T. Kanda, H. Oba, K. Toyoda, S. Furui
Department of Radiology
Teikyo University School of Medicine
Itabashi-ku, Japan

We wish to comment on the December 2015 article of Ramalho et al¹ entitled “Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update” in theAmerican Journal of Neuroradiology.

First, the authors introduced the study of Stojanov et al,² in which gadobutrol (Gadavist; Bayer Schering Pharma, Berlin, Germany) was purported to cause hyperintensity in the dentate nucleus. However, this report lacks evidence because no hyperintensity in the dentate nucleus on T1WI could be noted in their presented figure, despite being seen in all other previous reports.³ In addition, Radbruch et al⁴ performed a replication study in which gadobutrol showed no correlation with hyperintensity in the dentate nucleus on T1WI. An animal study⁵ also denied the association between gadobutrol and hyperintensity in the dentate nucleus on T1WI. These results demonstrated that macrocyclic gadolinium-based contrast agents do not cause hyperintensity in the dentate nucleus.

Second, our group⁶ evaluated gadolinium deposition in the dentate nucleus, internal segment of the globus pallidus, frontal cortical lobe, white matter of the frontal lobe, and cerebral white matter. McDonald et al⁷ evaluated gadolinium deposition in the dentate nucleus, globus pallidus, thalamus, and pons. In addition, they confirmed the presence of extensive gadolinium deposits prominently clustered within the endothelial wall by using x-ray microanalysis. In the article by Ramalho et al, our work is mistaken for the great work of McDonald et al.

These 2 articles^6,7 were published at almost the same time. The submission of our article on November 20, 2014, was earlier than that of McDonald et al,⁷ submitted on January 5, 2015, but the acceptance was on March 24, 2015—namely, later than the acceptance of the work of McDonald et al on February 12, 2015. Our work and the work of McDonald et al progressed independently, and the work of McDonald et al was published a little earlier than our article.

References

1. Ramalho J, Semelka RC, Ramalho M, et al. Gadolinium-based contrast agent accumulation and toxicity: an update. AJNR Am J Neuroradiol 2015 Dec 10. [Epub ahead of print]
2. Stojanov DA, Aracki-Trenkic A, Vojinovic S, et al. 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. Eur Radiol 2016;26:807–15
3. Kanda T, Oba H, Toyoda K, et al. Brain gadolinium deposition after administration of gadolinium-based contrast agents. Jpn J Radiol 2016;34:3–9
4. Radbruch A, Weberling LD, Kieslich PJ, et al. High-signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evaluation of the macrocyclic gadolinium-based contrast agent gadobutrol. Invest Radiol 2015;50:805–10
5. Jost G, Lenhard DC, Sieber MA, et al. Signal increase on unenhanced T1-weighted images in the rat brain after repeated, extended doses of gadolinium-based contrast agents: comparison of linear and macrocyclic agents. Invest Radiol 2016;51:83–89
6. Kanda T, Fukusato T, Matsuda M, et al. 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
7. McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275:772–82

Reply

J. Ramalho
University of North Carolina Hospital
Chapel Hill, North Carolina
AND
Centro Hospitalar de Lisboa Central
Lisbon, Portugal

R.C. Semelka
University of North Carolina Hospital
Chapel Hill, North Carolina

M. Ramalho
University of North Carolina Hospital
Chapel Hill, North Carolina 
AND
Hospital Garcia de Orta
Almada, Portugal

R.H. Nunes
University of North Carolina Hospital
Chapel Hill, North Carolina
AND
Santa Casa de Misericórdia de São Paulo
São Paulo, Brazil

M. AlObaidy
University of North Carolina Hospital
Chapel Hill, North Carolina
AND
King Faisal Specialist Hospital and Research Center
Riyadh, Saudi Arabia

M. Castillo
University of North Carolina Hospital
Chapel Hill, North Carolina

We thank Dr Kanda and colleagues for their interest in our article “Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update”¹ and acknowledge them for their contributions to the awareness of gadolinium accumulation in the brain. Below, we will attempt to address their comments and concerns.

At the time our article was written, the study by Stojanov et al² reported that gadobutrol (Gadavist; Bayer Schering Pharma, Berlin, Germany) caused T1 hyperintensity in the dentate nucleus. Their findings were unexpected and highlighted the need for evaluation of each gadolinium-based contrast agent (GBCA). In fact, after our article was submitted to the American Journal of Neuroradiology, Radbruch et al³put forward new information regarding gadobutrol deposition in the dentate nucleus. By replicating the work of Stojanov et al, they concluded that no signal-intensity increase was seen with this agent, explaining the lack of it in the image provided by Stojanov et al. More recently, Cao et al⁴ found that unenhanced high T1 signal hyperintensity was observed in the dentate nucleus after multiple administrations of gadopentetate dimeglumine (Magnevist; Bayer HealthCare Pharmaceuticals, Wayne, New Jersey) but not after multiple administrations of gadobutrol, corroborating the findings of Radbruch et al. As stated in our article, the more stable macrocyclic GBCAs such as gadoteridol (ProHance; Bracco Diagnostics, Princeton, New Jersey) and gadoterate meglumine (Dotarem; Guerbet, Aulnay-sous-Bois, France) are not associated with substantial MR imaging changes, supporting the idea that gadolinium accumulation differs according to the stability of the agent used.^5,6

Although the animal study by Jost et al⁷ demonstrated a lack of association between gadobutrol (Gadavist) and T1 dentate nucleus hyperintensity, we recommend caution with extrapolating data from animal studies to humans. In that study, gadopentetate dimeglumine injection led to a moderately elevated dentate nucleus-to-pons signal-intensity ratio, not statistically significant, which differs from findings in human studies.^4⇓–6 Moreover, a more recent animal study performed by Robert et al⁸ showed that repeated administrations of that agent were associated with progressive and significant T1 hyperintensity in the dentate nucleus.

We remind our readers that no brain MR imaging changes have been noted in human studies after repeated administrations of the more stable GBCAs gadoteridol, gadoterate meglumine, and gadobutrol. Despite the work of Robert et al,^8,9 more human studies are needed to definitively exclude deposition of these agents in humans.

Although Dr Kanda claims that his article¹⁰ was submitted before the one by McDonald et al,¹¹ the latter was accepted and published first. Like most investigators, we do not have access to articles not yet published. Nevertheless, our article correctly quotes the number of patients studied, the GBCAs given, and the neural structures evaluated in both articles.

Last, we apologize for misciting the statement related to gadolinium deposits in the endothelial wall. As pointed out by Dr. Kanda and colleagues, this sentence is found in the article by McDonald et al¹¹ and not the article by Kanda et al.¹⁰

References

1. Ramalho J, Semelka RC, Ramalho M, et al. Gadolinium-based contrast agent accumulation and toxicity: an update. AJNR Am J Neuroradiol 2015 Dec 10. [Epub ahead of print]
2. Stojanov DA, Aracki-Trenkic A, Vojinovic S, et al. 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. Eur Radiol 2016;26:807–15
3. Radbruch A, Weberling LD, Kieslich PJ, et al. High-signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evaluation of the macrocyclic gadolinium-based contrast agent gadobutrol. Invest Radiol 2015;50:805–10
4. Cao Y, Huang DQ, Shih G, et al. Signal change in the dentate nucleus on T1-weighted MR images after multiple administrations of gadopentetate dimeglumine versus gadobutrol. AJR Am J Roentgenol 2016;206:414–19
5. Kanda T, Osawa M, Oba H, et al. High signal intensity in dentate nucleus on unenhanced T1-weighted MR images: association with linear versus macrocyclic gadolinium chelate administration. Radiology 2015;275:803–09
6. Radbruch A, Weberling LD, Kieslich PJ, et al. Gadolinium retention in the dentate nucleus and globus pallidus is dependent on the class of contrast agent. Radiology 2015;275:783–91
7. Jost G, Lenhard DC, Sieber MA, et al. Signal increase on unenhanced T1-weighted images in the rat brain after repeated, extended doses of gadolinium-based contrast agents. Invest Radiol 2016;51:83–89
8. Robert P, Violas X, Grand S, et al. Linear gadolinium-based contrast agents are associated with brain gadolinium retention in healthy rats. Invest Radiol 2016;51:73–82
9. Robert P, Lehericy S, Grand S, et al. 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. Invest Radiol 2015;50:473–80
10. Kanda T, Fukusato T, Matsuda M, et al. 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
11. McDonald RJ, McDonald JS, Kallmes DF, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology 2015;275:772–82