Narcolepsy is a lifelong currently incurable neurological disorder, it is characterized by diurnal somnolence (excessive daytime sleepiness), disrupted night sleep, bizarre hallucinations, and cataplexy.
Narcolepsy is not life-threatening. In fact, many people go on with their lives without even realizing they have it. However, it can be damaging to social relationships and employment, and can even increase the risk of getting into a serious accident.
Epidemiology of narcolepsy
Incidence: according to the National Institutes of Health 1 in 2000 people, or 300,000 people in total. In the USA alone. This is about the same incidence as the devastating neurological disease Multiple Sclerosis.
Sex ratio: more often found in men than women.
Age-onset: between the age of 15 to 30 years old.
Is narcolepsy genetic?
There is no clear inherited genetic pattern for narcolepsy as there is in diseases like Huntington’s disease or cystic fibrosis. However, people with narcoleptic relatives have a higher risk of developing narcolepsy than the general population (X10-40 folds).
This clearly suggests that there is some form of genetic predisposition that runs in families. In identical twins, if one twin has narcolepsy, there is a 30% chance that the sibling will develop narcolepsy.
So, we’ve reached the conclusion that narcolepsy has some genetic component involved, but that can’t be the whole story. Environmental factors surely play a role as well.
In order to get a deeper understanding of genetics and environmental factors, let’s talk about some history and scientific research.
Storytime
Sleep medicine is a relatively new field of medicine that really shined in the late 1960s led by William C. Dement who was the founder of this branch. In the early 1970s, doctor Dement presented this new field to many professional medical societies. During his presentations, he frequently showed videos of narcoleptics having cataplectic episodes.
In 1972, Doctor Dement was approached by a veterinarian after one of his talks. The veterinarian said that he has seen a dog with similar symptoms shown in the lecture. Unfortunately, that dog has been euthanized because they thought it had epilepsy. However, the vet had a clip of one of the episodes.
William Dement started showing that clip in his lectures about human narcolepsy. And in the next year, he was approached by a neurologist who had a friend with a dog with similar symptoms. That dog was a French poodle named Monic. It was donated to Stanford afterward.
EEG studies of Monic showed she did not have epilepsy. She had cataplectic attacks which were triggered by strong emotions such as being given a favorite meal, or toy.
Similar studies were conducted on other dogs with suspected cataplexy. These studies established the existence of canine narcolepsy (narcoleptic dogs).
The canine model of narcolepsy
Further studies were conducted, and it was concluded that narcolepsy in dogs was due to a single recessive gene.
Because of the resemblance of symptoms between human narcolepsy and narcoleptic dogs, it was theorized that the culprit gene in humans might be the same as that in dogs.
Many researchers chased this theory to locate the exact gene and its protein products, it took a long time and massive resources. And by the early 1990s, a team led by Dr. Emmanuel Mignot was finally able to narrow down the location of the canine narcolepsy gene to a very small region of a chromosome. There was still a lot of work to determine the exact location of the gene.
When Dr. Mignot and his colleagues were pursuing the human genes of narcolepsy, they discovered that particular genes for components of the immune system were present in about 85% of all narcoleptics. This is good news, but also bad. The location of these genes did not match the location of the canine narcolepsy gene.
By the late 1990s, the Mignot group got closer and closer to finding the exact location and end products of the canine gene using some advanced molecular genetic methods.
Hypocretin
At the same time, research programs at the University of California and San Diego as well as the University of Texas were investigating a newly discovered gene that was expressed in the hypothalamus. Researchers at the University of San Diego found that the sequence of this gene was similar to a gut hormone called secretin, but because the product of this gene was expressed in the hypothalamus, it was called hypocretin.
Orexin
Researchers at Texas University led by Dr. Kazunori Nagasawa studied the same gene in rats but using a different root. Here’s how they did it:
Neurotransmitters found in the central and peripheral nervous systems all have receptors on the surface of the cells. The binding of neurotransmitters to these receptors will result in the activation of the cell to produce a certain function.
Neurotransmitter receptors all have similar signal transductions inside the cell. This is evident by the uncanny resemblance of the genetic sequences of these receptors’ genes. So, if you take out a gene from a mix of genes that encodes a receptor of unknown origin. You will probably find a new gene. Thus, a new receptor that we don’t know what neurotransmitter it binds to. These are called orphan receptors.
Starting from two orphan receptors from the rat’s hypothalamus, the Nagasawa group found the peptide that binds to them. What they did next is super clever: they produced a synesthetic form of this peptide and injected it into the rat’s hypothalamus. This resulted in a dramatically increased appetite in the rats. And the peptide was then named orexin (the Greek word for appetite e.g. anorexia).
The Hypocretin/Orexin
The thing is, scientists who injected orexin into rats did that at the beginning of the day, which corresponds to the beginning of the sleep phase of rats. This was the major detour point. The injected orexin, which we know now is just another name for hypocretin, induced wakefulness preventing the rats from sleeping. And what do animals and humans do when they are awake? They eat more.
The Texas group did a very interesting thing afterward, they genetically engineered a mouse to knock out the orexin gene. These mice did not produce orexin, they ate less. Thus, supporting the idea of the orexin-appetite relationship. However, when a nighttime video was used to study rats’ behavior during their active phase, it was noticed that they slept more, and also frequently collapsed. They were having cataplectic attacks.
The Hypocretin/Orexin in humans
Now, that’s what I call a bedtime story. It has all the components of a successful story, dogs, rats, mice, and scientists injecting stuff inside brains. Hopefully, you’re still with me now. To recap:
- Hypocretin/Orexin is a peptide found in the hypothalamus that exerts its functions on broad areas of the brain
- The main function of this peptide is to arouse the animal from sleep and to maintain it in an awake state
- In rats, a deficit of hypocretin/orexin resulted in the induction of narcolepsy and cataplectic attacks
- There is no clear evidence of the relationship between the hypocretin/orexin system and appetite fluctuations.
After all these findings, can we apply this knowledge to humans? Unfortunately, it would only fit perfectly if narcolepsy was a genetically transmitted disease, which we concluded is not the case.
You might be thinking “Did this guy make me read about dogs, rats, and mice to tell me it was irrelevant to humans? Where’s the dislike button”. Thankfully, this isn’t YouTube. And these studies did not go to waste.
Scientists conducted a new study with the main goal of measuring the amount of hypocretin found in healthy subjects and in patients with narcolepsy. The bad news is that you can’t just stick a needle inside someone’s brain and take a sample. The good news is that you don’t need to do that, almost all products secreted by the brain can be found in the cerebral spinal fluid which can be sampled by a lumbar puncture (spinal tap).
Measurements found that healthy individuals had normal levels of hypocretin, whereas narcoleptics had significantly less.
Why are Hypocretin/Orexin levels low in narcoleptics?
The next question is why is this the case? To answer this, researchers studied the brains of deceased narcoleptics who had donated their brains to science. Specifically, they did their research on the hypothalamus of healthy people and narcoleptics.
Scientists found that there are little to no hypocretin cells in the hypothalami (plural of the hypothalamus) of narcoleptics and the ones left had signs of damage.
Let’s see what we have now:
- Narcolepsy develops in young middle-aged individuals
- It shares immune system genes
- There are a decreased number of hypocretin cells in the hypothalamic region with signs of damage
The analysis of this data will lead us to the undeniable conclusion that narcolepsy is an autoimmune disease. Just like multiple sclerosis, or Duchenne muscular dystrophy.
Symptoms of narcolepsy
1. Daytime sleepiness
This is frequently found to be a chief complaint by patients, it can be so bad that a person experiences an overwhelming, irresistible need to sleep even when he is eating, in the middle of a conversation, or engaged in physical activity.
It is present every day. However, it’s less prominent on some days and typically more evident when the patient is in a sedentary state such as watching TV, reading, or lying down.
2. Cataplexy
What is cataplexy?
- Cata = down
- Plexy or plexus = seizure
So, cataplexy literally means a falling-down seizure. 75% of people with narcolepsy will experience at least one episode of cataplexy. Typically a person with narcolepsy will have a cataplectic attack when he experiences a strong emotion, especially a positive one such as laughter.
Imagine what it would be like if every time you heard a joke or watched a good comedy show (e.g. the office US) you’d collapse into the floor. That is cataplexy and it’s a problem that narcoleptics have to deal with every day of their lives.
Note that most cases of cataplexy have subtle symptoms such as facial, head, or limb weakness.
Fortunately, cataplexy doesn’t involve the respiratory muscles, nor the ocular muscles (muscles of the eye). Individuals describe being aware of oncoming episodes which generally last a short period of time.
Cataplexy in children
It can be triggered by exhaustion, tiredness, and stress. And often is described as the child having “puppet-like” movements, but it usually evolves into the typical presentation as the child ages.
3. Hypnagogic hallucinations
Seen in 30% of narcoleptics, frequently described as having vivid dreams shortly after sleep onset, and can even occur prior to falling asleep. These hallucinations are commonly visual but can be auditory. Frequent dreams, nightmares, and lucid dreams are also common.
Hypnopompic dreams which are dreams upon awakening do occur as well, but they are not specific to narcolepsy. This is also the case for “sleep paralysis” which occurs in 50% of narcoleptics as well as healthy patients. And I think it’s safe to assume that sleep paralysis has nothing to do with alien abductions.
Narcolepsy is also associated with psychiatric disorders. Mainly, depression.
4. Disrupted night sleep
This is characterized by sleep fragmentation, increased lighter sleep, and reduced deep sleep with disrupted Rapid Eye Movement (REM) sleep which is essential for “rebooting” your brain and for the body to recover its strength.
5. Weight gain
Narcolepsy is often associated with weight gain which can lead to a misdiagnosis of obstructive sleep apnea syndrome.
Diagnosis of narcolepsy
The criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM–5) to diagnose narcolepsy involve:
- Subjective daytime sleepiness at least 3 times per week over the past 3 months plus one of the following:
- Cataplexy
- Hypocretin deficiency
- Nocturnal EEG Recordings in favor of narcolepsy
Treatment of narcolepsy
Since narcolepsy is an autoimmune disease, there is no curable treatment. We only offer a symptomatic treatment:
Good sleep hygiene
This is the first-line treatment choice, it is especially good to avoid or reduce the use of pharmaceutical solutions. Here are some tips used to help good sleep hygiene:
- Set a regular bedtime
- Wind down before sleep
- Stop work early
- Try different relaxing activities
- Clear out your sleeping environment and avoid having objects such as your phone or computer near the bed
- Avoid eating heavy meals, consuming alcohol and caffeinated beverages before sleep
- If you cannot sleep, don’t lie in bed and worry about it. Try to engage in other activities until you feel sleepy again
- If you feel sleepy during the day, schedule a couple of naps during the day. Maybe just for 15 minutes
This can be difficult for narcoleptics to follow, but it can be helpful.
Pharmacological treatment
- Stimulants
- Antidepressants
- Sleeping pills
- Anticataplectic medications
The most commonly used stimulant, other than caffeine, is methylphenidate (Ritalin) which is taken during the day to reduce sleepiness. Unfortunately, it has some adverse side effects including headaches, nervousness, and gastrointestinal problems.
Treatment of cataplexy
A number of antidepressants have shown effectiveness in the treatment of cataplexy. These drugs include clomipramine and imipramine which are tricyclic antidepressants, and fluoxetine (Prozac) which belongs to the Selective Serotonin Reuptake Inhibitors (SSRIs) family.
The new drug on the block
Recently, a new drug was introduced for the treatment of narcolepsy. Sodium oxybate (Xyrem). The mechanism by which Xyrem works is still unknown. Unfortunately, it can be and is abused, and thus its controversial use.
The name of this drug might sound familiar because of its infamous use as a date rape drug, it enhances the effect of alcohol and can easily be slipped into drinks reducing inhibition and consciousness as well as inducing amnesia and facilitating sexual assault.
Conclusion
Finding better treatments for narcolepsy is an important goal for sleep researchers. Although narcolepsy is not life-threatening, it seriously compromises the quality of life for those afflicted and can be psychosocially devastating. But with proper management, narcoleptics can live normal and productive lives at a personal and professional level.
If you are narcoleptic or you know a relative with narcolepsy, I would love to hear your story.