Another 2015 study in Radiology reports findings consistent with gadolinium deposition within the brains of patients with normal renal function (eGFR >60).  The study by Ramalho 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”, compared gadodiamide (Omniscan) and gadobenate dimeglumine (MultiHance).  The findings related to multiple administrations of gadodiamide are “in agreement with other investigators, who documented signal intensity changes associated with this contrast agent despite the presence of normal renal function”.  The authors also reported that, “A significant trend toward relative change in signal intensity was seen in the dentate nucleus (DN), but not in the globus pallidus (GP) after serial applications of gadobenate dimeglumine, suggesting that some gadolinium deposition also may occur with this agent”.

For the first time in the literature, the study established gadolinium accumulation related to the use of gadobenate dimeglumine, which is better known as MultiHance.  Of note is the fact that there are no unconfounded cases of NSF associated with the linear ionic gadolinium-based contrast agent (GBCA), MultiHance.  However, in this study, the patients in each group had received only one brand of GBCA.  Group 1 was comprised of 23 patients that had received between 3 and 11 doses of Omniscan, and Group 2 included 46 patients that had received between 3 and 11 doses of MultiHance.  All patients had normal liver and renal function. 

The study was a single-center, retrospective longitudinal observational cohort study from the University of North Carolina at Chapel Hill.  The review of MR imaging records in the hospital database found 200 consecutive patients who underwent at least four brain MRI examinations with at least three including GBCA administration.  After applying various exclusion criteria, the study population was made up of 69 patients.  None of the patients had a history of targeted or whole-brain radiation therapy, or MS.  Patients with an unknown diagnosis and any other diseases that may result in T1 shortening in the deep gray matter of the brain were excluded.  None of the 69 patients had congenital metabolic diseases, congenital malformations, Langerhans cell histiocytosis, NSF, or a history of parenteral nutrition.

The authors noted that before December 2006, their center used gadodiamide (Omniscan) as the only GBCA for all enhanced MRIs, irrespective of the patient’s level of renal function.  From December 2006 to June 2007, patients with normal renal function still received gadodiamide.  That is noteworthy since it was in 2006 that the connection was made between the use of GBCAs and the disease known as NSF in renally impaired patients.  After June 2007, their center administered gadobenate dimeglumine (MultiHance) to all adult patients, and the use of gadodiamide (Omniscan) was discontinued.  Since 2008, all MRI exams have been registered in the hospital database.

I won’t provide all image and data analysis details here.  However, I do want to provide some details.  Quantitative analysis was performed for both baseline and final unenhanced T1-weighted images.  The minimum number of GBCA administrations for a given patient was three.  Two radiologists independently performed region of interest measurements.  Oval regions of interest were placed in the globus pallidus (GP), thalamus (TH), dentate nucleus (DN), and middle cerebral peduncles (MCPs) on both sides to include as much as of the anatomic structure as possible, but to avoid any lesions, vessels, or artifacts.

The GP-to-TH signal intensity ratio (GP:TH) and DN:MCP were determined with the first and last MR images of all patients in each group.  A total of 364 regions of interest were drawn in Group 1, and 696 were drawn in Group 2.  Twelve discrepancies between readers were resolved by consensus reading.

According to the study, patients who received gadodiamide showed a significant increase in DN:MCP and GP:TH over time according to the number of previous GBCA administrations.  Conversely, those who received gadobenate dimeglumine did not show a significant increase in signal intensity ratios over time.  However, gadobenate dimeglumine (MultiHance) showed a significant trend toward an increase in signal intensity in R_change only for DN:MCP (P = .013), suggesting gadolinium deposition in these structures.

The authors noted that, “High T1 signal intensity in the DN is an indirect sign of gadolinium deposition, as shown by McDonald et al, who at histologic analysis confirmed gadolinium deposition in neural tissues after multiple administrations of gadodiamide and its high correlation with T-1 weighted signal intensity changes”.

Ramalho and colleagues concluded that their, “Rate-of-change data indirectly showed a considerable difference between gadolinium accumulation between the two GBCAs studied; however, it also suggested gadolinium deposition with gadobenate dimeglumine in the DN, although it was considerably less than that with gadodiamide”.

The authors said, “Further longitudinal studies should be performed to evaluate and compare different GBCAs individually, since other properties besides their classification into macrocyclic or linear and ionic or nonionic may contribute to differences in signal intensity in sites of deposition.”

Hopefully the research into gadolinium retention will not stop with the brain.  Gadolinium has been found throughout the bodies of NSF patients, and it would seem that varying amounts of it might be found in the bodies of patients with normal renal function as well, but it will not be found unless someone looks for it.

For more information about Gadolinium and Gadolinium-Based Contrast Agents see Background on Gadolinium and Background on GBCAs.

Sharon Williams

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Ramalho, J., Castillo, M., AlObaidy, M., Nunes, R. H., Ramalho, M., Dale, B. M., & Semelka, R. C. (2015). High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: Evaluation of Two Linear Gadolinium-based Contrast Agents. Radiology, 150872. http://doi.org/10.1148/radiol.2015150872

Recent articles referenced by Ramalho et al:

Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., & Takenaka, D. (2013). 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, 131669. doi:10.1148/radiol.13131669.  Retrieved from http://pubs.rsna.org/doi/abs/10.1148/radiol.13131669

Errante, Y., Cirimele, V., Mallio, C. A., Di Lazzaro, V., Zobel, B. B., & Quattrocchi, C. C. (2014). Progressive Increase of T1 Signal Intensity of the Dentate Nucleus on Unenhanced Magnetic Resonance Images Is Associated With Cumulative Doses of Intravenously Administered Gadodiamide in Patients With Normal Renal Function, Suggesting Dechelation. Investigative Radiology, 49(10), 685–690. http://doi.org/10.1097/RLI.0000000000000072

Quattrocchi, C. C., Mallio, C. A., Errante, Y., Cirimele, V., Carideo, L., Ax, A., & Zobel, B. B. (2015). Gadodiamide and Dentate Nucleus T1 Hyperintensity in Patients With Meningioma Evaluated by Multiple Follow-Up Contrast-Enhanced Magnetic Resonance Examinations With No Systemic Interval Therapy. Investigative Radiology. http://doi.org/10.1097/RLI.0000000000000154

Radbruch, A., Weberling, L. D., Kieslich, P. J., Eidel, O., Burth, S., Kickingereder, P., … Bendszus, M. (2015). Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent. Radiology, 150337. http://doi.org/10.1148/radiol.2015150337

McDonald, R. J., McDonald, J. S., Kallmes, D. F., Jentoft, M. E., Murray, D. L., Thielen, K. R., … Eckel, L. J. (2015). Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology, 150025. http://doi.org/10.1148/radiol.15150025

Kanda, T., Fukusato, T., Matsuda, M., Toyoda, K., Oba, H., Kotoku, J., … Furui, S. (2015). Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy. Radiology, 142690. http://doi.org/10.1148/radiol.2015142690

Kanda, T., Osawa, M., Oba, H., Toyoda, K., Kotoku, J., Haruyama, T., … Furui, S. (2015). High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration. Radiology, 140364. http://doi.org/10.1148/radiol.14140364.