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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE - Based on reviews from literature on Sleep Disorders

May 2010

Reviewed and edited by:

Brian J. Murray, MD, FRCPC, DABSM

Neurology and Sleep Medicine, Sunnybrook Health Sciences Centre, Assistant Professor, University of Toronto, Toronto, Ontario

Thomas E. Scammell, MD

Associate Professor of Neurology, Harvard Medical School, Boston, Massachusetts

Narcolepsy: How often is the Diagnosis Missed?

Narcolepsy, although uncommon, is not a rare disorder. The estimated prevalence differs across populations and is estimated to be about 1 in 2000 individuals in the US and Europe,^1,2 a figure that would extrapolate to about 15,000 patients in Canada. However, it is suspected that narcolepsy is often misdiagnosed or undiagnosed, so the actual prevalence may be higher than many clinicians appreciate.³ Narcolepsy usually begins during the second decade of life,⁴ but it can begin in young childhood or after the age of 40. In a study conducted in France and Canada, the first of two age-related prevalence peaks occurred in the second decade, but a second peak occurred at about age 35 in both countries.⁵

The Four Classic Symptoms

The classic tetrad of narcolepsy symptoms includes, in addition to excessive daytime sleepiness (EDS), cataplexy, hallucinations and sleep paralysis (Table 1).⁶

Table 1.

Cataplexy is defined by sudden partial or complete loss of voluntary muscle control⁷ triggered by a strong emotion such as laughter or anger. The vivid hallucinations encountered in narcolepsy generally occur during the transitions between wakefulness and sleep, and are often frightening but recognizable as unreal. Sleep paralysis is a temporary inability to move or speak upon awakening that lasts for a minute or two. While all individuals with narcolepsy have some degree of EDS, concomitant cataplexy has been reported in up to 60% of patients.^4,8 When cataplexy is the main complaint, the risk of a delayed diagnosis of narcolepsy may be increased.⁹ The proportion of individuals who present with all four symptoms is relatively modest.¹⁰ The median interval between symptom onset and diagnosis in one study was 10.5 years.¹¹

Of all the symptoms of narcolepsy, EDS is the most commonly reported initial symptom, the most frequent reason to seek medical attention, and the greatest factor impairing daily activities.^12,13 EDS is characterized by a strong and often irresistible urge to doze off despite adequate sleep at night. The naps taken by individuals with narcolepsy are often restorative, but sleepiness may recur within a few hours. Naps, even when short, are frequently accompanied by dreams. The prominent association of EDS with dreaming is probably driven by a loss of regulation of rapid eye movement (REM) sleep, which allows REM sleep to occur soon after the onset of sleep at night and at any time of the day.¹⁴

The severity of EDS, measured with subjective scales such as the Epworth Sleepiness Scale (ESS), and objective tests such as the multiple sleep latency test (MSLT), may vary considerably between individuals and across the day. Many people with narcolepsy experience sudden or severe sleepiness that impairs tasks requiring sustained attention, such as schoolwork or driving a car. EDS is usually worst during periods of inactivity,¹³ and individuals with EDS may come to recognize their own vulnerable times so they can adjust their schedules accordingly. However, EDS often impairs quality of life, including social function due to how the sleepiness is perceived by others.^6,15

Cataplexy is one of the best diagnostic markers of narcolepsy as it occurs in almost no other disorder. The severity of cataplexy varies widely so that in some individuals, the attacks are limited to specific muscle groups such as those in the face, whereas others experience rapid loss of muscle tone in all limbs resulting in collapse.⁷ Episodes range in duration from a few seconds to a few minutes. In some cases, cataplexy is sufficiently subtle that patients may not volunteer this history without specific questions regarding weakness associated with emotional factors, such as laughter, surprise, anger or frustration. Cataplexy, like EDS, worsens in individuals who have fatigue from disrupted nocturnal sleep.⁷

Establishing the diagnosis of narcolepsy can be a challenge. The combination of EDS plus cataplexy is almost always due to narcolepsy.¹³ Hallucinations or sleep paralysis, though not unique to narcolepsy, can increase suspicion of the diagnosis. Still, polysomnography followed by the MSLT is fundamental in diagnosing most patients and also helps rule out other factors that could contribute to the patient’s sleepiness. In most people with narcolepsy, the daytime MSLT shows rapid entries into sleep and frequent episodes of REM sleep during the day.

Focus on Dominant Symptoms

There are a number of non-pharmacological approaches that can reduce EDS, but most patients also require medications to combat drowsiness. Of the non-pharmacologic approaches, most involve improving sleep routines, including getting sufficient sleep at night and scheduling naps in the day, which have been shown to reduce the burden of narcolepsy.¹⁶ For EDS, stimulants such as amphetamines have been widely used in the treatment of narcolepsy but these are associated with a variety of side effects, including headaches, insomnia and loss of appetite, and they pose some risk of abuse.17 More recently, guidelines have placed a greater emphasis on targeting therapies to specific symptoms, including wake-promoting drugs for EDS and agents that affect REM sleep to control cataplexy and other symptoms.¹⁸

According to most current guidelines, including those from the American Academy of Sleep Medicine and the European Federation of Neurological Sciences, modafinil is a first-line wake-promoting agent for individuals with narcolepsy (Table 2).^18,19 Although not effective against cataplexy, modafinil is well tolerated and has a low risk of abuse.²⁰ The mechanism of action for promoting wakefulness is not entirely clear, but animal studies suggest it enhances dopamine signalling.¹³ In addition to subjective improvements in EDS, several randomized, controlled studies have associated modafinil with objective improvements in measures of daytime sleepiness.^21,22 Unlike many other medications, modafinil has a specific indication for t
epsy.

Table 2.

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Similarly, many guidelines identify sodium oxybate as a first-line choice for the treatment of narcolepsy in individuals with both EDS and cataplexy.^18,19 Like modafinil, sodium oxybate, also known as gamma hydroxybutyrate (GHB), has been evaluated in a series of relatively large, randomized, placebo-controlled studies that have led to a specific indication for treatment of narcolepsy with cataplexy. In a multicentre study conducted in the US, the 9-g dose reduced cataplexy attacks by 69% relative to baseline at four weeks.²³ In an extension trial, the benefits persisted over 12 months with no evidence of tolerance or additional adverse effects.24 While additional studies have reaffirmed long-term efficacy,^25,26 one advantage of sodium oxybate over other options, such as amphetamines, is that abrupt cessation of this therapy does not lead to withdrawal symptoms.²⁷ It has also been shown to be effective for EDS in a study focused on this specific symptom.²⁸ The authors of the EDS study reported significant objective and subjective improvements in wakefulness relative to placebo in 228 patients. They emphasized that the efficacy of this agent against EDS and cataplexy had not been demonstrated in large studies with other agents.

Stimulants can also substantially reduce cataplexy.²⁹ Most guidelines list these drugs as second-line choices because of their potential adverse effects.^18,19 These include sympathomimetic side effects.³⁰ However, amphetamines can be potent wake-promoting agents and may be a reasonable choice in individuals with symptoms that do not improve much with first-line agents.

Outside of regulatory labelling, there are numerous agents included in current guidelines as having potential utility in the control of EDS, cataplexy or other symptoms of narcolepsy. These include a variety of antidepressants, such as venlafaxine, clomipramine and fluoxetine, which have also been associated with efficacy against both EDS and cataplexy;³² and selegiline, a monoamine oxidase inhibitor which may improve both EDS and cataplexy.^31,32

Due to the heterogeneity of symptoms and how they impact the lives of patients, there is no simple treatment algorithm that can be applied to all individuals with narcolepsy. Rather, treatment should be individualized, recognizing that patients who do not respond to first-line agents may require alternative agents, many of which do not now carry a specific indication for this disorder. Combined with behavioural approaches that minimize the impact of narcolepsy on daily activities, even patients with a significant disease burden can typically anticipate a good quality of life.

Summary

Narcolepsy, particularly when symptoms are mild to moderate, often remains undiagnosed by physicians unaccustomed to the manifestations of this disease. Including narcolepsy in the differential diagnosis of individuals complaining of excessive daytime sleepiness is the first step towards delivering effective therapy. Cataplexy also may go unrecognized unless specifically addressed when eliciting the patient’s history. First-line treatments for both EDS and cataplexy are often very effective. Initial treatment choice should be influenced by the dominant complaints, recognizing that there are many options for those unimproved by first-line agents.

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