INTRODUCTION TO HYPERSOMNIA
Hypersomnia and excessive daytime sleepiness are complex traits whose formal study is in its infancy, and whose socioeconomic burden is enormous. The term hypersomnia is used to refer to excessive sleepiness during the day, often accompanied by prolonged sleep periods (i.e., more than 10 hours per night). There are several different classification systems for the hypersomnia syndromes, but broadly speaking, hypersomnia can be classified as primary or secondary, and the primary hypersomnias can be classified based on clusters of symptoms and test results or based on underlying cause.
PRIMARY VERSUS SECONDARY HYPERSOMNIA
Hypersomnia is judged to be “secondary” if it is caused by a problem with night time sleep, inability to get enough sleep, or other medical problems that result in sleepiness. For example, patients with obstructive sleep apnea, who have multiple interruptions in breathing throughout the night, are frequently sleepy during the day, but their hypersomnia is judge to be secondary to their sleep apnea. Secondary hypersomnia can be triggered by infections, depression, kidney failure, chronic fatigue syndrome, and neurodegenerative diseases such as Parkinson’s disease and myotonic dystrophy. The primary hypersomnias, in contrast, occur in the absence of such medical problems and despite normal quality and quantity of night time sleep (and sometimes despite exceptionally long periods of night time sleep). The primary hypersomnias are thought to arise from problems with the brain’s systems that regulate sleep and wake.
CLASSIFYING PRIMARY HYPERSOMNIAS BY SYMPTOMS AND SLEEP TEST RESULTS
One common classification of primary hypersomnia syndromes is that of the International Classification of Sleep Disorders, which divides hypersomnia syndromes primarily between narcolepsy, idiopathic hypersomnia, and the recurrent hypersomnias. Narcolepsy is further divided between that with cataplexy (brief episodes of muscle weakness triggered by strong emotion) and that without cataplexy. Idiopathic hypersomnia is characterized as having either long sleep time (> 10 hours/night) or normal sleep time. The recurrent hypersomnias involve severe periods of sleepiness lasting days, interspersed with periods of more normal alertness, and include such entities as Kleine-Levin syndrome.
What is Idiopathic Hypersomnia (IHS)? The main symptom of IHS is pervasive daytime sleepiness despite adequate, or more typically, extraordinary sleep amounts (e.g., > 10 hours per night). Additional symptoms and complaints commonly include unrefreshing or non-restorative sleep, and sleep inertia and sleep drunkenness (difficulty awakening from sleep, accompanied by feelings of grogginess and disorientation upon awakening). Symptoms usual start in the mid-to-late teens or early twenties, although it can begin at a later age. Symptom intensity often varies between weeks, months, or years, sometimes worsen just prior to menses in women, and can spontaneously remit in 10-15% of patients. Sleep is usually described as “deep” and arousal from sleep is usually difficult, often requiring multiple alarm clocks and morning rituals to ensure that patients arise for school or work. In contrast to the short and generally refreshing daytime naps observed in genuine narcolepsy, those in IHS patients can be very long – on the scale of hours – and are unrefreshing. Some patients exhibit hypersensitivity to sedating medications such as anesthetics, sleeping pills, or alcohol.
What causes Idiopathic Hypersomnia? IHS is a disorder of the nervous system in which there often appears to be over production of a small molecule that acts like a sleeping pill (e.g., a sedative-hypnotic drug such as Versed®), or anesthetic (e.g., propofol). Although the exact composition of this small molecule is yet to be determined, much is known about how it interacts with γ-aminobutyric acid (GABA), a principal player in the brain mechanisms that promote sleep. In the presence of this substance, the inhibitory and sleep promoting actions of GABA are enhanced at the receptors at which it acts.
Diagnosing IHS: The symptoms of IHS can be mimicked by other disorders, so it is important for a sleep physician to evaluate for other contributing causes including depression or other mood disorders, insufficient sleep time, and disturbance of circadian rhythms (e.g., advanced sleep phase syndrome and delayed sleep phase syndrome). In clinical experience, hypothyroidism and iron deficiency with or without anemia can also cause excessive sleep and daytime sleepiness and should be assessed for and corrected as appropriate. IHS is then diagnosed by a night-time sleep test (polysomnogram) followed by multiple sleep latency testing (MSLT) the day after. During the MSLT, the patient is given an opportunity to fall asleep on 4 or 5 occasions at 2-hour intervals. The polysomnogram rules out certain causes of secondary hypersomnia, including that caused by obstructive sleep apnea. Current criteria for the diagnosis of IHS by MSLT requires falling asleep in an average of less than 8 minutes in all the nap opportunities, without frequent dream sleep (which distinguishes it from narcolepsy). Unfortunately, several groups of researchers have shown that patients who otherwise seem to have IHS have a normal MSLT, raising concerns that this test may not be accurate to make the diagnosis in all patients. If the results do not paint a clear picture (e.g., there is a compelling history of excessive sleep, sleepiness, or slowed reaction times, but a normal or ambiguous MSLT result), diagnosis can be clarified with a lumbar puncture to obtain cerebrospinal fluid (CSF) in order to measure hypocretin (to test for narcolepsy with cataplexy), and determine to what extent a patient’s CSF might enhance GABA receptor function in human cells grown in a petri dish in the laboratory (thought to underlie many cases of idiopathic hypersomnia and narcolepsy without cataplexy).
What is Narcolepsy? The main symptoms of narcolepsy are daytime sleepiness and abnormal features of dream sleep (i.e, rapid-eye-movement, or, REM, sleep). A subgroup of patients (~ 1/3rd) have disrupted nocturnal sleep, although sleep time across 24 hours is typically normal. The usual age of onset is in the mid-to-late teens although it can begin in the pre-teens or at a later age, and it is a life-long illness. Narcolepsy occurs in two forms with different underlying causes: narcolepsy with cataplexy and narcolepsy without cataplexy. Narcolepsy without cataplexy shares some features in common with narcolepsy with cataplexy and other features with idiopathic hypersomnia. The remainder of this section refers to narcolepsy with cataplexy. Daytime sleepiness in narcoleptics typically occurs as irresistible urges to fall asleep – sometimes referred to as “sleep attacks” — at random intervals throughout the waking day. These short bouts of sleep are usually refreshing or ‘restorative’ in quality, as is night-time sleep. Abnormal features of dream sleep include: hallucinations, sleep paralysis, and cataplexy. Patients can experience dream-like auditory or visual hallucinations upon falling asleep or dozing that are termed hypnagogic hallucinations. Sleep paralysis can be a frightening sensation of feeling paralyzed and unable to move upon falling asleep or awakening from sleep that lasts for several minutes. Cataplexy is a symptom unique to narcolepsy in which the patient experiences a sudden loss of muscle tone for tens of seconds to minutes, and these are provoked by emotional situations such as laughter, hearing or telling a joke, fear, or anger. Cataplexy varies greatly in intensity and duration from a patient’s knees buckling or jaw becoming lax briefly, to the eyelids and head drooping (thus, mimicking sleep to an observer), to the patient falling down and being unable to move for several minutes. It is a critical distinction that conscious awareness of the environment is preserved in patients during an attack of cataplexy although it might appear to an observer that the patient has “passed out” or “fainted”. A substantial proportion of patients with narcolepsy have disrupted dream sleep that can manifest as acting out dreams (e.g., rapid-eye-movement (REM) – sleep behavior disorder) and periodic leg movements in sleep.
What causes narcolepsy with cataplexy? Narcolepsy is a disorder of the nervous system in which there is immune system mediated destruction of brain cells that contain hypocretins (aka orexins). These brain cells are located in a brain region called the hypothalamus and are critical to maintenance of wakefulness, continuity of sleep, and coordination the timing and features of dream sleep (i.e., rapid-eye-movement, or REM, sleep).
Diagnosing Narcolepsy: Cataplexy is a symptom that occurs almost exclusively in patients with narcolepsy, so its presence strongly suggests this diagnosis. However, cataplexy can sometimes be subtle or mild, making additional testing necessary. As in idiopathic hypersomnia, diagnosis depends on ruling out causes of secondary hypersomnia and a polysomnogram with multiple sleep latency test (MSLT). On the MSLT, it takes less than 8 minutes on average for patients to fall asleep, and dream sleep is observed on at least two naps. Patients with narcolepsy without cataplexy show the same results on MSLT as those with cataplexy. In cases with persistent diagnostic uncertainty (e.g., because cataplexy is subtle or not clearly present), testing for hypocretin within cerebrospinal fluid (by lumbar puncture) can be valuable. Patients with narcolepsy with cataplexy will demonstrate low or undetectable hypocretin levels.
CLASSIFYING PRIMARY HYPERSOMNIAS BY UNDERLYING CAUSE
As the above discussion shows, different primary hypersomnia syndromes sometimes have overlapping clinical features because they were defined before the underlying causes were known. In practice, it can be helpful to cluster primary hypersomnia syndromes by underlying cause when it is known. Cerebrospinal fluid analysis is helpful in this regard, because it allows distinction between hypocretin-deficient narcolepsy (i.e., narcolepsy with cataplexy) and the primary hypersomnias related to abnormal functioning of the GABA system (which researchers at Emory have recently shown to be the case in many patients with IHS, narcolepsy without cataplexy, and others requiring extraordinary amounts of sleep (e.g, > 70 hours/week) but with normal MSLT results. These observations support the consideration of these latter syndromes as a single entity; the proposed revisions to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) create a new category termed major hypersomnolence disorder that encompasses many patients with these hypersomnia subtypes, although is not specifically based on underlying cause.