Etiology
The etiology is unknown at present.
Central nervous system (CNS) pathology, such as head trauma, stroke, brain or hypothalamic tumors, CNS infections or inflammation, arteriovenous malformations or CNS cysts, and multiple sclerosis, have been reported to lead to narcolepsy syndromes.[6][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Paraneoplastic anti-Ma antibodies have been found to be associated with narcolepsy, especially associated with germ cell testicular tumors.[22][32][33][34] An association with Niemann-Pick disease type C, Norrie disease, and Prader-Willi syndrome has also been reported.[35][36][37][38]
A genetic predisposition for narcolepsy has been found.[1]
Most cases of narcolepsy are sporadic; however, there are familial clusterings suggesting either a genetic or an environmental link.[39][40]
Pathophysiology
Several pathophysiologic mechanisms have been proposed, including:
Hypocretin (orexin) deficiency[1]
Hypocretin (orexin) deficiency is a clinical marker of narcolepsy type 1, and is caused by the loss of hypocretin-producing neurons in the hypothalamus. A causal relationship between hypocretin signaling deficiency and narcolepsy is established, as animal models without hypocretin neurotransmission display narcolepsy.[41] Autoimmune processes caused by variants of the human leukocyte antigen (HLA) gene are a likely etiologic mechanism that may explain the targeted destruction of hypothalamic hypocretin-producing cells.[42]
Other autoimmune processes:
Some people with narcolepsy have elevated levels of anti-Tribbles homolog 2 antibodies (Trib2).[43][44][45][46]
Anti-streptococcal antibodies seem to be elevated at disease onset.[47][48]
Interleukin 6, C-reactive protein, tumor necrosis factor (TNF) alpha receptor, and possibly TNF alpha seem to be elevated in serum of people with narcolepsy.[49][50][51]
In Japan, polymorphisms of TNF alpha receptor are linked to narcolepsy.[52]
Intravenous immunoglobulins seem to improve hypocretin levels and cataplexy.[53][54]
Genetic predisposition
Although not diagnostic for narcolepsy type 1, the human leukocyte antigen (HLA) HLA-DQB1*0602 haplotype has been found to be present in nearly all patients with narcolepsy and cataplexy upon HLA typing.[1] In a small portion of patients with narcolepsy type 2, cataplexy develops later and diagnosis changes to narcolepsy type 1: all these patients are HLA-DQB1*0602 positive. In patients with narcolepsy but not cataplexy, around 15% to 20% have hypocretin deficiency, and nearly all are HLA-DQB1*0602 positive. In contrast, the allele is present in 12% to 38% of the general population.[1]
Genome-wide association studies in narcolepsy have also found associations with T-cell receptor loci (TRA [MIM 186880], TRB [MIM 186930]), IL10RB [MIM 123889], IFNAR1 [MIM 107450], CTSH [MIM 116820], P2RY11 [MIM 602697], and ZNF365 [MIM 607818].[55][56][57] These findings suggest autoimmune-mediated hypocretinergic neuronal destruction that might involve antigen presentation by DQ0602 to CD4+ T cells.
One study has reported that 8 Japanese families with narcolepsy showed linkage to a site on chromosome 4p13-q21, which may act in concert with the HLA-signaled predisposition.[58]
Linkage disequilibrium with sites on chromosome 6 (near the HLA region) or chromosome 21 has been proposed as a predisposing factor for narcolepsy.[59][60]
Cholinergic hypersensitivity[61]
Serotonin or norepinephrine pathway-specific dysfunction[62][63]
Dopamine pathway dysfunction[64]
Classification
International classification of sleep disorders - third edition, text revision (ICSD-3-TR)[1]
Narcolepsy type 1 (with hypocretin deficiency)
Narcolepsy type 2 (without hypocretin deficiency)
Narcolepsy type 1 or type 2 due to medical conditions
See Diagnostic criteria for details of criteria.
Diagnostic and statistical manual of mental disorders, 5th edition, Text Revision (DSM-5-TR)[2]
A sleep-wake disorder characterized by recurrent periods of an irrepressible need to sleep, lapsing into sleep, or napping, occurring within the same day. These periods have occurred at least three times per week over the past three months with the presence of at least one of the following:
episodes of cataplexy occuring at least a few times per month
in individuals with long standing disease, brief (seconds to minutes) episodes of sudden bilateral loss of muscle tone with maintained conscious that are precipitated by laughter or joking
in children or individuals within 6 months of onset, spontaneous grimaces or jaw-opening episodes with tongue thrusting or a global hypotonia, without any obvious emotional triggers
cerebrospinal fluid hypocretin deficiency
rapid eye movement sleep latency ≤15 minutes on nocturnal polysomnography, or mean sleep latency ≤8 minutes on multiple sleep latency testing with ≥2 sleep-onset REM-sleep periods
Subtypes include:
Narcolepsy with cataplexy but without hypocretin deficiency
Narcolepsy without cataplexy and either without hypocretin deficiency or hypocretin unmeasured
Narcolepsy with cataplexy or hypocretin deficiency due to a medical condition
Narcolepsy without cataplexy and without hypocretin deficiency due to a medical condition
Severity defined as:
Mild: Need for naps only once or twice per day. Sleep disturbance, if present, is mild. Cataplexy, when present, is infrequent (occurring less than once per week).
Moderate: Need for multiple naps daily. Sleep may be moderately disturbed. Cataplexy, when present, occurs daily or every few days.
Severe: Nearly constant sleepiness and, often, highly disturbed nocturnal sleep (which may include excessive body movement and vivid dreams). Cataplexy, when present, is drug-resistant, with multiple attacks daily.
Narcolepsy classification based on etiology[3][4][5][6]
Primary
Secondary to medical disorders; for example:
Central nervous system (CNS) disorders: head trauma, encephalomyelitis, CNS tumors, multiple sclerosis
Muscle disorders: myotonic dystrophy
Prader-Willi syndrome
Niemann-Pick type C
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