Intracranial Gadolinium Retention: "Nothing More to See Here ... Move Along ... "

HomeRadiologyVol. 294, No. 2 PreviousNext Reviews and CommentaryFree AccessEditorialIntracranial Gadolinium Retention: “Nothing More to See Here… Move Along…”Emanuel Kanal Emanuel Kanal Author AffiliationsFrom the Department of Radiology, University of Pittsburgh Medical Center, 200 Lothrop St, Room D132, Pittsburgh, PA 15213-2582.Address correspondence to the author (e-mail: [email protected]).Emanuel Kanal Published Online:Nov 26 2019https://doi.org/10.1148/radiol.2019192315MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In See also the article by Minaeva and Hua et al in this issue.Dr Emanuel Kanal is the chief of the 24/7 Division of Emergency Radiology, the director of Magnetic Resonance (MR) Services, and a professor of radiology and neuroradiology in the Department of Radiology of the University of Pittsburgh Medical Center. He graduated from Yeshiva University in New York in 1977 and from the University of Pittsburgh School of Medicine in 1981. Dr Kanal serves as a consultant and Special Government Employee to the Food and Drug Administration on MR safety issues for both the Division of Medical Imaging and the Drug Safety group. He is the founder and a past president of the American Board of MR Safety and is the creator of the MR safety simulator MagnetVision, as well as the Magnetic Resonance Safety Implant Risk Assessment app.Download as PowerPointOpen in Image Viewer It was my one of my first days as a radiology resident, and the film images hanging in front of me were from the almost–brand-new technology—a CT scanner, one of the first in the nation—that had only recently made its debut at our institution. After reviewing the cross-sectional anatomic findings in the first few patients of the day, I suddenly came across new findings in the next patient presented to us. “What’s that?!,” I said with some concern, pointing to images from the head CT in front of us. “What’s what?” responded the concerned attending radiologist who was tasked with teaching me about this new technology. “That!” I said, pointing out the distinct symmetric hyperdensities in the globus pallidus. “Oh…you scared me! That’s nothing. Those are just calcifications in the basal ganglia,” responded my mentor. I recall being puzzled, because in my vast experience of two or three head CT studies that I had already seen that morning, I had never seen such hyperdensities in these locations before. “Nothing?,” I questioned. “The last few patients that we saw didn’t have these. Why didn’t they have calcifications in the basal ganglia–and why does this person have calcifications in their basal ganglia?,” I insisted.I remember his response like it was yesterday. Paraphrasing only a bit, he confidently declared: “I don’t know, but it’s nothing–that’s normal. Forget about it. Just move along…”It’s closing in on 40 years later now. I still don’t know why the basal ganglia calcify in some patients and not in others. Oh, we know that metals deposit in the basal ganglia. Like calcium. Like iron. Like manganese. Like gadolinium…. But at least for some metals, like calcium, we accept that they can precipitate in these (and other) locations in the brain and that it is simply normal to see this in some patients. We don’t even mention it in the dictations anymore—it’s normal, and we’ve learned to “move on.”In this issue of Radiology (1), Minaeva and colleagues have furthered our understanding of the issues related to intracranial gadolinium retention. We have known for several years that a small amount of intravenously administered gadolinium is retained in various organs of the body, including the brain. While the caudate nucleus and globus pallidus continue to be singled out as the predominant locations in which residual gadolinium can be found, other intracranial locations also accumulate gadolinium in smaller quantities. This study adds to this knowledge base in two major ways. First, the study documents that gadolinium was heterogeneously distributed within cortical regions in the brains of rats to whom the linear agent, gadopentetate dimeglumine, was administered. Importantly, no T1 shortening was evident in these cortical regions, in which gadolinium was found at similar concentrations as seen in the dentate nucleus, where T1 shortening is typically observed. Second, the study demonstrates the strong affinity of gadolinium to biodistribute and co-locate intracranially in similar distributions to iron, and the authors theorize that gadolinium may be transported across an intact blood-brain barrier. To date, it has been accepted that gadolinium likely enters the brain parenchyma by circumventing the blood-brain barrier through the blood-cerebrospinal fluid barrier via the glymphatics (2,3). If the conjecture by Minaeva and colleagues is substantiated, this would add to the complexity of the available biodistribution pathways of gadolinium retained within the brain parenchyma.The study by Minaeva et al again demonstrates the substantial discrepancy between retained gadolinium concentrations measured in tissue specimens versus signal intensity changes at MRI as first reported by Kanda et al 5 years ago. This also supports the findings by Frenzel et al (4) regarding the different molecular forms of residual gadolinium, because each may have different relaxivities and concentrations.Once again, we find ourselves facing more questions than answers—but the answer to the single most important question continues to evade us so far:What is the clinical relevance—if any—of this small amount of gadolinium retained in various molecular forms and locations not only in the brain but the body in general?Strong opinions—and emotions—abound. Many physicians believe that macrocyclics are “safer” than linear agents—after all, less material seems to be retained with most macrocyclic gadolinium-based contrast agents than with most linear agents. The European Medicines Agency has gone so far as to withdraw the marketing authorizations for the linear agents (5,6). Others feel that this is unwarranted, and that there are demonstrated safety and/or efficacy or relaxivity advantages for some of the linear agents over the macrocyclic agents (7,8). Brain parenchymal T1 shortening following repeated intravenous administration is seen only—or at the very least predominantly—with linear agents and not (as much?) with the macrocyclic agents. Yet we know virtually nothing about the actual toxicities of ANY of the molecular forms in which retained gadolinium is found. For example, it has been shown that only linear agents seem to be found in the brain in a water-insoluble form (4). But perhaps this form is arguably safer than if it is retained in the original water-soluble form in which it had been intravenously administered, as found predominantly with the macrocyclic agents? Could one not make the argument that the linear-associated insoluble form might be less biologically reactive, and might be, in a sense, more chemically inert? Perhaps the presence of water-insoluble gadolinium in the basal ganglia might be similar to finding calcium in the basal ganglia—an incidental finding, with no known clinical relevance or concern? And as we know today that the gadolinium-based contrast agents routinely enter the cerebrospinal fluid via the glymphatic pathway even in individuals with normal renal function (2,3), perhaps we should recall the higher neurotoxicity of the macrocyclic agents compared with the linear agents when directly administered at high doses intraventricularly in rats (9)?Some patients feel that the gadolinium they received was associated with the development of substantial—albeit subjective—disabling symptoms, such as brain fog, pain, and poor mentation (10). There is speculation that this is part of a disease spectrum related to gadolinium administration, while others feel that it is premature to reach such a conclusion without more objective and quantifiable science to support such claims. Perhaps studying this particular population might be a good place to begin to focus our energies to attempt to ascertain if any objective findings may support such a theory.To date, there do not seem to be any physicians who dogmatically claim that residual gadolinium, in any or all molecular forms, is “safe” or clinically irrelevant. Indeed, my own admitted personal bias is a concern that there may be adverse health consequences related to gadolinium agents of which we may not yet be sufficiently aware. Yet one thing remains abundantly clear: THE single most important issue remains unresolved at this time, and that is that the clinical significance and relevance—if any—to retained (general and) intracranial gadolinium, in whatever form(s) it may be found, is still not known.The results by Minaeva et al help remind us how much is still unknown regarding gadolinium metabolism, biodistribution, and clearance in humans with normal and those with abnormal renal function. It therefore seems appropriate for us to focus our governmental, industrial, and academic resources, as well as our talent, time, and funding, to address this specific question: Are there clinically relevant toxicities or concerns related to the reported quantities, distributions, and molecular forms of retained gadolinium in humans—or is this normal, and there’s nothing more to see here… move along?Only focused concerted research efforts targeting this specific question will close this frustrating chapter in the somewhat tarnished life story of gadolinium-based contrast agents.Disclosures of Conflicts of Interest: E.K. Activities related to the present article: is a consultant for Bracco Diagnostics, GE Healthcare, and Guerbet; has been paid for software acquisition by Bracco Diagnostics. Activities not related to the present article: Siemens has supported and sponsored some of E.K.'s MR safety education courses. Other relationships: disclosed no relevant relationships.References1. Minaeva O, Hua N, Franz ES, et al. Nonhomogeneous gadolinium retention in the cerebral cortex after intravenous administration of gadolinium-based contrast agent in rats and humans. Radiology 2020;294;377–385. Link, Google Scholar2. Naganawa S, Nakane T, Kawai H, Taoka T. Gd-based contrast enhancement of the perivascular spaces in the basal ganglia. Magn Reson Med Sci 2017;16(1):61–65. Crossref, Medline, Google Scholar3. Öner AY, Barutcu B, Aykol Ş, Tali ET. Intrathecal Contrast-Enhanced Magnetic Resonance Imaging-Related Brain Signal Changes: Residual Gadolinium Deposition? Invest Radiol 2017;52(4):195–197. Crossref, Medline, Google Scholar4. Frenzel T, Apte C, Jost G, Schöckel L, Lohrke J, Pietsch H. Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents: Comparative Study in Rats. Invest Radiol 2017;52(7):396–404. https://doi.org/10.1097/RLI.0000000000000352. Crossref, Medline, Google Scholar5. PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension for some marketing authorisations. European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2017/03/news_detail_002708.jsp&mid=WC0b01ac058004d5c1. Published March 10, 2017. Accessed September 29, 2019. Google Scholar6. Kanda T. The New Restrictions on the Use of Linear Gadolinium-based Contrast Agents in Japan. Magn Reson Med Sci 2019;18(1):1–3. Crossref, Medline, Google Scholar7. ACR response to the European PRAC recommendations. American College of Radiology. http://www.acr.org/About-Us/Media-Center/Press-Releases/2017-Press-Releases/20170404-ACR-Response-to-the-European-PRAC-Recommendations. Published April 4, 2017. Accessed November 25, 2017. Google Scholar8. Gulani V, Calamante F, Shellock FG, Kanal E, Reeder SB; International Society for Magnetic Resonance in Medicine. Gadolinium deposition in the brain: summary of evidence and recommendations. Lancet Neurol 2017;16(7):564–570. Crossref, Medline, Google Scholar9. Vogler H, Platzek J, Schuhmann-Giampieri G, et al. Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast agent for magnetic resonance imaging. Eur J Radiol 1995;21(1):1–10. Crossref, Medline, Google Scholar10. The Lighthouse Project. Gadolinium Toxicity. http://www.gadoliniumtoxicity.com. Accessed September 29, 2019. Google ScholarArticle HistoryReceived: Oct 14 2019Revision requested: Oct 23 2019Revision received: Oct 28 2019Accepted: Nov 4 2019Published online: Nov 26 2019Published in print: Feb 2020 FiguresReferencesRelatedDetailsCited ByScreening Breast MRI and Gadolinium Deposition: Cause for Concern?Colleen HNeal2022 | Journal of Breast Imaging, Vol. 4, No. 1Current and Future MR Contrast AgentsEricLancelot, Jean-SébastienRaynaud, PierreDesché2020 | Investigative Radiology, Vol. 55, No. 9Accompanying This ArticleNonhomogeneous Gadolinium Retention in the Cerebral Cortex after Intravenous Administration of Gadolinium-based Contrast Agent in Rats and HumansNov 26 2019RadiologyRecommended Articles Gadolinium Retention: A Research Roadmap from the 2018 NIH/ACR/RSNA Workshop on Gadolinium ChelatesRadiology2018Volume: 289Issue: 2pp. 517-534Gadolinium Deposition in Human Brain Tissues after Contrast-enhanced MR Imaging in Adult Patients without Intracranial AbnormalitiesRadiology2017Volume: 285Issue: 2pp. 546-554Comparison of Human Tissue Gadolinium Retention and Elimination between Gadoteridol and GadobenateRadiology2021Volume: 300Issue: 3pp. 559-569Gadolinium Retention in Human Brain, Bone, and SkinRadiology2021Volume: 300Issue: 3pp. 570-571Quantitative Susceptibility Mapping: Basic Methods and Clinical ApplicationsRadioGraphics2022Volume: 42Issue: 4pp. 1161-1176See More RSNA Education Exhibits Gadolinium Deposition in Brain: An Updated ReviewDigital Posters2019Quantitative Susceptibility Mapping: Basics and Clinical ApplicationsDigital Posters2020Shedding light on the Substantia Nigra: Anatomy, Function, Imaging Technique and Pathophysiology.Digital Posters2022 RSNA Case Collection β-Propeller protein-associated neurodegeneration (BPAN)RSNA Case Collection2020Fahr's SyndromeRSNA Case Collection2021Fahr’s syndromeRSNA Case Collection2021 Vol. 294, No. 2 Metrics Altmetric Score PDF download