Brain Gadolinium Deposition Varies With Contrast Agent in MS

Caroline Helwick  

May 25, 2017

NEW ORLEANS — For contrast-enhanced imaging in multiple sclerosis (MS), all gadolinium-based agents accumulate in body tissue but to greatly varying degrees. While the long-term effect of gadolinium deposition remains unknown, some experts recommend avoiding linear agents and using   gadolinium enhancement only occasionally.

"The concern is deposition of recognizable levels of gadolinium in the brain and bone, and we don't know what the long-term effects of that are…. But gadolinium is a safe agent when used with appropriate selection and with clinical indication," said Ken Maravilla, MD, professor of radiology and neurological surgery at the University of Washington, Seattle, and director of the Diagnostic Imaging Sciences Center MR Research Laboratory. 

"If we understand the basic physiology about how contrast agents work and how they differ, we can make a better judgment as to what's the better agents to use in our patients."  

At the Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting here, Dr Maravilla described safety concerns and indicated that of the two classes of gadolinium-based contrast agents (GBCAs), gadolinium deposition is much greater with linear agents than with macrocyclics. 

"Naysayers say that adverse long-term effects have not been seen. More cautious people, like myself, are saying that we don't yet know but this deposition is certainly worrisome," he said. "We think we should be cautious, especially when we have alternatives that are not medically different. In my opinion, we should use macrocyclics as much as possible."

A panel of MS specialists also addressed this topic in a press briefing. They agreed that with concern growing over gadolinium accumulation, clinicians should reserve gadolinium-enhanced MRI for select cases, and not use it for routine monitoring.

Recent Concern Over Gadolinium

The two types of GBCAs, linear and macrocyclic, have different chemical structures. Studies of their use have shown that, regardless of the agent's class, gadolinium is retained in the brain, bones, and skin — but greater deposition occurs with the linear GBCAs.  

Studies have not, however, identified adverse health effects related to this retention beyond the rare condition of nephrogenic systemic fibrosis (NSF) that can occur in patients with pre-existing renal insufficiency.

Three linear agents have accounted for 97% of NSF cases; these have been labeled group 1 agents by the US Food and Drug Administration (FDA) and they are considered contraindicated for patients with stage IV renal disease. These agents include gadodiamide (Omniscan, GE Healthcare), gadopentetate (Magnevist, Bayer), and gadoversetamide (OptiMArk, Guerbet).

"Restriction of group 1 GBCAs to patients with normal renal function has resulted in a marked decrease in the incidence of NSF, to virtually zero cases now," Dr Maravilla noted.

Of recent concern, however, are case reports of thickening and hardening of the skin and other tissues in patients with normal kidney function who received GBCAs and did not have NSF. Some of these patients demonstrated gadolinium retention. 

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency recently reviewed the data, and while it identified no adverse health effects, the Committee recommended suspending the marketing authorization of group 1 agents plus another linear agent not yet associated with NSF (gadobenate [MultiHance, Bracco]).   

Macrocyclics are much more "stable" in terms of "holding onto" the gadolinium so that it is not released into tissues, Dr Maravilla explained.  "But the linear agents basically dissociate almost immediately…. Ten times more gadolinium is released from the lower-stability agents, though in all cases it's a very tiny amount."

In autopsy specimens, Dr Maravilla's laboratory documented substantially higher deposition in the basal ganglia for linear agents vs macrocyclics. Approximately 58,000 ng/g tissue has been shown with linear agents, but only 78 ng was "left behind" by macrocyclics, he reported.

His group has also found 20 times more deposition in bone for the linear agents, which, considering the amount of bone mass in the body, could be another cause for concern, he added.  

The FDA and CMSC Weigh In

These developments led the FDA to begin investigating the potential risks associated with GBCAs. In a statement issued May 22, the FDA indicated that it had identified no adverse health effects of gadolinium retention in the brain; therefore, it did not recommend restricted use of GBCAs at this time.

The FDA did, however, suggest limiting GBCAs to "circumstances in which additional information provided by the contrast agent is necessary." 

MS experts at the press briefing supported this concept.

"The FDA concluded, after studying this issue for 2 years, that gadolinium does accumulate," said David K.B. Li, MD, professor emeritus of radiology and director of the MS/MRI Research Group at the University of British Columbia, Vancouver, Canada. "They have not found evidence of adverse effects, but the absence of evidence does not mean there is no harm. Use of gadolinium is important in MS diagnosis and monitoring, but it should be used judiciously."

In fact, "judicious use" of GBCAs will be a formal recommendation by the CMSC in its forthcoming 2017 guideline update for MRI use, according to Dr Li, who noted this is a change from the major guideline update of 2015, which promoted the routine use of gadolinium.

The 2017 MRI guideline update, still in development, will address the data on gadolinium safety and provide clinicians with benchmarks for when to use gadolinium enhancement, such as in a new diagnosis of MS and for unexplained breakthrough disease activity.

How Should Gadolinium Be Used?

Dr Maravilla and other experts felt the deposition of gadolinium is most worrisome for patients who receive multiple injections for one reason or another, and for children with MS, who will likely undergo multiple contrast-enhanced MRI exams over a lifetime. Dr Maravilla said he does not see a safety issue with its occasional use, "given the information we have now."

"In any discussion of the use of gadolinium, consider the risk versus the benefit — and one of the risks is not using it to get information in patients with a good clinical indication," he said.  

David E. Jones, MD, assistant professor of neurology at the James Q. Miller MS Clinic of the University of Virginia Health System in Charlottesville, agrees gadolinium is not always necessary and he encouraged clinicians "to know the question they are asking with the MRI."

If there is a need to identify new lesions, gadolinium enhancement does this, and it helps clinicians' time new disease activity, "but routine monitoring with gadolinium may not have as much value as most people think," he maintained.

With the recent public airing of these theoretical safety concerns, the occasional patient has questioned his use of gadolinium. Many more, however, have questioned his choice not to use contrast. 

"Some people with MS are very interested in what's going on with their MRIs, and validly so," Dr Jones said. "They are more likely to ask me, 'Are you sure you don't want to use gadolinium?'"  

Jerry Wolinsky, MD, emeritus professor of neurology at The University of Texas Health Science Center at Houston, told Medscape Medical News, "You have to have a working dialogue with your local neuroradiologist, who should be the one choosing the agent. We [neurologists] certainly could be recommending that we would prefer macrocyclics, especially in patients who are likely to be exposed to agents more than average, but often it's the hospital that makes decisions based on the cost of the compound," he said.

"Some radiologists, depending on how involved they are and how much they are following what their hospital pharmacy is doing, may not actually realize that they went for something that is perhaps theoretically not the safest, as opposed to what's a bit less expensive," Dr Wolinsky said. "They may not be following the field." 

Dr Maravilla has consulted for Guerbet and Bracco. Dr Li has consulted for Biogen-Idec, EMD-Serono, Genzyme, Novartis, Nuron Biotech, Opexa, and Vertex Pharmaceuticals. Dr Jones has consulted for Biogen-Idec and Genzyme.

Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting. Presented May 24, 2017.  

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