Narcolepsy. Kelly Carden, MD St Thomas Medical Partners Sleep Specialists September 30, 2017 TSS Annual Meeting

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1 Narcolepsy Kelly Carden, MD St Thomas Medical Partners Sleep Specialists September 30, 2017 TSS Annual Meeting

2 Conflict of Interest Disclosures 1. I do not have any potential conflicts of interest to disclose, OR X 2. I wish to disclose the following potential conflicts of interest: Type of Potential Conflict Details of Potential Conflict Grant/Research Support Consultant Speakers Bureaus Financial support Other FBI BOD AASM, ASMF, ABSM, APSS. Sec/Tr AASM, ASMF, ABSM. Reviewer - UpToDate X 3. The material presented in this lecture has no relationship with any of these potential conflicts, OR 4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:

3 Narcolepsy The History Clinical presentation Prevalence Pathophysiology Diagnosis Treatment

4 History of Narcolepsy 1877/78 - Syndrome first described Westphal and Fisher (Germany) Gelineau gave narcolepsy its name 1902 Loewenfeld gave cataplexy its name 1935 Stimulants introduced Late 1950 s TCAs introduced, useful in cataplexy 1960s methylphenidate available - Sleep-onset REM periods 1970 MSLT described

5 History of Narcolepsy Canine model described by Knecht & Mitler 1980s - Association with HLA-DR Association with HLA-DQB1* Hypocretin/orexin identified almost simultaneously by DeLecea and Sakurai 1990s - Hypocretin mutations in animals 2000s - Hypocretin deficiency in human narcolepsy 2002 Xyrem approved by the FDA

6 A Case To Ponder A 23 year old woman is referred for evaluation of excessive sleepiness after having fallen asleep while driving. She reports that her sleepiness has been present since high school, and several times each day she struggles to remain awake. She is worried that this sleepiness is impacting on her job performance, and her boyfriend complains that she often dozes off on dates.

7 She occasionally feels weak in the knees when laughing. Once, she fell to the ground while laughing during a party and could not get up for 1-2 minutes. She gets about 8 hours of sleep each night. She wakes up 2 or 3 times each night and sometimes has trouble returning to sleep.

8 If she is sleepy while driving, she may imagine seeing an animal in the road. Sometimes when waking from sleep it feels like she is dreaming though she is sure she is awake. Several times she has been terrified to find herself unable to move for a minute after awakening.

9 Symptoms of Classic Narcolepsy (Narcolepsy Type I) 1) Excessive daytime sleepiness Variable patient to patient Most evident under boring, monotonous, or relaxing circumstances May vary over course of the day EDS often transiently relieved with brief naps

10 Clinical Presentation: EDS May feel the onset or experience sleep attacks Memory lapses and automatic behavior Impaired attention / concentration Decreased work performance Increased drowsy driving crashes Visual disturbances

11 Clinical Presentation: EDS Frequency of Daytime Sleep Episodes Reported Duration of Daytime Naps 1-2/Day 3-4/Day >5Day < 10 min min min min 1-2 hrs > 2 hrs Adapted from Honda Y, Juji T, eds. HLA in Narcolepsy. Tokyo: Springer-Verlat, 1988

12 Clinical Presentation: Automobile Accidents Sleepiness Related MVA in Patients with Sleep Disorders * Men Women % * * *p<0.01 versus controls 10 0 OSA Narcolepsy Control Adapted from Aldrich MS. SLEEP 1989;12.

13 Symptoms of narcolepsy 2) Cataplexy Brief episodes of muscular weakness* Twitches, esp of facial muscles may be seen May be mild or partial, unilateral / bilateral Consciousness is maintained Usually precipitated by: laughter, anger, amusement, excitement/surprise, elation, while fighting sleep attack DTRs are transiently absent In children - facial hypotonia (droopy eyelids, mouth opening, tongue protrusion)

14 Clinical Presentation: Cataplexy Sites of Cataplexy Legs / knees Jaw Slurred speech Falling to ground Adapted from Anic-Labat et al. SLEEP 1999;22.

15 Clinical Presentation: Cataplexy Emotions Triggering Cataplexy Laughing Joking Anger Stress Sex Adapted from Anic-Labat et al. SLEEP 1999;22.

16 Sleep 1999; 22: Swiss Narcolepsy Scale Measures frequency of 5 potential symptoms: Q1 Inability to fall asleep Q2 Feeling bad or not well rested in the morning Q3 Taking a nap during the day Q4 Weak knees/buckling of the knees during emotions such as laughing, happiness, or anger Q5 Sagging of the jaw during emotions such as laughing, happiness, or anger Bassetti CL. Spectrum of narcolepsy. In: Baumann CR, Bassetti CL, Scammell TE, eds. Narcolepsy: Pathophysiology, Diagnosis, and Treatment. Springer Science+Business Media; 2011: Sturzenegger C, Bassetti CL. The clinical spectrum of narcolepsy with cataplexy: a reappraisal. J Sleep Res. 2004;13(4):

17 What do these three have in common?

18 Symptoms of Narcolepsy 3) Hypnagogic / hypnopomnic hallucinations Vivid, dream-like hallucinations at the beginning or end of sleep 4) Sleep paralysis Inability to move upon awakening Respiration ongoing but some patients c/o abnormal breathing Brief Unsettling/unnerving

19 Symptoms of narcolepsy 5) Sleep maintenance insomnia Spontaneous awakenings during the night 6) Automatic Behavior Driving, writing incoherently Poor memory Inattention Conversations

20 Clinical Presentation: Symptom Prevalence % EDS Cataplexy Hypnagogic Sleep Fragmented Hallucinations Paralysis Sleep Highest Reported Prevalence Adapted from Honda Y, Juji T, eds. HLA in Narcolepsy. Tokyo: Springer-Verlat, 1988

21 Clinical Presentation: Symptoms Excessive daytime sleepiness (EDS) Cataplexy Hypnagogic hallucinations Sleep paralysis Fragmented nocturnal sleep Other associated features Tetrad Pentad

22 Associated sleep disorders Obstructive sleep apnea Periodic limb movements REM behavior disorder Sleepwalking & sleeptalking C/o vivid dreaming Nightmares

23 Age at Onset of Symptoms Vivid Hypnagogic Hallucinations Sleep Paralysis ABSOLUTE FREQUENCY N = 180 Cataplexy EDS/Sleep Attacks AGE OF ONSET (yrs) Adapted from Handbook of Sleep Disorders, page 199 by courtesy of Marcel Dekker Inc.

24 Prevalence Narcolepsy with cataplexy Western Europe & N. America Japan Israel Multiple Sclerosis (US) Minimal gender differences Adapted from Mignot E. Neurology 1998;50(Suppl 1).

25 Clinical Presentation: Associated Features Psychosocial problems Depression Frequent Misdiagnoses Major depression Thyroid disorder Chronic fatigue syndrome Schizophrenia Headaches Weight gain (average BMI = 28) Decreased Quality of Life

26 Narcolepsy: Disabling Disorder 100 Quality of Life Comparison SF-36 Score General Population Epilepsy Narcolepsy Parkinson's 0 Physical Function Role limitationsphysical Bodily Pain General Health Vitality Social Function Role limitationsemotional Mental Health Adapted from Beusterien et al. SLEEP 1999; 22

27 Pathophysiology: What Causes Narcolepsy? Genetic Predisposition HLA DR2, DQB1*0602, DQA1*0102 Possible autoimmune disease Loss of Hypocretin/Orexin neurons (in the hypothalamus) Instability of sleep/wake system

28 What causes narcolepsy? Most narcoleptics do not have mutations in the genes coding for hypocretin or its receptors, to date there is only one case of reported preprohypocretin mutation First degree relatives with 1-2% risk (10-40 x risk of average population) Only 1/3 of monozygotic twins will both develop narcolepsy

29 Orexin/Hypocretin & Narcolepsy in Canine and Murine models Dogs with nonsense mutations in the hypocretin receptor gene have narcolepsy Mice lacking hypocretin have narcolepsy Mice lacking hypocretin neurons have narcolepsy

30 Hypocretin/Orexin & Narcolepsy CSF levels of hypocretin are very low in most narcoleptics with cataplexy Narcoleptics with cataplexy have lost >90% of their hypothalamic hypocretin neurons Narcoleptics without cataplexy or with atypical cataplexy usually have normal CSF levels of hypocretin

31 Pathophysiology: Hypocretin Cell Loss in Human Narcolepsy Normal Narcolepsy 50 microns Courtesy J. Siegel, UCLA

32 10% 24%

33 CSF orexin useful in: Patients unable to discontinue psychotropic medications before MSLT False-negative MSLT Atypical cataplexy If HLA typing negative, it is not recommended to do CSF evaluation

34 2 Hit hypothesis Some say we have supporting evidence in..finland (etc)

35 H1N1 Swine Flu Vaccination Pandemrix is AS03, a so-called adjuvant system, which is an agent added to a vaccine to boost its efficiency. AS03 contains squalene, which is extracted from shark liver oil.

Finland Experience Nearly all of the Finnish children had narcolepsy with cataplexy, and all of them had the HLA DQB1*0602 subtype (Partinen, 2012).

36 Finland Experience Nearly all of the Finnish children had narcolepsy with cataplexy, and all of them had the HLA DQB1*0602 subtype (Partinen, 2012). In Finland, like other nations, an increase occurred only among the very young. Those older than 20 years did not experience an increase in narcolepsy above background levels

37 H1N1 Vaccine

38 Three States of Being in Sleep Medicine Can you name them?

39 Three States of Being Wake NREM REM

40 Ascending arousal regions Control of NREM Control of REM

41 My Analogy 3 position light switch Dimmer switch

42 Orexin activates arousal regions Orexin TMN Raphe LC PPT LDT ( REM-on ) Neurons neurons Motor Neurons

43 Orexin stabilizes the flip-flop GABA? Glutamate Orexin Homeostatic Sleep Drive Stabilizes Behavioral State GAL GABA Circadian Waking Drive ORX NE 5-HT

44 Diagnosis: Evaluation History Sleepiness, cataplexy, other dissociated REM sleep features Polysomnography (PSG) Exclude other causes for EDS (sleep apnea) Document sleep duration Identify and treat associated conditions SOREM on PSG* Multiple Sleep Latency Test (MSLT) Objective sleepiness Sleep onset REM periods (SOREMPs)

45 Diagnosis: Polysomnographic Findings Short sleep latency Sleep onset REM period in 50% of narcolepsy patients Sleep fragmentation (REM and NREM) Increased number of arousals Increased stage 1 sleep Low(ish) sleep efficiency Frequently associated with periodic leg movements

46 Diagnosis: Polysomnographic Findings

47 Pathophysiology: Sleep / Wake Fragmentation Untreated Patient Control Normal and narcoleptic 24-hour PSG recordings Adapted from Rogers AE et al. SLEEP 1994;17

48 New in the ICSD-3, 2014 New classification system Narcolepsy I (aka hypocretin deficiency syndrome, narcolepsy-cataplexy, narcolepsy with cataplexy). ICD-10 code G Narcolepsy II (aka narcolepsy without cataplexy). ICD-10 code G ~ 15-25% of cases reported New diagnostic criteria

49 Narcolepsy I Diagnostic Criteria A and B must be met: A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring > 3 months B. One or both of the following: Cataplexy + MSL of <8 min and >2 SOREMPs. A SOREMP within 15 minutes of SO on preceding MSLT may replace on of the SOREPs on the MSLT Low CNS hypocretin (<110 pg/ml or <1/3 mean values of normal subjects)

50 Subtypes Narcolepsy I Narcolepsy Type I due to a medical condition Seen with lesions of the posterior hypothalamus, midbrain, or pons Lesions are usually due to tumors, strokes, trauma, or multiple sclerosis. May involve the orexin neurons or their connections to REM- and wake-regulatory regions. Narcolepsy without cataplexy with low CSF Hypocretin-1 levels If diagnostic criteria A and B2 are met.

51 Narcolepsy II Diagnostic Criteria A E must be met: A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring > 3 months B. MSL of <8 min and >2 SOREMPs. A SOREMP within 15 minutes of SO on preceding MSLT may replace on of the SOREPs on the MSLT C. Cataplexy is absent (note 10% may develop changes their classification).

52 Narcolepsy II Diagnostic Criteria A E must be met: D. Either CSF hypocretin 1 concentration has not been measured or it is not low (it is >110 pg/ml or > 1/3 mean values of normal subjects). E. The hypersomnolence and/or MSLT findings are not better explained by other causes such as insufficient sleep, OSA, DSPS, meds or the withdrawal of meds.

53 Preparing for MSLT Step one: Discontinue sleep-altering/rem suppressant drugs 14 days before test (or more five times the half life of drug/metabolites) Traditional stimulants Modafinil & Armodafinil SSRIs, exception need off Prozac 6 weeks! TCAs and MAOIs Benzodiazepines, sedatives and muscle relaxers Weight loss drugs, for example phentermine AND..ask about recreational drugs (e.g. MJ is REM suppressant/rebound on w/d)

54 Preparing for MSLT Step two: Actigraphy and Sleep Diaries Actigraphy is strongly recommended in the ICDS-3 prior to PSG/MSLT 7 hours TIB (or more) x 7d

55 Practice Parameters

56 Clinical Practice Guideline for the use of the Multiple Sleep Latency Test and Maintenance of Wakefulness Test (Expected publication: Summer 2019)

57 Standardized protocol Diagnosis: MSLT Always performed after a nocturnal polysomnogram, TST at least 6 hours (PP), goal at least 7 hours (ICSD-3) Five 20-minute naps. Four nap ok if 2 SOREMPs already. Naps every 2 hours. No smoking or vigorous activity 30 min before each nap. No napping in between. Measures sleep latency and REM sleep onset

58 Diagnosis: MSLT Adults* Adapted from Mitler et al. Psychiatric Clinics of North America, 1987;10.

59 Other aspects of running the MSLT First nap begins 2-3 hours after morning wake-up Each nap opportunity lasts 20 min after lights out OR 15 min after onset of sleep Sleep environment must be quiet and comfortable. If not (sirens, construction, etc), note it and maybe repeat the nap Toxicology screen to check for illicit drugs / medications that can alter the MSLT HLA testing in some centers

60 Quiz - Question 1 (true or false): It is ok to run a MSLT after a split night study.

61 Quiz - Question 1 (true or false): It is ok to run a MSLT after a split night study. NO!

62 Quiz - Question 2 (true or false): The conventional recording montage for the MSLT includes central EEG (C3-A2, C4-A1) and occipital (O1-A2, O2-A1) derivations, left and right eye electrooculograms (EOGs), mental/submental electromyogram (EMG), and electrocardiogram (EKG).

63 Quiz - Question 2 (true or false): The conventional recording montage for the MSLT includes central EEG (C3-A2, C4-A1) and occipital (O1-A2, O2-A1) derivations, left and right eye electrooculograms (EOGs), mental/submental electromyogram (EMG), and electrocardiogram (EKG). TRUE!

64 Quiz - Question 3 (true or false): Sleep onset for the clinical MSLT is determined by the time from lights out to the first epoch of any stage of sleep.

65 Quiz - Question 3 (is true): Sleep onset for the clinical MSLT is determined by the time from lights out to the first epoch of any stage of sleep. including stage 1 sleep. Sleep onset is defined as the first epoch of greater than 15 sec of cumulative sleep in a 30-sec epoch.

66 Quiz - Question 4: In order to assess for the occurrence of REM sleep, in the clinical MSLT the test continues for 15 minutes from after the first epoch of sleep. Is this duration of 15 minutes determined by clock time or determined by a sleep time of 15 minutes?

67 Quiz - Question 4: In order to assess for the occurrence of REM sleep, in the clinical MSLT the test continues for 15 minutes from after the first epoch of sleep. The duration of 15 minutes determined by clock time

68 Scoring the MSLT Score sleep stages of each nap Sleep latency - Good alpha helps a lot. Normal is > 10 min. REM latency is taken as the time of the first epoch of sleep to the beginning of the first epoch of REM sleep regardless of the intervening stages of sleep or wakefulness. REM sleep - It needs to be definite (scoring manual) REM sleep. Transient atonia or eye movements during NREM sleep are common in narcolepsy but don t count. Can see REM without atonia as well.

69 Short MSLT latencies Acute or chronic sleep deprivation (Did the patient get at least 6 hours of sleep on the prior night?) Actigraphy data? Disorders that produce sleepiness: OSA, PLMS, sedating drugs, circadian phase delay/rhythm disorders, etc (Should you even run a MSLT if the prior night s baseline study revealed OSA? What if pt was just begun on CPAP?)

70 Sleep-onset REM periods About 20% of normal young people may have REM sleep in one nap (usually in the AM) REM sleep in >2 naps is suggestive of narcolepsy, but can be caused by by other things that increase REM pressure (e.g. OSA, withdrawal from REM-suppressing drugs, REM sleep deprivation, etc)

71 Treatment of Excessive Sleepiness - Examples Methylphenidate (Ritalin, Concerta) Dextroamphetamine (Dexedrine, Adderall) Modafinil (Provigil) Armodafinil (Nuvigil) Gamma Hydroxybutyrate (Xyrem) Typical dose 20 mg SR 1-2x/day and/or mg 2x/day 10 mg SR each AM or 5-30 mg 2x/day mg each AM or 200 mg 2x/day mg per day g at bedtime and 3-4 hours later Side effects Restlessness, hallucinations, tachycardia, hypertension Insomnia, tachycardia, dry mouth, decreased appetite Headache (34%), nausea (11%), nervousness (7%) Headache (17%), nausea (7%), dizziness (5%), insomnia (5%) AM sedation, nausea, dizzyness

72 Treatment of cataplexy - Examples Venlafaxine (Effexor) Fluoxetine (Prozac) Clomipramine (Anafranil) Gamma Hydroxybutyrate (Xyrem) Typical dose mg XR each AM mg each AM mg at bedtime g at bedtime and 3-4 hours later Side effects Few side effects, nausea Same, dry mouth Anticholinergic effects, somnolence, weight gain AM sedation, nausea, dizzyness

73 Pharmacotherapy: Fragmented Nocturnal Sleep Variable clinical practice, often not treated If treated, does not normalize daytime alertness Can use sedative/hypnotics or sedating antidepressants Avoid hypnotics with daytime carryover GHB is also effective*

74 Behavioral Interventions Limited effectiveness as only therapy e.g. napping, improving sleep habits Sleepiness/fragmented sleep exacerbated by: Poor sleep hygiene Shift work Alcohol & recreational drugs Drowsy driving precautions

75 Conclusions Narcolepsy is a disabling and prevalent disorder Narcolepsy is an impaired ability to maintain wakefulness and a tendency for elements of REM sleep such as paralysis and hallucinations to intrude into wakefulness. Narcolepsy is due to impaired signaling by orexin (hypocretin)

76 Conclusions The disorder can be reliably and objectively diagnosed Diagnosis often aided by the PSG/MSLT with the appropriate protocol Treatment is effective and improves quality of life Understanding of narcolepsy is advancing rapidly

77 Thank You!!

Narcolepsy. Jon R. Doud, MD Pulmonary Physician Midwest Center for Sleep Disorders Aurora, IL

Narcolepsy. Jon R. Doud, MD Pulmonary Physician Midwest Center for Sleep Disorders Aurora, IL Narcolepsy Jon R. Doud, MD Pulmonary Physician Midwest Center for Sleep Disorders Aurora, IL Narcolepsy A central nervous system disorder that is an important cause of persistent sleepiness. The second