A review with emphasis on narcolepsy-related excessive daytime sleepiness and cataplexy.

Narcolepsy is a chronic and substantially disabling medical condition characterized by overwhelming daytime sleepiness. It is difficult to put together an all-inclusive definition of narcolepsy due to its protean and evolving clinical presentation. The disorder can be difficult to recognize and treat, especially if the physician involved in the case is not updated on the appropriate diagnostic and therapeutic steps to reach optimal control of this condition. Narcoleptics endure the daunting challenge of living with their condition in the setting of insufficient resources and lack of understanding from the lay community.

Recent developments in the field of sleep medicine make it imperative to produce updated guidelines for the diagnosis and treatment of narcolepsy. The goal of this article is to provide practicing physicians with a brief overview of narcolepsy and an updated review of its pharmacotherapy.

Clinical Picture

In 1880, Dr Jean-Baptiste-Edouard Gelineau1 published the first case of a rare, sudden, and undeniable urge to sleep. Gelineau named this condition “narcolepsy.”

The patient with narcolepsy is caught in a vicious cycle of overwhelming sleepiness perpetuated by a disrupted nocturnal sleep architecture that is not conducive to restful sleep. Daytime functioning is severely affected by sleepiness, and this is further complicated by intrusion of rapid eye movement (REM) sleep phenomena in the awake state, making the patient literally “trapped in a land of bad dreams.”

The classic tetrad of narcolepsy symptoms includes:

1. Excessive daytime sleepiness (EDS).
2. Cataplexy: a sudden, partial, or complete loss of voluntary muscle tone in response to strong emotion.
3. Sleep paralysis during the transition from wakefulness to sleep or vice versa.
4. Hypnagogic or hypnopompic hallucinations: hallucinations occurring during the transition from wakefulness to sleep (hypnagogic) or from sleep to wakefulness (hypnopompic).

However, about 30% to 50% of patients with narcolepsy do not have all the above-mentioned symptoms at presentation. Patients can show nocturnal sleep disruption, insomnia, nightmares, REM behavior disorder, periodic limb movements during sleep, and automatic (“absent-minded”) behavior. Narcolepsy may present in a variety of forms or syndromes that include:

1. Narcolepsy with cataplexy.
2. Narcolepsy without cataplexy.
3. Familial narcolepsy.
4. Human leukocyte antigen (HLA) narcolepsy with normal cerebrospinal fluid (CSF) hypocretin-1.
5. Symptomatic narcolepsy.
6. Psychogenic narcolepsy.

Epidemiology

According to The International Classification of Sleep Disorders. Diagnostic & Coding Manual,2 narcolepsy with cataplexy affects 0.02% of the populations of the United States and Western Europe. Both sexes are affected with a slight preponderance of males. Cases of narcolepsy without cataplexy are seen in 10% to 50% of the narcoleptic population.

Diagnostic Tests

Careful documentation of clinical information from the patient and the patient’s close contacts, along with an array of diagnostic tests, will increase the chance of a correct diagnosis and minimize the risk of treatment mismanagement.3

The following three tests are used in diagnosis:

1. Nocturnal polysomnogram (PSG)4 with a minimum of 6 hours of uneventful sleep, followed by a multiple sleep latency test (MSLT)5 where the mean sleep latency is £ 8 minutes and the sleep onset REM periods (SOREMPs) are ? 2. The PSG should be preceded by a 2-week sleep log (and/or actigraphy) to avoid running the test in the setting of sleep deprivation. This log will also help in establishing the right timing of PSG lights on/lights off. The standard four two five MSLT nap opportunities should begin 1.5 to 3 hours after the final wake-up from the PSG.

2. A CSF hypocretin-1 test with a £ 110 pg/mL or a third of mean normal control values.6 Only a limited number of centers in the United States can test this marker locally; one of them is the Center for Narcolepsy at the Stanford University School of Medicine in California (www.med.stanford.eduschool/Psychiatry/narcolepsy/).

3. A genetic test for the HLA subtype DQB1*0602, which is the HLA subtype most specifically associated with narcolepsy. However, this HLA subtype can also be found in 12% to 38% of the general population. Typing of HLA is at best useful to exclude the diagnosis of narcolepsy in very selected cases or when a secondary etiology is suspected.2

Narcolepsy Therapy

Narcolepsy diagnosis and therapy are truly a blend of science, art, and compassion. Therapy must be comprehensive and should not be limited only to the pharmacologic approach. On the contrary, a number of other issues must also be addressed to successfully treat or prevent the devastating consequences of narcolepsy.7-9 Supporting the patient’s emotional, familial, and social dimensions, and advocating for medical insurance and occupational issues, should be part of the treatment plan. Physicians should encourage their patients to be actively involved in their own disease management, and both physicians and patients should be proactive in engaging in legislation initiatives and community awareness about narcolepsy.

Some medications for narcolepsy-related excessive daytime sleepiness

Narcolepsy Pharmacotherapy

The latest published American Academy of Sleep Medicine (AASM) guidelines for the treatment of narcolepsy date back to 2001.10 Since then, significant advances have been accomplished, and an updated consensus on the pharmacotherapy recommendations should be expected in the near future. A number of excellent reviews11-15 and editorials16 on the topic have been published over the last few years by experts in the United States and abroad. With the current developments in the field, no narcolepsy patient should be left treated with suboptimal regimens. It is also imperative to conduct adequately powered head-to-head clinical and cost-effectiveness studies comparing different wake-promoting medications to determine which agent(s) has the best safety and efficacy profile for narcolepsy symptoms.17 The “superior” psychostimulant should effectively promote wakefulness, have minimum impact on sleep, and show minimal tolerance, dependence, and withdrawal/rebound effect.

Narcolepsy-related EDS Rx

The treatment of EDS uses psychostimulants, which are drugs that produce a behavioral activation that is accompanied by an increase in arousal, motor activity, and alertness. They can be regarded as sympathomimetic (amphetamine, methylphenidate, dextroamphetamine, selegiline, pemoline) and non-sympathomimetic drugs (caffeine, modafinil).

Traditional sympathomimetic psychostimulants were for a long time the mainstay of therapy for narcolepsy-related EDS, even though there have been only a few randomized placebo-controlled trials with these drugs. They improve EDS and sleep onset latency time. Sympathomimetic drugs enhance monoamine neurotransmission (dopamine, noradrenaline, and serotonin) by increasing release and inhibiting reuptake of these neurotransmitters. Methylphenidate18 is the most frequently prescribed stimulant for narcolepsy in the United States, followed by dextroamphetamine (Disomer of amphetamine). Both have comparable effectiveness. Pemoline is a milder stimulant with a lower potency compared to the amphetamines. However, due to reported liver toxicity, it is now rarely used in clinical practice. Fortunately, the potential for abuse with sympathomimetic drugs is uncommon in patients with narcolepsy.

Caffeine is a natural alkaloid that acts as an adenosine receptor antagonist promoting wakefulness. There is evidence that activation of a subgroup of adenosine receptors causes an inhibition of cortical acetylcholine release, which may also contribute to promoting wakefulness. Caffeine is an inexpensive drug that may play a role in narcolepsy treatment, particularly in maintaining wakefulness between the daily dosing of other wakefulness promoters.13 However, there is little scientific data on the effect of caffeine on narcolepsy-related EDS19 as there have been no placebo-controlled trials of caffeine therapy in narcolepsy.

Modafinil (Provigil®) is an alertness-promoting agent of unclear mechanism of action. It is most likely involved in dopamine reuptake inhibition. Modafinil was approved by the Food and Drug Administration (FDA) in 1998, and has been shown to improve objective (MSLT and mean wakefulness test or MWT sleep onset latency) and subjective (Epworth Sleepiness Scale) measures of EDS in patients with narcolepsy.20,21 Modafinil is less potent than traditional sympathomimetic stimulants in promoting alertness, but it does not have their numerous side effects.22 Modafinil has no effect on cataplexy and has limited potential for abuse.23 It is considered first-line treatment for narcolepsy-related EDS. However, there is no data yet comparing the efficacy of modafinil to sympathomimetic psychostimulants in human narcolepsy. If necessary, changing therapy from sympathomimetic drugs to modafinil is safe and feasible.24

Sodium oxybate (Xyrem®), the sodium salt of gamma-hydroxybutyrate, was first approved for treatment of cataplexy. However, it has also shown beneficial effects on EDS in narcolepsy patients, and received additional FDA approval for this indication in November 2005.25,26 Further evidence of effectiveness in EDS has been recently published or is about to be published.27,28 Due to its potential for diversion and abuse, a centralized pharmacy (The Xyrem Success Program)29 distributes and monitors the medication. The program can be contacted at (866) 997-3688 or accessed through www.xyrem.com. It supplies physicians who prescribe sodium oxybate with educational materials and enrolls them into a registry. Specialized prescription forms are then provided, and, upon approval, the patient is contacted for delivery of the medication and counseling.

If treatment of EDS with modafinil or sodium oxybate alone is unsatisfactory, combining both of them or supplementing with “as needed” or appropriately scheduled traditional sympathomimetic psychostimulants is generally effective.

Armodafinil (Nuvigil®), the longer half-life enantiomer of modafinil, received an “approvable letter” from the FDA on May 1, 2006. Actual approval is contingent upon finalizing the product label. It is formulated to be effective over a shorter period,30 which should allow for multiple dosing during the day. Besides its effectiveness in treating EDS, preliminary data indicates that armodafinil does not affect intended sleep in narcoleptics and other patients with EDS.31

To date, there have been no head-to-head trials between sympathomimetic drugs, caffeine, modafinil, and sodium oxybate that look at the efficacy and long-term safety of these medications in narcolepsy.

Narcolepsy-related Cataplexy Rx

While narcolepsy-related EDS can be managed with stimulant drugs, these medications often do not provide significant relief from cataplexy. Consequently, additional drugs have to be used to reduce the frequency and severity of cataplexy. Drugs that increase aminergic signaling decrease cataplexy. Sodium oxybate is also effective in cataplexy by an unknown mechanism. The most frequently recommended anticataplectics include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), sodium oxybate, and non-selective serotonin reuptake inhibitors/non-tricyclic antidepressants (NSSRI/NTCAs).

TCAs potentiate the activity of endogenous amines by blocking their reuptake into presynaptic neurons. In addition, TCAs have varying degrees of anticholinergic activity, blocking primarily muscarinic acetylcholine receptors and causing familiar side effects such as dry mouth. They are generally active on cataplexy at doses at or below usual antidepressant dose range efficacy. Imipramine was the first reported TCA with anticataplectic activity.32 Numerous case series but no double-blind studies have shown the effectiveness of protriptyline33 and several other TCAs on cataplexy (desipramine, clomipramine, etc).

SSRIs enhance the effect of endogenous monoamines and catecholamines by blocking their uptake into presynaptic neurons, which terminates their activity. They are relatively more selective toward the serotoninergic transporter. These agents are generally effective on cataplexy, although higher doses were needed and effects less pronounced than with classic TCAs. However, fluoxetine34 seems as effective in control of cataplexy as clomipramine, a TCA. Other SSRIs include paroxetine, fluvoxamine, etc.

Sodium oxybate is effective for controlling cataplexy35 and received FDA approval for this indication in July 2002. Further studies confirmed this effectiveness,36,37 but its mechanism of action is unknown. It may act through its own receptors and via stimulation of GABA-B receptors, with major effects on silencing dopaminergic neurons. It provides a slow and continuous improvement of cataplexy over long periods of time, and patience is required to obtain full efficacy. It has beneficial effects on insomnia, a major complaint in patients with narcolepsy, and has immediate beneficial effects on disturbed nocturnal sleep. Of note, contrary to antidepressant therapy for cataplexy, sodium oxybate interruption does not abruptly result in a rebound of cataplexy. When used with antidepressants for cataplexy or with stimulants for EDS, it often leads to slowly reducing and occasionally stopping conventional therapy using those medications. Clinicians consider sodium oxybate as a first-line therapy for all narcolepsy patients.

Sodium oxybate is typically administered twice during the night, with the patient lying in bed both times because the drug causes immediate initiation of sleep. Patients take the first dose at the beginning of the night of sleep and the second 3 to 4 hours later when they awake either spontaneously or with the help of an alarm clock.

NSSRI/NTCAs are a group of drugs that proved effectiveness in the treatment of cataplexy. (See figure 2 on page 50.) Venlafaxine is an atypical antidepressant that blocks the reuptake of both norepinephrine and serotonin. It is effective decreasing frequency of cataplexy attacks at doses at or below the antidepressant effect,16 especially when the extended release form is used. In another study, reboxetine decreased cataplexy frequency, improved sleepiness, and reduced sleep-onset REM periods (SOREMPs) in MSLT.38 Other medications in this group include duloxetine, atomoxetine, and viloxazine.

Some Novel Therapies

Immune-based therapy. New-onset narcolepsy wiith cataplexy in an 8-year-old boy failed to respond to immunosuppression with prednisone at 1 mg/kg/day for 3 weeks.39 However, four patients with new-onset narcolepsy with cataplexy successfully received therapy with intravenous immunoglobulin at 1 mg/kg/day over 2 days, repeated three times at 4-week intervals (cataplexy resolved, but EDS did not show a clear improvement).40

Hypocretin cells transplantation. Though cell transplantation still yields disappointing results in several diseases,41 it may someday provide a cure for narcolepsy.

Summary

Narcolepsy is a chronic and potentially devastating medical condition, especially if unrecognized and undertreated. Recent advances in the field mandate that the physician keep up-to-date with new research and treatment developments. Likewise, an update on consensus guidelines for pharmacotherapy is needed. Narcolepsy patients deserve a comprehensive approach for their treatment that addresses the medical, psychological, and social issues involved (including family, school, workplace, insurance, and legislation aspects). Non-pharmacologic interventions should also play an important role in the treatment plan, including structured nocturnal sleep and daytime naps, avoidance of irregular sleep-wake schedules, adequate diet and exercise, and driving caution for patients with EDS or cataplexy. Patients with narcolepsy should consider enrolling in the Narcolepsy Network Inc as a support and advocacy group.

Carlos E. Sotelo, MD, DABSM, is a somnologist, pulmonologist, and intensivist. He practices at Physicians Medical Group, PC, in Grants Pass, Ore, and is the medical director of the sleep laboratory at Grants Pass Imaging & Diagnostic Center. He serves as a member of the Continuing Medical Education Committee of the American Academy of Sleep Medicine.

ACKNOWLEDGMENT
The author is indebted to the Narcolepsy Network Inc, especially Sharon D. Smith, president of its board of trustees, for its contribution in the preparation of this article.

The painting “The Dream” by Maureen B. Garnier, a narcolepsy patient, shows a woman sleeping under her tree of life. She looks peaceful, however, she is in a world where bizarre is ordinary and there is no rest. “Sometimes she feels as though she would like to score her head and peel back the flesh to clean out her brain, clear out the webs, dust out the weary,” Garnier writes. “The Dream” is printed with the permission of the Narcolepsy Network Inc, North Kingstown, RI. Posters of “The Dream” can be ordered by contacting the Narcolepsy Network at Narnet@narcolepsynetwork.org or (888) 292-6522. To learn more about narcolepsy and the Narcolepsy Network, please visit their Web site www.narcolepsynetwork.org.

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