Differential Diagnosis and Treatment of Excessive Daytime Sleepiness
Scott M. Leibowitz, MD, and Jed E. Black, MD
Excessive daytime sleepiness (EDS) is an extremely common complaint in the general medical and psychiatric population. In this light, physicians should have a solid working knowledge of the differential diagnosis, preliminary evaluation, and range of treatment options for this complaint. Despite the enormous impact of EDS and its varied causes on productivity, quality of life, and overall health, there is a surprising deficit in knowledge in many general medical practitioners. A more thorough understanding of EDS and its attendant causes should be part of the knowledge base of all general medical personnel.
• List the primary causes of excessive daytime sleepiness (EDS).
• Generate a differential diagnosis of
diseases causing EDS.
• Understand the causes of fragmented sleep.
• Differentiate between primary disorders of hypersomnolence.
• Understand the appropriate treatment options available for the various causes of EDS.
Primary care physicians and psychiatrists.
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Primary Psychiatry. 2005;12(8):57-66
Dr. Leibowitz is a fellow in sleep medicine at the Stanford Sleep Disorders Center at Stanford University in California.
Dr. Black is the director of the Stanford Sleep Disorders Center and assistant professor in the Department of Psychiatry and Behavioral Sciences at Stanford University.
Disclosure: Dr. Leibowitz has received research support from GlaxoSmithKline. Dr Black has received research support from Cephalon, GlaxoSmithKline, and Orphan Medical.
Please direct all correspondence to: Jed E. Black, MD, 401 Quarry Road, #3301 Stanford, CA 94305; Tel: 650-723-6601; E-mail: firstname.lastname@example.org.
Excessive daytime sleepiness (EDS) is a common problem plaguing society’s health, well-being, and productivity. While insufficient sleep is the most common cause of EDS, there are many pathologic disorders which, despite sufficient sleep quantity, produce ongoing EDS. Disorders that cause sleep fragmentation, such as obstructive sleep apnea and periodic limb movement disorder, can cause significant EDS despite adequate hours of sleep. Additionally, there are several primary disorders of somnolence that arise from central nervous system dysfunction. Narcolepsy is one such disorder that is well known to clinicians but frequently misunderstood. Idiopathic hypersomnia, the recurrent hypersomnias, and EDS associated with central nervous system disorders must also be considered in the differential of EDS to provide appropriate evaluation and patient management. EDS associated with psychiatric disorders is less common than often presumed, but still should be a consideration in the work-up. This review summarizes the various clinical syndromes of primary EDS and provides an overview of evaluation and management of the patient suffering from EDS.
The sleep-wake system is a complex and dynamic system which governs the general states of arousal or somnolence at all times. These dynamic and interrelated states predispose the individual either to wakefulness or sleep. An individual’s degree of somnolence may be impacted by multiple determinants, including quantity or quality of sleep, circadian clock time, concentration, motivation, environmental influences, medications, primary sleep disorders, acute or chronic medical conditions, and/or acute and chronic psychiatric conditions. “Pathologic” sleepiness or excessive daytime sleepiness (EDS) is a complaint found in patients who experience somnolence at unwanted times which adversely affects their daytime function.
A distinction should be noted between EDS and fatigue, although these descriptors are frequently used interchangeably in clinical practice. The patient with EDS will often struggle to maintain wakefulness in monotonous situations while the patient with the complaint of fatigue may have EDS, but may as readily have no feeling of sleepiness and may be experiencing listlessness or lethargy rather than a tendency to fall asleep. While there is considerable overlap between these two complaints, and both complaints may be indicative of a significant problem, the former is a more specific symptom complex, usually indicative of a specific physiologic state, while the latter is a nonspecific complaint which may represent any number of chronic or acute physiologic or psychological processes.
The American Academy of Sleep Disorders defines EDS in the International Classification of Sleep Disorders1 (ICSD) as “a complaint of difficulty in maintaining desired wakefulness or a complaint of excessive amount of sleep.” The ICSD elucidates that excessive sleepiness (also referred to as somnolence or hypersomnia) is a subjective report of difficulty maintaining the alert awake state, usually accompanied by a rapid entrance into sleep when the person is sedentary. The severity criteria for sleepiness in the ICSD are based on frequency and degree of associated daytime impairment. This review summarizes the clinical presentation, the differential diagnosis, diagnostic armamentarium, and treatment options for the patient complaining of EDS.
Epidemiology of Sleepiness
There is considerable variability in the literature in terms of the prevalence of reported EDS. This variability is likely due to the inconsistent measures of EDS and subsequent differences in investigation, definition, and classification of the complaint. A review by Partinen and Hublin2 of 24 epidemiologic studies conducted from 1976–1997 found a range of .03% to 36% across studies, depending on how EDS was defined.2 While the prevalence of “sleeping too much” fell in the range of .03% to 4%, the prevalence of “perceived sleepiness” ranged from 10% to 15%.2 The largest and most comprehensive representative population survey was performed across four Western European countries (the United Kingdom, Germany, Spain, and Italy). Substantial EDS, defined by meeting three parameters of marked sleepiness during >3 days/week, was reported in 15% of this combined population.3 In the United States, smaller population surveys have been conducted. Two recent polls4,5 suggested that 15% to 16% of the US population over 18 years of age may experience EDS that interferes with daily activities a few days a week or more; they did not differentiate between causes of EDS.
Evaluation of the Patient with Excessive Daytime Sleepiness
Of key importance in evaluating the patient complaining of EDS is a detailed history and physical exam. Obtaining a detailed sleep history in addition to a medical history is essential. Documentation of total daily 24-hour sleep time and daily sleep pattern, number of nocturnal awakenings, prolonged sleep latencies, snoring, witnessed apneas, symptoms of restless legs syndrome (RLS), periodic limb movements, and restless sleep are highlights of the sleep history that should be covered at minimum. Medical conditions and alcohol or drug abuse can be significant contributors to EDS and, if suspected, appropriate evaluation should ensue. Special note should also be made of chronic sedating medications.
Sleep history should be supplemented with questionnaires evaluating degree of sleepiness and impact on daily living. These questionnaires include, but are not limited to, the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale, and the Sleep-Wake Activity Inventory. The ESS is the most commonly used questionnaire due to its ease of use and small, but statistically significant, correlation with sleepiness measured by an objective test of sleepiness known as the multiple sleep latency test (MSLT).6,7 While a normal value of the ESS is considered to be <10, this test is neither highly specific nor sensitive for the existence of pathological sleepiness and these values are not entirely representative of true level of sleepiness; however, the ESS serves as a useful screen for those who are severely sleepy.8 With the ease of use of the ESS and the high prevalence of sleepiness in the general public, we advocate the administration of this tool to all adult patients in any clinical practice. To further characterize a patient’s sleep, nightly sleep logs can be helpful in establishing circadian tendencies and patterns of sleep. If the patient is unable to give a reliable history or nightly sleep times are in question, several days of actigraphy monitoring, a device that registers movement by the patient, may be a useful tool in evaluating patterns of waking and sleep.
Once a thorough history and physical are performed, if a physical sleep problem is considered, the primary diagnostic tool available is the nocturnal polysomnogram (PSG). The PSG is used to evaluate sleep disturbances leading to sleep fragmentation, including sleep-related breathing disorder (SRBD), periodic limb movement of sleep (PLMS), rapid eye movement (REM)-sleep behavior disorder, and/or, more rarely seen, nocturnal seizures.
To objectively evaluate the degree of sleepiness of an individual, the MSLT can be used. The MSLT consists of four or five 20-minute polysomnographically monitored daytime nap opportunities separated by 2-hour intervals wherein the patient is placed in a sleep laboratory bed in a dark room with instructions to fall asleep. The primary assessments made by the MSLT are the rapidity of sleep onset, which correlates to degree of sleepiness, and to establish the presence of REM sleep, if sleep occurs during the nap opportunity. REM sleep episodes (a period of sleep during which dreams occur) at or close to sleep onset are known as sleep-onset rapid eye movement (SOREM) periods.
Typical sleep latencies in the normal adult are 10–20 minutes while pathological sleepiness is manifested by a latency of <5–6 minutes.9 The MSLT should be performed immediately following a nocturnal PSG in order to exclude other causes of EDS due to either sleep fragmentation or insufficient sleep. If the PSG is positive for other causes of EDS, these conditions should be adequately treated before an evaluation of EDS with an MSLT is pursued.
The maintenance of wakefulness test (MWT) is another diagnostic test used in the sleep laboratory. Rather than evaluate the tendency to fall asleep, as the MSLT does, the MWT assesses the capacity to maintain wakefulness in a sedentary setting during the patient’s regular waking hours and is often used to evaluate impact of treatment for obstructive sleep apnea (OSA)-related EDS in heavy equipment operators and/or airline pilots.
Syndromes of Sleepiness
Insufficient sleep is the most common cause of EDS in western culture. Although the exact prevalence is unclear, Sleep in America polls conducted by the National Sleep Foundation in 2002 found that 37% of adults reported sleeping <7 hours/night and 68% of adults reported sleeping <8 hours/night.4 Although sleep requirements vary between individuals, it was found in these same polls that total weeknight sleep times averaged 6.9 hours, compared to 7.5 hours on weekends. This discrepancy in weeknight versus weekend sleep times implies ongoing voluntary sleep restriction during the week with compensation on the weekends through sleep time extension.
The number of hours of experimental sleep loss in normal volunteers is directly proportional to the degree of increased daytime sleepiness, as assessed by the MSLT.10 The effects of sleep deprivation may be cumulative,9 but this accumulated sleep debt may be countered by extending sleep time over several days.11 Insufficient sleep may be due to voluntary lifestyle choices, job or school demands, shift work, or poor sleep hygiene.
Shift work comprises as much as 16% of the workforce in the US.12 Some research has suggested that despite subjectively experiencing adequate daytime sleep, shift workers lose an average of 5–7 hours of sleep/ week, compared to diurnal workers.13 Additionally, studies have consistently shown that individuals who engage in regular night shift work experience more disrupted sleep as well as sleepiness during waking hours, compared to day workers.14,15
Insufficient sleep is expected to lead to frank EDS, however a constellation of other subjective complaints are more commonly seen. These include complaints of tiredness, lack of energy, or fatigue. Additionally, decrements in attention, learning capacity, short-term memory, and/or psychomotor performance, with or without EDS, may be present. Moreover, irritability, poor impulse control, or other forms of mood instability may exist alone or in concert with the above-noted features in individuals with insufficient sleep.
The body’s sleep/wake cycle is controlled or influenced by an internal pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus that provides regulatory signaling which oscillates on a circadian or approximately 24-hour pattern. This internal “clock” is influenced by a number of external factors called zeitgebers. Zeitgebers regulate and synchronize circadian rhythms; the strongest zeitgeber is sunlight. The SCN facilitates potent central nervous system (CNS) alerting activity during the day and activity that promotes sleep at night. Light and other zeitgebers reset the timing or “phase” or the SCN when we travel to a new time zone. Additionally, genetically determined individual variability in circadian phase exists resulting in some individuals manifesting “night owl” sleep-wake behavior while others are “morning larks.” If an individual’s circadian phase does not coordinate with social or work demands, sleep time may be curtailed and residual EDS may occur.
Circadian rhythm disorders are chronic conditions that occur when sleeping patterns are not synchronized with environmental cues for sleep and wakefulness. These disorders manifest when a patient cannot sleep at a suitable time or desires to sleep at an unsuitable time. Examples of these disorders include, but are not limited to, advanced sleep phase syndrome, which is characterized by propensity to fall asleep in the early evening with subsequent early morning awakening; delayed sleep phase syndrome, characterized by inability to fall asleep at traditional evening times with subsequent difficulty arising in the morning; jet lag, where an individual’s internal circadian rhythm is desynchronized with the external environment due to travel across multiple time zones; and shift work sleep disorder (SWSD), where work demands the constant adjustment and readjustment of the sleep phase resulting in EDS during work hours and curtailed, fragmented sleep in off-hours.
Several physical conditions may lead to fragmented sleep, predominately in the form of microfragmentation. Microfragmentation is seen on an electroencephalogram (EEG) as cortical microarousals typically originating from a disturbance in breathing (eg, OSA, central sleep apnea [CSA], mixed apneas, upper airway resistance syndrome [UARS], or snoring), or a disturbance due to abnormal movements during sleep, most commonly in the form of periodic limb movements of sleep (PLMS). These microarousals may lead to awakenings from sleep at various times during the sleep period, but often the patient is unaware of these problems. Microarousal activity has been postulated to disrupt the normal restorative processes of sleep and has been demonstrated to produce sleepiness and/or daytime performance deficits when induced by various sensory stimuli in normal subjects.16,17
Fragmented sleep in adults, and especially in children, however, may not lead to EDS. While children with sleep-related breathing disorders (SRBD) are generally sleepier than normals, children with SRBD more often tend to display inattention, irritability, and/or hyperactivity,18-20 and their degree of sleepiness tends to increase with severity of SRBD, as opposed to EDS.21,22 In addition, recent evidence strongly suggests that children with primary snoring in the absence of OSA suffer significant neurobehavioral deficits compared to children who do not snore, probably in part due to increased susceptibility to sleep fragmentation.23 The link between sleep fragmentation and attention-deficit/hyperactivity disorder (ADHD) in children has also been found in children with PLMS. A surprising percentage of children diagnosed with ADHD have been found to have PLMS, and conversely, a substantial number of children with PLMS were also found to have ADHD.24,25
Sleep-Related Breathing Disorder
SRBD is highly prevalent in North America with an estimated 20% of adults with mild to asymptomatic disease and at least 5% of adults with significant disease.26 In children, studies have shown a prevalence of primary snoring to be between 10% and 25% in children 3–12 years of age,27,28 while the prevalence of OSA has been found to be between 1% and 3% in the general pediatric population.29
OSA is a condition where cyclical or repetitive obstructive respiratory events occur during sleep with microarousals occurring at the termination of a respiratory event.30,31 In addition to the increased occurrence of micro-arousal activity, alterations in the pattern of sleep stage activity, known as “sleep architecture,” are commonly observed. Specifically, reductions in slow-wave sleep (stages 3 and 4) and REM sleep percentages, with corresponding increases in lighter sleep, typify these changes. Sleep-related EEG alterations, however, do not consistently correlate with measures of sleepiness severity.32 Additionally, it was demonstrated that patients with OSA will complain more often of fatigue and “lack of energy” than of frank sleepiness.33
In addition to OSA, two other types of apneas have been described: CSA and mixed sleep apnea.34 CSA occurs when the drive to breathe during sleep is intermittently absent, while mixed sleep apnea begins as a central event but changes to an obstructive event as respiratory effort begins in the midst of airflow cessation. While CSAs appear to be a unique physiologic event, mixed apneas appear to be essentially obstructive events in which respiratory effort is undetected at the beginning of the apnea. Both apneas are associated with arousals and fragmented sleep with resultant EDS; however, patients with pure CSA less commonly complain of this problem, compared to those with OSA.35,36 CSA may be seen in infants with immature central respiratory control systems, while in adults it may occur with cerebrovascular or neuromuscular disease, hypoventilation syndromes, or in association with the Cheyne-Stokes breathing. CSA is notably present in patients with low cardiac output heart failure.37
UARS is a sleep breathing disorder in which there is increased breathing effort during periods of increased upper airway resistance but in the absence of hypopneas or apneas.38 UARS patients have frequent micro-arousals associated with increased respiratory effort and possibly suffer from EDS. Snoring is often the first symptom reported by patients (or more commonly bedpartners or room/housemates) later diagnosed with OSA or UARS. Snoring alone implies increased resistance of the upper airway during sleep, although data are mixed regarding the true consequences of snoring with regard to EDS.
Periodic Limb Movement Disorder
PLMS are repetitive flexions of the toes, feet, legs, thighs, and/or the arms during sleep, lasting 0.5–5 seconds in duration, recurring every 5–90 seconds. Intermittently, cortical microarousals will occur with movements. Cross-sectional studies predict PLMS occurs in approximately 3.9% to 5% of the adult population39 and approximately 1.2% of children40 in the absence of other sleep disorders. Some controversy exists regarding the impact of PLMS on sleep disturbance and subsequent daytime functioning in adults. When PLMS occur at rates of >5/hour of sleep, they may be associated with EDS. Periodic limb movement disorder (PLMD) may also be diagnosed.41 Several studies have shown no positive correlation of EDS with the number of PLM-arousal complexes per hour of sleep as measured by MSLT.42,43 Based on conflicting data, the significance of PLMS and associated arousals remains poorly understood and clinical correlation is required to understand the significance of each individual case.
Restless Legs Syndrome
A separate but related disorder from PLMD is RLS, a syndrome consisting of an uncomfortable or unpleasant feeling; that occurs predominately in the legs, but may involve the arms: it occurs more often in the evening time and usually relieved by moving or stretching. While PLMD is a PSG diagnosis, RLS is, by definition, a subjective diagnosis based on the patient’s report. While 80% to 85% of all patients with RLS have PLMS, as few as 18% of patients with PLMD experience RLS symptoms.44 Although the mechanism of both disorders likely involves problems with dopamine production and/or utilization, these are distinctly different disorders as classified by the ICSD.1 While RLS is predominately a waking phenomenon, patients do report significantly interrupted sleep and sleep curtailment, often reporting as little as 4 hours of sleep/night due to these uncomfortable sensations.45
Primary Disorders of Excessive Daytime Sleepiness
Many disorders are regarded as primary disorders of EDS. Considered in this review are narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, and posttraumatic hypersomnia.1 Similar to patients with disorders of EDS, individuals with these CNS-mediated EDS syndromes are commonly misdiagnosed as suffering a mood disorder and inappropriately treated with antidepressant therapy.
Narcolepsy is the most well-known and well-studied of the primary disorders of EDS. Epidemiologic studies46,47 have shown that narcolepsy has a prevalence of approximately 1 in 2,000, worldwide, but may have significant variability based on ethnic background. Narcolepsy is characterized by EDS with an increased propensity to fall asleep throughout the day. When in sedentary situations, patients will need to exert an extra effort to avoid nodding or dozing. This tendency toward sleep often manifests as the irresistible or uncontrollable urge to sleep, described as “sleep attacks.” Contrary to popular belief, “sleep attacks” are not sudden lapses into sleep, but rather represent episodes of profound sleepiness similar to that experienced by those with marked sleep deprivation or other severe sleep disorders. ESS scores of >15 are common in untreated patients.48,49 In addition to frank sleepiness, the EDS of narcolepsy, as in other sleep disorders, can cause related symptoms, including poor memory, reduced concentration or attention, and irritability.
Because narcolepsy likely represents a disorder of sleep-state boundary control, patients with narcolepsy will often present with other symptoms in addition to EDS including cataplexy, hypnagogic or hypnopompic hallucinations, and sleep paralysis, all of which manifest features that create the appearance of REM-sleep phenomena intruding into wakefulness. Patients with narcolepsy may also report automatic behaviors and up to 90% of patients will complain of disrupted nocturnal sleep.50 Symptom onset typically begins during adolescence or young adulthood; however, narcolepsy has been seen to occur in early childhood as well into the third or fourth decade of life, or later. The impact of narcolepsy on the individual is dramatic; studies have shown that effect on quality of life is equal to that of Parkinson’s disease.51 Diagnosis of narcolepsy may be elusive as no symptom or sign of narcolepsy is specific to it; cataplexy unrelated to narcolepsy may occur, although rarely, either as an isolated symptom or in conjunction with other conditions.
Cataplexy is the partial or complete loss of bilateral voluntary muscle tone in response to strong emotion. The range of severity of cataplectic events is broad. Reduced muscle tone may be minimal, occurring only in a few muscle groups, causing minimal symptoms such as bilateral ptosis, head drooping, slurred speech, or dropping things from the hand. On the other extreme, cataplexy can be so severe that total body paralysis occurs, resulting in complete collapse of the affected individual. Cataplectic events usually last from a few seconds to 2 or 3 minutes, but occasionally will continue longer.52 During an event, patients are usually alert and oriented despite the inability to respond. Any strong emotion is a potential trigger for cataplexy; although, laughter and other positive emotions are a more common trigger for cataplexy than negative emotions.53 Startling stimuli, stress, physical fatigue, or sleepiness may also be important triggers or factors that exacerbate cataplexy.
Based on epidemologic studies, it appears that patients with narcolepsy experience cataplexy 60% to 100% of the time, depending on how cataplexy is defined. Typically, patients will begin to experience cataplexy either simultaneously or within a few months of developing EDS, but in some cases, cataplexy may not develop until many years after initial onset of EDS.52
Hypnagogic or hypnopompic hallucinations occur at the transition from wakefulness to sleep (hypnagogic) or from sleep to wakefulness (hypnopompic). These hallucinations exist in many forms; they may be visual, tactile, auditory, or multi-sensory, and are usually brief in duration but will occasionally continue for a few minutes. Hallucinations may simultaneously contain a combination of elements from both dream sleep and consciousness; and are often bizarre or disturbing to patients. Patients who experience these episodes have occasionally been misdiagnosed with a psychotic syndrome and inappropriately treated with antipsychotics. Antipsychotics provide no benefit to these patients.
Sleep paralysis is the inability to move during the transition from sleep to wakefulness or from wakefulness to sleep, which may last from a few seconds to minutes. This phenomenon, like hypnogogic hallucinations, appears to be an intrusion of a component of REM-sleep, specifically REM-sleep atonia, into wakefulness. Episodes of sleep paralysis can be quite alarming to patients, especially if combined with a hypnogogic event. Often, patients will report a terrifying experience of the sensation of being unable to breathe. Accessory muscle activity is absent during these episodes, however, diaphragmatic activity continues and air exchange remains adequate, in the same way that air-exchange continues during the atonia of REM-sleep.
Fragmented nocturnal sleep is another “hallmark” symptom of narcolepsy. Patients with narcolepsy have many more and longer nocturnal awakenings than controls, a seemingly paradoxical finding.54 However, narcolepsy is a condition of disrupted continuity of both wakefulness and sleep, with intrusion of each of these states into the other at various inappropriate times. Another symptom commonly reported in narcolepsy patients are automatic behaviors; “absent-minded” behavior or speech that is often nonsensical and that the patient does not remember. Hypnogogic hallucinations, sleep paralysis, and automatic behavior are seen in healthy individuals as well as patients with narcolepsy; however, these symptoms are far more common and occur with much greater frequency in patients with narcolepsy.
Diagnosis of Narcolepsy
The diagnosis of narcolepsy is dependent on clinical history, coupled with confirmatory diagnostic testing. The primary diagnostic tool used to confirm the diagnosis of suspected narcolepsy is the MSLT. The MSLT usually demonstrates substantially reduced sleep latency and SOREMs in patients with narcolepsy. In normal controls with adequate, non-fragmented nocturnal sleep, REM sleep does not occur during daytime naps. During nocturnal sleep, the first REM period will usually not occur until at least 90 minutes after sleep onset. Average MSLT sleep latencies for untreated narcolepsy with cataplexy is approximately 2–3 minutes48; however, substantial variability across patients and within patients can, at times, be seen. SOREM periods are not specific for narcolepsy. Sleep deprivation, REM-suppressant medication rebound, altered sleep schedule, OSA, or delayed sleep-phase syndrome are a few circumstances where SOREMs will be commonly seen on the MSLT. However, the occurrence of >2 of these events during the MSLT, in the setting of objective marked sleepiness and without another explanation for their occurrence is suggestive of narcolepsy.
When cataplexy accompanies EDS, a straightforward diagnosis of narcolepsy can be made. In these cases, nocturnal PSG is not an essential diagnostic tool; however, it still remains an important part of the evaluation process. The nocturnal PSG is used in this setting primarily to exclude other conditions that occur in narcolepsy at a higher than normal rate (OSA, PLMD, and REM-sleep behavior disorder) and could add to the sleepiness or nocturnal sleep disruption and daytime sleepiness the patient may be experiencing.55
In addition to the MSLT, a number of adjunctive tests exist which may help to confirm the diagnosis of narcolepsy in the patient with a confusing clinical presentation. Hypocretin, an excitatory, wake-promoting neurotransmitter produced in the hypothalamus, is found to be low or undetectable in the cerebrospinal fluid (CSF) of many, but not all, patients with narcolepsy.56,57 Such low levels of CSF hypocretin are not specific for narcolepsy. However, when used to assess patients for narcolepsy, low CSF hypocretin is a more specific test than the MSLT and may be more sensitive as well.
A very strong, but incomplete correlation exists between narcolepsy (with cataplexy) and the HLA subtype DQB1* 0602. Unfortunately, this subtype is very common in the general population (approximately 20% in the combined US population) and as a result, not at all specific or sensitive for narcolepsy.47 HLA testing should be reserved for the sleep physician evaluating the possibility of narcolepsy in a patient with a high degree of clinical suspicion.
Idiopathic hypersomnia (previously labeled “idiopathic CNS hypersomnia”), is another important primary disorder of EDS that should be considered in the patient complaining of sleepiness. This diagnosis has historically been given to individuals who complain of EDS when other disorders causing hypersomnolence have not been found or clearly characterized. There are numerous documented cases of patients having been misdiagnosed with idiopathic hypersomnia when in fact; they suffered from other disorders causing EDS, such as narcolepsy without cataplexy, DSPS, or upper airway resistance syndrome.58
True idiopathic hypersomnia is believed to be less common than narcolepsy, but estimation of prevalence is difficult because there are no strict diagnostic criteria and specific biological markers have not yet been definitively identified. The first symptoms tend to occur in late adolescence or early adulthood. No cause for idiopathic hypersomnia has been clearly identified, but viral illnesses, including those that may lead to Guillain-Barre syndrome, hepatitis, mononucleosis and atypical viral pneumonia may be a harbinger of the onset of sleepiness in a subset of patients. EDS may occur as part of the acute illness but persist after the other symptoms subside. HLA-Cw2 and HLA-DR11 have occurred with increased frequency in some rare familial cases.59 However, most patients with idiopathic hypersomnia have neither a family history nor an obvious associated viral illness. Autonomic nervous system dysfunction has been associated with some of these cases, including orthostatic hypotension, syncope, vascular headaches and peripheral vascular complaints. Little is known about the pathophysiology of idiopathic hypersomnia. No animal model is available for study. Neurochemical studies using CSF have suggested that patients with idiopathic hypersomnia may have altered noradrenergic system function.60-62
Clinically, symptoms of idiopathic hypersomnia vary in presentation among individuals. It is not uncommon for idiopathic hypersomnia to be mistaken for narcolepsy. Because the predominant symptom in both disorders is EDS and both diseases have similar age of onset, it is understandable that one may be mistaken for the other. However, with careful history taking and diagnostic testing, essential differences between the disorders become apparent. Patients with idiopathic hypersomnia present with EDS but without cataplexy or significant nocturnal sleep disruption.63 The sleepiness of which they complain will typically interfere with normal daily activities. Occupational and social functioning may be severely impacted by sleepiness. Nocturnal sleep time tends to be long and unrefreshing, and patients are usually difficult to awaken in the morning. They may become irritable or even abusive in response to the efforts of others to rouse them. In some patients, this difficulty may be substantial and include confusion, disorientation, and poor motor coordination, a condition called “sleep drunkenness.”64 These patients often take naps, which may be prolonged but again, usually non-refreshing. No amount of sleep ameliorates EDS. “Microsleeps,” with or without automatic behavior, may occur throughout the day.
PSG studies of patients with idiopathic CNS hypersomnia usually reveal shortened initial sleep latency, increased total sleep time and normal sleep architecture (in contrast to narcoleptic patients, who exhibit significant sleep fragmentation). Mean sleep latency on MSLT is usually reduced, often in the 8–10 minute range, but sometimes dramatically shorter. Also in contrast to narcolepsy, SOREMs are not typically seen.
As with narcolepsy, other disorders producing EDS (such as insufficient sleep, sleep-related breathing disorders, PLMDs, other sleep fragmenting disorders, psychiatric diseases, or circadian rhythm disorders) must be ruled out before the diagnosis of idiopathic hypersomnia is made. Treatment of idiopathic CNS hypersomnia is often difficult and poorly responsive to medications. Lifestyle and behavioral modifications, including good sleep hygiene, are appropriate, but treatment with stimulant or wake-promoting medication, as with narcolepsy, is usually necessary.51
Another group of disorders to consider in the differential diagnosis of a patient who presents with EDS, although somewhat rarer, are the recurrent hypersomnias. The Kleine-Levin syndrome is a form of recurrent hypersomnia, which occurs primarily in adolescents.65 There is a male preponderance. It is characterized by the occurrence of episodes of EDS, and frequently, but not always, accompanied by hyperphagia, aggressiveness and hypersexuality. These episodes may last days to weeks and be separated by asymptomatic periods of weeks or months. During symptomatic periods, individuals sleep up to 18 hours/day and are usually drowsy (often to the degree of stupor), confused and irritable the remainder of the time. Additionally, during these episodes, PSG studies will show long total sleep time with high sleep efficiency and decreased slow-wave sleep. MSLT studies demonstrate short sleep latencies and SOREMs.66 The etiology of this syndrome remains obscure. Symptomatic cases of Klein-Levin syndrome associated with structural brain lesions have been reported, but most cases are idiopathic. Single-photon emission computed topography studies have demonstrated hypoperfusion in the thalamus in one patient and in the nondominant frontal lobe in another.67 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.
Another form of recurrent hypersomnia is menstrual-related periodic hypersomnia, in which EDS occurs during the several days prior to menstruation.68,69 The prevalence of this syndrome has not been well characterized. Likewise, the etiology is not known, but presumably the symptoms are related to hormonal changes. Some cases of menstrual-related hypersomnia have responded to the blocking of ovulation with estrogen and progesterone (birth control pills).70
Another less commonly seen form of the recurring hypersomnias is idiopathic recurring stupor. There have been numerous cases reported in which, in the absence of obvious cause, individuals are subject to stuporous episodes lasting from hours to days. This syndrome affects predominantely middle-aged males. The individuals are normal between episodes, which occur unpredictably. Elevated plasma and CSF levels of endozepine-4, an endogenous ligand with affinity for the benzodiazepine recognition site at the γ-aminobutyric acidA receptor, has been found in several of these patients.71 EEG data collected during symptomatic episodes have shown fast background activity in the 13–16 Hz range. Administration of flumazenil, a benzodiazepine antagonist, has produced transient awakening with normalization of the EEG.72 In some cases, the episodes resolved spontaneously after several years. Similar cases have been reported in children.73
Nervous System Disorders and Eexcessive Daytime Sleepiness
Patients with disorders of the central or peripheral nervous systems will often complain of EDS as well. In some chronic diseases of neurological origin, EDS may be the predominate complaint. It may be a dominant clinical feature in many toxic or metabolic encephalopathic processes. Structural brain lesions, including strokes, tumors, cysts, abscesses, hematomas, vascular malformations, hydrocephalus, and multiple sclerosis plaques are known to produce EDS. It appears that in these patients, somnolence may result either from direct involvement of discrete brain regions or due to effects on sleep continuity (for example, nocturnal seizure activity or secondary SRBD).
Patients who experience a head trauma or have been afflicted with encephalitis may have the chronic sequela of EDS. Victims of “encephalitis lethargica,” described by Von Economo in the early 20th century, were found to have lesions in the midbrain, subthalamus and hypothalamus. Additionally, posttraumatic narcolepsy with cataplexy is well documented.74 EDS may be seen in patients with epilepsy, due to medication effects or nocturnal seizure activity.75 EDS may be associated with numerous infectious agents affecting the central nervous system, including bacteria, viruses, fungi and parasites. Perhaps the best known is trypanosomiasis, which is called “sleeping sickness” because of the prominent hypersomnia. Certain inflammatory mediators have been shown to cause sleepiness. These agents have been hypothesized to be the origin of EDS in acute infectious illness, where EDS occurs without direct invasion of the central nervous system. These mediators include cytokines, interferon, interleukins, and tumor necrosis factor.76 EDS may also persist chronically after certain viral infections.77
Various neurodegenerative disorders, including Parkinson’s disease, Alzheimer’s disease, other dementias of varied causes, and multiple system atrophy all have been shown to commonly have sleep disruption and EDS.78-80 Patients with neuromuscular disorders or peripheral neuropathies have an increased incidence of SRBD (CSA or OSA), pain and PLMS, and may develop EDS due to disrupted sleep of these origins.81 Patients with myotonic dystrophy often suffer from EDS, even in the absence of SRBD.82
Chronic Medical Conditions and Excessive Daytime Sleepiness
Chronic medical conditions may also cause significant sleep disturbance and manifest clinically as either EDS or fatigue. Patients with fibromyalgia frequently characterize their sleep as being restless, light, and unrefreshing.83 These patients often have a characteristic EEG finding during sleep of alpha-frequency activity intrusion during delta-frequency activity or “alpha-delta” sleep.84 Alpha activity is characteristic of the EEG pattern seen during quiet wakefulness with the eyes closed and does not occur during the deep sleep (wherein delta activity occurs) in normal controls. This EEG finding has been reported to also occur in rheumatoid arthritis and chronic fatigue syndrome.84-86 Researchers have found a positive correlation between the frequency of alpha-delta sleep and severity of overnight pain in patients with fibromyalgia and a inverse correlation between frequency of alpha-delta sleep and subjective sleep depth and refreshing sleep.87,88
Other chronic medical conditions may have a significant impact on sleep continuity and on daytime function. Patients with severe congestive heart failure have highly fragmented sleep, with frequent arousals and sleep changes.89 Additionally, >50% of patients with heart failure suffer from SRBDs.90 A recent study has shown that at least 21% of patients with CHF complained of EDS and 48% of patients complained of being awake more than 30 minutes during the course of the night.91
Patients with cancer also have increased reports of EDS. Prevalence rates of 54% to 68% for “feeling drowsy” and 21% to 40% for being “overly sleepy” have been found in studies of this population.92,93 Causes of EDS reported in this population may be related to increased risk of primary sleep disorders due to age alone (average age of onset of cancer is 55 years old); insufficient sleep due to insomnia, depression, or pain; disruption or erratic hormone secretion due to the malignancy or chemotherapy, with subsequent sleep disruption or shortened sleep periods; effects of cytokines and inflammatory mediators induced by cancer cells, biotherapy, or radiotherapy; and/or side effects from chemotherapy or other adjunctive medications.94
Endocrine disorders comprise another chronic disease group wherein patients may complain of EDS. It has long been observed that sleepiness is a symptom of hypothyroidism. Additionally, there are considerable data to show that hypothyroidism is a risk factor for the development of OSA.95 It is not clear whether the sleepiness that hypothyroid patients experience is due to a direct effect of the hypothyroid state on sleep or to coexisting SRBD. Patients with acromegaly have also been shown to have an increased prevalence of sleep apnea, with rates between 39% and 58.8% in various studies.96,97 On the other hand, patients with growth hormone deficiency consistently report a reduced level of energy, fatigue, and impaired sleep quality.98
Psychiatric illness, especially depression, has been thought to be a significant cause of EDS. While it is true that tiredness, fatigue and/or lack of energy are reported by an overwhelming majority of patients with major depression, evaluation of true EDS with subjective rating scales and objective measures suggests that frank sleepiness or a high sleep propensity may be much less common than the complaint of fatigue or lack of energy.99 There are only a few studies evaluating objective measures of sleepiness, such as MSLT, in depression, but these studies suggest that only a minority of these patients suffer EDS that is clinically relevant and that the majority are actually in the normal range of alertness.100
Treatment of Excessive Daytime Sleepiness
Depending on the etiology of EDS, treatment modalities differ greatly. Typically, regardless of the cause, appropriate behavioral interventions should be introduced. These include extension of the nocturnal sleep period, structured bedtimes and/or wake times, appropriate timing of light therapy in the case of circadian rhythm disorders, and scheduled naps. Risks of driving while sleepy should be explained to patients with EDS and these patients should be instructed to take appropriate measures to eliminate driving risks (eg, avoid driving while sleepy; if driving and sleepy, pull-over and take a short nap; use appropriate alerting agents when indicated).
Circadian Rhythm Disorders
Patients with advanced sleep phase syndrome and delayed sleep phase syndrome may effectively shift their biological clock by the use of bright light therapy (phototherapy) either in the evening or in the morning, respectively, and avoidance of bright light in the morning and the evening, respectively.101 The use of properly timed melatonin administration appears to have an impact on phase-shifting as well, although not as greatly as phototherapy.102 Regular, fixed wake times with fixed daytime and nighttime routines helps to reinforce the phase shift as well.
Sleep-Related Breathing Disorders
Continuous positive airway pressure (CPAP) is the first-line therapy for treatment of SRBD. CPAP acts as a “pneumatic splint” to brace open the airway via a nasal or nasal-oral interface, providing continuous positive pressure to the upper airway while sleeping. By stabilizing the airway walls, the tendency for the upper airway to collapse is alleviated, breathing disturbances are ameliorated, and sleep continues much less interrupted. Studies have shown that CPAP therapy significantly improves subjective and objective measures of daytime sleepiness in patients with OSA.103,104 Alternatives to CPAP for the treatment of OSA include a variety of soft tissue and/or maxillary-mandibular surgical interventions. These procedures address the various points of obstruction in the upper airway and/or any anatomic variants that predispose an individual to SRBD. Additionally, mandibular advancing dental devices are a third-line treatment option for mild to moderate OSA in patients intolerant of CPAP who are not candidates for surgery. A discussion of these interventions is beyond the scope of this paper.
Periodic Limb Movement Disorder
The pathophysiology of PLMS is not well understood but evidence exists that both an alteration in brain iron metabolism and central dopaminergic dysfunction may play a role.105 The use of dopaminergic agents has been found to be remarkably effective in treating PLMS. Thus, dopamine agonists have become first line agents for the treatment of PLMS in terms of tolerability, efficacy, and continuity of sleep.106,107
In treating the primary disorders of EDS, pharmacotherapy, in addition to behavioral interventions, provides the mainstay of treatment. Clearly, before initiation of pharmacotherapy is begun, a definitive diagnosis of the cause of EDS is essential. The most significant impact on the treatment of narcolepsy in recent history has been the full characterization of the use of sodium oxybate (the sodium salt of γ-hydroxybutyrate) and its effect on cataplexy, daytime sleepiness, and nocturnal sleep fragmentation. While sodium oxybate’s sleep-promoting effect appears to be largely mediated via GABAB receptor agonism, the mechanism whereby it improves cataplexy and EDS is unknown. Low dose sodium oxybate (50 mg/kg [Scrima]; 60 mg/kg) in narcolepsy has been studied in some capacity for 35 years; however, not until the last 10 years have thorough investigations in the form of multi-center trials been conducted. These trials have extensively characterized the dose-response impact of sodium oxybate on the enhancement of nocturnal sleep, on improvement of cataplexy, and improvement of EDS.108,109 These findings support the view that sodium oxybate is the optimal first-line agent for the treatment of narcolepsy.
While sodium oxybate has demonstrated its efficacy in treating all symptoms of narcolepsy, alerting agents provide a critical adjunctive component in the treatment of patients with narcolepsy, specifically for the treatment of EDS. Once considered first-line agents for the treatment of patients with narcolepsy, it is now considered a useful addition to the use of sodium oxybate in our clinical practice. Clinically, common practice is to combine two agents when one does not adequately ameliorate symptoms. The use of modafinil as an adjunct to sodium oxybate has been shown to provide significantly greater improvement in measures of EDS than either agent alone. While some patients may wish to avoid medications and attempt to take extra naps during the day, it is rarely successful in alleviating EDS to the degree that these patients function at or near normal capacity. While alerting agents may not eliminate daytime symptoms, they have been shown to produce substantial improvement in EDS associated with narcolepsy.110
Modafinil is a novel alerting agent whose mechanism of action is not fully characterized. Its therapeutic effect of promoting wakefulness appears to be largely dopaminergic. Similar to traditional stimulants, modafinil appears to function as a dopamine transporter inhibitor, but unlike the amphetamines, it does not induce dopamine release. This difference in activity may account for the improved tolerability of modafinil over traditional stimulants, as well as its almost complete lack of street use, abuse, or addiction by illicit users.111 In addition to its use in narcolepsy, after multiple trials regarding safety and efficacy, it has been approved by the Food and Drug Administration for use in SWSD and in the residual sleepiness associated with fully treated OSA. Of course in these conditions, adequate compliance with optimal CPAP or other primary airway treatment, as well as structured and adequate sleep, are of paramount importance before the initiation of pharmacotherapy.
In addition to modafinil, commonly used stimulants include methylphenidate, dextroamphetamine, and methamphetamine.110 Side effects are not uncommon with any alerting agent. Agitation, anxiety, tremor, and palpitations are just a few of the commonly reported side effects associated with traditional stimulants. Some patients may report a rebound hypersomnia as the dose wears off and/or tolerance (tachyphylaxis) may occur with time. Traditional stimulants are still an important resource in the arsenal of medications for the treatment of narcolepsy, but in our clinical practice, have become second-line agents behind sodium oxybate and/or modafinil for treatment of EDS associated with narcolepsy.
Cataplexy is an important aspect to address in the treatment of narcolepsy; however, the various agents and modes of action implicated in this aspect of narcolepsy expand beyond the scope of this paper.
EDS is an important problem in our society and produces significant decrements in quality of life and productivity. There are many causes of EDS that must be considered by the clinician before contemplating diagnostic testing and treatment. Patterns of sleepiness and chronicity of the complaint should be well established before initiating a diagnostic work-up and treatment plan. Insufficient sleep, chronic medical problems, and medications are all confounding variables that may contribute to EDS and may be a primary cause of EDS or may exacerbate a primary sleep disorder or primary disorder of hypersomnolence. Despite the development of several methods to diagnose and quantify EDS, each has its limitations. Fortunately, in most cases of EDS, treatment options exist to ameliorate symptoms and improve quality of life. PP
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