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Update in Non-Respiratory Sleep Medicine: A Case-B ...
Update in Non-Respiratory Sleep Medicine: A Case-Based Approach
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Welcome to this session on updates in non-respiratory sleep medicine. Our objective today is to cover four really important topics, so we'll start with rest of the slides, then move on to insomnia, hypersomnia, narcolepsy, and finally end with pediatric, the most important topic, pediatric sleep medicine. So we are really excited to have you today and thankful to the Sleep Network and this amazing panel. Today I'm Dave Balachandran, I'm from MD Anderson Cancer Center. You'll be hearing about rest of the slides just very shortly from Sai Venkatesh from Emory. We have Lilith Sargason who will talk to us about insomnia from UT McGovern in Houston, Texas. And finally, Dr. Karen Okori who will talk to us about pediatric sleep medicine who is from Stanford University. So with that, let me introduce Dr. Venkatesh Sia. Thank you, Dave. Thanks for organizing this. Good morning. I'll be giving an update in Restless Leg Syndrome. I'm Sai Venkatesh Sia from Emory University, Atlanta, and I have no disclosures. And if you want to answer the questions and if you want to follow on, please scan this bar code. So the objectives of today's talk would be using a case-based format, we shall emphasize the first-line treatment option for chronic persistent RLS, we shall understand the long-term effects of opioid therapy for refractory RLS, and we shall also evaluate some newer treatment options for drug-resistant RLS. So let's begin with case number one. A 35-year-old woman is referred for evaluation of sleep onset insomnia. At 10 p.m., she usually gets an irresistible urge to move her legs, and she must get out of bed to pace around her house for relief. She's finally able to fall asleep after around two and a half hours later. So these symptoms occur at least four nights each week. So she does not endorse any history of snoring or any witnessed apneas or BMI, Malampetit score, the EPFOR score, all are normal. And you check her serum ferritin level, and it's 300 nanograms per mL, and transfer and saturation is 45%. She has no medical comorbidities and is on no medications. So okay, so what would be your first treatment choice? Please go ahead and answer. having votes being cast. Okay, so it's interesting, there is a nice split. The correct answer is alpha-2-delta calcium channel ligands such as gabapentin, pregabalin, or gabapentin-enacardone. So this is the RLS foundation treatment algorithm that was updated and was published in the Mayo Clinic Proceedings a couple of years ago, but this concept has been going on over the past few years. So the first choice for chronic persistent RLS is alpha-2-delta calcium channel ligands unless there are contraindications. And dopamine agonists, which were previously the first choice, are no longer the first choice. They are the second choice because of the side effects of augmentation and impulse control behavior disorders. Augmentation occurs, by definition, means that there is an increased severity of the symptoms and the symptoms occur earlier in the evening and the symptoms spill over from the legs to the torso and to the upper extremity. So this typically happens in 40 to 70% of these individuals when they're on dopamine agonists long-term. And impulse control behavior disorders such as pathological gambling, compulsive shopping, hypersexuality can occur. So typically around five to six percent, but in the literature it's been described between five to 30%. So because of these side effects, the dopamine agonists are no longer the first choice. But that said, there are certain contraindications to alpha-2-delta calcium channel ligands. If somebody has obesity and its complications, if somebody has past or present moderate or severe depression, or if they have gait instability, or if they have disorders causing respiratory failure, or if they have prior history of substance use disorder, then alpha-2-delta calcium channel ligands are contraindicated. So the bottom line is dopamine agonists are no longer the first choice for chronic persistent RLS. And the first choice now is the alpha-2-delta calcium channel ligands, such as gabapentin, pregabalin, or gabapentin and carbyl, unless there are contraindications. Moving on to the second case, a 40-year-old woman. She was diagnosed with RLS. She was started on low-dose ropinarol, with initial good response of symptoms. That's what is expected. Over the course of the next five years, for persistent symptoms, the dose of ropinarol was increased to a maximum of four milligrams per night. Now she has RLS symptoms in the early evening that involves her arms as well as her legs. So basically, she's got augmentation. So her serum protein levels are 300 nanogram per mL, and transfer and saturation is 45%. She's on no other medications, no concern for sleep disordered breathing. You taper her off ropinarol while adding gabapentin. Her symptoms are only slightly better, so you decide to start her on low-dose opioids. She's obviously very concerned about the long-term effects of opioids because of all the negative press the opioids are receiving. So what would be your advice to the patient? So which of the following statements is correct about patients on opioids for RLS? Please go ahead and pick one. Okay, let's see. Once again, interesting. It's a nice split. So, but the correct answer is D. Sixty percent saw either a decrease in their dose or they saw no change. So this is the data from the National RLS Opioid Registry that was published earlier this year in Journal of Neurology. This is a two-year longitudinal data in patients treated with opioids for RLS in the community. So what they did in this registry was they collected data on opioid doses, past and current RLS treatments, the RLS severity, psychiatric comorbidities, and opioid abuse risk factors. They were collected at registry entry and every six months thereafter. So as per this registry, the commonest opioids that were used were methadone followed by oxycodone and hydrocodone. So this is a busy slide. I highlighted some of the Syrian points. So when we look at the demographics, the mean age was around 65 years. There was a slight preponderance of women, so and overwhelming majority were white, 98 percent, and 90 percent had history of augmentation. And when we look at their IRLS score, which basically indicates the severity, it was moderate. Their mean values were around 13. So when we look at the overall severity of RLS in the overall cohort, there was no change in RLS severity over the two-year follow-up period. So initially like 25 percent had severe RLS. At the end of two years, 25 percent had severe RLS. But you can see the distribution. Some individuals got better and an equal proportion got worse. So there was pretty much no change over the two-year follow-up period. And when we look at the change in the daily opioid dose, the median change in the daily opioid dose from baseline to two years was zero morphine milligram equivalents, so with the interquartile range of zero to ten. So 41 percent of these individuals increased their dose during the follow-up, but it was only a slight increase of around 10 morphine milligram equivalents. So 59 percent decreased their dose or saw no change. And when we look at the individuals who increased their opioids substantially, such as more than 25 or more than 50 morphine milligram equivalents, those were only a minority, eight and four percent respectively. When we look at the characteristics of these individuals who increased their opioids substantially, they were either switching opioids or they had discontinued the non-opioid RLS medication. They had at least mild insomnia at baseline, history of depression, men age younger than 45 years and they were on opioid use for comorbid pain. 95 percent had one of these following characteristics. So the takeaway point is, this is the class 4 evidence, that opioid doses increase in roughly 40 percent of the patients in most by small amounts, so over a two-year period in refractory RLS. And interestingly, 80 percent of those who stayed on opioids, they remained on the same opioid at the two-year time point and the median morphine milligram equivalent dose at the two-year time point was the same compared to baseline. As expected with opioids, the most common side effects were constipation, drowsiness, itching, etc. So moving on to the case number three, you know, a 50 year old woman presents with RLS. She has RLS symptoms for more than 20 years. She was initially on Pramipexole with good response for a few years, subsequently developed augmentation. She was switched to Gabapentin. She couldn't tolerate it. She had to stop it due to dizziness. She was started on low-dose opioids, which improved her symptoms slightly, but they went on to medium-dose opioids. Unfortunately, she still has very distressing symptoms. So her serum ferritin, I mean, her IRLS score is 30, suggesting that severe RLS symptomatology. Her serum ferritin is 150 nanograms per ml and transfer in saturation is 35. Since there is no good correlation between serum and brain iron levels, you try IV iron, but she has no response whatsoever. She's willing to try any option to help with the disabling symptoms. So what would be your options? Pick one, please. Okay, let's see, okay, only a minority got it right. The correct answer is non-invasive peripheral nerve stimulation. So this is the RESTful study, which was published earlier this year in Sleep Journal. So this is non-invasive peripheral nerve stimulation for medication refractory primary RLS. It's a multicenter, prospective, randomized, double-blind, sham-controlled trial. They were connected to seven sleep centers in the U.S. So the medication refractory RLS was defined as having failed one or more medications specific for RLS. And there are a bunch of exclusion criteria listed here, but some of the notable ones, if somebody had severe peripheral neuropathy or if they had any skin condition that might affect the application site, those were excluded. So how does this device work? These are a pair of therapy units that are worn externally and bilaterally over the peroneal nerve at the head of the fibula. So the electrodes, they generate a pulse generator, and they cause stimulation for 30 minutes. You can use it up to four times a day. So how this device works is it stimulates the afferent peroneal nerve fibers, and that evokes a sustained increase in tibialis anterior muscle tone. So through this mechanism, this system engages the similar neuromuscular circuitry such as the voluntary leg movements, such as walking or standing, which are known to relieve RLS symptoms. So basically, this therapy unit mimics the neuromuscular circuitry, such as voluntary leg movements, which are known to relieve the RLS. But this system is compatible with sleep, unlike walking or standing. So this is the flow diagram of the study. So they had like 133 patients randomized. In the first stage, there were like 68 randomized dratonic motor activation herein so after called TOMAC. And the other group was assigned to the sham control. And pretty much barring one or two dropouts, pretty much everybody completed the trial. So when we look at the baseline demographics, you can see that there was a slight preponderance of women. So the mean age was around 56 years. So once again, overwhelming majority were white. And the duration of RLS symptoms, the mean duration was around 22 years. And the IRLS score was pretty severe, 25, the mean values. So they measured the efficacy. The primary endpoint was the clinical global impression improvement responder rate at week four. And they were looking at a value of much improved or very much improved. So when we look at the TOMAC group, 45% met the primary endpoint compared to the sham, which was 16%, which was statistically significant. There are a bunch of key secondary endpoints, such as the patient global impression improvement responder rate. So the IRLS score, medical outcome studies, sleep problem index one and two, and a bunch of other indices, all of them, they were favorably statistically significant towards TOMAC compared to the sham. So this is a graphic which shows some of the salient results. So the primary endpoint is the CGII responder rate, which was 45% for TOMAC compared to 16% for sham. So the PGII, the patient global impression improvement responder rate, that also showed statistically significant difference. And the IRLS score, the lesser the better, so it was much better with TOMAC compared to the sham. And same with the MOS one and MOS two scores. The lesser the number, the better. So you can see that TOMAC performed very well compared to the sham. And when we look at the mean CGII scores, the TOMAC value was around 2.6 compared to 3.5 for the sham group. So they also, what they did was at the end of the four week trial, they, in an open label fashion, they combined all the patients and put them on TOMAC for the next four weeks and they analyzed the data. You can see at the end of eight weeks, these primary outcome improved from 45 to 61%. So and the IRLS score was further reduced from minus 7.2 to minus 8.7, and there was a further reduction in the MOS two scores. So and this same group had one more publication in sleep, in which they did a 24 week extension. What they did was at the end of eight weeks, once again, they put one group in sham and one group in TOMAC and followed them for the next 24 weeks. And you can see the primary outcome improved even much further from 61 to 73%. And the IRLS score improved much further from 8.7 to minus 11.3, whereas the sham reverted back to normal. So there were no grade two or higher device related adverse events. So most of the adverse events were self-limited, such as administration side discomfort and skin irritation. And yeah, they did not require any intervention. So the bottom line is tonic motor activation produced significant improvement in IRLS symptoms. So but you have to be careful. There was a large placebo effect also. But we need larger studies and longer duration follow up. So but it's a potential treatment option in medication refractory IRLS. It's not in the experimental arena. The April of this year, FDA granted marketing authorization to the company manufacturing this device for an indication of primary moderate to severe drug resistant IRLS. So the device hopefully should arrive within the next year or so. And there might be an option which may be available for our patients who have exhausted all drugs and are still disabling symptoms. So that's all I got. So thank you very much for your kind attention. Please don't forget to evaluate the session in the app. Thank you, Dr. Venkatesai. If you don't mind, we'll wait until the end of all the presentations for questions. Good morning, I'm Dr. Sargisyan and I'm from McGovern Medical School and I'll be speaking about insomnia. And I'll start with a poem, Insomniac. There are some nights when sleep plays coy, aloof and disdainful and all the wiles that I employ to win a service to my side are useless as wounded pride and much more painful, Maya Angelou. Today I hope to share with you something about insomnia and how to treat it both behaviorally and pharmacologically. This is a QR code for the questions, please. Let's begin with a question. We have a 55-year-old woman with hypertension, diabetes, obesity who comes to clinic stating that she hasn't slept well since her mom died when she was 22 years old. She cannot fall asleep for two to three hours, is a light sleeper and wakes up in the early morning and cannot fall asleep. Upon detailed questioning, she endorses snoring and waking up gasping for air especially after alcohol use. Her upward sleepiness score is 10. What is your first step? Okay, sorry, the answer wasn't showing up for me over here. So yes, the answer is to obtain a polysomnogram, 95%, that's amazing, thank you, good morning. So let's please first rule out sleep disorder, breathing. Of course, we institute treatment in parallel, not necessarily sequentially, but this is very important. So insomnia, as we know, is a concern or dissatisfaction with sleep, even either falling asleep, staying asleep, or waking up too early, despite adequate opportunity and correct environment for it. We like sleep at night to be contiguous, and when anything disrupts it, this is very concerning for both the nighttime and the next day functioning. In order to have the same vocabulary, these are the parameters that studies address, medications improve, as well as behavioral therapy, so I'd like to quickly mention what they mean. Sleep onset latency is how fast we fall asleep, the wake after sleep onset is the time in minutes of a person spending awake at night, number of awakenings is self-explanatory, total sleep time, and the perceived sleep efficiency, or the percentage of time in bed actually spent asleep. And of course, these things have negative impact on next day functioning. We may be more sleepy, have fatigue, have somatic complaints, and have cognitive or mental occupational dysfunction, as well as social isolation and mood disorders. So we know the impact of insomnia on next day functioning, quality of life, but also just all mental, physical life outcomes, and sleep in general is proportionate to general health status, and this is both objectively and subjectively. Insomnia is very prevalent, highly, both in the U.S., Canada, as well as Europe, 50% of patients who present to primary care doctors have insomnia, only a third mention it, and only 6% directly ask for help, and up to 70% of primary care physicians do not ask their questions about, do not ask their patients anything about their sleep. The financial impact of insomnia in the U.S. ranges from $20 to $100 billion a year, which is astronomical, and a lot of this is due to the cost of treatment, but also loss of productivity, accidents, hospitalizations after them, and so this is a large problem, a lot of potential for improvement. And I'd like to mention there's primary insomnia, however, there's also secondary insomnia, and secondary may be due to other sleep disorders, but also any comorbidity, cardiovascular, psychiatric, et cetera, and addressing insomnia, even when it is secondary, in a targeted manner is absolutely paramount, and this actually happens to be a rising population of patients with insomnia. As far as treatment goes, cognitive behavioral therapy for insomnia, or CBTI, in the acute term, meaning about four weeks, and in four-week increments, is found to be equally adequate to medications or pharmacotherapy, however, CBTI has a better safety profile and durability, it's been shown over a one- to two-year period to have a better lasting effect, while upon discontinuation of medication, the effect is immediately gone, and therefore, in the long-term, CBTI is the first-line treatment, and it improves all the parameters that you can see below. So when choosing pharmacotherapy, however, we must, of course, weigh the benefit and risk profile, and here I've sort of indicated that disadvantages outweigh the risk, the benefits, but I do wanna mention that this should be a case-by-case, patient-specific decision, and in some patients, especially in the acute term, pharmacotherapy can be not only helpful, but what's the correct thing to do. So let's move on to our patient again. She now returns, she has hypertension, diabetes, obesity, she returns to clinic. We did a sleep study which showed moderate OSA, she's now on auto-positive airway pressure, five to 20 centimeters of water, her EPOOR sleepiness score is down from 10 to six, sleep onset latency is still two hours, and she still awakens early morning, cannot fall asleep. What is the best next step? All right, thank you very much. I agree with 59% of you. Screen for a mood disorder and refer to formless CBTI with a sleep trained sleep psychologist. Here I've chosen CBTI as the right answer. Her insomnia is long-standing since she was 22 and of course she is at high risk for also having mood disorders. So just the landscape of insomnia medication starting a long time ago with alcohol, opium, laudanum is the combination of the two. The first actual sleep medication was chloral hydrate, still available, not much prescribed thankfully. Barbiturates were invented and were the mainstay for a long time until they were replaced by benzodiazepines and we know in the 1990s we got the Z drugs or the non benzodiazepine benzodiazepine receptor agonists and here we are. So I would like to show you everything sort of that's being used for insomnia. The unregulated category is largely plant-based. Notice how melatonin is also on that list. Valerian root is probably the best studied. Data is very unclear and really ineffective in all of these and these are unregulated. The most commonly over-the-counter available formulations for sleep aids contain the first-generation antihistamines because of their sedating effect. However, their anticholinergic side effect profile is really prohibitory for many people but also just creates more problems than good. These are not recommended officially as sleep aids despite their ubiquity and the how much they're being used. A more tricky category are the prescription but off-label medications and notice how they're sort of divided under antidepressant, antipsychotic, and anticonvulsants and the general rule of thumb is these should not be used in patients without the comorbid condition that requires them in the first place. So Seroquel or Keatopine may be great in someone who has schizophrenia with insomnia. However, without a psychiatric diagnosis they are not recommended to be used due to the burden of side effects without a justification of benefit. Of course, if for example there's restless leg syndrome and gabapentin, you see that on the list, that may be a case where you may choose a medication off this list for your patient. So what do we want to achieve when we try to put someone to sleep, so to say? Either we are trying to promote sleep or we are trying to promote decreased wakefulness. So you can see the classes of medications GABA, GABAinergic or promoting GABA, melatonin, and then the wake neurotransmitters in the left upper corner, and then the orexin system. This is kind of a general rubric of how they are intended to work. So the benzodiazepines are gamma-aminobutyric acid agonists. I've listed them in the order of their duration of action from shortest to longest, and of course these medications have a lot of problems, especially in the elderly population, with some signals for possible increased rates of falls and fractures, and also possibility of dementia, of course tolerance and dependence that builds with them, and difficulty tapering them with withdrawal, a challenging withdrawal profile. And so these are, although useful at times, they are no longer our go-to these days. The Z drugs are more selective for this GABA receptor that you see over here. They're more selective for the alpha subunit, and therefore they do not have the same side effects of sedation and sleep drunkenness in the morning as much. However, those are still possible. The Z drugs I've also listed in order of duration of action, with Sonata being very short-acting, half-life is one hour, and it is a good option to take in the middle of the night as long as there's four more hours of bedtime left, or time in bed. And the same goes for the short-acting sublingual zolpidem, which can be used middle of night for awakenings. Others are recommended beginning of the night with a seven to eight hour guaranteed time in bed in order to not have dysfunction upon getting up in the morning. Melatonin agonist, of course melatonin would be in this class, however I'm listing just the FDA approved for insomnia medications, Remeltion. It is a one dosage eight milligram option. It's a great usage for patients with higher proclivity towards medication side effects, specifically the elderly, and this is a sticking point. There's separate studies and data looking at patients over the age of 55 and also 65 with safety profiles and long-term safety, specifically for insomnia, because especially sleep maintenance insomnia becomes much more prevalent and common in older age. Remeltion typically is not the greatest in terms of efficacy. It is used best for early insomnia, meaning sleep onset insomnia, and doesn't do so much for duration or sleep maintenance. Fluvoxamine, you can see in the bottom, it significantly raises blood levels of Remeltion and make that toxic, and that's the reason. Doxepin is a wonderful drug. It is a tricyclic antidepressant, however at these low doses that are recommended for insomnia, three milligram or six milligram, it only has the H1 antagonist effect and does not have anti-cholinergic side effects, and so it is safe in most patients, including the elderly, and I think it's likely underutilized, so I encourage everybody to look into using this medication more. It can have a risk of serotonin syndrome when administered with other medications that increase serotonin levels, so that is the caveat. But I would like to spend extra couple of minutes on the orexin system. So orexin 1 and 2 are, or A and B, excuse me, are neuropeptides that are made in the lateral hypothalamus and periphernical area. They're made from these precursor peptides, and they have receptors, OX1R and OX2R, with different selectivity. And just the amount of projections and the complexity of the orexin system is mind-boggling, and I think understood, so not understood well. You can see all of the functions that it carries, including thermoregulation, food and appetite, energy metabolism, cardiovascular health, spontaneous physical activity, which essentially SPA, it's when we fidget, when we stand and we can't stand still, so just spontaneous movement, and it projects widely through the CNS. So here's another schematic drawing showing the main projections. You can see in the center the lateral hypothalamus and the posterior hypothalamus that create orexin. The solid arrows are stimulatory and the broken ones are inhibitory. So notice on the left side of the graph that orexin has stimulatory projections to all of our wake-promoting neurotransmitter areas, meaning our monoamines, so noradrenaline, serotonin, histamine, acetylcholine, and thus it produces or promotes wakefulness. And then please notice on the right side that GABA and adenosine inhibit orexin, therefore reducing its wake-promoting action. Also, anyone have coffee today so far? One, two. Notice adenosine, that is where caffeine reduces its levels and has an effect on orexin also. On the bottom, you see dopamine and the ventral tegmental area on the bottom left. So orexin also suppresses or orexin induces dopamine and the reward system, so inhibiting orexin also reduces or dampens the reward system. And so the medications that I'll show you that target this are a good option in those with substance use disorder, while a lot of the other medications that are addictive and have other challenges may be worse options. So that's one thing to think about. And then finally, I'll point out on the bottom right, suprachiasmatic nucleus, which is our center for wakefulness. It stimulates wakefulness and also produces or rather makes the pineal gland produce melatonin, which is soporific, has projections to the orexin system as well. So by loss of orexin signaling, we can cause cataplexy, but also sleepiness, which would be the opposites of what orexin does. So you can see here how by loss of orexin, we can reduce the motor excitatory system and remove inhibition of the motor inhibitory system, but also reduce stimulation of the wake-promoting systems and remove inhibition of the sleep-promoting systems. And this is part of the side effect profile is possible cataplexy-like symptoms. So DORAs, I like the acronym DORAs, dual orexin receptor antagonists. There's three of them. For now, more are in the works. Suvorexant was the first. Lemborexant, and just last year, duradurexant came out. It has the shortest duration of action, about eight hours. Still remains to be seen whether that reduces next day sleepiness or not. So this again may be a good option for those who either must be functional in the morning or have higher, worse metabolism and are of older age. And this is, these medications have a lot of potential. They are safe and again, likely will see a rise in their use. So final question, which of these medications is also being studied for and showing positive results for PTSD insomnia, MDD insomnia, and Alzheimer's disease-associated insomnia? And it is Suvorexant. So great data coming forth about its use in secondary insomnia. Already some data exists for Alzheimer's disease with positive outcomes. And so again, just the amazingness of these medications. And the last sentence I like to say is we must choose a medication that fits our patient, the specific sleep parameter we're trying to treat, and to choose wisely for each individual as usual. Thank you very much. So we're gonna switch gears to talk a little bit about hypersomnia and narcolepsy and give you an update on that. I've already introduced myself. Here's the QR code, but you probably already have it. The learning objectives for this portion of the talk will be to review the literature for the last, approximately last year on hypersomnia, describe the most recent approaches to evaluating hypersomnolence, and examine some of the latest treatments we have now for narcolepsy. So we'll start with the case. This is a 44 year old woman who presented with spontaneous hypothalamic syndrome with severe weight gain, headache, secondary amenorrhea. These patients have asthenia, insomnia, and daytime somnolence. An MRI is done, and you can see there's some pretty significant abnormalities here. And this patient has cranial pharyngeal myobrata cancer case because I work at MD Anderson. Here's our poll. Let's see. The first step to evaluate excessive daytime sleepiness, EDS, would be the following. Let's see if I can get it to work. And it is not working. Where is it? Oh, you can see it. Oh, you're right. So you can read a chain of toxicology screen, CSF, orexin levels, serum HLA. Repeat, be repeated MRI with gadolinium to look at her hypothalamus. C, obtain clinical history including snoring, sleep time, and the cataplexy. D, evaluate EDS with polysomnography and multiple sleep latency testing. Still getting votes. It's tapering down like popcorn in a popper. Okay, great. And excellent. Most of you picked the answer that I would choose, obtain a really good history, because as we'll learn, there's a lot of sleep disorders associated with craniofragioma. And this recent study came out, two recent studies came out on this patient, this kind of rare patient population that sort of runs the gamut of sleep disorders. And it's really important to get a very detailed history on these patients because of where that lesion is. As we just heard, it's near that orexin component. It's near the hypothalamus. It's in the cell. It's near the pituitary gland. It's near the suprachiasmatic nucleus. So you can imagine these patients can be obese. These patients can have sleep apnea related to that. They can have circadian rhythm problems related to abnormalities in suprachiasmatic nucleus. And because they can lose orexin and other things, they can develop secondary narcolepsy and they can also develop idiopathic hypersomnolence. The triangular figure you have here with the Venn diagram really describes a study of about 56 patients that was done in France. And they actually looked at these patients, did MSLT, and they found that hypersomnia phenotype is really common in these patients. Over half of them had hypersomnia. Eleven of them actually fit the definition of idiopathic hypersomnia. About six actually had secondary narcolepsy. They actually had cataplexy as well as SORAMs. And then interesting enough, and this is why it's really important in this discussion, isolated SORAMs really have to put in the clinical context. And in this one, a few patients did have that but they didn't have symptoms of EDS. So this is the polysomnogram from that patient. It was actually pretty normal. She did not have sleep apnea. But you can see down here is the MSLT and she had several naps. There were no SORAMs. So this patient was actually one of the patients we identified with the idiopathic hypersomnia related to this. So the takeaway from this is that it's really important to get that clinical history on these patients. This patient had idiopathic hypersomnia. The ISCD3TR, which came out in the spring, updated our definitions for these central hypersomnias, starting with narcolepsy type 1, which has EDS for more than three months with cataplexy, or an MSLT with at least two SORAMs. Or you can use the definition with CSF hypocretin levels or orexin levels less than 110 picograms. Narcolepsy type 2 also has EDS but without cataplexy, but does have an MSLT with at least two SORAMs. And that's really important. And the hypocretin level, if you obtain one, must be above 110 picograms. And if it is less than 110 picograms, despite the lack of cataplexy, it moves back into narcolepsy type 1. Idiopathic hypersomnolence has the sleepiness but without the SORAMs. But in this diagnosis, you have to be very careful about excluding other things. Obviously insufficient sleep syndrome can cause idiopathic, what we call idiopathic hypersomnolence, or hypersomnia. So you have to take that out of there and you have to look for other sleep causes. So here again, that concept of making sure you have a really great clinical history is really important in order to do this. So what do we have learned about narcolepsy over the last several years is that there are several comorbidities and some things that happen with obesity. And we just learned that, as you know, narcolepsy is when there's deficiency of these orexin neurons, producing neurons. And we just saw from Dr. Sardin's slide, those widespread projections. You can imagine this disease can have many systemic causes. One of the most common things is obesity. Adolescents and children who are recently diagnosed with obesity tend to have 20 to 30 pounds of weight gain immediately after diagnosis. And probably that might be either hypothalamic or orexin mediated. There's significant mood disturbance and depression and anxiety in these patients, and that needs to be addressed as well. There's also movement disorders such as restless legs, as we just heard about from Dr. Venkatesh's presentation, as well as leg movement disorders that also need to be addressed. And we're learning that there's also parasomnias, and we'll get into a little bit more detail in a minute, but I want to put up this slide to show you that when we have a narcolepsy, it's our opportunity to really investigate. These patients have a really high symptom burden. It really impacts their lives, as you know. They can't go to school as well. They can't hold a job as well. And it's really incumbent on us to look for all these different areas so we can really try to improve their quality of life. So let's talk a little bit more about the parasomnias that create narcolepsy. This study came out in 2022, and it was actually looking at a group of patients with narcolepsy, narcolepsy type 1, 2, and idiopathic hypersomnia, and tried to look at the parasomnias. Now, as I mentioned to you again, orexin, as we learned, is really important for the control of REM sleep. So we've known for some time that patients with narcolepsy have a clustering of things like REM sleep behavior disorder, shouting, sleeping, talking. But we're also learning that they also have significant non-REM parasomnias that can occur, including sleep eating, and that can contribute to their obesity that we mentioned just a little bit ago. They can also have other REM intrusion, along with the cataplexy, with sleep paralysis, and hypnagogia. And so you can see all those manifestations in these patients. With narcolepsy type 2, we still see some REM, but you can see there's less of the non-REM parasomnias. And with idiopathic hypersomnias, you can still get some of that abnormalities of REM sleep with the sleep paralysis and hypnagogia, but less likely to have REM sleep behavior disorder or that some of the non-REM parasomnias. So again, these patients you have with narcolepsy, you really have to look for these things because they can have a wide variety of parasomnias. So again, clinical history is really important. What have we learned about some newer trends in diagnosis, in particular, idiopathic hypersomnia? I think idiopathic hypersomnia is something that, as sleep physicians, we tend to call it separate. It's sometimes actually pretty hard to distinguish between medication use, lifestyle, and those kind of things, as well as with narcolepsy type 2, even though we have the MSLT. Some investigators, because of that, have suggested not only should you do a polysomnogram and an MSLT, as you might do in the part of the workup for excessive daytime sleepiness, but extend that. And initially, we want to get at least 11 hours, if you remember from the definition of sleep during a 24-hour period. And there are protocols that I think we need to be aware of to extend the sleep time 24 hours or even up to 32 hours in order to make that diagnosis. Now, alternatively, you can use actigraphy to do this, but if you do have a patient that needs it, there are protocols available, and I have the citations here that you can use. Another group looked at the different types of central hypersomnias and tried to see what kind of PSG characteristics could we pull out that may shed some light on this. And they found out that narcolepsy type 1 was really different than narcolepsy type 2 and idiopathic hypersomnia. The sleep efficiency was less, the arousal index was up, there was more WASO, as we just learned that term, and there was increased levels of N2. Actually, narcolepsy type 2 and idiopathic hypersomnia had less differences between them, but there was really a distinction between 1 and NT2 and idiopathic hypersomnia. I'm gonna finish with a little bit of what we've learned in the last five years or so about the pharmacology of narcolepsy. What I have in front of you is a little picture of the brain. You can see some of the nuclei, in particular the hypocretin in the hypothalamus that you see right there, or hypocretin or orexin, whatever you wish to call it. The adrenergic system, that's really important for wakefulness, and some of the sleep neurons that are important. And the drugs that we have for narcolepsy really approach by attacking those areas. These are some of the ones that we've had for some time. The initial treatments we had were mostly the amphetamines and the adrenergic drugs, like modafinil and armadafil, that may work on dopamine and noradrenaline to potentiate wakefulness. At that time, in order to suppress cataplexy, we had drugs like the tricyclic antidepressants and SSRIs, which worked on serotonin. More recently, then we started having sodium oxidate that came in. There are three currently available formulations. One is the original one, there's a low salt version, and then recently on the market there is a once a day, once a night actually, formulation that is longer acting. But some of the more recent medications that have come in the last few years include pitolicent, which works on histamine. It acts as a histamine antagonist, which actually it's a receptor antagonist, which really means it increases the activation of histamine to allow for more wakefulness, and it also has some potency against cataplexy as well. Another more recent drug is solarium fentol, which works on the dopamine and noradrenaline systems, and that primarily promotes wakefulness, but doesn't have much effect on cataplexy. As we heard, orexin is a really important target. There's a very important study looking at some of these new hypocretin and orexin receptor 2 agonists, as opposed to the antagonists, the doors that we just learned about. These are ones to replace the orexin that's missing in patients with narcolepsy, and there's a lot of excitement, a lot of interest in these, and there was a trial which actually showed improved EDS, improved control of cataplexy, but unfortunately the drug was hepatotoxin and did not come to market, and this was just published this spring in the New England Journal. But I think that's a story that's evolving, and I think we will get these type of drugs soon, and hopefully soon. So just to summarize what we learned today, again, the most important thing when you're dealing with EDS is to take a very careful and directed history, and do the testing that you need to get the diagnosis. Please evaluate for the comorbid illnesses. It could be sleep apnea, it could be insomnia, it could be restless legs, all the topics we're learning about today. And there are new treatments available, the histamine drugs, the adrenergic drugs, and hopefully this new class of orexin agonists that will add to our armamentarium in treating narcolepsy. Thank you. Okay, more than I thought. That's good, makes me happy. All right, so here's a QR code to help us. You'll get it again. But I'm going to talk about, so you know, pediatric sleep is a broad topic. I'm going to focus it down on something called restless sleep disorder. Hopefully you guys have kind of heard about this. We're going to review the diagnostic criteria, a little bit of what the proposed mechanisms are, and some updates on the treatment for this. So we have a case. I apologize if this sounds too familiar to your own personal experience, but we have seven-year-old, has ADHD, difficulty staying on task at home and at school, and everyone's frustrated. Okay, so presents with six months of restless sleep, unrefreshing sleep, hyperactive, daytime sleepiness, and the parents are thinking about medication but really want to optimize sleep first. So we do a sleep study, AHI is 0.5, the lowest oxygen saturation is 95%, PLMI is 4.5, but you do notice some large non-periodic movements observed throughout the night. So movements are associated with arousals, but no limb movements or apneas. Our BMI is 65th percentile, yawning throughout the visit, she's constantly poking at her mom, she needs a lot of redirection, and no oral breathing, turbinates are fine, tonsils are 2+. So we have our seven-year-old young, or actually I think I made a patient here. So what would be the most appropriate next step in the management of this patient? Would you trial CPAP? Would you counsel the parents on sleep hygiene and give reassurance? Would you start a stimulant or would you check some serum iron and ferritin? All right, excellent. Sorry for those who are still voting, but we have a little bit of a split here. So the answer I thought would be the next step that I would choose is actually to check serum ferritin, serum iron and ferritin. But of course, counseling the parents on good sleep hygiene is always a good answer too. So the reason why is that serum iron and ferritin may offer a treatable target for RSD and improve sleep quality. And just as a reminder, it's always good to treat sleep disorders before you start a child on any ADHD medication. So there is actually now new, restless sleep has been a very common complaint. I am sure for those of you who see kids, have always heard it. Sometimes it's always like, is it sleep apnea? Is it something else? Well, actually now there's been sufficient evidence to actually have it be its own entity, its own diagnosis. So this is from an article in 2020 that's kind of confirming that they have criteria recommendations that have been reviewed by a committee and actually endorsed by the International Restless Leg Syndrome Study Group Executive Committee. So it's about eight different criteria. And so that's all of it listed here, but I summarize it a little bit here. So it's for children six to 18 years of age. You have large body movements, greater than five per hour. And this is actually a visual diagnosis. You got to see that on that video. That's why the polysomnography is important. They have restless sleep reported for at least three times a week for about three months, similar to the year insomnia, right? So it's more chronic. They have some daytime symptom impairment or symptoms. So ADHD, they're sleepy, something's going on. And the symptoms are not better explained by some other diagnosis, RLS, PLMD, or OSA. This is, I like this because it just kind of highlights that these are a little bit distinct. There's some overlaps, right, but they're different. So restless sleep disorder, RSD, you do have the same, like similar daytime symptoms that you might have with RLS or PLMD, but RSD specifically, you do need that PSG in addition to the clinical symptoms. And it's more of these bigger body movements as opposed to what you might pick up on your usual leads. And then we'll talk a little bit about that with the pathophysiology that is kind of still being discovered. This is from Del Rosso et al. This is just showing like an example of what we're talking about by big body movements. Oh, let's see. Well, I can't get that cursor over. Oh, it's backwards, okay. So here, you see there's like not much going on. The kid is actually has normal EEG, breathing well, and then just has this big body movement out of nowhere and then just goes back to normal sleep. So this is just an example of what you might see on a PSG. So here's some proposed mechanisms of pathophysiology. One is iron deficiency or low iron stores within the brain more specifically. So children with RSD actually I found have a mean ferritin of less than 20. This is actually lower than those seen in RLS or PLMD. And I put in the bottom right-hand corner there, people are like, well, what are the normal values again? I don't remember it. Like everything in PEDS, it's by age, it's variable. So just you see that for kids one to five, it's like 2.47. If you get a little older, it goes up to 45. Of course, there's some ranges. So if you wanna take a quick shot of that to know what are normal values. But the hypothesis is that low iron stores affect the dopaminergic pathways involved in motor activities similar to other sleep-related movement disorders. And studies that show that after you treat with iron, there's improvement that kind of supports this hypothesis. The other proposed mechanisms include just sleep instability. So in RSD patients, the EEG and the PSG shows evidence of increased sleep instability in the form of cyclic alternating pattern. So this cap, it's a quasi-periodic EEG activity. So you have trains of phasic EEG activation that come in the middle of the background. And so the percentage of increased cap that you see within the non-REM sleep is a sign of physiologic instability. This has actually been described decades ago. But this is something that people feel is related to RSD. Another proposed mechanism of action is that you have this, you're typical, you're awake, you have sympathetic activation, increased heart rate, and you're supposed to go to sleep. You have the parasympathetic activation and a lower heart rate. I'm, of course, oversimplifying a very complex process. But patients with RSD have actually increased sympathetic activation during N3 and REM sleep specifically. This is actually similar to what you see in PLMD. This is different than what you see in RLS, where you actually see more of that activation during the time when they're drowsy and trying to fall asleep. So when we're talking about treatment options, iron supplementation really is the, when you look in the literature, that's kind of the mostly commonly studied option. So checking a fasting serum iron profile and ferritin levels, ideally in the morning. I say that, although those who work in pediatrics, you can't always get a fasting sometimes, it's hard. This is the ideal, usually do what you can. If the ferritin is less than 50, usually you wanna start iron supplementation. Your goal ferritin level is 50 to 100. If you're starting an enteral dose or PO dose, anywhere between one to six milligrams of elemental iron in pediatrics, so milligram per kilogram per day, up to 50 to 65 milligrams per day, typically for about three months. And these are just reminders of how to optimize absorption, right? So on an empty stomach with vitamin C, avoid dairy, avoid antacids, those kinds of things. The limitations, right? So in pediatrics, kids don't always swallow pills. Iron, I don't know if you guys have ever tasted it yourselves. I did as a resident, it's disgusting. There's actually some new flavors that they have, so it makes it a little bit more palatable, but you can actually also have some staining of the teeth. And then poor absorption, just in general, we don't absorb iron that well. So you can have constipation, GI upset, nausea, things like that. So an iron infusion already has an established utility in adults, so people have seen, well, can we do that in our kids? So there's a recent retrospective study, Ingram et al, where they looked at 63 patients who had underwent an iron infusion, about 60 with a newer formulation called ferric carboxymaltose. 30 of those patients were doing it for RLS, 22 for PLMD, 17 for RSD. And they looked at outcomes of symptoms, ferritin, and adverse events. And this is just showing where you see on the, oh, there we go. So this is showing that just about 70% of them had some improvement. Most of them actually had improvement in restless sleep, more than 50% did have that. About 30% had improvement in their sleep maintenance, and it kind of continues on. This slide is showing side effects. And so around 10% had some side effect. Most of the side effects that we saw were GI discomfort, a little bit of behavior change, no anaphylaxis, which I know is always the concern people have for iron infusions. So the limitations, obviously, this is a retrospective, single-centered study. There was no validated symptom assessment tool that was used, but it does kind of give us some additional support that iron supplementation may be a good option. Now if we're looking at, well, what about iron IV versus Enterol, which is always a question, which is better? Well, there is another, it's a small retrospective clinical case series by Del Roso et al. So they looked at 30 patients, 15 oral, and 15 were getting the ferric carboxymaltose, and the outcomes were the same. We're looking at iron, or outcomes they looked for, iron, ferritin levels. They did this time use the clinical global impression scale that has been talked about earlier, and looked for adverse events as well. So what they did show is that we have clinical serologic improvement that was more prominent with IV iron, which is actually not a big surprise, and the adverse events that were more commonly seen with oral iron, constipation, noncompliance, versus IV iron, there was one case of syncope, but there was no other anaphylaxis or any severe adverse events seen. So the conclusion was IV ferric carboxymaltose may be an effective, safe option for RSD. Obviously, more studies are needed. All right, so back to our case. So his ferritin was 17, transferrin saturation was 21%. So which of the following are the treatment options that you would do for this young patient? Would you take oral iron with food, or which of the following is true? So take oral iron with food that will reduce adverse events and increase absorption. Oral iron must be in the pill form to achieve the right dose. An IV iron infusion has a high risk of anaphylaxis, or oral or IV iron repletion options are reasonable for this patient. All right, so I think most people got what I would choose, which is I think oral or IV iron repletion are both reasonable for this patient. So, oh, and this is just a reminder that taking food with iron will reduce symptoms, but it will also actually reduce absorption. So enteral iron comes in many forms, like I mentioned, and the new IV formulations do have a much lower risk of anaphylaxis. So our patient started on oral iron, but stopped after one week, made their stomach hurt. So you prescribe an IV iron infusion. You follow up four weeks later, and the parents report improvement in sleep with decreased restlessness and daytime sleepiness. So they asked, though, when do we recheck a level? So this is going back to that study that we saw in Ingram et al. So repeat serum ferritin studies, generally about eight to 12 weeks after an infusion. You can check, then three months thereafter. Granted, if getting labs are tough for your patient, I always say you can just follow clinically. But, you know, and then if that ferritin level starts to drop, symptoms start to come back, sometimes I just do a lower dose of iron to just try to maintain that ferritin level above 50. But this is showing that within zero to four weeks after the infusion, the level's at its highest. This is showing it's actually above 200. And then this is showing at four to eight weeks, this is showing four to eight weeks, eight to 12 weeks, and this is greater than 12 weeks, the levels are all around at least above 100. So there actually is pretty good staying power in these IV iron infusions. So take-home points, RSD, this is a new diagnosis. It is distinct from RLS and PLMD, though right now a lot of the treatments are very similar. The proposed pathophysiology varies from iron stores, CAP, and sleep instability, and increased sympathetic activation. You can do oral or IV iron supplementation, may be both effective and safe. But we really need more studies. So those of you who see kids, feel free to contribute to the literature. Thank you so much for your attention. Thank you.
Video Summary
In this video presented by a panel of sleep medicine experts, updates in non-respiratory sleep medicine are discussed. The session covers four important topics: restless leg syndrome (RLS), insomnia, hypersomnia, and narcolepsy, with a focus on pediatric sleep medicine. The panelists discuss the diagnosis, treatment, and recent advancements in each area. Restless leg syndrome is primarily treated with alpha-2-delta calcium channel ligands, such as gabapentin, pregabalin, or gabapentin-inicarbin. Dopamine agonists, which were previously the first choice, are now the second choice due to side effects. For insomnia, cognitive-behavioral therapy for insomnia (CBTI) is recommended as the first-line treatment, with medications being used on a case-by-case basis. Hypersomnia, including narcolepsy and idiopathic hypersomnia, can have comorbidities such as obesity, mood disorders, and movement disorders, and may be treated with medications such as stimulants and histamine agonists. An update in pediatric sleep medicine includes the recognition of restless sleep disorder as its own entity, with specific diagnostic criteria. Treatment options for restless sleep disorder include iron supplementation, both oral and intravenous, with a focus on increasing ferritin levels. The panel emphasizes the importance of accurate diagnosis and tailored treatment plans for patients with sleep disorders.
Meta Tag
Category
Sleep Disorders
Session ID
1012
Speaker
Diwakar Balachandran
Speaker
Caroline Okorie
Speaker
Lilit Sargsyan
Speaker
Saiprakash Venkateshiah
Track
Sleep Disorders
Keywords
sleep medicine
non-respiratory sleep medicine
restless leg syndrome
insomnia
hypersomnia
narcolepsy
pediatric sleep medicine
diagnosis
treatment
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