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  • Updated 04.11.2021
  • Released 07.22.1994
  • Expires For CME 04.11.2024

Narcolepsy

Introduction

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 involving 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. In the United States, the annual direct medical costs are 2-fold higher in patients with narcolepsy than in matched controls without narcolepsy ($11,702 vs. $5261, respectively; P < .0001) (116).

Key points

• Narcolepsy is characterized by excessive daytime sleepiness.

• The classic form of narcolepsy (narcolepsy type 1) features cataplexy, sleep paralysis, and hypnagogic hallucinations, in addition to excessive daytime sleepiness.

• Some patients with otherwise typical features of narcolepsy do not have cataplexy; this is a condition referred to as narcolepsy type 2, also known as narcolepsy without cataplexy and in the past monosymptomatic narcolepsy.

• Pediatric narcolepsy has clinical features that may differ from those in the adult, masquerading as behavioral alterations or attention-deficit/hyperactivity disorder.

• 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.

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 (96). Excessive sleepiness has been noted by physicians for centuries. Caffe and Foot described pathologic sleepiness (26; 44); subsequently, Westphal and Fischer reported episodic loss of muscle tone associated with sleepiness (122; 43). 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 (47). Lowenfeld introduced the term “Kataplectische Starre” (cataplectic spells) to describe these atonic episodes (71). The term "sleep paralysis" was introduced by Kinnier Wilson, although the phenomenon had been described as "night palsy" by Weir Mitchell in 1876 (123). Adie suggested that narcolepsy was a specific disease entity as opposed to a heterogeneous syndrome (01).

Subsequently, Yoss and Daly (126) 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 (118). Three reports published in 1963 confirmed the discovery (100). The first consensus definition of narcolepsy was adopted by participants of the First International Symposium on Narcolepsy in 1975 (92).

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 (67) and in knockout mice with narcolepsy (27). Selective loss of hypocretin immunoreactivity has been reported in the hypothalamus of humans (94; 115). 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 (85).

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 (04). The National Institute of Neurological Disorders and Stroke has published a fact sheet on narcolepsy (88).

ICDS-3 classification

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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