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Diagnostic Algorithm for Hypersomnias
Diagnostic Algorithm for Hypersomnias Y Dauvilliers and V C De Cock, Sleep-Disorders Center, Montpellier, France ã 2013 Elsevier Inc. All rights reserved.
Glossary Chronic hypersomnia: Constant complaint of excessive daytime sleepiness that occurs every day for at least 3 months. Excessive daytime sleepiness: Propensity to fall asleep at inappropriate times, a condition aggravated by rest and improved by sleep.
A complaint of excessive daytime sleepiness (EDS) should be explored by a clinical interview using validated questionnaires and sleep tests to distinguish between fatigue, somnolence, and vigilance impairment in order to diagnose hypersomnia syndromes and to identify their causes.
First Step The first step is to evaluate the phenotype of EDS by using a clinical interview.
Phenotype of EDS A clinical interview on the nighttime sleep quality and duration, the number and duration of daytime naps, and their refreshing characteristics is first required. Patients with EDS typically complain of drowsiness that interferes with daytime activities, unavoidable napping, or both, with a large variability between patients. Sleep episodes can be irresistible, of short duration, and associated with dreaming. The method of awakening and the usual waking schedule should be determined. The age at onset of EDS, the kind of circumstances that existed at its onset, and the factors that led to exacerbation or improvement also need to be reviewed (Figure 1).
Fatigue: Fails to lead to rapid onset of sleep in daytime naps. Fatigue symptoms may be characterized by impairment in concentration and memory, lack of motivation, and impression of low energy, all conditions partially improved by rest. Sleepiness: Propensity to fall asleep; a normal feeling when reaching usual bed time or after prolonged wakefulness.
Other Associated Symptoms The presence of sleep disturbances, such as insomnia, or abnormal movements or behaviors during sleep or during nocturnal awakenings needs to be reviewed systematically. Patients must be asked systematically for the presence of snoring, nocturia, headache, discomfort of the limbs during periods of inactivity and/or repetitive agitation, cataplexy, hypnagogic, or hypnopompic hallucinations, sleep paralysis, and automatic behavior. The daily schedule including the usual bedtime, time to sleep onset, number and timing of awakenings, time of final awakening, with a comparison of the patient’s weekday and weekend schedules is also required. A sleep diary may be helpful to record the regularity of sleep–wake habits. Information regarding environment may also disclose other important contributing factors. Other medical conditions need to be screened, requiring a general physical examination. Patients with neurological, cardiological, rheumatological, and other system-related disorders may note sleepiness and fatigue as a result of the disease process and/or treatment. A psychiatric assessment is also useful. Finally, current and past medication and other substances used need to be considered.
Bed-Partner Interview Severity of EDS The severity of EDS often helps in differentiating the etiology of hypersomnia. In mild sleepiness, a person might fall asleep while reading a book or while sitting quietly. Greater degrees of sleepiness may be associated with bouts of irresistible sleep or sleep attacks that intrude on such activities as driving, having a conversation, or eating meals. This degree of sleepiness may place the patient at significant risk for accidents. Severe sleepiness can also lead to unconscious microsleep episodes or lapses. Patients may note missing an exit on the highway or experiencing a brief delay in performing a task. Sleep questionnaires should be used to quantify the severity of the complaint. The Epworth sleepiness scale (ESS) is the most widely used questionnaire. It measures the average sleep propensity in eight sporadic situations over a recent period of time. A score of >10 confirms the complaint of EDS.
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The bed partner can participate in the evaluation of the severity of the EDS, especially in the context of overreporting and underreporting periods of EDS. The bed partner can also comment on the intensity of snoring, duration, and frequency of apneas, and the presence of nocturnal behaviors.
Second Step The second step is to confirm or exclude the clinical suspicion of hypersomnia through objective measurements.
Polysomnography Followed by a Multiple Sleep Latency Test A polysomnogram (PSG) during the night followed immediately by a multiple sleep latency test (MSLT) is highly
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Diagnosis of Hypersomnias | Diagnostic Algorithm for Hypersomnias
Short and refreshing naps
Presence of sleep deprivation
IH without long sleep time
Long and non-refreshing naps
Absence of sleep deprivation
Absence of cataplexy
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Sleep-disordered breathing
Presence of cataplexy
Non-organic hypersomnia
Substance or druginduced sleepiness
PLMD-RLS
Hypersomnia due to medical condition
IH with long sleep time
Narcolepsy without cataplexy
Hypersomnia and narcolepsy due to medical condition
Narcolepsy with cataplexy
Narcolepsy due to medical condition
Figure 1 Clinical algorithm for chronic hypersomnia. Reproduced from Dauvilliers Y (2009) Diagnostic algorithm for hypersomnias. In: Kushida C (ed.) Handbook of Sleep Disorders, 2nd edn., pp. 277–297. New York: Informa Healthcare.
recommended to assess the daytime sleepiness. The patient is instructed not to fight sleep. The MSLT consists of five nap opportunities, scheduled at 2-h intervals, starting 1.5–3 h after awakening. Psychotropic drugs must be discontinued at least 2 weeks (depending on the half life of the medication) before the recording. Each test is terminated after a 15-min sleep period or after 20 min if the patient does not fall asleep. We measure both sleep and rapid eye movement (REM) sleep latencies. A mean sleep latency below 8 min confirms the EDS. Latencies below 5 min indicate severe sleepiness. It is considered as normal if sleep occurs after 10 min. Between these two values, the interpretation depends on the clinical status of the patient. Several normal subjects without any symptoms of EDS experience low MSLT latencies while others with a clear complaint of EDS do not fall asleep during the MSLT. There is a poor correlation between the ESS and MSLT results, indicating that these two measures explore different components of sleepiness (Figure 2). A sleep-onset REM period (SOREMP) is defined as the occurrence of REM sleep within 15 min after sleep onset, with a higher risk of narcolepsy in the presence of at least two SOREMPs.
PSG Followed by a ‘Maintenance of Wakefulness’ Test An alternative of MSLT is the maintenance of wakefulness test (MWT). It objectively assesses the patient’s ability to maintain wakefulness rather than the drive to fall asleep. The patient is seated comfortably in bed, with low lighting behind. The patient receives the instruction to try to stay awake. During two or four daytime 20- or 40-min sessions depending on the protocol used, the patient is asked to stay awake as long as possible. The test ends after 15 s of any sleep stage, indicating an insufficient ability to fight against sleep. We recommend that the four-trial 40-min protocol with a cut-off of 19 min (limit of the 95% confidence interval) be considered as abnormal. The MWT is mostly used to measure the effectiveness of a treatment especially for research or legal purposes (case of driver’s license suspension). The MWT provides a more
sensitive indicator of the variation of sleepiness and alertness than MSLT. The MSLT seems to measure physiological degrees of sleepiness in relation to the sleep drive while MWT measures alertness in relation to the wake drive.
Twenty-Four-Hour Continuous PSG In rare circumstances, a 24-h continuous PSG is necessary to assess the degree of sleepiness, especially in the condition of idiopathic hypersomnia (IH) with long sleep time. In this condition, the MSLT latency is longer than in narcolepsy, sometimes in the normal range and sometimes questionable. Hence, it may be difficult to wake the patient up in preparation for the test or keep the patient awake between naps; second and of more concern, waking up the patient in the morning in view of the first MSLT session precludes documenting the abnormally prolonged night sleep, which is of major diagnostic value.
Third Step Mostly used in research, the following tests are sometimes used for the final diagnosis in the context of chronic hypersomnia.
Cerebrospinal Fluid Hypocretin-1 Measurement Cerebrospinal fluid (CSF) hypocretin-1 levels lower than 110 pg ml 1 or one-third of mean normal control values are alternatively proposed as highly specific (99%) and sensitive (87–89%) for narcolepsy cases with clear-cut cataplexy and highly specific (99%) but not sensitive (16%) for cases with mild atypical or absent cataplexy, and for cases with familial or HLA-negative narcolepsy. The measurement of CSF hypocretin-1 is clinically indicated in the five following conditions: (1) The MSLT results are equivocal (e.g., a long mean sleep latency or one SOREMP only); (2) Patients presented severe or complex psychiatric, neurological, or medical disorders that may compromise the
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Diagnosis of Hypersomnias | Diagnostic Algorithm for Hypersomnias
MSLT £ 8 minutes
MSLT > 8 minutes
³ 2 SOREMPs
<2 SOREMPs
Idiopathic hypersomnia with or without long sleep time
Sleep disordered breathing
Narcolepsy without cataplexy
Idipathic hypersomnia with long sleep time
Hypersomnia due to medical condition
Insufficient sleep syndrome
Rarely: insufficient sleep syndrome sleep-disordered breathing
Non organic hypersomnia
Narcolepsy with cataplexy
Sleep disordered breathing
Narcolepsy due to medical condition
PLMD
PLMD
Figure 2 Multiple sleep latency test (MSLT) for chronic hypersomnia. MSLT, multiple sleep latency test; SOREMPs, sleep-onset REM periods; PLMD, periodic limb movement disorder. Reproduced from Dauvilliers Y (2009) Diagnostic algorithm for hypersomnias. In: Kushida C (ed.) Handbook of Sleep Disorders, 2nd edn., pp. 277–297. New York: Informa Healthcare.
validity of the clinical interview; (3) Patients taking psychotropic medications (e.g., anticataplectics or stimulants) without the possibility of stopping these medications; (4) Children being too young (<6–8 years of age) to follow MSLT instructions, but there are some limitations due to ethical issues; and (5) Individuals (e.g., without insurance coverage) who cannot afford polysomnographic testing.
HLA Typing The presence of HLA DQB1*0602 genotype is only a supportive criterion for the diagnosis of narcolepsy with cataplexy. The presence of the HLA DRB1*1501-DQB1*0602 alleles is found in 80–95% of the caucasian narcoleptics with cataplexy and only in 20% of the general population. It is no longer in the inclusion criteria for narcolepsy in the revised classification of sleep disorders.
Diagnostic Criteria for Hypersomnia Disorders Narcolepsy with Cataplexy Clinical features Daytime sleepiness In a majority of patients with narcolepsy, EDS is the first symptom to appear, occurring mainly in childhood or young adulthood. It is also the most severe symptom and the most frequent cause for consultation. The sleep episodes have several characteristics: (1) often irresistible, despite the subject making desperate attempts to fight sleepiness; (2) usually of short duration, depending on environmental factors; (3) frequently associated with dreaming; (4) restoring normal vigilance for one to several hours. The refreshing value of short naps is of significant diagnostic value, except in children who are frequently tired upon awakening.
Cataplexy Other Tests Performance tests including the psychomotor vigilance test and driving stimulation tasks can be used to assess alertness and the neurocognitive impairment that results from the EDS. Cognitive evoked potential recordings may be performed in particular cases to evaluate sleep inertia upon awakenings. Finally, brain computed tomography (CT scan) or magnetic resonance imaging (MRI) should be performed in cases of clinical suspicion of a hypersomnia associated with a neurological condition.
A history of sudden muscle weakness with buckling of the knees, laxity of the neck or jaw muscles, or complete loss of muscle tone triggered by laughter, anger, or hearing or telling a joke suggests cataplexy. Cataplexy is specific to narcolepsy and is the best diagnostic marker of the disease. All striated muscles (but not the diaphragm) can be affected leading to a progressive collapse of the subject. Patients remain fully conscious during the episode. The duration of cataplexy varies from a second to several minutes. Cataplexy worsens with poor sleep and fatigue. Patients may also rarely experience ‘status cataplecticus’ with continual cataplectic episodes, lasting several
Diagnosis of Hypersomnias | Diagnostic Algorithm for Hypersomnias
hours and confining the subject to bed. It can occur spontaneously or more often upon withdrawal from anticataplectic/ antidepressant drugs.
Other symptoms Episodes of partial paralysis at the onset or termination of sleep (sleep paralysis) and dreamlike auditory, visual, or tactile hallucinations occurring at sleep onset (hypnagogic) or upon awakenings (hypnopompic) may be reported frequently and with severe intensity in 50% of patients with narcolepsy. However, these symptoms were not specific of narcolepsy, being present in a milder form in 20% of the general population. Several other features may be observed in narcolepsy but with less diagnostic value: (1) A higher body mass index with rapid weight gain at the onset especially in children; (2) Poor sleep at night and parasomnias including sleep talking and REM sleep behavior disorder; and (3) Depression. Familial component: up to 2–5% of narcolepsy cases are familial with several relatives affected with narcolepsy and cataplexy.
Laboratory features PSG plus MSLT The diagnosis of narcolepsy with cataplexy is essentially clinical, but requires whenever possible a nocturnal PSG recording followed by MSLT. The aim of the nighttime PSG is to eliminate other causes of daytime sleepiness and to assess for the presence of sufficient sleep (>6 h) before the MSLT. Nighttime PSG may show a shortened REM sleep latency (less than 15 min) in 40% of cases, a fragmentation in REM sleep with imperfect loss of muscle tone. The MSLT should document a mean sleep onset latency equal or less than eight minutes and two or more SOREMPs. This latter criterion may however be absent in young children and elderly patients with clear-cut cataplexy.
CSF hypocretin-1 measurement CSF hypocretin-1 levels lower than 110 pg ml 1 or one-third of mean normal control values are alternatively proposed as a highly specific (and definite) but moderately sensitive criteria.
HLA typing The presence of the human leukocyte antigen (HLA) DQB1*1501-DQB1*0602 alleles, found in 80–95% of patients but in 20% of the general population, is only a supportive criterion.
Narcolepsy Without Cataplexy
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Laboratory features PSG plus MSLT PSG plus MSLT are required to ascertain the diagnosis of narcolepsy without cataplexy reporting the presence of a mean sleep onset latency of 8 min and two or more SOREMPs. The association with HLA DQB1*0602 is weaker and the decrease in CSF hypocretin-1 level is less frequently encountered (10–20%).
Narcolepsy Due to Medical Condition Rare cases of secondary narcolepsy have been reported in patients with brain lesions located in the posterior hypothalamus, the mesencephalon, and the pons, caused by tumors, multiple sclerosis, encephalitis, cerebral ischemia, head trauma, and neurodegeneration. Symptomatic narcolepsy without cataplexy can be observed in muscular dystrophy type 1, rarely in Parkinson’s disease and multiple system atrophy, and in young children suffering from Niemann–Pick disease type C. In absence of cataplexy, the diagnosis of narcolepsy must be confirmed by a PSG followed by MSLT reporting the presence of a mean daytime sleep latency of less than or equal to eight minutes and two or more SOREMPs. Finally, the determination of hypocretin-1 levels in the CSF represents a sufficient alternative criterion for the diagnosis.
IH with Long Sleep Time IH is a rare condition of EDS approximately ten times less frequent than narcolepsy. IH remains a relatively poorly defined condition due to the absence of specific symptoms. The age at onset varies from childhood to young adulthood. There is a slight female predominance. Family cases existed in 20–30% of cases.
Clinical features Nighttime and daytime sleepiness IH with long sleep time is characterized by three major symptoms: (1) Constant daily EDS with unwanted naps, longer (more than 1 h) and less irresistible than in narcolepsy, and nonrefreshing irrespective of their duration; (2) Uninterrupted and prolonged sleep at night with more than 10 h of sleep (frequently above 12 h during holidays and weekends); and (3) Laborious awakening after nighttime or daytime sleep, frequently with difficulty in reacting adequately to external stimuli upon awakening for up to 3 h, a state referred to as ‘sleep drunkenness’ or ‘sleep inertia.’ Episodes of automatic behavior can occur during this drowsy state, especially in the morning.
Clinical features Narcolepsy without cataplexy has been described as a phenotypic variant of narcolepsy with cataplexy, but is now individualized as a diagnostic entity in the new International Classification of Sleep Disorders, 2nd edn (ICSD-2). Apart from cataplexy, the clinical diagnostic criteria are similar to that of narcolepsy with cataplexy. The prevalence of narcolepsy without cataplexy when compared with narcolepsy with cataplexy is still subject to debate, initially considered as a ratio from 2–3 to 10, respectively, with recent data suggesting a larger frequency.
Other symptoms Although cataplexy needs to be absent, sleep paralysis and hypnagogic or hypnopompic hallucinations may be present.
Laboratory features Both polysomnography and MSLT are required to assess objective EDS, to ascertain the diagnosis, and to rule out some other causes of hypersomnia, especially narcolepsy, periodic limb movement (PLM) disorder, and sleep apnea
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syndrome. PSG demonstrates normal sleep, except for its prolonged duration. Sleep efficiency is above 90%, nonrapid eye movement (NREM) sleep and REM sleep in normal proportions, micro-arousal, sleep apnea/hypopnea, and PLM indexes are less than 10 h 1. MSLT may show a mean sleep latency of less than 8 min with less than two SOREMPs. However, MSLT latency is mostly longer than in narcolepsy. It is more relevant to perform a 24-h continuous PSG on an ad libitum sleep–wake protocol in order to document a major sleep episode at night (more than 10 h) and a daytime sleep episode (at least one nap of more than 1h), but the procedure still awaits standardization and validation. Cognitive evoked potential recording could also be performed in order to evaluate sleep inertia upon awakenings. Brain CT scan or MRI may be required to exclude the possibility of hypersomnia associated with a neurological disorder. HLA typing and/or CSF hypocretin-1 levels are of no help in the positive diagnosis of IH.
months, during which normal sleep patterns are observed. The evolution throughout life is favorable in most cases, with a progressive disappearance of symptoms after 5–10 years’ duration. The best-characterized recurrent hypersomnia is Kleine– Levin syndrome (KLS), a rare disorder defined by constant hypersomnia and cognitive (feeling of unreality and confusion) and behavioral disturbances with overeating and, less frequently, hypersexuality during symptomatic episodes. Kleine–Levin cases are more frequent in men. Recurrent hypersomnia may also be in relation to menstruation; in this case, it is referred to as ‘menstrual-related hypersomnia.’ This condition generally occurs within the first months after menarche. Oral contraceptives are frequently effective for treatment and may also help in the positive diagnosis assessment. Diagnosis is mainly clinical. To confirm hypersomnia and to exclude epilepsy and organic pathology, electroencephalographic and PSG recordings, and structural and functional cerebral imaging are required.
IH Without Long Sleep Time
Behaviorally Induced Insufficient Sleep Syndrome
The age at onset, gender effect and familial component are similar to those found in IH without long sleep time. The prevalence of this condition is unknown.
As sleep deprivation is common in our society, patients with complaints of EDS should always be asked about their schedule during the week and during the weekends. Insufficient sleep is the most frequent cause of EDS. Behaviorally induced insufficient sleep syndrome is a disorder that occurs in individuals who fail to obtain sufficient nocturnal sleep. Patients have difficulty in waking in the morning, sometimes experience sleep drunkenness-like episodes, and complain about EDS. Symptoms disappear on weekends and during the holidays. Children may exhibit hyperactivity rather than sleepiness. The diagnosis is established during the clinical interview, utilizing a sleep diary and or actigraphy.
Clinical features IH without long sleep time remains poorly defined clinically due to the absence of specific symptoms such as cataplexy or sleep apnea. IH without long sleep time is characterized by isolated EDS. Daytime sleep episodes may be more irresistible and more refreshing than in IH with long sleep time, establishing a bridge with narcolepsy without cataplexy. Nocturnal sleep is normal, rarely prolonged (more than 6 h but less than 10 h), and mostly refreshing. ‘Sleep inertia’ is rarely reported. Cataplexy is always absent. Sleep paralysis and hypnagogic or hypnopompic hallucinations are rare. Mood changes are also frequently reported as they are IH with long sleep time.
Laboratory features Both PSG and MSLT are necessary to assess objective EDS and to ascertain the diagnosis. Nighttime PSG results are the same as those observed for IH with long sleep time. However, MSLT must demonstrate a mean sleep latency of less than 8 min with less than two SOREMPs. A 24-h continuous PSG recording on an ad libitum sleep– wake protocol and cognitive evoked potential recordings are not relevant for this condition. As in IH with long sleep time, HLA typing and/or CSF hypocretin-1 levels are of no help. Finally, neurological and psychological evaluations, brain CT scan, and/or MRI could be of interest to rule out differential diagnoses.
Recurrent Hypersomnia Recurrent hypersomnia is an exceptional condition primarily affecting teenagers and characterized by recurrent episodes of excessive sleep (at least 16 h per day) lasting from a few days to several weeks. The episodes are typically separated by weeks or
Hypersomnia Due to a Medical Condition Hypersomnia associated with neurological disorders Brain tumors or stroke provoking lesion or dysfunction in the thalamus, hypothalamus, or brainstem can cause hypersomnia that may mimic clinical symptoms of IH with long sleep time but with frequent alterations in sleep continuity. Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, or multiple system atrophy and also genetic disorders (Niemann–Pick C, Prader Willi syndrome, Myotonic dystrophy) are sometimes associated with hypersomnia. Although intrinsic hypersomnia exists in those neurological disorders, other etiologies of hypersomnia such as sleep apnea syndromes, drugs, and periodic leg movements need first to be excluded. Posttraumatic hypersomnia is another etiology of chronic hypersomnia, occurring mainly in head trauma with initial coma. Posttraumatic hypersomnia occurs 6–18 months after the trauma; however, insomnia is the most frequent sleep symptom within this condition.
Hypersomnia associated with infectious disorders Hypersomnia following a viral infection such as mononucleosis, Guillain Barre´ syndrome, pneumonia, hepatitis, or Whipple’s
Diagnosis of Hypersomnias | Diagnostic Algorithm for Hypersomnias
disease may rarely mimic clinical symptoms of IH with long sleep time several months after the acute infection. Human African trypanosomiasis (HAT), ‘sleep sickness,’ which is due to the transmission of trypanosomes by tsetse flies, is a frequent cause of severe hypersomnia in Western and Eastern Africa. After an extensive immune reaction during the initial stage, severe sleep and wakefulness impairment follows. The possibility of HAT needs to be assessed in travelers and individuals migrating from Africa.
Hypersomnia associated with metabolic or endocrine disorders Hypersomnia in diabetes, hepatic encephalopathy, hypothyroidism, and acromegaly are rarely reported. Sleep-related breathing and periodic leg movement disorders, frequently associated with these conditions, may also explain the relative frequency of such hypersomnias.
Hypersomnia Due to Drug or Substance Patients affected with medical disorders may report sleepiness, but also fatigue as a result of treatment for their disorders. Numerous medications are potentially responsible for EDS including hypnotic, anxiolytic, antidepressant, neuroleptic, antihistaminic, antiepileptic (except for lamotrigine), and antiParkinsonian drugs. However, the relationship between the current use of drugs and the complaint of EDS is not always easy to ascertain. Dosing of drugs, drug–drug interactions, liver or renal impairments, and individual susceptibility may explain the large variability in the EDS phenotype. Several substances including alcohol yield sedative effects, which also depend on the dosage and individual susceptibility. Diagnosis is mainly clinical; blood or urine drug screens may be necessary in particular cases.
Hypersomnia Not Due to a Substance or Known Physiological Condition This entity, also named ‘nonorganic hypersomnia,’ refers to several causes of hypersomnia including depressive disorders, seasonal affective disorder (SAD), abnormal personality traits, and conversion episodes. Most of the patients affected with psychiatric disorders suffer from insomnia; however, some (mainly with atypical depression) may also present with a complaint of EDS. The complaint of EDS may be rather similar to that of patients with IH with long sleep time, except that it may vary from day to day and is often associated with poor and fragmented sleep at night. Hypersomnia associated with SAD is considered a clinical subtype of nonorganic hypersomnia. Patients with winter depression report hypersomnia, fatigue, loss of energy, craving for carbohydrates, change in appetite, and weight gain. Light therapy for 14 days in the morning, effective in this condition, may help in the positive diagnosis assessment. PSG studies in hypersomnia with mood disorders are rare and show a long time in bed without sleep, which leads to a low sleep efficiency. The MSLT does not demonstrate a short mean sleep latency and REM sleep is totally absent during daytime naps in depressed patients. Finally, a 24-h continuous
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PSG reveals a low total sleep time and a low percentage of slow wave sleep. A diagnosis of fatigue appears more likely in this condition.
Hypersomnias of Noncentral Origins Sleep-related breathing disorders are the most frequent pathology associated with EDS. Questioning and evaluating patients who complain of sleepiness for associated symptoms and signs such as loud snoring, obesity, headaches, hypertension, fatigue in the morning, nocturia, reduced libido, and witnessed episodes of apnea provide essential clinical information for this diagnosis. Sleep-related movement disorders include several conditions such as restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). Nocturnal sleep disturbances and/or complaints of EDS can be reported in these conditions; however, the relationship between PLMD and EDS is still a subject of debate. Circadian rhythm sleep disruption may lead to insomnia or EDS, or both. A sleep diary may be helpful to assess the regulatory of sleep–wake schedule.
Conclusion EDS is a common complaint in modern societies. Drowsiness and naps may be limited to sedentary situations; however, EDS may lead to impaired performance, accidents at work or while driving. Clinicians should always question their patients with a complaint of EDS for potentially insufficient sleep, insomnia, medical or psychiatric conditions, and drug use. Physicians have several methods to distinguish sleepiness from fatigue, to affirm the existence of daytime somnolence, and to appropriately diagnose the different causes of hypersomnia. Some progress has been made in the identification of the different phenotypes of chronic hypersomnia; however there is still a definite need to further develop sleep laboratory investigations to assess the correct diagnosis of insufficiently recognized and poorly defined etiologies of hypersomnia. Lastly, studies at the genetic, biological, and pharmacological levels are also needed to further our understanding of the pathophysiology of chronic hypersomnia and to develop specific treatments in the future.
See also: Diagnosis of Hypersomnias: Diagnosis of Hypersomnia in Children: Screening and Case Finding; Diagnostic Tools for Hypersomnias.
Further Reading Arand D, Bonnet M, Hurwitz T, et al. (2005) The clinical use of the MSLT and MWT. Sleep 28(1): 123–144. Arnulf I, Konofal E, Merino-Andreu M, et al. (2002) Parkinson’s disease and sleepiness: An integral part of PD. Neurology 58: 1019–1024. Arnulf I, Zeitzer JM, File J, et al. (2005) Kleine–Levin syndrome: A systematic review of 186 cases in the literature. Brain 128: 2763–2776. Bassetti C and Aldrich MS (1997) Idiopathic hypersomnia: A series of 42 patients. Brain 120: 1423–1435.
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Diagnosis of Hypersomnias | Diagnostic Algorithm for Hypersomnias
Benbadis SR, Mascha E, Perry MC, et al. (1999) Association between the Epworth sleepiness scale and the multiple sleep latency test in a clinical population. Annals of Internal Medicine 130(4 pt 1): 289–292. Billiard M and Dauvilliers Y (2001) Idiopathic hypersomnia. Sleep Medicine Reviews 5: 349–358. Billiard M, Dolenc L, Aldaz C, et al. (1994) Hypersomnia associated with mood disorders: A new perspective. Journal of Psychosomatic Research 38: 41–47. Billiard M, Guilleminault C, and Dement WC (1975) A menstruation-linked periodic hypersomnia. Kleine–Levin syndrome or new clinical entity? Neurology 25: 436–443. Carskadon MA and Dement WC (1981) Cumulative effects of sleep restriction on daytime sleepiness. Psychophysiology 18(3): 107–113. Carskadon MA, Mitler MM, and Roth T (1986) Guidelines for the multiple sleep latency test (MSLT): A standard measure of sleepiness. Sleep 9: 519–524. Dauvilliers Y (2009a) Diagnostic algorithm for hypersomnias. In: Kushida C (ed.) Handbook of Sleep Disorders, 2nd edn., pp. 277–297. New York: Informa Healthcare. Dauvilliers Y, Arnulf I, and Mignot E (2007) Narcolepsy with cataplexy. Lancet 369: 499–511. Dauvilliers Y, Baumann CR, Carlander B, et al. (2003) CSF hypocretin-1 levels in narcolepsy, Kleine–Levin syndrome, and other hypersomnias and neurological conditions. Journal of Neurology, Neurosurgery, and Psychiatry 74: 1667–1673. Dauvilliers Y, Gosselin A, Paquet J, et al. (2004) Effect of age on MSLT results in patients with narcolepsy–cataplexy. Neurology 62: 46–50. Dauvilliers Y, Mayer G, Lecendreux M, et al. (2002) Kleine–Levin syndrome: An autoimmune hypothesis based on clinical and genetic analyses. Neurology 59: 1739–1745. Dauvilliers Y, Montplaisir J, Molinari N, et al. (2001) Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 57: 2029–2033. Doghramji K, Mitler MM, Sangal RB, et al. (1997) A normative study of the maintenance of wakefulness test (MWT). Electroencephalography and Clinical Neurophysiology 103: 554–562. Guilleminault C and Brooks SN (2001) Excessive daytime sleepiness: A challenge for the practicing neurologist. Brain 124: 1482–1491. Guilleminault C and Mondini S (1986) Mononucleosis and chronic daytime sleepiness: A long-term follow-up study. Archives of Internal Medicine 146(7): 1333–1335. Guilleminault C, Quera-Salva MA, and Goldberg MP (1993) Pseudo-hypersomnia and pre-sleep behaviour with bilateral paramedian thalamic lesions. Brain 116: 1549–1563. Guilleminault C, Yuen KM, Gulevich MG, et al. (2000) Hypersomnia after head-neck trauma: A methodological dilemma. Neurology 54: 653–659. Hening WA (2004) Subjective and objective criteria in the diagnosis of the restless legs syndrome. Sleep Medicine 5: 285–292. Johns MW (1991) A new method for measuring daytime sleepiness: The Epworth sleepiness scale. Sleep 14: 540–545. Masel BE, Scheibel RS, Kimbark T, et al. (2001) Excessive daytime sleepiness in adults with brain injuries. Archives of Physical Medicine and Rehabilitation 82(11): 1526–1532.
Mignot E, Lammers GJ, Ripley B, et al. (2002) The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Archives of Neurology 59: 1553–1562. Mignot E, Lin L, Finn L, et al. (2006) Correlates of sleep-onset REM periods during the multiple sleep latency test in community adults. Brain 129: 1609–1623. Nicolas A, Lesperance P, and Montplaisir J (1998) Is excessive daytime sleepiness with periodic leg movements during sleep a specific diagnostic category? European Neurology 40: 22–26. Nofzinger EA, Thase ME, Reynolds CF, et al. (1991) Hypersomnia in bipolar depression: A comparison with narcolepsy using the multiple sleep latency test. The American Journal of Psychiatry 148: 1177–1181. Ohayon MM (2000) Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Research 97: 153–164. Overeem S, Mignot E, van Dijk JG, et al. (2001) Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. Journal of Clinical Neurophysiology 18: 78–105. Poryazova R, Siccoli M, Werth E, et al. (2005) Unusually prolonged rebound cataplexy after withdrawal of fluoxetine. Neurology 65: 967–968. Rosenthal NE, Sack DA, Gillin JC, et al. (1984) Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Archives of General Psychiatry 41: 72–80. Sangal RB and Sangal JM (1997) Measurement of P300 and sleep characteristics in patients with hypersomnia: Do P300 latencies, P300 amplitudes, and multiple sleep latency and maintenance of wakefulness tests measure different factors? Clinical Electroencephalography 28: 179–184. Sangal RB, Thomas L, and Mitler MM (1992) Maintenance of wakefulness test and multiple sleep latency test: Measurement of different abilities in patients with sleep disorders. Chest 101: 898–902. Silber M (2006) The investigation of sleepiness. In: Guilleminault C (ed.) Excessive Sleepiness: Sleep Medicine Clinics, vol. 1, pp. 1–7. Philadelphia: W.B. Saunders (1). Vgontzas AN, Bixler EO, Kales A, et al. (2000) Differences in nocturnal and daytime sleep between primary and psychiatric hypersomnia: Diagnostic and treatment implications. Psychosomatic Medicine 62: 220–226. Voderholzer U, Riemann D, Gann H, et al. (2002) Transient total sleep loss in cerebral Whipple’s disease: A longitudinal study. Journal of Sleep Research 11: 321–329. Wagner DR (1996) Disorders of the circadian sleep–wake cycle. Neurologic Clinics 14: 651–670. Young T, Palta M, Dempsey J, et al. (1993) The occurrence of sleep-disordered breathing among middle-aged adults. The New England Journal of Medicine 328: 1230–1235.
Relevant Websites http://www3.unil.ch/wpmu/eunn/links/ – European Narcolepsy Network. http://www.montp.inserm.fr/u1061/SiteU1061/cnrnh/web/narcolepsie.html – Centre National de Reference Narcolepsie et Hypersomnie.
Glossary Chronic hypersomnia: Constant complaint of excessive daytime sleepiness that occurs every day for at least 3 months. Excessive daytime sleepiness: Propensity to fall asleep at inappropriate times, a condition aggravated by rest and improved by sleep.
A complaint of excessive daytime sleepiness (EDS) should be explored by a clinical interview using validated questionnaires and sleep tests to distinguish between fatigue, somnolence, and vigilance impairment in order to diagnose hypersomnia syndromes and to identify their causes.
First Step The first step is to evaluate the phenotype of EDS by using a clinical interview.
Phenotype of EDS A clinical interview on the nighttime sleep quality and duration, the number and duration of daytime naps, and their refreshing characteristics is first required. Patients with EDS typically complain of drowsiness that interferes with daytime activities, unavoidable napping, or both, with a large variability between patients. Sleep episodes can be irresistible, of short duration, and associated with dreaming. The method of awakening and the usual waking schedule should be determined. The age at onset of EDS, the kind of circumstances that existed at its onset, and the factors that led to exacerbation or improvement also need to be reviewed (Figure 1).
Fatigue: Fails to lead to rapid onset of sleep in daytime naps. Fatigue symptoms may be characterized by impairment in concentration and memory, lack of motivation, and impression of low energy, all conditions partially improved by rest. Sleepiness: Propensity to fall asleep; a normal feeling when reaching usual bed time or after prolonged wakefulness.
Other Associated Symptoms The presence of sleep disturbances, such as insomnia, or abnormal movements or behaviors during sleep or during nocturnal awakenings needs to be reviewed systematically. Patients must be asked systematically for the presence of snoring, nocturia, headache, discomfort of the limbs during periods of inactivity and/or repetitive agitation, cataplexy, hypnagogic, or hypnopompic hallucinations, sleep paralysis, and automatic behavior. The daily schedule including the usual bedtime, time to sleep onset, number and timing of awakenings, time of final awakening, with a comparison of the patient’s weekday and weekend schedules is also required. A sleep diary may be helpful to record the regularity of sleep–wake habits. Information regarding environment may also disclose other important contributing factors. Other medical conditions need to be screened, requiring a general physical examination. Patients with neurological, cardiological, rheumatological, and other system-related disorders may note sleepiness and fatigue as a result of the disease process and/or treatment. A psychiatric assessment is also useful. Finally, current and past medication and other substances used need to be considered.
Bed-Partner Interview Severity of EDS The severity of EDS often helps in differentiating the etiology of hypersomnia. In mild sleepiness, a person might fall asleep while reading a book or while sitting quietly. Greater degrees of sleepiness may be associated with bouts of irresistible sleep or sleep attacks that intrude on such activities as driving, having a conversation, or eating meals. This degree of sleepiness may place the patient at significant risk for accidents. Severe sleepiness can also lead to unconscious microsleep episodes or lapses. Patients may note missing an exit on the highway or experiencing a brief delay in performing a task. Sleep questionnaires should be used to quantify the severity of the complaint. The Epworth sleepiness scale (ESS) is the most widely used questionnaire. It measures the average sleep propensity in eight sporadic situations over a recent period of time. A score of >10 confirms the complaint of EDS.
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The bed partner can participate in the evaluation of the severity of the EDS, especially in the context of overreporting and underreporting periods of EDS. The bed partner can also comment on the intensity of snoring, duration, and frequency of apneas, and the presence of nocturnal behaviors.
Second Step The second step is to confirm or exclude the clinical suspicion of hypersomnia through objective measurements.
Polysomnography Followed by a Multiple Sleep Latency Test A polysomnogram (PSG) during the night followed immediately by a multiple sleep latency test (MSLT) is highly
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Diagnosis of Hypersomnias | Diagnostic Algorithm for Hypersomnias
Short and refreshing naps
Presence of sleep deprivation
IH without long sleep time
Long and non-refreshing naps
Absence of sleep deprivation
Absence of cataplexy
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Sleep-disordered breathing
Presence of cataplexy
Non-organic hypersomnia
Substance or druginduced sleepiness
PLMD-RLS
Hypersomnia due to medical condition
IH with long sleep time
Narcolepsy without cataplexy
Hypersomnia and narcolepsy due to medical condition
Narcolepsy with cataplexy
Narcolepsy due to medical condition
Figure 1 Clinical algorithm for chronic hypersomnia. Reproduced from Dauvilliers Y (2009) Diagnostic algorithm for hypersomnias. In: Kushida C (ed.) Handbook of Sleep Disorders, 2nd edn., pp. 277–297. New York: Informa Healthcare.
recommended to assess the daytime sleepiness. The patient is instructed not to fight sleep. The MSLT consists of five nap opportunities, scheduled at 2-h intervals, starting 1.5–3 h after awakening. Psychotropic drugs must be discontinued at least 2 weeks (depending on the half life of the medication) before the recording. Each test is terminated after a 15-min sleep period or after 20 min if the patient does not fall asleep. We measure both sleep and rapid eye movement (REM) sleep latencies. A mean sleep latency below 8 min confirms the EDS. Latencies below 5 min indicate severe sleepiness. It is considered as normal if sleep occurs after 10 min. Between these two values, the interpretation depends on the clinical status of the patient. Several normal subjects without any symptoms of EDS experience low MSLT latencies while others with a clear complaint of EDS do not fall asleep during the MSLT. There is a poor correlation between the ESS and MSLT results, indicating that these two measures explore different components of sleepiness (Figure 2). A sleep-onset REM period (SOREMP) is defined as the occurrence of REM sleep within 15 min after sleep onset, with a higher risk of narcolepsy in the presence of at least two SOREMPs.
PSG Followed by a ‘Maintenance of Wakefulness’ Test An alternative of MSLT is the maintenance of wakefulness test (MWT). It objectively assesses the patient’s ability to maintain wakefulness rather than the drive to fall asleep. The patient is seated comfortably in bed, with low lighting behind. The patient receives the instruction to try to stay awake. During two or four daytime 20- or 40-min sessions depending on the protocol used, the patient is asked to stay awake as long as possible. The test ends after 15 s of any sleep stage, indicating an insufficient ability to fight against sleep. We recommend that the four-trial 40-min protocol with a cut-off of 19 min (limit of the 95% confidence interval) be considered as abnormal. The MWT is mostly used to measure the effectiveness of a treatment especially for research or legal purposes (case of driver’s license suspension). The MWT provides a more
sensitive indicator of the variation of sleepiness and alertness than MSLT. The MSLT seems to measure physiological degrees of sleepiness in relation to the sleep drive while MWT measures alertness in relation to the wake drive.
Twenty-Four-Hour Continuous PSG In rare circumstances, a 24-h continuous PSG is necessary to assess the degree of sleepiness, especially in the condition of idiopathic hypersomnia (IH) with long sleep time. In this condition, the MSLT latency is longer than in narcolepsy, sometimes in the normal range and sometimes questionable. Hence, it may be difficult to wake the patient up in preparation for the test or keep the patient awake between naps; second and of more concern, waking up the patient in the morning in view of the first MSLT session precludes documenting the abnormally prolonged night sleep, which is of major diagnostic value.
Third Step Mostly used in research, the following tests are sometimes used for the final diagnosis in the context of chronic hypersomnia.
Cerebrospinal Fluid Hypocretin-1 Measurement Cerebrospinal fluid (CSF) hypocretin-1 levels lower than 110 pg ml 1 or one-third of mean normal control values are alternatively proposed as highly specific (99%) and sensitive (87–89%) for narcolepsy cases with clear-cut cataplexy and highly specific (99%) but not sensitive (16%) for cases with mild atypical or absent cataplexy, and for cases with familial or HLA-negative narcolepsy. The measurement of CSF hypocretin-1 is clinically indicated in the five following conditions: (1) The MSLT results are equivocal (e.g., a long mean sleep latency or one SOREMP only); (2) Patients presented severe or complex psychiatric, neurological, or medical disorders that may compromise the
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MSLT £ 8 minutes
MSLT > 8 minutes
³ 2 SOREMPs
<2 SOREMPs
Idiopathic hypersomnia with or without long sleep time
Sleep disordered breathing
Narcolepsy without cataplexy
Idipathic hypersomnia with long sleep time
Hypersomnia due to medical condition
Insufficient sleep syndrome
Rarely: insufficient sleep syndrome sleep-disordered breathing
Non organic hypersomnia
Narcolepsy with cataplexy
Sleep disordered breathing
Narcolepsy due to medical condition
PLMD
PLMD
Figure 2 Multiple sleep latency test (MSLT) for chronic hypersomnia. MSLT, multiple sleep latency test; SOREMPs, sleep-onset REM periods; PLMD, periodic limb movement disorder. Reproduced from Dauvilliers Y (2009) Diagnostic algorithm for hypersomnias. In: Kushida C (ed.) Handbook of Sleep Disorders, 2nd edn., pp. 277–297. New York: Informa Healthcare.
validity of the clinical interview; (3) Patients taking psychotropic medications (e.g., anticataplectics or stimulants) without the possibility of stopping these medications; (4) Children being too young (<6–8 years of age) to follow MSLT instructions, but there are some limitations due to ethical issues; and (5) Individuals (e.g., without insurance coverage) who cannot afford polysomnographic testing.
HLA Typing The presence of HLA DQB1*0602 genotype is only a supportive criterion for the diagnosis of narcolepsy with cataplexy. The presence of the HLA DRB1*1501-DQB1*0602 alleles is found in 80–95% of the caucasian narcoleptics with cataplexy and only in 20% of the general population. It is no longer in the inclusion criteria for narcolepsy in the revised classification of sleep disorders.
Diagnostic Criteria for Hypersomnia Disorders Narcolepsy with Cataplexy Clinical features Daytime sleepiness In a majority of patients with narcolepsy, EDS is the first symptom to appear, occurring mainly in childhood or young adulthood. It is also the most severe symptom and the most frequent cause for consultation. The sleep episodes have several characteristics: (1) often irresistible, despite the subject making desperate attempts to fight sleepiness; (2) usually of short duration, depending on environmental factors; (3) frequently associated with dreaming; (4) restoring normal vigilance for one to several hours. The refreshing value of short naps is of significant diagnostic value, except in children who are frequently tired upon awakening.
Cataplexy Other Tests Performance tests including the psychomotor vigilance test and driving stimulation tasks can be used to assess alertness and the neurocognitive impairment that results from the EDS. Cognitive evoked potential recordings may be performed in particular cases to evaluate sleep inertia upon awakenings. Finally, brain computed tomography (CT scan) or magnetic resonance imaging (MRI) should be performed in cases of clinical suspicion of a hypersomnia associated with a neurological condition.
A history of sudden muscle weakness with buckling of the knees, laxity of the neck or jaw muscles, or complete loss of muscle tone triggered by laughter, anger, or hearing or telling a joke suggests cataplexy. Cataplexy is specific to narcolepsy and is the best diagnostic marker of the disease. All striated muscles (but not the diaphragm) can be affected leading to a progressive collapse of the subject. Patients remain fully conscious during the episode. The duration of cataplexy varies from a second to several minutes. Cataplexy worsens with poor sleep and fatigue. Patients may also rarely experience ‘status cataplecticus’ with continual cataplectic episodes, lasting several
Diagnosis of Hypersomnias | Diagnostic Algorithm for Hypersomnias
hours and confining the subject to bed. It can occur spontaneously or more often upon withdrawal from anticataplectic/ antidepressant drugs.
Other symptoms Episodes of partial paralysis at the onset or termination of sleep (sleep paralysis) and dreamlike auditory, visual, or tactile hallucinations occurring at sleep onset (hypnagogic) or upon awakenings (hypnopompic) may be reported frequently and with severe intensity in 50% of patients with narcolepsy. However, these symptoms were not specific of narcolepsy, being present in a milder form in 20% of the general population. Several other features may be observed in narcolepsy but with less diagnostic value: (1) A higher body mass index with rapid weight gain at the onset especially in children; (2) Poor sleep at night and parasomnias including sleep talking and REM sleep behavior disorder; and (3) Depression. Familial component: up to 2–5% of narcolepsy cases are familial with several relatives affected with narcolepsy and cataplexy.
Laboratory features PSG plus MSLT The diagnosis of narcolepsy with cataplexy is essentially clinical, but requires whenever possible a nocturnal PSG recording followed by MSLT. The aim of the nighttime PSG is to eliminate other causes of daytime sleepiness and to assess for the presence of sufficient sleep (>6 h) before the MSLT. Nighttime PSG may show a shortened REM sleep latency (less than 15 min) in 40% of cases, a fragmentation in REM sleep with imperfect loss of muscle tone. The MSLT should document a mean sleep onset latency equal or less than eight minutes and two or more SOREMPs. This latter criterion may however be absent in young children and elderly patients with clear-cut cataplexy.
CSF hypocretin-1 measurement CSF hypocretin-1 levels lower than 110 pg ml 1 or one-third of mean normal control values are alternatively proposed as a highly specific (and definite) but moderately sensitive criteria.
HLA typing The presence of the human leukocyte antigen (HLA) DQB1*1501-DQB1*0602 alleles, found in 80–95% of patients but in 20% of the general population, is only a supportive criterion.
Narcolepsy Without Cataplexy
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Laboratory features PSG plus MSLT PSG plus MSLT are required to ascertain the diagnosis of narcolepsy without cataplexy reporting the presence of a mean sleep onset latency of 8 min and two or more SOREMPs. The association with HLA DQB1*0602 is weaker and the decrease in CSF hypocretin-1 level is less frequently encountered (10–20%).
Narcolepsy Due to Medical Condition Rare cases of secondary narcolepsy have been reported in patients with brain lesions located in the posterior hypothalamus, the mesencephalon, and the pons, caused by tumors, multiple sclerosis, encephalitis, cerebral ischemia, head trauma, and neurodegeneration. Symptomatic narcolepsy without cataplexy can be observed in muscular dystrophy type 1, rarely in Parkinson’s disease and multiple system atrophy, and in young children suffering from Niemann–Pick disease type C. In absence of cataplexy, the diagnosis of narcolepsy must be confirmed by a PSG followed by MSLT reporting the presence of a mean daytime sleep latency of less than or equal to eight minutes and two or more SOREMPs. Finally, the determination of hypocretin-1 levels in the CSF represents a sufficient alternative criterion for the diagnosis.
IH with Long Sleep Time IH is a rare condition of EDS approximately ten times less frequent than narcolepsy. IH remains a relatively poorly defined condition due to the absence of specific symptoms. The age at onset varies from childhood to young adulthood. There is a slight female predominance. Family cases existed in 20–30% of cases.
Clinical features Nighttime and daytime sleepiness IH with long sleep time is characterized by three major symptoms: (1) Constant daily EDS with unwanted naps, longer (more than 1 h) and less irresistible than in narcolepsy, and nonrefreshing irrespective of their duration; (2) Uninterrupted and prolonged sleep at night with more than 10 h of sleep (frequently above 12 h during holidays and weekends); and (3) Laborious awakening after nighttime or daytime sleep, frequently with difficulty in reacting adequately to external stimuli upon awakening for up to 3 h, a state referred to as ‘sleep drunkenness’ or ‘sleep inertia.’ Episodes of automatic behavior can occur during this drowsy state, especially in the morning.
Clinical features Narcolepsy without cataplexy has been described as a phenotypic variant of narcolepsy with cataplexy, but is now individualized as a diagnostic entity in the new International Classification of Sleep Disorders, 2nd edn (ICSD-2). Apart from cataplexy, the clinical diagnostic criteria are similar to that of narcolepsy with cataplexy. The prevalence of narcolepsy without cataplexy when compared with narcolepsy with cataplexy is still subject to debate, initially considered as a ratio from 2–3 to 10, respectively, with recent data suggesting a larger frequency.
Other symptoms Although cataplexy needs to be absent, sleep paralysis and hypnagogic or hypnopompic hallucinations may be present.
Laboratory features Both polysomnography and MSLT are required to assess objective EDS, to ascertain the diagnosis, and to rule out some other causes of hypersomnia, especially narcolepsy, periodic limb movement (PLM) disorder, and sleep apnea
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syndrome. PSG demonstrates normal sleep, except for its prolonged duration. Sleep efficiency is above 90%, nonrapid eye movement (NREM) sleep and REM sleep in normal proportions, micro-arousal, sleep apnea/hypopnea, and PLM indexes are less than 10 h 1. MSLT may show a mean sleep latency of less than 8 min with less than two SOREMPs. However, MSLT latency is mostly longer than in narcolepsy. It is more relevant to perform a 24-h continuous PSG on an ad libitum sleep–wake protocol in order to document a major sleep episode at night (more than 10 h) and a daytime sleep episode (at least one nap of more than 1h), but the procedure still awaits standardization and validation. Cognitive evoked potential recording could also be performed in order to evaluate sleep inertia upon awakenings. Brain CT scan or MRI may be required to exclude the possibility of hypersomnia associated with a neurological disorder. HLA typing and/or CSF hypocretin-1 levels are of no help in the positive diagnosis of IH.
months, during which normal sleep patterns are observed. The evolution throughout life is favorable in most cases, with a progressive disappearance of symptoms after 5–10 years’ duration. The best-characterized recurrent hypersomnia is Kleine– Levin syndrome (KLS), a rare disorder defined by constant hypersomnia and cognitive (feeling of unreality and confusion) and behavioral disturbances with overeating and, less frequently, hypersexuality during symptomatic episodes. Kleine–Levin cases are more frequent in men. Recurrent hypersomnia may also be in relation to menstruation; in this case, it is referred to as ‘menstrual-related hypersomnia.’ This condition generally occurs within the first months after menarche. Oral contraceptives are frequently effective for treatment and may also help in the positive diagnosis assessment. Diagnosis is mainly clinical. To confirm hypersomnia and to exclude epilepsy and organic pathology, electroencephalographic and PSG recordings, and structural and functional cerebral imaging are required.
IH Without Long Sleep Time
Behaviorally Induced Insufficient Sleep Syndrome
The age at onset, gender effect and familial component are similar to those found in IH without long sleep time. The prevalence of this condition is unknown.
As sleep deprivation is common in our society, patients with complaints of EDS should always be asked about their schedule during the week and during the weekends. Insufficient sleep is the most frequent cause of EDS. Behaviorally induced insufficient sleep syndrome is a disorder that occurs in individuals who fail to obtain sufficient nocturnal sleep. Patients have difficulty in waking in the morning, sometimes experience sleep drunkenness-like episodes, and complain about EDS. Symptoms disappear on weekends and during the holidays. Children may exhibit hyperactivity rather than sleepiness. The diagnosis is established during the clinical interview, utilizing a sleep diary and or actigraphy.
Clinical features IH without long sleep time remains poorly defined clinically due to the absence of specific symptoms such as cataplexy or sleep apnea. IH without long sleep time is characterized by isolated EDS. Daytime sleep episodes may be more irresistible and more refreshing than in IH with long sleep time, establishing a bridge with narcolepsy without cataplexy. Nocturnal sleep is normal, rarely prolonged (more than 6 h but less than 10 h), and mostly refreshing. ‘Sleep inertia’ is rarely reported. Cataplexy is always absent. Sleep paralysis and hypnagogic or hypnopompic hallucinations are rare. Mood changes are also frequently reported as they are IH with long sleep time.
Laboratory features Both PSG and MSLT are necessary to assess objective EDS and to ascertain the diagnosis. Nighttime PSG results are the same as those observed for IH with long sleep time. However, MSLT must demonstrate a mean sleep latency of less than 8 min with less than two SOREMPs. A 24-h continuous PSG recording on an ad libitum sleep– wake protocol and cognitive evoked potential recordings are not relevant for this condition. As in IH with long sleep time, HLA typing and/or CSF hypocretin-1 levels are of no help. Finally, neurological and psychological evaluations, brain CT scan, and/or MRI could be of interest to rule out differential diagnoses.
Recurrent Hypersomnia Recurrent hypersomnia is an exceptional condition primarily affecting teenagers and characterized by recurrent episodes of excessive sleep (at least 16 h per day) lasting from a few days to several weeks. The episodes are typically separated by weeks or
Hypersomnia Due to a Medical Condition Hypersomnia associated with neurological disorders Brain tumors or stroke provoking lesion or dysfunction in the thalamus, hypothalamus, or brainstem can cause hypersomnia that may mimic clinical symptoms of IH with long sleep time but with frequent alterations in sleep continuity. Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, or multiple system atrophy and also genetic disorders (Niemann–Pick C, Prader Willi syndrome, Myotonic dystrophy) are sometimes associated with hypersomnia. Although intrinsic hypersomnia exists in those neurological disorders, other etiologies of hypersomnia such as sleep apnea syndromes, drugs, and periodic leg movements need first to be excluded. Posttraumatic hypersomnia is another etiology of chronic hypersomnia, occurring mainly in head trauma with initial coma. Posttraumatic hypersomnia occurs 6–18 months after the trauma; however, insomnia is the most frequent sleep symptom within this condition.
Hypersomnia associated with infectious disorders Hypersomnia following a viral infection such as mononucleosis, Guillain Barre´ syndrome, pneumonia, hepatitis, or Whipple’s
Diagnosis of Hypersomnias | Diagnostic Algorithm for Hypersomnias
disease may rarely mimic clinical symptoms of IH with long sleep time several months after the acute infection. Human African trypanosomiasis (HAT), ‘sleep sickness,’ which is due to the transmission of trypanosomes by tsetse flies, is a frequent cause of severe hypersomnia in Western and Eastern Africa. After an extensive immune reaction during the initial stage, severe sleep and wakefulness impairment follows. The possibility of HAT needs to be assessed in travelers and individuals migrating from Africa.
Hypersomnia associated with metabolic or endocrine disorders Hypersomnia in diabetes, hepatic encephalopathy, hypothyroidism, and acromegaly are rarely reported. Sleep-related breathing and periodic leg movement disorders, frequently associated with these conditions, may also explain the relative frequency of such hypersomnias.
Hypersomnia Due to Drug or Substance Patients affected with medical disorders may report sleepiness, but also fatigue as a result of treatment for their disorders. Numerous medications are potentially responsible for EDS including hypnotic, anxiolytic, antidepressant, neuroleptic, antihistaminic, antiepileptic (except for lamotrigine), and antiParkinsonian drugs. However, the relationship between the current use of drugs and the complaint of EDS is not always easy to ascertain. Dosing of drugs, drug–drug interactions, liver or renal impairments, and individual susceptibility may explain the large variability in the EDS phenotype. Several substances including alcohol yield sedative effects, which also depend on the dosage and individual susceptibility. Diagnosis is mainly clinical; blood or urine drug screens may be necessary in particular cases.
Hypersomnia Not Due to a Substance or Known Physiological Condition This entity, also named ‘nonorganic hypersomnia,’ refers to several causes of hypersomnia including depressive disorders, seasonal affective disorder (SAD), abnormal personality traits, and conversion episodes. Most of the patients affected with psychiatric disorders suffer from insomnia; however, some (mainly with atypical depression) may also present with a complaint of EDS. The complaint of EDS may be rather similar to that of patients with IH with long sleep time, except that it may vary from day to day and is often associated with poor and fragmented sleep at night. Hypersomnia associated with SAD is considered a clinical subtype of nonorganic hypersomnia. Patients with winter depression report hypersomnia, fatigue, loss of energy, craving for carbohydrates, change in appetite, and weight gain. Light therapy for 14 days in the morning, effective in this condition, may help in the positive diagnosis assessment. PSG studies in hypersomnia with mood disorders are rare and show a long time in bed without sleep, which leads to a low sleep efficiency. The MSLT does not demonstrate a short mean sleep latency and REM sleep is totally absent during daytime naps in depressed patients. Finally, a 24-h continuous
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PSG reveals a low total sleep time and a low percentage of slow wave sleep. A diagnosis of fatigue appears more likely in this condition.
Hypersomnias of Noncentral Origins Sleep-related breathing disorders are the most frequent pathology associated with EDS. Questioning and evaluating patients who complain of sleepiness for associated symptoms and signs such as loud snoring, obesity, headaches, hypertension, fatigue in the morning, nocturia, reduced libido, and witnessed episodes of apnea provide essential clinical information for this diagnosis. Sleep-related movement disorders include several conditions such as restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). Nocturnal sleep disturbances and/or complaints of EDS can be reported in these conditions; however, the relationship between PLMD and EDS is still a subject of debate. Circadian rhythm sleep disruption may lead to insomnia or EDS, or both. A sleep diary may be helpful to assess the regulatory of sleep–wake schedule.
Conclusion EDS is a common complaint in modern societies. Drowsiness and naps may be limited to sedentary situations; however, EDS may lead to impaired performance, accidents at work or while driving. Clinicians should always question their patients with a complaint of EDS for potentially insufficient sleep, insomnia, medical or psychiatric conditions, and drug use. Physicians have several methods to distinguish sleepiness from fatigue, to affirm the existence of daytime somnolence, and to appropriately diagnose the different causes of hypersomnia. Some progress has been made in the identification of the different phenotypes of chronic hypersomnia; however there is still a definite need to further develop sleep laboratory investigations to assess the correct diagnosis of insufficiently recognized and poorly defined etiologies of hypersomnia. Lastly, studies at the genetic, biological, and pharmacological levels are also needed to further our understanding of the pathophysiology of chronic hypersomnia and to develop specific treatments in the future.
See also: Diagnosis of Hypersomnias: Diagnosis of Hypersomnia in Children: Screening and Case Finding; Diagnostic Tools for Hypersomnias.
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Relevant Websites http://www3.unil.ch/wpmu/eunn/links/ – European Narcolepsy Network. http://www.montp.inserm.fr/u1061/SiteU1061/cnrnh/web/narcolepsie.html – Centre National de Reference Narcolepsie et Hypersomnie.