Narcolepsy

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.

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]

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.

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.

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.