Gadolinium Toxicity

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New study did not find signal increases in brain after repeat administrations of Gadovist.

A new study by Radbruch et al concerning gadobutrol has been published online ahead-of-print in Investigative Radiology.  The paper, High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted Images: Evaluation of the Macrocyclic Gadolinium-Based Contrast Agent Gadobutrol, did not find signal increases in the dentate nucleus (DN) or in the globus pallidus (GP) after serial administrations of gadobutrol (Gadovist, Bayer Healthcare).  The study included 30 patients who had received at least 5 MRI examinations with only Gadovist.

The findings are in contrast to a previously published study by Stojanov et al that we reported about.  That paper was titled, 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-bases contrast agent, gadobutrol (European Radiology, 2015). 

Radbruch and his colleagues concluded that their finding “adds further support to the hypothesis that the molecular structure of a gadolinium-based contrast agent as either macrocyclic or linear is a crucial factor for its potential to cause gadolinium deposition in the brain”.  The authors also noted that future studies are needed to assess this hypothesis.

I agree that additional research is needed.  I would be interested to find out if gadolinium from macrocyclic agents is being deposited in the brain, but perhaps in smaller quantities than from linear agents.  If so, it might be that the amount of deposited gadolinium has to reach a certain level before signal increases are detected on magnetic resonance images (MRI).  Still to be determined are the long-term effects of any amount of gadolinium deposition in the brain or elsewhere in the body.

Sharon Williams

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Radbruch, A., Weberling, L. D., Kieslich, P. J., Hepp, J., Kickingereder, P., Wick, W., … Bendszus, M. (2015). 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, 50(12). Retrieved from http://journals.lww.com/investigativeradiology/Fulltext/2015/12000/High_Signal_Intensity_in_the_Dentate_Nucleus_and.1.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 age. European Radiology. http://doi.org/10.1007/s00330-015-3879-9

MultiHance found to leave residual gadolinium in the brain

A new study by Weberling et al, Increased Signal Intensity in the Dentate Nucleus on Unenhanced T1-Weighted Images after Gadobenate Dimeglumine Administration, found increased signal intensity (SI) in the dentate nucleus (DN) after serial injections of the linear gadolinium-based contrast agent (GBCA) gadobenate dimeglumine (MultiHance, Bracco Diagnostics Inc.).  The study included 50 patients that had a minimum of 5 consecutive brain MRI scans with MultiHance.  All MRIs were performed between March 1, 2014 and December 31, 2014 in the German Cancer Research Center, Heidelberg, Germany.  45 of the patients had an estimated glomerular filtration rate (eGFR) greater than 60, and 5 had an eGFR between 45 and 60.

Like the 2015 study by Radbruch et al, the exclusion criteria included: history of brain hemorrhage, stroke, or brain ischemia; edema, tumor, or other lesions located in the cerebellum or pons; history of intracranial infection, such as meningitis or encephalitis; missing or unsatisfactory unenhanced T1-weighted MRI scans; and missing documentation of the contrast agent administered.

The study found an increased SI in the DN-to-CSF (cerebrospinal fluid) and DN-to-pons ratios on unenhanced T1-weighted images in patients that had at least 5 MRIs with the gadolinium-based contrast agent MultiHance.  The authors said, “Because the previous work by McDonald et al showed that SI correlates with gadolinium retention in the respective area, the SI increase found herein likely reflects the specific potential of gadobenate dimeglumine to release gadolinium”. (more…)

NSF Diagnosis made 10 years after patient’s last dose of contrast

On May 27, 2015, JAMA Dermatology published a Case Report by Larson et al that described a biopsy-confirmed case of “Nephrogenic Systemic Fibrosis Manifesting a Decade after Exposure to Gadolinium”.   According to the report, a long-term hemodialysis patient was exposed to a gadolinium-based contrast agent several times between 1998 and 2004 during magnetic resonance angiography (MRA) of his abdominal vessels and arteriovenous fistula.  Ten years later, in 2014, he developed new dermal papules and plaques.  The diagnosis of NSF was made based on the findings of a biopsy of affected skin which showed thickening of collagen, CD34+ spindle cells, and increased mucin in the dermis.  (Information about the agent(s) and dosages are not provided).

Prior to this case, the authors noted that the longest documented time after exposure to gadolinium to NSF manifestation was 3 ½ years.

This case shows that even in patients with severe renal disease retained gadolinium can take many years before causing “visible” evidence of a problem.  The authors concluded that, “Although the use of gadolinium contrast agents in patients with kidney failure has markedly decreased, patients with exposure to gadolinium years to decades previously may manifest the disease”. (more…)

Study reports Increasing Signal Intensity within the Brains of Patients with Multiple Sclerosis after multiple injections of the macrocyclic GBCA Gadovist – All Patients had Normal Renal Function

On June 25, 2015, European Radiology published a new study online ahead of print that reports increasing signal intensity on brain MR images after repeated administrations of the macrocyclic agent, gadobutrol (Gadovist, Bayer Healthcare, Berlin, Germany). The study by Stojanov et al is titled, 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. This is the first study to report a correlation between the cumulative dose of a macrocyclic, gadolinium-based contrast agent (GBCA), and gadolinium deposition within the dentate nucleus (DN) and globus pallidus (GP) in patients with relapsing-remitting multiple sclerosis (RRMS).  All patients had normal renal function at the beginning and end of the study.

Liver function was also normal at the beginning of the study; however, the authors noted that at the end of the study there was a significant increase (p=0.004) in GGT, gamma-glutamyl transpeptidase.  The other liver function parameters remained normal.

Since all patients had normal renal function at the beginning and end of the study, there was no correlation between renal function and signal intensity within either dentate nucleus or globus pallidus.  The authors noted that, “This suggests that gadolinium deposition within the brain may occur even in patients with normal renal function”. (more…)

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