On June 25, 2015, European Radiology published a new study online ahead of print that reports increasing signal intensity on brain MR images after repeated administrations of the macrocyclic agent, gadobutrol (Gadovist, Bayer Healthcare, Berlin, Germany). The study by Stojanov et al is titled, 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. This is the first study to report a correlation between the cumulative dose of a macrocyclic, gadolinium-based contrast agent (GBCA), and gadolinium deposition within the dentate nucleus (DN) and globus pallidus (GP) in patients with relapsing-remitting multiple sclerosis (RRMS). All patients had normal renal function at the beginning and end of the study.
Liver function was also normal at the beginning of the study; however, the authors noted that at the end of the study there was a significant increase (p=0.004) in GGT, gamma-glutamyl transpeptidase. The other liver function parameters remained normal.
Since all patients had normal renal function at the beginning and end of the study, there was no correlation between renal function and signal intensity within either dentate nucleus or globus pallidus. The authors noted that, “This suggests that gadolinium deposition within the brain may occur even in patients with normal renal function”.
The study included 58 patients with relapsing-remitting multiple sclerosis (RRMS), each of whom had between 4 and 6 MRIs with gadobutrol (Gadovist). Gadovist was administered from 27 to 168 weeks from the first MRI with contrast. The patients were classified in three groups based on the length of time between first and last contrast administration – group 1: 27 weeks involved 29 patients, group 2: 96-98 weeks involved 20 patients, and group 3: 168 weeks involved 9 patients.
The study evaluated the dentate nucleus-to-pons and globus pallidus-to-thalamus signal intensity (SI) ratios, and renal and liver functions, after multiple intravenous administrations of 0.1 mmol/kg gadobutrol at 27, 96-98, and 168 weeks. The authors compared SI ratios based on the number of administrations, total amount of gadobutrol administered, and time between injections.
Two experienced radiologists conducted the quantitative analysis. Regions-of-interest were placed around the right dentate nucleus, central pons, right globus pallidus, and right thalamus. Agreement on the correct ROI placement was reached by consensus.
The study found that, in patients with RRMS, the signal intensity (SI) within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images after multiple gadobutrol injections. Administration of the same total amount of gadobutrol over a shorter period of time caused greater SI increase.
The authors noted that the results found by Kanda et al (2014) and their study, “Suggest that T1W hyperintensities within the dentate nucleus in patients with MS may be caused by a larger cumulative dose of gadolinium, rather than the disease itself”.
Interestingly, a 2009 study by Roccatagliata et al reported hyperintensity of the dentate nucleus on unenhanced T1-weighted MR images of patients with the secondary-progressive subtype of multiple sclerosis (SPMS). At the time of that study, it appears that no one considered the possibility that the hyperintense signal in the dentate nucleus might be the result of gadolinium deposition from the GBCA administered for the MS patients’ MRIs. The study does not include any information related to the number of contrast-enhanced MRIs or the gadolinium-based contrast agent the patients received. The authors concluded that the findings were associated with increased clinical disability, lesion load, and brain atrophy.
Stojanov and colleagues reported that the patients in their study with RRMS (relapsing-remitting multiple sclerosis) had a lower cumulative gadolinium dose and shorter disease history than the SPMS (secondary-progressive multiple sclerosis) patients reported on by Roccatagliata et al (2009).
Based on these findings, one has to wonder if retained gadolinium is a contributing factor to the clinical disability and brain atrophy seen with MS. It would seem that other neurological diseases that are monitored by the use of contrast-enhanced MRI should also be investigated as soon as possible. I am especially thinking of diseases like Alzheimer’s disease and Parkinson’s disease which seem to be affecting increasing numbers of people.
To learn more about the toxic effects of retained gadolinium from gadolinium-based contrast agents, see the Background section of our website.
Sharon Williams
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Stojanov, D. A., Aracki-Trenkic, A., Vojinovic, S., Benedeto-Stojanov, D., & Ljubisavljevic, S. (2015). 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 age. European Radiology. http://doi.org/10.1007/s00330-015-3879-9
Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., & Takenaka, D. (2014). 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, 270(3), 834–41. http://doi.org/10.1148/radiol.13131669
Roccatagliata, L., Vuolo, L., Bonzano, L., Pichiecchio, A., & Mancardi, G. L. (2009). Multiple Sclerosis: Hyperintense Dentate Nucleus on Unenhanced T1-weighted MR Images Is Associated with the Secondary Progressive Subtype. Radiology, 251(2), 503–510. http://doi.org/10.1148/radiol.2511081269
Gadolinium Toxicity 
This is a completely flawed study. It was rejected by two prestigious medical journals before it was accepted for publication in European Radiology. It is not a controlled study and the claims of the centers nucleus and the globes pallidus showing increase signal is suspect. The images displayed in study do not show a substantial increase in signal at all. Martin Prince et al, who is a well published Neuroradiologist out of Columbia showed no increase in signal with gadobutol in these two brain regions which would be in line with the evidence found so far with other Macrocyclic gadolinium based contrast agents which have shown to gad retention even in autopsy studies.
The author of this paper is not well known, nor well published. When data conflicts as is does between Stojanov et al and prince et al. I will lean toward the results of Prince et al all day long.
Something here definitely does not pass the smell test.
Jack, thank you for your comments. Our goal is to provide factual information related to gadolinium-based contrast agents, and that is why we rely heavily on the facts presented in peer-reviewed articles published in various scientific journals. Since we aren’t medical professionals, we are not aware of some of the facts that you mentioned. I am not familiar with the study by Prince et al that you referred to, but if you can tell me where I might find it, I would like to read it as well.