Hypersomnolence …

Richard P Knudsen MD FAASM CNP FAAP

Sleep Disorders

Updated 11.04.2024
Released 01.22.2001
Expires For CME 11.04.2027

Hypersomnolence

Author: Richard P Knudsen MD FAASM CNP FAAP

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Editor: Antonio Culebras MD FAAN FAHA FAASM

Hypersomnolence

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Introduction

Overview

Hypersomnolence is deleteriously prevalent, especially in modern society. This common medical complaint has various causative underpinnings. Sleep medicine, as a growing subspecialty field, can evaluate the nature of the problem and improve life and longevity with a great number of scientifically effective interventions. The cost to society, if sleepiness is left unaddressed, is profound given the negative effects on health and on education and on work-related issues, including workableness and propensity toward accidents and clashes. Fitness to drive behind-the-wheel is a challenging dilemma given an aging and senior population with alertness issues. The socioeconomic burden of disabling excessive daytime sleepiness is vast and is best addressed by all (58).

Hypersomnolence, or excessive daytime sleepiness, is a frequent complaint of patients and is a symptom associated with many medical conditions, including intrinsic sleep disorders, such as narcolepsy and obstructive sleep apnea or insufficient nighttime sleep. Though a nearly universal experience, sleepiness is often ignored or minimized by patients, often increasing their risk for industrial or motor vehicle mishaps. In this article, discussion will focus on the differential diagnosis, evaluation, and treatment of this often overlooked symptom complex. Information from the International Classification of Sleep Disorders (3rd edition) is highlighted. Newer therapeutic agents, deemed somnolytics, are reviewed.

Key points

	• Hypersomnolence, or excessive daytime sleepiness (EDS), is a common symptomatic clinical complaint.
	• Causes frequently include underlying, coexistent medical disorders.
	• Consequences include impaired job performance, diminished intellectual acuity, curbed psychosocial functioning, risk of serious accidents, and grave physical and medical health consequences.
	• The diagnostic evaluation, including the administration of the Multiple Sleep Latency Test (MSLT), can lead to a diagnosis of narcolepsy or idiopathic hypersomnia.
	• Stimulant therapy may be prescribed to overcome sleepiness.

Historical note and terminology

EDS is a public health issue. However, it remains largely undervalued, scarcely diagnosed, and poorly supported. Variations in the definition of EDS and limitations in clinical assessment lead to difficulties in its epidemiological study, but the relevance of this symptom from a socioeconomic perspective is inarguable. EDS might be a consequence of several behavioral issues leading to insufficient or disrupted sleep, as well as a consequence of sleep disorders including sleep apnoea syndrome, circadian disorders, central hypersomnolence disorders (narcolepsy and IH), other medical or psychiatric conditions, or medications. Furthermore, EDS can have implications for health as it is thought to act as a risk factor for other conditions, such as cardiovascular and neurodegenerative disorders. Because of the heterogeneous causes of EDS and the complexity of its pathophysiology, management will largely depend on the cause, with the final aim of making treatment specific to the individual using precision medicine and personalized medicine.

(116)

Hypersomnolence is one of the most common complaints that patients raise to their physicians. However, investigation of underlying physiologic causes did not begin in earnest until the 1930s (153). After rapid eye movement sleep was identified in the 1950s (11), and careful neurophysiologic studies separated non-REM sleep into 3 stages (N1, N2, and N3, based on progressive trending toward delta or SWS/slow wave sleep), a new awareness arose that sleep was a diverse and functionally important mechanism in the maintenance of homeostasis. Sleep medicine developed substantially as a discipline in the 1960s and 1970s, fueled by new interest in the diagnosis and treatment of narcolepsy and of obstructive sleep apnea (159; 124).

The term “hypersomnolence” describes excessive sleepiness, a persistently increased debt toward sleep, and an abnormally high likelihood of drowsiness when sleep is not desired or anticipated. Dauvilliers accurately states, “Hypersomnolence is not just characterized by daily episodes of an irrepressible need to sleep or daytime lapses into sleep. The term usually harbors much more in the way of disabling symptoms. Accordingly, it often includes impaired vigilance or sustained attention; automatic behaviors; cognitive complaints, especially linked to poor memory; and it can be accompanied by increased need for sleep and severe sleep inertia” (41). Other terms sometimes used synonymously include excessive daytime somnolence, excessive daytime sleepiness, or hypersomnia, although hypersomnia is best used to denote excessive amounts of sleep. Hypersomnolence can be assessed by subjective or by objective measures. Physiologic functions that reflect hypersomnolence include pupillometry, other autonomic functions, and EEG activity. The most commonly utilized formal and objective measure of hypersomnolence is the Multiple Sleep Latency Test. This clinical test is performed in a sleep laboratory, where recordings of EEG, surface EMG, and eye movements aid in the identification of latency to fall asleep during several daytime nap attempts.

As an overview, the classifications of hypersomnia (not due to a sleep-related breathing disorder), according to ICSD-3 (International Classification of Sleep Disorders-3) and DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders), include:

	• Narcolepsy type 1 (NT1) (with cataplexy – THE pathognomonic feature) • Narcolepsy type 2 (NT2) (without cataplexy) • Idiopathic hypersomnia (IH)
		- Kleine-Levin syndrome (recurring hypersomnia)
	• Hypersomnia due to a medical disorder • Hypersomnia due to a medication or substance • Hypersomnia associated with a psychiatric disorder
		- Insufficient sleep syndrome

A reappraisal by European experts and led by Dauvilliers and colleagues stresses the importance of creating a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence, containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity (41; 73).

In 2014, the American Academy of Sleep Medicine released the ICSD-3, which is an adaptation of nomenclature and diagnostic criteria previously in the field (06). For example, narcolepsy with cataplexy is now alluded to as narcolepsy type 1, also known as hypocretin (orexin) deficiency syndrome. The previous criterion of “daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months” remains in place; however, now either cataplexy with multiple sleep latency test (MSLT) less than 8 minutes and two sleep onset REM periods (SOREMPs) or CSF Hcrt-1 measured concentrations less than 110 pg/mL are valid as qualifying criteria. REM onset within 15 minutes of sleep onset during the preceding polysomnogram may replace one of the SOREMPs during the succeeding MSLTs. Also, among the changes, narcolepsy type 2 can be reclassified to type 1 if cataplexy develops over time.

Briefly, on a historical note, the milestones of narcolepsy are:

	1880 - Narcolepsy first described by the neurologist, Gelineau. Gelineau described the cataplectic falls as “astasias.”
	1930 - Daniels noted the association of daytime sleepiness with cataplexy, hypnagogic hallucinations, and sleep paralysis.
	1960 - Yoss and Daly noted SOREMPs during sleep in narcoleptic patients.
	1975 - First International Symposium on Narcolepsy.
	1999 - Hypocretin mutations discovered to cause narcolepsy in mice and dogs.
	2000 - Human narcolepsy realized to be stemming from hypocretin (orexin) deficiency.
	2013 - Epitope (antigenic determinant) of hypocretin (orexin) uncovered.
	2014 - FDA approval of a dual orexinergic receptor antagonist (DORA) in the clinical treatment of insomnia; novel somnogenic agent.
Adapted from (67).

Clinical manifestations

Presentation and course

Sleepiness is considered excessive when it interferes with daily activities such as reading, driving, working, or interacting with others. Some patients request evaluation for hypersomnolence, but many do not recognize their sleepiness as a problem and, therefore, may not seek attention until pressed to do so by significant others, co-workers, or by near-miss events. Hypersomnolent individuals may or may not complain of their need to sleep for an excessive number of hours. Irritability and cognitive dysfunction are frequent concerns. Bed partners may relay significant information about sleep habits and nighttime behaviors of which the patients are, for the most part, essentially unaware. Automobile accidents are among the most serious of consequences stemming from excessive sleepiness: the 102 Sleep in America poll indicated that 60% of behind-the-wheel adults have driven a motor vehicle while drowsy, and 13% have actually fallen asleep while driving at least once per month (102).

A most common clue to the practitioner is a patient’s tendency to fall asleep precipitously when left alone in a waiting area or an examination room. Other clinical signs may include decreased blink rate, eye rubbing, ptosis, bobbing, yawning, slow lateral eye movements, and even head nodding. The severity of hypersomnolence can be assessed, in part, based on situations in which the patient reports sleepiness. For example, patients who fall asleep only during extended, semi-recumbent sessions in front of their television probably have less severe sleepiness than those who fall asleep while speaking on the phone, driving on a highway, or while eating a meal (60). Patients with significant sleep disorders sometimes choose words like "lack of energy," "tiredness," or "fatigue" rather than "sleepiness" to describe their chief complaint (29). The recurrent hypersomnia, classified as Kleine-Levin syndrome, has a more varied presentation, including possible accompanying symptoms of cognitive dysfunction, altered perception, eating disorder (megaphagia), and disinhibited behavior (eg, hypersexuality). This is in addition to the episodic dyscontrol syndrome, excessive daytime sleepiness, and prolongation of sleep duration.

Prognosis and complications

The prognosis depends, intuitively, on the diagnosis. In all patients with hypersomnolence, safety issues are extremely important. In one assessment of motor vehicle crashes in the United States, driver sleepiness was thought to be the cause in 1% to 3% (86). A study reviewing 10 years of motor vehicle collisions in Spain established that sleepiness was one of the most likely causes of these accidents (74). A third study demonstrated that industrial plant workers with subjective hypersomnolence were substantially more likely to have had a documented injury during the past 2 years than other workers (94). This increased risk disappeared 1 year after interventions toward the education of workers concerning sleep disorders and their implications and treatments. Employment, lifestyle, and interpersonal relationships also can be seriously threatened by sleepiness and associated irritability and compromised mental state. Psychosocial characteristics of children with central disorders of hypersomnolence include reduced school attendance, lowered grades, reported poorer quality of life, and less participation in activities, plus increased reported injuries (13). Psychiatric symptoms may include withdrawal, depression, somatic complaints, thought problems, and aggressiveness (127). Early effective treatment renders a favorable impact on behavior and psychosocial health (126). Obstructive sleep apnea syndrome is associated with increased risk for comorbid hypertension, heart disease, stroke, diabetes, metabolic syndrome, and earlier demise. Narcolepsy and idiopathic hypersomnia often require significant lifestyle changes despite substantial benefits of awake-promoting medication and cogniceuticals. Narcolepsy is chronic and rarely remits but may have periods of worsening or improvement during an individual's lifetime, given stressors and other such factors. Idiopathic hypersomnia has been known to improve in some individuals over the course of 5 years to 10 years, but it may also represent a lifelong condition (64). Interestingly, obesity accompanies narcolepsy with cataplexy (NT1) but not necessarily narcolepsy without cataplexy (NT2) (140).

Controversy surrounds a possible link between a certain H1N1 vaccination formulation and onset narcolepsy-cataplexy (40). The facts are still unfolding. Research supported by the National Science Foundation upholds the concept that H1N1 influenza (swine flu) and other winter infections are associated with the onset of narcolepsy in a temporal manner, suggesting causality. Lifelong risk could be increased after either H1N1 infection or vaccination toward clinical onset narcolepsy in those genetically predisposed. In 2010, there was an alarming rise in the number of cases of sudden-onset narcolepsy among youth in countries including Sweden, Finland, Norway, United Kingdom, Ireland (tenfold increase in 2010) (50), France, the United States, Canada, and China. No increase was observed in other age groups (15; 109). Investigations suggest that an adjuvanted version of the 2009 H1N1 vaccination is incriminated (49). According to the Department of Vaccines and Immune Protection, National Institute for Health and Welfare in Helsinki, Finland, and the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), the increased risk of narcolepsy in vaccinated, compared to unvaccinated children and adolescents, was 6- to 13-fold. The European Medicines Agency has, as of July 2011, recommended the restricted use of Rx Pandemrix, and the manufacturer, GlaxoSmithKline, is required to carry out nonclinical and clinical studies in order to further explore the association between Rx Pandemrix vaccination and narcolepsy. The Helsinki Sleep Lab detected that the majority of youths with narcolepsy, when HLA-typed, were all positive for the narcolepsy risk allele DQB1*0602/DRB1*15 (113). Based on the presence or absence of antibody response against a viral protein, the Finnish group found no serological evidence of influenza A H1N1pdm09 virus infection as a contributing factor in childhood narcolepsy after the Pandemrix Vaccination Campaign in Finland (95).

Clinical vignette

A 21-year-old college student complained of not being able to keep up with coursework because of daytime sleepiness. He fell asleep in classes and slept through his alarm clock when his roommates were not there to intervene and awaken him. He stated that his problem had onset during his high school years when he noted a much greater need to sleep compared to his teenage peers. He typically fell asleep for several hours after returning home from school, only to awaken feeling groggy (sleep inertia) and sometimes disoriented for a span of up to 20 minutes. At clinical presentation, he slept between 11:00 PM and 9:00 AM (10-hour timespan) and had never enrolled in educational coursework that might begin before 10:00 AM because of his sleep-related limitations. He verbally denied the usage of any form of psychoneuroactive pharmacotherapy. He often fell asleep not only in classes but also in the dining hall and while on the phone, especially if he was seated for longer than roughly 30 minutes. On weekends he usually slept from midnight to the next afternoon, or a total of 13 to 14 hours. He tried over-the-counter stimulants with only modest improvement and regularly drank at least 2 liters of caffeinated drinks daily. He did not snore and denied cataplexy, hypnagogic/hypnopompic hallucinations, or sleep paralysis. There was no family history of any similar such disorder. He felt that his symptoms might have worsened after a bout of infectious mononucleosis (EBV) that he had contracted during his high school years. His urinary toxic screen was negative.

The patient, in compliance with the protocol from his accredited sleep lab, maintained a sleep log for a period of one entire month. The sleep diary revealed that he generally fell asleep between 11:30 PM and midnight, slept daily until 9:15 AM or later, and missed at least one morning class per week. On each weekend night, he slept 10 to 14 hours. A subjective measure of sleep propensity, the Epworth Sleepiness Scale, registered a high score of 17 on a scale of 0 to 24 whereby, typically, Epworth Sleepiness Scale (ESS) scores greater than 10 of 24 are interpreted as significant. A nocturnal polysomnogram, performed after increasing sleep by 30 to 60 minutes each night, revealed a reduced sleep latency of 7 minutes but did not unveil any other specific sleep disorder, such as obstructive sleep apnea, central sleep apnea, non-REM parasomnia, or restless leg syndrome, which could better explain the ongoing source generator(s) of the hypersomnolence. On the following day, in the sequential five nap attempts of a Multiple Sleep Latency Test, he fell asleep on average, quite pathologically, within a mere 1.9 minutes. He had no sleep-onset REM periods (two or more of which would raise the possibility of narcolepsy). The diagnosis established was that of idiopathic hypersomnia. Medical options and lifestyle adjustments were reviewed and discussed.

Initial trials of pemoline and modafinil yielded only mild improvement in his symptoms. A trial of methylphenidate at doses up to 45 mg daily eventually improved morning functioning, alertness, class attendance, and attention, although studying in the evenings remained a problem. Given his insurance coverage, he was able to access armodafinil and found this agent, overall, preferable in terms of efficacy and sustained benefit. Scheduled naps and regularization of the sleep-wake cycle (overcoming circadian misalignment), combined with medications, eventually provided effective control of the patient's otherwise disabling symptoms and, thus, an improved quality of life and overall functionality.

Biological basis

Anatomic localization

Hypersomnolence may result from different types of organic pathology in any one of several neuroanatomical sites. Sleepiness can arise from a reduction in wakefulness normally maintained by the ascending reticular activating system, a heterogeneous but functionally associated group of neurons located in the upper pontine and midbrain tegmentum. Neurocircuitry projections travel, caudo-cephalad, through a ventral pathway to the hypothalamus, subthalamus, basal forebrain, and cortex and also through a dorsal pathway to the thalamus and on upward, superiorly, to the cortex. These ascending pathways are subserved by a number of different neurotransmitters, including cholinergic, monoaminergic, histaminergic, and glutaminergic substances and the related receptors. One study found an association between loss of serotonergic neurons in the dorsal raphe nucleus and hypersomnolence in patients comorbidly involved with underlying myotonic dystrophy (110). Thalamic strokes can result in sleepiness with impaired stage N3 sleep. Hypothalamic infarctions and a variety of brainstem diencephalic lesions are frequently associated with poor regulation of the sleep-wake cycle. Such lesions can produce secondary, acquired narcolepsy (orexinopenia) (03).

Autopsied brains of patients with narcolepsy show absence of dorsal and lateral hypothalamic neurons that normally produce a wakefulness-promoting neuropeptide called either hypocretin or orexin (117). In some cases, secondary narcolepsy also may arise because of hypocretin deficiency or receptor nonrecognition, altering hypocretinergic transmission (132). It has been asserted that parallel alertogenic pathways exist, beyond hypocretin neurons, whereby subpopulations of inhibitory neurons in the lateral hypothalamus and glutamatergic neurons in the nearby supramammillary nucleus have been found to be wake-promoting as well. Importantly, this could open up new therapeutic targets for disorders of excessive sleepiness, such as hypersomnia and narcolepsy (51).

Pathophysiology

Any disruption in the complex regulation or interrelatedness of sleep and wakefulness can cause hypersomnolence. Disorders apt to reduce the tonic release of neurotransmitters that activate the thalamus, hypothalamus, and mesial forebrain can cause sleepiness. Imbalances in the numerous neurotransmitters that modulate sleep cycle regulation could cause specific derangements with the phenotypic expression of idiopathic hypersomnia. Transmitters known to have a role in sleep include serotonin, histamine, acetylcholine, norepinephrine, and dopamine. Neuropeptides referred to as either hypocretins or orexins are produced by dorsal and lateral hypothalamic nests of neurons, which project widely to cortical and subcortical structures that prove critical to sleep-wake regulation, alertness, and stabilization of vigilance states. Of important and additional interest, the hypocretin system is also involved in the regulation of food intake, reward, metabolism, hormone release, and body temperature regulation (106). Hypocretin promotes wakefulness whereby Hcrt1/OxA hypothalamic neurons likely excite locus coeruleus neurons that project to the medial prefrontal cortex and, thus, activate EEG and facilitate wakefulness (42). Absence of hypocretin, or its receptor function, has been identified in animal models of narcolepsy (108). Humans struggling from narcolepsy and with cataplexy (astasias) have low or undetectable levels of hypocretin in cerebrospinal fluid (97), and brain autopsies generally demonstrate, histopathologically absence of certain hypocretin-elaborating neurons (117). This association of a neurodegenerative disease with deficiency of a specific neurotransmitter is reminiscent of other conditions, such as Parkinson disease coupled with dopamine deficiency or Alzheimer disease and its associated acetylcholine deficiency. Multiple investigations demonstrate that CSF hypocretin-1 levels less than 110 pg/mL are diagnostic for narcolepsy with cataplexy in the appropriate clinical context; normal levels are typically greater than 200 pg/mL. Of note, scientifically, there is a shift from ascertainment of CSF orexin-A analyte via radioimmunoassay to, more currently, quantitative mass spectrometry. This, albeit more expensive and technically challenging, renders improved precision and reproducibility (52). Certain patients with narcolepsy type 1 reveal fluctuations in symptoms and in CSF marker levels (hypocretin, histamine, and tele-methyl histamine) without necessarily an association, either absolutely or relatively (83). The diagnostic utility could include its potential when multiple sleep latency test is difficult to perform or interpret (due to, for example, psychotropic drugs, insufficient sleep or confounding sleep disorder, complex neurologic disorder, or psychiatric diagnosis) or with youths, or others, unable to cooperate with the multiple sleep latency test. A major implication of CSF hypocretin-1 measurements is the opportunity for early diagnosis with the goal of intervention, such as IVIG, close to disease onset--thus, affording an improved prognosis in general. Indeed, Dauvilliers and colleagues, in case reports, detected a dramatic decrease in cataplexy after a close-to-onset prescribed IVIG 1g/D protocol intervention (36). The drawbacks are the expense and the involvement of a lumbar puncture procedure. Of note, the pathophysiology concerning both idiopathic hypersomnia and narcolepsy without cataplexy is largely unknown.

Regarding orexinergic antagonists, the pharmaceutical industry has offered a proprietary agent, which is a prescribed moiety indicated for the treatment of both initiation-onset insomnia and maintenance insomnia. This sedative is termed a “DORA,” or dual orexin receptor antagonist. The particular compound, suvorexant, was approved by the FDA in August 2014. It is considered novel and “first in class,” and it basically ushers in a new era in the field of sleep medicine and beyond. Rather than inducing GABAergic mechanisms to facilitate sleepiness, it is an “antiwakefulness” agent inhibiting the activity of the hypothalamic arousal system. Similar agents, such as almorexant, daridorexant, lemborexant, filorexant, and seltorexant, are under review. Generally, they are purported as competitive receptor antagonists of the OX1 or OX2 orexin receptors. Studies uphold efficacy in the treatment of adult chronic insomnia, which, in turn, uphold the validity of the role of endogenous orexin systems in insomnia (23). Orexinergic pathways are profoundly important, not solely in regard to wakefulness, but also in regard to reward, addiction, coordination of emotion (limbic link), and appetite (energy homeostasis). Overmedicating with an orexin receptor antagonist could, hypothetically, elicit a “narcolepsy syndrome.” Potential adverse effects of these CNS depressants are fatigue, headache, lethargy, vertigo, and complex sleep behaviors. Driving safety may be an issue (56; 17; 33; 156).

CSF orexin-A/hypocretin levels can be obtained. Traditionally, human leukocyte antigen (HLA) testing would precede. If positive, and an MSLT is negative or unavailable, it may be considered. It may also be medically warranted if there is suspicion that cataplexy is of psychogenic origin. The CSF specimen must be nonhemolyzed to avoid a false positive result. It is reportedly stable when frozen for up to 120 days. Levels of less than 110 pg/mL suggest NT1. If it is an intermediate level between 111 to 200 pg/mL, another neurologic sleep disorder should be considered (158).

Identifiable structural lesions are responsible for hypersomnolence in only a small fraction of cases. To underscore, as delineated by Trotti and Bliwise, in a retrospective review approximately one third of patients with idiopathic hypersomnia underwent brain MR imaging (147). The primary reason was due to an apparent focal neurologic sign or symptom. The most frequent finding was, merely, chronic microvascular ischemic changes. These revelations did not alter clinical management. An interesting case presentation from Osman and colleagues described brain MRI findings in a patient presenting as sleep-like coma who was found on neuroimaging to suffer from acute bilateral thalamic ischemic infarctions (111).

An Italian group reported, for the first time in humans, the brain structures whose neural circuitry is specifically associated with emotion-induced cataplexy. Via fMRI and other modalities, they found a marked increase in neural activity in the mesolimbic areas; namely the amygdala, nucleus accumbens, and ventromedial prefrontal cortex (centers of, or subserving, emotion and reward) (96). The French group led by Dauvilliers and colleagues utilized (18) FDG-fluorodeoxyglucose-positron emission tomography (PET) to demonstrate early evidence for possible cerebral hypermetabolism in the wake state in both narcolepsy type 1 and in idiopathic hypersomnia (38). More specifically, in narcolepsy type 1 they found higher right superior occipital gyrus glucose metabolism, whereas in idiopathic hypersomnia they detected higher middle orbital cortex and supplementary motor area metabolism. These published findings need confirmation. Tondelli and colleagues described their results, which indicate in pediatric patients with recent-onset narcolepsy type 1, reduced grey matter volume in the cerebellum and in the medial prefrontal cortex along with increased volume in the right hippocampus and in the frontal lobe when compared to controls (146). These subtle structural brain changes involve attentional and limbic circuitry. In applying high-resolution SPECT (single photon emission computed tomography) to scan subjects with idiopathic hypersomnia in the resting state of wakefulness, Boucetta and colleagues detected decreases in cerebral blood flow in the medial prefrontal cortex, which is associated with greater daytime sleepiness (24). Regional cerebral blood flow was also reduced in the posterior cingulate cortex and putamen whereas increases in regional cerebral blood flow were noted in the amygdala as well as in the temporo-occipital cortices. Hypothalamic volumes were reduced in narcolepsy type 1, which is easy to surmise given the orexinergic transmission deficits in that neuroanatomic location (55).

Functional changes leading to hypersomnolence are complex and still under research investigation. In narcolepsy, an association with specific human leukocyte antigen (HLA) markers suggests a heredofamilial/genetic vulnerability. Almost all patients with hypocretin deficiency are HLA-DQB1*0602 positive. Other human leucocyte antigens implicated are HLA-DRB1*1501 and HLA-DR2. In contradistinction, depletion of hypocretin-containing neurons and associated histological changes suggests an immune-mediated pathophysiology. Regarding neurotransmission in pediatric narcolepsy type 1, Franco and colleagues found an impairment of CSF histamine turnover compared to controls; this could support the use of histaminergic therapy against narcolepsy (48).

Recurrent hypersomnia is intriguing in that the profound sleep occurrences reiterate with lengthy episodes in patients who are otherwise normal in alertness, cognitive functioning, and behavior between attacks. During the sleepiness episodes of Kleine-Levin syndrome, most frequently found in adolescent males, there is associated increased appetite, hypersexuality, and aggressive behavior. Irritability and depression, along with confusion and amnesia and abnormal speech, can accompany the clinical vignettes. SPECT scans demonstrate hyperperfusion in the thalamus, hypothalamus, and cingulate gyrus.

Other illnesses induce hypersomnolence through chronic sleep deprivation or sleep disruption. Common clinical examples include behaviorally induced insufficient sleep syndrome, obstructive/central sleep apnea syndrome, circadian rhythm sleep disorder, and environmental sleep disorder (eg, discomfort, noise, pets). Depression, an affective disorder with associated neurovegetative symptomatology, neuropsychoactive drugs or other substances, posttraumatic hypersomnia, and various medical illnesses can also cause sleep disruption or sleep deprivation and consequent hypersomnolence (05).

Physiological manifestations of hypersomnolence include increased sleep propensity, short sleep latencies on the Multiple Sleep Latency Test, miosis, increased fluctuation of pupil diameter (hippus) (155), gastrointestinal disturbances (eg, dysmotility) and cognitive impairment (particularly in executive performance and in speed of mentation). Lucidity is blunted.

Differential diagnosis

Confusing conditions

Some of the most common diagnostic entities among hypersomnolent patients include depression, behaviorally induced insufficient sleep syndrome, obstructive/central sleep apnea syndrome, inadequate sleep hygiene, narcolepsy, idiopathic hypersomnia, restless legs syndrome, and other conditions that cause insomnia. Circadian rhythm disturbances and use of sedative medications or depressants such as alcohol should also be considered. Many medications not used for sedation may also induce hypersomnolence; these medications include certain antidepressants, antipsychotics, anticonvulsants, and cardiovascular drugs (121). Brainstem disorders including traumatic brain injury (TBI), acute demyelinating encephalomyelitis, infarctions, neoplasms (infiltrative pilocytic astrocytoma, glioblastoma multiforme, hypothalamic hamartoma), Kleine-Levin syndrome, neurosarcoidosis, histiocytosis X, encephalitis lethargica, fatal familial insomnia, multiple sclerosis, neurodegenerative disorders, or multiple systems atrophy can all promote and lead to hypersomnolence. Patients with Parkinson disease commonly experience hypersomnolence, and those who use dopaminergic agonists such as pramipexole or ropinirole may have sudden onset of irresistible sleep, including while operating heavy machinery (53). Excessive daytime sleepiness can also arise in patients with neuromuscular disorders, who are at risk for central sleep apnea, obstructive sleep apnea, and (at least in myotonic dystrophy) central nervous system abnormalities that may cause hypersomnolence in the absence of sleep apnea. Hypersomnolence is more prevalent in older persons who have more inefficient nocturnal sleep. Other medical illnesses that can disrupt sleep hygiene include gastroesophageal reflux disorder, hypothyroidism, diffuse metabolic encephalopathies, and conditions that cause chronic pain.

The most common cause of hypersomnolence among patients seen at sleep centers is sleep-disordered breathing (SBD) and, within that particular category, usually obstructive sleep apnea syndrome (OSAS) (120). Narcolepsy is more uncommon, and true idiopathic hypersomnia is even rarer yet, if properly assessed. Some degree of hypersomnolence is prevalent and perhaps indigenous amongst older persons and, also, is commonly encountered in a number of neurodegenerative syndromes. But the untoward condition of hypersomnolence is notably becoming increasingly more common in otherwise healthy young adults who, situationally, suffer with lifestyle-related chronic insufficient sleep syndrome (80). Lissak states that there is a growing body of evidence associating excessive and addictive use of digital media with adverse neurologic consequences and poor sleep (81). Further, it is espoused that screen time reduction was effective in decreasing ADHD-related behaviors. Many are “overexposed to the laptop.”

A particularly intriguing source generator of excessive daytime sleepiness (EDS) is the rare disorder called non-24-hour sleep-wake disorder, or N24. It is also referred to as free-running disorder or hypernychthemeral syndrome. In short, in this circadian rhythm sleep disorder, the individual’s biological clock fails to synchronize to a 24-hour day. Sleep time is gradually and progressively delayed until failed attempts to fight against the internal rhythm result in severe and cumulative sleep deprivation/insomnia/dyssomnia. Fully unsighted/blind folks are especially susceptible. An agent has been released to manage the condition, Rx tasimelteon, a melatonin receptor agonist, which was FDA approved in 2014. This, in conjunction with both photo- and scototherapy (optimized light/dark luminosity exposure) may invite improved entrainment.

To summarize, the certain causes of hypersomnolence include the following:

Physiological causes
Sleep deprivation or insufficiency and sleepiness related to lifestyle and irregular sleep-wake schedule—lifestyle choices, societal demands
Pathological causes
Primary sleep disorders
	• Obstructive sleep apnea syndrome (OSAS) • Central sleep apnea syndrome (CSAS) • Narcolepsy (? Niemann-Pick type C; ? Prader-Willi syndrome) • Idiopathic hypersomnolence (IH) (genetic predisposition) • Circadian rhythm sleep disorders
		- Jet lag - Delayed sleep phase syndrome (DSPS) - Irregular sleep-wake pattern - Shift work sleep disorder - Non-24-hour sleep-wake disorders (N24)/hypernychthemeral syndrome
	• Periodic limb movements disorder (PLMD) • Restless legs syndrome (RLS) • Insufficient sleep syndrome (behaviorally induced) • Inadequate sleep hygiene
Other hypersomnias
	• Recurrent or periodic hypersomnia
		- Kleine-Levin syndrome (KLS) - Kleine-Levin syndrome without compulsive eating (KLS-WOCE) - Menstrual-related hypersomnia - Recurrent hypersomnia with comorbidity - Idiopathic recurrent stupor - Seasonal affective disorder (SAD)
		- Occasionally due to insomnia
	• Medication-related hypersomnia
		- Benzodiazepines - Nonbenzodiazepine hypnotics (eg, phenobarbital, Z-drugs) - Sedative antidepressants (eg, tricyclics, trazodone) - Antipsychotics - Nonbenzodiazepine anxiolytics (eg, buspirone) - Antihistamines - Narcotic analgesics, including tramadol
	• Toxin and alcohol-induced hypersomnolence, including anesthetics
General medical disorders
	• Hepatic failure • Renal failure • Respiratory failure • Electrolyte disturbances • Cardiac failure • Hypovitaminosis - D • Severe anemia • Systemic lupus erythematosus (SLE) • Endocrine causes
		- Hypothyroidism - Acromegaly - Diabetes mellitus (DMII) - Hypoglycemia - Hyperglycemia
Psychiatric or psychological causes
	• Depression • Psychogenic unresponsiveness or sleepiness
Neurologic causes
	• Brain tumors or vascular lesions affecting the thalamus, hypothalamus, or brainstem • Posttraumatic hypersomnolence • Multiple sclerosis (MS)/demyelinating disease • Encephalitis lethargica and other encephalitides and encephalopathies, including Wernicke encephalopathy • Cerebral trypanosomiasis (African sleeping sickness) • Neurodegenerative disorders
		- Alzheimer disease (AD) - Parkinson disease (PD) - Multiple system atrophy (MSA)
	• Myotonic dystrophy • Other neuromuscular disorders causing sleepiness secondary to sleep-related respiratory disturbance.

Sforza and colleagues wonder, based on serological testing in multiple patients, about the role of Epstein Barr virus or mononucleosis as a possible cause of idiopathic hypersomnia (135).

Surgery with general anesthesia elicits, especially in patients with prior sleep disorders, hypersomnolence that can persist in vulnerable populations. This may relate to changes in GABA-related neural circuitry caused by anesthetic neurotoxicity or other potential mechanisms (71).

Diagnostic workup

Specialists suggest certain topics to be covered in the clinical intake interview of patients with narcolepsy-like symptomatology. These include general sleepiness (including triggers), cataplexy, nocturnal sleep (including restless limb syndrome, REM sleep behavior disorder (RBD), sleep disordered breathing (SDB), hallucinations, sleep paralysis, automatic behaviors, dreams, weight change, eating habits, mood, medications, family history, comorbidities (seasonal affective disorder, diabetes mellitus, enuresis/nocturia, sleepwalking/somnambulation, and other NREM parasomnia, etc.), and medications (especially neuropsychoactive agents) (144). Maness and colleagues stress that symptoms of the central disorders of hypersomnolence extend beyond excessive daytime sleepiness to include nonrestorative sleep, fatigue, and cognitive dysfunction (89). They share much in common with myalgic encephalomyelitis or chronic fatigue syndrome, renamed systemic exertion intolerance disease. It was determined that the systemic exertion intolerance disease (common comorbidity in patients with hypersomnolence) group exhibited more profound fatigue and was less likely to respond favorably to traditional wake-promoting agents.

When suspected causes of hypersomnolence include obstructive sleep apnea syndrome, other forms of sleep-disordered breathing, narcolepsy, idiopathic hypersomnia, or periodic limb movements, a nocturnal polysomnogram (NPSG) is often indicated (08). Polysomnography, performed in a sleep disorders laboratory, includes recording of EEG (central, occipital, and sometimes other derivations), chin muscle tone (surface EMG), and eye movement (electro-oculogram); this information is used to define the stages of sleep, namely, awake and non-REM (N1, N2, and N3), and REM. Polysomnography often also includes the physiological monitoring of chest and abdominal movement, airflow at the nose and mouth, snoring, body position (supine, lateral, or prone), oxyhemoglobin saturation, electrocardiogram (EKG), and limb movement (surface EMG). The polysomnogram helps to assess patients for many of the sleep disorders that can cause hypersomnolence. Obstructive apneas and hypopneas, leading to brief arousals, are the most commonly recorded causes of sleep fragmentation. The number of 10-second or longer apneas and hypopneas followed by arousal or hypoxemia is recorded as the "apnea hypopnea index" (AHI). More than five to 10 events per hour in an adult, and even fewer in children, may well have significant impact on sleepiness or many other aspects of health maintenance. Frequent periodic leg movements and associated arousals during sleep may also cause excessive sleepiness in some individuals, though polysomnographic and Multiple Sleep Latency Test data from a series of 1,124 patients did not confirm any such tendency (30). As Lerousseau summarizes, if excessive daytime sleepiness persists after obstructive sleep apnea is optimally managed, consider the possibility of other situations, such as depression, sleep insufficiency, use of intoxicants, obesity (obesity hypoventilation syndrome, OHS), restless legs syndrome, or circadian sleep-wake cycle disorder (77).

Daytime sleepiness itself can be assessed in several different ways. The earliest attempt to measure sleepiness systematically was the Stanford Sleepiness Scale (SSS), which depended on a self-rating of current level of wakefulness on a 7-point scale, with descriptors ranging from "wide awake" to "almost in reverie" (54).

Table 1. The Stanford Sleepiness Scale

Please record the scale value that best describes your state of sleepiness:

Score	State before testing
1.	Feeling active and vital; alert; wide awake
2.	Functioning at a high level, but not at peak; able to concentrate
3.	Relaxed; awake; not at full alertness; responsive
4.	A little foggy; not at peak; let down
5.	Fogginess; beginning to lose interest in remaining awake; slowed down
6.	Sleepiness; prefer to be lying down; fighting off sleep; woozy
7.	Almost in reverie; sleep onset imminent; lost struggle to remain awake

A more objective assessment, the Multiple Sleep Latency Test (MSLT), was first developed in the late 1970s as an in-laboratory measure of ability to fall asleep, in order to realize the degree of sleepiness after sleep-deprivation. It is the only scientifically validated objective determination of sleepiness. Soon after its inception, its application reverted toward the identification of hypersomnolence and of bona fide narcolepsy (26). The test may be affected by a variety of influences, such as physiological, motivational, physical, and pharmacological factors. The mean sleep latency decreases following sleep deprivation and following sleep fragmentation; it increases with age by 0.6 minute per decade. For baseline Multiple Sleep Latency Test data:

Population	Mean (min)	SD	2SD Range (min)
Narcolepsy Idiopathic hypersomnia Normal controls 4 naps [5 naps]	3.1 6.2 10.4 (11.6)	2.9 3.0 4.3 (5.2)	0 to 8.9 0.2 to 12.2 1.8 to 19 (1.2 to 20)
Data derived from (10).

Multiple Sleep Latency Test (MSLT) guidelines were updated by the American Academy of Sleep Medicine (AASM) in 2005 (82). The test measures how quickly a recumbent subject falls asleep, in a dim lit room, when allowed to do so. Technologists monitor EEG, chin EMG, eye movement (EOM), and sometimes additional parameters or functions. Four or five daytime nap attempts are scheduled, at 90- to 120-minute intervals, in recognition of the circadian influence on sleepiness: the main outcome is the mean sleep latency. This latency tends to be shorter in patients with experimentally induced sleep deprivation or chronic sleep disorders. Therefore, in order for the MSLT to be valid and interpretable, 6 hours of polysomnographically defined sleep should be recorded during the night prior to the nap testing (05). In general, urine toxicology screening is important and advised – by protocol and by guideline. Many pediatric patients over the age of 13 years who manifest positive drug screens for THC (popularized cannabis) met MSLT criteria for narcolepsy or had multiple SOREMPs (44).

To delineate, the AASM Standards of Practice Committee MSLT Protocol details:

1.	Start the MSLT 1 1/2 to 3 hours after wake up. Perform (after 6+ hours of prior NPSG) five nap opportunities unless the patient has two SOREMPs within the first four nap opportunities.
2.	Do not offer an MSLT after a split night or PAP titration trial. Your program may elect to cancel the MSLT if the patient slept fewer than 6 hours, as ascertained via previous night’s polysomnogram.
3.	Collect a sleep log for the week, or longer, prior to the MSLT.
4.	Sleep rooms should be dark and quiet during testing. Room temperature should be set based on the patient’s comfort level.
5.	Be sure the patient is following physician instruction regarding medication (including hypnotic agents, psychotropics, chronobiologicals, alcohol, stimulants, and caffeine). Smoking should be stopped at least 30 minutes prior to each nap. Stimulating activities by the patient should end at least 15 minutes prior to each nap. No caffeinated beverages or bright sunlight on the day of the test are allowed. A light breakfast is recommended at least 1 hour prior to the first trial, and a light lunch is recommended immediately after the termination of the second (noon) trial.
6.	Sleep technologists who perform MSLTs should be experienced in conducting the evaluation.
7.	The conventional recording montage for the MSLT includes central and occipital EEG, left and right eye EOGs, EMG, and EKG.
8.	Before each nap, the patient should be asked if they need to go to the bathroom or need other adjustments for comfort. Start each nap with biocalibration.
9.	At the start of each nap, tell the patient: “Please lie quietly, assume a comfortable position, keep your eyes closed, and try to fall asleep.”
10.	Sleep onset for the MSLT is the time from lights out to the first epoch of any stage of sleep, including stage 1 sleep (N1). Sleep onset is defined as the first epoch of greater than 15 seconds of sleep in a 30-second epoch. If there is not evident sleep, the sleep latency is defaulted to 20 minutes. The test continues for 15 minutes after the first epoch of sleep. The duration of 15 minutes is determined by “clock time,” not sleep time. REM latency is the time of the first epoch of sleep to the beginning of the first epoch of REM sleep (SOREMPs).
11.	A nap is stopped after 20 minutes if sleep does not occur.
12.	The MSLT report should include the start and end times of each nap or nap opportunity, latency from lights out to the first epoch of sleep, mean sleep latency, and number of sleep-onset REM periods. Importantly, (from a clinical, scientific and economic standpoint) Kwon and colleagues ascertained that a single MSLT is sufficient and need not be repeated or verified on a second effort because results of test-retest were quite comparable if not essentially identical when controlling for confounding factors (70). This remains a source of ongoing debate, however, amongst somnological experts.

Of note, pediatric norms for the MSLT exist and can be referenced at: (25). Further, within the realm of pediatric sleep medicine, one could consider the review of the CSHQ (Children’s Sleep Habits Questionnaire) and the PSQ (Pediatric Sleep Questionnaire) and other neuropsychiatric measures in relation to the aforementioned Stanford Sleepiness Scale and Epworth Sleepiness Scale for assessment of sleepiness. Chen and colleagues designed a thoughtful sleep disturbance scale for children (SDSC) that (Table 4) houses an impressive list of exploratory factors (28).

Additionally, two or more naps that depict REM sleep raise the diagnostic possibility, in the appropriate clinical setting, that narcolepsy may be the cause of the hypersomnolence. Other possible causes of daytime sleep-onset REM sleep periods include obstructive sleep apnea and withdrawal from stimulant medication; youth and male gender also increase the likelihood of this finding (29). Though one study demonstrated that 3.9% of 539 people in a population had two or more sleep-onset REM periods, another study of over 500 community adults in Wisconsin (ages 35 to 70 years, 97% Caucasian) reveals that 13.1% of males and 5.6% of females had multiple sleep-onset REM periods. These results suggest that multiple REM periods during the MSLT may be more common than previously suspected and that abnormal MSLT findings should always be interpreted within the clinical context for each patient (98; 138). The diagnosis of hypersomnolence should not be made solely on the basis of strict cutoffs. However, a mean sleep latency of less than 5 minutes duration of onset usually suggests abnormal and severe daytime sleepiness. Many patients with sleep disorders have mean sleep latencies of 8 minutes or less; values above 10 minutes to 12 minutes are generally considered normal (129). In practice, scores must be carefully interpreted in combination with the clinical history, recent medication regimen, anxiety or other factors that affect ability to sleep, and amount and quality of sleep obtained throughout the previous night.

In 1982 a variant of the Multiple Sleep Latency Test was proposed. In the Maintenance of Wakefulness Test (MWT), subjects are monitored while they attempt to stay awake, rather than sleep, for 20 minutes and up to 40 minutes. They sit comfortably, rather than lie supine, in a dimly lit room (100). The Maintenance of Wakefulness Test has some face validity as a measure of ability to stay awake - more crucial to daily functioning than the ability to fall asleep - and shows results that can differ substantially from those of a traditional Multiple Sleep Latency Test (131). The Federal Aviation Administration (FAA) currently uses the Maintenance of Wakefulness Test to monitor pilots with known sleep disorders, such as sleep apnea (46). However, no studies have been performed to test whether the Maintenance of Wakefulness Test better predicts important health-related outcomes. Fewer normative data are available than for the Multiple Sleep Latency Test, and detection of sleep-onset REM periods is less likely. Technology is proposed whereby a fully automated, objective sleepiness analysis technique based on a single channel of EEG uses a 1-dimensional slice of the EEG spectrum representing a nonlinear transformation of the underlying EEG generators to compute a novel index called the Sleepiness Index. Sleep latency correlates tightly with the calculated Sleepiness Index (141).

In 1991, a brief, self-reported patient questionnaire, the Epworth Sleepiness Scale (ESS), was developed to measure the subject's perceived likelihood of falling asleep in each of eight commonly encountered sedentary scenarios (59). The individual rates their propensity toward dozing on a progressive 4-point scale for each clinical situation; the summed scores range from 0 to 24, and scores above 10 begin to raise concern. Subjective and objective measures of sleepiness are not well-correlated (02), and few data are available to show that either method predicts motor vehicle crashes, poor work performance, or other resultant offshoot consequences from sleepiness.

Table 2. Epworth Sleepiness Scale

How likely are you to doze off or fall asleep in the following situations, in contrast to just feeling tired? 0= would never doze 1= slight chance of dozing 2= moderate chance of dozing 3= high chance of dozing Situations (8 total): (heed: adult vs. pediatric versions)
	• Sitting and reading • Watching TV • Sitting, inactive in a public place (eg, a theater or a meeting) • As a passenger in a car for about an hour without a break • Lying down to rest in the afternoon when circumstances permit • Sitting and talking to someone • Sitting quietly after a lunch without alcohol • In a car, while stopped for a few minutes in traffic
Thus, the minimum score of the ESS could be, conceivably, zero; likewise, the maximum score could be (3 points x 8 situations) 24. Clinicians regard, as a general cut-off, 10 or greater to be indicative of hypersomnolence of concern.
In 2017 the Australian group analyzed the validity of the ESS in nonadults. Through Rasch analysis, they concluded that the ESS-CHAD (CHAD: children and adolescents) was both a reliable and internally valid measure of daytime sleepiness in adolescents 12 to 18 years old. This version of the Epworth Sleepiness Scale is devoid, unlike the standard ESS depicted above, of references to driving or alcohol (57). Question #3 is replaced with “sitting in a classroom at school during the morning” and question #7 deletes the phrase “without alcohol”. Question #8 is supplanted with “sitting and eating a meal.”

When clinical features suggest that medical illness may be a cause of hypersomnolence, a typical laboratory work-up could include a complete blood count to exclude anemia/polycythemia/leukemia, a basic chemistry panel (liver and kidney function; glucose; electrolytes), a thyroid profile, serum ferritin, TIBC, and tests of renal and hepatic function may prove revealing and relevant. Serum or urine toxicology screens can be guiding, particularly if the hypersomnolence seems to recur intermittently with predictable intervals. Careful histories can uncover features of a major depressive disorder, pain, or gastroesophageal reflux disease. A sleep log can be valuable to exclude the possibility of chronically insufficient sleep, poor sleep hygiene, or circadian rhythm disturbances and misalignments. In some cases, especially if there are associated abnormalities on neurologic examination, brain neuroimaging (particularly magnetic resonance imaging, with attention to the diencephalon and brainstem) may be indicated.

The working diagnosis of narcolepsy often emerges from the clinical history--which can include features such as cataplexy, hypnagogic or hypnopompic hallucinations, sleep paralysis, sleep attacks, metabolic perturbations (including weight gain), and insomnia with fractionated sleep (dysomnia), and – further – a history of problems in social interaction and academic performance. This is in addition to excessive daytime sleepiness – in combination with consistent findings from a formal Nocturnal Polysomnography and a Multiple Sleep Latency Test. Adjunctive testing may, in some cases, include human leukocyte antigen typing or cerebrospinal fluid levels of hypocretin-1 (97). The major clinical manifestations of narcolepsy (with percentage occurrences), given comorbid conditions, include:

Narcoleptic sleep attacks
Cataplexy
Sleep paralysis
Hypnagogic hallucinations
Disturbed night sleep
Automatic behavior
Sleep apnea
Periodic limb movements in sleep
REM sleep behavior disorder
Sleep-related eating disorder

100%
75%
25% to 50%
20% to 40%
70% to 80%
20% to 40%
up to 30%
10% to 60%
up to 12%
up to 9%

The onset of symptoms within narcolepsy can be abrupt or can be insidious. The peak onset is in the second decade of life. In the majority of presentations, daytime sleepiness is the first and most severe symptom. It is worsened with physical inactivity. The sleep episodes are short, irresistible, restorative, and oftentimes accompanied by dreaming. The sleep episodes are also the prime thrust toward seeking specialized consultation. Most cases are sporadic. Often the first sign is a decline in school performance. This serious, chronic disorder has a pervasive impact on quality of life, including in the spheres of education, work, and interpersonal relationships. Accidents are frequent. Anxiety intrudes. Loneliness and isolationism are real threats. The sleepiness may be misdiagnosed as a learning disorder or as attention deficit hyperactivity disorder. Cataplexy may be misperceived as epilepsy, hyperekplexia, drop attacks, syncope, pseudocataplexy, or a psychogenic disorder. Beyond these particular mimics, childhood cataplexy differs from the presentation in adults with a prominent facial involvement–already present–without clear emotional triggers. The childhood “cataplectic facies” (sagging, drooping) is frequently accompanied by active motor phenomenon of the tongue and perioral muscles (119).

The French group has designed a valid and clinically reliable tool for the quantification of narcolepsy symptoms to both monitor and enhance management. The Narcolepsy Severity Scale (NSS) is a 15-item scale with reasonable psychometric properties. The NSS temporal scores are reportedly stable. As a brief clinical instrument, it can help optimize care of patients with narcolepsy type 1 (37).

Cataplexy involves a sudden decrement in muscle tone (with loss of reflexes and F-waves) often precipitated by emotion, excitement, stress, fatigue, or by meals. The postural muscles are commonly involved, with bilaterality. Knee-buckling, jaw-sagging, head-drooping, and collapse, with consciousness maintained at the start, are common. Blurred vision, speech difficulty, and irregular respiration may be present. Monosynaptic stretch reflexes are suppressed. Triggering emotions or activities include laughing, joking, anger, stress, and sex. The literature relies on the term “orgasmolepsy” in reference to generalized cataplexy attacks during sexual intercourse. An Italian group reported that pitolisant induced a favorable clinical response, anecdotally, by case report (114).

The established diagnostic criteria (AASM) for narcolepsy with cataplexy (narcolepsy type 1) are:

(1) Excessive daytime sleepiness occurring almost daily for at least 3 months.
AND the presence of either 2a and 2b, or both:
	(2a) Definite history of cataplexy, defined as sudden and transient (less than 2 minutes) episodes of loss of muscle tone that are generally bilateral and triggered by emotions (usually laughing and joking), and diagnostic support should, whenever possible, be confirmed by nocturnal polysomnography (with a minimum of 6 hours of sleep) followed by a daytime MSLT with mean daytime sleep latency of 8 minutes or shorter and with two or more SOREMPs. (The time from sleep onset to REM sleep should be less than 15 minutes in at least two naps). Sometimes, the MSLT must be repeated.
	(2b) Hypocretin-1 concentrations in the cerebrospinal fluid 110 ng/L or less, or a third of mean control values.
(3) The hypersomnia is not better explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder (CAVEAT!).

In young children, narcolepsy may sometimes present as longer night sleep time or as resumption of previously discontinued daytime naps.

In pediatric patients with narcolepsy type 1 it was established that they suffered from high rates of inattention, withdrawal, aggression, rule-breaking behaviors, and thought problems (neuropsychiatric issues) in conjunction with the classic pentad. They may also develop medical comorbidities including gastrointestinal distress and neurosensory organ challenges such as hyposmia (136). A thorough review concerning associations between neuropsychological, neurobehavioral, and emotional functioning in pediatric patients with narcolepsy type 1 or idiopathic hypersomnia is well presented by Ludwig and colleagues (85).

The American Academy of Sleep Medicine criteria (ICSD-3) for establishment of the diagnosis of idiopathic hypersomnia include excessive daytime sleepiness for at least 3 months, a mean sleep latency of less than 8 minutes, less than two sleep-onset REM (SOREMs) periods on the MSLT, and the absence of other sleep disorders by history and on polysomnography. Standards have classified two types of idiopathic hypersomnia: idiopathic hypersomnia with long sleep time (more than 10 hours of nocturnal sleep) and that without long sleep time (nocturnal sleep of more than 6 but less than 10 hours) (05).

In further efforts toward the establishment of a valid psychometric research tool for the qualitative assessment of cataplexy and excessive daytime sleepiness in pediatric patients with narcolepsy, Wang and colleagues designed a child-friendly instrument that is currently utilized in phase 3 clinical trials of sodium oxybate in children and adolescents (154). The main concepts of cataplexy included: weakness, pain, dizziness, triggers, and situations. They ardently subdivided the main concepts of symptoms and settings as well. This was industry sponsored and is in further dynamic development. Also, in a related aspect, Vandi and associates have undertaken video recordings—under emotional stimulation (selective funny movies)—to capture paroxysmal hypotonic phenomena in subjects with narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, and subjective excessive daytime sleepiness (149).

Rach and colleagues contend that, via electroretinography, they can diagnostically differentiate between bona-fide narcolepsy (N1) and idiopathic hypersomnia (IH) (122). To detail, they purport as identifiable biomarkers: “reduced cone a-wave amplitude and prolonged cone and rod b-wave latencies in N1 as compared to controls and prolonged photopic negative response-wave latency in IH.”

Management

Hypersomnolent patients should be advised that they have increased risk for motor vehicle crashes, accidents while operating dangerous machinery, or lapses during sedentary situations. The safest way to avoid risk is to avoid these activities until the causes of the sleepiness are diagnosed and effectively managed. Patients who drive despite this advice should pull off the road in a safe manner at the first sign of sleepiness. The New Jersey State Legislature enacted a law allowing prosecution of drivers who cause accidents when falling asleep at the wheel, particularly due to insufficient sleep (104). Disorders of hypersomnolence may be reportable to the motor vehicle bureau in some states. In some instances, the ability to work may be compromised. In many cases, disability is reversible after proper treatment of the underlying maladies.

Chronic insufficient sleep hygiene is a common cause of mild to moderate hypersomnolence. Patients are sometimes unaware of the paucity of time they spend slumbering. Some individuals with erratic sleep schedules (morning vs. evening) may obtain 7 hours in 1 day but never sleep enough continuous hours to allow the natural cycles of sleep to fulfill their restorative needs. Patients with professions or lifestyles that demand rotating shift work or with circadian changes in sleep hours are also at risk for clinically significant hypersomnolence. The first step in treatment of insufficient sleep syndrome may be to ask patients to complete a sleep log, recording hours in bed and hours slept. Practitioners can offer instruction on sleep hygiene, including minimization of ambient light and noise, elimination of excessive use of alcohol or caffeine, curtailment of social media and “gadget” usage, and maintenance of consistent/cyclical sleep hours. On average, an adult requires, physiologically, 8.0 to 8.5 hours of sleep per night, although the amount varies considerably between individuals. The amount of sleep that a person needs is usually defined as the amount that produces feelings of restoration and optimum daytime alertness. Extension of the sleep period by 1 hour per day for 1 month while keeping a sleep diary is generally recommended (02). In some cases where sleep has been restricted, the use of strategically placed naps and of caffeine intake may minimize the inherent risk toward accidental traumatic injury from long-distance highway driving (118). For patients with circadian rhythm sleep disorder of the shift work type, use of armodafinil (enantiomer of modafinil), an alertness-promoting agent, has been demonstrated to reduce sleepiness and to mildly improve performance (34).

Treatment of obstructive sleep apnea syndrome usually begins with sleep laboratory titration of continuous positive airway pressure, administered by a nasal or full face mask, to a level that maintains patency of the airway. Patients then use the prescribed apparatus and splinting pressure, ideally each night for substantial duration at home. Significant improvement in sleepiness often occurs within 1 week, sometimes after the first night of treatment. If improvement is not seen rapidly in patients with at least moderate sleep apnea (apnea hypopnea index over 20 events per hour), problems may include nasal congestion, mouth breathing, or mask leak. If no improvement is seen with adjustments, or the patient is unable to tolerate and abide by the apparatus, subjects sometimes consult an otorhinolaryngologist or an oral and maxillofacial surgeon about the possibility of uvulopalatopharyngoplasty, maxillary and mandibular advancement, or other offered surgical procedures. Surgical management is not effective in all cases, however, and some patients may continue to require respiratory support even after an intervention. Dental devices may also play a role in remission of symptoms. Many patients are advised to enlist in a gradual weight-loss program, as obesity is a common contributing factor. Excess girth predisposes to both obstructive sleep apnea and obesity hypoventilation syndrome. For some patients, and especially those with mild to moderate sleep apnea, an oral appliance that advances the mandible and, thus, enlarges the upper airway during sleep can provide significant relief. Another FDA-approved (2014) modality is termed upper airway stimulation. This entails an indwelling electrical source, embedded in the chest wall, in order to stimulate the hypoglossal nerve at a certain duty cycle. The surgically chosen branches of cranial nerve XII, when pulsed, render the tongue protruded cyclically such that the airway is patent rather than collapsed during nighttime effort at sleep. This involves no mask and no hose. The pulse can be fine-tuned. In a similar fashion, on a daytime basis, eXciteOSA offers a schedule of 20 minutes per day for 6 weeks in order to tone up the otherwise relaxed glossal musculature; this overcomes the sleep-related partial airway collapse. Further, in regard to neurostimulation in sleep medicine, there is an electrical device that is implanted transvenously in order to stimulate the phrenic nerve activating diaphragmatic contractions. This is approved for central sleep apnea and may, as well, benefit a patient with a high spinal cord lesion, independent from mechanical ventilation. When sleep apnea is severe and refractory to common methods of medical and surgical management, tracheostomy may, albeit rarely, be required.

Narcolepsy is managed with a combination of traditional medication approaches and behavioral strategies. The behavioral approach includes education, sleep hygiene, strategic napping, reoccurring assessments, manipulation of body and skin temperature, cognitive behavioral therapy, tai chi, identification and avoidance of “triggers,” and psychosocial adjustments (19). Narcolepsy is presently an incurable, chronic, underdiagnosed, and frequently devastating disorder. IVIG treatment initiated before 9 months of disease duration has some clinical efficiency, suggesting an early onset autoimmune process in narcolepsy with cataplexy (66). Sleepiness is often first treated with modafinil or armodafinil (similar agent with longer half-life), two alertness-promoting agents that may have fewer side effects than traditional stimulants (07), though some patients do find methylphenidate or dextroamphetamine to have a more direct potent effect. Armodafinil is the (R)-enantiomer of its predecessor, modafinil and is touted to have a considerably longer half-life of 10 to 15 hours. This could translate, clinically, toward patient-preferred, longer duration of effect and enhanced overall compliance (via less frequent dosing) (107). Adverse side effects of stimulants can include nightmares, palpitations, anxiety, and psychomimetic material.

Sodium oxybate (gamma-hydroxybutyrate or GHB) is approved for treatment of cataplexy, and this agent was demonstrated in a pilot study to increase daytime sleep latency in narcoleptics on the Maintenance of Wakefulness Test (88; 148). It is also approved for the management of excessive daytime sleepiness stemming from either narcolepsy or idiopathic hypersomnia. Sodium oxybate is effective and well-tolerated for patients with refractory cataplexy and seems to persistently improve sleep architecture and clinical symptoms over time (04). Mayer, in Germany, finds the product worthwhile for all three symptoms: namely, excessive daytime sleepiness, cataplexy, and otherwise fragmented night-time sleep (92). One study demonstrated significant dose-related increases in the duration of stage N3 sleep with a substantial decrease in the frequency of nocturnal awakenings, which coincided with marked reduction in the severity and frequency of narcolepsy symptoms (22). The Pediatric Sleep Center in Paris determined that sodium oxybate was well tolerated and efficacious in childhood narcolepsy with cataplexy (76). Further improvement in mean sleep latency was observed with the combination of sodium oxybate and modafinil (21). As a clinical caveat, sodium oxybate concentrations remained two to five times higher than endogenous levels 4 hours after both nighttime doses, as determined by gas chromatography/mass spectrometry. It is advised, then, that the morning breastmilk should be expressed and discarded given proportional contamination (16). The United States FDA approved a new formulation of oxybate product that results in 92% less sodium by offering a unique composition of cations (calcium, magnesium, potassium). The agent (low sodium oxybate), in a global phase 3 multicenter study, demonstrated efficacy and safety in the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy when compared to placebo; it is FDA-cleared in those with narcolepsy who are 7 years and older. Similarly, it has been studied and approved for the treatment of excessive daytime sleepiness due to idiopathic hypersomnia in adults.

Other agents that may reduce cataplexy include tricyclic antidepressants such as protriptyline, clomipramine, imipramine, and pitolisant (vide infra). Behavioral strategies include the implementation of regular nocturnal sleep schedules and encouragement of brief, strategically timed daytime naps as an adjunct to pharmacotherapy. Disease self-awareness is key as well. Of special note, pediatric patients with narcolepsy have high levels of treatment-resistant ADHD symptoms. The ADHD symptoms remain largely unresponsive to psychostimulant therapy, in contrast to the bona fide narcolepsy symptoms (75).

The Swedish group at the University of Gothenburg devised a 21-point questionnaire with the aim of improving the design of treatment options for young patients with narcolepsy type 1. Domains included, within the psychosocial factor structure, item titles of sadness, aloneness, anger, anxiety, irritability, alertness, confidence, laziness, and perseverance. This instrument proved to possess good discrimination, reliability, and stability (27).

As a caveat, patients with a combination of both insomnia and hypersomnia may turn toward substances as treatment; this could include heroin, alcohol, and cocaine (43). Finger and colleagues underscore that the barriers to therapy adherence in narcolepsy are complex and include cognitive deficits (impaired executive function), depressive symptomatology, and excessive daytime sleepiness itself (47). Varallo and colleagues stress that denial along with both mental and physical disengagement were significantly and negatively associated with quality of life (150).

Kleine-Levin syndrome (alias: Sleeping Beauty syndrome), characterized by recurrent episodes of hypersomnia, morbid hunger, hypersexual behavior, and cognitive disturbances, is often not clinically recognized. When recognized, it is usually considered best left untreated beyond supportive care. To underscore the diagnostic challenges, atypical Kleine-Levin syndrome can present as an unspecified nonorganic psychosis. Singh and colleagues reported a case involving–instead of core symptoms (other than hypersomnia)–clinical depersonalization, derealization, persecutory delusions, anorexia, and apathy (139). Multiple antipsychotics were borne out to be nonefficacious. It remains a diagnosis of exclusion. Lithium, prophylactically – and perhaps carbamazepine – can be of benefit in extreme cases involving frequent bouts (99). Indeed, in a large, open-label, controlled study it was determined that the benefit/risk ratio of LiCO3 therapy was superior to abstention and that therapy was likely both neuroprotective and antiinflammatory (78). Others have reported clinical benefit from valproate (103). Kleine-Levin syndrome is known to be a devastating disorder, “robbing” the patient of time and experiences and fruitful, satisfying relationships. Incidentally, Kleine-Levin syndrome has a probable genetic form, as evidenced by its discovery in monozygotic twins (115) with the documented allele, DQB1*06:01.

Idiopathic hypersomnia is of debatable dimension. Rassu and colleagues have attempted to better quantify symptom severity and their consequences in idiopathic hypersomnia; their 14-point idiopathic hypersomnia severity scale aids in quantifying the severity of the three major idiopathic hypersomnia symptoms (excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia) and consequences (123). Idiopathic hypersomnia is often treated with R-modafinil or classic stimulants. Sodium oxybate may be significantly beneficial (79) and has achieved FDA approval for idiopathic hypersomnia in adults. This includes the more recent formulation with calcium, magnesium, and potassium with, thus, lesser intrinsic sodium load. Some patients with idiopathic hypersomnia respond to mild stimulants at low doses, but others are poorly responsive even to amphetamines at the highest tolerated levels. Care should be taken when prescribing psychostimulants at doses beyond those recommended; psychosis, psychiatric hospitalizations, tachyarrhythmias, hypertension, and anorexia or weight loss were observed at significantly higher rates in patients who had received at least one stimulant at a dosage greater than or equal to 120% of the maximum recommended by the American Academy of Sleep Medicine Standards of Practice Committee (12). Other related adverse effects can include personality change, irritability, insomnia, aggressiveness, rapidity of thought, tremor and jitteriness or nervousness, hypertension, tolerance and drug dependence, palpitations, or headache. To summarize, the available wake-promoting agents include (with doses and neurotransmitter systems enhanced):

Agent	Dose	Systems enhanced
Amphetamine or D-amphetamine	50 to 60 mg/day	NE, DA, 5HT
Methamphetamine	5 to 25 mg/day	NE, DA, 5HT
Methylphenidate	10 to 60mg/day	NE, DA
Dexedrine	10 to 40 mg/day
Selegiline	5 to 10 mg/day	DA, NE, 5HT
Mazindol	4 to 8 mg/day
Modafinil	200 to 400 mg/day	? ?
Armodafinil (R-Modafinil)	150 to 250 mg/day	? ?
Sodium oxybate	4500 to 9000 mg/night	? ?
Caffeine	20 to 500 mg/day	Adenosine A2a antagonism
Pitolisant	8.9 to 17.8 mg q am	H3 Histamine receptor antagonist/inverse agonist
Solriamfetol	150 to 300 mg qd	NE, DA

Maski and colleagues published an American Academy of Sleep Medicine clinical practice guideline regarding the treatment of central disorders of hypersomnolence (91). To summarize salient aspects of this important resource:

• For adults with narcolepsy: Modafinil, pitolisant, solriamfetol, and sodium oxybate were strongly recommended, whereas armodafinil, dextroamphetamine, and methylphenidate were conditionally recommended only.

• For adults with idiopathic hypersomnia: Modafinil was strongly recommended, whereas clarithromycin, methylphenidate, pitolisant, and sodium oxybate were only conditionally recommended. Agents as recommended for other conditions including Kleine-Levin syndrome, alpha-synucleinopathies, posttraumatic hypersomnia, hypersomnia due to or secondary to medical conditions or genetic disorders were only in the conditional level.

Again, this salient task force manuscript includes notable potential side effects and warnings from each agent under review.

Importantly, it appears that stimulant misuse in patients with narcolepsy or idiopathic hypersomnia is extremely low, reducing, somewhat, the concern amongst providers (90).

Until recently, there were no approved drug treatments or trials in the pediatric age group. A retrospective study now documents the safe use of treatments commonly used in adults and young children. These treatments would be centered toward modafinil or armodafinil for treatment of sleepiness, venlafaxine as prescription intervention for cataplexy, and sodium oxybate for management of all symptoms (09). More detailed guidelines are needed. Another special population is the elderly; notably, lower dosages of alerting agents are to be prescribed in the older population because metabolic clearances are reduced, and the pharmaceutical effects are predictably more profound (35). Hypersomnolence may persist in obese patients beyond that attributable to obstructive sleep apnea. Bariatric surgery and avoidance of diets high in fats may help (112).

Caffeine, as commonly known, is frequently administered as a preventative agent in an attempt to ward off drowsiness and to improve wakefulness. This molecule, a methylxanthine (competitive adenosine receptor antagonist) is the most widely consumed psychoactive drug globally. Given its wide availability (in many forms), it is reportedly consumed by over 85% of adults. According to Katz and colleagues, authors from Boston Children’s Hospital, Division of Respiratory Diseases, it is typically found in over 30% of tested children undergoing MSLT at their center (62). Sleep specialists note, importantly, that the risks to sleep, and alertness, of regular caffeine use are greatly underestimated by both the general population and by physicians. They contend that regular daily dietary caffeine intake is actually associated with disturbed sleep and associated daytime sleepiness. Further, certain clinical scientists espouse that rather than enhancing performance, caffeine merely restores performance degraded by sleepiness. Further, of concern, sleep physicians--on formal review--rarely document the caffeine intake history during clinic visits for patients complaining of excessive daytime sleepiness (128).

Further, novel pharmacotherapies may involve gene therapy, plasmapheresis, immunomodulatory therapy, orexin agonists (133), hypocretin replacement therapies--including CNS Hcrt neuronal transplantation and transformation of stem cells into hypothalamic neurons--and peptidergic- or monoaminergic- or GABAergic-based modalities, most notably slow-wave sleep (SWS) enhancers. Some compounds are in Phase III trials. Idiopathic hypersomnia and treatment refractory hypersomnolence have been managed within trials of histamine H3 antagonists (eg, pitolisant) and with either clarithromycin or flumazenil, both serving as presumed negative allosteric modulators of the GABA-A receptor (125; 63; 20).

Pitolisant warrants some detailed elaboration; this agent, an inverse agonist of the H3 histamine receptor (H3R competitive antagonist), was developed in Europe and licensed for use in the European Union March 2016. Pitolisant modulates other neurotransmitter systems as well, leading to increased release of acetylcholine and DA in the cerebral cortex without increased release of DA in the striatal complex (143). It is an orphan drug and is approved for the treatment of excessive daytime sleepiness related to narcolepsy type 1 and narcolepsy type 2 (both narcolepsy with and without cataplexy). It was shown to significantly decrease the Epworth Sleepiness Scale and to improve the Maintenance of Wakefulness Test scores. Pitolisant may also prove to be efficacious as a first-line therapy for cataplexy itself (14). The recommended dosage range is 4.5 to 36 mg depending on the host. It has a long half-life, so is to be taken early in the day. As a warning, the metabolism is yet to be completely characterized. It crosses the placenta. It is reportedly well tolerated, with the exception of certain reported cases of neuropsychiatric material and nausea (142). There may be cardiac irritability in those with a propensity. Safety and efficacy studies are in progress within the pediatric narcolepsy subpopulation. Its place in managing the sleepiness of patients with obstructive sleep apnea who are intolerant of CPAP is under review (41).

Another first in class wake promoting agent has been approved; this is a dopamine and norepinephrine reupdate inhibitor (DNRI). This selective agent, solriamfetol, was found in the TONES studies to reduce sleepiness and increase wakefulness in patients with either narcolepsy or obstructive sleep apnea. This novel agent seems to improve measures of functional status, health related quality of life (QOL), and work productivity, particularly at the 150 and 300 mg daily dosage schedules/regimens. Unlike conventional stimulants, there was no rebound insomnia nor withdrawal effect, nor cardiac effect. In a randomized study of solriamfetol for excessive daytime sleepiness in narcolepsy, Thorpy and colleagues noted adverse events greater than 5% to include headache, nausea, decreased appetite, nasopharyngitis, and anxiety (145). This phenylalanine derivative is recognized as showing significant improvement in patient’s and clinician’s global impression of change (01). According to Malhotra and colleagues, this effective treatment has been demonstrated to exhibit long-term efficacy and safety (87). Schweitzer and colleagues determined that solriamfetol improved excessive daytime sleepiness in obstructive sleep apnea regardless of primary obstructive sleep apnea therapy adherence and that primary obstructive sleep apnea therapy use was unaffected with solriamfetol (134).

Yet another novel agent has been studied in mice as efficacious as modafinil in terms of wake-promotion, without certain related potential side effects, such as aggressivity. A Swiss study by Luca and colleagues reveals promise with lauflumide (NLS-4) as a new potent wake-promoting compound (84). It is reportedly a selective dopamine reuptake inhibitor, blocking (83%) dopamine transporter (DAT), higher than methylphenidate and, importantly, without deleterious side effects on peripheral adrenergic systems involved in hypertension.

The FDA has announced the approval of a sodium oxybate extended-release, once-at-bedtime oral suspension for cataplexy or excessive daytime sleepiness in adults with narcolepsy. The AAP and the AASM have endorsed this agent, given its more convenient administration, which is improved delivery system without nighttime disruption for otherwise necessary second dosing. This agent has a higher salt content than the newer preparation of oxybate: 1640 mg to be exact. This, chronically, could impact general health. There is greater dosage flexibility with the twice nightly dosage preparation, given options clinically and strategically, toward asymmetric weighting of formulaic amounts of active ingredient.

Also, a norepinephrine reuptake inhibitor is under review, along with a combination of modafinil with an astroglial connexin inhibitor (THN102) (143). This modafinil/flecainide combination induced regional brain activation localized to the cortico-amygdala-striatal zone (152).

Further, reboxetine is in a phase 2 trial entitled CONCERT (clinical outcomes in narcolepsy and cataplexy: an evaluation of reboxetine treatment) with the primary outcome measure the number of cataplexy attacks compared to placebo; ESS and Maintenance of Wakefulness Test were secondary outcome measures.

New symptomatic and causal treatment will perhaps include hypocretin replacement and immune-modifying strategies (61). Presently, CSF hypocretin levels are attainable at the Rochester, MN branch of Mayo Clinic; as a caveat, Zhan and colleagues noted that ELISA cannot replace radioimmunoassay in the measurement; radioimmunoassay is recommended as the first choice (160). This approach is noted to be highly specific and sensitive; however, longer incubation times, the need for special equipment, and the experimental process producing radioactive material are not conducive factors toward its use.

Lastly, and innovatively--albeit early in the establishment of clear, accepted efficacy--Lai and associates utilized multiple sessions of repetitive transcranial magnetic stimulation to gain remission of symptoms in patients with narcolepsy type 1 (72). He and colleagues reported the clinical benefits, as a single case study, and claimed that this modality is superior to pharmacotherapy in that it upholds efficacy, safety, and tolerability. This treatment strategy stresses that noninvasive neuromodulation has been employed for various other neuropsychiatric disorders (epilepsy, stroke, depression, anxiety, obsessive-compulsive disorder) with certain utility and durability. His patient received 25 sessions of 10 Hz treatments over the left dorsolateral prefrontal cortex and, through the modification of cortical excitability, reportedly offered enduring improvement (72). A group at Emory University explored deep brain stimulation of the hypothalamus for narcolepsy type 1 and other sleep disorders, with support toward feasibility (130).

Outcomes

In a limited trial, a Danish group noted no beneficial effect rendered from early IVIg treatment in regard to post-H1N1 narcolepsy phenotype or hypocretin deficiency (65), yet immunological mechanisms are clearly considered instrumental to the onset of narcolepsy in genetically susceptible persons. In addition to this viral agent and its inoculation preparation, S pyogenes also seems to trigger onset narcolepsy such that ASO titers, if drawn, may reflect, by elevation, recent infectious exposure. The identification of autoantibodies to Tribbles homologue 2 in some patients with narcolepsy further supports an underlying autoimmune provocation (151). The discovery of the epitope, or antigenic determinant, is a major breakthrough toward the further upholding of an immune and probably autoimmune basis for the onset of the disease (45). Overall, the scientific evidence in support of a dysimmune process includes strong HLA associations, T-cell receptor polymorphisms, low CD40L levels and relative lymphopenia, elevated anti-Tribbles 2–specific antibodies, alteration of CSF cytokine profiles (39), reduced CSF beta-amyloid, seasonal association with extrinsic aggressors, and anti-Ma immunopathology, as well as the epitope discovery (68). Formally, however, based on the Witebsky criteria, narcolepsy does not yet qualify as an autoimmune disease in that actual autoantibodies have not been found to date (137). However, given the strong evidence toward the support of immunopathology (cross-auto-reactivity and molecular mimicry), earlier and stronger consideration of the administration of immunomodulatory agents is warranted, along with the establishment of an active surveillance system for swift recognition and safety monitoring (69).

Certain COVID-19-related developments in sleep-wake medicine are noteworthy. Moura documented both insomnia and excessive daytime sleepiness within the spectrum of complaints in long COVID syndrome (101). Beyond insomnia and feelings of nonrestorative sleep, Bhat’s group expanded “coronasomnia” to include disrupted sleep continuity and changes in the sleep cycle as well as decreased sleep quality arising due to stresses related to fear of the virus (18). Wu’s team speculated that the COVID-19 vaccine may potentially trigger the relapse of hypersomnia (thus, secondary) and that caution is warranted when administering the COVID-19 vaccine to patients with hypersomnia secondary to infection (157).

Given the benefit of a decrease in social and professional constraints on sleep-wake habits during the imposed coronavirus lockdown, patients with either narcolepsy or idiopathic hypersomnia noted a reduction in their symptoms of central and neurologic hypersomnia (105). A freer napping schedule was appreciated. The reallocation of time usually spent commuting toward longer sleep time, hobbies, and family time was enjoyed. Advocacy efforts are aimed at facilitating workplace and schedule accommodations for this population.

Of note, regarding outcomes, there is a case report serving to warn emergency physicians to be on the lookout for GHB as a part of the differential diagnosis of altered mental status. McIntosh and Mayeux underscore that a mistimed second dose of oxybate led toward CNS toxicity (93).

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

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Richard P Knudsen MD FAASM CNP FAAP

Dr. Knudsen of Arizona Sleep Center has no relevant financial relationships to disclose.
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Antonio Culebras MD FAAN FAHA FAASM

Dr. Culebras of SUNY Upstate Medical University at Syracuse has no relevant financial relationships to disclose.
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Linda M Selwa MD
Ronald D Chervin MD
Douglas B Kirsch MD

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Hypersomnolence

Differential Diagnosis

depression
Doose S (MAE)
insufficient sleep syndrome
obstructive sleep apnea
inadequate sleep hygiene
- restless legs syndrome
- insomnia
- narcolepsy
- idiopathic hypersomnia
- alcohol
- circadian rhythm disturbance
- antidepressants
- antipsychotics
- anticonvulsants
- cardiovascular drugs
- diencephalic and brainstem disorders
- infarctions
- neoplasms
- encephalitis lethargica
- fatal familial insomnia
- Kleine-Levin syndrome
- neurodegenerative disorders
- multiple systems atrophy
- neuromuscular disorders
- central nervous system abnormalities
- gastroesophageal reflux disorder
- hypothyroidism
- diffuse metabolic encephalopathies
- conditions that cause chronic pain
- sleep-disordered breathing

Also Relevant

Drug-induced insomnia and excessive daytime sleepiness
Fatigue in multiple sclerosis
Idiopathic hypersomnia
Myotonic dystrophy
Posttraumatic sleep disturbance
- Sleep and chronic pulmonary disorders
- Sleep and epilepsy
- Sleep and neuromuscular and spinal cord disorders

Clinical Categories

Sleep Disorders

Hypersomnolence …

Hypersomnolence

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Anatomic localization

Pathophysiology

Epidemiology

Differential diagnosis

Confusing conditions

Diagnostic workup

Table 1. The Stanford Sleepiness Scale

Table 2. Epworth Sleepiness Scale

Management

Outcomes

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Fatal familial insomnia

Sleep and mental disorders

Sleep paralysis

Sleep and epilepsy

Narcolepsy

Confusional arousal

Restless legs syndrome

REM sleep-related parasomnias

Hypersomnolence

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Anatomic localization

Pathophysiology

Epidemiology

Differential diagnosis

Confusing conditions

Diagnostic workup

Table 1. The Stanford Sleepiness Scale

Table 2. Epworth Sleepiness Scale

Management

Outcomes

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Fatal familial insomnia

Sleep and mental disorders

Sleep paralysis

Sleep and epilepsy

Narcolepsy

Confusional arousal

Restless legs syndrome

REM sleep-related parasomnias

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to access the full version.