Editorial – I believe the FDA needs to do more to regulate the use of linear and macrocyclic gadolinium-based contrast agents administered for enhanced MRIs and MRAs.

Since January 2014, I am aware of nine studies that have reported finding evidence of gadolinium deposition within the brain tissues of patients exposed to gadolinium-based contrast agents or GBCAs.  In most of those studies, the patients did not have severe renal disease, in fact, most were described as having “normal renal function” or an eGFR >60.   Despite the increasing number of new studies that indicate that gadolinium is remaining in the brain, some still question whether there is any clinical significance.  Speaking as someone who has been adversely affected by retained gadolinium, I believe that there is clinical significance, and I am not alone.  Members of our MRI-Gadolinium-Toxicity support group have reported symptoms that are consistent with what is known about the toxic effects of gadolinium.  Since we released the results of our 2014 Survey of the Chronic Effects of Retained Gadolinium from Contrast MRIs, our support group has almost tripled in size and another affected patient recently started a group on Facebook.  I believe the problems related to gadolinium retention are significant, but they are not being recognized.

Gadolinium is a toxic metal.  It is neurotoxic.  It inhibits mitochondrial function and induces oxidative stress.  Like mercury and lead, gadolinium has been found to affect vascular reactivity, even at low doses or concentrations.  The free gadolinium ion (Gd3+) is a potent calcium channel blocker that can impact physiological processes that depend upon calcium (Ca2+) for proper function.  One GBCA was found to cause a proliferation of multiple myeloma cells.  Based on those facts, it would seem that any amount of gadolinium found within the brain, or elsewhere in the body, should be cause for serious concern.  (Works referenced are listed at end).

I first wrote to the FDA about issues related to gadolinium retention from GBCAs in October of 2012.  That is when I first shared personal accounts of other patients with normal renal function who had been adversely affected by retained gadolinium.  Long before the recently published studies reporting gadolinium retention in patients with normal renal function, patients had been trying to get someone to recognize that they were retaining gadolinium and suffering from the effects of Gadolinium Toxicity.  Those patients and others are still waiting to have their gadolinium-related health issues recognized and properly treated.

While the FDA and Radiology community decide how to deal with this serious issue, more unsuspecting patients are being put at risk of retaining gadolinium from their contrast-enhanced procedures.  I believe that doctors and patients need to be made aware that there are new concerns about MRI contrast agent safety beyond what has been published about NSF and gadolinium retention in the renally impaired.  They need to know that evidence of residual gadolinium has been found within patients’ brains after repeated administrations of a GBCA, regardless of the patient’s level of renal function at the time of his or her MRI with contrast.

If patients were truly fully-informed about the potential risks, and then still decided to have a contrast-enhanced MRI that would be their decision.  But how could anyone make a fully-informed decision when the professionals still do not have all the facts?  I believe that someone needs to determine, with some certainty, what long-term health risks are caused by varying amounts of retained gadolinium.

While a contrast-enhanced MRI might more clearly define diseased tissues, could the gadolinium left behind in the brain, and elsewhere in the body, put the patient at greater risk of disease progression or even lead to new health problems?  What are the long-term effects of a toxic metal like gadolinium on brain tissue?  Will residual gadolinium increase the risk of developing Alzheimer’s disease, Parkinson’s disease, or MS?  Do repeated contrast-enhanced MRIs, each of which appears to leave more toxic gadolinium in the brain, affect the progression of any ongoing disease process?  Are patients’ worsening symptoms being blamed on the disease or other condition that they have, when in fact, their symptoms have been caused by the toxic effects of the gadolinium they retained?  I believe that these are important questions that must be answered.

I realize that there is still much to be learned about how retained gadolinium might affect the brain and the rest of the human body.  However, as someone who is well-informed about gadolinium retention from GBCAs, I believe I have an obligation to speak up on behalf of all those patients who do not yet know about this potentially serious problem.

I understand that this is a difficult situation for members of the Radiology community, but it can become a catastrophic one for a patient that retains gadolinium in his or her brain or elsewhere in their body.

Based on what we know now about gadolinium retention from GBCAs, I believe the time has come for decisive action by the FDA.

To learn more about the toxic effects of retained gadolinium from gadolinium-based contrast agents, see the Background section of our website.

Sharon Williams

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Recent studies reporting evidence of Gadolinium (Gd) deposition in the brain –

Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., & Takenaka, D. (2013). High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-based Contrast Material. Radiology, 131669. http://doi.org/10.1148/radiol.13131669

Errante, Y., Cirimele, V., Mallio, C. A., Di Lazzaro, V., Zobel, B. B., & Quattrocchi, C. C. (2014). Progressive Increase of T1 Signal Intensity of the Dentate Nucleus on Unenhanced Magnetic Resonance Images Is Associated With Cumulative Doses of Intravenously Administered Gadodiamide in Patients With Normal Renal Function, Suggesting Dechelation. Investigative Radiology, 49(10), 685–690. http://doi.org/10.1097/RLI.0000000000000072

Kanda, T., Osawa, M., Oba, H., Toyoda, K., Kotoku, J., Haruyama, T., … Furui, S. (2015). High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration. Radiology, 140364. http://doi.org/10.1148/radiol.14140364

McDonald, R. J., McDonald, J. S., Kallmes, D. F., Jentoft, M. E., Murray, D. L., Thielen, K. R., … Eckel, L. J. (2015). Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology, 150025. http://doi.org/10.1148/radiol.15150025

Quattrocchi, C. C., Mallio, C. A., Errante, Y., Cirimele, V., Carideo, L., Ax, A., & Zobel, B. B. (2015). Gadodiamide and Dentate Nucleus T1 Hyperintensity in Patients With Meningioma Evaluated by Multiple Follow-Up Contrast-Enhanced Magnetic Resonance Examinations With No Systemic Interval Therapy. Investigative Radiology. http://doi.org/10.1097/RLI.0000000000000154

Radbruch, A., Weberling, L. D., Kieslich, P. J., Eidel, O., Burth, S., Kickingereder, P., … Bendszus, M. (2015). Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent. Radiology, 150337. http://doi.org/10.1148/radiol.2015150337

Kanda, T., Fukusato, T., Matsuda, M., Toyoda, K., Oba, H., Kotoku, J., … Furui, S. (2015). Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy. Radiology, 142690. http://doi.org/10.1148/radiol.2015142690

Ramalho, J., Castillo, M., AlObaidy, M., Nunes, R. H., Ramalho, M., Dale, B. M., & Semelka, R. C. (2015). High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: Evaluation of Two Linear Gadolinium-based Contrast Agents. Radiology, 150872. http://doi.org/10.1148/radiol.2015150872

Robert, P., Lehericy, S., Grand, S., Violas, X., Fretellier, N., Idée, J.-M., … Corot, C. (9000). 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. Investigative Radiology, Publish Ah. Retrieved from: http://journals.lww.com/investigativeradiology/Fulltext/publishahead/T1_Weighted_Hypersignal_in_the_Deep_Cerebellar.99302.aspx

Stojanov, D. A., Aracki-Trenkic, A., Vojinovic, S., Benedeto-Stojanov, D., & Ljubisavljevic, S. (2015). Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol. European Radiology. http://doi.org/10.1007/s00330-015-3879-9
 

Gd is neurotoxic; it inhibits mitochondrial function and induces oxidative stress –

Ray, D. E., & et al. (1996). Neurotoxic Effects of Gadopentetate Dimeglumine: Behavioral Disturbance and Morphology after Intracerebroventricular Injection in Rats. AJNR. American Journal of Neuroradiology, February(17), 365–373. Retrieved from http://www.ajnr.org/content/17/2/365.full.pdf

Ray, D. E., Holton, J. L., Nolan, C. C., Cavanagh, J. B., & Harpur, E. S. (1998). Neurotoxic potential of gadodiamide after injection into the lateral cerebral ventricle of rats. . American Journal of Neuroradiology , 19 (8 ), 1455–1462. Retrieved from http://www.ajnr.org/content/19/8/1455.abstract

Roman-Goldstein, S. M., Barnett, P. A., McCormick, C. I., Szumowski, J., Shannon, E. M., Ramsey, F. L., Mass, M., et al. (n.d.). Effects of Gd-DTPA after osmotic BBB disruption in a rodent model: toxicity and MR findings. Journal of computer assisted tomography, 18(5), 731–6. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8089321

Hui, F., & Mullins, H. (2009). Persistence of Gadolinium Contrast Enhancement in CSF: A Possible Harbinger of Gadolinium Neurotoxicity? American Journal of Neuroradiology, January(30), E1. Retrieved from http://www.ajnr.org/content/30/1/e1.full.pdf

Feng, X., Xia, Q., Yuan, L., Yang, X., & Wang, K. (2010). Impaired mitochondrial function and oxidative stress in rat cortical neurons: implications for gadolinium-induced neurotoxicity. Neurotoxicology, 31(4), 391–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20398695

Xia, Q., Feng, X., Huang, H., Du, L., Yang, X., & Wang, K. (2011). Gadolinium-induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons. Journal of neurochemistry, 117(1), 38–47.  Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21198628

Gadolinium affects vascular reactivity –

Vassallo, D., & et al. (2011). Toxic effects of mercury, lead and gadolinium on vascular reactivity. Braz J Med Biol Res, 44, 939–946. Retrieved from http://www.scielo.br/pdf/bjmbr/v44n9/1088.pdf

Gadolinium is a potent blocker of calcium channels –

Ersoy, H., & Rybicki, F. J. (2007). Biochemical safety profiles of gadolinium-based extracellular contrast agents and nephrogenic systemic fibrosis. Journal of Magnetic Resonance Imaging : JMRI, 26(5), 1190–7. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2709982&tool=pmcentrez&rendertype=abstract

GBCA promotes Multiple Myeloma cell growth –

Fulciniti, M., et al, & Dana Farber Cancer Institute Harvard Medical School. (2009). Gadolinium Containing Contrast Agent Promotes Multiple Myeloma Cell Growth: Implications for Clinical Use of MRI in Myeloma (poster presentation). Retrieved from http://myeloma.org/pdfs/ASH2009_Fulciniti_1809.pdf