Complex systems in the brain control sleep and wakefulness. In narcolepsy, specific neurons related to sleep and wakefulness are absent or do not function correctly. This can affect how a person sleeps and wakes up.
Pathophysiology studies physical and biological changes and abnormalities in the body that occur due to a condition or disease.
Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime sleepiness. Doctors divide it into narcolepsy type 1 and narcolepsy type 2, depending on the presence or absence of cataplexy (a temporary loss of muscle control).
In this article, learn more about the abnormal processes or changes associated with narcolepsy.
Narcolepsy is a long-term neurological sleep disorder associated with excessive daytime sleepiness (EDS) and sudden sleep episodes during the daytime.
In addition to EDS, narcolepsy has the following symptoms:
- sleep paralysis
- hypnagogic hallucinations
- disrupted nighttime sleep
It affects 1 in 2,000 Americans. However, experts believe it may go undiagnosed or misdiagnosed in many people.
Doctors characterize narcolepsy as abnormal rapid eye movement (REM) sleep. This abnormality is due to a person’s brain regulating REM sleep incorrectly.
Because of this, people with narcolepsy experience frequent and sudden transitions between sleep and awake states. Boundaries between sleep and awake states become unstable, causing elements of one state to intrude into another. This may cause symptoms such as sleep paralysis and hypnagogic hallucinations.
The pathophysiology of narcolepsy affects the neurological processes involved in keeping people awake and helping them fall asleep.
This section explores the processes involved in typical wakefulness and narcolepsy types 1 and 2.
Typical wakefulness
During typical wakefulness, the neurotransmitter hypocretin (also called orexin) increases the activity of the reticular activating system (RAS). The RAS is a network of neurons in a person’s brain that controls sleep and arousal states, including waking, non-REM sleep, and REM sleep.
Learn more about sleep cycle stages here.
The RAS activates different nuclei found in the central nervous system (CNS), which generate wakefulness-promoting neurotransmitters. These prevent REM sleep and help maintain muscle tone and wakefulness throughout the day.
These neurotransmitters include:
- ventral tegmental area for dopamine
- locus coeruleus for norepinephrine
- basal forebrain for acetylcholine
- raphe nucleus for serotonin
- tuberomammillary nucleus for histamine
The RAS also inhibits the ventrolateral preoptic area (VLCO), which is a sleep-promoting brain region. This suppresses gamma-aminobutyric acid (GABA), which is the key sleep-promoting neurotransmitter that suppresses wakefulness-promoting neurotransmitters during sleep. Suppression of GABA also increases muscle tone and the activity of motor neurons.
Meanwhile, hypocretin decreases during typical REM sleep, causing a decrease in RAS activity and promoting a loss of muscle tone.
Narcolepsy type 1
Narcolepsy type 1 occurs when there is a
The RAS no longer stimulates the release of wake-promoting neurotransmitters and inconsistently suppresses the VLCO, leading to EDS.
When wake-promoting neurons are inconsistently activated, they do not suppress REM-promoting neurons. This can cause a person to experience abnormal REM sleep manifestations such as sleep paralysis, hypnopompic hallucinations, and hypnagogic hallucinations.
In people without narcolepsy, sleep-promoting and wake-promoting systems suppress each other to create typical sleep-wake circuits. In people with narcolepsy type 1, disruption of these systems leads to unwanted or rapid transitions between sleep and awake states, causing sleep disruption.
Narcolepsy type 2
The pathophysiology of narcolepsy type 2 is not well understood. People with narcolepsy type 2
People with narcolepsy type 2 do not experience cataplexy. However, in people with unknown hypocretin levels, about one-quarter to one-fourth are likely to develop cataplexy over time.
The cause of narcolepsy is unknown. However, experts believe it relates to the neurotransmitter hypocretin.
Narcolepsy type 1 causes
About 90% of people with narcolepsy type 1 have a low to unmeasurable hypocretin level in their cerebrospinal fluid (a clear liquid that protects the brain and spinal cord).
The reason for this deficiency is not fully understood. It may be genetic. For example, the HLA gene DQB1*0602 occurs in
However, not everyone with this gene will have narcolepsy since the gene is also present in 20% of the general population.
There was an increase in narcolepsy type 1 cases in 2009 following a live H1N1 pandemic influenza vaccine (Pandemrix) in Scandinavia. It also led to an increase in the risk of narcolepsy of between
Narcolepsy type 2 causes
The causes of narcolepsy type 2 are less understood. They may be associated with a
Secondary narcolepsy may also occur when the brain area that produces hypocretin becomes damaged.
Potential causes include:
According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), the
In addition, any of the following should be present:
- hypocretin deficiency
- cataplexy episodes occurring several times a month
- less than 15 minutes of REM sleep latency, or two or more sleep-onset REM periods, and a mean sleep latency of less than eight minutes
Sleep latency is the time it takes for a person to transition from full wakefulness to sleep.
A doctor will likely require a person to get at least six hours of sleep daily for at least two weeks. To ensure this, they may ask a person to wear a device called an actigraph and ask them to take note of their sleep patterns in a sleep log.
If the person is getting a minimum of six hours of sleep, the doctor will ask them to undergo the following tests:
- Polysomnogram (PSG): This is a sleep study done in a sleep clinic while a person is fully asleep. Here, doctors observe a person’s sleep patterns, breathing, heart rate, and other functions to rule out other sleep disorders.
- Multiple sleep latency test (MSLT): A person will undergo an MSLT the day after the PSG. In it, a person will take four or five 20-minute naps within 2 hours. A positive test result will show a rapid onset of REM sleep (in less than 15 minutes) at least twice during the test, and less than eight minutes of mean sleep latency across trials.
A cerebrospinal fluid analysis that checks for low levels of hypocretin-1 in the cerebrospinal fluid can also help confirm the diagnosis.
There is no cure for narcolepsy. However, lifestyle changes and medications can help manage the condition. Lifestyle changes include:
- taking naps of between 15–20 minutes throughout the day
- maintaining a regular sleep schedule
- practicing sleep hygiene
Medications for narcolepsy may include stimulants.
- Stimulants: Modafinil or armodafinil are first-line treatment options for EDS. Amphetamines are the second-line treatment for EDS.
- Sodium oxybate: A doctor may prescribe a form of gamma-hydroxybutyrate to treat cataplexy.
- Selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs): These include fluoxetine and venlafaxine to help manage symptoms of sleep paralysis, hypnagogic hallucinations, and cataplexy.
A person experiencing persistent EDS and very strong urges to sleep throughout the day, despite having at least six hours of sleep, should consult a doctor.
If the doctor suspects a person has narcolepsy, they may refer the person to a sleep specialist for further testing.
Sleep regulation depends on a complex network of systems in the CNS. These systems work alongside each other to ensure complete transitions between sleep and awake states.
Narcolepsy is a rare sleep disorder that disrupts regular sleep and awake cycles and makes the transitions unstable, leading to sleep disruptions and fragmentation. This also causes abnormal elements of one cycle to intrude into the other, which can cause a person to experience abnormal REM sleep manifestations, including cataplexy, hypnagogic hallucinations, and sleep paralysis.