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Three recent retrospective studies have reported finding evidence of increased signal intensities in the brains of pediatric patients who had undergone multiple MRIs with a gadolinium-based contrast agent (GBCA). The studies by Hu et al, Roberts et al, and Flood et al, add to the mounting evidence of gadolinium deposition in the brain of both children and adults exposed to GBCAs.
The study by Hu et al involved 21 patients, each of whom received multiple MRI exams with a GBCA over the course of their medical treatment. The number of exams ranged from 5 to 37 (19 out of 21 had more than 6 serial GBCA MRI exams), and the duration of treatment from first to most recent exam ranged from 1.2 to 12.9 years. The patients were between 0.9 and 14.4 years of age at the time of their first GBCA exam. Signal intensity ratios in the dentate nucleus and globus pallidus increased between the first and most recent MRI exam in all 21 patients receiving a GBCA.
The authors concluded that the data provided supports the growing evidence of potential gadolinium deposition in the brain. The observation of signal intensity increases in the dentate nucleus and the globus pallidus on unenhanced T1-weighted images are consistent with prior studies in adults. They noted that “additional studies are warranted to determine whether intracranial gadolinium deposition is the source responsible for these hyperintense structures and whether changes in standard practice of care are needed”.
Hu, H. H., Pokorney, A., Towbin, R. B., & Miller, J. H. (2016). Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams. Pediatric Radiology, 1–9. http://doi.org/10.1007/s00247-016-3646-3
Roberts et al found that the number of prior gadolinium-based contrast agent doses in pediatric patients is significantly correlated with progressive T1-weighted dentate hyperintensity. Sixteen pediatric patients were included for analysis. The patient ages ranged from 2 months to 14 years at the time of the first contrast dose. The number of doses before the last brain MR imaging examined ranged from 4 to 16. Hyperintensity was visible within the dentate nucleus on unenhanced images in the patients who had received at least 7 prior doses of GBCA.
The authors note that “pathologic evaluation of the brain in patients with normal renal function who were administered GBCAs has shown that gadolinium is deposited not only in the dentate nucleus but throughout the brain, including the frontal lobe white matter and frontal cortex”. “While the clinical significance of the long-term retention of gadolinium in the brain is unknown, it is particularly concerning for pediatric patients, who are undergoing neurodevelopment.” (more…)
A recent review article by Ramalho et al summarizes the literature on gadolinium-based contrast agents or GBCAs that are administered for contrast-enhanced MRIs, and it ties together information on agent stability, and animal and human studies. The article, “Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update”, also emphasizes that the low-stability agents are the ones most often associated with brain deposition of gadolinium that has been reported in the literature since 2014.
Since the article has Open Access at AJNR.org, I will not go into all of the details of it. However, there are some facts contained in the paper that I want to present here that are relevant to why GadoliniumToxicity.com exists. In 2014, Hubbs Grimm and I created this website as a way to alert people to a problem that was not yet recognized by the FDA and medical industry. That problem was gadolinium retention in patients with normal renal function. We knew the facts were in the published literature, but they just had not been seen by the right people yet. Thankfully, that has now begun to change.
Nephrogenic Systemic Fibrosis (NSF)
No review of GBCAs would be complete without some background information on NSF.
In 2006, the association between the administration of GBCAs and the development of Nephrogenic Systemic Fibrosis (NSF) in patients with severe renal disease was reported by Grobner and then by Marckmann et al. NSF predominantly involves the skin, but it is a systemic disease that may also affect other organs such as the lungs, liver, heart, and muscles. The exact pathophysiology of NSF remains unknown, but as the review states, the dissociation of gadolinium ions from their chelating ligands has been accepted as the primary etiology. That is more likely to occur in patients with renal failure than in those with normal renal function since the excretion rate is reduced in those with renal failure. The article indicates that most cases of NSF reported in the literature have been associated with the administration of nonionic, linear gadodiamide (Omniscan, GE Healthcare), nonionic, linear gadoversetamide (OptiMARK, Covidien), and with ionic, linear gadopentetate dimeglumine (Magnevist, Bayer HealthCare Pharmaceuticals).
After limiting the use of GBCAs in patients with renal failure and using more stable GBCAs, there have been no new cases of NSF reported since mid-2009. According to the paper, from 2009 to 2014, confidence in the safety of GBCAs had been largely restored. However, since 2014, numerous studies have been published that reported finding evidence of gadolinium deposition in neural tissues in patients with normal renal function. (more…)
The November 2015 issue of Pediatrics includes a case study by Miller et al. The article, MRI Brain Signal Intensity Changes of a Child During the Course of 35 Gadolinium Contrast Examinations, describes the quantitative signal intensity changes in the brain of a pediatric patient who had 35 MRIs with a linear gadolinium-based contrast agent (GBCA) between the ages of 8 and 20 years. The authors report that progressive increases were the most evident in the dentate nuclei, the globus pallidus, and the thalamus. They noted that the pattern of regional brain hyperintensity observed is consistent with findings from recent adult studies.
High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted images was first reported by Kanda et al in late 2013 and has been found to be the result of gadolinium deposition in the brain.
Miller, J. H., Hu, H. H., Pokorney, A., Cornejo, P., & Towbin, R. (2015). MRI Brain Signal Intensity Changes of a Child During the Course of 35 Gadolinium Contrast Examinations. Pediatrics, peds.2015–2222–. http://doi.org/10.1542/peds.2015-2222
Kanda, T., Ishii, K., Kawaguchi, H., Kitajima, K., & Takenaka, D. (2013). 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, 131669. http://doi.org/10.1148/radiol.13131669
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.
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