Hot Topic: Prodromal synucleinopathies - REM sleep behaviour disorder

In this first episode, we are gonna talk about REM sleep behavior disorder. And for this, I have Laura Pérez Carbonell as a guest, who is a consultant in sleep medicine and neurology at the Sleep Disorders Centre at Guy's Hospital in London. Thank you very much Laura, for joining us today.

Dr. Laura Perez-Carbonell: Thank you so much, Eduardo, for having me. A real pleasure to be here.

Dr. Eduarduo de Pablo Fernandez: So it's not very common that we have a sleep specialist in [00:01:00] the MDS Podcast. I wanted to start the interview with you telling us a bit about yourself, how you train in sleep medicine, and if there is any more formal fellowships or ways to reach this training as this may be interesting to some of the listeners.

Dr. Laura Perez-Carbonell: I guess this is a long-standing question, and we all feel that we need to find our own path to training in sleep. In Europe, there are a few places where you can have some dedicated training to sleep as a neurologist. In my case, I decided to do my master's in sleep medicine at University of Barcelona where I later completed my PhD.

I decided to do this after I completed my training in neurology in Madrid, in Spain. And then I moved here to the UK to do a fellowship in sleep medicine at Guy's and St Thomas' where I'm working now. I guess that for those that are very much [00:02:00] interested in training in sleep and want to develop their work in this field within Europe I guess the certification of expert in sleep medicine by the European Sleep Research Society is the way to go.

And then I'm aware that there are other countries that have their own paths, but generally it's not a very well-standardized field to train in and it's very much something that every one of us have decided to do in our own way and looking for our own path.

Dr. Eduarduo de Pablo Fernandez: Thank you for sharing that. So let's start with REM sleep behavior disorder. First of all, can you tell us a bit what is REM sleep and what happens during a REM sleep behavior disorder?

Dr. Laura Perez-Carbonell: Yeah. So REM sleep is one of the sleep stages that we have in a full cycle of sleep. So we have non-REM sleep, which is non-rapid eye movement sleep going from N1 and 2 and 3, lighter to deepest sleep stages. And then we have REM sleep, [00:03:00] rapid eye movement sleep that happens periodically in each cycle that we have throughout the night.

But it's more dense, it tends to be more frequent towards the second half of the night. So it happens from the first sleep cycle that we have, but it tends to be more prolonged towards second half, end of the night. In this sleep stage, characteristically, we tend to have more dreaming or the sort of dreams that we more frequently recall.

And from a physiological point of view the main characteristic is that we have, apart from the rapid eye movement the muscles in our body should be relaxed, should be atonic. So muscle atonia is the neurophysiological characteristic of this stage. In REM behavior disorder or REM sleep behavior disorder, we see that patients actually have this physiological muscle atonia altered.

So, they have a loss of muscle atonia in REM sleep, and they therefore end up [00:04:00] acting out their dreams. They can do things such as punch or kick, they can flail their arms, they can shout out. They can also do slightly nicer things like singing or laughing. And all of these behaviors, movements, or vocalizations seem to go alongside the content of their dreams.

More typically, these dreams are quite vivid and quite action-packed, involving things like needing to defend themselves from a threat being attacked by an animal, by a person. But they can also have other, again, nicer content. They sometimes are playing sports or they're just having a conversation with someone in their dream.

Dr. Eduarduo de Pablo Fernandez: Excellent. And can you tell us this can happen in the context of neurodegenerative disorders or it can happen also in isolation, right?

Dr. Laura Perez-Carbonell: Yes, absolutely. We consider secondary forms of RBD, those that happen on [00:05:00] established neurodegenerative conditions such as alpha-synucleinopathies, and we will talk about this in a bit more detail later on. But also in the context of other neurological disorders very typically, for instance, for us to see in the sleep clinic are patients with narcolepsy type 1 that have comorbid REM behavior disorder at night.

There are also other forms that seem to be mainly triggered by medications mainly certain antidepressants but can also be triggered by beta blockers. And then we have what we call isolated REM sleep behavior disorder, isolated RBD which is the, the form that happens in isolation as its name indicates, and it's linked with the future risk to develop an overt synucleinopathy.

Dr. Eduarduo de Pablo Fernandez: Excellent. We will talk about this a bit later on. But if you can tell us a bit more about the diagnosis, how can we confirm the diagnosis? [00:06:00] And I guess because in some areas the access to sleep studies or sleep units is quite restricted, how can we have a secure and accurate diagnosis without sleep studies?

And also we can discuss a bit about the future, how things are moving to just make the diagnosis outside a hospital.

Dr. Laura Perez-Carbonell: Absolutely. Yeah. We do have several screening questionnaires that, that help identify possible RBD patients. And to date remain to consider the polysonography as the gold standard to confirm the diagnosis, to identify loss of REM atonia and, alongside a, a suggestive clinical history we can confirm the diagnosis.

But we are aware that, availability for polysonography is a challenge in certain parts of the world. And it's also a, a difficult thing even when it's available. It's a big ask for patients that are vulnerable or live far away from a sleep lab to be [00:07:00] investigated this way.

I guess that one of the things that is probably going to be the next step in order to diagnose RBD in a slightly easier or closer way for patients is to bring the studies to their homes. And there is some work that has been done with the use of home video polysonography which seems to be a good option to obtain all the information that we have, but avoiding needing to ask patients to come to a sleep lab when that may not be available or may be far away from where they live.

Probably the future will bring us also other opportunities that involve using some limited signals rather than a full standard polysonography. Deciding or choosing specific signals that can help us identify the sleep stage in which we're at the muscle activity during REM sleep and maybe also video.

Because of course, if we were able to capture movements, even if there were no full-blown [00:08:00] episodes of RBD, but even smaller, shorter movements identifying REM sleep can be very helpful as well. So a lot of work is being done at the moment by various groups around the world and there is, of course this introduction of use of machine learning models automatic analysis of combined outputs that are obtained by a, a limited set of signals rather than a full video PSG to try and identify or differentiate patients with RBD from those that don't have RBD.

If we're thinking more in the setting of general population trying to identify as many patients as possible, particularly for those with isolated RBD that we know are at a high risk to develop a neurodegenerative condition. We will need to have a stepwise approach and quite likely in the future we'll need to implement protocols where we use screening questionnaires, maybe adding some intermediate step with an interview that can be done remotely, [00:09:00] and then introducing some simpler devices, limited PSG devices that can help us then confirm the diagnosis.

But yeah, I think that there are a few things that need to be developed and there will need to be some works being done to try and generalize the methods that we use in this context.

Dr. Eduarduo de Pablo Fernandez: Excellent. And going back to the neurophysiological studies, so what I understood is that things are moving in a way like epilepsy, where you can have electrophysiological recordings in an ambulatory way. And I would like you to comment a bit on some of the limitations of the video polysomnography as an inpatient because sometimes this is something that we as clinicians challenged in someone that we think suffers from REM sleep behavior disorder but comes back with a normal polysomnography.

Can you comment a bit on that?

Dr. Laura Perez-Carbonell: So I think that's a very important question. I think that, of course being in an unfamiliar environment it n- never helps, [00:10:00] and particularly for those sleep labs that are based in for instance within a ward, a hospital ward it can get very noisy, it can get very disruptive.

So I think every sleep lab tries to be as calm as an environment as possible. But there are things that can affect the sleep quality, and some patients don't feel that they had a good night's sleep when they stay over in a sleep lab. So that is a limitation.

There are other patients as well where because of their short total sleep time they have, or because of the effect of certain medications, we might not be able on a single night to record REM sleep, and that is quite a common reason for us to end up repeating studies. So I think there are inherent limitations or challenges for in-lab sleep studies.

On the other hand, I think it's also good to have a controlled environment, from a technical point of view. There are, of course, some limitations that you see when studies are done at [00:11:00] home. But probably with simpler devices, that's something that we should be able to overcome and and with some education to patients or bed partners to resolve on the night.

Dr. Eduarduo de Pablo Fernandez: Interesting point, yeah. Let's move on now to talk about REM sleep behavior disorder in the context of manifest Parkinson's disease. So it's quite a common symptom overall, and I would like you to talk about the prevalence, if there is any data on the course, because one of the things is it can fluctuate a lot during the course of the disease.

And maybe if you can talk a bit about how to manage the symptoms of REM sleep behavior disorder with pharmacological and also non-pharmacological therapies.

Dr. Laura Perez-Carbonell: Yeah. I think if we consider those studies that have used video polysonography to estimate prevalence of RBD in Parkinson's this has been estimated between 25 and 50% roughly. And it's estimated as well that about 20% of those really the RBD started [00:12:00] quite likely before the onset of motor dysfunction.

Over time, if we follow up cohorts of patients with Parkinson's, it seems that the prevalence of RBD increases. And it seems that also at an individual level if we do follow-up polysonography studies we tend to see an increment in the amount of REM sleep without atonia over time.

So that's something that we can see on the follow-up of these patients. I think clinically it's slightly more challenging to assess. First of all, because it's a condition like in many sleep disorders where patients are very often not aware of the episodes. So unless they frequently wake up because of their dreams, or because they have fallen out of bed or they've injured themselves. Sometimes it's more often a bed partner really reporting you what's going on and whether they have improved or not.

So I think part of the sort of [00:13:00] fluctuation and uncertainty on what the course is expected to be over time from a clinical point of view relies on the fact that we depend on that witness that is seeing the patient act out their dreams at night. If there is no bed partner, it is sometimes difficult to estimate how are things going.

From a treatment point of view, I think the crucial part of the conversation when a patient has suspected RBD or confirmed RBD is to talk about safety to ensure that the bedroom environment is adjusted in a way that we try to mitigate any risks. So try to avoid sleeping on the side of the bed that is close to a radiator.

Trying to have, pillows, cushions on the floor, padded bed rails, soft headboard. So that there are simple things that can be considered. Removing bedside table, not having glass close to them. Those sort of things that they very often, to some extent, have already implemented when you see them in clinic because they realize [00:14:00] they have to change a few things in order to avoid injuring themselves.

And also, of course, trying to keep the bed partner safe if they carry on sharing the bed. At least having a long pillow in between the two of them, maybe a bigger bed if that's at all possible. So there are a few things there to discuss because safety is of course a concern whenever these, these episodes are described.

From a pharmacological point of view, I think that also it's an important point to review the whole list of medication these patients are on because very often they are on medications that might make RBD worse or can worsen loss of REM atonia. More often medications such as SSRIs, SNRIs, tricyclics, mirtazapine.

So there are loads of antidepressants that that can really make things worse, even if they might have not been the triggering factor for their RBD initially. But if they are on these treatments, [00:15:00] certainly this can be worsening symptoms. Beta blockers such as bisoprolol, propranolol can worsen also REM behavior disorder episodes.

There are some case reports of oral cholinergic drugs. So I think, full review of the medications they take on a regular basis is important. Also having a discussion about their alcohol intake habits. Whether they drink close to bedtime, whether they drink in excess because really what we know is that, if someone is drinking excessively and then they all of a sudden don't drink on a single night, RBD can be exacerbated.

But also alcohol itself can have sleep-disrupting effects. So it's overall not an ideal substance in this context. From a pharmacological point of view, talking about targeting the control of symptoms of RBD really the evidence comes mainly from observational studies, small RCTs.

We don't really have large randomized double-blind control studies. It's [00:16:00] the, the evidence that we have is is small and is mainly from observational or small randomized controlled trials. I'd say that likely melatonin is the first option that we would feel more comfortable to start a patient on.

And the reason is that we know it can help. It can help reduce the loss of REM atonia and it can help control their symptoms with a good safety profile. Because other options that have been, classically used in this context, like clonazepam we know it can be extremely helpful but we have to be quite cautious with the potential risk of confusion, risk of falls.

Of course, if there is untreated sleep apnea, we are concerned about using something like clonazepam as well. So in the context of patients with established neurodegenerative conditions we have to be careful with the use of this medication and if needed, try to keep it at a minimum dose.

There's some evidence as well on, on [00:17:00] the use of transdermal rivastigmine, especially if there is comorbid cognitive impairment. So that's something that we would consider as well. And the fourth-line therapies such as gabapentin or quetiapine, sodium oxybate.

So there are other options with even less solid evidence than the others.

Dr. Eduarduo de Pablo Fernandez: Excellent. And you mentioned there the potential side effects, particularly in the context of people with neurodegenerative disorders, and I guess the decision needs to be individualized. But when do you normally start the pharmacological treatment? Is because sometimes I guess it's difficult to assess the impact of the symptoms, as you mentioned earlier.

Is it something that you offer to everybody complaining of symptoms of REM sleep behavior disorder, or do you try to assess the impact to the patient or the bed partner a bit more and balance the risks?

Dr. Laura Perez-Carbonell: Yes. So I would say more the the second, the latter. So it is very much individualized and I guess that we all have a [00:18:00] conversation that is mainly around safety. So safety of the patient, safety of the bed partner. So if there are concerns from that point of view, which is unfortunately commonly the case then we discuss pharmacological options to start with.

So I would say that very often patients end up needing a medication. But it's also true that for some patients, over time they are so mindful of how the episodes present they make all these adjustments in a very meticulous way and some people decide to not carry on with their medication knowing, what are the benefits and what are the, the risks.

So I think it's individualized and I think, you know, an honest conversation, open conversation with them is, and the bed partner, if possible, is needed.

Dr. Eduarduo de Pablo Fernandez: Excellent. Let's move on now to talk about isolated REM sleep behavior disorder which w-we all know that it's now like a well-established [00:19:00] prodromal presentation for some neurodegenerative disorders mainly Parkinson's disease. So it can happen many years before the, the onset of the motor symptoms and there have been longitudinal multicenter studies that have provided solid evidence for this.

Can you tell us a bit more about isolated RBD? Why is it so important, the risk of development of neurodegenerative disorder and what the outcomes of this may be?

Dr. Laura Perez-Carbonell: Yeah, as you mentioned is isolated RBD is strongly linked with the later development of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, multiple system atrophy. The largest cohort studies that have followed up patients for the long term estimate that roughly seventy-five percent of patients with isolated RBD develop a synucleinopathy within a roughly 12-year follow-up, and the annual phenoconversion rate is estimated at six percent roughly.

So it is a strong predictor, [00:20:00] and there is a lot of evidence out there demonstrating this. Whether patients will end up developing Parkinson's or dementia with Lewy bodies, I think that there's approximately an equal risk between those two outcomes. There are some works that favor DLB, others that favor Parkinson's.

What we can see over and over again is a minority of the isolated RBD patients developing multiple system atrophy. It's mainly either Parkinson's or dementia with Lewy bodies. And I guess if we consider the phenotype, particularly for those that develop Parkinson's disease, it's generally a form of the condition that seems to be more aggressive, so faster progression of motor symptoms.

Generally, they present with a rigid akinetic motor presentation rather than tremor type Parkinson's. They generally have more orthostatic hypotension, early cognitive decline, hallucinations, excessive [00:21:00] daytime sleepiness. So it seems to be overall quite an aggressive form of Parkinson's if associated with RBD. And if considering the ongoing body first versus brain first subtypes we believe that probably when RBD is presenting, generally as an isolated form first and then going on to develop Parkinson's disease, it would be considered within the body first subtype presenting with autonomic dysfunction, involvement of the enteric nervous system, hyposmia and then over time, the motor symptoms established parkinsonism.

Dr. Eduarduo de Pablo Fernandez: And you made a, a very interesting point there that REM sleep behavior disorder has been a-- associated with worse prognosis, with rapid progression of the disease, higher risk of dementia, and so on. So it has an added prognostic value. So obviously having isolated REM sleep behavior disorder sometimes for years [00:22:00] gives an excellent window of opportunity for an early diagnosis, early interventions.

And there has been a lot of advances in biomarkers and different investigations that have been trying to make a the diagnosis of Parkinson's disease from moving to clinical diagnosis from more like a, a biological basis. Are there any futures that can make a diagnosis or predict what proportion of these people are gonna develop Parkinson's disease or other neurodegenerative disorders in the near future?

And is there any results from this test that can help us to tell these people apart?

Dr. Laura Perez-Carbonell: Yeah. So that, that's of course, a very interesting field and I guess that now that we're all thinking about studies to prevent progression, disease-modifying trials this is a, a very important topic to, to investigate and to discuss. In the largest studies that look into specific biomarkers over time, it seems that the strongest predictive factor [00:23:00] for phenoconversion remains to be motor dysfunction.

Either assessed by quantitative motor testing or with, MDS-UPDRS Part 3. So on examination it remains to be the strongest predictor for phenoconversion. Also the presence of other things such as hyposmia or mild cognitive impairment at baseline, erectile dysfunction also have a strong predicting effect for phenoconversion.

When we talk about the ones that are closer to phenoconversion so, progression within the next five years for instance having worse motor dysfunction at baseline abnormal DAT SPECT imaging seem to predict that phenoconversion in the shorter term. We are of course now in an era where we are introducing at least from a research point of view other biomarkers. The use of digital tools for instance, and this is quite likely going to be a game changer in the near future where digital tools that allow us to [00:24:00] assess motor dysfunctions being the, the strongest predictor for future phenoconversion will help us assess patients and monitor patients remotely.

So not needing really to have them in an office. We should be able to capture those that might be at a closer point to phenoconvert before they do phenoconvert because of course, we would like to prevent that. There's also quite a lot of evidence being published on the detection of alpha-synuclein by various tests and in patients with isolated RBD.

This has been demonstrated to be present in CSF but also on skin and other tissues of living subjects with RBD. So I think that probably the future will look very much like a situation where we need to combine different of these biomarkers. Clinical biomarkers, those that can be assessed remotely by digital tools and wearables but [00:25:00] also biofluid biomarkers, neuroimaging and so the the combination of all these data should allow us to try to identify within the synucleinopathy spectrum those patients with isolated RBD that are at a higher risk to phenoconvert in the near future.

And those are the ones that should be perfect candidates for clinical trials, disease-modifying therapies.

Dr. Eduarduo de Pablo Fernandez: I absolutely agree. And as, as you mentioned earlier, I think probably like a stepwise approach escalating for those that test positive for some of this combination of markers and need to be escalated to the next step. Now just my closing question just going back to the clinical settings.

So we have these people that come to our clinics, and there is a risk of a neurodegenerative disorder, but we are still clinical practice a bit limited in terms of prediction as about what we discuss about the [00:26:00] long-term risk and the timing of progression. And I'm aware that this is an area where you have done a lot of research.

I would like to ask you just how do you approach these conversations about risk disclosure with people with RBD? What are the pros and the cons of these discussions, and how do you approach these conversations?

Dr. Laura Perez-Carbonell: Yeah. So this is a very important point as well, very complex issue. Because there can be a very long latency to ended up developing a neurodegenerative disease. We can't really offer to our patients at the moment disease-modifying therapies or preventive treatments.

So it is a tricky point. But I think we all agree that it's something that, first of all, we need to do a lot more research on. We've done some but we need larger cohorts with good representation with different backgrounds et cetera.

We should be looking into what are the views of patients more, [00:27:00] more widely. The sparse evidence that we have now indicates that the majority of them want to know about their risk. But of course, these studies are biased by the fact that these patients are already included in research.

So what is, what are the views of the wider iRBD community would need to be explored. We all have different ways to approach this, and this comes across the studies that have been published on this topic as well, that th- there is quite variable practices among clinicians seeing patients with isolated RBD, and we probably need more structured guidelines.

I think that ultimately it should be, again, very much an individualized conversation, but we should all be taking into account and this is what I do in my clinic routinely, what are the patient's preferences, so patient's autonomy to decide whether they want to know or not know.

And this is a difficult part of the conversation [00:28:00] because you, you want to get a sense of how they feel without already disclosing the risk. But that involves knowing the patient and getting to have a conversation with them in person to get a feeling of how much they've read online, how much they would like to know.

And then if they are happy to receive more information discuss things like lifestyle modifications and of course research engagement as well possibilities that they might be interested in. We have to be mindful about things that are, of course, concerning for every clinician seeing patients with isolated RBD, which is, do they have comorbid depression, anxiety?

What is the patient's support network if we disclose this information? There's nothing really that we can offer from a preventive point of view, so do they have the support that they may need? What is their previous knowledge? 'Cause very often now we have to get a sense of what they know, [00:29:00] but I would say that more commonly than not, they have already read something online.

And so it's important as well to try and give them reliable resources and information. If possible and if also present in clinic, having some relative, bed partner someone to discuss with when we are discussing with patients as well. So yeah, again, very much a stepwise approach where you would try to get a sense of whether they want to know or not, and a feeling of the potential impact on their mental health guiding them on where to look for more information if they want to know more after the conversation.

Dr. Eduarduo de Pablo Fernandez: Thank you. Very interesting points to take home there. Thank you very much Laura, for joining us today and sharing your knowledge and expertise. And thank you very much to the listeners, and I hope you enjoyed the discussion today. Bye-bye for now.

Dr. Laura Perez-Carbonell: Thank you so much. Pleasure to be here. [00:30:00]