New Gadolinium Data Contrast With Concern Over Brain Effects

Ingrid Hein

May 05, 2017

NEW ORLEANS — Children with cancer who receive five to 15 half doses of the intravenous gadolinium-based contrast agent gadobenate show no evidence of gadolinium deposition in the brain, according to a new study.

These results are in contrast to reports that gadolinium accumulates in the brain, which have recently dogged the contrast agent. In fact, earlier this year, because of increasing alarm over the possible risk of deposition in the brain, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee recommended suspending marketing authorization for four contrast agents that contain gadolinium.

As the Swiss scientist Paracelsus explained, "the right dose differentiates a poison from a remedy," Günther Schneider, MD, from Saarland University Medical Center in Homburg, Germany, said here at the American Roentgen Ray Society 2017 Annual Meeting.

Unlike other contrast agents, gadobenate effectively enhances images even when you use less of it. "A half dose had the same effect as a full dose of the other contrast agents," he told Medscape Medical News.

Even in patients undergoing chemotherapy, which is known to cause a blood–brain barrier disruption, we did not see a difference, he reported. "We feel pretty safe using it in the MRI workup of our patients."

Lower Dose, Less Risk

Dr Schneider and his colleagues looked at the use of gadobenate dimeglumine (MultiHance, Bracco) for diagnosis and therapy monitoring in 34 pediatric oncology patients.

The 17 girls and 17 boys, with a mean age of 7 years, received five to 15 half-dose injections (0.05 mmol/kg body weight) during MRI over a period of 9 months to 7 years.

The control group consisted of 24 pediatric patients — eight girls and 16 boys, with a mean age of 8 years — who had not been exposed to gadobenate.

Investigators compared the two groups to see if high signal intensity in certain brain areas (primarily the dentate nucleus and globus pallidus) could be identified on unenhanced T1-weighted spin-echo images.

The images, taken 4 weeks after the final injection, were read by five independent readers. The readers looked at signal intensity in the dentate nucleus, globus pallidus, pons, and thalamus in the two groups. The researchers used unpaired t-tests to compare signal-intensity values and nucleus–pons and globus pallidus–thalamus signal-intensity ratios between the two groups.

The difference in signal-intensity values was not significantly different between the gadobenate and control groups. Even patients who received 15 injections over 6 years had no increases in signal intensity, the researchers report.

Table. Signal Intensity Values

Region of the Brain Gadobenate Group Control Group
Dentate nucleus 366.4–389.2 368.3–374.3
Globus pallidus 360.5–392.9 377.0–383.4
Pons 370.5–374.9 364.4–385.4
Thalamus 356.9–371.0 363.2–376.8


Even though we didn't see any gadolinium 4 weeks after the last injection, "that's not to say gadolinium isn't there," said Dr Schneider.

It is important to use the contrast agent only when necessary, and when the benefits outweigh the risks, he explained. "We still don't know the effects. We still have to find out what chemical structure we have with gadolinium deposition in the brain."

However, he pointed out that no gadolinium has ever been found inside the neurons. "Direct neurotoxicity would be caused when something enters the neuron; up until now, we don't see any evidence of harm."

Confusion About Contrast Agents

There is a lot of confusion about the safety of contrast agents, said Dr Schneider.

Previous research has shown that gadolinium is associated with nephrogenic systemic fibrosis in patients with acute or chronic renal insufficiency. Gadolinium was still used after these findings were published, but not in adult patients with low renal function. No evidence of other adverse effects has ever been shown.

More recently, however, gadolinium deposits were found in the brains of autopsied patients, as reported by Medscape Medical News.

Other studies have also found depositions in the brain, including one on the safety of gadoterate meglumine (Dotarem). "That's considered the most stable agent, and the researchers saw deposition with it," Dr Schneider reported.

Still, he asserted, if used when necessary in patients with a tumor that needs to be followed, the benefits of enhancing images with a contrast agent outweigh the risks.

"Giving contrast agents when it doesn't give you additional information should be avoided," he said. "But when you need to see enhancement, that changes a patient's therapy."

And with a lower dose, the risks are much lower. Even with nephrogenic systemic fibrosis, most of the cases had received very high doses of gadolinium. "Only very few were seen with a standard dose, already showing us that dosing is important for any kind of side effects," said Dr Schneider.

"The most important question is, does it do any harm?" he said. "Until now, we haven't seen any, but we still don't know enough about it."

The most important question is, does it do any harm?

"This was a first pass at opportunistic data that were extracted from patients already undergoing scans," said Dennis Shaw, MD, from the Seattle Children's Hospital. "But we need to do further investigation. We have very little data."

"It's such a useful agent that we should understand it well, because we need it," he pointed out. "We don't see any clear adverse effects at present, but obviously we need to proceed with an abundance of caution here because our patients are going to be living a long time with whatever we do."

Dr Schneider and Dr Shaw have disclosed no relevant financial relationships.

American Roentgen Ray Society (ARRS) 2017 Annual Meeting: Abstract 2912. Presented May 3, 2017.

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