Welcome to our educational event titled RBD, Past, Present, and Future, sponsored by the American Academy of Sleep Medicine and co-sponsored by the Inter-Society Collaboration Presidential Committee and the International RBD Study Group. So this is part one of a two-part series where we will highlight clinical aspects of the disorder, the diagnosis, pathophysiology, and treatment. Part two of the series will take place on Tuesday, May 25th at 9 a.m. Central Time. And we are so delighted that we have had over 350 attendees worldwide register for the series today. And we really hope to be able to do more of these in the future. So I will be introducing each speaker in a bit, but I just wanted to take a minute now to discuss the format. So today's hour will consist of three 15-minute pre-recorded talks. If you have any questions, please type them into the chat. We have planned a live Q&A session during the last 10 minutes, and I'll be moderating this. The second webinar will have a similar format, and Dr. Alex Videnovich from Harvard University will be moderating that session. And just so you know, both webinars will be recorded, and if you pre-registered, you will receive a link to the recording within a few days. And both webinars will be released on demand, free of charge at the end of this month. So without further ado, I think we should go ahead and start the talks. So I will be the first speaker. My name is Miranda Lim. I'm an associate professor at Oregon Health and Science University and at the Portland VA, and you can see my background here. So at this moment, I'm going to turn it over to the Academy team to show the first talk. Hello, everyone. My name is Miranda Lim. I'm a neurologist, also boarded in sleep medicine. My clinical and research practice is based at the Portland VA and Oregon Health and Science University. I'd like to thank the organizers for inviting me and putting on this webinar series. It's jointly hosted by the AASM and the International RBD Study Group. There are two webinars with six speakers in total. So I will be kicking off the series by spending the next 15 minutes talking about REM sleep behavior disorder, the history, epidemiology, and the pathophysiology, highlighting the past, present, and future perspectives. The only disclosure I have is support from an NIH award to support the creation of the North American Prodromal Cynoglenopathy Consortium, or NAPCS, to create a registry of patients with RBD. So here's the outline for my talk. I should note that the other speakers to follow will be discussing clinical features, diagnosis and treatment, and also association with neurodegeneration. Okay, so to begin with the history, the story begins with this now famous foundational paper published in sleep in 1986 by Carlos Schenck, colleagues, and the now late Mark Mahowald from the University of Minnesota that described the first five index patients with RBD with these violent moving nightmares. So the authors described the first index patient from 1982, who was 67 years old, and their second index patient, who actually became quite famous and was the subject of several articles in the lay press, including this one in the New York Times Magazine. This is a photo of this patient and his homemade device that he rigged up in order to keep him from falling out of bed at night. So Dr. Schenck also wrote a book about these index patients, Paradox Lost, Midnight in the Battle of Sleep and Dreams. So from the second index patient came this riveting description of a dream. Once he grabbed his wife's neck with both hands while dreaming that he had just staggered a deer with a blow to its head and was going to break its neck, which was in fact his wife's neck. Since then, his wife has generally slept apart from him. So I'm gonna play a video given to me by one of my patients with RBD, which I think very nicely illustrates this kind of dream content and behavior during REM sleep that Dr. Schenck and the Minnesota Group first described. So in 1996, the Minnesota Group published a follow-up study in neurology called Delayed Emergence of a Parkinsonian Disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. And while there had been case reports that RBD was associated with multiple system atrophy and Lewy body dementia, this was actually the first evidence of RBD as the sole heralding clinical manifestation of Parkinsonism. And as you can see in this table, 11 out of the 29 male patients, or 38% of them, developed Parkinson's disease with an average delay of 13 years. And all these patients, it should be noted, were over the age of 50. This Minnesota Group also published another follow-up study later in 2013 from these same 29 male patients. And in the 16 years elapsed since the 1996 study, a total of 21 out of the 26 remaining patients, three of them were lost to follow-up, or 81% of these RBD patients eventually developed a Parkinsonian disorder or dementia with an average delay of 14 years. And that same year in 2013, a group from Barcelona, including Alex Aranzo, Joan Santamaria, and others, also published strikingly similar findings in Lancet Neurology from their European cohort. And they found that 36 of 44, or 88, or I'm sorry, 82% of patients eventually developed neurodegeneration. And this was mostly actually Lewy body dementia confirmed by post-mortem pathology. So I won't talk much more about this other than just to mention this historical perspective, since neurodegeneration and the association with RBD will be covered by other speakers to follow, including actually Dr. Joan Santamaria, the last author on this study. Okay. So in the next section, I'll talk a little bit about the epidemiology of RBD. So the prevalence overall is estimated to be about 1% in the general population. There was a community phone survey done a few years back, which found two to 3% of people reported violent behaviors during sleep. And the prevalence does fluctuate depending on the referral bias, right? So it may be higher in certain populations if they're coming from sleep centers or, for example, cohorts of patients with strokes like brain stem infarcts. The three initial case series of 50 to 100 patients each described, in general, this very large male bias, male to female ratio of 9 to 1, with an average age onset in the 60s. However, there have been multiple newer case series since then that have come out that have come out that have found a slightly different picture. And those with earlier onset RBD, for example, less than 50 years old, the male-female ratio is more balanced at 2 to 1. And 40% of young women with RBD seem to be associated with autoimmune disease. And there's also an association with antidepressant use, as well as a narcolepsy co-diagnosis. So the known risk factors for RBD so far are increasing age, male sex, low education, history of smoking, a history of farming or occupational pesticide exposure, a history of head trauma or traumatic brain injury, a history of post-traumatic stress disorder or PTSD. And I have these in blue here with some references showing that most of this evidence is quite new, just in the past couple of years. And so I think I just want to spend one or two minutes talking about these last two risk factors. So my group just recently published this study in SLEAP last year, examining TBI and PTSD as risk factors for RBD diagnosis in a large cohort of veterans from the Portland VA. So out of nearly 400 veterans who underwent in-lab polysomnography, almost 10% of them met criteria for RBD based on the American Academy of Sleep Medicine criteria for REM sleep without atonia, plus a history of dream enactment. So out of the veterans with comorbid TBI and PTSD, you can see that over 20% of them met criteria for RBD. PTSD alone was 15%, whereas TBI alone and controls were substantially less at 5%. But note that this is still higher than the 1% that's been described in the general population from other cohorts. And the statistical analyses revealed that PTSD and TBI plus PTSD increased the odds of an RBD diagnosis by over twofold. And so I think this all makes sense. PTSD is beginning to be identified as a risk factor for Parkinson's disease as well. This is a large prospective longitudinal study in over 7,000 subjects from Taiwan. It was published in 2017, and they found that PTSD increased the risk of developing Parkinson's disease with a hazard ratio of 3.46. Okay, so in this section, I'm going to move to talk about the pathophysiology of RBD. The vast majority of what we know about the pathophysiology of RBD is from animal studies. So this is a schematic of a mouse brain showing how the sublateral dorsal nucleus in the pons normally projects to motor neurons in the spinal cord to then inhibit muscle activity during REM sleep. And you can see this trace of EEG and EMG from an animal showing non-REM sleep transitioning to REM sleep, and how the EMG, the muscle tone in the neck, also similarly decreases to REM sleep without atonia. So the first animal model was actually created in a cat by Michelle Jauvet in France, who lesioned the pontine tegmentum, tegmentum means roof, so the kind of the top of the pons, and produced REM sleep without atonia. So this area of the pontine tegmentum is actually the same general region that contains the sublateral dorsal nucleus that I mentioned in the previous slide. The other name it can go by is the subseruleus nucleus. And this region contains neurons that are highly active during REM sleep. And when they are active, they actually inhibit the nucleus magnocellularis in the spinal cord via glycine, which is the inhibitory neurotransmitter that acts there. And that is what inhibits muscle activity. This is the same schematic presented in a little bit different way, but what it highlights is this potential putative mechanism of the action of melatonin. So melatonin is a treatment used to suppress dream enactment behavior in RBD. And some have hypothesized that melatonin acts to restore inhibition within the spinal cord and muscle, thereby restoring normal atonia during REM sleep. And other speakers that will follow me will discuss the treatment with melatonin and other agents. So finally, I just want to spend the last minute or so talking about how RBD not only has a fascinating past and present, but there's actually still much to be discovered about RBD. And there's some really exciting future directions. So I mentioned earlier, there are these newer risk factors that are being uncovered as we speak, such as the role of antidepressants and autoimmune phenomenon, and then acquired neurotrauma like TBI and PTSD. And some have even proposed that this overlap between RBD and PTSD might be considered a completely separate parasomnia called trauma-associated sleep disorder. And it's unknown what the neurodegenerative link is, if any, with that. And this was Vince Mislowich and colleagues that published this first case series on that. Finally, the fundamental brain circuits that control REM and non-REM are still being discovered to this day, using pretty innovative techniques and animal models that have resulted in very high impact publications that will really eventually rewrite all of our current sleep textbooks. So lastly, I would like to acknowledge those from my research group at the Portland VA, our laboratory animals and our human subjects who have all contributed to the knowledge of RBD over the years. I also want to thank the NIH and my co-investigators in the NAPCS consortium, including the co-PIs Yoel Ju, Brad Beauvais, and Ron Postuma, who's one of our later speakers, and also co-investigators from these other 10 sites across North America. And finally, this is a photo showing members from the International RBD Study Group community who have been incredible partners in co-discovery. So thank you. Okay, so we're going to move on to the second talk today, which is entitled RBD Clinical Features. And this will be given by Dr. Elena Antelmi. So Dr. Elena Antelmi is an assistant professor at the University of Verona in Italy in the Parkinson's disease and movement disorders division. Dr. Antelmi's main clinical and scientific interests are sleep medicine and movement disorders. Her research is focused on prodromal synucleinopathy and particularly on REM sleep behavior disorder and biomarkers of phenoconversion, along with other sleep disorders like restless leg syndrome, hypersomnia, and narcolepsy. She's co-authored more than 100 articles in international peer-reviewed journals. Okay, so I will turn it over to the academy team to show her talk. Good morning, everybody. I'm Elena Antelmi from the University of Verona, and I'm going to speak about REM sleep behavior disorder and its clinical features. I have nothing to disclose. So REM sleep behavior disorder, as said, is an REM parasomnia. I will start with an explicative video of one of my patients. He's suffering from a really severe form of isolated RBD, and indeed he's on several medications. He's taking melatonin up to 12 milligrams, and cronazepam up to 2 milligrams, and even sodium oxidase at 4 grams each night. But anyway, the episodes are still present, and you will see that whenever he enters in his REM sleep, he will present this really severe, violent, and energetic episode. I will show you the video. So he's wearing, he's kicking, and he's as if he was having with someone. And then we'll have plenty of these episodes during each REM stage of his night. So this video is really explicative. You will see the energetic behavior that we usually see in this patient with the RBD. These are the latest diagnostic criteria. So in order to have a diagnosis of RBD, a patient should have several episodes of deep related vocalization or complex motor behavior. And these behavior are documented even by polysomnography or by the clinical interview to occur during the REM sleep stage. And the polysomnography should demonstrate the presence of REM sleep without atomia. And later on, Professor Santamaria will tell you about the criteria for in order to speak of REM sleep without atonia. So usually the vocalization and the behavior that we observe occur simultaneously with the dream content. And indeed, upon awakening, the patient typically is awake, alert, coherent, and he can remember dream content, which is quite coherent with the acting out of his dream. So dream and acting behavior in RBD can range from excessive body movement and lean jerking to complex goal-directed movement, like the one that we have just seen in my patient, such as gesturing, punching, kicking, sitting up, while to leave the bed, I must say, is really, really rare. Dreaming patient and behavior are often of defense against attack by unknown people of animals. And these behavior usually occur in the second half of the night. As we know that REM phase usually is more frequent in the second half of the night. So this is a really large report from the Barcelona group of up to 200 consecutive patients with a video PSG proven RBD. And as you see, 44% of these patients were not aware of their dream content, of the dream and acting behavior, and 17% of them reported a good sleep quality. So of course, in most of these cases, the bed partner were essential in order to convince the patient to seek medical help. And to leave the bed, as reported even in this court, is really rare. And most of these patients will develop in time a dementia with Lewy body. So as I say, the dreammentation is usually that of bad dreams. So these patients usually dream to be chased or attacked by someone or fearful animals of dangerous situation. These data are again from the Barcelona court. And as you can see, male versus female more frequently present episodes in which they assault their bed partner. And so you can also imagine the medical legal consequences of this. They usually swerve, they usually sit up in the bed. And the dream content is usually to be attacked by someone, female instead tend to have more calmer and gentler episodes, so less violent and energetic. And usually they dream to, for example, of children or people in dangerous situation, so different from male. So RBD can be isolated or it can be also secondary to other condition. So usually a neurodegenerative condition, while the second most common cause of RBD is narcolepsy type 1. And it has been reported also in other autoimmunoparanoplastic encephalopathies or in brain stem lesion, whenever the nuclei which are involved in regulating the REM muscle atonia are first involved by the lesion, also due to medication, mainly antidepressant or beta blockers. This is an example of RBD in a patient with narcolepsy type 1. As you can see, the episode is really, really less violent than the one that we saw before. So she's thinking, singing. So for sure, less violent. This instead is a 19-year-old guy, and he has got something different. I mean, he has got a parasomnia overlap. This means that he has parasomnia during non-REM sleep, but also during REM sleep. So now he's in non-REM sleep, and he will have a confusional arousal, as you see. From non-REM sleep. During the same night, he will have this other episode, really brief, during REM sleep. So this is parasomnia overlap, and this is common in the young. So I'm not worried, and we are not worried of secondary RBD, narcolepsy, or of parasomnia overlap syndrome, because these people won't have the same prognosis of isolated RBD, because we all know now that isolated RBD will evolve in up to 90% of patients in clinical Parkinsonism. We know that isolated RBD is a prodromal of clinical Parkinsonism, and a prodromal, in particular, of an alpha-synuclein-mediated neurodegenerative condition. What about instead of RBD narcolepsy type 1? So narcolepsy type 1 is characterized by a pentadox symptom, which consists in sleep attacks in REM sleep, cataplexy, impaired nocturnal sleep with RBD, hypnagogic or hypnobombing hallucination, and sleep paralysis. She is an 80-year-old female, and you will see this episode. So she has sleep onset in REM sleep, and this behavior, which are, of course, RBD, but very, very gentle, and she has got a kind of subcontinuous gesturing, so really different from the RBD that we see in isolated RBD. And this gesturing is really similar to what we observe in another condition. So this is a patient with Morvan syndrome, so a really severe form of encephalopathies, and in this case, he has got what is called oneiric stupor, which is the motor pattern of a gripnex cytata that we see in Morvan syndrome, in fatal familial insomnia, or in alcohol withdrawal syndrome. So it's a subcontinuous gesturing different from RBD. So in RBD, the motor pattern is like this one. I will show you again. RBD is a short, really energetic patient, usually, so the state, the underlying state is that of REM sleep, while in the oneric stupor you will see subcontinuous gesturing, in the case of this patient is another patient with the Morvan syndrome, and he is eating, and so very subcontinuous gesturing of daily life, so it's different from RBD because it's subcontinuous, it's longer, it's very calm and stereotyped, the eyes are maybe open, and this state is not that of REM sleep, it's a mixture of REM sleep and non-REM sleep. So to conclude, there is, there are differences between isolated RBD or RBD in narcolepsy type 1. So the age of the onset is different in isolated RBD, usually, the usual patient is a male, he is 50, while in RBD, the onset is in childhood or early adulthood, the features are different, very complex, energetic in isolated RBD, while more calm, more discreet, calm and subcontinuous in narcolepsy. This is because the physiology and the pathophysiology is different, so in isolated RBD, we have the destruction of the brainstem nuclei which control REM muscle atonia, while in RBD, in narcolepsy, we have a state of under instability due to the hypocritin deficiency. Also, the associated symptoms and difference, of course, in isolated RBD, we can have other prodromal symptoms like cognitive impairment, depression, autonomic symptoms, motor symptoms, while in narcolepsy, we will have all the other pent-up symptoms that I told you before, and then alpha-synuclein deposit may be found in isolated RBD at several levels of the nervous system, and even in the CSF, while in narcolepsy type 1, we will have a low level of hypocritin in the CSF, and this is the hallmark of narcolepsy type 1, and of course, the prognosis will be different, neurodegeneration in isolated RBD, while of course, no neurodegeneration in narcolepsy type 1. So, this is the end of my presentation. I thank the American Academy of Sleep Medicine, of course, and the RBD Study Group for all the study that we are still doing together. Thank you. Okay, so now we are at our third and final talk. This is entitled RBD Diagnosis and Management, and this will be given by Dr. Joan Santamaria. Dr. Santamaria is an emeritus professor at the Biomedical Research Institute in Barcelona, Spain. This is affiliated with the Hospital Clinic of Barcelona, where he built most of his career. In 1988, he started the Clinical Neurophysiology and Sleep Laboratory at the Hospital Clinic of Barcelona, where he collaborated with other giants in the field of sleep and neurology, including Drs. Edward Tolosa, Alex Aranzo, Francesc Graus, and Josep Dalmau. His work on clinical imaging and neurophysiological evaluation of REM sleep behavior disorder, in collaboration with Innsbruck University, has contributed significantly to the advancement of our knowledge of RBD. So, thank you, Dr. Santamaria, and we'll go on to your talk. Hi, my name is Joan Santamaria. I'm going to talk about diagnosis and management of REM sleep behavior disorder. Thank you, the organizer, for inviting me. I have no conflicts of interest to disclose. Well, the diagnosis of RBD relies on the presence of four criteria. These consist, first, of repeated episodes of sleep-related vocalization or complex motor behaviors. This can be obtained by clinical history or in patients in whom this is not available. We can fulfill this criteria by observation of the episodes during a single night or polysomnography. The second criteria is that these behaviors are documented in the polysomnography to occur during REM sleep or presumed to occur during REM sleep based on clinical history. These are the same, but this is how it is. The third is that polysomnography shows REM sleep without zirconia, according to the last version of the same manual for the scoring of sleep. And the fourth is that there is no other cause that can better explain the disturbance. So, using these criteria, you end up with four types of patients. The first type is patients with the highest diagnostic certainty because they have clinical history of dream and active behaviors. You can observe the behaviors during REM sleep in the polysomnography, and there is increased EMG activity satisfying the criteria for REM without zirconia. The second type is patients who have no history of dream and active behavior because they sleep alone. They are not aware of that. The partner is not a good informant, many reasons for that. But when you record the polysomnography, you see the behaviors, the typical behaviors, and the EMG shows REM without zirconia. The third type is patients who have REM without zirconia. They have a clinical history, but you are unable to see the behaviors in REM sleep. So, you cannot prove that the complaints of the patients are due to REM sleep abnormalities because during a polysomnography recording, you cannot show any of these behaviors. You only can presume that they occur during REM sleep. And finally, there is a patient who has clinical history, a typical one. The behaviors can be seen during polysomnography, but the quantification of EMG does not show sufficient REM sleep without zirconia to satisfy the criteria. So, these are provisionally diagnosed with RBD. So, but these are the four types of patients that under the current criteria are diagnosed with RBD. How can you score EMG activity in REM sleep? As you know, normally there is no gene EMG activity in REM, as you show in the left side of this slide. Whereas in RBD, there is excessive amount of EMG in the gene, in this case, during REM. Not only the gene is the muscle that shows excessive amount of activity, and in some patients, the gene may be silent or almost inactive, like in this example, but the limb show increased amount of EMG activity, in this case, phasic activity, which is associated to limb movement and is responsible for the behavior of the patient. So, that's why using the limb as well as the gene is reasonable. So, what are the scoring criteria of the last version of the SM scoring manual? Well, they recommend to score REM without zirconia according to the following criteria. We have one type of EMG activity in the gene, which is called excessive tonic gene activity. It's sustained muscle activity, at least half the epoch or 30-second epoch should have increased gene EMG amplitude more than two times the baseline, more than 10 microvolts. In this case, it's more than half, it's 100% of the epoch, which has this increased tonic activity. There's another type of EMG activity, which is transient muscle activity or phasic, which can be recorded not only in the chin, but in the limbs. And to score that, you need to divide the 30-second epoch in 10 three-second mini-epochs that has been done here and is marked with the different colors, each one three seconds. And you see the first and second mini-epochs contain no phasic activity, whereas the next eight mini-epochs of the 30-second epoch contain excessive phasic activity. So this 30-second epoch should be considered abnormally and showing phasic activity in more than 50% of the epoch. The last type of gene EMG activity is what is called any. And this activity has twice the amplitude of the stage rheumatonia level without regarding the duration of the activity, and including bursts of five to 15 seconds. This is also scored in three-second mini-epochs, as you can see here. And you see that the gene shows activity continuously. You don't need, in this type of measurement, you don't need to say if it's tonic or phasic. It's simply any EMG activity. So when you know these three types of the activity, how is an epoch of REM sleep diagnosis of excessive REM, excessive EMG activity or exhibiting REM without the tonia? So the criteria say that one of the following should be present. Excessive tonic EMG activity, as I defined previously. Excessive phasic activity in the gene or limb, as defined previously. Or excessive any gene or limb EMG activity, which is defined as at least 50% of three-second mini-epochs containing this excessive EMG activity. Okay? So if you have one of the three, it's enough to diagnose that that particular epoch is contained REM without the tonia. So once you've done that with all the epochs, you can give the REM without the tonia index as the percentage of sustained REM epochs that meet the criteria above. So there is no obligation of recording all types, different types of EMG activity. You may have REM without the tonia diagnosed with excessive tonic gene, with excessive phasic gene, with excessive any gene, or with excessive phasic gene and phasic limbs. But the recommended, most recommended option is to use gene NE plus bilateral phasic limb activity recorded in the flexor digitorum superficialis. I will show you in a moment why. For all these type of measurements, we have cutoff values, and you need to remember particularly this, which is the recommended for by the international classification of the disorder, that this is based on the CIMBAR work. 27% of 32nd epochs in REM should have excessive abnormal activity to the inverse orbit. Why this combination of upper limb flexor digitorum superficialis and chin is recommended because it has higher discriminative power at this level. It relates with the movements of the patient and is prone, less prone to artifacts. And you can see that if you use the upper limb, flexor digitorum superficialis has almost no overlap between activities encountered in patients and in controls, and the area under the core of this rock core is almost one. Whereas if you use the lower limb, the tibialis anterior, this is much lower. So this is the reason why this combination is the recommended. Differential diagnosis, particularly of the clinical history, you may find patients, we have obstructive liparnia, severe obstructive liparnia, which during the arousals from REM or REM sleep, they may show behaviors that remind of RVD. And this is an example, a patient is severe obstructive liparnia and they do not, you will show these movements. So if you ask the partner, does your partner moves, dreams and acts during sleep, you may answer yes, and it's not RVD, but obstructive liparnia. The same may happen with patients with severe periodically movements during sleep. This may happen during non-REM sleep and typically patients with a history of periodical movements, but may appear in some cases, mimicking REM sleep behavior disorder. Look at this patient particularly, excuse me, which has these periodic movements, which are very important and vigorous and lead to arousals and normal motor and vocal manifestation. And finally, you may find in the other side of the coin, excessive EMG activity in the legs, particularly, which is associated with minimal movements. Now we may be physiological that this is little distal movements, you see, during REM sleep. This may be physiological. This is not RVD. Okay, let's move to the final part, management of RVD. If you find a patient in which you suspect isolated RVD, I think video polysomnography is necessary because the consequences of this diagnosis are relevant. And you also have to exclude and treat obstructive, if present, obstructive liparnia of severe PLMS because this may clarify the issue and if the patient has RVD, they may improve also the clinical symptoms, although it cannot cure them obviously. When you have the evidence that the patient has RBD, you have to inform the patient, although some doctors think, well, you know, you only, the patient has almost no symptoms, daytime is normal. Why do we need to tell him that he's in risk of developing a neurodegenerative disease, et cetera, et cetera. So, I think you have to tell the patient because he may find out eventually in the internet or talking with somebody else and the information will not be as good as the one you will give to him or her. So you have to tell about the diagnosis, tell that you will do periodic follow-ups to monitor treatment and to develop, and to develop the appearance of neurodegenerative disease if that is the case. Well, there are some non-pharmacological measures that you have to take. Most of us take protective measures to avoid injuries to the patient or to the bed partner. This is an example of a pallet bed trails that one of our patients had. You can also avoid drugs that can worsen RBD or antidepressant practically, some beta blockers, malinibutors. And you have symptomatic treatment, which is based on clonazepam and melatonin, based on clinical experience. All the most data are low-level studies, case series and case report, and a few randomized control studies. Objective monitoring of the response in RBD is difficult. So this is complicated issue. Three recent randomized control trials have shown that clonazepam 0.5 milligram was similar to placebo in 40 probable, meaning not diagnosed polysomnographically RBD in PT patients. So the dose was low, 0.5. I don't think this can be definitive information. And there are two melatonin prolonged release studies, one in idiopathic RBD patients, the other in Parkinson's disease RBD patients, in which two, four or six milligrams were similar to placebo. Again, these were based on questionnaires and the doses were different to the ones that have been used in case reports previously. So I don't think we have enough arguments to stop using these two drugs. If you choose clonazepam up to two milligrams, starting at 0.5, once at nine, incrementing by fractions of 0.25, according to the response, you have to be aware of the side effects and the cautions in neurodegenerative diseases. And melatonin, three to 12 milligrams, also based on previous experience, have less side effects in patients with cognitive problems and also, and you may use that in this context. Other drugs are less well-known. Thank you very much for your attention. Okay, great. Thank you so much. So that concludes our three talks. And in the last 10 minutes or so, we'd like to take some time to answer some of these great questions that have been posted in the chat live. Okay. So first, the first question came from David Coleman. RBD is lack of atonia during dreams. Is there any understanding as to why patients always seem to be acting out nightmares instead of regular dreams? And so I'm gonna hand this to Elena and tell me to answer this. So it's likely that ulcerous nuclein aggregates at present and not only in the brainstem nuclei, but also in other parts of the brain, as for example, in the amygdala or in the mesial part of the brain. And so this can explain the fearful nature of this dream and the anxious nature of this dream. Then there is also another explanation, but so that the violent nature of the movement can trigger by itself the violent nature of the dream. But in my view, I'm more in agreeing with the first hypothesis that of the involvement of other structure of the brain. I think because of the generative generation has already started there in the other part of the brain, not only in the brainstem. Okay, thank you. The second question is from Data Nadger. And this is, what is the role of magnocellular neurons in the medullary center in RBD? So I'll answer this. This is something that I just briefly introduced in my talk. So normally REM sleep is associated with generalized atonia of skeletal muscles. And what the magnocellular neurons in the medulla do is they actively inhibit the final common pathway of the spinal motor neurons. And specifically they project from the ventral lateral reticulospinal tract to suppress these anterior horn cells in the spinal cord. And as I mentioned, the inhibitory neurotransmitter involved this glycine. So I hope that answers your question there. Thank you. The next question is from David and this is, should we consider allowing for a diagnosis of RBD based on only clinical grounds and not require polysomnography? And this is a very interesting question. I'm glad you asked this. It says that you're suggesting that the alternative criteria for RBD diagnosis could replace the requirement of demonstrating RSWA on PSG with documented improvement of symptoms after a therapeutic trial of melatonin. And so I would like Dr. Juan Santamaria to answer this. Hi, well, if you do that, I think you're going to make many mistakes. That's my opinion. We've made those mistakes already. So a patient comes to you, it looks like 100% RBD clinical history, perfect. And you end up with alternative diagnosis. And the screening questionnaires are good for screening, but I think if you want to make 100% certainty, you need to prove that the patient is doing all these behaviors during REM sleep associated with it. That's my opinion. And I don't think you can exchange that for any type of questionnaires or diagnostic criteria, whatever they are. I don't think we are so good yet. Yeah, thank you. I have another question for Dr. Santamaria. And this is, what is the difference between the choice of therapeutic drugs for neurodegenerative diseases with RBD? So Parkinson's plus RBD versus narcolepsy with RBD versus solitary RBD. Well, that should be for Elena actually, no? Management, either one. Elena, if you would like to take that, please do. Can you hear me? I mean, because, yes, you can hear me. No, I can hear you. Different management, completely different. I mean, as Professor Santamaria said, in a patient with the isolated RBD, usually we give chloramazepam or melatonin as the first-line treatment. While in a patient with RBD and narcolepsy, the first choice is the sodium oxidate, because, I mean, in a patient with narcolepsy, RBD is due to the instability of the herium. So you try to inhibit the herium's lip. So you give sodium oxidate, which is a GABAergic. And so you will have more slow wave sleep and less herium sleep. So you will have also less RBD. And so this is the first treatment in this patient. Sodium oxidate in RBD, in narcolepsy. And it can be used also at the third-line treatment. I mean, there are also some sporadic report in patients from our group, in patients with isolated RBD, but just before all the other drugs that are treated. Okay, great. Thank you. Thank you. The next question is, can you comment on the role of alcohol use, abuse, or withdrawal in RBD? And I'll go ahead and answer this since I touched upon the risk factors. And so there have been two very recent studies very large population-based studies published on this, examining the association between alcohol intake and the likelihood of probable RBD. The caveat is both of these studies use just the single screening questionnaire or another kind of questionnaire and was not PSG-based. One of these studies was based in Hong Kong and found that current drinkers had a 23% higher likelihood of having probable RBD. And the other study was a part of the Canadian longitudinal study that Ron Postuma is the senior author on, and he's one of the speakers in webinar two. And they examined 30,000 people and found that alcohol was a risk factor for probable RBD as well. So I think it's a very interesting area to explore. It's still very early. Okay. And there is also the withdrawal of alcohol because there is the rebound of the, so alcohol is the GABA-IRG kernel. So if you have, if there is the withdrawal, then you will have, of course, the rebound of a RBD and all that. So in that case, it's another kind of, but I mean, also if you stop alcohol, you can have a RBD. Yeah, yeah, great. Thank you for clarifying that too. And the next question I have is for Dr. Santa Maria. So this just came in. What is the incidence of OSA and RBD? And is there any role of CPAP efficacy on outcome of RBD? Well, I think the incidence of OSA and RBD is the incidence in the general population. I don't think there are population studies to compare, but it's something that you see often in just, it's not very high or very low. It's just the regular pattern, but it poses you an interesting problem because since this may mimic RBD, I mean, severe OSA, we tend not to diagnose isolated RBD, at least in the first study when we saw a patient with probable RBD and OSA. We just first treat obstructive zytoamnia with CPAP and then study the patient again. And then we can see cleanly if he has or not RBD. Then when we have, answering the second part of the question, when we have patients that have both diseases, which have different causes and different treatment, something happen when you treat OSA with CPAP effectively, several patients, a percentage of patients tell you that they feel better of RBD. So somehow the interruption of sleep, epoxy or whatever factor seems to stimulate abnormal behaviors of RBD behaviors. And if you remove that from the equations, patients may improve that. That's why we do both things. We don't diagnose RBD unless OSA is treated effectively. And we prove again, that in REM sleep there are abnormal behaviors without apneas. And then we treat them and a percentage of patients tell you that they feel better. They don't have the behaviors as they used to have before. That's an interesting association. Thank you. I think we only have time probably for one more question. And Dr. Antelme, would you be able to answer why do you believe that antidepressant use and not depression per se is associated with RBD? Okay. I think that depression is a comorbid condition because it is a prodromal as well of probably a neurodegenerative condition. Antidepressant, several studies have shown that it has a direct effect on the control of muscle tone during REM sleep, especially by the increase of the serotonin, which can interfere with the other monoamine that inhibits the alpha motor neuron during the REM sleep. So antidepressant may treat, may worsen the control of muscle tone during REM sleep. And so this is the primary effect. And then of course can trigger RBD in patients which are predisposed to this one. But I think that the main effect is that, and this has been shown in several studies, is that on the control of muscle tone during REM sleep because there is the interference with the other monoamine which inhibits alpha motor neurons. Thank you. Okay. So I would like to thank all our speakers and everyone who attended today and for these great questions. There's a couple of questions we didn't get to answer, but they relate to neurodegeneration. And so I think I just wanted to remind you that our second webinar, which is on that topic, RBD, neurodegeneration, biomarkers, and clinical trials will be on Tuesday, May 25th at 9 a.m. Central time. And Alex Videnovich from Harvard University will moderate that. So feel free to save those questions and ask them again. And just as a summary, both webinars are recorded. And so if you pre-registered, you'll receive a link to the recording within a few days. And both webinars will be released on demand, free of charge at the end of the month.

educational event

RBD

clinical aspects

diagnosis

pathophysiology

treatment

pre-recorded talks

live Q&A session

polysomnography