"Idiopathic Hypersomnia Review" Elyana Matayeva (12.02.20)
December 06, 2020"Idiopathic Hypersomnia Review" Elyana Matayeva (12.02.20)
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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.