Home Educatione-Learning Excessive Sleepiness: Evaluation and Management
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Excessive Sleepiness: Evaluation and Management

Volume 25, Lesson 24

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Alon Y. Avidan, MD, MPH

Dr. Avidan is Associate Professor of Neurology, Department of Neurology, University of California, Los Angeles, Los Angeles, California.

Dr. Avidan has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within this chapter:

Takeda Pharmaceuticals – speaker bureau
Cephalon – speaker bureau
Sepracor – speaker bureau
Pfizer – speaker bureau

Objectives

  1. Become familiar with The International Classification of Sleep Disorders: Diagnostic and Coding Manual, Second Edition (ICSD-2) classification for hypersomnias of CNS origin.
  2. Become familiar with the epidemiology of narcolepsy.
  3. Discuss the etiology and pathophysiology of narcolepsy.
  4. Discuss the diagnostic workup for the diagnosis of narcolepsy and idiopathic hypersomnia.
  5. Be able to list the diagnostic criteria for narcolepsy.
  6. Understand the rational of new and emerging therapies in the treatment of narcolepsy and its associated symptoms.

Key words: automatic behaviors; cataplexy; human leukocyte antigen; hypnagogic hallucinations; hypocretin/orexin; idiopathic hypersomnia; maintenance of wakefulness test; multiple sleep latency test; narcolepsy; REM sleep; sleep attacks; sleep paralysis

Abbreviations: EDS = excessive daytime sleepiness; HLA = human leukocyte antigen; ICSD = International Classification of Sleep Disorders; KLS = Kleine-Levin syndrome; MSL = mean sleep latency; MSLT = mean sleep latency test; PSG = polysomnogram; REM = rapid eye movement; SOREMP = sleep onset REM period

Sleepiness vs Fatigue

Unlike fatigue, tiredness, and weakness, sleepiness is associated with a severe irresistible sleepiness during inappropriate times. Fatigue is usually associated with other comorbid conditions such as cardiopulmonary disease, endocrine disorders, viral illness, neuromuscular disease, and chronic fatigue syndrome and is usually not accompanied by episodes of inappropriate sleep unless disrupted sleep is part of the clinical picture.1

The etiologies for sleepiness (hypersomnia) are many, but in the United States, they are most likely related to sleep deprivation (insufficient sleep), mood disorders, primary sleep disorders unrelated to CNS disorders (ie, sleep apnea, circadian rhythm abnormalities) and sleep disorders when the lesion is in the CNS (“CNS hypersomnia”). Examples of CNS hypersomnias include narcolepsy and idiopathic hypersomnia.

Narcolepsy

Narcolepsy is a clinical pentad consisting of severe EDS, disturbed nocturnal sleep, cataplexy, hypnagogic hallucinations, and sleep paralysis; the later three being abnormal manifestations of REM sleep intrusion into wakefulness.1-3 Historically, narcolepsy was the first primary sleep disorder to be identified and characterized, with reports dating from more than 100 years ago. The delineation of a tetrad of symptoms consisting of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis provided a succinct focus for the disorder’s clinical aspect. The discovery that narcolepsy is associated with frequent occurrences of rapid eye movement at the onset of sleep helped to identify narcolepsy as a specific disorder associated with REM sleep regulation disorder.2,3 REM sleep behavior disorder (RBD) is a condition seen with increased frequency in adults with narcolepsy. The condition is defined by the abnormal augmentation of limb or chin electromyographic tone during REM sleep associated with dream enactment.

The onset of narcolepsy with cataplexy is most common during adolescence or young adulthood, but it can be encountered in early childhood. The onset of cataplexy is usually during the first few years after the onset of cataplexy, but it may occasionally develop before or long after the onset of hypersomnolence.1

The discovery of sleep apnea, the improved characterization of other syndromes of excessive daytime sleepiness, the use of the multiple sleep latency test (MSLT), and the discovery of association of narcolepsy with specific human leukocyte antigen (HLA) markers has helped to clarify the clinical feature of narcolepsy.2

Epidemiology of Narcolepsy
The prevalence rate of narcolepsy is about 1 in 4,000 in North America and Europe. There is no evidence of any gender predilection. Data suggest a higher prevalence in countries such as Japan (1 in 600) and a much lower prevalence in countries such as Israel (1 in 500,000). The prevalence in the United States is estimated to be between 0.03% and 0.07%. Unfortunately, of the 125,000 Americans who suffer from narcolepsy, only 35% (43,000) are adequately diagnosed and receiving medical treatment.

Narcolepsy Symptoms
EDS is usually the first and most common symptom to appear and is often the most disabling. Many physicians erroneously think that sleep attacks are unique to narcolepsy or that excessive daytime drowsiness without sleep attacks cannot be due to narcolepsy. Sudden sleep episodes or sleep attacks can occur with any cause of sleepiness, including sleep deprivation, sleep apnea, idiopathic hypersomnia and medication-related drowsiness.2 When present, this is an indication of the severity of sleepiness rather than a marker of qualitative different processes. Other symptoms are believed to be manifestations of REM sleep intrusion. These include cataplexy, hypnagogic hallucinations, and sleep paralysis.1 The propensity for early-onset REM sleep probably accounts for hypnagogic hallucinations and sleep paralysis, which probably reflects intrusion of dream imagery and REM sleep atonia into the waking state.

Cataplexy: Cataplexy is characterized by sudden skeletal muscle weakness triggered by intense emotions such as laughter (the most common trigger), anger, fear, embarrassment, excitement, and sexual arousal. Cataplexy occurs in the majority of patients with narcolepsy (about 70%), and, in most cases, is a unique feature of narcolepsy.1 When present, it is virtually diagnostic of narcolepsy.2,4-8 Attacks may be localized to specific body areas (eg, the face) or involve all skeletal muscle groups in a generalized fashion. The cataplexy spell is episodic, without altered consciousness, lasting seconds to minutes. Cataplexy may occur several times daily or less than once per month. Consciousness is uniformly preserved at the onset, but prolonged periods may be associated with auditory, visual, or tactile hallucinations and may lead directly into REM sleep.

Sleep Paralysis: Sleep paralysis is an episode of inability to move during sleep onset or upon awakening that lasts a few seconds or minutes.1 It occurs in 25% to 50% of patients with narcolepsy. Patients describe the sensation of struggling to move, and the paralysis usually ends spontaneously or after mild sensory stimulation, but it sometimes continues even after vigorous attempts at arousal. The inability to move lasts for a few seconds or minutes during sleep onset or offset.

Hypnagogic and Hypnopompic Hallucinations: Hypnagogic (drowsiness preceding sleep) and hypnopompic (drowsiness preceding wakefulness) hallucinations occur in about 20% to 40% of patients with narcolepsy. Hypnopompic hallucinations occur during the transition from sleep into wakefulness and may accompany sleep paralysis, or they may occur independently. Visual dream-like hallucinations are the rule, although there may be auditory or tactile hallucinations.

Disrupted Nocturnal Sleep: Disrupted nocturnal sleep occurs in the majority (about 70%-80%) of patients with narcolepsy. In some patients, it may be the prominent complaint, but it is not the major cause of daytime sleepiness. In addition to cataplexy, hypnagogic hallucinations, and sleep paralysis, which make up the narcolepsy tetrad, disrupted nocturnal sleep makes up the “narcolepsy pentad.”

Automatic Behaviors: Automatic behaviors may be due to chronic sleepiness. These are amnesic episodes associated with semipurposeful activity that may occur in up to 8% of patients with narcolepsy, as well as in patients with other sleep disorders. These episodes usually happen during monotonous or repetitive activities, last for seconds to 30 min or more, and may be associated with brief lapses of speech, irrelevant words, or remarks.

Classifications of Narcolepsy
The ICSD-2 classifies conditions characterized by primary hypersomnolence into a single category titled, “Hypersomnias of central origin not due to a circadian rhythm disorder, sleep-related breathing disorder, or other case of disturbed nocturnal sleep.”

Narcolepsy With Cataplexy: Narcolepsy with cataplexy is characterized by EDS and cataplexy. Sleepiness here is maximal during monotonous activities and may appear as irresistible sleep attacks. Patients who have narcolepsy with cataplexy are often noted to have nocturnal sleep disruption. At times, sleep disruption can be severe enough to impose further exacerbation of daytime sleepiness.

Narcolepsy Without Cataplexy: Narcolepsy without cataplexy is similar to narcolepsy with cataplexy in most clinical respects except for the lack of definite cataplexy.9

Narcolepsy Due to a Medical Condition: Narcolepsy with and without cataplexy is found in a number of medical and neurologic conditions. Genetic disorders associated with narcolepsy include type C Niemann-Pick disease10 and Prader-Willi syndrome.11 Structural lesions in the hypothalamic region, including tumors, sarcoidosis, and multiple sclerosis, may also cause secondary narcolepsy.12,13 Symptomatic narcolepsy may also been seen in several neurologic disorders not having demonstrable hypothalamic involvement, including acute disseminated encephalomyelitis, multiple system atrophy, and head injury.14-16

Narcolepsy, Unspecified: Narcolepsy, unspecified is defined by the ICSD-2 as a temporary classification for patients who meet clinical and laboratory criteria for narcolepsy but require additional evaluation for more precise classification.

Recurrent Hypersomnia: The recurrent hypersomnias are rare conditions in which there are prolonged episodes of severe EDS separated by periods of normal alertness and function.

Recurrent Hypersomnia: Kleine-Levine Syndrome—In Kleine-Levin syndrome (KLS), which typically affects adolescent boys, patients may sleep for all but a few hours daily for periods lasting days to weeks.17 The hypersomnia in KLS is often accompanied by variable disturbances of mood, cognition, and temperament, often including increased appetite and significantly aggressive or hypersexual behavior. Episodes may occur up to 10 times yearly, often with gradual improvement over time.9 No specific etiology for KLS has been yet established, but intermittent hypothalamic dysfunction or autoimmune etiologies have been proposed.18

Recurrent Hypersomnia: Menstrual-Associated Hypersomnia—Menstrual-associated hypersomnia is a poorly characterized condition in which episodic sleepiness coincides with the menstrual cycle, and it is postulated to be secondary to hormonal influences.

Idiopathic Hypersomnia With Long Sleep Time: Idiopathic hypersomnia with long sleep time is characterized by pervasive daytime sleepiness despite longer than average nighttime sleep.19,20 Prolonged nighttime sleep of 10 or more hours with few or no awakenings still leaves these patients unrefreshed or confused (sleep drunkenness) upon morning waking. Daytime naps tend to be longer and less refreshing than those of patients with narcolepsy. The condition most often develops during early adulthood with a chronic but stable course.

Idiopathic Hypersomnia Without Long Sleep Time: Although earlier classifications allowed the diagnosis of idiopathic hypersomnia only in the context of a prolonged nighttime sleep period, patients with comparable daytime sleepiness but normal to only slightly prolonged nighttime sleep have been reported.19,21 As a result, idiopathic hypersomnia without long sleep time has been established as a separate diagnostic entity in ICSD-2. Although the severe, pervasive daytime somnolence and unrefreshing naps seen in this condition are identical to those seen in idiopathic hypersomnia with long sleep time, the nighttime sleep period is less than 10 h.

Behaviorally Induced Insufficient Sleep Syndrome: Habitually insufficient total nighttime sleep results in excessive daytime sleepiness. Review of a sleep diary or sleep history of patients who are affected usually reveals a chronically shortened nighttime sleep period that is either less than the patient’s premorbid baseline. For children and adolescents, the sleep period is substantially reduced from the normal sleep period for their age. Daytime symptoms are those found in sleep deprivation and include sleepiness, irritability, disturbed mood, and impaired school or work performance. Symptoms remit with lengthening of the nighttime sleep period, but transiently longer sleep periods, for example on weekends, holidays, or vacations, often do not provide complete relief.

Hypersomnia Due to a Medical Condition: Hypersomnia due to medical condition may be diagnosed when sleepiness is thought to be the direct result of a medical or neurologic condition, but the patient does not meet clinical or laboratory criteria for a diagnosis of narcolepsy. The severity of daytime somnolence and length of nighttime sleep vary considerably among patients.

Variety of Conditions: A variety of conditions may underlie this disorder. Associated neurologic disorders may include encephalitis, cerebrovascular accidents, brain tumor, head trauma, and Parkinson disease.22-24 Common genetic conditions associated with sleepiness include Prader-Willi syndrome and myotonic dystrophy.25,26 Associated endocrinopathies such as hypothyroidism and hypoadrenalism, and toxic-metabolic disorders such as hepatic encephalopathy and renal failure, have been implicated. Drug-induced and psychiatric causes are classified elsewhere.

Hypersomnia Due to Drug or Substance: Hypersomnia due to a drug or substance is characterized by excessive nighttime sleep, daytime somnolence, or excessive napping related either to the use of drugs or alcohol, or related to their discontinuation.27 Sleepiness is often seen in patients who abuse sedative-hypnotic compounds such as alcohol, benzodiazepines, barbiturates, γ-hydroxybutyric acid (GHB), or nonbenzodiazepine sedatives. Somnolence may also complicate the use of medically indicated prescription medications, including antihistamines, antiepileptic drugs, and analgesics. Hypersomnia may also occur following abrupt withdrawal of stimulant use, or it may occasionally occur following nonabrupt cessation after prolonged prior use.

Hypersomnia Not Due to Substance or Known Physiologic Condition (Nonorganic Hypersomnia, Not Otherwise Specified): In hypersomnia not due to substance or known physiologic condition, excessive nighttime sleep, daytime somnolence, or excessive and nonrefreshing napping is associated with an identifiable psychiatric diagnosis, which sometimes becomes apparent only with time and detailed evaluation. Associated psychiatric conditions may include mood disorders, somatoform disorders, conversion disorders, and other psychiatric disturbances.28,29 Individuals who are affected often demonstrate intense preoccupation with their symptoms and may miss substantial amounts of school or work. Sleep diaries often reveal a prolonged bedtime in conjunction with delayed sleep latency and fragmented nighttime sleep with variable daytime napping. The condition most commonly appears during early adulthood. Despite patients’ subjective complaints, objective sleepiness may be difficult to document on MSLT.

Physiological (Organic) Hypersomnia, Unspecified (Organic Hypersomnia, Not Otherwise Specified): Chronic sleepiness for at least 3 months time with MSLT evidence of excessive of excessive sleepiness may be classified as physiological (organic) hypersomnia, unspecified, provided that the symptoms are believed to be physiologic and do not meet criteria for other disorders of excessive somnolence.

Clinical Course
The narcolepsy syndrome usually begins in the second or third decade of life, rarely before the age of 5 years or after the age of 60 years. With some patients, the onset is insidious; a decline in school performance from one year to the next may be the first indication of the disorder. In other patients, an apparent abrupt onset may be attributed to psychological stress, head trauma, minor infection, fever, drug abuse, or pregnancy.

Pathophysiology of Narcolepsy
The pathophysiology and pathogenesis of narcolepsy is remarkable for the tendency of REM sleep to occur within minutes of falling asleep. This is the “electrophysiologic signature” of narcolepsy. Narcolepsy is believed to represent a possible aberrant monoaminergic regulation of cholinergic REM sleeps mechanisms.

Recent evidence suggests that loss of hypocretin-1 secreting cells in the hypothalamus, possibly on an autoimmune basis, plays a pathogenetic role in the majority of cases.30,31 Despite the substantial clinical similarities between narcolepsy without cataplexy and narcolepsy with cataplexy, some evidence suggests that the underlying pathophysiology of the two conditions is not identical.

Cerebrospinal fluid hypocretin-1 levels are most often normal in patients with narcolepsy without cataplexy, whereas they are substantially decreased or undetectable when cataplexy is present.31 This suggests that the underlying cause or causes for narcolepsy without cataplexy may not involve the loss of hypocretin-1 secreting hypothalamic neurons.

Animal Studies in Narcolepsy
Recent animal models of narcolepsy have contributed considerably to a better understanding of the disease, its etiology, and its pathophysiology. In Doberman pinschers and Labrador retrievers, narcolepsy is transmitted as a single autosomal recessive gene (carnarc1) through mutations on the hypocretin-2 receptor. The model implicates hypocretins and the hypocretin-2 receptor in the pathophysiology of narcolepsy and regulation of REM sleep.32-35

The role of hypocretin in narcolepsy is supported by the finding that hypocretin levels are abnormally low or undetectable in the cerebrospinal fluid of most patients with narcolepsy.24,36-41 Values below 110 pg/mL or one-third of mean normal control values are highly diagnostic for narcolepsy in the absence of a severe brain abnormality.24,42 Neurochemical abnormalities have been observed in the brains of both animals and humans with narcolepsy. The most consistent abnormalities were observed in the amygdala, where increased dopamine and metabolite levels were found. An increase in M2 receptors in the pontine reticular formation, a region associated with REM sleep, was also found. Serotonergic transmission does not seem to be affected by narcolepsy.

The pathophysiology of cataplexy includes inappropriate REM sleep motor atonia during periods of wakefulness and probably reflects an underlying deficit of hypocretin and an imbalance between excitatory and inhibitory motor systems.

Genetics of Narcolepsy
Although up to one-half of all patients with narcolepsy have one or more first-degree relatives with narcoleptic symptoms, early diagnosis should be considered with care especially when it is solely based on symptoms and other causes of excessive daytime sleepiness. Over the last 2 decades, class II HLAs governed by the major histocompatibility complex have classified the genetic basis of the disease. Narcolepsy is associated with both HLA DR2 and HLA DQ1.43-45 DQB1*0602 is a more sensitive marker for narcolepsy and appears to be correlated to both the frequency and severity of cataplexy.38,45 Although a few patients with narcolepsy/cataplexy do not carry the HLADR2 or HLA-DQ1 antigens, the incidence of DR2 and DQ1 exceeds 90% in Japanese or Caucasian patients with narcolepsy and cataplexy. This suggests that narcolepsy may result from an autoimmune insult within the CNS.44 However, attempts thus far to confirm this hypothesis have been disappointing. Although the HLA antigen may be important in the pathogenesis of narcolepsy, it is neither sufficient nor necessary for disease expression The DR2 appears to occur almost as frequently in narcolepsy without cataplexy as it does in the narcolepsy-cataplexy syndrome.44

Narcolepsy is rarely transmitted from generation to generation; most cases occur sporadically. First-degree relatives of individuals with narcolepsy are usually unaffected but do have an increased rate of excessive daytime sleepiness. Discordance for narcolepsy has been reported in monozygotic twins, suggesting that, in addition to genetic factors, environmental triggers such as head trauma and infection may play a role in the development of the disease.44

Narcolepsy-cataplexy was previously believed to have an underlying autoimmune etiology. A recent study reviewing markers of immune response to β-hemolytic Streptococcus (antistreptolysin O [ASO]; anti-DNAse B [ADB]) and Helicobacter pylori [Anti Hp IgG], two bacterial infections known to trigger autoimmunity, found ASO and ADB titers were highest close to narcolepsy onset.46 These data implicated streptococcal infections as significant environmental trigger for narcolepsy. Two separate studies also reported an increased prevalence of autoantibodies against Tribbles homolog 2 (TRIB2) in patients with narcolepsy suggesting a subgroup within narcolepsy-cataplexy might be affected by an anti-TRIB2 autoantibody-mediated autoimmune mechanism47 and that anti-TRIB2 autoantibodies are strongly associated with narcolepsy close to cataplexy onset.48

Diagnosis: Subjective Assessment
Epworth Sleepiness Scale: The Epworth sleepiness scale (ESS) is an important instrument for assessing the degree of daytime sleepiness among patients with sleep complaints. This eight-item questionnaire asks patients to rate their propensity to fall asleep during different activities and situations (such as while watching TV or sitting and reading) on a scale from 0 (no chance of dozing) to 3 (high chance of dozing). The maximum score on this scale is 24; however, scores of greater than 10 are often considered to be consistent with some degree of daytime sleepiness. Scores greater than 15 are considered to be consistent with severe daytime sleepiness.49,50

Sleep Diary: During the clinical evaluation of narcolepsy, a sleep log of several weeks duration may provide important information about the patient’s sleep habits.

Diagnosis: Sleep Studies
Nocturnal Polysomnogram: Sleep studies are generally required for an accurate diagnosis of narcolepsy because of a variety of conditions that can cause excessive sleepiness. A complaint of sleepiness not explained by another medical condition is a clear indication for polysomnography.51 Most typically, the nocturnal polysomnogram (PSG) followed by the MSLT is required.52 The PSG is performed with the patient medication free and on a regular schedule and after obtaining sufficient sleep for 10 to 21 days prior. It can determine the presence and severity of sleep apnea, periodic limb movements of sleep, and nocturnal sleep disturbances. Polysomnographic features of narcolepsy include sleep disruption, repetitive awakenings, and decreased REM sleep latency. The occurrence of a REM sleep onset (typically within less than 20 min of sleep onset) during the PSG occurs in approximately 50% of patients with narcolepsy and cataplexy, and is very rare in control subjects.53 A sleep-onset REM period (SOREMP) at night is highly predictive of narcolepsy.

MSLT: The MSLT is performed during the main period of wakefulness and is designed to determine a patient’s propensity to fall asleep.52,54,55 To be a valid test, MSLT is usually performed the following day after the nocturnal PSG.56 Current criteria for narcolepsy include a mean sleep latency (MSL) ≤8 min and ≥2 SOREMPs.9 However, recent large studies have shown that between 4% and 9% of the general population may have multiple SOREMPs on routine clinical MSLTs, and up to 2% to 4% of these patients report daytime sleepiness that meets MSLT criteria for narcolepsy.57,58,59 Sleep-onset REM periods can also occur with depression, sleep wake-schedule disorders, drug and alcohol withdrawal, and REM sleep deprivation from sleep apnea.60,61,57,58,59 However, the absence of sleep-onset REM periods on an MSLT does not exclude narcolepsy, and their presence does not by itself confirm the diagnosis. The sleep-onset REM periods must be interpreted cautiously, particularly when sleep apnea is present.

Up to one-third of the general population may have a MSL of 8 min or less.52 The finding of a short MSL alone, without any SOREMP, should be interpreted cautiously together with the clinical picture.60 A very short MSL is likely to reflect a real CNS abnormality. The MSL is highly sensitive to sleep deprivation.60,62 The 2-week sleep log prior to testing is therefore very helpful, and information about sleep quantity from the previous night’s PSG is critical in the eventual interpretation of the study. The MSLT can also be of some value in detecting sleepiness in patients who might otherwise deny sleepiness.63

MSLT—Protocol for MSLT for Narcolepsy

A. The MSLT consists of five nap opportunities performed at 2-h intervals. The initial nap should begin about 1.5 to 3 h after termination of the nocturnal polysomnogram. The conventional MSLT recording montage includes central EEG and occipital derivations, left and right eye electro-oculograms, mental or submental electromyogram, and ECG.

B. The MLST should be performed following PSG recorded during the patient’s major sleep period. The test should not be performed after a split-night sleep.

C. The patient should maintain a sleep diary for 2 weeks prior to sleep testing, which consists of the following questions:

  • What time did you go to bed last night?
  • What time did you turn off the light intending to sleep last night?
  • How long did it take you to fall asleep?
  • What time did you plan to wake up?
  • What time did you actually wake up?
  • Rate how rested/refreshed you feel now: 1 = very rested; 10 = not at all
  • Rate the quality of your sleep last night: 1 = excellent; 10 = very poor
  • How many times did you wake up during the night?
  • Estimate the amount of time you spent awake after you fell asleep (in minutes).
  • How long did you nap yesterday (in minutes)?

D. A Current medication list should be obtained, including over-the-counter and illicit drugs, stimulants, stimulant-like substances, and REM-suppressing medications. Medications that may suppress REM include antiepileptic drugs such as phenytoin, carbamazepine, fluoxetine, antidepressants, lithium, venlafaxine, chlorpromazine, haloperidol, progesterone, β-blockers, clonidine, diphenhydramine, loratadine, promethazine, barbiturates, and benzodiazepines.

E. Patients should not be on any CNS acting agents for at least 15 days prior to the PSG and MSLT. Urine toxicology screening may be needed to verify the absence of medications and illicit drugs on the night of the sleep study or the morning before the MSLT.

F. The use of usual medications, such as antihypertensives, is generally planned by the physician prior to the MSLT so that the undesired properties of the stimulating or sedating medications are minimized.

G. Patients should be asked if they need to use the bathroom or need other adjustments for comfort prior to each nap opportunity on the MSLT.

H. Drug screening for stimulants, opiates and benzodiazepines may be considered, especially if the clinician suspects a history of substance abuse.63

I. Psychiatric evaluation and psychological testing are helpful when mood disorders, psychosis, malingering, or conversion disorder are suspected.

Management
Behavioral Therapy: The management of patients with narcolepsy is very rewarding. The first step should be a patient and family education and counseling about the syndrome, the importance of good sleep hygiene, the risks associated with sleepiness while driving and in the work place, and the role of medications. Adequate sleep at night is important because sleep deprivation or insufficient sleep will aggravate symptoms. It is customary to recommend that patients take power naps. One-to-three 20-min naps daily can lead to improvement in alertness and psychomotor performance without exacerbating nocturnal sleep disruption. Although few studies have been conducted regarding the effects of naps in narcolepsy, many clinicians and patients believe that naps are helpful.

Pharmacotherapy
Pharmacotherapy: Treatment for EDS—The treatments for EDS are summarized in Table 1.


Table 1Pharmacotherapy for Sleepiness Associated With Narcolepsy and Cataplexy

Medication Available Dosage Adult Starting Dose Dosing Regimen Adult Maintenance Dose Potential Side Effect
Armodafinil
(Nuvigil)
50, 150, 250 mg 150-250 mg QD 150-250 mg Headache, GI irritability, nausea
Modafinil
(Provigil)
100, 200 mg 100-200 mg QD QD 100-400 mg/d Headache, GI irritability, nausea
Methylph-enidate
(Ritalin)
5, 10, 20 mg 5-10 mg QD-BID QD-TID 20-60 mg/d Headache, tachycardia arrhythmia, anorexia weight loss, dependence and abuse
Methylph-enidate
Extended release

(Metadate CD)
(Metadate ER)
(Ritalin LA)
(Ritalin SR)



10, 20,
30 mg
SR
10, 20
mg SR
20, 30,
40 mg
SR
20 mg
SR



10-20 mg QD



QD-BID



20-60 mg/d



Headache, tachycardia arrhythmia, anorexia weight loss, dependence and abuse
Methylph-enidate
(Concerta)
18, 27, 36, 54 mg SR 18 mg QD QD 18-54 mg/d Headache, tachycardia arrhythmia, anorexia weight loss, dependence and abuse
Amphetamine/
dextroamph-etamine
(Adderall)
5, 7.5, 10, 12.5, 15, 20, 30 mg 10 mg QD QD-BID 10-60 mg/d Headache, tachycardia arrhythmia, anorexia weight loss, dependence and abuse, hypertension
Amphetamine/
dextroamph-etamine
extended release
(Adderall XR)
5, 10, 15, 20, 30 mg SR 10-20 mg QD QD 10-60 mg/d Headache, tachycardia arrhythmia, anorexia weight loss, dependence and abuse, hypertension
Dextroamph-etamine
(Dexedrine)
5 mg 5, 10, 15 mg SR 10 mg QD QD-BID 10-60 mg/d Anorexia, weight loss, headache, tachycardia, arrhythmia, behavioral changes, hypertension, seizures
Sodium oxybate
(Xyrem)a
2.25 to 4.5 g in 4.5 to 9.0 mL of fluid 2.25 g Taken at bedtime and again 2-3 h later 2.25-4.5 g Confusion, impaired waking, exacerbation of sleepwalking, hallucinations, psychosis, respiratory depression, abuse

aSpecific FDA indication for cataplexy.

 


Treatment for EDS: CNS Stimulants—CNS stimulants increase wakefulness, vigilance, and performance, and decrease the sense of fatigue. Prior to the introduction of modafinil, CNS stimulants were probably the mainstay pharmacologic treatment for sleepiness. Those used most commonly in the United States include methylphenidate, dextroamphetamine, and pemoline.

Treatment for EDS: Methylphenidate—Methylphenidate can help improve the mean sleep latency on MSLT and computerized driving test performance. Formulations include 5, 10, and 20 mg tabs and 20 mg sustained-release tablets. Methylphenidate may be given at a dose of up to 60 mg/d divided into bid or tid dosing. Side effects include nervousness, insomnia, akathisia, and headaches. Stimulants are schedule II medications.

Treatment for EDS: Dextroamphetamine—Formulations include 5 mg tablets/5, 10, and 15 mg capsules. Dextroamphetamine may be given at a dose of up to 60 mg/d divided into bid or tid dosing. Side effects include cardiovascular effects, insomnia, and psychosis.

Treatment for EDS: Pemoline—Pemoline is an oxazolidine derivative. Over the last few years, it has fallen out of favor due to potential hepatotoxicity and need for follow-up liver function tests periodically. It is a schedule IV drug.

Treatment for EDS: Methylphenidate—Methylphenidate is a commonly prescribed antinarcoleptic drug with a faster mode of action. It may be given at a dose of 30-60 mg/d and has lower incidence of side effects. Ninety-two percent of patients had marked moderate improvement in sleep tendency; 91% of patients had decreased psychic tension; and 83% of patients had improvement in cataplexy. Adverse side effects include headaches, dry mouth, stomach discomfort and sweating. Methylphenidate is a schedule II drug.

Treatment for EDS: Modafinil and Armodafinil—Modafinil and armodafinil are specific wake-promoting agents indicated for the management of EDS in narcolepsy, as well as for management of sleepiness in shift-work disorder (SWD) and to improve sleepiness in patients with obstructive sleep apnea who are not sleep deprived and are compliant with their continuous positive airway pressure machine. These agents are generally well tolerated, but potential side effects are mild to moderate and include headaches and GI irritation. Both are schedule IV drugs with a lower abuse potential relative to schedule III or II drugs. Lower doses may be used in the elderly and patients who are hepatically impaired. Evaluation for an individual patient’s response may take place as early as 1 week posttherapy because steady state is reached in 4 days.

Pharmacotherapy: Treatment of Abnormal REM Sleep Intrusions—The treatment for cataplexy and sleep paralysis is in the form of tricyclic antidepressants. Current therapy focuses on symptom management through a variety of REM sleep-suppressing medications that are used off-label. These include tricyclic antidepressants and serotonin-selective reuptake inhibitors. Once these medications are abruptly discontinued, they may precipitate a marked increase in the number and severity of attacks, the so-called “rebound cataplexy.”

Anticataplectic agents probably inhibit cataplexy through the blockade of serotonin and norepinephrine reuptake. Proposed treatment of cataplexy includes the following: protriptyline, between 5 to 30 mg per day; imipramine, 50 to 250 mg per day; clomipramine, 20 to 200 mg per day; and nortriptyline, 50 to 200 mg per day.

Tricyclic antidepressants are effective in about 80% of patients. At times, fluoxetine is useful especially in patients that cannot tolerate the anticholinergic side effects of tricyclic antidepressants. Patients with severe cataplexy tolerance to the effects of tricyclics may develop requiring gradual withdrawal followed by a 2-week drug holiday to restore efficacy.

Sodium oxybate, an endogenous metabolite of γ-aminobutyric acid, received US Food and Drug Administration (FDA) approval for the treatment of cataplexy and for the management of daytime sleepiness in narcolepsy. Reduction in cataplexy is seen within 2 weeks. Significant reduction in cataplexy was achieved within 4 weeks and long-term effectiveness was maintained. This drug has abuse potential with some important CNS adverse events, including death. Even at recommended doses, its use has been associated with confusion, depression, neuropsychiatric events, and respiratory depression.

Physicians who elect to prescribe dosages higher than those approved by the FDA have the responsibility to periodically to assess whether or not the presumed added benefit of higher doses overweighs potential or actual side effects.

Pharmacotherapy: Clinical Follow-up—It is advised that scheduled long-term follow-up for all patients with hypersomnia monitors for symptom exacerbation and interval development of comorbid medical, psychiatric, and sleep disorders. The follow-up appointment will also ensure that any new symptoms, such as cataplexy and other REM intrusion phenomena, in a patient who previously only exhibited sleepiness are identified and treated. Continuous regular clinical monitoring will also help assess for medication compliance, monitoring for treatment-specific adverse events, and ensure the optimal titration of treatment modalities based on the patient’s current clinical status.

Complications and Consequences of Narcolepsy
About two-thirds of patients with narcolepsy report to have fallen asleep while driving, and 80% have fallen asleep at work. Motor vehicle accidents are common, and people with narcolepsy have greater work impairment and poorer driving records than people with epilepsy. Many have a high prevalence of depression that probably reflects a psychosocial problem and the effects of a chronic illness, but there is little to suggest that narcolepsy is associated with specific psychopathology. Narcolepsy impacts a person’s psychological and social functioning, especially because disease onset occurs at a time of increasing responsibility at school or work. Patients often experience social isolation to avoid potentially embarrassing situations.


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