"Idiopathic Hypersomnia Update" Lynn Marie Trotti (10/06/2021)

October 12, 2021

ID7026

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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.