The Diagnosis and Management of Narcolepsy

ABSTRACT: Narcolepsy is a chronic neurological sleep disorder that is characterized by excessive sleepiness and can have negative effects on daytime activities and quality of life. This article provides an overview of the clinical manifestations, diagnosis, and treatment options for this condition.

Narcolepsy is a chronic neurological sleep disorder in which the brain’s natural sleep-wake cycle is disrupted. It is categorized as a central disorder of hypersomnolence, with a primary complaint of daytime sleepiness not caused by disturbed nocturnal sleep or misaligned circadian rhythms.¹ Approximately 1 in every 2000 to 3000 people is affected by narcolepsy,^2,3 and the disorder occurs nearly equally in men and women.⁴ Although symptoms typically present in adolescence or early adulthood (with peaks at ages 15 and 35), diagnosis is commonly delayed about 10 years, particularly in women.^1,4 This diagnostic delay may be due to variations in symptom onset and presentation.^2,4 

In recent years, the medical community has developed a greater understanding of the clinical features and pathophysiological basis for narcolepsy, but the disorder remains underrecognized and underdiagnosed.² Narcolepsy has been linked to significant patient and societal burden, such as increased healthcare system utilization and costs and decreased employment rates and occupational productivity.^3,5 If left untreated, the disorder can have negative effects on social, educational, and occupational functioning.^4,5 In particular, narcolepsy is associated with driving difficulties and an increased risk of motor vehicle accidents.^3,4

This article provides an overview of the clinical features of narcolepsy, as well as strategies for managing and treating the condition.

Pathology

The pathophysiological basis for narcolepsy is complex and may involve a variety of factors. Deficiency in hypocretin, a neurotransmitter that is produced in the lateral hypothalamus and is involved in maintaining wakefulness and preventing rapid eye movement (REM)sleep, underlies narcolepsy especially in the presence of cataplexy.^1,2 In addition, genetics play a role in the pathogenesis of narcolepsy. The human leukocyte antigen (HLA) subtype DQB1*0602 is strongly associated with narcolepsy with cataplexy and low hypocretin levels. Familial association also points to the influence of genetics. The risk of developing narcolepsy is 10 to 40 times higher in first-degree relatives of affected patients.^1,2 However, twin studies show fairly low concordance rates among monozygotic twins, suggesting an environmental influence as well.² Seasonal and infectious factors have been proposed as potential environmental triggers.¹ Lastly, the HLA association may also implicate autoimmunity in the pathogenesis of narcolepsy.^1,2 

Clinical Presentation

The combination of excessive daytime sleepiness, cataplexy, sleep-related hallucinations, and sleep paralysis collectively form the symptom tetrad for narcolepsy. 

The primary symptom of narcolepsy is excessive daytime sleepiness—ie, the inability to stay awake and alert during major waking episodes of the day. It occurs most often in sedentary or monotonous situations and can range from abrupt sleep attacks with no prodromal symptoms to unintended lapses into sleep.^1,2 These patients generally fall asleep for only seconds to minutes and awaken from these brief naps feeling refreshed.² 

Clinicians treating a patient with excessive daytime sleepiness should determine and measure the patient’s sleepiness, review nocturnal sleep and daily activities, assess comorbid conditions, review medications that affect sleep, and evaluate any other contributing primary sleep disorders that may cause excessive daytime sleepiness.⁶ 

Signs of REM sleep dissociation, most specifically cataplexy, are also part of the symptom profile. Cataplexy is a brief and sudden loss of muscle tone with retained consciousness that is precipitated by strong emotion, often laughter.^1,2 Episodes of cataplexy start abruptly, are often bilateral, and generally last for <2 minutes.¹ Cataplexy typically presents within a few years of excessive daytime sleepiness and is found in more than half of patients with narcolepsy.² The frequency and severity of cataplexy can vary, with severity ranging from neck weakness to complete collapse.¹

Sleep-related hallucinations can be visual, auditory, or tactile. The hallucinations occur at sleep-wake transitions, most commonly at sleep onset (ie, hypnogogic). Patients with narcolepsy may also experience sleep paralysis, which is the temporary inability to move voluntary muscles that occurs while conscious at sleep-wake transitions. Hypnogogic hallucinations and sleep paralysis can cause fear and anxiety surrounding sleep in patients who experience these symptoms.² 

Although not part of the symptom tetrad, difficulty maintaining nocturnal sleep is commonly seen in patients with narcolepsy.^1,2 Patients may also experience vivid dreaming during nocturnal sleep and brief naps and automatic behaviors (repetitive behaviors without awareness).² Comorbid sleep disorders (eg, REM sleep behavior disorder, periodic limb movement disorder, and sleep-disordered breathing) as well as depression and anxiety are also common.^1,2 Note: Increased mortality rates have been reported in individuals with narcolepsy, although it is unclear whether this is a consequence of narcolepsy, comorbid conditions, or both.⁷

Patients frequently report impairments in social, educational, and occupational functioning related to excessive daytime sleepiness.^1,2 Both patients and clinicians should also be concerned about sleepiness while driving due to the increased risk of motor vehicle crashes.^1,6 

Although a physical examination does not yield any findings specific to narcolepsy or excessive daytime sleepiness, it can provide clues to other underlying sleep disorders, such as obstructive sleep apnea.⁶ Clinicians should be aware that, aside from cataplexy, the symptoms of narcolepsy are also observed in other sleep disorders and in some medical and psychiatric conditions. Cataplexy, if present, can help to exclude other causes for the patient’s symptoms, but clinicians must carefully differentiate true cataplexy from cataplexy-like episodes. Therefore, to make the proper diagnosis, clinicians must thoroughly evaluate all narcolepsy symptoms and consider each in the differential diagnosis. If a diagnosis of narcolepsy is suspected, then the diagnosis should be confirmed with objective testing.^1,2 

Diagnosis

A diagnosis of narcolepsy is established by subjective assessment with a sleep history and objective measurement with sleep testing.

The multiple sleep latency test (MSLT) is an objective test that is indicated in the diagnosis of narcolepsy. The MSLT is a validated measure of the physiological tendency to fall asleep and is performed over the course of a day following a nocturnal polysomnogram. The test consists of 5 nap opportunities given at 2-hour intervals under standard conditions. For each nap, the sleep latency (time from lights out to the first epoch of sleep) and presence of sleep-onset REM periods (first epoch of REM sleep within 15 minutes of sleep onset) are recorded.⁸ 

The MSLT is positive if the following 2 criteria are met:  

• Mean sleep latency of all naps is ≤8 minutes.

• 2 or more sleep-onset REM periods are present (either 2 on MSLT or 1 on MSLT and 1 on the preceding polysomnogram) (Figure).¹ 

There are several factors to consider when using the MSLT in the diagnosis of narcolepsy. 

• A nocturnal polysomnogram must be performed on the night preceding the MSLT to rule out other sleep disorders and ensure a total sleep time of at least 6 hours.

•  The MSLT should be performed using standard procedures. 

•  Adequate sleep and a standardized sleep-wake schedule should be documented by a sleep log or actigraphy for at least 1 week prior to the MSLT.

•  Medications that influence sleep should be stopped 2 weeks prior to the MSLT, confirmed by a urine drug screen.^1,8 

•  Positive findings on the MSLT can also be seen in other sleep disorders, so it is important to interpret the MSLT in the context of the clinical history.¹ 

Since a deficiency in hypocretin often underlies the development of narcolepsy, consideration could also be given to measuring hypocretin in the cerebrospinal fluid (CSF) as a diagnostic test for narcolepsy. Low or undetectable CSF hypocretin is diagnostic for narcolepsy.^1,2 In fact, between 90% to 95% of patients with narcolepsy and cataplexy have low or undetectable levels of CSF hypocretin.¹ Although measuring CSF hypocretin is a highly sensitive and specific test for narcolepsy, it is not readily available and is rarely used in practice at this time.^1,2 

HLA typing is another consideration in the workup for narcolepsy. Approximately 98% of patients with low CSF hypocretin are HLA DQB1*0602 positive. The HLA association may implicate autoimmunity in the etiology of narcolepsy, possibly accounting for the selective loss of hypocretin-producing neurons in the hypothalamus.^1,2 However, clinicians should remember that, although the presence of HLA subtype DQB1*0602 supports the diagnosis of narcolepsy, it is not diagnostic.¹

Based on the results of the complete diagnostic workup, patients are classified as either narcolepsy type 1 or 2 (Table). The major distinctions between the 2 types revolve around the presence or absence of cataplexy and CSF hypocretin.

Management and Treatment

Management of narcolepsy focuses on behavioral and pharmacological intervention to control the symptoms of excessive daytime sleepiness and cataplexy, if present. To date, there is no known cure for this sleep disorder; treatment goals should focus on improving patient quality of life and maintaining the highest degree of functionality. Because human narcolepsy involves loss of the hypocretin-producing neurons of the lateral hypothalamus, current research initiatives involve genetic intervention and hypocretin-based therapies.⁹ 

Behavioral Intervention 

A cardinal feature of narcolepsy is the inappropriate blending of sleep into the waking state, making it important to focus on developing behaviors that strengthen the natural human circadian rhythm and reinforce a consistent sleep-wake cycle—ie, the human body clock. Therefore, any sleep schedule with rapidly changing sleep-wake times (>2 hours) is strongly discouraged. Patients are advised not to pursue a profession that requires schedule adjustments, such as careers in transportation (eg, truck drivers), safety (eg, police officers, firefighters, air traffic controllers), or healthcare (rotating or on-call shifts).¹⁰ 

It is recommended that patients have a regular sleep schedule that allows for at least 8 to 9 hours of total sleep time. Patients should also practice good sleep hygiene, which includes avoiding heavy meals or alcohol intake that may disrupt sleep. To provide the foundation for good quality rest, they should seek a sleep-inducing environment that is dark, has a lower room temperature, and is free of noise and electronic devices.¹⁰ 

Planned naps taken at midday and no later than early evening are beneficial to sustain daytime alertness. It is important that these naps be short (15-30 minutes), because longer sleep time during the day may disrupt the natural homeostatic drive to accumulate a sleep debt, which facilitates sleep onset and consolidation at night.¹⁰ 

Pharmacotherapy

•Wake-promoting agents. Prior to 1998, the main drug therapies used to treat excessive daytime sleepiness were CNS stimulant medications that were classified as amphetamines. A newer category of medications classified as wake-promoting agents, which includes modafinil and armodafinil, are now considered first-line therapy.¹¹

The suggested dosing regimen for modafinil is 100 mg to 200 mg in the morning upon awakening and again in the early afternoon. Armodafinil is recommended at a daily dose of 150 mg to 250 mg. Patients taking either of these medications should be advised that food intake at the time of drug administration may delay absorption by 2 to 4 hours.¹⁰ 

Patients may experience common side effects of wake-promoting agents, such as headache, dry mouth, nausea, and jitteriness. Slow upward titration of dosage, usually over a 2 to 4 week period, is helpful in resolving these symptoms. Some patients taking these drugs have periods of elevated blood pressure, so appropriate monitoring should be standard in patients with a cardiovascular history. Additionally, patients should be cautioned that these drugs may reduce the efficacy of oral contraceptives and an additional barrier method should be used for up to 1 month after stopping the drug.¹⁰ 

•Amphetamines. CNS stimulant medications are still used in the treatment of narcolepsy. These medications are effective for reducing sleepiness and for the short-term enhancement of both cognitive and motor tasks.¹⁰ Methylphenidate is commonly used to treat the excessive daytime sleepiness associated with narcolepsy, but other stimulants (eg, dextroamphetamine and amphetamine/dextroamphetamine) may also be appropriate. 

A sample dosing regimen for methylphenidate is 10 mg upon awakening, 10 mg at noon, and a 5 mg to 10 mg dose as needed in midafternoon. Be aware that if the last dose of methylphenidate occurs too late in the day (after 3-4 PM), it may contribute to sleep-onset insomnia later at night. Clinicians may also consider the slow or extended-release formulations, such as methylphenidate ER, that may provide a clinical response with less frequent dosing. Note: Stimulant medications are associated with the development of tolerance and carry a high potential for abuse if not taken correctly. Treatment recommendations are to prescribe no more than a total of 60 mg daily in 3 divided doses and should start treatment at the lowest dose available.¹⁰

Common side effects of stimulants include palpitations, irritability, and insomnia. The side effect profile for these medications also includes cardiovascular effects, so clinicians should exercise caution in patients with a cardiovascular history.¹⁰ 

 •Sodium oxybate. In addition to managing excessive daytime sleepiness with wake-promoting agents and stimulants, clinicians may choose a newer treatment geared toward improving both cataplexy and disturbed nocturnal sleep. Sodium oxybate is the sodium salt of gamma hydroxybutyrate and is a CNS depressant. The drug has a rapid onset of action and almost immediate sedative effects. Studies have shown that sodium oxybate improves sleep architecture, increases the amount of deep sleep, and decreases nocturnal awakenings and daytime cataplectic events.¹²

Dosing of sodium oxybate starts at 2.25 g at bedtime and 2.25 g 2.5 to 4 hours later (short half-life of 90 to 120 minutes), for a total of 4.5 gm per night. Clinicians should progressively titrate upward over a 6- to 8-week period, with the medication taking as long as 2 to 3 months to achieve full efficacy. Therapeutic doses are usually in the 6 g to 9 g range.^10,13 Patients should be counselled to take this medication at bedtime and at least 2 hours after eating, to prepare both doses ahead of time, and to set an alarm clock to awaken for the second dose if necessary.¹³ 

Common side effects of sodium oxybate include nausea, vomiting, dizziness, and somnolence, with other adverse reactions being depression, confusion, sleepwalking, and respiratory depression. The use of alcohol or sedative hypnotics while taking sodium oxybate is strictly contraindicated. Additionally, due to its high sodium content, clinicians should be careful when prescribing sodium oxybate for patients who are required to monitor salt intake for other medical conditions.¹³

Due to high potential for abuse and illicit misuse, patients are only eligible to receive sodium oxybate if enrolled in a restricted distribution program that monitors prescription and distribution through a central pharmacy in the United States.¹³ 

•Antidepressants. The first medications used to treat cataplexy were the tricyclic antidepressants, but the newer selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are now used more commonly in clinical practice to treat cataplexy. The newer antidepressants are preferred because of their lesser side effect profile compared to the older antidepressants.¹⁰ 

A recommended starting dose for fluoxetine is 20 mg in the morning, with gradual titration to 60 mg in 2 divided doses daily. Another option is venlafaxine at a starting dose of 75 mg to 150 mg daily. Patients taking either medication may experience common side effects such as nausea, anorexia, insomnia, sexual dysfunction, and urinary retention.¹⁰ 

Narcolepsy is an underrecognized, chronic sleep disorder that can have profound effects on quality of life. The diagnosis is made with careful symptom analysis and objective measurement through sleep testing. Once diagnosed, treatment involves both behavior modification and pharmacotherapy. Narcolepsy is an important disorder with both personal and public health effects, and clinicians should consider the possibility of this diagnosis in patients experiencing excessive sleepiness.

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