Narcolepsy is a chronic sleep disorder and is one of the central disorders of hypersomnolence (CDHs). This term refers to conditions that cause excessive daytime sleepiness, meaning that patients have trouble staying awake during the day (1). CDH-type sleepiness isn't caused by temporary loss of sleep or by misaligned circadian rhythms (a preferred sleeping schedule that's shifted from times that are typical of the rest of the population --- jet lag is an example). Rather, the problem in the CDHs is internal, and it happens over an extended period of time (generally, for at least three months).

Some people with CDHs may feel increasingly drowsy during as the day goes along, and need to take a nap. They may or may not feel refreshed when they wake up, and they may feel drowsy again later. Others may have sleep attacks, which cause them to fall asleep suddenly, without feeling drowsy first. Others may become sleepy when doing something that isn't mentally stimulating, such as sitting in the passenger seat of a car. Some may be able to put naps off by doing something active. Many sleep for at least hours per night, yet are still tired during the day.

Daytime sleepiness can be assessed with an easy-to-use quiz called the Epworth Sleepiness Scale (2). The quiz has 8 simple questions and a basic scoring system. Higher scores (10 or more points) indicate the possibility of excessive sleepiness and suggest that seeing a doctor may be a good idea; scores of 16 or more are strongly suggestive of excessive daytime sleepiness and the need to see a doctor. In addition to this scale, physicians can study sleep with specialized tests, such as an MSLT (Multiple Sleep Latency Test) and polysomnography. The MSLT measures sleep latency, which is how quickly a person falls asleep. Polysomnography measures a variety of physiological states while a person is sleeping. Both are used for studying sleep and for diagnosing sleep disorders.

Other central disorders of hypersomnolence include Kleine-Levin syndrome, idiopathic hypersomnia, insufficient sleep syndrome, and hypersomnia due to medical/psychiatric disorders or to medications or other substances. Overall these conditions are rare to very rare, with narcolepsy being the most common.

Narcolepsy has been reported in people of a wide variety of ethnicities and locations around the world. It is more common in males than females. For example, of 1779 published case histories in which sex was known, 1049, or 59% of patients were male. Studies about prevalence of narcolepsy vary widely. For example, one recent meta-analysis estimated that it occurs in roughly 25-50 people per 100,000 (3) in the United States. This figure would translate to roughly 75,000 to 150,000 US patients.

Clinical information

People with narcolepsy have trouble controlling their sleep-wake cycles. One of the most prominent problems they have is the need to sleep during the day, when they may need to take naps. Many also have sleep attacks, which occur suddenly. Another common problem in narcolepsy is cataplexy, a condition that may look like a fainting spell or a seizure, but is not. Cataplexy is sudden loss of muscle function. It tends to occur when a person laughs or feels a strong emotion. Patients may have severe symptoms, such as suddenly losing control of their arms and legs and dropping to the ground (see photo at top right), or they may have relatively mild symptoms, such as experiencing loss of control of the muscles of the jaw, which may cause slurred speech. Cataplexy may also be triggered by being startled or by lights and sounds.

For an excellent video presentation of cataplexy and sleep attacks, see the video link on the right. It was made by a young woman who was creating an instructional dance video. She experienced cataplexy and sleep attacks while her camera was running, and she decided to make it publicly available as an educational tool. She also experienced what she called "memory bobbles" which were brief periods of disorientation that occured with sleep attacks and cataplexy.

There are two forms of narcolepsy: type 1 and type 2, which were first used in 2014 (4). Type 1 is also called narcolepsy with cataplexy, and type 2 is also called narcolepsy without cataplexy. As the names imply, type 1 includes cataplexy, while type 2 does not.

The most common clinical features of narcolepsy are listed below. Some of these features are common during sleep or when the patient is awakening.

Common problems in narcolepsy



•  Irrepressible need to sleep/sleep attacks
•  A need for naps during the daytime
•  Excessive daytime sleepiness
•  Fatigue or loss of energy
•  Sleep hallucinations
•  Sleep paralysis
•  Cataplexy
•  Headache
•  Memory loss
•  Obesity or overweight

Sleep hallucinations (also called hypnagogic hallucinations or hypnopompic hallucinations) are auditory or visual hallucinations associated with sleep. They occur because REM-type sleep occurs when someone is drifting off to sleep or waking up. REM sleep is the stage when dreaming occurs, and when it occurs as a person is falling asleep, the person may have hallucinations that may be frightening, and may seem real. Sleep paralysis is an inability to move or speak when falling asleep or awakening. The cause for these problems are not known, but may involve genetic factors and/or REM cycle abnormalities.

Causes of narcolepsy

The causes of narcolepsy are complex. Many cases are associated with a gene allele called HLA DQB1/06:02. This term HLA refers to a gene called Human Leukocyte Antigen, and the rest of the term specifies a certain sequence of the gene. Most people with narcolepsy have this allele, but roughly 15-25% of the normal population also has it as well. (5-7). Practically speaking, this means that having the HLA DQB1/06:02 allele increases the risk for narcolepsy, and is useful in diagnosing someone with narcoleptic symptoms, but having it does not cause the condition.

Other genes have been associated with narcolepsy. One is hypocretin (HCRT; see below), and most people with narcolepsy have no or very low levels of hypocretin protein in their cerebrospinal fluid. Other genes associated with narcolepsy include myelin oligodendrocyte glycoprotein i>MOG; 8) and CCR1/CCR3 (9). In addition, studies have found associations between narcolepsy and as-yet unidentified genes on chromosomes 4, 14, 19 21, and 22 (10).

Although most cases of narcolepsy are sporadic (occuring apparently at random and without an identifiable cause), it can also run in families (7). Estimates for the frequency of familial cases among all cases of narcolepsy are as low as 1% and as high as 10% (7, 8).

As noted, narcolepsy is strongly associated with deficiency of hypocretins (also called orexins) (reviewed in 11). Hypocretins are brain chemicals that help keep people alert (there are other factors in this process). They also have a role in ensuring that REM sleep does not happen at the wrong times (such as when falling asleep or waking up). In people who don't have narcolepsy, hypocretin is released in the brain by a small group of neurons during periods of wakefulness. These neurons are damaged in narcolepsy patients, and many of them die, meaning that narcolepsy patients have a deficiency of a substance that helps keep people awake. Most people with familial forms of narcolepsy have normal levels of hypocretin in their CSF.

It is possible to test cerebrospinal fluid for levels of one type of hypocretin (hypocretin-1; hypocretin 2 is the other known hypocretin). Blood tests are not useful for detecting hypocretin.

Researchers have found evidence that points to autoimmunity as a problem in narcolepsy. This term means that a person's immune system begins to attack his own body. At this time, there is no definitive proof for this idea.

There are also environmental factors involved in narcolepsy. For example, disease onset is associated with head trauma, exposure to heavy metals, weed killers, and insecticides (reviewed in Akintomide). There is also strong evidence linking increased risk to infection with type H1N1 influenza as well as a European H1N1 vaccine used in 2009 (12-15). Infection with streptococcus bacteria is also associated with narcolepsy (16, 17).

Diagnosis and Testing

Criteria for diagnosing both types of narcolepsy have been established (4). They are as follows (information here has been taken from reference 4):

Narcolepsy type 1 (also narcolepsy with cataplexy). There are two main criteria for diagnosing type 1 narcolepsy. First, the person have either daily sleep attacks or a daily irrepressible need to sleep. This problem must exist for at least three months. Additionally, the patient must have one or both of the following:

• Cataplexy and a mean sleep latency of ≤8 minutes and two or more sleep onset REM periods (SOREMPs). This term refers to the onset of REM sleep when a person falls asleep (REM sleep does not usually begin until 90 minutes after a person falls asleep). To obtain sleep latency, the patient must undergo an MSLT test that is performed according to standard techniques. A SOREMP within 15 minutes of sleep onset on a nocturnal polysomnogram may replace one of the SOREMPs on the MSLT.
• CSF hypocretin-1 concentration is either ≤110 pg/mL or <1/3 of mean values obtained in normal subjects with the same standardized assay. Hypocretin-1 should be measured by immunoreactivity.

The book also notes that young children with narcolepsy have excessive nocturnal sleep and/or may return to daytime napping they had stopped napping. Additionally, if a clinician has a strong suspicion of this condition but the MSLT criteria is not met, repeating the MSLT may be a good idea.

Narcolepsy type 2 (also narcolepsy without cataplexy). As with type 1 narcolepsy, the patient must have daily periods of an irrepressible need to sleep or daytime sleep attacks, and the problem must have occurred for at least 3 months. Also as above, the patient must have a mean sleep latency of ≤8 minutes and two or more sleep onset REM periods (SOREMPs). In this condition, cataplexy is absent. If it develops after diagnosis is made, the patient should be classified as having type 1 narcolepsy.

Hypocretin levels in type 2 narcolepsy may be >110 pg/mL or >1/3 of mean values obtained in normal subjects. Measuring them is not required for diagnosis of this condition. However, if they are measured and found to be low as noted above, the patient should be classified as having type 1 narcolepsy.

The final criteria for type 2 narcolepsy is that excessive sleepiness and/or MSLT findings can't be explained by any other condition or by any kind of drug or medication.

Overall, type 1 narcolepsy can be diagnosed based on excessive sleepiness and low CSF hypocretin. If a patient does not have cataplexy and hypocretin levels are normal or have not been measured, type 2 narcolepsy can be diagnosed (though with the caveat the cataplexy can develop at a later date and that hypocretin testing can help refine the diagnosis).

Differential Diagnosis

The differential diagnosis for narcolepsy includes the conditions below. For more information, see references 4 and 5.

Epilepsy and fainting. Cataplexy can resemble both of these problems. It can be distinguished from them because it is often triggered by laughter or stimulation by another emotion. In addition, and unlike seizure or fainting patients, cataplexy patients are usually responsive during the event. Most recover almost immediately. In contrast, seizures can occur when a person is quiet or not experiencing strong emotions, and they may have warning signs. Afterward, the person will recover slowly.

A person who collapses from cataplexy is typically aware what is happening, and may describe the event as beginning in his or her knees. Fainting, on the other hand, tends to begin in the head. Cataplexy does not involve nausea or dizziness, but does involve a loss of consciousness.

Idiopathic hypersomnia (or IHS) is a condition in which people sleep excessively. However, unlike people with narcolepsy, IHS patients do not fall asleep suddenly and don't have cataplexy. People with IHS usually feel sleepy during the day. They may also sleep a lot at night, and may not wake up feeling refreshed, either in the mornings or after a nap. Narcolepsy patients tend to feel refreshed upon awakening, though they may feel tired again soon.

There are two types of IHS. In the first, the patient doesn't sleep excessively at night (9 hours or less). Patients with the second form sleep longer than usual at night. In both types, there is excessive daytime sleepiness, and patients may take naps that may last up to several hours. The naps are not refreshing. Patients may also have trouble with memory and concentration. Increased appetite doesn't appear to be a feature of IHS, but many people with narcolepsy are overweight or obese (over 70% in of subjects our literature survey).

Kleine-Levin syndrome. KLS, like IHS, is a condition in which people sleep excessively. However, unlike IHS and narcolepsy, excessive sleepiness in KLS is episodic. This term means that it happens from time to time, in episodes. A sleepiness episode typically lasts for days to weeks, but can last for months in extreme cases. During an episode, a person may sleep for 18 hours a day or more, may eat voraciously, and may feel disconnected from reality. Some patients (usualy males) may have hypersexual feelings. In between episodes, patients sleep and act normally, and may not have good memories of the sleepy periods. An important point about KLS is that it with time, it becomes more mild and appears to eventually disappear. The course of disease may last for several years.

Sleep deprivation and the effects of shift work can cause excessive daytime sleepiness. These problems can typically be ruled out by changing sleep habits. The use of sleep diaries are often helpful.

One important consideration is to ensure that a patient is not seeking stimulants for reasons unrelated to disease. It has also been noted that clinicians should rule out malingering when considering a diagnosis of narcolepsy (4, 5).

References

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