Narcolepsy 

Updated: Sep 04, 2019
Author: Sagarika Nallu, MD; Chief Editor: Selim R Benbadis, MD 

Overview

Practice Essentials

Narcolepsy is characterized by the classic tetrad of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Narcolepsy is thought to result from genetic predisposition, abnormal neurotransmitter functioning and sensitivity, and abnormal immune modulation.

Signs and symptoms

Manifestations of narcolepsy are as follows:

  • EDS

  • Cataplexy (brief and sudden loss of muscle tone)

  • Hypnagogic/hypnopompic hallucinations

  • Sleep paralysis

Children rarely manifest all 4 symptoms.[1]

Features of EDS are as follows:

  • EDS is the primary symptom of narcolepsy

  • EDS must be present for at least 3 months to justify the diagnosis

  • Severe EDS leads to involuntary somnolence during activities such as driving, eating, or talking

  • Sleepiness may be severe and constant, with paroxysms of falling asleep without warning (ie, sleep attacks)

Features of cataplexy are as follows:

  • If severe and generalized, cataplexy may cause a fall

  • More subtle forms exist with only partial loss of tone (eg, head nod, speech alteration, and knee buckling)

  • Respiratory and extraocular movements are preserved

  • Cataplexy is usually triggered by emotions (especially laughter and anger)

Features of sleep paralysis are as follows:

  • Usually, the patient is unable to move upon awakening

  • Less commonly, the patient is unable to move upon falling asleep with consciousness intact

  • Paralysis is often accompanied by hallucinations

  • Respiratory and extraocular muscles are spared

  • Paralysis occurs less frequently when the person sleeps in an uncomfortable position

  • Paralysis can be relieved by sensory stimuli (eg, touching or speaking to the person)

The following are also common features of narcolepsy:

  • A tendency to take short and refreshing naps during the day; these may be accompanied by dreams

  • Trouble sleeping at night[2]

  • Nocturnal compulsive behaviors (eg, sleep-related eating disorder and nocturnal smoking[3]

  • Obesity

Features of narcolepsy in children are as follows:

  • Restlessness and motor overactivity may predominate

  • Academic deterioration, inattentiveness, and emotional lability are common

  • At disease onset, children with narcolepsy and cataplexy may display a wide range of motor disturbances that do not meet the classic definition of cataplexy

  • Motor disturbances may be negative (hypotonia) or active (eg, perioral movements, dyskinetic-dystonic, or stereotypic movements)

  • Motor disturbances may resolve later in the course of the disorder[4]

  • Cataplectic facies is an unusual facial feature only recently described in children with narcolepsy with cataplexy, usually at disease onset. The typical manifestations of cataplectic facies include repetitive mouth opening, tongue protrusion, and ptosis. Interestingly, the usual triggering emotions, such as laughter or joking, are not always present, hampering diagnosis.

See Clinical Presentation for more detail.

Diagnosis

Sleep studies are an essential part of the evaluation of patients with possible narcolepsy. The combination of an overnight polysomnogram (PSG) followed by a multiple sleep latency test (MSLT) showing sleep latency ≤8 minutes and 2 or more sleep-onset random eye movement periods (SOREMPs) strongly suggests narcolepsy while excluding other sleep disorders. A PSG the night prior to the MSLT is required and should document at least 6 hours of sleep and should rule out other sleep disorders like obstructive sleep apnea (OSA). An alternative criterion is a cerebrospinal fluid hypocretin level of ≤110 pg/mL.

See Workup for more detail.

Management

Nonpharmacologic measures include sleep hygiene, such as the following[5] :

  • Maintaining a regular sleep schedule, usually 7.5-8 hours of sleep per night

  • Scheduled naps during the day, in some cases

Pharmacologic treatment of excessive somnolence in narcolepsy includes stimulants such as the following:

  • Methylphenidate

  • Modafinil

  • Armodafinil

  • Amphetamines

  • Solriamfetol

  • Codeine (in patients for whom stimulant treatment is problematic)[6]

Pharmacologic treatment of cataplexy includes the following:

  • Sodium oxybate (also treats EDS)

  • Antidepressants (eg, clomipramine and fluoxetine; off-label use)

Histamine H3 antagonists/inverse agonists[7, 8]

  • Pitolisant is a nonscheduled therapy option indicated for excessive daytime sleepiness in adults with narcolepsy
  • In clinical trials, approximately 75-80% of patients had a history of cataplexy

See Treatment and Medication for more detail.

Background

Narcolepsy is characterized by the classic tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. However, this tetrad is seen only rarely in children.

Narcolepsy frequently is unrecognized, with a typical delay of 10 years between onset and diagnosis. Approximately 50% of adults with the disorder retrospectively report symptoms beginning in their teenage years. This disorder may lead to impairment of social and academic performance in otherwise intellectually normal children. The implications of the disease are often misunderstood by patients, parents, teachers, and health care professionals.

Narcolepsy is treatable. However, a multimodal approach is required for the most favorable outcome.

Diagnostic criteria (DSM-5 and ISCD-3)

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defines narcolepsy as recurrent episodes of irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day. These must have been occurring at least three times per week over the past 3 months. There also must be the presence of at least one of the following:[9]

  • Episodes of cataplexy occurring at least a few times per month

  • Hypocretin deficiency

  • REM sleep latency ≤15 minutes, or a mean sleep latency ≤8 minutes and two or more sleep-onset REM periods (SOREMPs)

Narcolepsy can be categorized as mild, moderate, or severe based on the frequency of cataplexy, need for naps, and disturbance of nocturnal sleep. In addition, the DSM-5 identifies five subtypes as follows:[9]

  • Narcolepsy without cataplexy but with hypocretin deficiency

  • Narcolepsy with cataplexy but without hypocretin deficiency

  • Autosomal dominant cerebellar ataxia, deafness, and narcolepsy

  • Autosomal dominant narcolepsy, obesity, and type 2 diabetes

  • Narcolepsy secondary to another medical condition

The American Academy of Sleep Medicine's International Classification of Sleep Disorders, Third Edition (ICSD-3) reclassified narcolepsy into two types (narcolepsy type 1 and narcolepsy type 2).[10, 11] In the previous edition of the manual, narcolepsy was categorized as either narcolepsy with cataplexy or narcolepsy without cataplexy.[12] The change in nomenclature reflects the fact that some patients demonstrate hypocretin deficiency (the fundamental cause of narcolepsy), but may not demonstrate cataplexy at the time of diagnosis although they may eventually.

Narcolepsy type 1 is distinguished by sleepiness plus cataplexy and a positive multiple sleep latency test (MSLT), or sleepiness plus hypocretin deficiency. Narcolepsy type 2 requires sleepiness and a positive MSLT and the absence of type-1 markers. And, the hypersomnia and/or MSLT findings must not be better explained by another sleep, neurologic, mental, or medical condition or by medicine or substance use.[10]

Whenever possible, the diagnosis of narcolepsy should be confirmed by polysomnography (PSG) followed by a multiple sleep latency test (MSLT); the MSLT should show sleep latency 8 minutes or less and 2 or more sleep-onset REM periods (SOREMPs). A SOREMP on PSG the night preceding the MSLT may replace one of the SOREMPs on the MSLT. This change in the SOREMP requirement means that clinicians need to pay closer attention to the early stage scoring of night PSGs. An alternative criterion for diagnosis is a CSF hypocretin level of 110 pg/mL or lower.

Pathophysiology

Narcolepsy is thought to result from genetic predisposition, abnormal neurotransmitter functioning and sensitivity, and abnormal immune modulation. Current data implicate certain human leukocyte antigen (HLA) subtypes and abnormal hypocretin (orexin) neurotransmission, which leads to abnormalities in monoamine and acetylcholine synaptic transmissions, particularly in the pontine reticular activating system.[13, 14]

Understanding of the neurochemistry of narcolepsy began with research involving narcoleptic dogs (eg, special laboratory-bred Dobermans and Labradors). In these animal models, the disorder is transmitted in an autosomal recessive fashion with full penetrance and is characterized mainly by cataplexy.[15] Muscarinic cholinergic stimulation increases cataplexy in these animals, and cholinergic blockade eliminates the symptom. Nicotinic agents have no effect on the cataplexy.

Receptor subtypes such as the alpha1-noradrenergic receptor appear to mediate cataplexy. Prazosin, an alpha1-antagonist, worsens symptoms in human and canine subjects.

The pons is not the only neuroanatomic site that is responsible for mediating cataplexy; the mesocorticolimbic dopaminergic system also has been implicated. This connection with the limbic system in part explains the relationship of cataplexy to emotion.

The centrality of hypocretin transmission in the pathophysiology of narcolepsy was demonstrated when hypocretin knockout mice displayed cataplexy and sleepiness.[16, 17] Further evidence for impaired hypocretin functioning in humans was found with the discovery of low levels of hypocretin in the cerebrospinal fluid (CSF) of narcoleptic patients.[18]

Subsequently, abnormal immune modulation was associated with the clinical development of narcolepsy in children in Scandinavia and Finland. After vaccination against the H1N1 influenza virus with a vaccine using a potent ASO3 adjuvant, narcolepsy in Finnish children increased 8- to 12-fold. All affected children who underwent HLA typing were found to have the HLA DQB*0602 allele.[19, 20]

Rapid eye movement sleep

Dysfunction and inappropriate regulation of rapid eye movement (REM) sleep are thought to exist in narcolepsy.[21] Neuroanatomic control of REM sleep appears to be localized to the pontine reticular activating system.

The brain contains REM-on cells, which fire selectively during REM sleep periods, and REM-off cells, for which the converse holds true. Most REM-on cells function through cholinergic transmission, whereas REM-off cells are noradrenergic or serotonergic. In narcolepsy, monoamine-dependent inhibition of REM-on cells may be defective.

Symptoms can be viewed as REM sleep components intruding into wakeful states. For example, cataplexy and sleep paralysis represent an intrusion of REM sleep atonia, whereas hallucinations represent an intrusion of dreams.

Hypocretin

The hypocretin system plays an important role in the pathophysiology of human narcolepsy. Patients with narcolepsy have been found to have little or no hypocretin in their CSF.[22] Postmortem pathologic examination of the brains of people with narcolepsy with cataplexy have demonstrated dramatically reduced numbers of hypocretin neurons. Hypocretin deficiency is theorized to produce instability of sleep and wake states, thereby preventing the person from sustaining more continuous sleep or wakefulness.

A large majority of patients with narcolepsy without cataplexy have normal CSF hypocretin levels. However, a small pathologic study of the brains of patients who had narcolepsy without cataplexy showed partial loss of hypocretin neurons in the hypothalamus.[23, 24, 25]

Investigators have identified low levels of histamine (a neurotransmitter that may help maintain wakefulness) in the CSF of patients with hypocretin-deficient narcolepsy.[26] Low CSF histamine levels are not limited to hypocretin-deficient narcolepsy, however; they are also seen in narcolepsy patients with normal CSF hypocretin levels and in patients with idiopathic hypersomnia.[26, 27]

It is noteworthy that low CSF histamine levels have not been found in patients with hypersomnia secondary to obstructive sleep apnea syndrome.[27] The CSF histamine level may serve as a biomarker reflecting the degree of hypersomnia of central origin.[26, 27]

CNS nuclei for wakefulness and the relevant neurotransmitters generated in those nuclei include the following:

  • Locus ceruleus – Norepinephrine

  • Raphe nucleus – Serotonin

  • Tubomammillary nucleus – Histamine

  • Ventral tegmental area – Dopamine

  • Basal forebrain – Acetylcholine

These areas also inhibit REM sleep.

Hypocretin neurons, thought to be autoexcitatory, project from the lateral hypothalamus into these regions and serve to maintain wakefulness. A deficiency of hypocretin neurons may decrease the threshold for transitioning between wakefulness and sleep (so-called sleep state instability). This is a proposed explanation for the sleepiness and REM intrusion into wakefulness found in narcolepsy.[14]

Destruction of hypocretin-producing neurons appears to be an autoimmune process.[28] A study in a mouse model found that the serum of narcolepsy patients was reactive with over 86% of hypocretin neurons from the mouse hypothalamus.[29] levels of a specific autoantigen against Tribbles homolog 2 (Trib2) have been found to be higher in narcolepsy patients with cataplexy than in normal controls or patients with other inflammatory neurologic disorders. High Trib2-specific antibody titers correlated with more severe cataplexy.[29]

The autoimmune model of narcolepsy inspired trials of intravenous (IV) immunoglobulin (IVIG) therapy in narcoleptic patients with low levels of hypocretin-1. In these trials, IVIG reportedly improved cataplexy and sleepiness in many cases, but the effects did not last long. IVIG did not normalize CSF hypocretin levels, except in 1 patient.[30] In 2 children given IVIG early after diagnosis of narcolepsy, the cataplexy and sleepiness improved, but some components of the disease worsened in 1 child.[31]

Genetic factors

The genetics of narcolepsy are complex. Whereas the concordance is only 35% in monozygotic twins, the risk is as high as 40% in first-degree relatives.[32] Narcolepsy with cataplexy can be produced in animal models by disrupting the gene that encodes the hypocretin (orexin) receptor or ligand gene, thereby disrupting hypocretin neurotransmission.[16]

There is a striking association between narcolepsy and the HLA haplotype DQA1*01:02-DQB1*06:02. A study in individuals of European descent found that nearly all of those with a diagnosis of narcolepsy with cataplexy carry the HLA haplotype DQA1*01:02-DQB1*06:02, compared with only 24% of the general population.[33] Thus, carriage of this haplotype may be necessary but not sufficient for the development of narcolepsy.

A study of genome-wide expression in narcolepsy patients and controls showed an independent effect of allelic dosage of DQB1*06:02 on DQB1*06:02 mRNA levels and protein.[34] This finding supports the suspicion that the risk of narcolepsy is higher in DQB1*06:02 homozygotes than in heterozygotes, suggesting that HLA is functionally involved in the occurrence of narcolepsy.[34]

A genome-wide association study proposed a protective variant (DQB1*06:03). This allele may protect against autoimmune disorders; it is almost never seen in patients with narcolepsy.[35]

Genome-wide association studies in Caucasians, with replication in 3 ethnic groups, have revealed associations between single-nucleotide polymorphisms (SNPs) in the T-cell receptor alpha locus and narcolepsy.[36] This association further supports the autoimmune basis of narcolepsy.

An SNP in the purinergic receptor subtype P2Y11 gene (P2RY11) also appears to be associated with narcolepsy.[37] P2RY11 has been identified as an important regulator of immune cell survival; the disease-associated P2RY11 correlates with a 3-fold lower expression of P2RY11 in CD8+ T-cells and natural killer cells, as well as with decreased P2RY11-mediated resistance to adenosine triphosphate–induced death in those cells.

A genome-wide association study that investigated 202 candidate genes in a replication study in 222 narcoleptic patients and 380 controls identified 6 genes that were associated with narcolepsy: NFATC2, SCP2, CACNA1C, TCRA, POLE, and FAM3D. These gene associations with narcolepsy were further supported by gene expression analyses showing that these same genes are also associated with essential hypersomnia, which is similar to narcolepsy.[38]

Epidemiology

United States statistics

The prevalence of narcolepsy in the US is 0.02-0.18%, which is comparable to that of multiple sclerosis.[39, 40] The frequency among first-degree relatives is 1-2% (10-40 times greater than that in the general population). The reported prevalence of narcolepsy in select populations is as follows:

  • North American blacks, 0.02%

  • Northern Californians, 0.05%

  • Southern Californian Caucasians, 0.07%

International statistics

Narcolepsy with cataplexy affects 0.02% of adults worldwide.[41] The reported prevalence of narcolepsy in select populations is as follows:

  • Israeli Jews and Arabs, 0.002%

  • Czech Caucasians, 0.02%

  • Finnish Caucasians, 0.026%

  • United Kingdom Caucasians, 0.04%

  • French Caucasians, 0.05%

  • Fujisawa Japanese teenagers, 0.16%

  • Japanese general population, 0.18%

  • Irish general population, 0.005%[42]

Sex- and age-related demographics

The male-to-female ratio in narcolepsy is 1.64:1. The age-of-onset distribution is bimodal, with the highest peak occurring at 15 years and a less pronounced peak occurring at 36 years. However, narcolepsy has been reported in children as young as 2 years.

Prognosis

With proper management and treatment, patients with narcolepsy usually lead meaningful and productive personal and professional lives. If left untreated, narcolepsy may be psychosocially devastating.[43] Narcoleptic children may suffer poor school performance, social impairment, ridicule from peers, and dysfunction in other activities of normal childhood development.

Affected adults often perceive narcoleptic symptoms as embarrassing, and social isolation may result. They may encounter interpersonal stress in relationships, sexual dysfunction, and difficulty working as a consequence of either the disease itself or its treatment.

Job impairment may result from sleep attacks, memory problems, cataplexy, interpersonal problems, and personality changes. These symptoms may lead coworkers to perceive narcoleptics as lazy, inattentive, and lacking motivation. In one study, 24% of narcoleptic patients had to quit working and 18% were terminated from their jobs because of their disease.

People with narcolepsy sometimes are falsely suspected of illegal drug use. Patients should inform employers concerning their stimulant medications because they may test positive for amphetamines on screening preemployment drug tests.

Patient Education

Educate patients, parents, teachers, and other care providers concerning the symptoms, prognosis, and safety precautions. Advise patients of the increased risk of sleep-related driving accidents. Advise patients with narcolepsy about driving responsibilities.

As of March 1994, only 6 states in the United States (California, Maryland, North Carolina, Oregon, Texas, and Utah) had guidelines for narcoleptic drivers. In contrast, most Canadian provinces have guidelines, as does the United Kingdom, but whether such guidelines are effective in reducing traffic-related morbidity is unknown.[44]

For patient education information, see the Sleep Disorders Center, as well as Narcolepsy.

 

Presentation

History

The classic tetrad of narcolepsy consists of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Children rarely manifest all 4 symptoms.[1] EDS is the primary symptom of narcolepsy and must be present for at least 3 months to justify the diagnosis.

Sleepiness is a normal experience that cycles and invariably occurs after prolonged wakefulness. In healthy persons, mild sleepiness is apparent only during boring, sedentary situations (eg, falling asleep while watching television). In persons with narcolepsy, severe EDS leads to involuntary somnolence during activities that normally engage attention, such as driving, eating, or talking. Sleepiness in narcolepsy may be severe and constant, with paroxysms during which patients may fall asleep without warning (ie, sleep attacks).

Patients with narcolepsy tend to take short and refreshing naps (ie, rapid eye movement [REM]-type naps) during the day. Their daytime naps may be accompanied by dreams.

A significant number of narcolepsy patients have trouble sleeping at night.[2] In addition, patients may have nocturnal compulsive behaviors, including sleep-related eating disorder and nocturnal smoking.[3]

Obesity is another common feature of narcolepsy. The combination of narcolepsy and obesity may promote the development of obstructive sleep apnea.

Cataplexy

Cataplexy is a brief and sudden loss of muscle tone and represents REM sleep intrusion during wakefulness. If severe and generalized, it may cause a fall. More subtle forms may cause only partial loss of tone (eg, head nod and knee buckling). Case reports of facial muscle involvement, especially in children with narcolepsy, have been reported.[45] Respiratory and extraocular movements are preserved. The most characteristic feature of cataplexy is that it usually is triggered by emotions (especially laughter and anger).

Cataplexy is seen in about 70% of patients with narcolepsy. Its presence in conjunction with EDS strongly suggests the diagnosis of narcolepsy.

Sleep disturbances

Patients with narcolepsy may experience sleep paralysis, which is the inability to move upon awakening—or, less commonly, upon falling asleep with consciousness intact. It often is accompanied by hallucinations. Respiratory and extraocular muscles are spared. Sleep paralysis occurs less frequently when patients sleep in uncomfortable positions. It can be relieved by sensory stimuli, such as touching or speaking to the person.

Sleep-related hallucinations may be either hypnagogic (ie, occurring at sleep onset) or hypnopompic (ie, occurring at awakening). These hallucinations are usually vivid (dreamlike) visual, auditory, or tactile in nature.

Disrupted nocturnal sleep is also a common feature of narcolepsy. Consequently, because of daytime naps, total sleep time in 24 hours is essentially unchanged in narcoleptic patients.

Young children

The classic picture of narcolepsy may be somewhat different in young children. Children may deny EDS because of embarrassment. In some cases, restlessness and motor overactivity predominate. Academic deterioration, inattentiveness, and emotional lability are common.

At disease onset, children with narcolepsy and cataplexy may display a wide range of motor disturbances that do not meet the classic definition of cataplexy. These motor disturbances, which may be negative (hypotonia) or active (eg, perioral movements, dyskinetic-dystonic movements, or stereotypic movements), may resolve later in the course of the disorder.[4]

In a study of 51 prepubertal patients with narcolepsy, the initial complaints, as well as the typical misdiagnoses, varied by age.[46] Children younger than 5 years presented with unexplained falls and “drop attacks,” aggressive behavior, sudden irritability, and abrupt dropping of objects. Atonic seizures were the most common misdiagnosis in this age group.

In children aged 5-10 years, the most common initial complaint was inattentiveness, followed by repetitive sleepiness and then by difficulty with morning arousal associated with aggressive behavior and abrupt falls in school.[46] These children often were misdiagnosed as having attention deficit hyperactivity disorder (ADHD), learning disability, depression, or another neurologic disorder.

In children aged 10-12 years, poor academic performance was a common complaint.[46] Other presenting symptoms included inappropriate low level of alertness, falling asleep in class, and inability to wake up in the morning.

Questionnaires

Several questionnaires are available for evaluating sleepiness. Of these, the most commonly used is the 8-question Epworth Sleepiness Scale. Patients respond to each question with a numerical score ranging from 0 (not at all likely to fall asleep) to 3 (very likely to fall asleep); thus, the lowest possible total score is 0, and the highest possible score is 24. Although there is some controversy as to precisely what score constitutes abnormal sleepiness, it is generally considered that total scores higher than 10 warrant investigation.

Physical Examination

Physical examination findings are normal in patients with narcolepsy. A careful neurologic examination should be performed to exclude other causes of the patient’s condition, including an underlying structural abnormality. There are no specific physical findings that suggest narcolepsy, though obesity may be associated with the disorder. During an episode of cataplexy, patients typically demonstrate atonia of muscles of the limbs and neck and loss of deep tendon reflexes.

 

DDx

Diagnostic Considerations

Idiopathic hypersomnia is similar in presentation to narcolepsy, but patients with this condition have no sleep-onset rapid eye movement (REM) period, and naps are unrefreshing.[47] In addition, idiopathic hypersomnia is not associated with cataplexy. Idiopathic hypersomnia can be difficult to distinguish from narcolepsy, though the advent of the modern sleep laboratory has aided in diagnosing these challenging cases.

Differentiation of these 2 disorders can provide valuable insight for therapy. Although amphetamines are used for treatment of both idiopathic hypersomnia and narcolepsy, the excessive daytime sleepiness (EDS) in patients with idiopathic hypersomnia is often resistant to stimulant treatments. In addition, sodium oxybate, which is very costly, is not approved for use in idiopathic hypersomnia.

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Prader-Willi syndrome

  • Kasabach-Merritt syndrome

  • Syndrome of autosomal dominant cerebellar ataxia, deafness, and narcolepsy[48]

  • Delayed sleep-phase syndrome

  • Autism

  • Depression

  • Diencephalic lesions

  • Drug abuse

  • Insufficient sleep syndrome

  • Kleine-Levin syndrome[49]

  • Medication effect

  • Norrie disease[50]

  • Poor sleep hygiene

  • Posttraumatic narcolepsy[51]

  • Increased intracranial pressure

  • Conversion disorder, factitious disorder, and malingering

Differential Diagnoses

 

Workup

Approach Considerations

Sleep studies are an essential part of the evaluation of patients with possible narcolepsy. The combination of an overnight polysomnogram (PSG) followed by a multiple sleep latency test (MSLT) can provide strongly suggestive evidence of narcolepsy while excluding other sleep disorders.

Human leukocyte antigen (HLA) typing may provide collateral data, but it is more useful for excluding the diagnosis by documenting that the patient does not have either DQB1*0602 or DQA1*0602. HLA typing is less valuable for confirming the diagnosis, in that HLA-DR2 and DQw1 are present in 20-30% of the general population.

Measurement of hypocretin (orexin) levels in the cerebrospinal fluid (CSF) may help establish the diagnosis.[18] CSF hypocretin levels lower than 110 pg/mL are included in the diagnostic criteria for narcolepsy in the second edition of the International Classification of Sleep Disorders (ICSD-2). On the other hand, high CSF hypocretin levels do not exclude the diagnosis of narcolepsy.

In most cases, imaging studies are unrevealing. A few small studies have implicated magnetic resonance imaging (MRI) changes of the pons within the reticular activating system. Imaging studies such as MRI are useful for excluding rare causes of symptomatic narcolepsy. Structural abnormalities of the brain stem and diencephalon may present as idiopathic narcolepsy. In patients with secondary narcolepsy, MRI of the brain may show various abnormalities that correspond to the underlying cause.

Sleep Studies

An overnight PSG followed by an MSLT can exclude other causes of excessive daytime sleepiness (EDS), especially sleep apnea, and can provide information about EDS by measuring sleep latency and sleep-onset rapid eye movement periods (SOREMPs). The overnight PSG findings typically are normal in narcolepsy, though they may show sleep fragmentation. All central nervous system (CNS) stimulants and sedative-hypnotics should be discontinued 2 weeks before the PSG and MSLT.

The MSLT involves 5 opportunities to nap at 2-hour intervals over the day. More than 2 SOREMPs and a mean sleep latency of less than 8 minutes strongly suggest narcolepsy. These findings are not completely specific and also can be seen in patients with severe sleep deprivation, delayed sleep phase disorder, or severe sleep apnea. For these reasons, a PSG of the previous night is necessary for interpretation of the MSLT; MSLT cannot be used alone to confirm or rule out narcolepsy.

Diagnosing narcolepsy in children presents numerous difficulties. One study found that 85% of children with narcolepsy also suffered from sleep-disordered breathing. Serial MSLTs may be required, and usually multiple confounding factors are involved (eg, increased alertness in the novel environment of the sleep laboratory). Furthermore, normative MSLT values for children have not been established.

 

Treatment

Approach Considerations

Treatment of narcolepsy has both nonpharmacologic and pharmacologic components. Sleep hygiene is important. Most patients improve if they maintain a regular sleep schedule, usually 7.5–8 hours of sleep per night. Scheduled naps during the day also may help.[5]

Pharmacologic treatment of narcolepsy involves the use of central nervous system (CNS) stimulants such as methylphenidate, modafinil, dextroamphetamine sulfate, methamphetamine, and amphetamine, or solriamfetol, a dopamine/norepinephrine reuptake inhibitor. These medications help reduce daytime sleepiness, improving the symptom in 65–85% of patients. In patients for whom stimulant treatment is problematic, subjective benefit from treatment with codeine has been reported.[6]

Nonpharmacologic Measures

In addition to a regular sleep schedule (usually 7.5–8 hours of sleep per night) and, in some cases, scheduled naps during the day, the following nonpharmacologic measures are also important:

  • Providing emotional support and career or vocational counseling to patients and parents

  • Assisting with documentation for special academic needs, insurance, disability forms, and attaining a driver’s license

  • Questioning patients about high-risk behaviors such as alcohol and drug use, which may exacerbate symptoms

  • Inquiring about depression, family conflict, and other psychosocial problems

Children should be encouraged to participate in after-school activities and sports. A well-designed exercise program can be beneficial and stimulating. School personnel should have the narcoleptic children refrain from activities if they appear drowsy. Avoidance of foods high in refined sugars may improve daytime sleepiness.

Pharmacologic Treatment

Methylphenidate is the stimulant most frequently used for treatment of narcolepsy. It improves sleep tendency in a dose-related fashion. Undesirable side effects include headache, irritability, nervousness, and gastrointestinal complaints. Nocturnal sleep may be impaired, with a resulting decrease in total sleep time.

Modafinil is a novel wake-promoting agent.[52] The mechanism of action is not understood, but it does not appear to involve altering levels of dopamine or norepinephrine. Unlike traditional medications, modafinil does not appear to affect total sleep time or suppress rapid eye movement (REM) sleep; the most common adverse effect is headache.[53] Its safety in children has not been established.

In a meta-analysis of 9 randomized controlled trials including 1054 patients, modafinil was shown to provide significant benefit to narcoleptic patients with respect to eliminating excessive daytime sleepiness (EDS) and decreasing sleep attacks, naps, and the duration and periods of somnolence each day, in comparison with placebo.[54] Whereas modafinil improved the quality of life in narcoleptic patients as compared with placebo, it did not diminish the number of attacks of cataplexy.

Armodafinil[55] is an enantiomer of modafinil that has fewer side effects. It is indicated for the treatment of EDS associated with narcolepsy. The most common adverse effects are headache, nausea, dizziness, and difficulty sleeping. Its safety has not been established in children younger than 17 years.

Solriamfetol, a dopamine/norepinephrine reuptake inhibitor (DNRI), was approved in 2019 for EDS in adults with narcolepsy. Approval was based on a phase 3 trial where 239 patients with narcolepsy were randomized to receive solriamfetol 75 mg, 150 mg, or 300 mg (two times the maximum recommended daily dose), or placebo once daily. Compared to the placebo group, patients randomized to 150 mg showed statistically significant improvements on the maintenance of wakefulness test (MWT) and on the Epworth sleepiness scale (ESS) at week 12. These effects were apparent at week 1 and consistent with the results at week 12. At week 12, a higher percentage of patients treated with solriamfetol 150 mg (78.2%) reported patient global impression of change (PGIc) scale improvement relative to placebo (39.7%; p < 0.0001).[56]

Sodium oxybate[57, 58] is the only treatment for cataplexy that has been approved by the US Food and Drug Administration (FDA). It is also used to treat EDS. Sodium oxybate is a CNS depressant and should not be used with alcohol or other CNS depressants.

In a double-blind, placebo-controlled randomized study, the use of sodium oxybate (6 mg or 9 mg per night) was shown to reduce nocturnal sleep disruption in narcoleptic patients.[59] After 8 weeks of treatment, patients exhibited increases in the duration of stage 3 sleep. Changes in sleep were measured by means of nocturnal polysomnography (PSG). The benefits of sodium oxybate included improvements in total sleep time, decreased stage 1 sleep, and diminished wakening after sleep onset.[59]

In August 2019, the FDA approved pitolisant. It is a nonscheduled, first-in-class histamine3 (H3) receptor antagonist/inverse agonist indicated for excessive daytime sleepiness in adults with narcolepsy. The efficacy of pitolisant was evaluated in 2 multicenter, randomized, double-blind, placebo-controlled studies in patients (n=261) with narcolepsy with or without cataplexy. In both studies, pitolisant demonstrated a statistically significant improvement in the Epworth Sleepiness Scale (EDS) score.[7, 8]  

Amphetamines are commonly used as an off-label treatment for narcolepsy. There is a clinical consensus that tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) potently reduce cataplexy; however, one meta-analysis found no good-quality evidence that antidepressants are effective for narcolepsy or improve quality of life and found scarce evidence of efficacy for cataplexy.[60]

Research into future treatments is focusing on preventing the loss of hypocretin (orexin)-producing neurons by targeting the proposed autoimmune-driven mechanism of narcolepsy. Trials of intravenous (IV) immunoglobulin (IVIG) are in their infancy. Future research may also investigate the restoration of hypocretin signaling with agonists or gene therapy.

Treatment in pediatric patients

For children younger than 7 years who have narcolepsy, pemoline was previously considered the initial drug of choice. However, the FDA concluded that the overall risk of liver toxicity from pemoline outweighed the benefits, and the drug was removed from the US market in 2005.

Currently, no FDA-approved pharmacotherapy is available for children with narcolepsy. However, the medications used to treat narcolepsy in adults have been used off-label in the pediatric population with positive results. In particular, methylphenidate and modafinil have proved effective for patients 6–15 years old.[61]

Diet and Activity

Patients with narcolepsy should avoid heavy meals and alcohol. Activity recommendations include the following:

  • Patients should take scheduled short naps

  • Patients should participate in an exercise program

  • Patients should avoid driving, operating heavy machinery, or other potentially hazardous activity when sleepy

  • Patients with narcolepsy with cataplexy should wear a life preserver when engaged in water activities, should never perform water activities solo, and should educate the rest of their party about cataplectic attacks

Long-Term Monitoring

Children with narcolepsy should be monitored by both the primary pediatrician and the pediatric neurologist. Regular follow-up is necessary for monitoring drug effectiveness, response to treatment, and potential side effects; it should be done at least annually and, if the patient is on a stimulant, preferably every 6 months. A sleep medicine specialist, if available, also should see the patient regularly. Patients should contact narcolepsy support groups.

 

Medication

Medication Summary

The main focus of pharmacologic therapy for narcolepsy is symptomatic treatment of excessive somnolence and cataplexy with central nervous system (CNS) stimulants and antidepressants. Stimulants improve wakefulness, and antidepressants (eg, clomipramine, fluoxetine, duloxetine, and venlafaxine) reduce cataplectic attacks. 

Sodium oxybate, a CNS depressant and a salt of gamma hydroxybutyrate (GABA metabolite), is indicated for cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy.

Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is indicated for EDS in patients with narcolepsy.

Pitolisant is a nonscheduled, first-in-class histamine3 (H3) receptor antagonist/inverse agonist indicated for excessive daytime sleepiness in adults with narcolepsy.

Stimulants

Class Summary

Stimulants increase wakefulness, vigilance, and performance. They are thought to alter midbrain dopaminergic activity, but the precise mechanism of action is unknown. Interpatient variability in the dosage required to alleviate excessive daytime sleepiness (EDS) is considerable and unpredictable. In some patients, daytime sleepiness is completely relieved with methylphenidate 5 mg/day; in others, higher dosages are required. Initiate treatment at low dosages, and individualize therapy as appropriate.

Methylphenidate (Ritalin)

Methylphenidate is a piperidine derivative that is the most commonly prescribed treatment for narcolepsy. Its efficacy has been demonstrated in randomized, double-blind, dose-response, and placebo-controlled trials.

Modafinil (Provigil)

Modafinil is pharmacologically distinct from other stimulants. It does not appear to act via the dopaminergic system.

Armodafinil (Nuvigil)

R-enantiomer of modafinil (mixture of R- and S-enantiomers). Elicits wake-promoting actions similar to sympathomimetic agents, although pharmacologic profile is not identical to sympathomimetic amines. In vitro, binds dopamine transporter and inhibits dopamine reuptake. Not a direct- or indirect-acting dopamine receptor agonist. Indicated to improve wakefulness in individuals with excessive sleepiness associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), or shift-work sleep disorder.

CNS Depressants

Class Summary

Cataplexy in patients with narcolepsy can be treated with the CNS depressant sodium oxybate. Other agents that are used off-label for cataplexy are tricyclic antidepressants (TCAs; eg, clomipramine, desipramine, and imipramine), selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, paroxetine, and sertraline), and serotonin-norepinephrine reuptake inhibitors (SNRIs; eg, venlafaxine and duloxetine). The strongest evidence is for clomipramine, fluoxetine, and sodium oxybate.

Sodium oxybate (Xyrem)

Sodium oxybate (Xyrem)

Sodium oxybate, also known as gamma hydroxybutyrate (GHB), is a CNS depressant used to treat patients with EDS and cataplexy. The onset of therapeutic effects is often delayed. The precise mechanism by which sodium oxybate produces an effect on cataplexy is unknown.

Because of sodium oxybate's history of abuse as a recreational drug, the FDA approved it as a Schedule III Controlled Substance. A limited distribution program that includes physician education, patient education, a patient and physician registry, and detailed patient surveillance has been established. Under this program, prescribers and patients will be able to obtain the product only through the Xyrem Success Program and only from a single centralized pharmacy (1-866-997-3688). Sodium oxybate is available as an oral solution (500 mg/mL).

Dopamine/Norepinephrine Reuptake Inhibitors

Class Summary

The mechanism of action by which solriamfetol improves wakefulness in patients with excessive daytime sleepiness associated with narcolepsy is unclear, but is thought to be mediated through its inhibition of dopamine/norepinephrine reuptake. 

Solriamfetol (Sunosi)

Dopamine/norepinephrine reuptake inhibitor (DNRI). It is indicated to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy.

Histamine H3 Antagonist/Inverse Agonist

Pitolisant (Wakix)

Selective histamine 3 (H3) receptor antagonist/inverse agonist. It is indicated for treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy.

 

Questions & Answers

Overview

How is narcolepsy characterized?

What are the signs and symptoms of narcolepsy?

What are clinical features of excessive daytime sleepiness (EDS) in narcolepsy?

What are clinical features of cataplexy in narcolepsy?

What are clinical features of sleep paralysis in narcolepsy?

What are the clinical features of narcolepsy?

What are the signs and symptoms of narcolepsy in children?

What is the role of sleep studies in the diagnosis of narcolepsy?

What are the nonpharmacologic treatments for narcolepsy?

Which medications are used in the treatment of narcolepsy?

How is cataplexy treated in narcolepsy?

What is narcolepsy?

What are the DMS-5 diagnostic criteria for narcolepsy?

What are the DSM-5 categorizations of narcolepsy?

What are the ICSD-3 classifications of narcolepsy and how are they diagnosed?

What is the pathophysiology of narcolepsy?

What is the role of rapid eye movement (REM) in the pathophysiology of narcolepsy?

What is the role of hypocretin system in the pathophysiology of narcolepsy?

Which neurotransmitters are generated in CNS nuclei relative to narcolepsy?

How are hypocretin neurons affected in patients with narcolepsy?

What is the role of genetics in the pathophysiology of narcolepsy?

What is the prevalence of narcolepsy in the US?

What is the global prevalence of narcolepsy?

Which patient groups have the highest prevalence of narcolepsy?

What is the prognosis of narcolepsy?

What is included in patient education about narcolepsy?

Presentation

Which clinical history findings are characteristic of narcolepsy?

What is cataplexy in narcolepsy?

What are the sleep disturbance symptoms of narcolepsy?

Which clinical history findings are characteristic of narcolepsy in young children?

What is the role of sleep questionnaires in the evaluation of narcolepsy?

Which physical findings are characteristic of narcolepsy?

DDX

How is idiopathic hypersomnia differentiated from narcolepsy?

Which conditions are included in the differential diagnoses of narcolepsy?

What are the differential diagnoses for Narcolepsy?

Workup

Which studies are included in the evaluation of narcolepsy?

What is the role of sleep studies in the diagnosis of narcolepsy?

Treatment

How is narcolepsy treated?

What are the nonpharmacologic treatment options for narcolepsy?

What are the nonpharmacologic treatment options for children with narcolepsy?

What is the role of methylphenidate in the treatment of narcolepsy?

What is the role of modafinil in the treatment of narcolepsy?

What is the role of armodafinil in the treatment of narcolepsy?

What is the role of sodium oxybate in the treatment of narcolepsy?

What is the role of amphetamines in the treatment of narcolepsy?

What types of narcolepsy treatments are currently being investigated?

What is the role of medications in the treatment of children with narcolepsy?

Which diet and activity modifications are used in the treatment of narcolepsy?

What is included in long-term monitoring of patients with narcolepsy?

Medications

What is the role of pharmacologic therapy for narcolepsy?

Which medications in the drug class CNS Depressants are used in the treatment of Narcolepsy?

Which medications in the drug class Stimulants are used in the treatment of Narcolepsy?

Which medications in the drug class Histamine H3 Antagonist/Inverse Agonist are used in the treatment of Narcolepsy?

Which medications in the drug class Dopamine/Norepinephrine Reuptake Inhibitors are used in the treatment of Narcolepsy?