Narcolepsy

Abstract

T h e ne w e ngl a nd jou r na l o f m e dicine n engl j med 373;27 nejm.org December 31, 2015 2654 Review Article N arcolepsy, one of the most common causes of chronic sleepiness, affects about 1 in 2000 people. Despite the frequency of narcolepsy, the average time from the onset of symptoms to diagnosis is 5 to 15 years, and narcolepsy may remain undiagnosed in as many as half of all affected people with narcolepsy, since many clinicians are unfamiliar with this disorder. 1 Fortunately, awareness of narcolepsy and other sleep disorders is increasing, and over the past several years researchers have made great progress in understanding narcolepsy. Clinicians now recognize two types of narcolepsy. Type 1 is caused by extensive loss of hypothalamic neurons that produce the neuropeptides orexin-A and -B (also referred to as hypocretin-1 and -2); type 2 includes most of the same symptoms, but its cause is unknown. This review focuses on the symptoms and pathologic and neurobiologic features of narcolepsy and provides a framework for diagnosis and effective treatment. S ymp t omsNarcolepsy usually begins between the ages of 10 and 20 years with the sudden onset of persistent daytime sleepiness, although it can also develop gradually. In many persons with narcolepsy, the sleepiness is severe, resulting in difficulty focusing and staying awake at school, at work, and during periods of inactivity (e.g., when watching a movie). Quite often, the diagnosis is made only after serious problems have arisen, such as declining grades at school, poor performance at work, or a motor vehicle accident. Although it may appear to be challenging to distinguish daytime sleepiness due to narcolepsy from that caused by insufficient sleep, especially in teenagers, people with narcolepsy are sleepy every day, even with adequate nighttime sleep. In contrast to people with disorders such as obstructive sleep apnea who have poor-quality sleep, those with narcolepsy usually feel refreshed after a full night's sleep or a brief nap, but their sleepiness returns 1 to 2 hours later, especially when they are sedentary. Narcolepsy is also characterized by disordered regulation of rapid-eye-movement (REM) sleep. REM sleep normally occurs only during the usual sleep period and includes vivid, storylike dreams, rapid (saccadic) eye movements, and paralysis of nearly all skeletal muscles, except the muscle of respiration. REM sleep can occur in persons with narcolepsy at any time of day, and the classic elements of REM sleep often intrude into wakefulness, creating peculiar intermediate states.The most dramatic of these REM sleep-like states is cataplexy -sudden episodes of partial or complete paralysis of voluntary muscles. These episodes are triggered by strong emotions (Fig. 1), most often by positive emotions such as those associated with laughing at a joke or unexpectedly encountering a friend. In some people, however, cataplexy can be triggered by intense negative emotions, such as frustration or anger. The paralysis usually evolves over many seco...

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

“…People with narcolepsy are prone to gaining weight (11). Rodent models of narcolepsy also tend to develop late onset obesity (23,24).…”

“…Nevertheless, the present study demonstrates the utility of orexindeficient and orexin receptor-deficient mouse models to assess pharmacological and mechanistic approaches for the treatment of narcolepsy. There have been several investigations published in this regard (11,28,29), but our study is distinct in treating the core defect in narcolepsy as opposed to other studies that assess drug effects on narcolepsy symptomatology.…”

“…However, patients with narcolepsy type 2 show no cataplexy and normal orexin-A levels in CSF. Narcolepsy-cataplexy, or narcolepsy type 1 (11), is characterized by a marked instability of sleep/ wake state transitions, resulting in nonrapid eye movement (NREM) sleep-related symptoms (e.g., excessive daytime sleepiness, "sleep attacks," and fragmented nighttime sleep), and rapid eye movement (REM) sleep-related symptoms (e.g., cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations). In polysomnography, narcolepsy-cataplexy patients show markedly reduced daytime sleep latency, and sleep-onset REM periods (SOREMs).…”

Orexin/Hypocretin and Organizing Principles for a Diversity of Wake-Promoting Neurons in the Brain

“…Most of us take this rapid wakefulness adjustment for granted, assuming that we will not fall asleep in the middle of laughing or talking. This is not so for patients suffering from the sleep-wake disorder narcolepsy, which affects about 1:2000 people and where sleep and paralysis suddenly and uncontrollably intrude into normal wakefulness [2,3]. Most cases of human narcolepsy are associated with reduced levels of orexin/hypocretin peptides in the CSF and lack of central orexin/ hypocretin-producing neurons in the brain [4][5][6][7].…”

Measurement of narcolepsy symptoms: the narcolepsy severity scale

“…1,2 Disrupted nighttime sleep is also frequent and should be considered as the fifth narcolepsy symptom. Following the breakthrough discovery of hypocretin deficiency, narcolepsy with cataplexy was recently renamed Narcolepsy Type 1 (NT1, or hypocretin-deficiency syndrome), according to the third edition of the International Classification of Sleep Disorders.…”