[LUM#11] A new treatment for narcolepsy
When the inability to resist sleep becomes a nightmare! This is the daily reality for nearly 20,000 people in France who suffer from narcolepsy. To better treat this condition, Yves Dauvilliers, a neurologist specializing in sleep medicine, and his team at Montpellier University Hospital have recently developed an innovative treatment.
Narcolepsy, the most severe sleep disorder in humans, typically develops in people between the ages of 15 and 20. While difficulty staying awake is the main symptom of this neurological condition, it is not the only one. Sleepiness can sometimes be accompanied by weight gain, hallucinations, sleep paralysis, and frequently by cataplexy—in other words, a “loss of muscle strength triggered by positive emotions such as laughter, ” explains Yves Dauvilliers of the Neuropsychiatry: Epidemiological and Clinical Research Laboratory, and coordinator of the four narcolepsy reference centers recognized by the Ministry of Health, with the Montpellier University Hospital serving as the lead institution.
80,000 neurons destroyed
Narcolepsy, an autoimmune disorder with both genetic and environmental causes, and its underlying mechanisms have only been well understood by researchers for the past twenty years or so. “The human brain contains more than 100 billion neurons,” explains Yves Dauvilliers, “and narcolepsy destroys 80,000 of them by targeting exclusively hypocretin neurons.”
Hypocretin is a neurotransmitter whose main role is to promote wakefulness. “It’s because hypocretin neurons are activated that you’re able to engage in waking behaviors—in other words, eating, talking, and walking,” the researcher explains. “Fortunately for people with narcolepsy, hypocretin isn’t the only one playing this role; otherwise, they’d be asleep 24 hours a day.”
In fact, other neurotransmitters such as dopamine, norepinephrine, histamine, and acetylcholine can partially take over when hypocretin neurons disappear. The goal of narcolepsy treatments is therefore to increase the presence of these molecules in the synaptic cleft connecting two neurons in order to stimulate the wakefulness signal. “Neurons release their neurotransmitters into the presynaptic button but then reuptake some of them to prevent further protein synthesis,” explains Yves Dauvilliers. “Medications work by blocking the reuptake of these neurotransmitters to increase their levels and thereby promote wakefulness.”
Mitigating the risk of side effects
Amphetamines, which inhibit dopamine reuptake, were thus used as the first treatment for narcolepsy. Due to their significant side effects, they were gradually replaced by Ritalin, which is also prescribed for hyperactivity, and today by Modiodal or Wakix, which increases histamine levels.
While these latest treatments are effective, their effects are not always sufficient or long-lasting. “There’s sometimes a sort of ‘rebound effect,’” the researcher explains. “Over time, people start to feel a bit drowsy again. Unfortunately, if you increase the doses too much, you risk side effects such as headaches, irritability, high blood pressure…” ” Hence the need for a new treatment.
It’s now a reality. After four years of research and testing at the Montpellier Reference Center, the new drug—developed in collaboration with JAZZ Pharmaceuticals—received U.S. marketing authorization last March and is expected to receive European approval by the end of the year. “This innovative treatment no longer acts solely on dopamine reuptake but also on norepinephrine, and has therefore proven to be ‘highly effective, well-tolerated, and without loss of efficacy over time, at least during a one-year evaluation, ’” says Yves Dauvilliers.
Twice the resistance to sleep
For three months, the 250 patients in the cohort were ableto self-assess their sleepiness using the Epworth Sleepiness Scale. This questionnaire covers eight everyday situations in which patients are likely to fall asleep: while reading, watching TV, driving, etc. Their resistance to sleep was also tested in a laboratory setting. Seated in a room with no external stimuli and bathed in soft lighting, their goal was to stay awake for 40 minutes without falling asleep. This test was repeated four times, each at two-hour intervals. “Under such conditions, people with narcolepsy generally fall asleep after 10 or 12 minutes. Previous treatments increased their resistance by 3 or 4 minutes; with this one, it has doubled,” reports Yves Dauvilliers. This is enough to earn Montpellier its nickname as the “city where the sun never sets”—even for people with narcolepsy.
A difficult diagnosis
At the forefront of research, the Montpellier Narcolepsy Reference Center is also working to improve the diagnosis of the condition. “Only one-third of people with narcolepsy receive treatment. It takes 8 to 10 years to get a diagnosis,” reveals Yves Dauvilliers, a sleep specialist at the university hospital. “People think that sleep deprivation is the only factor causing drowsiness, but at age 15 or 20, it’s not normal to be drowsy in class if you’ve had enough sleep at night.” Hence the importance, at an age when one’s professional future is often at stake, of ensuring that this drowsiness does not mask an underlying condition.
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