Narcolepsy

Narcolepsy is a neurological sleep disorder marked by daytime sleepiness and associated with cataplexy, hypnagogic hallucinations, and sleep paralysis. There are 2 types of narcolepsy: type 1 is associated with cataplexy and type 2 has no association with cataplexy. A decreased level of orexin is noted in patients with type 1 narcolepsy. Diagnostic criteria are made using sleep studies that show a decrease in REM latency. Management includes good sleep hygiene. Medications that act as CNS stimulants and antidepressants are used to target the cataplexy. Narcolepsy is a life-long disorder with no definitive cure.

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Overview

Definition

Narcolepsy is a neurological disorder affecting the normal sleep–wake cycle, resulting in daytime sleepiness. The disorder is associated with cataplexy (emotionally triggered loss of muscle tone), hypnagogic hallucinations (auditory hallucinations that occur while falling asleep), and sleep paralysis (brief immobility upon awakening).

Epidemiology

  • Narcolepsy type 1: 
    • Prevalence: 25–50 in 100,000 people
    • Men = women
    • Begins in adolescence to early 20s (onset can range from 5–40 years of age)
  • Narcolepsy type 2:
    • 20–35 in 100,000 people
    • Less well studied

Etiology

Narcolepsy type 1:

  • Orexin (hypocretin) deficiency: 
    • Orexin: neurotransmitter produced by lateral hypothalamus
    • Acts on locus coeruleus, raphe nuclei, and tuberomammillary gland, producing excitatory effect of wakefulness
    • In narcolepsy 1: loss of neurons in lateral hypothalamus
  • Genetic factors: 
    • Certain forms are familial.
    • 95% of patients have DQB1*0602 haplotype (subtype of DQB1 gene).
    • 96% of patients with this haplotype also have orexin deficiency. 
  • Environmental triggers:
    • Neurons that produce orexin may be destroyed due to autoimmune processes triggered after streptococcal pharyngitis or influenza.

Narcolepsy type 2:

  • Orexin levels normal
  • Etiology unknown

Secondary narcolepsy:

  • Lesions affecting posterior hypothalamus and midbrain (e.g., tumors, strokes, vascular malformations, inflammatory processes such as sarcoidosis)
  • Associated with syndromes (Prader-Willi syndrome)

Clinical Presentation

  • Daytime sleepiness:
    • Most common symptom
    • Sleeping at inappropriate times (not excessive)
    • “Sleep attacks”: no warning sign and lasting < 30 minutes
    • Usually wake up well rested in the morning 
  • Cataplexy (60%–70%):
    • Emotionally triggered (e.g., laughing) transient muscle weakness
    • Begins in face and may progress to full drop attacks.
    • Patient is conscious. 
    • Usually lasts 2 minutes
    • 60% of patients present within 5 years of onset of disease.
  • Hypnagogic hallucinations (< 5%): 
    • Frightening and vivid visual, tactile, or auditory hallucinations that occur as patient is falling asleep
  • Sleep paralysis (< 5%):
    • Inability to move upon awakening
    • Lasts approximately 2 minutes
  • Comorbidities:
    • Restless legs syndrome
    • Obstructive sleep apnea (mild obesity is common in narcolepsy patients)
    • Depression
    • Anxiety
    • ADHD

Diagnosis

Investigations

  • Sleep studies:
    • Polysomnography (PSG):
      • Demonstrates:
        • Spontaneous awakenings
        • Reduced sleep efficiency
        • Increased light non-REM sleep
      • REM sleep within 15 minutes (versus 80–100 minutes in healthy individuals)
    • Multiple sleep latency test (MSLT):
      • Performed the morning after PSG
      • Patient is placed in sleep-inducing environment and allowed to fall asleep spontaneously.
      • Each nap session continues for 15 minutes after sleep onset to detect REM sleep.
      • Repeated at 2-hour intervals until patient has had 4–5 opportunities to nap
      • Patients with narcolepsy take < 8 minutes to fall asleep (versus 10–15 minutes in healthy patients).
  • Laboratory investigations:
    • CSF analysis: 
      • Measures orexin levels 
      • Low levels (< ⅓ of normal value) suggestive of narcolepsy
      • Done when sleep testing cannot be performed
    • Genetic testing for DQB1*0602:
      • Nonspecific

Diagnostic criteria

Narcolepsy type 1:

  • Daily periods of irrepressible need to sleep:
    • 3x/week
    • For ≥ 3 months
  • 1 or both of the following:
    • Low levels of orexin/hypocretin in CSF
    • Cataplexy and MSLT ≤ 8 minutes 

Narcolepsy type 2:

All criteria must be met.

  • Daily periods of irrepressible need to sleep:
    • 3x/week
    • For ≥ 3 months
  • Mean sleep latency of ≤ 8 minutes (MSLT)
  • Cataplexy is absent.
  • Normal levels of orexin in CSF
  • Findings not better explained by other causes, e.g.: 
    • Insufficient sleep
    • Obstructive sleep apnea
    • Delayed sleep phase disorder
    • Effect of medication, illicit substances, or their withdrawal

Management

The goal of therapy is to improve alertness, so performance and safety are adequate for important activities such as school or work.

  • Safety: 
    • Commercial drivers or workplace injury must be discussed.
    • Appropriate authorities notified
  • Sleep hygiene:
    • Maintain regular and adequate sleep schedule.
    • Scheduled daytime naps
    • Avoid substances that may affect sleep schedule, e.g., caffeine.
  • Avoid medications/drugs that may worsen sleepiness:
    • Benzodiazepines
    • Opiates
    • Antipsychotics 
    • Alcohol
    • Prazosin
  • Monitoring co-morbidities (psychiatric and obesity)

Pharmacological treatment

In patients with excessive daytime sleepiness and impaired daily functioning (majority of patients), medical intervention may be indicated. More than 1 medication may be needed to combat symptoms.

  • Daytime sleepiness:
    • Modafinil:
      • 1st line
      • Non-amphetamine CNS stimulant 
      • Well tolerated with low abuse potential
    • Amphetamines and methylphenidate:
      • 2nd line
      • Preferred in children
      • Higher risk of adverse effects (e.g., hypertension, tachycardia, psychosis, anorexia, abuse)
      • Newer options for patients not tolerating other options:
        • Solriamfetol (approved in 2019): selective dopamine and norepinephrine reuptake inhibitor
        • Pitolisant (approved in 2020): oral histamine H₃ receptor inverse agonist
  • Cataplexy:
    • Aim is to suppress REM sleep by increasing norepinephrine and serotonin.
    • Serotonin-norepinephrine reuptake inhibitor (SNRI):
      • Venlafaxine
      • Atomoxetine
      • Fluoxetine
    • Tricyclic antidepressants (TCAs):
      • Protriptyline or clomipramine 
      • Used when triggers are known and short term (e.g., stress)
      • Have anticholinergic side effects
    • Sodium oxybate:
      • Drug of choice for severe cataplexy
      • Mediates effect via GABA receptors
    • Pitolisant
Table: Comparison of medications used to manage narcolepsy
Medication Mechanism of action Side effects
Modafinil
  • Not well known
  • May work as a dopamine reuptake inhibitor
  • Well tolerated
  • May cause headaches, anorexia, nausea
  • Sympathomimetic side effects (tachycardia, hypertension)
  • Rare abuse potential
Sodium oxybate
  • Not well known
  • May work through GABA B receptors
  • Nausea and dizziness
  • Weight loss
  • Urinary incontinence
  • Mood swings, worsening of depression, or psychosis
  • Sleepwalking
  • Abuse: restrictive prescription
Amphetamines Increase catecholamines in synaptic cleft
  • Nervousness, agitation, tics, anxiety, or psychosis
  • Insomnia
  • Anorexia
  • Sympathomimetic side effects (tachycardia, hypertension)
  • Higher risk of abuse
Methylphenidate Blocks dopamine and norepinephrine reuptake by neurons
  • Sympathomimetic side effects (tachycardia, hypertension)
  • Arrhythmias
Solriamfetol Selective dopamine and norepinephrine reuptake inhibitor with wake-promoting effects Similar to modafinil
Pitolisant Histamine H3 receptor inverse agonist
  • Well tolerated
  • May cause headaches, insomnia, nausea, and QT prolongation

Narcolepsy in Children

Etiology and diagnosis of narcolepsy in children is the same as in adults.

Epidemiology

  • ↑ Trend in incidence 
  • Age of onset is typically 5–7 years.

Clinical presentation

  • Daytime sleepiness:
    • Sleeping during sedentary activities (e.g., sitting in classroom, reading a book)
    • Lasts 20–30 minutes
    • Doesn’t refresh the child
    • Habitual napping is uncommon in healthy children > 6 years of age and should raise suspicion. 
  • Cataplexy (80%):
    • More specific symptom
    • Characterized by oculo-bucco-facial weakness (“cataplectic facies”)
      • Jaw dropping open
      • Ptosis
      • Head rolling
  • Hypnagogic hallucinations and sleep paralysis (50%–60%)

Management

Behavioral modification:

  • Education about disorder being life long; no cure
  • Planned naps are essential.
  • Regularly scheduled bedtimes 
  • Optimize schooling with special accommodation.
  • Caution while swimming
  • Psychosocial support to detect development of anxiety or depression

Medical management:

  • Amphetamines and methylphenidate:
    • 1st line for children
    • Monotherapy
  • Sodium oxybate: if cataplexy is presenting complaint

Clinical Relevance

The following conditions are other types of sleep disorders:

  • Insomnia: sleep disorder marked by symptoms that interfere with duration and/or quality of sleep despite adequate opportunity for sleep
  • Circadian rhythm sleep–wake disorder: recurrent patterns of sleep disruption due to alteration of circadian system or misalignment between individual’s inner circadian rhythm and sleep–wake cycle. Subtypes include delayed sleep phase disorder, advanced sleep phase disorder, shift-work disorder, and jet lag disorder.
  • Parasomnias: pattern of sleep disorder marked by unusual actions, activities, or physiological events that occur during sleep or sleep–wake transitions. Symptoms may include abnormal movements, emotions, dreams, and autonomic activity.
  • Restless legs syndrome: condition marked by overwhelming urge to move one’s legs, accompanied by unpleasant sensations, which are relieved with movement. Patient complaint occurs during evening and is associated with sleep disturbance.
  • Obstructive sleep apnea: episodic apnea, or cessation of breathing during sleep, in which period of apnea lasts for more than 10 seconds. Usually due to partial or complete collapse of upper airway and is associated with snoring, restlessness, daytime headache, and somnolence.

References

  1. Scammell TE. Narcolepsy (2015). N Engl J Med;373:2654. https://pubmed.ncbi.nlm.nih.gov/26716917/
  2. Nishino S, Ripley B, Overeem S, et al. (2000). Hypocretin (orexin) deficiency in human narcolepsy. Lancet. https://pubmed.ncbi.nlm.nih.gov/10615891/
  3. Carskadon MA, Dement WC, Mitler MM, et al. (1986). Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. https://pubmed.ncbi.nlm.nih.gov/3809866/
  4. Dauvilliers Y, Bassetti C, Lammers GJ, et al. (2013). Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomized trial. Lancet Neurol. https://pubmed.ncbi.nlm.nih.gov/24107292/
  5. Ganti et al. (2016). First Aid for the Psychiatry Clerkship, 4th ed. (p. 165).
  6. Le T, Bhusan V, Sochat M, et al. (Eds.) (2020). First Aid for the USMLE Step 1, 30th ed. (p. 556).

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