Epidemiology and Clinical Features

Narcolepsy is a disabling sleep disorder characterized by severe excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations including cataplexy, sleep paralysis, hypnagogic hallucinations, and sleep onset REM periods (American Academy of Sleep Medicine 2005; Dauvilliers, Billiard, and Montplaisir 2003b; Scammell 2003). Recent advances in pathophysiology demonstrated that narcolepsy is caused by the loss of hypothalamic neurons producing hypocretin (Mignot et al. 2002; Dauvilliers et al. 2003a; Peyron et al. 2000; Thannickal et al. 2000; Crocker et al. 2005; Blouin, Thannickal, Worley, Baraban, Reti, and Siegel 2005). Epidemiological data with a young and bimodal age at onset, frequent triggering factors and a tight HLA DQB1*0602 association, suggest an autoimmune hypothesis (Mignot, Tafti, Dement, and Grumet 1995; Carlander, Dauvilliers, and Billiard 2001; Chabas, Taheri, Renier, and Mignot 2003). Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons, in response to yet unknown environmental factors, is the most probable hypothesis. The treatment of narcolepsy has evolved significantly over the last few years, but current therapies are only symptom-based. Hypocretin-based therapies and immune-based therapies are part of the research projects for the development of new treatments in narcolepsy (Dauvilliers and Tafti 2006).

The prevalence of narcolepsy with cataplexy was estimated between 0.05 and 0.067% in the United States (Dement, Carskadon, and Ley 1973), with same results in other countries (Hublin et al. 1994; Ohayon, Priest, Zulley, Smirne, and Paiva 2002), except in Japan with a higher prevalence (Honda 1979) and in Israel with a lower prevalence (Lavie and Peled 1987). One study reported an incidence of 1.37 in 100,000 inhabitants per year (Silber, Krahn, Olson, and Pankratz 2002). There are epidemiological evidences of an immune etiology in narcolepsy, the young and bimodal age at onset (Dauvilliers et al. 2001a), the frequent onset of symptoms after a major circumstance such as psychological stress or an abrupt change of sleep schedules (Orellana, Villemin, Tafti, Carlander, Besset, and Billiard 1994), the low concordance rate of monozygote twins (Dauvilliers et al. 2004c; Mignot 1998) and the tight association with HLA DQB 1*0602 (see below) (Mignot, et al. 2001). Recently, few studies have revealed a March peak and a September trough in the birth pattern of narcolepsy patients with clear-cut and frequent cataplexy (Dauvilliers et al. 2003c; Picchioni, Mignot, and Harsh 2004). Therefore, environmental events during early development may influence narcolepsy severity or the likelihood of developing the disease that also may suggest an autoimmune etiology. In contrast to most other well-defined autoimmune disorders, there is no clear association with other autoimmune diseases, no predominance of female and any blood or CSF inflammatory markers (Dauvilliers, Billiard, and Montplaisir 2003b; Mignot et al. 1995; Dauvilliers and Tafti 2006).

20.1.1 Excessive Daytime Sleepiness

Daytime sleepiness is the most severe symptom, the most frequent cause for consultation and mostly the first symptom to appear (Dauvilliers et al. 2003b; Scammell 2003). Daytime sleepiness occurs daily, recurring typically at 2-h intervals, exacerbated during inactivity, with large variability between patients. Most of those sleep episodes are irresistible, of short duration and frequently associated with dreaming. Except in cases of children, the refreshing value of short naps is of significant diagnostic value. Severe sleepiness can also lead to unconscious microsleep episodes or lapses.

20.1.2 Cataplexy

Cataplexy is a sudden loss of voluntary muscular tone, without any alteration of consciousness, in relation with strong emotive reactions such as laughter, joking, All striated muscles (but not the diaphragm) can be affected leading to a progressive collapse of the subject. Cataplexy is specific to narcolepsy and is the best diagnostic marker of the disease (Dauvilliers et al. 2003b; Scammell 2003). The duration of cataplexy varies from a second to one or two minutes and its frequency varies from less than one episode per year to several episodes per day. Patients may also rarely experience "status cataplecticus" characterized by long episodes of cataplexy lasting to several hours. Several neurophysiological and pharmaceutical findings suggest that cataplexy is equivalent to the loss of muscle tone of REM sleep occurring during the waking state (Dauvilliers et al. 2003b; Scammell 2003).

20.1.3 Associated Features

Other symptoms of dissociated REM sleep experienced by narcoleptic patients include sleep-related hallucinations and sleep paralysis characterized by an inability to move the limbs or the head either at sleep onset or upon awakening. Auditory, visual, somesthetic hypnagogic (at sleep onset) or hypnopompic (upon awakening) hallucinations, or sleep paralysis are present in around 50% of narcoleptic patients (Dauvilliers et al. 2003b; Scammell 2003), therefore more frequent than in the general population (Ohayon 2000).

Nocturnal sleep is also disrupted with frequent sleep awakenings, usually worsening with advancing age (Dauvilliers et al. 2003b). Finally, patients with narcolepsy are frequently associated with a high body mass index and with a rapid weight gain at onset of the condition (Kotagal, Krahn, and Slocumb 2004).

20.1.4 Diagnostic Criteria

The diagnosis of narcolepsy with cataplexy is essentially clinical. In the recent International Classification of Sleep Disorders (American Academy of Sleep Medicine 2005), the diagnosis of narcolepsy with cataplexy is based on the presence of both excessive daytime sleepiness (occurring almost daily for at least 3 months) and clear-cut history of cataplexy. Unfortunately, cataplexy rarely occurs in the presence of the clinician, and a clear history is not always possible. It is therefore recommended to confirm the clinical diagnosis with a nocturnal polysomnography followed by a daytime multiple sleep latency test (MSLT) (American Academy of Sleep Medicine 2005), during which sleep latency should be below 8 min with at least two sleep onset REM period (SOREMP). This criterion may, however, be absent in young children, elderly and in rare patients with clear-cut cataplexy (Dauvilliers, Gosselin, Paquet, Touchon, Billiard, and Montplaisir 2004b).

The presence of the human leukocyte antigen HLA DQB1*0602 genotype, as it is neither sensitive nor specific in narcolepsy (see below), is only a supportive criterion. HLA DQB1*0602 is neither necessary, nor sufficient for the development of the disease. CSF hypocretin-1 levels lower than 110 pg/ml or one-third of mean normal control values are alternatively proposed as a definite diagnostic criteria (American Academy of Sleep Medicine 2005).

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