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Right arrow Contemporary Reviews in Sleep Medicine
(Chest. 2006;130:913-920.)
© 2006 American College of Chest Physicians

Hypersomnias of Central Origin*

Timothy J. Young, MD and Michael H. Silber, MBChB

* From the Sleep Disorders Center, Mayo Clinic College of Medicine, Rochester, MN.

Correspondence to: Michael H. Silber, MBChB, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905; e-mail: msilber{at}mayo.edu

Abstract

Hypersomnia related to CNS disorders can be due to a variety of conditions. In this review, we discuss the diagnosis and treatment of narcolepsy with and without cataplexy, idiopathic hypersomnia, recurrent hypersomnia, and related illnesses. Research has provided insight into the underlying etiologies of these disorders, such as the genetic influences on disease development and the fundamental role of hypocretins in narcolepsy. We define the current utility of diagnostic testing, including sleep studies, neuroimaging techniques, and laboratory investigations. New treatment options for hypersomnia are discussed.

Key Words: hypersomnia • idiopathic hypersomnia • narcolepsy • recurrent hypersomnia

Hypersomnia is a common complaint. Estimated to afflict up 9% of the adult population,1 hypersomnia is defined as the inability to maintain an alert state during the major waking episodes of the day. The problem has critical implications for human productivity and safety. Excessive daytime sleepiness (EDS) can result in injuries on the job, on the road, and in other circumstances where full attentiveness is required. This review will focus on hypersomnia that is not related to sleep-related breathing disorders, with attention to advances in understanding and treating these varied conditions.

The maintenance of alertness relies on a complex interplay of neuronal pathways and chemicals (Table 1 ), which in turn are influenced by extrinsic factors. Because maintaining an awareness of the environment is a requirement of all higher organisms, the primary mechanisms are located in the most phylogenetically conserved regions of the brainstem and diencephalon. The ascending reticular activating system projects from the level of the pons and midbrain to the intralaminar thalamic nuclei, portions of the hypothalamus, and basal forebrain. Key neurotransmitters along these pathways are acetylcholine, catecholamines, and serotonin.2 Cholinergic cells are active during wakefulness and rapid eye movement (REM) sleep. Noradrenergic cells originating in the pontine locus ceruleus project to the cerebral cortex and fire most actively during wakefulness. Serotoninergic cells are located in the tegmental raphe nuclei, and also fire during wakefulness and fall silent during REM sleep.


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  		Table 1.. Neurotransmitters Involved With Sleep and Wakefulness*

 
Other neurotransmitters that promote and maintain alertness include histamine, produced in the tuberomammillary nucleus, dopamine, produced in the ventral tegmental area, and the more recently discovered peptides hypocretin 1 and 2 (orexin A and B).3 The hypocretins are synthesized in the dorsolateral hypothalamus, where deficiencies are implicated in the pathogenesis of narcolepsy and related disorders. Hypocretin-synthesizing neurons project widely to the brainstem and forebrain, suggesting that these peptides may be primary players in the alerting system. Endogenous neurochemicals that promote sleep are {gamma}-amino butyric acid, galanin, adenosine, and various cytokines and peptides. Exogenous factors also play a crucial role in establishing and promoting a desirable sleep-wake cycle. The most important of these is retinal exposure to sunlight, which in turn stimulates the suprachiasmatic nucleus and other nuclei of the hypothalamus to influence circadian rhythms.4 Health conditions, motivational factors, and the ingestion of medications and other substances (including caffeine) also influence our level of alertness. However, the length of time since the last period of sleep is likely the single most important determinant of human sleepiness.

The second edition of the International Classification of Sleep Disorders,5 published in 2005, reclassified hypersomnias. Whereas the first edition grouped most disorders of hypersomnolence as dyssomnias along with obstructive sleep apnea and restless legs syndrome, the new edition established hypersomnias of central origin as a unique category (Table 2 ). Focusing on the CNS as the site of the disease process allows for conceptualization of the pathophysiologic mechanisms that are responsible for these disorders.


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  		Table 2.. Hypersomnias of Central Origin

 
Narcolepsy

Recognized since the 19th century, narcolepsy represents the best understood hypersomnia, due in large part to advances made in the past decade. The tetrad of EDS, cataplexy, sleep paralysis, and hypnagogic hallucinations, described by Yoss and Daly6 in 1957, is well-known, but it is neurochemical discoveries in the last 10 years that have elucidated the characteristic intrusion of REM sleep into wakefulness.

Narcoleptic patients experience EDS, often for some years, before developing cataplexy. EDS develops insidiously and is most pronounced in monotonous situations. This leads to irresistible daytime naps, which can be refreshing. The average age of onset is from the teens to the early twenties,7 and chronic sleepiness can have a significant impact on academic, social, and vocational endeavors.8 Cataplexy, which is present in 64 to 80% of narcoleptic individuals,7 is the most specific symptom and occurs when skeletal muscle atonia is triggered by strong emotion. Laughter is the most common precipitant, but anger, surprise, or excitement can also provoke an attack.9 The episodes are brief, usually lasting less than 2 min, and result in muscle weakness in the limbs, neck, and face. It is thought that the descending motor inhibitory pathways are excessively activated, leading to inhibition of the lower motor neurons. Muscle strength and deep tendon reflexes are transiently lost but consciousness is preserved, which is an important distinction from sleep. Documentation of quadriceps areflexia during an observed or provoked attack is diagnostic of narcolepsy.10

Hypnagogic hallucinations are present in up to 86% of narcoleptic patients vs approximately 25% in healthy populations.1112 Often visual, although sometimes auditory or tactile, hypnagogic hallucinations in narcolepsy likely represent fragments of dream imagery encroaching on wakefulness. Sleep paralysis may be due to residual REM atonia on awakening. It is present in 63% of narcoleptic patients, but is also reported by about 6% of healthy subjects.1213 Disturbed nocturnal sleep is also common in patients with narcolepsy, but the total amount of sleep over 24 h is normal.14 The association of narcolepsy with REM sleep behavior disorder (RBD) was recently reinforced in a study15 of narcoleptic patients, utilizing a questionnaire and telephone interview method. This suggested that the prevalence of RBD is 36%, approaching the prevalence of RBD seen in patients with neurodegenerative disorders such as Parkinson disease.15

Hypocretins, first discovered in 1998, play multiple roles in vertebrate behavior, including feeding activities, movement, and arousal. Hypocretin knockout mice16 and dogs with a mutation in the hypocretin receptor gene exhibit features of narcolepsy.17 Levels of hypocretin are low or undetectable in the cerebrospinal fluid (CSF) of human subjects with narcolepsy.18 To date, only a single case of human narcolepsy has been shown to be related to a mutation in the hypocretin gene.19 The more recent focus has been on mechanisms of CNS hypocretin underproduction. Magnetic resonance spectroscopy studies of narcoleptic patients have demonstrated reduced thalamic N-acetyl aspartate/creatine-phosphocreatine levels compared to control subjects.20 Autopsy studies on the brains of patients with sporadic human narcolepsy have shown profound loss of hypothalamic hypocretin neurons with some studies showing associated gliosis.21 Similar losses were noted in neurons containing neuronal activity-regulated pentraxin and prodynorphin, the role of which in hypersomnias is less well-defined.2223

There is a clear genetic component to narcolepsy, with human leukocyte antigen (HLA) DQB1*0602 representing the main susceptibility allele.24 The allele is found in 85 to 93% of patients with narcolepsy who experience cataplexy.25 Narcoleptic patients without cataplexy are less likely to carry the allele (35 to 56%), which is also present in 12 to 38% of individuals in control populations.26 Therefore, genetic screening is not helpful in clinical practice. The risk of narcolepsy developing in a first-degree relative has been estimated at about 1 to 2%.27

Nonspecific serum auto-antibodies are no more frequent in narcoleptic patients than control subjects,28 and specific antibodies against hypocretin peptides are not present in the serum or CSF of patients with narcolepsy.29 However, serum IgG from narcoleptic patients has been reported to enhance the contractile response of mice to a muscarinic agonist.30 A recent study31 reported that IgG from the CSF of 20 HLA DQB1*0602-positive narcoleptic patients with cataplexy bound protein extract from the rat hypothalamus, suggesting that an autoimmune process directed against undetermined antigens may indeed underlie the loss of hypothalamic neurons.

Hypocretin underproduction may not be the exclusive pathway to narcolepsy. Up to 10% of narcoleptic patients with cataplexy, and approximately 86% of patients with narcolepsy without cataplexy, have normal levels of CSF hypocretin.12 Furthermore, CSF hypocretin levels can be low in patients with a variety of neurologic conditions such as diencephalic stroke, Guillain-Barré syndrome, Creutzfeldt-Jakob disease, and acute head trauma without evidence of clinical narcolepsy, while normal levels have been found in patients with Niemann-Pick type C disease with severe cataplexy.12

Narcolepsy is initially diagnosed by clinical history, but the diagnosis should generally be confirmed by sleep laboratory testing. After the discontinuation of psychotropic medications for 2 weeks and ensuring adequate sleep time for at least 1 week, polysomnography is performed predominantly to rule out obstructive sleep apnea. A multiple sleep latency test (MSLT) is performed the following day. Patients are given four to five daytime nap opportunities, and the mean time to sleep and the presence of REM sleep within 15 min is evaluated. The MSLT is a helpful but imperfect diagnostic tool in patients with narcolepsy and other hypersomnias, as clear definitions of abnormal values are lacking. A recent metaanalysis32 of healthy and control subjects found a mean sleep latency for a four-nap test of 10.4 min with a wide SD of 4.2 min. In contrast, pooled data demonstrated that patients with narcolepsy have a mean sleep latency of 3.1 ± 2.9 min. The current diagnostic criteria for narcolepsy are a mean sleep latency of < 8 min and sleep onset REM sleep (SOREM) periods on at least two of the nap opportunities in the absence of untreated sleep apnea, sleep deprivation, or sudden withdrawal of REM sleep-suppressant medications.33

Neither HLA typing nor CSF hypocretin levels are routinely indicated in the clinical evaluation of narcolepsy. Patients with narcolepsy without cataplexy present with EDS, and have abnormally short mean sleep latencies and SOREM periods on MSLT, but have not experienced typical cataplexy. They may report atypical symptoms such as episodic fatigue or muscle weakness, as well as more classic sleep paralysis, hypnagogic hallucinations, and automatic behaviors with memory lapses. They are less likely to be HLA DQB1*0602-positive, but if they do carry the allele, are more likely to have low CSF hypocretin levels.1234

Narcolepsy due to a medical condition, also known as secondary narcolepsy, has been recognized as a distinct clinical entity for decades, with pathology most often localized to the brainstem or diencephalon. Cataplexy is not always present. Head trauma, tumors (especially pituitary adenomas and craniopharyngiomas), vascular malformations, and multiple sclerosis have been associated with the narcoleptic phenotype.353637 In general, CSF hypocretin levels are normal or unreported, but occasional cases of secondary narcolepsy have been noted to have hypocretin deficiency, including patients with diencephalic stroke38 and a family with autosomal-dominant cerebellar ataxia.39

Treatment of narcolepsy is primarily directed at reducing EDS. Regular nocturnal sleep times with adequate time in bed should be emphasized. In addition, scheduled daytime naps have been shown to improve the symptoms of severe daytime sleepiness.40 To enhance alertness further, pharmacologic therapy with stimulants is offered in a stepwise fashion (Table 3 ).


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  		Table 3.. Stimulant Medications*

 
Therapy with modafinil is usually started first because of reasonable efficacy, a favorable side effect profile, and a lack of the peak and trough effects of shorter duration agents. Approved in 1998, this wake-promoting agent works via an unknown mechanism and appears to have minimal potential for addiction.41 Headache is the most common adverse reaction, but, unlike amphetamines, modafinil does not produce sympathomimetic effects. Conventional stimulants that increase synaptic amine availability, including methylphenidate, dextroamphetamine, and methamphetamine, are introduced if sleepiness persists. Side effects such as palpitations and anxiety are not uncommon, and must be weighed against the benefits of increased alertness. High-dose stimulants carry a risk of side effects such as weight loss and psychiatric disturbances. Prescribers should consider objective documentation of residual sleepiness with maintenance of wakefulness testing before exceeding recommended dosing guidelines.42

Cataplexy has traditionally been controlled with tricyclic antidepressants, and more recently with selective serotonin reuptake inhibitors and venlafaxine. The approval in 2002 of sodium oxybate for the treatment of cataplexy adds another treatment option.4344 The drug binds {gamma}-hydroxybutyrate, and, to a lesser extent, {gamma}-amino butyric acid-B receptors in the brain. It is taken at bedtime and again 2.5 to 4 h later. Sodium oxybate may improve nocturnal sleep continuity and increase slow-wave sleep.45 Patients with narcolepsy report improved daytime alertness when receiving therapy with the drug, and sodium oxybate received additional US Food and Drug Administration approval in late 2005 for the treatment of EDS in narcolepsy patients. Its potential for abuse was demonstrated in the street drug {gamma}-hydroxybutyrate, and sodium oxybate is available only through a single central pharmacy. Side effects include dizziness, vomiting, sleep walking, and enuresis. It can also produce respiratory depression and should not be used with other sedatives.

Attempts at immunomodulation in a limited number of narcoleptic patients have been reported.46474849 One pediatric case report utilizing prednisone demonstrated no benefit,46 and a woman receiving plasma exchange had short-lived relief of cataplexy.47 The response of five patients undergoing treatment with IV Ig was varied4849; three had marked improvement in cataplexy, but objective improvement in the results of testing of the maintenance of wakefulness was seen in only one patient.

Idiopathic Hypersomnia

Idiopathic hypersomnia (IH) has been recognized for more than a century. Less common and less well-defined than narcolepsy, early descriptions overlapped with cases of von Economo encephalitis and classic narcolepsy. In the second half of the 20th century, a syndrome of excess daytime sleepiness without cataplexy was better characterized by Roth50 and others.5152 They noted the feature of "sleep drunkenness," which is a difficulty in achieving full alertness on waking despite adequate or prolonged sleep. The current definition distinguishes IH with and without long sleep time.5 In the former, patients have EDS despite documented nocturnal sleep times of at least 10 h. They rarely awaken during sleep, have extreme difficulty with arousal, and take long unrefreshing naps. Patients with IH without long sleep time have EDS but tend to sleep < 10 h per night and are less likely to have sleep drunkenness. In the largest series reported,50 25% of 42 patients had prolonged sleep time, 60% napped during the day, and 21% reported sleep drunkenness.

The diagnosis of IH with long sleep time is often made clinically. However, overnight polysomnography should show a short initial sleep latency and prolonged sleep period. The subsequent MSLT usually demonstrates pathologic sleepiness with a mean sleep latency of < 8 min and less than two SOREMs. If MSLT sleep latency is normal, it has been suggested that the documentation of excessive daily sleep can be achieved with prolonged monitoring of 24 to 36 h. IH without long sleep has fewer specific clinical features, and thus polysomnography followed by an MSLT is essential for diagnosis. The overnight sleep time is < 10 h, and the MSLT must show a mean sleep latency of < 8 min with less than two SOREMs. Unlike narcolepsy, no laboratory abnormalities are associated with IH, and no clear genetic predisposition has been identified. Treatment parallels that of EDS in narcolepsy patients, but the response to medication is variable.

Recurrent Hypersomnia

Recurrent hypersomnia is a rare disorder. The symptoms most often occur in adolescent boys as an episodic triad of hypersomnia, hyperphagia, and behavior changes such as hypersexuality, which is subclassified as Kleine-Levin syndrome. However, a similar syndrome has been noted in women, particularly in the perimenstrual period, as well as in middle-aged adults.53 The overall ratio of male to female cases is 4:1. The periods of hypersomnia last days to weeks and occur on average four times per year.54

In a recent review55 of 186 patients with Kleine-Levin syndrome reported in the literature, 61% had identified a potential trigger such as a viral illness or other infection. The median age of onset was 15 years. Episodes occurred approximately every 3 to 4 months, and, when termination was reported, the median duration of disease was 4 years. The median daily sleep duration during an attack was 18 h. In addition, the patients exhibited a wide range of behavior changes including aggression; cognitive disturbances with defects in attention, concentration, and memory; hallucinations and delusions; megaphagia, generally without bulimia; disturbance of mood; and various forms of inappropriate or excessive sexual behavior.

No findings of focal abnormalities on neurologic examination have been reported, although a few patients have exhibited autonomic dysfunction. Laboratory study findings are generally normal, including serum testosterone levels and CSF examination results. One patient was reported56 to have mildly low CSF hypocretin levels during episodes. Polysomnography shows increased total sleep time, with frequent awakenings and an increased percentage of stage 1 sleep.53 MRI during attacks is unrevealing, but single photon emission CT scan studies have shown reduced cerebral blood flow, most often in the thalamus, with less consistent reductions within the frontotemporal regions.57 Of four autopsy studies of patients with recurrent hypersomnia, three had inflammatory changes in the hypothalamus.53 As with narcolepsy, an autoimmune process is suspected but has not yet been proven.58 The disease process is usually self-limited after 4 to 8 years, with full recovery. However, some authors5960 have stressed that chronic impairment of cognitive function can be seen, with corresponding cortical hypoperfusion.

A wide range of treatment modalities has proven to be ineffective for recurrent hypersomnia, including drug therapy with tricyclic antidepressants, selective serotonin reuptake inhibitors, and neuroleptics, and electroconvulsive therapy. Stimulants may improve sleepiness during episodes, while lithium treatment appears to reduce the frequency, severity, and length of relapses.61

Behaviorally Induced Insufficient Sleep Syndrome

Behaviorally induced insufficient sleep syndrome is due to chronic sleep deprivation. Although its voluntary nature clearly differentiates it from the other disorders classified under "Hypersomnias of Central Origin" in the second edition of the International Classification of Sleep Disorders, the consequences of insufficient sleep do involve CNS mechanisms. Individuals may complain of difficulty with attention and concentration, irritability, fatigue, and other physiologic responses to reduced sleep. The insufficient sleep is secondary to volitional choices, social pressures, and work-related factors, and can result in serious injury on the job or while driving. Patients may describe "catching up" with prolonged sleep periods on weekends or vacation. Laboratory testing is usually unnecessary but, if performed, shows reduced sleep latency and increased sleep efficiency on polysomnography, and a short sleep latency on MSLT with less than two SOREMs. Because insufficient sleep syndrome may be more common in adolescents and young adults, it should be distinguished from delayed sleep phase disorder. Patients often self-treat daytime sleepiness with caffeine and other stimulants, but a recent task force review62 recommended only limited use of these substances for the syndrome. Patients should be strongly encouraged to increase their time in bed.

Hypersomnia Due to Medical Condition, Drug, or Substance

Hypersomnia can be attributed to a wide variety of metabolic, infectious, or toxic medical conditions. However, the problem may also be a direct consequence of disease processes within the CNS, including Parkinson disease63 and myotonic dystrophy,64 and less common disorders such as Niemann-Pick type C disease65 and Prader-Willi syndrome.66 A 2001 study67 of 71 patients with traumatic brain injuries showed that posttraumatic hypersomnia was relatively common (47%), with only 11% of patients with EDS demonstrating obstructive sleep apnea on polysomnography. A detailed review of medications and substances that cause EDS is beyond the scope of this article. However, patients who complain of sleepiness and fatigue should be questioned carefully about their use of prescribed and over-the-counter medications, as well as their use of alcohol and illicit drugs. Special attention should be paid to anticonvulsants (eg, carbamazepine), narcotic analgesics, anxiolytics (eg, clonazepam), tricyclic antidepressants, and dopaminergic agents (eg, pramipexole or ropinirole).

Hypersomnia Not Due to Substance or Known Physiologic Condition

This entity is most often attributable to psychiatric conditions. Patients complain of poor, nonrestorative sleep, with frequent daytime naps and multiple other somatic complaints. Mood disorders, including atypical depression and seasonal affective disorder, are often comorbid conditions. The underlying pathophysiology in varied psychiatric conditions has been attributed to hyperarousal resulting in a poor quality of nocturnal sleep and daytime hypersomnolence.68 The sleep latencies found on MSLT are usually normal.

Footnotes

Abbreviations: CSF = cerebrospinal fluid; EDS = excessive daytime sleepiness; HLA = human leukocyte antigen; IH = idiopathic hypersomnia; MSLT = multiple sleep latency test; RBD = rapid eye movement sleep behavior disorder; REM = rapid eye movement; SOREM = sleep onset rapid eye movement sleep Learning Objectives: 1. Assess hypersomnia related to CNS disorders having multiple etiologies, including narcolepsy, recurrent hypersomnia, behaviorally induced insufficient sleep syndrome, idiopathic hypersomnia, and medical conditions and drugs.

This research was supported by Mayo Piscopo Funds.

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Both authors receive grant monies from the National Institutes of Health. Dr. Silber is president, American Academy of Sleep Medicine.

Received for publication February 24, 2006. Accepted for publication May 17, 2006.

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