Science Is Waking Up To The Curious Story Of Narcolepsy
Perhaps because we all need sleep, we have an enduring interest in tales of people who sleep continuously or cannot stay awake – popular characters such as Sleeping Beauty and Rip Van Winkle are just two examples.
Totally somnolent characters in films, such as Rat Race (2001), Moulin Rouge! (2001) or Deuce Bigalow: Male Gigolo (1999) all highlight our fascination – and amusement – with such sleepy individuals. But funny as they may seem, the sad fact is that these characters are all almost certainly based on the medical condition known as narcolepsy.
Narcolepsy is characterised by a constant, irrepressible need for sleep. The disorder affects about one in 3,000 people, mostly starting in teenage years.
It was first named by a French physician, Jean-Baptiste-Édouard Gélineau, from the Greek terms for “stupor” and “seizures”. Gélineau also observed cataplexy, which is the hallmark of classic narcolepsy.
Cataplexy entails loss of muscle activity in the face or body – resulting in sagging of the head to full body collapse to the ground – triggered by strong emotional responses, such as laughter. One of Gélineau’s patients reported collapsing to the ground at the Paris Zoo watching monkeys making faces.
Subsequent research based on better understanding of the sleeping brain showed cataplexy was the loss of postural muscle activity we all get during rapid-eye movement (REM, or dreaming) sleep, intruding on the waking state. This loss of muscle activity can be as subtle as a partial closure of the eyes due to loss of activity in the muscles encircling the eye, or as obvious as a total body collapse.
Jean-Baptiste-Édouard Gélineau coined the term narcolepsy from the Greek terms for ‘stupor’ and ‘seizures’.
Other intrusive REM phenomena common in narcolepsy include the inability to move immediately before falling asleep or on waking (sleep paralysis), or visual hallucinations caused by awake dreaming.
Despite the profound sleepiness and drive to sleep exhibited by people with narcolepsy, most would describe their night-time sleep as disturbed. Essentially, it’s difficult for them to maintain wakefulness or sleep for consistent periods, so they have insomnia with constant micro-sleeps during the day.
Some people are also described as having “partial narcolepsy”, when they have irrepressible sleepiness without any of these REM intrusive behaviours. But only a few people have true partial narcolepsy, while many others may have sleepiness due to other causes.
These days, it’s understood that people with classic narcolepsy have a faulty “sleep switch”. Just as a faulty light switch results in a light flickering on and off, their sleep-wake transition is constantly going on and off.
The “sleep switch” is actually a complex brain system acting as master controller for all aspects and behaviours associated with sleep. It’s located predominantly in the lateral hypothalamus and adjacent brain areas.
A dominant part of the switch is a small cluster of brain cells containing the neurotransmitter hypocretin, which regulates appetite, wakefulness and arousal, and is also known as orexin.
In classic narcolepsy, there’s a degeneration or complete loss of hypocretin neurones, while adjacent neurones with other neurotransmitters are preserved. In effect, narcolepsy is a highly selective degeneration of hypocretin neurones, which makes it very different to other brain degenerative disorders with more widespread effects, such as Alzheimer’s or Parkinson’s diseases.
A Hundred Years Of Sleep
But why do some people get such a selective neurodegeneration? To answer that question, we need to go back to World War I, when Austro-Hungarian flying ace Constantin von Economo was dragged out his precarious profession by his wealthy parents and pushed into the safer pursuit of neuropathology.
People with narcolepsy fight an irrepressible need for sleep. Erich Ferdinand/flickr, CC BY
These historic findings have led researchers over the years to believe that narcolepsy has an environmental trigger in people susceptible to the condition. One vulnerability factor is a group of genes, called HLA genes, that determine immune responses.
In 1984, the late Yutaka Honda identified that 100% of his patients with classic narcolepsy had a particular type of HLA gene, in contrast to 25% of the general population. Other researchers in Europe and North America confirmed these findings.
Some years before his death, along with a number of others, I had dinner with a very jetlagged Honda, who exhibited frequent micro sleeps during the main course. The irony of this scene never left me – and it’s probably a very good way to understand how someone with narcolepsy feels.
Solving The Mystery
Recently, 1,300 cases of classical narcolepsy were observed in people who were given GSK’s Pandemrix H1N1 flu vaccine (out of a total of 30 million Europeans given the vaccine). This led to a flurry of activity to try to identify diagnostic blood factors for narcolepsy, as well as proteins responsible for this side effect.
Constantin von Economo identified narcolepsy among encephalitis lethargica sufferers.
There were a number of dead ends, and one paper had to be retracted due to failure to replicate initial lab findings, but last month major progress was made. Scientists found a part of the H1N1 virus that resembled the hypocretin receptor.
They used antibodies from Finnish patients who had developed narcolepsy following Pandemrix vaccination, and added them to cells that were engineered to have a human hypocretin receptor on its surface.
The antibodies bound to the hypocretin receptors, suggesting they may also latch onto these receptors in people and cause degeneration of the hypocretin system in the brain and, therefore, narcolepsy.
This insight, as well as some evidence that antibodies from some non-vaccinated patients with H1N1 infection binds to the hypocretin receptor, provides more data that viral agents act as a trigger for narcolepsy.
By understanding how environmental factors trigger narcolepsy, we may be able to develop treatments that could protect the hypocretin receptor, or allow it to recover. At present, treatment for narcolepsy involves using stimulant drugs such as dexamphetamine or modafinil to keep people awake, and certain types of antidepressants to prevent cataplexy.
The “date-rape” drug gamma-hydroxybutyrate (GHB) is a powerful agent in people who have severe cataplexy and who don’t respond to antidepressants. GHB blocks the emotional triggering of loss of muscle tone and also improves sleep quality at night. It has just become available in Australia but is appropriate for only carefully selected patients.
Narcolepsy has devastating effects on quality of life; promising young students’ careers are stopped in their tracks, and sufferers are often unemployable as they try to deal with intractable sleepiness and cataplexy attacks.
Often, it takes years to get diagnosed, with a further cost to their lives. But people treated with appropriate therapy combinations, quality specialist care and flexible employers can do well over time.
The mystery of narcolepsy is slowly being solved by painstaking research. There’s hope that sufferers of this unusual condition will not indefinitely stay sleeping beauties.
Author: Ron Grunstein, Professor of Sleep Medicine, University of Sydney