"Idiopathic Hypersomnia Review" Elyana Matayeva (12.02.20)

December 06, 2020

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00:40So now I'm delighted to introduce
00:42Doctor Eliana, Matt,
00:43Eva as our speaker this afternoon,
00:45Doctor Matt Eva completed her
00:47medical training at the New York
00:49College of Osteopathic Medicine,
00:51an residency at Nassau
00:53University Medical Center.
00:54She was a fellow in pulmonary and
00:56critical care medicine and then
00:58Sleep Medicine at Norwalk Hospital.
01:00In this year joined the faculty at Vassar
01:03Brothers Medical Center in Poughkeepsie,
01:05NY.
01:05She's published several case reports
01:07and chest and is involved in research,
01:10currently examining cases of extrapulmonary
01:13tuberculosis within our hospital
01:14at trial examining the impact of a
01:17vitamin C cocktail for treatment of
01:19septic shock and retrospective observation.
01:21ULL study looking at critical illness.
01:23Polyneuropathy Doctor Montaivo
01:25is scheduled to give this talk.
01:27Last year's asleep fellow,
01:28just as Covid was beginning to
01:30impact Connecticut hospitals.
01:32So we unfortunately had to cancel.
01:34But I'm delighted that she was.
01:37We're willing to return again today,
01:39virtually to provide this review
01:41of idiopathic hypersomnia,
01:42so please join me.
01:43Join me in giving me her
01:45warm welcome this afternoon.
01:47And with that I'll turn
01:49it over to you Eliana.
01:51Thank
01:51God after Tobias, thank you
01:53for giving me this opportunity.
01:55I was excited to give this lecture as a
01:58fellow so this was a literature review.
02:01Part of my fellowship Grand Rounds review
02:04of idiopathic hypersomnia and I do not
02:08have any financial disclosures to give.
02:12So just to give a presentation outline,
02:15as a fellow, I was inspired by
02:17a particular case which I will
02:19discuss today to illustrate age
02:21opathic hypersomnia will review,
02:23but the Physiology will review the clinical
02:25evaluation of the patient contrasted
02:27with narcolepsy type one and two,
02:29and then discuss the some of the treatment
02:32updates as well as emerging treatments.
02:35For for this condition.
02:36So I picked up this patient after
02:39some time that she was already being
02:42evaluated at our Norwalk Sleep Clinic.
02:44This was a 52 year old female who
02:47initially presented for evaluation
02:48of hypersomnia and non restorative
02:50sleep for over 20 years.
02:52So it was interesting that she would
02:54go to bed at 8:00 PM fall asleep like
02:57she would say within 5 minutes or less.
03:00There was no snoring.
03:01No witnessed Apneic episodes by her
03:03bed partner. No gasping for air.
03:05No Brooks is no nocturia and she would
03:08wake up at 7:00 AM with alarm Clock.
03:11What was impressive was her sleep inertia,
03:13which would last more than 30 minutes
03:15at a time to a point where her husband
03:17had to bring her two mugs of coffee to
03:20bed in order for her to kind of start
03:22moving and be able to get out of bed.
03:25She worked in a city and so she
03:27also slept on the way to work on a
03:29train and then she napped another
03:31two to four hours during the day,
03:33try to sneak in her naps at
03:35work strikes again.
03:36If she was home,
03:38she would sleep up to four
03:40hours in afternoon.
03:41She denied a history of cataplexy.
03:44There was no sleep paralysis or
03:46did not hypnagogic hallucinations.
03:48She never had vivid dreams and
03:50freshly couldn't even remember any
03:52of her dreams denied having any
03:55history of Parasomnias her daughter,
03:57who was at this point a teenager,
04:00also has Hypersomnolence Ann.
04:01Mom has Parkinson's no use of alcohol.
04:04No user ballistic drugs or smoking.
04:06She's not on any medications
04:09or an an anti depressants.
04:11Worked in administrations and you know,
04:13takes care of her family members.
04:16Her on a physical exam was
04:19significant for BMI of 30.
04:22Mallampati was two and an
04:24extra conference was 12 inches,
04:26so PSG was done which essentially
04:29essentially showed a good
04:31sleep efficiency of 95.1%.
04:33Sleep onset was 3.5 minutes,
04:35but ram latency from sleep onset was
04:39about 141 minutes or hi was actually 3.5.
04:44So this is just to see the hypnogram
04:47to demonstrate that she rather fell
04:49asleep quite quickly and the RAM on set
04:52was over 90 minutes into her sleep onset.
04:55MSIT was done an what you see here
04:57is that her average sleep latency
04:59was one minute and 30 seconds
05:01and there were no ramsley naps.
05:06So that brings us to Asia Pathic hypersomnia,
05:09which is defined as quote, unquote,
05:12chronic neurologic disorder that manifests
05:15as pathologic daytime sleepiness.
05:17Just to go into histories that in
05:19general lot of things in Sleep Medicine
05:22are more or less young and kind of GNU,
05:25GNU, GNU diagnosis established,
05:27but the first time you get the
05:29Kuiper Sammy kind of gets on this,
05:32our medical map is around 1956 when
05:34Doctor Bedrich Roth Equal was a check
05:36neurobiologists and your physiologists
05:38and sleep researcher identify that this
05:40condition as this sleep drunkenness
05:42and kind of coined this term.
05:45And he thought of it as a symptom
05:48as well as a syndrome in 1966 that
05:51the demands accordingly wrote that,
05:53and I think this is important
05:56because it this takes it apart,
05:58takes it as a separate entity
06:01from narcolepsy.
06:01Those patients without cataplexy or sleep
06:04paralysis holes of failed to show sleep,
06:07onset REM periods in laboratory tests,
06:09probably do not have narcolepsy,
06:11and should be relegated to
06:13another diagnostic category.
06:14Another 10 years.
06:16Dash is by.
06:17Again,
06:17Doctor Roth reports about 642 cases
06:20of patients with narcolepsy and
06:22hypersomnia and coins this term age
06:25opathic hypersomnia is to separate
06:27this patients from narcoleptics
06:28and there are two categories.
06:30There's defined as Paula symptomatic form
06:33where they have excessive daytime sleepiness,
06:36nocturnal sleep duration more than 12 hours,
06:39and sleep inertia,
06:40and then there's a monosymptomatic
06:42form which is basically access
06:45if there are no sleep 1979.
06:47We have a diagnosis or diagnosis
06:51established of idiopathic.
06:53Dennis hypersomnolence and it was
06:54defined quote unquote as a disorder
06:57of excessive daytime somnolence
06:59without irresistible need to
07:01sleep as a scene and narcolepsy,
07:03and again now with saying there
07:05should be no so Rams on PSG.
07:10All. This is a huge opathic hypersomnia
07:13dynamic diagnostic criteria in
07:15the Inter internal international
07:17classification of sleep disorders.
07:18First addition to go over this very
07:22quickly is basically all the following
07:24criteria must be met so they have
07:27to be daily daytime sleepiness.
07:30Which would be present for
07:32at least three months.
07:33No cataplexy,
07:34which becomes very important as to which
07:36are differentiated from narcolepsy type one.
07:39No MSL? T evidence of narcolepsy.
07:42An electrophysiology evidence of
07:43hypersomnolence dis defined as
07:45either mean sleep latency animus
07:47Lt of less or equal to 8 minutes,
07:49or at least 11 hours of sleep for 24 hours,
07:52which could be documented over 24 hour PSG.
07:55I'm not sure how many labs
07:57actually do 24 hour PSG,
07:59but another way to look at it is to
08:02do actigraphy and calculate that
08:04amount of sleep time through that.
08:06One of the most important thing
08:08to do is to make sure we rule
08:11out insufficient sleep time,
08:13which we can do with the Sleep Diaries.
08:16And Actigraphy here is especially important.
08:18No other disorders substance use.
08:20Better explains the symptoms.
08:21So in a way,
08:23it becomes sort of diagnosis of exclusion.
08:28So. If we this this table was published
08:31in Chest in 2015 and it basically kind
08:34of gives you diagnostic criteria in
08:37comparison with narcolepsy type one.
08:40I collected tattoo and idiopathic
08:42hypersomnia and you see that what
08:45connects all of them is this daily
08:48periods of irrepressible need to sleep.
08:51But again, you have mean sleep
08:53latency of less than 8 minutes,
08:55which applies to all of them.
08:58And then the so ramps start
09:00differentiating the narcolepsy,
09:01fromage opathic hypersomnia.
09:03So in idiopathic hypersomnia need to
09:06have fewer than two storms on SLT.
09:08And that's also including the
09:10storm and not PSG itself.
09:14Another way to look is at cataplexy,
09:17but presence of cataplexy
09:19applies to narcolepsy type one,
09:21and there's by default should be no
09:24cataplexy for each opathic hypersomnia.
09:27Yes Sir, for hypocretin one
09:29concentration less than 110.
09:30Guess it's not a very common
09:33diagnostic tool that we use to
09:35diagnose narcolepsy type one,
09:37but it would be that that level is
09:39normal in neck electric Type 2 as well
09:42as idiopathic hypersomnia patients.
09:46Again, Actigraphy has a role in
09:49diagnosing to look at the, you know,
09:52insufficient sleep time versus the
09:54amount of time that patients actually
09:57sleep in a 24 hour period. Very imp.
10:00Wouldn't you always calculate?
10:02Make sure that we don't have insufficient
10:05sleep syndrome and rule out,
10:07maybe even other issues like
10:10psychiatric issue that can predispose
10:13somebody to hypersomnolence as well.
10:16So Epidemiology will prevalence
10:17is not really well known. Why?
10:20Because we don't really have the
10:22robust studies, to my knowledge,
10:24reports are suggestive of idiopathic
10:26hypersomnia being 5 to 1010 times
10:29less common than narcolepsy.
10:30Or is it because we kind of
10:32misdiagnosed it or don't recognize it?
10:35I'm not really sure estimated
10:37to be about 1% of patients in a
10:41neurological respiratory sleep centers.
10:42So going back to the Wisconsin sleep
10:45Cohort basically showed that about 20
10:48three point 838% of men and 22.90% of
10:51women in that cohort showed Msellati
10:53findings of sleep onset of less than,
10:56equal or less than 8 minutes.
10:58We know it's higher,
11:00more prevalent,
11:01and woman an age events at various and
11:04it will range between 10 to 30 years.
11:08So is there genetic predisposition,
11:10family history of excessive sleepiness
11:13or another central hypersomnia
11:15disorder is seen in about 34 to
11:1738% of patients diagnosed with IH.
11:19There is a parent child transmission which
11:22is observed about 12.5% of IH patients.
11:25Or for example,
11:26if there's if these patients don't
11:28carry the official diagnosis,
11:30then you know if you do the history
11:33you'd find out that maybe one of their
11:36parents or first degree relatives would.
11:39Would be sleeping for more
11:40than 9.5 hours per night.
11:45We know that. There is Association
11:48and will between narcolepsy Type 1.
11:50And HLA DQ B 10602 allele and
11:53it's not observed in idiopathic
11:55hypersomnia like I've said before,
11:57CSF hypocretin one concentrations are normal
12:00in patients with each of at the copper.
12:03Sonya well now there is.
12:05There was some, you know discussions
12:07and talks about the role of histamine.
12:13And the reduce use of histamine has
12:15been observed in narcolepsy type one,
12:18as well as IH, but was normally no say.
12:22So this chart is essentially
12:24demonstrates you know the level of
12:27hypocretin levels in narcolepsy.
12:28Type one and you can see
12:31where the blue arrow is.
12:32That tends to be low.
12:34It's, but it's normal.
12:36In narcolepsy,
12:37without cataplexy as well as
12:39normal in idiopathic hypersomnia.
12:44So this was the study done
12:49by Doctor Scott Akashi.
12:52I'm mispronouncing the name and it
12:54basically shows that the lower CSF
12:57histamine levels mostly observed in
12:59non medicated patients and significant
13:02reductions in histamine levels were
13:04observed only in non medicated patients
13:07with hypocretin deficient narcolepsy
13:09with cataplexy and idiopathic hypersomnia.
13:11But then. Um, another study comes
13:15along and kind of disproves this.
13:20So, uh, is CSF.
13:22Histamine biomarker reflecting
13:23the degree of hypersomnia over H?
13:27And basically TMH is a stable metabolite
13:32of histamine and this group has measured.
13:38Histamine levels in CSF in patients
13:40with different ideologists of
13:42excessive daytime sleepiness,
13:44so narcolepsy type ones
13:46narcolepsy without cataplexy,
13:48Type 2 as well as in patients with
13:51age opathic hypersomnia and those
13:54with unspecified hypersomnia.
13:56And when they did their final analysis,
14:00basically they saw no
14:01significant associations.
14:06So then all the glances turned to Gabo.
14:11And you know God is promising.
14:14So I guess I'm starting the slide
14:16saying that there was a study that
14:19looked at 32 hyper somnolent patients,
14:21and so again a function GABA A.
14:24But what does it mean?
14:26So um Garba is receptors are the
14:29major inhibitory neurotransmitter
14:31receptors in mammalian brain.
14:33Just to give a quick background they are
14:37located in the postsynaptic membrane.
14:40And there's fasic,
14:42which is fast inhibition.
14:44Uh, and each is a form of GABAA consists
14:48of five homologous or identical
14:51subunits around an essential chloride
14:55ion selective channel created by Gabo.
14:59We don't know how many isoforms of
15:02these receptors actually do exist.
15:04And these receptors can inactivate
15:06widespread regions of the brain
15:09and therefore dampen consciousness
15:11and therefore regulate sleep.
15:13An obviously GABA A receptors are
15:16responsive to wide variety of drugs.
15:18We all know and use Benzodiazepine's which
15:21are used for sedatives and hypnotic effects.
15:25But then the question is,
15:27you know why is it a sign of hope?
15:31Well,
15:31because we haven't agonist of GABA A
15:34receptors flumazenil which was shown
15:36to improve vigilance and some patients
15:38with hepatic encephalopathy as well,
15:40and those who are sleep deprived.
15:43We don't necessarily know
15:45for sure why it works,
15:47and we also know that the benefit
15:50of this medication is short lived.
15:55Um? So like I said before, you know,
15:59this is a demonstration of the eyes,
16:02a form which is made of two A2 beta and
16:06one gamma subunit, and when the receptors
16:09are activated by the binding of GABA,
16:12the ion channel opens, allowing
16:15chloride ions to pass into the neuron.
16:18Negatively charged ions enter.
16:22In the influx of these negative
16:25charges inhibits neuron firing action
16:28potential and then you get sedation.
16:31Also, GABA is actually known to bind
16:34between Alpha subunit, an beta,
16:36which is was demonstrated on this.
16:39Picture. Um?
16:43And benzos can only buy in
16:46between Gama an Alpha subunit.
16:52So essentially to think about it is
16:54to say deficit of wakefulness means
16:57excessive activity of GABA a system.
17:00And how do we address it?
17:03How do we manage it?
17:05So the team at Emory speak speculate the
17:08existence of this endogenous ligands
17:11that can affect the receptor function.
17:14Essentially, that can normalize
17:16the receptor function.
17:18And they enrolled 10 men and 20 two
17:21women who were who had chronic primary
17:24hypersomnia they have for sleep in a
17:28scale beyond that mean would be about 17.
17:31And despite the fact that they've
17:34had plenty of hours of sleep.
17:37The main subject was what
17:39they were all mostly.
17:40Name it 30s and the mean BMI was 20,
17:43about 25.
17:44And daytime sleepiness was
17:47also confirmed with the MSLT.
17:50So they identify the presence of
17:52endogenous substance in the CSF
17:55of patients with hypersomnolence,
17:57which increases GABA a inhibitory effects.
18:00This endogenous substance was shown
18:02to act to increase the influx of
18:06chloride ions through GABA a receptor,
18:09increase the inhibition of the neuron.
18:13So it does not activate.
18:14There is the government sector itself,
18:16it just makes it more efficient.
18:19An flumazenil prevents the binding.
18:23Um Overture gabaa receptor.
18:26So when it?
18:29When the GABAA receptor is exposed
18:32to this endogenous ligands as well
18:34As for marginals at the same time,
18:37the function of the receptor
18:39returns to normal.
18:40Therefore, be fewer negatively charged.
18:42Chloride ions entering the neuron,
18:44and therefore they will be normal
18:46level of inhibition in less sedation.
18:53Again, benzos benzodiazepine's.
18:54An indulgent molecules are not the same,
18:58and in general more research is needed.
19:02Needed to understand this phenomenon.
19:06Well, the next question is,
19:09is there role of circadian regulation in
19:12hypersomnia and we would be looking and
19:15we know that the circadian master Clock
19:18is located in suprachiasmatic nucleus,
19:21is driven by a network of transcriptional
19:25feedback loops of circadian Clock genes.
19:28Um? There was a study done by Lippert
19:31who basically investigated dynamics
19:33of expression of circadian Clock genes
19:36in dermal fibroblast of patients with
19:38idiopathic hypersomnia had 10 of them
19:41in comparison to those who were healthy
19:44and they saw that there was a circadian
19:47ask ask isolation of Clock genes and
19:49basically these were so you have on the left.
19:53You have healthy controls and a jetpack.
19:55Patients with opathic hypersomnia and
19:57you see that there is a difference in.
20:00Amplitude. Are related to each of the genes,
20:05so amplitude of the rhythmically
20:07expressed genes, BML, 1P1, and P or two.
20:10It was significantly dampened an patients
20:14in A5 internal fab list of patients with IH.
20:18So that suggests that there is an abnormality
20:21in the circadian Clock in iih patients.
20:28So to kind of summarize is you know
20:31so far what I've found in literature.
20:35A lot of it is not definite and
20:38still being studied and investigated.
20:41We know that hypocretin
20:43deficiency is not present.
20:44We know super spinal fluid
20:46from patients with age.
20:48Have been shown to enhance activity
20:50of GABA a GABA A receptors.
20:56Well, the next I guess approach
20:59to look at if there is immunol
21:03kind of immunological effects.
21:06So this was a study by Donna Karan
21:09Honda and they assessed immuno
21:12immunoglobulins IgG profiles in
21:14narcolepsy with cataplexy patients who
21:17had who are positive for each other.
21:20HLA DQ B 10602 allele.
21:23Um, as well as patients with
21:26age opathic hypersomnia,
21:27as well as those who are healthy controls.
21:31So the distribution of serum
21:34IgG significantly differed among
21:36patients with narcolepsy type one.
21:38Those with my age and those
21:41who are healthy controls,
21:43so decreased IgG one decreased IgG 2 levels.
21:47Stable expression of IgG three an
21:50increase in proportion of IgG four
21:53was seen in narcolepsy type one.
21:55However, in contrast to that to
21:58narcolepsy type one and Type 1.
22:01In patients with idiopathic
22:03hypersomnia IgG one and I just do I
22:08did you 2 just imbalance was present.
22:11There was a decrease in IgG.
22:13Two increase in IgG,
22:15three analogy for levels.
22:17And that favors the theory of role
22:22of immunological differences between
22:25type One narcolepsy and idiopathic
22:29hypersomnia and the fact that.
22:33IgG one IgG to ratio.
22:36Energetic hypersomnia.
22:38Uh was increased,
22:40appoints out to a role of type
22:43one helper T cell involvement.
22:50Well, a lot of these symptoms we
22:53have already discussed to this point,
22:55but guess two reviewed one last time
22:57is to say well symptoms of iih,
23:00what to look for when we are
23:03interviewing our patients.
23:04Long sleep duration more than 9 hours.
23:06They've these patients will have
23:08prolonged and unrefreshing naps,
23:10so there tends to be no benefit an
23:12you know prescribing them kind of
23:14scheduled naps is there is benefit
23:16with narcoleptics type one patients
23:19sleep inertia and sleep drunkenness.
23:21Basically the it's to mean prolonged
23:24and pronounced difficulty with awakening
23:27from nocturnal sleep and daytime naps.
23:30Sensation of this brain fog cognitive
23:33dysfunction so 79% of patients
23:36with age report memory problems
23:39and attention problems.
23:44Well, I guess on PSG you know roll out
23:47a sleep related breathing disorder.
23:50One thing to do. Sleep efficiency
23:53tends to be greater than 90%.
23:56They've been proposition of abnormalities
23:58in a slow wave sleep percentage,
24:01and there was a very small
24:03study that suggested increasing
24:05spindle activity in Egypt.
24:07Ethic cover somnia patients
24:09compared to those with narcolepsy.
24:12MSL T shows and mean sleep latency
24:15of equal or less than 8 minutes,
24:17no more than once or anonymous Lt.
24:19OK an I as I've mentioned before,
24:22objectively measured sleep time or.
24:25Sleep off 660 minutes.
24:30So differential diagnosis for ages,
24:32mainly narcolepsy type one and Type 2 and
24:37I think the you know there are a lot of.
24:41There's a lot of overlap in symptoms
24:43between the three of three conditions,
24:46but the biggest one to know is the
24:49cataplexy would only be present in Type 1.
24:52By the definition.
24:55So here we discuss cataplexy.
24:58Excessive daytime sleepiness is
25:01present in all three sleep paralysis.
25:05Is present mostly in type one type
25:09two and only 20% of idiopathic
25:12hypersomnia patients sleep.
25:14Hallucinations again mostly
25:16present in type one.
25:18Narcoleptic patients in about
25:2025% of patients with IH.
25:23And having all these symptoms together
25:26kind of brings you more to diagnosis
25:29of narcolepsy type one and not so much
25:34of idiopathic hypersomnia narcolepsy
25:36Type 2 fragmented nocturnal sleep,
25:39so people with narcolepsy type
25:421 have lower sleep efficiency.
25:45But it's not typical in patients
25:47with age opathic hypersomnia,
25:49REM sleep behavior disorder may be
25:52seen in type one or collect ICS.
25:55It hasn't really been studied
25:57in those with IH.
25:59Um, sleep drunkenness is tends to be
26:03rare in narcolepsy, but common in age.
26:08Opathic hypersomnia.
26:09Um?
26:10Glow nocturnal sleep times armor
26:12would be unaware side for narcolepsy,
26:15but more common for idiopathic
26:17hypersomnia and the fact that naps in
26:20it's very subjective kind of to ask,
26:22do you feel refreshed or not?
26:24But Narcoleptics will tell you that
26:26the naps tend to be refreshing for
26:29them while they're not refreshing.
26:31For patients with idiopathic hypersomnia
26:34and they tend to take long naps.
26:37So how can you know this umbrella
26:42of differential diagnosis for
26:44hypersomnolence is is huge?
26:47You know you start with,
26:49well.
26:49Is there insufficient sleep time
26:51you consider delayed sleep phase syndrome?
26:54Hypersomnia may happen due to
26:56medical issues such as Parkinson,
26:58My atonic dystrophy and hypersomnia
27:00is can occur also due to psychiatric
27:03issues and it's interesting that.
27:06Looking at the Diagnostic and
27:08Statistical Manual of Mental Disorders,
27:115th edition,
27:12hypersomnia is an optional clinical
27:15diagnostic criteria of several mental
27:17disorders and that would be included,
27:20including bipolar one Bipolar 2,
27:23which is more typical for bipolar 2.
27:28So patients with major depressive disorder,
27:32persistent depressive disorder,
27:34patients with schizoaffective disorder
27:37on other spectrum of schizophrenia,
27:41these patients will have this unusually
27:45high Epworth sleepiness scale.
27:49But what's important about them is this.
27:51This degree of sleepiness
27:52tends to vary from day to day.
27:55An night sleep tends to be very poor quality.
27:59Someone will report insomnia and again
28:02objective hypersomnolence is not
28:04going to be demonstrated on an SLT.
28:07And Hypersomnolence going back
28:09to Parkinson's hypersomnolence
28:11effects about observed in 16 to
28:1450% of patients with Parkinson's,
28:16and about 28% of patients who
28:20have my atonic dystrophy.
28:24Also, even viruses can produce both
28:27somebody to hypersomnolence like viral
28:30pneumonias infectious mononucleosis,
28:32hepatitis B Valley virus,
28:34Guillain Barre syndrome. Um?
28:37So the the the differential
28:41diagnosis is pretty big.
28:44And those who are loan sleepers but
28:46loan sleepers will feel refreshed
28:48after a long time sleeping.
28:51So this is was mostly kind of endorsed by the
28:54patients who have age opathic hypersomnia.
28:57So we want to ask,
29:00you know what helps you treatment wise.
29:03Um, you know,
29:0582% of patients will say,
29:07well, coffee, caffeine.
29:10It's interesting Lee,
29:11but you know 81% of patients still say that,
29:15yeah, daytime naps they feel
29:17subjectively that they help
29:19scheduling of their nocturnal sleep.
29:22Anne, it's very important with
29:25patients who have hypersomnolence
29:27to strongly advise and recommend
29:30to avoid operating heavy machinery.
29:34Due to increased risk of accidents.
29:37So um, pharmacologic treatment well?
29:42There are currently no medications
29:45that are officially approved by
29:48FDA for specific specifically
29:50for the treatment of IH.
29:53So you know what?
29:54What do we do?
29:55Well,
29:56we we treat it like hypersomnolence
29:58like we would address in Narcos.
30:00Sing so stimulance and these are very common,
30:06frequently used so we have methylphenidate,
30:09which blocks reuptake of norpin Efron
30:13dopamine into presynaptic neurons and the
30:16side effects would include irritability,
30:19insomnia, GI upset psychosis.
30:21Hypertension,
30:22palpitations and then there
30:25is suggestion feta mean.
30:28Which promotes the release of dopamine,
30:30an open a friend from their
30:31storage sites in a person optic
30:33nerve terminal and the side
30:34effects would be similar.
30:38And we have a wakefulness
30:40promoting medications,
30:41and there is Modafinil which increases
30:44the dopamine levels in the brain by
30:47binding to the dopamine transport
30:49inhibiting dopamine reuptake.
30:51And then we have armodafinil,
30:53which is our anatomy of Modafinil and
30:57both have the side effects of headaches,
31:00nausea, insomnia, nervousness.
31:02And the biggest thing to advise to your
31:06patients is must use birth control.
31:08Other than or in addition
31:11to contraceptive pills.
31:18On you other some new wakefulness
31:21promoting medications we have so nosey.
31:24Which is a dopamine opener
31:26friendly uptake inhibitor,
31:27an ad shown to improve sleepiness in
31:29narcolepsy type one and two as well
31:32as excessive daytime sleepiness in
31:34patients with obstructive sleep apnea.
31:37Side effects include headache,
31:38nausea, decreased appetite,
31:40increased anxiety, and psychosis.
31:42Contraindicated in patients who
31:44take monoamine oxidase inhibitors
31:46due to hypertensive reaction,
31:48and may be used with ocps safe to use.
31:55Another new kid on get relatively new kid
31:58on the block is Patella St Way kicks.
32:01It's an H3 inverse agonist
32:03like an antagonist,
32:04therefore increases the
32:06level of histamine in CSF.
32:08And it's indicated for the treatment
32:11of excessive daytime sleepiness
32:12and narcolepsy type one and two.
32:14What's great about it is that
32:16it's not a controlled substance,
32:18and there's a minimal risk of abuse.
32:21But again,
32:22must use birth control other than or
32:24in addition to contraceptive pills,
32:26adverse effects, insomnia, anxiety, mostly.
32:30And.
32:33New therapies are looking at treating
32:38GABA related hypersomnia essentially.
32:40Um so. I've mentioned it in
32:44the beginning of this talk.
32:47The role of flumazenil for the treatment of.
32:51Hypersomnolence and you do about the cover.
32:53Sonia and this was the study.
32:56Which looked at 153 patients which had
33:00hypersomnolence due to domestic abuse,
33:04Anya and other conditions so
33:06little it looked at evaluation of
33:09cerebrospinal fluid from patients
33:12whose hypersomnia persisted despite
33:15trying wake promoting medications.
33:20And basically you know they
33:23have increased GABA current.
33:28Sorry. Our increased garbled current.
33:32There's a issue with the GABA,
33:36a lag and and this increased activity of
33:40that current can obviously be reversed
33:43with using flumazenil and they did.
33:46Intravenous injection of flumazenil,
33:49which improved objective measures of
33:51vigilance and reduced subjective sleepiness.
33:57So as you can see, they looked
34:00at the CSF of patients with
34:02narcolepsy type one and two patients
34:04with idiopathic hypersomnia.
34:05They had a 30.
34:07Six of them are patients with
34:10obstructive sleep apnea with
34:11hypersomnolence an as well as
34:14other hypersomnolence as well.
34:18So they they gave flumazenil sublingually
34:21about 6 milligrams to these patients and
34:25the starting dose was about 6 milligrams,
34:28four times a day, and then they titrated to
34:32the effective dose or total of 12 milligrams
34:36four times per day so that those would
34:40not exist exceed 60 milligrams per day.
34:43And in between. If they still had.
34:46Issues with sleeping as
34:48they were also prescribed.
34:50Aflam adonal cream.
34:53Which would be applied to the forms
34:56at bedtime, or four times a day,
34:59if the sublingual dose was not enough.
35:06All. So 96% on 96 patients out of 153 with.
35:15Hypersomnolence reported improvement
35:16of excessive daytime sleepiness,
35:19one treated with flumazenil so
35:21prior to initiating flumazenil,
35:24the average score was a 1515.1,
35:27even though these patients were
35:31already taking wake promoting agents.
35:35An after the treatment average score
35:38dropped by about four to five to 10.3,
35:42which which is significant.
35:44Um and 59 patients.
35:46Out of these, 96 continued on taking the
35:50medication at the seven months of follow up.
35:54And the. Affect persisted.
35:59So it's interesting,
36:0072% of women reported a
36:03positive response to the drug.
36:05Whereas only 48% of men had a positive
36:09response and those who had the most
36:13significant sleep inertia were the
36:15ones whom were more likely to respond.
36:19Side effects observed,
36:21dizziness, anxiety, headache.
36:25Um? Another oh,
36:29another medication that was looked at.
36:33And the biotic clarithromycin.
36:37Because it is also to happens
36:39to be a negative allosteric
36:41modulator of the GABA a receptor.
36:44OK, so this was a two week randomized
36:48placebo controlled double blind
36:50crossover trial of clarithromycin
36:52500 milligrams which was taken with
36:55breakfast as well as lunch in patient
36:58with hypersomnolence syndromes.
36:59But they excluded those
37:02with narcolepsy Type 1.
37:04Um, and these patients had evidence
37:07of abnormal cerebral spinal fluid
37:09potentiation of GABA A receptor,
37:11and the primary outcome measure
37:14was median reaction time on
37:17psychomotor vigilance task at 2 E.
37:20At week two.
37:21And the secondary outcome was
37:24Epworth Sleepiness Scale.
37:26So subjects were randomized
37:28such as equal number received
37:30each intervention first.
37:32So 10 received clarithromycin.
37:35First an Jen received placebo.
37:38And then there was a switch.
37:45And looking at it, you'd see that
37:48with PPT there was no improvement,
37:51but it upward sleepiness
37:53scale decreased four points.
37:59So there was a benefit in 64% of patients
38:03and 38% of patients continued therapy.
38:05When I when I spoke to the lab,
38:09they basically told me that at that
38:11time at least they were about six
38:14months of continuation of therapy and
38:17adverse effects that were reported
38:19would be GI side effects, taste,
38:22perversion as well as antibiotics resistance.
38:26Sirem
38:29this was a chart review.
38:32AC and clinical series of
38:34treatment of refractory patients.
38:37So they had 46 H patients,
38:40247 patients with narcolepsy
38:42type one and they showed that it
38:46actually decreased essm between
38:48three to four and a half points.
38:52But the mean those in Egypt hypersomnia
38:55patients was 4.3 grams per night,
38:57which is lower than the ones given
39:01to patients with narcolepsy Type 1.
39:04And of course,
39:05the biggest things to console and discuss
39:07with your patience is respiratory depression.
39:10You know chance of abuse of this drug,
39:12respiratory depression?
39:13Um, as well as a central
39:16nervous system depression.
39:18Side effects.
39:20While most side effects would be
39:23patients don't like the taste of it,
39:26nausha is probably the most common one.
39:29Dizziness, headache.
39:35So now circling back to where we
39:38started from the current day.
39:40A lot of treatment options were
39:42discussed with this patient and she
39:45is more reluctant to worthless,
39:47wasn't more left and to try new things.
39:51She was on armodafinil 150 milligrams,
39:54which it took at 7:30 AM.
39:59She's reported some residual.
40:01Sleepiness and reported
40:03having some insomnia symptoms.
40:06Um, trying different doses was
40:08about the same effect for her,
40:10but her essm range between 9:00
40:12and 12:00 and for her that meant
40:15being functional during the day
40:17and being able to carry on through
40:20her daily activities.
40:21Thank you.
40:31Great, thank you so much for
40:32that presentation Eliana.
40:33I just want to open it up to questions.
40:38And I think I'd love to
40:40hear about anybody else.
40:42Is kind of experiences with the practical
40:44approval of some of these medications.
40:47You know, there are these specific
40:50com pounding pharmacies that are
40:52needed to get these formulations
40:54of medications and I know some
40:57of us have tried to do this,
40:59but I invite anybody to kind of share
41:02your own anecdotes about how that's
41:05worked and what the efficacy has been.
41:08With that and then ask,
41:10ask any questions to Eliana.
41:26Hello Andy Petroff I'm a
41:31neurologist and epileptologist.
41:34The flumazenil, at least you can have
41:37there been any pet studies on it?
41:41'cause there is a ligand and it's
41:44available here and variety of other places.
41:48So are there any differences
41:51with the hypersomnia in terms
41:54of the flumazenil binding?
41:56The related question, of course,
41:59is that flumazenil preferentially binds
42:01to microglia engliah rather than neurons,
42:04so it isn't very specific
42:06for Gabaergic neurons.
42:09I'm not familiar with the pet studies.
42:11I did not look at those when I was doing
42:14my literature review, and honestly. Um?
42:19I mean, I would my assumption would be
42:21that it had to be at least. Similarly,
42:24I don't know if you can add on to that.
42:30Well, as I said,
42:32the other related question,
42:34did the Emory people discussed the
42:37molecular weight of this endogenous
42:40pro GABA a receptor function agent?
42:43Is that a protein?
42:46Is it more than 600 Daltons,
42:49or is it a small molecule?
42:55I would have to review that again actually.
42:58Right and the? Has there been
43:02any work using the new histamine
43:07promoting agent or inverse
43:10agonist of histamine in this?
43:15Idiopathic hypersomnia hasn't been
43:16used as the beneficial effect.
43:18I, from my knowledge, as
43:20far as that is, you know,
43:23we tried to use it and not collapse.
43:26It has some effect, but I don't
43:28think we know for sure effective it
43:32in idiopathic hypersomnia. Yeah,
43:34I don't believe we're
43:36talking bout Petola sent.
43:38I think I don't believe that that was
43:42this approved for age specifically.
43:45Although I don't know if anyone
43:47else has had experience using it,
43:49I have not used it in patients other
43:51than those with narcolepsy personally.
43:57Thank you very nice talken.
44:01Not really aware of these newer
44:04developments and I appreciate
44:06the review and the update.
44:09Thank you yeah. What
44:11do you think?
44:12Doctor Montaivo about the diagnosis of IH?
44:14I've suspected personally that
44:16we're probably missing this,
44:17and in some patients where
44:19we get an MSL T in it,
44:22you know sometimes shows a
44:24short mean sleep latency.
44:25But if we don't see the store and then
44:28we have an alternative explanation
44:30for a short mean sleep latency,
44:33and sometimes we suspect sleep deprivation,
44:35or if we don't have actigraphy.
44:38We chalk it up to to not having had
44:42sufficient sleep leading up to the study.
44:44Do you think we're missing this,
44:46or is it truly quite a rare diagnosis?
44:49I think
44:50it's not as rare. I think we just
44:52kind of looking for narcolepsy.
44:55And if we don't see the
44:57evidence of it on our testing.
45:00Then you know we either just saying,
45:02well, you don't have narcolepsy or
45:04we kind of don't think too often to
45:07consider idiopathic hypersomnia you know
45:09we started thinking about other things.
45:11Could this be medications or
45:13the use of illicit drugs?
45:15Or some kind of psychiatric
45:17comorbid disorder?
45:17And I guess a lot of these
45:20people having this issue do
45:22present with depression as well.
45:24And psychiatric issues.
45:27Yeah yeah, very
45:28common for that.
45:29And in a narcolepsy to see depression,
45:31right? Or a great well if there's
45:35no other questions, I think well,
45:37well and there and thank you so much.
45:40I just want to let people know what the.
45:44That talk is for next week,
45:46so December 9th we're going
45:48to have our next joint,
45:50Harvard Yale Conference,
45:50and it's going to be on the cost of
45:53insufficient sleep with Janet Mulligan,
45:55who is a professor of neurology
45:57at Harvard Medical School in Beth
45:59Israel Deaconess Medical Center.
46:00So please join us for that.
46:02That is our next to last
46:04talk for the semester,
46:06which I feel like has just flown by then.
46:09Thank you everyone and have a
46:11great rest of the afternoon.
46:12Thank you. Bye bye.
46:15Thank you bye.