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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 geneticpredisposition, 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 hallucinations

Sleep paralysisChildren 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, sleepattacks)

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 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]

ObesityFeatures 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 motordisturbances 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]SeeClinical Presentationfor more detail.

Diagnosis
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Sleep studies are an essential part of the evaluation of patients with possible narcolepsy. Thecombination of an overnight polysomnogram (PSG) followed by a multiple sleep latency test (MSLT)showing sleep latency 8 minutes or less and 2 or more sleep-onset random eye movement (REM) periodsstrong suggests narcolepsy while excluding other sleep disorders. An alternative criterion is acerebrospinal fluid hypocretin level of 110 pg/mL or less.

SeeWorkupfor 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 casesPharmacologic treatment of excessive somnolence in narcolepsy includes stimulants such as thefollowing:

Methylphenidate

Modafinil

Armodafinil

Amphetamines

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)SeeTreatmentandMedicationfor more detail.

Background

Narcolepsy is characterized by the classic tetrad of excessive daytime sleepiness, cataplexy, hypnagogichallucinations, 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 otherwiseintellectually 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-2)

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)defines narcolepsy asrecurrent episodes of irrepressible need to sleep, lapsing into sleep, or napping occurring within the sameday. These must have been occurring at least three times per week over the past 3 months. There alsomust be the presence of at least one of the following :[7]

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, needfor naps, and disturbance of nocturnal sleep. In addition, theDSM-5identifies five subtypes as follows:[7]

Narcolepsy without cataplexy but with hypocretin deficiency

Narcolepsy with cataplexy but without hypocretin deficiency

Autosomal dominant cerebellar atazia, deafness and narcolepsy
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Autosomal dominant narcolepsy, obesity, and type 2 diabetes

Narcolepsy secondary to another medical conditionThe American Sleep Disorders AssociationsInternational Classification of Sleep Disorders, SecondEdition (ICSD-2)diagnostic criteria for narcolepsy with cataplexy are (1) EDS daily for more than 3months and (2) a definite history of cataplexy (ie, sudden and transient episodes of loss of motor tonetriggered by emotions).[8]ICSD-2 diagnostic criteria for narcolepsy without cataplexy are the same as

those for narcolepsy with cataplexy, but without the presence of typical cataplexy.

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 lessand 2 or more SOREMPs. An alternative criterion is a CSF hypocretin level of 110 pg/mL or lower. Thehypersomnia must not be better explained by another sleep, neurologic, mental, or medical condition orby medicine or substance use.[8]

Pathophysiology

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

system.

[9] [10]

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 inan autosomal recessive fashion with full penetrance and is characterized mainly bycataplexy.[11] Muscarinic cholinergic stimulation increases cataplexy in these animals, and cholinergicblockade eliminates the symptom. Nicotinic agents have no effect on the cataplexy.

Receptor subtypes such as the alpha1-noradrenergic receptor appear to mediate cataplexy. Prazosin, analpha1-antagonist, worsens symptoms in human and canine subjects.

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

The centrality of hypocretin transmission in the pathophysiology of narcolepsy was demonstrated whenhypocretin knockout mice displayed cataplexy and sleepiness.[12, 13] Further evidence for impairedhypocretin functioning in humans was found with the discovery of low levels of hypocretin in thecerebrospinal fluid (CSF) of narcoleptic patients.[14]

Subsequently, abnormal immune modulation was associated with the clinical development of narcolepsyin children in Scandinavia and Finland. After vaccination against the H1N1 influenza virus with a vaccineusing a potent ASO3 adjuvant, narcolepsy in Finnish children increased 8- to 12-fold. All affected childrenwho underwent HLA typing were found to have the HLA DQB*0602 allele .[15, 16]

Rapid eye movement sleep

Dysfunction and inappropriate regulation of rapid eye movement (REM) sleep are thought to exist innarcolepsy.[17] Neuroanatomic control of REM sleep appears to be localized to the pontine reticularactivating system.

The brain contains REM-on cells, which fire selectively during REM sleep periods, and REM-off cells, forwhich the converse holds true. Most REM-on cells function through cholinergic transmission, whereasREM-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 hallucinationsrepresent an intrusion of dreams.


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Hypocretin

The hypocretin system plays an important role in the pathophysiology of human narcolepsy. Patients withnarcolepsy have been found to have little or no hypocretin in their CSF .[18] Postmortem pathologicexamination of the brains of people with narcolepsy with cataplexy have demonstrated dramaticallyreduced numbers of hypocretin neurons. Hypocretin deficiency is theorized to produce instability of sleepand 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 showedpartial loss of hypocretin neurons in the hypothalamus.[19, 20, 21]

Investigators have identified low levels of histamine (a neurotransmitter that may help maintainwakefulness) in the CSF of patients with hypocretin-deficient narcolepsy.[22] Low CSF histamine levels arenot limited to hypocretin-deficient narcolepsy, however; they are also seen in narcolepsy patients withnormal CSF hypocretin levels and in patients with idiopathic hypersomnia.[22, 23]

It is noteworthy that low CSF histamine levels have not been found in patients with hypersomniasecondary to obstructive sleep apnea syndrome.[23] The CSF histamine level may serve as a biomarkerreflecting the degree of hypersomnia of central origin.[22, 23]

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

Locus ceruleusNorepinephrine

Raphe nucleusSerotonin

Tubomammillary nucleusHistamine

Ventral tegmental areaDopamine

Basal forebrainAcetylcholineThese areas also inhibit REM sleep.

Hypocretin neurons, thought to be autoexcitatory, project from the lateral hypothalamus into these regionsand serve to maintain wakefulness. A deficiency of hypocretin neurons may decrease the threshold fortransitioning between wakefulness and sleep (so-called sleep state instability). This is a proposedexplanation for the sleepiness and REM intrusion into wakefulness found in narcolepsy.[10]

Destruction of hypocretin-producing neurons appears to be an autoimmune process.[24]A study in amouse model found that the serum of narcolepsy patients was reactive with over 86% of hypocretinneurons from the mouse hypothalamus.[25]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 orpatients with other inflammatory neurologic disorders. High Trib2-specific antibody titers correlated withmore severe cataplexy.[25]

The autoimmune model of narcolepsy inspired trials of intravenous (IV) immunoglobulin (IVIG) therapy innarcoleptic patients with low levels of hypocretin-1. In these trials, IVIG reportedly improved cataplexyand sleepiness in many cases, but the effects did not last long. IVIG did not normalize CSF hypocretinlevels, except in 1 patient.[26] In 2 children given IVIG early after diagnosis of narcolepsy, the cataplexyand sleepiness improved, but some components of the disease worsened in 1 child .[27]

Genetic factors

The genetics of narcolepsy are complex. Whereas the concordance is only 35% in monozygotic twins, therisk is as high as 40% in first-degree relatives.[28]Narcolepsy with cataplexy can be produced in animalmodels by disrupting the gene that encodes the hypocretin (orexin) receptor or ligand gene, therebydisrupting hypocretin neurotransmission.[12]

There is a striking association between narcolepsy and the HLA haplotype DQA1*01:02-DQB1*06:02. Astudy in individuals of European descent found that nearly all of those with a diagnosis of narcolepsy withcataplexy carry the HLA haplotype DQA1*01:02-DQB1*06:02, compared with only 24% of the general


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population.[29] Thus, carriage of this haplotype may be necessary but not sufficient for the development ofnarcolepsy.

A study of genome-wide expression in narcolepsy patients and controls showed an independent effect ofallelic dosage of DQB1*06:02 on DQB1*06:02 mRNA levels and protein .[30] This finding supports thesuspicion 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. [30]

A genome-wide association study proposed a protective variant (DQB1*06:03). This allele may protectagainst autoimmune disorders; it is almost never seen in patients with narcolepsy.[31]

Genome-wide association studies in Caucasians, with replication in 3 ethnic groups, have revealedassociations between single-nucleotide polymorphisms (SNPs) in the T-cell receptor alpha locus andnarcolepsy.[32] This association further supports the autoimmune basis of narcolepsy.

An SNP in the purinergic receptor subtype P2Y11gene (P2RY11) also appears to be associated withnarcolepsy.[33] P2RY11 has been identified as an important regulator of immune cell survival; the disease-associated P2RY11correlates with a 3-fold lower expression of P2RY11 in CD8+ T-cells and natural killercells, as well as with decreased P2RY11-mediated resistance to adenosine triphosphateinduced deathin those cells.

A genome-wide association study that investigated 202 candidate genes in a replication study in 222narcoleptic patients and 380 controls identified 6 genes that were associated with narcolepsy: NFATC2,SCP2, CACNA1C, TCRA, POLE, andFAM3D. These gene associations with narcolepsy were furthersupported by gene expression analyses showing that these same genes are also associated withessential hypersomnia, which is similar to narcolepsy.[34]

Epidemiology

United States statistics

The prevalence of narcolepsy in the US is 0.02-0.18%, which is comparable to that of multiple sclerosis.[35,36] The frequency among first-degree relatives is 1-2% (10-40 times greater than that in the generalpopulation). 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.[37] The reported prevalence of narcolepsy inselect 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%[38]

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 highestpeak occurring at 15 years and a less pronounced peak occurring at 36 years. However, narcolepsy hasbeen reported in children as young as 2 years.


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Prognosis

With proper management and treatment, patients with narcolepsy usually lead meaningful and productivepersonal and professional lives. If left untreated, narcolepsy may be psychosociallydevastating.[39] Narcoleptic children may suffer poor school performance, social impairment, ridicule frompeers, 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 aconsequence of either the disease itself or its treatment.

Job impairment may result from sleep attacks, memory problems, cataplexy, interpersonal problems, andpersonality 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% wereterminated from their jobs because of their disease.

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

Patient Education

Educate patients, parents, teachers, and other care providers concerning the symptoms, prognosis, andsafety precautions. Advise patients of the increased risk of sleep-related driving accidents. Advisepatients 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 haveguidelines, as does the United Kingdom, but whether such guidelines are effective in reducing traffic-related morbidity is unknown.[40]

For patient education information, see theSleep Disorders Center,as well asNarcolepsy.
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