Narcolepsy

Original Editor - Ragy Tadrous

Top Contributors - Ragy Tadrous, Lucinda hampton and Chelsea Mclene  

Introduction

Narcolepsy, a disorder of rapid onset rapid eye movement (REM) sleep, is characterized by excessive daytime sleepiness, frequent uncontrollable sleep attacks, sleep fragmentation. It may be associated with cataplexy, sleep paralysis, and hypnagogic hallucinations.

Types of narcolepsy

1. Type 1 (formerly narcolepsy with cataplexy) and narcolepsy
2. Type 2 (formerly narcolepsy without cataplexy).

Epidemiology

Prevalence:

• 14 per 100,000 people for narcolepsy type 1
• 65.4 per 100,000 people for narcolepsy type 2.

Incidence:

• highest in the late teens to early twenties
• 50% greater female predominance in the U. S. according to data 2008-2010

Aetiology/Causes

Primary Narcolepsy

Narcolepsy type 1 occurs when nearly all of the neurons that contain orexin (also called hypocretin) are lost. The reason remains elusive but it is thought to be an autoimmune process possibly triggered by an infection. It is believed to result from a combination of factors that lead to a lack of hypocretin (a chemical in the brain that promotes wakefulness0. The main causes of narcolepsy include:

1. Autoimmune disorders: In many cases, especially those with cataplexy (Type 1 Narcolepsy), the body's immune system mistakenly attacks and destroys the brain cells that produce hypocretin.
2. Genetic factors: While most cases are sporadic, up to 10 percent of individuals with narcolepsy with cataplexy report having a close relative with similar symptoms, suggesting a genetic component.
3. Environmental factors: These may interact with genetic predisposition to trigger the autoimmune response.
4. Brain injuries: Secondary narcolepsy can result from traumatic injuries to parts of the brain that regulate wakefulness and REM sleep.
5. Tumors or other diseases: These can affect the same brain regions and produce narcolepsy-like symptoms.
6. Vaccine-related: An increased incidence of narcolepsy was observed in some European countries following the 2009-2010 H1N1 "swine flu" vaccination campaign, particularly with the Pandemrix vaccine.
7. Neuronal loss: In Type 1 Narcolepsy, there's typically a severe and highly selective loss of hypocretin-producing neurons.

It's important to note that in many cases, the exact cause remains unknown, and it's likely a combination of these factors that leads to the development of narcolepsy..

Characteristics/Clinical Presentation

Narcolepsy consists of excessive daytime sleepiness combined with the intrusion of REM sleep-associated phenomena (hypnagogic hallucinations, sleep paralysis, and possibly cataplexy) into wakefulness.

Excessive Daytime Sleepiness

Excessive daytime sleepiness (EDS) of narcolepsy presents as an increased propensity to fall asleep, nodding or easily dozing in relaxed or sedentary situations, or a need to exert extra effort to avoid sleeping in these situations. EDS is characterised by persistent sleepiness, regardless of how much sleep an individual gets at night.   

Additionally, people with narcolepsy can experience "sleep attacks" which manifest as an irresistible or overwhelming urges to sleep. They commonly occur from time to time during wakeful periods in untreated narcolepsy patients. Sleep attacks are not instantaneous lapses into sleep, as is often thought by the general public, but represent the episodes of profound sleepiness experienced by those with marked sleep deprivation or other severe sleep disorders.

In addition to frank sleepiness, EDS can cause related symptoms, including poor memory, reduced concentration or attention, and irritability. Although people with narcolepsy feel refreshed following a short nap, this does not last long, and they become sleepy again within a few hours.

Cataplexy

Cataplexy is transient muscle weakness triggered by emotion and is a specific feature of narcolepsy type 1. Cataplexy is thought to represent intrusion of REM sleep and its associated muscle atonia during wakefulness. It often begins in the facial muscles and can manifest with slackening of the jaw or brief dropping of the head. However, episodes can be more dramatic and, if the trunk and limb muscles are affected, can result in collapsing to the ground.

Episodes can last from a few seconds to 2 minutes, and patients are usually alert and oriented during the event despite their inability to respond.  While scary, the episodes are not dangerous as long as the individual finds a safe place in which to collapse. Positive emotions such as laughter more commonly trigger cataplexy than negative emotions; however, any strong emotion is a potential trigger. Startling stimuli, stress, physical fatigue, or sleepiness may also be important triggers that exacerbate cataplexy.

Deep tendon reflexes disappear in cataplexy, so checking reflexes during a witnessed episode can be clinically valuable.

Cataplexy usually has its onset at about the same time as the sleepiness associated with narcolepsy, but it can arise even years later. The symptoms of cataplexy may appear weeks or even years after the onset of EDS. In about 10 percent of cases of narcolepsy, cataplexy is the first symptom to appear and can be misdiagnosed as a seizure disorder.  

Hypnagogic/Hypnopompic Hallucinations

Hallucinations are very vivid and sometimes frightening images that can accompany sleep paralysis and usually occur when people are falling asleep (hypnagogic) or waking up (hypnopompic). Hallucinations may be visual, tactile, auditory, or multisensory events, and are usually brief but occasionally persist for a few minutes.

These hallucinations may contain combined elements of dream sleep and consciousness and are often bizarre or disturbing to patients. The hallucinations are often vivid and usually visual, although other types of hallucinations are possible. Unlike those that occur in psychotic disorders, the hallucinations experienced by people with narcolepsy tend to be associated with preserved insight that they are not real.

Sleep Paralysis

Sleep paralysis is a potentially terrifying experience, that is similar to REM-induced inhibitions of voluntary muscle activity. It occurs around the edges of sleep when people are falling asleep or awakening. Patients find themselves temporarily unable to move limbs, speak, or breathe deeply whilst remaining fully aware of their condition and able to recall it later. Sleep paralysis may be anxiety-provoking at first; but with time, most patients learn that the episodes are benign, rarely last more than a few minutes and end spontaneously.

Sleep paralysis can be associated with a sensation of fear or suffocation, especially when initially experienced. Although accessory respiratory muscles may not be active during these episodes, diaphragmatic activity continues, and air exchange remains adequate. Sleep paralysis may occur as an independent and isolated phenomenon in up to 3% to 5% of the normal population, but occurs in approximately 50% to 60% of narcoleptics. As with cataplexy, people remain fully conscious.  Even when severe, cataplexy and sleep paralysis do not result in permanent dysfunction—after episodes end, people rapidly recover their full capacity to move and speak.

Fragmented sleep and insomnia

Although they are very sleepy, people with narcolepsy generally cannot stay asleep for very long. Their sleep tends to be extremely fragmented, and they often wake up several times a night. Sleep may be disrupted by insomnia, vivid dreaming, sleep apnoea, acting out while dreaming, and periodic leg movements. Other commonly reported symptoms to include automatic behaviour (“absent-minded” behaviour or speech that is often nonsensical which the patient does not remember) and fragmented nocturnal sleep (frequent awakenings during the night).

Automatic behaviours

Individuals with narcolepsy may experience temporary sleep episodes that can be very brief, lasting no more than seconds at a time. A person falls asleep during an activity (e.g., eating, talking) and automatically continues the activity for a few seconds or minutes without conscious awareness of what they are doing. This happens most often while people are engaged in habitual activities such as typing or driving. They cannot recall their actions, and their performance is almost always impaired. Their handwriting may, for example, degenerate into an illegible scrawl, or they may store items in bizarre locations and then forget where they placed them. If an episode occurs while driving, individuals may get lost or have an accident. People tend to awaken from these episodes feeling refreshed, finding that their drowsiness and fatigue has temporarily subsided.

Associated Co-morbidities

Narcolepsy is associated with a wide range of medical and psychiatric comorbidities. Some of the key comorbidities include:

• Sleep apnea: Increased rates of sleep apnea have been well established in narcolepsy patients.
• Obesity: Narcolepsy patients are frequently overweight, and rapid weight gain often accompanies the onset of narcolepsy.
• Psychiatric disorders: There's a significant relationship between narcolepsy and psychiatric conditions, including depression, anxiety disorders, and eating disorders.
• Diabetes: Higher prevalence rates of diabetes are observed among narcolepsy patients.
• Chronic obstructive lung disease: This condition is more prevalent in narcolepsy patients.
• Musculoskeletal issues: Low back pain and arthritis are more common in people with narcolepsy.
• Cardiovascular issues: Narcolepsy patients tend to have lower cardiopulmonary fitness compared to the general population.
• Migraine headaches: Some studies have suggested an association, though findings have been inconsistent.

These comorbidities can complicate the diagnosis and treatment of narcolepsy, as there may be symptom overlap. It's important to note that the presence of these comorbidities can significantly impact the quality of life and overall health of individuals with narcolepsy..

Classification

The current diagnostic criteria for narcolepsy are outlined in the third edition of the International Classification of Sleep Disorders (ICSD-3), which were published by the American Academy of Sleep Medicine in 2014. The diagnostic criteria for both types of narcolepsy are outlined in the table below.

Type 1 Narcolepsy
Both criteria A and B must be met:
A	The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months.
B	The presence of one (or both) of the following:
	Cataplexy and a mean sleep latency of 8 minutes and two or more SOREMPs on an MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal PSG may replace one of the SOREMPs on the MSLT.
	CSF hypocretin-1 concentration, measured by immunoreactivity, is either 110 pg/mL or < 1/3 of mean values obtained in normal subjects with the same standardised assays.
Type 2 Narcolepsy
Criteria A-E must be met:
A	The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months.
B	A mean sleep latency of 8 minutes and two or more SOREMPs are found on an MSLT performed according to standard techniques.
C	Cataplexy is absent
D	Either CSF hypocretin-1 concentration has not been measured or CSF hypocretin-1 concentration measured by immunoreactivity is either >110 pg/mL or > 1/3 of mean values obtained in normal subjects with the same standardised assay.
E	The hypersomnolence and/or MSLT findings are not better explained by other causes such as insufficient sleep, obstructive sleep apnoea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal.

Diagnostic Tests

The diagnostic tests for narcolepsy include:

1. Polysomnography (PSG): An overnight sleep study that records brain activity, eye movements, muscle activity, and breathing. It can reveal if REM sleep occurs early in the sleep cycle and rule out other sleep disorders.
2. Multiple Sleep Latency Test (MSLT): Performed the day after PSG, it involves five 20-minute nap opportunities spaced 2 hours apart. It measures how quickly a person falls asleep and if they enter REM sleep. Narcolepsy is indicated by:
   • Mean sleep latency of ≤8 minutes
   • Two or more sleep onset REM periods (SOREMPs)
3. Actigraphy: A wrist-worn device that records sleep-wake patterns over 1-2 weeks, used to rule out insufficient sleep or circadian rhythm disorders.
4. Cerebrospinal Fluid (CSF) Hypocretin-1 Test: A lumbar puncture to measure hypocretin-1 levels. Low levels (<110 pg/mL or <1/3 of mean normal values) indicate type 1 narcolepsy.
5. Sleep diary: Patients record sleep times and symptoms over 1-2 weeks.
6. Urine drug screen: Performed on the day of MSLT to ensure results aren't affected by medications.

These tests, combined with clinical history and examination, are used to diagnose narcolepsy and differentiate between type 1 and type 2 narcolepsy.

Differential Diagnosis

It has many differentials and the client needs to be assessed by a relevant specialist.

1. Narcolepsy is associated with a diagnostic delay of 8 to 15 years, and this delay may be more prolonged in females with narcolepsy.
2. It has many differentials and the client needs to be assessed by a relvant specialist.
3. This diagnostic delay may be attributable to several factors such as the mildness or gradual onset of initial symptoms, the lack of recognition of the condition by the patient or clinician, and mistaken diagnosis with other sleep disorders such as sleep deprivation or obstructive sleep apnea.
4. Furthermore, there is a high comorbidity burden in patients with narcolepsy, and the overlap of symptoms present in some disorders may also contribute to the lack of recognition of narcolepsy. It is important that clinicians have an awareness of narcolepsy, as delayed diagnosis results in delayed treatment, which increases the burden of the disease with detrimental effects on health care resource use, employment, and quality of life.

Management

Medical Management

Medications used to treat narcolepsy include:

1. For excessive daytime sleepiness:

• Modafinil (100-400 mg): Wake-promoting agent with fewer side effects than stimulants.
• Armodafinil (100-300 mg): Similar to modafinil.
• Methylphenidate (10-60 mg): Stimulant with less appetite reduction and blood pressure increase than amphetamines.
• D-amphetamine sulfate (5-60 mg): Stimulant that promotes wakefulness.

1. For cataplexy:

• Venlafaxine (37.5-75 mg twice daily)
• Fluoxetine (20-60 mg once daily)
• Sertraline (50-150 mg once daily)
• Protriptyline (5-10 mg twice daily)

1. For both excessive sleepiness and cataplexy:

• Sodium oxybate (3-9g per night): Improves nighttime sleep and reduces daytime sleepiness and cataplexy.

1. Other medications:

• Pemoline (20-115 mg): Milder stimulant, but with potential liver toxicity.

Common side effects of these medications can include nausea, headache, dry mouth, insomnia, and in some cases, more serious effects. Dosages should be determined and monitored by a healthcare profession

Non-pharmacological treatments for narcolepsy include:

1. Structured daytime napping: Single long naps are generally better than multiple short naps.
2. Sleep hygiene: Maintaining a regular sleep schedule and creating a good sleep environment.
3. Dietary practices: Scheduled intake of non-prescription stimulants like tea or coffee.
4. Alcohol minimization or abstinence.
5. Counselling: Helps with lifestyle reorganization and improving quality of life.
6. Cognitive Behavioral Therapy (CBT): Addresses beliefs, behaviors, and provides education about the condition.
7. Strategic scheduling of alertness-requiring activities.
8. Exercise: Potentially beneficial, though more research is needed.
9. Relaxation techniques: May help reduce anxiety that can exacerbate symptoms.
10. Professional advocacy: Can assist with work arrangements and accommodations.
11. Patient education: Improves understanding and management of the condition.
12. Systematic desensitization and stimulus control: Aimed at reducing cataplexy attacks.
13. Imagery rehearsal therapy: Helps with reducing hypnagogic hallucinations.
14. Lucid dreaming techniques: May help reduce hypnagogic hallucinations and improve coping.

These strategies aim to complement medical treatments, improve symptom management, and enhance overall quality of life for individuals with narcolepsy.

Role of Physiotherapy

The relationship between sleep and physical activity in people with narcolepsy is not fully known and is likely complex.

People with narcolepsy are less physically active than people without this condition. People with narcolepsy exhibit more barriers to physical activity than controls, and generally have fewer opportunities to participate in activities due to time constraints associated with sleeping and social isolation. A vicious cycle can then be set up with inactivity promoting worse sleepiness, and then the symptoms of the disease reducing habitual physical activity (Matoulek et al., 2017). Less spontaneous activity has also been noted in narcolepsy patients. Similarly, fewer steps are also taken by narcolepsy patients, with 35% fewer steps per day shown compared to healthy non-sedentary adults.

There are many comorbidities associated with narcolepsy, with data from a Danish National Patient Registry shows that patients with narcolepsy have a higher prevalence of diabetes, obesity, chronic obstructive lung disease, low back pain and arthritis and exhibit a trend towards higher mortality compared to controls. Furthermore, disease onset is frequently accompanied by a rapid weight gain, resulting in overweight or obesity. Exercise could play a vital role in the management of these conditions and improve the quality of life in people with narcolepsy.

Lastly, evidence from a cross-sectional study showed that cardiopulmonary fitness was inversely related to the degree of sleepiness and the number of cataplexy attacks per month. Results from this study also showed that patients with narcolepsy have lower cardiopulmonary fitness compared to the general population. Exercise could potentially be used as a non-pharmacological method to manage narcolepsy-related symptoms.