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…)

New study of Gadolinium retention in brains of rats raises more questions than it answers

On June 22, 2015, an article in Investigative Radiology was published online ahead of print.  The study by Robert 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”, describes for the first time “an animal model reproducing closely the recent clinical observations of cerebellum T1 signal hypersignal”.  “It also introduces an animal model to investigate the mechanism of the brain retention observed after repeated administrations of some GBCA.”

After 20 intravenous injections of 0.6 mmol of gadolinium per kilogram (4 injections per week for 5 weeks) of gadodiamide (Omniscan) or gadoterate meglumine (Dotarem) to healthy rats, they found that repeated injections of gadodiamide are associated with “progressive and persistent T1 signal hyperintensity in the deep cerebellar nuclei (DCN), with Gd deposition in the cerebellum in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed”.  Although repeated doses of gadoterate meglumine (Dotarem) did not cause signal increases, detectable concentrations of gadolinium were found in the cerebellum, cerebral cortex, and subcortical brain of the rats that were injected with it.  (more…)

Study suggests Gadolinium Deposition in Dentate Nucleus with MultiHance – Patients had normal renal function

Another 2015 study in Radiology reports findings consistent with gadolinium deposition within the brains of patients with normal renal function (eGFR >60).  The study by Ramalho et al, High Signal Intensity in Globus Pallidus and Dentate Nucleus on Unenhanced T1-weighted MR Images: Evaluation of Two Linear Gadolinium-based Contrast Agents”, compared gadodiamide (Omniscan) and gadobenate dimeglumine (MultiHance).  The findings related to multiple administrations of gadodiamide are “in agreement with other investigators, who documented signal intensity changes associated with this contrast agent despite the presence of normal renal function”.  The authors also reported that, “A significant trend toward relative change in signal intensity was seen in the dentate nucleus (DN), but not in the globus pallidus (GP) after serial applications of gadobenate dimeglumine, suggesting that some gadolinium deposition also may occur with this agent”.

For the first time in the literature, the study established gadolinium accumulation related to the use of gadobenate dimeglumine, which is better known as MultiHance.  Of note is the fact that there are no unconfounded cases of NSF associated with the linear ionic gadolinium-based contrast agent (GBCA), MultiHance.  However, in this study, the patients in each group had received only one brand of GBCA.  Group 1 was comprised of 23 patients that had received between 3 and 11 doses of Omniscan, and Group 2 included 46 patients that had received between 3 and 11 doses of MultiHance.  All patients had normal liver and renal function.  (more…)

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