Narcolepsy: Symptoms, Causes, Diagnosis, Treatment, Epidemiology, and Research

It is a long-term neurological disorder that involves a decreased ability to regulate sleep-wake cycles.

Symptoms include periods of excessive sleepiness during the day that generally last from seconds to minutes and can occur at any time.

About 70% of those affected also experience episodes of sudden loss of muscle strength, known as cataplexy .

Less commonly, there may be an inability to move or vivid hallucinations while sleeping or waking up. People with narcolepsy tend to sleep roughly the same number of hours per day as people without, but the quality of sleep tends to be worse.

The exact cause of narcolepsy is unknown, with several possible causes. In up to 10% of cases, there is a family history of the disorder. Often, those affected have low levels of the neuropeptide orexin, which may be due to an autoimmune disorder.

Traumas, infections, toxins, or psychological stress can also play a role. Diagnosis is usually based on symptoms and sleep studies, after ruling out other possible causes.

Excessive daytime sleepiness can also be caused by other sleep disorders such as sleep apnea, major depressive disorder, anemia, heart failure, alcohol use, and insufficient sleep. Cataplexy can be confused with seizures.

While there is no cure, a number of lifestyle changes and medications can help. Lifestyle changes include taking regular short naps and sleep hygiene. Medications used include modafinil, sodium oxybate, and methylphenidate.

Although initially effective, tolerance for the benefits can develop over time. About 0.2 to 600 per 100,000 people are affected. The condition often begins in childhood. Untreated narcolepsy increases the risk of motor vehicle collisions and falls.

The term “narcolepsy” is a French term, it was used for the first time in 1880 by Jean-Baptiste-Édouard Gélineau , who used the Greek νάρκη (narkē), which means “numbness”, and λῆψις (lepsy) which means “attack” .

Signs and symptoms of narcolepsy

There are two main characteristics of narcolepsy: excessive daytime sleepiness and abnormal rapid eye movement sleep or REM sleep.

The first, excessive daytime sleepiness (EDS), occurs even after adequate night’s sleep.

A person with narcolepsy is likely to doze or fall asleep, often in inappropriate places and times, or simply be very tired during the day.

Narcoleptics cannot experience the amount of deep restful sleep that healthy people experience, as they are not “sleeping too much.” In fact, narcoleptics live their entire lives in a constant state of extreme sleep deprivation.

Daytime naps can occur with little warning and can be physically irresistible. They are usually refreshing, but only for a few hours or less. Intense dreams can be experienced regularly, even during very short naps.

A second major symptom of narcolepsy is abnormal REM sleep. Narcoleptics are unique in that they enter REM sleep early in sleep, even when sleeping during the day.

The classic symptoms of the disorder, often referred to as the “tetrad of narcolepsy,” are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness.

Other symptoms can include automatic behaviors and nighttime wakefulness. These symptoms may not occur in all patients.

Cataplexy is an episodic loss of muscle function, ranging from mild weakness such as sagging in the neck or knees, sagging facial muscles, weakness in the knees often referred to as ‘knee buckling’ or inability to speak clearly. , up to a complete body collapse.

Episodes can be triggered by sudden emotional reactions and can last from a few seconds to several minutes. The person remains conscious throughout the episode. In some cases, cataplexy can resemble seizures.

Speech is usually slurred and vision is impaired (double vision, inability to focus), but hearing and consciousness remain normal.

Cataplexy also has a serious emotional impact on narcoleptics, as it can cause extreme anxiety, fear, and avoidance of people or situations that can trigger an attack.

Cataplexy is generally considered to be unique to narcolepsy and is analogous to sleep paralysis because the generally protective paralysis mechanism that occurs during sleep is inappropriately activated.

The opposite of this situation (not activating this protective paralysis) occurs in rapid eye movement behavior disorder. Waking periods at night.

Sleep paralysis is a brief inability to move or speak while sleeping or waking up. These episodes can last from a few seconds to several minutes. After the episode ends, people quickly regain their full ability to move and speak.

Hypnopompic hallucinations refer to the same sensations upon waking from sleep. These hallucinations can manifest in the form of visual or auditory sensations.

Automatic behaviors can also occur. A person may fall asleep momentarily but continue to do the previous activity, such as driving, without being conscious.

These behaviors occur when a person continues to function (talking, putting things away, etc.) during sleep episodes, but wakes up with no memory of performing such activities.

There are wide variations in the development, severity, and order of occurrence of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals.

Excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not be.

A rare subset of narcoleptics also experience a heightened sense of taste and smell known as the superfast phenomenon. Many people with narcolepsy also suffer from insomnia for long periods of time.

Normally, when an individual is awake, brain waves show a regular rhythm. When a person falls asleep for the first time, brain waves become slower and less regular, which is called non-rapid eye movement sleep (NREM).

After about an hour and a half of NREM sleep, brain waves begin to show a more active pattern again, called REM sleep (rapid eye movement sleep), when the most remembered sleep occurs.

Associated with EEG observations evaluated during REM sleep, muscle atony is present called REM atony.

In narcolepsy, the order and duration of NREM and REM sleep periods are altered, and REM sleep occurs at the onset of sleep rather than after a period of NREM sleep.

Additionally, some aspects of REM sleep that normally occur only during sleep, such as lack of muscle control, sleep paralysis, and vivid dreams, occur at other times in people with narcolepsy.

For example, lack of muscle control can occur during wakefulness in an episode of cataplexy; it is said that there is an intrusion of REM atony during wakefulness.

Sleep paralysis and vivid dreams can occur while sleeping or waking up. Simply put, the brain does not go through the normal stages of falling asleep and deep sleep, but instead goes directly into (and out of) rapid eye movement (REM) sleep.

As a consequence, nighttime sleep does not include as much deep sleep, so the brain tries to “catch up” during the day, hence excessive daytime sleepiness.

People with narcolepsy can visibly fall asleep at unexpected times (movements such as head shaking are common).

People with narcolepsy quickly fall into what appears to be very deep sleep, and they wake up suddenly and can become disoriented when they do (dizziness is common).

They have very vivid dreams, which they often remember in great detail. People with narcolepsy can dream even when they only fall asleep for a few seconds.

Along with vivid dreams, people with narcolepsy have been known to have auditory or visual hallucinations before falling asleep.

Narcoleptics can gain excess weight; children can gain 20 to 40 pounds (9 to 18 kg) when they first develop narcolepsy; in adults, the body mass index is about 15% higher than average.

Causes of narcolepsy

The exact cause of narcolepsy is unknown, and it can be caused by a number of different factors. Part of the mechanism involves the loss of orexin-releasing neurons within the lateral hypothalamus.

In up to 10% of cases there is a family history of the disorder. There is a strong link with certain genetic variants.

In addition to genetic factors, low levels of orexin peptides have been correlated with a history of infection, diet, contact with toxins, such as pesticides, and brain injury due to brain tumors or strokes.

Genetics

The primary genetic factor that has been strongly implicated in the development of narcolepsy involves an area of ​​chromosome 6 known as the human leukocyte antigen (HLA) complex.

Specific variations in human leukocyte antigen genes are strongly correlated with the presence of narcolepsy; however, these variations are not necessary for the condition to occur and sometimes occur in individuals without narcolepsy.

These genetic variations in the human leukocyte antigen complex are believed to increase the risk of an autoimmune response to orexin-releasing neurons in the lateral hypothalamus.

The human leukocyte antigen-DQB1 * 06: 02 allele of the human leukocyte antigen-DQB1 gene was reported in more than 90% of patients, and alleles of other leukocyte antigen genes such as the human leukocyte antigen-DQA1 * 01: 02 have been linked.

A 2009 study found a strong association with polymorphisms at the TRAC gene locus (single nucleotide polymorphism database ID rs1154155, rs12587781, and rs1263646).

A 2013 review article reported additional but weaker links to the TNFSF4 (rs7553711), Cathepsin H (rs34593439), and P2RY11-DNMT1 (rs2305795) gene loci.

Another genetic locus that has been associated with narcolepsy is EIF3G (rs3826784).

Vaccine

A link between the GlaxoSmithKline Pandemrix H1N1 flu vaccine and childhood narcolepsy was investigated due to the higher prevalence of narcolepsy in Irish, Finnish and Swedish children after vaccination.

The Finnish National Institute of Health and Welfare recommended the suspension of vaccinations against Pandemrix until further investigations are conducted on 15 reported cases of children developing narcolepsy.

In Finland, in mid-November 2010, doctors reported 37 cases of childhood narcolepsy. This can be compared to the normal average of 3 cases of childhood narcolepsy per year.

“The incidence of cataplexy narcolepsy in children / adolescents in the Swedish population increased during the pandemic and the vaccination period, with a rapid decline in incidence during the post-pandemic period.”

They concluded that these results “provide strengthened evidence that vaccination with Pandemrix during the pandemic period may be associated with an increased risk of narcolepsy with cataplexy in predisposed children / adolescents aged 19 years and younger.”

In 2013, the link between Pandemrix and narcolepsy was confirmed by a registry study by the Swedish Medical Products Agency, with a three-fold increased risk for people under the age of 20.

Pathophysiology

Orexin, also known as hypocretin, is a neuropeptide that acts within the brain to regulate appetite and wakefulness, as well as a number of other cognitive and physiological processes.

While there are billions of cells in the human brain, only 10,000-20,000 neurons secrete orexin peptides; all of these neurons project outside the lateral hypothalamus.

Loss of these orexin-producing neurons causes narcolepsy, and most people with narcolepsy have a reduced number of these neurons in their brains.

During normal REM sleep, hyperpolarization of the spinal alpha motor neuron and brainstem results in almost complete atony of skeletal muscles through an inhibitory descending reticulospinal pathway.

Acetylcholine may be one of the neurotransmitters involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy has characteristics normally seen only in normal REM sleep.

Diagnosis

A physician obtains a thorough medical history from the patient and performs a physical examination. These are the essential first steps in making an accurate diagnosis.

From there, the doctor will likely refer the patient to the sleep technologist, so that they can perform specialized tests in the sleep lab or clinic to confirm the diagnosis.

Three tests that are commonly used in the diagnosis of narcolepsy are the polysomnogram, the multiple sleep latency test (MSLT), and the administration of the Epworth Sleepiness Scale.

When diagnostic tests are analyzed, people with narcolepsy fall asleep quickly, enter REM sleep early, and can often wake up during the night.

The polysomnogram also helps detect other possible sleep disorders that could cause daytime sleepiness.

With the Overnight Polysomnogram, you will take multiple continuous measurements overnight while your patient is sleeping. This allows you to document any abnormalities in your sleep cycle.

Polysomnography tests can also help you identify if your patient experiences REM sleep episodes during their sleep cycle at abnormal times, eliminating the possibility that the symptoms they are experiencing are due to another condition.

Even if your patient shows definite cataplexy with his narcolepsy, he still needs to do a sleep study to rule out other possible sleep disorders, such as sleep apnea, that contribute to his excessive daytime sleepiness.

The Epworth Sleepiness Scale is a short questionnaire administered to determine the likelihood of the presence of a sleep disorder, including narcolepsy. A polysomnogram should be done before a multiple sleep latency test.

For the multiple sleep latency test, a person has a chance to sleep every 2 hours during normal waking hours. The patient is generally taken for an overnight sleep study.

The next day, the patient will have multiple tests where they will be asked to nap after sleeping through the night (usually eight hours).

Observations are made of the time it takes to reach various stages of sleep (sleep-onset latency). This test measures the degree of daytime sleepiness and also detects how soon REM sleep begins.

Again, people with narcolepsy fall asleep quickly and enter REM sleep early. Occasionally, a multiple sleep latency test can result in a false negative for a narcoleptic.

The system that regulates sleep, arousal, and transitions between these states in humans is composed of three interconnected subsystems: the orexin projections of the lateral hypothalamus , the reticular activation system, and the ventrolateral preoptic nucleus.

In narcoleptic individuals, these systems are all associated with deficiencies due to a greatly reduced number of hypothalamic orexin-projecting neurons and significantly fewer orexin neuropeptides in cerebrospinal fluid and neural tissue, compared to non-narcoleptic individuals.

Those with narcolepsy generally experience REM sleep within five minutes of falling asleep.

While people who do not have narcolepsy (unless they are significantly sleep deprived) do not experience REM until after a period of slow wave sleep, which lasts for about the first hour or so of a sleep cycle.

Measuring orexin levels in a person’s cerebrospinal fluid taken in a lumbar puncture can help diagnose narcolepsy, with abnormally low levels serving as an indicator of the disorder.

This test can be helpful when the results of multiple sleep latency tests are inconclusive or difficult to interpret.

Classification

The 2001 International Classification of Sleep Disorders (ICSD) divides primary hypersomnia syndromes into narcolepsy, idiopathic hypersomnia, and recurrent hypersomnias (such as Klein-Levin syndrome).

He also divides narcolepsy into that with cataplexy and that without cataplexy.

This international classification of the version of sleep disorders defines narcolepsy as a disorder of unknown cause ‘characterized by excessive sleepiness that is typically associated with cataplexy and other REM sleep phenomena, such as sleep paralysis and hypnagogic hallucinations. ».

It also establishes basic categorical standards for the diagnosis of narcolepsy, through 2 sets of well-defined criteria, as follows. Minimum diagnostic criteria for narcolepsy established # 2:

  • A “complaint of excessive sleepiness or sudden muscle weakness.”
  • Associated features including: sleep paralysis; Major Sleep Episode Disorder; hypnagogic hallucinations; automatic behaviors.

In the absence of clear cataplexy, it becomes much more difficult to make a firm diagnosis of narcolepsy. “Various terms, such as essential hypersomnia, primary hypersomnia, ambiguous narcolepsy, atypical narcolepsy, etc., have been used to classify these patients, who may be in the developmental phase of narcolepsy.”

Since the international classification of sleep disorders in 2001, the classification of primary hypersomnia has been evolving steadily, as new research has shown a greater overlap between narcolepsy and idiopathic hypersomnia.

The third edition of the International Classification of Sleep Disorders is currently being finalized, and its new classification will label narcolepsy caused by orexin deficiency as “type 1 narcolepsy,” which is almost always associated with cataplexy.

The other primary hypersomnias will remain subdivided based on the presence of REM sleep-onset periods.

They will be labeled “type 2 narcolepsy,” with 2 or more REM sleep-onset periods on the multiple sleep latency test; and “idiopathic hypersomnia,” with less than 2 REM sleep-onset periods.

However, “there is no evidence that the pathophysiology or therapeutic response is substantially different for hypersomnia with or without REM periods of sleep onset in the multiple sleep latency test.”

Given this currently understood overlap of idiopathic hypersomnia and narcolepsy, the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) is also updating its classification of primary hypersomnias.

Narcolepsy without cataplexy is reclassified as major somnolence disorder (MSD).

In addition, major sleepiness disorder will encompass all hypersomnolence syndromes not explained by low orexin levels, including idiopathic hypersomnia (with and without prolonged sleep time) and heavy sleepers (people requiring more than 10 hours of sleep / day).

To further complicate these updated classification schemes, an overlap between cataplexy narcolepsy and idiopathic hypersomnia has also been reported.

A subgroup of narcoleptics with long sleep times, comprising 18% of narcoleptics in one study, had symptoms of narcolepsy with cataplexy and idiopathic hypersomnia (prolonged sleep time and uncomfortable naps).

This subgroup is believed to have dysfunction in multiple activation systems, including orexin and gamma-aminobutyric acid (GABA).

Treatment

People with narcolepsy can be substantially helped, but not cured. Treatment is tailored to the individual, based on symptoms and therapeutic response.

Lifestyle adjustments

Although most narcolepsy patients are prescribed medications to help maintain alertness, there are also things you can suggest that they do for themselves to increase their alertness.

Here are some guidelines for good sleep hygiene:

  • Get at least 7 hours of sleep.
  • Maintain a consistent sleep schedule, getting up and going to bed at the same time every day, even on weekends or during vacations.
  • Set a bedtime that allows for at least 7 hours of sleep.
  • Don’t go to bed unless you are sleepy.
  • If you don’t fall asleep after 20 minutes, get out of bed.
  • Establish relaxing rituals at bedtime.
  • Use your bed only for sleeping.
  • Make your room calm and relaxing, with a pleasant and cool temperature.
  • Limit exposure to light at night.
  • Reduce your fluid intake before going to bed.

Medicines

The main treatment for excessive daytime sleepiness in narcolepsy are central nervous system stimulants such as methylphenidate, amphetamine, dextroamphetamine, modafinil, and armodafinil.

In late 2007, the Food and Drug Administration issued an alert for serious adverse skin reactions to modafinil.

Another drug used is atomoxetine, a norepinephrine reuptake inhibitor (NRI) that is non-stimulant and has no side or recreational effects.

Another Food and Drug Administration-approved treatment option for narcolepsy is sodium oxybate, also known as sodium gamma-hydroxybutyrate (GHS).

It can be used for cataplexy associated with narcolepsy and excessive daytime sleepiness associated with narcolepsy.

Narcolepsy has sometimes been treated with selective serotonin reuptake inhibitors and tricyclic antidepressants, such as clomipramine, imipramine, or protriptyline, as well as other medications that suppress REM sleep.

Venlafaxine, an antidepressant that blocks serotonin and norepinephrine reuptake, has proven useful in treating cataplexy symptoms, however it has notable side effects, including sleep disruption.

Establish positive sleep habits

No matter who you are, you will feel sleepy the next day after a poor night’s sleep, and this is particularly true for narcolepsy patients.

Most adults require seven to nine hours of sleep; teens generally need around nine to ten. Help your patient establish good sleep habits by offering these tips:

Set consistent times for going to bed and getting up in the morning to create a regular routine for your brain and body.

Keep the room comfortable and quiet. Eliminate any distractions like the TV, cell phone, or computer.

Avoid stimulating activities like watching TV or checking email if they wake up during the night. Reading a magazine or book for 10 minutes or listening to music can help them fall asleep. Avoid coffee and other stimulants in the late afternoon or at night.

Remind patients that if they take a drug that promotes wakefulness in the evening to keep them awake and prevent sleep attacks, they should take it early in the day so that it goes away before bed at night.

Daytime naps do not replace nighttime sleep. Ongoing communication between the healthcare provider, the patient, and members of the patient’s family is important for optimal management of narcolepsy.

Taking naps during the day

In many cases, regular planned short naps can reduce the need for drug treatment of excessive daytime sleepiness, but only improve symptoms for a short period.

A 120 minute nap provided benefit for 3 hours in patient alertness, while a 15 minute nap will provide no benefit.

The patient may find daytime naps refreshing and improves alertness for a few hours afterward.

But they should limit their naps to 20 minutes as it can be difficult for them to wake up from a deep sleep after taking a long nap. Not to mention, long afternoon naps can make it harder for you to fall asleep at night.

Schedule your naps around the times you think are the hardest to keep awake. Many people find the time to be 2 pm or 3 pm

If you have severe drowsiness, you may need an extra nap in the late morning. Also, they may want to take a nap before driving to improve their alertness.

Avoid alcohol, caffeine, and nicotine

The patient can worsen his symptoms using substances like these, particularly the use of alcohol at night.

Avoiding sedatives

Medicines for depression , allergies, seizures, or anxiety can increase or cause drowsiness. Make sure that as a patient you inform your doctor about all the medications you are taking.

Exercise regularly

Regular, moderate exercise at least four to five hours before bedtime can help you sleep better at night and feel more awake during the day.

Avoid a heavy meal

Narcolepsy patients may feel especially sleepy after eating a heavy meal; especially a high carbohydrate meal. Have your patients cut down on their meals.

Your patients may not realize they have narcolepsy and it can take years to recognize it. Since there are many different medical conditions that cause fatigue, you may not even consider narcolepsy at first.

epidemiology

In the United States, this condition is estimated to affect up to 200,000 Americans, but fewer than 50,000 are diagnosed. It is as widespread as Parkinson’s disease or multiple sclerosis and is more prevalent than cystic fibrosis, but it is less well known.

Narcolepsy is often mistaken for depression, epilepsy, or the side effects of medications. It can also be confused with poor sleep habits, recreational drug use, or laziness.

Narcolepsy can occur in both men and women at any age, although its symptoms are usually first noticed in adolescents or young adults. There is strong evidence that narcolepsy can be inherited.

About 10 percent of people diagnosed with cataplexy narcolepsy have a close relative with this neurological disorder.

While the symptoms of narcolepsy are often mistaken for depression, there is a link between the two disorders.

Research studies have yielded mixed results on the occurrence of depression in narcolepsy patients. The figures cited by different studies range between 6% and 50%.

There is an average delay of 15 years between onset and correct diagnosis that can contribute substantially to the disabling characteristics of the disorder.

Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented.

For this to occur in the crucial adolescent years, when education, self-image development, and occupational choice development are taking place is especially devastating. While cognitive decline does occur, it may just be a reflection of excessive daytime sleepiness.

The prevalence of narcolepsy is approximately 1 in 2,000 people. It is a reason for patient visits to sleep disorder centers, and with its onset in adolescence, it is also a major cause of learning difficulties and truancy.

Normal adolescents often already experience excessive daytime sleepiness due to an increase in maturation of the physiological tendency to sleep accentuated by multiple educational and social pressures; this can be disabling with the addition of narcolepsy symptoms in susceptible adolescents.

In clinical practice, differentiating between narcolepsy and other conditions characterized by excessive sleepiness can be difficult. Treatment options are currently limited.

There is a paucity in the literature of double-blind controlled studies of possible effective drugs or other forms of therapy.

The mechanisms of action of a few available therapeutic agents have been explored, but detailed studies of the mechanisms of action are needed before new classes of therapeutic agents can be developed.

Narcolepsy is an underdiagnosed condition in the general population. This is in part because its severity varies, so it can be easily confused with other diseases. Some people with narcolepsy do not suffer from loss of muscle control.

Society and culture

In 2015, it was reported that the British Department of Health was paying for drugs with sodium oxybate at a cost of £ 12,000 a year for 80 people who are taking legal action over problems related to the use of the Pandemrix swine flu vaccine.

Sodium oxybate is not available for people with narcolepsy through the National Health Service.

Investigation

Histamine Targeted Medications

‘Based on the role of histamine in keeping people awake (and thus the common side effect of antihistamines like diphenhydramine causing drowsiness), drugs that act on histamine are being developed for the treatment of drowsiness excessive ”.

It remains to be seen whether these H3 antagonists (ie, compounds such as pitolysants that promote the release of the wake-promoting amine histamine) will be particularly useful as wake-promoting agents.

Drugs targeting Gamma-Aminobutyric acid

Given the possible role of hyperactive type A gamma-aminobutyric acid (GABAA) receptors in primary hypersomnias (narcolepsy and idiopathic hypersomnia), drugs that could counteract this activity are being studied to assess their potential to improve sleepiness.

These currently include clarithromycin and flumazenil:

Flumazenil

Flumazenil is the only gamma-aminobutyric type A receptor antagonist on the market as of January 2013, and is currently manufactured only as an intravenous formulation.

Given its pharmacology, researchers consider it to be a promising drug in the treatment of primary hypersomnias.

The results of a small, double-blind, randomized, controlled clinical trial were published in November 2012.

This research showed that flumazenil provides relief for the majority of patients whose cerebrospinal fluid (CSF) contains the unknown ‘somnogen’ that enhances the type A function of gamma-aminobutyric acid, making them more susceptible to the sleep-inducing effect of gamma acid. -aminobutyric.

For one patient, daily administration of flumazenil via sublingual lozenges and topical cream has proven effective for several years.

A case report from 2014 also showed improvement in symptoms of primary hypersomnia after treatment with a continuous subcutaneous flumazenil infusion.

At first, the supply of generic flumazenil was thought to be too low to meet the potential demand for treatment of primary hypersomnias. However, this shortage has been alleviated, and dozens of patients are now being treated with flumazenil off-label.

Clarithromycin

In a test tube model, clarithromycin (an antibiotic approved by the Food and Drug Administration for the treatment of infections) was found to return the function of the gamma-aminobutyric acid system to normal in patients with primary hypersomnias.

Therefore, the researchers treated some patients with unlabeled clarithromycin, and most felt their symptoms improved with this treatment.

In order to further help determine whether clarithromycin is truly beneficial for the treatment of narcolepsy and idiopathic hypersomnia, a small, double-blind, randomized, controlled clinical trial was completed in 2012.

‘In this pilot study, clarithromycin improved subjective sleepiness in gamma-aminobutyric acid-related hypersomnia. Larger trials of longer duration are required. ‘

In 2013, a retrospective review evaluating long-term use of clarithromycin showed efficacy in a large percentage of patients with gamma-aminobutyric acid-related hypersomnia.

“It is important to note that the positive effect of clarithromycin is secondary to an effect similar to the benzodiazepine antagonist, not its antibiotic effects, and treatment should be maintained.”

Orexin receptor agonists

Oryxin-A (eg, hypocretin-1) has been shown to strongly promote arousal in animal models, but unfortunately it does not cross the blood-brain barrier.

Therefore, companies have developed orexin receptor antagonists, such as suvorexant, for the treatment of insomnia. It is also likely that an orexin-A receptor agonist will be found and developed for the treatment of hypersomnia.

L-carnitine

Abnormally low levels of acylcarnitine have been seen in people with narcolepsy. These same low levels have been associated with primary hypersomnia in general in mouse studies.

“Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity.”

Administration of acetyl-L-carnitine was shown to improve these symptoms in mice. A subsequent human trial found that narcolepsy patients who received L-carnitine spent less total time during daytime sleep than patients who received a placebo.