Narcolepsy

History

• Daily excessive daytime sleepiness for at least 3 months, associated with: ^r1c1
  • Frequent short naps (5-15 minutes) during daytime, usually refreshing and associated with dreams ^r1c2
  • Sudden, brief sleep episodes (ie, sleep attacks) during stimulating situations (eg, driving, walking, talking) ^c3
    • Sleep attacks are generally longer in children, up to 2 to 3 hours ^r7
  • Nocturnal insomnia ^r2c4
• Presence of cataplexy ^r1c5
  • Characterized by transient loss of motor tone triggered by strong emotions (eg, joy, amusement)
    • May affect all muscles (except diaphragm and extraocular muscles) or be segmental, affecting the face, speech muscles, or limbs
    • Generally bilateral; consciousness is preserved
  • Duration of seconds to minutes
  • Associated with type 1 narcolepsy
  • Occurs in 60% to 70% of patients ^r2
• Presence of hypnagogic or hypnopompic hallucinations ^r1c6c7c8c9
  • Vivid sensory images that occur at sleep onset (hypnagogic) or awakening (hypnopompic)
  • Hallucinations can be visual, auditory, or tactile
  • Occur in 30% to 60% of type 1 narcolepsy patients and 15% of type 2 narcolepsy patients ^r1
• Sleep paralysis ^r1c10c11
  • Transient inability to move or speak at sleep onset
  • Lasts seconds to minutes
  • Occurs in 50% of type 1 narcolepsy patients ^r1
    • Sleep paralysis prevalence is unknown in type 2 narcolepsy patients

Physical examination

• Physical examination of patients with suspected narcolepsy is unremarkable and no objective findings assist in diagnosing the disorder; however, during cataplectic episodes, deep tendon reflexes are diminished or absent ^r1c12c13

Causes ^c14

• May be caused by autoimmune destruction of orexin A neurons in the brain, particularly the lateral hypothalamus ^r1
  • Orexin A is a neuropeptide involved in regulation of wakefulness, arousal, and appetite
  • Orexin A in cerebrospinal fluid level of 110 pg/mL or less, or less than one-third of control values, is common in patients with narcolepsy ^r8c15

Risk factors and/or associations

Primary diagnostic tools

• Diagnosis is based on the clinical manifestation of excessive daytime sleepiness, a polysomnogram followed by multiple sleep latency test, and presence or absence of cataplexy ^r8c19c20
  • Diagnosis is confirmed with cerebrospinal fluid orexin A measurement, obtained via lumbar puncture
• HLA typing can be obtained for further supportive evidence (when present) for narcolepsy, and it is particularly useful in children owing to its relative noninvasiveness; however, HLA results are no longer included in diagnostic criteria
• Historically overdiagnosed owing to a dependence on the multiple sleep latency test, which has high false-positive (and false-negative) rates for diagnosis ^r2
  • Consider both clinical history and other tests (eg, orexin A test) to reliably diagnose

Laboratory

• Orexin A level of 110 pg/mL or less, or below one-third of control values—obtained via lumbar puncture—is indicative of type 1 narcolepsy ^r9c21
• Obtain HLA typing, particularly in children
  • Positive finding of HLA-DQB1*06:02 haplotype is supportive of a narcolepsy diagnosis, but it is not diagnostic because it lacks specificity ^r2

Functional testing

• Polysomnography^r10 and multiple sleep latency test^r11c22c23
  • Indicated for all adult patients and children aged 6 years and older^r7 with signs and symptoms suggestive of narcolepsy according to clinical presentation ^r1
    • Discontinue any sedating or stimulatory medications 2 weeks before the test to avoid inaccurate results (ie, washout) ^r11
    • Demonstrate a regular sleep-wake cycle by maintaining a sleep diary or by using actigraphy (measurement of activity and rest by a small, worn sensor) during that time ^r1
    • At least 6 hours of nocturnal sleep are necessary before performing the test ^r11
  • Overnight polysomnogram (of at least 6 hours) helps to exclude other causes of night sleep disruption (eg, sleep apnea, periodic limb movement disorder) ^r1
  • Next day multiple sleep latency test can measure the ability to sleep reflected by sleep latency during 20-minute nap opportunities (5 nap opportunities at 2-hour intervals), including the following 2 parameters: ^r11
    • Mean sleep latency: arithmetic mean of all naps or nap opportunities
    • Number of sleep-onset rapid eye movement periods during naps
  • Continuous 24-hour polysomnogram is performed in toddlers and children younger than 6 years ^r7
  • Results
    • Sleep latency of 8 minutes or less and 2 or more sleep-onset rapid eye movement periods are diagnostic of narcolepsy ^r1
      • Diagnostic specificity of multiple sleep latency test is 60%; when 2 or more sleep-onset rapid eye movement periods are present, diagnostic specificity increases to 95%
    • High false-positive and false-negative rates for diagnosis ^r2
      • Among patients without narcolepsy, 6% of males and 1.5% of females have test results that are diagnostic for this condition ^r2
      • 6% of patients with sleep-disordered breathing and 4% of patients with other sleep disorders test positive on the multiple sleep latency test ^r2
      • Some patients with orexin A deficiency and diagnosis of narcolepsy with cataplexy have normal multiple sleep latency test results ^r2
      • Underlies the importance of interpreting multiple sleep latency test results within the clinical context

Procedures

Most common

• Disorders with excessive daytime sleepiness
  • Idiopathic hypersomnia ^r13c25
    • Like narcolepsy, patient complains of excessive sleep
      • 10 or more hours of nighttime sleep plus daytime naps (total sleep time typically does not exceed 12 hours on weekdays, but may be as long as 19 hours on weekends or holidays) ^r13
    • Differentiate from narcolepsy by:
      • Lack of restive naps during the day
      • Prolonged sleep
      • Diagnosis established through a series of sleep studies
        • Epworth sleepiness scale ^r14
          • For a diagnosis of idiopathic hypersomnia, symptoms have to be present for 3 months or longer ^r13
        • Overnight polysomnogram
          • Differentiates idiopathic hypersomnia from narcolepsy and other sleep disturbances (eg, obstructive sleep apnea, periodic leg movement disorder)
        • Multiple sleep latency test ^r11
          • Less than 2 sleep-onset rapid eye movement periods ^r13
          • Mean sleep latency of 8 minutes or less
  • Sleep apnea ^c26
    • 1 or more pauses in breathing or shallow breaths during sleep
      • Breathing pauses can last from a few seconds to minutes and may occur 30 times or more per hour ^r15
      • Typically, normal breathing resumes, sometimes with a loud snort or choking sound
      • Sleep quality is poor, which results in excessive daytime sleepiness with frequent episodes of falling asleep, similar to narcolepsy
    • Differentiate from narcolepsy by history of pause in breathing during sleep, detected by polysomnography with apnea-hypopnea index of 5 or more (ie, number of apnea or hypopnea episodes per hour) ^r16
  • Advanced sleep phase syndrome ^c27c28
    • Circadian rhythm disorder defined by a stable sleep schedule that is several hours earlier than the desired sleep schedule, to the degree that the patient experiences significant difficulty keeping to a desired sleep schedule
    • Patients with advanced sleep phase syndrome are sleepy; they retire to bed early in the evening and wake up early in the morning. Sleep attacks are not reported
    • Differentiate by history of very early awakening associated with early bedtime and, if needed, polysomnography to exclude narcolepsy ^r17
  • Delayed sleep phase syndrome
    • Most prevalent circadian rhythm disorder; defined by delayed onset of sleep beyond the conventional bedtime, associated with difficulty in awakening at the desired time
    • Results in daytime sleepiness due to sleep deprivation; sleep attacks are not reported
    • Differentiate by history of late bedtime associated with difficulty arising at a desired (typically more conventional) time and, if needed, polysomnography to exclude narcolepsy
  • Depression with excessive daytime sleepiness ^c29d1
    • Disruption or irregularity in the circadian sleep-wake cycle resulting in excessive sleepiness or wakefulness at inappropriate times of day or night
    • Sleep attacks are not reported
    • Occurs in patients with depressive disorders and usually responds well to treatment of depression
    • Differentiate by history of depression and response to treatment of depression; if needed, perform multiple sleep latency test to exclude narcolepsy ^r1
  • Restless leg syndrome or periodic limb movement during sleep with subsequent excessive sleepiness ^c30
    • Irresistible urge to move the legs to avoid uncomfortable sensations, resulting in sleep disruption
    • Most patients with restless leg syndrome also have periodic limb movement during sleep, which results in nighttime awakening and daytime sleepiness
    • Sleep attacks are not reported
    • Differentiate from narcolepsy by history of restless legs when trying to sleep or periodic limb movements that disrupt sleep and multiple sleep latency test to exclude narcolepsy ^r1
• Disorders with cataplexy
  • Cataplexy-like episodes in sleepy or nonsleepy patients (without narcolepsy) ^c31
    • Differentiate by involvement of only the lower limbs, triggered by positive and negative emotions ^r1
  • Cataplexy-like episodes in psychiatric patients ^c32
    • Differentiate by: ^r1
      • Prolonged duration
      • Unusual triggers and circumstances
      • Psychiatric history

Recommendations for specialist referral

• Refer to pediatric neurologist when narcolepsy is suspected in children, especially those younger than 6 years, owing to the difficulty in making the diagnosis
• Neurologic consultation is recommended when the diagnosis is unclear and assistance is needed for medication management

Drug therapy

• Stimulant medication is prescribed as first line drug therapy to decrease daytime sleepiness and improve symptoms in a large majority of patients ^r27
• Treatment of excessive daytime sleepiness ^r19
  • Wake-promoting agent
    • Modafinil ^r19c33
      • Typically provided as first line alternative to central nervous system stimulants
      • Modafinil Oral tablet; Children: Initially, 50 mg PO once or twice daily depending on age and weight. If needed, may increase, but do not exceed 200 to 400 mg/day. ^r28
      • Modafinil Oral tablet; Adolescents 17 years and older: 200 mg PO once daily as a single dose in the morning. While doses up to 400 mg PO once daily have been well tolerated, there is no consistent evidence that doses greater than 200 mg/day confer additional clinical benefit. Max: 400 mg/day PO.
      • Modafinil Oral tablet; Adults, including Geriatric Adults: 200 mg PO once daily as a single dose in the morning. While doses up to 400 mg PO once daily have been well tolerated, there is no consistent evidence that doses greater than 200 mg/day confer additional clinical benefit. Max: 400 mg/day PO.
    • Armodafinil
      • Armodafinil Oral tablet; Adults, including Geriatric Adults: 150 mg to 250 mg PO once daily as a single dose in the morning. In geriatric adults, use lowest effective dose due to the possibility of adverse effects from decreased drug elimination.
    • Solriamfetol ^r20r29
      • Dopamine and norepinephrine reuptake inhibitor
      • Solriamfetol Oral tablet; Adults: Initially, 75 mg PO once daily upon awakening. If needed, may increase to 150 mg PO once daily after at least 3 days. Max: 150 mg/day. Consider the use of lower doses and close monitoring in those likely to have decreased renal function, such as the geriatric adult.
  • Central nervous system stimulants ^r27c34
    • Methylphenidate ^c35
      • Given in daily divided doses
        • Therapy is initiated with immediate-release formulation until an effective daily dose is determined, then total daily dose is converted to a sustained-release formulation
      • Use caution when prescribing to patients with history of drug dependence or cardiac diseases ^r21c36c37
      • Methylphenidate Hydrochloride Oral tablet; Children and Adolescents 6 years and older: 5 mg PO twice daily before breakfast and lunch. Increase by 5 to 10 mg/day at weekly intervals. Max: 60 mg/day.
      • Methylphenidate Hydrochloride Oral tablet; Adults: Average dose 20 to 30 mg/day; range 10 to 60 mg/day PO in 2 to 3 divided doses, 30 to 45 minutes before meals.
    • Amphetamines ^c38
      • Dextroamphetamine
        • Dextroamphetamine Sulfate Oral tablet; Children 6 to 11 years: 5 mg PO once daily in the morning. May titrate daily dose by 5 mg increments at weekly intervals. Max: 60 mg/day. Use minimum effective dose.
        • Dextroamphetamine Sulfate Oral tablet; Adults, Adolescents, and Children 12 years and older: Initially, 10 mg PO once daily in the morning. May titrate by 10 mg increments at weekly intervals to the minimum effective dose. Daily dose may be given in 1 to 3 divided doses at 4 to 6 hour intervals. Avoid late evening doses. Reduce dose if anorexia or insomnia occur. Usual dosage range: 5 to 60 mg/day PO, given in divided doses. Max: 60 mg/day PO.
      • Amphetamine-dextroamphetamine
        • Amphetamine Aspartate, Amphetamine Sulfate, Dextroamphetamine Saccharate, Dextroamphetamine Sulfate Oral tablet; Children 6 to 11 years: 5 mg PO once daily in the morning. Titrate by 5 mg increments at weekly intervals to minimum effective dose. Daily dose may be given in 1 to 3 divided doses at 4 to 6 hour intervals. Max: 60 mg/day.
        • Amphetamine Aspartate, Amphetamine Sulfate, Dextroamphetamine Saccharate, Dextroamphetamine Sulfate Oral tablet; Adults, Adolescents, and Children 12 years and older: Initially, 10 mg PO once daily. Titrate by no more than 10 mg/day at weekly intervals to the minimum effective dose. Max: 60 mg/day PO.
• Treatment of excessive daytime sleepiness and cataplexy ^r26
  • γ-aminobutyric acid receptor agonist ^c39
    • Sodium oxybate ^r19r30c40
      • Central nervous system depressant
      • Administer orally daily, increasing dose every 4 weeks; may take 8 to 12 weeks to have optimal effect ^r19
      • Prescribing requires enrollment in the Xyrem Risk Evaluation and Mitigation Strategy program;^r23 information is available from a pharmacist
      • Patients treated with sodium oxybate should not actively experience obstructive sleep apnea or should be fully adherent to nasal CPAP device therapy
      • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing less than 20 kg: Specific dosing recommendations are not available; consider a lower starting dosage, lower weekly dosage increases, and lower total maximum dosage. For patients weighing 20 to 29 kg, the initial dosage is 2 grams or less/night PO, divided into 2 equal doses, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by no more than 1 gram/night (0.5 gram/dose) at weekly intervals. Max: 6 grams/night. For patients who sleep more than 8 hours/night, the first dose can be given at bedtime or after an initial period of sleep. Unequal dosages may be required for some patients to achieve optimal treatment.
      • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing 20 to 29 kg: 2 grams or less/night PO initially, divided into 2 equal doses, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by no more than 1 gram/night (0.5 gram/dose) at weekly intervals. Max: 6 grams/night. For patients who sleep more than 8 hours/night, the first dose can be given at bedtime or after an initial period of sleep. Unequal dosages may be required for some patients to achieve optimal treatment.
      • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing 30 to 44 kg: 3 grams or less/night PO initially, divided into 2 equal doses, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by no more than 1 gram/night (0.5 gram/dose) at weekly intervals. Max: 7.5 grams/night. For patients who sleep more than 8 hours/night, the first dose can be given at bedtime or after an initial period of sleep. Unequal dosages may be required for some patients to achieve optimal treatment.
      • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Children and Adolescents 7 to 17 years weighing 45 kg or more: 4.5 grams or less/night PO initially, divided into 2 equal doses, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by no more than 1.5 grams/night (0.75 grams/dose) at weekly intervals. Max: 9 grams/night. For patients who sleep more than 8 hours/night, the first dose can be given at bedtime or after an initial period of sleep. Unequal dosages may be required for some patients to achieve optimal treatment.
      • Sodium Oxybate (Gamma Hydroxybutyrate Or Ghb) Oral solution; Adults: 4.5 grams/night PO initially, divided into 2 equal doses of 2.25 grams, the first given at bedtime and the second given 2.5 to 4 hours later. May increase dosage by 1.5 grams/night (0.75 grams/dose) at weekly intervals. Effective dosage range: 6 to 9 grams/night. Doses more than 9 grams/night have not been studied and should not ordinarily be administered.
  • Pitolisant ^r24r25
    • First and only medication not categorized as a controlled substance that is FDA-approved for treatment of symptoms of narcolepsy ^r25
    • Pitolisant Oral tablet; Adults: 8.9 mg PO once daily in the morning upon awakening for 1 week. Then, increase to 17.8 mg PO once daily for 1 week. After that, adjust to efficacy and tolerability. Max: 35.6 mg/day PO; limit to 17.8 mg/day PO in CYP2D6 poor metabolizers. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
• Treatment of cataplexy, severe hypnagogic hallucinations, or severe sleep paralysis ^r2
  • Venlafaxine ^r31c41c42c43
    • Off-label indication
    • Venlafaxine Hydrochloride Oral tablet, extended-release; Adults: Initially, 75 mg PO once daily. If needed, may increase further by 75 mg/day at intervals of no less than every 4 days. Max: 225 mg/day.
  • Fluoxetine ^r31c44c45c46
    • Off-label indication
    • Fluoxetine Hydrochloride Oral capsule; Adults: 20 mg/day PO initially. May increase the dose every month by 10 to 20 mg if needed. Max: 80 mg/day. May divide into 2 doses if dosage is 20 mg/day or more, given at morning and at noon.
  • Clomipramine ^r31c47c48c49
    • Off-label indication
    • Clomipramine Hydrochloride Oral capsule; Adults: Initially, 25 mg PO once daily, may gradually increase in the first 2 weeks to 100 mg/day PO, given in divided doses. Max: 250 mg/day. After titration, the total daily dose may be given at bedtime to minimize daytime sedation.

Nondrug and supportive care

• Counsel patients to improve sleep hygiene ^r2c50
  • Maintain regular sleep schedule to get adequate sleep (most patients require 7-9 hours^r32)
  • Schedule regular naps throughout the day to improve alertness ^r26
  • Allow 1-hour period before bedtime for relaxation ^r32
• Avoid stimuli (eg, alcohol, heavy meals) that promote sleep attacks ^r18c51c52
• Avoid stimulants (eg, caffeine, nicotine) 6 hours before bedtime ^r32
• Engage in regular exercise to promote wakefulness (but not close to bedtime) ^r18c53

Comorbidities

• Sleep disorders, such as sleep apnea ^r26
  • Should be treated as in non-narcoleptic patients

Special populations

• Pregnant and/or breastfeeding women
  • Consider potential risks of medical therapy for narcolepsy along with potential benefits. No teratogenicity has been shown, but none of the drugs typically used for narcolepsy have been specifically studied ^r4
    • If a patient being treated becomes pregnant, can reassure her about the absence of teratogenic effects associated with central nervous system stimulants, antidepressants, or sodium oxybate. May withdraw medications during pregnancy as further caution
      • For those maintained on medical therapy during pregnancy, consideration is given to temporarily discontinue some or all of the drugs used near delivery due to their possible effects on the newborn (eg, sedation, withdrawal)
    • For women who want to become pregnant, either stop medication before pregnancy occurs or monitor closely for pregnancy and stop medical therapy with first positive pregnancy test
    • Because all the medications employed in narcolepsy pass into breast milk, patient should feed baby formula if she wants to continue or resume medical therapy after delivery