Epidemiological studies on excessive daytime sleepiness (EDS) have used varying definitions of excessive sleepiness, limiting the ability to compare prevalence across studies. Research using large population samples has shown that up to 33% of American adults suffer from EDS.
EDS with symptoms of functional impairment has been found in 15.6% of the general adult population. It can occur at any age, one study found that 41.5% of US teenagers reported feeling sleepy during the day.
EDS presents with a wide range of comorbidities, including sleep disorders, obesity, and psychiatric problems. It is also associated with personal and occupational hazards that can affect public safety. Excessive daytime sleepiness, hypersomnolence and hypersomnia are terms that are often used interchangeably. However, their meanings are different and may vary depending on the classification system used.
Hypersomnolence refers to a symptom of the Classification of Sleep Disorders-3 , corresponding to sleep disorders, while hypersomnia is used to name specific sleep disorders.
Other definitions come from its association with mental disorders, in which the term hypersomnia is used to refer to a symptom criterion. On the other hand, when it is a disorder identified with a specific criterion, it is defined as a hypersomnolence disorder, characterized by daytime sleep and/or significant sleep disorder, and is not related to narcolepsy, circadian rhythm sleep disorders. wakefulness or, substance use.
| Presentation |
Patients with EDS may complain of ≥1 of the following: excessive sleepiness; inadvertently falling asleep, sleep attacks (falling asleep without prodromal symptoms of drowsiness); episodes of prolonged, non-restorative main sleep; recurrent naps on the same day and sleep inertia (prolonged difficulty waking up, with irritability, automatic behavior or confusion). They may also feel fatigue.
| Consequences of excessive daytime sleepiness |
EDS is associated with both physical and mental comorbidities and contributes to motor vehicle accidents and deaths. A study of car crashes found that the mortality rate is similar to that of crashes caused by high blood alcohol levels. Excessive sleepiness in physicians and other health care providers is associated with increased risk of medical errors. EDS is closely related to psychiatric and functional comorbidities.
Parents of children with EDS report depression and anxiety symptoms. Adolescents who report SDE are also likely to have a lower grade point average, even when controlling for socioeconomic factors.
The relationship between EDS and psychiatric comorbidities is complex and may be bidirectional with respect to depression and anxiety. In children, this bidirectionality can translate into emotional and behavioral concerns, including attention deficit/hyperactivity disorder, conduct problems, and peer problems.
| Common Causes of Excessive Daytime Sleepiness |
The most common cause of EDS is insufficient sleep.
A cross-sectional study of truck drivers found a mean sleep duration of 5.6 hours, while 46% of them reported hypersomnia. In the US, specialists recommend that adults ages 18 to 60 sleep at least 7 hours a night.
In the US, a significant proportion of adults do not sleep that many hours. A CDC (Centers for Disease Control and Prevention) survey showed that one-third of respondents slept <7 hours per night.
Shift work is a major contributor to insufficient sleep and circadian dysregulation, which contribute to the development of EDS. Similarly, insufficient sleep is common in adolescents, and should be an important consideration when evaluating those with EDS. Another survey identified that 45.7% of adolescents reported suffering from EDS more than once/week.
Physical comorbidities are also associated with incident daytime sleepiness. A longitudinal study also confirmed an association between overweight and obesity with the onset and persistence of EDS. It also found an association with sleep apnea and diabetes mellitus. Other respiratory disorders such as asthma and gastroesophageal reflux disease can disrupt nighttime sleep and cause daytime sleepiness.
Psychiatric comorbidities associated with EDS include mood disorders (depression, bipolar disorder).
The presence of SDE in subjects with these disorders may moderate the treatment effect and increase the risk of relapse into a mood episode. Among sleep disorders, obstructive sleep apnea (OSA) is often associated with EDS. Repeated night awakenings, obesity, hypercapnia, and tissue damage in waking brain regions, secondary to hypoxia, occurring in the context of OSA, can potentially lead to EDS.
On the other hand, circadian sleep-wake rhythm disorders such as delayed sleep-wake phase disorder or jet lag disorder that result from a misalignment between the biological clock and social requirements can present with EDS, especially when the patient needs to be awake but their level of alertness secondary to their internal biological clock is at its lowest point. These circadian sleep-wake rhythms can also lead to insufficient sleep.
Central excessive sleep disorders are characterized by excessive sleepiness not attributable to nocturnal sleep disorders or circadian misalignment, and are often caused by primary abnormalities of the central nervous system. These include narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, and Kleine-Levin syndrome.
Narcolepsy is clinically characterized by severe EDS . Cataplexy , present in almost two- thirds to three-quarters of patients, is highly specific for the diagnosis. Hypnagogic and hypnopompic hallucinations and sleep paralysis may have a presentation similar to that of cataplexy. These symptoms also result from rapid eye movement (REM) intrusion into wakefulness, but are less specific phenomena.
Cataplexy is characteristic of narcolepsy type 1, and consists of a loss of muscle tone in the face, neck or legs, most often triggered by sudden positive emotions, usually related to joy, or sometimes anger or feelings . shocks. Patients with type 2 narcolepsy do not have cataplexy.
Although hypnagogic and hypnopompic hallucinations can occur in any sensory modality, they are usually visual in nature. These patients may occasionally present with automatic behaviors secondary to short episodes of microsleep during the day.
Most patients with narcolepsy are thought to have an autoimmune disorder.
The pathological basis of narcolepsy type 1 is the loss of hypocretin-1 (also known as orexin-A) synthesized in the neurons of the hypothalamus. This can be diagnosed clinically by measuring hypocretin-1 levels in the cerebrospinal fluid (CSF) or, more commonly, using a surrogate marker of a combination of cataplexy and short latencies to REM sleep, in a multiple sleep latency test ( MSL). However, almost 24% of patients with narcolepsy without cataplexy have low or absent hypocretin-1 in the CSF, which characterizes type 1 narcolepsy.
Narcolepsy type 2 is also characterized by short REM sleep latencies, but is not associated with cataplexy. Low CSF hypocretin-1 levels should be normal. The pathogenesis of narcolepsy type 2 is uncertain. Idiopathic hypersomnia also presents EDS, but without cataplexy or REM sleep intrusions. The typical phenotype consists of episodes of prolonged non-restorative nighttime sleep, severe sleep inertia, and daytime naps that are often long and unrestorative.
Other patients with a less specific phenotype may resemble those with narcolepsy type 2, in addition to the absence of premature REM sleep. Recently, it has been proposed that these fall into the same classification as "narcolepsy spectrum disorder" but, until now, this terminology has not been incorporated into any formal nosology.
Kleine-Levin syndrome is a rare sleep disorder, usually occurring in adolescent males and characterized by periods of remission-relapse, excessive sleepiness, cognitive impairment, altered perception, disordered eating (hyperphagia or anorexia), depressed mood and disinhibited behavior, including hypersexuality. Episodes can last from 2 days to 5 weeks and occur at least once every 18 months, with periods of normal cognition and sleepiness between episodes. The disorder usually resolves spontaneously by age 30.
| Assessment |
> History
Evaluation of SDE should begin with a complete medical history. The sleep history should include information on bedtime and waking times, weekdays and weekends, total daily sleep time, sleep habits, and daytime routines. To discover a sleep-wake circadian rhythm disorder, it is very helpful to know the patient’s time preferences, both for going to bed and waking up. A history of loud snoring and pauses in breathing, with episodes of choking, occurring during the night suggest a high probability of sleep apnea.
The presence of cataplexy suggests narcolepsy.
Other nighttime symptoms that may be associated with daytime sleepiness are symptoms suggestive of restless legs syndrome , characterized by periods of insomnia associated with the need to move the legs, which is relieved by movement. This syndrome is generally associated with periods of leg movements during sleep, but these movements are common, especially in older people.
Rarely, periodic leg movements during sleep can cause EDS without accompanying restless legs syndrome, a condition known as periodic limb movement disorder.
The history should also evaluate for symptoms suggestive of depression, reflux, gastrointestinal, pain or respiratory conditions, and a history of allergies or asthma, which may cause disruption of nighttime sleep, resulting in daytime sleepiness. It is also important to collect data from a bed partner, as they can be useful in identifying symptoms suggestive of OSA or periodic limb movements. Likewise, it is important to know all the medications and substances that the patient uses.
Over-the-counter medications that can cause sedation include antihistamines and pain relievers. Various medication prescriptions can cause increased sedation, such as α-2-benzodiazepine agonists, sleep medications, dopamine agonists, anticonvulsants, opioids, and other psychotropics such as antipsychotics and some antidepressants. Substance abuse can also cause daytime sleepiness.
Alcohol is the most commonly used sedative substance, but marijuana and opioids can also cause daytime sedation.
On the other hand, benzodiazepines and other sedatives/hypnotics can be misused/abused and cause daytime sleepiness. However, there may also be symptoms resulting from withdrawal from substances such as cocaine and other stimulants, including caffeine, which may present with excessive sleepiness.
It is important to distinguish between drowsiness and fatigue . The latter is a lack of energy with a reduction in the ability to perform physical activities that were previously done easily. It may be accompanied by mental fatigue with poor concentration and memory but is generally not associated with inappropriate episodes of sleep during the day.
Although sometimes fatigue can be associated with chronic medical, neurological or psychiatric illnesses, or occurs in isolation, as in chronic fatigue syndrome. On the contrary, unlike environmental or intrinsic factors, sleep disorders should be looked for in EDS. Women with OSA are more likely to report fatigue than drowsiness as their primary symptom.
> Measurement scales
Measurement scales are a useful complement to medical history and sleep records. Although there are several sleepiness scales, the 3 most used are: the Epworth scale, the Stanford scale and the Karolinska scale. Because the Stanford and Karolinska scales measure momentary sleep, they may be more useful for assessing sleep over a specific period. and are commonly used in research studies. The Epworth scale can be useful for general understanding of the level of sleepiness, and therefore, has greater clinical application.
> Physical examination
The physical examination for evaluation of excessive sleepiness should take into account:
a) Signs related to disorders that are commonly associated with this symptom.
b) The alert level during the exam.
High body mass index and increased neck circumference are risk factors for OSA.
The crowded oropharynx. with erythematous pharyngeal walls, may also suggest an increased risk of OSA. Other physical abnormalities may include: midface hypoplasia, micrognathia, retrognathia, enlarged tonsils, or deviated septum. It is also important to evaluate for signs of insulin resistance, such as acanthosis nigricans, as well as signs of acromegaly and hypothyroidism, which suggest an increased risk of OSA.
Generally, physical examination signs in patients with circadian sleep-wake rhythm disorders, narcolepsy, or idiopathic hypersomnia are normal. However, a cataplexy attack is accompanied by hypotonia, (transient) areflexia, and sometimes facial twitching. Transient areflexia is specific to cataplexy. In patients with suspected central hypersomnolence disorders, neurological examination may reveal a disorder affecting the brainstem, thalamus, or hypothalamus.
Many factors contributing to EDS can be elucidated by primary care physicians, but when a central hypersomnolence disorder is suspected or the cause is uncertain, referral to a sleep specialist is recommended.
OSA is usually diagnosed through tests that can be done at home, but treatment of the associated breathing disorders generally requires the involvement of a sleep disorders specialist.
SDE testing consists of 3 main modalities: actigraphy, polysomnography (PSG), and Iterative Sleep Latency Test (MSLT). Objective measures of SDE include measurement of long sleep duration, as measured by wrist actigraphy or continuous PSG, and measurement of mean sleep latency, as measured with the MSLT.
Actigraphy , a relatively inexpensive and non-invasive technique, provides a surrogate sleep-wake marker, and may be particularly useful in identifying sleep insufficiency and circadian sleep-wake rhythm disorders. Actigraphs are wristwatch-like devices that measure movement, and serve as surrogates for wakefulness.
They can be used by the patient at home, for several days or weeks, and can be a useful complement to the recording of events during sleep. However, sleep logs may overestimate total sleep, and actigraphy may underestimate awakening time and overestimate sleep time. These limitations must be taken into consideration during the interpretation of these measures.
Average daily sleep times , of at least 660 minutes in adults, can help identify idiopathic hypersomnia. PSG quantifies sleep and respiratory abnormalities. It consists of night-time monitoring, in a sleep laboratory, with sensors that provide information on electroencephalography, electrooculography, respiratory parameters (including airflow, respiratory effort, snoring and pulse oximetry), body position, electrocardiography and electromyography. This helps detect sleep disorders, periodic limb movements, and other causes of disrupted nighttime sleep that can result in daytime sleepiness.
Rapid eye movements during sleep that appear 15 minutes after sleep onset on PSG are highly suggestive of narcolepsy. These episodes are in addition to the number of open eyes in REM sleep onset (SOREM) episodes required for the diagnosis of narcolepsy.
The gold standard for objective assessment of SDE is the MSLT. To carry it out, patients can take 4 or 5 naps with 2-hour intervals, and their awakenings are monitored and their propensity to fall asleep measured. It is designed to objectively quantify sleepiness under standardized conditions and detect the presence of EDS.
For the test to be a valid diagnostic method for diagnosing central hypersomnolence disorders, it is important to avoid prior sleep deprivation and discontinue all psychotropic medications that may affect sleep propensity and influence REM sleep, at least 2 weeks or 5 half-lives before the study.
Performing the test while the patient is taking antidepressants or other medications that may affect sleep latency or REM latency prevents valid interpretation. Therefore, MSLT should not be used if those medications cannot be stopped safely. To ensure adequate sleep before the MSLT, actigraphy and sleep recording are used for 1 to 2 weeks prior to the test and PSG, performed the night before the MSLT.
Patients are counseled to discontinue illicit drugs, medications that can affect sleep/wake, and supplements or over-the-counter medications, such as melatonin and diphenhydramine. Urine drug testing may be indicated, since its absence is important when excessive drowsiness is a student.
A mean sleep latency (MSL) measured by MSLT of less than 5 minutes indicates drowsiness, while a value >10 minutes is normal. However, it is necessary to complement the interpretation with clinical judgment. Although in the International Classification of Sleep Disorders 3, the MSL cut-off value is 8 minutes, this value should be used with caution in the clinical context.
The presence of ≥2 SOREMs (including a SOREM that occurred on PSG prior to MSLT) is considered abnormal. After ruling out other causes, such as insufficient sleep, rotating shift work, moderate or severe OSA, or, if discontinuation of REM-suppressing medications has not been done for at least 2 weeks, in conjunction with a short MSL (generally defined as 8 minutes), indicates narcolepsy.
An MSL less than, greater than, or equal to 8 minutes with less than 2 SOREM supports the diagnosis of idiopathic hypersomnia. However, some patients with the classic phenotype of idiopathic hypersomnia may have a normal MSL on the MSLT.
An alternative criterion for diagnosis is a total daily sleep time of at least 660 minutes. Wrist actigraphy for 1 week, allowing the patient to sleep whenever desired, is a more practical method to evaluate this parameter.
| Human leukocyte antigen and CSF hypocretin-1 testing |
Studies have identified DQB1*06:02, an HLA antigen, associated with narcolepsy. DQB1*06:02 is found in 90% to 95% of African American, Caucasian, and Japanese patients with narcolepsy type 1, and 45% to 50% of patients with narcolepsy type 2. However, almost 25% of the general population may have this gene, which significantly limits its specificity in clinical practice.
To help make a In narcolepsy type 1, the concentration is measured by immunoreactivity, and ≤110 pg/ml or less than one-third of the mean values obtained in healthy subjects with the same standardized assay.
Indications for this test include suspected narcolepsy, when a valid MSLT cannot be performed, such as when psychotropic medications cannot be discontinued, the presence of untreated OSA, insufficient sleep or rotating shift work, or in children. ≤5 years.
Human leukocyte antigen testing should always be performed first, as essentially all patients with low CSF hypocretin-1 levels and narcolepsy will have the DQB1*06:02 antigen. It is important to understand that patients with narcolepsy type 2 and Idiopathic hypersomnia have diagnostic levels of narcolepsy, hypocretin-1 levels can be measured in the CSF.
The test may also be useful in distinguishing cataplexy from functional disorders in certain patients with EDS, associated with neurodegenerative disorders or autoimmune encephalopathies. Currently, it is not a widely used test.
| Treatment |
If SDE is secondary to other causes, it must first be identified and treated. It should be noted that there are no head-to-head trials showing superiority of a single agent and the proposed algorithm is to balance current evidence, drug abuse potential and side effect profiles. The patient’s preference and the price of the medications to be chosen should also be considered.
| Non-pharmacological treatment |
Non-pharmacological treatments and behavioral therapies are useful as complementary therapeutic options. The most important aspect of behavioral management of EDS is to ensure that the patient obtains sufficient sleep. Additional modalities may include scheduled naps, distraction, exercise, sleep hygiene measures, and behavioral therapy.
Scheduled naps can be a useful adjunct in the treatment of narcolepsy, but they are rarely sufficient if they are the only treatment.
Distraction techniques such as chewing gum have been shown to have a moderate degree of usefulness in promoting wakefulness. Physical activity has been shown to improve wakefulness in animal models of narcolepsy. Another important nonpharmacological approach in patients with OSA and EDS is to improve adherence to continuous positive airway pressure during sleep, as it has been shown to reduce daytime sleepiness.
| Pharmacotherapy |
In the US, pharmacological treatment of EDS includes FDA-approved and non-FDA-approved medications, and can target the underlying cause or symptom of excessive sleepiness. The medications approved by the FDA are: modafinil, armodafinil, dextroamphetamine, mixed amphetamine/dextroamphetamine, methylphenidate, sodium oxybate, solriamfetol and pitolisant. There are no FDA-approved treatments for idiopathic hypersomnia.
> Methylphenidate and amphetamines .
Dextroamphetamine d, methylphenidate, and amphetamine/dextroamphetamine mixture are approved by the FDA for the treatment of narcolepsy. However, methylphenidate and many amphetamine preparations are used for the management of idiopathic hypersomnia, and are included as a therapeutic option for clinical practice by the American Academy of Sleep Medicine. Methylphenidate primarily inhibits catecholamine reuptake, while amphetamines elevate extracellular dopamine.
Dosage is usually adjusted according to effect, with a maximum recommended dose of 100 mg/day for both amphetamine and methylphenidate. Release preparations are preferred to avoid peak and trough effects of short-acting drugs. When starting these medications, the appearance of tachycardia and high blood pressure and anorexia with weight loss should be taken into account. An electrocardiogram should be performed before prescribing amphetamines, as these medications can increase the QT interval.
Other studies have found an increased risk of psychosis and anorexia, especially at doses higher than therapeutic ones. According to the FDA, these medications are comparable to Schedule II controlled substances, indicating a moderate risk of abuse. Some patients develop tolerance to the stimulant effects but there is no evidence that “drug holidays” prevent this.
> Modafinil and Armodafinil
These medications are approved by the FDA for the treatment of EDS due to narcolepsy, persistent drowsiness after adequate treatment of OSA, and rotating shift work disorder. They are also included as a therapeutic option for idiopathic hypersomnia in the AASM practice parameters. Armodafinil is the R-enantiomer of modafinil, with somewhat more persistent concentrations.
Its mechanism of action is uncertain. Generally, treatment with modafinil is started with 200 mg in the morning, and armodafinil, 150 mg in the morning, but many patients require higher doses or twice a day. Side effects are rare with these medications, but a potentially serious effect of Stevens-Johnson syndrome.
Other possible side effects are headache, nausea, dry mouth and anorexia. They can also interfere with the action of contraceptives. Long-term studies have shown moderate efficacy in narcolepsy. Both modafinil and armodafinil are schedule IV controlled substances, indicating a possible but low potential for abuse.
> Solriamfetol
This medication is approved by the FDA for the treatment of EDS in narcolepsy and persistent drowsiness in appropriate treatment of OSA. It is the only dopamine/norepinephrine reuptake inhibitor approved for the treatment of a hypersomnolence disorder.
For OSA, treatment is started with 37.5 mg/day for OSA, and for narcolepsy, with or 75 mg/day and a maximum dose of 150 mg/day. The most common side effects are headache, nausea, anorexia, tachycardia and anxiety, depending on the dose. It should not be used with monoamine oxidase inhibitors. Currently, solriamfetol is a type IV drug.
> Pitolisant
It is a product recently approved by the FDA for the treatment of EDS accompanying narcolepsy; reducing the frequency of cataplexy. It has a unique mechanism of action; acts as a histamine H3 antagonist/inverse agonist receptor; modulates the release of other wake-promoting neurotransmitters, such as dopamine, norepinephrine and acetylcholine. The starting dose is 8.9 mg (maximum dose: 35.6 mg/day).
The most common side effects are: headache, nausea and anxiety. An electrocardiogram should be done before use as it may increase the QT interval. It may reduce the effectiveness of oral contraceptives and interfere with the action of antidepressants and serotonin reuptake inhibitors. Serum medication levels may be increased by concomitant use of selective serotonin reuptake inhibitors and tricyclic antidepressants.
> Sodium oxybate
It is a first-line drug for the treatment of cataplexy; improves EDS, especially if used in combination with modafinil. It is taken in 2 divided doses before bed and 2 to 4 hours later. Total daily dose: 6 to 9 g. Side effects are: sedation, nausea, weight loss, nocturnal enuresis and sleepwalking.
It is a respiratory depressant and should never be combined with alcohol or hypnotics, or used in patients with OSA, moderate to severe lung disease, and other causes of hypoventilation. It is a substance whose dose must be increased gradually and requires special local registration.
> Others
There are treatments with limited availability for Kleine-Levin syndrome. Evidence suggests that lithium, generally titrated to a blood level in the upper range for the treatment of mania, may decrease the frequency and duration of episodes of Kleine-Levin syndrome. Other antiepileptic mood stabilizers have also been studied for the treatment of this syndrome, but they appear to be less effective. In some patients, amantadine may be beneficial in improving drowsiness.
An important consideration for treatment is the potential for abuse with several of these agents, particularly methylphenidate, amphetamines, and sodium oxybate. For stimulants such as methylphenidate and amphetamines, data suggest that guideline-recommended doses may be relatively safe from the standpoint of abuse potential.
Although a history of substance use should not be a contraindication to the treatment of central hypersomnolence disorders, the physician may want to consider other therapeutic options with less potential for abuse, such as pitolisant.
Most medications used to treat EDS have been shown to have teratogenic effects in animal studies and there are no detailed practice parameters on treatment during pregnancy. The decision about whether to discontinue medications in pregnancy should be based on decision-making principles after weighing risks and benefits.
Treatment of EDS secondary to medical conditions varies, and evidence is often limited. The AASM list of practice parameters for modafinil is a treatment option for EDS due to Parkinson’s disease, myotonic dystrophy, and multiple sclerosis.
Conclusion
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