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. Interestingly, the authors said that, “although the debate about NSF started with reports on skin pathologies and pain has been reported as one of the major symptoms of NSF, little attention has been paid on a potential involvement of small fibers in the skin.” NSF research focused mainly on the activation of fibroblasts that is likely triggered by the release of gadolinium from GBCAs.

The authors said that although it is unclear whether the findings of the current animal model will appear in humans or translate into clinical symptoms, the significant findings of the study require more research.

My thoughts –

I am encouraged by the findings of the study by Dr. Radbruch and his colleagues. As far as I know, it is the first study that links gadolinium-based contrast agents to a recognized disorder that is unrelated to the patients’ level of renal function and can be confirmed with a skin biopsy or other testing.  Hopefully, it will lead to additional studies that confirm the link between gadolinium-based contrast agents and the symptoms reported by patients after their MRIs with a GBCA.  In our MRI-Gadolinium-Toxicity support group, quite a few people have been diagnosed with SFN since their contrast-enhanced MRIs. Based on members’ symptoms, I suspect that many more may have SFN, but they have not been tested. Some people, like me, were put on medication to treat neuropathic or burning pain.  I think testing members of our support group for SFN would provide an excellent research opportunity.

The paper is available to the public.
Radbruch, A., Richter, H., Bücker, P., Berlandi, J., Schänzer, A., Deike-Hofmann, K., … Jeibmann, A. (2020). Is Small Fiber Neuropathy Induced by Gadolinium-Based Contrast Agents? Investigative Radiology, 55(8). Retrieved from https://journals.lww.com/investigativeradiology/Fulltext/2020/08000/Is_Small_Fiber_Neuropathy_Induced_by.1.aspx

Sharon Williams