February 24, 2019 – Researchers from Finland, led by Dr. Aida Kiviniemi, found that gadolinium deposits can be detected in both enhancing and non-enhancing gliomas, adjacent normal brain tissue, and necrosis.  The authors said that to their knowledge, “this is the first study to provide quantitative data of gadolinium retention in gliomas and neighboring normal brain with respect to tumor enhancement and type of GBCA used”.   “The levels of gadolinium in the tumor and normal brain correlated suggesting a possible transit of gadolinium to the surroundings of the brain lesion.  The most powerful predictor of gadolinium retention was the type of GBCA administered with significantly higher gadolinium accumulation detected with linear (gadodiamide and gadopentetate dimeglumine) relative to macrocyclic (gadoterate meglumine and gadobutrol) agents.”  The study, Gadolinium retention in gliomas and adjacent normal brain tissue: association with tumor contrast enhancement and linear/macrocyclic agents, was recently published online in Neuroradiology.

The retrospective study included 69 patients with primary glioma who underwent contrast-enhanced magnetic resonance imaging (MRI) prior to surgery.  Gadoterate meglumine (Dotarem, Guerbet) was used in 60 patients, gadobutrol (Gadovist, Bayer Healthcare) in 2, gadodiamide (Omniscan, GE Healthcare) in 4, and gadopentetate dimeglumine (Magnevist, Bayer Healthcare) in 3 patients.  None of the patients suffered from renal failure.  The researchers concluded that gadolinium retention is higher after exposure to linear gadolinium-based contrast agents (GBCAs) Omniscan and Magnevist compared with the macrocyclic agent Dotarem.

Gadolinium was measured from histologically viable tumor, normal brain, and necrosis within the sample, when available.  Gadolinium was detected in 39 of 69 (57%) tumor samples, 8 out of 13 (62%) normal appearing brain samples, and 12 out of 14 (86%) necrotic tissue samples.  The researchers found that gadolinium deposits were highest in gliomas with noticeable contrast enhancement and in patients who received a linear GBCA, rather than a macrocyclic GBCA.  The authors noted that “7 out of 21 (33%) patients with non-enhancing gliomas showed detectable gadolinium”.  Among these, 6 had received Dotarem and 1 Gadovist, respectively.

Of the 8 patients with gadolinium detected in normal brain tissue, 2 had received the linear agent gadodiamide (Omniscan), and 6 the macrocyclic agent gadoterate meglumine (Dotarem).  The gadolinium concentration was significantly higher after exposure to the linear agent compared to the macrocyclic agent.  Gadolinium in necrotic specimens was also significantly higher after exposure to the linear agent Omniscan compared with the macrocyclic agent Dotarem.

The authors noted that gadolinium deposition in normal brain tissue has been reported in autopsy studies, but “the exact mechanism behind the retention in normal brain remains unsolved”.  “A small but significant correlation between the amount of gadolinium in the tumor and normal brain was detected implying passage of gadolinium from the site of pathologic brain lesion. While further studies are needed to confirm this association, an interesting question arises whether gadolinium transverses from the region of brain lesion to neighboring sites in other brain abnormalities such as ischemia, infection, or multiple sclerosis.”

My thoughts

This study adds to a growing body of research that reports finding evidence of gadolinium deposition in tumors and normal brain tissue of patients without severe renal disease.  While the concentration of gadolinium is usually significantly higher after administration of a linear GBCA than it is with a macrocyclic GBCA, all GBCAs appear to leave deposits of gadolinium in brain tissue.  Gadolinium from macrocyclic agents was detected in non-enhancing gliomas; this seems to indicate that seeing no enhancement on brain MRIs performed with a macrocyclic agent does not mean there is no gadolinium in the patient’s brain, even when a tumor is present.  Both the linear agent Omniscan and the macrocyclic agent Dotarem were found to deposit in normal brain tissue in this study.

As of now, the clinical significance of gadolinium deposition in various regions of the brain is still unknown.  Despite not having any proof of harm caused by brain deposition, in 2017, the European Medicines Agency (EMA) recommended suspending the use of certain linear GBCAs due to gadolinium accumulation.  However, as of 2/24/2019, the US Food and Drug Administration (FDA) has not suspended the use of any gadolinium-based contrast agents; the FDA requires that all GBCAs carry a warning label and patients receive a Patient Medication Guide prior to their MRIs with contrast.

Brain deposition of gadolinium, including in patients with normal renal function, is well-documented.  Due to gadolinium’s toxic effects, I believe it is imperative for patient safety that the clinical significance of gadolinium deposition in the brain, and elsewhere in the human body, is determined as soon as possible.  It will require the expertise of more than just Radiologists to make that determination.

Sharon Williams
_____________________________________________________________
References
Kiviniemi, A., Gardberg, M., Ek, P., Frantzén, J., Bobacka, J., & Minn, H. (2019). Gadolinium retention in gliomas and adjacent normal brain tissue: association with tumor contrast enhancement and linear/macrocyclic agents. Neuroradiology. http://doi.org/10.1007/s00234-019-02172-6

EMA (2017) EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans. In: https://www.ema.europa.eu/documents/press-release/emas-final-opinion-confirms-restrictions-use-linear-gadolinium-agents-body-scans_en.pdf

FDA (2017) FDA drug safety communication: FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings. In: https://www.fda.gov/Drugs/DrugSafety/ucm589213.htm