Narcolepsy

Antonio Culebras MD (Dr. Culebras of SUNY Upstate Medical University has no relevant financial relationships to disclose.)
Originally released July 22, 1994; last updated January 29, 2017; expires January 29, 2020

Overview

In this article, the author reviews the current information on narcolepsy, a disease that has progressed in only 50 years from a quasi-psychiatric condition to a true neurologic disorder. New knowledge of the etiology and mechanism of the disease relative to the hypocretins has opened a major pathway to understanding excessive sleepiness not only in narcolepsy but also in other sleep disorders. Most cases of narcolepsy with cataplexy are associated with the loss of approximately 50,000 to 100,000 hypothalamic neurons containing hypocretin. Pharmacologic treatment remains symptomatic but increasingly effective.

Key points

 

• Narcolepsy is characterized by excessive daytime sleepiness.

 

• The classic form of narcolepsy (narcolepsy type 1) features cataplexy, sleep paralysis, and hypnagogic hallucinations.

 

• Some patients with otherwise typical features of narcolepsy do not have cataplexy; this is a condition referred to as monosymptomatic narcolepsy or narcolepsy without cataplexy (narcolepsy type 2).

 

• The observation that narcolepsy was associated with human leukocyte antigens (HLA)-DR2 was the first indication of a biologically based source.

 

• The discovery of a significant decrease of the neurotransmitter hypocretin-1 levels in cerebrospinal fluid in patients with narcolepsy-cataplexy provided a new test to diagnose the condition.

 

• Administration of gamma hydroxybutyrate (GHB) (sodium oxybate) has been confirmed as an efficacious treatment of narcoleptic symptoms.

Historical note and terminology

It is plausible that Dante's sleep, dreams, hallucinations, and falls are clues to a lifelong pathologic trait and that Dante may have known of or had narcolepsy (Plazzi 2013). Excessive sleepiness has been noted by physicians for centuries. Caffe and Foot described pathologic sleepiness (Caffe 1862; Foot 1866); subsequently, Westphal and Fischer reported episodic loss of muscle tone associated with sleepiness (Westphal 1877; Fischer 1878). Gelineau introduced the term "narcolepsy," derived from the Greek words narcos meaning somnolence and lepsy meaning seized, in his description of sleep attacks and muscle weakness following intense emotion in a 38-year-old wine barrel retailer (Gelineau 1880). Lowenfeld introduced the term “Kataplectische Starre” (cataplectic spells) to describe these atonic episodes (Lowenfeld 1902). The term "sleep paralysis" was introduced by Kinnier Wilson, although the phenomenon had been described as "night palsy" by Weir Mitchell in 1876 (Wilson 1928). Adie suggested that narcolepsy was a specific disease entity as opposed to a heterogeneous syndrome (Adie 1926).

Subsequently, Yoss and Daly (Yoss and Daly 1957) described the classic narcoleptic tetrad of hypnagogic hallucinations, sleep paralysis, excessive sleepiness, and cataplexy. In 1960 Vogel reported the occurrence of REM sleep at the onset of sleep in a single narcoleptic subject (Vogel 1960). Three reports published in 1963 confirmed the discovery (Rechtschaffen et al 1963). The first consensus definition of narcolepsy was adopted by participants of the First International Symposium on Narcolepsy in 1975 (Passouant 1976).

The observation that narcolepsy was associated with human leukocyte antigens (HLA)-DR2 was the first indication of a biologically based source. In 1999, independent observers discovered abnormal hypocretin (Hcrt) (orexin) neurotransmission in a canine model of narcolepsy (Lin et al 1999) and in knockout mice with narcolepsy (Chemelli et al 1999). Selective loss of hypocretin immunoreactivity has been reported in the hypothalamus of humans (Peyron et al 2000; Thannickal et al 2000). The discovery of a significant decrease of Hcrt-1 levels in CSF in patients with narcolepsy cataplexy provided a new test to diagnose the condition (Mignot et al 2002).

The ICDS-3 classifies narcolepsy within the central disorders of hypersomnolence. It makes a further subclassification as follows: narcolepsy type 1 and narcolepsy type 2 (American Academy of Sleep Medicine 2014).

Table 1. Narcolepsy Type 1

 

• Criteria A and B must be met.

   

A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months.

   

B. The presence of 1 or both of the following:

     

1. Cataplexy and a mean sleep latency of less than or equal to 8 minutes and 2 or more sleep onset REM periods (SOREMPs) on a multiple sleep latency test (MSLT) performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may replace 1 of the SOREMPs on the MSLT.

     

2. CSF hypocretin-1 concentration, measured by immunoreactivity, is either less than or equal to 110 pg/mL or less than one third of mean values obtained in normal subjects with the same standardized assay.

 

• Patients with sleepiness and low or absent CSF hypocretin-1 levels are classified as having narcolepsy type 1, even if they do not manifest cataplexy.

Table 2. Narcolepsy Type 2

 

• Criteria A to E must be met.

   

A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months.

   

B. A mean sleep latency of less than or equal to 8 minutes and 2 or more sleep onset REM periods (SOREMPs) are found on a MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may replace 1 of the SOREMPs on the MSLT.

   

C. Cataplexy is absent.

   

D. Either CSF hypocretin-1 concentration has not been measured or CSF hypocretin-1 concentration measured by immunoreactivity is either greater than 110 pg/mL or greater than one third of mean values obtained in normal subjects with the same standardized assay.

   

E. The hypersomnolence and/or MSLT findings are not better explained by other causes such as insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal.

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