Study Addresses Use of GBCAs in Multiple Sclerosis Patients

A comprehensive, longitudinal study of MS patients that followed them from the time of their diagnosis for an average of five years, has found that while gadodiamide does accumulate in the brain early in the disease, there is no discernible clinical impact.

At the same time, the study found that there were some indications of greater disease severity in patients who had undergone more magnetic resonance imaging (MRI) studies using these agents.

The findings, published July 8 in the online issue of Neurology, the medical journal of the American Academy of Neurology, are the result of work conducted by researchers at the Jacobs School of Medicine and Biomedical Sciences. It is the latest research to address the ongoing controversy in the MS community about use of gadolinium-based contrast agents, known as GBCAs.

Free gadolinium is highly toxic, and for clinical use, it has to be complexed with chelating molecules. There are different types of GBCAs — linear and macrocyclic are the two most frequently used — and structural differences in the molecules can impact their stability.

Recently, a general consensus has emerged that linear, but to a lesser extent macrocyclic GBCAs, are associated with the development of gadolinium deposition in the brain.

GBCAs are powerful contrast agents that are injected in many MS patients undergoing MRI on a routine basis, in order to better detect acute inflammation and other signs of disease progression in the brain.

Four of those agents have been banned in Europe and in 2017 the U.S. Food and Drug Administration recommended that GBCAs only be used in certain cases when deemed absolutely necessary.

“Our data could become an important reference contributing to regulatory decisions about the use of GBCA in MS,” says Robert Zivadinov, MD, PhD, professor of neurology and senior author on the paper. He also directs UB’s Buffalo Neuroimaging Analysis Center (BNAC) and the Center for Biomedical Imaging at UB’s Clinical and Translational Science Institute.

Many studies have found depositions of these contrast agents in the brains of patients who have undergone multiple repetitive scans. But no previous, large, case-control, longitudinal study followed MS patients since their first clinical sign of the disease.

In contrast, the UB study followed 203 MS patients from the time they were diagnosed with MS, and all were followed in the BNAC at some point between 2003 and 2016. They all received identical doses of GBCA exclusively on the same MRI at Buffalo General Medical Center.

“This study is one of the first to investigate the longitudinal association between well-established clinical and MRI outcomes of disease severity and gadolinium deposition,” Zivadinov says. “The findings from this study should be incorporated into a risk-versus-benefit analysis when determining the need for GBCA administration in individual MS patients.”

Of special concern, the Jacobs School authors note, are areas of high intensity within some brain regions that have been identified in patients receiving GBCAs.

“But is it the gadodiamide creating the hyperintensity or is it the disease progression?” The study’s main finding was that there was no clear association between GBCA deposition in the brain and development of disease progression.

“The study didn’t find any correlation between deposition in the brain and clinical or MRI outcomes, such as accumulation of lesions, brain atrophy or disease severity, at least in the first five years of the disease,” Zivadinov explains. “Over the 4.5 years of follow-up, we didn’t find that GBCA deposition contributed to patients being more disabled.”

This study also was the first to study GBCA in MS patients in comparison to such a large group of healthy controls — 262.

Because of blood-brain barrier disruption that can be characteristic of MS — and because these agents are administered more frequently to MS patients — Zivadinov notes that they may be more susceptible to accumulating gadolinium in their brains.

The results showed similar GBCA deposition in MS patients who had between five and eight doses of gadodiamide, while patients with fewer than five doses behaved similarly to healthy controls.

At the same time, 8.9 percent of MS patients who received fewer than five doses did have hyperintensity in the part of the brain — called the dentate nucleus — involved in voluntary motor function and cognition, which is often affected by MS; none of the healthy controls did.

And while there was no discernible clinical impact, the researchers did find that patients who received more than eight GBCA doses had more brain lesions and more advanced atrophy of gray matter, compared to patients who had fewer than eight doses.

“Therefore, we cannot completely rule out that gadolinium deposition may have an impact on disease progression or clinical outcome,” Zivadinov says.

One unusual finding of the study was that it found more gadolinium deposition in male patients than in female patients, a finding that Zivadinov says is of interest, but should be interpreted with caution.

He notes that one possible explanation is that males receive a higher dose because they tend to weigh more and dosage is based on weight.  

Patients in the study were treated through UBMD Neurology.

Study co-authors from the Jacobs School are:

• Niels P. Bergsland, PhD, research assistant professor of neurology
• Michael G. Dwyer III, PhD, assistant professor of neurology and biomedical informatics
• Jesper Hagemeier, PhD, senior biostatistician and research scientist at BNAC
• David W. Hojnacki, MD, associate professor of neurology
• Channa M. Kolb, MD, assistant professor of neurology
• Deepa Preeti Ramasamy, MD, clinical trial neuroimager at BNAC
• Ferdinand Schweser, PhD, assistant professor of neurology and biomedical engineering
• Bianca Weinstock-Guttman, MD, professor of neurology