A recent study by Alkhunizi et al., Gadolinium Retention in the Central and Peripheral Nervous System: Implications for Pain, Cognition, and Neurogenesis, found that gadolinium was retained, not only in the cerebrum, but also in the spinal cord and peripheral nerves of rats exposed to multiple administrations of linear and macrocyclic agents. Healthy rats were injected daily for 20 days with the linear gadolinium-based contrast agent (GBCA) gadodiamide or the macrocyclic agent gadoterate meglumine. Gadolinium (Gd) retention in the cerebrum, spinal cord, and peripheral nerves occurred with both agents; however, significantly more was retained from the linear agent gadodiamide.
The study also assessed the functional implications of Gd retention on hippocampal neurogenesis and sensory and cognitive processing. In rats, gadodiamide, but not gadoterate meglumine, led to pain hypersensitivity. The authors said their results show that repeat administration of gadodiamide leads to heat and mechanical hyperalgesia in rats, suggesting that the linear GBCA might have triggered the sensitization of spinal cord nociceptive neurons. Neither agent was found to affect spatial working memory performance, hippocampal cellular proliferation, or hippocampal neurogenesis.
Interestingly, the authors commented that “retention of gadolinium in the spinal cord and peripheral nerves might contribute to sensory symptoms and burning pain in the torso and extremities described by some patients after GBCA administration.” They also said, “eventually, attention must be drawn to the long-term effects of such metal retention in the central and peripheral nervous system, especially in children and adults with medical conditions necessitating multiple MRI examinations, such as brain tumors, spinal cord abnormalities, or multiple sclerosis.”
I agree that attention must be drawn to the long-term effects of metal retention in the body, but not eventually, it needs to happen now.
I think this is an important study because the focus is not just on the gadolinium that was retained in brain tissue. While the brain is vital to our survival, it is important to investigate where else it is being retained and to consider what adverse effects that might have on the human body. In the study by Alkhunizi et al., the results show that Gd retained in the spinal cord and peripheral nervous system can adversely affect nociceptive neurons. According to Krames (2014), nociceptive pain is the most common type of pain and results from signaling of noxious or potentially harmful stimuli by nociceptors around the body. Could that explain many of the neuropathic symptoms that patients have described after their MRIs with a gadolinium-based contrast agent?
Alkhunizi, S. M., Fakhoury, M., Abou-Kheir, W., & Lawand, N. (2020). Gadolinium Retention in the Central and Peripheral Nervous System: Implications for Pain, Cognition, and Neurogenesis. Radiology, 192645. https://doi.org/10.1148/radiol.2020192645
Krames, E. S. (2014). The Role of the Dorsal Root Ganglion in the Development of Neuropathic Pain. Pain Medicine, 15(10), 1669–1685. https://doi.org/10.1111/pme.12413
Results of a study to determine whether individuals with proposed gadolinium deposition disease (GDD) have elevated serum levels of pro-inflammatory and pro-fibrotic cytokines were recently published. GDD has been reported in patients with normal renal function after MRIs with a gadolinium-based contrast agent (GBCA). The study by Maecker et al., “An initial investigation of serum cytokine levels in patients with gadolinium retention”, also sought to determine whether specific cytokines are correlated with certain symptoms considered to be characteristic of GDD. The study involved 24 participants who were recruited between May 2016 and June 2017 and met the proposed GDD diagnostic criteria. Some of the participants were recruited from our MRI-Gadolinium-Toxicity support group. A control group of 64 subjects provided serum samples before their flu vaccination. Serum cytokine levels were obtained with Luminex serum cytokine assay using eBiosciences/Affymetrix human 62-plex kits.
In patients who had retained gadolinium, serum levels of 14 cytokines, including 9 pro-inflammatory cytokines, were “statistically significantly elevated” compared to controls (p ≤ 0.05). (more…)
A recent study by Radbruch et al. used a mouse model to assess intraepidermal nerve fiber density (IENFD) after injection of gadolinium-based contrast agents (GBCAs). The study, “Is Small Fiber Neuropathy Induced by Gadolinium-Based Contrast Agents?”, was published in Investigative Radiology. Radbruch and his colleagues investigated changes of small fibers in the epidermis of mice as a potential cause of patient complaints about burning pain in their arms and legs after administration of a GBCA. As a possible additional marker for damage of small fibers, the appearance of terminal axonal swellings (TASs) was assessed. Small fiber neuropathy (SFN) is a disorder of thinly myelinated Aδ-fibers and unmyelinated C-fibers, and it is typically associated with burning pain in the lower arms and legs. The authors noted that the cause of SFN remains unknown in up to 50% of cases.
The study involved 6 groups of 8 mice that were intravenously injected with one dose (1 mmol/kg body weight) of either a macrocyclic GBCA (gadoteridol, gadoterate meglumine, gadobutrol), a linear GBCA (gadodiamide or gadobenate dimeglumine), or saline. Four weeks after injection, the mice were euthanized, and footpads were assessed using immunofluorescence staining. Intraepidermal nerve fiber density (IEFND) was calculated, and the median number of terminal axonal swellings (TASs) per IEFND was determined. They found a significant reduction of IEFND in the footpad of mice for all GBCAs tested compared with the control group. There was a significantly larger decrease of IEFND for the linear GBCAs compared to macrocyclic GBCAs. They found a significant increase of TAS/IEFND for the linear GBCAs, whereas only a “trend without significance” was found for the macrocyclic agents.
The authors noted that, to the best of their knowledge, the study is the first to investigate a correlation between small fiber degeneration and GBCA exposure. (more…)
The article, “Establishing Reference Intervals for Gadolinium Concentrations in Blood, Plasma, and Urine in Individuals Not Previously Exposed to Gadolinium-Based Contrast Agents” by Layne et al., was published in Investigative Radiology earlier this year. Their study set out to determine whether healthy people who have never received a gadolinium-based contrast agent (GBCA) have detectable concentrations of gadolinium (Gd) in their blood and urine, and to then develop a reference range for Gd concentrations in blood and spot urine. A secondary aim of the study was to determine whether spot urine Gd concentrations are equivalent to those in timed 24-hour urine collections. In the majority (93.3%) of their 120 healthy volunteers, the Gd concentrations were undetectable in blood, plasma, spot urine samples, and 24-hour urine collections. No participants had detectable concentrations of Gd in their plasma. The authors noted that those subjects who did have detectable Gd concentrations in their spot urine samples had considerably lower concentrations than those identified in the reference interval published on the Mayo Clinic web site, which is less than 0.8 mcg/g creatinine.
Proposed Gadolinium Reference Intervals, Layne et al. (2020):
- Whole blood: <0.008 ng/mL or <0.050 nmol/L
- Plasma: <0.009 ng/mL or <0.057 nmol/L
- Spot urine: <0.036 μg/g creatinine or <0.0250 nmol/mmol
More Study Details –
Twenty subjects also did a timed 24-hour urine collection, and urine Gd concentrations were measured in samples from those collections. None of the 24-hour urine collections had detectable Gd concentrations, and those 20 subjects also did not have detectable Gd in their spot urine specimens.
Study participants were recruited from the staff at Guy’s and St Thomas’ NHS Foundation Trust, London, and students from King’s College London who are based at St Thomas’ Hospital. Potential subjects completed a basic health questionnaire to determine suitability for inclusion in the study. Participants had to be 18 years or older with no significant medical history, no history of smoking or vaping within the previous 6 months, and no prior exposure to gadolinium or GBCAs. All participants had an estimated glomerular filtration rate (eGFR) of 70 or greater. Of the 120 subjects, 79 (65.8%) were female and 41 (34.2%) were male. The median age was 29.6 years.
Although no subjects reported having an MRI with a GBCA, detectable concentrations of Gd were found in 10 of the 120 subjects. Four of those 10 reported undergoing an MRI without contrast in the past, which could not be confirmed, so those 4 were excluded from further data analysis.
The authors noted that it is possible that subjects had a degree of background Gd exposure from anthropogenic gadolinium which is known to be in tap water. (more…)