8 things we now know about the toxicity of gadolinium to the brain

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

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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).

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

Gadolinium-based contrast agent (GBCA) toxicity

…and leave a comment!

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

Why is CLIPPERS breaking its shackles to the pons?

CLIPPERS is unusual enough you would think. Nothing to do with barbing and shearing I assure you. CLIPPERS stands for Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. The striking feature of CLIPPERS is inflammation in the pons, the chunky middle part of the brainstem. This distinguishes it from other neurological inflammatory disorders such as multiple sclerosis (MS) and neuromyelitis optica (NMO).

By Images are generated by Life Science Databases(LSDB). - from Anatomography[1] website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, Link
By Images are generated by Life Science Databases(LSDB). – from Anatomography[1] website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, Link

CLIPPERS has however now broken loose from its shackles to the pons, and is spreading down into the spinal cord. Sacrilege you might say.

By BruceBlaus - Own work, CC BY 3.0, Link
By BruceBlausOwn work, CC BY 3.0, Link

This disruptive and subvertive action was reported in two prestigious neurology journals. The first paper in the journal, Neurology, is titled CLIPPERS with diffuse white matter and longitudinally extensive spinal cord involvement. The second is reported in the journal, Brain, as CLIPPERS with lesions distributed predominantly in spinal cord.

"What's in a name?" Jack Dorsey on Flikr. https://www.flickr.com/photos/jackdorsey/170257936
“What’s in a name?” Jack Dorsey on Flikr. https://www.flickr.com/photos/jackdorsey/170257936

What is it about neurological inflammatory disorders that makes them so rebellious? Why do they defy convention and disregard their defining features. I discussed a similar phenomenon in my previous blog post titled Why is neuromyelitis optica (NMO) endlessly surprising neurology? NMO refused to play by the rules and was punished by having it’s named changed to NMOSD. Perhaps it’s time for CLIPPERS to suffer the same fate….starting with a shorter acronym perhaps?

 

Check out more on CLIPPERS in Neurochecklists

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The emerging links between depression and MND

At first, it seemed like a single drop, but it is quickly turning into a trickle. The first inkling was a study of >1,700 people with motor neurone disease (MND) which was published in the journal Neurology titled Depression in amyotrophic lateral sclerosis. The authors found that depression is a very frequent diagnosis shortly before people are diagnosed with MND.

Von Vincent van Gogh - The Yorck Project: 10.000 Meisterwerke der Malerei. DVD-ROM, 2002. ISBN 3936122202. Distributed by DIRECTMEDIA Publishing GmbH., Gemeinfrei, Link
Von Vincent van Gogh – The Yorck Project: 10.000 Meisterwerke der Malerei. DVD-ROM, 2002. ISBN 3936122202. Distributed by DIRECTMEDIA Publishing GmbH., Gemeinfrei, Link

Surely a coincidence, I thought. A rogue finding, or even an understandable response to illness. My excuses were however debunked by another paper published soon after in the Annals of Neurology. Titled Psychiatric disorders prior to amyotrophic lateral sclerosis, the study found that depression may precede the diagnosis of MND by more than 5 years. The authors also report a high frequency of other psychiatric conditions preceding the diagnosis of MND, such as anxiety and psychosis

Depression. Nils Werner on Flikr. https://www.flickr.com/photos/130721398@N06/25363062843
Depression. Nils Werner on Flikr. https://www.flickr.com/photos/130721398@N06/25363062843

 

And just off the press is this report from Nature Communications titled Genetic correlation between amyotrophic lateral sclerosis and schizophrenia. What do we make of this? Is this just the tip of the iceberg? Surely more studies are needed before any firm conclusions. Perhaps this may lead to some early biomarker that enables neurologists to stop the process of progression to full blown MND. Perhaps.

https://pixabay.com/en/sky-clouds-rays-of-sunshine-414199/
https://pixabay.com/en/sky-clouds-rays-of-sunshine-414199/

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Masitinib, a breakthrough drug shattering neurology boundaries

In the process of writing a blog post on the research findings altering neurological practice, my sight fell on the drug, Masitinib. I was completely unaware of this tyrosine kinase inhibitor, one of the promising drugs in the fight against multiple sclerosis (MS). We are likely to hear a lot more about Masitinib in MS in the coming months.

By Zeldj - Own work, CC BY-SA 4.0, Link
By ZeldjOwn work, CC BY-SA 4.0, Link

Masitinib is however not flexing its muscles just in neuro-inflammation. On the contrary, it is seeking laurels far afield, in the realm of neuro-degeneration. I was indeed pleasantly surprised to find that researchers are studying the impact of Masitinib on two other horrible scourges of neurology. The first report I came across is the favourable outcome of a phase 3 trial of Masitinib in motor neurone disease (MND) or amyotrophic lateral sclerosis (ALS). The drug reportedly ‘reached its primary objectives‘ of efficacy and safety. In this trial, Masitinib was used as an add-on to Riluzole, the established MND drug. It’s all jolly collaborative at this stage, but who knows what threat Masitinib will pose to Riluzole in future! You may read a bit more on Masitinib and MND in this piece from Journal of Neuroinflammation.

By Capilano1 - Own work, CC BY-SA 4.0, Link
By Capilano1Own work, CC BY-SA 4.0, Link

The second report I came across is the potential of Masitinib in the treatment of Alzheimer’s disease (AD). This is at the phase 2 trial stage, and already showing very good outcomes in people with mild to moderate AD. Masitinib was used as an add-on drug to the conventional AD medications Memantine, Donepezil, Galantamine and Rivastigmine. These drugs can therefore rest comfortably on their thrones…at least for now! You can read a bit more on Masitinib and AD in this article from Expert Review of Neurotherapeutics.

Alzheimer's Disease. Hamza Butt on Flikr. https://www.flickr.com/photos/141735806@N08/28007367952
Alzheimer’s Disease. Hamza Butt on Flikr. https://www.flickr.com/photos/141735806@N08/28007367952

The question however remains, why should one drug work well on such disparate diseases? I know, this feels like deja vu coming shortly after my last blog post titled Alzheimers disease and its promising links with diabetes. In that post I looked at the promise of the diabetes drug, Liraglutide, in the treatment of Alzheimers disease. I have however also reviewed this type of cross-boundary activity of drugs in my older posts, Will riluzole really be good for cerebellar ataxia? and old drugs, new roles? Perhaps Masitinib is another pointer that, as we precisely define the cause of diseases, they will turn out to be merely different manifestations of the same pathology. Food for thought.

Benjah-bmm27 assumed. Own work assumed (based on copyright claims). Public Domain, Link
Benjah-bmm27 assumed. Own work assumed (based on copyright claims). Public Domain, Link

 

As I said, this wasn’t the post I set out to write. So watch out for my next blog post, the major research outcomes altering neurological practice.

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Alzheimers disease and its promising links with diabetes

In the excellent book, The Innovators Prescription, the authors predict that precision medicine will replace intuitive medicine, and diseases will be defined by their underlying metabolic mechanisms, and not by the organs they affect, or the symptoms they produce. Clayton Christensen and colleagues argue that this precise definition of diseases will lead to more effective treatments. But they also show that precision medicine will show that many different diseases actually share the same underlying metabolic derangements. Many disparate diseases will therefore turn out to be just mere manifestations of the same metabolic disease.

Precision Medicine Conference at Harvard. Isaac Kohane on Flikr. https://www.flickr.com/photos/52786697@N00/16892093678
Precision Medicine Conference at Harvard. Isaac Kohane on Flikr. https://www.flickr.com/photos/52786697@N00/16892093678

A clear indication that precision medicine will blur the boundaries between diseases is the recent suggestion that the anti-diabetes drug Liraglutide may help to treat Alzheimer’s disease (AD). Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist which is effective in type 2 diabetes, a condition which is worlds apart from Alzheimer’s disease. So far removed from each other, it would be easy to dismiss any links as tenuous. But the headlines were emphatic: Drug used to treat diabetes could cure Alzheimer’s, and Diabetes drug could influence brain activity in Alzheimer’s. 

diabetes-1326964_1280

It is however no hype: there is evidence that Liraglutide may benefit people with Alzheimer’s disease. Trials in animal have shown that Liraglutide promotes neuronal survival, learning and memory, and reduces neuroinflammation and amyloid plaque formation. One such study is titled Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Beyond animals, small human trials have shown that Liraglutide improves brain glucose metabolism in Alzheimer’s disease.

beta-amyloid-plaques. vestque on Flikr. https://www.flickr.com/photos/35049835@N00/16867428955
beta-amyloid-plaques. vestque on Flikr. https://www.flickr.com/photos/35049835@N00/16867428955

Why should Liraglutide work so well in both diabetes and Alzheimer’s, diseases with apparently different pathologies? The answer lies in insulin resistance, the underlying mechanism of type 2 of diabetes; there is now evidence that insulin resistance contributes to dementia. If this is the case, Liraglutide, by improving glucose metabolism, could potentially treat both diabetes and Alzheimer’s disease.

Sugar Cubes. David Pace on Flikr. https://www.flickr.com/photos/63723146@N08/7164573186
Sugar Cubes. David Pace on Flikr. https://www.flickr.com/photos/63723146@N08/7164573186

To explore this potential further, there is now a large multicentre trial exploring the real benefit of Liraglutide in Alzheimer’s disease. Titled Evaluating Liraglutide in Alzheimer’s Disease or ELAD, it is recruiting people with mild disease, aged between 50-85 years old, and who do not have diabetes. As they say, watch this space!

Brain Aging. Kalvicio de las Nieves on Flikr. https://www.flickr.com/photos/118316968@N08/19444505382
Brain Aging. Kalvicio de las Nieves on Flikr. https://www.flickr.com/photos/118316968@N08/19444505382

Going back to the subject of precision medicine, why not visit my other blog, The Doctors Bookshelf where I will soon be reviewing The Innovators Prescription

Minocycline-induced vasculitic neuropathy

This is a quick post to highlight the association of minocycline and neuropathy.

By Elbreapoly (Own work) [Public domain], via Wikimedia Commons
By Elbreapoly (Own work) [Public domain], via Wikimedia Commons

This comes from an article in Neurology titled Vasculitic neuropathy following exposure to minocycline. Minocycline is an antibiotic commonly used in the treatment of acne. Vasculitic neuropathy on the other hand is as bad as neuropathies come-in the cases reported here, one developed stroke, and another severe systemic symptoms.

By Ben Mills - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6051872
By Ben MillsOwn work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6051872

 

Worse still, stopping the treatment doesn’t resolve the problem, the patients requiring long-term immunosuppression.What a hero-to-zero move by minocycline, a fall from grace to infamy.

acne

The learning point however: ask your next patient with severe neuropathy if they have been treated for acne!

Metronidazole-two case lessons for neurologists

I came across two articles recently which highlighted neurological complications of metronidazole I was previously unaware of.

321-Metronidazole by Chris on Flikr. https://www.flickr.com/photos/chrisinplymouth/3947569729
321-Metronidazole by Chris on Flikr. https://www.flickr.com/photos/chrisinplymouth/3947569729

 

The first is a case report of metronidazole-induced encephalopathy in the journal Neurocritical Care. I admit I only read the abstract and the key word there is involvement of the dentate nuclei.

 

Metronidazole by Chris on Flikr. https://www.flickr.com/photos/chrisinplymouth/3949517597/
Metronidazole by Chris on Flikr. https://www.flickr.com/photos/chrisinplymouth/3949517597/

 

The second case report is of metronidazole-induced ataxia in the journal Movement Disorders.

 

These are rather uncommon side-effects and should not deter from prescribing metronidazole. But it is just worth looking more carefully at that medication list if your next patient  has unexplained encephalopathy or ataxia.