What would it be like if your muscles went slack and you collapsed every time you laughed out loud or felt a rush of joy? It is not a fatal illness, but hardly an easy life. The 2019 film "Ode to Joy" features a protagonist, Charlie, who is afraid of happiness. Whenever he laughs hard or feels an intense emotion such as surprise, anger or excitement, his strength drains away and he falls to the ground. It is a textbook case of cataplexy, a symptom commonly seen in patients with type 1 narcolepsy, a form of sleep disorder.
Narcolepsy is often pictured as falling asleep suddenly, anywhere. Many patients do report overwhelming bouts of drowsiness during the day even after a full night's sleep. They doze off in class or in meetings, fall asleep in mid-sentence, and some cause traffic accidents after losing the fight against sleep behind the wheel. The clinical term is a sleep attack. The nature of the disease is somewhat different, however. Symptoms vary widely from patient to patient, so it is more accurate to understand narcolepsy as a chronic neurological disorder in which the boundary between sleep and wakefulness becomes unstable.
Narcolepsy is broadly divided into type 1 and type 2 based on levels of hypocretin-1 in the cerebrospinal fluid. Hypocretin, also known as orexin, is a neurotransmitter known to maintain wakefulness in the hypothalamus. It is not simply a stimulant that wakes the brain up; it keeps both alertness and muscle tone stable. When that signal disappears, the boundaries between sleep, wakefulness and even REM sleep, the stage in which dreaming occurs, grow loose. Type 1 narcolepsy, which comes with cataplexy, occurs when the neurons that produce orexin are lost. With orexin signaling in short supply, patients struggle to stay awake during the day, and the disorder encroaches on waking hours to produce cataplexy, sleep paralysis and hallucinations. Why the neurons are lost is not yet clearly understood, though an autoimmune response in which the immune system mistakenly attacks orexin neurons is considered the leading suspect.
As with most diseases, narcolepsy is not diagnosed on symptoms alone. Overnight polysomnography is needed first to rule out other sleep disorders. The next day, a multiple sleep latency test has patients take repeated naps to measure how quickly they fall asleep and how early they enter REM sleep, and orexin levels in the cerebrospinal fluid are measured if necessary. The condition is not common. The U.S. Food and Drug Administration estimates that type 1 narcolepsy affects about one in every 2,000 people. In South Korea, one study based on 2019 national health insurance statistics reported 8.4 confirmed narcolepsy diagnoses per 100,000 people, though the actual number of patients may be higher. Symptoms often emerge in adolescence, but the condition is easily mistaken for a child who simply sleeps a lot or a student who lacks willpower, and it resembles attention deficit hyperactivity disorder, sleep deprivation and depression, making diagnosis difficult. Cataplexy — the loss of strength at moments of intense emotion, as in the film — is an important clue, but it does not appear in every narcolepsy patient, another factor that complicates early diagnosis.
Treatment has been as difficult as diagnosis. Existing drugs have focused on easing individual symptoms such as daytime sleepiness and cataplexy. Wake-promoting agents such as modafinil and solriamfetol reduce daytime drowsiness, while oxybate-class drugs and some antidepressants are prescribed to control cataplexy. Some patients have had to take several drugs at once, and in many cases daytime sleepiness or nighttime sleep disruption persisted even with medication. Above all, these drugs left the underlying cause — the loss of orexin neurons — untouched, suppressing only the symptoms on the surface. That is why oberoforexton, a new narcolepsy drug approved by the FDA last month, is drawing attention. Oberoforexton selectively stimulates the orexin 2 receptor, artificially restoring the orexin signaling that was severed by the loss of neurons. It is the first drug to target orexin deficiency, the root of the disease, rather than suppress its symptoms. According to the global Phase 3 trial that formed the basis of the FDA approval, narcolepsy patients who took oberoforexton twice a day for 12 weeks showed improvement in their ability to stay awake during the day and in subjective sleepiness, and the frequency of cataplexy fell. Scores reflecting quality of life also rose into the average range for the general population. Physicians expect the drug to mark the start of a shift in narcolepsy treatment, which has long meant adding one drug per symptom. It is not a cure, however. It cannot revive orexin neurons that have already been lost, nor block the autoimmune response believed to cause the disease. More data is also needed on how well it works over the long term and whether unexpected side effects emerge.
