (repetition time msec/echo time msec, /8 14; section thickness, 5 mm with 1.5-mm gap) or T1-weighted three-dimensional MPRAGE sequence ( /2.92; section thickness, 1.0 mm; field of view, 250 mm). Data Collection Measurements of signal intensity in a circular region of interest within the globus pallidus, thalamus, dentate nucleus, and pons (mean diameter, 5 mm; range, 3 9 mm) were obtained on unenhanced axial T1-weighted MR images for all patients. Bilateral measurements were averaged from the globus pallidus, thalamus, and dentate nucleus; single measurements were obtained from the pons. All measurements were performed by a radiology resident with a neuroscience-specific research degree (PhD) (T.F.F., with 3 years of postgraduate experience). The investigator who obtained the measurements was not blinded to the patient s history of contrast material exposure. Measurement screenshots were saved and reviewed by three attending pediatric neuroradiologists (N.V.S., J.A.M., and D.M.M., with 6, 2, and 4 years of experience, respectively) to ensure appropriate measurement location by consensus agreement. No measurement disagreements were noted. The signal intensity measurements were transcribed into software (Excel, version 2011; Microsoft, Redmond, Wash). Statistical Analysis The primary outcome measure was whether repeated exposure to GBCAs resulted in a statistically significant increase in brain intraparenchymal signal intensity relative to that in GBCA-naive control subjects. To evaluate the primary outcome measure, globus pallidus thalamus and dentate nucleus pons signal intensity ratios were calculated for all patients. In the pre- and post-gbca comparison group, the signal intensity for each neuroanatomic ratio was compared within the patients exposed to contrast material such that the signal intensity ratio on unenhanced T1-weighted images from each patient at the time of the last contrast-enhanced brain MR examination was compared with that at the time of the first contrastenhanced examination (before administration of contrast material) by using the nonparametric Wilcoxon signed rank test. In the two-group comparison, signal intensity ratios from the last contrast-enhanced brain MR examination were compared with those in agematched GBCA-naive control subjects by using the nonparametric Wilcoxon rank sum test. Seven patients with MPRAGE sequences were common to 224 radiology.rsna.org n Radiology: Volume 282: Number 1 January 2017

4 Figure 1 Figure 1: Column scatter graphs show intraparenchymal signal intensity increases with repeated exposure to linear GBCA. ns = not significant, *** = statistically significant. A, B, Two-group comparison of intraparenchymal signal intensity ratios, comparing GBCA-exposed patients with age-matched GBCA-naive control subjects, demonstrates increased signal intensity after repeated contrast material exposures within, A, dentate nucleus (DN) but not, B, globus pallidus (GP) (P,.001 and P =.21, respectively; Wilcoxon rank sum test). Magenta line in A and B indicates mean; blue lines indicate 6standard errors of mean. C, D, Comparison of intraparenchymal signal intensity ratios before and after GBCA exposure demonstrates increased signal intensity after repeated contrast material exposures within, C, dentate nucleaus (DN) but not, D, globus pallidus (GP) (P,.001 and P =.12, respectively; Wilcoxon signed rank test). both groups. All comparisons in both groups were made between the same image acquisition sequence (eg, spinecho or MPRAGE sequences only compared with spin-echo or MPRAGE sequences, respectively; Table). Secondary outcome measures included evaluation of the relationship between neuroanatomic signal intensity ratios (from the last contrast-enhanced brain MR examination in patients exposed to contrast material [MPRAGE sequence only]) and total cumulative gadolinium dose, age, sex, and total number of and mean time between contrast-enhanced examinations. These comparisons were performed by using the nonparametric Spearman correlation coefficient for all variables but sex, which was analyzed with the nonparametric Wilcoxon rank sum test. All analyses were performed with software (T.F.F.) (Microsoft Excel and GraphPad Prism, version 6 [Graph- Pad Software, La Jolla, Calif]). P,.05 was considered indicative of a statistically significant difference. Results The Table describes pertinent patient characteristics, including age, sex, contrast material exposure, clinical history, and image acquisition sequences. The dentate nucleus pons and globus pallidus thalamus signal intensity ratios from GBCA-exposed patients at the time of their last contrast-enhanced examination were compared with those in the age-matched GBCA-naive control subjects (age of patients exposed to contrast material vs age of GBCAnaive subjects, P =.59; Wilcoxon rank sum test). This two-group comparison analysis demonstrated that, in patients exposed to contrast material, the signal intensity ratio on unenhanced T1- weighted MR images was increased within the dentate nucleus (Fig 1, A; mean signal intensity ratio: for the GBCA-naive group and for the GBCA-exposed group, P,.001) but not within the globus pallidus (Fig 1, B) (mean signal intensity ratio: for the GBCA-naive group and for the GBCA-exposed group, P =.21) relative to that in GBCA-naive control subjects. Similarly, the pre- and post- GBCA comparison (before and after repeated GBCA exposures) demonstrated Radiology: Volume 282: Number 1 January 2017 n radiology.rsna.org 225

5 Figure 2 Figure 2: Axial unenhanced T1-weighted spin-echo brain MR images show dentate nucleus signal intensity increases with repeated exposure to linear GBCA in pediatric brain. Left, image in 6-year-old girl before contrast material exposure. Right, MR image in same patient at the age of 9 years, after eight GBCA-enhanced examinations. Arrows indicate increased bilateral signal intensity in dentate nucleus. an increased signal intensity ratio on unenhanced T1-weighted MR images within the dentate nucleus (Figs 1, C, 2) (mean signal intensity ratio: for the pre-gbca group and for the post-gbca group, P,.001), but not in the globus pallidus (Fig 1, D) (mean signal intensity ratio: for the pre- GBCA group and for the post-gbca group, P =.12) after repeated contrast material exposures. The increased signal intensity in the dentate nucleus among patients exposed to contrast material was analyzed relative to the total cumulative gadolinium dose, patient age, sex, total number of contrast-enhanced examinations, and mean time between contrastenhanced examinations (Fig 3). There was a statistically significant relationship between the dentate nucleus pons signal intensity ratio and the total cumulative gadolinium dose (r = 0.4; 95% confidence interval [CI]: 0.03, 0.67; P =.03) but not between the ratio and patient age (r = 0.23; 95% CI: 20.15, 0.56; P =.22), sex (mean signal intensity ratio: for boys and for girls; P =.88), total number of contrast-enhanced examinations (r = 0.13; 95% CI: = 20.25, 0.48; P =.49), or mean time between contrast-enhanced examinations (r = 20.06; 95% CI: 20.42, 0.32; P =.75). Sex was analyzed with the Wilcoxon rank sum test, and all others variables were analyzed with the Spearman correlation coefficient. Discussion In our study, we demonstrated that dentate nucleus pons signal intensity ratios in normal pediatric brains increased with repeated exposure to a linear GBCA on unenhanced T1-weighted MR images and that this effect occurs in a cumulative dose-dependent manner. These findings within pediatric brains are consistent with those in the adult literature, which has previously established a statistically significant relationship among cumulative GBCA exposure, increased brain signal intensity (on unenhanced T1-weighted MR images), and intracranial gadolinium deposition (8 10,12,13). Furthermore, although we did not directly confirm intracranial gadolinium deposition by means of postmortem analysis, we demonstrated a significant relationship between cumulative GBCA exposure and increased signal intensity in relatively normal brains, providing indirect evidence that intracranial deposition can occur in the setting of an intact blood-brain barrier (12,13). Increased dentate nucleus pons signal intensity ratios on unenhanced T1-weighted MR images in pediatric patients with repeated exposure to a linear GBCA are consistent with the adult data and are likely related to intracranial gadolinium deposition, as discussed earlier (8 10,12,13). However, the lack of a corresponding statistically significant increase in globus pallidus thalamus signal intensity ratios is contrary to the findings in adult studies (8 10,12,13). One possible explanation for this discrepancy is that pediatric patients needed more GBCA exposure to demonstrate the signal intensity ratios found in adults. In addition, we did not 226 radiology.rsna.org n Radiology: Volume 282: Number 1 January 2017

6 Figure 3 Figure 3: Scatterplots show correlation of dentate nucleus (DN) signal intensity with, A, total cumulative gadolinium dose (r = 0.4; 95% CI: 0.03, 0.67; P =.03) but not with, B, patient age (r = 0.23; 95% CI: 20.15, 0.56; P =.22), C, number of linear GBCA-enhanced examinations (r = 0.13; 95% CI: 20.25, 0.48; P =.49), or, D, mean time between GBCA-enhanced examinations (r = 20.06; 95% CI: 20.42, 0.32; P =.75). Analysis was performed with Spearman correlation coefficient. identify a significant relationship between pediatric brain dentate nucleus pons signal intensity ratios and the number of contrast-enhanced examinations, which has been shown in several adult studies (8 10,12). This discrepancy again may be related to differences in cumulative gadolinium exposure; our finding of a significant correlation between dentate nucleus pons signal intensity ratio and cumulative GBCA dose supports this explanation. However, additional possibilities may exist. The clinical significance of our findings is unknown; however, because gadolinium can be toxic and pediatric patients may undergo multiple contrast-enhanced examinations over their lifetime, the clinical benefits versus potential harm of GBCA deposition should be analyzed before administration of linear GBCA to children. Study limitations include a small single-center retrospective design, which limits generalization of the results. Exclusion of patients with evidence of brain abnormality prevented analysis of many patients with much greater GBCA exposure. Furthermore, we assessed only one of the nine U.S. Food and Drug Administration approved GBCAs, again limiting generalization of findings (4). Many linear and macrocyclic GBCAs are associated with increased parenchymal signal intensity in adult patients (8 12,17,18); whether these agents affect the pediatric brain in a similar manner has yet to be evaluated. Intracranial gadolinium was not confirmed with postmortem analysis, as performed in adult studies (12 14). T1 mapping may be more appropriate to accurately assess T1-weighted image signal intensity, as previously suggested (10). In summary, dentate nucleus signal intensity ratios in normal pediatric brains increase with repeated exposure to a linear GBCA on unenhanced T1-weighted MR images, consistent with findings in the adult literature and likely secondary to intracranial gadolinium deposition. Further studies with larger patient cohorts, different GBCAs, and postmortem pathologic analysis are needed to confirm pediatric intracranial gadolinium deposition and determine its clinical significance, especially within the vulnerable pediatric population, because these patients may potentially have repeated gadolinium exposure over their lifetime. Until understanding improves, clinicians and radiologists should proceed with caution and administer linear GBCAs to children only when absolutely necessary. Disclosures of Conflicts of Interest: T.F.F. disclosed no relevant relationships. N.V.S. disclosed no relevant relationships. J.A.M. disclosed no rel- Radiology: Volume 282: Number 1 January 2017 n radiology.rsna.org 227

7 evant relationships. D.M.M. disclosed no relevant relationships. References 1. Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadolinium-dtpa complex: a potential NMR contrast agent. AJR Am J Roentgenol 1984;142(3): Tweedle MF, Eaton SM, Eckelman WC, et al. Comparative chemical structure and pharmacokinetics of MRI contrast agents. Invest Radiol 1988;23(Suppl 1):S236 S Caravan P, Ellison JJ, McMurry TJ, Lauffer RB. Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 1999;99(9): Hao D, Ai T, Goerner F, Hu X, Runge VM, Tweedle M. MRI contrast agents: basic chemistry and safety. J Magn Reson Imaging 2012;36(5): Lauffer RB, Brady TJ. Preparation and water relaxation properties of proteins labeled with paramagnetic metal chelates. Magn Reson Imaging 1985;3(1): Beckett KR, Moriarity AK, Langer JM. Safe use of contrast media: what the radiologist needs to know. RadioGraphics 2015;35(6): Dillman JR, Ellis JH, Cohan RH, Strouse PJ, Jan SC. Frequency and severity of acute allergic-like reactions to gadoliniumcontaining i.v. contrast media in children and adults. AJR Am J Roentgenol 2007; 189(6): Ramalho J, Castillo M, AlObaidy M, et al. High signal intensity in globus pallidus and dentate nucleus on unenhanced T1-weighted MR images: evaluation of two linear gadolinium-based contrast agents. Radiology 2015;276(3): Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology 2014;270(3): Kanda T, Osawa M, Oba H, et al. High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 2015;275(3): Stojanov DA, Aracki-Trenkic A, Vojinovic S, Benedeto-Stojanov D, Ljubisavljevic S. Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol. Eur Radiol 2016;26(3): McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275(3): Kanda T, Matsuda M, Oba H, Toyoda K, Furui S. Gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;277(3): Murata N, Gonzalez-Cuyar LF, Murata K, et al. Macrocyclic and other non-group 1 gadolinium contrast agents deposit low levels of gadolinium in brain and bone tissue: preliminary results from 9 patients with normal renal function. Invest Radiol 2016;51(7): Roberts DR, Holden KR. Progressive increase of T1 signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in the pediatric brain exposed to multiple doses of gadolinium contrast. Brain Dev 2016;38(3): Miller JH, Hu HH, Pokorney A, Cornejo P, Towbin R. MRI brain signal intensity changes of a child during the course of 35 gadolinium contrast examinations. Pediatrics 2015; 136(6):e1637 e Radbruch A, Weberling LD, Kieslich PJ, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015;275(3): Cao Y, Huang DQ, Shih G, Prince MR. Signal change in the dentate nucleus on T1-weighted MR images after multiple administrations of gadopentetate dimeglumine versus gadobutrol. AJR Am J Roentgenol 2016;206(2): radiology.rsna.org n Radiology: Volume 282: Number 1 January 2017