Narcolepsy causes excessive daytime sleepiness, sleep paralysis, and, in some cases, cataplexy (a sudden loss of muscle tone). This sleep disorder affects approximately 1 in every 2,000 people. Despite the prevalence of narcolepsy, it is not well understood — even by many clinicians. This insufficient understanding can lead to delayed diagnosis and increased time until treatment. Understanding the pathophysiology of narcolepsy — that is, the biological dysfunctions that cause or result from the condition — is an important step toward understanding the causes, treatments, and prognosis (outlook) of this disorder.

What Is Narcolepsy?

Narcolepsy affects many individuals. One study found that the prevalence (rate of people living with the condition) and incidence (rate of new cases) of narcolepsy was higher in women compared with men. Prevalence was also highest in people aged 21 to 30, and the incidence rates were highest in those in their late teens to 20 years. This study also showed that type 2 narcolepsy (without cataplexy) was more common than type 1 narcolepsy (with cataplexy).

Cataplexy is usually triggered in people with narcolepsy by extreme emotional states. Cataplexy is one of many symptoms of narcolepsy, including:

• Excessive daytime sleepiness
• Falling asleep suddenly and without warning
• Decreased alertness and focus
• Sleep paralysis (the inability to move while falling asleep or when waking)
• Changes in rapid eye movement (REM) sleep patterns
• Hypnagogic hallucinations (hallucinations that occur at sleep onset)
• Hypnopompic hallucinations (hallucinations that occur when waking up)

Narcolepsy is characterized by these symptoms due to the pathophysiology underlying the disease.

Narcolepsy and Hypocretin

The cause of narcolepsy is unknown. However, scientists believe that the pathophysiology of narcolepsy centers on the neurotransmitter (brain chemical) hypocretin.

There is substantial evidence that suggests narcolepsy may be caused by a deficit in hypocretin-producing neurons (brain cells) in a region inside of the brain called the hypothalamus. Research on people with narcolepsy shows that hypocretin levels in the cerebrospinal fluid (the fluid surrounding the brain and spinal cord) are lower in people with type 1 narcolepsy. Those with type 2 narcolepsy also have hypocretin deficiency, but to a lesser extent than people with type 1.

Genetic studies shed some light on how hypocretin might be playing this role in narcolepsy. When scientists remove the gene responsible for producing hypocretin in mouse models, these animals develop symptoms comparable to those observed in humans with narcolepsy. A genetic mutation in the type 2 hypocretin receptors in the brain has been shown to cause canine narcolepsy.

Further research in animals shows that hypocretin neurons in the hypothalamus act as the switch between states of sleep and wakefulness. Importantly, in sleep studies conducted in those with narcolepsy, people displayed a higher frequency of sleep-wake transitions, as well as an abnormal number of transitions to and from rapid eye movement (REM) sleep. More sleep-state transitions were associated with lower levels of hypocretin in these same individuals. It is possible that hypocretin in the brain also acts as a switch between sleep states, and dysfunction in hypocretin causes narcolepsy.

Genetics of Narcolepsy

There are also genes associated with narcolepsy. The most well-known genetic association with narcolepsy is related to the immune system. Researchers in one study demonstrated that, across several ethnic groups in the United States, almost everyone who has type 1 narcolepsy carries the human leukocyte antigen (HLA) allele HLA-DQB1*0602. Further, this DQB1 allele (genetic variant) was tightly associated with the expression of the HLA-DQA1*0102 allele in people with type 1 narcolepsy. Altogether, these complex interactions indicate that narcolepsy may have both a genetic and an autoimmune component.

Genome-wide association studies (GWAS) further illustrate the role of other gene mutations in narcolepsy. Specifically, one GWAS study in a Japanese population found that narcolepsy was associated with mutations in the CPT1B (carnitine palmitoyltransferase 1B) and CHKB (choline kinase beta) genes. The CPT1B gene is related to mitochondrial activity (a cellular mechanism important for energy production) that may reduce hypocretin activity. The CHKB gene is related to acetylcholine, which is a brain chemical messenger also implicated in sleep. Yet another study found mutations in a gene that codes for the receptors of T cells (a type of immune cell) in people with narcolepsy, further suggesting an autoimmune component of the disease.

Pathophysiology of Narcolepsy Informs Treatment

There is no cure for narcolepsy, but understanding these pathophysiological mechanisms can influence the way doctors treat the condition.

Stimulants such as Provigil (modafinil) have classically been used to treat narcolepsy by keeping the individual awake. Antidepressants have also been used to help with some of the symptoms of narcolepsy such as cataplexy, hallucinations, and sleep paralysis.

New advances in narcolepsy treatment are emerging. These treatment options, informed by pathophysiology, include hypocretin replacement, gene therapy that targets hypocretin, and immunotherapy methods that prevent hypocretin cell death. Research has also implicated the histamine system in narcolepsy, and addressing this system has already yielded a medication called Wakix (pitolisant). However, more research and clinical trials are needed for all of these treatment options.

Building a Community

MyNarcolepsyTeam is the social network for people with narcolepsy and their loved ones. On MyNarcolepsyTeam, more than 6,600 members come together to ask questions, give advice, and share their stories with others who understand life with narcolepsy.

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