Good morning, everybody. It's 8.30, so we'll get started. My name is Miriam Lewis. I'm from the University of Florida in Jacksonville, and I'd like to start by thanking you for coming today. I know it's the last day and very early in the morning, so I appreciate you being here. So this session is New Horizons in Disorders of Central Hypersomnia, Updates on Diagnosis and Management. I'm very honored to have a very distinguished panel of speakers today. Dr. Agrawal will be discussing difficult-to-treat narcolepsy. Dr. Malhotra will be talking about idiopathic hypersomnia, and Dr. Okori will be presenting us with pediatric hypersomnia. But before we get to our distinguished speakers, I think what we'll do first is discuss the new guideline that was published by the American Academy of Sleep Medicine regarding the multiple sleep latency test maintenance of wakefulness test protocols. I have no disclosures, and this is the objective for this talk. So in December of 2021, the AASM published recommended protocols for the MSLT-MWT in adults, and this was a much-needed publication, as the last guidance we had on this topic was way back in 2005 by the AASM. This new AASM consensus guideline incorporates the new recommendations by the National Sleep Foundation regarding sleep duration and the new diagnostic criteria for diseases of hypersomnia per the International Classification of Sleep Disorders. It also aims to establish more standardized protocols and improve the consistency of the tests being performed. And so in this new consensus, the task force really addressed five main areas for both the MSLT as well as the MWT. And I will be going through these first for the MSLT and then for the MWT. And so the five main areas were patient preparation prior to the test, and this should be occurring weeks before the patient comes to the lab, medication use as well as substance abuse, test scheduling, optimal test conditions, as well as documentation on the report that you will be finalizing and signing. So let's begin with the patient preparation for the MSLT. So there's four new considerations, if you will, that the task force highlighted. The first is the sleep-wake documentation. The task force recommends now, at minimum, a two-week sleep diary and or actigraphy, unlike the previous recommendation, which was one week, to be obtained prior to the MSLT. And this is to document jet lag. Sorry, I'm jet lagged. To document any deviations in work schedule or social jet lag, right? Ideally, you should be documenting seven hours of sleep with an absolute minimum of six hours that are needed for you to be able to proceed with the MSLT. The second main consideration for test preparation are comorbid sleep disorders. The task force recommends that all and any comorbid sleep conditions be well-treated prior to testing. And so for patients, for example, who have OSA, confirmation of compliance on CPAP should be obtained with an optimal minimum of six hours of usage. OK, so if your patient is only using it for four hours, you may want to keep postponing that MSLT until they start using it a little bit more. And also, confirmation of compliance from non-CPAP therapies for OSA patients should also be obtained prior to the MSLT. The third consideration is medication use, and I will discuss that in greater detail in the next slide. And finally, caffeine consumption. So the task force recommends that a frank discussion be had with your patient regarding what is acceptable caffeine consumption. And as much as possible, try to get your patient to taper off caffeine completely before the MSLT. OK, so now I'm going to move on to medication use and substance abuse. So the current consensus has identified certain medications, which I'll show you in a second, that need to be tapered prior to the MSLT as they can potentially interfere with the results. The task force recommends that a tailored plan needs to be developed between the patient and the clinician regarding how this taper will occur. For the majority of medications, a two-week washout period may be sufficient. However, longer or shorter periods may be indicated depending on the medication being considered. And the task force recognizes that in some patients, you may not be able to safely discontinue their medications at all. And here's the list of medications. I know it's really tiny and you can't see it, but you can look it up in the guideline. I suspect that in a couple of years, this table will just get bigger as more and more drugs come on the market, OK? All right, I'm going to move on to test scheduling. So there's not been any major changes with test scheduling compared to the 2005 publication. However, the task force reiterated that you should try to schedule the MSLT when your patient has a consistent sleep-wake schedule. In addition, the testing period should ideally match the patient's typical sleep-wake period. And that means if you need to delay the start of the MSLT to accommodate the patient's sleep phase cycle, by all means, do so. One important caveat, though, is the MSLTs being conducted at night for shift work disorders. This has not been systematically evaluated, and as of now, the task force recommends against the routine use of MSLTs at night for shift work disorders. OK, I'm moving on to optimal test conditions. In here, there's been a lot of changes, so please bear with me. OK, once again, four main areas of consideration. The first is drug screening on the day of the MSLT. The task force felt that this should be left at the discretion of the clinicians, depending on the community that they dwell in, as long as the clinical circumstances. With that, however, they do highlight two important points. First, remember that THC has a long half-life, and therefore a two-week washout period may not be sufficient. And second, there were several articles cited in the consensus where up to 33 of patients undergoing MSLTs had positive drug tests, and that more than 80% did not report them. So even though it's not mandatory, again, use your discretion if you're going to perform it on your patients. The second domain, or consideration, is caffeine. Now, I previously mentioned that prior to having the patient undergo the test, you should try to taper their caffeine intake. The task force goes on even further and says to have your patient avoided entirely on the day of the test as much as possible, as it can delay both non-REM and REM latencies. The third consideration is your data acquisition at night. Again, quite a few changes have been recommended. It is now recommended that an attended polysomnography be performed the night before the MSLT. The idea is to try to capture one of those REM episodes if you're considering narcolepsy. You must now ensure at least seven hours of total recording time on the PSG, and a minimum of six hours of total sleep time before ending the PSG and going on to the MSLT. Therefore, split-night studies should be avoided. And if you have a patient who has OSA, your PSG should be performed with the patient on stable CPAP settings, or equivalent treatment if they're not on CPAP. What about the data acquisition during the daytime or during the naps? Again, lots of changes. First change is keep your frontal leads on for the EEG. Second recommendation is patients no longer need to change out of their nighttime clothing and change into street clothing, which was in the 2005 publication. They can stay in their pajamas. Additionally, stimulating activities now need to be stopped 30 minutes prior to each nap, including devices, which is different than the previous publication that was 15 minutes. Ongoing AV monitoring is now recommended between the naps. To try to capture cataplexy or other abnormal behaviors. Now the choice of recording and saving that data is left up to the lab. For your OSA patients, this is new, your naps should be performed while they're on CPAP or equivalent. And patients should not lay in bed in between naps as this can reduce the sleep latency. All right, finally, documentation for the MSLT. What should you be reporting in your final report? So three major changes or recommendations. The first one is that medications used within 24 hours and during the MSLT, as well as any changes to medications in the last two weeks should be noted on your report. Additionally, data from the pre-study sleep actigraphy or diary, as well as any CPAP compliance, if applicable, should also be noted in your report. As well as any deviations from ideal testing conditions, caffeine consumption, smoking, cell phone usage, et cetera, should also be noted. In addition to all of your other usual parameters that you would include in your final report. Okay, very briefly, so that was the MSLT. So very, very briefly, let's look at the MWT. And again, the same five areas were looked at. With regards to patient preparation for the MWT, it is essentially the same as for the MSLT, except you don't need to do a two-week sleep diary because you're obviously testing for a very different parameter. For medication use, unlike the MSLT, remember that your medications should not be discontinued because again, you're testing for a different parameter. Test scheduling remains the same as the MSLT. Now for optimal test conditions, it's by far the same as the MSLT, with one exception. In the old guidelines, the patient was asked to go in the bed for the wake trial. In the new guideline, the patient is now permitted to sit in the recliner during the wake trial. And the documentation is the same as in the MSLT. And with that, I thank you for your attention and I will hand it over to Dr. Agarwal. Good morning, everybody. Thanks for inviting me for this talk. This is a very interesting session. I thought I would make it very clinical with anecdotes. I think those are one of the easiest way to learn something new. So there are three cases and see how you guys think about. Again, the answers are not perfect. It's a discussion and I would like to see your perspective too. I recently moved from Baylor in Houston to New York, but we had a multidisciplinary narcolepsy board, sort of like tumor board. And in this particular board, we had sleep specialists, pulmonologists, neurologists, psychiatrists, psychologists. So clinical pharmacists, a really interesting group of people will sit together and brainstorm on difficult cases. And some of these cases are from the lessons we learned from those clinics. By conflicts, I do write questions for American Board of Internal Medicine for the Sleep Medicine Board. But none of these questions are ABI and related. These are the objectives and this is the link. I think in the ARS, it will come again. So first case is a case which came to us for the first time, 23-year-old PhD student. He has seen several sleep physicians in past and has moved to Houston for the PhD studies. He was diagnosed with quote-unquote narcolepsy. And when we first saw him, he did not have any prior documentation. He was frustrated about his difficulty in falling asleep and excessive daytime sleepiness. He has to take break from his graduate studies because he just could not work or take classes. He had variable sleeps and he would take occasional naps on the weekend. One thing which was very interesting, he would say once a month, this phase comes in my sleep schedule would reverse and he would be awake whole night. So we were not entirely sure. We got some of the records later on and this is what we found. Initially, symptoms started, let's say called time zero. His PhD actually showed AHI of 5.1. But MSLT showed mean sleep latency of 5.5 minutes and zero sleep onset REMS. So we questioned the diagnosis. And then he was prescribed Ormodafinil which was covered by his insurance, 250 milligrams every morning. And he was not very consistent in taking it. His symptoms continued, he was diagnosed with depression. But we were not entirely sure whether it was a psychiatrist who diagnosed it or whether there was a standardized scale which was used. We were not sure. And he was prescribed Lamotrigine for possible bipolar disorder, but later on discontinued. And after five years, he was accepted to the PhD program. He came to our city. And interestingly, while he was doing the PhD program, he used to take a semester break because he just could not work in his classes and his grades were falling apart. So he was not doing well and he really needed help. So next is the poll. What will you do at this point? And I think you have to scan the code and choose an option. In the interest of time, I'm gonna move forward. And I'm happy to see that you all will do what we did, obtain more data, not just jump on changing the medication. And I think this brings us to a very important point in narcolepsy management. Our knee-jerk reaction is try to increase the dosage of medications. But you'll see this case, it was not necessarily the right idea. So we started with something very simple, a sleep diary. Sleep diary is often underappreciated. And we lucked out because he was a PhD student, very meticulous in taking the data. So he completed almost 20 weeks of sleep diary. In fact, he got so tired of filling the sleep diary, he printed out Excel spreadsheets and he will bring this to the office. And he was not taking any medication. In fact, we wrote a letter for his program director and he gave him some time off for this particular study. He did not consume caffeine. So as perfect as it gets from a patient, from a clinical perspective. And this is what we found. The initial sleep diary. And look carefully. This is the next view. Next view. Next view. And then there are so many Excel spreadsheet. And then we did an actigraphy. And then we see that the time of sleep is getting shorter and shorter. And this is about time he started going back to school. So he had to put the alarm on and wake up. Any takers what the diagnosis here is? Sorry, I cannot hear. Circadian rhythm disorder. Any idea which one this might be? You're absolutely right. So this was actually not narcolepsy. It was misdiagnosed at narcolepsy. This was non-24 hour sleep-wake rhythm disorder. And these are the ASM criteria how to diagnose it. But the idea here is not to talk about non-24 hour. Idea here is when you see a narcolepsy patient, you need to make sure whether you are dealing with a real narcolepsy patient or not. Because there are several mimickers which could lead to hypersomnia. And these are the ICSD-3 central disorders of hypersomnolence. Type one, type two narcolepsy. Very important insufficient sleep syndrome. Hypersomnia caused by medical conditions. Hypersomnia caused by medications and substances. Psychiatric condition, idiopathic hypersomnia, Klein-Levin syndrome. And these all come into the picture. And even though a person who's diagnosed with a type of narcolepsy can still be impacted by other things. For example, this patient had depression at some point of time. So it was a combination of two things. So if the patient was not optimally treated, had narcolepsy, you would first treat the depression rather than jumping on increasing the dose of medication or class of medication. So this is the message one. Before making change, confirm the diagnosis. Moving on to the second. This is kind of a step from the protocol which Miriam just discussed. And I'm gonna test how much you learn from it, how many of you were truly awake. So this is the next question. The question is, if you do an MSLT, and all of these, it will be suboptimal except one. So it's kind of double negative, but really the idea is in which case it will be optimal. First is a patient with a history of severe sleep apnea who used CPAP every night, whole night, for more than seven hours. Residual AHI is pretty good. A shift work disorder where MSLT was done at usual 7 a.m., 9 a.m., et cetera. Patient with severe depression, PHQ-19 out of 27. Patient that takes a nap in the waiting area between second and third nap trials. And a patient whose total sleep time was five hours, 52 minutes, in the night, primed to MSLT, and had a AHI of four. So one of them would be optimal. The rest all would be suboptimal. All right. So I'm going to move forward. And you were right. The majority chose the first one, which were optimal conditions. Patient has obstructive sleep apnea, but it was optimally treated. But in the rest of all the cases, there were some errors, some factors which would impact the diagnosis of MSLT. So the message here is that MSLT is not a perfect test. It's not that we are making the diagnosis of diabetes or hypertension. You order a blood test, you get a number, and that number is helpful in making diagnosis. Usually if it's done in good lab conditions, it is fairly accurate. MSLT depends on so many factors. So we have been constantly evolving in our lab to incorporate some of these new measures. For example, adequate sleep documentation, ideally more than 7 hours but at least 6 hours. How many of you actually raise hand who do actigraphy prior to MSLT? So a fair number, about one-fifth of the room have used actigraphy. And it's hard because often it's not covered by the insurances. Make sure OSA patients are optimally controlled, PAP and Nordic night, which is actually one of the most common things we see patients have sleep apnea and they're misdiagnosed as other idiopathic hypersomnia. And develop a plan regarding prescription medication, OTC agents and other substances. And as we saw earlier, it has to be stopped at least two weeks prior. Often it's not possible. Many patients are on chronic medications and they cannot stop it. So MSLT is far from a perfect test and that's the second message. All right, the final case. This is about the medication. A 48-year-old accountant with narcolepsy, cataplexy, he has been on sodium oxalate for the last 10 years. And cataplexy and hypersomnia were reasonably well controlled. He was an accountant and he would work late during the tax season. And at that time, every year, it was predictable that around the tax time, March, April, May, he would have more episodes of cataplexy. And he knew that it's related to sleep deprivation. But he was recently diagnosed with heart failure with reduced ejection fraction. He was recommended a low-salt diet. And as you know, sodium oxalate is a medication which has a substantial amount of sodium. So what do you do now? What would you recommend at this point in time? I guess the first point is, is there a risk-benefit ratio? If the medication is working so well, do you really want to go ahead and change it? The first thing is change it to calcium, magnesium, potassium, and sodium oxalate. Add pitolicant and change sodium oxalate to suluryamphetol. And there are a few learning points here. Remember, this patient has narcolepsy and cataplexy. And cataplexy often is a little bit harder to treat as opposed to just excessive daytime sleepiness. So keep that in mind. I'm curious to see what others think about this. And when we have our narcolepsy board meetings, we are up in arms. We really talk about whether we should change the medication, which class to choose. It's really a very difficult decision when you're optimizing the management of these narcolepsy patients. So about 16% felt that we should not change it. We should continue the current medication. Some said that we change it to this newer medication, which has lower salt load. And a few said that use the pitolicant and suluryamphetol. And I don't know what the right answer would be, but we decided to change, in this case, to option B, which has lower sodium load. I would say option C might have been better, might have been potentially a good option if it was changing to that class. I guess adding a second medication does not really address the burden of salt in that case. And these are the ASM guidelines. It talks about what medications are effective on a cataplexy component. This one does not talk about the newer one, the Zywave. But you'll see the pitolicant and sodium oxalate are the two medications which are impactful on cataplexy. We are still learning more about pitolicant. And our experience has been fairly good when we prescribe those medications. It's harder to get approved, similar to other medications with narcolepsy. And then for dextroamphetamine, it says conditional. So use it as a second or third line. We typically try to avoid it. So this is the final message. In patients with cataplexy symptoms, carefully select treatment options. It is quite difficult to manage sometimes. And that's all I have for this talk. Well, thanks very much. It's my pleasure to be here. Thank you to the organizers for having me here. There are a couple of disclosures that are listed there that are potentially relevant. LevaNova is a company that has a hypoglossal nerve stimulator. Eli Lilly has terzapatid, a weight loss drug. Zol has a number of diagnostic and therapeutic things in the sleep space, including edemar and phrenic nerve stimulation. And Jazz used to have Solarymphatol, which will be relevant to some of this later. So first, I want to define idiopathic CNS hypersomnia. As you just heard from Dr. Agarwal, it's actually a little bit tricky to do that. And I'll explain why. Idiopathic CNS hypersomnia is estimated to affect 20 to 50 million cases per million. It's roughly half as common as narcolepsy. That varies with the studies. You have to rule out other causes of sleepiness, which is not a surprise to anybody in the room here. MSLT shows a sleep onset latency less than eight minutes without sleep onset REMS consistently occurring, which would put you in the narcolepsy bucket. The age of onset of symptoms is around 17 years on average, but the diagnosis is often delayed up to 13 years, suggesting patients don't come to clinical fruition. I tried to read about the neurobiology of this in preparation for the talk, and there's very little that's of substance there. There's theories about GABA and histamine being important, catecholamines, et cetera, but there really wasn't much to say there that would provide any insight, so I didn't dwell on it. That's hard to see, but the diagnostic criteria listed there. What I want to point out for emphasis was this one here. The total 24-hour sleep is greater than 660 minutes, 11 hours, typically 12 to 14 hours, and 24-hour polysomnography, or by actigraphy in association with a sleep log, so you have to have at least one of the following here, MSLT with a sleep onset latency less than eight, or that 24-hour criteria. I don't know that anybody beats that, but what I'd like to talk about a little bit is what you just heard, and that is some of the issues with MSLT reproducibility. It turns out it's a good test for type 1 narcolepsy. It's not a very good test for much of anything else. So Emmanuel Mignot was involved in this paper, but it was from Europe, and they did repeat PSG with MSLT, and the conclusion was the following, confirming results from previous studies, they found PSG with modified MSLT accurately and reliably diagnosed hypocretin-deficient narcolepsy type 1 with an accuracy of .88, reliability of .8. Patients with NT1, narcolepsy type 1, had stable clinical and electrophysiological presentation over time that suggested a stable phenotype. In contrast, the PSG MSLT results for patients with hypersomnolence and normal CSF hypocretin had poor reliability, 0.32, and low reproducibility, so it effectively makes that test fairly useless in terms of if you do a PSG with MSLT for idiopathic hypersomnia, it's worse than a coin toss. I don't want to be too disparaging of it because I still use them clinically, but just be careful with that test. If you get a negative result, consider repeating it. If you have a positive result, don't necessarily take that to the bank. So I'd like to talk a little bit about residual sleepiness in obstructive sleep apnea. It's sort of more within my power alley in terms of the content, but also many people believe that what happens with CPAP-treated patients with sleep apnea, the residual sleepiness may be a form of idiopathic hypersomnia. It's a bit semantics, as I'll talk about. So in terms of obstructive sleep apnea, you're probably aware of this publication we had some years ago suggesting about a billion people worldwide with an apnea hypopnea index over five. It's a really very common problem. Not all these patients have sleepiness, though. So Raphael Heinzer in Switzerland and I had this paper in the Lancet Respiratory looking at the prevalence figures. What was striking here is if you draw the bar at an AHI over 15, there was really no debate that these people need treatment, it's about 23% of women, about 50% of men had evidence of sleep apnea. That's with a high bar with an AHI of 15 or greater. You might say, who cares, these people are at home, this is a community-based sample with polysomnography, why not just leave them alone unless they come to clinical fruition? Well, in multivariate analysis, the apnea hypopnea index here was predictive of hypertension, diabetes, and depression, so it's hard to say just ignore these people unless they come to clinical fruition because they're clearly afflicted by diseases that we all take seriously. The point I'd like to make, though, is that sleep apnea prevalence is increasing, as you've seen here by Paul Peppard, but the majority of them don't have sleepiness. So when you look at the Terry Young data on this, the apnea hypopnea index is greater than 5, it was about 24% of men and 9% of women. If you look at an AHI over 5 with sleepiness, it was only 4% of men and 2% of women, and so the minority of sleep apnea patients, by that definition, had sleepiness. Prevalence figures have increased over time, as I showed you, but the minority of patients have sleepiness. I think that's an important point, and there's a major difference, obviously, between clinic-based samples where people have symptoms and community-based ones. If you do see residual sleepiness in these patients, think about the differential diagnosis. It's easy to reach for medications, as we heard from Dr. Agarwal, but worthwhile going through the differential diagnosis. Sometimes there's poor adherence with PAP therapy. Sometimes there's residual or complex disease where the apnea hypopnea index hasn't resolved despite treatment. There may be chronic partial sleep deprivation. CPAP is good for quality of sleep, not so much for quantity of sleep, so make sure they're not sleep-deprived. Disorders of sleep fragmentation like PLMs, comorbid medications like SSRIs can be fatiguing or cause sleepiness. Or there may be legitimate residual sleepiness in sleep apnea, which some people call idiopathic. One point to make about CPAP here, though, it generally improves subjective but not so much objective sleepiness. So these are forest plots from meta-analyses here, points of improvement on the upward sleepiness care, points of improvement in terms of sleep latency. Sleep latency doesn't really budge very much, whereas the upward does improve, but a little bit. So if you look at the magnitude of improvement with CPAP, it's about two or three points on the upward scale. And these are some data from France talking about residual sleepiness, and it's kind of interesting. So if you look at sleepy patients at baseline, the upward goes from 15 to 6 on CPAP, and so these people are no longer sleepy, but a good 18% had residual sleepiness, quite a big number. And among the ones not sleepy who got CPAP, 6% developed sleepiness on CPAP, suggesting, again, this problem with residual sleepiness on CPAP is a real phenomenon. When you look at a meta-analysis of 10 randomized double-blind placebo-controlled trials of modafinil or r-modafinil, you do see some improvements in the upward sleepiness score by a couple points. Maintenance and wakefulness tests, you do see some improvements there as well. The functional outcome of sleep questionnaire improved by one point over placebo in three studies. So not a home run, but certainly perhaps a base hit. When you look at solary emphatol or Sanosi, and I'll point out I was involved in some of these studies, if you look at the change here in Epworth on the y-axis, the change here in the maintenance and wakefulness test on the y-axis, you do see some improvements in a dose-dependent fashion. So as you go to higher doses of solary emphatol, you see improvements in Epworth, which are sustained over time, you see improvements in the MWT as well, and you get a bigger bang for your buck with higher doses. And the good news is that these are reasonably well-tolerated. When you look at treatment-associated adverse events, it's really quite manageable. Placebo does about the same as some of these other things, so the drugs are quite well-tolerated for the most part. I did say, I want to say something about the long-term safety and maintenance and efficacy of solary emphatol in patients with residual sleepiness, and it's independent treatment. So here's group A and group B. You can see that there are improvements in the Epworth sleepiness score in both of these different groups, suggesting long-term safety and efficacy with ongoing therapy. This is looking at the effects of solary emphatol in a long-term trial of participants with sleep apnea who are with or without treatment. The bottom line here is the drug effect looks the same in both of those groups. Suffice it to say, we obviously emphasize treatment of sleep apnea because the drug isn't going to help the intermittent desaturations or hypoxia or other sort of end-organ things, but it's nice to know that the magnitude of the effect is comparable with the groups with and without adherence to primary airway therapy. There is a little bit here on mechanisms. So SIGGRAD-VC has done some work in mirroring models, looking at chronic sleep disruption and seeing 50 percent loss in noradrenergic neurons that are alerting, 25 percent loss in these orexinergic neurons, reduced dendritic projections in these wake-promoting neurons. These effects persist even after four weeks of recovery, suggesting there may be permanent effects of sleep disruption in that context. And similarly, if you look at chronic intermittent hypoxia, there's some effects there as well. Significantly increased oxidative injuries in certain wake-promoting neurons compared to sham. These are dopaminergic neurons and noradrenergic neurons shown there, 40 percent loss in dopaminergic and noradrenergic neurons at six months. So you can just see again that sleep apnea may have these effects, which in theory could be permanent. I did want to share with you this Delphi conference. This says it's in peer review. It was actually accepted. It's now in press as of yesterday or two days ago. These are recommendations for clinical management of excessive sleepiness and obstructive sleep apnea. York Steer from the UK and I were the co-chairs of this committee. You can see some familiar names there. This is a global consensus where we had to herd cats from around the world to get recommendations. This is soon to be published. It's not yet available, but just got accepted for peer review. Bottom line here is that there was a consensus achieved on 32 different statements, which was hard to do. The panel agreed excessive sleepiness is a patient-reported symptom. It didn't require MSLT. Interestingly, MSLT and actigraphy were insufficiently available around the world to put that into recommendations. We said initially, well, why don't we just have MSLTs be done? Firstly, they're not that reproducible for anything other than type 1 narcolepsy, and secondly, they're not available in many countries or many areas, so we didn't have that. It's based on patient-reported outcomes is how excessive sleepiness is defined. The importance of subjective objective evaluation of excessive sleepiness in the initial evaluation, serial management of sleep apnea was recognized. The differential diagnosis of residual sleepiness and obstructive sleep apnea was discussed. Optimizing airway therapy, like troubleshooting, issues affecting effectiveness was addressed. The panel recognized occurrence of residual excessive daytime sleepiness and sleep apnea despite optimal airway therapy, and the need to evaluate patients for underlying causes. So it's not rocket science there, but there is some new information in this DELPHI conference that will soon be published. Conclusion here is that excessive daytime sleepiness in patients with sleep apnea is a public health issue requiring awareness, recognition, and attention. Implementation of these statements may improve patient care, long-term management, and clinical outcomes in people with sleep apnea. I did want to make two other points before I end here. One is about what we call the language of sleepiness. And what's interesting here is different patients use different terms. OSA patients in Ron Cherven's work report fatigue more than sleepiness, even though the textbooks say we have to distinguish sleepiness from fatigue. Sleepiness is a sleep disorder, fatigue is lack of energy. Patients don't read the textbooks, and so fatigue was actually the most common symptom in some of Ron Cherven's work. The upward sleepiness score, as we know, is good but not great. Truly asymptomatic patients may be quite rare. So this is a paper we just published a few months ago. Look at the language of sleepiness, and there's lots of different terms there. I can't think clearly, I need to sleep in, I don't dream, I get overtired, I lack energy. There's a whole bunch of different terms there, and we're doing these cluster analyses to identify different patterns. Suffice it to say it's early days still, but there are a couple take-home messages. One is that these symptom clusters may capture patient-reported outcomes better than the upward, or at least in some patients, there are certain descriptors that they use that patients don't read the textbooks, as I said. And truly asymptomatic sleep apnea may be quite rare in the sleep clinic because most patients have some complaint if you dig deeply into the history of what they might be reporting. So that's just a look to the future a little bit. I did want to say a little bit about these orexin agents too. My topic today was about idiopathic hypersomnia, so in theory this is not relevant. These data came out in the New England Journal a couple months ago. It's probably an important thing to know. First thing is that this trial was stopped prematurely because of hepatotoxicity, so it's quite a small study. In this phase two trial involving patients with narcolepsy type one, orexin receptor two agonist resulted in greater improvement on measures of sleepiness and cataplexy than placebo over a period of eight weeks, but it was associated with hepatotoxicity. The reason I'm showing you this is look at the upward sleepiness scores. I thought this was a typo when I saw it at first. The upwards improvement by 14 points with this thing. It's really kind of stunning in terms of the improvement seen. Suffice it to say this trial was stopped because of hepatotoxicity, but I think some of these orexin agonists are gonna be very powerful agents when they get ready for prime time. So I'll conclude by saying the following. Idiopathic CNS hypersomnia is important and treatable, but it's somewhat hard to diagnose in part because of the MSLT being somewhat of a moving target Sleep apnea works well in sleep apnea, but 10 to 20% have residual sleepiness. You need to think about the differential diagnosis there. Words describing sleepiness may need to be better studied and better defined. Orexin agonist for narcolepsy are a thing of the future. It's really quite an exciting time. There's lots of agents that are coming down the pipeline. It's quite an exciting time. So I'll stop there and thank you all for your attention. And now I'd like to have Dr. Okori come and discuss pediatric hypersomnia. So I'm a pediatric pulmonologist and sleep specialist at Stanford. I have no financial disclosures, but as is the nature of pediatrics, we will be discussing a couple off-label medications. So the objectives are really just to kind of go through a case that's a little bit on a tougher side. It's gonna be more of a clinical talk and just highlight some, you know, what updates we do have in terms of diagnosing and maybe what's down the pipeline. So we have a 16 year old patient has a history of depression and anxiety and complaints of excessive sleepiness for the past 10 months it's affecting his ability to go to school. He's missing already 30% of his schooling. He tends to actually even avoid social interactions because he gets embarrassed that he falls asleep. In 10th grade denies any recreational drugs or alcohol. I didn't put it up here, but also doesn't really use caffeine doesn't like how it makes him feel. Feel support by his parents, but actually even avoiding getting his driver's license because he's so afraid of how sleepy he is. So this is how you know it's a big deal. Review systems, he has some sleep paralysis, no cataplexy that he knows of, no hallucinations, some fragmented sleep, no snoring, restless sleep or oral breathing. For meds, he's on fluoxetine and Ariperazole for the past three years. His exam is normal, so just BMI is 97th percentile. He's just sleepy appearing, no evidence of area obstruction, normal muscle tone, everything else is normal. So the challenge is always the awareness of pediatric hypersomnia, right? Especially for our teens. A lot of times they're confused for just being kind of lazy or, oh, it's just a typical teen thing. They don't want to wake up. So I think just really having awareness and looking out for this by pediatricians and parents. And then hypersomnia does present differently in kids and it varies by age, right? So young children may have, if they have sleepiness, actually present as being paradoxically hyperactive. They may have more behavioral issues and attention. They may not be able to actually verbalize. I loved actually looking at the language of sleepiness because I think it's really interesting to see what kids actually, how they describe it too. And then it's also with pediatrics, right? It always varies by age. That's with everything, right? So depending on the age, right? So kids zero to three months, you might expect 14, 17 hours of sleep in a 24-hour period. For teens, up to eight to 10 per hour. I mean, sorry, eight to 10 hours in a 24-hour period as well. So it really just varies by age and you have to really get a good history. This is just showing it. I like this is for those who are kind of figuring out, like how do I even start to assess or figure out what's going on with kids? Because they come in, parents are like, they're sleepy. This paper, Owens et al, they went through, just published in 2020, just like how do you assess for sleepiness? How do you work through it? We're gonna focus on the left side here just for the purpose of this talk, but you have excessive sleepiness, it's uncontrollable, it's severe, it's frequent. I'm gonna avoid saying it's not episodic, but let's say it's continuous. We're just gonna focus that way. But I like how it just kind of goes through all the different differentials and if you kind of feel like you don't know where to start. Now, this on the left is just showing you all the different scales that we have to kind of assess sleepiness in children that are available. But the challenge is there weren't as many specific screening tools. So a lot of them just looked at sleepiness, but the literature was really lacking at looking at central hypersomnia-specific pediatric scales. And so a group out in Boston, I believe, they developed the development and validation of the Pediatric Hypersomnolence Survey. So this was just published. And so this is for children eight to 18 years of age. And so they developed this, it's a survey and it's based on focus groups of parents, patients, and teachers. So they're trying to look at kids from all different environments and it assesses four factors, right? So it adds to the literature because it's not just looking at sleepiness, it's also looking at symptoms of cataplexy, looking at remulated phenomenon, and looking at fatigue as well. It underwent a multi-site validation study. So it used patients with narcolepsy, other sleep disorders, and controls. And then they did, just to see how well it distinguished from different types of diagnoses. So here's an example. This is actually, it's available online, it's free, I think, through the Boston Children's website. So if you wanted to access it yourself and look through it. But you can see that the questions vary from I fall asleep in class to my dreams are very real to even doing homework makes me tired, takes a long time, just kind of goes through, actually the full scope of things are really important for children. So the study actually, or this survey was found actually to correlate well with the MSLT testing, which we've been discussing as an imperfect test. But it actually correlated relatively well for what it's worth. It actually also correlated well with the upward sleepiness scale and it really distinguished, or discriminated between the different groups and was sensitive and specific for narcolepsy and idiopathic hypersomnia. A score of greater than 24 or a sleepiness sub-score of greater than eight is thought to have a high risk for central hypersomnolence. And I think the benefit of this is it kind of tells you, well, okay, which kids do we really need to kind of go down the route of trying testing or not? Testing for pediatric patients could be really, it's tough for anybody, but especially for a pediatric patient. So it kind of tells you that risk versus reward. It gives you a sense of, would this be a high yield test to go down? So with our patient we described, his score was 25. So in this case, okay, this patient's at high risk for central sort of hypersomnolence, such as narcolepsy or idiopathic hypersomnia. So the patient wants to discuss some testing. He's like, so what do we do, doc? Where do we go from here? So you say, well, okay, well, first line, we do a sleep study, we do an MSLT as we've discussed, but the patient says, my depression, anxiety are out of control. I can't stop my medications, it's not safe, right? So you say, okay, well, we could do a sleep study, make sure it's not something else. We won't do an MSLT. We could do something called, you know, get a hypocretin level. You know, knowing that cataplexy can actually lag in pediatric patients, right? So they can have hypersomnia first, and then they can have cataplexy later. But he was just like, you're gonna do what? You're gonna put, no, we're not doing that, right? And then you go, well, we could do this HLA test. There's some limitations, like some like 12 to 30% of people have it, they're not gonna, it could give us some information, right? So you could explore that. And they say, well, we'll think about it. They come back a year later. And those of you who deal with pediatric patients, this is very realistic. And they're like, okay, now things are worse. Okay, now we actually kind of, now things are actually progressing. We now have some speech slurring, and my head's kind of dropping when I laugh hard. And this is really embarrassing, Doc. It's getting really worse. And so remains on the floccitin and aripiprazole. Mental health has actually worsened. He attributes this to his worsening hypersomnia. And he'd like to consider the testing again. He's like, okay, tell me again, what do we do? How do we move forward? I can't stop my medications, though. So your assessment, you figure, okay, we have worsening hypersomnia. And it looks like he's developed some partial cataplexy. That's something that we see more in children, right? So they don't necessarily have the full loss of muscle tone, but they might have it partially where you see more in the face than the neck. So you start to consider alternative pathways for diagnosis. So we do an actigraphy. So for, let's say, or I would love a patient who actually did a sleep diary. But let's say we do actigraphy for 14 days. He has average sleep duration of 12 to 13 hours a night. Regular timing, some fragmentations noted. The sleep study, we do a sleep study. It shows AHI 0.6. Minimum saturation is 94%. PLMI is 4.8. Sleep latency is two minutes. REM latency is 35 minutes. We do see some REM sleep without atonia that is noted. He does eventually say, okay, let's do that. Lumbar puncture. And you find his hypocretin level is 50. So you diagnose this patient with type 1 narcolepsy. So now what are your treatment options? So we have limited FDA approved options for pediatric patients, which is often the case for pediatrics. So there's traditional stimulants that you can use that help with excessive daytime sleepiness. But remember, he was really bothered by this cataplexy. So it wouldn't address that. So the other medications for sodium oxibate or lower sodium oxibate is actually FDA approved for patients seven years and older. And that does treat excessive daytime sleepiness and cataplexy, as we've already kind of discussed in the other talks too. And just to go back to the recent guidelines, there are a couple recommendations for pediatrics in there. So the ASM does recommend the use of sodium oxibate versus no treatment for the treatment of pediatric narcolepsy. It also does mention the use of modafinil versus no treatment for the treatment of narcolepsy. And I just have to note here, modafinil, its use is limited in pediatrics. There are some case reports about Stevens-Johnson syndrome. And I think that's kind of limited some of it. And so it's technically an off-label recommendation that the ASM has said. But of course, anything in pediatrics, we often just do the discussion in a shared mental model and thinking about risks and benefits of each medication. So what other options are maybe down the pike or kind of coming? I just wanted to highlight the Pitolsan, which was already discussed by my colleagues. That's something that has already been established in the adult world. In pediatrics, there's a recent phase three double-blinded, randomized, placebo-controlled, 11-center, five-country study that had kids six to 17 years of age. They had narcolepsy with and without cataplexy. And then when they looked at treatment-emergent adverse events, it's interesting, the placebo group actually had a few more. So some had headache and insomnia were the most common complaints, but actually seemed to be well-tolerated. And then to the right, this is actually showing the sleepiness scale. This is using the pediatric daytime sleepiness scale. And this is showing the green as the modafinil and showing that we have a decrease in some improvement with the Pitolsan. So this is just showing that it might be kind of, if I'm thinking of like what's the next thing that might be available for pediatric patients, I think this might be it. A note of note in Europe, the Pitolsan was recently approved in the EU for patients six and older for treatment of narcolepsy with and without cataplexy. Okay, so what do we do now for our patient? So after shared decision-making, you decide to do some sodium oxidate to treat both the excessive daytime sleepiness and the cataplexy. You wanna reduce polypharmacy, right? So for reduce of serious drug reactions, he's gonna work with a psychiatrist to try to reduce his medication, thinking that some of this hypersomnia may be contributing to his depression and anxiety. And of course, once you start the sodium oxidate, just really carefully monitor his mood and have frequent check-ins. And then non-pharmacologic interventions are key in pediatrics. So we really have to try to talk about strategic napping, daily exercise, things like that. And it's really important to offer social support, right? So this is a 16-year-old kid. I'm sure many of you remember when you were 16. This is a really tough age. So really kind of seeing if I can get accommodations at school for naps, extra time for assignments, connect them with support groups. I just really wanna highlight that's really critical in this age. And I think this is a case that highlights, which I'm sure many of you see in this teen with comorbid psychiatric conditions that really makes diagnosis and treatment more challenging. And the limited FDA-approved medications always makes just the conversation that much more challenging with pediatrics. But I think I'm really hopeful. I think I liked, as Dr. Malhotra said, the future is exciting. I do think we have things coming down the pike for our patients with hypersomnia. I think there's more recognition of it. So thinking of ways using this pediatric hypersomnia survey might help you hone in on these patients a little bit sooner. I mean, I think you said symptoms start at 17. They're not diagnosed till 30, right? Can we catch them a little bit earlier? And knowing that off-label medications are often used in pediatric patients, but you just have to have that discussion about risks and benefits to make sure you're going as safe as you can. All right. Thank you. Thank you for your attention.

central hypersomnia

narcolepsy

idiopathic hypersomnia

pediatric hypersomnia

multiple sleep latency test

maintenance of wakefulness test

American Academy of Sleep Medicine

diagnosis

treatment options