Brain cell loss may help explain narcolepsy without cataplexy
Single-patient study found changes similar to type 1 disease
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Excessive daytime sleepiness is a common symptom of narcolepsy, including narcolepsy without cataplexy. (Photo from iStock)
Editor’s note: This story includes discussion of suicide. If you or someone you know needs help, the national suicide and crisis lifeline in the U.S. is available by calling or texting 988. There is also an online chat at 988lifeline.org. Internationally, find a suicide prevention helpline at findahelpline.com.
A woman with narcolepsy who did not have cataplexy — a sudden loss of muscle control triggered by strong emotions — had a marked reduction in brain cells involved in wakefulness regulation, a change similar to one previously reported in type 1 narcolepsy (NT1).
While these findings are based on a single patient, a 42-year-old woman, they suggest that near-complete loss of brain cells responsible for producing corticotropin-releasing hormone (CRH), a signaling molecule involved in the body’s response to stress and wakefulness regulation, may contribute to excessive daytime sleepiness without triggering cataplexy.
The woman’s case, “Postmortem Evidence of CRH Neuron Reduction in Narcolepsy Without Cataplexy With Borderline Hypocretin-1 Levels,” was published as a short report in the Journal of Sleep Research by a team of researchers in the Netherlands and France.
Brain changes may help explain symptoms
In narcolepsy, the brain cannot properly regulate sleep-wake cycles. As a result, people may feel an uncontrollable urge to sleep during the day, among other symptoms, such as cataplexy. There are two main types: NT1 and NT2. NT1 is marked by a lack of hypocretin, also called orexin, a signaling molecule that helps regulate sleep and wakefulness. In NT2, hypocretin levels are usually normal, and the precise underlying causes remain unclear.
Recent research suggested that NT1 is also linked to loss of CRH-producing brain cells in a small area of the brain called the paraventricular nucleus (PVN). Until now, it was unknown whether narcolepsy without cataplexy may also involve loss of CRH-producing brain cells. In this study, the researchers examined the brain of a woman with narcolepsy but no cataplexy to see if similar changes were present.
The woman developed excessive daytime sleepiness at age 15. She often fell asleep during the day but felt refreshed after short naps. She also experienced vivid dream-like hallucinations while falling asleep and episodes of sleep paralysis, when a person temporarily cannot move as they wake up or fall asleep.
An overnight sleep test found generally normal nighttime sleep without notable breathing problems. Multiple Sleep Latency Test assessments, a form of testing that measures how quickly someone falls asleep during scheduled daytime naps, showed that she fell asleep relatively quickly and entered rapid eye movement (REM) sleep soon after falling asleep several times. These early REM episodes are among the findings doctors use to diagnose narcolepsy.
Two spinal fluid tests performed eight years apart measured hypocretin-1 levels of 100 picograms/mL and 122 picograms/mL, suggesting a partial loss of hypocretin. She also carried the HLA DQB1*06:02 genetic variant, which is commonly linked to narcolepsy, and brain MRI scans showed no structural abnormalities.
Researchers examined donated brain tissue
The woman was treated with medications to improve daytime alertness, starting with modafinil (available in the U.S. as Provigil and generics) to promote wakefulness. Later, Wakix (pitolisant), which increases the activity of histamine in the brain to help people stay awake, was tried but stopped because it caused insomnia. Methylphenidate, a stimulant that increases brain activity and alertness, successfully promoted wakefulness.
Several years later, she developed severe depression and anxiety and died by suicide. After her death, her brain tissue was donated for research. The researchers compared her hypothalamus, a brain region involved in sleep regulation, with tissue from a control subject and from a person diagnosed with “typical” NT1.
The researchers found that the patient had an almost complete loss of CRH-producing brain cells in the PVN, similar to what has previously been reported in NT1. The part of the brain containing hypocretin-producing cells was missing from this sample of tissue, so they could not be counted directly. However, the spinal fluid tests already suggested that hypocretin was reduced.
“Although limited,” the researchers noted, “these findings suggest that narcolepsy without cataplexy, accompanied by borderline low [cerebrospinal fluid] hypocretin-1 levels, is associated with a marked reduction in CRH neurons in the PVN, which may contribute to excessive daytime sleepiness and impaired wakefulness regulation without triggering cataplexy.”
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