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Narcolepsy
Jennifer M. Slowik, DO, MS
Kevin A. Carter, DO, FAASM
image BASICS
DESCRIPTION
  • Disorder characterized by excessive daytime sleepiness often associated with cataplexy (sudden bilateral weakness of skeletal muscles) and other rapid eye movement (REM) sleep phenomena, such as sleep paralysis and hypnagogic hallucinations (e.g., vivid auditory or visual perceptions without an external stimulus that occur as one is falling asleep).
  • Frequently overlooked disorder, with an average of 15 years of symptoms prior to diagnosis
  • System affected: nervous
EPIDEMIOLOGY
Incidence
  • Onset usually in teenage years
  • Bimodal distribution peak at 15 and 35 years of age
  • Predominant sex: male > female (1.6:1)
  • Incidence: 0.74/100,000 persons/year
Prevalence
  • Narcolepsy type 1 (with cataplexy): 25 to 50/100,000 people
  • Narcolepsy type 2 (without cataplexy): 20 to 34/100,000 people
ETIOLOGY AND PATHOPHYSIOLOGY
  • Narcolepsy type 1 is a neurodegenerative disorder resulting from selective loss of neurons containing hypocretin (orexin) in the hypothalamus; may be autoimmune (associated with influenza A, H1N1 vaccine, and Streptococcus pyogenes).
  • Orexin neurons also regulate metabolism, feeding, reward and autonomic tone; weight gain especially in children from reduction of metabolism
  • 90-95% of patients with narcolepsy type 1 have low hypocretin in CSF
  • The cause of narcolepsy type 2 is not well established.
  • Possible involvement of immune system and environmental influences
Genetics
  • Increased incidence in families with positive history: 1-2% in first-degree relative of index case (10 to 40 times the general population)
  • Twin concordance is 25-31% (suggests environmental contribution).
  • Most are sporadic
  • 85-95% of patients with narcolepsy and cataplexy have human leukocyte antigen (HLA) DQB1*0602; 45% of patients with narcolepsy without cataplexy express this antigen. HLA DQB1*0602 is present in 24% of the general population.
  • Autosomal-recessive inheritance pattern
  • 12% of Asians, 25% of Whites, and 38% of African Americans are gene carriers.
RISK FACTORS
  • Obesity
  • Head trauma
  • CNS infectious disease
  • Anesthesia
  • Psychological stress
  • Family history
  • Recent influenza A, streptococcal infection, or H1N1 vaccine
COMMONLY ASSOCIATED CONDITIONS
Obstructive sleep apnea (up to 25%), obesity, anxiety
image DIAGNOSIS
PHYSICAL EXAM
  • A complete exam is useful to rule out other causes of hypersomnia.
  • If cataplexy is witnessed, examiner will be unable to elicit deep tendon reflexes.
DIFFERENTIAL DIAGNOSIS
Excessive daytime sleepiness is present in 4% of the general population, although most individuals are not narcoleptic. Possible etiologies include the following:
  • Sleep apnea syndromes (40-50% of those with excessive somnolence); increased incidence in narcolepsy, up to 26% prevalence
  • Epileptic seizures and syncope
  • Idiopathic hypersomnia (5-10% of those with excessive somnolence)
  • Psychiatric (depression, substance abuse/withdrawal)
  • Sleep related movement disorders (restless leg syndrome, periodic limb movements of sleep)
  • Iatrogenic secondary to medication (benzodiazepines, opioids, antihistamines, &bgr;-blockers, and some antipsychotics, antidepressants, and anticonvulsants)
  • Poor sleep hygiene and habits leading to sleep deficit
  • Circadian rhythm disorders (jet lag, shift work, delayed or advanced sleep phase disorders)
  • Seizures
  • Niemann-Pick type C
  • Hypersomnia related to a medical condition, such as Parkinson disease
  • Kleine-Levin syndrome (recurrent hypersomnia that lasts days to weeks and recurs months later)
  • Menstrual-associated hypersomnia
Pediatric Considerations
Narcolepsy is rare before the age of 5 years. Excessive daytime sleepiness is more often attributable to obstructive sleep apnea (OSA), poor sleep hygiene, and the increased sleep requirements early in life. Recommended amount of sleep decreases with age: newborns 16 to 18 hr/day; preschool-aged children 11 to 12 hr/day; school aged children and teens 10 hr/day; adults 7 to 8 hr/day.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Epworth Sleepiness Scale: score ranges from 0 to 24 and >10 is suggestive of a sleep disorder rather than generalized fatigue (1)[A].
  • Stanford Sleepiness Scale: patients select one of seven statements that best describe energy level, concentration, and sleepiness. Statements 4 to 7 may indicate excessive sleepiness.
  • Nighttime polysomnography (PSG): Monitoring of patients in a sleep laboratory will usually document fragmented sleep with a normal amount of REM sleep but rapid onset REM (within 15 minutes of sleep onset) and decreased sleep efficiency (2)[A]. The PSG is useful to rule out other causes of excessive daytime sleepiness, including sleep apnea syndromes and nocturnal myoclonus.
  • P.703

  • Multiple sleep latency test (MSLT): begins ≥90 minutes after nighttime test (2)[A]
    • The patient is monitored during 4 to 5, 20 minute naps taken at 2-hour intervals; rapidity of sleep onset and type of sleep pattern are documented. The supportive test includes mean sleep latency (time to fall asleep) of ≤8 minutes and ≥2 sleeponset REM periods.
    • Sensitivity 77%; specificity 97%; positive predictive value 73%
  • Maintenance of Wakefulness Test (MWT): used to assess ability to remain awake to determine restrictions (e.g., driving), assess treatment response. Not usually performed during the initial evaluation.
Follow-Up Tests & Special Considerations
  • HLA typing for DQB1 in ambiguous cases
  • Low CSF hypocretin-1 level: 99% specificity, 87% sensitivity in patients with cataplexy; useful in children when unable to do an MSLT
Diagnostic Procedure/Other
  • Narcolepsy type 1 (2)[C]
    • Excessive daytime sleepiness daily for ≥3 months
    • One of the following:
      • Cataplexy with sleep latency ≤8 minutes with ≥2 sleep-onset REM periods within 15 minutes of the onset of sleep (SOREMP)
      • Low CSF hypocretin-1 level <110 pg/mL or <1/3 of mean values in normal subjects
  • Narcolepsy type 2 (2)[C]
    • All above without the cataplexy and low hypocretin-1
  • Diagnosis of exclusion
image TREATMENT
GENERAL MEASURES
  • None of the currently available medications enables people with narcolepsy to consistently maintain a fully normal state of alertness.
  • Drug therapy should be supplemented by various behavioral strategies: Avoid shift work, heavy meals, and caffeine later in the day.
  • Well-timed 20-minute naps may be helpful.
  • Avoid sedating drugs and alcohol.
  • Use safety precautions, particularly when driving. People with untreated narcoleptic symptoms are involved in automobile accidents roughly 10 times more frequently than the general population. However, accident rates are at normal levels among patients who have received appropriate medication therapy.
MEDICATION
First Line
  • Excessive daytime sleepiness (EDS)
    • Modafinil (Provigil) (3)[A]:
      • Structurally distinct from amphetamines
      • 200 to 400 mg/day divided BID; start with 100 mg/day and increase over 3 to 4 days; maximum of 300 mg/dose, 400 mg/day 3.
      • First-line treatment: 60% effective and 20% partially effective
      • Half-life of 14 hours, can dose daily
      • Fewest adverse effects (headache, GI upset, increased metabolism of oral contraceptives) with less rebound hypersomnia and does not affect BP; tolerance limited
      • No decrease in cataplexy
    • Armodafinil (Nuvigil):
      • Enantiomeric form of modafinil with slightly longer half-life of 15 hours
      • 150 to 250 mg every morning
  • Cataplexy:
    • Sodium oxybate (Xyrem):
      • 2.5 to 9 g; may take 3 months for full response
      • Preferred treatment for narcolepsy with cataplexy and disturbed nocturnal sleep
      • Give 1/2 dose once in bed and 1/2 dose 2 to 4 hours later.
      • Date rape drug; abuse potential (3)[A]
      • Can use with modafinil in severe cases
      • May worsen sleep-disordered breathing in patients with OSA
      • Expensive with short half-life
    • Tricyclic antidepressants
      • Protriptyline: 5 to 60 mg/day
      • Clomipramine: 10 to 150 mg/day
      • High side-effect profile: dry mouth, sedation, urinary retention, impotence
    • Serotonin-norepinephrine reuptake inhibitors
      • Venlafaxine: 37.5 to 75 mg BID
      • Fluoxetine: 20 to 80 mg/day
      • Work by suppressing REM sleep
    • The patient may develop a tolerance to the anticataplectic drugs and can have rebound cataplexy when a drug is withdrawn.
    • Although often used, quality evidence is lacking to demonstrate improvement in cataplexy symptoms from antidepressants (4)[A].
  • Auxiliary symptoms (e.g., hypnagogic hallucination, sleep paralysis) require treatment less often than EDS and cataplexy but anticataplectics are useful when symptoms are problematic (4)[C].
Second Line
  • EDS
    • Amphetamines
      • Methylphenidate (Ritalin): initial dose 10 to 60 mg/day divided BID or TID; maximum dose 60 mg/day (3)[B], short-acting, most potent amphetamine available. Can be used in combination with modafinil and armodafinil. Dextroamphetamine: initial dose 10 mg/day; can increase by 10 mg weekly to a maximum dose 60 mg/day divided BID or TID (3)[B]
      • Contraindicated in patients with HTN
      • Adverse reactions: headaches, irritability, hypertension (HTN), psychosis, anorexia, habituation, rebound hypersomnia
      • If the patient develops a tolerance to stimulants, switch drugs rather than increase dose; there is little cross-tolerance
  • Cataplexy
    • Selegiline: selective MAO-B inhibitor
      • Anticataplectic effective for excessive daytime sleepiness; 20 to 40 mg/day divided morning and noon (3)[B]
      • Doses >20 mg require a low-tyramine diet because the drug begins to lose selectivity.
ISSUES FOR REFERRAL
  • Unresponsive to primary medications
  • Patient support groups can be very beneficial.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Frequent BP checks and regular follow-ups (approximately every 6 months) are recommended.
DIET
Selegiline: Doses >20 mg require a low-tyramine diet because the drug begins to lose selectivity.
PATIENT EDUCATION
  • Narcolepsy information from the National Institute of Neurological Disorders and Stroke at www.ninds.nih.gov/disorders/narcolepsy/narcolepsy.htm
  • Narcolepsy Network, Inc., North Kingstown, RI 02852; www.narcolepsynetwork.org
PROGNOSIS
Narcolepsy is a lifelong disease. Symptoms can worsen with aging. In women, symptoms can improve after menopause.
REFERENCES
1. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14(6):540-545.
2. American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
3. Mohsenin V. Narcolepsy—master of disguise: evidence-based recommendations for management. Postgrad Med. 2009;121(3):99-104.
4. Vignatelli L, D'Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2008;(1):CD003724.
Additional Reading
&NA;
  • Leschziner G. Narcolepsy: a clinical review. Pract Neurol. 2014;14(5):323-331.
  • Zaharna M, Dimitriu A, Guilleminault C. Expert opinion on pharmacotherapy of narcolepsy. Expert Opin Pharmacother. 2010;11(10):1633-1645.
Codes
&NA;
ICD10
  • G47.419 Narcolepsy without cataplexy
  • G47.411 Narcolepsy with cataplexy
  • G47.429 Narcolepsy in conditions classified elsewhere w/o cataplexy
Clinical Pearls
&NA;
  • Narcolepsy is a frequently missed disorder, with an average of 15 years of symptoms before a definitive diagnosis is made.
  • The classic tetrad of symptoms includes excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations but only cataplexy is pathognomonic for the disorder.
  • The International Classification of Sleep Disorders has specific diagnostic criteria for narcolepsy.
  • Medications are helpful but not curative.