Causes and Risk Factors of Narcolepsy

Narcolepsy is a rare neurological disorder that causes excessive daytime sleepiness, sudden sleep attacks, sleep dysfunction, and sometimes involuntary loss of muscle control called cataplexy. Narcolepsy is normally caused by damage to the hypocretin-secreting cells of the anterior hypothalamus in the brain.

There are several factors that contribute to the condition, including an abnormal autoimmune response, underlying susceptibility due to genetic immune traits, evocative environmental factors, and sometimes head injury or other damage to the hypothalamus of the brain.

Common Causes

The most common mechanism of narcolepsy is an autoimmune process that damages hypocretin-secreting cells in the anterior hypothalamus of the brain. The hypocretin-secreting cells are incorrectly targeted and destroyed by immune T cells, leading to the deficit or absence of hypocretin throughout the brain.

Type 1 Narcolepsy

The neurotransmitter hypocretin is important for maintaining the normal function of the hypothalamus which is involved in the regulation of sleep-wake cycle activity. This form of hypocretin-deficient narcolepsy is called type 1 narcolepsy and usually comes with the symptom of sudden muscle weakness in response to an emotion (cataplexy).

Type 2 Narcolepsy

Not every case of narcolepsy is obviously connected to hypocretin, and research is still being performed to understand why some people without a hypocretin connection experience narcolepsy. When this happens, it is called type 2 narcolepsy. 

People with type 2 narcolepsy often have a less severe decline in hypocretin than in type 1 narcolepsy, and they lack the symptom of sudden emotional muscle weakness (cataplexy). The cause of type 2 narcolepsy is not currently well understood, and it may include several conditions that contribute to the symptoms.

Genetic and Environmental Risks

Genetics appear to play a role in narcolepsy, but not everyone with the genetic predisposition to narcolepsy will experience it.

A subset of people with a genetic element to their narcolepsy have immediate relatives who experience narcolepsy. Though this only occurs in 1% or 2% of first-degree relatives of people with narcolepsy, this still puts the likelihood of narcolepsy disproportionately high relative to the general population.

Environmental factors have been proposed as helping to explain the relative risks of individuals who may have the same genetic predisposition. This may be due to the immune system’s reaction to a common virus. Exposure to certain kinds of toxins is also thought to trigger immune responses that induce narcolepsy. 

Higher environmental risks of narcolepsy are found among craft-based trades such as metalwork, woodwork, ceramics, and painting. Construction, landscaping, agriculture, and custodial workers may experience even higher narcolepsy risks, especially in places with histories of toxins and pollutants (i.e., in buildings with lead and asbestos or in soils contaminated with arsenic, pesticides, or fertilizers).

Narcolepsy is just one of many possible negative outcomes related to environmental neurotoxin exposure. Poor ventilation and lack of personal protective equipment (PPE) may increase the risk posed by particulate byproducts that cause excessive immune responses and toxicity to brain cells.

Head Trauma

Head trauma often causes sleep disturbances. In cases of a moderate or severe injury to the head, symptoms of narcolepsy can temporarily manifest for weeks or months. This usually takes the form of type 1 narcolepsy and about half the time a decline in hypocretin is detectable. In the other half of head trauma induced narcolepsy cases, no mechanistic cause can be identified. 

Often symptoms of narcolepsy will subside within half a year of the initial trauma as the brain heals and resumes hypocretin production. People with head trauma who are still experiencing excessive daytime sleepiness (EDS) at six months are more likely to continue experiencing narcolepsy.

Multiple Sclerosis

Multiple sclerosis is a degenerative neurological disease that may cause sleep disorders including narcolepsy. Autoimmune processes may leave lesions in hypocretin-producing regions of the brain.

Sarcoidosis

Sarcoidosis is a disease that causes inflammation in different parts of the body. If inflammation occurs in the brain tissues that produce hypocretin (in a condition known as neurosarcoidosis), the tissue can be damaged or interrupted leading to a drop in hypocretin and ultimately resulting in narcolepsy.

Tumors

Tumors are a common, non-immune response that can cause narcolepsy. When a tumor begins to form in the brain, it can take resources from surrounding tissue as well as apply pressure to nearby regions of the brain, potentially impacting the hypothalamus.

Stroke

A stroke can similarly affect sleep and may rarely result in narcolepsy. When the blood supply to the hypothalamus is disrupted, cell death can occur and disrupt the function of pathways important for sleep.

Many people experience increased daytime sleepiness after a stroke, and occasionally multiple symptoms of narcolepsy become apparent and may be disruptive to the recovery process.

Genetics

HLA DQB1*0602 is an allele or variant of the HLA gene found in about one-fifth of the general population. The vast majority of people with the HLA DQB1*0602 allele do not experience narcolepsy, so the cause of narcolepsy type 1 is thought to be multifactorial. 

The HLA series of genes code for proteins used in the body’s immune response. When the antigen protein is altered, presenting a similar appearance to normal cells, it makes it possible for immune cells to misidentify hypocretin-producing cells in the brain as a target.

On very rare occasions a mutation in the genes responsible for making hypocretin-producing cells or hypocretin-responsive neurons causes narcolepsy. Currently identified genes include:

• Hcrt
• Hcrtr1
• Hcrtr2

It is likely that other yet unidentified genes may be involved in the network of neural connections used for sleep regulation.

Lifestyle Risk Factors

There is little known about what specific lifestyle risk factors may contribute to narcolepsy. Awareness and mitigation of workplace or home exposure to environmental toxins may decrease an individual’s risk of developing narcolepsy.

Generally, healthy lifestyle decisions like eating healthy, exercising, and not smoking may decrease the risk of contributing events like a stroke, but these are not typically the main cause of narcolepsy.

One notable exception to consider is the 2009 European H1N1 vaccine. Avoidance of this may have been an important way to reduce the likelihood of developing narcolepsy. The version of the H1N1 vaccine distributed in Europe resulted in a slight increase in narcolepsy among people with the HLA-DQB1*0602 and HLA-DQB1*0301 allele. 

On rare occasions, the presence of a particular form of the influenza antigen within the vaccine may have triggered an immune response in which the body attacked hypocretin-producing cells in the brain. Typically the narcolepsy symptoms began two months after the vaccine was administered. This vaccine has subsequently been removed from the market and was not used outside of Europe.

A Word From Verywell

If you are concerned that you may be experiencing symptoms of narcolepsy, it is important to seek evaluation by a board-certified sleep physician or neurologist. The condition is diagnosed with a diagnostic polysomnogram and multiple sleep latency test (MSLT). If present, medications may be prescribed that may reduce sleepiness, optimize sleep quality, and improve cataplexy. Though the condition cannot be currently cured, treatment of narcolepsy may provide significant relief.