Hello, I'm Dr. Carlos Sheng from the Minnesota Regional Sleep Disorder Center, Hennepin County Medical Center, and University of Minnesota Medical School. And my topic today is parasomnias, things that go bump in the night. My entire career in sleep medicine and sleep research has involved the parasomnia, so I'm delighted to be able to share my experience with you. Next slide, please. Next slide, please. So the definition of parasomnias, and this comes from the International Classification of Sleep Disorders, 3rd edition text revision, and I was on the task force to develop this edition of the International Classification of Sleep Disorders, are basically undesirable behavioral autonomic nervous system and experiential events that occur during entry into sleep, during any stage of sleep, both non-REM sleep and REM sleep, and during partial or full arousals from any stage of sleep. You can really gather from this definition is that virtually all of sleep carries a vulnerability for parasomnias, and this extends through the entire lifespan. Next slide, please. So behaviors can be inappropriately released with the parasomnias, involving sex with a condition called sexsomnia, eating with a condition called sleep-related eating disorder, aggression with REM sleep behavior disorder, the dream-enacting parasomnia, sleepwalking and sleep terrors, which are the non-REM sleep parasomnias, and I have videos to demonstrate the sleepwalking and sleep terrors, also locomotion, mainly with sleepwalking, and fear that you see with sleep terrors, also known as pavor nocturnus. We should also keep in mind that sleep itself is an instinctual behavior. Next slide, please. So as I already mentioned, all of sleep carries a risk for parasomnias involving any age group as well, and there are major gender and age differences with the parasomnias. Furthermore, parasomnias are surprisingly common. Finally, parasomnias can appear spontaneously, called primary parasomnias, or can be triggered by medications or emerge with another sleep disorder, particularly obstructive sleep apnea and restless leg syndrome, which are called secondary parasomnias. Next slide, please. Now the parasomnias I'm going to discuss involving adults, and first of all, begins with REM sleep behavior disorder, known as RBD, the primary dream enactment parasomnias, also disorders of arousal from non-REM sleep, sleepwalking sleep terrors arising from slow wave, also now called N3 sleep, sexsomnia, which is a recognized variant of confusional arousals in sleepwalking, fourth, sleep-related eating disorder, which is a non-REM sleep parasomnia arising mainly from intermediate sleep, known as N2 sleep, and it's not classified as a disorder of arousal because it does not generally emerge from N3 or slow wave sleep. And finally, I'm going to touch briefly on the psychiatric parasomnia known as sleep-related dissociative disorder. Next slide, please. Now with RBD, next slide, virtually all antidepressant medications can trigger RBD, except for bupropion and trazodone, and this carries major management implications. RBD in middle-age and older adults carries a greatly increased risk for future alpha synuclein neurodegeneration, particularly Parkinson's disease and dementia of Lewy bodies. This is a very hot area. I'm part of an NIH grant studying this association prospectively and also with the International RBD Study Group. This is a major scientific venture to identify risk factors for the conversion of REM sleep behavior disorder into a recognized alpha synuclein neurodegeneration, and I will discuss this a bit further. As I already mentioned, RBD is the earliest and strongest predictor of future Parkinson's disease in middle-age and older adults. Furthermore, the worldwide prevalence of RBD is more than 1%, and I reviewed this in this recent article in the journal Sleep Research. So I mean, the last I knew, the worldwide prevalence of schizophrenia was 1%, so RBD is just as common as schizophrenia. Notable figures that we know of with RBD and Parkinsonism, Alan Alda, Scientific American Magazine in February of 2023, discussed his REM behavior disorder and Parkinson's disease. The actor Robin Williams, who tragically died, as we all know, he had REM behavior disorder and dementia of Lewy bodies. His widow wrote a really impassioned editorial in the journal Neurology, and even Don Quixote had almost certainly RBD and dementia of Lewy bodies, and this was discussed in the journal Royal Society of Medicine, so anyone who's interested can pursue these articles. Next slide. So RBD carries a major risk for sleep-related injuries involving ecchymosis, subdural hematomas, lacerated arteries, nerves, and tendons, fractures including high cervical fractures, dislocations, abrasions, rug burns, tooth chipping, hair pulling. So we're talking about life-threatening injuries in addition to more common, less severe injuries. But when someone is acting out his dream with eyes closed, attending to the dream world, and unaware of the sleeping environment in his bedroom, this scenario carries great risk for injuries, and you can see the consequences. Next slide, please. We've published on inadvertent murder, attempted murder related to REM sleep behavior disorder, and even parasomnia pseudo-suicide. We had to review the medical records of this adolescent who ran across the road in the middle of the night, and he was deemed to try to commit suicide when, in fact, it was a parasomnia episode. And clearly, there are major psychosocial, religious, and life insurance implications. So even medical examiners need to know about parasomnias and the risk for life-threatening injuries. Next slide, please. So there was an interesting study from Italy on aggressive dream content without daytime aggressiveness in REM sleep behavior disorder. And the major findings, my findings were that men with RBD have significantly more aggressive dreams than control men. However, men with RBD are not more aggressive in wakefulness than control men using validated rating skills. So basically, the aggressiveness during sleep with RBD is not a nocturnal extension of increased aggressiveness during the daytime. They're completely separate entities. The sleep aggression is separate from basically a wakeful non-aggression. Next slide. Now what are the behaviors with the dreaming? These people do not enact their usual dreams. The dreams have changed in that they were confronted or attacked by unfamiliar people, animals, or insects. Now with PTSD nightmares, you relive the scenario of the trauma. So it's all very familiar, but with RBD, the altered dreams involve unfamiliar people or animals or insects, a very different type of basically nightmare compared to PTSD nightmares. So with the unfamiliar people, animals, the behaviors range from minimal limb-twitching and jerking, complex behaviors involving hand-waving, hand-grabbing, reaching, and searching motions and gestures, the vigorous and violent behaviors such as punching and kicking, and a whole range of vocalizations involving simple talking, yelling, swearing profanities, prolonged talking with anger, laughter, or nonsensical. One of our very first patients would fall asleep saying a prayer, which his wife Harriet heard, and then once he fell asleep and entered his dream enacting mode, he would swear. So you could see a major sleep state-dependent activation of language that was not activated during his waking life. He went from saying a prayer while awake on the point of going to sleep to swearing during his dream enacting behaviors. Next slide, please. So the altered dreams involve dream process change involving vivid, intense, full-of-action, unpleasant dreams, the dreamers being threatened or attacked by unfamiliar people, animals, or insects, which are dream content change. The dreamer is rarely the primary aggressor, and interestingly, no sexual dreams of RBD, which I think would surprise Sigmund Freud quite a lot. Next slide. So marriage. Usually, patients of RBD have been married for decades before the onset of RBD, so the spouses know that the late-onset sleep aggression with violence is not a reflection of the waking personality. Often, the spouses even choose to sleep in the same bed to protect the person of RBD from becoming injured. They're very loving wives. There's only been three published cases of divorce or marital discord, and these involve people who are not married that long. So the spouse was really frightened about marrying someone with this type of behavior during sleep. Next slide, please. Now RBD is the only parasomnia that requires polysomnographic documentation to confirm the diagnosis. I'll show you an example. REM sleep without atonia, in other words, REM sleep without the usual muscle paralysis of REM sleep, is the hallmark objective finding for diagnosing RBD. And this is really wonderful to have an objective finding to diagnose this particular sleep disorder, especially since this carries a major risk for future Parkinson's disease and dementia of Lewy bodies, so you really have to be certain about the diagnosis. And this type of objective finding of REM sleep without atonia is the objective hallmark that can give you confidence in diagnosing RBD and then discussing with the patient and spouse about the increased risk of future Parkinson's disease and dementia. Next slide, please. So the top panel is normal REM sleep. And if you look at the chin EMG, the third channel down, it is flat. That is normal REM atonia. And the two channels above it, you'll see characteristic rapid eye movement. So this is normal REM sleep. All the EMGs, you can see the bottom, the right leg, left leg, left arm, right arm, show no muscle tone, no muscle twitching. Now in contrast, panel B, look at the chin electromyogram, tremendous increase in tone and phase of twitching. And also down below, you see the right leg and left arm showing increased tone and twitching. So this is an obvious example of REM sleep without atonia that helps diagnose RBD. It's really not a subtle finding. It's pretty obvious when you have it. Okay. Next slide, please. Now we also know through the really outstanding basic science research that there are two nuclei in the brainstem, one in the pons, one in the medulla that are responsible for the establishment of REM atonia. And by interfering with these two nuclei, you then produce REM without atonia and REM sleep behavior disorder. If you look at the first publication here, genetic inactivation of glutamate sublateral dorsal nucleus recapitulates REM sleep behavior disorder, and this is in rats. And the second article is ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder. And the GABA and glycine inhibitory neurons are genetically inactivated. So this is a beautiful example of how basic science research can pinpoint the nuclei responsible for the normal muscle paralysis of REM sleep, and that damage to these two nuclei not only produces REM sleep without atonia, but also the dream and acting behaviors that are the hallmark of RBD, in this case in rats, but also then in humans. Next slide, please. So if you look at the bottom right, you see the SLD, which is a sublateral dorsal nucleus in the pons, and then it activates the inhibitory nucleus that you can see in the medulla that then paralyzes the spinal motor neurons and the alpha motor neurons in the spinal cord that then shut down the muscle. So this is a beautiful scheme of how muscle paralysis of REM sleep is generated, and damage to these two nuclei can result in REM sleep behavior disorder. And just to give you a sneak preview, these are the nuclei that are attacked by alpha synuclein in the disease process of Parkinson's disease and dementia of Lewy bodies. It comes up from the gut, and obviously the lower brainstem is as close to the spinal cord as you can get, and that's why RBD is really like the signal node of future Parkinson's disease and dementia of Lewy bodies, because these lower brainstem nuclei are first attacked by alpha synuclein, and it's really, it's a wonderful kind of signal node that allows us now to try to generate some type of neuroprotective agent to prevent the progression to frank Parkinson's disease and dementia of Lewy bodies. So the, really the whole scheme is very well known. Okay. Next slide, please. Now what is the, what are the diagnostic criteria for RBD? As I already mentioned, it's the only parasomnia that requires video polysomnography. I showed you the example of normal REM sleep, and in the lower panel, REM sleep without atonia, the hallmark of RBD. Next slide. You need repeated episodes of sleep-related vocalization and or complex motor behaviors. These behaviors are documented by polysomnography to occur during REM sleep or based on clinical history of dream enactment are presumed to occur during REM sleep, and C, polysomnographic recording demonstrates REM sleep without atonia. This is the sine qua non for diagnosing RBD, and of course, you have to have no better explanation for the RBD behaviors. Next slide. The observed vocalizations or behaviors often correlate with simultaneously occurring dream mentation leading to the frequent report of acting out one's dreams. Now I've been asked many times, why don't you include dream enactment behaviors as one of the diagnostic criteria? The reason is that not every patient with RBD is aware of dream enactment behavior. It could be someone with early dementia who may have problems with recall, and so we don't want to really narrow the diagnostic criteria to include the absolute requirement of dream enactment behaviors, but certainly most patients with RBD are aware of acting out their dreams. The most current evidence-based data that are in accordance with the American Academy of Sleep Medicine, 30-second epoch scoring guidelines should be utilized, and more than 20% of all of REM sleep should have loss of REM atonia, and often it's far more than that. Next slide, please. Now I already mentioned that the comprehensive RBD literature has shown that up to 35% of patients of RBD, especially those of neurodegenerative disorders, are not aware of their dream enacting behaviors, and that's why dream enactment is not a required diagnostic criterion for RBD. Next slide. What's the differential diagnosis? You know, RBD is not the only condition that involves dream enacting behaviors. There's now a growing literature in adults with non-REM sleep parasomnias involving adult sleepwalking and sleep terrorists where they can report some dream enacting behavior. The dreams are not nearly as elaborate as the dreams of RBD, but still it is dream enacting behavior. And the hot new area is obstructive sleep apnea, pseudo-RBD, that arousals induced by apnea during REM sleep can induce dream and dream enactment, and there's a lot of research going on in the sleep medicine field on obstructive sleep apnea, pseudo-RBD. So that's why you need polysomnography. If you don't detect REM without atonia and then you detect obstructive sleep apnea, that patient complaining of dream enacting behaviors may have obstructive sleep apnea, pseudo-RBD, especially if there's no evidence of REM without atonia. So that's another reason why you need polysomnography, not just to rule in RBD, but to rule it out and to rule in other conditions such as obstructive sleep apnea and OSI, pseudo-RBD, or even non-REM sleep parasomnia with dream enacting behavior. Now there are less common conditions that can have associated dream enactment, severe periodic limb movement disorder, and occasionally nocturnal seizures with REM sleep, seizures inducing dream enactment behavior, but this is quite uncommon. Next slide, please. So the first textbook on RBD came out in 2018. I was the lead editor, and this is a nice scheme that a friend of mine who's a graphic artist designed. At the bottom right, you can see the scheme of loss of REM atonia, increased tone, loss of twitching. But look all around the figure on the bottom right, all the conditions associated with loss of REM atonia and RBD. Bottom left, you have acute toxic metabolic factors, acute medication withdrawal states. Going up, brainstem tumors and stroke, neurodevelopmental disorders, narcolepsy or cataplexy. Up to 60% of patients of narcolepsy type 1, which is narcolepsy with cataplexy, have RBD. Next to it, antidepressants, which I'm going to discuss later on. Neurodegenerative disorders and other neurological disorders, autoimmune, paraneoplastic disorders, and severe stress, including severe post-traumatic stress disorder, can impinge on the rematonia mechanisms, inducing loss of rematonia and RBD. So clearly, rematonia is a highly vulnerable entity that can be attacked and rendered compromised by a large variety of neuropathological factors and other pathological factors, including medications. Next slide. Next slide. So how about medication-induced RBD, which disrupts the neurochemistry generating rematonia? And you can refer to that scheme that I showed you before. So virtually all antidepressants, except for bupropion, the dopaminergic neuroadrenergic agonist, can induce RBD, not trazodone either. So both bupropion and trazodone should be safe therapies for depression or insomnia with RBD. You can see beta blockers, selegiline, anticholinergics, rivastigmine. And so unless otherwise contraindicated, bupropion should be the antidepressant medication of choice in treating a depressed patient with RBD. Next slide, please. So there was a comprehensive literature review on medication-induced RBD. And here are the classes of antidepressants found to induce RBD, the whole variety of tricyclic antidepressants, SSRIs, SNRIs, MAO inhibitors, and again, no report of bupropion or trazodone-inducing RBD. So I think the lesson learned for psychiatrists is that when you prescribe these medications and you want to ask patients about side effects, ask them if their dreams have changed and if they appear to be acting out their dreams, or if their bed partners is noticing that they're engaging in complex behaviors during sleep that may be dream enactment since this could be a medication side effect of antidepressant-induced RBD. So I think the psychiatrist should be proactive in asking. It's a simple little question to ask, but it may yield an important comment from the patient, and then you may have to adjust your therapy accordingly. Next slide, please. Now, the first case of antidepressant-induced RBD was from our center, and that was fluoxetine-induced RBD. And the outcome from this case is different from another case published a number of years later in the Journal of Clinical Sleep Medicine, which I will now discuss. Next slide, please. So our first case was a 31-year-old married man with depression and OCD, was prescribed 40 milligrams daily fluoxetine, and he immediately developed RBD with dream enactment, confirmed by video polysomnography. We studied him a total of eight times in sleep, and we found that he had no symptoms of RBD. He had no symptoms of sleep apnea, and he immediately developed RBD with dream enactment, confirmed by video polysomnography. We studied him a total of eight times in the sleep lab, and REM without atonia and RBD was found in all studies, including the last study, 19 months after he had stopped taking fluoxetine. So this is a long-lasting effect that outlived the discontinuation of fluoxetine 19 months earlier. Also by history, his RBD persisted for 27 months after stopping fluoxetine. He then moved away and was lost to follow-up. Now contrast this case with our next case. Next slide. So this is a 59-year-old married man with depression who developed RBD immediately after starting 40 milligrams daily fluoxetine. So both cases, the immediate RBD starting 40 milligrams a day of fluoxetine with the RBD persisting for 30 years before presentation for sleep evaluation and video polysomnography, that confirmed RBD. Remarkably, his RBD resolved six weeks after stopping the fluoxetine and repeat video polysomnography documented substantial return of REM atonia, greatly decreased the electromyographic twitching and no RBD behaviors. He then was started on bupropion therapy of depression, and bupropion, without any surprise to us, did not induce any RBD, which supports our common knowledge that bupropion should be considered the antidepressant of choice in the depressed patient with RBD. Next slide, please. Therefore, these two cases demonstrate strikingly divergent outcomes with fluoxetine-induced RBD and discontinuation. So we just don't know, but prudence would tell us to stop the offending agent, re-evaluate and consider bupropion as an alternative antidepressant, but also trazodone too. Remember, trazodone is an antidepressant. It's not used much as an antidepressant, but at higher doses, it can still be an effective antidepressant. Next slide, please. Okay, so this is the second, this is the case of paroxetine-induced RBD, cessation of RBD when both SSRIs in this particular 50-year-old man who had prior fluoxetine therapy and then more recent paroxetine therapy, fortunately for this man, discontinuation of both SSRIs resulted in cessation of RBD, so this is a happy outcome. Next slide. Carl Drognamjic, who's one of the speakers of this symposium, he first reported on venlafaxine or effexor-induced RBD. Mirtazapine also has been reported, as you can see. Next slide. You can read these cases from these reports. John Winkleman published an important article on how serotonergic antidepressants are associated with REM sleep without atonia, which is the first step towards frank RBD. They studied 15 subjects taking serotonergic antidepressants, and they had significantly more electromyographic activity in the submental electromyogram during REM sleep than the controls, and this correlated with age and REM sleep suppression. Therefore, they concluded that individuals taking serotonergic antidepressants may be at increased risk of developing frank RBD, particularly with increasing age. Next slide. Kelly Barron published an article on the prevalence and characteristics of REM sleep without atonia in patients taking antidepressants, and they concluded that patients taking SSRIs and SNRIs has significantly higher prevalence of REM sleep without atonia, and therefore, these patients are predisposed to developing frank clinical REM sleep behavior disorder, and this reinforces what I already mentioned. Please ask your patients after initiating therapy with antidepressants if they have noticed any change in their dreams, and if they appear to be physically active in their sleep and acting out their dreams, and recruit their bed partners with their observations. Next slide, please. Duloxetine-induced RBD. This is a 62-year-old woman with violent dream and acting behaviors associated with increased tonic and phasic chin EMG activity during REM sleep triggered by duloxetine therapy of anxiety and somatoform disorders. RBD symptoms were gradually reduced and completely ceased after discontinuation of duloxetine for 37 days, and this was the first reported case of duloxetine-induced RBD. Next slide, please. So what is the risk for neurodegeneration with antidepressant-induced RBD? There was a recent study from Italy that basically is reassuring that they studied 10 patients with antidepressant RBD and 29 patients with RBD without any antidepressant exposure, and basically, they did dermal alpha-synuclein biopsies, and it was detected in 93.1% antidepressant negative patients, and so they concluded that patients with antidepressant-related RBD have clinical and neuropathological features suggesting a lower risk of neurodegenerative evolution than those with IRBD. And there was no difference, you can see, in terms of non-motor symptoms. Motor symptoms were polysomnographic features. So it's reassuring to some extent now that the neurodegeneration risk of RBD with antidepressants seems to be low. Next slide, please. Psychiatric outpatients with major depressive disorder. This is a study from Hong Kong, very interesting. First of all, the prevalence of video polysomnography-verified RBD was 9% in a population of Middle Asian, older, major depressive disorder patients, so it was really a high prevalence rate. They also had associated olfactory and color vision deficits that are biomarkers for alpha-synuclein neurodegeneration, and so the authors concluded that patients with RBD and major depressive disorder may represent a high-risk subtype of patients with major depressive disorder with an underlying alpha-synuclein neurodegenerative disorder. And so the implication is that psychiatrists should routinely ask questions of patients who are Middle Asian, older, with major depressive disorder, and also, if possible, family and spouse about RBD and refer suspected cases for sleep medicine evaluation. Here's a single-question screen that's been validated for screening for RBD, which I think you can utilize in your practice. Have you ever been told or suspected yourself that you seem to, quote, act out your dreams while asleep? For example, punching, flailing your arms in the air, making runny movements, et cetera? A very simple, validated screen that can be used to validate your practice, but it can also be used to validate your sleep. So, for example, punching, flailing your arms in the air, making runny movements, et cetera. A very simple, validated screen that they can then lead for further evaluation by a sleep medicine specialist, and of course, video polysomnography to confirm the suspected diagnosis of RBD. Next slide, please. So, chronic RBD, what are the neurological disorders? Far and away, neurodegenerative cerebral vascular disorders, but as you saw in that figure I showed you before from the introduction to the textbook, virtually all types of neurological disorders can cause RBD, and the location of the lesion is critical, as Alex Aranzo from Barcelona wrote in this publication. So, as I mentioned before, remetonia is a highly vulnerable entity that can be damaged by a whole variety of neuropathological disorders and other pathological conditions. Next slide, please. So, RBD at the time of diagnosis can be associated with a neurological disorder or be unassociated with a neurological disorder called idiopathic or isolated RBD. Then, what happens to these idiopathic RBD patients over time? Next slide, please. So, as we followed up these patients at our center, we found that 38 percent of our original 29 older male patients ended up with a Parkinsonian disorder, mainly Parkinson's disease and dementia of Lewy bodies. Next slide, please. So, as we followed these patients along, we were astounded to find that 81 percent of these older males at 16-year further follow-up developed a Parkinsonian disorder. I mean, that's amazing, and nothing else. It's a very highly prevalent but also highly specific association. The mean interval between the onset of RBD to the onset of Parkinsonism or dementia was 14 years, and this affords a really great window of opportunity for neuroprotective intervention, and that's why we have this NIH study to look into neuroprotective agents to administer to these patients of idiopathic RBD. Next slide, please. The Barcelona group, same outcome. They had an 82 percent conversion rate. We had an 81. It's the same. Mean latency in their group, 11 years, and they had a breakdown of nearly 50-50 Parkinson's disease and dementia of Lewy bodies, and also multiple system atrophy and mild cognitive impairment, six. So, two different groups, two different countries, same outcome data. Next slide, please. And here's a meta-analysis showing the high risk of a neurodegenerative phenoconversion, five-year follow-up, 33 percent from idiopathic RBD to frank neurodegeneration, 82 percent at 10.5 years, and 97 percent at 14-year follow-up. Next slide, please. Now, there are early onset cases under the age of 18, and we're not going to go into cases under the age of 50 that really show greater gender parity. You know, the older male patients are much more male predominant. The younger case is milder RBD and more associated with narcolepsy and cataplexy. The parasomic overlap disorder is a group of patients with RBD and a non-REM parasomnia, association with psychiatric disorders, antidepressant use, and perhaps also association with autoimmune diseases. Next slide, please. How about children? Far and away, the number one cause is narcolepsy with cataplexy, and sometimes the RBD can precede the onset of narcolepsy in these children. Also, cataplexy therapy with SSRIs, venlafaxine, TCAs, same therapies for major depression. Also, children with neurodevelopmental disorders can have RBD, parasomic overlap disorder, which is RBD and a non-REM sleep parasomnia, and sometimes also brainstem tumors can induce RBD because of the location of the tumor affecting the two nuclei in the brainstem that generate normal REM atonia. Next slide, please. There's an acute RBD, in other words, acute onset RBD, generally associated initially with drug and alcohol withdrawal states, but now we know you can have vascular causes, tumors, autoimmune, paraneoplastic disorders, inflammatory disorders, post-surgical, and alcohol withdrawal states. So we have to be aware of not just chronic RBD, but acute RBD that has quite a broad differential diagnosis. Next slide, please. How do you treat RBD? We do have some standards that have been developed. Next slide. First of all, maintain the safety of the sleeping environment. Pharmacotherapy is mainly clonazepam at bedtime and melatonin, either alone or in combination. And for treatment-resistant cases, primepaxilol is number three. These are conditional recommendations. A clinician should use his or her clinical knowledge and experience to strongly consider the patient's values and preferences to determine the best course of action, which I think is very reasonable. Next slide. Let me shift now to the non-REM sleep parasomnias. Next slide. So soon after we first reported on RBD, we published in 1989 the differential diagnosis of sleep-related injury in the American Journal of Psychiatry. And lo and behold, number one were the non-REM parasomnias, 54 cases of sleep terrors and sleepwalking. RBD was number two of 36. Seven patients had the psychiatric parasomnia called nocturnal dissociative disorders, and then three others had less common conditions. Next slide. So the diagnosis of disorders of arousal from N3 sleep in general include recurrent episodes of incomplete awakening from sleep, inappropriate or absent responsiveness to efforts of others to intervene or redirect a person during the episode, limited or no associated cognition or dream imagery, and partial or complete amnesia for the episode. Next slide. Sleepwalking, you have to meet the general criteria for disorders of arousal, and the arousals are associated with ambulation and other complex behaviors out of bed. Look at the prevalence in adults, anywhere from 1.5 to 4.3 percent, depending on the studies. Now, there are precipitating factors. In predisposed people, there's a family history, which plays a strong role. Sleep deprivation is the most potent factor, including irregular sleep-like behaviors. Sleep deprivation is the most potent factor, including irregular sleep-like schedule. Sleep disordered breathing is a newly recognized trigger for sleepwalking in someone who's predisposed. Either physical or emotional stress in women, the premenstrual period, in children, febrile states, and also travel and sleeping in unfamiliar places can be a potent precipitating factor. Next slide. Here's the polysomnogram. You can see the third channel is a scoring channel showing slow waves, and then at the bottom, this is an old polysomnogram, actually a paper polysomnogram, where the sleep technologist at 1.09.06 in the morning wrote vocalizing punching motions. So, this is a violent non-REM perisomny episode. Next slide. We'll see a sleepwalking video in the lab. This is a young adult female, and you'll see her in basically deep, non-REM sleep. There's no inkling just looking at her that she's going to do anything. She's really in deep, slow-wave sleep at 1.27 in the morning, and then suddenly, she inappropriately stands up and walks and clearly demonstrates being unaware of where she's located, and she almost falls out of bed. It's like locomotor activation coming out of the deepest stage of non-REM sleep, and this, you can see why there's a risk for injury. Okay, next slide. I'm going to show you a video now of a violent sleep terror episode. No, next slide. Thank you. We have just witnessed a vivid example of a night terror, a power nocturnus associated with violent behavior. This episode arose abruptly from slow wave or delta sleep. Next will be a woman who also experienced anxiety. We can stop there. We can go to the next slide. Thank you. Basically, this man has this abrupt arousal from deep non-REM sleep. He misperceives the environment, he's terrified, and he reacts with violence to protect himself. So intense fear triggers immediate intense violence. So let's now address medication-induced sleepwalking. There was a systematic review from Australia. Next slide, please. Primarily four classes of medications were found to induce sleepwalking. Number one by far, benzodiazepine receptor agonists, particularly zolpidem. Also serotonergic antidepressants, bupropion, older generation antipsychotics. But for our purposes, zolpidem is far and away number one. Next slide, please. Key messages. A broad range of non-REM sleep parasomias exist and usually be effectively managed. The bed partner is urged to provide witness accounts. The therapy should first focus on managing triggering factors and comorbidities, particularly obstructive sleep apnea, restless sleep syndromes, precipitating medications, especially zolpidem and other sedative hypnotics, insufficient sleep and sleep deprivation, and both psychological and physical stress. Next slide, please. Precipitating factors also can include alcohol use or abuse. Oversized medications, medical disorders such as hyperthyroidism, migraines, head injury, and a variety of psychiatric disorders. Next slide, please. Sleep terrors, diagnostic criteria, you have to meet the general criteria. Arousals are characterized by, as we saw in the video, episodes of abrupt terror, typically beginning with an alarming vocalization, such as a frightening scream. There is intense fear and signs of autonomic arousal, including myadriasis, tachycardia, tachypnea, and diaphoresis. In adults, you can have dream imagery, dream enactment, and subsequent recall for episodes. Look at the prevalence rate, up to 6.5% in children, and in adults, even up to the age of 65, it can be around 2%. And sometimes, and then beyond 65, years of age, 1%. So not uncommon. Next slide, please. So how do you manage disorders of arousal? You want to maximize the safety of the sleeping environment, especially the removal of weapons. You want to minimize precipitating factors, particularly obstructive sleep apnea, restless sleep syndrome, discontinued triggering medications, the use of door alarms, proper sleep hygiene, including a very regular sleep-like schedule, and also ensuring sufficient total sleep time. Stress reduction. Sometimes counseling may be helpful for learning how to best reduce your own particular stress. Self-hypnosis can be highly effective in people who are disposed to learning self-hypnosis. Relaxation techniques, and as a final resort, pharmacotherapy, particularly benzodiazepines, imipramine, and buspirone. Next slide, please. Confusional arousals. A common focus on sex-dominant and inappropriate sexual behavior during sleep meets the general criteria for non-REM sleep disorder arousal. The episodes are characterized by mental confusion or confused behavior, which occurs while the patient is in bed. There is an absence of terror or ambulation outside the bed. Next slide. What are the clinical or pathological subtypes of confusion arousals? Number one is sleep-related abnormal sexual behavior. That's the official designation in the International Classification of Sleep Disorders, also known as sexsomnia or sleep sex. Typically occurs in bed, less commonly associated with sleepwalking, and we're really discussing problematic sexual behaviors emerging during sleep, often are chronic and recurrent, with major interpersonal, clinical, and occasional criminal consequences. It's male-predominant in sleep clinic referrals. Next slide, please. I did a literature review in an editorial I wrote recently, and there have been 220 published cases, 84% males, age range 14 to 77 years, not associated with dreaming. It's a deep non-REM sleep parasomnia, not associated with dreaming, not associated with any type of daytime paraphilia. Sexsomnia, the most common causes are a history of other non-REM sleep parasomnias, and to a lesser extent, obstructive sleep apnea, triggering abrupt arousals with sexual behaviors in men. Sexsomnia is rarely the only parasomnia, but could be the only parasomnia if obstructive sleep apnea was causing the confusion arousals with sexual behaviors. Up to five total parasomnias have been reported in patients with sexsomnia, so it was part of a very complex set of parasomnia behaviors. And sexsomnia usually is the last parasomnia to emerge in a patient with multiple parasomnias. And a very important conclusion is that a purported first-time sexsomnia episode resulting in a legal charge should be viewed with extreme skepticism. Sexsomnia can be associated with RBD in several published cases, which is a different form of parasomnia overlap disorder. Next slide, please. The whole range of sexuality can be expressed as sexsomnia, as you can see here. There's complete amnesia for the sexsomnia episode, but a frequent source of shame, guilt, confusion, and relationship stress from being told about one's objectionable nocturnal behavior upon awakening in the morning. Imagine waking up, no idea what happened the night before, and you're told by your bed partner about all your inappropriate sexual behavior. It's terrible. It's really very demoralizing. However, sometimes the sexsomnia is pleasurable for the bed partner, but again, it's disconcerting for the patient to be told about pleasurable sex when you have no memory of it. Next slide, please. Here are literature that you can read to learn more about sexsomnia. I don't have time to review it now, obviously. Next slide, please. Therapy is often very effective, either clonazepam at bedtime, paroxetine, sometimes other medications. Obviously for obstructive sleep apnea triggered cases, either standard CPAP, BiPAP, or even another therapy of obstructive sleep apnea involving mandibular advancement device can also control the secondary sexsomnia, because sexsomnia in these cases is secondary to the obstructive sleep apnea, so regardless of how you treat the primary problem of obstructive sleep apnea with CPAP, BiPAP, or mandibular advancement device, the secondary sexsomnia will also be controlled. Next slide, please. Now sleep-related eating disorder involves circadian misalignment in eating, so you have two instinctual behaviors that become pathologically intertwined, sleeping and eating. Now this is a female predominant disorder. Anywhere from 60% to 83% of patients reported series are females, and this is a young adult, the beginning of middle-aged adult problem. Nightly frequency of nocturnal eating is more than 50% of reported cases, and in these cases, half of them, they have an overweight or obese status. Interestingly, this is not a hunger-driven behavior. These patients do not recall any hunger. Sometimes they're so desperate, they have a second dinner before bedtime. The prevalence of sleep-related eating disorder can be very high, depending on the population being studied. As you can see, anywhere from 2.2% to 16.7%. Next slide. So the diagnosis from the International Classification of Sleep Disorders, you need recurrent episodes of dysfunctional eating that occur after an arousal from sleep during the main sleep period. One or more of the following must be present with the recurrent episodes of involuntary eating. First is excessive weight gain or obesity. Second, destabilization or precipitation of diabetes mellitus, type 1 or type 2. Third, you can have hypertrichlyceridemia or hypercholesterolemia. Fourth, a variety of dental problems, not just cavities, but also chipped teeth from eating frozen food. You can have allergic reaction from carelessly eating foods to which one is allergic. You can also have secondary depression, waking up in the morning realizing, I did it again. I ate out of control. It's very demoralizing. And third, there should be at least partial loss of conscious awareness during the eating episode with subsequent impaired recall. Next slide, please. SRED appears to be a final common platform disorder that can emerge from a broad range of clinical conditions, such as non-REM sleep parasomnia, restless sleep syndrome, obstructive sleep apnea, circadian rhythm disorder, medications. It really is a final common pathway disorder that you can see here. Even intense separation reactions related to death or a relationship dissolution. However, once sleep-related eating disorder emerges, regardless of its origin, it demonstrates a typical longitudinal high-frequency course. Next slide. So how do you treat it? First of all, like any other parasomnia, you want to treat any comorbid disorder, such as treating comorbid obstructive sleep apnea, treating comorbid restless-like syndrome or periodic limb movement disorder. You want to eliminate any triggering or aggravating medication, particularly zolpidem. Next slide, please. In terms of pharmacotherapy, for sleepwalking and idiopathic subtypes, topiramate is far and away number one, dopaminergic, such as primopexol, SSRIs can be highly effective, sometimes bupropion, trazodone, alone or in combination. But this is one of the most difficult parasomnias to treat. And I would say in about 60 to 75% of the cases, medications can be highly effective. Next slide, please. Here is the literature. John Winkelman wrote a very nice article about topiramate therapy. And also, we published on two cases of sleep-related eating disorder responding very well to low-dose sertraline. And we reviewed in this article the cumulative literature on the various pharmacotherapies of sleep-related eating disorder in the Varghese article. So I would refer that for you for the full literature review on the treatment of sleep-related eating disorder. Next slide. Differential diagnosis, the night-eating syndrome is wakeful eating before sleep and or during a nocturnal awakenings. That's an important differential diagnosis. And then you have unusual conditions with abnormal nocturnal eating, such as Klein-Levin syndrome, known as periodic hypersomnia, peptic ulcer disease, diabetes mellitus, a very rare condition, neurological condition called Kluver-Busse syndrome. And also, finally, the sleep-related dissociative disorder, the psychiatric parasomnia, where you have an altered eating personality during the nocturnal sleep period. And that leads into, I think, my last slide. Next slide, please. Yes, this is a recent publication of mine, two cases of sleep-related dissociative disorder with nocturnal eating episodes. And from the abstract, two female patients, age 53 and 40 years old, with prominent histories of multimodal abuse, typical of sleep-related eating, I'm sorry, typical sleep-related dissociative disorder, with childhood emotional and food deprivation abuse in case one, and childhood emotional and sexual and physical abuse in case two. Both patients were affected by, quote, sleep phobia and had recurrent nocturnal eating episodes. So, we have to include sleep-related dissociative disorder in the differential diagnosis of sleep-related eating disorder. Next slide. Sleep-related dissociative disorder is a psychiatric parasomnia emerging from electroencephalographic wakefulness during wake-sleep transitions, or during awakenings after interval, from N3, or slow-wave sleep, diagnosis, sleep-related dissociative disorder, emotional abuse, including at bedtime. In most cases, we have daytime dissociative disorders. Most cases have a history of severe comorbid psychiatric disorders that you can see here. It's in the differential diagnosis of sleepwalking. Therapy requires very specialized dissociative disorder therapy, pharmacotherapy of comorbid psychiatric disorders. Furthermore, clonazepam can disinhibit nocturnal dissociative disorders in some cases, in contrast to being therapeutic in disorders of arousal from non-REM sleep. So, that could be a red flag if a patient with a presumed non-REM sleep parasomnia gets worse with clonazepam, that patient, in fact, may have a sleep-related dissociative disorder. Next slide. And here are the references. And you'll read some fascinating case reports as well. Thank you very much. I appreciate your attention. Now, while I'm waiting for any questions, I do want to mention that in relation to REM sleep behavior disorder and the risk for neurodegeneration, I'm frequently asked, what do you tell patients when you diagnose? Well, you have to mention the risk, because people will go to the internet, and this is all over the internet, in terms of the high risk of future neurodegeneration of REM sleep behavior disorder. So, you need to broach the subject, or else the patient and the spouse will get very upset with you, saying, why didn't you mention it? But you have to use clinical judgment about how much information you reveal. You just mentioned that, especially in patients age 50 and older, that's the high-risk group. That's where the data come from. We don't know about younger adults. Middle-aged and older adults diagnosed with REM sleep behavior disorder, you have to mention there is a potential risk for future neurodegeneration. How much information do you want? And maybe you should be evaluated by a neurologist for a baseline neurological evaluation, and then be followed up. So, you need to broach the subject, and depending on their level of education, level of medical sophistication, you can provide more or less information to them, and also communicate with a primary physician, who can then have a more detailed discussion. All right. Let me go to the chat for questions. But that's an important issue in terms of the medical responsibility in addressing the issue of future neurodegeneration of patients with RBD. In terms of sleep-related eating disorder, I think these patients really get extremely frustrated, and even if you put a door alarm on their room, that will make them feel even worse. So, the deprivation to food access is far worse than even eating during the night. I had one patient who paid her three teenage children to sleep in sleeping bags in the kitchen to prevent her from eating. She got so frustrated when the children denied her access to food, that she paid them more money so that they would go back to their bed and let her eat in peace. So, that tells you how strong the drive is to eat with sleep-related eating disorder. Oh, one second. Oh, could you give us an idea of the prevalence of complex sleep behaviors associated with the various classes of hypnotics? We really don't have that data yet. The literature review identified the most commonly reported medications, but we really don't know the prevalence, unfortunately. Since lemborexin can increase REM, is there a higher instance of risk of RBD or other parasomnias? There are some case reports, but it's still too early in the game to know. And I think, basically, anytime you prescribe any kind of new neuroactive agent, you need to ask about RBD behaviors. We need to learn more about this in relation to new medications on the market. This is an excellent question, and I think this needs to be followed up. Ask the patient and have the patient talk to the bed partner as well. I think psychiatrists really need to be proactive in questioning patients about any type of parasomnia when prescribing medication. A lot of patients may think, well, I'm seeing a psychiatrist, they really don't care that much about my sleep. It's not as primary a problem as depression or anxiety. So I think we need to, just like sleep physicians, need to question patients who have obstructive sleep apnea about sexsomnia, because patients will say, what is why a sleep doctor doesn't care about sex? You know, he's a sleep doctor, but the two can become intertwined. So we both have to be very proactive. Psychiatrists inquiring about parasomnias is a medication side effect, and sleep doctors need to really talk about abnormal sexual behaviors or abnormal eating behaviors during sleep. Let's see. Okay, here's another one. Okay, for treatment of clonazepam, what is the typical dosing? Would you then need to increase the dose over time due to development of tolerance? That's an important question. For treating REM sleep behavior disorder, the usual dose, depending on the patient's age, is anywhere from 0.25 milligrams to 2 milligrams. And I would try titrate very gradually to determine what dose works the best to make sure there's no side effects. Sometimes we have to add on a melatonin. Some sleep doctors now go straight to melatonin to begin with, anywhere up to 18 milligrams at bedtime. And we start generally at 6 milligrams and titrate up to 18 milligrams. So depending on your own familiarity of these medications, with clonazepam, 0.25 milligrams, slowly work your way up by 0.25 milligram increments to 1 to 2 milligrams at bedtime. And with melatonin, from 6 to 18 milligrams at bedtime for treating REM sleep behavior disorder alone or in combination. Let's see if there's any other questions. Do we have any idea of the mechanism of action to why trazodone and bupropion do not lead to RBD? Excellent question. Well, they're not, you know, bupropion is not serotonergic, as trazodone can be. We just don't know. That's a great question, and particularly with the trazodone. But I think medications with serotonergic effects, I think I'm most at risk. Now, I'm glad you've asked this question because I keep asking my colleagues who are basic scientists who do research with mice and rats of RBD, test out these antidepressant medicines and really get a good handle about the neurochemistry subserving medication-induced RBD. They haven't done it yet. They did recently publish an article about narcolepsy with RBD in mice. So I'm hoping the next step can be testing out the antidepressants. The next step can be testing out the antidepressant-induced RBD and get a good handle. But I wish I could answer better, other than bupropion has no serotonergic effect. See, this is a really great field in terms of parasomnias working with basic scientists. It's clinicians working with basic scientists so that we help them to understand what's important for them to test, and they help us in understanding what's going on in the clinical front in terms of the underlying mechanisms. So the next frontier should be medication-induced RBD. What are the mechanisms in the animal model? And the leading centers are in Lyon, France, and also University of Toronto for the basic scientists working in this field. Now, we have an international RBD study group that meets every June, and basic scientists come along with clinicians, and we have good interchange. So that's when I can kind of keep nudging the basic scientists to test the medication-induced RBD in their mouse and rat models. So we hope to host the international RBD study group meeting in June of 2026, because that will mark the 40th anniversary of our first paper in 1986 published in SLUI. And so that would be a nice occasion in Minneapolis to have, you know, we have 150 members of the international RBD study group, clinicians, but also basic scientists. Next year we'll be meeting in Holland. We just had a meeting in Oxford, England this past June. It's a very active group for obvious reasons. You know, the whole link with neurodegeneration is a very compelling topic and of great public health importance. Okay, I think that's it. Thank you.

parasomnias

sleep medicine

REM sleep behavior disorder

neurodegenerative diseases

polysomnographic evidence

sexsomnia

sleep-eating disorders

medication management

Dr. Carlos Sheng