Brain, Vol. 124, No. 8, 1482-1491,
August 2001
© 2001 Oxford University Press
Invited review |
Excessive daytime sleepiness
A challenge for the practising neurologist
Stanford Sleep Disorders Clinic, Stanford Hospital and Clinics, Stanford University and Medical Centre, Stanford, California USA
Correspondence to:
Christian Guilleminault and Stephen N. Brooks, Stanford Sleep Disorders Clinic, Stanford Hospital and Clinics, Stanford University and Medical Centre, 401 Quarry Road, Suite 3301, Stanford, CA 94305, USA E-mail: cguil{at}stanford.edu
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Abstract |
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The complaint of excessive daytime sleepiness, commonly encountered in neurological practice, may arise from a variety of disorders. The list of possibilities spans virtually every major area of medicine, neurology and psychiatry. A clear, detailed history is invaluable in negotiating these numerous diagnostic considerations; however, the symptom may be expressed in terms that do not directly denote somnolence (e.g. `tiredness' or `fatigue'). Accurate diagnosis is important, not only because of the negative impacts of sleepiness and its root causes on health and social function, but because excessive sleepiness is generally remediable with appropriate treatment. As our understanding of the neurological underpinnings of alertness and sleepiness deepens, improved treatment methods are bound to emerge.
sleepiness; somnolence; hypersomnia; narcolepsy; sleep-disordered breathing
ASPS = advanced sleep phase syndrome; EDS = excessive daytime sleepiness; DSPS = delayed sleep phase syndrome; MSLT = multiple sleep latency test; OSA = obstructive sleep apnoea; OSAS = obstructive sleep apnoea syndrome; PLMS = periodic limb movements of sleep; REM = rapid eye movement; SRBD = sleep-related breathing disorders; SOREMPs = sleep onset REM sleep periods; UARS = upper airway resistance syndrome
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Introduction |
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Excessive daytime sleepiness (EDS) is a common complaint encountered in neurological practice. Neurologists are likely to encounter patients with EDS, not only because of the neurological nature of the symptom itself, but also because many primary neurological disorders are associated with disordered sleep, including Alzheimer's disease and other types of dementia, Parkinson's disease, other neurodegenerative conditions, peripheral neuropathy, neuromuscular disorders, epilepsy and chronic pain syndromes.
According to the National Sleep Foundation 2000 Omnibus Sleep in America Poll: `a sizable proportion of adults (43%) report that they are so sleepy during the day that it interferes with their daily activities a few days per month or more; and, one out of five (20%) experience this level of daytime sleepiness at least a few days per week or more'. A recent study (Powell et al., 1999
) demonstrated that decreased performance due to sleepiness may be worse than that associated with alcohol intoxication.
EDS exacts a significant toll on individuals and on society. On the individual level, the symptom itself not only reduces personal effectiveness at school or work, but it also leads to problems with concentration, memory and mood, which have further negative impacts on performance. On the societal level, the negative impacts of sleepiness are likewise significant. In a recent study of professional truck drivers, 40% of long-haul drivers reported difficulties staying alert during at least 20% of their drives, and 20% admitted to dozing off at least twice while driving (Hakkanen and Summala, 2000). Each year, in the United States, >50 000 motor vehicle accidents are attributed to driving while sleepy (Mahowald, 2000).
Sleepiness may be thought of as a physiological state or `urge' which promotes the onset of sleep, and which is reversed or satiated (although not always) by the attainment of adequate sleep. Patients may use other terms, such as `tiredness' or `fatigue' to describe sleepiness, thus leading to potential semantic confusion. It is important for the examiner to be precise in eliciting the medical history, since the pathways for evaluating and treating sleepiness may diverge considerably from those addressing other symptoms, such as physical fatigue.
In the recent past, progress has been made in the understanding of several syndromes associated with EDS. Genetic features have been identified which may predispose individuals to this symptom. These probably act in concert with environmental factors to bring about full expression of sleepiness.
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Anatomy and physiology of sleepiness |
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The neurological substrates of sleepiness are incompletely understood. Sleepiness may reflect the waning of processes maintaining wakefulness, or it may result from distinct neural systems acting to promote sleep. Numerous areas of the brain are known to participate in the initiation and maintenance of sleep and alertness, such as the brainstem reticular activating system, locus coeruleus, dorsal raphe and other brainstem nuclei, basal forebrain, thalamus, hypothalamic loci and cortex (McCarley, 1999
). It remains to be determined how these and other brain structures act and interact to produce EDS in various disorders. Many neurotransmitters and peptides are also known to play significant roles in the expression of alertness and sleep, including norepinephrine, serotonin, dopamine, GABA (gamma aminobutyric acid), acetylcholine, histamine, glutamate, adenosine, substance P, interleukin-1 and prostaglandins, to name but a few (Zoltoski et al., 1999). The recently discovered hypocretins appear to have central importance in animal and human narcolepsy (see section on narcolepsy); as further work in this area proceeds, it will be interesting to see whether these substances are involved in other clinical disorders associated with EDS. |
Diagnosis and evaluation of sleepiness |
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Daytime sleepiness is common but often unrecognized. As with most medical conditions, diagnosis of EDS begins with a precise history. The patient may present complaints of `tiredness' or `fatigue' rather than more specific symptoms of `sleepiness' or `drowsiness'. Such questions as: `Do you take naps (or would you, if given the opportunity)?', `Do you doze easily in passive or monotonous situations?', `Do you sleep later on weekends and holidays than during the workweek?' and `How long does it take to fall asleep at night?' may help the physician to distinguish true sleepiness from other, less specific complaints. Safety concerns should also be addressed in the history; patients should be queried about any difficulties or mishaps whilst driving or operating machinery. Even if some degree of sleepiness is acknowledged by the patient, secondary problems with performance or neurocognitive function may be ignored or denied. Patients commonly deny symptoms, and physicians may not recognize problems related to EDS. Performance alone may not always be the best indication of sleepiness, as motivation may temporarily override a performance decrement. Compensatory strategies may also be invoked, e.g. an increase in errors may be avoided at the expense of a slower pace. Individuals might also accept lower levels of achievement.
Various tools have been developed to assess sleepiness more objectively, but each of these has shortcomings. These instruments explore different aspects of sleepiness, and several tools may be needed to evaluate a given patient. Investigators must recognize the limitations of the available methods and select them according to the clinical problem being addressed.
For quite some time, introspective behavioural scales and performance tests have been used to measure sleepiness. Subjective scales query the individual's perception of alertness/sleepiness. One problem with this approach is that subjects must have insight into the problem and be able to distinguish sleepiness from other factors affecting performance. The Stanford Sleepiness Scale (Hoddes et al., 1972) and the Karolinska Sleepiness Scale (Akerstedt, 1996) assess the momentary degree of alertness/sleepiness. These scales are useful in tracking symptoms during a given time epoch; they are less helpful in examining more global feelings of sleepiness. The Epworth Sleepiness Scale (Johns, 1991) offers a more appropriate method for assessing `overall' sleepiness. It consists of eight questions, each scored with a degree of severity ranging from 0 to 3. One limitation of this scale is that it asks subjects to imagine themselves in situations which they may actually experience rarely or never. Semantic issues also may lead to confusion. There may also be individual variation of scores over time.
In our own experience, visual analogue scales, on which the subject indicates a response along a linear 100 mm line (between extremes with labels such as `very sleepy' and `very alert'), have been at least as valid as any other approach. It is also useful to ask other individuals who are close to the subject (spouse, bed-partner, co-worker) to complete scales such as the Epworth Sleepiness Scale or visual analogue scales; this adds information which is not entirely subjective to the individual.
Performance tests have been used to measure sleepiness, but they are often susceptible to habituation to task and can only be used when a ceiling effect has been reached. The less problematic tests involve measurements of simple or complex reactions. Lapses in reaction time provide an index of sleepiness. Computerized systems are commercially available and permit calculation of multiple parameters, such as mean reaction time, variability of speed of response, longest 10 reaction times, etc.
More objective tests, relying on measurement of physiological parameters, are widely available. Pupillography (Schmidt and Fortin, 1982), based on changes in pupil stability with level of alertness, has been used to assess sleepiness, but is limited by eyelid ptosis, which occurs with drowsiness and tends to obscure the pupil. Sensory evoked potentials are rarely employed. Most commonly, objective testing is based on polygraphic monitoring. The Multiple Sleep Latency Test (MSLT) (Carskadon et al., 1986) is performed immediately after an overnight polysomnogram (to ensure adequate sleep during the prior night and to exclude obvious causes of nocturnal sleep disruption, which would explain the daytime symptoms). The test consists of four or five opportunities to nap, spaced across the day at 2-h intervals. Standardized conditions are employed; the subject is placed in a quiet, dark, comfortable room and asked not to resist sleep. Monitored parameters include EEG, EMG and eye movements. During each nap, the subject is allowed 20 min to achieve sleep onset. If sleep does not occur, that portion of the study is terminated at 20 min. If sleep onset does occur, monitoring continues for an additional 15 min to look for sleep onset rapid eye movement sleep periods (SOREMPs). Outcome measures are mean sleep latency (time from lights-out to unequivocal sleep onset) and presence or absence of SOREMPs. The Maintenance of Wakefulness Test (Doghramji et al., 1997) employs a protocol similar to that of the MSLT, but the subject is asked to try to remain awake, and each phase is terminated immediately if sleep onset occurs within 20 min. The Maintenance of Wakefulness Test is often used for legal purposes (e.g. in the decision whether to reinstate a suspended driver's license) to document the patient's ability to stay awake. On the MSLT, mean sleep latency >10 min is considered normal, <8 min is pathological and the 8–10 min range is considered a `grey' zone. Presence of two or more SOREMPs is also pathological. Mean sleep latency <10 min on the maintenance of wakefulness test is considered abnormal.
In the evaluation of sleepiness, several methods of assessment may be employed (e.g. Epworth Sleepiness Scale, MSLT and a reaction time test), although the results of the various tests often lack correlation within individual subjects. Practically speaking, for the generalist or neurologist, simple subjective measures, such as the Epworth Sleepiness Scale or visual analogue scales, represent reasonable starting points in the assessment of EDS. More expensive, objective studies are probably best left to specialized sleep disorders centres.
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Syndromes of sleepiness |
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Insufficient sleep
The most common cause of daytime sleepiness is insufficient sleep, which may reflect poor sleep hygiene (behaviours impacting sleep) or self-imposed or socially dictated sleep deprivation. Again citing the National Sleep Foundation 2000 Omnibus Sleep in America Poll: `only one-third (33%) of adults say they get at least the recommended 8 h or more of sleep per night during the workweek; and one-third (33%) of adults say they get fewer than 6.5 h of sleep per night during the workweek'. It should be noted that the proverbial 8 h sleep requirement has been challenged; recent epidemiological evidence suggests that the actual sleep requirement in the general population may be closer to 7 h (Ohayon et al., 1997a
).
Busy people tend to regard sleep as a bank from which time can be borrowed as necessary to allow them to accomplish more by prolonging wakefulness. Thus, a sleep-debt is accumulated over time. If the sleep-debt is not repaid in sleep, per se, some other currency must be used—this usually takes the form of daytime dysfunction and may include cognitive impairment, disordered mood, suboptimal performance, physical fatigue or mental drowsiness (Pilcher and Huffcutt, 1996; Dinges et al., 1997).
It is important to recognize the variation in sleep need among individuals. The proverbial 8 h of sleep will be sufficient for most individuals but inadequate to prevent sleep deprivation in those who require more. Adolescents generally need more sleep than adults, but are even less likely to obtain adequate amounts (Carskadon, 1990; Mercer et al., 1998). Sleep diaries (detailed patient accounts detailing sleep timing and characteristics) are helpful in documenting patterns of insufficient sleep; naps and longer sleep times on weekends are important clues.
Fragmented sleep
Sleep quality is as important as sleep quantity. Continuity appears to be the single most important factor in determining whether sleep is refreshing. Sleep may be fragmented by periods of wakefulness, which are obvious to the patient or bed-partner, but more occult fragmentation results from brief arousals, which lack recognizable cognitive or behavioural features. The causes of sleep fragmentation are various and will be addressed below.
Sleep-related breathing disorders
Sleep-related breathing disorders (SRBD) represent a very common (but under-diagnosed) cause of sleep fragmentation, and hence, daytime sleepiness. These disorders are a consequence of abnormal anatomy (crowding of the airway) superimposed on normal sleep physiology (reduction in muscle tone). During inspiration, pressure in the airway becomes negative relative to atmospheric pressure. If the airway pressure reaches a certain threshold, some degree of airway collapse and narrowing will occur. While the brain is awake, sufficient tone is maintained in the muscles of the airway to avoid significant airway collapse. With sleep onset, however, muscle tone diminishes and the soft tissues of the airway become more compliant. If the airway pressure reaches the critical threshold, complete or partial airway collapse will ensue. Any factor, such as anatomical crowding of the airway, which contributes to airway pressure negativity, will tend to facilitate airway narrowing during sleep.
Obstructive sleep apnoea (OSA) was the first described SRBD. It usually, but not invariably, occurs in individuals who snore. In OSA, complete collapse of the airway occurs during sleep; this leads to episodes of cessation of breathing, which last for >10 s, cause blood oxygen desaturation and tend to fragment sleep. Either increased mechanical effort or hypoxaemia may trigger brief (usually only a few seconds) arousal in the brain. The arousal immediately restores muscle tone to waking levels; airway muscles tighten and stiffen, airway patency increases and breathing resumes. As the brain returns to sleep and muscle tone once again declines, the apnoeic process tends to recur, often frequently, throughout the night. Patients with OSA face increased risks of developing hypertension, cardiac arrhythmia, myocardial infarction and stroke (Hla et al., 1994; Lavie et al., 2000; Nieto et al., 2000; Ohayon et al., 2000; Peppard et al., 2000). Other associated symptoms and health problems include nocturia, impotence, headache, gastro-oesophageal reflux and depression. When OSA is associated with daytime sleepiness, the disorder is called obstructive sleep apnoea syndrome (OSAS). Prevalence of OSAS has been calculated from a cohort to be 4% for males and 2% for females, between the ages of 30 and 60 years in the USA (Young et al., 1993), and 2% in a representative sample of the UK population (Ohayon et al., 1997b). Most studies have looked at Caucasians; prevalence of OSAS in other ethnic groups is not well known. OSAS has important negative effects including reduced productivity, cognitive dysfunction, irritability, judgement error and increased accident rates.
Less dramatic forms of SRBD occur. There may be partial airway collapse during sleep, leading to episodes of reduced airflow (termed `hypopnoeas'), short of frank apnoea. An even more subtle form of SRBD, called upper airway resistance syndrome (UARS) has been described (Guilleminault et al., 1993). In UARS, episodes of increased airway resistance occur during sleep, due to mechanisms similar to those described in OSA. Although oxygen desaturation and significant limitation of airflow do not occur in UARS, breathing is maintained at the expense of increased respiratory effort and resultant sleep fragmentation. Unless special instrumentation is used to monitor oesophageal pressure (a sensitive indicator of respiratory effort), this disorder may be overlooked. Patients with UARS suffer the same daytime consequences as do those with OSA.
Periodic limb movements of sleep
Periodic limb movements of sleep (PLMS) represent another very common cause of sleep fragmentation. Originally termed `nocturnal myoclonus' by Symonds (Symonds, 1953), these are repetitive involuntary movements (not true myoclonus) of the limbs (usually the legs, but occasionally the arms), which occur during sleep. The pathogenesis of the movements is unclear; motor oscillators have been proposed in both brain (Bucher et al., 1997; Tergau et al., 1999) and spinal cord (Lee et al., 1996; Trenkwalder et al., 1996). PLMS appear predominately in light non-REM sleep, are less common in slow wave sleep and are rarely seen in REM sleep. The movements may or may not be associated with brief EEG arousals. In sufficient quantity, they fragment the sleep and impact daytime function. The exact prevalence of PLMS is unknown, but it increases with age and approaches 30% by age 50. PLMS occur in the great majority of individuals with restless legs syndrome, which has an estimated prevalence of ~5% (Chokroverty and Jankovic, 1999), but most patients with PLMS do not have symptoms of restless legs syndrome. PLMS and restless legs syndrome are associated with several medical conditions, including iron deficiency (Sun et al., 1998), folate deficiency, renal disease (Winkelman et al., 1996), peripheral neuropathy (Ondo and Jankovic, 1996), parkinsonism (Trenkwalder, 1998) and spinal disorders (Lee et al., 1996). The movements tend to be exacerbated by caffeine, neuroleptics and antidepressants. Many patients with PLMS are unaware of their leg movements, and the diagnosis may be suggested by the bed-partner. The movements are usually responsive to pharmacological treatment. We favour dopaminergic agonists as first-line therapy, but several other classes of drugs have been found to have efficacy, including benzodiazepines, opioids, anti-convulsants and beta-blockers.
Other medical conditions
A variety of medical conditions may be associated with sleep fragmentation, including arthritis, fibromyalgia, spondylosis, chronic pain of any nature, nocturnal angina, epilepsy, asthma, chronic destructive pulmonary disease, alcoholism, urinary dysfunction and gastrointestinal disorders (e.g. peptic ulcer disease), gastro-oesophageal reflux and irritable bowel syndrome (Chokroverty, 1999).
Primary disorders of alertness
Narcolepsy
The prevalence of narcolepsy is estimated to be 0.03–0.05%. Onset of symptoms may occur at virtually any age, but peak onset occurs in adolescence (with a secondary peak in the fourth decade). EDS is usually the presenting symptom, but some patients also have associated features including cataplexy (sudden, transient loss of muscle tone, usually in response to an emotional stimulus), sleep paralysis, hypnogogic or hypnopompic hallucinations and disrupted nocturnal sleep. The daytime sleepiness often becomes irresistible, leading to episodes of sleep at inappropriate times, so-called `sleep attacks'. Periods of automatic behaviour may also occur, a reflection of brief intrusions of sleep (`micro-sleeps') into the drowsy state.
The pathogenesis of human narcolepsy remains elusive, although there have been recent advances in the understanding of this disease, as will be discussed below. The clinical expression of the disorder is likely to depend upon an interplay between one or more genetic factors and environmental triggers. A genetic basis is suggested by association with specific HLA alleles and increased prevalence in first-degree relatives (40 times that in the general population) (Guilleminault et al., 1989). That genetic factors alone are insufficient to explain the disorder is supported by the infrequent familial cases and the low concordance rate (25–30%) of narcolepsy between identical twins.
Honda and colleagues first described the associations between narcolepsy and HLA-DR2 and HLA DQ6 in the Japanese population (Honda et al., 1986). The association has been confirmed in 96% of Caucasians with narcolepsy (Mignot et al., 1994). The incidence of HLA-DR2 varies among ethnic groups, with a lower incidence in African-Blacks. HLA-DQ6 (and more particularly DQß1*0602) is a more sensitive marker for narcolepsy across ethnic groups. DQ ß1*0602 also occurs more often in narcoleptics with cataplexy (76%) than in those without cataplexy (41%) (Mignot et al., 1994). The strong HLA associations suggest that an autoimmune process may be involved. Overall, HLA typing is of limited usefulness in diagnosing narcolepsy, because the subtypes of interest occur not infrequently in normal individuals, and the HLA associations are strongest in individuals with cataplexy (who also pose the least diagnostic difficulty); however, HLA negativity might cause one to question the diagnosis.
Important advances in the understanding of narcolepsy have been reported recently. In 1998, de Lecea and colleagues reported finding a hypothalamic-specific mRNA encoding the precursor of a pair of peptides homologous to secretin (de Lecea et al., 1998). They named the peptides hypocretin 1 and hypocretin 2 (Hcrt1 and Hcrt2) to denote their hypothalamic specificity and their resemblance to secretin.
Lin and colleagues found a mutation in the hypocretin 2 receptor gene in narcoleptic dogs (Lin et al., 1999). Around the same time, Chemilli and co-workers observed narcoleptic-like behaviour in preprohypocretin knockout mice (Chemelli et al., 1999). Nishino and colleagues hypothesized that human narcolepsy involves a disruption in hypocretin neurotransmission (Nishino et al., 2000). They measured CSF hypocretin in nine narcoleptic patients with cataplexy and eight controls. Hypocretin 1 was detected in all control samples (250–85 pg/ml). In seven of nine patients, hypocretin levels were below the limits of detection of the assay (<40 pg/ml).
Very recently, pathological studies of brains of narcoleptics (compared with age-matched controls), performed simultaneously at University of California at Los Angeles and at Stanford, have demonstrated absence of hypocretin neurones in the hypothalamus (Peyron et al., 2000; Thannickal et al., 2000).
Along with the clinical history, polysomnographic studies are essential in confirming the diagnosis of narcolepsy. Overnight recordings often demonstrate shortening of REM sleep latency, as well as disruption of sleep architecture with brief awakenings. MSLT results are abnormal, with mean sleep latencies usually <5 min and the occurrence of SOREMPs. Measurement of CSF hypocretin may become an important diagnostic and research tool in narcolepsy.
Presently, the treatment of narcolepsy consists of behavioural changes, education, support and medications. For EDS, stimulants or wakefulness-promoting medications are used. The amphetamines, methylphenidate, pemoline and modafinil have all been used with some success (Mitler et al., 1994) (see Table 1). These agents differ somewhat in efficacy (Mitler et al., 1994). The alerting effects of the stimulants are related to their actions on release of dopamine and inhibition of its reuptake (Nishino et al., 1998). Although modafinil, which is not a stimulant in the traditional sense, has some effect on dopamine reuptake, the mechanism of its action in promoting wakefulness is still debated. Recent animal studies suggest that it may act on the tuberomammillary nucleus and the hypocretin neurones in the hypothalamus (Scammell et al., 2000). It is best to initiate these medications in low doses and titrate the dose upward as needed and as tolerated. Unfortunately, in doses high enough to alleviate EDS in narcolepsy, the stimulants often produce side-effects. Common side-effects include nervousness, irritability, tremor, anorexia, gastrointestinal symptoms, headache, sweating and palpitations. In most cases, these untoward symptoms are minor and tolerable. However, more significant side-effects, such as tachycardia, hypertension, dyskinesia, stroke and psychosis have been reported. Some patients tolerate modafinil better than the other agents. Headache is commonly reported with modafinil but is seldom severe and usually abates within a few days. Pemoline is thought to be the safest stimulant for use during pregnancy, but it has fallen out of favour due to the potential for hepatic toxicity and is no longer available in some countries. Some narcoleptic patients find caffeine to be helpful as an adjunct to more efficacious agents. Other drugs that help alleviate EDS in some patients include protriptyline, monoamine oxidase inhibitors and codeine. It should be noted that even with maximum recommended doses, none of the presently available drugs restore the narcoleptic patient to a state of normal alertness (Mitler et al., 1994).
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In the 1960s, imipramine was found to be effective in reducing cataplexy. Other tricyclic antidepressants were later used. These agents continue to be the most commonly used anticataplectic medications (particularly imipramine, clomipramine and protriptyline) but are not ideal because of their side-effect profiles. In addition to anticholinergic effects, the tricyclics may produce weight gain, sexual dysfunction, orthostatic hypotension and antihistaminic symptoms. The tricyclics probably act against cataplexy by virtue of their inhibitory actions on catecholamine reuptake (particularly norepinephrine) (Nishino and Mignot, 1997
). Newer antidepressant medications [including SSRIs (selective serotonin reuptake inhibitors) and dual-action agents] have been used to treat cataplexy with fewer side-effects than the tricyclics (see Table 2). Amphetamine-like substances also have some anticataplectic properties because of their adrenergic and, less importantly, dopaminergic effects. Unless the patient has mild cataplexy, however, a second drug is usually necessary. The practitioner should warn the patient that rebound cataplexy, sometimes severe, may occur if medications are reduced or discontinued. This should be kept in mind if, for example, the patient is switched from amphetamine to modafinil, which has no anticataplectic actions. Sleep paralysis and hypnagogic hallucinations also respond to the medications used to treat cataplexy.
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Gamma-hydroxybutyrate is an endogenously occurring hypnotic substance that is effective in consolidating sleep. It is known to promote both REM and slow wave sleep. Studies of narcoleptic patients taking gamma-hydroxybutyrate have found improvement in sleep disruption, EDS, cataplexy, sleep paralysis and hypnagogic hallucinations (Lammers et al., 1993
; Mamelak et al., 1986). Gamma-hydroxybutyrate has a rapid onset of action and is short acting. It is usually given at bedtime, and a second dose is often needed during the night. Side-effects include nausea, vomiting (usually transient), weight loss, occasional residual drowsiness and enuresis (uncommon). At the time of this writing, gamma-hydroxybutyrate is only available as an investigational drug, having been restricted because of reports of recreational use among the general population. It is hoped that the substance will be cleared for clinical use in narcolepsy in the near future. Other agents, which have been used to consolidate nocturnal sleep in narcoleptics, include benzodiazepines, trazadone and melatonin (controversial). Narcoleptic patients who also suffer from sleep-disordered breathing tend to tolerate continuous positive airway pressure poorly because of their disturbed nocturnal sleep; they may benefit from the use of short-acting hypnotics. Pharmacological treatment of narcolepsy should be supplemented with behavioural changes. Scheduled brief naps of 10–20 min duration are often very useful in helping the narcoleptic patient negotiate daytime activities. Naps may be repeated throughout the day. Many patients report transient improvement in alertness for 90–120 min following a nap. Dietary changes may also be helpful, as many patients report that symptoms are worse after high carbohydrate meals. The patient should be cautioned about driving or performing dangerous activities while drowsy.
As with any chronic, debilitating disease, education and support are essential to patient well-being. Healthcare providers should be willing to educate teachers, employers and family members of patients about narcolepsy. Education and support groups are also available under the auspices of the Narcolepsy Network and the National Sleep Foundation. Patients should be made aware of these resources and encouraged to use them.
Idiopathic CNS hypersomnia
This disorder is characterized by EDS, but without cataplexy or nocturnal sleep disruption (Billiard et al., 1998). It is believed to be less common than narcolepsy, but prevalence is difficult to determine, because strict diagnostic criteria are lacking, and no specific diagnostic marker is currently available. Onset of symptoms occurs in adolescence or early adulthood. Aetiology of the disorder is not known, although viral illnesses may herald the onset of sleepiness in a subset of patients. Familial cases are known to occur, with increased frequency of HLA-Cw2. HLA typing in sporadic cases is unrevealing. Patients with idiopathic CNS hypersomnia report increased total sleep times. No amount of sleep ameliorates the EDS, and naps are generally not refreshing. Occupational and social functioning may be severely impacted by sleepiness. Polysomnography usually reveals shortened initial sleep latency, increased total sleep time and normal sleep architecture. Mean sleep latency on MSLT is usually reduced, often in the 8–10 min range, but SOREMPs are not seen. Treatment is often less than satisfactory and includes stimulant medication (see Table 1
) and lifestyle modifications.
Kleine–Levin syndrome
This uncommon disorder is a form of periodic hypersomnia, which occurs primarily in adolescents (Critchley, 1967). The initial report of a male preponderance has not been confirmed. It is characterized by the occurrence of episodes of EDS, usually accompanied by hyperphagia, aggressiveness and hypersexuality, lasting days to weeks and separated by weeks or months. During symptomatic periods, individuals sleep up to 18 h per day and are often drowsy, confused and irritable the remainder of the time. The aetiology of this incapacitating syndrome is obscure. Treatment with stimulant medication is usually only partially effective. Effects of treatment with lithium, valproic acid or carbamazepine have been variable, but generally unsatisfactory. Fortunately, in most cases, episodes become less frequent over time and eventually subside. The syndrome must be distinguished from menstrual-related periodic hypersomnia (Billiard et al., 1975 ), in which symptoms occur during the several days prior to menstruation. This syndrome responds to the blocking of menstruation with oestrogen and progesterone (birth control pills).
Circadian disorders
The normal circadian cycle, regulated by the supra-chiasmatic nucleus of the hypothalamus, is a major determinate of alertness or sleepiness across the 24-h period (Turek, 2000). The cycle is entrained by factors such as physical activity and, especially, environmental light. If this physiological cycle becomes desynchronized with the major sleep period or with the daily schedule, EDS may be experienced. Transient situations of this sort, such as jet-lag, pose no diagnostic difficulty, but more chronic conditions may be overlooked if a careful sleep history is not taken.
Delayed sleep phase, i.e. a circadian driven tendency for the major sleep period to begin and end at later times, is common during puberty and may be associated with hormonal changes occurring at that time (Carskadon et al., 1993). Delayed sleep phase syndrome (DSPS) (Weitzman et al., 1981) is less common. In DSPS, the shifting of the major sleep period causes disruption of `normal' activities and often conflict within the family. School performance typically suffers, particularly in morning classes, when the individual is in a state of suboptimal alertness. Often, a psychological or psychiatric component (including disorders of personality) is part of the picture. Treatment programmes may be doomed to failure unless this aspect is addressed. Another chronic circadian disorder, known as advanced sleep phase syndrome (ASPS) (Baker and Zee, 2000), involves the shift of the major sleep period to an earlier time; this condition often occurs in the elderly population. The sleep of patients with DSPS and ASPS is normal in quality and architecture, but it occurs at times which conflict with societal dictates and which the patients may find problematic. DSPS may be mistaken for insomnia, as the patient may simply complain of difficulty with sleep initiation. Likewise, the patient with ASPS may be diagnosed with depression because of a complaint of early awakening. A careful history, perhaps supplemented with sleep diaries or actigraphy (a portable method for monitoring motor activity over time) usually eliminates any diagnostic uncertainty. Circadian rhythm disorders, such as ASPS and DSPS, can be treated with exposure to bright (5000–10 000 lux) broad-spectrum (non-UV) light. The timing of the light exposure is critical to shift the phase of the sleep period in the desired direction. Exposure to light prior to the circadian nadir of the core body temperature (which typically occurs around 2–3 h before habitual wake-up time) tends to delay the sleep phase; light exposure after the temperature nadir tends to advance the sleep phase.
EDS is a common problem for shift-workers, who tend to have reduced total sleep times per 24-h period, in addition to their circadian disruptions (Akerstadt, 1996). Much less common are patients with a `non-24-h sleep–wake syndrome' (International Classification of Sleep Disorders—Revised). Most of these individuals are blind and lack effective input to the supra-chiasmatic nucleus from the optic nerves (Leger et al., 1999). Therefore, they are unable to entrain the circadian clock with environmental light. Their circadian clock behaves as in `free-running' conditions, and the major sleep period tends to be progressively delayed each day. Over time, the major sleep period will work its way around the 24-h clock; the patient will, thus, experience symptoms which vary according to the synchrony of the circadian clock and the 24-h clock. This disorder may rarely occur in patients with structural abnormalities involving the hypothalamus. Another uncommon circadian disturbance is known as `irregular sleep–wake pattern' (International Classification of Sleep Disorders, Revised). These individuals do not exhibit a consistent major sleep period; rather they have irregular periods of sleep and wakefulness across the 24-h epoch, behaving as if they do not have a circadian timekeeper. This condition may be induced by social or environmental factors or because of intrinsic brain pathology. The possibility of a structural lesion should be strongly considered if the disorder has an acute presentation.
Nervous system disorders and EDS
EDS may be associated with disorders of the central or peripheral nervous systems. EDS is a clinical feature of many toxic or metabolic encephalopathic processes. These disorders often present with other symptoms and signs, but EDS may dominate the picture, particularly in chronic cases. Structural brain lesions, including strokes, tumours, cysts, abscesses, haematomas, vascular malformations and multiple sclerosis plaques are known to produce EDS. Somnolence may result from direct involvement of discrete brain regions (especially the brainstem reticular formation or midline diencephalic structures) or because of effects on sleep continuity (e.g. nocturnal seizure activity or secondary SRBD).
EDS has also been reported following encephalitis or head trauma. Even post-traumatic narcolepsy with cataplexy has been described (Francisco and Ivanhoe, 1996). Epileptic patients may suffer from EDS as a consequence of medication effects or less obviously due to nocturnal seizure activity (Manni and Tartara, 2000). Sleep disruption and EDS are common in neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease and other dementias and multiple system atrophy (Askenasy 1993; Chokroverty 1996; Trenkwalder 1998). Patients with neuromuscular disorders or peripheral neuropathies may also develop EDS because of associated SRBD (central or obstructive apnoea), pain or PLMS (George, 2000).
Psychiatric disorders and EDS
Psychiatric disorders are often associated with disrupted sleep. This is especially true of depression. While the majority of depressed patients with sleep disruption suffer from insomnia, some of them have EDS. This subset of patients is often diagnosed with `atypical' depression or depression with the DSM-IV atypical features specifier (which includes mood reactivity, increased appetite, leaden `paralysis' and rejection sensitivity along with hypersomnia) (Diagnostic and statistical manual of mental disorders: DSM-IV-TR). These patients are thought to respond better to MAO inhibitors and possibly norepinephrine reuptake inhibitors than to other types of antidepressants.
There are also patients who might be said to have `psychogenic hypersomnia' (Vgontzas et al., 2000). Generally, they are young adults who complain of EDS and have MSLT mean sleep latencies in the 7–10 min range. Overnight studies demonstrate long times in bed and poor sleep efficiency (ratio of total sleep time to total time in bed). These patients often develop symptoms after a prolonged period of stress or following a period of disrupted sleep. They respond to stress management, to improved sleep hygiene with reduction of time in bed and to reduced sleep time. Exposure to bright light immediately after arising in the morning (using commercially available light boxes) has also been found to be useful.
Drugs and EDS
Obviously, numerous drugs can produce EDS, including sedatives, hypnotics, anxiolytics, antihistamines, antidepressants, antihypertensives, anticonvulsants, and neuroleptics. There is considerable variation in individual susceptibility in this regard. It is also important to remember that drug–drug interactions or metabolic derangements (such as liver disease) may lead to EDS with doses of drugs which might otherwise seem insignificant. Withdrawal from stimulant drugs usually produces some degree of rebound hypersomnia.
Recently, it has been reported that dopamine agonists may induce EDS in parkinsonian patients (Frucht et al., 1999; Olanow et al., 2000).
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Although progress has been made in understanding EDS, there is still much to learn. Most patients with this troubling (and often debilitating) symptom can be helped with proper treatment. It is important for physicians who see these patients to understand that the clinical presentation of EDS may be couched in terms such as `tiredness' or `fatigue', which do not denote primary sleepiness. Physicians must also appreciate the rather broad scope of the differential diagnosis of this common symptom.
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S.N.B is supported by an unrestricted grant from Cephalon, Inc.
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Received October 31, 2000. Revised February 27, 2001. Accepted April 5, 2001.
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