For nearly 30 years, gadolinium-based contrast agents (GBCAs) have been used to aid diagnosis in clinical MRIs and have been considered safe for patients without severe renal insufficiency. Recent studies have shown that traces of gadolinium may be retained in a patient’s brain after use, however, sparking a firestorm of passionate debate.

Now, some are pushing to limit the use of certain GBCAs. Is this an overreaction based on limited evidence or a warranted exercise of caution? Do the risks of not using these powerful agents actually outweigh concerns about gadolinium deposits in the brain? Here are five things every radiologist should know about the issue:

1 Recent Research Has Shown Gadolinium Retention in the Brain

Concerns about gadolinium retention in the brain came to the forefront of the professional press in the wake of a trio of eye-opening studies. In 2013, Tomonori Kanda, MD, PhD, of Japan’s Hyogo Cancer Center, rang alarm bells by demonstrating abnormal T1 shortening in the brains of patients who had undergone repeated prior administration of GBCAs, specifically gadopentetate dimeglumine and gadodiamide (Radiology 2014;270:834–841). This was followed by a Mayo Clinic study showing gadolinium deposits in postmortem tissue samples in a small group of patients (Radiology 2015;275:772–782) and another study from researchers at the University of Heidelberg Medical Center in Germany, also finding abnormal T1 shortening due to gadolinium retention (Radiology 2015;275:783-91).

The third study, by Alexander Radbruch, MD, JD, and colleagues, added a key bit of context that continues to color the debate on how to approach the issue today: the class of GBCA used seemed to play a significant role, and those where the gadolinium is bound to the chelating agent in a macrocyclic molecular structure did not see the same increase in MRI signal intensity as those who underwent scans exclusively using GBCAs with a linear molecular structure.

As research showing the connection between GBCA use and gadolinium retention in the brain began to mount, the question became how will industry and medical regulators respond. Enter the European Medicines Agency (EMA), a European Union body roughly equivalent to the FDA. The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) shocked the imaging world in March 2017 by recommending the following four GBCAs, all linear agents, be removed from the market:

• Gadobenic Acid (MultiHance)
• Gadoversetamide (Optimark)
• Gadodiamide (Omniscan)
• Gadopentetic Acid (Magnevist) (Note: a specific formula featuring low gadolinium concentration and designed to be injected directly into joints was exempted)

“Linear agents have a structure more likely to release gadolinium, which can build up in body tissues. Other agents, known as macrocyclic agents, are more stable,” PRAC said in a press release¹. (One month later, the committee announced it would be examining the issue again, but the impact of its initial recommendation remains.)

2 The Clinical Implications Are Unclear

While there’s evidence showing GBCAs can leave traces of gadolinium behind, the question of clinical significance is murkier. The mechanisms of GBCA toxicity haven’t been confirmed in living human subjects, and the FDA announced in May 2017 that it “has not identified adverse health effects from gadolinium retained in the brain after the use of gadolinium-based contrast agents for magnetic resonance imaging” though they “are continuing to assess the safety” of GBCA use². Advocacy groups, though, argue otherwise. A research review published in the journal Biometals noted a small patient-advocacy group survey in which 17 former patients with repeated exposure to GBCAs reported extremely high rates of experiencing pain (100 percent), muscle symptoms (88 percent) and ocular symptoms (76 percent), among other abnormalities (Biometals 2016; 29:365–376).

For its part, the American College of Radiology (ACR) said current research doesn’t support PRAC’s recommendation to scuttle most of the linear agents.

“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,” according to an April 2017 ACR statement³. “Further, linear agents have significant and well-documented diagnostic utility, and in some instances may have more desirable pharmacologic properties or a lower acute reaction risk than macrocyclic agents.”

A 2016 research letter published in JAMA addressed one specific concern head-on: whether GBCA use can result in the manifestation of Parkinson disease symptoms. Blayne Welk, MD, MSc, of Western University in London, Ontario, Canada, says the investigation was spurred by a plausible hypothesis due to the selective deposition of gadolinium in the globus pallidi. Damage to this brain structure can spur Parkinsonian symptoms.

Using data from multiple linked administrative databases in Ontario, Welk and his team looked at nearly 100,000 patients age 67 or older who underwent an MRI with at least one dose of gadolinium between 2003 and 2013, comparing them with unexposed patients. An adjusted analysis found no significantly increased hazard of parkinsonism among patients with cumulative gadolinium exposure (JAMA 2016;316:96-98).

The study couldn’t evaluate the type of agent used on each patient and Welk acknowledged there is variability with the risk of gadolinium retention and the type of agent. “The inclusion of lower risk agents will bias things towards the null, however, with such a large population, we were powered to find even small differences,” Welk says. “Unfortunately a lot of the reports of ‘gadolinium toxicity’ are very nonspecific, and not measurable with administrative data.”

3 It’s Not as Simple as Macrocyclic vs. Linear

Complicating matters even further is the revelation that, while macrocyclic agents may indeed be more stable, all GBCAs can leave behind traces of gadolinium. A 2016 study published in Investigative Radiology involving autopsies of nine patients who had received a contrast-enhanced MRI with only a single type of GBCA revealed that gadolinium deposition occurs in brain and bone tissue with the use of both macrocyclic and linear agents. Lead author Nozomu Murata MD, PhD, with colleagues from the University of Washington, Seattle, and Toho University Ohashi Medical Center, Tokyo, also reported that bone levels measured 23 times higher than brain levels (Invest Rad. 2016;51:447–453).

Even among the increasingly maligned linear agents, efficacy and safety profiles can vary. The fact that the PRAC recommendations seemed to ignore this fact and lumped most linear agents together has become a source of frustration for Emanuel Kanal, MD, director of magnetic resonance services and professor of radiology and neuroradiology at the University of Pittsburgh Medical Center.

“It’s an amazing recommendation … the agents they wish to discard include the one with the highest relaxivity,” says Kanal, referring to MultiHance (Bracco Diagnostics). “It produces the strongest signal enhancement per administered dose of all the neuroradiologic agents we use today.”

MultiHance also has an outstanding risk profile for nephrogenic systemic fibrosis (NSF), adds Howard Rowley, MD, professor of radiology at the University of Wisconsin–Madison and president of the American Society of Neuroradiology.

“If that agent were banned in the U.S., I’d lose the most effective agent with an unrivaled safety profile for NSF,” he says. “And why would I lose it? Because of a theoretical risk of something, and that’s not a good trade-off for me.”

4 Taking Agents Away Could Be More Harmful

“My main concern is that, as a side effect of the current press and PRAC recommendations, patients may actually be hurt by not receiving gadolinium,” Rowley says. GBCAs have been an incredibly effective and prolific tool for radiologists, having been administered to some 100 million patients since their introduction.

“That’s a real-world experiment,” Rowley adds. “The scientific and medical community is, I think, in agreement that these agents have extremely beneficial diagnostic capabilities and very low risk compared to just about anything else in medicine, and I’m talking about antibiotics, anticoagulants, medical procedures … as far as we can tell, and this is still true with the observation of gadolinium deposition, these are some of the safest things we use in medicine and they have a very large benefit.”

A study group formed by the National Institutes of Health (NIH) Clinical Center to investigate gadolinium deposition in the brain seemed to echo concerns about the loss of linear agents from the radiologist’s toolbox. While advising radiologists to strongly consider macrocyclics, the “choice of contrast agents should be individualized at each imaging center, and it is appropriate to use linear agents when clinically indicated,” according to the group’s statement, published in the Journal of the American College of Radiology (JACR) (J Am Coll Radiol. 2016 Mar;13(3):237-41).

“Missing a diagnosis is not an issue of efficacy only, it’s a safety issue,” Kanal says. “And the potential to discard an agent that’s been shown to be the most sensitive of our neuroradiologic agents, to not recognize the safety implications of that statement, is amazing.”

5 Radiologists Have an Opportunity to Take Charge

Given the risks of not using GBCAs to obtain an accurate diagnosis, it could be tempting to do nothing or dismiss concerns about retention in the brain as “gadolinium phobia.” However, this would be a mistake, according to Hans-Klaus Goischke, MD, a physician from Bad Brückenau, Germany, who wrote in the JACR that radiologists must not confuse the lack of conclusive results related to gadolinium toxicity in the brain with safety (J Am Coll Radiol. 2016 Aug;13(8):890). Improved documentation would be a step in the right direction.

“The problem of documentation of MRI examinations is very bad,” Goischke says. “The radiologist community has no interest in documentation.” Most patients do not know the type of contrast used in their examinations or the dose, he adds, and making this information more explicit and having providers review before subsequent GBCA administration would be a clear step in the right direction.

Current research may not support singling out any one agent or class of agents with blanket recommendations against use, but Kanal believes the solution to this issue is actually relatively straightforward: caution should be used before administering any agent and never based on the referring physicians request alone. In every case, a radiologist should review a request for a contrast exam and provide a signature if they believe the patient would benefit. These are prescription drugs, and their use should always be confirmed by the expert in the best position to evaluate the balance of risks and benefits.

“You’ll hear some who will say ‘I don’t have time in my practice to review every case of contrast before it’s administered,’” Kanal says. “In this day and age where we have found potential safety concerns regarding gadolinium-based contrast agents, we have no choice but to behave as the physicians we are and oversee the safe execution of all MRI examinations on our patients. Our patients would expect nothing less.”

References

¹PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension for some marketing authorisations. March 2017. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Gadolinium-containing_contrast_agents/human_referral_prac_000056.jsp&mid=WC0b01ac05805c516f. Accessed April 1, 2017.

²FDA.gov.; 2017. https://www.fda.gov/Drugs/DrugSafety/ucm559007.htm. Accessed May 24, 2017.

³ACR Response to the European PRAC Recommendations. April 2017. https://www.acr.org/About-Us/Media-Center/Press-Releases/2017-Press-Releases/20170404-ACR-Response-to-the-European-PRAC-Recommendations. Accessed April 20, 2017.