On August 25, 2020, I wrote an open letter to the FDA, Radiologists and Researchers about the symptoms of gadolinium toxicity that have not, as yet, been recognized by the FDA or medical community as being caused by retained gadolinium (Gd). I believe part of the problem stems from the fact that histopathological examination has not found any evidence that deposited Gd caused “harm” in the brain. However, the lack of physical evidence and abnormal blood tests does not mean that harmful events have not taken place in patients’ bodies. What if gadolinium affected the function of cells, especially nerve cells, and triggered a cascade of adverse events, experienced by the person as decidedly abnormal and unpleasant sensations? Would that be easily detected on histological examination of tissue, or blood tests?
In my letter, I reviewed facts that we already know about Gd from the literature, in terms of both its retention after contrast administration and its effects at a cellular level. Given that Gd has been shown to induce mitochondrial toxicity, interfere with ion channels, create neuronal hyperexcitability, and affect inflammatory processes, could Gd be affecting not only the part of the brain that controls many processes, but also peripheral and autonomic nerve endings, as well as dorsal root ganglia, to produce the many and varied symptoms that patients are experiencing?
We know that retention of Gd has been demonstrated in humans, that unexplained symptoms are occurring, and the neuronal effects of Gd have been demonstrated experimentally. Could it just be that the connection has not yet been made, and when considered together, all these facts might explain how patients’ symptoms are being caused by retained Gd from gadolinium-based contrast agents (GBCAs)?
I believe many symptoms of gadolinium toxicity can be explained by Gd-induced small fiber neuropathy (SFN) and long-standing neuropathic pain. Interestingly, as you will see in my letter, many symptoms of SFN are the same as the clinical symptoms associated with nephrogenic systemic fibrosis (NSF), which makes sense to me since the cause is the same.
Symptoms of Gadolinium Toxicity: Can their cause be explained? is available for download as a PDF and it will be posted in Our Research in the Research section of our website. The reason for making my letter available to the public now is to inform doctors, researchers, and affected patients about gadolinium-related facts that do not seem to be widely recognized. My hope is that more research will be conducted that involves evaluation and testing of patients who have retained gadolinium and are experiencing SFN-like symptoms, which, until now, have been unexplained and perplexing to clinicians who are not familiar with the potential toxic effects of retained gadolinium.
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…)
A preclinical study by Bower et al. found that gadolinium-based contrast agents (GBCAs) have a toxic effect on mitochondrial respiratory function and cell viability in human neurons. The study, Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases with Reduced Kinetic Stability of the Agent, was published online ahead of print in Investigative Radiology. For the study, neurons modeling a subset of those in the basal ganglia were tested, because the basal ganglia region is one of two brain regions that displays the greatest T1-dependent signal hyperintensity changes. Multiple studies have shown that T1-signal intensity changes in the brain are the result of gadolinium deposition. The authors noted that there is increasing evidence that all agents (linear and macrocyclic) remain in human brain tissue for some period of time, where they may be taken up into various cell types, including glia and neurons.
Reports of possible clinical symptoms experienced by patients after a contrast-enhanced MRI have been published. However, until this study, it was unknown whether GBCAs induce toxic effects on the cellular function of human neurons. This study provides the first definitive evidence that GBCAs induce mitochondrial toxicity and cell death in cultured human neurons. The authors said that the “magnitude of the measured toxicity broadly increases as the kinetic stability of the contrast agent decreases, and the lower stability agents induce toxicity at concentrations that fall within the range detected in some autopsy patients”. “For all agents, the magnitude of the toxicity increases with concentration.” (more…)
On May 18, 2018, Dr. Richard Semelka added Head Pain to the recently revised primary clinical diagnostic findings for Gadolinium Deposition Disease (GDD) and he described two critical diagnostic features of GDD. First, symptoms of GDD must start within minutes to one month after administration of a gadolinium-based contrast agent (GBCA). Second, the symptoms experienced by the patient after GBCA administration must be new, and not preexisting.
There are now 6 symptoms that stand out to Dr. Semelka as critical diagnostic findings for GDD. He said that it is imperative that individuals have at least 3 of the symptoms, but he prefers to see 5/6 to be certain of the diagnosis.
The 6 main clinical criteria for Gadolinium Deposition Disease, as described by Dr. Semelka are:
1. Intense burning of the skin and skin substrate. Arising in early stage (early on after GBCA): This can be an all over feeling in the body, but often may be localized to the trunk region or distal extremities.
2. Intense boring pain in bones or joints. Arising in early stage (early on after GBCA): This can be any bones or any joints. Often the joints may be peripheral but can also be large joints like the knee or hip. Any bones can have severe point pain, but rib pain is quite distinctive for the disease.
3. Brain fog. Arising in early stage (early on after GBCA): Many terms have been used for this: mental confusion sounds more scientific, but brain fog gets the point across well and succinctly. Brain fog is also a prominent feature of lead toxicity, which is another heavy metal toxicity.
4. Muscle vibrations (muscle fasciculations) and skin pins and needles/tingling (early on after GBCA). These symptoms may represent part of the same process that is causing brain fog. Muscle vibrations/twitching and pins and needles skin sensations generally reflect nerve disease (neuropathy).
5. Head pain (early on after GBCA). Headache is both a very common occurrence and shows tremendous variability. GDD sufferers describe it as a head pain, and unlike any other type of head-ache they have previously experienced. These two properties provide differentiating features for this entity. Some describe it as a burning pain and as an extreme tightness feeling (like a tight bathing cap on their head).
6. Distal arm and leg skin/skin substrate thickening, discoloration, and pain. Arising in the subacute stage (2 weeks +): This is very much like the principal features of NSF, but generally less severe. Instead of woodiness, doughiness; instead of redness, pinkness; instead of extreme joint contractures, stiffness of joints and decreased range of motion. Skin tightness is a feature of GDD as well. This symptom complex should be expected.