Gadolinium Warning Leaves MS Patients, Doctors More Cautious About Scans


Multiple sclerosis specialists say they are working closely with their patients to help them understand the benefits and potential risks of gadolinium-based contrast agents (GBCAs) used in MR scans, as this form of imaging has been a tool to identify the need for therapeutic interventions to combat disease progression.

At this time, there’s widespread agreement about a need to understand more about the potential effects of gadolinium lingering in the body after imaging tests, particularly those done repeatedly on the brains of people with MS.

“The whole scientific community, including the FDA (Food and Drug Administration), is investigating further to find the right answers to this issue” said Mahadevappa Mahesh, PhD, MS, a professor of radiology and medicine at the Johns Hopkins University School of Medicine, Baltimore.

In a recent article in the Journal of the American College of Radiology, Dr. Mahesh and his co-authors addressed the “growing concerns regarding retention of GBCAs long after MR scans.”

The issue of so-called “gadolinium deposition disease” gained traction after a 2014 study found gadolinium deposits in the brains of patients with normal kidney function who had undergone GBCA-enhanced MR scans. Since then, more than 70 studies have examined persistent gadolinium deposition in the brain, bone, kidneys, liver, and spleen.

Dr. Mahadevappa Mahesh

Prior to these studies, problems with gadolinium deposition were thought to be limited to patients with impaired kidney function who are at risk for nephrogenic systemic fibrosis, which resembles scleromyxedema.

The risk for both gadolinium deposition disease and nephrogenic systemic fibrosis appears to be higher with gadolinium agents with linear chelating agents than with macrocyclic chelating agents. In the macrocyclic agents, the chelate is a ring structure with four nitrogen atoms that bind to the Gd3+ ion. The macrocyclic agents tend to bind more tightly to the Gd3+ ion, which is believed to be why they show a better toxicity profile than most linear GBCAs.

However, risks also vary among gadolinium agents in the linear and macrocyclic classes. To date, no prospective studies have linked gadolinium deposition disease to any adverse health effects, although there are anecdotal reports of headache, pain, and other symptoms after GBCA administration, according to Dr. Mahesh and his coauthors.

The European Medicines Agency in July 2017 said there was no evidence that gadolinium accumulation has harmed patients, but moved to suspend the marketing of several linear GBCAs seen as most likely to build up in the body and to reduce use of others.

The U.S. Food and Drug Administration has taken a different tack, opting to educate patients with the information needed to participate more in the selection of agents for their MRI tests. In 2017, the FDA required that patients receive a medication guide when physicians order MRIs with GCBA. The FDA statement notes gadolinium remains “in patients’ bodies, including the brain, for months to years after receiving these drugs. Gadolinium retention has not been directly linked to adverse health effects in patients with normal kidney function, and we have concluded that the benefit of all approved GBCAs continues to outweigh any potential risks.”

“It is not known how gadolinium may affect you, but so far, studies have not found harmful effects in patients with normal kidneys,” the FDA says in the medication guide. “Rarely, patients have reported pains, tiredness, and skin, muscle or bone ailments for a long time, but these symptoms have not been directly linked to gadolinium.”

The FDA statement advises physicians to “minimize repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, do not avoid or defer necessary GBCA MRI scans”.

The FDA also has asked the makers of GBCAs to conduct further research in animals and humans to see if there are any ill effects from the accumulation of this metal.

Stanley L. Cohan, M.D., PhD, who is medical director for the Providence Multiple Sclerosis Center in Portland, Oregon, said good scientific studies of potential risks from gadolinium are needed, but stressed that MS patients should not be scared away MR scans, which are a valuable diagnostic tool.

“What I’d love to see actually are some studies done by biologists on the effect of this molecule on nerve function and on nerve structure. To my knowledge, there are no such studies,” Dr. Cohan said.

The frequency of gadolinium scans needs to be examined, but these scans have aided notable advances in MS care in recent decades, he said.

Image credit: ZEPHYR/Science Source
Top image credit: ZEPHYR/Science Source

Dr. Cohan emphasized the importance of giving patients reliable information about the risks and benefits of scans. Various nonprofessional web sites fail to balance information on MR scans, he said. “I’m a little suspicious of where that’s all heading. And the only reason I really object is that it may frighten patients unduly.”

Yet, definitive answers about the safety or risk of gadolinium accumulation may prove elusive, said Susan A. Gauthier, DO, MPH, an MS specialist at Weill Cornell Medicine and New York-Presbyterian. People undergoing MR scans of the brain often already have a neurological disease. Still, there may be a path ahead, she said. The accumulation of gadolinium generally occurs within the basal ganglia and patients with multiple sclerosis typically do not exhibit symptoms related to this region.

“Therefore, potentially if patients began to experience extrapyramidal symptoms, which localize to the basal ganglia, we would say ‘Well, that’s unusual for MS, maybe that may be toxicity related’,” Dr. Gauthier said.

Dr. Susan A. Gauthier

Alternatives to the use of gadolinium in MR scans are being studied for tracking MS lesions. Dr. Gauthier and her colleagues, for example, recently receive a grant from the National Institutes of Health for research into using quantitative susceptibility mapping (QSM) as a potential alternative method for tracking MS lesions.

Still, Dr. Gauthier noted that MR scans with GBCAs are needed to obtain more detailed information about the brain in MS patients. The scans can detect worsening of disease even when patients report feeling well.

Just as regular glucose monitoring allows patients with diabetes and their physicians to head off serious complications, it’s the MRI that provides the check on otherwise unnoticed worsening of MS, she added.

MRI has transformed the ability to diagnose patients very early,” she said. “In the past, we used to have to wait for people to have two relapses, and there could be 5 or 10 years between a relapse. In the meantime, those patients are accumulating inflammatory lesions.

“MRI has transformed the ability to diagnose patients very early,” she said. “In the past, we used to have to wait for people to have two relapses, and there could be 5 or 10 years between a relapse. In the meantime, those patients are accumulating inflammatory lesions.“

“The ability to do an MR scan at the time somebody is having their first symptom has allowed us to start treatment very early on and we feel that that is really the best chance to influence a patient’s ultimate disease course,” Dr. Gauthier said. “The inflammatory activity in the first couple of years seems to be the most influential as far as the impact on long-term disability.”

The introductions of new MS drugs in recent years have allowed the creation of new goals, referred to as NEDA for “no evidence of disease activity.” This means no new relapses, no progression and no new activity detected by MRI, said Kathleen Costello, MS, ANP-BC, who is the associate vice president for clinical care for the National MS Society.

NEDA “doesn’t tell the whole story, as it does not specifically address important symptoms such as cognitive function, but it can indicate that the person is having a positive response to whatever treatment they are taking,” Ms. Costello said.

She urged reviewing the MRI guidelines developed by the Consortium of Multiple Sclerosis Centers.

Ms. Kathleen Costello

There are situations where gadolinium is very helpful, but there may be other situations where it is it not needed, such as the case of a patient whose condition appears to be stable, she said.

“This is part of shared decision making. If patients have the information about the use of gadolinium as well as information on the accumulation of gadolinium, then they can have an informed conversation with their healthcare provider,” Ms. Costello said. “That’s a conversation that I think should happen.”

Click here to review the 2018 Revised Guidelines of the Consortium of MS Centers MRI Protocol for the Diagnosis and Follow-up of MS

Dr. Gauthier currently receives industry funding for research from Genzyme and Mallinckrodt.

Dr. Mahesh, Dr. Cohan, and Ms. Costello reported having no relevant financial disclosures for this article and subject.