1 https://www.youtube.com/watch?v=P7BR5rwUbak

2 Narcolepsy: Theory and Treatment UpdateHeather Kirkpatrick, Ph.D., ABPP Megan Meade-Higgins, PsyD. Laci Zawilinski, Ph.D. Genesys Regional Medical Center Flint, MI

3 We have nothing to discloseDisclosures We have nothing to disclose

4 Goals and Objectives Gain an understanding for the typical treatment for narcolepsy as well as emerging effective treatments Develop awareness of this disorder and its immune related causes Synthesize information regarding the effect of this disorder on the patient

5 Case Examples

6 The patient voice—Narcoleptic symptoms“It’s hard to plan my day, because sometimes I get sleep attacks. It won’t go away unless I close my eyes for 5-10 minutes and kind of sleep.” “People in my field don’t understand that you need to take a nap. I always have to be on call.”

7 What is narcolepsy? Narcolepsy is a neurologically based, chronic, hypersomnic sleep disorder that is associated with REM sleep disturbances and includes: Poor sleep-wake cycles Poor overnight sleep and periods of extreme daytime sleepiness Sudden irresistible bouts of sleep that can strike at any time lasting a few seconds to several minutes

8 Who gets narcolepsy? Males and females equally throughout the worldNarcolepsy typically appears in childhood, adolescence or young adulthood (between ages of 7-25) Symptoms can sometimes present later in life and are lifelong 1:3000 Americans

9 Symptom Review

10 Excessive daytime sleepinessMain Symptoms Excessive daytime sleepiness Cataplexy Sleep paralysis Hallucinations Cohen, 2012

11 1) Excessive daytime sleepiness (EDS)“a persistent sense of mental cloudiness, a lack of energy, a depressed mood, or extreme exhaustion” (NIH fact sheet, 2016) Most common symptom of narcolepsy Add to symptom 1)- Difficulties with focus, concentration, memory lapses at school, work or home; HOWEVER, people tend to awaken from these unavoidable sleeps feeling refreshed and their fatigue subsides for an hour or 2; sometimes very brief, a few seconds- about 40% of people perform automatic behaviors during these times ie: habitual, “second nature” activities like driving, taking notes; cannot recall actions, almost always impaired

12 2) Cataplexy Sudden loss of muscle tone and a loss of voluntary muscle control while awake Resembles interruption of muscle activity while in REM sleep that inhibits movement- same group of neurons becomes inactive during cataplectic attacks Usually occurs several weeks/months after onset of EDS 50% of people develop cataplexy within 1 yr; 85% in 3 years

13 Cataplexy Can be minor or result in complete physical collapse where individuals are unable to move, speak or keep their eyes open During any type of episode, people remain fully conscious (distinguishing it from seizure disorders) Can occur spontaneously, but usually has a trigger, ie: sudden, strong emotion, ie: fear, anger, stress, excitement, or humor Laughter is allegedly the most common trigger!

14 3) Sleep paralysis Temporary inability to move or speak before falling asleep or waking Similar to REM inhibitions to voluntary muscle activity Lasts a few seconds to minutes; person remains fully conscious Feels as if person is undergoing cataplectic attack affecting the entire body Neither cataplexy nor sleep paralysis results in permanent dysfunction; after episodes, people rapidly recover their full capacity to move and speak

15 4) Hallucinations Can accompany sleep paralysis and occur when falling asleep, waking, or during sleep Hypnagogic- occur during sleep onset Hypnopompic- occur during waking Images are unusually vivid, seem real, can be frightening; sometimes involve other senses besides sight

16 Symptoms of narcolepsyMost people with narcolepsy do not have difficulty falling asleep but do have trouble staying asleep REM sleep disturbances may include insomnia, vivid dreaming, sleep talking, acting out while dreaming, leg movements 10-25% of people with narcolepsy display all four symptoms during the course of illness

17 Symptoms of narcolepsyTend to begin subtly and may change over time Contrary to myth, people with narcolepsy do NOT spend more time asleep than others in 24 hours May fall asleep in inappropriate times and places, which may be dangerous, ie: driving, hazardous activities

18 Symptoms of narcolepsyIf left untreated, narcolepsy can affect psychological, social and cognitive function and undermine academic and social activities, ie: An increase in work-related and transit accidents, Sexual dysfunction Neuropsychological alterations (ie: increased reaction time, decreased executive function) Overall reduction in quality of life (school, jobs, marriages, social life)

19 Differential DiagnosesOther sleep disorders (ie: sleep apnea) Viral or bacterial infections Mood disorders (ie: depression) Chronic illnesses Medications, caffeine, alcohol, nicotine Sleep deprivation and interruption of work-sleep cycle

20 Etiology of narcolepsyHypocretin, aka Orexin Genetic factors Autoimmune Hypothesis Environmental factors

21 Hypocretin, aka Orexin Click to add text Click to add text

22 Hypocretin, aka Orexin Most people with narcolepsy have low levels of the neurotransmitter HYPOCRETIN which promotes and sustains wakefulness People who have narcolepsy have greatly reduced numbers of hypocretin-producing neurons

23 Hypocretin, aka Orexin

24 Genetic factors Most cases of narcolepsy are sporadic, aka no known family history Only 25% of monozygotic twins have narcolepsy BUT some families do show a tendency: up to 10% of people with narcolepsy have a close relative with same symptoms

25 Genetic factors Majority of people who have narcolepsy have a specific human leucocyte antigen (HLA) gene variant called DQB1*0602 Also have specific alleles at a gene called the T-cell receptor alpha (TCRA) Variations in these genes may predispose an individual to develop narcolepsy through a route that involves changes in autoimmune system function when other causative factors are also present

26 Genetic factors Other genes may contribute to the development of narcolepsy Groups of neurons especially in brain stem and central brain interact to control sleep Studies on dogs with narcolepsy have found a gene mutation that disrupts the signal from hypocretins produced by neurons in the hypothalamus and produces narcolepsy symptoms

27 AUTOIMMUNE HYPOTHESISPeople with narcolepsy have greatly reduced numbers of hypocretin-producing neurons and certain genetic subtypes They may have an increased susceptibility to immune attack on hypocretin neurons in the hypothalamus leading to their degeneration and destruction Reasons for this are still unknown and being studied… If need more on studies, NIH fact sheet has details.

28 AUTOIMMUNE HYPOTHESIS and Environmental FactorsNarcolepsy onset generally follows a seasonal pattern – higher in spring and summer, following winter upper airway infection season Studied close to onset, people with narcolepsy have high levels of antibodies to a marker called ASO which is a response to a bacterial infection such as strep throat

29 AUTOIMMUNIE HYPOTHESIS and Environmental FactorsALSO… Growing evidence suggests exposure to H1N1 virus (swine flu) or a special form of the vaccine (Pademrix, administered in Europe) may act as rare triggers for the disease Not understood if infectious agents are direct triggers or increase likelihood of autoimmune response and disease indirectly

30 Other Environmental factorsSome narcolepsy can be caused by traumatic injury to the parts of the brain involved in REM sleep Tumor growth, vascular malformations, other disease processes Infections, exposure to toxins, dietary factors, stress, hormonal changes (puberty, menopause), alterations in sleep schedule

31 How is narcolepsy diagnosed?Clinical exam Thorough mental health history Sleep journal (cataplexy most specific symptom- rarely present outside narcolepsy)

32 How is narcolepsy diagnosed?Polysomnogram (PSG) Multiple Sleep Latency Test (MSLT)- Performed during the day Measures time it takes to fall asleep and if REM is intruding during waking hours Pinpoints occurrence of abnormally timed REM episodes through EEGs Person takes multiple naps IF person enters REM within a few minutes of sleep onset in at least two of the naps, narcolepsy is indicated

33 How is narcolepsy diagnosed?Now with autoimmune hypothesis: Human leukocyte antigen (HLA) typing may also help diagnose narcolepsy HLA typing is a marker of viral infection, and most HLA-associated disorders are autoimmune Certain alleles (genetic information) located on chromosome 6 are strongly associated with narcolepsy/cataplexy GOLD-STANDARD TEST: Cerebrospinal fluid (CSF) is tested, and if level of hypocretin is low, hypocretin deficiency can be established as the cause of narcolepsy

34 Treatment Review

35 Treatment of NarcolepsyPharmacologic Interventions Non-Pharmacologic Excessive Daytime Sleepiness Cataplexy Both Goal: improve sleep attacks normal alertness Goal: improve sleep attacks during intense emotions

36 Treatment of NarcolepsyExcessive Daytime Sleepiness Cataplexy Both Goal: improve sleep attacks Non-Pharmacologic Interventions Pharmacologic Interventions Non-Pharmacologic Goal: normal alertness Cataplexy Goal: improve sleep attacks during intense emotions Modafinil first line treatment; non amphetamine, increase dopaminergic signaling Started at 200mg in am and titrated up to 300mg-400mg as needed Persistent daytime sleepiness may benefit from 200mg in am and 200mg in afternoon Armodafinil active R enantiomer of modafinil----Similar to modafinil Methylphenidate- CNS stimulant Started at 10mg BID, 2nd dose no later than 3pm Amphetamines—CNS stimulant Dextroamphetamine and lisdexamfetamine Second line Starting dose 5mg BID IR and then switch to ER Methylphenidate Modafinil Armodafinil Amphetamines

37 Treatment of NarcolepsyExcessive Daytime Sleepiness Cataplexy Both Goal: improve sleep attacks Pharmacologic Interventions Non-Pharmacologic Interventions Goal: normal alertness Target: Cataplexy Goal: improve sleep attacks during intense emotions REM sleep-suppressing drugs Antidepressants Venlafaxine, atomoxetine, fluoxetine Venlafaxine mg in the am TCAs—decrease uptake of aminergic NTs Sodium oxybate—may act through GABA-B receptors, precise mechanism unknown Given 3g dose as a liquid at bedtime, second dose 2.5 to 4 hours later to start Can go up to 4.5 mg twice per night Dose dependent side effects REM Sleep Suppressing Meds Antidepressants TCAs Sodium Oxybate

38

39 Medications: Adverse & Side EffectsModafinil: good choice for older patients; uncommon side effects, side effects = headache, nausea, dry mouth, anorexia, diarrhea May increase blood pressure—used cautiously in people with heart disease Decreases effectiveness of oral contraceptives Methylphenidate: sympathomimetic side effects can be problematic May increase systolic blood pressure High doses psychosis, anorexia, or require psych hospitalization

40 Medications: Adverse & Side EffectsAmphetamines: Cardiovascular events, psychiatric events REM-Sleep-suppressing drugs Abrupt withdrawal can trigger status epilepticus—severe rebound cataplexy that can last up to 72 hours Sodium oxybate “date rape drug” and potential for abuse, nausea, dizziness, urinary incontinence, and worsening of sleep walking

41 Medications: Efficacy & SummaryModafinil, methylphenidate, and amphetamines are treatment of choice for daytime sleepiness May choose modafinil due to: Existence of RCTs and placebo-controlled studies with improved daytime sleepiness Less adverse effects REM sleep suppressing medication (e.g., venlafaxine, fluoxetine, atomoxetine) as first line for cataplexy May choose venlafaxine due to: Data from clinical trials are lacking but extended release venlafaxine to be effective at a dose of 37.5 to 150mg every morning

42 Treatment of NarcolepsyDaytime Sleepiness Cataplexy Both Pharmacologic Interventions Non-Pharmacologic Interventions Goal: normal alertness Goal: improve sleep attacks Goal: improve sleep attacks during intense emotions Psychosocial Support Psychotherapy

43 Beyond Meds Support Groups Identification of ResourcesPsychosocial Support Behavioral Interventions CBT-N Psychotherapy Support groups that focus on coping skills and identification of community resources to assist with medical or administrative issues

44 Beyond Meds Behavioral Interventions Avoid certain drugs Sleep HygieneBenzos, opiates, antipsychotics, and ETOH Theophylline or excessive caffeine Prazosin Sleep Hygiene Increased EDS Can worsen cataplexy Behavioral Avoid certain drugs Benzos, opiates, antipsychotics, and alcohol  increased daytime sleepiness Theophylline or excessive caffeine --? Increased daytime sleepiness Prazosin-can worsen cataplexy Sleep hygiene 1=-2 well timed 20 min naps Psychosocial Support Support groups that focus on coping skills and identification of community resources to assist with medical or administrative issues

45 Cognitive-Behavioral Therapy for Narcolepsy (CBT-N)Target: Distress/Disability Goal: symptom modification through learning Empirical evidence: Guidelines from several countries recommend use of cognitive and behavioral strategies as adjunctive treatment to lessen patient dysfunction & obtain best response w/ lowest possible med dose CBT-N vs Control= sig improvement in quality of life and EDS in CBT-N group Agudelo, H. A., Correa, U. J., Sierra, J. C., Pandi-Perumal, S.R., & Schenck, C.H. (2014). Cognitive behavioral treatment for narcolepsy: Can it complement pharmacotherapy? Sleep Science, 7,

46 CBT-N Components Cognitive Behavioral EducationalModification of beliefs, motivations, and emotions that may maintain narcolepsy Behavioral Techniques aimed at changing sleep-disordered behavior or sleep related disorder variables that are not compatible Educational Nature of disease Mechanism of drug action Medication precautions Therapeutic relationship Techniques aimed atchanging sleep-disordered behavioror sleep related disorder variables that are not compatible Agudelo, H. A., Correa, U. J., Sierra, J. C., Pandi-Perumal, S.R., & Schenck, C.H. (2014). Cognitive behavioral treatment for narcolepsy: Can it complement pharmacotherapy? Sleep Science, 7,

47 The patient voice--Meds“All the meds I tried, they didn’t work well. They make me anxious.” “My wife doesn’t want me to take the meds. She says I have changed. I have no patience anymore, and am more aggressive.”

48 Case Examples

49 Case Examples 23 year old European American woman presents to PCP to establish care. Diagnosed with Narcolepsy approximately 5 months ago but looking back, believes that symptoms began as a teenager “I slept all summer at the age of 16” CC: “the narcolepsy medications make me really anxious and I can’t sleep”

50 Case Example--June HPI: increased sleepiness- increased day time sleepiness- takes many naps throughout the day +cataplexy- 2 years ago, noticed knees give way/pt collapses while laughing which is limiting social interactions. Pt admits to sleep paralysis- describes this as waking up and being aware of surroundings but can't move because it feels as though someone is putting pressure on chest. 

51 Case Example--June HPI: increased sleepiness- Pt states she has always had increased day time sleepiness- takes many naps throughout the day, over past 2 years has had frequent sleep attacks- increased sleepiness, can't keep eyes open, needs to "nod off" for a few minutes, wakes up and improved for a few hours. If pt does not sleep, starts getting shaky. Sleep attacks occur about twice a day. Most amount of time pt can be up w/o sleep attack is 4 hours. Sleep attacks occur whiles driving as well- is able to predict when it is going to happen as sleepiness develops over several minutes- pt has never fallen asleep while driving. Pt has never been formally worked up for this before-was taking un-prescribed adderall last year 10mg daily-made her feel "high" which she did not like. Pt started then taking un-prescribed ritalin 10mg daily, better response than adderall. +cataplexy- 2 years ago, noticed knees give way/pt collapses while laughing which is limiting social interactions. Some association w/anxiety as well. Pt admits to sleep paralysis- describes this as waking up and being aware of surroundings but can't move because it feels as though someone is putting pressure on chest.  Pt reports some snoring at night, has never been told that she stops breathing while sleeping; was supposed to have sleep study but never completed this. Pt currently smoking 1 pack per week x 7 years- Denies HA, changes in vision, N/T, weakness, slurred speech, seizure-like activity, loss of bowel or bladder control, tongue trauma. 

52 ROS normal except for sleepiness/fatiguePE all within normal limits Past Medical History · History of Anxiety · History of Chronic lower back pain Social History Medical marijuana daily Current every day smoker (305.1) (F17.200) 

53 Vital Signs [Data Includes: Current Encounter]Temperature: 97.6 F Heart Rate: 72 Respiration: 16 Systolic: 120, LUE, Sitting Diastolic: 62, LUE, Sitting Height: 5 ft 3 in Weight: 147 lb 4 oz BMI Calculated: 26.08 BSA Calculated: 1.7 LMP: 10Mar2016 Pain Scale (0-Least, 10-Worst): 0

54 Case—PCP Initial Plan Increased day time sleepiness-1. seizures vs OSA vs anemia vs metabolic vs psychiatric sx, r/o narcolepsy. 2. Order EEG, sleep study, CBC, B12, folate, TSH, psychology referral. 

55 Pulmonology/Sleep Medicine ConsultSuspects Narcolepsy Orders polysomnography Multiple Sleep Latency test Confirmed diagnosis of Narcolepsy (age 23)

56 Pulmonology/Sleep Medicine consult1. Narcolepsy (suspected dx) 2. Cataplexy 3. Hypnagogic Hallucinations 4. Excessive daytime sleepiness, signs and symptoms consistent with possible narcolepsy 5. GERD 6. Dyspnea 7. Nocturia 8. Snoring 9. Uncompensated short-term memory deficit 10. Sleep drunkenness 11. Unable to concentrate 12. Nicotine Dependence

57 Pulmonary/Sleep Medicine workupPolysomnography rules out apnea Multiple Sleep Latency Test reports “excessive daytime sleepiness with REM onset multiple naps” Confirms diagnosis of Narcolepsy

58 Neurology workup Abnormal EEG“rare, focal sharp waves are consistent with a hemispheric dysrhythmia best seen in the right frontal, temporal and parasaggital areas. The record is consistent with a lowered seizure threshhold.” Recs MRI of brain to r/o hypothalamic lesion Recs repeat EEG with sleep deprivation

59 Okay, so we have narcolepsy with cataplexy4/2016 amphetamine and dextroamphetamine (Adderall) Paranoia, anxiety and “overthinking” Change to methylphenidate (Ritalin) 8/2016 Severe anxiety, cataplexy is worse; Mother passed away recently Prefers amphetamine and dextroamphetamine (Adderall). Changes to Adderall 20mg qam, Adderall 10mg qhs, fluoxetine 20mg daily 9/2016 Pt. declines evening dose of stimulant and has d/c fluoxetine Physician orders dexedrine

60 Okay, so we have narcolepsy with cataplexy10/2016 Psychology referral completed Anxiety bad; some bereavement Change to modafinil 12/2016 Modafinil better Change to modafinil bid 3/2017 Pt. uses stimulants sparingly; using kratum oil SSRI for depression

61 Kratom Oil Kratom is a tree-like plant in the same botanical family as the coffee tree and gardenia (Rubiaceae), native to Southeast Asia. Kratom has been used for centuries in Thailand, Malaysia, and Indonesia to combat fatigue and, empirically, to treat pain and opioid withdrawal symptoms. Effects are reported to be dose-dependent. Doses of 1-5 g have a stimulant effect and increase energy. Moderate to high doses (5-15 g) have opioid-like effects, including euphoria. Doses > 15 g can cause extreme sedation and stupor, similar to opioids.

62 Kratom Kratom is currently legal in most states.Acute adverse effects include anxiety - sedation -itching irritability - nausea aggression - constipation Common presentations of overdose include palpitations and seizures. Withdrawal symptoms include myalgia, insomnia, fatigue, and chest discomfort.

63 CBT-N June Anx/Dep Behavioral Dream work CBT Grief SupportScheduled Naps Relaxation Behavioral Guided dream imagery Hypnosis Dream work

64 Case Example--Felix 53 year old Latino manDiagnosed with narcolepsy approximately 15 years ago Managing by self until recently—5 hour energy drinks Trial of stimulants—Adderall, Modafinil, armodafinil

65 CBT-N Felix Adjustment Behavioral Career Coun CBTChallenge assumptions “lazy” Education about narcolepsy Adjustment Scheduled Naps Sleep Satiety Relaxation Sleep Hygiene Behavioral Exploration of job-person fit now he has disability Boundary counseling Career Coun

66 Therapy Notes Both individuals were very unhappy with the medication side effects of stimulants Both responded well to counseling designed to aid their adjustment to living with a chronic disorder Both came to the conclusion that this was a disease they would need to “manage” and that currently a “cure” was not available.

67 Therapy Notes Both were eager to explore behavioral strategies to help manage their symptoms

68 Questions What has surprised you? Where are your growing edges?What can you take home?