"Idiopathic Hypersomnia Update" Lynn Marie Trotti (10/06/2021)
October 12, 2021"Idiopathic Hypersomnia Update" Lynn Marie Trotti (10/06/2021)
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- 00:00OK, so good afternoon everyone
- 00:03and welcome to sleep seminar.
- 00:05So I just before we get started
- 00:07I do want to introduce just a
- 00:09couple of just a couple of points.
- 00:11First that we do have these lectures
- 00:14available for credit and that the
- 00:16code for the lecture does need
- 00:18to be tested by 3:15 PM today.
- 00:20And if you don't if you missed the code,
- 00:22don't worry, it will show up in the chat.
- 00:24OK if you have questions during the
- 00:26talk please use the chat feature and
- 00:28then we'll get to them at the end so.
- 00:31Now it's my great pleasure to introduce
- 00:33Doctor Marie Lynn Marie Trotti.
- 00:35Dr Trotty is an associate professor
- 00:37of neurology and also associate
- 00:39professor of Pediatrics at Emory
- 00:41University School of Medicine.
- 00:43She serves as the associate Sleep
- 00:45Medicine Fellowship director at
- 00:46Emory and directs the Sleep Medicine
- 00:49rotations there and she is the
- 00:51director of the Restless Leg Syndrome
- 00:53Foundation Quality Care Center.
- 00:55Doctor Trotti received her medical
- 00:56degree from Baylor College of
- 00:58Medicine and then she moved to Emory
- 01:00where she was a medical intern.
- 01:01A neurology resident,
- 01:02a chief resident and then
- 01:04a fellow in Sleep Medicine.
- 01:06She joined the faculty at Emory,
- 01:07where she received a Masters in Clinical
- 01:09Research and where she's an active educator,
- 01:11clinician, and researcher.
- 01:13She has served on multiple local,
- 01:16national,
- 01:16and international committees
- 01:17and working groups,
- 01:18and notably for this presentation,
- 01:20she served on the American
- 01:22Academy of Sleep Medicine,
- 01:23Central Disorders of Hypersomnolence
- 01:24Task Force that led to the updated
- 01:27hypersomnia treatment guidelines,
- 01:28which were just published in the Journal
- 01:30of Clinical Sleep Medicine in September.
- 01:32She has received numerous awards,
- 01:34including the Hypersomnia Foundation.
- 01:36Impact award in 2020.
- 01:38She serves on several editorial
- 01:39boards including the Journal of
- 01:41Clinical Sleep Medicine and she's
- 01:43an associate editor for Sleep.
- 01:44She's published widely in areas
- 01:47of hypersomnia,
- 01:47restless leg syndrome and movement
- 01:49disorders and the overlap of
- 01:51sleep and neurologic disorders
- 01:53such as Parkinson's disease.
- 01:54However,
- 01:55her primary research focus is the
- 01:57pathophysiology and treatment of
- 01:59central hypersomnolence disorders,
- 02:00so we feel really excited and fortunate
- 02:02to have doctor Trotty join us today
- 02:04to discuss idiopathic hypersomnia.
- 02:06Clinical update welcome.
- 02:09Thank you so much.
- 02:10I am very excited to be here.
- 02:12I see some familiar faces
- 02:14and names on the zoom.
- 02:15I wish we could be in person,
- 02:18but I'm excited to be here
- 02:20to talk with you all today.
- 02:22So without further ado up my CME
- 02:26disclosure is that I am a speaker for
- 02:30Medscape on some of their CME content.
- 02:34This has been mitigated by
- 02:37the appropriate offices.
- 02:38My non financial.
- 02:39Disclosures are these I will
- 02:40be discussing off label use of
- 02:42approved medications and depending
- 02:43on where the conversation goes,
- 02:45might discuss unapproved medications.
- 02:47Also important to know that although
- 02:50I do not have any intellectual
- 02:52property related to anything,
- 02:53I will be talking about today.
- 02:55Several of my collaborators here at
- 02:57Emory and Emory themselves have some
- 02:59intellectual property related to the
- 03:01use of GABA agents for the treatment
- 03:04of excessive daytime sleepiness.
- 03:06And finally,
- 03:07I'm a member of the Board of the ASM.
- 03:10I'm very opinionated,
- 03:11but all of those opinions are my own and
- 03:14do not necessarily reflect those of the ASM.
- 03:17So here we go.
- 03:20Idiopathic hypersomnia.
- 03:22Just to get us all on the page,
- 03:24same page to start here or the
- 03:27diagnostic criteria in the ICS D3.
- 03:30It is required that there be
- 03:32excessive daytime sleepiness for
- 03:34at least three months and then it
- 03:36is required that a number of things
- 03:39get ruled out because idiopathic
- 03:41hypersomnia implies that there is
- 03:42not another cause for the symptoms,
- 03:45and so there cannot be cataplexy because
- 03:47then you would have narcolepsy type one.
- 03:49There cannot be multiple sleep
- 03:51on sat REM periods between the
- 03:54overnight study and the MSLT,
- 03:56because then you would have narcolepsy and.
- 04:00Finally,
- 04:00you have to exclude some
- 04:03number of other things,
- 04:05specifically institution sleep durations,
- 04:07but any other disorder that
- 04:09might explain the symptoms should
- 04:11theoretically be ruled out.
- 04:13It is not only a disorder of exclusion,
- 04:16however you do need at least one objective
- 04:20confirmation of the hypersomnolence,
- 04:23and so there's three ways you can do that.
- 04:25Typically what we do is the multiple
- 04:27sleep latency test showing a mean sleep
- 04:29latency of less than eight minutes,
- 04:31and I say typically we do that because
- 04:33the differential includes narcolepsy
- 04:35and that's how we diagnose narcolepsy.
- 04:38But as we'll talk about in a minute,
- 04:39that's probably not a great way to
- 04:42diagnose idiopathic hypersomnia,
- 04:43and so you can also for those people
- 04:45who have long sleep durations,
- 04:47make the diagnosis either through
- 04:4924 hour PSG showing at least 11
- 04:51hours of measured sleep time should
- 04:52you happen to practice with the
- 04:54place where that is a thing you
- 04:56can obtain and get reimbursed for,
- 04:57or you can do at least seven days
- 05:00of actigraphy showing an average
- 05:02estimated total sleep time of that
- 05:05same 11 hour cutoff for 24 hour period.
- 05:08So that's in a nutshell.
- 05:10UM,
- 05:10those are the working criteria
- 05:13for the diagnosis.
- 05:14They are imperfect,
- 05:16like all diagnostic criteria and and I
- 05:20anticipate maybe these will continue.
- 05:23Hopefully this will continue to be
- 05:25refined as we continue to collect more
- 05:27and more data about what this disorder is.
- 05:30But I think it's important to know
- 05:33where our starting point is up with
- 05:35the criteria that we have right
- 05:37now and and the first is that the
- 05:39MSLT doesn't seem to do a good job
- 05:42of distinguishing people we think
- 05:44clinically have idiopathic hypersomnia.
- 05:49And by that I mean that if you take
- 05:51clinical populations and these are three
- 05:54different series from three different
- 05:56expert groups for hypersomnia disorders.
- 05:59And you take people who are suspected
- 06:01to have idiopathic hypersomnia or
- 06:03who have problematic sleepiness.
- 06:04That is not better explained
- 06:06by something else.
- 06:07And you do the MSLT on them less than half.
- 06:12I haven't been sleep latency
- 06:13of less than 8 minutes,
- 06:14so we know the MSLT is really
- 06:17good for narcolepsy type one.
- 06:18There's something maybe about
- 06:20the sleepiness of idiopathic
- 06:22hypersomnia that is not being
- 06:25captured reliably with the MSL team,
- 06:27and so I point this out not to
- 06:28pick on the diagnostic criteria,
- 06:30but just to say if you think
- 06:32someone has idiopathic hypersomnia
- 06:33and their MSLT shows immune sleep
- 06:35latency of more than 8 minutes.
- 06:37That's probably not surprised.
- 06:41The other issue with the MSLT for making
- 06:45this diagnosis is that the the MSLT
- 06:47based diagnosis is not stable overtime,
- 06:50so again in narcolepsy type one that
- 06:53disorder for which the MSLT was optimized.
- 06:55If you repeat the MSLT you generally
- 06:58get the same narcolepsy diagnosis,
- 07:01but for the central disorders of
- 07:03hypersomnia other than narcolepsy type
- 07:05one that turns out not to be the case,
- 07:07so they figure that you're looking at our
- 07:09old data now that we did with Omar Neurology.
- 07:12Residents looking at people who had
- 07:14had two multiple sleep latency tests,
- 07:16the first of which either showing narcolepsy
- 07:19type 2 idiopathic hypersomnia or normal.
- 07:22Despite clinically problematic sleepiness,
- 07:23and then you can see the arrows tell
- 07:27you all the directions that people
- 07:29diagnosis changed on repeat testing,
- 07:31despite the fact that they were
- 07:32still symptomatic,
- 07:33and so this turned out to be just over half
- 07:36of people's diagnosis changed on repeat MSLT.
- 07:39A number of groups have
- 07:40looked at this subsequently,
- 07:41and the story tends to be the same,
- 07:43which is for narcolepsy type one.
- 07:45It is generally repeatable
- 07:47upwards of 90% of the time.
- 07:50You get the same diagnosis,
- 07:51but for narcolepsy type 2 idiopathic
- 07:54hypersomnia and people whose
- 07:55first MSLT is normal even though
- 07:57they themselves are not normal,
- 07:59they have problematic sleepiness.
- 08:01The repeatability is much poorer.
- 08:05And that is because of changes
- 08:07across the eight minute threshold
- 08:09changes across the two minutes.
- 08:11The bonds at rent threshold for both.
- 08:16So this is really why the ISD
- 08:18three incorporated this other way
- 08:21of confirming the IH diagnosis.
- 08:23By measuring long sleep durations because
- 08:25they knew that the MSLT was missing.
- 08:28Some of these patients and we needed
- 08:30to be able to capture them. And so.
- 08:33This can be done with extended PSG.
- 08:37These this is how it is done often in Europe,
- 08:39particularly in research settings,
- 08:41but often in clinical settings as well.
- 08:44And there are several different
- 08:45protocols for doing this.
- 08:47I'm showing you two different protocols here.
- 08:51Both from different groups in France.
- 08:53The first was really just ad Lib
- 08:55sleep overnight and then a long
- 08:57as you want morning nap and long
- 08:59as you want afternoon nap and so
- 09:00a little less than 24 hours to see
- 09:02how much people would sleep.
- 09:04This is where the 11 hour cutoff in the
- 09:07ICS D3 comes from is from this study.
- 09:09Subsequently,
- 09:10another French group has proposed that
- 09:12what we should do instead is 32 hours
- 09:15of bed rest monitoring during which
- 09:17you see how much sleep people obtain
- 09:19and when they looked over just the
- 09:22first 24 hours of that monitoring,
- 09:24they thought a 12 hour cutoff was
- 09:27better for differentiating people with
- 09:30idiopathic hypersomnia from controls.
- 09:32This is obviously logistically
- 09:34challenging up before sleep.
- 09:36Labs for payers and and and so on,
- 09:40but when available this is a nice way
- 09:42of documenting long sleep durations.
- 09:44Of course,
- 09:44not all patients with idiopathic
- 09:46hypersomnia have long sleep duration,
- 09:48so this is only going to identify
- 09:51and diagnose this
- 09:52subset. Over here I would
- 09:54say we usually do actigraphy.
- 09:55More commonly activities also not
- 09:57reimbursed all that well by pairs,
- 10:00but at least it is less of a money
- 10:02loser than an unreimbursed 24 hour PSG,
- 10:05and so we pretty routinely do
- 10:08actigraphy before PSG MSLT,
- 10:10and otherwise if we want to confirm
- 10:12the diagnosis and people who have a
- 10:14phenotype of long superacion with IH,
- 10:16and this is example of one of my patients
- 10:19who had a PSG normal having MSLT normal.
- 10:23Despite the fact that I was convinced
- 10:25she had idiopathic hypersomnia,
- 10:26so then she took a week off work
- 10:29so she could do this actigraphy
- 10:31and indeed it showed an average
- 10:33estimated total sleep time of over
- 10:3512 hours per 24 hour period,
- 10:37so we could confirm her diagnosis.
- 10:41I took her fee is not as good as
- 10:43we might like, but the I do think
- 10:45an important caveat is that it
- 10:47is not actually measuring sleep.
- 10:49It is measuring movement as a
- 10:52surrogate for wakefulness and lack
- 10:55of movement is a surrogate for sleep.
- 10:58And So what we like to do is have these
- 11:01patients not just wear their actigraphy
- 11:04for the week before their PSG MSLT,
- 11:06but also where they're active.
- 11:08Your fee for the night of their PSG,
- 11:10so we can at least see.
- 11:12In an individual person,
- 11:13how well did the actigraphy capture
- 11:16their sleep in the sleep lab?
- 11:18That may not be the same as the
- 11:20accuracy that it has in their home,
- 11:22but at least gives us some benchmark for was.
- 11:25The actor could be good,
- 11:26pretty good or terrible.
- 11:27This is my cautionary tale of a patient
- 11:30who came to see me for excessive daytime
- 11:33sleepiness and her first seven days
- 11:35of actigraphy are the first seven bars,
- 11:37and that's what this table is
- 11:40summarizing over her first seven days.
- 11:42For average total sleep time estimated
- 11:46by her actigraphy was 11 hours and
- 11:4944 minutes for 24 hour period.
- 11:51This last night is the night
- 11:52that she was in the Sleep lab,
- 11:54and so we just took the ACT to watch,
- 11:57and we adjusted the window to
- 11:59the PSG lights out and lights on,
- 12:02and did the audit scoring city actor
- 12:05watch and the human expert scoring
- 12:07for the PSG and the actigraphy
- 12:09that night is you would kind of
- 12:11guess looking at the bar was.
- 12:137 hours, 4 hours,
- 12:16420 minutes.
- 12:18Or PSG actually showed a measured
- 12:21sleep duration of 26 minutes now.
- 12:24There were a lot of weird things
- 12:26about this case.
- 12:26I assume she normally sleeps more
- 12:28than 26 minutes at home,
- 12:30but this is my record for the most
- 12:33discrepancy between actigraphy
- 12:35and simultaneous PSG in a patient.
- 12:38I do think the authors of the ICS
- 12:40D3 did a really nice job of saying
- 12:43when the science was not sufficient,
- 12:45but they had to make recommendations
- 12:47anyway because we need to be able
- 12:49to diagnose disease and so they
- 12:51straight up say actigraphy has
- 12:53not been validated for this use.
- 12:55There's a lot that needs to be validated.
- 12:57One is whether the accuracy of
- 12:59Actigraphy is the same,
- 13:01and NIH population as indeed many
- 13:03other populations in which it's
- 13:04been studied it might.
- 13:06Plus,
- 13:06if we even be better because I accuracy
- 13:09is related to sleep efficiency,
- 13:11the cutoff of 11 hours was just pulled
- 13:14from PSG data for convenience and so
- 13:16it may be a very different cutoff to
- 13:19make the distinction by actigraphy,
- 13:22and then I think it also is less important
- 13:26to distinguish IH from controls,
- 13:29although that's important.
- 13:29We also want to be able to distinguish
- 13:32I ate from other hypersomnia disorders
- 13:34for our medical decision making.
- 13:36And then each device has accuracy
- 13:39issues that need to be validated and
- 13:42then settings within that device.
- 13:44So to that end, I highlight this study
- 13:47by by Jesse Cook from David Plants
- 13:50Group looking at just one device
- 13:53in people with clinical idiopathic
- 13:55hypersomnia and then this is the actor
- 13:58watch there's two settings you can
- 14:01adjust standard Lee in the device,
- 14:03the sensitivity and how long
- 14:04someone has to be a mobile.
- 14:06Before you decide that they
- 14:08are asleep or not, IMO,
- 14:09before you decide they are awake and you
- 14:12can see just by varying those two factors,
- 14:16you get a really broad.
- 14:19Do friends in how well the sleep
- 14:23time measured simultaneously
- 14:24with PSG and the active watch?
- 14:27How how that agreement was the
- 14:29default setting for the active watch
- 14:32are here in blue overestimating,
- 14:34with almost every combination of settings so.
- 14:37Validating actigraphy for this purpose is
- 14:40going to involve a lot of detailed work.
- 14:44It also raises the question of,
- 14:46you know,
- 14:47in the ICSE 2 there was idiopathic
- 14:50hypersomnia without long sleep time
- 14:51less than 10 hours and with long
- 14:54sleep time more than 10 hours.
- 14:56Now we have this 11 hour cutoff as as
- 14:58a as one of the diagnostic criteria,
- 15:01but many people with IH don't have long
- 15:04sleep durations and so it's really
- 15:06not clear whether IH with and without
- 15:08long sleep durations are the same thing.
- 15:11Or are they just severity on a spectrum?
- 15:15They really different disorders
- 15:16and so this was a cluster analysis
- 15:19that looked at MSLT variables and
- 15:21then characteristics of the daytime
- 15:24naps that people took and then just
- 15:26did a cluster analysis and then
- 15:28subsequently looked at how the MSLT
- 15:30based diagnosis aligned with the
- 15:34clusters that the computer created
- 15:37and what you see is unsurprisingly,
- 15:40I think in cluster 3 narcolepsy
- 15:42with cataplexy cluster.
- 15:43By itself, it is a pretty distinct.
- 15:45Phenotype,
- 15:45but then these other two clusters
- 15:48in cluster two was primarily people
- 15:50with idiopathic hypersomnia with long
- 15:53sleep time defined by the ICS D2.
- 15:55The other cluster was this mix of narcolepsy,
- 15:58without cataplexy and idiopathic hypersomnia,
- 16:01without long superacion,
- 16:03and so suggesting there's something
- 16:05meaningfully different in the phenotype
- 16:07that the width and without long sleep
- 16:10time that segregated into different clusters.
- 16:13I'm trying to get at that same question.
- 16:15These are clinical data looking at
- 16:19IH patients and separating them out
- 16:21based on long sleep duration and look
- 16:25then looking at them clinically and
- 16:28looking at it this way that people
- 16:29with long sleep durations are more
- 16:31likely to have difficulty waking up in
- 16:33the morning with with more sleep inertia.
- 16:35They are less likely to be refreshed by naps,
- 16:38they are.
- 16:40More likely to have fatigue,
- 16:43they are less likely to have
- 16:46an abnormal MSLT.
- 16:47And so suggesting there is some
- 16:50important difference in the phenotype.
- 16:52We looked at this in hypersomnia
- 16:54foundation registry,
- 16:55so this was a this is an ongoing
- 16:58registry of people with hypersomnia
- 16:59disorders who self input data about
- 17:02their diagnosis and their symptoms,
- 17:05and so it doesn't have the
- 17:06precision of the clinic
- 17:07based study I just showed you,
- 17:08but much bigger sample because
- 17:11it is an international registry,
- 17:13but we found essentially the
- 17:15same thing, which is the people.
- 17:18With long sleep,
- 17:18durations tend to have more sleep.
- 17:21In our show they have more brain fog.
- 17:23They have more cognitive
- 17:25complaints they have.
- 17:29Just a different phenotype.
- 17:31It seems like the difficulty in
- 17:33wakening the unrefreshing sleep
- 17:35and the long sleep durations
- 17:37tend to segregate together,
- 17:38so that may be a meaningful
- 17:41difference diagnostically.
- 17:44Another important question is,
- 17:46given that our current diagnostic
- 17:48tools are imperfect and we don't
- 17:50yet understand the biology enough
- 17:52to develop a biomarker that
- 17:54would let us make this diagnosis,
- 17:56what else can we mine about
- 17:58this disease to help us improve
- 18:01diagnosis and so specifically,
- 18:02can we take the clinical features
- 18:05of IH and translate any of
- 18:08those into diagnostic measures?
- 18:10So keep in mind, in the ICS D3,
- 18:11the supportive features are
- 18:13unrefreshing naps lasting.
- 18:14At least an hour.
- 18:16A PSG sleep efficiency of at
- 18:18least 90% and then severe.
- 18:20Prolonged sleep inertia.
- 18:22Great difficulty waking up in the morning,
- 18:24sometimes called sleep inertia.
- 18:25Sleep drunkenness because it
- 18:27is so pronounced and then the
- 18:29ancillary symptoms of iih fatigue,
- 18:31autonomic symptoms.
- 18:33Cognitive dysfunction.
- 18:34So long unrefreshing naps,
- 18:36I believe firmly are part
- 18:38of the experience of IH,
- 18:41but they have all the same measurement
- 18:43issues that the nocturnal sleep does
- 18:46that the MSLT does that is potentially
- 18:48going to be a challenging thing to
- 18:52operationalize as part of the diagnosis.
- 18:55I also tend to think that high
- 18:57sleep efficiency should be
- 18:58a supportive feature of IH.
- 19:00I am a little skeptical when
- 19:02someone comes in with a lower sleep
- 19:04efficiency and a diagnosis of iih,
- 19:06but it is worth saying this is a
- 19:08meta analysis from David plant
- 19:09and several years ago.
- 19:11If you look at what's published
- 19:13about sleep efficiency and I ate,
- 19:15it is actually that it is not different
- 19:18from controls in in meta analysis,
- 19:20and so I think that's an important
- 19:23question to some work that's being
- 19:25done now looking at spectral analysis.
- 19:27And other more sophisticated ways of looking
- 19:30at the PSC might shed some light on that.
- 19:34But I think really where there's a lot of
- 19:35interest now is what can we do with this?
- 19:37Sleep, drunkeness, right?
- 19:39So normal,
- 19:41sleep, inertia,
- 19:41physiologic state,
- 19:42we all go through it when
- 19:44we're transitioning from being
- 19:45asleep to being awake.
- 19:46But it is usually really short,
- 19:48especially if we're not sleep
- 19:49deprived or waking up during the
- 19:51biological right or from N 3.
- 19:53But in people with idiopathic hypersomnia,
- 19:55not all of them, but many of them,
- 19:57it is often very pronounced.
- 19:59It is sometimes the worst feature
- 20:01of the disease,
- 20:02and so this is a historical.
- 20:03Note from Bed Rick Ross describing
- 20:06this disorder which he called
- 20:08hypersomnia with sleep drunkenness,
- 20:10in which the sleep drunkenness
- 20:12was sometimes worse than daytime
- 20:14sleepiness or even sometimes
- 20:16happened without daytime sleepiness.
- 20:18He subsequently would decide that
- 20:20these folks had idiopathic hypersomnia,
- 20:23but I think it tells you how fundamental
- 20:25it is to the phenotype that it was
- 20:28initially identified as its food disorder.
- 20:31It does seem pretty tightly
- 20:33related to idiopathic hypersomnia.
- 20:35These were all the data I could
- 20:37find a few years ago looking at
- 20:40sleep drunkenness by diagnosis.
- 20:41About half of people with
- 20:44idiopathic hypersomnia have
- 20:45really pronounced sleep inertia.
- 20:47Come and it's pretty rare in
- 20:49narcolepsy type one, it's about 8%.
- 20:51They'll be at the numbers there.
- 20:53Get a little bit small.
- 20:54I really could not find a good estimate
- 20:57in narcolepsy Type 2 numerically.
- 21:00It's very similar to age,
- 21:01but with a very very small sample size.
- 21:03I think it will turn out to be like
- 21:05many things in narcolepsy Type 2,
- 21:07which is some people have a phenotype
- 21:08that's a little bit more like narcolepsy.
- 21:10Type one may be undiagnosed.
- 21:13Type of creating efficiency and
- 21:14some people haven't seen it.
- 21:15Typed it as much more like
- 21:18the pathic hypersomnia.
- 21:20We looked at sleep inertia in the
- 21:23hypersomnia foundation registry
- 21:24with a variety of questions
- 21:26to measure sleep inertia,
- 21:27and that's basically what we found,
- 21:29which is it is most common
- 21:31in idiopathic hypersomnia.
- 21:32It's relatively uncommon in
- 21:33that narcolepsy type one,
- 21:35although depending on how
- 21:37you ask the question,
- 21:39you may see some of it in
- 21:41narcolepsy type one and then sort
- 21:43of intermediate in in narcolepsy,
- 21:45type 2,
- 21:45but all measures of sleep inertia
- 21:46with all the ways that we thought
- 21:48to ask it and hypersomnia.
- 21:49Foundation were endorsed most often
- 21:52by the idiopathic hypersomnia group.
- 21:57It would be nice to have questionnaires
- 21:59that value were validated and asked
- 22:02about sleep inertia in a standard way.
- 22:05We have borrowed the sleep Inertia
- 22:07questionnaire from the psychiatry literature.
- 22:09This is a scale that was developed
- 22:11to capture these sleep inertia
- 22:13that people with depression.
- 22:14How and breaks down questions really,
- 22:17in four domains,
- 22:18cognitive difficulties, behavioral,
- 22:20different difficulties,
- 22:22physiologic things like balance
- 22:24and then emotional.
- 22:27Pinky and I age you see the
- 22:29first three a lot.
- 22:31You are less likely to see things
- 22:32like dread about starting today.
- 22:34I don't think people would.
- 22:35I age don't want to wake up.
- 22:36I think they can't wake up up,
- 22:39but when we have looked at this in
- 22:42our folks with sleepiness disorders,
- 22:45we see what you would expect,
- 22:47sort of based on what we've
- 22:49talked about so far,
- 22:49which is that people who sleep the
- 22:52longest also tend to have the highest
- 22:54sleep inertia as sort of a construct.
- 22:57Validity it also correlates with
- 22:59the number of alarm rings people
- 23:01report takes to to wake them up,
- 23:04but not particularly related
- 23:05with mean sleep latency,
- 23:06number of sewer, and so on.
- 23:10I'm I do think we could not
- 23:11just ask about sleep inertia.
- 23:13We can measure sleeping here,
- 23:14so this is done in healthy control.
- 23:16Studies of sleep inertia all the time,
- 23:19and so we could do this as a measurement
- 23:21potentially even in the sleep lab as
- 23:23part of the PSG or part of the MSLT,
- 23:26maybe for the ambulatory setting as well,
- 23:28especially with things like smartphones.
- 23:30We already know the measures that capture
- 23:32sleep inertia well and healthy controls.
- 23:35The only downsides are of
- 23:36course not everybody with IH
- 23:37has pronounced sleep inertia,
- 23:39so you won't capture.
- 23:40Everybody with this it's also not
- 23:42specific to video pathic hypersomnia
- 23:44you will catch people who have a
- 23:46delayed sleep phase syndrome with
- 23:48measures of sleep inertia and also
- 23:50people who are sleep deprived.
- 23:51So important things on the differential
- 23:54for idiopathic hypersomnia,
- 23:55but I think there's enough promise there
- 23:58that that we do need some data these.
- 24:01This was one group that looked at
- 24:03this question a number of years ago.
- 24:04Now to say, could we just add vote
- 24:09potentials to what we're already doing
- 24:13instrumentation wise and in the.
- 24:15In these patients,
- 24:17as they are waking up and see if we
- 24:20can capture sleep inertia through
- 24:23either a behavioral measure or
- 24:26changes in the evoked potential,
- 24:28and they in fact demonstrated
- 24:30sleep inertia in their behavioral
- 24:32measures for the number of errors,
- 24:34but also with a revoked potential saw.
- 24:37This lengthening of the P300 latency,
- 24:40which is one of the measures and evoked
- 24:43potential across a variety of sleepiness.
- 24:45Disorders.
- 24:48So potentially it does require
- 24:49sort of extra add on to what we are
- 24:52already doing in the sleep lab.
- 24:54So what we decided to do was borrow
- 24:56a tool from the sleep deprivation
- 24:58literature which is the psycho
- 24:59Motor vigilance task.
- 25:00It is a 10 minute simple reaction time task
- 25:03and we just added it to our MSLT protocol.
- 25:06So anybody who comes in for an
- 25:09MSLT has this 10 minute PDT before
- 25:12and after nap two and before and
- 25:15after NAP 4 because we were hoping
- 25:17that we would be able to capture.
- 25:19This sleep owners are patients
- 25:21were reporting by looking at the
- 25:23change during the MSLT nap.
- 25:24And then, uhm,
- 25:25we also looked at it in some non
- 25:27sleepy can not sleep it controls
- 25:29and what you're looking at here
- 25:31on the left is actually just at
- 25:34baseline before nap too.
- 25:37The distribution of lapses when
- 25:39it takes at least a half a second
- 25:42to press the button in response
- 25:44to a stimulus and what we saw was
- 25:46people who are sleepy are much worse
- 25:49at the Pvt then controls,
- 25:52but actually not different by sleepiness,
- 25:54diagnosis and then on the right here.
- 25:58When we looked at the difference
- 26:00before and after the nap,
- 26:02how much people got worse with a short nap?
- 26:05Again controls.
- 26:06We don't see an effect here that
- 26:09controls don't really get worse
- 26:11on the PPT with a short nap.
- 26:13If they're not sleep deprived which
- 26:15are controlled by definition or not.
- 26:17But all of this sleepy people get worse,
- 26:22or at least all those sleeping groups
- 26:23have an average worsening of Pvt performance.
- 26:26So we are capturing sleep inertia in the
- 26:29sleep lab in a way that differentiates
- 26:31sleepy participants from controls,
- 26:33but is not unique to idiopathic hypersomnia.
- 26:37Then this is,
- 26:39uhm,
- 26:39another Group One of the French
- 26:42groups looking at the Pvt before
- 26:45nighttime sleep on the PSG and
- 26:48then in the morning after waking
- 26:50up from the PSG 30 minutes later
- 26:53and then several hours later,
- 26:56and their question was not so much.
- 26:57How was it different by diagnosis?
- 27:00But how did it relate
- 27:01with self reported sleep?
- 27:03Inertia or sleep drunkenness using their
- 27:05idiopathic hypersomnia severity scale which.
- 27:08Looks at a variety of symptoms of
- 27:11idiopathic hypersomnia, including
- 27:12sleep inertia and sleep drunkenness,
- 27:14and they found that there's a very strong
- 27:17relationship between self reported
- 27:19sleep inertia and sleep drunkenness,
- 27:21and Pvt worsening.
- 27:23After a night of sleep.
- 27:25So the red and black were the
- 27:26people with severe sleep inertia.
- 27:27The green was mild sleep inertia,
- 27:29and the blue was no sleep inertia,
- 27:31and you can really see this worsening.
- 27:33People know, I think, unsurprisingly,
- 27:34when they have sleep inertia.
- 27:38Well, the ancillary symptoms help us.
- 27:41That's harder.
- 27:42I think fatigue is very nonspecific,
- 27:46and certainly is not easier
- 27:47to measure than sleepiness.
- 27:49It's probably harder to
- 27:50measure than sleepiness,
- 27:51and so I don't think the fatigue of
- 27:54IH is particularly going to help us.
- 27:58There are commonly autonomic symptoms,
- 28:00and people with IH as well as the other
- 28:03central disorders of Hypersomnolence UM,
- 28:06which theoretically can
- 28:07be objectively tested.
- 28:08I think the issues we run into
- 28:10there is it's still a subgroup,
- 28:12or some people.
- 28:13It might be a medication effect,
- 28:15even in the unmedicated group
- 28:17you can still see it,
- 28:18but it also doesn't really answer what's
- 28:20the cause and and what's the effect.
- 28:23I do think that cognitive symptoms
- 28:26add to disease burden a lot.
- 28:28Similarly nonspecific but measurable,
- 28:30it might be a subgroup of people with IH,
- 28:34but it might be something David plant
- 28:36has advocated that for IH instead of
- 28:38looking for the one perfect test,
- 28:40we need to just think of a multimodal
- 28:43diagnosis where you you know
- 28:44if you maybe have six different
- 28:46tests to choose from.
- 28:47If you need at least three of them,
- 28:49you get the diagnosis,
- 28:51so cognitive dysfunction might
- 28:52fit well in that sort of a model.
- 28:55I showed you, our Pvt data at baseline,
- 28:57which.
- 28:57Differentiated all sleepy
- 28:59people from controls,
- 29:00but did not differentiate by diagnosis.
- 29:03Another group has reported on the
- 29:05sustained attention to response task.
- 29:07A different test of attention,
- 29:10but found a very similar thing,
- 29:12which is that regardless
- 29:13of why you are sleepy,
- 29:15people who are sleepy
- 29:16have impaired attention.
- 29:17It's worse than controls,
- 29:19but doesn't add to the diagnosis between
- 29:22the central supporters of hypersomnia.
- 29:27I was told to give a clinical focused
- 29:29update and so I am not going to say
- 29:31much about the pathophysiology of
- 29:33idiopathic hypersomnia it helps,
- 29:35so we don't really know anything about the
- 29:38pathophysiology of idiopathic hypersomnia,
- 29:40so there'd be a limited amount.
- 29:41I could say, even if I wanted to.
- 29:44But but let me just pause and
- 29:46say there are a number of sort
- 29:49of threads out there about what
- 29:51idiopathic hypersomnia might be up.
- 29:54There is known as I talked
- 29:57about a minute ago.
- 29:58There's known to commonly
- 30:00be autonomic symptoms,
- 30:01more commonly in IH than in controls.
- 30:06There's been very little
- 30:08beyond symptoms done.
- 30:10There is one small study looking
- 30:11at heart rate variability,
- 30:13showing differences between
- 30:14people with IH and controls,
- 30:16basically at rest,
- 30:19higher parasympathetic activity.
- 30:21But after arousal from sleep,
- 30:22higher sympathetic activity in
- 30:25the IH patients versus controls.
- 30:28The one theory is that because
- 30:30people they've had a hypersomnia
- 30:32tend to be night owls.
- 30:34This may be a circadian problem.
- 30:38They can't meet criteria for delayed sleep,
- 30:40wake phase disorder,
- 30:41but maybe there is a more subtle
- 30:44dysfunction of the circadian system.
- 30:46Some preliminary work looking
- 30:49at circadian clock.
- 30:53Mechanics within peripheral skin
- 30:55fibroblasts have suggested that the
- 30:58period length may be too long and
- 31:01people with idiopathic hypersomnia,
- 31:03which might explain some of these
- 31:05long nocturnal sleep periods,
- 31:06but also that the amplitude may be reduced,
- 31:10which could possibly contribute to
- 31:12this sort of feeling of like I'm
- 31:15never reached full wakefulness that
- 31:17are people with my age describe.
- 31:20And then work by my colleagues here at Emory,
- 31:22suggesting that maybe people with
- 31:24idiopathic hypersomnia are producing
- 31:26a substance that abnormally activates
- 31:28GABA a receptors and then triggers a
- 31:31soporific pathway through the GABA system.
- 31:34I don't think these theories are multiple
- 31:37are mutually exclusive necessarily,
- 31:40but but neither are any of them really
- 31:44fully conclusive at this point in time,
- 31:46so it's still a lot of work to
- 31:49be done in that regard.
- 31:50So for the rest of my time,
- 31:51I'm going to turn and talk more
- 31:56about treatment strategies.
- 31:58I think by the time people
- 32:00come to clinical attention,
- 32:02nonpharmacologic strategies
- 32:03or not usually enough.
- 32:07I think people generally need
- 32:09pharmacology by the time it gets
- 32:11severe enough for them to seek
- 32:14medical treatment in my experience.
- 32:15But I do think there's potentially a
- 32:18role for non pharmacologic strategies
- 32:20as adjunctive treatment and I certainly
- 32:22believe that patients are looking for
- 32:25nonpharmacologic strategies to add to
- 32:27or to lower their their medication.
- 32:30Burden.
- 32:32One thing that I think is really
- 32:34important is that this is not Mark Alexi
- 32:36in the sense that it's very common for us.
- 32:38With our narcolepsy type one
- 32:40patients to recommend napping as a
- 32:42treatment strategy right to write
- 32:44accommodation letters so they can
- 32:45take naps at school or not.
- 32:47So at work because people with
- 32:49narcolepsy type one often can take a
- 32:5115 minute nap and wake up and feel
- 32:53much better in people with idiopathic
- 32:56hypersomnia not generally are not refreshing,
- 32:58they tend to have sleep inertia
- 33:00for a prolonged period of time.
- 33:02When they wake up from naps
- 33:03and then that's are not short.
- 33:04They are very long and so it is
- 33:07actually I would say more common
- 33:08for my patients with IH to try very,
- 33:11very hard to avoid maps because they
- 33:14make them feel so bad and so I don't
- 33:17generally recommend maps as a strategy
- 33:19for people with high age unless they
- 33:21have a pretty atypical phenotype.
- 33:23But Despite that,
- 33:24I do think accommodations for school
- 33:26or work can still be really helpful,
- 33:28because there does tend to be a phase delay,
- 33:31and because it can take people several
- 33:33hours to wake up in a way that it
- 33:36doesn't take the rest of us later start
- 33:38times or unexpectedly showing up for
- 33:40work can be a helpful accommodation.
- 33:44And then,
- 33:45although the literature is pretty
- 33:47limited on the objective testing of
- 33:50cognitive function in IH patients.
- 33:53What data are there?
- 33:54Do suggest similar cognitive profile to
- 33:56other disorders of excessive sleepiness,
- 33:59and certainly accommodations
- 34:02that target that extra time.
- 34:07Brakes and so on can can be helpful.
- 34:11And then of course, there is a counseling
- 34:14and support aspect here as well.
- 34:16There are safety issues
- 34:17in terms of sleepiness.
- 34:19While driving, we know people with
- 34:22hypersomnia disorders including IH,
- 34:24are more likely to have car accidents.
- 34:26We know that if you give them Modafinil,
- 34:28you improve their on road driving,
- 34:30but do not normalize it compared
- 34:32to controls and so important
- 34:34counseling there and then counseling.
- 34:36Of course, about medication side effects.
- 34:38I'm a big believer in patient groups.
- 34:42I think it's hard to get a diagnosis
- 34:44of something you've never heard of
- 34:45and don't know anybody else has ever
- 34:47had it and it has a terrible name.
- 34:49Like idiopathic hypersomnia is like,
- 34:51well, we don't know what it is.
- 34:53And so I think it can be really
- 34:56profoundly meaningful for people
- 34:57with this diagnosis to meet
- 34:59other people with this diagnosis.
- 35:01I do warn people,
- 35:02the people who gravitate,
- 35:03I think to Facebook groups and so
- 35:05on May not be the typical patient.
- 35:08I think you tend to see the
- 35:10more severe patients,
- 35:10and so I think it needs to be taken
- 35:11a little bit with a grain of salt.
- 35:13But in general I'm a big believer in
- 35:15in resources for patients so they
- 35:17can get to know other people with the
- 35:21disorder and and form pure support that way.
- 35:24Uh Jason Ong has done some really nice
- 35:28preliminary work on the development of CBTH.
- 35:31So unlike CBT I where the idea is you
- 35:35can actually fix the insomnia with
- 35:39cognitive behavioral therapy for insomnia.
- 35:43The idea was CBT H is not that.
- 35:46I don't think anyone,
- 35:48especially Jason,
- 35:49thinks that you will cure hypersomnia,
- 35:52narcolepsy, IH whatever with CBT.
- 35:56But there's plenty of symptoms
- 35:59in the hypersomnia disorders that
- 36:02could benefit from a structured CBT
- 36:05sort of support and training,
- 36:07and so this was a pilot study that they
- 36:10did in published across narcolepsy
- 36:12type 1/2 and IH who also had at least
- 36:16mild depression and did a combination
- 36:18of individual or group CBT eight.
- 36:20So it was basically designed
- 36:22based on stakeholder intervention.
- 36:24What was known about CBT for other?
- 36:26Chronic diseases,
- 36:27and then what is known specifically about.
- 36:31These disorders and and although
- 36:33it was a small pilot study mostly
- 36:36to look at feasibility,
- 36:38they did find significant improvement
- 36:40in depression severity as well as a
- 36:43measure of global self efficacy, right?
- 36:45These are chronic diseases that are
- 36:47hard to manage and so increasing
- 36:49self efficacy is potentially going
- 36:52to be really helpful.
- 36:54But as I said,
- 36:55the mainstay of what we do is medications,
- 36:57so these are the new clinical practice
- 37:00guidelines from the ASM for the
- 37:03central disorders of hypersomnia.
- 37:05I'm actually only showing you on this slide.
- 37:07Three of the disorders that are
- 37:10covered in that guideline.
- 37:11We do know that narcolepsy type
- 37:13one in our club today.
- 37:15Two are different,
- 37:16but this guideline has continued
- 37:17to lump the narcolepsy together
- 37:19because most of the studies lumped
- 37:21in narcolepsy together and these
- 37:23are evidence based pipelines.
- 37:25Uhm, the ASM gives things strong.
- 37:28Recommendations for conditional
- 37:30recommendations for conditional
- 37:32recommendations against or
- 37:34strong recommendations against
- 37:36depending on the strength of the
- 37:38evidence in the context of patient
- 37:41preferences and values and so on.
- 37:43You can see here for idiopathic hypersomnia,
- 37:47we made one strong for recommendation,
- 37:49which is for Modafinil,
- 37:51and then we make 4 conditional
- 37:53recommendations or methylphenidate sodium
- 37:56oxybate to listen and clarithromycin.
- 37:59So a couple of comments about this.
- 38:02I will not talk further
- 38:03about methylphenidate.
- 38:04This is based on clinical data that's
- 38:06published showing that methylphenidate
- 38:08helps people with idiopathic hypersomnia.
- 38:11There's not a randomized controlled trial.
- 38:13I think we believe it probably does help.
- 38:15It helps for lots of other
- 38:17kinds of sleepiness.
- 38:20Patrol assignment there's data out
- 38:22of France showing that that Oleson
- 38:24helps with idiopathic hypersomnia.
- 38:26Again, in a clinical series,
- 38:27not a randomized controlled trial.
- 38:29Realistically, here in EU.
- 38:30S that is really hard to get
- 38:33cover for people with high age
- 38:35'cause it is really expensive,
- 38:37so it does have a conditional
- 38:39for recommendation,
- 38:39but I don't generally use it.
- 38:41In my age patients.
- 38:42And we'll talk more about sort
- 38:45of for my son in a little bit,
- 38:47but I definitely want to talk
- 38:48more about sodium oxybate.
- 38:49So these guidelines were finished before
- 38:53the lower sodium oxybate clinical trial,
- 38:56and idiopathic hypersomnia released
- 38:57any data so we could not incorporate
- 39:00those data into this guideline.
- 39:01That's why there's not any comments
- 39:03on lower sodium oxybate the sodium
- 39:06oxybate data that led to the
- 39:08conditional recommendation was
- 39:09a clinical series out of France,
- 39:11not a clinical trial.
- 39:14So.
- 39:16Briefly,
- 39:16UM Modafinil I think has been for
- 39:19a long time and should continue to
- 39:23be one of the first line treatments
- 39:26for idiopathic hypersomnia.
- 39:29It is worth knowing because occasionally
- 39:31sways insurance companies that there
- 39:33are now two published randomized
- 39:35controlled trials of Modafinil.
- 39:37They both used a dose of
- 39:38200 milligrams once a day,
- 39:40which is a lower dose than
- 39:41most of my age patients are on.
- 39:43I generally need to titrate
- 39:45up to 400 milligrams.
- 39:47But between the two studies,
- 39:48there were about 100 participants,
- 39:50so pretty good size in combination,
- 39:52almost all of whom met them without
- 39:54long flight sleep time criteria from
- 39:56the ICS D2 and what you're looking at
- 39:59here is just a meta analysis of the
- 40:02on treatment Epworth at three weeks.
- 40:04A reduction in the word Apple Group
- 40:07versus the placebo group of five points.
- 40:09So similar to what we would see and
- 40:11with Modafinil and other disorders,
- 40:13and similarly on the MWT used
- 40:15in both studies.
- 40:16And improvements in 4.7 minutes and
- 40:18the ability to maintain wakefulness.
- 40:21So unsurprising,
- 40:21I think because I think we
- 40:24all know clinically,
- 40:25the Modafinil helps plenty of
- 40:27people with idiopathic hypersomnia.
- 40:28Not all of them, but plenty.
- 40:30But now objective randomized
- 40:33controlled trial data,
- 40:35particularly with most of the sample
- 40:37added in this 2021 publication.
- 40:41Really, what I wanna talk about
- 40:43is lower sodium oxybate,
- 40:45so calcium, magnesium,
- 40:47potassium,
- 40:47sodium, oxybate.
- 40:49So recall that sodium oxybate has at
- 40:52least if you were on the 4.5 grams,
- 40:55twice a night dose,
- 40:57almost your daily maximum
- 40:59recommended amount of sodium in it.
- 41:02And so now there is this mixed salt oxybate,
- 41:07often referred to as lower sodium oxybate,
- 41:10which is 92% less sodium than sodium oxybate.
- 41:15The approval for the treatment of
- 41:17narcolepsy for kids older than seven
- 41:20and an adult back in July of 2020.
- 41:22But the reason we're talking about
- 41:24it today is of course last month or
- 41:27we talked over now two months ago.
- 41:29It got approval for the treatment
- 41:31of IH in adults,
- 41:33which made it the very first
- 41:35medication FDA approved for
- 41:37idiopathic hypersomnia,
- 41:39which is a really big deal.
- 41:43It is still oxybate,
- 41:45which means it is still covered by
- 41:47a REMS program by the FDA to try to
- 41:50mitigate the risk of this medication.
- 41:52It is a schedule three drug.
- 41:54It is a one to one dose Ng with
- 41:57sodium oxybate because it is
- 41:59the same active ingredient.
- 42:00I'm gonna dig a little bit into
- 42:02the data and support this for
- 42:04idiopathic hypersomnia as of
- 42:06Friday these weren't published yet.
- 42:08I don't think they've been
- 42:09published since then,
- 42:09but these are data from their
- 42:12abstracts from clinicaltrials.gov
- 42:13and from the package insert.
- 42:18Be a they did an interesting study design.
- 42:22So further narcolepsy trials where they
- 42:24already knew sodium oxybate worked.
- 42:26They said well, for lower sodium
- 42:28oxybate same active ingredient.
- 42:29Let's do a double blind withdrawal
- 42:31study where you type train people
- 42:34up on the medicine open label.
- 42:36Keep people on their stable dose
- 42:38of the medication open label and
- 42:40then do a double blind withdrawal.
- 42:43Some people stay on medicine,
- 42:44some people go to placebo.
- 42:47And see how much worse the placebo
- 42:50group group guests for narcolepsy,
- 42:53where they already knew oxybate worked.
- 42:55This is a pretty reasonable study design.
- 42:57It keeps people on placebo for the
- 43:00shortest possible amount of time.
- 43:02It is interesting to me.
- 43:03They decided to do the same thing for
- 43:05IH when they didn't have any data
- 43:08showing that oxybate was helpful,
- 43:09but nevertheless that is what they did
- 43:12and so there was a screening period.
- 43:14People could be on other wake
- 43:16promoting medications or die.
- 43:18Rams excuse me sodium oxybate.
- 43:20And then there were changed to lower
- 43:23sodium oxybate or lower sodium oxybate
- 43:25was added if they were on another way
- 43:28promoting medication for a stable dose
- 43:30in period before this randomization.
- 43:32So who were the IH patients up there?
- 43:35154 adults meeting ICS D Two
- 43:38or three IH criteria?
- 43:39Median age of 3971% women.
- 43:43Their efforts had to be at least 11.
- 43:46He's fit well with our clinical
- 43:48picture of who has IH 41% had
- 43:51not ever been treated for IH,
- 43:53but the majority had been treated before
- 43:56in fact and 58% of them stayed on a wake
- 44:00promoting medication during this study.
- 44:02A handful had been on sodium oxybate and
- 44:04were transitions to lower sodium oxybate.
- 44:06They couldn't have other causes
- 44:09of hypersomnia or untreated OSA.
- 44:11They could not have had a major
- 44:13depression episode within the last
- 44:14year or any current suicidal ideations
- 44:16or history of suicide attempt.
- 44:17Couldn't, of course,
- 44:18beyond sedating medications,
- 44:20alcohol,
- 44:20cannabinoids that would be dangerous
- 44:22with lower sodium oxybate couldn't have
- 44:25a history of substance abuse disorder.
- 44:27What they did that was different than
- 44:30the narcolepsy studies was to allow
- 44:32people to either take the twice nightly
- 44:34dosing that we are used to for oxidates or,
- 44:36once nightly dosing,
- 44:38the rationale being that
- 44:39case series from France,
- 44:41then so the people with IH because
- 44:43they're bad at waking up have a
- 44:45really hard time waking up to,
- 44:46say,
- 44:46take a second dose in sodium oxidate after
- 44:48they've only been asleep for four hours.
- 44:50So here they actually let the
- 44:53the treating investigator decide
- 44:55once or twice nightly dosing,
- 44:57and so the total.
- 44:58Nightly dose varied depending on whether
- 45:00they were taking it once or twice.
- 45:02Actually they ended up with most people.
- 45:043/4 taking two doses.
- 45:06Of lower setting oxybate,
- 45:09so their primary outcome was the
- 45:11Epworth UM and during the time
- 45:13they were open label on oxybate
- 45:16the Epworth were quite low.
- 45:18When they put people from lower sodium
- 45:20oxybate 2 placebo there Equifax
- 45:21quite a lot worse and the people who
- 45:23stayed on treatment it didn't.
- 45:25So a seven point difference in the Epworth.
- 45:28It's not really an apples to apples
- 45:31comparison with a traditional parallel
- 45:33group design like the Modafinil
- 45:35studies I showed you, but certainly.
- 45:37People taken off of lower
- 45:39sodium oxybate got worse.
- 45:41They also looked at the global
- 45:43impression of change and people felt
- 45:45worse when they came off the medication
- 45:47and then the idiopathic paper.
- 45:49Samia severity scales force
- 45:52again worsening when people
- 45:55were were randomized to SIBO.
- 45:5911% of people withdrew due to adverse
- 46:01events at some point and another 154
- 46:05who started the study only about 110.
- 46:07Actually ended up randomized,
- 46:09not necessarily because of AES,
- 46:11but there was a decent amount of attrition.
- 46:16The other people who withdrew anxiety
- 46:19was most common reason for withdrawal,
- 46:22but you can see a handful of reasons
- 46:24why people with through and then
- 46:25during the open label dose in the most
- 46:28common adverse events for nausea,
- 46:29headache, dizziness,
- 46:31insomnia and again anxiety.
- 46:34And so I think not surprising given
- 46:36what we know about sodium oxybate
- 46:38and how it works in narcolepsy,
- 46:40but know that that is now an option.
- 46:42Lower sodium oxybate for idiopathic
- 46:44hypersomnia I think.
- 46:45We still have work to do in
- 46:46figuring out where in the treatment
- 46:48algorithm that should fall,
- 46:49especially given the exclusion
- 46:52criteria for the clinical trial.
- 46:54A couple of other points about
- 46:56the treatment of idiopathic
- 46:57hypersomnia for some people to sleep,
- 46:58inertia is really a problem and so
- 47:00needs to be addressed separately in
- 47:02addition to the wake promoting medication,
- 47:05lower sodium oxybate seems like
- 47:06a good idea for that now.
- 47:08If people otherwise qualify and
- 47:10it's otherwise appropriate to
- 47:11put them on lower sodium oxybate,
- 47:13it does seem to have helped
- 47:15with that piece of things.
- 47:17What many people do is set two alarms,
- 47:22one for when they need to wake up,
- 47:23and one an hour earlier.
- 47:25Wake up just enough to swallow their wake
- 47:27promoting medication angle back to sleep,
- 47:29and then when the second
- 47:30alarm goes off an hour later,
- 47:31they actually have a level of
- 47:33medication in their system that
- 47:35makes it easier for them to wake up.
- 47:37Sometimes.
- 47:38If they really can't even wake up enough
- 47:40to take medication an hour earlier,
- 47:43we those things at bedtime.
- 47:45There's a nice key series Carlos Shank
- 47:48looking at using boubyan bupropion for that.
- 47:51Who knew there is a delayed release
- 47:54methylphenidate at bedtime?
- 47:56480 HD that when I can get up for
- 47:57my age patients II quite like and
- 47:59sometimes we just use Lotus wake
- 48:01promoting medications for the people in
- 48:04whom there is a circadian component.
- 48:05There seems to be a phase delay component.
- 48:08Melatonin light ways to shift the
- 48:10phase earlier may be helpful.
- 48:13And then in treatment refractory
- 48:14cases reassess the diagnosis.
- 48:16Make sure it's right combination therapy.
- 48:18And then here's what I'm going to
- 48:20talk very briefly about service
- 48:21for maintenance and as an L we did
- 48:23a study of floor three mice in a
- 48:25couple of phone number of years ago.
- 48:27Now it was a twenty person just
- 48:29pilot randomized controlled trials.
- 48:30They crossover.
- 48:31We did not see an improvement
- 48:33in reaction times,
- 48:34but we did see significant improvements
- 48:37in our subjective self reported
- 48:39outcomes and so we use it when people
- 48:41have failed many other things.
- 48:44We at least try it.
- 48:45It is very important to know this
- 48:47safety communication from the FDA,
- 48:49which is that clarifies,
- 48:50may increase mortality in people
- 48:51with heart disease.
- 48:52This comes from the cleric or study,
- 48:54which is a very large,
- 48:55randomized controlled trial
- 48:56that thought it would show.
- 48:57Clarithromycin helped people with MI
- 48:59or angina and in fact found the opposite,
- 49:02which that is that it increased
- 49:04mortality in people with
- 49:06a history of MI or angina.
- 49:07In their post hoc analysis,
- 49:09this was only people who are not on saturns,
- 49:12but the only randomized
- 49:14component was clarithromycin.
- 49:16So now I know it was not covered in
- 49:18the clinical practice guideline,
- 49:19'cause there wasn't enough
- 49:20data to make a recommendation,
- 49:22but we do sometimes use a flumazenil as well.
- 49:25It has to be compounded,
- 49:27it cannot be taken orally because of
- 49:29a very large first pass metabolism.
- 49:31So we compound it into either a
- 49:34transdermal cream at that goes
- 49:36on the venous plexus right here,
- 49:39or these little lozenges that go
- 49:41under the tongue to be dissolved.
- 49:43We just looked at our clinical data.
- 49:46In in our first 153 people on film as well,
- 49:49about 60% say yes.
- 49:50This helps with my sleepiness.
- 49:52Only about 40% of people stay
- 49:54on it for a variety of reasons.
- 49:57We do Council people that in
- 50:00that first 153 people,
- 50:01two people had a stroke equivalent to
- 50:04180 and one of radio graphic vasculopathy
- 50:07both had pre-existing risk factors
- 50:08that potentially there is a risk.
- 50:10There.
- 50:11More commonly dizziness and anxiety,
- 50:13or what we saw.
- 50:15Finally,
- 50:16I think when we now we start to have
- 50:18more treatment options for patients,
- 50:20we get to start thinking about
- 50:22which treatment for which patients.
- 50:24So what are the key symptoms
- 50:25beyond sleepiness?
- 50:26We need to manage?
- 50:27What are the important comorbidities
- 50:29that might lead you away from
- 50:31a treatment like lower sodium,
- 50:32oxybate or substance abuse
- 50:35or cardiac comorbidities?
- 50:37And then of course for people
- 50:39of childbearing potential,
- 50:40what are their plans for childbearing
- 50:42and not just Modafinil and armodafinil,
- 50:45but control is on?
- 50:46Now two interferes with hormonal
- 50:48birth control to decrease its
- 50:50efficacy at preventing pregnancy.
- 50:52Important to use a different
- 50:54form of birth control.
- 50:55Comorbid mood disorders are tough.
- 50:57I don't think idiopathic hypersomnia
- 50:59is protective against those up,
- 51:01but there are cautions for many
- 51:04mood disorders with with all of
- 51:06these treatments and then comorbid
- 51:08medical disorders often will
- 51:10guide our treatment option,
- 51:12particularly with cardiac
- 51:14related comorbidities limiting.
- 51:17Some of our instead of being
- 51:19uses and and so on.
- 51:20And with that I thank you all
- 51:22very much for your attention.
- 51:24We do,
- 51:24I think have a few minutes for questions.
- 51:26I would love to answer any questions.
- 51:29Well,
- 51:30thank you so much. That was fabulous.
- 51:32Fabulous Overview,
- 51:33really concentrating on.
- 51:34I think all of our clinical experience,
- 51:36how difficult it is to really make
- 51:38a diagnosis in these patients.
- 51:39Be confident in the diagnosis
- 51:41and then of course treat them.
- 51:43And I'm gonna ask people to either
- 51:45put their questions in the chat.
- 51:47I'll be happy to read them or unmute.
- 51:49But one question I had about the oxidates.
- 51:52You know what?
- 51:53And I know we weren't really
- 51:54talking about pathophysiology,
- 51:56but what do you think the mechanism
- 51:58of action might be?
- 51:59In idiopathic hypersomnia, you know,
- 52:01in narcolepsy you know we understand
- 52:03there's these patients have fragmented
- 52:05sleep and a lot of you know sleep state
- 52:07dysregulation and it's sort of intuitively.
- 52:09Oh, we consolidate their sleep.
- 52:10They're better, but these people have
- 52:12long sleeve with high efficiency.
- 52:14Why?
- 52:14Why should this work right
- 52:16right? No, I agree.
- 52:18And actually mean before that case series
- 52:20from France came out a few years ago.
- 52:23I didn't ever use oxidative my age
- 52:25patients for exactly that reason.
- 52:27It didn't make sense to me, right?
- 52:29I I think there's a few possibilities.
- 52:31One is that there may be something wrong
- 52:34with the sleep that people with IH get that
- 52:37we don't see with our traditional tools.
- 52:40I like e.g as much as the next person,
- 52:42but you're still measuring the scalp
- 52:43and trying to get it the thalamus.
- 52:45There's a lot,
- 52:45you know that happens in there,
- 52:47so it it may be that oxybate
- 52:49is fixing something with the
- 52:50nocturnal sleep that we can't see.
- 52:52Maybe people need a lot of sleep.
- 52:54Because there's something
- 52:56missing that's possible.
- 52:57It's also possible that some of
- 52:59the effects of oxybate or not.
- 53:01It's not just that it changes
- 53:02nighttime sleep and said it suppresses
- 53:04dopamine and norepinephrine,
- 53:05and so you get this rebound in the morning,
- 53:08and so it might actually have
- 53:09some of its mechanism through the
- 53:11traditional ways that we think
- 53:12Modafinil and amphetamines are right.
- 53:14Promoting through increasing dopaminergic
- 53:17and noradrenergic neurotransmission.
- 53:19So I don't think we know.
- 53:21Great thank you. Alright,
- 53:24anybody questions from the audience.
- 53:26I want to give you a chance, I see.
- 53:28I see a few faces. Who undone I Brian?
- 53:30I didn't know if you had a question,
- 53:33you may be able to unmute yourself if you do.
- 53:35If not, just feel free to put it in the chat.
- 53:42I guess while we're waiting for people
- 53:44to question it so it sounded to me
- 53:46like your approach for diagnosis is,
- 53:48you still rely on the PSG with MSLT,
- 53:51but everybody gets the seven
- 53:54days of Actigraphy beforehand.
- 53:56Yeah, and are you using the actor?
- 53:58Watch what? What do you use we
- 54:00doing is the actor watch
- 54:02and which setting do you
- 54:03keep it on, 'cause you may?
- 54:06We haven't even just like Jesse's paper.
- 54:08We did not. We have not changed that.
- 54:10We still stay on the on the
- 54:13default settings up the UM.
- 54:16You know, I think the problem with actigraphy
- 54:19is that really to make the diagnosis,
- 54:21people need to be able to sleep
- 54:23adlib and it is really hard to
- 54:26sleep 11 hours every night and still
- 54:28have a job and so many people with
- 54:32IH or curtailing or sleep time.
- 54:34Nine hours, you know,
- 54:35we're just still plenty of sleep,
- 54:37but you may not catch it on actigraphy.
- 54:40It looks like we're starting to see any
- 54:42change in insurance coverage for any of
- 54:44the medicine for idiopathic hypersomnia.
- 54:46Hi Karen, I'm not yet it just happened,
- 54:51but absolutely in every appeal
- 54:52letter I right now,
- 54:53and medicines are denied for IH.
- 54:55I say the only FDA approved medication with
- 54:58indication is the way it is very expensive.
- 55:00This is a cheaper alternative.
- 55:03Trusted insurance companies will
- 55:05act in their self interest.
- 55:07Uh, I'm hoping that'll be that'll
- 55:09cause pressure and moved out
- 55:11and it will be paid for.
- 55:13Brian, hi, Brian says, uh,
- 55:15do you think the sleep of my
- 55:18age is qualitative differently
- 55:19and can capture it with EG.
- 55:22You know I,
- 55:23I think our traditional measures
- 55:24are not capturing it well,
- 55:26but I think that some of the data
- 55:29that's coming out now looking
- 55:32at either spectral analysis or.
- 55:35How often people are shifting
- 55:37between states may capture some
- 55:38of the stuff that we are missing,
- 55:40so I think we don't.
- 55:42Have as much we haven't got as much
- 55:44data out of the E as we as we can,
- 55:46and so I'm hoping that will be
- 55:48helpful diagnostically as we.
- 55:52You know, as we learn more
- 55:53about that and then a related
- 55:55question about percent slow wave,
- 55:56percent RAM, it's not grossly
- 55:58different NIH than than other people.
- 56:01And so those those sort of traditional
- 56:04measures don't get us a long way.
- 56:06Potential mechanism for
- 56:08clarithromycin or flumazenil.
- 56:09We started using those because they
- 56:11act at GABA a receptors to decrease
- 56:14this increased activity that we see
- 56:16in sleepy patients so flumazenil.
- 56:21Is a negative allosteric modulator of GABA
- 56:23a receptors for information may have some
- 56:26more directly antagonistic properties.
- 56:28Were saying they didn't actually know
- 56:29what the mechanism of clarithromycin
- 56:31is because it is a dirty drug.
- 56:32It does lots of things.
- 56:33It's an anti inflammatory.
- 56:34It's an antibiotic and so my current funding
- 56:37is a mechanistic study of clarithromycin.
- 56:39They try to figure out why it's working,
- 56:41but we started it because we think
- 56:43there's a problem of increased
- 56:45activation of the sedating GABA a system.
- 56:53If a patient fails, Modafinil and oxidate,
- 56:55would you give sinoussi a
- 56:56try or go to clarithromycin?
- 56:57Are from as you know.
- 56:58I think Susie is so rampant.
- 57:00All sorry Jimmy RCMP office I think so
- 57:04ramped all is a surprisingly good medication.
- 57:08I it's mechanistically similar
- 57:09to a lot of what we use,
- 57:11and so I was not super optimistic
- 57:13when it was being developed,
- 57:15but the clinical trials was a pretty robust
- 57:18benefit on the MWT especially and I had.
- 57:20Had some very nice responders
- 57:22of people who didn't do well
- 57:24with armor standard medications.
- 57:26It's fair to get paid for in IH,
- 57:27so I treat a lot of like PRD eyes of
- 57:305.1 when I watch cats as sleep apnea
- 57:33with positional therapy and then I
- 57:35can get so rampant all so absolutely.
- 57:37I like I like so ramp at all
- 57:40when I can get it paid for.
- 57:42I use a lot of traditional stimulants.
- 57:45I use methylphenidate.
- 57:46I use the amphetamines and
- 57:48so I generally do those.
- 57:50Also,
- 57:51before I would go to clarithromycin
- 57:52are for now and I'll come.
- 57:54I would generally whether I would
- 57:56do oxybate or clarithromycin or
- 57:59flumazenil first really depends
- 58:01on the psychiatric comorbidities.
- 58:04For somebody with a lot of depression,
- 58:05I worry about oxidate,
- 58:06but otherwise I would generally
- 58:08probably try Oxidate first.
- 58:14Do you have time for one more?
- 58:15Do we need to stop because
- 58:15of the other right now?
- 58:16I think there's just the
- 58:17one more from Christine,
- 58:18one who says it's a great talk.
- 58:20But do you think the residual
- 58:21sleepiness was treated?
- 58:22OSA has an overlap with IH
- 58:25I do. I mean, I think that there's probably
- 58:28two reasons why people have residual
- 58:31sleepiness after OSA is treated right.
- 58:34One is that probably for the people
- 58:35with a lot of hypoxemia for a lot
- 58:37of years before they get diagnosed.
- 58:39They have chronic damage
- 58:41to wake promoting regions.
- 58:43Or it's just irreversible, right?
- 58:45There's animal data that that suggests
- 58:48that's a plausible mechanism for Sleeping S,
- 58:50but for lots of people with
- 58:52sleep apnea and sleepiness,
- 58:53I think they probably just
- 58:55have two diagnosis,
- 58:56especially the people with pretty mild sleep
- 58:58apnea and pretty substantial sleepiness.
- 59:00It may be that the battery is just common
- 59:02enough that you can have sleep apnea and
- 59:05narcolepsy even have sleep apnea, and I ate.
- 59:07And so absolutely I think there's a
- 59:10group of people who we treat their OSA.
- 59:13And they're still sleepy.
- 59:15The reason they're still sleepy is
- 59:17because they probably had IH all along.
- 59:20Well, thank you. This is we are at time.
- 59:22I think the questions would keep
- 59:24going on and on but we really
- 59:25really appreciate your time and
- 59:27your expertise today thanks.
- 59:28Thank you for coming and
- 59:30thanks everybody for joining.
- 59:31Have a great afternoon.
- 59:33Bye bye bye.