Japanese research linking brain MR imaging irregularities with one of two common contrast agents raises the possibility that a toxic component of the agent may remain in the body long after administration. However, leading U.S. experts on MR imaging contrast media say larger trials are necessary and that the research is not definitive in any sense.
The study published in the November 2013 issue of Radiology focused on patients who had received gadolinium-based contrast agents (GBCAs) for brain MR imaging studies. GBCAs have enabled significant improvements in diagnostic imaging since their arrival in the late 1980s, but the gadolinium ion itself is toxic and must be bound with non-metal ions for safe use.
Lead author Tomonori Kanda, M.D., Ph.D., of Teikyo University School of Medicine in Tokyo and the Hyogo Cancer Center in Akashi, Japan, and colleagues compared unenhanced T1-weighted MR brain images of 19 patients who had undergone six or more contrast-enhanced brain studies with 16 who had six or fewer unenhanced exams. Researchers found areas of hyperintensity on MR images in two brain regions: the dentate nucleus (DN) and globus pallidus (GP). The hyperintensity of both DN and GP correlated with the number of GBCA administrations.
“Our data suggest that MRI hyperintensity in regions of the brain was associated with gadoliniumbased contrast agents,” Dr. Kanda said. “Because gadolinium has a high signal intensity in the body, our data may suggest that toxic gadolinium remains in the body for a long time, even in patients with normal renal function.”
Nevertheless, Dr. Kanda emphasized that there is currently no proof that gadolinium is responsible for hyperintensity on brain MR imaging. Further research based on autopsy specimens and animal experiments will be needed to clarify the relationship and determine if the patients with MR imaging hyperintensity in their brains have symptoms.
“Because patients who have multiple contrast material injections tend to have severe diseases, a slight symptom from the gadolinium ion may be obscured,” Dr. Kanda said.
There are two types of GBCA—linear and macrocyclic—with distinct chemical compositions. Since the patients in the study received only the linear type, additional research is needed to see if the macrocyclic type can prevent MRI hyperintensity, according to Dr. Kanda.
U.S. experts are paying close attention to the research but stress that the clinical significance of the study has yet to be determined. “These findings are nothing to panic or overreact about, but they merit attention and further investigation,” said Jeffrey C. Weinreb, M.D., of Yale University School of Medicine in New Haven, Conn., and presenter of an RSNA 2013 session on MR contrast safety. “The clinical significance of this research will be a big question going forward.”
Because of the enormous value of GBCAs to medicine, additional research is critical, said Emanuel Kanal, M.D., chairman of the American College of Radiology MR Safety Committee from 2002-2012 and a leading authority on MR contrast agents from the University of Pittsburgh Medical Center. Initially developed for detecting disease in the brain and spinal cord, GBCAs are now used for imaging throughout the body and are a key component of MR angiography.
“If the potential benefits of GBCA were small, people would say, ‘forget it, it’s not worth using it,’” Dr. Kanal said. “But society needs these agents. Patients need to know that the markedly increased sensitivity afforded by GBCA is available for them, but they also need to be assured that it’s safe. A theoretical loss of GBCA would represent a major blow to diagnostic medicine.”
Dr. Kanal suggested that pharmaceutical companies who manufacture GBCAs simultaneously spearhead retrospective and prospective studies on much larger populations to determine whether the effects reported by Dr. Kanda are associated with each of the GBCAs—and if they are associated with them equally.
“This is a perfect time to study these contrast agents and make sure that there are no unanticipated harmful effects down the road—especially any that may be related to inadvertent and previously unanticipated gadolinium accumulation dynamics,” Dr. Kanal said.
Meanwhile, Dr. Kanda is expanding his research to study patients who received the macrocyclic type of GBCA. He also is looking to confirm the initial results of his Radiology research through post-mortem examination.
“I am now using inductively coupled plasma mass spectrometry to evaluate the dentate nucleus of autopsy specimens,” Dr. Kanda said. “Because our studies were only on imaging data, this approach may prove gadolinium deposition in the brain.”
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