Gadolinium-Based Contrast Agents and Brain Safety: Signal vs Noise

Tricia Ward

Disclosures

June 26, 2017

Gadolinium-based contrast agents (GBCAs) used in MRI and angiography contain a chelated form of the toxic heavy metal that was assumed to clear the body shortly after intravenous administration.[1]

In 2014, Dr Tomonori Kanda of Japan was the first to report increased signal intensity in the brains of people who underwent repeated GBCA-imaging tests.[2] Subsequent studies confirmed the association and provided more insights. Notably, Mayo clinic researchers compared postmortem neuronal tissue samples from 13 patients who underwent at least four GBCA-enhanced brain MRIs between 2000 and 2014 with those from 10 patients who did not receive GBCA and found that GBCA exposure is associated with neuronal tissue deposition in patients with normal renal function.[3]

Class Effect? Linear vs Macrocyclic GBCA

The observed T1 shortening is presumed to result from the gadolinium ion escaping from its chelating ligand molecule which can be linear or macrocyclic. Macrocyclic ligands are organized in a ring structure that prevents certain mechanisms of dechelation and should lose less gadolinium per unit time than linears. Studies in rats have demonstrated that more gadolinium is retained in bone and other organs when they are given linear GBCAs vs macrocyclic GBCAs.[4,5]

The original Japanese discoverers of the phenomenon showed an association with administration of a linear ionic agent (gadopentetate dimeglumine) but not a macrocyclic gadolinium chelate (gadoteridol).[6] This class effect was confirmed by German researchers.[7] However, in a related discussion chaired by the editor of Radiology, Alexander Radbruch, MD, JD (University of Heidelberg Medical Center) warned that "every agent may be different, [and we] need to study each individually."

Ramalho and colleagues[8] confirmed the finding of increased brain signal intensity in people who underwent repeated gadolinium-enhanced imaging tests with a linear nonionic GBCA (gadodiamide), but not in those who received a linear ionic contrast agent (gadobenate dimeglumine). It was assumed that these distinctions reflect differences in stability and elimination of ionic and nonionic linear GBCAs.

Table. FDA-Approved Gadolinium-Based Contrast Agents

Generic Name Trade Name Structure
Gadodiamide Omniscan Linear nonionic
Gadoversetamide Optimark Linear nonionic
Gadopentetate dimeglumine Magnevist Linear ionic
Gadobenate dimeglumine MultiHance Linear ionic
Gadoxetate disodium Eovist/Primovist Linear ionic
Gadofosveset trisodium Ablavar Linear ionic
Gadoterate meglumine Dotarem Macrocyclic ionic
Gadobutrol Gadavist/Gadovist Macrocyclic nonionic
Gadoteridol ProHance Macrocyclic nonionic

Radiotherapy/Iatrogenic Effects

Chemotherapy and radiation therapy can disrupt the blood-brain barrier, which was proposed as an explanation for the increased brain signals; however, Robert McDonald, MD, who led the Mayo clinic autopsy study, noted in a video discussion that the treatment zone was far away from the dentate nuclei where the gadolinium deposition was found and that deposits were seen in some patients who did not receive radiation. About a third of the detected gadolinium in that analysis had crossed an intact blood-brain barrier.

Similarly, an Italian study of 102 patients with meningioma found an increase in T1 hyperintensity of the dentate nuclei of the cerebellum of those who had multiple GBCA-MRIs, even though none had undergone interim treatment such as radiotherapy.[9]

Impairment of renal function is a risk factor for deposition of gadolinium in tissues, including the brain,[10] because elimination is delayed, but the brain signal observations were largely in patients with normal renal function. [11]

Number of Scans vs Contrast Agent Used

A dose-response relationship has been reported with a higher degree of brain signal or deposit found with increasing exposure. In the Mayo clinic study there was a direct relationship between total cumulative lifetime gadodiamide dose and the degree of T1 shortening seen.[3] Those patients had undergone four or more GBCA-enhanced scans with the linear agent, gadodiamide. In the Italian analysis of patients with meningioma, the effect was seen in those who had six or more gadodiamide-enhanced scans but not in those who had five or fewer.[9]

The Mayo researchers conducted another autopsy study in pediatric patients and found gadolinium deposits in postmortem brain tissue from three patients who had undergone at least four MRI scans with gadodiamide.[12] This contrasts with a Swiss study presented at ARRS 2017 that found no evidence of gadolinium deposition in the brain in 34 pediatric oncology patients who received five to 15 half-doses of gadobenate, a linear ionic GBCA. Some of these patients had undergone chemotherapy.

Radbruch's Heidelberg team has further studied individual GBCAs, and their data suggest that the type of agent is more important than the number of scans. They found little signal effect after 20 consecutive MRI exams with macrocyclic GBCAs only (gadoterate meglumine and gadobutrol).[13] They even tentatively suggest a decrease in preexisting hyperintensities over time when linear GBCAs are changed to macrocyclic GBCAs.[14]

Clinical Effects Unknown

The clinical significance of gadolinium deposits and increased brain signal is not known. The Mayo investigators have not shown any association with damage to neurons or neural tissues. Neither they nor Kanda were able to confirm whether the deposits were intact gadolinium-chelate or free gadolinium.

Last year, a study published in JAMA compared almost 100,000 patients 66 years of age or older who had undergone gadolinium-enhanced MRI versus 150,000 patients who had had a non-gadolinium MRI; they found no significant link between GBCA exposure and parkinsonism.[15] More than 80% of the GBCA-exposed group had a single gadolinium-enhanced MRI and only 2.5% had four or more. The analysis used linked administrative databases from Ontario, Canada, that did not capture the specific GBCA used.

Gadolinium may also deposit in other body structures such as bone and skin. The Gd3+ ion is similar in size to Ca2+ and can compete with it.[4] In a discussion chaired by the editor of Radiology, Michael Tweedle, PhD (Ohio State University Medical School) suggested looking everywhere calcium is deposited, and the panelists speculated that the gadolinium may be replacing another deposit.

So far, the reports have been on imaging studies from patients with cancer or multiple sclerosis. Although none of the FDA-approved GBCAs are approved for cardiac imaging, they are commonly used off-label for that indication.[16]

Response of Government Agencies and Professional Societies

In March 2017, the European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee (PRAC) recommended suspending marketing authorization for four linear GBCAs.

In response, the American College of Radiology (ACR) Committee on Drugs and Contrast Media announced its disagreement with the PRAC recommendation. "At this time, there is no compelling evidence that any GBCAs, including linear ones, pose any safety risk with respect to brain deposition of gadolinium," the statement read.

The PRAC recommendation is being re-examined in light of requests from contrast developers affected by the decision. That update is scheduled to be completed in July.

The Radiological Society of North America position statement advises that the potential risk associated with residual gadolinium concentrations in the brain must be weighed against the clinical benefit of the diagnostic information or treatment result that MRI or MRA may provide for each individual patient.

The authors of an National Institutes of Health perspective concede that there is no evidence suggesting that gadolinium deposition in the brain alters neurologic function, but until more is known, they suggest that institutions consider the use of a macrocyclic GBCA rather than a linear agent.[16] They also encourage intra- and interdepartmental research programs to evaluate T1 shortening in the brain and other organs in patients who have received multiple doses of GBCAs.

On May 22, 2017, the FDA completed its review of the risk of brain deposits following repeated exposure to GBCA-MRI. They did not identify any evidence to date that gadolinium retention in the brain from any of the GBCAs is harmful, and concluded that restricting GBCA use is not warranted at this time.

The FDA continues to advise healthcare professionals to consider limiting GBCA use to clinical circumstances in which the additional information provided by the contrast is necessary, and to reassess the necessity of repetitive GBCA MRIs in established treatment protocols.

In addition, the FDA's National Center for Toxicological Research (NCTR) is conducting a study on brain retention of GBCAs in rats and further research on how gadolinium is retained in the body.

Proceed With Caution

MRI practitioners remain concerned. The Consortium of Multiple Sclerosis Centers will include a recommendation of judicious use of GBCAs in its forthcoming 2017 guideline update for MRI use. In an email to Medscape, Megan Strother, associate professor of radiology (Vanderbilt University Medical Center, Nashville, Tennessee) agreed with this cautious approach. "We just don't have the longitudinal data to draw prognostic conclusions at this time," she wrote.

A survey published in Pediatric Radiology found that half of pediatric radiology departments in the United States had switched from a linear GBCA to a macrocyclic GBCA within the past year.[17] Radiologists were more aware of brain gadolinium deposit issue than were non-radiologist physicians (87% vs 26%; P < .0001).

The manufacturers of one linear GBCA (gadoversetamide [Optimark]; Guerbet) added information to the label about retention in various organs, such as the brain and skin. The FDA is currently reviewing the labels of other GBCAs to determine whether changes are needed.

Follow me on Twitter: @_triciaward

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