When it comes to imaging the nervous system, nothing but an MRI will do for the fastidious neurologist. CT has its uses, such as in detecting acute intracranial bleeding, but it lacks the sophistication to detect or differentiate between less glaring abnormalities. It also comes with a hefty radiation dose. MRI on the other hand, relying on powerful magnetic fields, is a ‘cleaner’ technology.

SLEIC 6. Penn State on Flickr. https://www.flickr.com/photos/pennstatelive/4946556307

MRI scans on their own are however often insufficient to sate the craving of the neurologist for precision. A plain MRI scan, for example, will not tell if a multiple sclerosis lesion is old or new, and it may fail to detect subtle but significant lesions such as low grade brain tumours or lymphoma. Many lesions on routine MRI scan are also ill-defined and non-specific, and could pass for abscesses, vasculitis, inflammation or just small vessel disease (wear and tear) changes.

The Brain. I has it. Deradrian on Flickr. https://www.flickr.com/photos/mgdtgd/3507973704

To silence the niggling doubts, the neurologist often requests an MRI scan with contrast. The idea is to use a dye to separate the wheat from the chaff, the active lesions from the silent ones. This works because sinister lesions have a bad and dangerous habit of disrupting the blood brain barrier. All such insurgencies across the hallowed BBB is sacrilege, a sign that something serious is afoot, (or is it underfoot?). Contrast dyes, on the other hand, are adept at detecting these breaches, traversing them, and staining the sinister lesion in the process. This stain appears on the MRI scan as contrast enhancement. MRI with contrast is therefore invaluable, and a positive study is a call to arms.

By © Nevit Dilmen, CC BY-SA 3.0, Link

Without any doubt, gadolinium is the favoured dye for contrast MRI scans. Gadolinium (Gd) is a lanthanide rare earth metal and it is one of the heavier elements of the periodic table with atomic number 64. It is named after the thrice-knighted Finnish chemist Johan Gadolin, who also discovered the first rare earth metal, yttrium.

Periodic table model. Canada Science and technology Museum on Flickr. https://www.flickr.com/photos/cstmweb/4888243867

We know a lot about some of the risks of injecting gadolinium into the body, such as its tendency to accumulate in people with kidney impairment (who cannot excrete it efficiently). We also know that it may cross the placenta to damage the developing baby. These are however hazards with simple and straight-forward solutions: avoid gadolinium in pregnancy, and don’t use it in people with poor renal function.

By Hi-Res Images ofChemical Elements – http://images-of-elements.com/gadolinium.php, CC BY 3.0, Link

Much more challenging is the problem of gadolinium deposition in the brain of people with normal renal function. This is concerning because it is unpredictable, and because it has the potential to compromise brain structure and function. This blog has previously asked the question, “Is gadolinium toxic?“. The question remains unanswered, and regulatory agencies are still studying the data to provide guidance to doctors. Patient groups on the other hand have been up in arms, as one would expect, impatiently waiting for answers. What then is the state of play with gadolinium? Should neurologists and their patients really be worried? Below are 8 things we now know about gadolinium and its potential brain toxicity.

By Peo at the Danish language Wikipedia, CC BY-SA 3.0, Link

•••

1. Gadolinium deposition is related to its insolubility at physiological pH

The toxic potential of gadolinium is thought to be the result of its insolubility at physiological pH. Furthermore, gadolinium competes against calcium, an element fundamental to cellular existence. This competition is obviously detrimental to the body.

064 Gadolinium-Periodic Table of Elements. Science Activism on Flickr. https://www.flickr.com/photos/137789813@N06/22951789105

2. The less stable gadolinium agents are the most toxic

There are two forms of gadolinium based contrast agents (GBCAs): the less stable linear GBCAs, and the more stable macrocyclic GBCAs. The linear GBCAs are more toxic, of which Gadodiamide (Omniscan) stands out. Other linear agents are gadobenate dimeglumine (MultiHance), gadopentetate dimeglumine (Magnevist), gadoversetamide (OptiMARK), gadoxetate (Eovist), and gadofosveset (Ablavar). The macrocyclic GBCAs, even though safer, are not entirely blameless. They include gadobuterol (Gadavist), gadoterate meglumine (Dotarem), and gadoteridol (ProHance). Therefore, choose your ‘gad’ wisely.

By زرشکOwn work, CC BY-SA 3.0, Link

 

3. Gadolinium deposits in favoured sites in the brain

It is now established that gadolinium deposits in three main brain areas. The most favoured site is the dentate nucleus of the cerebellum. Other popular regions are the globus pallidus and the pulvinar. This deposition is, paradoxically, visible on plain T1-weighted MRI scans where it shows as high signal intensity.

By Polygon data were generated by Database Center for Life Science(DBCLS)[2]. – Polygon data are from BodyParts3D[1], CC BY-SA 2.1 jp, Link

4. The risk of deposition depends on the number of injections

The risk of gadolinium deposition in the brain is higher with multiple administrations. Stated another way, and to stretch this paragraph out a bit longer, the more frequently contrast injections are given, the higher the chances gadolinium will stick to the brain. The possible risk threshold is 4 injections of gadolinium. The fewer the better…obviously!

Number-04. StefanSzczelkun on Flickr. https://www.flickr.com/photos/stefan-szczelkun/3931901057

5. Gadolinium also deposits outside the brain

The favoured site of gadolinium deposition outside the brain is the kidney, where it causes nephrogenic systemic fibrosis, a scleroderma-like disorder. This however occurs mostly in people with renal impairment. Gadolinium also deposits in other organs outside the brain including bone, skin, and liver. (Strictly speaking, this item has nothing to do with the brain, but it helped to tot up the number to 8 in the title of this blog post, avoiding the use of the more sinister se7en).

By JudgefloroOwn work, CC BY-SA 4.0, Link

 6. Harm from gadolinium brain deposition has not been established

Whilst we know for sure that gadolinium deposits in the nervous system, harm from deposition has not been definitively established. There are, however, reports that gadolinium deposition may produce muscle and eye symptoms, and chronic pain. There are also reports of cognitive impairment manifesting as reduced verbal fluency.

Words words words. Chris Blakeley on Flickr. https://www.flickr.com/photos/csb13/4276731632

7. Precautions may reduce the risk of gadolinium brain deposition

The current recommendation is not to withhold the appropriate use of gadolinium, but to observe simple precautions. Sensibly, use GBCAs only when absolutely necessary. Also consider preferentially using macrocyclic GBCAs and evaluate the necessity for giving repeated GBCA administrations.

 

By IntropinOwn work, CC BY-SA 3.0, Link

 

8. There are emerging ways to avoid gadolinium toxicity

The safest use of gadolinium is not to use it at all. There are some developments in the pipeline to achieve this, although probably not in the very near future. Such developments include manganese based contrast agents such as Mn-PyC3A. A less definitive option is to mitigate the effects of gadolinium by using chelating agents; two such potential agents are nanoparticles and 3,4,3-LI(1,2-HOPO).

 •••

Why not get the snapshot view of gadolinium toxicity in the neurochecklist:

Gadolinium-based contrast agent (GBCA) toxicity

…and leave a comment!

•••

MRI scan. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/30805879596

18 thoughts on “8 things we now know about the toxicity of gadolinium to the brain

  1. This is great. we do hope that future developments will soon address these limitations to the use of gadolinium.
    congratulations Dr. Ibrahim

    Like

      1. Thanks, Dr. Ibrahim! Do you believe there is hope for those who have already been poisoned? Like if Berkeley ever gets the HOPO chelator funded, do you think it could be not only preventative but also a cure?

        Like

      2. I think poisoning is too strong a term to describe the situation based on the current evidence. I am not sure however whether chelators will remove gadolinium that has already been deposited. We just have to wait and see I guess

        Like

  2. My name is Scott Norris and I’m a long-term brain cancer survivor (diagnosed in 1999). 

    Over the past 18 years I’ve had two left frontal craniotomies, six weeks of standard radiation, a gamma knife radio-surgery procedure and 12 months of chemo. 

    I am currently stable and undergoing no other treatments except for being followed with MRIs with contrast. To date, I’ve had approximately 60-70 MRIs with contrast (Gadolinium / Gadobutrol / Gadavist).

    I was recently informed by a radiology professional that my most recent brain scan of February 2018 shows T1 hyperintensity of the globus pallidus and of the dentate nuclei due to gadolinium deposition.

    I came across a August 14, 2017 LIVESTRONG.COM article, “Side Effects of MRI With Contrast” (https://www.livestrong.com/article/178926-side-effects-of-mri-with-contrast/).

    In the article it mentions that blood clotting issues are a common side effect of MRI contrast agents.

    Since January of this year I have been diagnosed with two blood clots in my upper right thigh which, according to the author of the aforementioned article, are a common side effect of MRI contrast agents.

    I was just wondering if you had other information or sources citing blood clotting issues and MRI contrast agents.

    Thank you so much for your time.

    Sincerely,
    Scott Norris
    San Jose, California, USA

    Like

    1. Thanks for sharing your experience Scott. I hope things turn out well eventually. I’m afraid I haven’t researched the link between gadolinium and blood clots specifically – maybe something for a future blog post. With best wishes

      Like

      1. Thanks! If you come across anything related to the topic please let me know. All my best, Scott

        Like

  3. Hi!
    This was very informative for me. I have MS as well as 2 Meningiomas. I have been having MRIs since 1990 using Omniscan,Multihance and now Gadavist. I have free Gad in my Ankle,knee and cerebellum. Over the last year I have now been having symptoms like paroxysmal Dystonia we are thinking Is coming from the free Gadolinium but no one wants to believe it. The funny thing is I am a MRI Technologist. I know this is real. My neurologist put me on Trileptal, an anti seizure medication, and it has helped. I have not taken any MS medication in almost 20 years as I have not needed it, my lesions have been stable and not progressed. I am very very blessed. I do believe more research needs to be done on the Gadolinium Toxicity.
    Thank you again for your information! It was extremely helpful for me!
    Bonnie Justice
    Graham,NC

    Like

    1. Thanks for sharing your experience Bonnie. There is indeed a lot that is unknown, and I agree more research is needed. Luckily there is increasing awareness. Wishing you the best

      Like

    2. Dear Bonnie,

      Thank you for sharing your experience. I have been going through something similar and have been feeling all alone.

      Over the span of 20 years of living with brain cancer (GBM), I have undergone two left frontal craniotomies, six weeks of standard radiation therapy, a Gamma-Knife radiosurgery procedure, 12 months of chemotherapy and 70 MRIs.

      Each of my MRIs for the past 10 years, since my second left frontal craniotomy, has shown no evidence of tumor recurrence.

      I do have, however, visible gadolinium deposits in my brain, an estimated 1 gram or more in my bones, and a lab test of my hair which indicates excessive levels of gadolinium in my body.

      Since my March 2019 MRI something quite unexpected and severely debilitating has happened. In response to the trend away from linear GBCAs to macrocyclic GBCAs my treating facility switched to the macrocyclic agent Dotarem. Long story short, since that MRI my symptoms have progressed to the point to where my legs are nearly paralyzed—I need a walker to effortfully and slowly get around the house, and I need a wheelchair to get to doctor appointments. My neurologist has turned a blind eye to my symptoms, as have many in the radiology department at my treating facility. And I also have side effects similar to dystonia. (“Paralysis or severe weakness of the legs” is a documented side effect of Dotarem on the following site: https://www.drugs.com/cons/dotarem.html; however, it is not listed in the Dotarem Prescribing Information, the only valid safety information reference approved by the FDA which the manufacturer adheres to.)

      The theory behind the switch to macrocyclics, as my wife and I were informed, is that the macrocyclic agents have a reduced chance of gadolinium deposition within the body as well as a reduced risk for Nephrogenic Systemic Fibrosis (NSF) which is found in patients who have renal insufficiency. (I do NOT have renal insufficiency, yet an acupuncturist noted that I am showing signs of fibrosis in my legs.)

      First of all, the macrocyclic agents are obviously having unintended consequences. As Dr. Robert McDonald of the Mayo Clinic has said, “As macrocyclic agents are taking over the market, we’re seeing quite a few complaints of gadolinium deposition disease from these agents.”  

      And secondly, Dr. Richard Semelka (an expert on gadolinium toxicity/deposition) in his paper, “Presumed Gadolinium Toxicity in Subjects With Normal Renal Function: A Report of 4 Cases,” concludes that, “Vigilance to identify additional cases and investigate strategies for prevention and treatment is warranted.”

      The fact that very few acknowledge (or even know how to treat) these side effects should be very concerning to all.

      Thanks so much for listening. Hope to hear from you.

      Scott Norris
      San Jose, California

      cc: Dr. Imam

      Like

      1. Thanks for sharing your experience Scott and my sympathies. It is clearly an emerging concern and there is a need to limit, and to use the safest, contrast agents. Hopefully research into the alternative agents I mentioned in the blog post will lead to a situation where gadolinium will be discarded in future

        Like

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