Primary Hypersomnia

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:

• 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.

• The hypersomnolence occurs at least three times per week for at least 3 months.

• The hypersomnolence is accompanied by significant distress or impairment in cognitive, social, occupational, or other important areas of functioning.

• 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). 

• The hypersomnolence is not attributable to the physiological effects of a substance.

• 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)

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]

1. The patient experiences at least two recurrent 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. 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).
5. 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:

• Hypersomnia
• Intense dreaming
• Frequent hypnogogic hallucinations

Cognitive changes:

• Bradyphrenia - almost always present during an episode
• Anterograde amnesia
• Derealization - almot all patients
• Disinhibited behavior - hyperphagia (57%) and hypersexuality (43%–53%)

Neuropsychiatric symptoms:

• Eating disturbances - 80%
• Depressed mood - 48%
• Hallucinations/illusions - 33%
• Mild psychotic symptoms (grandiosity, delusions, hyperreligiosity, paranoia) - lasts hours to days
• Anxiety

Common symptoms:

• Headache
• Photophobia
• Phonophobia
• Orthostasis

Less common symptoms:

• Hypertension
• Bradycardia/tachycardia
• Ataxia
• 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]

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]

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.

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]

 

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.

The diagnostic criteria of idiopathic hypersomnia in ICSD-3 includes both objective testing parameters and clinical criteria, which are similar to DSM-5 criteria:[17, 48, 49]

• Daily periods of irresistible need to sleep or daytime lapses into sleep for more than 3 months

• Absence of cataplexy

• MSLT showing < 2 SOREMPs or no SOREMPs if the REM sleep latency preceding polysomnogram is 15 minutes or less

• The presence of at least one of the following:

  • MSLT showing a mean sleep latence of 8 minutes or less

  • Total 24-hour sleep time of 660 minutes or longer (typically 12 to 14 hours) on 24-hour polysomnography monitoring (performed after the correction of chronic sleep deprivation) or by wrist actigraphy in association with a sleep log (averaged over at least 7 days with unrestricted sleep)

• Insufficient sleep syndrome ruled out (if deemed necessary, by lack of improvement of sleepiness after an adequate trial of increased nocturnal time in bed, preferably confirmed by at least 1 week of wrist actigraphy)

• Hypersomnolence or MSLT findings that are not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance abuse. Drugs known to affect sleep, sleep latency, and daytime alertness must be carefully evaluated and should be withdrawn for a minimum of 2 weeks before objective tests.

Additional characteristics

The most typical referral is for the polysymptomatic form of primary hypersomnia and is characterized by the following:[1, 60]

• Excessive daytime sleepiness leading to prolonged naps that are not refreshing

• Sleep drunkenness

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. 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 (i.e., 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 irritability, hypersexuality, hyperphagia, impulsive behavior, depersonalization, hallucinations, depression, and disorientation.

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

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

An underlying rheumatologic disease, such as active rheumatoid arthritis or osteoarthritis, may cause daytime hyperoxia and sleepiness associated with poor nighttime sleep due to pain. Prior head trauma sequela or a current brain tumor can leave their specific mark on the neurologic examination.

Specific findings may suggest a degenerative neurologic condition (e.g., Parkinson or Huntington disease), endocrine dysfunction (e.g., hypothyroidism), viral and bacterial infections (e.g., hypersomnia secondary to viral encephalitis), pulmonary disease with secondary sleep-related breathing difficulties (e.g., chronic bronchitis) or musculoskeletal disorders (e.g., rheumatoid arthritis, fibromyalgia).

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

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

Mental status examination

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

Mood might be “down," tired,” or even “depressed,” with mood congruent and a decreased range of affect. If this is the case, the meaning of the words needs to be carefully qualified. Is it that the patient has depression (ie, major depressive disorder) or is it that he/she feels down as a reaction to oversleeping and decreased ability to function?

Thought processes should be coherent and goal directed. While suicidal ideation is not typical for hypersomnolence, because of the overlap between sleeping and affective disorders, standard questioning about the presence 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 should not reveal any significant deficits.

Recurrent hypersomnia

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

For secondary Kleine-Levin syndrome, patients tend to be older and have more frequent and longer episodes, but they present with clinical symptoms and treatment responses similar to those of primary cases.[11]

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

Patients should receive a complete blood count (CBC), screening biochemistry tests, and thyroid-stimulating hormone tests to exclude common physical disorders that may present with complaints of excessive tiredness, often expressed as excessive sleepiness by patients. 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 data collection validity and reliability. Commonly used scales for a quantitative, systematic assessment of excessive sleepiness are the Epworth Sleepiness Scale and the Stanford Sleepiness Scale. While helpful, these scales remain essentially subjective in nature, which raises questions about the characteristics of sleepiness as assessed by subjective methods (e.g., the Epworth and Stanford sleepiness scales) versus objective ones (e.g., polysomnography and the Multiple Sleep Latency Test).[80, 78]

Complete in-laboratory polysomnography (PSG) studies are essential to exclude other sleep disorders, particularly sleep breathing disorder, periodic limb movement disorder, 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.[79, 81]

A PSG study completion is required prior to the Multiple Sleep Latency Test 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 Multiple Sleep Latency Test results to be considered in diagnosing hypersomnolence. Typical PSG findings in idiopathic hypersomnia include shortened sleep latency, increased sleep efficiency (often >90%), and increased slow wave sleep[82, 10, 47, 56, 13]   It should be noted that these are nonspecific findings and could be present in behaviorally induced insufficient sleep syndrome (BIISS).[13]  Some studies report increased frequency of sleep spindles either throughout the sleep period or at the beginning and end of the night in idiopathic hypersomnia.[83, 69]  It should be noted that SOREMPs are rare in idiopathic hypersomnia (IH). Indices for arousal, apnea-hypopnea, and periodic limb movements (PLM) are generally less than 5 to 10 per hour. Other studies have a belief that PLM in a patient with excessive daytime sleepiness who does not have a diagnosis of restless legs syndrome (RLS) should not preclude giving a diagnosis of IH—occasionally higher indices are seen.[10, 47, 59, 61, 13]   

Sleep latency on the Multiple Sleep Latency Test is short, with a mean sleep latency time < 8 minutes.[3, 10, 47]  SOREMPs can occur in approximately 3–4% of naps but by definition will not occur more than once. This is contrasted with narcolepsy, where sleep-onset REM periods (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:

• A sleep period that is normal or prolonged in duration

• Normal REM sleep latency

• A mean sleep latency score of less than 8 on the Multiple Sleep Latency Test

• Fewer than 2 sleep-onset REM periods.

The Multiple Sleep Latency Test is performed to evaluate the presence of pathologic sleepiness. The subject is studied during 5 daytime naps taken 2 hours apart. According to 2 studies, the mean Multiple Sleep Latency Test score in hypersomnolence is slightly higher than the score in narcolepsy. The mean Multiple Sleep Latency Test score was found to be 6.5 ± 3.2 minutes for idiopathic hypersomnolence versus 3.3 ± 3.3 minutes for narcolepsy. Narcolepsy is excluded by the absence of sleep-onset REM periods on the 5-nap Multiple Sleep Latency Test.

In recurrent primary hypersomnia (ie, Kleine-Levin syndrome), routine electroencephalographic studies performed during hypersomnia show a general slowing of the background rhythm and paroxysmal bursts of theta activity. Nocturnal PSG shows prolonged sleep duration and decreased sleep latency (< 10 min). In addition, sleep-onset REM has been reported during symptomatic periods. (See the images below.)[66, 83, 3, 10, 47]

Severe idiopathic hypersomnolence is a disabling problem that often leads to permanent unemployment and responds poorly to medical treatment.[3, 83] Moreover, because the underlying cause of idiopathic hypersomnolence is unknown, treatment remains symptomatic in nature.

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 hypersomnolent patients had improved vigilance with flumazenil.[84]  Another study from a single sleep center reported subjective improvement in EDS in 53 idiopathic hypersomnia (IH) patients that were refractory to traditional psychostimulants, who were given clarithromycin, an antibiotic that has GABAA inhibitory properties. Long-term treatment, however, has potential side effects of antibiotic resistance, GI problems, and infections.[37]

The American Academy of Sleep Medicine practice parameters state that 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,sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for excessive sleepiness associated with narcolepsy and primary hypersomnias. Scheduled naps can 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.

Consultations

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

Activity

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

Oxybates  

The FDA approved calcium/magnesium/potassium/sodium oxybates (Xywav) for adults with idiopathic hypersomnia in August 2021. It 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 compared to placebo in change in the primary endpoint of Epworth Sleepiness Scale score (p < 0.0001), and secondary endpoints of Patient Global Impression of Change (p  < 0.0001) and the Idiopathic Hypersomnia Severity Scale (p value < 0.0001).[86]  

Stimulants

Therapy for idiopathic hypersomnolence involves maintaining the patient on daytime stimulants. The drug dose is titrated so that the patient stays alert during the day, but adverse effects should be avoided. Methylphenidate (Ritalin) and dextroamphetamine are the most commonly prescribed medications. Pitolisant, a wake-promoting agent that increases CNS histamine via blocking presynaptic H3 reuptake, appears promising, but is still in the new drug application (NDA) process in the United States pending FDA approval.[13]

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 idiopathic hypersomnolence.[87] It is a psychostimulant that enhances wakefulness and vigilance, but its pharmacologic profile is notably different from the 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, with its 1:1 racemic mixture has an estimated elimination half-life of 4 hours for the S-enantiomer and 15 hours for the R-enantiomer, functionally producing an estimated 9–14 hours half-life. Given the enantiomeric differences, armodafinil has a longer elimination half-life of around 10–15 hours.[82, 88, 13]

The mechanism of action of modafinil is not fully understood. Modafinil induces wakefulness in part by its action in the anterior hypothalamus. 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, is 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.[88, 84]  

Other Medications

Other medications that have been used in the treatment of this disorder include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), clonidine, levodopa, bromocriptine, amantadine, and methysergide. Patients develop tolerance to their medications; exercise caution in prescribing drugs.

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.

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. 

Daytime stimulants

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, 75]

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).[88, 84] 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.[89]

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. 

Calcium/magnesium/potassium/sodium oxybates (Xywav)

Indicated for adults with idiopathic hypersomnia. 

Class Summary

These agents have wake-promoting activities.

Modafinil (Provigil)

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)

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)

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)

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)

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)

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.