Hypersomnia and Narcolepsy
Timothy F. Hoban
Ronald D. Chervin
CLINICAL PRESENTATION
Sleepiness can be defined as high physiologic drive toward sleep, but the term is also frequently used to denote the conscious perception of the need or readiness for sleep. Occasional sleepiness is a normal experience in most individuals, for example at the end of the day or following premature waking from sleep. Excessive daytime sleepiness, however, defined as sleepiness that interferes with daytime activities, productivity, or enjoyment, is usually abnormal and may reflect insufficient sleep, disrupted sleep, or a primary sleep disorder such as narcolepsy. Th is chapter will examine clinical assessment of the sleepy patient, diagnostic classification of the major sleep disorders characterized by hypersomnolence, diagnostic and laboratory evaluation of sleepiness, and differential diagnosis. Management of narcolepsy and the hypersomnias is reviewed in Chapter 10.
Symptoms of sleepiness are variable in both frequency and severity. Mild sleepiness is sometimes noted only intermittently or during sedentary activities such as reading, watching television, or traveling for extended distances. Mild or moderate sleepiness is not always self-evident to the patient, since symptoms often subside with stimulating physical or mental activity, or may be misattributed to fatigue or boredom. Chronic sleepiness often evolves insidiously and many affected individuals do not realize that the sleepy state is abnormal.
Patients with moderate or severe sleepiness often have difficulty sustaining full alertness even during active and stimulating situations. These individuals are especially likely to fall asleep inadvertently during sedentary activities, or to take naps during daytime hours. Although some signs of sleepiness are usually apparent to the patient or family members, the severity of the sleepiness and associated impairment of attention and cognition is often underrecognized. When sleepiness is both chronic and severe, patients may experience recurrent “sleep attacks” characterized by the precipitous, unavoidable need to stop an activity and take a nap.
Associated clinical manifestations of sleepiness are likewise variable. Somnolent individuals often complain of fatigue, tiredness, lack of energy, inattention, impaired concentration, or emotional lability (1). Severely somnolent individuals may appear visibly sleepy and in extreme cases stuporous or encephalopathic. Visible signs of sleepiness on examination may include drooping of the eyelids, pupillary miosis, nodding of the head, or intermittent loss of postural tone.
Determining whether an abnormal degree of sleepiness is present is not always easy. Mild sleepiness near an individual’s habitual bedtime or transiently upon awakening is usually normal. Even more substantial sleepiness following sleep restriction or extended wakefulness does not always require detailed assessment if the underlying cause is identifiable and self-limited. Sleepiness that interferes with everyday activities or occurs at inappropriate times is almost always abnormal, particularly if the somnolence is chronic, recurrent, or severe. In general, sleepiness that does not improve when nighttime sleep is lengthened is often a sign of an underlying sleep disorder (2).
A detailed medical and sleep history is the most important element in the diagnostic evaluation of the sleepy patient. The history alone often allows accurate assessment of whether a patient’s sleepiness is likely to be the result of insufficient sleep, disrupted sleep (e.g., secondary to obstructive sleep apnea), or a
central nervous system disorder such as narcolepsy. Patients with excessive sleepiness commonly exhibit identifiable symptoms that help determine specific underlying causes. Such symptoms include snoring or observed apnea during sleep, restlessness or jerking of the legs, hypnagogic or hypnopompic hallucinations, sleep paralysis, automatic behavior, cataplexy, or other constitutional symptoms.
central nervous system disorder such as narcolepsy. Patients with excessive sleepiness commonly exhibit identifiable symptoms that help determine specific underlying causes. Such symptoms include snoring or observed apnea during sleep, restlessness or jerking of the legs, hypnagogic or hypnopompic hallucinations, sleep paralysis, automatic behavior, cataplexy, or other constitutional symptoms.
Snoring and Other Obstructive Symptoms During Sleep
Sleepiness often arises as a result of sleep-related breathing disorders (SRBDs), because of sleep fragmentation and most likely hypoxemia as well. Loud snoring is a cardinal symptom of obstructive sleep apnea (OSA) and upper airway resistance syndrome (UARS) and may be accompanied by mouth breathing, unusual body positions, or visible restlessness during sleep. Respiratory pauses are sometimes witnessed by bed partners or family members, sometimes terminating with a snort or gasp when breathing resumes. Such symptoms are most informative when present, but the absence of observed apnea and even snoring does not preclude the possibility of an underlying SRBD.
Restless Legs and Symptoms of Excessive Periodic Limb Movements
Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) may also be associated with excessive daytime somnolence, especially when the condition impacts the duration, quality, or continuity of nighttime sleep. Restless legs syndrome is characterized by an urge to move the extremities (with or without dysesthesias), motor restlessness, worsening of symptoms at rest, relief with activity, and exacerbation of symptoms during evening or nighttime (3). Children may exhibit “growing pains” as a symptom of RLS (4). The leg movements that accompany PLMD may range from gentle dorsiflexion of the toes or feet to fairly vigorous kicking movements with visible arousal from sleep. Arousals from sleep may accompany periodic limb movements, but the latter may not cause the arousals, and the presence of arousals does not reliably predict associated sleepiness (5,6).
Hypnagogic or Hypnopompic Hallucinations
Hypnagogic (at sleep onset) and hypnopompic (at waking) hallucinations are brief, dreamlike episodes that last seconds to minutes. Hallucinations are often vivid and sometimes distressing despite their brevity. Although these hallucinatory episodes are often reported by patients with narcolepsy, they may also occur in association with other sleep disorders, a variety of psychiatric conditions, and as a medication side effect (7,8).
Sleep Paralysis
Sleep paralysis is a condition in which muscle atonia, normally restricted to rapid eye movement (REM) sleep, occurs at the interface between sleep and wakefulness. Sleep paralysis may be complete or partial, and sometimes coincides with hypnagogic hallucinations. Although episodes usually last for only about a minute or less, they may be extremely frightening and accompanied by sensations of suff ocation. Episodes can often be terminated by extraneous stimuli such as noise or touch. Sleep paralysis is frequently reported by patients with narcolepsy, but may also be seen with other sleep disorders, as a familial condition, or as an occasional phenomenon in normal individuals (9, 10 and 11).
Automatic Behavior
Automatic behavior refers to episodes of purposeful but sometimes inappropriate behavior occurring during periods of sleepiness, usually with partial or absent subsequent recollection of the activity (12). Some varieties of automatic behavior are common and benign, such as briefly arising from bed while groggy to use
the bathroom and not remembering the event the next day. Other varieties may be more ominous, as when a drowsy driver arrives at a familiar destination with no recollection of how they got there. Automatic behavior that is prolonged, frequent, or potentially unsafe is usually indicative of significant sleepiness.
the bathroom and not remembering the event the next day. Other varieties may be more ominous, as when a drowsy driver arrives at a familiar destination with no recollection of how they got there. Automatic behavior that is prolonged, frequent, or potentially unsafe is usually indicative of significant sleepiness.
Cataplexy
Cataplexy is characterized by paroxysmal episodes of diffuse muscle weakness or paralysis, triggered by laughing or emotion. The phenomenon occurs when the muscle atonia normally restricted to REM sleep is inappropriately expressed during wakefulness. Unlike sleep paralysis, cataplectic episodes usually occur during sustained wakefulness and are triggered by strong emotions such as laughter, surprise, or anger. Cataplexy is typically brief, lasting seconds to minutes, but successive attacks precipitated by extreme emotional stimuli (status cataplecticus) may rarely last as long as 1 hour (13). Severity of muscle atonia during episodes is highly variable. Mild attacks may consist only of a brief sensation of weakness without loss of posture. Severe episodes may cause complete paralysis sparing only respiration, eye movements, and sphincters. Most often, loss of muscle tone is partial, and may take the form of knee buckling, head drop, slurred speech, or loss of postural tone. Consciousness is maintained during attacks, distinguishing them from syncope and atonic seizure, although some patients report falling asleep during the immobility of severe cataplectic attacks.
Other Constitutional Symptoms and Signs Associated with Specific Causes of Sleepiness
Episodes of hyperphagia, hypersexuality, and other behavioral disturbances can accompany sleepiness in individuals with recurrent hypersomnia (Kleine-Levin syndrome) or hypothalamic lesions (14,15).
Lethargy, weight gain, and cold intolerance may accompany somnolence in hypothyroid patients, who are also at increased risk for OSA (16).
Morning headache or other neurological complaints are nonspecific symptoms sometimes associated with sleepiness that is secondary to structural pathology within the central nervous system (17).
Sleepiness is extremely common in individuals with unipolar or bipolar depression, where associated symptoms of anhedonia, fatigue, or intermittent mania may be apparent (18, 19 and 20).
Developmental regression, dystonia, and seizures may accompany sleepiness and atypical cataplexy for individuals with narcolepsy secondary to Niemann-Pick Disease, type C (21).
CLASSIFICATION AND CLINICAL CHARACTERISTICS
The International Classification of Sleep Disorders, second edition (ICSD-2), published in 2005, established the current nosology for sleep disorders. Sleep disorders characterized primarily by hypersomnolence are categorized as hypersomnias of central origin not due to a circadian rhythm disorder, sleep–related breathing disorder, or other case of disturbed nocturnal sleep, as summarized in Table 4.1 and detailed in the text below (13).
Narcolepsy with Cataplexy
Narcolepsy with cataplexy is characterized primarily by excessive daytime somnolence and cataplexy. Sleepiness is usually most evident during sedentary or monotonous activities, but may also take the form of irresistible sleep attacks that may interrupt more active endeavors. Daytime sleep periods in patients having
narcolepsy with cataplexy are usually short and refreshing, but followed within hours by recurrent sleepiness. Severity of somnolence in affected patients ranges from mild to disabling.
narcolepsy with cataplexy are usually short and refreshing, but followed within hours by recurrent sleepiness. Severity of somnolence in affected patients ranges from mild to disabling.
TABLE 4.1 The ICSD-2 Classification for Hypersomnias of Central Origin (13) | ||
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Cataplexy is a phenomenon unique to narcolepsy but often develops years after onset of sleepiness. Episodes are most commonly triggered by “positive” emotional experiences such as laughter, elation, or surprise and less consistently by other emotions. Attacks may be localized to specific body areas (e.g., face) or involve all skeletal muscle groups in a generalized fashion. Respiration is never directly affected, but subjective sensations of choking or dyspnea are sometimes reported. The frequency of cataplexy in affected patients ranges from rare and isolated attacks to innumerable daily episodes.
Nonobligate clinical manifestations frequently exhibited by patients having narcolepsy with cataplexy include sleep attacks, sleep paralysis, hypnagogic hallucinations, and automatic behavior (described in the “Clinical Presentation” section). These phenomena affect a small proportion of normal sleepers as well. REM sleep behavior disorder (RBD)—episodes of complex motor behavior arising during REM sleep—has been reported with increased frequency in adults with narcolepsy (22). Nocturnal sleep disruption is frequently seen in individuals having narcolepsy with cataplexy, often taking the form of excessive night waking. Disrupted nighttime sleep in these patients is often sufficient to further exacerbate daytime sleepiness.
Onset of narcolepsy with cataplexy is most commonly observed during adolescence or young adulthood, but occasionally is encountered in younger children (23). Cataplexy usually develops several years after onset of sleepiness, but may sometimes arise before or long after the onset of somnolence. Laboratory evidence suggests that loss of hypocretin-1 secreting cells in the hypothalamus, possibly on an autoimmune basis, plays a pathogenetic role in the majority of cases (24, 25 and 26).
Narcolepsy without Cataplexy
Narcolepsy without cataplexy is similar in most clinical respects to narcolepsy with cataplexy except for the lack of definite cataplectic episodes. As some patients in
this category eventually develop cataplexy later in the course of their disease, the diagnostic classification may also change at that time (13).
this category eventually develop cataplexy later in the course of their disease, the diagnostic classification may also change at that time (13).
Despite the clinical similarities between narcolepsy without cataplexy and narcolepsy with cataplexy, some evidence suggests that the underlying pathophysiology of the two conditions is not identical. Cerebrospinal fluid (CSF) hypocretin-1 levels are most often normal for patients who have narcolepsy without cataplexy, whereas they are substantially decreased or undetectable in those who have narcolepsy with cataplexy (25,27). Recent postmortem analyses identified partial loss of hypocretin-secreting neurons in the hypothalamus in some cases of narcolepsy without cataplexy (28).
Narcolepsy due to Medical Condition
Narcolepsy with and without cataplexy has been reported in association with a variety of medical and neurological conditions (29). Genetic disorders associated with narcolepsy and cataplexy include Niemann-Pick disease type C (21,30), Prader-Willi syndrome (31), and possibly Coffin-Lowry syndrome (32). Structural lesions in the hypothalamic region, including tumors, sarcoidosis, multiple sclerosis, and neurocysticercosis may also cause secondary narcolepsy (33, 34 and 35). Symptomatic narcolepsy has also been reported in several neurological disorders not having demonstrable hypothalamic involvement, including acute disseminated encephalomyelitis, multiple system atrophy, and traumatic brain injury (36, 37, 38 and 39).
Narcolepsy, Unspecified
Narcolepsy, unspecified is defined by the ICSD-2 as a temporary classification for patients who meet clinical and multiple sleep latency testing (MSLT) criteria for narcolepsy but require additional evaluation for more precise classification.
Recurrent Hypersomnia
The recurrent hypersomnias are rare conditions in which prolonged episodes of excessive sleepiness are separated by periods of normal alertness and function. In Kleine-Levin syndrome, which most often affects adolescent males, patients may sleep for all but a few hours daily during episodes that last days to weeks (40). Somnolence is often accompanied by variable disturbances of mood, cognition, and temperament, often including increased appetite and significantly aggressive or hypersexual behavior (41). Episodes may occur up to 10 times yearly, but in most cases subside with advancing age (13,42). No specific etiology for Kleine-Levin syndrome has been established, but intermittent hypothalamic dysfunction or autoimmune etiologies have been postulated (43).
Menstrual-associated hypersomnia represents a poorly characterized condition in which episodic sleepiness coincides with the menstrual cycle, and is postulated to be secondary to hormonal influences (44).
Idiopathic Hypersomnia with Long Sleep Time
Idiopathic hypersomnia with long sleep time is characterized by pervasive daytime sleepiness despite longer-than-average nighttime sleep duration (45,46). Affected patients often report feeling unrefreshed or confused upon morning waking (sleep drunkenness) despite prolonged nighttime sleep periods of 10 or more hours. Daytime sleepiness is pervasive and often severe. Daytime naps are long and unrefreshing compared to those of narcoleptic patients. The condition most often develops during the early adult years with a chronic but usually stable course. The pathophysiology of the condition is unknown, but in contrast to narcolepsy with cataplexy, defects of hypocretin-1 metabolism have seldom been identified in affected patients (47).
Idiopathic Hypersomnia without Long Sleep Time
Idiopathic hypersomnia without long sleep time is characterized by constant, often severe daytime sleepiness in the context of nighttime sleep of normal or only slightly prolonged duration (45,48). Although the pervasive somnolence, sleep drunkenness, and unrefreshing naps seen in this condition are otherwise comparable to those seen in idiopathic hypersomnia with long sleep time, the nighttime sleep period is less than 10 hours.
Behaviorally Induced Insufficient Sleep Syndrome
Excessive daytime sleepiness often results primarily from habitually insufficient nighttime sleep (49). Review of the sleep history in affected patients reveals a chronically shortened nighttime sleep period that is either less than the patient’s premorbid baseline, and/or substantially less than normal for age. Daytime symptoms are those of chronic sleep deprivation, including sleepiness, irritability, disturbed mood, and impaired school or work performance. Symptoms remit with sustained lengthening of the nighttime sleep period, but transient periods of longer sleep on weekends or holidays are seldom sufficient to provide complete relief.
Hypersomnia due to Medical Condition
Hypersomnia due to medical condition may be diagnosed when chronic sleepiness represents the direct result of a coexisting medical or neurological condition, but clinical and MSLT criteria for narcolepsy are not fulfilled. Severity of daytime somnolence and length of nighttime sleep vary considerably among patients. Associated symptoms may include automatic behavior or sleep paralysis in the absence of cataplexy.
A variety of causes may underlie this disorder. Associated neurological conditions may include stroke, brain tumor, encephalitis, head trauma, and Parkinson’s disease (50, 51, 52 and 53). Genetic conditions associated with excessive sleepiness most notably include Prader-Willi syndrome and myotonic dystrophy (54, 55 and 56). Endocrine and toxic-metabolic causes include hypothyroidism, hypoadrenalism, hepatic encephalopathy, and renal failure. Drug-induced and psychiatric causes are classified elsewhere, as outlined in the following sections.
Hypersomnia due to Drug or Substance
Hypersomnia due to drug or substance
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