Narcolepsy

Introduction
Narcolepsy is a chronic neurological sleep disorder characterized by excessive daytime sleepiness (EDS) and abnormal manifestations of rapid eye movement (REM) sleep. It results from dysregulation of the sleep–wake cycle, often due to hypocretin (orexin) deficiency caused by the loss of hypocretin-producing neurons in the hypothalamus.
There are two main types:

• Narcolepsy Type 1 (NT1): With cataplexy and/or hypocretin deficiency.

• Narcolepsy Type 2 (NT2): Without cataplexy and with normal hypocretin levels.

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Epidemiology

• Prevalence: Approximately 0.02–0.05% of the population.

• Onset: Often between ages 10–30 years.

• Affects both sexes equally.

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Etiology and Pathophysiology

Causes

• Autoimmune-mediated destruction of hypocretin-producing neurons (most common in NT1).

• Genetic susceptibility (HLA-DQB1*06:02 allele strongly associated with NT1).

• Rarely secondary to brain injury, tumors, or infections affecting hypothalamic areas.

Pathophysiology

• Hypocretin (orexin) is a neuropeptide critical for stabilizing wakefulness and regulating REM sleep.

• Loss of hypocretin neurons causes unstable transitions between wakefulness and REM sleep, leading to inappropriate intrusions of REM phenomena during wakefulness.

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Clinical Features

Core Symptoms

1. Excessive Daytime Sleepiness (EDS)

   • Persistent inability to maintain wakefulness during the day.

   • Can occur even with adequate nighttime sleep.

2. Cataplexy (NT1 only)

   • Sudden, transient loss of muscle tone triggered by strong emotions (laughter, anger, surprise).

   • Consciousness is preserved.

3. Sleep Paralysis

   • Transient inability to move or speak upon awakening or sleep onset.

4. Hypnagogic or Hypnopompic Hallucinations

   • Vivid, dream-like hallucinations at sleep onset or awakening.

5. Disturbed Nocturnal Sleep

   • Frequent awakenings despite quick sleep onset.

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Diagnosis

Clinical Evaluation

• Detailed sleep history, symptom onset, and impact on daily functioning.

• Assessment for cataplexy and REM-related symptoms.

Objective Testing

• Polysomnography (PSG): Overnight sleep study to exclude other sleep disorders.

• Multiple Sleep Latency Test (MSLT): Performed after PSG; diagnostic if mean sleep latency ≤8 minutes and ≥2 sleep-onset REM periods (SOREMPs).

• CSF Hypocretin-1 levels: Low (<110 pg/mL) or one-third of normal in NT1.

Differential Diagnosis

• Idiopathic hypersomnia.

• Sleep apnea.

• Chronic insufficient sleep.

• Psychiatric disorders (e.g., depression).

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Management

Narcolepsy is a lifelong condition with no cure; treatment focuses on symptom control through pharmacologic and non-pharmacologic measures.

1. Non-Pharmacologic Measures

• Scheduled short naps during the day.

• Good sleep hygiene: consistent bedtime, dark/quiet sleep environment.

• Avoidance of shift work or irregular sleep schedules.

• Lifestyle adjustments to minimize injury risk during sudden sleep episodes.

2. Pharmacologic Therapy

For Excessive Daytime Sleepiness

• Modafinil: 200–400 mg orally once daily in the morning.

• Armodafinil: 150–250 mg orally once daily in the morning.

• Solriamfetol: 75–150 mg orally once daily in the morning.

• Pitolisant: Initial 8.9 mg orally once daily, titrated up to 35.6 mg daily.

• Amphetamine derivatives (e.g., dexamphetamine 5–60 mg/day in divided doses, methylphenidate 10–60 mg/day in divided doses) if first-line agents fail.

For Cataplexy and REM-Related Symptoms

• Sodium oxybate: 4.5–9 g per night in 2 divided doses (start at 4.5 g and titrate).

• Antidepressants (off-label for cataplexy via REM suppression):

  • Venlafaxine: 75–150 mg daily.

  • Fluoxetine: 20–60 mg daily.

  • Clomipramine: 25–75 mg daily.

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Prognosis

• Narcolepsy is chronic but symptoms can be managed effectively with a tailored regimen.

• Patients have an increased risk of accidents without proper treatment.

• Quality of life can improve significantly with adherence to therapy.