Narcolepsy: New Understanding of Irresistible Sleep

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Subspecialty Clinics: Sleep Disorders

Narcolepsy: New Understanding of Irresistible Sleep LOIS E. KRAHN, MD; JOHN L. BLACK, MD; AND MICHAEL H. SILBER, MBCHB Recently, low levels of a newly identified neuropeptide, hypocretin 1, were described in the cerebrospinal fluid of patients with narcolepsy. This neurochemical finding furthers our understanding of this enigmatic sleep disorder typically characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Narcolepsy appears to be fundamentally related to abnormally regulated rapid eye movement sleep. The diagnosis of this disorder remains challenging because of multiple other conditions that can cause daytime sleepiness and the difficulties in recognizing cataplexy based on patient report. The role of hypocretins in narcolepsy is unclear but intriguing because the cell bodies are restricted to the lateral hypothalamus, a brain region long associated with sleep regulation, with neuronal widespread projections to

areas including the locus ceruleus, ventral tegmental area, amygdala, and dorsal raphe. Hypocretins potentially modulate the activity of monoamines and acetylcholine, and therefore their absence leads to the multiple symptoms of narcolepsy. This article reviews the current understanding of the diagnosis and treatment of narcolepsy and discusses the possible implications of the hypocretin discovery. Mayo Clin Proc. 2001;76:185-194 CNS = central nervous system; CSF = cerebrospinal fluid; ECG = electrocardiography; EEG = electroencephalography; EMG = electromyography; EOG = electro-oculography; MSLT = multiple sleep latency test; NREM = non–rapid eye movement; PSG = polysomnography; REM = rapid eye movement

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The electroencephalographic (EEG) appearance changes from the very synchronized patterns of NREM sleep to desynchronized, mixed-frequency, low-amplitude rhythms, resembling those seen in wakefulness with the eyes open. Skeletal muscles become atonic with the exception of the diaphragm and the extraocular muscles. Penile tumescence, clitoral engorgement, and poikilothermia develop. Superimposed on these tonic changes are phasic muscle twitches, variable acceleration of heart and respiratory rates, runs of rhythmic theta EEG activity known as sawtooth waves, and the rapid eye movements that give the state its name (Figure 1). These movements are conjugate, irregular, and more commonly horizontal or oblique than vertical. Vivid hallucinatory dreams with strong emotional tones occur. The primary REM sleep generator lies in the rostral pontine reticular formation, but neurophysiologic changes of the state can be recorded from most areas of the nervous system, including the cortex, thalamus, hippocampus, medulla, and spinal cord.2 The onset of REM sleep appears to be related to a reduction in discharge of monoaminergic neurons in the locus ceruleus and raphe nuclei and an enhancement of brainstem cholinergic activity.3 The pathways mediating the skeletal muscle atonia are of particular importance in understanding narcolepsy. Excitatory axons arising from the pedunculopontine nuclei of the pontine tegmentum project to ventromedial medullary neurons. Axons of these neurons terminate on anterior horn cells of the spinal cord via inhibitory synapses, thus producing atonia of voluntary muscles.2

arcolepsy is a relatively poorly understood and underrecognized sleep disorder. Because excessive daytime sleepiness, a common complaint in contemporary American society, is the primary symptom, patients sometimes fail to recognize that they have a disease and do not seek treatment. Clinicians often assume that a patient’s excessive daytime sleepiness is due to inadequate nocturnal sleep rather than a medical disorder. Nevertheless, narcolepsy is a distinct medical disorder characterized primarily by abnormal rapid eye movement (REM) sleep regulation. Recently, a newly discovered central nervous system (CNS) neuropeptide, hypocretin 1, was reported as abnormally decreased in many patients with narcolepsy.1 THE NATURE OF REM SLEEP REM sleep is a state of consciousness different from both wakefulness and non-REM (NREM) sleep but shares some characteristics of both. It represents 20% to 25% of an adult’s sleep, occurring in about 5 periods during the night, each following a cycle of NREM sleep. The first commences approximately 90 minutes after the onset of sleep, with periods increasing in duration as the night progresses.

From the Department of Psychiatry and Psychology (L.E.K., J.L.B.), Sleep Disorders Center (L.E.K., M.H.S.), and Department of Neurology (M.H.S.), Mayo Clinic, Rochester, Minn. Address reprint requests and correspondence to Lois E. Krahn, MD, Department of Psychiatry and Psychology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Mayo Clin Proc. 2001;76:185-194

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Figure 1. Polysomnographic epoch showing cessation of electromyographic tone, sawtooth waves in the electroencephalogram, and rapid eye movements in the electro-oculogram. LOCFpz = left outer canthus, frontal electrode; ROC-Fpz = right outer canthus, frontal electrode; Fz-Cz = frontal-central electrode; CzOz = central-occipital electrode; C3-A2 = central reference electrode; CHN-CH2 = chin electromyogram; ECG-ECG2 = electrocardiogram.

THE HISTORY OF THE NARCOLEPSY SYNDROME Narcolepsy was first described in 1880 by Jean Baptiste E. Gelineau,4 a neuropsychiatrist in France, who recognized a group of patients who had irresistible sleep triggered by strong emotions. His recognition of excessive daytime sleepiness and cataplexy clarified that these symptoms represented a distinct neurologic disease.4,5 Sleep paralysis and hypnagogic hallucinations were added to excessive daytime sleepiness and cataplexy by Yoss and Daly6 in 1957, resulting in a tetrad of core narcoleptic symptoms. In 1960, Vogel7 observed REM sleep occurring at sleep onset in patients with narcolepsy. Several years earlier, REM sleep had been first observed and was known to typically occur 90 minutes after initially falling asleep. However, by 1963, Rechtschaffen et al8 recognized that many patients with the classic symptoms of narcolepsy experienced REM sleep within minutes, instead of an hour, after sleep onset. THE CLINICAL FEATURES OF NARCOLEPSY Most patients with narcolepsy are initially identified because of inappropriate, severe daytime sleepiness that interferes with their functioning. Essentially all patients with narcolepsy experience this potentially disabling symptom, which can lead to motor vehicle crashes, occupational difficulties, and social problems.9 However, excessive daytime sleepiness is not unique to narcolepsy and can be caused by a number of other conditions. Cataplexy is the symptom that is clearly most specific for narcolepsy. Cataplexy is often triggered when a patient

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experiences a strong emotion like laughter, anger, surprise, or excitement. Patients can have either partial or complete muscle weakness that can involve the face, neck, legs, or total body. During cataplexy, patients are aware of their surroundings but cannot move their body normally. They recall information if spoken to and can repeat this after the event. They do not lose consciousness, although with prolonged cataplexy, they can fall asleep. The ability to observe and recall events occurring during the cataplectic event is a helpful feature that allows discrimination between cataplexy and other states like seizures and sleep. Typical cataplectic episodes can last from several seconds to several minutes. Apart from the muscle atonia, which is characterized by a transient areflexia of the deep tendon reflexes, the patient is medically stable without cardiovascular or respiratory compromise. Several studies have indicated that because of the muscle atonia, electrophysiologic testing, such as Hreflex testing done with electromyography (EMG), yields abnormal results.10 This occurs because the spinal alpha motor neurons are inhibited postsynaptically by activated cells in the medial medulla. The H-reflex is a monosynaptic spinal reflex induced by electrical stimulation of the tibial nerve. It is the electrophysiologic parallel of the deep tendon reflex induced by stimulation of the Achilles tendon. The H-reflex is reduced during sleep and absent during REM sleep. This abnormal EMG finding strongly suggests that cataplexy represents a partial REM state. The muscle paralysis seen as a typical feature of normal REM sleep inappropriately intrudes into wakefulness leaving a subject unable to move certain muscles for a period of time. Why this partial REM state is typically triggered by strong emotions remains unexplained. However, this entity does represent a clear example of the mind-brain interface. A subject has a powerful emotional experience, and immediately, changes in the neurotransmitter levels, suspected to be related to excessive cholinergic stimulation and reduced noradrenergic activity, lead to muscle atonia.10-13 Clear-cut cataplexy coexisting with excessive daytime sleepiness points directly to the diagnosis of narcolepsy. Although no community-based study of narcolepsy has been published, approximately 25% of patients with narcolepsy are thought not to have cataplexy. Controversy exists regarding the patients with narcolepsy, based on abnormal REM sleep observed during a multiple sleep latency test (MSLT), who do not have cataplexy. The debate centers on whether narcolepsy with and without cataplexy represents the same or different diseases. Future studies of hypocretin or other neurotransmitters may soon settle this controversy. The other 2 classic symptoms found in narcolepsy are sleep paralysis and hypnagogic hallucinations. In sleep paralysis, a patient becomes transiently unable to move

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Figure 2. Histograms of a narcoleptic patient with a sleep-onset rapid eye movement episode (bottom) compared with a patient with idiopathic hypersomnia with no distinctive polysomnographic features (top). MI = movement; REM = rapid eye movement.

before sleep onset or just after awakening. Hypnagogic and hypnopompic hallucinations are vivid, frightening dreams, often with a sensation of flying, that similarly occur at the time of transition from sleep into wakefulness or the reverse. These symptoms may be very distressing to patients. Over time, symptoms have been found to be less specific than cataplexy in helping to distinguish a patient with narcolepsy from those with other sleep disorders. Both of these conditions have been known to occur in people without sleep disorders. Nonetheless, a relatively large group of patients with narcolepsy have the classic tetrad of symptoms—excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Sleep paralysis and hypnagogic hallucinations, like cataplexy, represent partial intrusion of REM phenomena into wakefulness. Both of these conditions occur at the time of sleep onset or awakening. Patients who have had narcolepsy for years to decades often develop disturbed nocturnal sleep with multiple awakenings. The nighttime sleep is often fragmented, distributed throughout the 24-hour time period, contributing to inappropriate sleepiness during the day14 (Figure 2). In contrast to cataplexy, in which the muscle atonia of REM sleep intrudes into waking, patients with narcolepsy may also develop REM sleep behavior disorder in which muscle tone is retained during REM sleep. These patients

may act out their dreams, kicking, thrashing their arms, and vocalizing.15 Recent studies have demonstrated that only 1% to 2% of narcoleptic patients have first-degree relatives with the disease in contrast to earlier observations that familial narcolepsy was common.16 However, in comparison with the 0.05% rate of narcolepsy in the general population, the 1% to 2% prevalence still does represent increased risk of narcolepsy within families. Nonetheless, narcolepsy is not purely a genetic disorder since unknown environmental factors influence disease onset, and only 25% to 31% of monozygotic twins are concordant for narcolepsy. THE DIAGNOSIS OF NARCOLEPSY Recognizing that a patient’s sleepiness is pathologic and potentially indicative of a medical disorder is the initial challenge facing a physician. Once sleepiness is identified as excessive, patients should be referred to a sleep disorders center for further evaluation (Table 1). No definitive test exists for narcolepsy at the present time. Sleep specialists conduct an interview and physical examination to develop the differential diagnosis of the patient’s presenting symptom. Accurately identifying cataplexy requires considerable experience as clinically normal people may describe feelings of weakness occurring with laughter. A questionnaire has been published that can identify cata-

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Table 1. Diagnostic Procedures to Confirm Narcolepsy 17

Cataplexy questionnaire Stanford Excessive daytime sleep questionnaire Epworth18,19 Wrist actigraphy20 Polysomnography21,22 Multiple sleep latency test23 Maintenance of wakefulness test24 Pupillometry25 Cataplexy testing26

plexy,17 but this instrument’s usefulness is limited because of its length and its reliance exclusively on the patient’s subjective description of an unusual condition. Excessive daytime sleepiness can be assessed using several approaches. The Epworth Sleepiness Scale is a published rating scale assessing 8 items on a scale from 0 to 3. Patients describe their tendency to fall asleep in a number of different situations. Scores greater than 8 are suggestive of pathologic sleepiness. This scale has been found to be useful in screening for potential sleep disorders, but it has several limitations.18,19 Its simplicity makes it easy for patients to complete but also means that it lacks precise information regarding the situations in which sleepiness may occur. It has not correlated well with some other sleep testing. Wrist actigraphy is a useful diagnostic test to obtain an objective measure of a patient’s sleep duration, sleep efficiency, and sleep-wake schedule outside the laboratory setting. The actigraph is a compact device worn on the wrist and is most often given to patients in conjunction with a sleep diary. It measures muscle motion, and depending on the unit, it can collect up to 4 weeks’ worth of information. Since it does not collect EEG data, it cannot confirm whether a patient is actually asleep but rather indicates decreased limb movement.20 The wrist actigraph can be useful in identifying patients with insufficient sleep. It also can be helpful for patients who have an irregular sleepwake schedule, as seen in delayed or advanced sleep phase or in shift workers. Polysomnography (PSG) is the “gold standard” of sleep diagnostic testing.21 To be valid, PSG should be done when a patient is well rested and taking a minimum of medications. Sleeping medications in particular should be tapered and discontinued prior to a sleep study. Medications that affect REM latency, such as antidepressants and stimulants, should also be discontinued. A PSG includes multiple channels of EEG, EMG, electro-oculography (EOG), electrocardiography (ECG), pulse oximetry, and respiratory monitoring. It permits the identification of sleep-related breathing disorders or movement disorders that could lead to fragmented sleep at night. Based on data collected

during the PSG, the EEG can be scored using the rules of Rechtschaffen and Kales22 and divided into specific stages of sleep, including stages I through IV sleep, NREM sleep, REM sleep, and awake. Several methods are used to measure excessive daytime sleepiness. The MSLT is a variant of the PSG that uses EEG, EOG, and EMG. The primary goal of the MSLT is to measure the time required for a subject to fall asleep during 4 to 5 scheduled nap opportunities that occur during the day.23 The data collected include the time to the first episode of sleep, as well as the emergence of any REM sleep. The presence of REM sleep during at least 2 naps is considered diagnostic of narcolepsy.27 To be valid, this test must be done when a patient is well rested and not taking medications that could affect the EEG. The MSLT is unreliable for the diagnosis of narcolepsy in the presence of another sleep disorder such as obstructive sleep apnea syndrome. Generally, obstructive sleep apnea is diagnosed and treated first, for example, with nasal continuous positive airway pressure. If the sleepiness persists or cataplexy is suspected once the patient has attained maximum improvement from such therapy, an MSLT is arranged. The maintenance of wakefulness test, which documents the patient’s ability to maintain alertness, represents a modification of the MSLT. The patient is tested on medications with 4 to 5 daytime sessions in a monotonous setting and is requested to fend off any impending sleepiness.24 Pupillometry is an additional technique for assessing excessive daytime sleepiness with which several measures, including diameter and light response, are determined and used as a marker of excessive daytime sleepiness, either as a diagnostic feature of narcolepsy or outcome of stimulant medication.25 Since cataplexy is the most specific sign of narcolepsy, there has been interest in developing a cataplexy test that could be used to diagnose narcolepsy. Unlike excessive daytime sleepiness, cataplexy occurs only rarely in the absence of narcolepsy. Attempts have been made to provoke cataplexy by telling jokes to a patient.10,26 More recently, an attempt has been made to standardize the cataplexy test by having susceptible patients view humorous videotapes while undergoing PSG monitoring. Assessing deep tendon reflexes before, during, and after a possible cataplectic episode is helpful in verifying that cataplexy has indeed occurred. The PSG can show reduced tone on the EMG.28 DIFFERENTIAL DIAGNOSIS OF EXCESSIVE DAYTIME SLEEPINESS When a patient presents with symptoms suggestive of narcolepsy, it is critically important to consider carefully whether other sleep disorders may be present (Table 2). The most common medical cause of excessive daytime

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sleepiness is likely obstructive sleep apnea. Another situation that needs to be considered before narcolepsy is diagnosed is whether a patient has fragmented nocturnal sleep due to restless legs syndrome or periodic limb movement disorder. Insufficient sleep syndrome is another cause of excessive daytime sleepiness. Many patients who have busy lifestyles are aware that they are getting inadequate sleep and do not undergo formal sleep evaluation,29 making it difficult to estimate the prevalence of this problem. Patients who have abnormal sleep-wake cycles due to a delayed or advanced sleep phase, shift work, or jet lag can also appear to be sleepy during the day. What sets these individuals apart is that over the course of a 24-hour period they have a normal sleep-wake pattern; however, their sleep may not occur at the conventional time. Untreated psychiatric disorders, including major depression, can make a patient appear sleepy, inattentive, and unmotivated. Chemical dependency, including alcohol or other drug dependence (prescription or street drugs), can make a patient appear to have excessive daytime sleepiness. Consequently many sleep disorders centers require that patients undergo urine drug testing as a part of their diagnostic testing. Idiopathic hypersomnia is a less well-defined condition. In this disease, patients experience excessive daytime sleepiness but without cataplexy and no abnormalities in REM sleep.30 An MSLT demonstrates decreased initial sleep latency with fewer than 2 sleep-onset REM periods. THE ETIOLOGY OF NARCOLEPSY The cause of narcolepsy is unknown; however, recent research has provided some intriguing data. Patients with narcolepsy are known to have an unusually high rate of a specific HLA subtype (HLA-DQB1*0602). This HLA subtype is found in narcoleptic patients of various ethnic backgrounds at rates higher than those found in the general population (25%). Furthermore, patients with narcolepsy have a greater tendency toward homozygosity of HLADQB1*0602.31 Of patients with severe cataplexy, 85% to 95% have this HLA subtype, while patients with narcolepsy not associated with cataplexy have a 40% rate of this HLA allele.16,31 Most diseases that are associated with a specific HLA subtype are autoimmune in nature. However, investigations into potential autoimmune markers in narcolepsy, both in humans and in dogs, have not been revealing to date. These include a small study of autoantibodies in humans and plasmapheresis in dogs.32 In the vast majority of patients, magnetic resonance imaging scans of the brain have not shown a specific lesion. However, it has been recognized that certain CNS lesions may be associated with narcolepsy.33 Lesions especially in the region of the diencephalon-third ventricle, including suprasellar pituitary neoplasms and sarcoidosis, have been

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Table 2. Differential Diagnosis of Excessive Daytime Sleepiness Obstructive sleep apnea Restless legs syndrome/periodic limb movement disorder Insufficient sleep syndrome Abnormal sleep schedule (advanced/delayed sleep phase) Major depression Alcohol or other drug dependence Idiopathic hypersomnia

found in a small percentage of patients with narcolepsy.33 A relationship has also been suggested with head injury and cranial irradiation.33-35 Overall, it is suspected that patients with secondary narcolepsy represent a distinct subgroup different from patients with idiopathic narcolepsy with their sleep disorder perhaps caused by CNS damage to a specific region containing hypocretin cell bodies. Secondary narcolepsy is not associated with the HLADQB1*0602 allele at rates higher than occur in the general population. Autopsy studies of patients with narcolepsy have a trend toward a relative increase in α1b-receptor binding in the brainstem. The data suggest that altered α-adrenergic receptor functioning is a possible cause of the disease.36 Similar studies of dopamine-receptor autoradiography have been unrevealing.37 The canine model of narcolepsy has permitted more invasive investigation of neurochemical factors in narcolepsy. Cholinergic stimulation in general triggers cataplexy in REM sleep, while increases in norepinephrine and serotonin levels inhibit both of these states. Human studies of abnormalities in monoamine metabolites, substance P, or somatostatin have been negative.38 Investigators have also studied whether narcolepsy involves a primary disruption of circadian rhythms. Compared with normal controls, narcoleptic patients are found to have an advanced temperature rhythm. However, this finding has not yet led to a more in-depth understanding of the pathophysiology of narcolepsy.39 THE ROLE OF HYPOCRETINS IN NARCOLEPSY Several discoveries in 1999 have suggested that abnormalities in the hypocretin (also known as orexin) neurotransmission system play an important role. Hypocretins are a newly described category of neurotransmitter with 2 components, hypocretin 1 and 2, whose cell bodies are located exclusively in the hypothalamus. The correct terminology is unresolved at this time. The term hypocretin was given to indicate that these peptides were hypothalamic members of the incretin family. Subsequently, 2 peptides, termed orexin-A and orexin-B, were identified by screening highresolution high-performance liquid chromatography fractions of various tissue extracts for orphan G protein–

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coupled cell surface receptor agonist activity.40 In the process, 2 receptors were found that reacted with the orexin peptides, which were “orexins” because these 2 peptides were found to stimulate food consumption and because they were expressed in the lateral and posterior hypothalamus, areas known to be active in the regulation of feeding behavior. It was shown that hypocretin 1 has the same sequence as orexin-A, and hypocretin 2 has the same sequence as orexin-B. Because of these nearly simultaneous research efforts, the nomenclature for the hypocretin (orexin) system is both confusing and controversial. The term hypocretin is used exclusively in this review. The lateral hypothalamic area, which contains hypocretin-containing cells, has been shown to be involved in the maintenance of waking states.41 A recent study indicated that hypocretin-containing cells were located primarily in the dorsomedial hypothalamic nucleus, the ventromedial hypothalamic nucleus, and the tuberal lateral hypothalamic area.42 In addition, numerous other structures involved in the sleep-wake cycle such as the locus ceruleus, the tuberomamillary nucleus, the pontine reticular formation, the raphe nuclei, the preoptic area, and the dorsal lateral tegmental nucleus were shown to have hypocretincontaining neurons. These observations suggest that hypocretin may have an effect on arousal and sleep.41,43 The role of hypocretin was confirmed when a mutation of the hypocretin receptor 2 gene was shown to cause canine narcolepsy.44 Narcolepsy in Doberman pinscher dogs is a disorder transmitted as a single autosomal recessive trait with full penetrance. The gene was named canarc-1, which is not genetically linked to canine major histocompatibility complex, unlike the tight linkage in human narcolepsy to HLA-DQB1*0602.45 By using positional cloning of the narcolepsy gene in Dobermans, the canine hypocretin receptor 2 gene was identified and was found to be associated with narcolepsy. Subsequent analysis revealed that narcoleptic dogs had a 116-bp deletion corresponding to the fourth exon. Therefore, the hypocretin receptor 2 transcripts from narcoleptic dogs were grossly abnormal, which likely disrupted the proper membrane localization of the hypocretin receptor 2 or caused loss of function in some other undefined ways. Since there was no published evidence suggesting significant sleep-wake effects for hypocretins, the discovery that a mutation in the hypocretin receptor 2 locus in canines with narcolepsy strongly suggested that hypocretins were major neuromodulators of sleep and the interaction between aminergic and cholinergic systems. Subsequently the systemic administration of hypocretin 1 (which also functions at the hypocretin receptor 2) was reported to reduce cataplexy and normalized sleep and waking durations in narcoleptic dogs.46

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More evidence that hypocretins are related to narcolepsy-like symptoms were created in a hypocretin knockout mouse model.47 Videotapes of knockout mice revealed periods of obvious behavioral arrest during the dark phase, which is the time that mice are most active. This behavior occurred in 100% of hypocretin null mice. Behavioral arrest was characterized as abrupt cessation of purposeful motor activity and sudden change in posture. Prior to the onset of behavioral arrest, lasting from 6 to 214 seconds, mice were ambulating, grooming, burrowing, and climbing. The EEG recordings from 6 knockout mice contained no seizure-related activities but rather sleep-onset REM sleep episodes. REM sleep time and REM episode duration were greater in the REM knockout mice during the dark phase. There was also an increase in NREM sleep time and a decrease in the wake time.47 No narcoleptic episodes were observed on videotapes of wild-type or heterozygotic mice. Preliminary research also supports the role of the hypocretin neurotransmitter system in human narcolepsy. The cerebral spinal fluid (CSF) of 9 narcoleptic patients with cataplexy, who were HLA-DQB1*0602 positive, was compared to that of 8 controls by iodine I 125 hypocretin 1 radioimmunoassay.1 Hypocretin 1 was detectable in all controls. However, 7 of the 9 narcoleptic patients lacked detectable levels of hypocretin 1. Of the 2 narcoleptic patients with detectable hypocretin 1, one had a level similar to that of the controls, and the other had a level greater than that of the controls. The HLA-associated autoimmune-mediated process may destroy the hypocretin-containing neurons in the lateral hypothalamus, thus producing narcolepsy in some patients and reducing the amount of hypocretin 1 expressed in the CSF. The other 2 patients with detectable levels of hypocretin 1 may have a receptor-mediated deficiency, which could also be immune mediated. The location of hypocretin-containing fibers and hypocretin receptor 2 in the rat CNS (mapping of these in humans has been only partially done42) supports a role for hypocretins in sleep-wake regulation as mediated by monoamines and acetylcholine (Figure 3). For example, hypocretin-containing neurons project to the locus ceruleus and the ventral tegmental area as well as the pontine reticular formation and associated cholinergic cell groups. Hypocretin neurons also project to the basal forebrain area, nucleus accumbens, and the amygdala, which are also consistent with interaction at the level of target projections for these neurotransmitters.40,41,50-52 Because hypocretin neurons are anatomically placed to modulate critical cholinergic areas in the pedunculopontine nuclei and the diagonal band of Broca, these neurons are anatomically placed to modulate critical cholinergic areas implicated in human narcolepsy that are involved in mediating REM cortical activation, REM sleep atonia, and cataplexy.

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Figure 3. Hypocretin projections in the rat brain. Schematic sagittal section of the rat brain, 0.4 mm lateral to the midline. Boundaries between the brain regions pictured here are approximations as are the locations of the various nuclei.48 The lateral hypothalamic area, the posterior hypothalamic area, and the dorsomedial hypothalamic nucleus contain the hypocretin-containing neuronal cell bodies with neurons that project widely. Importantly, in rat brain, hypothalamic areas associated with sleep control have either both receptor types or just hypocretin receptor 2. However, other structures involved in the sleep-wake cycle such as the locus ceruleus, the pontine reticular formation, the raphe nuclei, and the preoptic area were shown to have hypocretin receptor 1 immunoreactivity. The implications of this finding in the rat brain are unclear at this time.49 Am = amygdala; CA1, CA2, CA3 = hippocampal areas CA1, CA2, and CA3; CC = cingulate cortex; CMT = central medial thalamic nucleus; DHN = dorsomedial hypothalamic nucleus; IG = indusium griseum; LC = locus ceruleus; LHA = lateral hypothalamic area; MPA = medial preoptic area; PHA = posterior hypothalamic area; PMAHA = posteromedial amygdalohippocampal area; PTN = paraventricular thalamic nucleus; Ra = raphe nucleus and surrounding reticular activating area; SHN = septohippocampal nuclei; SN = subthalamic nucleus; 3V = third ventricle; 4V = fourth ventricle; VAMT = ventral anterior medial thalamic nucleus; VMH = ventromedial hypothalamic nucleus (adapted with permission from Paxinos and Watson48).

Because the phenotypes of human and canine narcolepsy are similar, an abnormality in hypocretin neurotransmission is likely to be involved in human narcolepsy.44 A recent report based on examination of 2 human brains by in situ hybridization of the perifornical area and peptide radioimmunoassays described widespread loss of hypocretin without any gliosis or inflammatory changes.42 Tissue from 16 human brains has also been described as showing a loss of 85% to 95% of hypocretin neurons with gliosis suggesting fliosis, which could be due either to inflammatory or to neurodegenerative processes.53 Thus, there is conflicting evidence, and whether gliosis is present in hypothalamic tissue of narcoleptics remains unresolved; however, these

articles both point to the pivotal role of hypocretin and are consistent with an autoimmune or toxic process. Because most cases of human narcolepsy are not familial but are strongly associated with HLA-DQB1*0602,16,45,54 an autoimmune process directed against elements of the hypocretin neurotransmission system must be considered. In HLA-DQB1*0602–associated disease, autoimmunemediated destruction of the neurons secreting hypocretins or neurons bearing the hypocretin receptors could cause narcolepsy. Alternatively, autoimmunity against the 5 elements of the hypocretin system (preprohypocretin, hypocretin 1, hypocretin 2, hypocretin receptor 1, and hypocretin receptor 2) might be involved. Finally, autoim-

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munity against neurotransmitters regulating hypocretin secretion or those downstream of the hypocretin system should be considered. In those individuals with familial narcolepsy, genetic alterations (eg, mutations and polymorphisms) in the genes of the components of the hypocretin neurotransmission system could be present, but preliminary studies of multiplex families have revealed only a single mutation.42 THE TREATMENT OF NARCOLEPSY The mainstay of treatment of excessive daytime sleepiness in narcolepsy is the use of stimulant medication. Ephedrine and amphetamines were first used in the 1930s55,56 and methylphenidate in 1956.57 The most common stimulants used currently in the United States are methylphenidate, amphetamine (dextro- and mixed dextro- and levoisomers), methamphetamine, pemoline, and modafinil. Apart from modafinil, all stimulants are centrally acting sympathomimetic agents that enhance the release of monoamines in the synaptic cleft and block their reuptake.58,59 Modafinil is a novel stimulant with an uncertain mechanism of action that may increase hypocretin activity, based on a recent study that awaits replication.47,60 The goal of stimulant therapy is to produce as near normal alertness as possible yet with a minimum of adverse effects. Dosage should commence low and be increased as needed and tolerated. The American Sleep Disorders Association recommends that maximum daily doses of methylphenidate and dextroamphetamine not exceed 100 mg, methamphetamine, 80 mg, and pemoline, 150 mg.59 Methylphenidate and dextroamphetamine have short durations of action of 3 and 5 hours.61 This often results in peak and trough effects with the patient oscillating between states of heightened alertness and severe sleepiness. Conventional stimulants with longer durations of action include methamphetamine with a serum half-life of 16 to 22 hours,62 pemoline, and sustained-release methylphenidate. Modafinil also has a longer half-life, and recommended dosage ranges from 200 to 400 mg daily.63 Many physicians are overcautious about increasing doses of stimulants because of fear of inducing tolerance, dependence, or toxic effects. Tolerance does occur in some patients,64 but abuse of the drugs is exceptionally rare in patients who do not have the problem of previous, unrelated chemical dependency.65,66 Discontinuing modafinil after 9 weeks’ therapy has been shown not to produce withdrawal symptoms.67 Sympathomimetic adverse effects, including anxiety, irritability, palpitations, tremor, anorexia, headache, and insomnia,59,64,68 are mostly dose related. Pemoline has been associated with a risk of acute hepatic failure 4 to 17 times greater than expected, and as a result, the manufacturers now recommend that serum ala-

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nine aminotransferase concentration be measured every 2 weeks.69 Modafinil does not usually produce sympathomimetic toxicity, but headache,63 nausea, nervousness,70 and rhinitis67 occurred more frequently than with placebo in controlled trials. The availability of modafinil has altered therapeutic approaches to narcolepsy. This agent has been studied in clinical trials far more extensively than any conventional stimulant, and large controlled studies have clearly indicated its effect in alleviating sleepiness.63,70,71 How effective is modafinil as a stimulant? No formal back-to-back studies comparing it with conventional stimulants have been performed. The mean level of alertness achieved by use of the drug in controlled studies, as measured by the maintenance of wakefulness test, still remained within the abnormal range,63 but similar data for other stimulants are not available. Long-term studies of 10 to 20 months have found that 62% to 71% of patients continued to use the drug.72,73 Indirect analyses, comparing data from different studies to published norms, suggested that 300 mg of modafinil daily resulted in alertness of 50% normal, compared with 65% to 75% with the use of 40 to 60 mg of methylphenidate or methamphetamine daily.59,74,75 Modafinil is a reasonable choice as an initial stimulant in patients newly diagnosed as having narcolepsy, in view of its long duration of action, its relative lack of adverse effects, and apparent low potential for the development of dependence. However, its cost as a new medication, the impression that it may be weaker in its effect than traditional stimulants, and its potential for interaction with other medications such as oral contraceptives76 need also to be considered. It should be tried in patients on conventional stimulants with pronounced fluctuations between peak and trough doses or other adverse effects, but patients already on high doses of methylphenidate may perceive an inadequate therapeutic response. Nonpharmacologic therapy includes prevention of sleep deprivation, regular sleep and wake times, work in a stimulating environment, and avoidance of shift work. Patients with narcolepsy should be educated about driving risks when undertreated.77 It is commonly stated that naps of even brief duration are helpful and improve recuperation, but objective data are contradictory.78-80 Stimulant therapy alone often improves control of cataplexy,61 possibly by reducing drowsiness. Tricyclic antidepressants have been used to treat cataplexy since 196068 and remain the most commonly used agents today. Imipramine, clomipramine, and protriptyline also have been used, without any definite evidence that they are more effective than other drugs.68 Selective serotonin reuptake inhibitors, such as fluoxetine and paroxetine, are alternative agents with fewer adverse effects.81,82 Hypnagogic hal-

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lucinations and sleep paralysis can be treated with tricyclic antidepressants.83 Insomnia is common in narcolepsy and can be treated with triazolam, which has been shown to increase total sleep time and sleep efficiency without affecting alertness the following day.84

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CONCLUSIONS The recognition of the role of hypocretin in narcolepsy is opening new avenues of investigation about the potential influence of this neuropeptide. Clearly, sleep and appetite abnormalities are associated with a large number of psychiatric and medical disorders. Narcolepsy is increasingly recognized as a distinctive disease with a very specific pathophysiology and neurochemical abnormalities. Narcolepsy may well serve as a model that permits further exploration of the mind-brain interface by studying cataplexy. Considering narcolepsy among other diagnostic possibilities is important. The clinician needs to question the patient carefully as to the possibility of cataplexy, sleep paralysis, and vivid dreams. Referral to a sleep disorders center facilitates appropriate diagnostic testing. Once narcolepsy is diagnosed, the availability of modafinil currently gives physicians a new treatment option, and in the future hypocretin therapy may become feasible.

17.

18. 19. 20. 21.

22.

23.

24.

25.

REFERENCES 1.

2.

3.

4. 5. 6. 7. 8.

9.

10. 11.

12. 13.

Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy [letter]. Lancet. 2000;355:39-40. Siegel J. Brainstem mechanisms generating REM sleep. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders Co Inc; 2000: 112-133. Hobson JA, McCarley RW, Wyzinski PW. Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science. 1975;189:55-58. Gelineau JBE. De la Narcolepsie. Lancette Fr. 1880;53:626-628. Culebras A. Sleep and narcolepsy [published correction appears in Arch Neurol. 1999;56:632]. Arch Neurol. 1999;56:117-118. Yoss RE, Daly DD. Criteria for the diagnosis of the narcoleptic syndrome. Proc Staff Meet Mayo Clin. 1957;32:320-328. Vogel G. Studies in the psychophysiology of dreams, III: the dream of narcolepsy. Arch Gen Psychiatry. 1960;3:421-428. Rechtschaffen A, Wolpert EA, Dement WC, Mitchell SA, Fisher C. Nocturnal sleep of narcoleptics. Electroencephalogr Clin Neurophysiol. 1963;15:599-609. Broughton RJ, Guberman A, Roberts J. Comparison of the psychosocial effects of epilepsy and narcolepsy/cataplexy: a controlled study. Epilepsia. 1984;25:423-433. Guilleminault C, Wilson RA, Dement WC. A study on cataplexy. Arch Neurol. 1974;31:255-261. Siegel JM, Nienhuis R, Fahringer HM, et al. Neuronal activity in narcolepsy: identification of cataplexy-related cells in the medial medulla. Science. 1991;252:1315-1318. Guilleminault C, Gelb M. Clinical aspects and features of cataplexy. Adv Neurol. 1995;67:65-77. Hodes R. Effects of age, consciousness, and other factors on human electrically induced reflexes (EIRs). Electroencephalogr Clin Neurophysiol Suppl. 1967;25:80-91.

26.

27.

28. 29. 30. 31.

32. 33. 34.

35. 36.

37.

193

Billiard M, Besset A, Cadilhac J. The clinical and polygraphic development of narcolepsy. In: Guilleminault C, Lugaresi E, eds. Sleep/Wake Disorders: Natural History, Epidemiology, and Longterm Evolution. New York, NY: Raven Press; 1983:171-185. Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Ann Neurol. 1992;32:3-10. Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep. 1997;20:1012-1020. Anic-Labat S, Guilleminault C, Kraemer HC, Meehan J, Arrigoni J, Mignot E. Validation of a cataplexy questionnaire in 983 sleepdisorders patients. Sleep. 1999;22:77-87. Johns MW. Sleepiness in different situations as measured by the Epworth Sleepiness Scale. Sleep. 1994;17:703-710. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14:540-545. Sadeh A, Hauri PJ, Kripke DF, Lavie P. The role of actigraphy in the evaluation of sleep disorders. Sleep. 1995;18:288-302. Guilleminault C, Anagos A. Narcolepsy. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders Co Inc; 2000:676-686. Rechtschaffen A, Kales A, eds. A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Bethesda, Md: US Dept of Health, Education, and Welfare; 1968. Publication 204. Carskadon MA, Dement WC, Mitler MM, Roth T, Westbrook PR, Keenan S. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep. 1986;9:519-524. Doghramji K, Mitler MM, Sangal RB, et al. A normative study of the maintenance of wakefulness test (MWT). Electroencephalogr Clin Neurophysiol. 1997;103:554-562. Yoss RE, Moyer NJ, Ogle KN. The pupillogram and narcolepsy: a method to measure decreased levels of wakefulness. Neurology. 1969;19:921-928. Dyken ME, Yamada T, Lin-Dyken DC, Seaba P, Yeh M. Diagnosing narcolepsy through the simultaneous clinical and electrophysiologic analysis of cataplexy. Arch Neurol. 1996;53:456-460. American Sleep Disorders Association. The International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. Rochester, Minn: American Sleep Disorders Association; 1997. Krahn L, Boeve B, Olson E, Herold D, Silber M. A standardized test for cataplexy. Sleep Med. 2000;1:125-130. Richardson JW, Fredrickson PA, Lin S-C. Narcolepsy update. Mayo Clin Proc. 1990;65:991-998. Aldrich MS. The clinical spectrum of narcolepsy and idiopathic hypersomnia. Neurology. 1996;46:393-401. Pelin Z, Guilleminault C, Risch N, Grumet FC, Mignot E, US Modafinil in Narcolepsy Multicenter Study Group. HLADQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. Tissue Antigens. 1998;51:96-100. Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50(2, suppl 1):S16-S22. Malik S, Silber M, Boeve B, Krahn L. Symptomatic (secondary) narcolepsy [abstract]. Sleep. 2000;23:A302. Plazzi G, Montagna P, Provini F, Bizzi A, Cohen M, Lugaresi E. Pontine lesions in idiopathic narcolepsy. Neurology. 1996;46: 1250-1254. Bassetti C, Aldrich MS, Quint DJ. MRI findings in narcolepsy. Sleep. 1997;20:630-631. Aldrich MS, Prokopowicz G, Ockert K, Hollingsworth Z, Penney JB, Albin RL. Neurochemical studies of human narcolepsy: alphaadrenergic receptor autoradiography of human narcoleptic brain and brainstem. Sleep. 1994;17:598-608. Aldrich MS, Hollingsworth Z, Penney JB. Dopamine-receptor autoradiography of human narcoleptic brain. Neurology. 1992;42: 410-415.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

194

38.

39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50.

51.

52.

53. 54. 55. 56. 57. 58. 59.

Narcolepsy

Strittmatter M, Isenberg E, Grauer MT, Hamann G, Schimrigk K. CSF substance P somatostatin and monoaminergic transmitter metabolites in patients with narcolepsy. Neurosci Lett. 1996;218:99102. Mayer G, Hellmann F, Leonhard E, Meier-Ewert K. Circadian temperature and activity rhythms in unmedicated narcoleptic patients. Pharmacol Biochem Behav. 1997;58:395-402. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92:573-585. Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18:9996-10015. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 2000;6:991-997. Date Y, Ueta Y, Yamashita H, et al. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci U S A. 1999;96:748-753. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98:365-376. Kadotani H, Faraco J, Mignot E. Genetic studies in the sleep disorder narcolepsy. Genome Res. 1998;8:427-434. John J, Wu M-F, Siegel JM. Systemic administration of hypocretin1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online. 2000;3:23-28. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999; 98:437-451. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. Compact 3rd ed. San Diego, Calif: Academic Press; 1997. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K. Distribution of orexin neurons in the adult rat brain. Brain Res. 1999;827:243-260. Gautvik KM, de Lecea L, Gautvik VT, et al. Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction. Proc Natl Acad Sci U S A. 1996;93: 8733-8738. Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. Distribution of orexin receptor mRNA in the rat brain [published correction appears in FEBS Lett. 1999;442:122]. FEBS Lett. 1998; 438:71-75. Broberger C, De Lecea L, Sutcliffe JG, Hokfelt T. Hypocretin/ orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol. 1998;402:460-474. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27:469-474. Mignot E, Lin X, Arrigoni J, et al. DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans. Sleep. 1994;17(8, suppl):S60-S67. Doyle JB, Daniels LE. Symptomatic treatment for narcolepsy. JAMA. 1931;96:1370-1372. Prinzmetal M, Bloomberg W. The use of benzedrine for the treatment of narcolepsy. JAMA. 1935;105:2051-2054. Daly DD, Yoss RE. The treatment of narcolepsy with methyl phenylpiperidylacetate: a preliminary report. Proc Staff Meet Mayo Clin. 1956;31:620-626. Parkes D. Introduction to the mechanism of action of different treatments of narcolepsy. Sleep. 1994;17(8, suppl):S93-S96. Mitler MM, Aldrich MS, Koob GF, Zarcone VP. Narcolepsy and its treatment with stimulants: ASDA standards of practice. Sleep. 1994;17:352-371.

Mayo Clin Proc, February 2001, Vol 76

60.

61. 62. 63. 64. 65. 66. 67. 68. 69. 70.

71. 72. 73.

74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84.

Engber TM, Koury EJ, Dennis SA, Miller MS, Contreras PC, Bhat RV. Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil. Neurosci Lett. 1998;241:95-98. Daly DD, Yoss RE. Narcolepsy. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Vol 15. New York, NY: American Elsevier Publishing Co Inc; 1974:836-852. Mitler MM, Hajdukovic R, Erman MK. Treatment of narcolepsy with methamphetamine. Sleep. 1993;16:306-317. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43:88-97. Parkes J, Baraitser M, Marsden C, Asselman P. Natural history, symptoms and treatment of the narcoleptic syndrome. Acta Neurol Scand. 1975;52:337-353. Rogers AE, Aldrich MS, Berrios AM, Rosenberg RS. Compliance with stimulant medications in patients with narcolepsy. Sleep. 1997;20:28-33. Mitler MM, Erman M, Hajdukovic R. The treatment of excessive somnolence with stimulant drugs. Sleep. 1993;16:203-206. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for excessive daytime somnolence in narcolepsy. Neurology. 2000;54:1166-1175. Bassetti C, Aldrich MS. Narcolepsy. Neurol Clin. 1996;14:545571. Littner M. Sleep practitioners need to be aware of new changes in the labeling of pemoline [letter]. Sleep. 1999;22:833. Broughton RJ, Fleming JA, George CF, et al. Randomized, doubleblind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology. 1997;49:444-451. Billiard M, Besset A, Montplaisir J, et al. Modafinil: a double-blind multicentric study. Sleep. 1994;17(8, suppl):S107-S112. Besset A, Chetrit M, Carlander B, Billiard M. Use of modafinil in the treatment of narcolepsy: a long term follow-up study. Neurophysiol Clin. 1996;26:60-66. Mitler M, Harsh J, Hirshkowitz M, Guilleminault C, US Modafinil in Narcolepsy Multicenter Study Group. Long-term efficacy and safety of modafinil (Provigil) for the treatment of excessive daily sleepiness associated with narcolepsy. Sleep Med. 2000;1:231-243. Mitler MM, Hajdukovic R. Relative efficacy of drugs for the treatment of sleepiness in narcolepsy. Sleep. 1991;14:218-220. Mitler M, Hajdukovic R, Erman M, Koziol JA. Narcolepsy. J Clin Neurophysiol. 1990;7:93-118. Modafinil for narcolepsy. Med Lett Drugs Ther. 1999;41:30-31. Garma L, Marchand F. Non-pharmacological approaches to the treatment of narcolepsy. Sleep. 1994;17(8, suppl):S97-S102. Helmus T, Rosenthal L, Biship C, Roehrs T, Syron ML, Roth T. The alerting effects of short and long naps in narcoleptic, sleep deprived, and alert individuals. Sleep. 1997;20:251-257. Mullington J, Broughton R. Scheduled naps in the management of daytime sleepiness in narcolepsy-cataplexy. Sleep. 1993;16:444456. Roehrs T, Zorick F, Wittig R, Paxton C, Sticklesteel J, Roth T. Alerting effects of naps in patients with narcolepsy. Sleep. 1986; 9(1, pt 2):194-199. Langdon N, Shindler J, Parkes JD, Bandak S. Fluoxetine in the treatment of cataplexy [letter]. Sleep. 1986;9:371-373. Montplaisir J, Godbout R. Serotoninergic reuptake mechanisms in the control of cataplexy. Sleep. 1986;9(1, pt 2):280-284. Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol. 1997;52:27-78. Thorpy MJ, Snyder M, Aloe FS, Ledereich PS, Starz KE. Shortterm triazolam use improves nocturnal sleep of narcoleptics. Sleep. 1992;15:212-216.

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.