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

What are the obstacles to creating reliable neurology checklists?

This is a follow up to my previous blog post on the value of checklists in medical practice. That post explored how checklists improve clinical practice and promote patient safety. It also cited Atul Gawande‘s call to Medicine to “seize the opportunity” and produce checklists for all aspects of clinical practice.

Neurology. MV Maverick. https://www.flickr.com/photos/themvmaverick/11396461045
Neurology. MV Maverick. https://www.flickr.com/photos/themvmaverick/11396461045

 

Picking up this gauntlet for neurology comes with peculiar challenges. Here are the 7 hurdles to overcome.

1. The challenge of a diverse specialty

Legume diversity. Global Crop Diversity Trust on Flikr. https://www.flickr.com/photos/croptrust/3594324633
Legume diversity. Global Crop Diversity Trust on Flikr. https://www.flickr.com/photos/croptrust/3594324633

Neurology consists of an astonishing diversity of sub-specialities. Any neurology checklist must exhaustively cover the major neurological categories such as stroke, epilepsy, movement disorders, headache, dementia, neuromuscular diseases, sleep disorders, neuro-inflammation, nervous system tumours, and neurological infections. These topics must be thoroughly covered with emphasis on their clinical features, investigations, and treatments. A useful database must also include rare neurological diseases, of which neurology has quite a few. This is reflected in my previous blog on the most perplexing diseases that excite neurologists.

2. The challenge of multiple associated specialties

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Neurological disorders cut across many diverse allied neurological specialties. Any dependable checklist database must cover these specialised fields which include neurosurgery, neuroradiology, neuroophthalmology, neuropsychiatry, neuropaediatrics, and pain management. It must also include important diseases which straddle neurology and general medicine. These include a long list of cardiovascular, nutritional, endocrine and gastrointestinal disorders. Furthermore, neurologists often have to deal with surgical complications especially in orthopaedics and following transplant surgery. Neurologists are also frequently called upon to attend to neurological problems that are unique to pregnancy. Any practical checklist application must therefore thoroughly address these areas.

Brain Cells Created From Skin Cells in Landmark Study. Day Donaldson on Flikr. https://www.flickr.com/photos/thespeakernews/15656329862
Brain Cells Created From Skin Cells in Landmark Study. Day Donaldson on Flikr. https://www.flickr.com/photos/thespeakernews/15656329862

3. The challenge of reliable content

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It goes without saying that the most important feature of any database is reliable content which alone will engender trust and confidence. A reliable checklist must obtain its material from dependable sources. Neurology is replete with reliable textbooks and reference websites, . Neurology is also bursting at the seams with journals such as Neurology, Brain, the JNNP, and Journal of Neurology, each churning out a bewildering array of neurology guidelines, review articles, ground-breaking studies, and fascinating case reports. The challenge is to keep a regular handle on these sources, sifting through for practical and established material. As important for the user is that any checklist must be fully referenced and hyperlinked to the source material.

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4. The challenge of practical functionality

Any practical checklist database must be available on the move, easily accessible and searchable. In other words, it must be in the form of a mobile application. The app must have a reliable search functionality. More importantly for users is the requirement that the application must serves as a prompt to remember important points across the breadth of neurological practice: history taking, investigations, differential diagnosis, and treatment. For the administrator, the technology must make it easy to update and edit content, keeping the content consistently up-to-date.

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5. The challenge of varied target groups

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In developing any form of medical resource, it is a challenge to define the target audience. The primary aim of a neurology checklist application is to ease the challenges medical professionals face in accessing relevant and practical information about neurology in a timely way. This may be on a busy ward round or clinic, but also when researching a topic or preparing a presentation. The core users of a neurology application will therefore clearly be neurologists and neurology trainees.

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By SpinningSpark real life identity: SHA-1 commitment ba62ca25da3fee2f8f36c101994f571c151abee7 – Created with Superliminal’s Magic Cube 4D, CC BY-SA 3.0, https://en.wikipedia.org/w/index.php?curid=17492843

In many places however other cadres of medicine cater for people with neurological diseases. Psychiatrists, neurosurgeons, paediatriciansgeneral physicians, obstetricians, ophthalmologists, specialist and general nurses, would likely access the database. Other health care professionals may also find areas of interest such as speech therapists, physiotherapists and occupational therapistsMedical students and researchers also require vast amounts of neurological information, often within restricted time frames.

A Tangle of Different Colours 001. Christina Quinn on Flikr. https://www.flickr.com/photos/chrisser/7909899736
A Tangle of Different Colours 001. Christina Quinn on Flikr. https://www.flickr.com/photos/chrisser/7909899736

6. The challenge of public access

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Specialised medical application are never aimed at non-medically trained people. The reality however is that the general public are closely involved in their care today, seeking reliable information to address their medical concerns. It is inevitable that patients and their families will access the checklist database. For this reason the language must be simple and clear, avoiding any sort of ambiguity.

7. The challenge of resources and pricing

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A checklist application, to be most beneficial, should ideally be free to use. A Wikipedia model would be a model to adapt. But creating a checklist database, with all the features mentioned above, would surely stretch resources in terms of time and funding. There will also be great demands on resources to maintain and enhance it. A balance must be struck between beneficence and realism. Such a balance should have, as with most applications, a free version with sufficient access of some sort, and a premium version with unlimited access. The developer must also be aware that potential users have limited resources to spread round their conflicting demands. Any premium account should be affordable, perhaps not more than the equivalent cost of a cup of coffee and a cake a month.

Muffin and coffee. Phil Gyford on Flikr. https://www.flickr.com/photos/philgyford/6534958441
Muffin and coffee. Phil Gyford on Flikr. https://www.flickr.com/photos/philgyford/6534958441 

 

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Is there any neurology checklist application that has taken the above challenges into consideration? This will be revealed in my next blog post, How simple checklists unlock excellent neurological practice?

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