Background
Primary hypersomnia, idiopathic hypersomnia (ICSD-3), and hypersomnolence disorder (DSM-5) refer to a central disorder of hypersomnia. The diagnostic criteria have changed over time and specifics differ depending on the organization. Similarities from all, however, include daily periods of irresistible sleep or daytime lapses into sleep, absence of cataplexy, and that the hypersomnolence is not better accounted for by either insufficient sleep or by another sleep disorder. In comparison, narcolepsy is characterized by well-defined clinical, polysomnographic, and immunogenetic features. [1, 2] The abrupt sleep attacks seen in classic narcolepsy are not present in this disorder.
Classification
In the literature, 3 possible subgroups of idiopathic CNS hypersomnia have been suggested.
Subgroup I
These patients have a positive family history, and associated clinical symptoms suggest dysfunction of the autonomic nervous system. These symptoms include headache, syncope, orthostatic hypotension, and peripheral vasoconstriction (cold hands and feet).
Subgroup II
This group includes patients who had a viral infection associated with neurologic symptoms, such as Guillain-Barré syndrome, infectious mononucleosis, or atypical viral pneumonia. Even after their infectious disease resolves, these patients continue to require significantly more nocturnal sleep and continue to feel very tired.
Although initially these patients are fatigued, they subsequently have difficulty differentiating fatigue from sleepiness. To fight tiredness, these patients nap and eventually present with complaints of excessive daytime sleepiness. Analysis of cerebral spinal fluid demonstrates moderate lymphocytosis (30-50 cells/µL with mild to moderate elevation in protein).
Subgroup III
These patients do not have a positive family or viral infection history, and the cause of the disorder truly is idiopathic.
Diagnostic criteria (DSM-5 and ICSD-3)
The specific DSM-5 criteria for hypersomnolence disorder are as follows:
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Self-reported excessive sleepiness (hypersomnolence) despite a main sleep period of at least 7 hours, with at least one of the following symptoms: 1) Recurrent periods of sleep or lapses into sleep within the same day; 2) A prolonged main sleep episode of more than 9 hours per day that is nonrestorative; 3) Difficulty being fully awake after abrupt awakening.
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The hypersomnolence occurs at least three times per week for at least 3 months.
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The hypersomnolence is accompanied by significant distress or impairment in cognitive, social, occupational, or other important areas of functioning.
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The hypersomnolence is not better explained by and does not occur exclusively during the course of another sleep disorder (eg, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep-wake disorder, or a parasomnia).
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The hypersomnolence is not attributable to the physiological effects of a substance.
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A coexisting mental disorder or medical condition does not adequately explain the hypersomnolence.
In addition, hypersomnolence disorder is specified by duration: acute (less than 1 month), subacute (1–3 months), persistent (more than 3 months); and by the severity based on degree of difficulty maintaining daytime alertness: mild (1–2 days a week), moderate (3–4 days a week), severe (5–7 days a week).
The American Sleep Disorders Association’s International Classification of Sleep Disorders, Third Edition (ICSD-3) has redefined the criteria of idiopathic hypersomnia to include varied presentations under the same diagnosis as opposed to distinguishing two separate forms (with and without long sleep time) that were characteristic of the ICSD-2 definition.
ICSD-3 classifies “Central disorders of hypersomolence” into ‘primary’ and ‘secondary’ groupings, with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH), and Kline-Levin syndrome (KLS) making up the primary disorders. The secondary disorders include hypersomnia due to a medical or psychiatric disorder, due to a drug or substance, and lastly, insufficient sleep syndrome (ISS).
ISCD-3 Central Disorders of Hypersomnolence (Open Table in a new window)
| Primary | Secondary |
|---|---|
Narcolepsy type 1 (NT1) Narcolepsy type 2 (NT2) |
Hypersomnia due to a medical condition Hypersomnia due to a psychiatric condition |
| Idiopathic hypersomnia (IH) | Hypersomnia due to a drug or substance |
| Kleine-Levin syndrome (KLS) | Insufficient sleep syndrome (ISS) |
Recurrent primary hypersomnia
Kleine-Levin syndrome (KLS) is a rare disorder that starts during adolescence and has a male gender preference. The patients have recurrent episodes of hypersomnia, which are often associated with compulsive overeating and hypersexuality. [3] The periods of hypersomnia occur for days to weeks at a time and recur several times a year. In between the symptomatic periods, the patients have normal sleep requirements and do not have excessive daytime sleepiness. Some patients may develop symptoms of irritability, impulsive behavior, depersonalization, hallucinations, depression, and confusion. The etiology of this disorder is not known, but genetic factors are believed to contribute, citing 2% to 5% of cases are of multiplex family origin. [4, 5, 6, 7, 8, 9] Metabolic, inflammatory, and autoimmune etiologies are suspected, though not yet confirmed. [10, 11, 12]
The disorder mainly affects males (68%). The median age of onset is 15 years (range, 4–82 years; 81% during the second decade), and the syndrome may last up to 8 years. The episodes recur every 3–4 months and may last up to 10 days, but they may last longer in women. (See Epidemiology.)
KLS may be precipitated by infections (72%), alcohol consumption (23%), sleep deprivation (22%), unusual stress (20%), physical exertion (19%), traveling (10%), head trauma (9%), and marijuana use (6%). Symptoms of infection-triggered KLS generally occur shortly after onset of fever (3 to 5 days). [13, 14, 15, 16]
ISCD-3 diagnostic criteria for KLS are as follows: [17]
- The patient experiences at least two recurrent episodes of excessive sleepiness of 2 days to 5 weeks duration.
- Episodes recur usually more than once a year and at least once every 18 months.
- The patient exhibits normal alertness, cognitive function, behavior, and mood between episodes.
- The patient must demonstrate at least one of the following during episodes: cognitive dysfunction, altered perception, eating disorder (anorexia or hyperphagia), disinhibited behavior (such as hypersexuality).
- The hypersomnia and related symptoms are not better explained by the other sleep disorders, other medical neurologic, or psychiatric disorders (especially bipolar disorder), or use of drugs or medications.
Characteristic symptoms of KLS include the following: [11, 14, 18, 19, 20, 4, 21, 22, 5, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41]
Sleep symptoms:
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Hypersomnia
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Intense dreaming
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Frequent hypnogogic hallucinations
Cognitive changes:
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Bradyphrenia - almost always present during an episode
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Anterograde amnesia
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Derealization - almot all patients
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Disinhibited behavior - hyperphagia (57%) and hypersexuality (43%–53%)
Neuropsychiatric symptoms:
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Eating disturbances - 80%
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Depressed mood - 48%
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Hallucinations/illusions - 33%
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Mild psychotic symptoms (grandiosity, delusions, hyperreligiosity, paranoia) - lasts hours to days
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Anxiety
Common symptoms:
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Headache
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Photophobia
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Phonophobia
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Orthostasis
Less common symptoms:
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Hypertension
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Bradycardia/tachycardia
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Ataxia
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Tachypnea
Clinical subtypes
KLS may be mild, moderate, or severe. When episodes consistently occur with a temporal relation to menstruation, it is referred to as subtype “menstrual/menstruation-related hypersomnia” and is extremely rare (18 known cases worldwide). [20, 42, 43, 44, 45, 46] Menstrual-related hypersomnia is diagnosed when excessive daytime sleepiness occurs on a periodic basis over a few days preceding menstruation. [47] It is assumed that the symptoms follow hormonal changes, but the etiology of the syndrome, as well as its prevalence and course, are virtually unknown.
The ICSD-3 classifies KLS as a recurrent hypersomnia. DSM-5 refers to the recurrent hypersomnia as seen in KLS as an “other specified hypersomnolence disorder, brief-duration hypersomnolence." [48, 49]
Etiology
Hypersomnolence is an idiopathic disorder. Although head injury or viral infections can cause a disorder resembling primary hypersomnia, the true causes for most cases remain unknown. No genetic, environmental, or other predisposition has been identified. [2] Rye et al postulated that there is a naturally occurring “somnogen” in the CSF of those with hypersomnolence that potentiated the inhibitory effects of GABAA in an in vitro setting. [50]
Excessive daytime sleepiness has been described in a subset of patients following viral illnesses such as Guillain-Barré syndrome, hepatitis, mononucleosis, and atypical viral pneumonia. Familial cases associated with HLA-Cw2, -Cw3, -DR5, -DR11, -DQ1, and –DQ3 genotypes have also been reported, and it is known that there are overlapping features found in both idiopathic hypersomnia and narcolepsy, though no consistent findings are agreed upon. HLA typing does not currently play a role in diagnosis of idiopathic hypersomnia. [51, 52, 53, 54, 55, 13] However, the majority of patients diagnosed with idiopathic hypersomnia have neither a positive family history nor a past medical history of viral illnesses.
A recent study highlighted expression dynamics of circadian clock genes in dermal fibroblasts, in which 10 patients with idiopathic hypersomnia were compared to healthy controls. They found the rhythmically expressed BMAL1, PER1, and PER2 were expressed less in cells from idiopathic hypersomnia patients over two circadian periods, and that the overall BMAL1 expression was reduced significantly. [56, 13]
In experimental animal studies, destruction of the nonadrenergic neurons of the rostral third of the locus ceruleus complex has produced hypersomnia. While trauma has been associated with excessive daytime sleepiness in a case series, cerebrospinal fluid (CSF) analysis for specific neurotransmitter metabolites did not differentiate patients with posttraumatic excessive daytime sleepiness from patients with narcolepsy or other patients with excessive daytime sleepiness. [57] Injury to the adrenergic neurons at the bundle of isthmus has led to hypersomnia associated with a proportional increase of both NREM and REM sleep. [58]
Montplaisir et al found decreased dopamine and indoleacetic acid in both narcolepsy and idiopathic hypersomnia patients. [59, 13]
Faull et al discovered dopaminergic dysregulation in narcolepsy and noradrenergic dysregulation in idiopathic hypersomnia. [60]
This evidence suggests the possibility of aminergic arousal system dysfunction in idiopathic hypersomnia. Feline studies have shown hypersomnia and monoamine dysregulation can be induced reproducibly via lesioning of the ascending noradrenergic pathways. [61, 13]
Evidence suggests that a dopamine system dysfunction may occur in narcolepsy, while a similar malfunction of the norepinephrine system may occur in idiopathic hypersomnia. Decreased CSF histamine levels have been reported in primary hypersomnia, as well as in narcolepsy, but not in non-CNS hypersomnias, suggesting that histamine may be an indicator of a central (versus a peripheral) origin for hypersomnias. [62]
A major advance in the understanding of the pathology of narcolepsy, a disorder closely related to primary hypersomnia, was made after the discovery of narcolepsy-associated genes in animals; ie, genes involved in the pathology of the hypocretin/orexin ligand and its receptor. [63, 64] Low CSF concentrations of hypocretin-1 and hypocretin-2 in HLA DQB1*0602 were also found in primary hypersomnia, and a generalized defect in hcrt-2 transmission may be present in this disorder. As hypocretin peptides excite the histaminergic system by the hypocretin receptor 2, [65] hypocretin deficiency may result in excessive daytime sleepiness via decreased histaminergic function. [62]
Epidemiology
Occurrence in the United States
While the rates of excessive daytime sleepiness complaints in the general population are between 0.5-5% of adults (in surveys without a specific consideration of causes/diagnoses), idiopathic hypersomnia is diagnosed in about 5-10% of individuals who are self referred to a sleep clinic with a chief complaint of daytime sleepiness. [66] A precise estimation of idiopathic hypersomnia prevalence is complicated by a lack of clear biologic markers or unambiguous diagnostic criteria.
A study by Ohayon et al suggested that excessive sleepiness is more prevalent than previously estimated. The study found that with 27.8% of 15,929 individuals from 15 US states reported excessive sleepiness. Even when using restrictive criteria of frequency at least 3 times per week for at least 3 months despite normal sleep duration, the prevalence was 4.7%. [67]
A recent large series found that idiopathic hypersomnia represented about 1% of 6000 patients seen in sleep centers—given that idiopathic hypersomnia is believed to be 60% as prevalent as narcolepsy, this raises the question of diagnostic accuracy. [68, 13]
Sex-, age- and family-related demographics
Gender ratio for hypersomnolence is unknown, though female predominance was found in some but not all of these studies. [69, 52, 68, 70] Approximately 33%–66% of idiopathic hypersomnia cases appear to be familial. [13]
As with narcolepsy and Klein-Levin syndrome, onset of hypersomnolence is most common during adolescence and rare in people older than 30 years. The diagnosis of idiopathic hypersomnia is complicated by the fact that differentiating between excessive versus long sleep or normal versus abnormal wakefulness is often difficult in this population.
Prognosis
After a typical onset between the ages of 15 and 30 years, untreated hypersomnolence presents a chronic but stable course. Idiopathic hypersomnia is a lifelong disorder, believed to have no tendency to remit spontaneously, though a few studies have reported up to 25% of patients that carry the idiopathic hypersomnia diagnosis demonstrate spontaneous improvement in excessive daytime somnolence. This seemingly conflicting data again raises the question of diagnostic accuracy.
Consequences of this disease are mostly social and professional in nature, sharing a psychosocial burden that is similar to narcolepsy. [71, 72, 73, 13]
Daytime sleepiness can lead to depression. Of note, in children, daytime sleepiness can present as hyperactivity. [66]
Patient Education
While treating patients with hypersomnolence, the patient's close family should be involved in the overall education and decision-making process.
Because these disorders may lead to marriage breakdown, extensive counseling for the patient's partners, educating them about the symptomatology and treatment options, must be part of a comprehensive management plan.
Patients often need significant support because they are at risk of being misunderstood as being incompetent or slothful. Therefore, education of relatives, friends, and colleagues helps the patient to function much better with this incurable disease.
For patient education information, see the Sleep Disorders Center, as well as Disorders That Disrupt Sleep (Parasomnias), the Hypersomnia Foundation, and Narcolepsy.
Medline Plus/National Institutes of Health (NIH) provides concise and to-the-point summaries of the diagnosis and recommendations for patients and families dealing with primary hypersomnia and Kleine-Levine syndrome.
The Mayo clinic offers an additional, more comprehensive patient resource on idiopathic/primary hypersomnia.
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Primary hypersomnia. Polysomnographic study demonstrates apnea (absence of carbon dioxide fluctuation indicating no flow), chest wall paradox, abrupt increase in tidal volume at the end of apnea, and oxygen desaturation. All of these features are consistent with obstructive sleep apnea.
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Primary hypersomnia. In contrast to obstructive sleep apnea, mixed apnea shows absence of respiratory efforts in the first segment of the apnea.
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Primary hypersomnia. Periodic limb movements show intermittent leg electromyogram activity accompanied by electroencephalogram arousals.
Tables
| Primary | Secondary |
|---|---|
Narcolepsy type 1 (NT1) Narcolepsy type 2 (NT2) |
Hypersomnia due to a medical condition Hypersomnia due to a psychiatric condition |
| Idiopathic hypersomnia (IH) | Hypersomnia due to a drug or substance |
| Kleine-Levin syndrome (KLS) | Insufficient sleep syndrome (ISS) |
