Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authorizations for 4 Linear Agents

Abstract

For magnetic resonance, the established class of intravenous contrast media is the gadolinium-based contrast agents. In the 3 decades since initial approval, these have proven in general to be very safe for human administration. However, in 2006, a devastating late adverse reaction to administration of the less stable gadolinium-based contrast agents was identified, nephrogenic systemic fibrosis. The result of actions taken by the European Medicines Agency and the US Food and Drug Administration, stratifying the agents by risk and contraindicating specific agents in severe renal dysfunction, has led to no new cases being identified in North America or Europe. Subsequently, in 2014, long-term deposition in the brain of gadolinium was first shown, after administration of 2 nonionic linear chelates, gadodiamide, and gadopentetate dimeglumine. This has led to an intense focus on the question of in vivo distribution, possible dechelation, and subsequent deposition of gadolinium, together with substantial clarification of the phenomenon as well as stratification of the agents on this basis. This review focuses on 8 critical questions regarding gadolinium deposition in the brain and body, with the answers and discussion therein important for future regulatory decisions and clinical practice. It is now clear that dechelation of gadolinium occurs in vivo with the linear agents and is responsible for this phenomenon, with key experts in the field recommending, except where there is no suitable alternative, a shift in clinical practice from the linear to macrocyclic agents. In addition, on March 10, 2017, the Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency recommended suspension of the marketing authorization for 4 linear gadolinium contrast agents-specifically Omniscan, Optimark, Magnevist, and MultiHance (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine)-for intravenous injection. Cited in the report was convincing evidence of gadolinium deposition in the brain months after injection of these linear agents. Primovist/Eovist (gadoxetic acid disodium) will remain available, being used at a lower dose for liver imaging, because it meets an important diagnostic need. In addition, a formulation of Magnevist for intra-articular injection will remain available because of its very low gadolinium concentration.

Intrapatient Comparison of the Hepatobiliary Phase of Gd‐BOPTA and Gd‐EOB‐DTPA in the Differentiation of Hepatocellular Adenoma From Focal Nodular Hyperplasia

“…Although the biases were substantial, we found that our findings (in all but one incongruent lesion Gd‐EOB‐DTPA was finally correct) are still significant enough to change our policy to the preferential use of Gd‐EOB‐DTPA. Even though a prospective study using both contrast agents in the same patients would help confirm our current findings, we would have considerable ethical difficulty with this approach in light of the current discussion concerning linear contrast agents and deposition in the brain …”

“…One might argue that, besides HBP, imaging diagnosis of these benign entities is generally based on a combination of all imaging parameters. In most circumstances, final diagnoses can be reached based only on typical findings . Although the aim of our study was to specifically clarify the utility of HBP in establishing a final diagnosis, future studies could address the question of the relative importance of HBP compared with other imaging parameters in typical cases.…”

Analysis of retention of gadolinium by brain, bone, and blood following linear gadolinium‐based contrast agent administration in rats with experimental sepsis

“…No adverse clinical or pathological consequences of Gd deposition in the brain have thus far been confirmed . However, precautionary recommendations have been made in the use of linear GBCA by professional organizations and the Food and Drug Administration . At a recent international workshop of experts held at the National Institutes of Health, the current state of knowledge regarding Gd deposition from GBCA was reviewed and the importance of identifying populations of patients who may be vulnerable to deposition of Gd from GBCA was acknowledged …”

“…The significance of this concern has been challenged by the broad radiology community and lack of current clinical evidence of deleterious effects . However, linear GBCA have been largely withdrawn in Europe in favor of macrocyclic agents, which do not undergo dechelation . The Food and Drug Administration has issued warnings regarding the use of GBCA in potentially vulnerable populations, such as children and those with blood–brain barrier (BBB) disruption .…”

One‐millimeter isotropic breast diffusion‐weighted imaging: Evaluation of a superresolution strategy in terms of signal‐to‐noise ratio, sharpness and apparent diffusion coefficient

“…Breast MRI is based on the dynamic contrast enhanced (DCE) technique with gadolinium injection in order to differentiate neoangiogenesis in malignant lesions from benign lesions . However, recent studies have questioned the use of external contrast agent, including its deposition in the brain or its adverse reaction in patients with renal failure . A screening of high‐risk women has to be performed by breast MR every year and the long‐term impact of these deposits on cognitive functions is still unknown.…”