Narcolepsy and Other Disorders of Excessive Daytime Sleepiness

By | March 12, 2015

Narcolepsy is a prime example of a disorder with dysfunction of a specific sleep state, in this case REM sleep. Isolated fragments of REM sleep intrude into wakefulness, and the result is the characteristic symptoms that invariably cause excessive daytime sleepiness. Narcolepsy in humans was first described in 1880 by the French neurologist Gelineau. Since that time, this sleep disorder has been observed in several dog breeds as well as in horses and sheep. These naturally occurring animal models have greatly facilitated investigations into the pathophysiological mechanisms of narcolepsy.

Prevalence

Narcolepsy is a more common disorder than many recognize. As a result, the need to identify and treat it offers a valuable opportunity to prevent medical, occupational, and social complications. When patients present with sleepiness, many other conditions, including insufficient sleep and breathing-related sleep disorder, are suspected before narcolepsy is considered. The average delay between onset of symptoms and diagnosis is 10 years.

In a U.S. community sample, narcolepsy was observed to have prevalence of 0.06%. All cases of narcolepsy met the diagnostic criteria on the basis of excessive daytime sleepiness and laboratory findings. In 64% of these cases the patient had cataplexy. Incidence data from the same study confirmed the long-standing impression that narcolepsy is slightly more common in men (1.72 per 100,000) than women (1.05 per 100,000). The disease most commonly starts in the second decade of life and is a chronic condition.

Narcolepsy is no longer believed to be a familial disease, although a small number of affected families have been identified. When narcolepsy is familial, the mode of inheritance is not a simple recessive or dominant one. The debate centers on whether narcolepsy is the result of an autoimmune or neurodegen-erative process. The association between 85% of cases of narcolepsy with cataplexy and a specific HLA allele (DQB 1*0602) is the basis of postulation about an autoimmune mechanism; despite several investigations, no confirmatory evidence had been found as of early 2004. The possibility of the presence of an extremely selective degenerative process stems from the autopsy finding of gliosis in the hypothalamus of narcolepsy patients.

Clinical Features

Narcolepsy is characterized by chronic excessive daytime sleepiness with episodic sleep attacks. Approximately 65%-75% of patients with narcolepsy have cataplexy, which is a condition in which an emotional trigger, most commonly laughter, provokes abrupt muscle atonia without loss of consciousness. Other associated symptoms of narcolepsy include sleep paralysis (isolated loss of muscle tone associated with REM in normal sleep) and hypnagogic and hypnopompic hallucinations (vivid dreaming occurring at the time of sleep onset and awakening that can be difficult to distinguish from reality). When related to the dissociated components of REM sleep, such as muscle atonia (cataplexy and sleep paralysis) and vivid dreams (hypnagogic and hypnopompic hallucinations), these phenomena can intrude into wakefulness. Disturbed nocturnal sleep has been added as a fifth part of this constellation of symptoms.

Pathophysiological Mechanism

In 2000, patients with narcolepsy were reported to have undetectable levels of a newly identified neuropeptide, hypocretin (also known as orexin), in cerebrospinal fluid. Hypocretin is synthesized by a small number of neurons in the anterior hypothalamus that project widely throughout the central nervous system (CNS). After studies of other sleep and neurological disorders, the absence of this neuropeptide appears to be highly specific (99%) for narcolepsy. Hypocretin influences sleep, appetite, and temperature. As of early 2004, the relevance of hypocretin as a neuromodulator in diseases other than narcolepsy was unknown. The genes for the ligands and receptors for hypocretin have been knocked out in mice with the development of excessive sleepiness, cataplexy, and obesity.

Investigation

The most important part of an evaluation for narcolepsy is a careful interview conducted as a screen for longstanding excessive daytime sleepiness and spells triggered by emotions. The definitive bedside test for cataplexy is demonstrating the transient absence of deep tendon reflexes during the episode. This procedure also aids in differentiating cataplexy from pseudocataplexy. However, cataplexy is difficult to provoke, and the episode is often too shortlived to allow a physical examination.

In most cases diagnostic testing in a sleep disorders center is necessary to supplement the clinical interview. The diagnosis must be as certain as possible before a life-long course of treatment is begun. An overnight sleep study is important for ruling out other causes of excessive daytime sleepiness. This study is ideally preceded by wrist ac-tigraphy to confirm adequate sleep in the weeks before testing and to eliminate sleep deprivation as the cause. If polysomnography reveals that the patient has obstructive sleep apnea or another primary sleep disorder, these conditions must be stabilized before reliable daytime testing can be conducted. The multiple sleep latency test quantifies the time to fall asleep during daytime naps and confirms the presence of inappropriate daytime REM sleep. Testing for hypocretin in the cerebrospinal fluid is not yet part of clinical practice.

Complications

Narcolepsy is associated with a reduction in quality of life beyond that of epilepsy. Without treatment, patients are at risk of motor vehicle accidents and occupational injuries related to sleepiness. Patients with narcolepsy have a higher-than-expected rate of obstructive sleep apnea, REM sleep behavior disorder, and periodic limb movements. New data indicate that patients with narcolepsy have higher rates of obesity, which may be linked to the hypocretin deficiency. Current pharmacological treatments for sleepiness do not appear to have a significant mitigating effect on weight gain.

Treatment

Treatment options for narcolepsy include methylphenidate or amphetamines, which target excessive daytime sleepiness. More-extended-release preparations of methylphenidate and amphetamines have the advantage of continuous drug delivery, which reduces the daytime variability in alertness that may occur with the immediate-release forms, which are taken twice or three times a day. Modafinil is a unique wake-promoting medication that was approved by the U.S. Food and Drug Administration (FDA) in 1999. Modafinil is not considered a psychostimulant and lacks sympathomimetic activity, and the mechanism of action is not well understood (. The newest treatment option is sodium oxybate (also known as gamma-hydroxybutyrate), which was approved by the FDA in 2002. This novel hypnotic is approved specifically for the treatment of cataplexy. An endogenous substance, sodium oxybate increases the amount of slow wave sleep and improves the continuity of sleep. Improving the quality of nocturnal sleep appears to reduce the severity of all of the classic narcolepsy symptoms. Because of the expense and inconvenience of consuming a liquid medication at sleep onset and 4 hours later, this medication is reserved for patients whose condition is more refractory to treatment. Taken as prescribed, sodium oxybate is well tolerated in general. Risks arise from combining it with other sedative agents and taking it in excessive amounts. Tricyclic antidepressants and, to a lesser degree, selective serotonin reuptake inhibitors (SSRIs) historically have been used to treat cataplexy. These agents increase the level of norepinephrine in the brain and thus suppress REM sleep-related symptoms. Patient education should emphasize the importance of a consistent sleep-wake schedule, the need for adequate sleep, the value of brief daytime naps, and refraining from driving a car when sleepy.

 

Selections from the book: “Textbook of Psychosomatic Medicine”, 2005.