Primary Hypersomnia

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Practice Essentials

Primary hypersomnia, idiopathic hypersomnia (ICSD-3-TR),[1]  and hypersomnolence disorder (DSM-5-TR)[2] refer to a central disorder of hypersomnia. The diagnostic criteria have changed over time and specifics differ depending on the classification. However, all these diagnoses include daily periods of irresistible, excessive sleep or daytime lapses into sleep in the absence of cataplexy, and require that the hypersomnolence is not due to insufficient sleep or another sleep disorder. Sleepiness is frequently associated with difficulties awakening, a phenomenon known as sleep inertia or sleep drunkeness.

Signs and symptoms

Clinical manifestations of hypersomnia include:

The polysymptomatic form of primary hypersomnia is the most common and is characterized by the following:

These patients do not feel refreshed following naps and, therefore, fight sleepiness as long as they are able. Patients are difficult to awaken from sleep or naps.

Some patients complain of headaches, fainting episodes, orthostatic hypotension, and peripheral vascular complaints of Raynaud phenomenon.

Diagnosis

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR)

The specific DSM-5-TR criteria[2]  for hypersomnolence disorder are as follows:

International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR)

The ICSD-3-TR has redefined the criteria of idiopathic hypersomnia (IH) 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.[1]   

ICSD-3-TR classifies “Central disorders of hypersomnolence” into "primary" and "secondary," with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH), and Kleine-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, due to insufficient sleep syndrome (ISS).[1]

Management

According to the American Academy of Sleep Medicine (AASM) 2021 guidelines, successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce maximum possible return of function, and regular follow-up to monitor response to therapy.

Modafinil, armodafinil, methylphenidate, amphetamines, and sodium oxybate are effective treatments for excessive sleepiness associated with narcolepsy and, by extension, are also used for primary hypersomnias.[3]

Background

Primary hypersomnia, idiopathic hypersomnia (ICSD-3-TR),[1]  and hypersomnolence disorder (DSM-5-TR)[2] refer to a central disorder of hypersomnia. The diagnostic criteria have changed over time and specifics differ depending on the classification. However, all these diagnoses include daily periods of irresistible, excessive sleep or daytime lapses into sleep in the absence of cataplexy, and require that the hypersomnolence is not due to insufficient sleep or another sleep disorder. Sleepiness is frequently associated with difficulties awakening, a phenomenon known as sleep inertia or sleep drunkeness. In comparison, narcolepsy is characterized by well-defined clinical, polysomnographic, and immunogenetic features.[4, 5] The abrupt sleep attacks seen in classic narcolepsy are not present in idiopathic hypersomnia.

Classification

In the literature, three possible subgroups of idiopathic CNS hypersomnia are described.

Subgroup I

These patients have a positive family history and present with clinical symptoms suggesting dysfunction of the autonomic nervous system. Symptoms include headache, syncope, orthostatic hypotension, and peripheral vasoconstriction (cold hands and feet).

Subgroup II

This group includes patients who had a viral infection 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 these patients are initially fatigued, they subsequently have difficulty differentiating fatigue from sleepiness. To fight tiredness, these patients nap and eventually present with excessive daytime sleepiness. Analysis of cerebral spinal fluid (CSF) 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; for this subgroup, the cause of the disorder truly is idiopathic.

Diagnostic criteria (DSM-5-TR and ICSD-3-TR)

The specific DSM-5-TR criteria[2] for hypersomnolence disorder are as follows:

In addition, hypersomnolence disorder is specified by duration: acute (less than 1 month), subacute (1–3 months), persistent (more than 3 months); and by 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, Text Revision (ICSD-3-TR) has redefined the criteria of idiopathic hypersomnia (IH) 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.[1]   

ICSD-3-TR classifies “Central disorders of hypersomnolence” into "primary" and "secondary," with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH), and Kleine-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, due to insufficient sleep syndrome (ISS).[1]

ISCD-3-TR Central Disorders of Hypersomnolence



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Recurrent primary hypersomnia

Kleine-Levin syndrome (KLS) is a rare disorder that starts during adolescence and has a male gender preference. Patients have recurrent episodes of hypersomnia, often associated with compulsive overeating and hypersexuality.[6] 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 confusion, depression, impulsive behavior, irritability, hallucinations, and depersonalization. KLS etiology is unknown but genetic factors are believed to contribute, with 2% to 5% of cases being of multiplex family origin.[7, 8, 9, 10, 11, 12] Autoimmune, inflammatory, and metabolic etiologies are suspected, though not confirmed.[13, 14, 15]

KLS 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).[16, 17, 18, 19]

ISCD-3-TR diagnostic criteria for KLS are as follows:[1]

  1. There are at least two episodes of excessive sleepiness of 2 days to 5 weeks duration.
  2. Episodes recur usually more than once a year and at least once every 18 months.
  3. The patient exhibits normal alertness, cognitive function, behavior, and mood between episodes.
  4. During episodes, the patient must demonstrate at least one of the following: altered perception, cognitive dysfunction, disinhibited behavior (such as hypersexuality), or eating disorder (anorexia or hyperphagia).
  5. The hypersomnia and related symptoms are not better explained by the other sleep disorders, other medical, neurologic, or psychiatric disorders, or use of drugs or medications.

Characteristic symptoms of KLS include the following:[14, 17, 20, 21, 22, 7, 23, 24, 8, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41]

Sleep symptoms:

Cognitive changes:

Neuropsychiatric symptoms:

Common symptoms:

Less common symptoms:

Clinical subtypes

KLS may be mild, moderate, or severe. KLS “menstrual/menstruation-related hypersomnia” is an extremely rare KLS subtype characterized by excessive daytime sleepiness occurring on a periodic basis over a few days preceding menstruation; to date, 18 known cases have been reported worldwide.[22, 42, 43, 44, 45, 46]  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-TR classifies KLS as a recurrent hypersomnia. DSM-5-TR refers to the recurrent hypersomnia as seen in KLS as an “other specified hypersomnolence disorder, brief-duration hypersomnolence."[1, 2]

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.[5]  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.[47]

Genetic contributors

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 have been reported. As a result, HLA typing does not currently play a role in diagnosis of idiopathic hypersomnia.[48, 49, 50, 51, 52, 16] Of note, the majority of patients diagnosed with idiopathic hypersomnia have neither a positive family history nor a past medical history of viral illnesses.

A study in which 10 patients with idiopathic hypersomnia were compared to healthy controls highlighted expression dynamics. The researchers found that the rhythmically expressed circadian clock genes BMAL1, PER1, and PER2 were expressed less in the dermal fibroblasts from idiopathic hypersomnia patients over two circadian periods, and that the overall BMAL1 expression was reduced significantly.[53, 16]

Monoamine neurotransmitters

In experimental animal studies, destruction of the noradrenergic neurons of the rostral third of the locus ceruleus complex resulted in hypersomnia. In a case series, trauma has been associated with excessive daytime sleepiness; however, 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.[54] 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.[55]  Decreased dopamine and indoleacetic acid levels have been found in both narcolepsy and idiopathic hypersomnia patients.[56, 16]

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.[57, 16]

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.[58]

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.[59, 60] 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,[61] hypocretin deficiency may result in excessive daytime sleepiness via decreased histaminergic function.[58]

Epidemiology

Frequency

While the rates of excessive daytime sleepiness complaints in the general US population are between 0.5% and 5% of adults (in surveys without a specific consideration of causes/diagnoses), idiopathic hypersomnia (IH) is diagnosed in about 5%–10% of individuals who are self-referred to a sleep clinic with a chief complaint of daytime sleepiness.[62] A precise estimation of idiopathic hypersomnia prevalence is complicated by a lack of clear biologic markers or unambiguous diagnostic criteria. As a result, the reported prevalence rates of IH vary broadly.

A 2012 study by Ohayon et al suggested that excessive sleepiness is more prevalent than previously estimated. The study found that 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%.[63]  

A 2023 study reported a much lower prevalence rate, estimating the rate of IH in US adults to be 32.12 per 100,000 persons in 2019, 35.71 per 100,000 persons in 2020, and 37.03 per 100,000 persons in 2021.[64]

A 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.[65, 16]

Sex-, age- and family-related demographics

IH prevalence varies between males and females. In the Wisconsin Sleep Cohort, the estimate prevalence of IH was 3.8% among both males and females, although female predominance was found in some studies.[66, 67, 49, 65, 68]  Approximately 33%–66% of idiopathic hypersomnia cases appear to be familial.[16]

As with narcolepsy and Kleine-Levin syndrome (KLS), onset of hypersomnolence is most common during adolescence and rare in people older than 30 years. The diagnosis of IH is complicated by the fact that differentiating between excessive versus long sleep or normal versus abnormal wakefulness is often difficult, especially during adolescence.

Prognosis

Typically starting between the ages of 15 and 30 years, hypersomnolence, when untreated, presents a chronic course. Idiopathic hypersomnia (IH) is a lifelong disorder, although a few studies have reported up to 25% of patients with IH demonstrate spontaneous improvement in excessive daytime somnolence; however, most patients show no tendency toward spontaneous remission. Such seemingly conflicting data findings raises the question of diagnostic accuracy. 

Hypersomnia consequences are mostly social and professional in nature, with a psychosocial burden similar to narcolepsy.[69, 70, 71, 16]    

Daytime sleepiness can lead to depression. Of note, in children, daytime sleepiness can present as hyperactivity.[62]

Patient Education

While treating patients with hypersomnolence, the patient's close family should be involved in the overall education and decision-making process.

Because hypersomnia can result in a range of social impairments, ranging from social isolation 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 hypersomnia is often misinterpreted as being indicative of professional incompetence or sloth. Education of relatives, friends, and colleagues can help patients 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 a comprehensive patient resource on idiopathic/primary hypersomnia.

History

The diagnostic criteria of idiopathic hypersomnia (IH) in ICSD-3-TR includes both objective testing parameters and clinical criteria, which are similar to DSM-5-TR criteria:[1, 2]

Clinical manifestations

Differential diagnosis and rule-outs

Additional characteristics

The most typical referral is for the polysymptomatic form of primary hypersomnia and is characterized by the following:[4, 72]

These patients do not feel refreshed following naps and, therefore, fight sleepiness as long as they are able. Patients are difficult to awaken from sleep or naps.

Some patients complain of headaches, fainting episodes, orthostatic hypotension, and peripheral vascular complaints of Raynaud phenomenon. Rarely, hypnagogic hallucinations and sleep paralysis may be observed or reported. During long periods of drowsiness, patients might develop automatic behavior, during which they act in a semicontrolled fashion. (During automatic behavior episodes, these patients may endanger themselves through risk of injury.)

In patients with the recurrent form (ie, Kleine-Levine syndrome), hypersomnia occurs for days to weeks several times a year; in between, patients do not have excessive daytime sleepiness. Some patients may develop symptoms of depersonalization, depression, disorientation, hypersexuality, hyperphagia, impulsive behavior, irritability, or hallucinations.

Physical Examination

The patient may appear overtired or even fall asleep in the physician’s office. The rest of the physical examination, however, might not reveal any particular features suggesting a diagnosis of hypersomnolence.

The aim of physical examination is to exclude alternate diagnoses. A diagnosis of obstructive sleep apnea should be considered for a patient presenting with hypersomnia associated with central obesity, macroglossia, micrognathia or retrognathia, crowded oropharynx, nasal obstruction, and tonsillar enlargement.

An underlying rheumatologic disease, such as active rheumatoid arthritis or osteoarthritis, may cause daytime hyperoxia and sleepiness following poor nighttime sleep due to pain. A neurologic examination can discover signs consistent with a past head trauma or a current brain mass or lesion. 

Specific findings may suggest cardiac pathology (eg, congestive heart failure), endocrine dysfunction (eg, hypothyroidism), bacterial or viral infections (eg, hypersomnia secondary to viral encephalitis), musculoskeletal disorders (eg, rheumatoid arthritis, fibromyalgia), degenerative neurologic conditions (eg, Parkinson or Huntington disease), or pulmonary disease with secondary sleep-related breathing difficulties (eg, chronic bronchitis).

An overweight patient with primary hypersomnia should be assessed for underlying endocrine problems and sleep apnea.

If psychomotor agitation or retardation is noted, mental disorders with secondary sleep disturbance need to be ruled out before making a diagnosis of primary hypersomnolence.

Mental status examination

Typical major depressive disorder commonly presents with decreased energy and tiredness, while atypical depression presents with hypersomnia. Similarly, soft speech, with a decreased rate of production and an increased latency of answers, might indicate excessive tiredness, but it may also indicate depression.

A “down," tired,” or “depressed” mood, with mood congruence and decreased range of affect can be indicative of depression (ie, major depressive disorder with secondary sleep disturbance) or a mood change that follows oversleeping (ie, a case of hypersomnia with secondary mood or affective changes).

Thought processes are usually coherent and goal directed. While suicidal ideation is not typical for hypersomnolence, because of the overlap between sleeping and affective disorders, a safety standard evaluation, including an assessment of suicidal and homicidal ideation is recommended.

Insight and judgment are most times good. Mild cognitive changes in the domains of attention, concentration and short-term memory are occasionally present, but most often the cognitive examination does not reveal any significant deficits.

Recurrent hypersomnia

On the neurologic examination, patients with Klein-Levin syndrome (KLS) may present with a number of nonspecific findings including dysarthria, nystagmus, and generalized hyperreflexia.

For secondary KLS, patients tend to be older, and have more frequent and longer episodes, but they otherwise present with clinical symptoms and treatment responses similar to those of primary cases.[14]

Approach Considerations

Hypersomnolence is a diagnosis of exclusion. Other causes of excessive daytime somnolence should be ruled out before a diagnosis of hypersomnolence is made.

A complete blood count (CBC), screening biochemistry tests, and thyroid-stimulating hormone tests are recommended to exclude common physical disorders that may present with excessive tiredness, often expressed as excessive sleepiness. A drug screen is indicated if substance-induced sleep disorder needs to be ruled out.

As excessive sleepiness is essentially a self-reported, subjective complaint, a number of tests have been created with the goal of increasing the diagnosis. Commonly used scales for a quantitative, systematic assessment of excessive sleepiness are the Epworth Sleepiness Scale and the Stanford Sleepiness Scale. While helpful, these are essentially subjective scales, which raises questions about the characteristics of sleepiness when assessed by subjective methods (eg, the Epworth and Stanford sleepiness scales) versus objective ones (eg, polysomnography and the Multiple Sleep Latency Test).[79, 77]

Polysomnography and Multiple Sleep Latency Test

Complete in-laboratory polysomnography (PSG) studies are essential to exclude other sleep disorders, particularly sleep breathing disorder, periodic limb movement disorder (PLMD), and narcolepsy. Nocturnal PSG findings in hypersomnolence include a short sleep latency, absence of arousals or awakenings, normal distribution of REM and NREM sleep, and normal to prolonged sleep duration.[78, 80]

A PSG study is required prior to the Multiple Sleep Latency Test (MSLT) to objectively characterize preceding sleep and uncover potential causes of sleep fragmentation. The PSG must have confirmed at least 6 hours of sleep for the MSLT results to be considered in diagnosing hypersomnolence. Typical PSG findings in idiopathic hypersomnia (IH) include shortened sleep latency, increased sleep efficiency (often >90%), and increased slow-wave sleep[81, 13, 82, 53, 16]  It should be noted that these are nonspecific findings, as they could also be present in behaviorally induced insufficient sleep syndrome (BIISS).[16] Some studies report increased frequency of sleep spindles either throughout the sleep period or at the beginning and end of the night in IH.[83, 67]  It should be noted that sleep-onset REM periods (SOREMPs) are rare in IH. Indices for arousal, apnea-hypopnea, and periodic limb movements (PLMs) are generally less than 5 to 10 per hour. Of note, other studies indicate that PLMD in a patient with excessive daytime sleepiness who does not have a diagnosis of restless legs syndrome (RLS) should not preclude a diagnosis of IH, as occasionally higher indices are seen.[13, 82, 56, 57, 16]   

Sleep latency on the MSLT is short, with a mean sleep latency time < 8 minutes.[6, 13, 82]  SOREMPs can occur in approximately 3–4% of naps but by definition will not occur more than once and can help differentiate IH from with narcolepsy, where SOREMPs (the occurrence of REM sleep within 20 minutes of sleep onset) are observed in two or more naps.

Breathing-related sleep disturbances and frequent limb movements disrupting sleep are not present.

The following PSG features are required for the diagnosis of hypersomnolence:

The MSLT evaluates the presence of pathologic sleepiness. The MSLT involves studying the patient during 5 daytime naps taken 2 hours apart. According to 2 studies, the mean MSLT score in hypersomnolence is slightly higher than the score in narcolepsy. The mean MSLT score was found to be 6.5 ± 3.2 minutes for IH versus 3.3 ± 3.3 minutes for narcolepsy. Further, narcolepsy is excluded by the absence of SOREMPs on the 5-nap MSLT.

Electroencephalography (EEG)

In recurrent primary hypersomnia (ie, Kleine-Levin syndrome), routine EEG studies during hypersomnia show a general slowing of the background rhythm and paroxysmal bursts of theta activity. Nocturnal PSG shows decreased sleep latency (< 10 min) and prolonged sleep duration. In addition, sleep-onset REM has been reported during symptomatic periods. (See the images below.)[62, 83, 6, 13, 82]



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Primary hypersomnia. Polysomnographic study demonstrates apnea (absence of carbon dioxide fluctuation indicating no flow), chest wall paradox, abrupt ....



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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.

Approach Considerations

Severe idiopathic hypersomnolence (IH) is a disabling problem that often leads to unemployment and responds poorly to medical treatment.[6, 83] Because the underlying cause of IH is unknown, treatment remains symptomatic in nature.

Per the American Academy of Sleep Medicine (AASM) practice guidelines, successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce maximum possible return of function, and regular follow-up to monitor response to therapy. Evidence for nonpharmacological options is extremely limited and evidence for pharmacological interventions is marginal.[84]

Scheduled naps might be beneficial to combat sleepiness in these patients.[85] Behavioral approaches and sleep hygiene techniques are recommended, although they have little overall positive impact on this disease.

Modafinil, armodafinil, methylphenidate, amphetamines, and sodium oxybate are effective treatments for excessive sleepiness associated with narcolepsy and, by extension, are also used for primary hypersomnias.[3]

Some limited evidence postulates that a CSF “somnogen” potentiates GABAA inhibitory effects and may increase excessive daytime sleepiness (EDS). Flumazenil is thought to competitively antagonize activity at the benzodiazepine recognition site, though it does not impact all GABA-ergic neurons. In a small study, 7 patients with IH had improved vigilance with flumazenil.[86]  Another study from a single sleep center of 53 patients with IH refractory to traditional psychostimulants reported subjective improvement in EDS following treatment with clarithromycin, an antibiotic with GABAA inhibitory properties. Long-term treatment, however, needs to account for the potential risks of antibiotic resistance, GI problems, and infections.[37]

Consultations

The diagnosis of hypersomnolence is made after excluding endocrine, neurologic, cardiopulmonary, and psychiatric disorders known to cause excessive sleepiness. Therefore, if an underlying cause is suggested, appropriate consultations with a specialist should be obtained.

Activity

Caution is recommended in activities in which hypersomnolence may be hazardous.

Pharmacologic Therapy

The treatment of idiopathic hypersomnia (IH) remains challenging due to the limited number of FDA-approved medications specifically indicated for this condition. According to the American Academy of Sleep Medicine (AASM) clinical practice guideline for the treatment of central disorders of hypersomnolence, modafinil is considered a strong option for treating IH. Lower-evidence treatments, qualified as “conditional,” include clarithromycin, methylphenidate, pitolisant, and sodium oxybate. With the exception of sodium oxybate, which is FDA approved for IH, the other medications use for IH should be considered off-label.[84]

Oxybates

The FDA approved calcium/magnesium/potassium/sodium oxybates (Xywav) for adults with IH in August 2021. Calcium/magnesium/potassium/sodium oxybates is a CNS depressant that contains salts of gamma hydroxybutyrate, an endogenous compound and metabolite of the neurotransmitter GABA.   

Approval was based on statistically significant and clinically meaningful differences between the active drug compared to placebo changes in the primary endpoint of Epworth Sleepiness Scale score (p < 0.0001), as well as the secondary endpoints of Patient Global Impression of Change (p  < 0.0001) and the Idiopathic Hypersomnia Severity Scale (p value < 0.0001).[87]  

Stimulants

Daytime stimulant treatments for IH aim to maintain alertness during the day. Modafinil and methylphenidate (Ritalin) are the most commonly prescribed medications for IH.

Modafinil and armodafinil

Modafinil, a 1:1 racemic mixture of (R)-(-) and (S)-(-) enantiomers, and armodafinil, the isolated (R)-(-) enantiomer, have proved clinically useful in the treatment of narcolepsy and other causes of excessive daytime sleepiness, such as IH.[88] Both drugs are psychostimulants that enhance wakefulness and vigilance, but their pharmacologic profile is different from amphetamines, methylphenidate, or cocaine. Modafinil is less likely to produce side effects such as jitteriness, anxiety, or excess locomotor activity or to lead to a hypersomnolent rebound effect. Modafinil  has an estimated elimination half-life of 4 hours for the S-enantiomer and 15 hours for the R-enantiomer, functionally producing an estimated half-life of 9–14 hours. Given the enantiomeric differences, armodafinil has a longer elimination half-life of around 10–15 hours.[81, 89, 16]

The mechanism of action of modafinil is not fully understood. Modafinil induces wakefulness in part by its action in the anterior hypothalamus. As its dopamine-releasing action in the nucleus accumbens is weak and dose dependent, the likelihood of a euphoric response, and, therefore, the abuse potential and tolerance, are small.

Modafinil has central alpha 1-adrenergic agonist effects (ie, it directly stimulates the receptors). Modafinil inhibits the reuptake of noradrenaline by the noradrenergic terminals on sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO). More significant, perhaps, is its ability to increase excitatory glutaminergic transmission and reduce local gamma-aminobutyric acid (GABA)–ergic transmission, thereby diminishing GABA(A) receptor signaling on the mesolimbic dopamine terminals.[89, 86]  

Other medications

Pitolisant is a wake-promoting agent that increases CNS histamine via blocking presynaptic H3 reuptake.[16]  While not directly approved for the treatment of IH, pitosilant is FDA approved for the treatment of narcolepsy and has shown promising results in retrospective studies for the treatment of excessive daytime sleepiness in IH.[3] Solriamfetol is a dopamine and norepinephrine reuptake inhibitor also approved for the treatment of excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea. Shown to activate TAAR1 receptors, which are involved in wake-promoting effects, solriamfetol, while promising, needs further data to support a treatment recommendation for IH.

Physician Legal Responsibilities

Physicians have a legal responsibility to know which medical conditions may impede driving ability, to diagnose these conditions in their patients, and to discuss the implications of these conditions.

The requirement to report unfit drivers varies among different jurisdictions, and interpretations of the law vary among the courts. Therefore, a physician’s risk of liability is unclear. Physicians may face legal action by their patients if they fail to counsel the patients on the dangers of driving associated with certain medications or medical conditions.

Physicians’ legal responsibilities to report patients with certain medical conditions, when required by law, override their ethical responsibilities to keep patients’ medical information confidential.

Guidelines Summary

American Academy of Sleep Medicine (AASM)

The American Academy of Sleep Medicine (AASM) released guidelines for the treatment of central disorders of hypersomnolence in adults and children in 2021. According to the guidelines, successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce maximum possible return of function, and regular follow-up to monitor response to therapy. Evidence for nonpharmacological options is extremely limited and evidence for pharmacological interventions is marginal. Modafinil is considered a strong option for treating IH. Lower-evidence treatments, qualified as “conditional,” include clarithromycin, methylphenidate, pitolisant, and sodium oxybate. With the exception of sodium oxybate, which is FDA approved for IH, the other medications use for IH should be considered off-label.[84]

 

Medication Summary

In August 2021, the FDA approved, calcium/magnesium/potassium/sodium oxybates (Xywav), the first drug indicated for idiopathic hypersomnia. It is a CNS depressant that contains salts of gamma hydroxybutyrate, an endogenous compound and metabolite of the neurotransmitter GABA.  It may be administered as either a once or twice nightly regimen. 

Patients often require drug therapy to treat daytime hypersomnolence. Prior to initiating therapy with stimulants, clearly establish a diagnosis and consider potential for abuse.[83, 74]

Modafinil, a wake-promoting agent, is approved for treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), and shift-work sleep disorder (SWSD).[89, 86] The studies have shown significant benefits on various objective measures and subjective estimates of excessive sleepiness.

The clinical efficacy of modafinil, combined with its improved safety over CNS stimulants, has made it the most prescribed medication for the treatment of excessive sleepiness associated with narcolepsy. Unlike many other medications used for excessive sleepiness, modafinil is not known to be abused. The most common adverse event reported in clinical studies was headaches; most were transient and mild to moderate in severity. Modafinil also has the potential for interactions with other drugs metabolized via cytochrome P450 enzyme pathways.

For Kleine-Levin syndrome, somnolence can decrease with stimulants (mainly amphetamines), while neuroleptics and antidepressants are of poor benefit. Lithium, rather than carbamazepine or other antiepileptics, was found to have a higher success rate for stopping relapses.[90]

Calcium/magnesium/potassium/sodium oxybates (Xywav)

Clinical Context:  Indicated for adults with idiopathic hypersomnia. 

Class Summary

Mixture of calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate (gamma-hydroxybutyrate [GHB]). GHB is an endogenous compound and metabolite of the neurotransmitter GABA. 

Modafinil (Provigil)

Clinical Context:  Modafinil, (1:1 racemic mixture of R- and S-modafinil) improves wakefulness, though the mechanism of action remains unclear. It may act at the dopamine receptor (DAT), inhibiting dopamine reuptake and may exert stimulant effects by decreasing GABA-medicated neurotransmission. It has wake-promoting actions similar to those of sympathomimetic agents, though no direct action on dopamine receptors themselves; wakefulness is not attenuated by known dopamine antagonists.

Armodafinil (Nuvigil)

Clinical Context:  Armodafinil is an R-enantiomer of modafinil (mixture of R- and S-enantiomers). It elicits wake-promoting actions similar to those of sympathomimetic agents, although its pharmacologic profile is not identical to sympathomimetic amines and has no direct action on dopamine receptors themselves.  Wakefulness is not attenuated by known dopamine antagonists. It may act at the dopamine receptor (DAT), inhibiting dopamine reuptake and may exert stimulant effects by decreasing GABA-medicated neurotransmission. It is not a direct- or indirect-acting dopamine receptor agonist. Armodafinil is indicated for the improvement of wakefulness in individuals with excessive sleepiness associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), or shift-work sleep disorder.

Methylphenidate (Ritalin, Daytrana, Methylin, Concerta)

Clinical Context:  Methylphenidate is used for symptomatic management of primary hypersomnolence whenever the patient needs to be alert or engages in activities in which hypersomnolence may be hazardous. The drug blocks the reuptake mechanism of dopaminergic neurons. Methylphenidate stimulates the cerebral cortex and subcortical structures.

Dextroamphetamine (Procentra, Dexedrine, Zenzedi)

Clinical Context:  This agent increases the amount of circulating dopamine and norepinephrine in the cerebral cortex by blocking the reuptake of norepinephrine or dopamine from the synapse.

Dextroamphetamine and amphetamine mixtures (Mydayis, Adderall XR)

Clinical Context:  This agent produces CNS and respiratory stimulation. The CNS effect may occur in the cerebral cortex and reticular activating system. Dextroamphetamine-amphetamine mixture may have a direct effect on alpha- and beta-receptor sites in the peripheral system and may also release stores of norepinephrine in adrenergic nerve terminals. The mixture contains various salts of amphetamine and dextroamphetamine. It is available as 5-, 7.5-, 10-, 12.5-, 15-, 20-, and 30mg scored tablets.

Amphetamine (Evekeo)

Clinical Context:  Amphetamines are noncatecholamine sympathomimetic amines that promote release of catecholamines from their storage sites in the presynaptic nerve terminals. Amphetamine 1:1 racemic mixture of dextroamphetamine and levoamphetamine (immediate release only) has an FDA indication for promoting wakefulness in narcolepsy.

Class Summary

These agents have wake-promoting activities.

What is the difference between primary hypersomnia and narcolepsy?What are the subgroups of idiopathic CNS hypersomnia?What are the DSM-5 diagnostic criteria for hypersomnolence disorder?What are the ASDA diagnostic criteria for idiopathic hypersomnia?How does the ICSD-3 classify central disorders of hypersomnolence?What is Kleine-Levin syndrome (KLS)?What are the subtypes of Kleine-Levin syndrome (KLS)?What causes primary hypersomnia?What is the prevalence of primary hypersomnia?What are the sexual predilections of primary hypersomnia?At what age is primary hypersomnia usually diagnosed?What is the prognosis of primary hypersomnia?What is included in patient education about primary hypersomnia?What are the ICSD-3 diagnostic criteria for idiopathic hypersomnia?Which clinical history findings are characteristic of primary hypersomnia?Which physical findings are characteristic of primary hypersomnia?Which mental status exam (MSE) findings are characteristic of primary hypersomnia?Which neurologic exam findings are characteristic of Kleine-Levin syndrome (KLS)?What should be considered prior to diagnosing primary hypersomnia?How is primary hypersomnia differentiated from behaviorally induced insufficient sleep syndrome (BIISS)?How is primary hypersomnia differentiated from normal sleep variation?How is primary hypersomnia differentiated from chronic insufficient sleep?How is primary hypersomnia differentiated from substance-induced sleep disorder, hypersomnia type?How is primary hypersomnia differentiated from upper airway resistance syndrome (breathing-related sleep disorder)?How is primary hypersomnia differentiated from posttraumatic hypersomnia?How is primary hypersomnia differentiated from other neurologic disorders?How is primary hypersomnia differentiated from hypersomnia due to other general medical conditions?How is primary hypersomnia differentiated from a major depressive disorder?How is primary hypersomnia differentiated from narcolepsy?How is primary hypersomnia differentiated from circadian rhythm sleep disorders?How is primary hypersomnia differentiated from dysthymia?How is primary hypersomnia differentiated from chronic fatigue syndrome?What are the differential diagnoses for Primary Hypersomnia?How is primary hypersomnia diagnosed?What is the role of PSG and MSLT in the workup of primary hypersomnia?What is the role of electroencephalography in the workup of primary hypersomnia?How is primary hypersomnia treated?Which specialist consultations are beneficial to patients with primary hypersomnia?Which activity modifications should be taken by patients with primary hypersomnia?Which medications are used in the treatment of primary hypersomnia?What is the role of modafinil and armodafinil in the treatment of primary hypersomnia?What are the physician&#39;s legal responsibilities to report patients with hypersomnia?What is the role of medications in the treatment of primary hypersomnia?Which medications in the drug class CNS Depressants are used in the treatment of Primary Hypersomnia?

Author

Adrian Preda, MD, DFAPA, Professor of Clinical Psychiatry and Human Behavior, Department of Psychiatry and Human Behavior, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Ana Hategan, MD, FRCPC, Associate Clinical Professor, Department of Psychiatry and Behavioral Neurosciences, Division of Geriatric Psychiatry, McMaster University School of Medicine; Geriatric Psychiatrist, St Joseph's Health Care Hamilton, Canada

Disclosure: Book royalties and/or honoraria for articles from American Psychiatric Publishing, Springer, and Current Psychiatry.

Additional Contributors

David R Bowman, MD, Psychiatrist, Deputy Chief, Joint Behavioral Health Clinic, Multi-Disciplinary Outpatient Clinic, Medical Review Officer, Clinical Practice Guidelines Champion, External Behavioral Health Consultant, Department of Behavioral Health, Moncrief Army Health Clinic

Disclosure: Nothing to disclose.

Acknowledgements

Jennifer S Morse, MD Associate Medical Director, Optum Health

Jennifer S Morse, MD is a member of the following medical societies: Academy of Psychosomatic Medicine, Aerospace Medical Association, and American Psychiatric Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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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.

Primary hypersomnia. In contrast to obstructive sleep apnea, mixed apnea shows absence of respiratory efforts in the first segment of the apnea.

Primary hypersomnia. Periodic limb movements show intermittent leg electromyogram activity accompanied by electroencephalogram arousals.

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.

Primary hypersomnia. In contrast to obstructive sleep apnea, mixed apnea shows absence of respiratory efforts in the first segment of the apnea.

Primary hypersomnia. Periodic limb movements show intermittent leg electromyogram activity accompanied by electroencephalogram arousals.

PrimarySecondary
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)