When treating narcolepsy, clinicians need to educate patients on the significance of symptoms of EDS and remain vigilant in making medication adjustments and detecting signs of depression.
By Leon Rosenthal, MD
Excessive daytime sleepiness (EDS) is the term used to describe an accentuated desire for sleep or the occurrence of actual sleep episodes that interfere with waking activities. People affected by significant EDS experience these symptoms on a daily and chronic basis. It represents a serious risk to the individual and conveys significant consequences to society in loss of work efficiency, disruption of family and social interactions, and significant risks of motor vehicle and/or industrial accidents. Patients who experience symptoms of EDS need to be evaluated to establish a diagnosis and implement effective therapy to minimize the negative effects of this potentially incapacitating experience. Among the conditions that need to be considered as a potential cause of EDS, narcolepsy represents a primary sleep disorder that ought to be recognized by health care professionals.
Symptoms Associated with Narcolepsy
The classic presentation of narcolepsy consists of EDS, cataplexy, hypnagogic hallucinations, and sleep paralysis. This constellation of symptoms is known as the narcoleptic tetrad. The prevalence of narcolepsy in the United States is estimated at 0.05%. Both genders are affected equally. Symptoms most commonly begin during the teenage years. EDS is usually the first symptom to appear and in some cases may precede manifestations of other symptoms by several years. Moreover, EDS is not always the initial symptom. Cataplexy may precede EDS in a small proportion of cases. Despite the ostensible variability in the presentation of narcolepsy, the great majority of patients experience the onset of symptoms before they reach 30 years of age.1
Cataplexy is a characteristic and unique feature of narcolepsy. Episodes of cataplexy involve sudden loss of muscle tone, which may affect the entire voluntary musculature or be localized to a group of skeletal muscles. Patients might experience momentary weakness, lasting a few seconds to a few minutes, with the head falling forward, facial sagging, slurred speech, or buckling of the knees. Severe episodes of cataplexy might result in the collapse of the affected individual. The attacks are usually elicited by laughter, but other emotions such as anger, stress, fatigue, or heavy meals might be identified as precipitating factors. Patients might experience episodes that could last up to an hour; these are described as status cataplecticus. During the episodes, consciousness remains clear with patients being able to have clear recollection of the events. While respiration and oculomotor muscle activity are not affected, patients might be unable to communicate during the episodes. The frequency of these episodes is variable (some patients experience several episodes per day and others report isolated instances during the year).
All patients with narcolepsy report EDS. Under some circumstances, the patient may be able to make an effort to stay awake; however, such an effort might be only partially successful, resulting in fluctuations in the level of alertness. These situations result in the occurrence of automatic behaviors, which consist of periods of semipurposeful activity without clear recollection of what actually happened. In this context, it is relevant to acknowledge that patients with narcolepsy complain, with some frequency, of memory problems. These complaints might be related to the severity of EDS.
Hypnagogic hallucinations (HH) are vivid perceptual experiences that occur during the transition from wake to sleep (experiences reported during the transition from sleep to wake are called hypnopompic hallucinations). Sleep paralysis (SP) consists of a generalized temporal loss of muscle tone that might occur between the transition from wake to sleep or from sleep to wake. It is usually experienced as an inability to move or speak while remaining entirely conscious of the surroundings.
Nocturnal sleep disturbances have also been identified as a relevant symptom in narcolepsy. In fact, it has been suggested that this symptom represents the fifth most important clinical finding of the condition. The cluster of all the symptoms described thus far has been identified as the narcoleptic pentad.
REM Sleep is Critical to the Understanding of Narcolepsy
Most of the clinical features of narcolepsy represent inappropriate intrusions of REM sleep into the sleep/wake cycle, for example, the atonia of REM sleep, when intruding into wakefulness, results in episodes of cataplexy. In the case of sleep paralysis, the motor inhibition of REM sleep is experienced at the time of the transition from wake to sleep, or from sleep to wake. Hypnagogic (or hypnopompic) hallucinations also represent the intrusion of oneiric activity in the same transitions as those described for sleep paralysis. The persistent intrusion of REM sleep into the sleep/wake cycle has enabled the operational definition of the sleep-laboratory criteria necessary for the diagnosis of narcolepsy.
Information Derived form the Sleep Laboratory Evaluation
The sleep laboratory evaluation should consist of an overnight polysomnography followed by a Multiple Sleep Latency Test (MSLT). The laboratory assessment enables the objective characterization of sleep and helps eliminate other sleep pathologies as potential causes of the patient’s clinical presentation. If the nocturnal polysomnography demonstrates severe obstructive sleep apnea, this condition should be treated first as normalization of ventilation during sleep might result in resolution of EDS and eliminate polysomnographic evidence of narcolepsy. Also, REM-behavior disorder has been reported in as many as 10% of patients with narcolepsy. Periodic limb movements during sleep are documented with some frequency during the sleep laboratory assessment.
The polysomnographic criteria for the diagnosis of narcolepsy consist of confirmation of EDS on the MSLT and multiple sleep-onset REM periods (SOREMP). A SOREMP is defined by the initiation of REM sleep within 15 minutes of sleep onset. These criteria have been proven to be reliable diagnostic tools (even when the reevaluation is done years after the initial diagnosis was established2 or when SOREMPs are quantified during repeated nocturnal sleep opportunities).3
The minimal criteria necessary for a diagnosis of narcolepsy require confirmation of symptoms of EDS and cataplexy. In this case, the need for polysomnographic assessment might be debatable, although still desirable when considering the implications of the diagnosis. Based on data from various clinic research reports, it is known that cataplexy is present in 64% to 100% of patients diagnosed with the condition.4 HH has been reported to be present in 28% to 82% of cases with the diagnosis of narcolepsy. As for SP, the frequency reported ranges between 27% and 80%. The full narcoleptic tetrad has been reported in 11% to 48% of cases. These numbers indicate that only a fraction of patients with the clinical diagnosis of narcolepsy present with the “classic” features of the condition. Furthermore, it is possible to encounter patients with EDS and polysomnographic evidence of narcolepsy but no clinical evidence of cataplexy, HH, or SP. They constitute what is recognized as the narcoleptic spectrum. As a group, these patients are less symptomatic than patients affected by the narcoleptic tetrad. In this context, cataplexy seems to represent a critical element in the severity of the condition. When comparing patients diagnosed with narcolepsy, those with cataplexy have more disturbed nocturnal sleep, report higher frequency of daily napping, and admit to higher frequency of accidents due to EDS.5
Is Narcolepsy a familial condition?
Less than 5% of patients diagnosed with narcolepsy have a familial history of the disorder. Most cases occur as sporadic manifestations, and an autoimmune reaction has been speculated but not confirmed. In this context, a high association of narcolepsy with the human leukocyte antigen (HLA) DQB1*0602 has been of interest. However, caution is advised against relying on HLA typing for diagnostic purposes, in particular, when considering that HLA-DQB1*0602-positive individuals (unaffected by narcolepsy) exist in the population at base rates ranging between 12% and 38%. In addition, some patients with narcolepsy (and cataplexy) have been tested negative for HLA-DQB1*0602.
New Discoveries in Narcolepsy Research
The recent discovery of the orexinergic/hypocretinergic system has significantly widened our understanding of sleep/wake mechanisms. Hypocretins (also known as orexins) are hypothalamic peptides produced by cells localized in a region within the lateral hypothalamus that project to regions involved in feeding, sleep, and autonomic functions.6 Research has documented hypocretin deficiency in the cerebrospinal fluid (CSF) of patients with narcolepsy and HLA-DQB1*0602 positivity. Furthermore, postmortem human studies have documented hypocretin deficiency in the narcoleptic brain.7 The available data indicate that the assay of CSF hypocretin-1 levels is likely to represent a future diagnostic tool for patients suspected of having a diagnosis of narcolepsy8; however, further research in this area is required to fully establish the sensitivity and specificity of this potentially useful diagnostic tool.
Treatment of Narcolepsy
Treatment of narcolepsy needs to be implemented in the context of good sleep hygiene practices. A regular sleep schedule is critical to the preservation of the sleep/wake cycle. Clinical lore has advocated the implementation of short naps, 10 to 20 minutes long, as a means to improve alertness in patients with narcolepsy. Research evaluating the effects of naps in this population has been scant, and the results from one study question the long-held belief that short naps are uniquely beneficial. In fact, a 2-hour nap opportunity was more beneficial when compared to a 15-minute nap opportunity in this particular study.9 Unfortunately, the benefit of the longer nap was shown to be lost 3 hours later and, thus, the transient benefit from daytime naps was corroborated.
Pharmacological intervention should be aimed at the patient’s symptoms. In the case of EDS, the use of wakefulness-promoting medications represents a critical intervention to improve the patient’s quality of life. Amphetamines and methylphenidate have been used for many years with some success. Modafinil is structurally different from traditional central nervous system (CNS) stimulants, has fewer cardiovascular side effects (when compared to traditional CNS stimulants), and has been well tolerated when used for prolonged periods of time.10 The liver metabolizes modafinil through the action of P450 enzymes, which turn lipophilic drugs into water-soluble compounds. Specifically, modafinil is an inductor of the 3A4 enzyme system and may impact the concentration of other drugs that are metabolized by this particular enzyme system. As a result of this effect, female patients who are prescribed modafinil should not rely only on the use of steroidal contraceptives as concentrations of these products might be reduced due to the possible induction of the 3A4 enzyme system.
Cataplexy (and the other auxiliary symptoms of narcolepsy) has traditionally been treated using tricyclics. Agents such as imipramine and protriptyline have been used with some success. The availability of newer antidepressants, including serotonin reuptake inhibitors and dual-action agents, has expanded the repertoire of medications available for treatment of these symptoms. The recent introduction to the US market of gammahydroxybutyrate (GHB) with the specific therapeutic indication of cataplexy makes this drug available in this market for the first time. The medication has been available in other countries for many years, but concerns about the recreational use/abuse of GHB have been present. GHB has profound hypnotic effects and decreases the frequency of episodes of cataplexy, which makes it a desirable intervention for the most severe cases of narcolepsy. The medication is dispensed as a liquid formulation and is taken at bedtime immediately upon retiring due to its fast absorption rate; however, due to its short half-life, a second dose is necessary 2.5 to 4 hours later. Studies evaluating the efficacy of the compound have established that doses of 3 to 9 g/night (taken in equally divided doses) produced significant clinical improvement among narcoleptic patients.11
Effective treatment of narcolepsy requires the patient’s understanding of the chronic nature of the condition and benefits from the support of family and friends. The clinician needs to remain vigilant of the potential need to make medication adjustments and detect symptoms or signs of depression, as patients might develop co-morbidity with psychiatric conditions. Also, as the illness is likely to begin in the early or mid teens, the health care professional should be prepared to educate patients on the significance of symptoms of EDS. In particular, patients should be advised against driving and/or operating machinery when symptomatic. In this context, it is also important to counsel patients on the implications of having a diagnosis of narcolepsy when making career choices or employment decisions. Alcohol, recreational drugs, and nonprescribed drugs should be avoided. Finally, patients should be encouraged to learn about their illness and become familiarized with resources such as the National Sleep Foundation and the Narcolepsy Network.
Leon Rosenthal, MD, is a staff physician at Sleep Medicine Associates of Texas, Dallas.
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