"Hypersomnia" Joel Oster (05.12.2021)

May 26, 2021

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00:06Alright.
00:10Let's see, people are filing in. Perfect.
00:21Alright, well good afternoon everybody.
00:22My name is Andres in truck and thank
00:25you again for joining us for yet
00:27another edition of the joint Yale
00:30Harvard Tufts Sleep Seminars and in
00:32the setting of the Yale Sleep Center,
00:34there occurs at 2:00 PM and
00:37every Wednesday and so today.
00:39We are lucky to hear from
00:41Doctor Auster from Tufts,
00:42will be introduced by Doctor Grover.
00:44But first I just want to take a
00:47moment to ensure that everyone is
00:49muted who is not speaking during the.
00:52Presentation if you are interested
00:54in receiving credit for attendance,
00:55please see the chat room for
00:57instructions and you can text the
00:59unique ID for this conference
01:01anytime between 1:45 PM and 3:15 PM
01:03to receive credit and if you're not
01:05already registered with the DLC Me,
01:07you will have to do that first and
01:09for questions in your presentation,
01:11please make sure to use the chat rooms
01:14throughout the hour and I will help
01:16moderate the discussion just to let
01:18you know that the recorded versions
01:20of these presentations are available
01:21online within a couple of weeks.
01:232 weeks at the link provided in the chat.
01:27So finally,
01:27as usual,
01:28please feel free to share the
01:30announcements for this weekly
01:31lecture series with anyone who
01:33you think might be interested or
01:35have them contact Debbie Lovejoy
01:37to be added to our mailing list.
01:39And so this turns out to be our
01:41last joint conference for the year,
01:43and so we're going to go out with a with
01:46a bang and looking forward to the talk,
01:49and so I will hand the mic over
01:51to Doctor Grover at Tufts.
01:55Hi good afternoon everyone.
01:57It's my pleasure to introduce my colleague,
02:00Doctor Joe Lasker.
02:01Today he's an esteemed colleague
02:04here at Tufts for many years and I'm
02:07it's really great working with him.
02:09It he's one of our adapter Oscar
02:12completed his medical degree from
02:14Boston University School of Medicine.
02:16He then went on to do his residency
02:19at Tufts Medical Center and
02:21followed by a year of fellowship
02:24in Neurology and now Fellowship.
02:27Add mass General Hospital in
02:30epilepsy and e.g enable potentials.
02:32He's he started his career at Leahy
02:36Clinic and he was there for some time
02:40and then he's been a tough since
02:432015 and he is a faculty associate
02:47professor here at Tufts Medical Center.
02:52And he's also in neurology,
02:54and he's the director of e.g.
02:57And the intraop neurophysiology.
03:00A clinic as well and he's,
03:02you know it's a pleasure to have
03:05a neurologist in our sleep center
03:07whose sleep boarded and has been a.
03:10Important part of our fellowship
03:12and and without further ado,
03:14I'd like to introduce Doctor Auster.
03:18Thank you for that very kind introduction
03:20and what an honor and privilege to be
03:23here today to lecture at this joint.
03:25Lecture series. As a.
03:29Individual has primarily been a clinician.
03:32I really leaned on the.
03:34Giants have great researchers,
03:36many of whom may actually be joining the
03:39session from the injunctive faculty.
03:43With this team I mentioned their work in
03:47passing and to make everyone an expert
03:50and maybe even a hypersomnia. Activist,
03:52these patients are very interesting.
03:54They're very challenging.
03:57They deserve our compassion and.
04:01To work with them is often difficult
04:03because of the lack of definitive therapies,
04:06particularly for idiopathic hypersomnia.
04:09And I will touch on those points
04:11throughout the lecture and hopefully
04:13leave you all with the state of the art.
04:16What is known about the general
04:19clinical aspects of hypersomnia?
04:20So in the upper left is a
04:22shot of Tufts Medical Center.
04:24And I Chinatown area Boston and
04:28hypersomnia is a particularly.
04:31Narcolepsy is a tetrad which is due
04:34to inappropriate sleepiness and
04:36then the other features that are
04:38the ancillary symptoms such as.
04:40Cataplexy from a strong emotion
04:42sleep paralysis.
04:43And here's my rendition of
04:45neurotransmitters in the brain causing.
04:48Hypnagogic phenomenon,
04:49but I was privileged to work on the
04:52most up-to-date 3rd edition of Netter.
04:54Neurology and this is from the chapter
04:56that myself and my mentor Paul Gross at Co.
04:59Author. This is van Gogh's.
05:04Rendition of Siesta after Malay, I believe.
05:09What struck?
05:11Me was that.
05:12It's somehow inappropriate with the flood of.
05:15Yellow and and and tinged orange shoes.
05:18It seems that this sleep is
05:20somehow inappropriate midday.
05:26Disclosures I cannot.
05:28Co investigator or principal investigator.
05:30Number of epilepsy trials.
05:31None for Sleep Medicine.
05:32I'm like coauthor in two editions of
05:35the Native neurology book I served.
05:37As an advocacy and advocate on the
05:39Epilepsy Foundation of New England.
05:42All my money is going to the institution.
05:46So there is no commercial support and
05:48there are no conflicts of interest.
05:51I will overview the current research that
05:54active on idiopathic hypersomnia and
05:57I'm going to touch on some off label.
06:00Items I'm not advocating for them,
06:02I'm just describing I want people
06:04to understand the breath of.
06:06The current state of the art
06:07with regards to that entity.
06:11So the learning objectives are to give
06:13you a comprehensive review of hypersomnia.
06:16It's under recognized especially
06:17as a primary disorder.
06:19And I'm going to start with the case,
06:21and then I'm going to conclude
06:22with another case of how even
06:24seasons Sleep Medicine experts
06:25fail to recognize it in a patient.
06:27Patients may not be adequately
06:29evaluated for secondary causes.
06:31Anne, this lecture will allow learners
06:32to understand both the neurobiology,
06:34the clinical features of the primary
06:36hypersomnia and those that are secondarily.
06:39'cause a middle ground disorder is epilepsy.
06:41Patients with epilepsy.
06:42There is some debate as to whether
06:45or not the sleep dysfunction and
06:47the sleepiness is part of the
06:49primary disorder or whether it's
06:50secondary due to the nature of the.
06:54Pathways and the neurotransmitters
06:55in the underlying substrate.
06:57The brain.
06:57So the second point is this lecture will
06:59review an overview of the neurobiology
07:01regarding sleep and weight normal substrates,
07:03and I will rely heavily on work of others.
07:06This lecture reviews the mechanisms that
07:08are known in primary and secondary insomnia,
07:11and then I plan to review the actual.
07:15Relevant 8 ASM practice parameters
07:16that are available.
07:17Many of them are quite of 13 or 15 years old.
07:22At this point there is a update up-to-date.
07:27It was an up to date chat that was
07:29generated to to the members to update
07:31some of those practice parameters,
07:32but they're not yet on the site.
07:35And this is particularly relevant because
07:37we will see how idiopathic hypersomnia
07:40entity is evolving in the literature and.
07:43May need to be caught up in our society.
07:47Practice points.
07:48So in Boston we like many other places,
07:51we have a number of higher
07:53centers of higher learning,
07:54and so we now have acquired a an array of
07:57young patients in their late teens and 20s
08:00who suddenly have a problem such as this.
08:03So I will describe a 22 year old
08:05patient who has difficulty staying
08:07awake during college even with
08:09nine hours of sleep at night.
08:11Falls asleep in class at another time,
08:13but notices curiously that he's refreshed
08:16with a very brief 5 to 10 minute nap.
08:19More recently,
08:19he would have to lean against something,
08:21especially if you became emotional
08:23in his legs or he'd have a feeling
08:25that his head might drop.
08:27But sometimes it would be so subtle
08:29that others might not detect it.
08:32He emerges from his naps,
08:33unable to move and awake.
08:35It might see scary images,
08:36but he's paralyzed.
08:37He can't scream.
08:38Can't talk.
08:39Units that,
08:39while he might have had sleepiness
08:41as a youngster while in high
08:43school earlier the symptoms have
08:44become more manifest recently when
08:46he really needs to be awake and
08:48concentrate and do his best the most.
08:50And in one of these colleges.
08:53So Ted Cruz is going to give us a nice
08:56visual of what it looks like to be sleepy.
08:59So you know,
09:00we can see a patient like this
09:02in the neurology clinic,
09:03and the differential might be
09:05myasthenia gravis or weakness.
09:06But this was a this was a state
09:08of the Union address,
09:10where depends on what side
09:11of the aisle you are,
09:13whether this sleeping this was
09:15appropriate or inappropriate,
09:16but excessive daytime sleepiness is
09:17generally an inappropriate response.
09:18That is time poorly to life circumstances.
09:21So based on the international
09:24classification of sleep disorders.
09:25EDS or excessive daytime sleepiness is
09:27excessive when it causes a subjective
09:30complaint or interferes with function.
09:32And its inability to maintain
09:34wakefulness and alertness during the
09:36major waking episodes of the day
09:38with sleep occurring inappropriately.
09:40Hypersomnia and hypersomnolence.
09:41No,
09:41it's just someone who's just a minor nuances,
09:44but it's used these these terms are
09:46using to tame interchangeably when.
09:48Sleepiness occurs that's inappropriate.
09:50When wakefulness is expected,
09:52and hypersomnia is as a disorder is
09:55characterized by hypersomnolence.
09:56Fatigue is everything else.
09:58So there are cytokines.
10:00Inflammatory processes,
10:01their psychiatric processes with
10:03fatigue is the subjective lack of
10:06physical and mental energy with
10:08a broad differential diagnosis.
10:09In the past, stimulants and sedatives,
10:12awake and asleep, was a binary enterprise.
10:15However,
10:16we learn from some of the great
10:19science behind,
10:20such as from Clifford Saper's lab
10:22and and others that sleep maybe
10:24a continuum where it's a dimmer
10:27switch and
10:27the primary hypersomnia is
10:30particularly narcolepsy involved.
10:32A loose dimmer switch where there is a
10:35continuum of promotion of wakefulness
10:37versus promotion of sleepiness.
10:40And this talk will show you some of the
10:43biological substrates to give you much
10:45more rationality behind that analogy.
10:48So sleep is a requisite for
10:50optimal function mune system.
10:51The cardiac cardiac muscle
10:53requires it to rest,
10:54and optimal optimally function and model
10:57and remodel memories consolidate at night.
10:59This pruning of the neurons and
11:01sprouting and numerous processes that
11:04occur verified by clinical studies
11:06and observation and sleep deck
11:08may be sub optimal to ones health,
11:10and it relates to the need for sleep
11:13which will talk about from some of the
11:16epidemiology belie wise and others.
11:18With characterized how that changes
11:20throughout the lifespan and sleep
11:22deprivation causes a physiological rebound
11:24in sleep patterns in a certain manner.
11:27And then primary secondary
11:28causes by alluded to May Co.
11:31Mingle with other disorders.
11:33So the epidemiology of hypersomnia
11:36pathological sleepiness is
11:37a major cause of mobility.
11:39Job loss, poor attention,
11:41impacts driving focus,
11:42focus,
11:42social functioning and really a
11:45non quantifiable societal cost.
11:46The prevalence varies in the literature up
11:49to 25% in US to one and 3300 or one in 5000.
11:54In the United States.
11:56And it may actually vary
11:59throughout the lifespan,
12:00particularly in in women,
12:02excessively daytime sleepiness has been
12:04reported to decrease in age in some studies,
12:07and there is a general equal gender ratio
12:11or female predominant up to two to one.
12:14For women who developed excessive daytime
12:17sleepiness and meet in a 10 year period,
12:19that's an 8% to EDS development.
12:228% of women.
12:23The strongest independent risk factors
12:25were insomnia, smoking and then,
12:27less important, more anxiety,
12:28depression, somatic symptoms,
12:29snoring, and obesity.
12:31But depression and we sleep architecture.
12:33In the neural pathways.
12:35That immediately by depression
12:36you'll see layers later in the
12:39talk are sharing somewhat of the
12:41same neurobiology and circuitry.
12:43So this is a an article that
12:45highlights how total sleep time
12:47changes naps wake after sleep onset,
12:50me altering women throughout the lifespan.
12:5420,000 patients have narcolepsy United
12:56States and about 3,000,000 worldwide.
12:58This is an estimate.
12:59It's the number one cause of
13:01sleepiness in the United States.
13:04Is not narcolepsy success, it's OSA.
13:07Narcolepsy is number 2.
13:09Approximately 5% of patients in
13:10the sleep center have a primary
13:12narcolepsy diagnosis,
13:13with comorbid occurrence with a number
13:15of other primary sleep disorders.
13:181/4 of patients with narcolepsy have OSA.
13:21The prevalence of narcolepsy is
13:2220 to 67 per 100,000 worldwide
13:24and it occurs most often.
13:26The second decade of life.
13:27Although the patient I showed you.
13:30In attack in the early 3rd Decade of life,
13:33but the diagnosis is often delayed,
13:34as in this case.
13:36This is from the Seminole Paper
13:38that's on the practice parameter
13:40of how to manage one of the two
13:43Seminole Papers on the ASM website.
13:45Back in 20.
13:46Oh seven.
13:47There were 13 primary sleep
13:49disorders that are.
13:51Identified in the category of hypersomnia.
13:55If you go on the hypersomnia foundation.org
13:58website which mentions the ICS D3,
14:00which is the most current classification
14:02of sleep disorders, there are eight.
14:05These include narcolepsy type,
14:06one with cataplexy, narcolepsy Type
14:082 which doesn't have cataplexy.
14:11Idiopathic hypersomnia, which people
14:12wonder if it's not collapse E Type 3.
14:15But many of those patients
14:18biologically heavy.
14:19May have a normal hypocretin level,
14:20so is it really just an alteration of
14:23different part of the pathway or not?
14:26Let's talk.
14:26I'm not going to spend a lot of time if
14:29at all inclined to live in syndrome,
14:32which is a truly remains an enigma
14:34with these periods of hypersomnolence
14:35and hyperphagia hypersomnia
14:37due to medical condition,
14:38hypersomnia do a substance.
14:40Psychiatric condition and insufficient sleep.
14:43Up to date you'll have a slightly different
14:46category if you subscribe to that,
14:48they break it down in in this way.
14:52We use the Epworth scale to
14:54quantify level of sleepiness.
14:55Is a validated scale that allows
14:57you to really distill out from a
15:00patient's history that they're
15:01sleeping from a neurologic 'cause
15:03they're not depressed they don't have.
15:06Athenia they don't have tiredness
15:08from from an inflammatory state.
15:09The normal level of sleepiness
15:11is a score less than 10.
15:13The maximum on these eight questions
15:15is 24 patients who have sleep
15:17apnea are often in the 11:50 range.
15:19In those patients that are narcoleptic,
15:21not not collect tix or really
15:23pathologically sleepy.
15:24Or 15 and above.
15:25We are not a good observer of when we
15:28have seizures and when we have states
15:31of partial awareness and when we're sleepy.
15:348 is borderline, but anything less
15:36than 8 to 10 is considered normal.
15:38Getting a good night's sleep
15:39across the lifespan.
15:40The need varies from infancy to old age and
15:43for adults they can get by on less sleep,
15:45but they're not at their best cognitively
15:47unless you get the requisite amount,
15:49so it needs to be continuous and have normal
15:51architecture and should contain all elements,
15:53including REM and slow wave.
15:54Yet patients who come to
15:56the sleep lab we often see.
15:58Reduced percentages of some
16:00of these entities,
16:01especially if they're an SSRI's
16:03that suppress these.
16:05And.
16:06Some what is a pseudo science behind
16:09how significant that may or may not be?
16:11Why incremental knowledge is
16:13accumulated to why goodnight sleep
16:14is important across the lifespan?
16:16This is a very nice article from
16:19Max Herskowitz who I believe
16:21started out of Tufts before he had
16:24a super illustrious career.
16:26All,
16:27and this is a very nice article that
16:29shows that Wausau increases over
16:31time and there's a decrease in RAM,
16:33slow wave and an increase in stage one.
16:36We think that stage one in Wausau.
16:39At least according to the blog Wise
16:41and and and that School of Epidemiology
16:44represents sleep instability.
16:45And at the ASM last June,
16:48which is virtual, a lot of those lectures,
16:51particularly by Doctor Masci,
16:53indicated that some patients
16:55with pathological
16:56sleepiness from a hypersomnia
16:57might have more. Stage one,
16:59and Wausau sleep has to be organized
17:02so that we have a coordinated
17:04endocrine and body response so that
17:06we can be at our best physiologically
17:09from a number of different plans.
17:12This is Doctor Robert Mccarley
17:14had the privilege to know.
17:16He partially the adenosine
17:18hypothesis and he is one of the
17:22most cited individuals for for the.
17:24Findings in schizophrenia with the
17:26morphometry of the superior temporal gyrus.
17:29But he also discovered portions of
17:31the ram nucleus many decades ago,
17:34and he also observed that adenosine in
17:36the basil forebrain rose incrementally
17:38while awake and therefore was believed
17:41to be responsible to increasing
17:43levels of sleepiness after being
17:45awake and with higher concentrations,
17:47it may actually inhibit arousal
17:49cause sleepiness.
17:50Anna decreases during sleep in that.
17:53Off my coffee is a noncompetitive
17:56antagonist of adenosine at the receptor.
17:58The adenosine receptor biology is known
18:01as it interacts with producing and Dom
18:04endogenous antigen from prostaglandins.
18:06An adenosine is either stored in a release
18:09and start to be formed inside of cells.
18:12Or or possibly on the surface and
18:14and its proposed as a modulator,
18:16it may cause some days of dilate
18:18by basil dilation.
18:19The weakness of this theory, however.
18:21Although it's observed,
18:23you know there's no patient that we
18:26prescribe enough Red Bull and coffee
18:28to mitigate the effects of hypersomnia,
18:31and this molecule doesn't really interact
18:33with the known neurobiology of the circuitry,
18:36such as at the ereckson receptor,
18:39the heterodimers formation,
18:40the VLP,
18:41all which initiates sleep onset,
18:43and the other pathways.
18:44So it may be an epiphenomenon,
18:47but it hasn't really led to a major
18:50insider inroad into those.
18:52Neuronal connectivity pathways,
18:53but adenosine is on the left.
18:56Caffeine is on the right.
18:58These these articles written.
19:02About 20 plus years ago are or more are very,
19:08very interesting.
19:09So hypersomnia we know results when
19:11sleep at night is inefficient,
19:13fragmented or normal.
19:14Sleep architecture is disturbed
19:16at secondary or there's an
19:17intrinsic problem for this.
19:18And how do we evaluate this complaint?
19:21Well,
19:21I put this type of slide up because
19:23there's nothing more gratifying to
19:25a sleep Doctor Who sees a lot of
19:28OSA patients to see RAM rebound.
19:30So this was a patient who suddenly
19:31had a very organized process after he
19:34came in for a second night after a
19:36diagnostic sleep study or polysomnogram
19:38where there was a very good.
19:40REM, rebound and we all felt good.
19:43Wow, what a success.
19:44This patient had continuous sleep until
19:46the helipad landed and caused him to wake up.
19:49And then he went back to sleep
19:51and lo and behold,
19:52the patient was able to maintain sleep.
19:55But narcolepsy has a sleep wake instability.
19:57An ram may intrude into the waking state.
20:00Now this is what we see as the sort
20:03of gospel on the ASM where this
20:05is the MSL T where we are right
20:08now when I'm giving my lecture at
20:11two or three in the afternoon,
20:13we have the greatest tendency to be
20:15falling asleep on MSL T with the
20:18sleep homeostatic drive or the OR the.
20:21Homeostatic drive is at its
20:22highest with the lowest of the
20:25circadian alerting sender signal,
20:26so process and process C are
20:28the most fire furthest apart.
20:30It's interesting that with the understanding
20:33of how fragmented sleep isn't,
20:35how incontinent patients are of
20:36their rent peers during the day,
20:39that we really don't have a good diagram
20:41of this for the primary hypersomnia.
20:44So maybe we will in the future,
20:46and this is obviously someone that
20:49got there early evening.
20:51No, I'm ram slow wave sleep such as
20:53you see in fleet recovery and they
20:55got more or increasing periods of REM
20:58throughout the night as the night went on.
21:00But here's a patient on the bottom here.
21:03This hymn of what Naka Lefty looks
21:05like and I would add I got this
21:07online so it's blurry.
21:09I want to give credit words do
21:10but some of our patients they even
21:13have much more sleep onset REM's
21:15during the day than this.
21:16So narcolepsy hypersomnia is a
21:18disease that spans a 24 hour period.
21:20That fragment sleep and fragments
21:22wake in these patients.
21:23I have an unpredictable lifestyle
21:26where neurotransmitters planktonic
21:27roles that wax and wane and sleep
21:29and wake are totally destabilized,
21:31like a very dysfunctional loose
21:34dial on a dimmer switch.
21:37So major neurologic mechanisms
21:38promote wakefulness from the
21:40reticular activating system,
21:41with ascential choline glutamate,
21:42noradrenergic systems and
21:44rim is parallel to that,
21:45and I'll show you more of that
21:48as this lecture proceeds.
21:50And termination phase is not simply.
21:55A switch it's a dialing up of wakefulness
21:58and a dialing down of the sleepiness.
22:02So anything that fragments this process,
22:03such as.
22:04Here's a ramp period where you're paralyzed,
22:06and if you're on your back supine,
22:08you have an airway that's closed
22:10and you have an arousal 'cause you
22:12can't breathe these fragmentations
22:14of your sleep will lead to profound
22:16EDS during the day or excessive
22:18daytime sleepiness.
22:20As an EG I like to show a parallel
22:23between EG and sleep and the brain
22:25from time of life to the time of death
22:28is never offline on the upper left.
22:30This is wakefulness, where you have a post,
22:33your predominant alpha rhythm
22:35reaching 8 to 8 more Hertz.
22:38On the right is drowsiness.
22:40Is that the same isn't in Fenton
22:42Cefal Opathy, where there stay there,
22:44or fragmentation of the alpha.
22:45Sleep is by no means a passive process.
22:48Look at how active these posts
22:50are beginning of stage two.
22:52Stage two is very busy with
22:54spindles and K complexes.
22:55Stajan 3 is not flat,
22:57but it's slow with this delta
22:59and ram it becomes active again
23:01with these eye movements.
23:03And low voltage e.g paraments not
23:05quite like wait but it is fast and
23:08it's mediated by almost the same.
23:10Neurotransmitters,
23:10but in a different location and nuclei
23:12in the brain, which we talk about.
23:14With encephalopathies or up foundation,
23:17the pathways are different.
23:18The classical awake or arousal
23:20system is involved in sleep,
23:22but it also involved in self allopathy.
23:25Is there is a impact of the thalamus
23:27where there is obtundation that
23:29occurs which disrupts that pathway
23:31and in the cases of metabolic ensup
23:34allopathy they may be triphasic waves.
23:37Furthermore, when there's this organ.
23:40Damage or there's Frank.
23:43Quarter to excitability.
23:44Some of these waves actually involve
23:47the hours for other source of the
23:49cortex that involve epilepsy,
23:51and we have a continuum from these long
23:55probability of ictal patterns too.
23:58Suppression versus versa question,
23:59which I'm not showing on this slide.
24:02These triphasic waves and
24:03then epileptiform discharges.
24:04But sleep is a completely
24:07different circuitry.
24:08Here are epileptiform discharges
24:09from her on the bottom panels.
24:11These are continuous here on the left.
24:13These are on one side on the right.
24:16The upper left is the a brain that
24:20has diffuse cortical damage and
24:22is flatline or brain dead and the
24:25upper right shows birth suppression
24:28that's induced by pharmaco therapies
24:31such as propofol or or.
24:35Other senators,
24:36but this is a very different circuitry,
24:38a very different look,
24:39very different pattern,
24:40and a very set of different pathways
24:43other than those that that involve
24:45sleeping wake as a epileptologist.
24:47I would digress.
24:48At this point a little bit to
24:50talk about epilepsy and sleep and
24:52patients with epilepsy or pwe.
24:54There's a high end,
24:56higher incidence of sleep disorders in
24:58this population, with 13% of patients.
25:01Also,
25:01having always say in the moderate to
25:03severe range and the hypoxemia and
25:06arousal that occurs in those patients,
25:08either from their epilepsy or and
25:10often their OSA may cause pseudo or
25:12sudden unexplained death in epilepsy.
25:14But OSA is a very highly treatable entity.
25:18Lack of sleep is one of the most
25:21important triggers of seizures with
25:23a third of patients in particular
25:25who may fly under the radar,
25:27and so you ask the question along
25:30with alcohol, stress medication,
25:32noncompliance, missed doses.
25:34Sleep fragmentation might
25:35actually decrease your TST,
25:36leading to seizures,
25:37total sleep time,
25:38and anything that can lead to the
25:40bus increase seizures.
25:41This is a little rectal discharge where.
25:44The sharp part.
25:45Anything that looks like it
25:47would hurt if you sat on it like
25:49a thumbtack is a sharp you.
25:51After going slow wave may actually be
25:54mostly hyperpolarization protective.
25:55But these are typical interictal
25:57discharges which are seen when the
25:59patient is not having a seizure
26:01and lack of sleep.
26:02Causes an increase of this.
26:04An interactive discharges are distributed
26:06differently in different stages of sleep.
26:08The highest rates are in these rolling
26:10delta waves which are highly synchronous.
26:12So impious traitor and stage in three and
26:14four much more in the stage two in stage one,
26:17it's very rare to have an
26:19interactive discharge in REM
26:21because of the hyper synchrony,
26:22but circadian effects may play a role.
26:25Anne.
26:26Less than 1% of seizures
26:28actually come out of RAM.
26:30The less synchronous the EG,
26:31such as when you're awake, are in REM.
26:34The less likely depolarization
26:35or seizures will occur.
26:37In temporal lobe epilepsy,
26:38there's a tendency for
26:40hours and then a seizure,
26:41and this is usually in the late
26:43afternoon with frontal lobe seizures.
26:45There are often brief events with
26:47tonic motor components out of sleep,
26:49with little to no postictal phase,
26:51and some syndromes are time locked
26:52somehow and we don't understand the
26:54neurobiology for the wait period
26:56such as juvenile myoclonic epilepsy,
26:58where there's a myoclonic jerk or
27:00series of falls in coordination in
27:02the morning with grand Mal epilepsy.
27:04Benign Epileptiform central temple
27:06central temporal epilepsy with
27:07spikes or rolandic seizures are
27:09typically seen in the morning,
27:11yet we have more rain periods in the morning,
27:14so that violates the principle in
27:16a way that that RAM is protective,
27:19but this may be an independent entity,
27:21Landau kleffner,
27:22which is one of the catastrophic seizure
27:24syndromes of childhood catastrophic,
27:26especially if you miss it because
27:28these brains are busy seizing away.
27:31You may have microcephaly,
27:32and when the brain is busy.
27:35Seizing particularly in posterior
27:36temporal area on the left with the
27:38language development areas are.
27:40And these patients have continuous
27:41spike and wave and sleep.
27:43These patients have profile language delays.
27:46But epilepsy patients commonly complain
27:48of EDS with the medication burden.
27:51Many of them are on rescue medications
27:54that are benzodiazepine's.
27:55This significant weight gain that can
27:57lead to OSA and confounding variables.
28:00Depression may also be a comorbid
28:02complication and changes the sleep
28:04architecture and REM density and so
28:06forth and other other other features.
28:09And after daytime seizures is a decrease
28:12in RIM increased in REM latency
28:14and more and one in fragmentation,
28:16probably law so.
28:18Epilepsy itself,
28:19even in the absence of Aedes and OSA,
28:22may cause sleep fragmentation so.
28:24Epilepsy might actually represent
28:25a primary hypersomnia,
28:26but the verdict is out and that's why I
28:29included at the beginning of the talk.
28:31This is a patient of ours that
28:34has a responsive neurostimulator,
28:36and these patients are so refractory
28:38that they are either failed surgery
28:41or they require.
28:44Italian of approach to their care,
28:46so these patients we do neurostimulation
28:47in any part of the pathway where the
28:50discharge is in the most robust,
28:51and this is a patient that not
28:53only has a cyclical pattern.
28:55Of the surrogate marker of irritability,
28:57these these devices.
28:58These many computers delineate in eracle
29:01discharges throughout the day and night.
29:03This patient has up to 3000 them
29:05through the through the day and night,
29:08and this patient can be noted to
29:10have electrographic seizures,
29:11but when we activate these devices,
29:13and this has become accepted in
29:16the literature, there isn't.
29:17It has been evolving literature on this.
29:20You change the distribution of when the
29:22interactive discharges and seizures
29:23and long episodes of those interactive
29:26discharges occur into the night period.
29:28So from 10:00 PM.
29:30To 5:00 AM.
29:31So this is relatively new.
29:32How this impacts sleep tiredness doesn't
29:34ameliorate the sleepiness of epilepsy.
29:36The verdict is yet to be found.
29:38We have about 13 or 14 these
29:40patients at our Medical Center,
29:41and most of them have converted to have their
29:44interactive discharges during the evening,
29:45which is convenient because if you
29:47have a seizure at night in your own
29:50bed rather than at the workplace,
29:51it may actually be beneficial.
29:53But is there a higher risk or not of SUDEP?
29:56But some of those studies are
29:57showing that these devices to improve
29:59student or stunned unexplained,
30:01definitely.
30:02I was very fortunate as I may have
30:05alluded to to Co.
30:06Author with my mentor Paul Gross
30:08and a chapter and the third.
30:11Nether Neurology Group and I'm going
30:13to give you neurotransmitter 101
30:16for the clinical sleep doctor here,
30:18so you'll have some understanding
30:20of the neurotransmitters involved
30:22in the primary master switch.
30:24If you will.
30:25Of sleep onset depends on on on VLP.
30:28Oh which I'll show in another
30:31slide in the which identifies get
30:34which which is social with GABA.
30:37And the posterior thalamus,
30:38which is closer to the reticular formation,
30:41is how I remember it.
30:43These are the pathways that promote
30:45wakefulness and the wakefulness,
30:47consciousness and REM are mainly
30:49assets you're calling dependent,
30:51but there are contributions from
30:53norepinephrine, glutamate and serotonin.
30:56The basil forebrain involved with
30:59acetal choline poster hypothalamus
31:01system in orexin hypocretin.
31:03It prints the brainstem,
31:05the roster lens, norepinephrine,
31:06dopamine, glutamate, serotonin,
31:07both widespread projections
31:09through the brain,
31:10including the forebrain cortex
31:11reticular activating system, non REM.
31:13Involves Gallup,
31:14GABA, and the VLP.
31:16Oh and the answer hypothalamus,
31:17basal forebrain and there are reciprocal
31:20innovations and REM has at least four
31:22parts which are new to another slide.
31:24So sleepiness away from this relatively
31:27controlled bitonic influences of
31:29these circuits that are dynamic.
31:31Throughout the day and night periods.
31:34Pearls,
31:35fan economy encephalitis lesion
31:36at the junction of the midbrain,
31:39which is looks like a Mickey
31:41Mouse sign and the diencephalon
31:43which is the the thalamus.
31:45And legions of that.
31:50See the VLP oh is very interior car.
31:52That's the master switch as I think of it as
31:56sleep onset a lesion there is
31:58going to cause an unbalanced.
32:02Operation of the wake pathways
32:04which are posterior so involved,
32:07conomo encephalitis,
32:07a lesion of the anterior region,
32:10would cause insomnia,
32:11whereas lesions of the posterior
32:13hypothalamus which these these promote,
32:16wakefulness allow the sleepy
32:18pathways to to take over.
32:20So these are the neural switches that
32:22are that are shut off or turned on,
32:23but it's not like a master switch,
32:25although I put one here.
32:26It's more like cliffs.
32:28Papers work where there is a
32:30a tendency for these pathways
32:33to either be wake promoting or
32:35sleep promoting and then I put
32:38in a very simple cartoon that I
32:40took from a drug package insert
32:42or another package insert.
32:44But about a website.
32:48But simplifies this even further.
32:52Histamine promotes wakefulness
32:53because histamine neurons activate
32:55the cortical subcortical neurons,
32:56including a wake promoting neurons
32:59outside of the hypothalamus.
33:00But it does something quite different.
33:03It modulates and stabilizes the tendency
33:06for the wake circuitry to take over.
33:09The predominant background of.
33:12Of of of. Flow if you will.
33:16I don't know what word to use a of
33:20the activity of the awake pathway.
33:22So, histamine neurons inhibit
33:23the RAM in the non REM sleep,
33:25promoting neurons and prevent
33:27REM intrusion at the wrong time.
33:30And these are the sleep promoting pathways.
33:33So this work really allows us to
33:35think of sleep more as a dial with a
33:39continuum where it's not a binary on off.
33:42There's a tonic continue of awake
33:44and sleep neurobiology based on
33:46the circuitry by these very elegant
33:48diagrams which I use with this team.
33:51From these researchers,
33:52the ram nucleus contains a somewhat of a.
33:55It's like a brain within a brain.
33:57There are four predominant glue
33:59groups of neurons in this.
34:01Core we sub cerulea's nucleus
34:04with is the glutamate ram on.
34:07Circuitry which causes muscle
34:09paralysis and cortical activation.
34:11So you're paralyzed, but someone awake.
34:14The sub cerulea's nucleus
34:16projects to the lateral medulla,
34:18releasing, releasing the GABA.
34:20But it's the this this activation of
34:24that pathway that causes the descending.
34:27Inhibitory neurotransmitter glycine
34:29onto the motor neuron pathways.
34:32Where people are paralyzed by the
34:35reticulospinal tract and the ram
34:37timing is mediated by GABA in the
34:40periaqueductal Gray in the dorsal.
34:42Para gigantis cellular reticular nucleus.
34:45In these regions,
34:46and so the breakdown is that
34:50narcolepsy cataplexy.
34:51Is a inappropriate muscle
34:54paralysis with the xrem on.
34:58Centers activated and REM behavioral
35:00disorders when they are failed
35:02to inhibit that pathway at night.
35:04Leading 2.
35:06Patients acting out their dreams now
35:08disease that involves these accumulations of,
35:11for example,
35:11synucleinopathies and pathology,
35:13such as in the BRAC stages of Parkinson's.
35:16They're sort of infiltrate all this and
35:19caused the REM behavioral disorder,
35:21we think,
35:22but that's beyond the scope of this talk.
35:26Alzheimer's disease is thought to
35:29be ameliorated by.
35:31Increasing.
35:35Sleep continuity an in particularly a small
35:39study involving drug suvorexant showed that.
35:44That the tower in the pathological proteins
35:46in Alzheimer's disease is accumulated
35:48less when there was sleep promotion.
35:50I don't believe there's any neurobiology
35:52indicated these patients with primary
35:54hypersomnia have less Alzheimer's,
35:56and I'm not indicating that's the case.
35:59I'm just merely raising the question.
36:02So cataplexy, we think occurs when those rim
36:05centers activating this muscle paralysis,
36:07and there's evidence that cataplexy
36:09is instituted from an emotional
36:11stimulus from the right amygdala,
36:13in particularly that acts on
36:15the sub cerulea's nucleus,
36:16and causes that paralysis.
36:19So we wake promoting agents and the
36:22sleep promoting age is the newer
36:24one which will get too involved.
36:26These other neurotransmitters,
36:28the H3 receptors have effect on
36:30excessive daytime sleepiness,
36:31particularly some of the newer agents.
36:33The one newer agent that I know of that's
36:36approved it causes an increase in the
36:40presynaptic histamine availability,
36:41causing you to be have more neurotransmitter
36:44transmitters and keep you awake more.
36:49So. This sleep fragmentation, though,
36:52is not unique to narcoleptics and and
36:54patients with primary sleep instability.
36:57An elderly person also may have a
37:00similar hypnogram to some some of our
37:04medical residents that are up at night.
37:07I'm call sleep will look like.
37:10Like this, we often don't do a
37:13daytime MSL T in our in our cohorts.
37:16Of these, these types of individuals,
37:18but we wonder if sleep intrusion
37:20would also occur.
37:21So our testing is never diagnostic
37:23unless you get a hypo cretin level,
37:25or you can actually visualize what
37:28part of the sleep Wake pathway.
37:30Anatomically. Is involved, so we use MSLT.
37:35The multiple sleep latency test
37:37versus the MSLMLMWT as a surrogate
37:40marker as to how sleepy they are
37:43and we accept this based on these
37:46papers from around 20 plus years ago.
37:49This is from the ASM website Twenty 05.
37:54Anne.
37:54These patients with narcolepsy have
37:56to have a mean sleep latency of
37:59less than eight with two sirens.
38:02Anything else?
38:03Once I went,
38:04no sound is idiopathic hypersomnia.
38:06And if you don't have a decreased
38:08mean sleep latency in that level,
38:10it's debatable whether or not
38:11you actually have.
38:12Pathological sleepiness to that degree,
38:14but MSL TMWT is a marker of degrees
38:17of sleepiness that's supportive or
38:20maybe supportive under the right
38:22circumstances of particularly narcolepsy.
38:25We are not able to assess ourselves when
38:28we are having excessive daytime sleepiness,
38:32we cannot access our assess ourselves.
38:34Sometimes when we have seizures.
38:38In particularly as we give a talk to our
38:42residents when they come in on safety,
38:45there are more errors and residents
38:47may almost reprobate Epworth
38:49score in the narcoleptic range,
38:51but even brief naps may promote alertness,
38:54but nothing substitute for sleep.
38:57Other than sleep.
38:59Idiopathic hypersomnia is
39:02an entity which we end up.
39:04Seeing a lot of these patients
39:06who come to us who do not meet the
39:09criteria for narcolepsy on testing
39:11and it's a management problem
39:13because pharmacotherapy is often
39:15off label for these individuals,
39:17or confined to PROVIGIL.
39:18NUVIGIL which the society ASM
39:20practice standards indicate may
39:22be options for those patients.
39:24But type one narcolepsy.
39:25There's there's all these features,
39:27with the exception of sleep drunkenness,
39:30which is very prominent.
39:31Idiopathic hypersomnia.
39:32There's no cataplexy in narcolepsy,
39:34two or IH.
39:37An naps a very refreshing and narcolepsy
39:40one sometimes not into, but rarely if at all.
39:43In IH.
39:45So these are.
39:47Some of the.
39:52The Coop so Coco Curring percentages
39:55of cataplexy in narcolepsy.
39:57Up to 50% triggered by emotionally
40:00triggered things in sleep paralysis
40:02occurs in about 4080% of these patients,
40:06along with the hypnopompic
40:09hallucinations. The.
40:13Pathologic mechanism is thought to be the
40:15deficiency of the hypocretin mechanism
40:17and signaling caused by selective loss
40:19of hypocretin producing neurons in the
40:21hypothalamus and it may be autoimmune.
40:23There's a clinical trial for those
40:26that have post traumatic type of.
40:28I've narcolepsy.
40:29I tried to publish a case years
40:31ago and was rejected summarily
40:33by many different channels.
40:35'cause it was like an evidence it's good
40:37to see that that constant may be emerging,
40:40but genetic factors which
40:43involved the QB one.
40:45Star 0602 are involved in the header dimer
40:48which may be dysfunctional along with
40:52environmental factors that contributed
40:54to the development occurrence of these.
40:58Semiologie, zven T1 and T2.
41:02This I took from the
41:05Internet from an article.
41:07Showing that the selective
41:09loss of hypocretin erection.
41:11In these areas around the third ventricle.
41:14A comic. From the.
41:17Tetrad of narcolepsy.
41:21The DSM Diagnostic Statistical Manual
41:245 allows you to define narcolepsy.
41:28Cataplexy, as long as his recurrent
41:31episodes of irrepressible need to sleep.
41:33Occurring at least three times
41:35a week over three months,
41:37but there needs to be one of these entities,
41:40such as cataplexy,
41:41hypocretin deficiency,
41:42and a positive.
41:44Quite diagnostic on label and SLT.
41:48I been sleep rating RAM latency in
41:50less than 15 minutes increase seating.
41:52Polysomnogram is also helpful.
41:54There are many decision making
41:56algorithms that are in the
41:57literature on what to do if you.
41:59Have a patient that doesn't quite
42:01satisfy that MSL T criteria.
42:04Well,
42:04some of these slides come from
42:06studies of residual sleepiness that
42:09may be based on industry where
42:11a market was created to give a
42:14drug after patients are treated
42:16with CPAP for treatment of OSA.
42:18But the neurobiology which is.
42:21Runs comment all these types of studies that.
42:24There is deep Gray and white
42:27matter problems changes in DWI,
42:29DTI diffusion, weighted not diffusion,
42:32tensor imaging as well as loss
42:35of of bold signal coupling.
42:38In many of these.
42:41Areas where I showed you slides about
42:44typically in the brainstem RAM areas,
42:47reticular activating systems
42:48and their projections,
42:50so the extrapolation is involved,
42:52that there is degeneration,
42:54arousal,
42:55neurons,
42:55and chronic sleep disruption
42:57for these residual patients
42:59with residual sleep apnea as a.
43:02As a as a form of verifying their
43:05complaint and looking for a treatment for it,
43:08and you can find these all over the Internet.
43:12There is a form of idiopathic hypersomnia.
43:17That has long sleep time and
43:19particularly long sleep time.
43:20It's weekly associated with evening
43:22chronotypes and young age, and it's not
43:24adequately diagnosed using the Ms Lt.
43:26Perhaps because it's time drunk.
43:29But we need to analyze these
43:32patients further. Unfortunately,
43:33this is the list of FDA approved,
43:36approved, indicated drugs and
43:38therapies for idiopathic hypersomnia.
43:39You see him there aren't any.
43:42It's very frustrating.
43:44Uhm? If you go on the.
43:48Internet you can find all the new drugs that
43:51are approved and the older drugs are there.
43:55There's only only sodium oxybate is
43:57approved as an anti cataplex tick.
44:00Uhm? In idiopathic hypersomnia,
44:04the symptoms are quite.
44:07Disabling these are hypersomnia
44:09complaints at their worst, brain fog,
44:11poor memory you need for multiple alarms,
44:14intentional naps and non
44:15refreshing with daily launch sleep.
44:17In many of these patients
44:20that have long sleep time.
44:22And comparing. Uhm?
44:27Longer sleep time too.
44:28Those without long sleep time you can
44:31see that the long sleep time patients
44:33have fireworks pathology subjectively
44:35and none of these are in the diagnostic
44:38criteria for making a diagnosis hypersomnia.
44:41Uhm?
44:43These are the current.
44:47Trials available in studies that
44:50are on the hypersomnia.org website.
44:52And there are some new studies
44:55looking at Tak 925 which is
44:57an erection Type 2 receptor.
45:00Agonist in patients with narcolepsy Type 1.
45:04There was, there was.
45:06A study with Modafinil for
45:08idiopathic hypersomnia,
45:09which seems to improve it but
45:11doesn't mitigate safety risks.
45:15There are some studies looking there's
45:17a study looking at sodium oxybate.
45:19Pretty pathic hypersomnia
45:20compared to patients narcolepsy
45:22which may have some benefit.
45:24All this is off label. Not advocating.
45:27I'm just describing clarithromycin.
45:28May provide some benefit.
45:30It was a trial.
45:31There's a trial of stimulation.
45:35Which I believe was shut down to the meeting.
45:38Lack of meeting primary
45:39endpoints and or funding.
45:40Levothyroxine and idiopathic hypersomnia,
45:41with long sleep time may
45:43be somewhat beneficial,
45:44but I don't think these are our fabricated,
45:46but they are mentioned in
45:49an evolving literature.
45:50I put up the practice parameters
45:52for the treatment of narcolepsy
45:53and hypersomnia is from our
45:55twenty 07 morganthaler paper and
45:57these are just the high points.
45:59There's drugs on there that aren't
46:00even available, such as root answering,
46:03which I believe was only used
46:05as a research drug.
46:07But we're left with all the older drugs here.
46:09The newer ones are not here yet.
46:12Perhaps in the updated practice
46:14parameters they will be.
46:15A need for peer reviewed literature
46:19involving special populations.
46:21Is it knowledge?
46:22And in this slide from that era,
46:24sodium oxybate for examples,
46:25categories categorized as a Schedule B.
46:27Right now it's it's.
46:28It's thought to be cause harm,
46:30but doesn't have a definite I believe.
46:33And then.
46:35Thinking of the new.
46:37Drugs that are out there to send versus soul,
46:40solar and fettle which are.
46:42Wake promoting agents.
46:44One being a H3 receptor antagonist.
46:48Soul reaffirm federal.
46:51Can cause cutey changes,
46:53insomnia,
46:53nausea, anxiety.
46:54It's going to just metabolise
46:57oral contraceptives and
46:59anticoagulants potentially.
47:02Limited in hepatic and renal
47:04conditions and the half-life.
47:06Or or maybe up to 20 hours.
47:09This one is not a controlled.
47:11The Mrs Patel assigned on the left on
47:14the right so knows these are scheduled
47:164 which is a dopamine norepinephrine.
47:19Meaning DNR I which has reduced
47:21or no interaction with ocps.
47:23It's also has the indication
47:25for residual sleepiness and OSA.
47:27If you've had it more than a month,
47:30it's half life is about 7 hours.
47:33So how do we evaluate our initial case?
47:36We do a careful history of
47:38physical looking for all the
47:40secondary causes that we can treat.
47:42We want to make sure that there aren't
47:45any environmental or other causes
47:47we want to do a supportive proof of
47:49pathology through an MSL team ornament WT.
47:52We want to make sure we
47:54inventory the environment.
47:55The behavioral aspects of the case.
47:58Do it as much supportive testing if we can.
48:01In the past we had a problem getting
48:03the hypocretin levels in the CSF,
48:04so I'm calling about.
48:05I don't want to say about 8 to 10 years
48:08of not being able to get a CSF hypocretin.
48:11Apparently it's now available
48:12at the male clinic.
48:14We want to treat the excessive
48:16daytime sleepiness complaint in
48:17these patients and particularly.
48:19As much of the athletes symptoms as possible,
48:22we schedule naps to give
48:23them refreshing apps,
48:24especially if they have not collected Type 1.
48:28We give them stimulants,
48:29we give them tricyclics and SSR
48:31eyes to inhibit the rim nucleus
48:33type of descending pathways onto
48:35the motor tracts and we treat any
48:37disorder in the evening or otherwise
48:39that fragment sleep that can lead
48:41to EDS that can trigger attacks.
48:43'cause these patients are ready at the
48:45get go to have rim or sleeping continents
48:48in an inappropriate time during the day.
48:51So with our initial case are 22 year old
48:54we excluded other causes of sleepiness.
48:56We. Finding normal polysomnogram
48:58we found a very diagnostic MSL T
49:01with sorum's and sleep incontinence
49:03REM incontinence during the day
49:05and we treated with wake promoting
49:07agents Modafinil than armodafinil,
49:09which is a slightly longer half life.
49:12And the patients to contain
49:14complained of cataplexy,
49:15which may often not be recognized.
49:18These patients also are somewhat reclusive.
49:20They're afraid of social interaction,
49:22and there also have an adverse aerial
49:25relationship with many of their doctors
49:27because they asked basically for them.
49:30From them,
49:30these controlled substances which leads
49:32to all sorts of of tough adverse aerial
49:35head-to-head interactions in the office.
49:37So these patients often don't
49:39volunteer the full plate of their
49:41existence was not only do they fail
49:43to be believed by multiple providers,
49:46they lack faith that it will be recognized.
49:49So it took some controlling to get
49:52to the hypnagogic phenomena patient,
49:54really thought that they were going to
49:56be diagnosed with a mental disorder,
49:59but.
49:59When we preempted by telling them that we
50:02expect you probably have this and maybe
50:05you didn't mention to us they opened
50:08right up an SSRI emulated those systems.
50:10So we want to recognize all the subtle
50:13manifestations of these types of
50:15disorders and truly advocate for this
50:17niche of patients that may be truly
50:20reclusive and somewhat marginalized
50:21from mainstream medical care.
50:24In particularly,
50:25these young patients with hypersomnia
50:27idiopathic hypersomnia after ASM last year,
50:29I wanted to study a cohort of these
50:32and these patients who have idiopathic
50:35hypersomnia and narcolepsy not group.
50:38There.
50:40Waso time rivals that of.
50:43Mild, moderate OSA.
50:47And this data is still being analyzed
50:49in under analysis for to be presented
50:52the ASM in a couple of weeks.
50:54So on that note,
50:55I want to close.
50:56I want us all to recognize these patients.
50:59There is a well developed neurobiology
51:02that's being understood by some very.
51:04Detailed.
51:07Neurobiology that is well beyond the
51:09scope and breadth of Emir clinician
51:11like myself and so I I site and cut
51:14and pasted these with the steam.
51:16These state of the art for idio
51:18hypersomnia is an evolution.
51:20And at this point I'll conclude and openly.
51:24Remaining part of the talk to discussion.
51:30Great, well thank you.
51:31Thank you very much like roster
51:33and appreciate a wonderful talk
51:35and thanks for a nice overview of
51:37sleepiness and the general population
51:39through the ages as well as the
51:43various causes of hypersomnia.
51:45And sort of thinking of things that we
51:47beyond what you think about his sleep clinic.
51:50I've seen in the past couple Sonia
51:52and so I have a question.
51:55I was hoping you could help us with and
51:58I see there's also a few in the chat,
52:01so in your experience of treating
52:03these patients other particular
52:05drugs that tend to work better for
52:07a specific cause of hypersomnia,
52:08so idiopathic Arbor summer Snorkel FC
52:10versus that that may perhaps be residual
52:13in somebody who has chronic epilepsy.
52:16It's a very good question.
52:17Recently this came up and we
52:19actually went outside our center
52:20to pull someone at another center.
52:22It's very difficult to tell
52:24because a lot of the stimulants.
52:27Provoke epileptiform discharges.
52:28It's felt without a lot of without
52:32a lot of authoritative evidence that
52:34may be Modafinil and armodafinil.
52:37Might be the safest.
52:39But there's little authoritative
52:41literature on what to do,
52:43which presents a problem.
52:45We always want to be on label and you know,
52:49we at the same time.
52:52With these conditions.
52:53There's a real potential to induce seizures,
52:57even in the.
53:00General population for drugs such as well
53:02buitron which is treating depression.
53:04So there is some cortical excitability,
53:07but what to do authoritatively?
53:09Is we generally start.
53:12These noncardiac talks and not noncardiac
53:15talks stimulants in young patients
53:17in particular because they have a
53:19whole trajectory of life ahead of them,
53:22so we generally don't reach
53:24for Dexedrine spansule's.
53:25Also, there's an addiction potential.
53:28We try to use drugs that have
53:31a smoother but lower peak.
53:34Type of. PK,
53:36which may mitigate sleepiness longer but not.
53:40Cars addiction and may not cause
53:42cortical irritability, but this is.
53:45Not authoritative,
53:46but there's little neurobiology and
53:48research that verifies it's very complicated,
53:50so the weird guy that looks at squiggles,
53:53I mean me, the epileptologist.
53:54The neurologist usually gets these
53:57patients in the sleep clinic.
53:59It's very tough.
54:00We try to advocate and help,
54:02but we are bound by.
54:04The forces of our lack of understanding.
54:08Thank you, thank you very much,
54:11Doctor Robert Thomas from Beth Israel,
54:13lifting and then no new biology of sleep,
54:16wake, explain, or even perhaps we
54:18can speculate on the long sleep or
54:21hypersomnia seasonal affective disorder,
54:23bipolar and depression. In short,
54:25no sleep with bipolar and mania.
54:29It's really interesting and
54:30then the obverse or the inverse.
54:32With client 11 you know that.
54:35What pathways what?
54:36Parallel pathways what part of the
54:39pathways are involved not involved?
54:42Are yet to be figured out we.
54:44Really still don't understand a lot of these.
54:48Diseases, processes, conditions.
54:51Very deep. Question of which I hope.
54:56As we do more research.
54:58You can answer.
54:59I don't know if anyone else has it better.
55:02Understanding about.
55:06You know what is? Idiopathic hypersomnia
55:09we have a normal hypocretin level or or
55:12a third or greater than 1/3 of normal,
55:14but no cataplexy. What part of the
55:16pathway mediates that, if at all?
55:18Or is it a completely separate entity?
55:20I just. You just don't know
55:22and then how do you treat it?
55:24Because there are no.
55:25Or I'm legal drugs for that?
55:27Will you do so we push?
55:30Treating this comorbid psychiatric
55:32conditions and behavioral therapy,
55:33we ally, fortunately enough,
55:35with a very quick cognitive behavioral.
55:38Provider who saves the day.
55:40Many of the times because often these
55:42young patients with hypersomnia they have a
55:45very significant phase delay and they are.
55:48Propagating that and they have self
55:51propagating factors of precipita
55:53or perpetuating factors of.
55:55Of sleep dysfunction.
55:57Insomnia, commingled with these disorders.
55:59So the borderland between
56:01psychiatry and neurology.
56:02I,
56:03I think about Mccarley and what he stood for,
56:07although his adenosine pathway doesn't
56:09quite have relevance in industry and
56:11maybe an effort epiphenomenon, but it's.
56:14It's a marker of something
56:15we have yet to understand,
56:18so that was a very rambly,
56:19long winded answer to that
56:20question or lack of.
56:24I am and so I think we have time for just
56:27one more and there is a related
56:31question to intersection two in
56:33psychiatric disorders and hypersomnia
56:35and is there any relationship between
56:39psychosis and hypersomnia? Well,
56:42yes, I believe. William Dimension Stanford
56:47pioneered those studies years ago.
56:51I don't want to misspeak, but I remember.
56:57When they took graduate students and.
57:00Sweet deprive them, and they did. You know?
57:05Persistence of wakefulness tests in
57:07their site. Piper reaction time,
57:11but if you really sleep deprived someone
57:14you can produce an affective psychosis so.
57:17Where does the circuitry? For that.
57:22Coming on these pathways in the
57:23frontal lobes, we don't know.
57:26Takeover become unleashed.
57:27Where does the neurobiology of of.
57:30From having a normal sleep wake period
57:33to one that sleep deprived where you
57:35become like fatal familial insomnia.
57:38These patients.
57:39Profoundly deranged and I don't know about.
57:43More appropriate medical term,
57:44but they the more sleep deprived
57:46you are chronically,
57:47the more tendency for psychosis do is,
57:49I think that's accepted.
57:52That's why this area is so fascinating.
57:54Maybe 50 years from now.
57:56Some other condition.
57:57It is very demanding.
57:58Patients will have answer.
58:01Great, well thank you.
58:02Thank you for a wonderful talk
58:04and for giving us a chance to
58:06think about hypersomnia and a
58:08little bit of a different way.
58:10They were traditionally approach
58:11it and so with this I'd like to
58:14close the conference and say that
58:15this is our last joint yell sleep.
58:18Harvard Tufts Seminar will
58:19resume our meetings next fall
58:20this coming fall in September.
58:22And then we still have a couple
58:24of meetings left for the Yale
58:26regularly seminars that occur
58:27at 2:00 o'clock on Wednesdays.
58:29And so if you do wish to receive CME credit,
58:32please go ahead and text the code.
58:36To the CME number,
58:37and we look forward to seeing you
58:39guys again in the next Wednesday.
58:42Take care everybody thank you.
58:43Bye bye.