Gadolinium Presence in the Brain and Body
Increased signal intensity (SI) in the dentate nucleus (DN) and globus pallidus (GP) brain areas on unenhanced T1-weighted (T1w) MR images have long been observed. Historically, these brain hyperintensities have been associated with multiple sclerosis (MS)1, with accompanying iron deposition2, manganese deposition3, brain irradiation4 and hepatic dysfunction5. The first association of repeated gadolinium-based contrast agent (GBCA) administrations and increased SI on non-contrast T1w images in the DN and GP brain areas was published by Kanda et al.6 This study stimulated intensive scientific investigations that aim to better understand the origin of this SI increase (Figure 1).
To date, no study has shown an association between the observed increased SI in the brain after repeated GBCA administrations and the occurrence of any clinical adverse events. Additionally, no causal relationship has been established between clinical signs and symptoms and the presence of small amounts of gadolinium (Gd) in the body in patients with normal renal function following use of a GBCA.
Bayer has an extensive non-clinical research program underway to further evaluate these clinical findings in more detail and is actively participating in the ongoing discussions with leading experts worldwide.
Figure 1. Summary of key findings of clinical imaging studies that try to associate various gadolinium based contrast agents with signal intensity increase in the brain based on Bayer's interpretation of these studies (click here for a more detailed summary of these clinical imaging studies)
Summary of current clinical observations
- Hyperintensity in the DN and GP brain areas has been observed after 5 or more administrations of multi-purpose linear GBCAs with standard dose (0.1 mmol Gd/kg body weight (BW)) in patients with normal renal function.6-15
- No robust proof for any visual and/or statistically significant measurable SI increase on T1w images of the brain has been observed after a high number (up to 50 or more) of administrations of macrocyclic GBCAs (Dotarem, Gadovist, ProHance).11, 12, 14, 16-27
- Similar brain hyperintensities as observed in adults were observed in pediatric studies21, 28-33 after multiple standard doses (0.1 mmol Gd/kg BW) of multi-purpose linear GBCAs.
- No SI increase was seen following up to 15–18 administrations of Primovist34, 35, a liver-specific linear GBCA with a dual elimination pathway administered at ¼ the dose of other linear GBCAs. However, one study has shown a SI increase following a significantly higher number of administrations (ranging from 11–37 injections) while no SI was seen in patients with less than 10 Primovist injections.36
- Despite differences in SI increase, no histopathological changes to brain tissue and no clinical adverse effects have been confirmed to be associated with this SI increase.38
- Traces of gadolinium can be found in bone and brain after administration of either linear or macrocyclic GBCAs, regardless of renal function. Explorative data on the presence of gadolinium in some brain areas as well as bone tissue are provided by some post-mortem (seven in total) studies37-43
- Reports of persistent or elevated gadolinium levels in certain areas of the body (blood, hair, nails, skin, and urine) have been reported with all GBCAs in a small number of patients who experience persistent symptoms which they associate with gadolinium presence.44, 45 To date, no adverse health effects have been confirmed to be associated with these findings.37-39
- Roccatagliata L, Vuolo L, Bonzano L, et al. Multiple sclerosis: hyperintense dentate nucleus on unenhanced T1-weighted MR images is associated with the secondary progressive subtype. Radiology. 2009;251(2):503–510.
- Popescu BF, Robinson CA, Rajput A, et al. Iron, copper, and zinc distribution of the cerebellum. Cerebellum. 2009;8(2):74–79.
- Valdés Hernández Mdel C, Maconick LC, Tan EM, Wardlaw JM. Identification of mineral deposits in the brain on radiological images: a systematic review. Eur Radiol. 2012;22(11):2371–2381.
- Kasahara S, Miki Y, Kanagaki M, et al. Hyperintense dentate nucleus on unenhanced T1-¬weighted MR images is associated with a history of brain irradiation. Radiology. 2011;258(1):222–228.
- Brunberg JA, Kanal E, Hirsch W, Van Thiel DH. Chronic acquired hepatic failure: MR imaging of the brain at 1.5 T. AJNR Am J Neuroradiol. 1991;12(5):909–914.
- Kanda T, Ishii K, Kawaguchi H, Kitajima K and Takenaka D. 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. 2014;270:834-41.
- Kanda T, Osawa M, Oba H, Toyoda K, Kotoku J, Haruyama T, Takeshita K and Furui S. High Signal Intensity in Dentate Nucleus on Unenhanced T1-weighted MR Images: Association with Linear versus Macrocyclic Gadolinium Chelate Administration. Radiology. 2015;275:803-9.
- Ramalho J, Castillo M, AlObaidy M, Nunes RH, Ramalho M, Dale BM and Semelka RC. High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: Evaluation of Two Linear Gadolinium-based Contrast Agents. Radiology. 2015;276:836-44.
- Errante Y, Cirimele V, Mallio CA, Di Lazzaro V, Zobel BB and Quattrocchi CC. 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. 2014;49:685-90.
- Quattrocchi CC, Mallio CA, Errante Y, Cirimele V, Carideo L, Ax A and Zobel BB. 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. 2015;50:470-2.
- Radbruch A, Weberling LD, Kieslich PJ, Eidel O, Burth S, Kickingereder P, Heiland S, Wick W, Schlemmer HP and Bendszus M. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology. 2015;275:783-91.
- Schlemm L, Chien C, Bellmann-Strobl J, Dorr J, Wuerfel J, Brandt AU, Paul F and Scheel M. Gadopentetate but not gadobutrol accumulates in the dentate nucleus of multiple sclerosis patients. Mult Scler. 2016.
- Weberling LD, Kieslich PJ, Kickingereder P, Wick W, Bendszus M, Schlemmer HP and Radbruch A. Increased Signal Intensity in the Dentate Nucleus on Unenhanced T1-Weighted Images After Gadobenate Dimeglumine Administration. Investigative radiology. 2015;50:743-8.
- Bae S, Lee HJ, Han K, Park YW, Choi YS, Ahn SS, Kim J and Lee SK. Gadolinium deposition in the brain: association with various GBCAs using a generalized additive model. European radiology. 2017.
- Kuno H, Jara H, Buch K, Qureshi MM, Chapman MN and Sakai O. Global and Regional Brain Assessment with Quantitative MR Imaging in Patients with Prior Exposure to Linear Gadolinium-based Contrast Agents. Radiology. 2017;283:195-204.
- Radbruch A, Haase R, Kieslich PJ, Weberling LD, Kickingereder P, Wick W, Schlemmer HP and Bendszus M. No Signal Intensity Increase in the Dentate Nucleus on Unenhanced T1-weighted MR Images after More than 20 Serial Injections of Macrocyclic Gadolinium-based Contrast Agents. Radiology. 2016:162241.
- Radbruch A, Weberling LD, Kieslich PJ, Hepp J, Kickingereder P, Wick W, Schlemmer HP and Bendszus M. High-Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted Images: Evaluation of the Macrocyclic Gadolinium-Based Contrast Agent Gadobutrol. Investigative radiology. 2015;50:805-10.
- Eisele P, Alonso A, Szabo K, Ebert A, Ong M, Schoenberg SO and Gass A. Lack of increased signal intensity in the dentate nucleus after repeated administration of a macrocyclic contrast agent in multiple sclerosis: An observational study. Medicine (Baltimore). 2016;95:e4624.
- Langner S, Kromrey ML, Kuehn JP, Grothe M and Domin M. Repeated intravenous administration of gadobutrol does not lead to increased signal intensity on unenhanced T1-weighted images-a voxel-based whole brain analysis. European radiology. 2017.
- Tibussek D, Rademacher C, Caspers J, Turowski B, Schaper J, Antoch G and Klee D. Gadolinium Brain Deposition after Macrocyclic Gadolinium Administration: A Pediatric Case-Control Study. Radiology. 2017:161151.
- Yoo RE, Sohn CH, Kang KM, Yun TJ, Choi SH, Kim JH and Park SW. Evaluation of Gadolinium Retention After Serial Administrations of a Macrocyclic Gadolinium-Based Contrast Agent (Gadobutrol): A Single-Institution Experience With 189 Patients. Investigative radiology. 2017.
- Muller A, Jurcoane A, Madler B, Ditter P, Schild H and Hattingen E. Brain relaxometry after macrocyclic Gd-based contrast agent. Clin Neuroradiol. 2017.
- Cao Y, Huang DQ, Shih G and Prince MR. Signal Change in the Dentate Nucleus on T1-Weighted MR Images After Multiple Administrations of Gadopentetate Dimeglumine Versus Gadobutrol. AJR American journal of roentgenology. 2016;206:414-9.
- Radbruch A, Weberling LD, Kieslich PJ, Hepp J, Kickingereder P, Wick W, Schlemmer HP and Bendszus M. Intraindividual Analysis of Signal Intensity Changes in the Dentate Nucleus After Consecutive Serial Applications of Linear and Macrocyclic Gadolinium-Based Contrast Agents. Investigative radiology. 2016;51:683-690.
- Lee JY, Park JE, Kim HS, Kim SO, Oh JY, Shim WH, Jung SC, Choi CG and Kim SJ. Up to 52 administrations of macrocyclic ionic MR contrast agent are not associated with intracranial gadolinium deposition: Multifactorial analysis in 385 patients. PLoS One. 2017;12:e0183916.
- Lim WH, Choi SH, Yoo RE, Kang KM, Yun TJ, Kim JH and Sohn CH. Does radiation therapy increase gadolinium accumulation in the brain?: Quantitative analysis of T1 shortening using R1 relaxometry in glioblastoma multiforme patients. PLoS One. 2018;13:e0192838.
- Behzadi AH, Farooq Z, Zhao Y, Shih G and Prince MR. Dentate Nucleus Signal Intensity Decrease on T1-weighted MR Images after Switching from Gadopentetate Dimeglumine to Gadobutrol. Radiology. 2018:171398.
- Radbruch A, Haase R, Kickingereder P, Baumer P, Bickelhaupt S, Paech D, Wick W, Schlemmer HP, Seitz A and Bendszus M. Pediatric Brain: No Increased Signal Intensity in the Dentate Nucleus on Unenhanced T1-weighted MR Images after Consecutive Exposure to a Macrocyclic Gadolinium-based Contrast Agent. Radiology. 2017;283:828-836.
- Hu HH, Pokorney A, Towbin RB and Miller JH. Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams. Pediatr Radiol. 2016;46:1590-8.
- Flood TF, Stence NV, Maloney JA and Mirsky DM. Pediatric Brain: Repeated Exposure to Linear Gadolinium-based Contrast Material Is Associated with Increased Signal Intensity at Unenhanced T1-weighted MR Imaging. Radiology. 2017;282:222-228.
- Roberts DR, Chatterjee AR, Yazdani M, Marebwa B, Brown T, Collins H, Bolles G, Jenrette JM, Nietert PJ and Zhu X. Pediatric Patients Demonstrate Progressive T1-Weighted Hyperintensity in the Dentate Nucleus following Multiple Doses of Gadolinium-Based Contrast Agent. AJNR American journal of neuroradiology. 2016;37:2340-2347.
- Renz DM, Kumpel S, Bottcher J, Pfeil A, Streitparth F, Waginger M, Reichenbach JR, Teichgraber UK and Mentzel HJ. Comparison of Unenhanced T1-Weighted Signal Intensities Within the Dentate Nucleus and the Globus Pallidus After Serial Applications of Gadopentetate Dimeglumine Versus Gadobutrol in a Pediatric Population. Investigative radiology. 2017.
- Ryu YJ, Choi YH, Cheon JE, Lee WJ, Park S, Park JE, Kim WS and Kim IO. Pediatric Brain: Gadolinium Deposition in Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted Images Is Dependent on the Type of Contrast Agent. Investigative radiology. 2018.
- Conte G, Preda L, Cocorocchio E, Raimondi S, Giannitto C, Minotti M, De Piano F, Petralia G, Ferrucci PF and Bellomi M. Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study. European radiology. 2017.
- Ichikawa S, Motosugi U, Omiya Y and Onishi H. Contrast Agent-Induced High Signal Intensity in Dentate Nucleus on Unenhanced T1-Weighted Images: Comparison of Gadodiamide and Gadoxetic Acid. Investigative radiology. 2017.
- Kahn J, Posch H, Steffen IG, Geisel D, Bauknecht C, Liebig T and Denecke T. Is There Long-term Signal Intensity Increase in the Central Nervous System on T1-weighted Images after MR Imaging with the Hepatospecific Contrast Agent Gadoxetic Acid? A Cross-sectional Study in 91 Patients. Radiology. 2017:162535.
- McDonald JS, McDonald RJ, Jentoft ME, Paolini MA, Murray DL, Kallmes DF and Eckel LJ. Intracranial Gadolinium Deposition Following Gadodiamide-Enhanced Magnetic Resonance Imaging in Pediatric Patients: A Case-Control Study.JAMA Pediatr. 2017.
- McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, Williamson EE and Eckel LJ. Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology. 2015;275:772-82.
- McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Paolini MA, Murray DL, Williamson EE and Eckel LJ. Gadolinium Deposition in Human Brain Tissues after Contrast-enhanced MR Imaging in Adult Patients without Intracranial Abnormalities. Radiology. 2017:161595.
- Roberts DR, Welsh CA, LeBel DP, 2nd and Davis WC. Distribution map of gadolinium deposition within the cerebellum following GBCA administration. Neurology. 2017;88:1206-1208.
- Murata N, Gonzalez-Cuyar LF, Murata K, Fligner C, Dills R, Hippe D and Maravilla KR. Macrocyclic and Other Non-Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal Function. Investigative radiology. 2016.
- Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku J, Haruyama T, Kitajima K and Furui S. 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. 2015;276:228-32.
- Fingerhut S, Niehoff AC, Sperling M, Jeibmann A, Paulus W, Niederstadt T, Allkemper T, Heindel W, Holling M and Karst U. Spatially resolved quantification of gadolinium deposited in the brain of a patient treated with gadolinium-based contrast agents. J Trace Elem Med Biol. 2018;45:125-130.
- Semelka RC, Commander CW, Jay M, Burke LM and Ramalho M. Presumed Gadolinium Toxicity in Subjects With Normal Renal Function: A Report of 4 Cases. Investigative radiology. 2016;51:661-5.
- Burke LM, Ramalho M, AlObaidy M, Chang E, Jay M and Semelka RC. Self-reported gadolinium toxicity: A survey of patients with chronic symptoms. Magn Reson Imaging. 2016;34:1078-80.