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2012 Letter to FDA about Gadolinium Toxicity is available to the public
On October 23, 2012, I sent a detailed letter to the FDA which expressed my concerns about gadolinium toxicity caused by retained gadolinium from Gadolinium-based Contrast Agents (GBCAs). Because of the many recently published studies about gadolinium deposition in the brain and bones of patients with normal renal function, I decided that it was the right time to make my letter available to the public. While some progress has been made, four years have passed since I wrote that letter and I am concerned that the full scope of the problem still might not be addressed.
While I believe that the FDA took my concerns about gadolinium retention seriously, things are moving much too slowly. By making my letter public, I hope it will stimulate more interest in the issue of gadolinium retention and the plight of the many patients who have been adversely affected by its toxic effects.
You can download a copy of my 2012 Letter to the FDA in the Advocacy section. Please share it with your doctors and other affected patients.
To the medical professionals that follow us, I hope you will take time to read my entire letter. I am not a trained medical professional or scientist. However, I believe you will find my comments well-reasoned and fact-based.
Sharon Williams
Study is first to report Gadolinium Toxicity in Patients with Normal Renal Function
“Presumed Gadolinium Toxicity in Subjects with Normal Renal Function – A Report of 4 Cases”, is a landmark paper which documents the first presumed cases of gadolinium toxicity. Richard C. Semelka, MD, Radiologist at the University of North Carolina at Chapel Hill, and his colleagues are the authors. This is the first study to describe a series of patients with normal renal function who developed symptomatology lasting beyond the immediate post-injection period after the administration of a gadolinium-based contrast agent (GBCA).
Two subjects were assessed at 2 months and at 3 months after GBCA administration (early stage), and 2 subjects were assessed at 7 years and 8 years after GBCA administration (late stage). Clinical features were similar between subjects, and included central torso pain (all), peripheral arm and leg pain (all), clouded mentation (2), and distal arm and leg skin thickening and rubbery subcutaneous tissue (one early and both late subjects). All subjects had evidence of gadolinium retention ranging from one month up to 8 years after disease development.
Regarding clinical findings, the authors note that “these 4 individuals showed features that resemble and are observed in NSF patients”. “Specifically, the glove-and-sock pattern of pain (seen in all patients) is essentially universally seen in NSF, and central torso pain (seen in 3 patients) is seen with some frequency, but not universally, in NSF patients. Skin thickening and doughiness of the hands was seen in the 2 subjects with late-stage disease and is also described as a feature that progressively develops with NSF.” They also noted that “headache and clouded mentation are vague and non-specific clinical symptoms; but they had new onset in 2 subjects”. While numerous recent studies report gadolinium deposition in the brain, no histopathological changes have been documented yet. They point out that a compound may be neurotoxic without being associated with histopathological signs.
These clinical features are comparable to the symptomatology reported by Burke et al, in which the most common self-reported symptoms included bone/joint pain and head/neck symptoms including headache, vision change, and hearing change (77.6% each). (more…)
More evidence of gadolinium deposition in children’s brains
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…)
Initial publication of symptoms of gadolinium toxicity
The results of a 9 question survey about gadolinium exposure and related symptoms in patients with normal renal function were reported in an article by Burke et al titled Self-reported gadolinium toxicity: A survey of patients with chronic symptoms. The survey provides the initial description in the medical literature of patients with normal renal function who self-described toxicity related to administration of gadolinium-based contrast agents (GBCAs). There were 50 respondents to the anonymous online survey. All 50 respondents (100%) received gadolinium-based contrast with an average of 4.2 doses. All 50 attribute their symptoms to gadolinium exposure.
Thirty-three (66%) subjects described the onset of symptoms immediately following GBCA administration and 16 (32%) within 6 weeks. The most common symptoms included bone/joint pain and head/neck symptoms including headache, vision change, and hearing change. Headache and bone/joint pain was described by more than 75% of the cases. Skin changes were seen in approximately 60% of respondents.
Other symptoms reported include: flu-like symptoms (30.6%); digestive symptoms described as nausea, vomiting, diarrhea (46.9%); chest symptoms described as difficulty breathing (42.9%); generalized whole body symptoms (30.6%); and other (75.5%).
The findings of the survey showed that subjects with normal renal function might develop disease following administration of the majority of GBCAs including macrocyclic agents.
Despite the limitations of the survey, the authors said that it was their opinion “that there most likely is toxicity associated with GBCA administration in patients with normal renal function”. They concluded that, “at the very least, this study highlights the need to further investigate the subject of patients with normal renal function who complain of severe long-lasting symptomatology following GBCA administration”.
My thoughts –
When Hubbs Grimm and I released the findings of the online symptom survey that we conducted in early 2014, we noted that the results presented in our paper should stimulate further professional investigation into gadolinium retention in all patient populations including those with normal renal function. It is good to see that the medical community is now looking into the issue of gadolinium retention in patients with normal renal function further.
Our paper, Gadolinium Toxicity – A Survey of the Chronic Effects of Retained Gadolinium from Contrast MRIs can be found in the Research section of our website.
Sharon Williams
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Burke, L. M. B., Ramalho, M., AlObaidy, M., Chang, E., Jay, M., & Semelka, R. C. (2016). Self-Reported Gadolinium Toxicity: A Survey of Patients with Chronic Symptoms. Magnetic Resonance Imaging. http://doi.org/10.1016/j.mri.2016.05.005
Gadolinium Toxicity 