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

10 remarkable breakthroughs that will change neurology

This is the age of rapidly advancing technology. Blink, and the scene changes unrecognisably. It would be unbelievable if we weren’t actually living it. What technological advances will impact Neurology in the near future? Here are my top 10 neurology-impacting technologies.

1. Nanotechnology to deliver clot-busting drugs

CSIRO [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons
CSIRO [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)%5D, via Wikimedia Commons

Clot-busting or thrombolysis is life saving treatment following stroke. This however requires getting to hospital within 4.5 hours of the event, and is given by intravenous injections. How much better if it would be if thrombolysis could be delivered by mouth, and at the point of contact with paramedics. Indeed this is the idea behind clot-busting nanocapsules. Nanoparticles may also have future applications in prevention of MS relapses.

2. Disease-monitoring wearables

What if people with epilepsy could predict their next seizure? Or if someone with multiple sclerosis (MS) could predict an impending relapse? Well,  wearable technology promises to do just that. This goes beyond the fitbit which measures basic biological processes; these technologies will monitor realtime data such as a watch that measures skin moisture for seizure-prediction, or an iPad strapped to the back to monitor walking speed of patients with MS. I predict this technology will rapidly spread to many other chronic neurological diseases.

3. Nanoscale-resolution brain imaging

From the humble X-ray to the CT scan, brain imaging has progressed in leaps and bounds to a proliferation of MRI modalities with ever-increasing resolution or power. But nanoscale resolution imaging promises to make things more SciFi than healthcare. With the ability to look at ‘every nook and cranny‘ of the brain, this technology will visualise brain connections with incredible detail. Imagine how this will enhance diagnostic accuracy (and diagnostic conundrums in equal measure). This work is still in mice butI’m sure human application will follow shortly.

4. High-resolution eye selfies

Mobile phones are ubiquitous and the camera function seems to be more valuable than the talk mode. What with the number of selfies proliferating like a rah over social media. This may however be of advantage to healthcare. As the camera resolution increases exponentially, eye-selfies may come to the aid of neurologists and  ophthalmologists who treat patients with a condition called idiopathic intracranial hypertension (IIH). In this condition the pressure of the fluid around the brain is elevated. This shows as a blurring of the margins of an area called the disc and this is seen in the back of the eye using an ophthalmoscope. With advanced mobile phone cameras patients with IIH could make an eye-selfie diagnosis or assist in monitoring their eyes themselves.

5. Wireless brain EEG monitoring

Thinker Thing. https://www.flickr.com/photos/thinkerthing/8075309856
Attribution: Thinker Thing. https://www.flickr.com/photos/thinkerthing/8075309856

 

The electroencephalogram (EEG) is an invaluable tool for making the diagnosis of epilepsy. The process requires a time-consuming application of several electrodes to specific points on the scalp. The electrodes are then connected by wires or leads to a machine which records the brains electrical activity. This cumbersome process is time consuming especially for patients that need to keep the wires on for days. To the rescue is the wireless brain helmetThis will not only make the recording easier, it will send the recording wirelessly to the physiologist who will interpret the test. More interestingly, it will allow receive signals sent by the physiologist which will be targeted to treat epilepsy or other conditions like depression. The NeuroPace’s RNS system is one such device leading the way.

6.Wireless drug delivery

This is another wireless technology which facilitates the direct delivery of drugs into the brainThe device, not thicker than a human hair, is implanted into the brain and wirelessly controlled to deliver the required dose of drug, at specified times. The likely beneficiary diseases are epilepsy and depression (again). It is still in the stage of trials in mice but coming to your neighbourhood hospital very soon. If you want the complicated details then see the journal Cell for the research paper titled Wireless Optofluidic Systems for Programmable In-vivo Pharmacology and Optogenetics. What a mouthful!

7. Suicide-prediction technology

By RyanJWilmot (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons
By RyanJWilmot (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)%5D, via Wikimedia Commons

A blood test to warn of the risk of impending suicide? Wouldn’t that be great? It is not a far-fetched dream if reports that a blood test for RNA biomarkers of suicidal thoughts fulfils its potential. This will have psychiatrists whooping for joy-or out of a job!

 8. Optogenetics

Optogenetics is the use of light to control cells. This has the potential to alter nervous system function with exciting prospects for disease treatment. Again epilepsy appears to be a prime beneficiary if this takes off. Imagine programming a brain cell or neurone to glow red when calcium flows into it. This glow then dampens the activity of neighbouring cells thereby inhibiting any rouge electrical impulse that may result in an epileptic seizure. The process requires the injection of a genetically engineered virus which infects the brain cells. This ability to modify brain cell behaviour also has implications for the treatment of Parkinson’s disease (PD) and depression among other things. More SciFi you say.

9. Gene therapy for muscular dystrophy

Genetic therapy is an old dog that is still barking. This is just as well because it remains the only hope for many genetic conditions.  Genetic therapy has had its ups and downs and a very recent high is the positive outcome in leukaemia. Neurology is however not too far behind if this report that muscular dystrophy gene therapy has been successful in dogs is translated to humans. The research is rather complex but the academically minded may be interested in details of the trial.

10. Molecular spies for early cancer detection

A molecular spy is an antibody probe that is directed at the brain to detect and destroy ‘rogue’ cells. The leading researcher for this is Sam Gembhir who is based at the Canary Center at Stanford for Cancer Early Detection. Best to hear it from the horse’s mouth- speaking here at a TED talk.

https://www.youtube.com/embed/yG1J5e6-uT4” target=”_blank”>

Follow the links below for more on this topic:

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Multiple sclerosis treatment: new kids on the block

Multiple sclerosis is a scourge. It frequently targets the young with devastating, often life-long, effects. It spares no parts of the central nervous system, affecting the brain, spinal cord and major nerves. There are several MS risk factors as discussed in my previous post MS risk factors: the top 6. In this post I address the treatments of MS. There are already several agents available and the most widely used are the Interferons. Other medications are the monoclonal antibodies such as Natalizumab and Alemtuzumab. Oral agents are also gaining ascendance and include Fingolimod and Cladribine. Other drugs include Fumarate and Teriflunomide. This article gives a good overview of MS treatments. The field is however rapidly advancing and I recommend this helpful update.

"Carswell-Multiple Sclerosis2" by derivative work: Garrondo (talk)Carswell-Multiple_Sclerosis.jpg: Robert Carswell (1793–1857) - Carswell-Multiple_Sclerosis.jpg. Licensed under Public Domain via Commons.
Carswell-Multiple Sclerosis2” by derivative work: Garrondo (talk)Carswell-Multiple_Sclerosis.jpg: Robert Carswell (1793–1857) – Carswell-Multiple_Sclerosis.jpg. Licensed under Public Domain via Commons.

MS however remains an elusive condition to treat. Current treatments may reduce episodes of relapses but seem to do little to stop the progression of the disease. Some new drugs are however breaking the mold.

A highly promising drug is Ocrelizumab. This drug excited the recent European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) as discussed in this article in Medscape. It appears to be highly effective and has the advantage of producing fewer side effects than most other agents.

Anti LINGO-1 is another promising treatment in development. Anti-LINGO 1 seems to repair damaged nerves.

"Neuron with oligodendrocyte and myelin sheath" by Neuron_with_oligodendrocyte_and_myelin_sheath.svg: *Complete_neuron_cell_diagram_en.svg: LadyofHatsderivative work: Andrew c (talk) - Neuron_with_oligodendrocyte_and_myelin_sheath.svg. Licensed under Public Domain via Commons.
Neuron with oligodendrocyte and myelin sheath” by Neuron_with_oligodendrocyte_and_myelin_sheath.svg: *Complete_neuron_cell_diagram_en.svg: LadyofHatsderivative work: Andrew c (talk) – Neuron_with_oligodendrocyte_and_myelin_sheath.svg. Licensed under Public Domain via Commons.

Most treatments of MS are directed at the relapsing remitting form but it is hopeful that a new drug, Masitinib, may break the glass ceiling with progressive MS. Masitinib is an oral agent currently in trial stages. This piece from the MS Society gives further details on Masitinib.

Nanotechnology is another development which may be applied to MS treatment. Nanoparticles may be used to deliver antigens that modulate the immune system. So far however, this technology is still in animal trials.

Nanoparticles. Attribution Christopher Johnson and Vilas G. Pol via Flikr https://www.flickr.com/photos/argonne/3974983988
Nanoparticles. Attribution Christopher Johnson and Vilas G. Pol via Flikr https://www.flickr.com/photos/argonne/3974983988

 

To keep a tab on developments in the MS world I recommend the BartsMS Blog.

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