Gadolinium-based contrast agents (GBCAs) are the only approved class of drugs for use with MRI in the United States.
There has been increasing concern among radiologists about potential legal exposure from its use. Several patients have come forward reporting adverse effects and there have been some high-profile cases, including a recent lawsuit that was dropped by Chuck Norris and his wife, Gena.
For radiologists this begs the questions; should we continue to use gadolinium-based agents? Are we putting ourselves at risk of legal exposure if we do so? Based on the current research, here’s what we know:
What is gadolinium retention?
Gadolinium is the metal found in all GBCAs, which are used as contrast agents for different types of MRI (largely neuro, vascular and liver). It has been found that small amounts of gadolinium may be retained in the body, including the brain, bones, skin and other parts. The period of retention may be months to years.
A 2017 FDA communication found that all forms of GBCAs were associated with the retention, although they found no evidence of harm caused. They acknowledged that there is ongoing research into the effects of gadolinium retention and that some patients are at greater risk of retention or reported side effects than others.
Those at increased risk of reported side effects include people who undergo multiple doses, pregnant women and young children.
The FDA adds: Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist, or MultiHance. Gadolinium stays in the body the least after Dotarem, Gadavist, or ProHance.
Reported side effects
Gadolinium-based contrast agents have been used in MRI for over 30 years now. It was in 2016 that the term “gadolinium deposition disease” was first described:
“In 2016, Semelka et al first described a constellation of self-reported symptoms in patients with normal renal function who had received GBCAs. Suggesting causation from correlation, the authors postulated this symptomatology to represent GDD and went on to propose diagnostic criteria for this newly proposed disease. To meet the diagnostic criterion for GDD, a patient must exhibit at least three of the following five broad symptom clusters within a period of hours to 2 months post-GBCA administration: (1) peripheral neuropathic pain in either a “glove and stocking” or generalized distribution; (2) joint stiffness, muscle spasms, buzzing sensation, and fatigue; (3) headache; (4) clouded mentation; and (5) distal extremity and skin substrate thickening, discoloration, and pain. Furthermore, it was proposed that GDD may clinically manifest after the initial infusion of GBCA or after multiple administrations in a dose-dependent manner.”
At this stage, GDD is still a proposed disease with further research being undertaken, however, since the disease was proposed, there has been a rash of lawsuits from patients who feel that they meet the criteria for the disease.
While FDA’s official position is still that GDD cannot be proven (or disproven) yet, they now require imaging centers to distribute literature informing patients of potential gadolinium risk. The European Medicines Agency went further by restricting the use of certain types of GBCAs.
There is significant confusion for both medical practitioners and patients because while regulatory bodies have issued these requirements, they’ve at the same time convened regulatory scientific panels who have made statements of “no causality.”
What can imaging centers do?
One thing that has radiologists nervous is that people often misconstrue a tendency for caution with an acknowledgment of causation. This creates an environment where they fear legal exposure.
First of all, at this stage, the only known and proven disease cases from GBCAs are nephrogenic systemic fibrosis in patients with impaired renal function. As such, FDA mandated black box warnings and advised caution with those patients. They report that there are no known harmful effects in patients with normal kidneys.
Secondly, distribute the literature and have conversations with patients based on what has been proven thus far. While there is a possibility of some or all of the listed side effects coming to fruition, that must be weighed up against the risk of not getting a clear enough image for accurate diagnosis. For example, FDA points out that “MRI with GCBA helps your doctors to see problems better than MRI without GCBA.”
Thirdly, having thorough knowledge of the different types of GCBAs and when to use them is a good practice. Class I GCBAs (or linear agents) such as Eovist, Omniscan or OptiMARK are associated with the highest levels of gadolinium retention. On the other hand, macrocyclic GCBAs such as Dotarim or Gadavist are associated with the least retention. Specifically, Gadoteridol has been associated with the very lease gadolinium retention on the brain. The chart below is from FDA:
We still await more data and research on any side effects of gadolinium retention, so perhaps an approach that looks to apply the least risk of retention first is a good step. Here’s a thought to conclude from a recent RSNA annual meeting:
“This is a nice time for radiologists to become more active in the decision-making about how these (agents) are chosen,” said H. Benjamin Harvey, MD, a neuroradiologist at Massachusetts General Hospital in Boston and assistant professor of radiology at Harvard Medical School. “My opinion is at this point, there’s too much industry thought; there’s too much marketing influence and there’s too many side deals that might be leading to one being chosen over another, not a data-driven approach.”