Good morning everyone. Thank you for getting up early and joining me today. I hope the Board Review course for the last two days and again today will have met your needs or exceeded them, I would hope. I appreciate everyone getting up early with me. And I don't know about you, but there's still way too much adenosine in my hypothalamus. So what did Dr. Shulman say yesterday, 200mg of caffeine should help? So we're going to go through some seat questions this morning and then have not as long of a day today, but some pretty good topics and great speakers. So let's get started. So we will start off with a question. Which of the following phenomena is responsible for desynchronized EEG pattern found during REM sleep? A, depolarization of the thalamocortical neurons? B, depolarizations of the anterior reticular formation? C, depolarization of the ventrolateral preoptic nucleus? Or D, adenosine A2 receptor-mediated hyperpolarization of the ventrolateral preoptic nucleus? And so yeah, tough question to start with. But neuroanatomy is fair game on this exam. There's usually one question, maybe two. But it's worth just at least having a few things in your brain on this, the more common questions that they like to ask. They want to know where REM starts. They want to know how REM stops. So this is a good one. They also like that melatonin pathway that we talked about yesterday. So let's see how you all did on this one. All right. So the majority of you got it right, the depolarization of the thalamocortical neurons. And so this is a great graphic to just take a quick look at it. I would not spend a lot of time on neuroanatomy if you're not a neurologist, but I would know a few things. So REM on, how do we start REM? It's the PPT and LDT like Dr. Doss said yesterday, subseruleus or sublateral nucleus, okay. Cholinergic and glutaminergic, REM on, and excitatory inputs depolarize the thalamocortical neurons and desynchronize the EEG. REM off, which means non-REM, is the VLPO which is GABA, basal forebrain GABA, parafacial area, GABA-nergic. So GABA's REM off, cholinergic, glutaminergic, REM on. REM off goes through inhibition of excitatory inputs, hyperpolarization of the thalamocortical neurons and then synchronized EEG. The other way I remember, if you can remember that the PPT and LDT are in the PONs, one of the ways I remember this is the PONs is right next to the brainstem. And what's irregular in REM, right, your heart rate, your respiratory rate. So the centers for those are in the brainstem. So that's how I think about it, right. So they're right next to each other. So PONs, things in the PONs affect REM. And that is the full description that I put in so you can have it from the SEEK question. I'm not going to read it all to you now. But for those of you who want to go through every single detail of this question, that will explain everything for you. Okay. So A was correct. B is incorrect because actually depolarizations of the anterior reticular formation is what happens for wakefulness. Depolarization as I mentioned of the ventrolateral preoptic nucleus is non-REM. And adenosine A2 receptor-mediated hyperpolarization of the ventrolateral preoptic nucleus, these excite the VLPO which is REM off and starts non-REM. So tough question to start with, but I thought that we should just get the neuroanatomy going because that's one, for me, I'm not a neurologist. It's tough to try to remember all these things. All right. Next question. We'll see how we do with this one. 55-year-old man with a medical history significant for hypothyroidism. His TSH most recently was 2.3. He came to the sleep clinic because of insomnia for the past five months despite participation in recommended behavioral sleep activities like good sleep hygiene practices. The patient still reports difficulties with sleep six nights per week. He goes to bed at 10, falling asleep at midnight. He wakes up spontaneously three times per night, unable to return to sleep after 4.45 a.m. He's not happy with his sleep and reports daytime irritability and fatigue and denies any symptoms of sleep apneas such as gasping, choking or witness apneas. He does not use any over-the-counter medication or illicit substances and there's a low clinical suspicion of other sleep disorders or somatic mental disorders. Although reluctant he would like to start taking quote, the right medication to help him with his insomnia. So which of the following hypnotics will best address this patient's insomnia? Suvarexet, triazolam, azapaclone and doxepin. I'll give you a few seconds to answer that one. I hope after the talks yesterday this is a little bit clearer for all of you. This is a fair question that when CBT-I doesn't work, what medication might work, that type of thing. I just do want you to have caution with hypnotics. But if you are going to prescribe them, prescribe them directed at the cause. So good. The majority of you got this right. So azapaclone. And the reason is, the patient had sleep onset and sleep maintenance insomnia. Remember he had over two hours to fall asleep and then he wakes up frequently and can't fall back asleep. So this is a great table to just, you know, one of those quick look-ats before the board. Suvarexet, which is the orexin receptor agonist is good for sleep maintenance insomnia. So it would have helped him for that 445 AM situation. Triazolam is good for sleep onset. So that would have helped him for the 10 p.m. to midnight. Azapaclone is a GABA A receptor agonist and it does both, sleep onset and sleep maintenance. Orexin is indicated for sleep maintenance insomnia. And then two medications that many of us prescribe and many primary care providers prescribe, triazodone and melatonin, as we all know, are not given the official indication for this. But nonetheless, just try to think of this when you get a hypnotic question. And so Suvarexet like I said would be good for sleep maintenance, triazolam, sleep onset and doxepin for sleep maintenance. Okay. We're doing very well so far. A 45-year-old patient with a history of OSA and hypertension is admitted to the hospital for gallbladder removal and is given morphine for postoperative pain. He's sleeping comfortably and using his CPAP device in the PACU without difficulty. 20 minutes later, the post-anesthesia nursing staff members request an urgent evaluation because his respiratory rate is now 7 and his oxygen saturation is 84%. So which of the following is the mechanism of action by which narcotics induce this effect? This was gone over yesterday. And so I hope some of you can get it. A is allosteric modulation of the GABA receptor. B is activation of the MU receptor. C is inhibition of the adenosine receptor. And D is blocking deactivation of dopamine. So it looks like we've got a lot of people voting pretty quickly. I hope that means everybody knows the answer to this one. And yes, very good, the MU receptor. So I will remind Dr. Doss that she went over that very well. And so why is A incorrect? Because allosteric modulation of the GABA receptor is what benzodiazepines do. Now it's entirely possible this patient was taking benzos or getting benzos as well. But the question was related to narcotics. C is correct. It's activation of the MU receptor in the CNS in the pre-Botzinger complex. And I'm going to ask a trivia question. Does anyone know where the word Botzinger came from? So this is a great sleep trivia comment. Unlike most nuclei in the brain that are named after the neurologist or the pathologist that found them or described them, this was named after the wine that they were drinking at a neurology conference in Germany when first the Botzinger complex was described. And you can still get Botzinger wine if you go to Germany. That's one of those funny things I learned along the way. So inhibition of the adenosine receptor, caffeine does that. I think we all are familiar with that. And then blocking deactivation of dopamine is cocaine. So these are sort of what affects these different receptors is one of the important things for the boards. Okay. You guys are doing really well. 19-year-old man with traumatic brain injury after a sporting accident is referred for evaluation of chronic sleep fragmentation and daytime sleepiness. Hypersomnia is common in patients post-TBI. After the accident he reports a poor academic performance related to problems with concentration that have persisted for the last six months. He denies any sleep-related complaints before the trauma. He was an otherwise healthy 19-year-old. He is now living with his girlfriend who says he does not snore. He does not take medications. On physical exam things are mostly normal, melampotty Class 2, neck size of 36 centimeters, BMI of 24, normal cranial nerve findings. And his upward is 16 out of 24. So here is his hypersomnia workup including a PSG and multiple sleep latency. And I will show you an actigraph after this. But I don't know if you guys can see this well enough. But on his PSG his sleep latency was 9 minutes, sleep efficiency 85. REM sleep percent was 12 and REM latency 14. Respiratory-related arousals were 4, periodic lip movements 8 and oxygen mean was 94. AHI was 3. The mean sleep latency there I think is pretty easy to see, his mean sleep latency. We don't have the exact number, but you can see he fell asleep 4, 4, 6 and 4. And on the first nap he did not fall asleep. But he had one sleep-onset REM during that. Here's his actigraphy. And remember the blue area here is lack of activity. So that means that they're likely sleeping. So it looks pretty consistent to me, right, 10 to 11 p.m. typically falling asleep and then waking up around 6. And so the question is, which is the most likely diagnosis according to test results? A, idiopathic hypersomnia? B, insufficient sleep syndrome? C, narcolepsy type 2? Or D, delayed sleep-wake phase disorder? And this is an important rule for all of you to know. And I believe Dr. Doss went over it yesterday. But I want to make sure that you all know this one because it's a little tricky. Okay. We got a lot of votes, which is great. And 70% of you got it right, narcolepsy type 2. And let's just go through that. So the ICSD 3rd Edition, this is the one you want to remember. A sleep-onset REM within 15 minutes on the preceding PSG can count towards one of the sleep-onset REMS for the MSLT. That is like one of the hardest rules to remember for those of us who are recertifying. Because we learned the two sleep-onset REMS in the MSLT. But for narcolepsy, now you can use that sleep-onset REM in the PSG. Therefore the patient had an MSLT with a mean sleep latency less than 8 minutes and two sleep-onset REMS. So that meets the diagnosis. So idiopathic hypersomnia is incorrect because of the MSLT results. Insufficient sleep syndrome is incorrect based on PSG and actigraphy. The actigraphy in particular showed that the patient slept a long period of time so they're not having a short sleep time. Narcolepsy type 2, it fits that definition, two sleep-onset REMS and a mean sleep latency less than 8 using that sleep-onset REM in the PSG. And then delayed sleep phase disorder was incorrect based on actigraphy. They don't fall asleep until the early morning hours. Okay. Moving right along, 33-year-old man with a history of HIV. Three months ago presented with RLS symptoms and started on primepaxil and low-dose codeine at night. Gabapentin did not work. He continued to have sleepiness and subsequently had PSG and MSLT that were consistent with narcolepsy type 2. He was started on modafinil therapy and titrated to maximum dose with still some residual sleepiness. Two weeks after reaching the maximum dose of modafinil he presents with fever, muscle aches, redness on his body. The redness started in spots and then coalesced and is on his chest and back. The rash is painful but not itchy. He also has crusting on his mouth with soreness. And there's a picture of the representative rash. So what is our question? Which of the following is the most likely cause of the patient's rash? The codeine, the modafinil, the betolacent, or the primaprexol? Let's see if people can get this one. It has been mentioned by Dr. Shulman I believe. But I want to make sure that we have it because it is one of those things that sleep doctors should know. And yes, the majority of you know this, modafinil is the culprit. I don't know about you, but I see a lot of people getting prescribed modafinil by primary care providers. And those of us who were around when it first came on the market knew this pretty well. But subsequently I think the clear association with Steven Johnson Syndrome has got lost. And people think of it as much safer than I think it probably is. But again, any medication can lead to Steven Johnson. But this is just one of the things that when it was finally approved it was a significant warning and it was the reason it wasn't approved for children. So who gets narcolepsy? When do you present with narcolepsy and you need an alerting medication? Well children do. But it was a big problem because nobody wanted to give it to children because of this reaction. So for those of you who don't remember Steven Johnson Syndrome, cytotoxic T cells reacting against keratocytes, massive cell death leading to necrosis of the epidermal layers, it's really terrible, usually preceded by medication exposure. And Bactrim is another common one. The oral mucosa and eyes are involved. And it is more common in patients with HIV and malignancy. So a good thing to sort of know. And so codeine is not known to be associated with Steven Johnson. Patolacent, SJS is not reported. However severe allergy and anaphylaxis has been reported. So be careful with that medication. And Pramapaxil is not reported. All right. Next one. You guys are doing very well. I did want to say, before I forget, the CHESS store is open for if you want to buy the Seek Question book, you can also buy the online library. I got an honorarium for being an editor, but I donated it to the CHESS Foundation. And I don't make any royalties off of it, but I think it's an excellent study guide. And I hope these questions yesterday and today show you that. Also if you do the online library, you can search by topic. So if you really want to review medications and sleep or neuroanatomy, you can search and get the questions just for that. Okay. Let's move on. A 20-year-old man experienced daytime sleepiness and difficulty getting out of bed in the morning. He sets three alarms to help him awaken at 6.30 a.m. and is often late to work, which starts at 8 a.m. He takes a nap on his lunch break to be able to stay alert for the rest of the workday. He denies any symptoms of restless leg, unusual behavior or movement during sleep. No symptoms of cataplexy, has no medical or psychiatric history, and is taking no chronic medications. So in the office, his Epworth is 19. And he says he falls asleep at 10 p.m. and wakes between 7 and 8 a.m. His PSG at a total sleep time of 475 minutes, sleep latency of 15 minutes, REM latency of 76 minutes, HI4 PLM Index 14, mean sleep latency on his MSLT was 7.6 and two sleep-onset REMs in 1 and 4. So our question is, a medication belonging to which of the pharmacologic classes below would be most appropriate to treat this patient? So A, serotonin and norepinephrine reuptake inhibitors? B, histamine 3 receptor antagonist, inverse agonist? Dopamine agonist? Or MT1 and MT2 melatonin agonist? So let's see how you do on this one. So we know he's sleepy, right, objectively sleepy and subjectively sleepy. So what are we going to do to help him? So good. 60% of you got this, the histamine 3 receptor antagonist inverse agonist. So why is that the correct answer? Well, answer A, serotonin and norepinephrine reuptake inhibitor, venofaxine is used for cataplexy. So remember the stem of the question said no cataplexy symptoms. So that is not correct. Then the histamine is correct. Histamine 3 receptor antagonist is pitolisant. And that is the medication that's good for narcolepsy type 2, which he met the criteria for, two sleep-onset REMs, short sleep latency, et cetera. So serotonin agonist, primaprexone, ropinerol are for RLS and PLMD, which he didn't really have. And then MT1 and MT2 melatonin agonist are for non-24-week disorder, which we didn't have any data to support that. So very good. You guys, the majority of you are getting these questions right, which is great. I hope that the conference has helped you and gotten you to a good point. A lot of this stuff has been covered. I picked these questions long before I sort of knew what everyone's slides looked like. So I think we've hit on most of them. Here's another question. A 32-year-old woman comes in for a follow-up for moderate severe OSA on AutoPAP for three months with good adherence but still sleepy. At board sleepiness scales 15 out of 24, the PAP download was unrevealing. She's on oral contraceptives and pregnancy test is negative. So what do you think I'm going to ask you about? I'm going to ask you what medication interferes with oral contraceptives, right. So in the absence of other causes of sleepiness, which medication should be recommended for the treatment of her sleepiness? Modafinil, armadafinil, I can never say this one, soliramfetol and then pitolicin. It's a sneaky one. But it's a good thing to know if you're treating people with sleepiness, that you want to think about all your possible drugs in your different patients and not just immediately go to modafinil. Which I already told you, A is not correct. All right. So there we go. Oh, good job, 67% got it right. So the reason is modafinil decreases effectiveness of oral contraceptives and so does armadafinil. And pitolicin is used for narcolepsy, not OSA with residual sleepiness. So if you're going to use it, that will give you the best effect without interfering with oral contraceptives. And I know that was a sneaky question. So I'm really proud of everyone for knowing that one. Okay. Next question. A 55-year-old man with a history of restless leg syndrome. The PCP started Pramopexol at 6 p.m. and titrated to a dose of 0.75 mg each evening. Two months ago he started waking up at 2 a.m. and had RLS symptoms impairing his ability to fall asleep again. Hemoglobin is 12, BUN is 24, ferritin is 73, and transferrin saturation is 23%. So which treatment should be recommended at this time? A, start ion therapy? B, add an additional dose of Pramopexol at bedtime? C, switch to gabapentin? Or D, switch to ropinerol? Let's see how we do with this. I'll give everyone a few seconds to think about it. So, ah, that was a good question. I tricked some of you. So the answer is actually C, switch to gabapentin. And so start ion supplementation, well the transferrin saturation was within normal limits. And the ferritin was 73. It's a tough call, but is that the best answer? So again, the boards will often do this, where they might give you an option that looks pretty good, but they want you to pick the best option. So B, is add an additional dose of Pramopexol at bedtime? That can worsen augmentation. So the majority of you knew that was not the correct answer. And the switch to gabapentin is now recommended, and remember gabapentin is now recommended as a first-line therapy as it's not associated with augmentation. That is a change in practice. And that is fair game on the boards. The one thing I want to say, and I think I'm going to mention it again today in some of my talks, you want to be aware of things that have changed from the boards four years ago to now, right. So the boards two years ago to now, anything new coming out might not be on the boards, right. Because it's not enough time for them to write the question and for it to go through the vetting process. So anything more than one or two years old is fair game. But anything in the last two years probably won't be on the boards. Or if it is, it's a question that doesn't count, you know how they put questions in just to see how people do. So be very careful with the ICSD criteria. Anything changed from ICSD-2 to ICSD-3 is fair game, right. Because they want you to know what changed. And so the paradoxical insomnia being the new name for a lot of the stuff we used to call psychophysiologic insomnia, those type of things, that's a good one. And this is a good one as well, gabapentinous first-line therapy. And then switching to ropinerol doesn't help. It actually might exacerbate augmentation as well. And so there are your different medications with the initial dose and maximum dose. Again, be careful with these. The augmentation does happen. So if you do have to use them, gabapentin doesn't work, just be aware of augmentation and know that you then have to switch to something else. Okay. Last question, and it is not an easy one. But I think it's an important concept. So bear with me on this one. I know it's the last few minutes. The pharyngeal critical opening pressure, PCRIT model describes the physiologic behavior of the upper airway as a starling resistor that permits or interrupts airflow and identifies conditions of individuals with or without sleep-disturbed breathing, Figure 1. So we start with the pressure upstream which is the upper airway, the PCRIT which is the collapsible part of the throat, and then the downstream which is the trachea. And that's what it looks like. So which of the following options in which pressure upstream and pressure downstream best describes a patient with partial interruption of airflow as with an obstructive hypopnea, meaning this section here, the PCRIT section here is partially closed? So is the pressure upstream bigger than the pressure in the PCRIT collapsible segment? And that's higher than the pressure downstream? And then so on. I will let you read those for yourself. So the most important thing is in an obstructive hypopnea, how does the airflow get through? It's important to know these different things. It's hard because they made it like the PUS, PDS, et cetera. But I want you to just give it a try. So you have a partial obstruction. So which one of these do you think might represent a partial obstruction? We still want airflow to get through. But it's not going to get through nice and easy. Okay. People are voting. Two more seconds. Okay. Good. The plurality got it right. So the correct answer is A, where the pressure upstream is higher than the PCRIT, right, because you want to be able to get the airflow from the upper airway into the collapsible segment and then into the downstream segment. So these are three different diagrams sort of showing that. So in subjects without extra collapsibility of obstructive apnea or hypopneas, the PCRIT is usually at minus 10. You have to generate minus 10 centimeters of water to collapse that segment. And people who have snoring or hypopnea, it's minus 5, so a little bit easier to collapse it. And then people who you can collapse at 0, or even sometimes they collapse on CPAP, right. Those of us who do CPAP titrations in our lab know that. They're on CPAP 7, 8 and they're still collapsing their airway. Those are people with obstructive airways. And so the one that adequately describes what we're looking at is here, Zone 2, where the pressure upstream is bigger than the pressure in the collapsible segment, which is bigger than the pressure in the downstream segment. Zone 3 here is no flow limitation. So they all, so nice laminar flow. And then this is an obstructive apnea. And then I went through all that. And then this is the rationale that was in the SEEK question, and it goes through it very nicely. We're at the last few seconds for this session. So I won't read through all of that for you. But I hope this was helpful. And we are about to get started on the rest of our day. So thank you for coming early. And I hope we went through some stuff that's important and will help you on the boards as well as in your practice.

adenosine

caffeine

hypothalamus

depolarization

insomnia

azapclone