Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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This article includes discussion of idiopathic hypersomnia (IH), which is characterized by excessive daytime sleepiness, difficulty awakening (sleep drunkenness), and undisturbed overnight sleep without cataplexy or known cause of excessive sleepiness. Excessive sleepiness (hypersomnolence) of unknown etiology, which cannot be explained by another disorder, would be considered idiopathic hypersomnia. This should be clearly distinguished from other disorders that could present with complaints of excessive daytime sleepiness, such as narcolepsy, behaviorally-induced insufficient sleep, circadian rhythm disturbance, obstructive sleep apnea, or from hypersomnolence secondary to a medical condition or medication. These patients frequently present in adolescence and may have symptoms of autonomic nervous system dysregulation, but they are most often affected because of inability to attend to daytime obligations such as school or work. Because the pathophysiology is unknown, management is limited to symptomatic treatment and education.
• The main symptom of idiopathic hypersomnia is an irresistible urge to sleep despite adequate, or even excessive, nocturnal sleep, which lasts at least 3 months.
• For idiopathic hypersomnia duration of sleep (with and without long sleep time) is no longer a criterion for subtype distinction; however, there is a growing body of support for reclassifying idiopathic hypersomnia by sleep duration.
• Idiopathic hypersomnia can be associated with symptoms of autonomic nervous system dysregulation (orthostatic hypotension, syncope, headache, and Raynaud-type phenomena) and with significant sleep inertia (aka “sleep drunkenness”).
• The diagnosis of idiopathic hypersomnia is based on clinical features along with testing to rule out other causes of excessive daytime sleepiness (nocturnal polysomnography, multiple sleep latency test, and actigraphy).
• The differential diagnosis includes other conditions of excessive daytime sleepiness such as narcolepsy, inadequate total sleep time, sleep disorders that impair sleep quality, circadian rhythm disturbances, or hypersomnolence secondary to medical condition or medication.
• Treatment of idiopathic hypersomnia is primarily symptomatic involving education (sleep hygiene and lifestyle modifications) and off-label usage of wake-promoting agents such as stimulants.
Prior to the use of polysomnographic studies, idiopathic hypersomnia (IH) was usually misdiagnosed as narcolepsy. Dement and colleagues first proposed that a diagnostic category other than narcolepsy should be used for patients who have excessive daytime sleepiness but do not have cataplexy, sleep paralysis, or sleep onset rapid eye movement episodes (33). Subsequently, various labels were proposed to designate this entity: essential narcolepsy (17), non-REM sleep narcolepsy (88), hypersomnia (93), hypersomnia with sleep drunkenness (97), idiopathic hypersomnia (96), idiopathic central nervous system hypersomnia (10), and again idiopathic hypersomnia (07). The previous sleep disorders classification parsed idiopathic hypersomnia into 2 categories based on sleep duration. Idiopathic hypersomnia with long sleep time (> 10 hours) entails excessive sleepiness with prolonged, unrefreshing naps lasting up to 3 or 4 hours, major sleep episodes of at least 10 to 14 hours in duration with difficulty waking up or sleep drunkenness, and no cataplexy. Idiopathic hypersomnia without long sleep time (< 10 hours) reflects excessive sleepiness and unintended, unrefreshing naps, with the major sleep episode lasting less than 10 hours, with difficulty waking up or sleep drunkenness, and no cataplexy (05). The 3rd edition of the International Classification of Sleep Disorders (ICSD-3) no longer dichotomizes idiopathic hypersomnia based on sleep duration (06) (see Table 1). However, built on efforts to better differentiate and refine the primary CNS hypersomnias, a number of experts in the field are calling for a reversal of this framework, given apparent differences between those with long versus short sleep time, particularly with idiopathic hypersomnia with short sleep and NT2 having hardly discernable phenotypes, suggesting excessive sleepiness (hypersomnolence) rather than true excessive sleep duration (hypersomnia) (38; 57).
Idiopathic hypersomnia diagnostic criteria (must meet criteria A to F)
A. Patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months
B. Cataplexy is absent
C. Multiple sleep latency test (MSLT) shows fewer than 2 sleep onset REM periods or no sleep onset REM periods if the REM latency on the preceding polysomnogram was < or = 15 minutes
D. Presence of at least 1 of the following:
1. MSLT shows a mean sleep latency of < or = 8 minutes
2. Total 24-hour sleep time is > or = 660 minutes on 24-hour polysomnographic monitoring (performed after correction of chronic sleep deprivation), or by wrist actigraphy in association with a sleep log (averaged over at least 7 days with unrestricted sleep)
E. Insufficient sleep syndrome is ruled out
F. Hypersomnolence and/or MSLT findings are not better explained by another sleep disorder, other medical or psychiatric disorder, or use of drugs or medications
• Severe and prolonged sleep inertia (sleep drunkenness)
• High sleep efficiency (> or =90%) on polysomnogram
• Total 24-hour sleep time required for diagnosis is adapted based on normal changes in sleep duration for development (children, adolescents) and cultural variance.
Source: International Classification of Sleep Disorders, American Academy of Sleep Medicine, 3rd edition (2014).
• Patients with idiopathic hypersomnia typically have prolonged (10+ hours) episodes of relatively undisturbed nocturnal sleep with high sleep efficiency (> 85%).
• Despite prolong nocturnal sleep periods, most patients with idiopathic hypersomnia have excessive daytime sleepiness and take daily naps that last more than an hour and are seldom refreshing.
• When waking from sleep, the majority of idiopathic hypersomnia patients have a feeling of “sleep drunkenness” (or sleep inertia) and may even have automatic behaviors that they are amnestic to.
• Autonomic dysfunction is common in individuals with idiopathic hypersomnia.
The onset of idiopathic hypersomnia is often insidious and occurs in the second decade of life with key feature of near constant daytime sleepiness and complaints that the patient almost never feels alert. Along with this background of excessive sleepiness, patients often have long episodes of daytime sleep, with naps lasting over 1 hour. Compared to the daytime sleep episodes that occur in patients with narcolepsy, those associated with idiopathic hypersomnia tend to be more resistible, longer in duration, and not as refreshing. However, this difference from narcolepsy is not absolute and some patients with idiopathic hypersomnia have irresistible daytime sleep episodes and refreshing naps (02; 14). The most important clinical distinction is the absence of cataplexy in patients with idiopathic hypersomnia.
Night sleep in idiopathic hypersomnia is typically long and consists of an average of 10 hours or more (up to 19 hours) (124). The nocturnal sleep is generally undisturbed in contrast to patients with narcolepsy, a condition in which fragmented nocturnal sleep is common (02). Nocturnal sleep is usually consolidated with sleep efficiencies exceeding 85% and normal distribution of NREM and REM sleep stages. Awakening is often difficult, even with the use of sophisticated alarm clocks, and patients may describe morning disorientation in time and space, slowing of thought and speech, and inappropriate “automatic” behaviors lasting from several minutes to an hour or more, which is a state referred to as “sleep drunkenness”. The presence of sleep drunkenness has been reported in 36% to 52% of patients with idiopathic hypersomnia (08; 121). Of significance, patients may report hypnagogic hallucinations and sleep paralysis, confirming that these symptoms are not specific to narcolepsy (02; 14). An interesting association in some patients with idiopathic hypersomnia is the presence of what appears to be autonomic nervous system dysregulation, which includes orthostatic hypotension, headaches, perceived temperature dysregulation, and Raynaud-type phenomena (06). Like narcolepsy, idiopathic hypersomnia is often associated with depressive symptoms (32).
According to a retrospective study, idiopathic hypersomnia has a prevalence of less than 1%, which is just 40% of the clinical prevalence of narcolepsy (14; 18; 08). However, in the absence of systematic studies, the prevalence of idiopathic hypersomnia remains to be determined. Features that distinguished idiopathic hypersomnia from a comparable group of 63 narcoleptics were prolonged and nonrefreshing daytime naps, a positive family history of daytime hypersomnolence, increased slow-wave sleep, and longer sleep latency on the multiple sleep latency test (08). Patients with idiopathic hypersomnia have a reduced quality of life as evidenced by trouble maintaining employment and academic schedules and increased risk for divorce (85).
Patients with idiopathic hypersomnia have more fatigue, higher anxiety and depression scores, and more frequent hypnagogic hallucinations (24%), sleep paralysis (28%), sleep drunkenness (36%), and unrefreshing naps (46%) than controls (121). In addition, they depend on others to awaken them, have mental fatigability, and have difficulty maintaining alertness during the day (122).
Idiopathic hypersomnia is usually a chronic, persistent disorder (14). However, a study suggested that symptom remission rates of nearly 33% were noted on 5-year follow up (52), which is in accordance with the results of repeated MSLT assessments in this patient population (118; 66). The complications of idiopathic hypersomnia are mostly related to impairment in daytime functioning due to the excessive sleepiness with significant impact on social, professional, and employment-related activities. The greatest mortality risk with idiopathic hypersomnia remains falling asleep while driving or fatigue-associated driving impairment (06).
A 23-year-old woman presented with a 2-year history of excessive daytime sleepiness. She reported that she “never” felt refreshed and had significant difficulty awakening from sleep. This caused difficulty with her ability to finish college. Her usual bedtime was 10 PM, and she was awoken by her mother by 7 AM. If not awoken by her parent, she would sleep until 10 AM or longer. She reported having a regular sleep schedule and no difficulty with sleep onset or sleeping through the night. After she was awoken, she reported feeling excessively sleepy, including feeling “sleep drunk,” which typically lasted 2 to 3 hours. She denied any nightmares, restless legs symptoms, cataplexy, hypnagogic hallucinations, or sleep paralysis. She drank 6 to 8 double espressos in the morning and coffee throughout the day without a favorable effect. The patient was unable to keep a job due to the sleepiness. She had been exposed to hexane and had developed a neuropathy that had been improving. Her family history was unremarkable, and review of systems was normal.
With a weight of 142 pounds and a height of 5 feet 2 inches, her BMI was calculated to be 26 kg/m2. Her vital signs revealed an arterial blood pressure of 113/64 mmHg, temperature of 98.0° F, pulse of 84 beats per minute, respiration rate of 16/min. On physical exam, she was awake and appropriate without neurologic deficit or other abnormalities noted.
An MRI of the head was unremarkable. Laboratory testing showed normal values for electrolytes, renal, hepatic, and thyroid function tests and hemoglobin A1c. An overnight polysomnogram showed a sleep onset latency of 13 minutes and a REM sleep latency (from the first 30-second epoch scored as sleep) of 43 minutes. The sleep efficiency (total sleep time divided by time in bed) was 92%. She snored lightly and had an apnea-hypopnea-index of 3 per hour. The 5-nap multiple sleep latency test revealed a mean sleep latency of 5.5 minutes without sleep-onset REM periods (SOREMPs) on any of the 5 naps.
She was diagnosed with idiopathic hypersomnia and was started on stimulant medication. Modafinil, 100 mg in the morning and 100 mg at lunchtime, improved her excessive daytime sleepiness significantly. Once her excessive daytime sleepiness improved, she was able to complete school and find a new job.
• The cause of idiopathic hypersomnia remains unknown.
• It is likely that the idiopathic hypersomnia syndrome is composed of several distinct disorders.
The exact cause of idiopathic hypersomnia remains unknown. There are limited data regarding the neurobiology and pathogenesis/pathophysiology of idiopathic hypersomnia, and there is no existing animal model for more detailed study. Many neurochemical studies regarding the disorder have been inconclusive. In a study comparing patients with idiopathic hypersomnia and narcolepsy type 1, using sleep diary and self-report measures, 2 subgroups emerged: 1 with family history and 1 with a postinfectious onset (22). These findings suggest the possibility of gene-environment interactions that can contribute to disease in a fashion similar to narcolepsy with hypocretin deficiency.
Neurotransmitters. From a structural perspective, the destruction of noradrenergic neurons of the rostral third of the locus coeruleus complex or of the noradrenergic bundle at the level of the isthmus in the cat leads to hypersomnia with a proportional increase of non-REM sleep and REM sleep, resembling idiopathic hypersomnia (90). This state is accompanied by a decrease of diencephalic norepinephrine (90). These findings are concordant with the observations of von Economo during the encephalitis lethargica epidemic, which highlighted that patients suffering from excessive sleepiness often had lesions at the junction of the posterior hypothalamus and midbrain (125). Additionally, therapeutic measures for idiopathic hypersomnia, such as stimulants and modafinil/armodafinil, which typically act on catecholamine (dopamine, norepinephrine) signaling mechanisms, indicate that there may be some contribution of these neurochemical pathways in the pathogenesis of idiopathic hypersomnia. Other aspects that have been evaluated as possibly contributing to the pathogenesis of idiopathic hypersomnia are histamine signaling, melatonin secretion abnormalities, immunologic and inflammatory processes, somnogens, and genetic factors.
In the 1980s, studies in less well-characterized clinical idiopathic hypersomnia patients found some differences in monoamine metabolites and suggested that idiopathic hypersomnia may have a component of disrupted dopamine signaling. One study found decreased dopamine and indoleacetic acid (tryptophan metabolites) compared to controls in the CSF of patients with narcolepsy and idiopathic hypersomnia (76).
Histamine has also been suggested as a biomarker in the pathophysiology of idiopathic hypersomnia, though the evidence is inconclusive (98). Histamine is a wakefulness producing neurotransmitter. Antihistamines (H1 antagonists) are well known to increase somnolence across many species including humans. Two studies evaluated CSF histamine in patients with hypersomnia of various origins. One small, uncontrolled study looked at CSF histamine in patients with multiple causes of excessive daytime sleepiness and found an inverse correlation of CSF histamine with a severity of reported sleepiness based on the Epworth Sleepiness Scale (15). Kanbayashi and colleagues found that CSF histamine was reduced (compared to controls) in patients with narcolepsy (type 1 and type 2), as well as idiopathic hypersomnia, but not in patients with obstructive sleep apnea (51). However, a larger study looking at histamine, t-methylhistamine, and hypocretin in various conditions that lead to hypersomnia failed to show differences in CSF histamine or t-methylhistamine levels in patients with idiopathic hypersomnia compared to controls (28). From a more clinical perspective, histaminergic compounds like pitolisant, an inverse H3 agonist, have been useful in the management of drug resistant conditions associated with hypersomnia, including idiopathic hypersomnia, through their resultant increases in brain histamine and other monoamine levels (60).
Investigators have reported on a potential 500-to-3000-dalton somnogen that potentiates γ-hydroxybutyrate (GABA) through activity at the benzodiazepine site on the α2 subunit of the GABAA receptor (98). However, attempts to replicate this finding in well-curated idiopathic hypersomnia cohorts have been unsuccessful (30). Nonetheless, blockade of the activity with a benzodiazepine antagonist, flumazenil, has yielded modest results in a small proportion of a cohort of mixed hypersomnia patients, suggesting that such a mechanism may play a role in certain individuals with otherwise unexplainable hypersomnolence (117).
Although hypocretin-1 is implicated in narcolepsy type 1, this neurotransmitter does not appear to be pathogenic in idiopathic hypersomnia (28).
Inflammatory/cytokines. Some studies indicate that idiopathic hypersomnia may have an immunological or inflammatory component, similar to narcolepsy type 1. Among patients with idiopathic hypersomnia, human leukocyte antigen-Cw2 was found in 22.2% compared to 5.7% in controls (p < 0.05) (76). Also, HLA-DR5, which is in linkage dysequilibrium with HLA-Cw2, was present in 38.8% of patients versus 14.6% of controls (76). Further studies, however, did not find any similar association with idiopathic hypersomnia and HLA haplotypes (14; 19). However, the poor associations with HLA regions may be explained by the variability of subjects exposed to a triggering factor (eg, infection, as in narcolepsy type 1) (65; 31), as well as the fact that idiopathic hypersomnia represents a heterogenous population. Nonetheless, additional data that indicate there may be an immunological component are the serum total IgG levels in 28 Japanese patients with idiopathic hypersomnia and long sleep times. Those patients with idiopathic hypersomnia had high IgG3 and IgG4 levels, low IgG2 level, and IgG1/IgG2 imbalance, which was different than healthy individuals (110).
Related to the immune-mediated-disease hypothesis is the observation that proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα) are elevated in disorders associated with excessive daytime sleepiness, such as sleep apnea, narcolepsy, and idiopathic hypersomnia. Although these cytokines are part of the innate immune system, their activity meets the criteria of a somnogen/sleep regulatory substance (54). Most notably, sleep deprivation also leads to sleepiness and daytime hypersecretion of IL-6. These findings suggest that IL-6 and TNFα are possible mediators of excessive daytime sleepiness in humans (123). Prostaglandin D2, an inflammatory molecule, may be another possible contender, given the finding that serum and CSF levels of lipocalin-type prostaglandin D synthase (LPGDS) were noted to be higher in NT1, NT1, and idiopathic hypersomnia patients, but this finding needs replication (127).
Genetics. A genetic basis for some cases of idiopathic hypersomnia is suggested by several investigations. Early studies indicated that a large minority of patients with idiopathic hypersomnia had a similarly affected first degree relative (80; Roth and Broughton 1980; 19). Although these data strongly suggest a genetic component, possibly autosomal dominant, the limited number of families studied has not permitted definitive determination of the mode of inheritance. A number of studies have sought to explore the genetic basis of sleep duration using genome-wide association studies. Unfortunately, sample size limitations and phenotype heterogeneity have limited the findings thus far. To date, the largest analysis of genetic contributions to sleep duration has come from a study of individuals in the UK Biobank (http://www.ukbiobank.ac.uk) (50). The findings confirmed a prior association (42) with the thyroid-specific transcription factor, PAX8, and identified a novel association with a multicascade serine/threonine kinase, VRK2 (04). However, the variants associated with the identified genes conferred insubstantial effects on sleep duration (2.6 min per PAX8 allele and 1.6-2.0 min per VRK2 associated variant), highlighting the difficulties in identifying the genetic contributors to such multifactorial phenotypes. Future study of extreme, well-phenotyped individuals and multiplex families may reveal more meaningful associations.
Additionally, circadian rhythm gene-expression analyses have revealed some abnormalities in individuals with idiopathic hypersomnia; however, causality has yet to be established. In 2014, a study by Lippert and colleagues evaluated gene expression of certain circadian clock genes in cultured dermal fibroblasts of patients with a diagnosis of idiopathic hypersomnia compared to that in normal healthy controls (63). This study revealed statistically significant reductions in the amplitude of the expected oscillation in the transcription of BMAL1, PER1, and PER2 (63). The authors postulated that the dampening of oscillations of these transcriptional factors in the SCN, which modulate pineal melatonin secretion, may explain the decreased melatonin secretion seen in idiopathic hypersomnia (111; 79). Another study by Materna and colleagues demonstrated an approximately 0.82 hour (95%, CI 0.44 to 1.20 hours) longer mean period length in patients with idiopathic hypersomnia (relative to controls), based on a BMAL1 promoter activity assay in fibroblasts (69). In concordance with the finding that melatonin and cortisol secretion is significantly delayed in individuals with idiopathic hypersomnia (79), these findings may suggest a genetically based abnormality in entrainment as a contributor to the pathophysiology of idiopathic hypersomnia.
In sum, despite a number of intriguing findings spanning the domains of CNS neurotransmitters, immunology, and genetics, the pathophysiology underlying idiopathic hypersomnia remains nebulous. A number of factors contribute to this elusive disorder, not the least of which include the poor objective characterization of this phenotype with the currently available diagnostic methods (see management section below), the genetic complexity, the unclear risk factors, and environmental exposures.
• The prevalence of idiopathic hypersomnia is difficult to estimate due to the relatively nonspecific nature of symptoms.
• In the general population the about 1 out of 50,000 to 1 out of 5000 individuals are estimated to have idiopathic hypersomnia.
• Among individuals presenting to a sleep center for excessive daytime sleepiness, 10% to 29% of individuals are estimated to have idiopathic hypersomnia.
Evaluation of the prevalence of idiopathic hypersomnia in the general population is difficult due to the limited number of patients with this condition and the difficulty of making a definitive diagnosis. For example, after excluding patients with symptoms and medication that might confound a diagnosis in patients with daytime sleepiness, Laffont and colleagues comprehensively evaluated 128 patients (16 to 77 years of age) in whom no clear diagnosis had been established for their daytime sleepiness and found that only 12% (15 patients) fit criteria for idiopathic hypersomnia. Using their own nomenclature they characterized the other subjects as having various disorders such as: mild hypersomnia type 1, hypersomnia associated with HLA type DR2-DQw1, mild hypersomnia type 2, patients with morning recovery from disrupted sleep, young “long sleepers” with difficulty waking up, poor short sleepers since childhood, and older poor sleepers with late onset of symptoms (56).
Despite the limited nature of epidemiological data, the prevalence of idiopathic hypersomnia patients compared to narcoleptic patients provides some indication of overall prevalence. For comparison, improvements in recognition and diagnosis of type 1 narcolepsy have pointed to an estimated prevalence of 0.02% to 0.03% (71). Based on review of a large cohort of over 6000 patients with sleep disorders in the United Kingdom, idiopathic hypersomnia was found to be 40% to 60% as prevalent as narcolepsy, depending upon what MSLT criteria are used (08). These findings are lower than those in earlier studies, probably because of improved identification of sleep disorders that were formerly diagnosed as idiopathic hypersomnia. Integrating these findings into a metaanalysis exploring the epidemiology, diagnosis, pathophysiology, and treatment of idiopathic hypersomnia suggested that the prevalence of idiopathic hypersomnia in the adult population is between 1 in 5000 and 1 in 50,000.
Clinically, approximately 10% to 29% of individuals referred to a sleep center for excessive daytime sleepiness ultimately receive a diagnosis of idiopathic hypersomnia (107; 100). For comparison, there is a population prevalence of about 1.6% for individuals who sleep more than 9 hours per day and are distressed or impaired by their sleep duration (81).
Prevention and risk factors are unknown.
Idiopathic hypersomnia is probably one of the most frequently misdiagnosed sleep disorders. Many other conditions produce such sleepiness and can mimic or coexist with a hypersomnia of central origin. All of these possible confounders need to be considered in the differential diagnosis as possibly causing or contributing to the excessive sleepiness in a patient with hypersomnia of central origin (77).
An exploration of the causes of excessive daytime sleepiness (EDS) in 16,583 randomly sampled Pennsylvanians identified 1742 sleepy individuals who were then recruited for laboratory evaluation. Regression analysis revealed that a report of being treated for depression is the most significant risk factor for the complaint of excessive daytime sleepiness (with increasing effects in younger individuals), followed by BMI, age, subjective estimate of typical sleep duration, diabetes, smoking, and finally sleep apnea (20). This emphasizes that potentially confounding medical/psychiatric disorders and their treatments (86; 41) precludes the diagnosis of a primary CNS hypersomnia, such as idiopathic hypersomnia, and their presence must be assessed and corrected (where possible) before a diagnosis can be made (American Psychiatric Association 2013; 06). Additionally, primary sleep disorders that affect the quality and quantity of sleep must be ruled out, including: upper airway resistance syndrome (UARS, a milder form of obstructive sleep apnea), other primary CNS hypersomnias (eg, Kleine-Levin syndrome and narcolepsy type 1 or 2), circadian sleep phase disorder, and behaviorally-induced insufficient sleep syndrome.
Hypersomnia due to a medical disorder includes irresistible urge to sleep and excessive daytime sleepiness for at least 3 months due to underlying medical or neurologic condition, and it does not meet criteria for narcolepsy. Associated conditions can include neurodegenerative diseases (eg, Parkinson disease or multiple system atrophy), posttraumatic brain injury, stroke or brain tumors (potentially involving the hypothalamus or midbrain), hypothyroidism, or metabolic derangement (chronic renal insufficiency, hepatic encephalopathy, neuroglycopenia) (27; 67; 06). Posttraumatic hypersomnia may closely mimic idiopathic hypersomnia. Hypersomnia usually develops 6 to 18 months after head trauma (44). Excessive sleepiness may be the first symptom of progressive hydrocephalus in the absence of other features of hydrocephalus. Systemic exertional intolerance disease (formerly known as chronic fatigue syndrome, or myalgic encephalomyelitis, despite a lack of evidence of CNS inflammation) is characterized by persistent or relapsing fatigue that does not resolve with bedrest. It is important to differentiate sleepiness (a propensity for dozing off) from fatigue (a lack of physical energy, or body “tiredness”), in any such patients (55). Additionally, there are a number of genetic syndromes that result in hypersomnia including autosomal dominant cerebellar ataxia, deafness, narcolepsy (129), Moebius syndrome (87; 119; 53), Coffin-Lowry syndrome (78), Niemann-Pick disease type C1 (120; 84; 89), Norrie disease (126; 87; 105), myotonic dystrophy (68), and Prader-Willi syndrome (87; 72).
Hypersomnia due to medication or substance is based on excessive daytime sleepiness and an irresistible urge to sleep due to substance/sedative use or withdrawal from stimulant medications. Substances or sedating medications can include alcohol, opiates, marijuana, benzodiazepines, non-benzodiazepine hypnotics, barbiturates, anti-epileptic medications, antipsychotic medications, anticholinergics, antihistamines, antidepressants, and/or combination of medications. Beyond the obvious psychotropic sedatives, a plethora of medications have drowsiness listed as a side effect, either through primary or off-target effects (41). Withdrawal from or abrupt cessation of stimulants such as amphetamines or caffeine can also lead to symptoms of hypersomnia. This can be distinguished from idiopathic hypersomnia with a careful and detailed history, and polysomnography is generally unnecessary.
Hypersomnia associated with psychiatric disorders (dysthymia and related mood disorders) can be distinguished from idiopathic hypersomnia based upon its onset later in life and findings of low-grade, chronic depression revealed through clinical interviews and psychometric testing. In fact, as noted above, depression conferred the highest risk of excessive daytime sleepiness (OR 6.85, p < 0.001) in a large multiple logistic regression model (20). The multiple sleep latency test often does not demonstrate a short mean sleep latency in depression associated hypersomnia, and continuous 24-hour polysomnography shows normal daytime wakefulness despite patients having relative motor quiescence. Thus, they may not move but they are awake (35). Treatment of hypersomnia may or may not improve depression scores, indicating that the relationship between mood disorders and hypersomnia is more complex than simple cause and effect (47), particularly in light of the fact that idiopathic hypersomnia patients will develop depression as a result of diagnostic delays and the psychosocial burden of their disease (32; 122). Thus, a concerted approach focused on treating both disorders is essential.
After addressing the primary medical and psychiatric conditions that may result in sleepiness, the most obvious disorders that contribute to excessive daytime sleepiness are the sleep disorders that impair sleep quality and quantity: sleep-disordered breathing (eg, obstructive sleep apnea), restless legs syndrome, periodic limb movement disorder, and circadian phase disorders (104). A less-commonly-known sleep breathing disorder is the upper airway resistance syndrome (UARS). Subjects with UARS may complain of excessive daytime sleepiness (46). Polysomnography discloses short alpha EEG arousals lasting 3 to 14 seconds that regularly interrupt snoring periods, which are polysomnographically scored as respiratory-event-related arousals (RERA). UARS is classified within obstructive sleep apnea by the American Academy of Sleep Medicine based on the most recent edition of the International Classification of Sleep Disorders (ICSD) (06). To make this diagnosis in adults, the calculated respiratory disturbance index (RDI) should be greater than 5 events per hour (with AHI less than 5 per hour) (45). Furthermore, circadian misalignment (most commonly problematic in those with delayed sleep phase syndrome) is a diagnostic consideration in patients whose main complaint is extreme difficulty awakening at the desired time and excessive morning sleepiness. However, these patients are not sleepy in the evening and go to bed extremely late in the night (128). The diagnosis can be confirmed with review of sleep diary and actigraphy.
Consideration of other primary CNS hypersomnias must also be given. In particular, type 1 narcolepsy is often differentiated through the telltale presence of cataplexy, which is a sudden loss of muscle tone in response to (usually positive) emotion (101). Differentiation of idiopathic hypersomnia from the non-hypocretin-deficient, type 2 narcolepsy is far more challenging, and clinical symptoms alone cannot provide a clear differentiation of the disorders (106), as they are nonspecific to any of the primary hypersomnias (100). Kleine-Levin syndrome is a rare disorder characterized by recurrent episodes of excessive sleepiness (episodes typically lasting 10 days, but possibly up to a few weeks) associated with cognitive dysfunction, altered perception of the environment, eating disorder (commonly hyperphagia), and/or disinhibited behavior (such as hypersexuality), with onset usually in adolescence, and gradual remission often over many years. Most remarkable is that these patients appear to return to a completely normal baseline in the months between the episodes of hypersomnia, and may suffer from a degree of amnesia or report derealization of the event (06).
Given the current epidemic of sleep deprivation (Centers for Disease Control and Prevention 2015), behaviorally-induced insufficient sleep syndrome must be considered in all individuals presenting with excessive daytime sleepiness, impaired concentration, and lowered energy level. A detailed history of the current sleep schedule is revealing, and actigraphy can also be useful in establishing a wake-sleep pattern (94).
Finally, normal variations in the amount of sleep needed per night can include adults who require longer sleep times, greater than 10 hours (in 24 hour period). They may be misdiagnosed with idiopathic hypersomnia because of extremely long sleep episodes at night. However, these patients are normally alert once they have slept their needed amount of sleep.
Autonomic dysfunction is often present in patients with idiopathic hypersomnia, most notably Raynaud phenomenon as well as symptoms of cold extremities (46%), orthostatic intolerance (32%), temperature intolerance (25%), palpitations (23%), and digestive issues (22%) (14; 122). Additionally, disturbed heart rate variability measures pointed to increased parasympathetic tone during sleep and wake in idiopathic hypersomnia patients (103). In a survey of idiopathic hypersomnia patients from a mixed clinical cohort and hypersomnia registry, the prevalence of autonomic disorders was higher than that of the general population (15% and 17%, respectively), the most common of which was postural orthostatic tachycardia syndrome (POTS), which was present in a higher proportion expected for the general population (7% and 13%, respectively) (70). In this study, the severity of autonomic symptoms in idiopathic hypersomnia patients was significantly higher than in controls and was correlated with the severity of daytime sleepiness, fatigue, and quality of life (70). Although it’s not clear why autonomic dysfunction is so prevalent in the idiopathic hypersomnia population, a number of possibilities have been proposed, such as deconditioning due to excessive sleeping and recumbency, overlapping (possibly autoimmune) pathophysiology, and shared genetic predisposition.
• Idiopathic hypersomnia is a diagnosis of exclusion, taking particular care to rule out conditions that cause fatigue (eg, anemia).
• There is not currently an approved clinical diagnostic procedure that is specifically designed to assess idiopathic hypersomnia.
• There are 3 ways that hypersomnia is objectively verified: a mean sleep latency less than 8 minutes on the multiple sleep latency test, greater than 660 minutes of sleep demonstrated on 24-hour polysomnography, or average nightly sleep duration of greater than 660 minutes over 7 days of actigraphically monitored sleep (accompanied by sleep logs).
The diagnosis of idiopathic hypersomnia is mainly based upon findings discovered during a clinical history. However, actigraphy, polysomnography, and multiple sleep latency testing (MSLT) are necessary to confirm the diagnosis and to rule out other sleep disorders. The most widely used test is overnight polysomnography, followed by the MSLT. This sequence of sleep studies allows sleep-disordered breathing, narcolepsy, periodic leg movements, and sleep fragmentation to be ruled out as causes of excessive daytime sleepiness.
One of the most common mistakes made performing the PSG-MSLT is to wake the patient up in the morning instead of letting them sleep in as long as they can. This leads an individual who may have a prolonged sleep requirement or a circadian rhythm delay to have shortened sleep latencies and risk a false positive result.
The MSLT was originally devised for the diagnosis of narcolepsy type 1 (23), where it is best validated (37). However, outside of narcolepsy type 1, its diagnostic utility is more limited (73; 118). A mean sleep latency cutoff of 8 minutes (with less than 8 minutes being suggestive of hypersomnia) has poor reliability, as upwards of 40% of idiopathic hypersomnia patients have mean sleep latencies of more than 8 minutes (leading to a false negative result) and anywhere from 10% to 25% of the general public have sleep latencies of less than 8 minutes (leading to a false positive result) (06; 36). Moreover, attempts to verify a diagnosis of idiopathic hypersomnia with a second MSLT revealed that 75% of those initially diagnosed as idiopathic hypersomnia were normal on repeat testing (66). Further corroborating evidence included the finding that 71% of hypersomniacs with long sleep time were noted to have a normal MSLT (121) and questioned the value of the MSLT as a diagnostic test in individuals with a clinical history suggestive of idiopathic hypersomnia. Maintenance of wakefulness testing (MWT) has also been used as a tool to determine treatment response and to assess a patient’s ability to remain awake in those whose hypersomnia may constitute a safety issue. However, like the MSLT, the MWT suffers from similar problems of reliability, and its uses remain controversial (43; 64).
The most recent version of the International Classification of Sleep Disorders has allowed for the usage of prolonged polysomnography in the objective documentation of excessive sleep (more than 660 minutes) (06). With prolonged polysomnographic monitoring, without provoked morning awakening, recordings are performed for up to 24 hours, and the subject is asked not to fight sleep. This test will typically show prolonged night sleep and 1 or 2 prolonged naps during daytime. Contrasting with narcolepsy, the macroarchitecture of sleep has generally been believed to demonstrate few or no awakenings, normal percentage of NREM sleep stages and REM sleep, and no sleep-onset rapid eye movement periods (SOREMPs) either at night or during daytime. However, a metaanalysis of polysomnographic studies of patients with idiopathic hypersomnia revealed a mix of expected and surprising findings, suggesting that, relative to controls, individuals with idiopathic hypersomnia have: (1) significantly greater total sleep time, (2) shorter nocturnal sleep onset latency, (3) relatively normal sleep efficiency (though this is in the context of much longer total sleep time), (4) reduced percentage of slow wave sleep, and (5) an increase in percentage of nocturnal REM sleep (91). The author of the meta-analysis noted that there was high heterogeneity among the studies analyzed, possibly explaining some of the findings that ran counter to conventional wisdom (91).
A group has proposed a 32-hour bed-rest protocol that follows a time-limited nocturnal polysomnogram (from 11 PM to 7 AM) and “modified MSLT,” (5 nap opportunities every 2 hours, between 9 AM and 5 PM, but where participants are awakened after 1 minute of sleep) (36). Although recognized as impractical for clinical study, the authors found that a cutoff of 19 hours was the optimal cutoff to discriminate between patients with idiopathic hypersomnia, those without idiopathic hypersomnia, and controls, suggesting a much more substantial sleep need in individuals with idiopathic hypersomnia (36). Importantly, the individuals with total sleep time greater than 19 hours were more frequently overweight, with higher frequency of sleep inertia and shorter sleep latencies on MSLT as well as undisturbed nocturnal sleep with high sleep efficiency and short sleep latency, in contrast to the meta-analysis by Plante (discussed above) and in keeping with conventional wisdom (36). As an aside, the authors also explored the diagnostic value of the current ICSD-3 criterion using at least 11 hours of sleep in a polysomnographically monitored, 24-hour period, revealing only 57% specificity for a diagnosis of idiopathic hypersomnia, suggesting that the current diagnostic strategy employing polysomnography may be lacking (36). Previously, other groups have developed similar prolonged sleep opportunity protocols, but, despite similarly validated cutoffs, they have not gained traction in the clinical domain (11). As an alternative to polysomnographic recording, an average sleep duration of greater than 10 hours on at least 7 days of conventional actigraphy can be used to confirm long sleep durations (06).
HLA typing is not sufficiently specific or sensitive to use for diagnosis of idiopathic hypersomnia. The HLA-DQB1*06:02 allele is highly prevalent (97%) in narcolepsy type 1, but is also found frequently (approximately 40%-50%) in narcolepsy type 2 and (approximately 12%-38%) in the general population (62; 74; 09). A CT scan or MRI scan of the brain may be required if a structural brain lesion is a consideration, but such a decision is usually guided by clinical history evincing other symptoms or abnormalities on neurologic examination (113). Although not currently validated for clinical practice, functional neuroimaging may prove promising in helping to diagnose idiopathic hypersomnia. One study using single-photon emission computed tomography (SPECT) suggested decreased regional cerebral blood flow in areas associated with the default mode network (21). Another study using positron emission tomography (PET) pointed to possible hypermetabolism in the salience network (29). These findings have yet to be replicated, and their application to diagnostic strategies has yet to be determined. Using functional MRI, a group found anatomic and functional differences in the brains of a small number of idiopathic hypersomnia patients, such that there was lower connectivity in the anterior (but not posterior) default mode network, a finding possibly analogous to the diminished connective seen in sleep-deprived individuals (92). Psychiatric evaluation may be necessary if a mood disorder is suspected. Thyroid panel, iron studies (iron, total iron binding capacity, percent saturation, and ferritin), complete blood count, vitamin B12, or other relevant blood work may be useful for ruling out other medical conditions that are associated with hypersomnia and fatigue.
• There are no FDA-approved therapies for idiopathic hypersomnia.
• Standard psychostimulants, such as modafinil/armodafinil and methylphenidate, are frequently employed in the treatment of the main symptom of excessive sleepiness.
• Response rates of idiopathic hypersomnia symptoms are quite variable, but general improvement in about 40% to 60% of patients can be expected.
• The variability in treatment response is likely due to idiopathic hypersomnia being a syndrome comprised of several distinct etiologies.
Treatment of idiopathic hypersomnia is similar to that of narcolepsy, however, with substantially less evidence to support the various therapies. Further, as there are no FDA-approved treatments for idiopathic hypersomnia, medications are used off-label and, thus, must be used cautiously with clearly expressed and documented patient understanding of the risks and benefits of such usage. Nonmedication treatment can include lifestyle modification, attention to sleep hygiene, and/or scheduled naps (01). A formal program of cognitive behavioral therapy for hypersomnia (CBT-H) was developed, demonstrating improvements in depressive symptoms (though not meeting the prespecified improvement rate of 50%) as well as global self-efficacy (82). Subjective sleepiness, as measured by the Epworth sleepiness scale, was also improved in the post-hoc subset analysis of the 12 idiopathic hypersomnia patients (82). Education about the impact of the condition on academic development, work, driving, and social life can assist patients as they attempt to live a normal life.
Modafinil and armodafinil (the R racemate of modafinil) have a benefit/risk profile in idiopathic hypersomnia similar to their effect on narcolepsy type 1 (16; 58). Modafinil has been reported to have a modest but significant effect on hypersomnia in children (48; 08). With response rates as high as 72% (after accounting for dropouts due to factors such as cost) (03), the American Academy of Sleep Medicine has concluded that modafinil might be an effective therapy for idiopathic hypersomnia (77), providing the recommendation of “option” based on an open-label clinical series in 15 patients with idiopathic hypersomnia that demonstrated improvement in symptoms of drowsiness and sleep attacks (16).
In light of variable response rates and intolerance of side effects to first-line monotherapy, a majority of patients with residual symptoms on monotherapy have been shown to respond to combination or alternate therapies (112). In these circumstances, other psychostimulant drugs such as dextroamphetamine and methylphenidate are the mainstays of treatment; however, due to their high potential for abuse and undesirable side effects, these medications are often reserved for second-line therapy, with a preference for long-acting agents (77). For unclear reasons, these medications do not often result in sustained benefits for idiopathic hypersomnia as they do in narcolepsy. This may result in attempts to achieve better clinical response by exceeding recommended maximum guideline dosages. Exceeding standard dosages often precipitates psychosis, headache, substance misuse, tachyarrhythmia, anorexia, or other significant side effects (12). In a small case series, an atypical dosing schedule, which consisted of evening dosing of long-acting methylphenidate and/or bupropion, demonstrated efficacy in combatting one of the more bothersome symptoms in idiopathic hypersomnia: morning sleep inertia (102).
Additional therapies have been employed in treatment-refractory idiopathic hypersomnia patients. Sodium oxybate, an agonist at the γ-hydroxybutyrate and GABAB receptors that promotes slow-wave sleep, was studied in 46 idiopathic hypersomnia patients, revealing a good response in 65% of the 39 patients that chose to fill the prescription (59). The antibiotic clarithromycin may be a negative allosteric inhibitor of the GABAA receptor, which prompted study of its effects in a retrospective chart review and small clinical trial, both of which showed modest benefits (116; 115). Similarly, the benzodiazepine receptor antagonist, flumazenil, was studied by the same group, with minor benefits in psychomotor vigilance task measures and subjective alertness (98). An inverse agonist targeting the autoinhibitory H3 histamine receptor, pitolisant, has been studied in idiopathic hypersomnia and narcolepsy with clinically significant improvements in excessive daytime sleepiness (60; 109). Another potential therapy, the GABAA receptor modulating steroid antagonist (GAMSA) GR3027, began phase 2a clinical trial enrollment of idiopathic hypersomnia patients in 2017. Finally, a trial of transcranial direct current stimulation demonstrated an improvement in sleepiness and attention compared to baseline evaluation (40). Hopefully, further investigations of these and other therapies targeting pathophysiologic mechanisms will result in the discovery of therapies with sustained efficacy for idiopathic hypersomnia.
Even if treated, most patients with idiopathic hypersomnia suffer from psychosocial impairments in their work and personal lives as well as score lower than healthy individuals on assessments of general health (32; 85). Nonetheless, outcomes can be favorable with stimulant medication, and are usually based on patient subjective reports. In a survey of patients from the Hypersomnia Foundation Registry, among 379 idiopathic hypersomnia patients on active therapy, 64.1% still reported excessive daytime sleepiness, 60.2% still required multiple alarms to awaken, and 61.1% had impaired alertness upon waking, and cognitive issues of brain fog and memory impairment persisted in 54.0% and 51.8%, respectively (114). Comparatively, fewer than 15% continued to require excessive sleep durations while on therapy (114). Clinical monitoring of therapeutic response can be performed with the maintenance of wakefulness test (MWT) or actigraphy; however, this is not common unless there is an indication (eg, commercial truck drivers). A few objective tests are employed in research (eg, the sustained attention to response task) (39) and the psychomotor vigilance test (34; 13) and can provide objective outcome measures, though they tend to not correlate with symptom reports/subjective measures (100).
Complications of treatment are medication-specific. In general, the psychostimulants used to treat idiopathic hypersomnia result in side effects through their action on the monoaminergic neurotransmitter systems. Medications that work primarily through reuptake inhibition (eg, modafinil) are generally better tolerated than those that also result in dopamine release or norepinephrine reuptake inhibition at higher doses (eg, amphetamine salts). Postmarketing monitoring revealed a risk for Stevens-Johnson syndrome in modafinil (Cephalon Inc. 2007b), and there is diminished hormonal contraceptive efficacy while taking this medication class (Cephalon Inc. 2007a; Cephalon Inc. 2007b). The traditional psychostimulants (eg, amphetamine salts and methylphenidate) are more sympathomimetic, resulting in a higher risk of toxicity, in addition to the higher risk of abuse (108; 61; 75). Sodium oxybate has a heightened risk of anxiety and depression with suicidal ideation. In addition, it carries a high sodium load, suggesting a need for caution in patients with heart failure or renal insufficiency (49; 83; 95).
No data are available on the effect of pregnancy on idiopathic hypersomnia or of idiopathic hypersomnia on pregnancy. Although FDA pregnancy categories no longer apply, given that all of the medications used to treat idiopathic hypersomnia are psychotropic and have the potential to cause harm to an unborn fetus, most of the relevant medications were previously in category C (ie, amphetamines, methylphenidate, modafinil, and armodafinil).
In patients with idiopathic hypersomnia, stimulant drugs should be discontinued in anticipation of surgery. The effects of anesthesia on idiopathic hypersomnia are unknown.
Logan Schneider MD
Dr. Schneider of Stanford University School of Medicine received a stock grant from Knit Health as an advisor, a stock option from Hatch Baby as an advisor, consulting fees from Harmony Biosciences and Jazz Pharmaceuticals for speakers bureau, and a consulting fee from Alphabet.See Profile
Michael J Howell MD
Dr. Howell of the University of Minnesota has no relevant financial relationships to disclose.See Profile
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