The gadolinium chelates (the GBCAs) are critical to disease diagnosis by MR, indeed to clinical medicine worldwide, and have proven to be overall a very safe class of contrast media. This review focuses on the current knowledge regarding accumulation of gadolinium in the brain (dentate nucleus and other structures) and body, with clinical recommendations based on that and other safety data, including in depth discussion of the European Medicines Agency (EMA) ruling. Also, it is important to recognize that the discussion of dechelation and long term deposition in the brain and body of insoluble Gd and Gd bound to macromolecules (not as the injected chelate) involves only the linear Gd chelates.
The established class of intravenous contrast media for magnetic resonance imaging is the gadolinium chelates, often referred to as the gadolinium-based contrast agents (GBCAs). These can be differentiated on the basis of stability in vivo, with safety and tolerability of the GBCAs dependent fundamentally on chemical and biologic inertness. This review discusses first the background in terms of development of these agents and early safety discussions (including hypersensitivity/allergic reactions), and second their relative stability based both on in vitro studies and clinical observations before and including the advent of nephrogenic systemic fibrosis (NSF). This sets the stage for the subsequent focus of the review, the current knowledge regarding accumulation of gadolinium in the brain and body, and specifically the dentate nucleus after intravenous administration of the GBCAs and differentiation amongst agents on this basis. The latest information in regard to evaluation of possible clinical symptomatology, and studies of cellular toxicity in vitro will also be included. Brief note will be made of possible alternative agents, which are very unlikely to be developed due to cost, toxicity, and the time required.
“The gadolinium chelates (the GBCAs) are critical to disease diagnosis by MR, indeed to clinical medicine worldwide, and have proven to be overall a very safe class of contrast media.”(1) However, the information available to date, from the initial conception of these agents in 1981 to the latest reports concerning safety, reveals a major difference between the macrocyclic and linear chelates. Specifically, Omniscan, Optimark, Magnevist, MultiHance and Primovist/Eovist (all being linear gadolinium chelates) are now known to be associated with dentate nucleus hyperintensity, specifically high signal intensity within the dentate nucleus on T1-weighted scans seen pre-contrast after multiple prior contrast injections. Dotarem, Gadovist and ProHance, the macrocyclic chelates, are not so associated.(2) It should be noted that of the linear gadolinium chelates, Primovist/Eovist has the lowest deposition, likely due to a combination of factors including lower injected dose and higher stability. Dentate nucleus hyperintensity is likely to reflect more general gadolinium deposition throughout the body (and specifically in the skin and bones), in these patients with normal renal function. In patients receiving a very high number of injections of the linear agents, hyperintensity is also observed in many other nuclei and structures within the brain. Initial reports suggest possible clinical symptomatology. The European Commission ruled in November 2017 to suspend the whole body marketing authorizations of the multi-purpose linear GBCAs (Omniscan, OptiMark, Magnevist, MultiHance). The approval for the macrocyclic (Gadovist, ProHance, Dotarem) agents remains unchanged, with continued approval - at this time, for special indications - three linear GBCAs (Primovist and MultiHance specifically for delayed liver imaging only and Magnevist 2 mmol/L for intra-articular use). This followed the March 10, 2017 recommendation of the Pharmacovigilance and Risk Assessment Committee (PRAC) of the European Medicines Agency (the equivalent of the FDA in Europe).(3) Cited in the report was convincing evidence of gadolinium deposition in the brain months after injection of the linear agents. These recommendations were based on an extensive review of the safety of the gadolinium agents that began in March 2016. A further update is contained in the publication “Dechelation (Transmetalation) - Consequences and Safety Concerns With the Linear Gadolinium-Based Contrast Agents, In View of Recent Health Care Rulings by the EMA (Europe), FDA (United States), and PMDA (Japan).”(4) “Given the concern with gadolinium deposition, use of exclusively the macrocyclic agents is advocated for CNS and body imaging. Two agents exist with hepatobiliary properties, with both linear in nature. This clinical application is important,” suggesting continued use restricted to delayed liver imaging.
1. Runge VM. Commentary on T1-Weighted Hypersignal in the Deep Cerebellar Nuclei After Repeated Administrations of Gadolinium-Based Contrast Agents in Healthy Rats: Difference Between Linear and Macrocyclic Agents. Invest Radiol. 2015;50(8):481-2.
2. Runge VM. Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus. Invest Radiol. 2016;51(5):273-9.
3. Runge VM. Critical Questions Regarding Gadolinium Deposition in the Brain and Body - Reflecting Possible Safety Issues - Following Injections of the Gadolinium-based Contrast Agents, with Clinical Recommendations and Reflection upon the EMA’s Pharmacovigilance and Risk Assessment Committee (PRAC) Recommendation for Suspension of the Marketing Authorizations for Four Linear Agents. Invest Radiol. 2017; 52(6):317-323.
4. Runge VM. Dechelation (Transmetalation) - Consequences and Safety Concerns With the Linear Gadolinium-Based Contrast Agents, In View of Recent Health Care Rulings by the EMA (Europe), FDA (United States), and PMDA (Japan). Invest Radiol. 2018; 53(10): 571–578.