Slide 1 The following slide set, with accompanying instructional notes and references, has been designed to serve as the foundation for a teaching curriculum.

The following slide set, with accompanying instructional notes and references, has been designed to serve as the foundation for a teaching curriculum on recognizing and treating narcolepsy. It is intended to be a resource for lecturers presenting to audiences with a broad range of experience and training including medical students, medicine and family practice residents, primary care physicians and physicians trained in sleep disorders medicine. Level I slides identify key topics and provide information appropriate for a one-hour presentation to health care professionals. Level II slides (identified in these notes) include greater detail -- study outcomes, illustrations, graphs or areas of controversy -- and are intended for a more advanced audience.

Objectives Recognize the clinical presentation of narcolepsy
Understand the consequences of narcolepsy Learn about our evolving understanding of narcolepsy Explore the pathophysiology of narcolepsy Review standard diagnostic criteria for narcolepsy Compare current treatments for narcolepsy and discuss possible future treatments Slide 2 Misdiagnosis is commonly reported by patients with narcolepsy. The first objective of this presentation is to provide methods for recognizing the symptoms of narcolepsy. Narcolepsy is a disabling disorder that was initially thought to be behaviorally-based but is now recognized to have a physiological basis. Recent research has focused on abnormalities of the hypocretin system as the cause of narcolepsy. Sleep laboratory testing can provide tools to reliably diagnose narcolepsy. Current treatments can provide substantial relief from the symptoms of narcolepsy; new treatments are under development.

Clinical Presentation of Narcolepsy
Prevalence Level of Disability Symptoms Consequences Slide 3 In this talk we are going to review the prevalence of narcolepsy and the level of disability usually encountered. There are several variants of narcolepsy, each with a distinct set of clinical symptoms. The following slides will review these symptoms and the consequences they have on the lives of patients with narcolepsy.

ICSD-2 Criteria for Narcolepsy
Characterized by excessive sleepiness Two variants are described: Narcolepsy With Cataplexy Narcolepsy Without Cataplexy A third diagnosis, Narcolepsy Due to Medical Condition, is used when the criteria for narcolepsy are met and the onset of the disorder appears to be the consequence of a medical condition Slide 4 The International Classification of Sleep Disorders, Second Edition1 defines narcolepsy as a disorder characterized by excessive sleepiness. The complaint of excessive daytime sleepiness occurring almost daily for at least three months is the essential feature for all diagnoses of narcolepsy. Two variants are defined: narcolepsy with cataplexy and narcolepsy without cataplexy. Cataplexy is defined by a set of clinical criteria. When present, it is highly specific for narcolepsy. A third diagnosis, narcolepsy due to medical condition, is used when the criteria for narcolepsy are met and the onset of the disorder appears to be the consequence of a medical condition. Narcolepsy due to medical condition may occur with or without cataplexy. 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

Narcolepsy With Cataplexy: Prevalence
Slide 5 Contrary to widely held views, narcolepsy is not a rare disorder. Well designed studies have shown that the prevalence of narcolepsy with cataplexy in western European countries and North America approaches 0.05% (range 0.02% %), or one case for every 2,000 people.2 This figure is not very different from that reported for multiple sclerosis (range 0.06% %), another common neurological disorder.3 Some studies have shown that narcolepsy may be more frequent in Japan and rare in Israel. 2. Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50(2 Suppl 1):S16-22. 3. Epidemiology (Accessed December 13, 2005, at Data from Mignot, 1998

Quality of Life in Narcolepsy
Slide 6 Narcolepsy is truly a disabling condition. This slide shows the results of a study using a standardized scale for quality of life, the SF-36.4 It compares the results of patients with narcolepsy to the general healthy population, and to patients with post-partum depression5, multiple sclerosis and Parkinson’s disease.6 Narcoleptic patients report significant role limitations due to physical problems, lowered vitality, lower social functioning and role limitations due to emotional problems. 4. Beusterien KM, Rogers AE, Walsleben JA, et al. Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep 1999;22(6): 5. Da Costa D, Dritsa M, Rippen N, Lowensteyn I, Khalife S. Health-related quality of life in postpartum depressed women. Arch Womens Ment Health 2006;9(2): 6. Riazi A, Hobart JC, Lamping DL, et al. Using the SF-36 measure to compare the health impact of multiple sclerosis and Parkinson's disease with normal population health profiles. J Neurol Neurosurg Psychiatry 2003;74(6):710-4. Data From Da Costa et al 2005, Riazi et al 2003 and Beusterien et al 1999

Clinical Presentation: Symptoms
Excessive daytime sleepiness (EDS) Cataplexy Hypnagogic hallucinations Sleep paralysis Fragmented nocturnal sleep Other associated features Tetrad Pentad Slide 7 The clinical presentation of narcolepsy includes the distinct set of symptoms listed here. The frequent association of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis in patients with narcolepsy has been called the clinical “tetrad.”7 Disturbed nocturnal sleep is so common in narcoleptics that it is often included as part of the narcolepsy “pentad”. Other less common features associated with narcolepsy include depression, headaches and frequent psychosocial problems. 7. Yoss RE, Daly DD. Criteria for the diagnosis of the narcoleptic syndrome. Proc Staff Meet Mayo Clin 1957;32(12):320-8.

From ICSD-2 except cataplexy estimate from Anic-Labat et al 1999
Symptom Prevalence From ICSD-2 except cataplexy estimate from Anic-Labat et al 1999 Slide 8 By definition, all narcoleptics have excessive daytime sleepiness. This slide illustrates, however, that not all of the other common symptoms are present in patients with the diagnosis of narcolepsy. Hypnagogic hallucinations and sleep paralysis occurred in 40% to 60% of patients and fragmented sleep in about 50%. In a large survey of patients with sleep disorders, Anic-Labat et al.8 found that 85.1% of narcoleptics had clear-cut cataplexy. All patients with cataplexy were diagnosed with narcolepsy. Of the other 920 subjects, 29 had “doubtful” cataplexy. 8. Anic-Labat S, Guilleminault C, Kraemer HC, Meehan J, Arrigoni J, Mignot E. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 1999;22(1):77-87.

Faces of Sleepiness Slide 9
Excessive daytime sleepiness is the hallmark of narcolepsy. Patients with narcolepsy always present with episodes of intense sleepiness on a background of chronic sleepiness or fatigue. Sleepiness also presents as frequent napping, described as refreshing as opposed to making symptoms worse. Napping may occur in inappropriate situations. However, situations that are typically associated with sleepiness (warm rooms, large meals or long car drives) are particularly challenging for narcoleptic patients.

Clinical Sleepiness “I’ve fallen asleep pretty much everywhere. I fall asleep at work, at the movies, in the car and at home. My most impressive story is that I fell asleep at the basketball arena during a playoff game. It was a close game and very exciting, but I was unable to keep my eyes open.” Slide 10 Narcoleptic patients may have different criteria for what they consider to be abnormal. Some patients report a “talent” for falling asleep in boring situations so that the time passes more quickly. Most report that their friends and colleagues are aware of their sleepiness and consider it to be abnormal.

Excessive Daytime Sleepiness (EDS)
Sleep attacks on a background of chronic sleepiness or fatigue Frequent napping, usually refreshing Memory lapses and automatic behaviors Impaired attention / concentration Decreased work performance Increased drowsy driving crashes Visual disturbances Slide 11 Many narcoleptic patients describe “sleep attacks” or episodes of irresistible sleep. Napping is common, and there is usually a period of alertness following a nap. Memory lapses and automatic behavior are common. Automatic behavior refers to episodes of amnesia associated with semi-purposeful activities, such as putting a roast in the dishwasher, driving miles past an exit on an expressway, or writing off the edge of a page. Impaired attention and concentration due to sleepiness lead to decreased performance at work and increased near and actual accidents associated with drowsy driving. Visual disturbances, usually due to drooping of eyelids, are often reported.

Quantification of Sleepiness
Slide 12 Several methods are available that attempt to quantify sleepiness. The Multiple Sleep Latency Test (MSLT) and Maintenance of Wakefulness Test (MWT) are “objective” measures of the tendency to fall asleep. The Epworth Sleepiness Scale is one of many “subjective” measures. The Epworth has been studied in a variety of clinical diagnoses and is particularly sensitive to the sleepiness associated with narcolepsy.9 The measures of sleepiness are correlated, but there is some evidence to suggest that they quantify different aspects of sleepiness. Use of the Epworth or other subjective measures of sleepiness is recommended in the evaluation of patients suspected of narcolepsy. The MSLT is used both to quantify sleepiness and to evaluate sleep architecture during naps (see below). 9. Johns MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the maintenance of wakefulness test and the Epworth sleepiness scale: failure of the MSLT as a gold standard. J Sleep Res 2000;9(1):5-11. From Johns 2000

Sleepiness While Driving
Narcolepsy Controls Do you drive? 48% 63% Fall asleep driving 66 6 Cataplexy driving 29 0 Sleep paralysis driving 12 0 Frequent near accidents 67 0 Led to accidents 37 5 Higher insurance 16 1 Suspended license 7 4 Slide 13 Level II Slide Narcolepsy symptoms, especially sleepiness, often occur while driving and can impair driving ability. This slide shows the frequency with which different symptoms are reported to occur while driving.10 Untreated individuals with narcolepsy have increased rates of motor vehicle accidents. This fact needs to be recognized and addressed when considering the diagnosis of narcolepsy. Treatment needs to be instituted to limit both the patient’s and the physician’s liability. 10. Broughton R, Ghanem Q, Hishikawa Y, Sugita Y, Nevsimalova S, Roth B. Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared to matched controls. Can J Neurol Sci 1981;8(4): From Broughton et al 1981

Driving Simulator Errors
Slide 14 Using a computer simulated driving program, Findley et al.11 demonstrated that impaired vigilance resulted in performance decrements in untreated narcoleptics when compared to control subjects and to a group of patients who complained of sleepiness but did not have narcolepsy or another disorder of sleep fragmentation. The narcoleptics hit more obstacles on the simulated road test. A similar deterioration in vigilance was demonstrated for patients with sleep apnea. 11. Findley L, Unverzagt M, Guchu R, Fabrizio M, Buckner J, Suratt P. Vigilance and automobile accidents in patients with sleep apnea or narcolepsy. Chest 1995;108(3): Adapted from Findley, 1995

Percentage of Patients with Sleep Related Motor Vehicle Accidents
* * * Slide 15 Level II Slide Sleep related automobile accidents are a serious safety hazard both for the driver who falls asleep and for others on the road. In this investigation, individuals with a sleep disorder and a complaint of hypersomnolence were 1.5 to 4 times more likely to have a sleep related automobile accident.12 In patients with hypersomnia, the incidence of sleep related automobile accidents per year of excessive sleepiness was 4% to 9%. The percentage of patients with sleep related automobile accidents was highest in narcoleptics. The percentage of patients with severe sleep apnea who had sleep-related automobile accidents was almost twice that of patients with mild or moderate sleep apnea. Mean sleep latency by MSLT did not differ significantly in patients with accidents and those without. This table above summarizes values in men; similar observations held in women. This study suggests that patients with a wide variety of sleep disorders, including narcolepsy, appear to be at increased risk for sleep related automobile accidents. The severity and duration of hypersomnia are two factors that may contribute to that risk. 12. Aldrich MS. Automobile accidents in patients with sleep disorders. Sleep 1989;12(6): *Significantly different from Controls Data from Aldrich, 1989

Neurocognitive Effects
Normal short- and long-term memory when controlled for alertness Auditory Verbal Learning Test Knox Cube Rey Complex Figure Test Symbol Digits Modality Test Wechsler Memory Scale Variable attention and concentration Strub and Black’s List of Letters Slide 16 Level II Slide Many narcoleptic patients complain of subjective memory problems. However, neurocognitive testing shows that their short and long-term memory functions are normal Several studies show attention and concentration deficits, most likely due to falling asleep.14, 15 Patients who are not awake and attentive do not encode memory and thus may feel they have a memory problem rather than a problem due to their sleepiness. 13. Aguirre M, Broughton R, Stuss D. Does memory impairment exist in narcolepsy-cataplexy? J Clin Exp Neuropsychol 1985;7(1):14-24. 14. Ollo C, Squires N, Pass H, Walsleben JA, Baker T, Gujavarty KS. Electrophysiological and neurophysiological assessment of cognitive function in narcolepsy. Sleep Research 1987;16:402. 15. Rogers AE, Rosenberg RS. Tests of memory in narcoleptics. Sleep 1990;13(1):42-52.

Performance Deficits Wilkinson Addition Test
Digit Symbol Substitution Test Slide 17 Narcoleptics have significantly lower scores on multiple performance measures, relative to control subjects. This slide shows results on two performance measures, the Wilkinson Addition Test and the Digit Symbol Substitution Test.16 Scores of the patients with narcolepsy were significantly lower on both tests. Note that both narcoleptics and controls showed a steady increase in performance throughout the day (five consecutive tests) on the Wilkinson Addition Test, suggesting a learning effect. There was no learning effect on the cognitively less demanding Digit Symbol Substitution Test. 16. Mitler MM, Gujavarty KS, Sampson MG, Browman CP. Multiple daytime nap approaches to evaluating the sleepy patient. Sleep 1982;5 Suppl 2:S Control Narcoleptic Adapted from Mitler et al 1982

Cataplexy Muscle weakness triggered by emotions
Joking, laughter, excitement, anger Brief duration, mostly bilateral May affect any voluntary muscle Knee / leg buckling, jaw sagging, head drooping, postural collapse Consciousness maintained at the start Slide 18 Cataplexy is defined as a sudden loss of muscle tone provoked by strong emotion. Using the most recent diagnostic classification system1, this symptom alone is not sufficient to diagnosis cataplexy. As much as 25% of the general population reports occasional muscle weakness episodes triggered by emotions. A key factor in differentiating cataplexy from other non-specific episodes of emotion-related muscle weakness is the triggering events. Patients with narcolepsy typically have cataplexy triggered by positive emotions such as joking, laughter, or excitement. Anger is another frequent and specific triggering event.8 Episodes of cataplexy triggered exclusively by negative emotions such as stress or fear, or associated with physical activity such as running, sports or sex are not specific for narcolepsy. Episodes of cataplexy are usually of brief duration, lasting a few seconds to a few minutes. They are generally bilateral and may affect any voluntary muscle. The most frequent reports are of knee buckling or leg weakness.8 However, the most specific sites for cataplexy are those involving the face, such as jaw sagging, facial flickering (involuntary trembling of facial muscles) or head drooping. Patients with cataplexy occasionally collapse to the ground, but rarely hurt themselves. Consciousness is typically maintained at the start of the episode, but an episode of sleep may follow cataplexy. 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. 8. Anic-Labat S, Guilleminault C, Kraemer HC, Meehan J, Arrigoni J, Mignot E. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 1999;22(1):77-87.

Triggers for Cataplexy
Slide 19 One of the most useful strategies to distinguish cataplexy from other known nonspecific episodes of muscle weakness is to ask about triggering factors.8 The most common triggering factor is laughing. The most specific triggering factor is weakness occurring while joking. Anger is very frequently a trigger for cataplexy. Stress frequently triggers cataplexy but by itself is not sufficient to diagnosis cataplexy. Sex occasionally triggers cataplexy but is neither specific nor sensitive to narcolepsy. 8. Anic-Labat S, Guilleminault C, Kraemer HC, Meehan J, Arrigoni J, Mignot E. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 1999;22(1):77-87. Adapted from Anic-Labat 1999

Muscles Affected by Cataplexy
Slide 20 Cataplexy most frequently affects legs and knees.8 However, attacks affecting the face, such as drooping of the jaw or facial flickering, are more specific for cataplexy. Milder episodes of cataplexy may manifest as slurred speech or blurred vision. Patients with cataplexy occasionally fall to the ground. These falls occur slowly so the patient rarely hurts themselves. 8. Anic-Labat S, Guilleminault C, Kraemer HC, Meehan J, Arrigoni J, Mignot E. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 1999;22(1):77-87. Adapted from Anic-Labat 1999

Clinical Report of Cataplexy
“At some point my friends discovered that I would collapse when I laughed. They invented a game called “flooring Ron” in which they took turns telling jokes. The jokes that made me fall to the ground won the game.” Slide 21 Patient complaints of cataplexy vary, and the situation that provokes the episodes of muscle weakness may be a key feature for distinguishing narcolepsy. Anic-Labat et al.8 used receiver operating characteristic analysis to determine that the best indicator may be telling or hearing a joke. 8. Anic-Labat S, Guilleminault C, Kraemer HC, Meehan J, Arrigoni J, Mignot E. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 1999;22(1):77-87.

Associated Features Sleep paralysis
Sudden inability to move on falling asleep or on awakening Episodes are generally brief and benign, end spontaneously Can cause significant anxiety Slide 22 Sleep paralysis is a potentially terrifying experience that occurs on falling asleep or upon awakening. Patients find themselves unable to move limbs, speak, or breathe deeply while fully aware of the condition and able to recall it later. Sleep paralysis may be anxiety provoking at first; but with time most patients learn that the episodes are benign, rarely last more than few minutes and end spontaneously. Sleep paralysis occurs in approximately 50% to 60% of narcoleptics. Sleep paralysis may occur as an independent and isolated phenomenon in up to 3% to 5% of the normal population. Recurrent isolated sleep paralysis is less common and is listed as a parasomnia associated with REM sleep in the ICSD-2.1 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

Associated Features (cont.)
Hallucinations Vivid hallucinations at sleep onset (hypnagogic) or awakening (hypnopompic) Auditory: sounds, music, someone talking to them Visual: colored circles, parts of objects Can be vividly realistic and anxiety provoking Slide 23 Hallucinations during sleep onset (either at night or during daytime naps) are referred to as hypnagogic hallucinations. Hallucinations that occur at awakening are referred to as hypnopompic. Hypnopompic hallucinations may be more characteristic of narcolepsy. Auditory hallucinations usually range from a collection of sounds to an elaborate melody or someone talking (often harshly). Visual hallucinations usually consist of simple forms such as colored circles or parts of objects. The hallucinations can be vividly realistic such that the patient acts on them upon awakening. Some patients have also noted hallucinations that include the sensation of picking, rubbing or touching of their body; changes in the location of body parts; and feelings of levitation or extracorporeal experiences.

Associated Features (cont.)
Psychosocial problems Depression Headaches Frequent Misdiagnoses Major depression Thyroid disorder Chronic fatigue syndrome Schizophrenia Slide 24 In addition to the more common pentad of symptoms there are other features reported as part of the initial clinical presentation. Narcoleptic patients frequently have significant concurrent psychosocial problems, with the disorder affecting their marriage and relationships with their family. Narcoleptics often report problems with teachers and/or employers. Depression may be present and related to unrecognized and uncontrolled symptoms of narcolepsy. Narcoleptic patients frequently complain of headaches, including migraine headache syndrome. Patients with narcolepsy may carry diagnoses of major depression, thyroid disorder, chronic fatigue syndrome and even schizophrenia that represent misdiagnosis.

Headaches May Be Common In Narcolepsy
Dahmen et al 1999 studied 68 narcoleptics Idiopathic headache syndrome: 81% Migraine: 54% (64% females, 35% males) DMKG Study Group 2003 studied 96 narcoleptics and age-matched controls Increased frequency of tension-type headache (60.3% in narcoleptics, 40.7% in controls) No difference in frequency of migraine (21.9% in narcoleptics, 19.8% in controls) Slide 25 Level II Slide In one study, narcolepsy patients appeared to have high rates of migraine headaches. According to a study by Dahmen et al.17, 81% of interviewed narcolepsy patients reported headaches and 54% met the International Headache Society criteria for migraine headaches. The overall incidence of migraines in the general population is 3% to 5%. A study by the German Migraine and Headache Society18 failed to replicate this finding, but did report an increased frequency of tension-type headaches in narcoleptics compared to an age-matched control group. 17. Dahmen N, Querings K, Grun B, Bierbrauer J. Increased frequency of migraine in narcoleptic patients. Neurology 1999;52(6): 18. The DMKG Study Group. Migraine and idiopathic narcolepsy--a case-control study. Cephalalgia 2003;23(8):786-9.

Age of Onset of Symptoms
Slide 26 The peak age of onset of symptoms is in the late teens with a smaller peak in the second half of the second decade of life.19 Many patients report that their symptoms began in childhood, occasionally before puberty. The condition has occasionally been reported after 50 years of age. This distribution is remarkably similar in various countries and cultures. 19. Broughton R. Narcolepsy. In: Thorpy M, ed. Handbook of Sleep Disorders. New York: Dekker; 1990: Data from Parkes 1985

Prepubertal Narcolepsy
Under-recognized / misdiagnosed Sleepiness may present as: Learning disability Attention deficit hyperactivity disorder Cataplexy may be mislabeled as psychogenic behavior May be secondary to other disorders Slide 27 Level II Slide The clinical presentation of narcolepsy in children, particularly before the age of puberty, is often different from the adult presentation and requires special awareness. Symptoms are most often detected in the classroom where the sleepiness associated with narcolepsy may present as an unrecognized or misdiagnosed learning disability or as attention deficit disorder. Muscle weakness episodes representing cataplexy may be mislabeled as psychogenic in origin. Finally, narcolepsy may be secondary to other neurologic disorders such as Niemann-Pick disease type C and diencephalic tumors. Measurement of hypocretin-1 levels in the cerebrospinal fluid may be useful in the pediatric population.

Narcolepsy Time Line Hypocretin in animals, 1998
Amphetamines used for treatment, 1935 Canine narcolepsy, 1973 1880 1900 1920 1940 1960 1980 2000 Slide 28 The disorder was initially described by Westphal in 1877 and the term “narcolepsy” was coined by Gélineau in 1880 to describe a specific grouping of symptoms. Stimulant medications were first used to treat the sleepiness associated with narcolepsy in the 1930s. Narcolepsy was originally thought to be a psychiatric condition but in the 1960s it was found to be linked to abnormalities of Rapid Eye Movement (REM) sleep20, specifically a tendency to achieve REM sleep shortly after falling asleep (sleep onset REM periods or SOREMPs). A canine model of narcolepsy was developed in the 1970s exhibiting sleepiness and cataplexy which was almost identical to that seen in humans.21 In the 1980s Honda and coworkers22 found a strong statistical link between narcolepsy and certain subtypes of the HLA-DR2 antigen, suggesting a genetic foundation for the disorder. In 1999 a series of discoveries identified the hypocretin system emanating from the lateral hypothalamus as an important regulator of sleep and wakefulness. Mutations in genes associated with this system cause narcolepsy in animals.23 A single mutation in the hypocretin gene has been shown to produce narcolepsy in a very young child with disease onset at six months.24 However, most human narcolepsy cases do not have mutations in hypocretin genes. Although most cases of human narcolepsy are not associated with hypocretin gene mutations, this system is functionally involved in human narcolepsy. Most cases of human narcolepsy are associated with a lack of hypocretin in brains and CSF.24 20. Vogel G. Studies in psychophysiology of dreams. III. The dream of narcolepsy. Arch Gen Psychiatry 1960;3:421-8. 21. Mitler MM, Boysen BG, Campbell L, Dement WC. Narcolepsy-cataplexy in a female dog. Exp Neurol 1974;45(2): 22. Honda Y, Asaka A, Tanaka Y, Juji T. Discrimination of narcolepsy by using genetic markers and HLA. Sleep Research 1983;12:254. 23. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999;98(3): 24. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6(9):991-7. Sleep Onset REM Period, 1960 Hypocretin in humans, 2000 Syndrome first described, 1877 HLA association, 1981

The Birth of a Syndrome 1880 Gélineau uses term “Narcolepsy”
Case description: 38 year old wine cask maker Symptoms include severe sleepiness and episodes of muscle weakness with laughter Described syndrome as a form of neurosis, placing it firmly in the realm of psychiatry for the next 80 years Slide 29 Level II Slide Passouant25 reviewed the work of Gélineau and his contributions to our understanding of narcolepsy. Gélineau’s descriptions of sleepiness and cataplexy (although he did not use the term) are valid today. He recognized the constellation of symptoms as an autonomous syndrome, but thought it was a type of “neurosis.” Passouant provides a brief biography of Gélineau. 25. Passouant P. Doctor Gélineau ( ): narcolepsy centennial. Sleep 1981;4(3):241-6.

Association with REM Sleep
1960 Vogel reports that narcoleptic patients transition from waking directly to REM sleep (Sleep Onset REM Periods) 1969 Rechtschaffen and Dement write several articles linking symptoms of narcolepsy to REM sleep phenomena This linkage stimulates development of the Multiple Sleep Latency Test Slide 30 Level II Slide In normal sleepers, REM sleep occurs approximately 90 minutes after sleep onset. In the early 1960s, several laboratories reported the appearance of REM sleep at sleep onset in narcoleptic patients. Vogel20 was the first to report the “Sleep Onset REM Period” or SOREMP in the night time sleep of narcoleptics. This led to speculation about the association between narcolepsy and REM sleep. Polygraphic recordings of cataplexy in narcoleptics, however, indicated wakefulness or light sleep during the attacks. 20. Vogel G. Studies in psychophysiology of dreams. III. The dream of narcolepsy. Arch Gen Psychiatry 1960;3:421-8.

Decreased chin muscle tone
Narcolepsy Is Characterized By Sudden Transitions From Wakefulness To REM Sleep Central EEG Occipital EEG LOC ROC Chin EMG R. + L. AT EMG Slide 31 Level II Slide Abbreviations used: EEG = electroencephalogram LOC = left outer canthus ROC = right outer canthus Chin EMG = submental electromyogram R. + L. AT EMG = combined right and left anterior tibialis electromyogram ECG = electrocardiogram HR = heart rate VtRIP = total volume by calibrated respiratory inductive plethysmography Normal sleep physiology is disrupted in narcolepsy. The components of REM sleep become disassociated. REM sleep typically occurs about 90 to 110 minutes after sleep onset and is defined by the presence of low-voltage mixed-frequency electroencephalogram (EEG) activity, absent muscle tone on electromyogram (EMG) and bursts of rapid eye movements.26 Narcolepsy is characterized by the sudden transition from wakefulness to REM sleep. This slide shows a tracing from the polysomnogram of a patient with narcolepsy. This patient was awake for the two minutes before the time of the 30-second tracing shown here. Note the rapid transition from non-REM stage 2 sleep to REM sleep, as shown by the loss of submental muscle tone, appearance of rapid eye movements and desynchronized EEG. In narcoleptics, REM sleep frequently occurs within 15 to 20 minutes of sleep onset; when this occurs it is frequently referred to as a SOREMP. 26. Rechtschaffen A, Kales A. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Los Angeles: Brain Information Service/Brain Research Institute; 1968. ECG Rapid Eye Movements Decreased chin muscle tone HR VtRIP

Motoneuron Inhibition
Awake REM 5 mV 5 ms 5 mV 5 ms Descending Inhibiting Influences Slide 32 Level II Slide REM sleep and cataplexy are characterized by atonia, or loss of muscle tone, which is detectable down to the level of the motoneurons. The monosynaptic fiber reflex is schematically shown on the right hand portion of this slide. Firing of the motoneuron causes muscle contraction. Muscle tone is maintained by asynchronous sustained firing of motoneurons. The atonia that occurs during REM sleep is the result of post synaptic inhibition of motoneurons which occurs at the level of the spinal cord. The neurotransmitter glycine plays a critical inhibitory role. The motoneuron becomes hyperpolarized during REM sleep, decreasing the number of action potential spikes and leading to the loss of muscle tone.27 As shown on the left hand portion of this slide, the H reflex, which tests the monosynaptic fiber reflex, is abolished in REM sleep. In narcolepsy this process is not limited to REM sleep but can occur during wakefulness. The result is cataplexy. 27. Chase MH, Morales FR. The control of motorneurons during sleep. In: Kryger M, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia: W.B. Saunders Company; 1994: Ia afferent  motoneuron Courtesy of GJ Lammers

Normal and narcoleptic 24-hour PSG recordings
Sleep / Wake Fragmentation Control Untreated Patient Slide 33 The sleep-wake pattern of patients with narcolepsy is abnormal. These are tracings from 24 hour ambulatory polysomnographic recordings from a normal subject and from a patient with narcolepsy.28 The normal pattern, shown on the upper tracing, has sleep consolidated into the nighttime hours. There is an orderly progression of sleep stages during the night. The pattern of the narcoleptic patient, in the lower tracing, is much different. Sleep is not consolidated and occurs throughout the 24 hour period. The patient enters REM sleep very shortly after falling asleep. Nocturnal sleep is very fragmented, with frequent awakenings from sleep. These daytime sleep episodes represent the excessive daytime sleepiness that is the hallmark of narcolepsy. It is interesting to note that narcoleptic patients usually do not have increased total sleep times over the 24-hour period. 28. Rogers AE, Aldrich MS, Caruso CC. Patterns of sleep and wakefulness in treated narcoleptic subjects. Sleep 1994;17(7):590-7. Normal and narcoleptic 24-hour PSG recordings Adapted from Rogers 1994

Circadian Rhythm Abnormalities
Compared to controls, narcoleptics have: Dampened temperature rhythms A shift to an earlier temperature low point A reduced sleep latency after temperature starts to drop From Mayer et al 1997 Slide 34 Level II Slide Fluctuation in alertness throughout the 24-hour day is regulated by: 1. A biological clock in the suprachiasmatic nucleus of the hypothalamus that controls the circadian rhythm 2. One or more neurotransmitter systems that, in homeostatic fashion, keep track of time since the last sleep period. When humans are tested for sleep tendency, a two-peak or biphasic pattern emerges within the 24 hour day. Sleep tendency is markedly increased in the early morning hours between 3 AM and 6 AM and there is a smaller but reliable afternoon peak between 1 PM and 3 PM.29 This is the “siesta effect” or “afternoon slump.” This afternoon peak in sleep tendency is not a function of whether or not one has eaten. Both periods of increased sleep tendency are potentiated by sleep promoting factors such as alcohol consumption and sleep deprivation. A mirror image of this pattern can be seen in performance. Errors and reduced productivity peak at the times of maximum sleep tendency. It is against this backdrop that therapeutic interventions for excessive sleepiness must be considered. The normal circadian rhythm, as measured by body temperature and hormone secretion, is dampened in narcolepsy.30 29. Mitler MM, Miller JC. Methods of testing for sleepiness [corrected]. Behav Med 1996;21(4): 30. Mayer G, Hellmann F, Leonhard E, Meier-Ewert K. Circadian temperature and activity rhythms in unmedicated narcoleptic patients. Pharmacol Biochem Behav 1997;58(2):

HLA-Narcolepsy Association
HLA-DR2 and DQB1*0602 are tightly associated with narcolepsy with cataplexy, as is multiple sclerosis Demonstrates a common genetic origin of susceptibility for narcolepsy with cataplexy Implicates the immune system in the pathophysiology of narcolepsy, BUT Narcolepsy is not associated with other autoimmune diseases IgG oligoclonal bands are not present in narcolepsy There is no evidence of cellular autoimmunity in narcolepsy Slide 35 The association of narcolepsy with human leukocyte antigens (HLA) was first described in Japan by Dr. Yutaka Honda in The first marker identified was HLA-DR2, occurring in 85% to 98% of all white patients with narcolepsy-cataplexy. The association is weaker in the black population. The tightest association across all ethnic groups has been found with HLA DQB1*0602. The association of HLA DQB1*0602 with narcolepsy is extremely high in patients with typical cataplexy, occurring in 85% to 100%.31 The finding that almost all patients with narcolepsy with cataplexy share a single HLA allele suggests a common genetic mechanism for the disorder. As most other HLA-associated disorders are autoimmune in nature (e.g., multiple sclerosis, myasthenia gravis and systemic lupus erythematosus), narcolepsy may also be an immune disorder. However, there is no definitive evidence to date that narcolepsy has an autoimmune etiology. 31. Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep 1997;20(11):

A 3-dimensional model of an HLA molecule with a bound peptide
HLA and Narcolepsy HLA-DR and HLA-DQ are associated with narcolepsy Slide 36 Level II Slide This computer model displays the three-dimensional structure of an HLA-DQ molecule. A peptide (in yellow) is bound to the HLA DQ molecule and is presented to the trimolecular complex (TCR). Human Leukocyte Antigen (HLA) DR and DQ molecules are polymorphic proteins encoded by the Major Histocompatibility Complex genes on the short arm of chromosome 6. These molecules are mostly expressed on the surface of lymphocytes and macrophages that bind antigenic fragments ("Antigen Presenting Cells"). The HLA/antigen complex is then recognized by a specific receptor, the T Cell Receptor Complex (TCR), expressed on the surface of T cells. These T cells are making contact with Antigen Presenting Cells using the TCR-Peptide HLA complex to initiate an immune response. Whether or not a particular peptide is bound by an HLA molecule depends on the subtype of HLA molecules carried by a given individual (e.g., HLA-DR1 to DR10 or DQ1 to DQ9). The ability of the DR2 and DQ1 HLA subtypes to preferentially bind a specific peptide is believed to play a critical role in narcolepsy.2 2. Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50(2 Suppl 1):S16-22. A 3-dimensional model of an HLA molecule with a bound peptide Peter Hjelmström © 1996

A 3-dimensional model of an HLA molecule with a bound peptide
Genetic Factors in Narcolepsy HLA-DR2 or DQB1*0602 is not sufficient to cause narcolepsy Additional gene(s) may be required Environmental factors play a role In some families, a non-HLA gene may confer narcoleptic susceptibility Slide 37 Level II Slide This slide depicts a view of the HLA-DQ molecule with a bound peptide in its polymorphic groove. The HLA-DQ molecule known as DQB1*0602 is strongly associated with narcolepsy. While this particular antigen is found in 25% of the general population, it occurs in 70% to 90% of patients with narcolepsy. It is seen in nearly 100% of patients with cataplexy.2 However, the presence of this HLA type is not sufficient to cause narcolepsy. In most cases, an additional gene or interaction with an environmental factor may be required to cause narcolepsy. 2. Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50(2 Suppl 1):S16-22. A 3-dimensional model of an HLA molecule with a bound peptide Peter Hjelmström © 1996

HLA DQB1*0602 Association Data from Mignot et al 2002 Slide 38
The HLA DQB1*0602 association in narcolepsy is very high only for patients with clear cataplexy. As shown on this slide, the prevalence of this antigen in the general population is approximately 25%.32 Thus, most subjects with HLA DQB1*0602 don’t have narcolepsy. Narcoleptic subjects without cataplexy but with SOREMPs on the MLST also have a mildly increased HLA DQB1*0602 frequency. The group of narcoleptic patients without cataplexy likely represents a genetically heterogeneous group with some of the subjects having the same pathophysiological mechanism as subjects with cataplexy and others having disorders of unknown etiology. 32. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59(10): Data from Mignot et al 2002

Potential Roles of HLA HLA-DQ is a genuine narcolepsy susceptibility gene No other gene found in critical 6p21 chromosomal segment Complex HLA-DQ allelic interactions and DQB1*0602 dosage effects Autoimmune lesion / molecular mimicry HLA-neurotransmitter systems interaction Slide 39 Level II Slide Two gene alleles in the HLA DQ region, HLA DQB1*0602 and HLA DQA1*0102, have been shown to be the narcolepsy susceptibility genes. No other gene has been found in the critical 6p21 chromosomal segment with the HLA DQ genes that could explain the association.33 Complex HLA DQ allelic interactions explain susceptibility and dosage effects. For instance, subjects who are homozygous (two copies) for DQB1*0602 are at an increased risk for narcolepsy, as are those with the DQB1*0602/0301 combination. In contrast, subjects with other combinations, such as DQB1*0602/0501 are protected against narcolepsy. Complex patterns such as these are typical of most other HLA association disorders with an autoimmune nature. HLA molecules present foreign antigens to immune cells. In the autoimmune disease model, the foreign antigen looks like a natural body component, a phenomenon called molecular mimicry. The foreign antigen triggers an immune response which recognizes the body component as foreign, leading to an autoimmune reaction. The HLA association suggests that narcolepsy results from an autoimmune lesion in the brain. However, this has never been objectively demonstrated. Another possible source for the HLA-narcolepsy association would be an interaction between HLA molecules and the neurotransmitter systems controlling sleep. For example, it has been suggested that HLA molecules might function as a receptor for natural neuropeptides or HLA molecules interact with lymphokines to promote sleep. This is an area of active research. 33. Mignot E. A hundred years of narcolepsy research. Arch Ital Biol 2001;139(3):

Environmental and Developmental Factors
Affects 0.03% to 0.1% of the general population Most cases of narcolepsy are sporadic 1% to 2% of first degree relatives have narcolepsy-cataplexy (relative risk = 20 to 40 times greater than general population) Familial clustering occurs in about 10% of cases Most monozygotic twins are discordant for narcolepsy Environmental factors are implicated Unknown antigen binding with HLA DQB1*0602 Head trauma, virus, toxins Sleep deprivation, change in sleep / wake cycle Developmental factors (puberty, aging) Slide 40 The predisposition to narcolepsy is not only genetic in origin -- other factors can contribute to the development of narcolepsy. This is best illustrated by studies that have looked at monozygotic twins. One hundred percent concordance of monozygotic twins would indicate complete genetic causality. In narcolepsy, most twins are discordant for narcolepsy. Case series indicate that only 25% to 30% of monozygotic twins are concordant for narcolepsy.2 Therefore, environmental factors must be implicated in triggering this disorder on top of a specific genetic predisposition. Several environmental factors have been postulated. For example, an unknown antigen such as a virus could bind with the HLA molecule triggering an immune response. Due to similarities with host structures this would then induce an autoimmune response. Other possible factors include changes in neuroanatomy or neurochemical pathways due to head trauma or toxin exposure. Sleep deprivation or changes in the sleep/wake cycle have been reported to precipitate narcolepsy. However, the specificity of environmental factors has not been established. Finally, it is important to note the effect of development on the occurrence of the disorder. Narcolepsy frequently starts around adolescence suggesting a precipitating role for the hormonal changes surrounding puberty. Aging can affect symptom severity. Many narcoleptics experience improvement in cataplexy with aging. 2. Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50(2 Suppl 1):S16-22.

Pathophysiology Animal Models Canine Narcolepsy Murine Narcolepsy
Cataplexy REM onset Sleepiness Drug response Murine Narcolepsy REM sleep onset Slide 41 Several animal models of narcolepsy have been developed. The dog model of narcolepsy was developed at Stanford University in the 1970s. The parallels between human and canine narcolepsy are striking. Canine narcoleptics exhibit cataplexy triggered by emotions, as with presentation of food or play, sleep onset REM periods, short sleep latency during and equivalent of MSLT trials and have their symptoms improved by drugs similar to those used to treat human patients Hypocretin knockout mice appear to have narcolepsy as well. These animals present with periods of immobility similar to cataplexy and rapid transition to REM sleep consistent with the diagnosis of narcolepsy.37 34. Babcock DA, Narver EL, Dement WC, Mitler MM. Effects of imipramine, chlorimipramine, and fluoxetine on cataplexy in dogs. Pharmacol Biochem Behav 1976;5(6): 35. Mitler MM, Dement WC. Sleep studies on canine narcolepsy: pattern and cycle comparisons between affected and normal dogs. Electroencephalogr Clin Neurophysiol 1977;43(5):691-9. 36. Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol 1997;52(1):27-78. 37. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999;98(4): Reprinted from Cell, Vol. 98(3) Copyright © 1999, with permission from Elsevier Science.

Animal Models Hcrtr2 12q13-21 Defects in the hypocretin / orexin system are responsible for narcolepsy in animal models Canine narcolepsy gene Hypocretin receptor 2 (Hcrtr2) Mouse narcolepsy Deletion of hypocretin peptide genes Slide 42 The genetic defects responsible for canine and mouse narcolepsy have been identified. The gene for canine narcolepsy was identified by position cloning as the hypocretin receptor 2 gene (Hcrtr2) on dog chromosome This discovery was the first published study suggesting the involvement of hypocretins in narcolepsy. Mouse narcolepsy is associated with the deletion of the hypocretin peptide genes.37 These two findings implicate the hypocretin system, also called orexin, in the pathophysiology of narcolepsy and the regulation of REM sleep. At the present time, the exact significance of these data for our understanding of the pathophysiology of human narcolepsy is uncertain. Preliminary study suggests low hypocretin levels in the CSF and brain of narcoleptic patients with cataplexy.24, 36 23. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999;98(3): 24. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6(9):991-7. 36. Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol 1997;52(1):27-78. 37. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999;98(4):

From de Lecea and Sutcliffe, 2005
Hypocretin System Locus Coeruleus Arcuate NPY Inputs Cortex Layer VIb Hypocretin Containing Cells of the Lateral Hypothalamus Slide 43 Level II Slide Hypocretins-1 and -2 are produced exclusively by a well-defined group of neurons localized in the lateral hypothalamus. The neurons project to the olfactory bulb, cerebral cortex, thalamus, hypothalamus and brainstem, particularly the locus coeruleus, (LC) raphe nucleus and to cholinergic nuclei and cholinoceptive sites (such as the pontine reticular formation (PRF)), thought to be important for regulation of sleep.38 A series of studies have now shown that the hypocretin system is a major excitatory system that controls the activity of monoaminergic (dopamine, norepinephrine, serotonin and histamine) and cholinergic systems with major effects on vigilance states. 38. de Lecea L, Sutcliffe JG. The hypocretins and sleep. Febs J 2005;272(22): Laterodorsal Tegmental Nucleus Other Peptides: CRF, CCK, MCH, etc From de Lecea and Sutcliffe, 2005

Hypocretin Cell Loss in Human Narcolepsy
Normal Narcolepsy Slide 44 Murine and canine narcolepsy can be caused by mutations of the hypocretin (orexin) precursor or hypocretin receptor genes. In contrast to these animal models, most human narcolepsy is not familial, is discordant in identical twins, and has not been linked to mutations of the hypocretin system. Thus, the cause of human narcolepsy remains unknown. Here we show that the brains of human narcoleptics have an 85% to 95% reduction in the number of hypocretin neurons.39 Melanin-concentrating hormone neurons, which are intermixed with hypocretin cells in the normal brain, are not reduced in number, indicating that cell loss is relatively specific for hypocretin neurons. The presence of gliosis in the hypocretin cell region is consistent with a degenerative process being the cause of the hypocretin cell loss in narcolepsy. 39. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000;27(3): Narcolepsy Normal Photomicrographs courtesy J Siegel, UCLA, 2000 Data from Thannickal et al 2000

Neuroanatomy Thalamocortical Loops: Hypothalamus:
EEG synchronization Hypothalamus: Integration of sleep and circadian influences Amygdala & Limbic System: Emotional triggering of cataplexy Pons: REM sleep generator Slide 45 Level II Slide Several regions of the brain are involved in the regulation of sleep and wakefulness and the organization of sleep stages. Thalamocortical loops are believed to be involved in EEG synchronization and are responsible for the desynchronized EEG patterns seen in both REM sleep and wakefulness. Lesions in the hypothalamus have long been associated with chronic daytime sleepiness and secondary narcolepsy. The hypothalamus is also involved in the integration of sleep and circadian influences. Recent data suggest that hypocretin containing cells, about 10,000 to 20,000 cells in the lateral hypothalamus, are missing in narcoleptic brains. This defect is believed to be the primary cause of narcolepsy with cataplexy in most human cases. The amygdala and limbic system are believed to be important for the emotional triggering of cataplexy. Functional magnetic resonance imaging (MRI) studies have shown that the amygdala and limbic system are highly activated during REM sleep. Pontine structures are important to the generation of REM sleep. Cross-section studies carried out above the level of the pons have shown recurring episodes of muscle paralysis occurring with the same periodicity as REM sleep, suggesting the pons is the site predominantly responsible for producing REM sleep. The spinal cord motoneurons are responsible for the production of muscle atonia during REM sleep and cataplexy in narcoleptics. Spinal Cord Motoneurons: REM sleep atonia, cataplexy

Neurotransmitters Cortex: Basal Forebrain: Posterior Hypothalamus:
Ach, Dopamine Basal Forebrain: Ach, Adenosine Posterior Hypothalamus: Hypocretin Amygdala & Limbic System: Ach, Dopamine Slide 46 Level II Slide The control of sleep-related processes at each of the anatomic sleep centers is regulated by the action of neurotransmitters. Abnormalities in these systems are responsible for the features of narcolepsy. Several neurotransmitter systems are involved in the regulation of sleep including acetylcholine, monoamines (dopamine, norepinephrine and serotonin), glycine and hypocretin/orexin. Acetylcholine projections (directly from the basal forebrain to the cortex and indirectly through cholinergic innervation of thalamocortical loops) are involved in cortical activation. This is evident in EEG desynchronization during REM sleep and wakefulness. Acetylcholine projections from the pons to the cortex are also involved in the EEG desynchronization of wakefulness. Acetylcholine and monoamine interactions in the pons are thought to be the key to the generation of REM sleep. Cholinergic neurons in the dorsal lateral pontine tegmentum project to the pontine reticular formation, a structure involved in the triggering of REM sleep. Injection of cholinergic antagonists into the reticular formation produces REM sleep and REM atonia in animals. The activity of aminergic cell groups such as the locus coeruleus and raphe magnus decreases dramatically during REM sleep. Feedback loops between cholinergic and certain aminergic cells are important for the rhythmic generation of the sleep-wake cycle. Projections from the pons to the spinal cord mediate the action of motoneurons involved in maintaining muscle tone. These motoneurons are inhibited by the neurotransmitter glycine which causes the muscle paralysis of REM sleep and cataplexy. Hypocretins (also called orexins) are hypothalamic peptides which have been linked with narcolepsy in animal models and humans. Hypocretin-containing cells are located exclusively in the posterior hypothalamus but project widely in the brain. These peptides are excitatory and project especially densely to monoaminergic cell groups. Deletion of the hypocretin gene in the mouse, or abolition of the hypocretin receptor 2 gene in dogs produces narcolepsy. Recent studies indicate that hypocretin peptides are low or absent in the cerebrospinal fluid and brains of most narcoleptic patients. A loss of stimulation of monoaminergic cell groups by hypocretin systems may explain most of the narcolepsy symptoms. Brainstem: Ach cell group Monoamine cell groups Spinal Cord: Glycine

Hypothalamic Regulation of Sleep
WAKE LATERAL HYPOTHALAMUS HYPOCRETIN CONTAINING NEURONS VENTROLATERAL PREOPTIC NUCLEUS Slide 47 Level II Slide Saper et al.40 recently presented a model of sleep regulation focusing on interactions between hypothalamic systems promoting waking and sleep. The ventrolateral preoptic nucleus (VLPO) is considered to be a key component of this system, inhibiting ascending arousal inputs and in turn being inhibited by them. Circadian inputs influence the dorsomedial nucleus via the subparaventricular zone. Hypocretin containing neurons in the lateral hypothalamus modulate the system by stimulating arousal centers. Without hypocretin, frequent transitions in and out of sleep occur, as well as intrusion of elements of REM sleep. 40. Saper CB, Cano G, Scammell TE. Homeostatic, circadian, and emotional regulation of sleep. J Comp Neurol 2005;493(1):92-8. SUBPARAVENTRICULAR ZONE DORSOMEDIAL NUCLEUS OF THE HYPOTHALAMUS SUPRACHIASMATIC NUCLEUS CLOCK INFORMATION After Saper et al 2005

Summary of Pathophysiology
Sleep physiology -- clinical signs Disassociated REM sleep features (paralysis, hallucinations) Inability to maintain wakefulness or any sleep stage No intrinsic circadian abnormality Neuroanatomy / Neurochemistry -- diagnostic value Loss of hypocretin containing cells in the perifornical area Pontine, hypothalamic and limbic abnormalities Secondary cholinergic and aminergic dysfunctions Slide 48 Narcolepsy is characterized by the disruption of the usual sleep-wake and rapid eye movement (REM)/non-REM cycles. Features of REM sleep may occur during waking. The normally orderly progression of sleep stages is disrupted and the narcoleptic is unable to maintain wakefulness or any sleep stage in the usual pattern. However, the intrinsic circadian rhythm, which regulates functions such as body temperature and hormone secretion as well as sleep and wakefulness, is not affected. Most cases of human narcolepsy with cataplexy are associated with a loss of hypocretin containing neurons. Hypocretin neurons project heavily to the pons and the limbic system. These target structures may be involved in the pathophysiology of narcolepsy. The hypocretin defect is believed to unbalance the cholinergic and aminergic systems involved in the regulation of sleep

Pathophysiology (cont.)
Genetic Familial aspects of human narcolepsy HLA DR and DQ association in humans Hypocretin gene mutations in animal models and in very rare human cases Slide 49 Several trains of evidence suggest a genetic origin for narcolepsy: First, there is a small but increased risk of narcolepsy in first-degree relatives of narcoleptics. Second, there is a very strong association between the presence of narcolepsy and specific HLA antigens. Last, hypocretin gene mutations have been shown to produce narcolepsy in animal models and in a very rare and unusual human case with disease onset at six months of age.

Approach to the Patient With Narcolepsy
Know the criteria for diagnosis Clinical assessment of sleepiness and cataplexy Polysomnographic and MSLT criteria for diagnosis Treatment options Slide 50 Clinicians assessing patients with excessive sleepiness should know published criteria for the diagnosis of narcolepsy, know how to assess patients clinically, know the polysomnographic and MSLT criteria for diagnosis, and, finally, be familiar with the range of therapeutic options. It is important to realize that the diagnosis of narcolepsy requires clinical and laboratory investigation. Therefore, patients should realize that the clinical suspicion of narcolepsy is not sufficient to warrant therapy.

ICSD-2 Criteria for Narcolepsy
Characterized by excessive sleepiness Should, whenever possible, be confirmed by a polysomnogram and Multiple Sleep Latency Test Alternatively, low or absent hypocretin-1 levels in the cerebrospinal fluid may be used to confirm the diagnosis Two variants are described: Narcolepsy With Cataplexy Narcolepsy Without Cataplexy Slide 51 The diagnostic evaluation of a patient with possible narcolepsy should include a thorough clinical history, nocturnal polysomnography and MSLT. All patients with narcolepsy complain of excessive sleepiness. It is suggested that a polysomnographic evaluation be performed to rule out other sleep-related co-morbid conditions such as sleep apnea. The MSLT gives an objective measurement of sleepiness severity and the presence of sleep onset REM periods can help confirm the diagnosis. Alternatively, hypocretin-1 levels in the CSF may be used to confirm the diagnosis.1 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

Evaluation History Polysomnography (PSG)
Sleepiness, cataplexy, other disassociated REM sleep features Polysomnography (PSG) Exclude other causes for EDS (insufficient sleep, apnea) Identify and treat associated conditions Multiple Sleep Latency Test (MSLT) Objective sleepiness Sleep onset REM periods (SOREMPs) CSF Hypocretin levels Slide 52 In order to meet the ICSD-2 criteria for narcolepsy, the clinician must obtain a careful history. This should include an assessment of sleepiness (many use the Epworth Sleepiness Scale as a starting point), a determination whether cataplexy is present or absent, and investigation of other elements of the narcolepsy tetrad. Polysomnography serves to exclude other causes of sleepiness such as sleep apnea. The night study should also document a minimum of six hours of sleep on the night before the MSLT. The MSLT typically confirms excessive sleepiness and provides evidence of SOREMPs. If a polysomnogram and MSLT cannot be obtained or would be invalid due to medications or other circumstances, consideration should be given to assessment of hypocretin levels in the cerebrospinal fluid.

Clinician’s Assessment of EDS
Does the patient look sleepy? Description of EDS Frequency, age of onset, circumstances Fatigue versus sleepiness Specific examples Work, social, situations, driving Corroboration Subjective sleepiness scales Epworth Sleepiness Scale Slide 53 The clinical assessment of sleepiness is important for distinguishing narcolepsy from other conditions. Assessment should include an evaluation of how they present — do they look sleepy? A detailed history of the pattern of their sleepiness is essential: how often does it occur, when did the symptoms start and under what circumstances do the sleep attacks occur? Patients with sleepiness due to narcolepsy typically report an onset in the teens or early 20’s. They report true sleepiness: falling asleep in inappropriate settings or the inability to stay awake. The sleepiness is similar to that experienced after extended sleep deprivation, as opposed to the fatigue one might report with chronic fatigue syndrome, depression or chronic disease. The sleepiness is improved by napping and typically has an adverse affect on all aspects of life. It is important to ask the patient and family members for specific examples of inappropriate sleep, such as at work, during social occasions or driving. Patients often underreport or don’t recognize the impact of sleepiness so it is important to ask family members and friends for corroboration.

Criteria for Cataplexy
Appropriate triggering events Characteristic sites of muscle weakness Consciousness is maintained initially Usual duration is less than 2 minutes In very rare cases, strong emotion or withdrawal from adrenergic or serotoninergic medications may provoke episodes of cataplexy in succession termed status cataplecticus lasting for many minutes up to an hour Slide 54 In order to accurately diagnose cataplexy, it is important to be as rigorous as possible in getting the patient’s history and description of symptoms related to muscle tone. The features listed on this slide are all essential for determining if a patient has cataplexy. Cataplexy should occur following appropriate emotional triggers such as joking, laughing or anger. The weakness occurs in characteristic sites such as the knees, legs or jaw. Consciousness is maintained during the initial portion of the cataplectic episode and the events are typically short, less than two minutes in duration.

Polysomnographic Findings
Short sleep latency Sleep onset REM period in 50% of narcoleptics Sleep fragmentation (REM and NREM) Increased number of arousals Increased stage 1 sleep Low sleep efficiency Frequently associated with periodic limb movements Slide 55 The most important reason to do a nighttime sleep recording in patients with possible narcolepsy is to rule out sleep disorders associated with excessive sleepiness. Obstructive sleep apnea, for example, may cause sleep fragmentation resulting in daytime sleepiness. It is difficult to diagnose narcolepsy without cataplexy in the presence of sleep fragmentation due to sleep apnea. Key polysomnographic features typical of narcoleptic patients include short sleep latency (less than five minutes), short latency to REM sleep (less than 20 minutes), and sleep fragmentation. The disruption of sleep is characterized by numerous arousals for no apparent reason, increased stage 1 sleep and reduced sleep efficiency (time asleep/time in bed). Periodic limb movements of sleep (PLMS) are also frequently seen in patients with narcolepsy. These limb movements may be treated with medications such as dopamine agonists, but treatment will not improve the other symptoms of narcolepsy and may even exacerbate the symptom of sleepiness.41 41. Boivin DB, Montplaisir J, Lambert C. Effects of bromocriptine in human narcolepsy. Clin Neuropharmacol 1993;16(2):120-6.

Polysomnographic Findings
Slide 56 This slide shows findings from overnight polysomnography in a control subject and a patient with narcolepsy. The normal pattern, shown on the upper tracing, shows an orderly progression of sleep stages during the night. Sleep begins with non-REM sleep and then cycles through periods of non-REM and REM sleep with few awakenings from sleep. REM occurs every 90 to 110 minutes and the duration of REM sleep increases across the night. The pattern of the narcoleptic patient, in the lower tracing, is much different. Nocturnal sleep is very fragmented, with frequent awakenings from sleep. The patient may enter REM sleep very shortly after falling asleep and may have more REM episodes which occur at irregular intervals.

Frequency of Periodic Limb Movements in Sleep Disorders
Slide 57 A periodic limb movement index greater than 15 per hour is considered to be abnormal.1 Although the variability in this index was high, the mean number of limb movements exceeded this cutoff in a sample of narcoleptic patients.42 In comparison, patients with obstructive sleep apnea and insomnia had much lower movement indices. 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. 42. Hornyak M, Kopasz M, Feige B, Riemann D, Voderholzer U. Variability of periodic leg movements in various sleep disorders: implications for clinical and pathophysiologic studies. Sleep 2005;28(3):331-5. Data from Hornyak et al 2005

Periodic Limb Movements of Sleep
Central EEG LOC ROC Chin EMG R. + L. AT EMG ECG Slide 58 Level II Slide Abbreviations used in this slide: LOC = left outer canthus ROC = right outer canthus Chin EMG = digastric electromyogram R. + L. AT EMG = combined right and left anterior tibialis electromyogram ECG = electrocardiogram HR = heart rate VtRIP = total volume by calibrated respiratory inductive plethysmography This slide shows a tracing from a polysomnogram of a narcolepsy patient who also has periodic limb movements of sleep. Note the recurrent movements in the leg EMG lead. These movements can be associated with arousals, causing further fragmentation of sleep. HR VtRIP Time in seconds

AASM Guidelines for the Multiple Sleep Latency Test (MSLT)
Standardized protocol Five naps at 2 hour intervals; 4 nap test only if 2 SOREMPs are recorded Always performed after a nocturnal polysomnogram ideally with a minimum of 6 hours of sleep Rooms should be dark, quiet and at a comfortable temperature After appropriate withdrawal of any psychotropic drugs Stimulants withdrawn 2 weeks prior to test No smoking 30 minutes prior to each nap No vigorous physical activity on the day of the test No caffeine or exposure to bright sunlight Slide 59 The Multiple Sleep Latency Test (MSLT) is a standard sleep laboratory procedure used to objectively assess sleep tendency during the day. The patient undergoes four or five 20-minute naps every two hours throughout the day in a standardized fashion.43 The MSLT should always be performed after a nocturnal polysomnogram to ensure adequate sleep prior to the study and rule out another disorder which could affect the results of the test. Medications which could affect ability to fall asleep, either sedatives or stimulants, should be withdrawn if possible prior to testing. The tests are scored for sleep latency (the rapidity with which one falls asleep) and occurrence of sleep onset REM periods. The sleepier the patient is, the shorter the sleep latency. 43. Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28(1): From Littner et al 2005

MSLT Practice Parameters
The MSLT is: A validated objective measure of the tendency to fall asleep Indicated as part of the evaluation of patients with suspected narcolepsy to confirm the diagnosis May be indicated in idiopathic hypersomnia Not routinely indicated for sleep apnea, insomnia or circadian rhythm disorders Slide 60 According to the clinical practice parameter43, the MSLT is the de facto standard for the objective measurement of sleepiness. It has validity in that the mean sleep latency values change in the expected direction with sleep deprivation or fragmentation and with the use of stimulants or hypnotics. The MSLT is an important component of the diagnosis of narcolepsy. It is useful in discriminating between narcolepsy and idiopathic hypersomnia (due to the absence of SOREMPs in idiopathic hypersomnia). The MSLT is not routinely indicated for the diagnosis of sleep apnea, insomnia or circadian rhythm disorders. 43. Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28(1): From Littner et al 2005

Mean Sleep Latency on MSLT
Slide 61 Arand et al.44 pooled data to derive an estimate of normal MSLT latencies. They grouped ten studies with 372 subjects studied with a four nap protocol and 13 studies with 284 subjects studied using a five nap protocol. The mean sleep latency was approximately 10 minutes with a range of 2 to 19 minutes. There was extensive overlap between normals and narcoleptic patients, as well as patients with other sleep disorders. There is a “floor effect” in narcoleptic patients, and the use of a standard deviation for development of a cutoff level was discouraged. They concluded that the MSLT should not be the “sole criterion for determining sleepiness or for certifying a diagnosis or response to treatment. Interpretation of test results should be made within the context of the individual patient history and as part of other medical information and testing.” 44. Arand D, Bonnet M, Hurwitz T, Mitler M, Rosa R, Sangal RB. The clinical use of the MSLT and MWT. Sleep 2005;28(1): From Arand et al 2005

Sleep Onset REM Period REM Central EEG Occipital EEG LOC ROC Chin EMG
R. + L. AT EMG Slide 62 Level II Slide Abbreviations used in this slide: LOC = left outer canthus ROC = right outer canthus Chin EMG = digastric electromyogram R. + L. AT EMG = combined right and left anterior tibialis electromyogram ECG = electrocardiogram HR = heart rate VtRIP = total volume by calibrated respiratory inductive plethysmography During the nighttime PSG and daytime MSLT evaluation, narcoleptics tend to have transitions to REM after abnormally short periods of NREM sleep, or even directly from wakefulness. These phenomena are termed sleep onset REM sleep periods (SOREMPs) and indicate abnormally high REM pressure. On this slide note the desynchronization of the EEG, the drop in chin EMG tone and occurrence of rapid eye movements in the EOG leads. ECG HR 10 seconds VtRIP

SOREMPs in Narcolepsy For 2 or more SOREMPs during MSLT:
Sensitivity was 0.79 Specificity was 0.98 Slide 63 In contrast to sleep latency, SOREMPs are highly sensitive and very highly specific for a diagnosis of narcolepsy. The specificity increases when other sleep disorders are ruled out. SOREMPs occur infrequently in obstructive sleep apnea patients. These conclusions are based on the results of a single MSLT study, with additional narcoleptics identified as a result of subsequent MSLT studies. From Arand et al 2005

Factors Affecting MSLT
Sleep disruption and other sleep disorders Sleep deprivation / extension Circadian factors / shift work Age-related effects Hypnotic agents / alcohol Stimulants / caffeinated substances Psychological stimulation Slide 64 Level II Slide The MSLT is the best validated objective measure of sleepiness. However, it can be affected by multiple factors which can lead to falsely positive or negative findings. This slide presents a list of factors that may invalidate MSLT results. Other causes of daytime sleepiness, such as sleep deprivation, shift work or other sleep disorders may lead to short sleep latency on the MSLT. Similarly, use of sedative/hypnotic medications or alcohol can lead to reduced sleep latencies and over estimate sleepiness. Any arousing stimuli, such as caffeinated substances or high anxiety states, can increase sleep latencies leading to falsely negative estimates of sleepiness. Compliance with MSLT guidelines will minimize the chance of interpretation problems.43 43. Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28(1):

Effect of Age on MSLT Latency in Normal Subjects
Slide 65 Level II Slide Age has a significant effect on MSLT latency. In reviewing pooled data, Arand et al.44 found that latency increased by 0.6 minutes per decade. From Arand et al 2005

Other Tests Not diagnostic Possibly diagnostic Diagnostic
Single daytime nap test or clinical EEG HLA typing Response to stimulants Pupillometry Maintenance of wakefulness test (MWT) Subjective sleepiness scales Possibly diagnostic 24-hour continuous recording Diagnostic Measurement of CSF hypocretin levels Slide 66 Other tests evaluated for efficacy in establishing the diagnosis of narcolepsy are listed on this slide. Single nap tests, HLA typing, response to stimulants, pupillometry, maintenance of wakefulness tests and subjective sleepiness scales have not been able discriminate between patients who have narcolepsy and those who have other diagnoses. It is possible to diagnose narcolepsy on the basis of 24-hour polysomnographic recording. The diagnosis would be based on frequent naps and SOREMPs. However, this approach is not generally practical. Recent studies indicate that most patients with cataplexy have low or undetectable CSF hypocretin levels. Measuring CSF hypocretin levels is an acceptable alternative diagnostic procedure.1 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

Effects of Age on MWT in Normals
Slide 67 Level II Slide The slide shows results from the Maintenance of Wakefulness Test (MWT). Like the MSLT, patients are given four to five opportunities to fall asleep. However, during the MWT they are asked to try to remain awake. Whether or not they fall asleep and latency to sleep onset are measured. Patients are awakened after sleep onset; sleep onset REM sleep episodes are not measured. The mean sleep latency can be reduced by disorders causing hypersomnolence such as narcolepsy, obstructive sleep apnea or sleep deprivation. The MWT has not been shown to discriminate between these disorders and therefore cannot be used to establish the diagnosis of narcolepsy, but can be used to assess the efficacy of treatments.43 Like the MSLT, the MWT has validity as a measure of sleepiness. Mean sleep latency increased on the MWT after administration of a stimulant. The MWT shows a “ceiling effect” in that almost 70% of subjects stayed awake for the entire 20 minute nap protocol (lower tracing) and 59% of subjects stayed awake for the entire 40 minute nap protocol (upper tracing). Using the preferred 40 minute protocol and a 95% confidence interval, approximately 2% to 6% of normal subjects fall into the abnormal range. There are significant age effects in the MWT as well, with an increase of 2.5 minutes per decade of mean latency.44 43. Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28(1): 44. Arand D, Bonnet M, Hurwitz T, Mitler M, Rosa R, Sangal RB. The clinical use of the MSLT and MWT. Sleep 2005;28(1): From Arand et al 2005

Cerebrospinal Fluid Hypocretin-1 Levels
Slide 68 The large majority (85% to 90%) of patients with narcolepsy with cataplexy have low or undetectable hypocretin-1 ligand in their cerebrospinal fluid. This hypocretin deficiency is tightly associated with the occurrence of cataplexy and HLA-DQ1*0602. Low CSF hypocretin 1 levels are very specific for narcolepsy when compared to other sleep or neurological disorders.32 The establishment of CSF hypocretin measurement as a new diagnostic tool for human narcolepsy is therefore encouraging. Previously, no specific and sensitive diagnostic test for narcolepsy based on the pathophysiology of the disease was available, and the final diagnosis was often delayed for several years after the disease onset (typically in adolescence). Many patients with narcolepsy and related disorders of excessive sleepiness are therefore likely to obtain immediate benefit from this new specific diagnostic test. Also, these results suggest that putative hypocretin agonists may hold promise in the treatment of narcolepsy and that CSF hypocretin measures may also be useful to determine the treatment strategy. However, it should be noted that this test is not yet widely used. 32. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59(10): From Mignot et al 2002

ICSD-2 Diagnostic Criteria
Narcolepsy with cataplexy Excessive daytime sleepiness with definitive cataplexy, confirmed by polysomnogram followed by MSLT or CSF hypocretin-1 levels below 110 pg/mL Narcolepsy without cataplexy Excessive daytime sleepiness, no clear cataplexy with positive polysomnogram and MSLT (sleep latency less than 8 min; 2 or more SOREMPs) Narcolepsy due to medical condition Excessive daytime sleepiness, with or without cataplexy, positive MSLT, and medical or neurologic condition associated with narcolepsy Slide 69 In the International Classification of Sleep Disorders, Second Edition1, narcolepsy has been divided into three diagnoses: Narcolepsy with cataplexy: Daily excessive daytime sleepiness (EDS) for three months; definite history of cataplexy (defined as sudden and transient episodes of loss of muscle tone triggered by strong emotions; confirmation by overnight polysomnogram (to exclude other sleep disorders) and a MSLT (mean latency less than eight minutes with two more sleep-onset REM periods) is recommended. Narcolepsy without cataplexy: Daily EDS for at least three months; no definite history of cataplexy; confirmation by overnight PSG (to exclude other sleep disorders) and a MSLT (mean latency less than eight minutes with two more sleep-onset REM periods) are required. Narcolepsy due to medical condition: Daily EDS for at least three months; either definite history of cataplexy or positive MSLT or decreased CSF hypocretin level; and a significant underlying medical or neurologic condition accounts for the EDS. Some of the disorders that have been documented as an etiology for secondary narcolepsy include tumors or sarcoidosis of the hypothalamus, multiple sclerosis plaques impairing the hypothalamus, head trauma, myotonic dystrophy, Prader-Willi syndrome, Parkinson’s disease and multiple system atrophy. 1. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

Differential Diagnosis for Narcolepsy
Sleep related breathing disorders Behaviorally induced insufficient sleep syndrome Idiopathic hypersomnia Depression, fatigue, malingering Drug use or drug withdrawal Delayed sleep phase syndrome Malingering and secondary gain Periodic limb movement disorder Kleine-Levin syndrome Slide 70 In the clinical work-up of patients with possible narcolepsy it is important to consider other diagnostic possibilities, including other disorders that can cause EDS. This slide lists common differential diagnoses in order of decreasing likelihood. The most common are sleep related breathing disorders (especially obstructive sleep apnea) and behaviorally induced insufficient sleep syndrome. Idiopathic hypersomnia is a disorder of unknown etiology which manifests as excessive sleepiness but has none of the features of disassociated REM sleep seen in narcolepsy. Patients with this disorder may respond to stimulants in a manner similar to narcoleptic patients. The fatigue associated with depression and other affective disorders is often mistaken for narcolepsy. Inquiry about any drugs that can cause drowsiness is essential. Circadian rhythm disorders, such as delayed sleep phase syndrome, can cause sleepiness during the usual waking hours and be mistaken for narcolepsy. Periodic limb movements of sleep can cause significant sleep fragmentation and present as daytime sleepiness. Periodic limb movements are prevalent in narcoleptic patients. The presence of cataplexy and SOREMPs serves to distinguish narcoleptic patients from those with periodic limb movement disorder. Kleine-Levin syndrome is a rare disorder characterized by periodic hypersomnia, hyperphagia and hypersexuality, typically occurring in males and beginning during adolescence.

Therapeutic Approaches
Pharmacotherapy Sleepiness Cataplexy Fragmented nocturnal sleep Compliance issues Behavioral interventions Psychosocial and educational interventions Slide 71 The goal of therapy is to control the symptoms of narcolepsy and return the patient to full social and work activities. Effective therapy for narcolepsy is usually multifaceted, involving pharmacologic, behavioral and psychosocial aspects.45 Pharmacotherapy has two main goals: Central nervous system (CNS) stimulants are used to treat excessive daytime sleepiness REM sleep suppressing drugs, most often non-sedating antidepressants, are often used to treat cataplexy and other REM sleep features Several studies have explored the use of sodium oxybate (or gamma hydroxybutyrate) as a treatment for daytime sleepiness46-49 as well as cataplexy.49-50 In addition, sedatives may be used to combat fragmented sleep. As with any chronic disease requiring long-term medication use, compliance issues complicate pharmacologic effectiveness. In addition, behavioral interventions, such as maintenance of good sleep hygiene and daytime napping, as well as psychosocial and educational support are essential to therapy and must be addressed. 45. Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30(12): 46. Mamelak M, Black J, Montplaisir J, Ristanovic R. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 2004;27(7): 47. Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 2006;29(7): 48. The Xyrem International Study Group. A double-blind, placebo-controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med 2005;1(4):391-7. 49. US Xyrem Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 2002;25(1):42-9. 50. US Xyrem Multicenter Study Group. Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Med 2005;6(5): 71

Sleepiness Stimulants Treatment objectives Effective medications:
Only effective treatment for EDS Establish accurate diagnosis prior to treatment Treatment objectives Alleviate daytime sleepiness Not to enhance performance on attention tasks Effective medications: Modafinil, methylphenidate, methamphetamine, dextroamphetamine Slide 72 Traditional stimulants effectively treat the excessive sleepiness of narcolepsy; recent evidence shows positive effects from modafinil and sodium oxybate.46, 51 Because of issues of tolerance and the potential for side effects, adverse reactions and abuse, it is essential to establish an accurate diagnosis of narcolepsy prior to initiating stimulant treatment. The object of stimulant treatment is to alleviate daytime sleepiness, thereby allowing the fullest possible return of normal function for patients at work, at school and at home. Medications currently recommended as effective stimulants in the treatment of narcolepsy include modafinil, methylphenidate, methamphetamine and dextroamphetamine. 46. Mamelak M, Black J, Montplaisir J, Ristanovic R. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 2004;27(7): 51. Wise MS, Arand DL, Auger RR, Brooks SN, Watson NF. Treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30(12):

Action of Stimulants U U U U Presynaptic Postsynaptic tyramine dopa
Methylphenidate and possibly modafinil Block re-uptake U U tyramine dopa dopamine Slide 73 Level II Slide This slide schematically illustrates the mode of action of currently prescribed stimulant drugs on the dopamine system. Recent studies have established that amphetamines and amphetamine-derivatives promote wakefulness by inhibiting the vesicular monoamine transporter, thereby increasing dopamine release and a reduction of presynaptic dopamine stores.52 Other compounds such as mazindol also inhibit dopamine reuptake from the synapse into the neurons. This results in increased dopamine levels in the synaptic cleft and potentiates the wake promoting effect of the neurotransmitter. Although modafinil has wake-promoting effects similar to the amphetamine derivatives, its mechanism of action is debated. It probably acts partially by blocking dopamine reuptake, but may have other, as yet unknown, mechanisms. GHB (sodium oxybate) may reduce cell firing without decreasing dopamine synthesis, resulting in an increased presynaptic store.52 52. Mignot E, Nishino S. Emerging therapies in narcolepsy-cataplexy. Sleep 2005;28(6): U GHB reduces cell firing but does not inhibit dopamine synthesis U Amphetamine-like stimulants inhibit VMAT, increase dopamine release

Potential Wake-Promoting Systems
Neurotransmitters Dopamine Histamine Hypocretins Pharmaceutical Agents Amphetamine-like compounds H3 receptor agonists Hypocretin agonists Sodium oxybate Slide 74 Level II Slide Drugs used to combat sleepiness are targeted at several wake-promoting systems. Amphetamine-like stimulants activate the release or block the reuptake of dopamine.36 Histaminergic systems have long been recognized as involved in maintaining wakefulness. Lesions of these systems produce sleepiness in animal models. H3 antagonists (autoreceptor antagonists that stimulate histaminergic transmission) are being developed as wake-promoting agents. H1 antagonists (over-the-counter antihistaminic agents) are frequently used to facilitate sleep. Hypocretins are potently alerting peptides when administered into the intracerebral ventricles. Hypocretin deficiency produces narcolepsy in animal models. Centrally active compounds which stimulate hypocretin receptors may provide better treatment for the sleepiness of narcolepsy and need to be developed. 36. Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol 1997;52(1):27-78. See Mignot et al 2002 for review

Treatment of Sleepiness
Modafinil 200 to 800 mg/day Moderate efficacy, long half life Best side effect profile Schedule IV, most expensive Methylphenidate 5 to 100 mg/day Short half life formulation, variable dosing Long acting formulation available Used alone or in combination Sympathomimetic effects, mood alterations Slide 75 The next few slides review the comparative advantages and disadvantages of the currently available stimulant medications for the treatment of narcolepsy. The efficacy, side effects and recommendations for use of stimulants were recently reviewed by a Task Force of the American Academy of Sleep Medicine in the context of reversing the effects of sleep loss.45, 51 Modafinil is chemically and pharmacologically distinct from the amphetamine derivative medications and does not appear to alter the release of dopamine or norepinephrine. However, an intact adrenergic system is necessary for the wake promoting effect.53 The effective dose is between 200 to 800 mg daily with recent evidence suggesting that a split-dose strategy can be more effective for some patients. It has a long half life and has been shown to have moderate efficacy in relieving EDS.54 It has the best side effect profile with fewer side effects than the amphetamines. It is the most expensive of the stimulant medications. It is felt to have less potential for abuse and is therefore a schedule IV drug, making it easier to prescribe for long-term use. It is generally used as the first line drug for treating the daytime sleepiness associated with narcolepsy. In the recent updated practice parameters45, modafinil received a recommendation of ‘standard for’ the effective treatment of sleepiness in narcolepsy. A ‘standard’ recommendation indicates a patient care strategy with a high degree of clinical certainty supported by Level I or overwhelming Level II evidence. Methylphenidate is an amphetamine derivative which is the most frequently used stimulant in narcolepsy.54 The drug has a short half life and can be given multiple times a day with a usual total daily dose of 5 to 100 mg. A long-acting formulation is available. It can be used alone or in combination with longer acting stimulants. Methylphenidate is one of the agents with the greatest effect in improving objectively measured sleepiness.55 Adverse reactions include sympathomimetic effects such as tremulousness and tachycardia, and alterations in mood. Amphetamines have the highest potential for abuse and are therefore listed as Schedule II medications. Methylphenidate and the related amphetamine stimulants, which have been used clinically for many years, received a ‘guideline’ recommendation45 as there is are limited Level I studies and limited studies on the benefit:risk ratio. A ‘guideline’ recommendation is a patient care strategy that reflects a moderate degree of clinical certainty and implies use of Level II or a consensus of Level III evidence. 45. Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30(12): 51. Wise MS, Arand DL, Auger RR, Brooks SN, Watson NF. Treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30(12): 53. Fry JM. Treatment modalities for narcolepsy. Neurology 1998;50(2 Suppl 1):S43-8. 54. Mitler MM, Hajdukovic R. Relative efficacy of drugs for the treatment of sleepiness in narcolepsy. Sleep 1991;14(3): 75

Dextroamphetamine / Methamphetamine 5 to 100 mg/day Short and long half life formulation Most efficacious Sympathomimetic effects, mood alterations Schedule II, most difficult to obtain Slide 76 Level II Slide Dextroamphetamine and Methamphetamine are indirect sympathomimetics which act by increasing dopamine activity in the central nervous system. Amphetamines can be used in combinations of short and long-lasting formulations, and are given multiple times a day with a usual total daily dose 5 to 100 mg. These agents are the most efficacious in reducing objective sleepiness.54 Side effects include sympathomimetic effects and mood alterations. Amphetamines have the highest potential for abuse and are therefore listed as Schedule II medications.53 In the recent updated practice parameters45, dextroamphetamine and methamphetamine received a recommendation of guideline for the effective treatment of sleepiness of narcolepsy. The indirect sympathomimetic stimulants, which have been used clinically for many years, received a ‘guideline’ recommendation as there is are limited Level I studies and limited studies on the benefit:risk ratio. 45. Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30(12): 53. Fry JM. Treatment modalities for narcolepsy. Neurology 1998;50(2 Suppl 1):S43-8. 54. Mitler MM, Hajdukovic R. Relative efficacy of drugs for the treatment of sleepiness in narcolepsy. Sleep 1991;14(3): 76

Modafinil Daily Dose Schedule Cost Efficacy Formulation Side Effects IV $$$$ + Long Methylphenidate 10-150 II $$ +++ Short and Long ++ Dextroamphetamine 5-100 Methamphetamine Slide 77 This table compares the dosing and cost information of the currently used stimulant medications. Modafinil has the least abuse potential and therefore is the easiest to prescribe (with Schedule IV status) but is the most expensive. The amphetamines and their derivatives have greater abuse potential and are Schedule II medications, but are the least expensive. This table also shows the relative efficacy, rates of side effects and available formulations for the currently available stimulant medications. The amphetamine-derivatives, methamphetamine, dextroamphetamine and methylphenidate, have been shown to have greater efficacy in improving measures of objective sleepiness. Modafinil is of moderate efficacy.54 Methamphetamine, dextroamphetamine and methylphenidate come in both long and short acting forms whereas modafinil has only a long acting formulation. Combining these medications allows for titration of effect to fit the individual’s needs. Modafinil has lower rates of side effects than amphetamines. 54. Mitler MM, Hajdukovic R. Relative efficacy of drugs for the treatment of sleepiness in narcolepsy. Sleep 1991;14(3):

Initiating Therapy for Sleepiness
Establish realistic goals on an individual basis Start with low dose and safest agent Titration to optimal dose within 10 days Supplement with short-acting stimulant if needed Expect drug and dose response variability It may be necessary to use high doses and / or switch to amphetamine-derivatives Slide 78 When initiating therapy for sleepiness from narcolepsy the clinician should follow these guidelines: Establish an individual treatment plan with realistic goals. Stimulants can control but not eliminate sleepiness. Start with the lowest dose and the safest agent. Titrate to optimal dose over the course of one to two weeks. Consider initiating a long acting medication and supplement with a short-acting stimulant as needed. Individuals will vary with regard to drug and dose response; a tailored regimen is often required. It may be necessary to use high doses or switch to more potent amphetamine-derivatives to eliminate sleepiness.

Reduction of Sleepiness -- Modafinil
* * * * * Slide 79 Therapy with stimulants leads to a demonstrable reduction in sleepiness. This slide shows the effect on objective sleepiness as measured by the MSLT, MWT and Epworth Sleepiness Scale of the use of 200 or 400 mg of the stimulant modafinil given in a single morning dose. Twenty five percent of narcoleptics using once daily dosing of modafinil had normal sleep latency compared to only 10% of those on placebo. The data come from two large multi-center clinical trials.55, 56 55. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol 1998;43(1):88-97. 56. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. Neurology 2000;54(5): *Significantly different from placebo (p< 0.05) Adapted from US Modafinil in Narcolepsy Multicenter Study Group 2000.

Reduction of Napping Untreated Treated Adapted from Rogers et al 1994
Slide 80 This slide shows the effect of stimulant medications on sleep episodes. Here are two 24-hour polysomnographic tracings.28 The top is the tracing of an untreated narcoleptic. Note the fragmented nocturnal sleep and multiple daytime sleep episodes. On the bottom is a tracing from a patient treated with stimulant medication. Sleep is more consolidated into the nighttime hours, although there is still an early sleep onset REM period. 28. Rogers AE, Aldrich MS, Caruso CC. Patterns of sleep and wakefulness in treated narcoleptic subjects. Sleep 1994;17(7):590-7. Treated Adapted from Rogers et al 1994

Pharmacotherapy: Relative Efficacy
Slide 81 The efficacy of drugs varies in controlling sleepiness. This slide shows a comparison of relative stimulant efficacy determined from previously published treatment-efficacy studies that employed measures of objective daytime sleepiness (MSLT or MWT). Each drug produced a clinically significant change above baseline toward normal levels. Dextroamphetamine and methamphetamine improved objective sleepiness measures the most, to 60% of normal levels or greater.54 54. Mitler MM, Hajdukovic R. Relative efficacy of drugs for the treatment of sleepiness in narcolepsy. Sleep 1991;14(3): Adapted from Mitler et al1991

*p<0.05 between treatment group and placebo
Quality of Life * * * * * * Slide 82 Adequate treatment of sleepiness causes dramatic improvement in the patient’s ability to function -- their quality of life. This study reports the results from 500 patients who took the SF-36 Quality of Life survey before and after nine weeks of treatment with the wake-promoting medication modafinil.4 Patients who were taking 200 and 400 mg of modafinil reported significant improvements in their ability to carry out their roles requiring physical functioning and in their vitality. Those who were taking the higher dose of modafinil also reported significant improvement in social functioning and their ability to carry out their roles due to emotional functioning. 4. Beusterien KM, Rogers AE, Walsleben JA, et al. Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep 1999;22(6): *p<0.05 between treatment group and placebo Adapted from Beusterien et al 1999

Long-term Management Treatment failures Pregnancy and nursing
Compliance Tolerance Other medical, psychiatric or sleep disorders Pregnancy and nursing Anesthesia Recreational drugs Slide 83 Pharmacologic therapy of sleepiness in narcolepsy is life-long, which raises multiple issues for the long-term management of these patients. As with any chronic medication, there are high rates of noncompliance, especially in adolescent patients.57 In one study of 43 narcoleptic adults followed with 24 hour ambulatory monitoring, only 51% took their prescribed dosage. The rest reduced their dose or took no medication during the observation period. Another reason for treatment failure is the development of tolerance to the stimulant medication and under dosing. Tolerance to the alerting effects of stimulants appears to occur with variable frequency, from 0% to 40% in reported studies.58 This can lead to under dosing of stimulant medication as can clinician hesitancy to use higher doses. The presence of other medical, psychiatric or sleep disorders which lead to disruption of sleep or sleep deprivation can also negate the effects of stimulants. No evidence exists that stimulants are safe for use in pregnant women and their use should be avoided during pregnancy unless no alternatives exist. There are no well controlled studies of stimulants in pregnant women. The teratogenicity risk is variable. Methamphetamine and modafinil are U.S. Federal Drug Administration Pregnancy Category C (associated with teratogenicity in animals, no studies in humans); dextroamphetamine is category D (evidence of risk to human fetuses but benefits may outweigh risks). There are no adequate animal or human studies with methylphenidate.58 Narcoleptics may experience unique problems with anesthesia. All of the medications used to treat narcolepsy are metabolized by the liver and can cause hepatic enzyme induction, which interferes with the metabolism and function of other medications such as anesthetics and pressor agents. Patients with narcolepsy may be at higher risk of having apneic episodes, cataplectic spells, and sleep paralysis when recovering from inhalation anesthesia. However, making the anesthesiologist aware of the condition allows adjustments to be made to improve the odds of an uneventful outcome. Recreational drugs can similarly interfere with the efficacy of narcolepsy medications. 57. Rogers AE, Aldrich MS, Berrios AM, Rosenberg RS. Compliance with stimulant medications in patients with narcolepsy. Sleep 1997;20(1):28-33. 58. Mitler MM, Aldrich MS, Koob GF, Zarcone VP. Narcolepsy and its treatment with stimulants. ASDA standards of practice. Sleep 1994;17(4):

Compliance With Stimulant Medication
Slide 84 It is essential to evaluate compliance with stimulant medications in all narcoleptic patients. This evaluation can be done by regular discussions with the patient and by comparing the number of pills prescribed with the time between prescriptions. One study showed that narcoleptic patients, like all other groups of patients studied, frequently take less medication than prescribed.58 Almost half of the treated subjects either reduced their dosage of stimulant medication or did not take any stimulant medication during the 24-hour monitoring period when they were expected to be on medication. Additionally, dosage reductions were quite substantial, with many subjects taking less than half the prescribed amount of stimulant. Given concerns about patients escalating their dosage or abusing their stimulant medications, it is interesting to note that no patient took more medication than had been prescribed. Compliance could not be predicted by gender, age or education. 57. Rogers AE, Aldrich MS, Berrios AM, Rosenberg RS. Compliance with stimulant medications in patients with narcolepsy. Sleep 1997;20(1):28-33. Adapted from Rogers et al 1997

Cataplexy and Disassociated REM Sleep Features
Sodium oxybate 3-9 g/night Miscellaneous treatments Venlafaxine (75 to 150 mg/day) Reboxetine (not available in US) Tricyclic antidepressants Protriptyline (10 to 60 mg/day) Clomipramine / Imipramine (25 to 150 mg/day) Anti-cholinergic side effects Selective serotonin re-uptake inhibitors Fluoxetine / Paroxetine (20 to 60 mg/day) Better tolerated but higher dose often needed Slide 85 For many years the most commonly used medication for cataplexy, as well as sleep paralysis and hypnagogic hallucinations, has been the nonsedating tricyclic antidepressant (TCA) protriptyline, which has been shown to reduce the number of cataplexy episodes. Clomipramine and imipramine are also effective and may have fewer side effects. Use is typically limited by anticholinergic side effects. Abrupt discontinuation can cause a rebound increase in cataplexy. Selective serotonin re-uptake inhibitors (SSRIs) may supplant TCAs because they are just as effective with fewer anticholinergic side effects. SSRIs such as fluoxetine and paroxetine have been shown to reduce cataplectic episodes but may require high doses for effectiveness. In the recent updated practice parameters45, the tricyclic and SSRI antidepressants received a recommendation of ‘guideline’ for the effective treatment of cataplexy in narcolepsy. This recommendation was primarily based upon clinical experience and committee consensus as there are limited Level I evidence studies for these agents. Sodium oxybate has been shown in 3 Level I evidence studies48, 49 to be effective in the treatment of cataplexy. It was given a recommendation of standard in the recent practice parameters45 for this indication. Sodium oxybate is unique as it taken at night as a divided dosage with the first dose at bedtime and the second dose generally 4 hours later. Total dosage is 3-9 gm/night. Sodium oxybate has also been shown to have moderate effects on daytime sleepiness in narcolepsy; while this indication also received a standard recommendation in the recent parameters, sodium oxybate is generally not used first-line for treating daytime sleepiness. It should be noted that there are no studies comparing sodium oxybate to either TCA or SSRI antidepressants for the treatment of narcolepsy. Given that sodium oxybate is a DEA Control Level I substance, many physicians first try a TCA or SSRI antidepressant for cataplexy. However, future research comparing these agents is needed to guide the clinician in medication selection. Other treatments such as venlafaxine and reboxetine (not available in the US) have a guideline recommendation based primarily upon clinical experience and committee consensus. 45. Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007;30(12): 48. The Xyrem International Study Group. A double-blind, placebo-controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med 2005;1(4):391-7. 49. US Xyrem Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 2002;25(1):42-9. 85

U U U U Presynaptic Postsynaptic norepinephrine serotonin dopamine
Protriptyline, imipramine and desipramine Block NE re-uptake Postsynaptic U norepinephrine U serotonin dopamine U Slide 86 Level II Slide The mode of action of the most commonly prescribed anti-cataplectic drugs is schematized on this slide. Tricyclic antidepressants (TCAs) such as protriptyline, imipramine and desipramine block the reuptake of norepinephrine and serotonin resulting in increased levels of serotonin and norepinephrine in the synaptic cleft. Serotonin-specific re-uptake inhibitors (SSRIs) predominantly block serotonin reuptake. Monoamine oxidase (MAO) inhibitors increase norepinephrine and serotonin levels in the synaptic cleft by blocking degradation mediated by the enzyme monoamine oxidase. Gamma hydroxybutyrate (GHB; sodium oxybate) acts by a completely different mechanism. This compound does not act directly on cataplexy; rather it appears to promote nocturnal REM, reducing disassociated REM-related events. It must be administered at night to promote anti-cataplectic effects the following day. The drug has a very unusual mode of action. It binds to specific receptors and reduces the firing of dopamine cells and dopamine release, increasing dopamine content in the neuron. Decreased dopamine release promotes REM sleep during the night. Dopamine levels are presumably replenished the following day resulting in better alertness and decreased cataplexy. GHB reduces cell firing but does not inhibit dopamine synthesis U Clomipramine, fluoxetine Block serotonin re-uptake

Cataplexy Treatment -- Protriptyline
Slide 87 Level II Slide In this study, use of protriptyline resulted in a significant reduction in the number of cataplexy episodes, measured by a self-report cataplexy severity scale.59 Note that cataplexy episodes were not eliminated but the subjects all showed marked clinical improvement. 59. Mitler MM, Hajdukovic R, Erman M, Koziol JA. Narcolepsy. J Clin Neurophysiol 1990;7(1): Dose Adapted from Mitler et al 1990

Cataplexy Treatment – GHB
Slide 88 Level II Slide Sodium oxybate (GHB), taken in the evening and once again during the night, reduced cataplectic attacks and other manifestations of REM sleep, such as sleep paralysis.50 Its elimination half-life is 1 to 2 hours. GHB increased NREM sleep stages 3 and 4, decreased nighttime awakenings and consolidated fragmented REM sleep. Recent studies have demonstrated a measurable improvement in patient-reported daytime sleepiness and sleep attacks.46 GHB given at bedtime and with a second dose upon awakening during the night, at least 3 hours before rising time, may also consolidate nocturnal sleep. If the patient wakes up during the night, he may experience dizziness and confusional states. Some patients also experience depressive mood while treated with GHB. One problem with GHB is the non-medical use of this compound to elicit altered states of consciousness with important social and legal implications. It has been approved for use in the United States. 46. Mamelak M, Black J, Montplaisir J, Ristanovic R. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 2004;27(7): Data from Xyrem International Study Group 2005

Treatment of Cataplexy
Not all patients require therapy Side effects and complications limit use Select drug and timing of administration to match its sedating or stimulating effects (e.g. sedating antidepressants at bedtime) Pregnancy and nursing Slide 89 Due to the intermittent nature of cataplexy and the variability in severity, not all patients require therapy for cataplexy. The decision to treat should be made on an individual basis and be determined by a combination of cataplexy severity and frequency, impact on the patient’s perception of functioning, and tolerance of the side effects and complications which limit medication use. The selection of drug and timing of administration should attempt to match the sedating or stimulating effect of the medication with the patient’s schedule. For example, a sedating antidepressant at bedtime may be more appropriate than a non-sedating one during the daytime. For women who are pregnant or nursing, it is important to check the Pregnancy Category rating for any proposed medication.

Fragmented Nocturnal Sleep
Generally untreated If treated, will not normalize daytime alertness Hypnotic compounds or sedating antidepressants can be used Avoid hypnotics with carryover effects Gamma hydroxybutyrate is also effective Slide 90 Level II Slide Fragmented nocturnal sleep is very common in narcolepsy patients. Hypnotic medications and GHB are effective in improving nocturnal sleep.60 If hypnotics are used, care should be taken to avoid long-acting preparations that may result in morning hangover. 60. Mamelak M, Scharf MB, Woods M. Treatment of narcolepsy with gamma-hydroxybutyrate. A review of clinical and sleep laboratory findings. Sleep 1986;9(1 Pt 2):285-9.

Compliance Barrier Solution
Always ask your patients “Are you having any difficulties taking your medication?” Barrier Unacceptable side effects Complex regimen Expensive / unavailable medications Patient and family prejudice Solution Change medication or dosing Simplify regimen Change medications or involve social services Education Slide 91 Successful therapy requires compliance with medication regimens. Since all patients may have trouble taking their medications, the National Institutes of Health has recommended all patients be asked about compliance. This should be done in a nonjudgmental manner since there is a desire on the patient’s part to please their healthcare professional with their answer and not to admit they made a mistake. Therefore, the recommended wording is “Are you having any difficulties taking your medication?” It is best to approach noncompliance as a series of barriers to use which must be discovered and solved. For example, the side effects of the medication (such as irritability from stimulants) may be unacceptable. In this case, changing the type or dose of medication may relieve the problem. Complex regimens requiring multiple drugs or more than one dose per day may be difficult to master. Simplifying the regimen to a once a day drug may improve compliance. Expensive drugs may be unaffordable to some patients and amphetamines in particular may be difficult to obtain. Pharmacies may be reluctant to carry amphetamines and healthcare professionals reluctant to prescribe them. Changing to medications that are less expensive or easier to obtain, involving social services or intervening with insurance companies may improve medication use. Finally, patients and family may believe the drugs are not necessary or be apprehensive about taking what they think are dangerous drugs. Since stimulants are the most effective pharmacological treatment for sleepiness it is important to educate the patient and family about them. They need to know that the risk of addiction in narcoleptic patients is small and that using these medications is no different than taking a medication every day to control hypertension.

Behavioral Interventions
Have limited efficacy by themselves (e.g. napping, improving sleep habits) Sleepiness / fragmented nocturnal sleep is exacerbated by: Poor sleep hygiene Shift work Alcohol and other recreational drugs Avoid driving and dangerous work when sleepy Slide 92 Although behavioral interventions have a great deal of appeal because they are non-pharmacologic, perceived to have no dangerous side effects, and are often low-cost, behavioral interventions alone have limited efficacy. For example, napping and improving the patient’s sleep hygiene will not result in adequate daytime alertness.58 However, patients can make their sleep/wake patterns worse if they have poor sleep hygiene. The patient who is not getting enough sleep will be profoundly sleepy during the day and needs to know that the effects of stimulants cannot overcome a sleep deficiency. Patients should be cautioned about working evening or night shifts and reminded that alcohol and the use of other recreational drugs can make their daytime sleepiness worse. Finally, all patients should be reminded to avoid driving and other dangerous work if they are drowsy. Other behavioral interventions, such as drug holidays, dietary/nutritional supplements, acupuncture and exercising, have not been demonstrated to be efficacious. 58. Mitler MM, Aldrich MS, Koob GF, Zarcone VP. Narcolepsy and its treatment with stimulants. ASDA standards of practice. Sleep 1994;17(4):

Napping and Improving Sleep Hygiene
Slide 93 Level II Slide There is a complex relationship between the symptom of unwanted daytime sleep and using planned daytime sleep to treat the sleepiness. Although such intervention makes very little sense in other disorders, such as prescribing scratching to treat a skin rash, in effect this approach has been used to limit daytime sleepiness in narcolepsy. Although regularly scheduled daytime naps and improved sleep hygiene are frequently recommended in textbooks as ways to decrease the use of stimulant medication, these interventions have rarely been studied. This graph shows the results of a study which examined the effect of prescribing napping and improved sleep hygiene regimens to narcolepsy patients already using stimulant medications.61 The subjects were divided into three groups depending on effectiveness of stimulant medication to control daytime sleepiness. Group 1 was the least sleepy to begin with, defined as less than ten minutes of unplanned sleep during their waking hours. After initiating a regimen of daytime naps, they had no significant change in the amount of unplanned sleep. They did not benefit from the addition of planned naps or improved sleep hygiene. Group 2 was the moderately sleepy group, defined as between ten and 60 minutes of unplanned daytime sleepiness. They also did not improve significantly with these interventions. However, Group 3, the sleepiest group of treated patients, with more than 60 minutes of unplanned daytime sleepiness before intervention, did benefit. The addition of napping and improved sleep hygiene reduced their unplanned daytime sleep by approximately 35 minutes per day. Although napping was effective in the sleepiest group, these patients might also benefit from increasing the dose of their stimulants or changing to a different drug. 61. Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep 2001;24(4): Adapted from Rogers et al 2001

Behavioral Management of Sleepiness
Common but controversial approaches: Drug holidays Dietary adjustments Nutritional supplements Psychotherapy Acupuncture Exercise Slide 94 Level II Slide The use of the behavioral interventions listed on this slide to treat the sleepiness of narcolepsy is controversial. Though they are commonly used, their efficacy has not been established. Drug holidays are intended to counter the development of tolerance. Patients undergo drug-free periods lasting days or weeks to reestablish the therapeutic effect with a lower dose of the stimulant drug. This practice appears to be based on clinical experience since there are no published studies demonstrating the efficacy of drug holidays.62 Little evidence supports the use of dietary supplements to treat the sleepiness of narcolepsy. A single report found that large doses of dietary tyrosine increased alertness. Tyrosine is a precursor of the catecholamines norepinephrine and dopamine which are involved in the regulation of alertness. However, repeat studies have not replicated the initial findings.58 Other nutritional supplements are currently untested and research into their efficacy remains to be done. Although psychotherapy may be helpful in coping with the disease, it will not eliminate the symptoms. Acupuncture and exercise, although advocated by some patients as helpful or curative, do not have proven utility in the treatment of narcolepsy. 58. Mitler MM, Aldrich MS, Koob GF, Zarcone VP. Narcolepsy and its treatment with stimulants. ASDA standards of practice. Sleep 1994;17(4): 62. Littner M, Johnson SF, McCall WV, et al. Practice parameters for the treatment of narcolepsy: an update for Sleep 2001;24(4):

Psychosocial & Educational Aspects
Refer to support groups (e.g. Narcolepsy Network) National Narcolepsy Registry participation Consider psychological impact Possible work, school and family interventions Medico-legal aspects (e.g. driving, Americans with Disabilities Act, confidentiality) Disability benefits Slide 95 Psychosocial and educational programs are essential to the treatment and management of narcolepsy. An overriding principle is to bolster the patient’s sense of control over their disorder whenever possible. It is important to consider the psychological impact of the disorder on the patient and on the patient’s close relatives and consider referring for counseling or psychotherapy. Especially in the initial stages, it is important to consider intervening at work, in school or with the family to try to foster better understanding of the patient’s lifelong disabling condition. It is also important to provide the patient with resources to deal with medico-legal aspects of their disability. Narcolepsy can impact driving privileges and providers should check local state regulations regarding reporting requirements. What patients do or do not say at the time of employment can impact their entitlement to disability payments and issues of confidentiality. Specific questions are best answered by qualified legal experts. Finally, it is important to assure that patients are considered for all applicable disability benefits.

Conclusions Narcolepsy is a disabling and prevalent disorder
The disorder can be reliably and objectively diagnosed Treatment is effective and improves quality of life Our understanding of narcolepsy is rapidly advancing Slide 96 In conclusion, the information that was presented in this talk demonstrates that narcolepsy is a disabling and prevalent disorder. The disorder can be reliably and objectively diagnosed by appropriately trained professionals. Treatment has been shown to be effective and not only improves the primary symptoms of sleepiness and cataplexy but also improves quality of life. Our understanding of narcolepsy is rapidly advancing, offering many new opportunities for treatment, and providing insight into the regulation of wakefulness and sleep.

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Slide 1 The following slide set, with accompanying instructional notes and references, has been designed to serve as the foundation for a teaching curriculum.

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Presentation on theme: "Slide 1 The following slide set, with accompanying instructional notes and references, has been designed to serve as the foundation for a teaching curriculum."— Presentation transcript:

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