Narcolepsy

Did You Know?

• In up to 10% of cases, there is a family history of the disorder.
• Selective destruction of HCRT/OX neurons with preservation of proximate structures suggests a highly specific autoimmune pathophysiology.
• The system regulating sleep and arousal involves three interconnected subsystems: orexin projections from the lateral hypothalamus, the reticular activating system, and the ventrolateral preoptic nucleus.

Signs and symptoms

Excessive daytime sleepiness occurs even after adequate nighttime sleep, leading to drowsiness or falling asleep at inappropriate times. Narcoleptics often do not experience restorative deep sleep due to abnormal REM regulation, and they typically have higher REM sleep density and more REM sleep without atonia. Daytime naps may occur with little warning, are physically irresistible, and can happen several times a day; these naps are refreshing only briefly. Vivid dreams are common even during short naps, and nighttime sleep is frequently fragmented with awakenings. A second main characteristic is abnormal REM sleep, where individuals enter REM at the beginning of sleep, even during daytime. The classic tetrad of symptoms includes cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness, though not all symptoms occur in every person.

Diagnosis

The ICSD-3 differentiates between narcolepsy with cataplexy (type 1) and without cataplexy (type 2), while DSM-5 uses narcolepsy for type 1 only and refers to type 2 as hypersomnolence disorder. ICD-11 identifies three types: type 1, type 2, and unspecified. For both subtypes, ICSD-3 requires daily periods of irrepressible need to sleep or daytime lapses into sleep lasting at least three months. Type 1 diagnosis requires cataplexy, or a mean sleep latency under 8 minutes with two or more sleep-onset REM periods, or hypocretin-1 concentration below 110 pg/mL. Type 2 requires mean sleep latency under 8 minutes, two or more SOREMPs, and hypocretin-1 above 110 pg/mL, with findings not better explained by other causes. DSM-5 criteria for narcolepsy include recurrent irrepressible need to sleep at least three times weekly for three months, plus one of: cataplexy, hypocretin-1 below 110 pg/mL, REM latency under 15 minutes, or MSLT showing sleep latency under 8 minutes with two or more SOREMPs. Hypersomnolence disorder diagnosis requires excessive sleepiness despite at least 7 hours of sleep, with recurrent daytime lapses, nonrestorative sleep of 9 or more hours, or difficulty staying awake after awakening, occurring at least three times weekly for three months with significant distress or impairment.

Treatment

People with narcolepsy can be substantially helped but not cured. Experimental approaches include gene editing to make other neurons produce orexin or hypocretin stem cell transplantation, which have restored function in mice. Future drug methods involve hypocretin agonists such as danavorexton or hypocretin replacement via intravenous, intracisternal, or intranasal routes, though intranasal delivery currently has low efficacy. General strategies include education of the person and family, sleep hygiene, medication adherence, and discussion of safety issues like driving. Regular follow-up monitors treatment response, assesses for other sleep disorders like obstructive sleep apnea, and addresses psychosocial issues. Planned regular short naps can reduce the need for pharmacological treatment of excessive daytime sleepiness, but only improve symptoms briefly; a 120-minute nap provides benefit for three hours, while a 15-minute nap provides none. Daytime naps do not replace nighttime sleep, and ongoing communication among healthcare provider, person, and family is important.

Research

Given the possible role of hyperactive GABAA receptors in primary hypersomnias, medications that counteract this activity are being studied. Flumazenil, the only GABAA receptor antagonist on the market as of January 2013, is manufactured only as an intravenous formulation but is considered promising. A small double-blind randomized controlled trial published in November 2012 showed flumazenil provides relief for most people whose CSF contains an unknown somnogen that enhances GABAA receptor function. For one person, daily sublingual lozenge and topical cream proved effective for several years, and a 2014 case report showed improvement with continuous subcutaneous infusion. The supply of generic flumazenil has eased, and dozens of people are now treated off-label. Clarithromycin, an FDA-approved antibiotic, was found in a test tube model to return GABA system function to normal; a small double-blind randomized controlled trial completed in 2012 showed it improved subjective sleepiness in GABA-related hypersomnia. A 2013 retrospective review found efficacy in a large percentage of people with GABA-related hypersomnia, noting the positive effect is secondary to a benzodiazepine antagonist-like effect, not its antibiotic properties.