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Updates on managing augmentation in RLS from Sleep Europe 2024 · VJNeurology Podcast

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  Hello and welcome to today's podcast from the Video Journal of Neurology.
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  We are an open access video journal sharing the latest news in neurology across all major disciplines.
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  Our regular podcast will bring you exclusive insights from renowned experts
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  on hot topics in their fields.
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  This episode will focus on the role of dopamine agonists in the treatment of
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  restless leg syndrome or RLS.
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  We spoke to experts at this year's Sleep Europe meeting in Seville,
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  Spain, who gave up-to-date advice on using dopaminergic agents.
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  These agents have historically been used to treat RLS, but they can cause augmentation
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  or worsening of symptoms.
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  First, you will hear from Celia Garcia-Malo, who discusses the pathophysiology
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  of RLS, highlighting the central role of iron and the importance of recommending
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  iron supplementation to patients.
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  She then goes on to introduce the impact of dopaminergic agents in the augmentation
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  of RLS and suggests alternative agents.
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  At the very beginning, we knew very, very little about the pathophysiology of restless legs syndrome.
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  But the more investigations we get, the more we get to know that iron is in the
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  core of the alterations in this disorder.
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  So for that reason, in the last years, we have been changing our hierarchy in
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  deciding when to recommend iron to our patients. and we are trying to do it in the first line.
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  In the first line treatment, we recommend iron supplementation.
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  And in the later decades, we got a lot of investigations about dopaminergic
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  agents such as levodopa and dopamine agonists.
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  But we are now aware about a complication occurring in these patients,
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  in patients receiving these medications.
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  The most important is augmentation phenomena.
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  And for this reason, in the last guidelines, we prefer not starting with these
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  medications for these patients because we now know that augmentation will come, will happen.
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  So, we are trying to start with
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  other medications such as alpha-2-delta ligands in most every patient and also
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  think about opioids because we are getting good results with low-potency opioids
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  for RLS and try to avoid dopamine agonists for this reason.
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  And, well, we also have some investigations on new targets, new therapeutic
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  options, such as, for example, perampanel, dipyridamol, peroneal nerve stimulator, also suvorexant.
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  And we are still getting more investigations about these medications because
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  the clinical trials are with very modest sample volume.
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  So still there's much more to investigate on all that.
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  Next, you will hear from Diego Garcia-Borreguero, who delves deeper into the impact
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  of dopamine agonists in RLS.
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  He explains further the biology of RLS and suggests alternative therapeutic
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  options, including agents that upregulate extracellular adenosine,
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  such as dipyridamole, or inhibit glutamatergic function, such as perampanel.
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  RLS is one of the most common, most prevalent neurological, both neurological and sleep disorders.
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  So within neurology, it's one of the most prevalent disorders and with a prevalence
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  in adults in Western countries of 2 to 3% of the adult population for clinically significant RLS.
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  If you go into the very severe forms, you will get into a 1% or something like that.
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  So it's both one of the most prevalent neurological disorders,
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  and at the same time, it's one of the most prevalent sleep disorders.
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  Second, only to obstructive sleep apnea and to insomnia.
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  Okay, having said that, the treatment for many years, the treatment of choice
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  for RLS has been based on the administration of dopamine agonists.
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  There are, both in Europe and in the United States, three different molecules,
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  three different dopamine agonists approved for the disorder.
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  These three different dopamine agonists are, all of them, very effective over the short term.
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  Extremely effective over the short term, and they have relatively little toxicity.
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  However, the problem with these agents is that over the long run,
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  over the mid and long run, they lose efficacy.
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  And at some point, they start not only losing efficacy, but also causing a iatrogenic
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  worsening of the disorder.
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  This is what we call RLS augmentation.
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  In other words, the RLS symptoms, the same symptoms that were being treated,
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  get worse as a result, not despite the treatment, as a result of the treatment.
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  And, well, the overall severity of the disorder aggravates. And this is a big problem.
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  This is a big problem so far because, well, the treatment options are few.
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  The main treatment option in these cases of augmentation has been so far the
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  administration of opioids, with all the consequences that these opioids might cause as well, no?
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  But so far, so far what we knew until now, the thing is that treatments for
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  RLS were based on chance.
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  That is, since we do not have, until recently, we did not have a good knowledge
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  of the pathophysiology involved in RLS.
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  Treatments were based on whatever it works. You try, and if it works,
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  and then you make an assumption based on that.
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  You make an assumption on the pathophysiology, not the other way around.
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  And that has been the main problem.
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  Another treatment option were gabapentinoids or alpha-2-delta ligands,
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  like gabapentin and pregabalin. But same thing.
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  The reuse didn't imply that we knew anything about the pathophysiology of the disorder.
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  Okay, but recent research has shown that it has allowed us to obtain some better
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  knowledge on what's going on in RLS.
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  Basically, it can be summarized as the following.
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  Corticalstriatal pathways, these are pathways that go from the cortex into the basal ganglia.
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  And these are pathways also that use a neurotransmitter called glutamate are hyperactive.
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  And that has been shown in animal models of RLS.
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  The reason for that is twofold. I mean, on the one hand, the centerpiece of
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  RLS is brain iron deficit, a brain iron deficiency.
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  The storage of iron in the brain is low, and as a result of that,
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  these corticostriatal pathways.
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  One of the receptors modulating their activity, which is the adenosine type
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  1 receptor, is down-regulated.
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  And that unleashes the hyperactivity of the entire pathway.
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  Adenosine is supposed to be like a break for an excessive glutamatergic function.
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  If that receptor is down-regulated, then the glutamatergic pathway is going
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  to be hyperactive. And that's the beginning, and that's what ultimately leads to symptoms.
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  Okay, having said that, that knowledge in the pathophysiology has led to two
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  different types of treatment so far.
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  One of them is the administration of drugs that ultimately increase adenosine,
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  extracellular adenosine.
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  Ideally, we would like to use adenosine type 1 receptor agonists,
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  but these drugs are very cardiotoxic.
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  So what we use is a very old drug that blocks the reuptake of adenosine into
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  the cell, and that's a dipyridamole, a drug that is normally being used as an anti-aggregant.
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  And the use of the drug has shown to improve RLS symptoms.
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  Other drugs that inhibit glutamatergic function are also able,
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  are also capable of improving RLS symptoms.
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  One example of that is parempanel.
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  Okay, so far the knowledge that we had until recently, What we are presenting at this meeting is that.
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  Previous treatments with dopaminergic agents, if any given patient has been
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  treated for over more than five years with a dopaminergic treatment,
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  say pramipexole, ropinirole,
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  rotigotine, the likelihood of these patients to respond to either a glutamatergic
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  drug or to an adenosinergic drug is going to be lower.
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  So, in other words, what you can say is any previous treatment with dopaminergics
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  will ultimately reduce future response to any other options.
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  Why is this the case? Well, because the treatment with dopaminergic agents.
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  What it ultimately will do, it will downregulate D2 and D3 receptors.
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  These are all D2, D3 agonists, and they will upregulate the D1 receptor,
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  which is a pro-nociceptive receptor.
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  It's a kind of receptor that increases the transmission of pain,
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  and we assume also of any abnormal sensations.
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  So there is an upregulation of the D1 receptor, and that will impair any response
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  to any future treatment.
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  And that links very much to new guidelines, in the sense that what you need
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  to avoid at all costs is the administration, the treatment of these patients
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  with dopaminergic agonists.
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  International guidelines have suggested in the past years,
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  have suggested that the main treatment strategy for previously untreated RLS
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  would be to spare any dopaminergic treatment,
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  to hold them for later,
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  for as late as you can, and not to start right away with them.
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  Again, these are very effective agents, but once you use them,
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  you are going to get into a loophole, and that will make the situation probably worse.
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  And American guidelines are currently discussing the possibility of...
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  Dopaminergics are very widely used in the United States, and the problem of augmentation
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  in the United States is even worse than in Europe, because they tend to use higher doses.
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  So American guidelines are thinking of getting into a recommendation by which
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  they would propose to wait with the use of any dopaminergic agents.
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  Finally, Ambra Stefani shares her views on augmentation in RLS,
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  highlighting the importance of preventing its development and recognizing it in the early stages.
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  She discusses some of the symptoms that suggest augmentation.
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  Actually, augmentation was first described in 1996, and then the criteria evolved over time.
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  And I think one of the major changes is that we realize how important this problem
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  is and how bothersome for patients and really difficult to treat so that now
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  when managing patients with RLS,
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  really one of the first things we need to think about is preventing the development of augmentation.
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  And also the diagnostic criteria for augmentation changed over time,
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  making it easier to recognize it in the very early stages.
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  So now we should already think about augmentation where we have just minimal
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  signs of it and do not wait till this is fully developed to recognize and treat it.
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  So, like the intake of the medication, the onset of symptoms at an earlier time
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  in the evening compared to the time before medication, the spreading to other body parts.
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  Usually, patients complain about symptoms in the legs.
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  And typically, when they start to be augmented, the arms are also involved.
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  Yes. Or kind of loss of efficacy of the medication. It's a kind of paradoxical
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  reaction so that when you increase the dosage of the medication,
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  symptoms worsen and if you reduce it, the symptoms improve.
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  Ambra Stefani now goes on to give her advice on managing augmentation,
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  suggesting a washout period where dopaminergic treatment is terminated or reducing
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  the dosage and combining with other agents.
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  She emphasizes that the approach needs to be considered individually for each
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  patient and discussed with the patient to have their input in treatment decisions.
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  I think it's also a kind of individual decision to be taken together with the patient.
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  I think like a drug, like a washout, like the cold turkey strategy,
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  is really efficacious, but it's really hard for the patient.
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  So whenever I try it, I really discuss with the patient.
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  I make them aware that they should expect a worsening of symptoms.
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  They can have a difficult few days or weeks.
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  And I do this only when I'm able also to provide a constant support to them.
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  And if they are really willing to do it and ready because it's a really hard
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  time and not all patients manage to go through this.
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  Otherwise, you can slowly reduce the dosage and combine with the start,
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  for example, treated with alpha 2-delta ligands.
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  And yes, with tapering of the dopamine agonist and overlapping times,
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  and this can take several weeks, months, and it's also usually working well.
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  Those are all the updates we have for you today thank you
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  so much for tuning in we hope you enjoyed listening to
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  Europe 2024 covering a variety of disorders including narcolepsy and sleep apnea. Until next time!