"Narcolepsy: Review and Update on Treatment" Glenda Bowen (05.05.2021)

May 16, 2021

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00:15Alright, good afternoon everybody.
00:16I think we're going to get started here.
00:19I'm Lauren Tobias and I'd like
00:21to welcome you to our Yale
00:23Sleep Seminar this afternoon.
00:24Just a few quick announcements
00:25before we get started.
00:27Please take a moment to
00:28make sure that you're
00:29muted in order to receive CME credit for
00:32attendance, please see the chat room.
00:34For instructions, there's a unique
00:36idea that you can
00:37chat that you can text anytime.
00:39Up until 3:15 PM today,
00:41and if you're not already
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00:44me will need to do that first.
00:46If you have any questions during
00:48the presentation, please feel free
00:49to make use of the chat room throughout
00:52the hour. Or you can unmute yourself and
00:55speak at the end and ask your questions.
00:57And please feel free to share
00:59announcements about this lecture
01:01series with anyone who you
01:02think may be interested. Or
01:04you can contact Debbie Lovejoy directly to.
01:06He added to our email list,
01:09so with that I'm going to turn it
01:13over to Doctor Mayer Creaker who is
01:16going to be introducing our
01:18speaker for this afternoon,
01:20so I'm delighted to introduce Glenda Bowen
01:23Ann and she's a Sleep Medicine fellow.
01:27Glenda went to medical school in Honduras
01:30and she interned in internal medicine in
01:33Danbury Hospital at the Yale program there.
01:37Did her residency there became chief resident
01:39and did a fellowship in pulmonary and
01:42critical care at the University of Vermont,
01:46and this year is a Sleep Medicine of
01:49fellow and she's currently board certified
01:52in internal Medicine pulmonary medicine.
01:55And she's going to be taking the
01:58critical care exams next year.
02:00Sleep Fellowship exams this year
02:02and and she's going to be not that
02:06far from us when she graduates.
02:08She will be in in practice and
02:11in western Massachusetts,
02:12and we hope to keep in contact with her.
02:16So Glenda is going to tell us
02:18everything we need to know about the
02:21diagnosis and management of narcolepsy.
02:23There been some exciting?
02:25A developments in that area,
02:27we're gonna hear from Glenda right now,
02:30Linda. Take it away.
02:33Thank you Doctor Krieger for your
02:36introduction, so I guess I'll
02:38just kind of get right to it.
02:41So narcolepsy is a disorder that causes
02:45a disabling level of daytime sleepiness.
02:49Our understanding of the pathogenesis and
02:52the clinical nature of narcolepsy has grown
02:55exponentially in the last two decades.
03:02During this talk.
03:05I want to review the
03:07pathophysiology of narcolepsy.
03:08I'll outline the diagnostic
03:11criteria of the disease.
03:13Talk about prognosis and goals of treatment.
03:16And review the recently updated
03:18practice parameters of the ASM
03:20for the treatment of narcolepsy,
03:23which include novel drugs that have
03:25recently been approved by the FDA.
03:31So here is the obligatory disclosure slide.
03:34I have no conflicts of interests.
03:40So you can text 21626 to 2034429435
03:43to record your attendance. I believe
03:46these instructions are in the chat.
03:53So I want to start with the case.
03:56A young lady that I saw
03:58as a brand new fellow.
04:00Miss Ma is 19 years old and she presented
04:03with excessive daytime sleepiness
04:05and episodes of acute onset loss of
04:09muscle tone that last less than a
04:12minute and are triggered by laughter and joy.
04:15These cataplexy episodes happen
04:17almost on a daily basis.
04:20She can sleep on demand.
04:22Her Epworth Sleepiness Scale is 19.
04:25She frequently misses social and family
04:28events because of excessive sleepiness.
04:31She must nap two to three hours in the
04:34afternoon to function in the evening.
04:36She schedules classes and
04:38workshops around her naps.
04:40If she doesn't nap,
04:42she can have two to three cataplexy
04:44episodes a day and her first
04:47cataplexy episode was at age 13.
04:49She has vivid dreams and excellent dream
04:52recall after naps and she doesn't snore.
04:59She had mononucleosis.
05:00When she was a teenager,
05:02she doesn't take any medication.
05:04She does have a project and IUD in place.
05:07She is a non smoker and drinks socially.
05:09She is in college and works as
05:12a waitress in the evenings.
05:17On physical exam she has normal
05:20vital signs for BMI is 23.3 and
05:23she's oh and overall healthy female
05:26with a normal physical exam.
05:29Given her degree of sleepiness,
05:31a PSG Ms Lt was ordered to work up
05:33a hypersomnia of central origin.
05:39This is the hypnogram from
05:41her diagnostic polysomnogram.
05:42We can see sleep stages at the top.
05:47Followed by micro arousals,
05:49the third graph depicts
05:51Apneas and High Papias,
05:53and finally her oxygen saturation levels.
05:56Her total sleep time was 455 minutes
05:59and her sleep efficiency was 91.6%.
06:03Her sleep latency was reduced at 4.5 minutes.
06:06Her REM latency was 5.5 minutes.
06:09She had six R.E.M periods.
06:11Her arousal an awakening
06:12index was 15 an hour.
06:14There was no evidence of sleep
06:17disordered breathing or periodic limb
06:19movements of sleep and her oxygen levels
06:22were normal throughout the night.
06:27She had a multiple sleep latency
06:29test the following day where she
06:32had three opportunities to nap.
06:34She slept during all Maps
06:35and her mean sleep latency.
06:37Her average mean sleep latency for
06:40these naps was 1.5 minutes and
06:42as you can see in the hypnogram,
06:45she had sleep onset REM periods or
06:48saw ramps during all three naps.
06:51A sorum is a ramp period that occurs
06:53within 15 minutes of sleep onset,
06:56including the sleep onset REM period that
06:59she had on the PSG on the prior night.
07:02She had a total of four saw reps.
07:06Given her clinical findings of excessive
07:08daytime sleepiness and cataplexy,
07:09as well as her PSG MSL T findings
07:12of mean sleep latency of less than
07:148 minutes and two or more storms,
07:17she was diagnosed diagnosed
07:19with narcolepsy Type 1.
07:24As a brand new sleep fellow,
07:25I was very excited about this case.
07:27She was the first patient with
07:29narcolepsy I ever took care of.
07:32I wondered how much I could
07:34improve her symptoms.
07:35I wondered what her prognosis was.
07:37What are the therapeutic options
07:39for patients with narcolepsy
07:41and what would be the best
07:43treatment specifically for her?
07:45What are the goals of therapy
07:47when treating these patients?
07:53As I learned about the disease,
07:55I came across this case report
07:58written in 1906 by Doctor Rogers.
08:01And he, when he describes narcolepsy,
08:03he writes. By narcolepsy I wish
08:06you to understand a condition.
08:09In which a patient with almost
08:12lightning like rapidity false
08:14into a sleep of short duration,
08:16the condition not being one of epilepsy.
08:23Narcolepsy is characterized by
08:26daytime sleepiness, cataplexy,
08:27and striking transitions from wakefulness
08:31into rapid eye movement sleep.
08:34It nearly always has profound
08:36and potentially disabling
08:38effects on affected patients.
08:40The incidence is anywhere
08:42from 20 to 67 per 100,000,
08:45and the ICS definition of narcolepsy
08:48states that the subject must have
08:51periods during the daytime in which
08:54there is an irrepressible need to
08:57sleep or actual lapses into sleep.
09:00Occurring for at least three
09:02months on a daily basis.
09:09In 1998, the CIA and colleagues
09:11identified a gene expressed in neurons
09:14in the paraventricular hypothalamus,
09:16which encoded for a proprotein
09:18precursor of two peptides that had
09:21features of neurotransmitters.
09:23Due to its hypothalamic expression
09:25pattern and the similarity of the
09:28peptide sequences to members of
09:30the Incretin family of hormones.
09:32It was named the hypocretin gene.
09:35Its function was unknown.
09:37One month later,
09:39Sacchari identified two peptides in
09:41the lateral and posterior hypothalamus,
09:44a brain region implicating
09:46in promoting feeding.
09:48They called these peptides or
09:50X and a an erection B from the
09:53Greek word orexis for appetite.
09:55These two groups simultaneously
09:57discovered the same neurotransmitter
09:58and gave it different names.
10:00I will use hypocretin,
10:02anorex and interchangeably
10:03throughout my talk.
10:08A year later. Chameli showed that
10:11orexin knockout mice exhibited behavior
10:13similar to humans with narcolepsy.
10:16The scientists documented frequent
10:18episodes of periods that what they called
10:21behavioral arrests in ereckson null
10:24mice using infrared video photography.
10:27As mice are active at night
10:30and sleep during the day.
10:33This graph depicts data for
10:35individual knockout mice,
10:36designated A through eye on the Y access.
10:40The columns represent the total
10:42number of episodes of behavioral
10:44arrest recorded in the first four
10:46hours after onset of darkness,
10:48and the measurements are depicted
10:51in the X axis to the left.
10:53The filled circles represent the mean
10:56duration of all reported episodes.
10:58The measurements depicted in
11:00the X axis to the right.
11:03The first column depicts the whole group,
11:06which had a mean number of 17
11:09behavioral arrests in four hours,
11:11lasting about 60 seconds.
11:13That same year,
11:15a group in Stanford University showed
11:17that a heritable form of canine
11:19narcolepsy is due to a mutation in
11:21the hypocretin receptor 2 gene.
11:27Soon after, researchers found that
11:29narcolepsy is caused by a highly
11:31selective and severe loss of the
11:33hypocretin neurons that results
11:35in low levels of hypocretin in the
11:37brain and the cerebral spinal fluid.
11:40I know this is a busy slide,
11:42but I wanted to show you in this study
11:45hypocretin was measured in the CSF of
11:48nine people with narcolepsy an 8 controls.
11:51The first nine rows in this table depict
11:53data for the narcoleptic patients.
11:56As you can see in the column to the far
11:58left seven of nine narcoleptic patients
12:01had hypocretin concentrations that were
12:04below the detection limit of the essay
12:06compared to normal levels in the controls.
12:12So how do orexin neurons maintain wake?
12:17Depicted in the figure and dark blue,
12:20these neurons excite various wake,
12:22promoting neurons,
12:23including those in the cortex.
12:25Basil, forebrain, tubero,
12:27mammillary nucleus,
12:27the jungle of pontine and
12:30lateral dorsal tegmental nucleus,
12:32dorsal Rath and Locust arulius.
12:34They heavily innervate several regions that
12:37promote arousal and suppress REM sleep,
12:39but maintaining weight is not the
12:43only function of orexin neurons.
12:46These neurons are influenced by input
12:49signals related to sleep wake states,
12:52circadian phase, motivational cues,
12:54and visceral cues such as hunger or thirst,
12:57and they innervate many brain regions.
13:01Their activity will ultimately result
13:04in long periods of wakefulness,
13:07suppression and regulation of REM sleep,
13:10enhanced responses to rewards,
13:12increased locomotion,
13:13and increased autonomic tone.
13:18But going back to the fact that narcolepsy
13:21is caused by the loss of orexin neurons.
13:25What causes this loss is
13:27destruction of these neurons.
13:29The first clue for an autoimmune disease
13:32etiology and narcolepsy was observed
13:35in the 1980s when a strong Association
13:38with HLA D R2 haplotype was discovered.
13:41Narcolepsy type One has the
13:44tightest HLA link in any disease.
13:46With the class 2D QB,
13:4810602 allele conferring an increase
13:51of an increased risk of 200
13:54fold of acquiring the disease.
13:56In those Houma Sigusr for this allele,
13:59the risk is doubled compared
14:01to that of heterozygous.
14:07In 2009 to 2010, a striking increase in
14:11narcolepsy cases was seen in Northern Europe,
14:15especially in children.
14:16This increase was quickly traced
14:19back to a widespread vaccination
14:22campaign against H1N1 Influenza,
14:24A that used a vaccine brand called Pandemrix.
14:30A meta analysis by Sarkan and included
14:33eleven studies that evaluated the risk
14:35of narcolepsy or the number of narcolepsy
14:39cases after Pandemrix vaccination.
14:41During the first year after vaccination,
14:44the relative risk of
14:45narcolepsy was increased.
14:465 to 14 fold in children and adolescents
14:49and two to seven fold in adults.
14:52In the countries where the
14:54Pandemrix vaccine was widely used.
14:59The most likely culprit,
15:02immune mediator of narcolepsy is
15:05likely CD 4T cell activation.
15:08This is a proposed model of T cell
15:12mediated killing of orexin neurons.
15:15An antigen presenting cell. Purple.
15:19First takes up a pathogen and
15:22presents fragments of pathogen
15:24proteins to a naive CD 4T cell.
15:30Seen here in light blue.
15:32It does this using a major
15:35histocompatibility complex Class 2 molecule.
15:38Perhaps the QB 10602?
15:40The naive CD 4T cells secrete
15:43cytokines to help clear the infection.
15:47Memory CD4T cells are formed
15:50from that initial infection.
15:52And then these activated memory CD4T
15:55cells cross recognized fragments of
15:58prepro orexin with the pathogen peptide
16:01and secrete cytokines that promote
16:04destruction of the orexin neurons.
16:07We have learned so much
16:10about narcolepsy Type 1.
16:12But what about narcolepsy Type 2?
16:15This remains one of the largest mysteries.
16:19Besides a lack of cataplexy,
16:21the symptoms of narcolepsy Type 2 are
16:24similar to those of narcolepsy type one.
16:27CSF ereckson levels are usually normal.
16:30It may be caused by a modest
16:33loss of erection, neurons,
16:35or a completely different process.
16:37Almost nothing is known
16:39about its neuropathology.
16:41Moving from pathophysiology
16:44to clinical features.
16:47Narcolepsy falls into the category of the
16:51Central disorders of Hypersomnolence.
16:54These include narcolepsy,
16:55type one narcolepsy,
16:56Type 2 and idiopathic hypersomnia,
16:58which I will refer to as IH.
17:04The common clinical feature among
17:06these is severe sleepiness,
17:08despite normal quality and timing of sleep.
17:12Cataplexy practically defines narcolepsy
17:14type one, and is absent in narcolepsy.
17:18Type 2 and IH. Sleep paralysis and sleep.
17:24Hallucinations are more
17:25common in narcolepsy type one,
17:27but can be seen in narcolepsy.
17:30Type 2 and IH.
17:33Fragmented nocturnal sleep is much
17:36more characteristic of narcolepsy
17:38and not typically seen in IH.
17:41REM sleep behavior disorder an REM
17:43without a tonia are seen in more than
17:46half of narcolepsy type one patients
17:48and in some patients with narcolepsy.
17:50Type 2.
17:53Sleep drunkenness is rarely
17:54seen in narcolepsy type one,
17:56sometimes seen in narcolepsy type
17:582 and is almost a hallmark in IH.
18:04Long nocturnal sleep times are seen
18:06in less than 20% of patients with
18:08narcolepsy, but are very common in IH.
18:13Naps are usually short and
18:16refreshing in narcoleptics,
18:17unlike in patients with idiopathic
18:19hypersomnia that have unrefreshing naps.
18:24But going back to the phenomenon of
18:28cataplexy, as I previously mentioned,
18:31this basically defines narcolepsy Type 1.
18:36The cataplexy episodes generally start
18:38with weakness in the neck or facial
18:41muscles before descending paralysis of
18:43voluntary muscles ensues over a few seconds.
18:46This happens usually in the
18:48context of an emotional stimulus.
18:50Usually a positive emotions
18:52such as joy or laughter.
18:54This picture illustrates the
18:56proposed mechanism of cataplexy.
18:58So the blue lines indicate
19:00activation of a neural pathway.
19:02The red lines indicate an inhibitory
19:05pathway and the dotted lines
19:07reflect lack of normal neural
19:10activity resulting from hypocretin
19:12deficiency due to narcolepsy Type 1.
19:14So positive emotions are processed
19:17in the prefrontal cortex,
19:19with activation of both the amygdala
19:22and hypocretin containing neurons
19:24within the lateral hypothalamus.
19:26In the absense of hypocretin neurons,
19:29there is reduced activity in brain
19:33regions that inhibit REM sleep.
19:36Causing increased activity in neurons.
19:38Promoting REM sleep atonia.
19:41Motor neurons are inhibited,
19:43and then cataplexy ensues.
19:49Moving on to the clinical classification.
19:51As I previously mentioned,
19:52narcolepsy falls into the Group of
19:55Central Disorders of Hypersomnolence
19:56and it is then divided into narcolepsy,
19:59type one and narcolepsy Type 2.
20:02With cataplexy and CSF hypocretin
20:05deficiency differentiating
20:06narcolepsy type one from Type 2.
20:12These are the criteria for diagnosis
20:15for not narcolepsy from the Icst 3.
20:18For narcolepsy type one, one or both of
20:22the following criteria should be met.
20:25The CSF hypocretin one concentration
20:27should be less than 110 picograms
20:30per ML or less than 1/3 of mean
20:34values obtained in normal subjects.
20:372nd. The presence of cataplexy with
20:41the mean sleep latency of less than
20:448 minutes with two or more sleep
20:47onset REM periods seen on PSG MSL T.
20:50For narcolepsy type 2.
20:52All four of the following criteria
20:55need to be met met.
20:56A mean sleep latency of less than 8
21:00minutes with two or more storms seen
21:02on PSG MSL T. Cataplexy is absent.
21:05Either hypocretin and CSF has not
21:08been measured, or if it has been,
21:11the level is over 110 picograms per
21:13ML or over a third of the normal
21:17value and last hypersomnolence and
21:19the MSL T findings are not better
21:21explained by other causes such
21:23as short sleeve shift work,
21:25sleep disorder,
21:26breathing medications or other substances.
21:31A brief word on CSF sampling and HLA testing.
21:37HLA DQ B 10602 positive ITI is 92100% in
21:41patients that have definite cataplexy,
21:43but it decreases with atypical
21:45cataplexy or in patients that
21:48don't have cataplexy do about 40%.
21:50It's important to keep in mind that
21:53about 20% of the general population
21:56who does not have cataplexy carried
21:59the exact same HLA subtype,
22:01so HLA testing should not be
22:04used to diagnose narcolepsy.
22:07Measuring hypocretin levels can
22:08provide a definitive diagnosis.
22:10In the right clinical context,
22:12but it is not always necessary to
22:14measure the hypocretin levels.
22:16If you have cataplexy in the
22:18characteristic PSG MSL T findings.
22:21Low hypocretin levels are diagnostic
22:23for type One narcolepsy,
22:25but normal levels don't rule out the disease.
22:30I want to talk about goals of treatment.
22:33So even on optimal conventional treatment,
22:36it is rare to fully normalize the sleep
22:39wake cycle of narcoleptic subjects.
22:42A major objective of treatment
22:44of narcolepsy is, of course,
22:46to alleviate daytime sleepiness.
22:49Other goals include controlling cataplexy,
22:51hypnagogic hallucinations,
22:52and sleep paralysis when they're
22:54present in troublesome to patients,
22:56but the ultimate goal should be to produce
22:59the fullest possible return of normal
23:02function for patients at work at school,
23:05at home, and socially.
23:09I would like to review the guidelines
23:12and recommendations from the practice
23:15parameters for the treatment of
23:17narcolepsy and other hypersomnia
23:19of central or origin from the ASM.
23:22And this just in an update of these
23:26guidelines was published on April 23rd.
23:29It includes some of the tried and true
23:32medications from the old practices
23:34guidelines that had been published in 2007,
23:37as well as novel therapies approved
23:39by the FDA in the last five years.
23:47Let's start with Modafinil.
23:49Which is recommended for treatment
23:51of daytime sleepiness and narcolepsy?
23:54It acts as an atypical, selective
23:57and weak dopamine reuptake inhibitor,
23:59which indirectly activates the release
24:01of orexin and histamine from the lateral
24:04hypothalamus into bruh mammillary nucleus.
24:06In amid analysis of over 1000 patients
24:10with narcolepsy type one and Type 2.
24:13Patients who received Modafinil at doses
24:15of 200 to 600 milligrams a day had
24:19decreased essm by two point 73 points
24:22had increased, mean sleep latency,
24:24latency on maintenance of,
24:26wakefulness, testing by two point,
24:2882 minutes and had a decrease in number
24:31and duration of severe somnolence episodes,
24:34sleep attacks and naps.
24:37Common adverse reactions include headache,
24:39nausea, diarrhea,
24:40dizziness, anxiety,
24:41dyspepsia and important to note,
24:44decreased efficacy of oral contraceptives.
24:46Patients should be advised to use
24:49barrier or mechanical methods of
24:52contraception when taking Modafinil.
24:54The approved recommended dose of Modafinil
24:57is 200 to 400 milligrams once daily,
25:00but studies indicate that the use
25:02of a split dose strategy provides
25:04better control of daytime sleepiness
25:06than a single daily dose.
25:12This study by Schwartz was designed to
25:14determine if a split dose of Modafinil
25:16would be more effective than a single
25:18morning dose for reducing sleepiness
25:20in the late afternoon and evening.
25:24Patients were randomized to take
25:26200 milligrams of Modafinil,
25:28a day, 400 milligrams.
25:30400 milligram split dose 200
25:32and 200 or 600 milligrams split.
25:35400 and 200.
25:37The split doses produced significantly
25:39greater mean improvements from baseline
25:42and sleep latency during make MWT than
25:46the 200 milligrams once daily regimen.
25:49There were significant improvements
25:51in clinical condition measured
25:53by clinical global impression of
25:55change scale with respect to evening
25:57sleepiness and the higher once daily
25:59dose and split dose regiments,
26:00then the 200 milligram once daily dose.
26:04No serious adverse events were reported.
26:09Armodafinil is a longer acting
26:12enantiomer of Modafinil.
26:14A study by harsh comparing our
26:17medicinal 150 milligram dose 250
26:19milligram dose and placebo showed
26:21significantly increased mean sleep
26:24latency and maintenance of wakefulness.
26:26Testing with armodafinil compared to placebo.
26:29There was improved overall
26:31clinical condition, memory,
26:33attention and fatigue and the most
26:36common adverse events were headache,
26:38nausea and dizziness.
26:43Sodium oxybate or zeiram.
26:45His recommended for the treatment
26:47of cataplexy daytime sleepiness and
26:50disrupted sleep due to narcolepsy.
26:53It is a sodium salt of gamma hydroxybutyrate,
26:56an endogenous metabolite of GABA.
27:00It was the first medication to treat
27:02both Cardinal symptoms of narcolepsy.
27:04Excessive daytime sleepiness and cataplexy.
27:07It has a short half life and so
27:09it must be given in divided doses.
27:11It's given at bedtime and
27:12then two to four hours later.
27:15The starting dose is 4.5 grams and then
27:17you increase .5 to 1 gram per night,
27:19every one to two weeks to a
27:21maximum dose of 9 grams per night.
27:24The prescription of sodium oxybate
27:26requires registration and training
27:27and distribution to the patient is
27:30all made through a central pharmacy.
27:32It's known as the **** **** drug.
27:34The compound has a very poor,
27:36but not necessarily deserved
27:38public reputation.
27:39It is easily synthesized and
27:41has been used recreationally.
27:43Side effects include confusion,
27:45enuresis and sleepwalking.
27:52In a study by the Xyron
27:55Multi Center Study Group,
27:57136 patients were randomized to
28:00receive sodium oxybate at doses of
28:04369 grams or placebo for four weeks.
28:07Compared to placebo weekly,
28:09cataplexy attacks were decreased by
28:12sodium oxybate at the six gram dose
28:15and significantly at the 9 gram dose.
28:17The Epworth Sleepiness Scale
28:19was reduced at all doses,
28:21becoming significant at the 9 gram dose.
28:25And the clinical global impression of
28:27change scale demonstrated a dose related
28:30improvement significant at the 9 gram dose.
28:37That same group did a study three
28:39years later in which they assess
28:41the efficacy of sodium oxybate
28:43for the treatment of narcolepsy,
28:45with an emphasis on excessive
28:47daytime sleepiness.
28:48228 patients were randomized to take
28:53sodium oxybate at doses of 4.569
28:57grams or placebo for eight weeks.
29:00The 9 gram of sodium oxybate nightly
29:03group had significant median increase of
29:05mean sleep latency over 10 minutes in
29:08the maintenance of wakefulness testing.
29:10Dose related decreases in
29:12median upward sleepiness,
29:14scale and frequency of weekly
29:16inadvertent naps were seen.
29:18And there were significant
29:20improvements in the clinical global
29:22impression of change scale in the
29:24groups treated with sodium oxybate.
29:29So this is not included in the guidelines,
29:31but I thought it was important to mention it.
29:34Siwave is a calcium, magnesium,
29:37potassium and sodium oxybate.
29:39Formulation that has 92%
29:41less sodium than sirem.
29:43It was approved by the FDA in July
29:472020 for the treatment of narcolepsy
29:50and patients age 7 or older.
29:52A dose of 9 grams of sirem has
29:55over 1600 milligrams of sodium,
29:58where the recommended daily intake
30:00is about 1500 to 2300 milligrams.
30:04In a multicenter study of 201
30:07patients comparing zywave to placebo.
30:11There was statistically significant
30:12reductions in the weekly number
30:14of cataplexy attacks and upward
30:16sleepiness scales.
30:19This medication is still given in
30:21two nightly doses and the price
30:24is also compatible to xyron.
30:25The main reason to choose one
30:28over the other is really just
30:30the reduced sodium intake.
30:32The adverse effects of this
30:35medication include headache, nausha,
30:37dizziness, decreased appetite,
30:39parasomnia diarrhea, hyperhidrosis,
30:40anxiety and vomiting.
30:45Amphetamines are recommended
30:46for the treatment of daytime
30:49sleepiness due to narcolepsy.
30:51These medications increase
30:53the release of dopamine,
30:55norepinephrine, and serotonin.
30:56Their wake promoting agents,
30:58but also can reduce
30:59cataplexy at higher doses.
31:01They are available in slow or
31:04extended release formulations
31:05in randomized clinical trials.
31:07Looking at afeta means and
31:09narcolepsy show that they increase
31:11mean sleep latency decrease.
31:13Subjective sleepiness,
31:14decreased driving errors,
31:16and improve ability to stay awake on
31:19maintenance of wakefulness testing.
31:21The adverse effects include tachycardia,
31:24hypertension,
31:25palpitations and sweating.
31:31Anti depressants such as tricyclic
31:34antidepressants and selective
31:35serotonin reuptake inhibitors,
31:37have been used off label to treat cataplexy.
31:44These medications are not included in
31:46the current update, but I do think
31:49it is important to review them.
31:52These medications suppress REM sleep.
31:56There was really limited evidence
31:58supporting this recommendation
31:59from the prior guidelines,
32:01so recommendation was based on clinical
32:04experience of Sleep specialist committee,
32:06consensus case reports and case studies.
32:09Important to mention that unlike
32:11with anxiety or depression,
32:13these medications are immediately
32:16active on cataplexy.
32:17We don't have to wait four to
32:19six weeks to see their effects.
32:21It is important to note that
32:24rebound cataplexy can happen with
32:26abrupt cessation of treatment.
32:32So behavioral interventions
32:33can help symptom management.
32:35Scheduled naps can be beneficial
32:38to combat sleepiness,
32:39but it seldom is enough.
32:42Wake promoting agents are needed.
32:45Good sleep hygiene.
32:47Keeping a regular sleep schedule,
32:49avoiding alcohol and
32:50sedatives is recommended.
32:52And accident prevention and
32:53safe driving are important,
32:55particularly in those patients
32:56operating heavy machinery or
32:58who work in transportation.
33:01I would like to move on to novel therapies.
33:05These have been approved by
33:06the FDA in the last five years
33:09and are now in the guidelines.
33:14Patala St tradename Wakix was approved
33:17by the FDA on Aug 2019 for excessive
33:21daytime sleepiness and on October 2020
33:24for cataplexy in adults with narcolepsy.
33:27It is an inverse agonist of the
33:31histamine three autoreceptor.
33:33As seen in the figure and label,
33:35one petola St binds to the H3 receptor
33:38and blocks inhibition of histamine
33:40synthesis in the presynaptic neuron.
33:43This causes increased histamine synthesis
33:45and release of histamine into the synapse.
33:47As you can see in Label 2.
33:51And then histamine binds to postsynaptic
33:53H1 receptors which then modulates the
33:55release of various transmitters that are
33:58involved in weight promotion promotion.
34:00Sorry, such as dopamine,
34:02noradrenaline, and ask the deal colon.
34:10The Harmony One trial compared
34:13Petola sent Modafinil and placebo
34:15in adults with narcolepsy,
34:17with and without cataplexy.
34:19The primary endpoint was Epworth
34:22Sleepiness score compared to baseline
34:25after eight weeks of treatment.
34:27There was improvement in ESS and mean
34:30sleep latency in MWT in all patrol
34:34ascent groups compared to placebo.
34:36I do have to note that Tillerson did
34:39not demonstrate noninferiority with
34:40respect to definitely on this trial.
34:45A subsequent trial,
34:47the Harmony CTP trial compared
34:49to to listen and placebo with
34:52the primary outcome of change,
34:54and weekly cataplexy attacks from baseline.
34:58It included adults with narcolepsy with
35:01three or more weekly cataplexy attacks.
35:05As you can see in the figure,
35:07the patrol Ascent group in blue,
35:09in the placebo group in red.
35:11Catullus and was associated with significant
35:15improvement in cataplexy attacks compared
35:17to placebo after seven weeks of treatment.
35:20In the Petola Sync Group,
35:23the weekly cataplexy attacks
35:25went from nine point 15 to 2.27,
35:28compared to 7.31 to 4.52
35:31in the placebo group.
35:33Secondary outcomes included decrease
35:35an upward sleepiness scale and
35:37increase in mean sleep latency
35:39in maintenance of wakefulness.
35:40Testing in the patrol said group.
35:44Adverse effects include insomnia,
35:46headache, nausha,
35:47an anxiety.
35:52A titration schedule is usually
35:55recommended when starting pitolisant.
35:57You start at 8.9 milligrams upon
36:00awakening for a week and then
36:03increase to 17.8 milligrams.
36:05If needed after a week you could
36:08increase to 35.6 milligrams,
36:10just like with Modafinil patrol
36:12ascent may reduce the effectiveness
36:14of hormonal contraceptives,
36:15it prolongs the cutie interval,
36:18and it is contraindicated in patients
36:20with renal and hepatic impairment.
36:27The FDA approved Solarian fatal brand
36:29names to know C for the treatment of
36:32excessive daytime sleepiness and adults
36:35with narcolepsy or obstructive sleep apnea.
36:38In March 2019, it is a dopamine and
36:42norepinephrine reuptake inhibitor.
36:43It is indicated at a once daily
36:46dose of 75 or 150 milligrams.
36:49Pawn awakening, and adverse effects
36:52of this medication include headache,
36:54decreased appetite, anxiety.
36:56Dry mouth or palpitations?
37:02In a phase three, double blind placebo
37:05controlled trial adults with type one
37:08and Type 2 narcolepsy were randomized
37:11to take sorry on petola doses of
37:1475150 or 300 milligrams or placebo.
37:16The primary endpoints of the study
37:19were changed compared to mean sleep
37:22latency on maintenance of wakefulness
37:24testing and upward sleepiness score.
37:27There was increased in the men sleep
37:30latency on MWT at the 150 and 300 milligram
37:34doses of sinoussi compared to placebo.
37:37There was also improved effort sleepiness
37:40scores seen at all doses compared to placebo.
37:45And there was improvement on the
37:47clinical global impression of change
37:49score at all doses compared to placebo.
37:55Here is a summary of recommendations
37:58in adult populations for the
38:00treatment of narcolepsy from
38:02the updated ASM guidelines.
38:05As you can see, Medef,
38:06Anil Catullus and sodium oxybate,
38:08Ansel Rhian fatal are strongly recommended
38:11for the treatment of narcolepsy.
38:13The tallest and an sodium oxybate are
38:16strongly recommended to treat both
38:19excessive daytime sleepiness and cataplexy.
38:21Dextroamphetamine can also be
38:23used to treat excessive daytime
38:25sleepiness and cataplexy.
38:31Moving on to investigational drugs.
38:38FT 218 is a controlled release formulation
38:41of sodium oxybate which requires a
38:43single dose at night compared to
38:46the two dose regimen currently used.
38:48The rest on trial assessed safety
38:51and efficacy of FT 218 and treatment
38:54of excessive daytime sleepiness
38:56and cataplexy and narcolepsy.
38:59Patients received FT 218 at
39:02doses of 4.5 grams, 6 grams,
39:057.5 grams, 9 grams or placebo.
39:09There was an increase in sleep
39:12latency in MWT and the FT.
39:14218 groups compared to placebo.
39:17The mean weekly cataplexy attacks
39:19were reduced in the treatment group,
39:21and there was improvement in clinical
39:23status assessed by the clinical
39:25global impression of change scale.
39:27It has been granted orphan drug
39:29designation from the FDA for
39:30treatment of narcolepsy and is
39:32pending full FDA approval.
39:37Reboxetine which is not
39:39approved in the United States,
39:41is a norepinephrine reuptake
39:43inhibitor originally developed
39:45for treatment of depression.
39:47The concert trial was conducted in the
39:50US in 2019, looking at reboxetine for
39:54treatment of cataplexy in narcolepsy.
39:5721 patients with narcolepsy type.
40:00One received reboxetine for two weeks
40:03and placebo for two weeks separated by
40:06one week of down titration and washout.
40:10There was a significant reduction of
40:12cataplexy attacks per week in the reboxetine.
40:15Group.
40:15There was significantly improved
40:17excessive daytime sleepiness
40:19symptoms compared to placebo,
40:21as measured by upward sleepiness
40:23for an 5 frequency of inadvertent
40:25naps and there was improved
40:27cognitive cognitive function.
40:29Improve sleep quality production,
40:30and sleep paralysis episodes
40:32and hypnagogic hallucinations.
40:37Other drugs being investigated.
40:39The combination of Modafinil and flecainide
40:42for excessive daytime sleepiness in
40:45narcolepsy and Parkinson's disease.
40:48The antiarrhythmic flecainide enhances
40:50wake promoting effects of Modafinil through
40:53inhibition of astroglial connections.
40:56Some melicent which is a histamine
40:59three receptor inverse agonist,
41:01has demonstrated wake promoting an
41:04anti cat affective effects in rodents.
41:08And there are two hypocretin,
41:10two receptor selective agonist Tak
41:12925 with which is a subcutaneous
41:15preparation and tag 994 which is
41:18an oral preparation that have shown
41:21to increase wakefulness and reduce
41:23cataplexy like episodes in mouse models.
41:30So going back to my patient Miss Ma.
41:34I decided to prescribe it to listen for
41:37excessive daytime sleepiness and cataplexy,
41:40as she was leery of starting sodium oxybate.
41:44I initially prescribed
41:45methylphenidate and asked her to
41:47continue with her scheduled naps.
41:49While we waited for insurance approval.
41:52This drug, of course,
41:54was denied by insurance and
41:56after lengthy discussions she
41:58agreed to start sodium oxybate.
42:01She was titrated to 3.75 grams twice nightly.
42:06And her upward sleepiness
42:08scale went from 19 to 5.
42:12For weekly cataplexy attacks
42:13that were seven to 10 per week.
42:16Where is zero in two months?
42:19She rarely needs to nap during
42:21the day she is in college.
42:23She plays softball and does trap.
42:26She is now able to attend more
42:28family and social events.
42:33I would like to finish with a couple
42:36of take home points to summarize.
42:38Although the cause of narcolepsy
42:40is not completely understood,
42:42it is increasingly evident that
42:45it is an autoimmune disease.
42:47The search for characteristic. I'm sorry.
42:57The search for characteristic narcolepsy
43:00autoantibodies has not been successful with
43:03no autoantibodies consistently found yet.
43:13I apologize.
43:22Can everybody see my screen?
43:30Yeah, but the slide is frozen.
43:33OK. Can you see it now?
43:37Yep, Yep Yep, OK, thank you.
43:41But delay in diagnosis or
43:43misdiagnosis may occur with
43:45significant consequences to patients.
43:50And the goal of treatment should be
43:52to produce the fullest possible return
43:55of normal function for patients.
43:59Although tremendous progress has been
44:01made in the treatment of narcolepsy,
44:04it still remains symptomatic and there
44:06is so much to learn about this disease.
44:12I want to thank Doctor Mosen
44:14in for encouraging me to take
44:16this patient under my care.
44:18Ann for precepting me
44:19during her initial visit,
44:21Doctor Tapawai consulted multiple times
44:23when making management decisions.
44:25As well as Doctor Tobias and
44:26Doctor Miner who gave me advice
44:28when putting together this talk.
44:30And of course Miss Ma,
44:31who allowed me to care for her
44:33and learn so much from her.
44:35Thank you.
44:51I'd be happy to take any
44:53questions if there are so.
44:54Are there any questions?
44:56Let's see there's.
44:57I think there's something in the chat.
45:00I have one there overheat high. Go ahead,
45:06OK. I thought the chat
45:08questions will be covered.
45:10Then there was a terrific presentation
45:13on a coverage of the whole.
45:16Field, including the new one.
45:18Drugs around the corner.
45:20Could you comment on the
45:23sensitivity of MSL T?
45:24As you know, it's is the gold standard,
45:28but then has issues with
45:31perhaps false negative results.
45:33And how do you handle those type of cases?
45:38Yeah, it's it's really kind of I.
45:40I can't remember off the top
45:42of my head the exact number in
45:45terms of sensitivity of MSL T,
45:47but it's really not a great test.
45:50You have to take into account the whole
45:53clinical context and also be sure to
45:56rule out other reasons why we could
45:58have MSL T findings that could give
46:01us a false positive for narcolepsy.
46:04Things like sleep deprivation,
46:06medications and substances could kind
46:09of taint the results of the MSLT,
46:11so it's really not a great break test.
46:15It's important to take everything
46:18else into clinical context.
46:21Yeah,
46:21it's sometimes difficult to
46:23differentiate type two with the
46:26idiopathic hypersomnia if there may
46:27be a lot of overlaps as far as their
46:31presentation sensitivity for MSL T,
46:33the first time is around 70%,
46:36so you tend to get like 30% negative
46:39or could be false negative rate, which
46:42is a pretty significant
46:44number, you know, yeah.
46:47That was a great
46:49talk. Glenda, thank you.
46:51Thank you. Yeah. So Glenda,
46:53we frequently see in in clinics,
46:56patients who are in their early 20s.
46:59They look like they have narcolepsy.
47:01They give a great history but they
47:04are on antidepressants and when
47:07we study them with an MSLT the
47:09results do not support a diagnosis
47:12of narcolepsy because they're
47:14on our REM suppressing agent.
47:17How do you think we should
47:19handle patients like that?
47:21Well, I mean. Like I mentioned always,
47:24ideally in an ideal world we would
47:26have them stop their antidepressants,
47:29but we know that that's not always possible.
47:33I do think that the clinical
47:36history is very important.
47:38If there's any question about a difference
47:41between type one and Type 2 narcolepsy,
47:43measuring CSF hypocretin
47:44levels might be useful,
47:46but I do think that the most important thing
47:49is to try to manage the patient symptoms.
47:53If the patient is presenting with
47:55excessive daytime sleepiness,
47:56of course using a wake
47:58promoting agent and then,
47:59like I mentioned,
48:00it may be helpful to check
48:02CSF hypocretin levels.
48:05OK, so does any. Are there any other
48:09questions that that people have?
48:14Hi this is a in where I put a question
48:17in the talk but I was just wondering.
48:20I haven't had a chance to read the new
48:23guidelines that came out recently,
48:24but I see that armor Daffodil is
48:26a conditional recommendation and
48:28monophony Liz a strong recommendation.
48:29Did they talk about why and the guidelines?
48:32They separated those two medicines
48:34out and one was strong.
48:35This woman was like a week or
48:37conditional recommendation.
48:38You know what Doctor we are?
48:40I would really have to
48:42get back to you on that.
48:44I did not see like why they would have,
48:47you know, made that difference,
48:49but yes, Ma definitely had
48:50a strong recommendation.
48:51I was going to have to get
48:53back to you on that one.
48:55Yeah, it's probably 'cause there's
48:56just. I would imagine there's just
48:58not as much information, but you know,
49:00usually what we do is, you know, we have.
49:02If we're going to use Medaugh alarm adapter
49:05will have a conversation with the patient,
49:07will talk about the advantage,
49:08disadvantage of having the opportunity
49:10to take that dose at noon and and
49:12some people just want take one
49:13pill and so just interesting 'cause
49:15that potentially could change.
49:17You know you would maybe.
49:18Say OK because of that recommendation
49:21we should be using more of a
49:25daffodil as the primary.
49:27Treatment if needed to be
49:28made for promoting medication.
49:30So just curious.
49:31Yeah, and I don't know when
49:33you're anxious parent.
49:34In my vast one year sleep fellow experience.
49:36Usually I find that patients have more
49:39headaches on Modafinil and armodafinil,
49:40so I don't know if that's if
49:43you've seen that. But yes, I'm.
49:45It's probably because there is lack of
49:47evidence for Arma definite that the
49:50recommendation was conditional. Yeah,
49:51I've seen it. Probably just
49:53anecdotally about equally between
49:55the two and most of the time.
49:57If they can plow through a week of treatment,
49:59usually the headaches with inside,
50:01so I kind of encourage them to continue
50:03for at least two weeks before they
50:06completely give up the medication,
50:08because the headaches but that,
50:09as you mentioned,
50:10that is a very common side effect
50:13with both of those pills.
50:14Yeah, yeah, it seems that Modafinil
50:16gives patients more flexibility
50:18as far as dosing as opposed to
50:20armodafinil there almost identical.
50:21Medications, as far as their
50:23efficacy adjust the dose dependency
50:26so it's once you take the armor,
50:28definitely don't want to take
50:30the second dose because of the
50:32longer acting nature of it, so,
50:34but definitely will be maybe a
50:37good starting medications and
50:38then perhaps switch over to Arma.
50:40Definitely if they need consistently two
50:43dosing per day. Yeah,
50:44so the the the original clinical
50:47trials done in in the US which
50:50led to registration by the FDA.
50:52The dosage was 400 milligrams of Modafinil
50:55and one shot in in in the morning.
50:58In the rest of the world.
51:00They didn't do that, it was,
51:02it was sort of a BID thing.
51:04Half of the dose in the morning,
51:07half the dosage at lunchtime,
51:09and that seems to actually work fairly well.
51:12And just like Doctor Motion and
51:14just mentioned, patients are able
51:16to titrate themselves that way.
51:17And sometimes they'll be.
51:19They'll be able to take 200 in the morning.
51:22100 lunchtime and maybe even another
51:25hundred at you know 4-5 o'clock in the
51:28evening if they're gonna be going to
51:31a concert or driving in the evening,
51:34so Modafinil gives a lot more flexibility.
51:38I have a question.
51:41So how do you
51:43know how and
51:44why the the? The app, the mean
51:48sleep latency for the Ms Lt
51:50was said at 8 minutes. How and why
51:55that was chosen?
51:58And I always think about a
52:00term pathologic sleeping.
52:01This is being less than five minutes.
52:04Does anybody use
52:05that term? Well,
52:06it used to be less than five,
52:09and it turns out that most narcolepsy
52:12patients are like way less than five an.
52:14I don't recall why it went to 8,
52:18but it suddenly went to 8 from 5.
52:21Ann and Ann. I don't remember
52:23the reason for it. I think
52:25it's because of the balance between
52:28the sensitivity and specificity,
52:29because if you.
52:30If you if you decrease it to five minutes,
52:34it's going to be more specific,
52:36but much less sensitive.
52:38And so the specificity of the
52:41test is like 95% the sensitivity
52:44is more like 70 to 80% so.
52:48You know combining those two
52:50features with those two numbers makes
52:53it most sensitive and specific.
52:56That's the reason, so
52:58it's sort of a sophistical
53:01thing. OK, one other one other
53:04question, and I've heard Doctor
53:06Maggio mentioned at the onset
53:09of. Sleep of Ram in the overnight
53:12sleep test when it's less than
53:1520 minutes, that alone is significant
53:18enough to make the diagnosis
53:20as far as he was concerned.
53:24So asleep on set run period,
53:26it is usually a onset of REM within
53:2915 minutes of achieving sleep.
53:31I haven't heard the the 20 minute criteria.
53:34It's usually with 15 and you should
53:36have two or more to make the diagnosis.
53:42So if you only had a 15 minutes only on
53:46the overnight test, you still committed to
53:48doing an MSL MSL T.
53:52To establish the diagnosis?
53:54Yes, for PSG and MSL T findings yet.
54:00One thing that I always wonder about
54:03is whether or not cataplexy that
54:05presses up cataplexy should
54:07be considered pathognomonic.
54:08Because when you look at the International
54:10Classification for Sleep Disorders,
54:12that's actually not part of their criteria.
54:15But there are sources outside of
54:17that that do suggest that it should
54:20be a pathognomonic
54:21criterion. You know,
54:22if the patient has cataplexy,
54:24then narcolepsy is the definite diagnosis.
54:26What do you think about that?
54:30I actually agree with that,
54:31specially with what we were talking about.
54:33The sensitivity and specificity of Ms Lt.
54:36I mean if the patient has
54:37kind of clear cut cataplexy,
54:39the MSL team not being such a great test.
54:42I think you know, treating them
54:45as a narcolepsy type one is valid.
54:51The only thing I would just say with
54:54that I think that to me that makes sense,
54:57except that remember,
54:58the cataplexy is basically a subjective
55:00finding that the patient gives you
55:02right so and now you're dealing with
55:04a very rare condition with controlled
55:07substance medications which you know
55:08include you know amphetamines and
55:10other potential medications of abuse.
55:12So I think you should still have, you know,
55:15objective testing to confirm the diagnosis,
55:17even with the obvious
55:19cataplexy DAG cataplexy.
55:20Symptom because I will tell you
55:22just from personal experience,
55:23I will see a lot of patients for second
55:25opinion who want me to prescribe them
55:28controlled substance and they give a
55:30great story and then when I tell them
55:32that before I'm going to prescribe
55:34any medicines I need to see objective
55:36testing or we need to repeat testing
55:39and then I never see them again.
55:40So you just gotta be careful with that.
55:43But I think if you have if you have that
55:46diagnosis then just in terms of the rent,
55:48suppression and and and.
55:50Medications you know.
55:51I personally will not do Ms,
55:53Lt and narcolepsy work up with
55:54someone who's on our rent.
55:56Suppressive medication.
55:57In the absence of a cataplexy symptom,
55:59because I just find that it gets
56:01very muddy and you have a potential
56:03false negatives and even potentially
56:04false positives if they just
56:06abruptly stopped the medication.
56:08So gets a little dicey there.
56:10But I know, you know,
56:11sometimes you really stuck.
56:12You want to help these patients,
56:14but it gets a little dicey when you have
56:17him on a REM suppressing medication.
56:21Alright, so one
56:23more question there, go ahead.
56:27You can come across any kind of
56:30mention of doing urine testing for
56:33either pro waking drugs to evade the
56:37effect of SLT or actually taking.
56:41Kind of asleep promoting
56:42agents prior to the testing.
56:46So say that again, Doctor Moses.
56:48So like doing drug testing prior to the MSL
56:51team. Yeah, I think we used to do
56:54urine test before MSL tear the Knights
56:56of PSG just to make sure that they
56:59are not on any either wake promoting
57:02or sleep promoting medications.
57:03Yeah, and some some labs will do also
57:06like active ticker fee or sleep Diaries
57:09just to ensure that they are not sleep
57:11deprived as well and then the urine testing
57:14before the the PSG MSL T to ensure.
57:17That there are no other substances that
57:19could kind of taint the results of the test.
57:22Yeah, and do you do any urine
57:24testing at your sleep center?
57:27So at Norwalk it's it's absolutely
57:30mandatory that they all get drug
57:32testing the morning of the MSL T,
57:34and I would strongly strongly
57:36caution not doing that.
57:38'cause that just seems so.
57:40We picked up positive we picked up cocaine.
57:42We picked up benzos.
57:44We picked up opiates.
57:45We picked up all sorts of stuff and so I
57:48think that's really absolutely necessary.
57:51Those are very nice study that looked
57:53at in the pediatric population and they
57:56found that essentially if someone was.
57:58Under 13 it was very very low yield,
58:01so we generally will not do it
58:03for anyone who's 3rd, 12 or under.
58:06But the 13 to 18 year old range you you
58:09you know there was a number of positives,
58:12and especially what I've seen is
58:14we've seen tremendous amount of
58:16positive marijuana because it's now,
58:17you know,
58:18approved and medical marijuana and
58:20they may not tell you about it.
58:22So I I definitely think that is.
58:25I could tell you many,
58:26many stories of positive urine drug
58:28screens that changed the diagnosis.
58:30Where if you didn't have that
58:32test result of positive cocaine,
58:34you would have given the person narcolepsy
58:36diagnosis and then also a Tigger free.
58:38In my opinion is mandatory and
58:40strongly recommended because again
58:41insufficient sleep and and I can also
58:43give you a bunch of other stories
58:45of people doing things that in the
58:47middle of the night that didn't.
58:49They don't want their parents to
58:51know about and they would have
58:53been diagnosed with narcolepsy
58:54if we didn't have to take a
58:56break. I agree with you.
58:59I think you're in testing at
59:02minimum should be done in in the
59:05era of drug abuse and overuse.
59:07Absolutely, I is it. Dan McNally.
59:10We we do drug testing on everybody
59:13and we also are very careful
59:16about not just looking by sleep
59:18Diaries or preferably actigraphy
59:20for their insufficient sleep,
59:22but also because of sleep phase delay.
59:25The individuals again, adolescence.
59:27With sleep phase delay shifting
59:30that Clock over to those morning
59:32hours makes you much more likely
59:35to have a REM sleep episode.
59:37That doesn't mean narcolepsy on your testing.
59:44Alright, so it's already past
59:463:00 o'clock and an I'd like
59:49to thank Linda for a wonderful presentation.
59:53And you have another 12 or 13 minutes
59:56to register your for your CME credits.
60:00So anyways, have a great
01:00:02week and thank you again,
01:00:04Glenda for a fantastic job. Thank you.