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Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: pathological confirmation

Pediatric Radiology volume 50, pages 388–396 (2020)Cite this article

Abstract

Background

Retained gadolinium from gadolinium-based contrast agents (GBCAs) used in MR exams has been inferred based on signal changes on serial brain MRI and subsequently demonstrated pathologically in adults. Retention has been similarly inferred in children but pathological demonstration in pediatric patients is limited. The long-term effects of retained gadolinium are unknown but are potentially of greater concern in children given their increased vulnerability from continuing development and their expected longer period of exposure. Several factors can influence gadolinium retention. In adults as well as in children, greater accumulation has been demonstrated based on MR signal changes with linear compared with macrocyclic gadolinium chelates, attributed to lower chelate affinity with linear agents. Effects of age at exposure on retention are unknown, while differences in GBCA washout rates are still under investigation and might affect gadolinium retention relative to time of GBCA administration.

Objective

The purpose of this study was to confirm whether gadolinium brain deposits are present in pediatric patients who received GBCAs and to quantify the amounts present.

Materials and methods

Brain autopsy specimens from 10 pediatric patients between 1 year and 13 years of age who underwent at least one contrast-enhanced MR exam were analyzed for elemental gadolinium using inductively coupled plasma mass spectrometry. Brain samples included white matter, basal ganglia (putamen, globus pallidus), thalamus, dentate nucleus and tumor tissue as available. Type and dose of contrast agent, number and timing of contrast-enhanced MR exams and renal function (estimated glomerular filtration rate [eGFR]) were documented for each child.

Results

Patient exposures ranged from 1 dose to 20 doses of GBCAs including both macrocyclic and linear ionic agents. Gadolinium was found to be present in brain tissue in all children and was generally highest in the globus pallidus. Those who received only macrocyclic agents showed lower levels of gadolinium retention.

Conclusion

This study demonstrates pathological confirmation of gadolinium retention in brain tissue of a series of pediatric patients exposed to GBCAs including not only linear ionic agents but also macrocyclic agents with both nonionic and ionic compounds. The distribution and deposition levels in this small pediatric population are comparable with the findings in adults. While the clinical significance of these deposits remains unknown, at this point it would be prudent to exert caution and avoid unnecessary use of GBCAs in pediatric patients.

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References

  1. McDonald JS, McDonald RJ, Jentoft ME et al (2017) Intracranial gadolinium deposition following gadodiamide-enhanced magnetic resonance imaging in pediatric patients: a case-control study. JAMA Pediatr 171:705–707

    PubMed  PubMed Central  Google Scholar 

  2. Marckmann P, Skov L, Rossen K et al (2006) Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 17:2359–2362

    PubMed  Google Scholar 

  3. Grobner T (2006) Gadolinium — a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 21:1104–1108

    CAS  PubMed  Google Scholar 

  4. Hatje V, Bruland KW, Flegal AR (2016) Increases in anthropogenic gadolinium anomalies and rare earth element concentrations in San Francisco Bay over a 20 year record. Environ Sci Technol 50:4159–4168

    CAS  PubMed  Google Scholar 

  5. Murata N, Gonzalez-Cuyar LF, Murata K et al (2016) 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. Investig Radiol 51:447–453

    CAS  Google Scholar 

  6. Frame EM, Uzgiris EE (1998) Gadolinium determination in tissue samples by inductively coupled plasma mass spectrometry and inductively coupled plasma atomic emission spectrometry in evaluation of the action of magnetic resonance imaging contrast agents. Analyst 123:675–679

    CAS  PubMed  Google Scholar 

  7. Xia D, Davis RL, Crawford JA, Abraham JL (2010) Gadolinium released from MR contrast agents is deposited in brain tumors: in situ demonstration using scanning electron microscopy with energy dispersive X-ray spectroscopy. Acta Radiol 51:1126–1136

    PubMed  Google Scholar 

  8. Abraham JL, Thakral C (2008) Tissue distribution and kinetics of gadolinium and nephrogenic systemic fibrosis. Eur J Radiol 66:200–207

    PubMed  Google Scholar 

  9. Bhagavathula N, Dame MK, DaSilva M et al (2010) Fibroblast response to gadolinium: role for platelet-derived growth factor receptor. Investig Radiol 45:769–777

    CAS  Google Scholar 

  10. Bleavins K, Perone P, Naik M et al (2012) Stimulation of fibroblast proliferation by insoluble gadolinium salts. Biol Trace Elem Res 145:257–267

    CAS  PubMed  Google Scholar 

  11. Port M, Idee JM, Medina C et al (2008) Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and their possible clinical consequences: a critical review. Biometals 21:469–490

    CAS  PubMed  Google Scholar 

  12. Sieber MA, Lengsfeld P, Frenzel T et al (2008) Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions. Eur Radiol 18:2164–2173

    PubMed  Google Scholar 

  13. Sieber MA, Lengsfeld P, Walter J et al (2008) Gadolinium-based contrast agents and their potential role in the pathogenesis of nephrogenic systemic fibrosis: the role of excess ligand. J Magn Reson Imaging 27:955–962

    PubMed  Google Scholar 

  14. Wedeking P, Kumar K, Tweedle MF (1992) Dissociation of gadolinium chelates in mice: relationship to chemical characteristics. Magn Reson Imaging 10:641–648

    CAS  PubMed  Google Scholar 

  15. White GW, Gibby WA, Tweedle MF (2006) Comparison of Gd(DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Investig Radiol 41:272–278

    Google Scholar 

  16. Darrah TH, Prutsman-Pfeiffer JJ, Poreda RJ et al (2009) Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics 1:479–488

    CAS  PubMed  Google Scholar 

  17. McDonald RJ, McDonald JS, Kallmes DF et al (2017) Gadolinium deposition in human brain tissues after contrast-enhanced MR imaging in adult patients without intracranial abnormalities. Radiology 285:546–554

    PubMed  Google Scholar 

  18. McDonald RJ, McDonald JS, Kallmes DF et al (2015) Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 275:772–782

    PubMed  Google Scholar 

  19. Kanda T, Fukusato T, Matsuda M et al (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 276:228–232

    PubMed  Google Scholar 

  20. Errante Y, Cirimele V, Mallio CA et al (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. Investig Radiol 49:685–690

    CAS  Google Scholar 

  21. Kanda T, Matsuda M, Oba H et al (2015) Gadolinium deposition after contrast-enhanced MR imaging. Radiology 277:924–925

    PubMed  Google Scholar 

  22. Kanda T, Oba H, Toyoda K, Furui S (2016) Macrocyclic gadolinium-based contrast agents do not cause hyperintensity in the dentate nucleus. AJNR Am J Neuroradiol 37:E41

    CAS  PubMed  Google Scholar 

  23. Kanda T, Ishii K, Kawaguchi H et al (2014) 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 270:834–841

    PubMed  Google Scholar 

  24. Kanda T, Osawa M, Oba H et al (2015) High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 275:803–809

    PubMed  Google Scholar 

  25. Birka M, Wentker KS, Lusmoller E et al (2015) Diagnosis of nephrogenic systemic fibrosis by means of elemental bioimaging and speciation analysis. Anal Chem 87:3321–3328

    CAS  PubMed  Google Scholar 

  26. Miller JH, Hu HH, Pokorney A et al (2015) MRI brain signal intensity changes of a child during the course of 35 gadolinium contrast examinations. Pediatrics 136:e1637–e1640

    PubMed  Google Scholar 

  27. Hu HH, Pokorney A, Towbin RB, Miller JH (2016) 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 46:1590–1598

    PubMed  Google Scholar 

  28. Roberts DR, Chatterjee AR, Yazdani M et al (2016) Pediatric patients demonstrate progressive T1-weighted hyperintensity in the dentate nucleus following multiple doses of gadolinium-based contrast agent. AJNR Am J Neuroradiol 37:2340–2347

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Roberts DR, Holden KR (2016) Progressive increase of T1 signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in the pediatric brain exposed to multiple doses of gadolinium contrast. Brain Dev 38:331–336

    PubMed  Google Scholar 

  30. Flood TF, Stence NV, Maloney JA, Mirsky DM (2017) Pediatric brain: repeated exposure to linear gadolinium-based contrast material is associated with increased signal intensity at unenhanced T1-weighted MR imaging. Radiology 282:222–228

    PubMed  Google Scholar 

  31. Radbruch A, Haase R, Kickingereder P et al (2017) 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 283:828–836

    PubMed  Google Scholar 

  32. Tibussek D, Rademacher C, Caspers J et al (2017) Gadolinium brain deposition after macrocyclic gadolinium administration: a pediatric case-control study. Radiology 285:223–230

    PubMed  Google Scholar 

  33. Kasper E, Schemuth HP, Horry S, Kinner S (2018) Changes in signal intensity in the dentate nucleus at unenhanced T1-weighted magnetic resonance imaging depending on class of previously used gadolinium-based contrast agent. Pediatr Radiol 48:686–693

    PubMed  Google Scholar 

  34. Espagnet MCR, Bernardi B, Pasquini L et al (2017) Erratum to: signal intensity at unenhanced T1-weighted magnetic resonance in the globus pallidus and dentate nucleus after serial administrations of a macrocyclic gadolinium-based contrast agent in children. Pediatr Radiol 47:1366

    PubMed  Google Scholar 

  35. Mithal LB, Patel PS, Mithal D et al (2017) Use of gadolinium-based magnetic resonance imaging contrast agents and awareness of brain gadolinium deposition among pediatric providers in North America. Pediatr Radiol 47:657–664

    PubMed  Google Scholar 

  36. Roberts DR, Welsh CA, LeBel DP 2nd, Davis WC (2017) Distribution map of gadolinium deposition within the cerebellum following GBCA administration. Neurology 88:1206–1208

    CAS  PubMed  Google Scholar 

  37. Valk PE, Dillon WP (1991) Radiation injury of the brain. AJNR Am J Neuroradiol 12:45–62

    CAS  PubMed  Google Scholar 

  38. Rubin P, Gash DM, Hansen JT et al (1994) Disruption of the blood-brain barrier as the primary effect of CNS irradiation. Radiother Oncol 31:51–60

    CAS  PubMed  Google Scholar 

  39. Adair JC, Baldwin N, Kornfeld M, Rosenberg GA (1999) Radiation-induced blood-brain barrier damage in astrocytoma: relation to elevated gelatinase B and urokinase. J Neurooncol 44:283–289

    CAS  PubMed  Google Scholar 

  40. Lim WH, Choi SH, Yoo RE et al (2018) Does radiation therapy increase gadolinium accumulation in the brain? Quantitative analysis of T1 shortening using R1 relaxometry in glioblastoma multiforme patients. PLoS One 13:e0192838

    PubMed  PubMed Central  Google Scholar 

  41. Jost G, Frenzel T, Boyken J et al (2019) Long-term excretion of gadolinium-based contrast agents: linear versus macrocyclic agents in an experimental rat model. Radiology 290:340–348

    PubMed  Google Scholar 

  42. Bussi S, Coppo A, Botteron C et al (2018) Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats. J Magn Reson Imaging 47:746–752

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Radiology, Seattle Children’s Hospital, University of Washington, 4800 Sand Point Way NE, M/S MA 7.220, Seattle, WA, 98105, USA

    A. Luana Stanescu, Dennis W. Shaw & Ezekiel Maloney

  2. Department of Radiology, University of Washington, Seattle, WA, USA

    Nozomu Murata, Kiyoko Murata & Kenneth R. Maravilla

  3. Department of Radiology, Toho University Ohashi Medical Center, Tokyo, Japan

    Nozomu Murata

  4. Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan

    Kiyoko Murata

  5. Department of Pathology, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA

    Joe C. Rutledge

Authors
  1. A. Luana Stanescu
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  2. Dennis W. Shaw
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Correspondence to A. Luana Stanescu.

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Dr. Maravilla is a consultant for and receives grant funding from Bracco Diagnostics and Guerbet.

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Stanescu, A.L., Shaw, D.W., Murata, N. et al. Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: pathological confirmation. Pediatr Radiol 50, 388–396 (2020). https://doi.org/10.1007/s00247-019-04535-w

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  • DOI: https://doi.org/10.1007/s00247-019-04535-w

Keywords

  • Brain
  • Children
  • Gadolinium
  • Gadolinium-based contrast agents
  • Magnetic resonance imaging
  • Retention