- Email: [email protected]
Risk Factors for Hypersomnias
Risk Factors for Hypersomnias M I Boulos, Sunnybrook Health Sciences Centre, Toronto, ON, Canada ã 2013 Elsevier Inc. All rights reserved.
Glossary Allele: Any of the alternative forms of a gene. Different alleles can result in different traits or diseases. At other times, different alleles will result in the same expression of a gene. Cataplexy: A sudden and transient loss of generalized muscle tone triggered by strong emotions, such as laughter. Coffin–Lowry syndrome: A rare X-linked disorder typically associated with moderate to severe intellectual disability, mental retardation, characteristic facial features, skeletal deformities, and tapering fingers in males. Females are much more mildly and variably affected. The gene locus has been mapped to Xp22.2, and mutations have been identified in affected patients in the RSK-2 gene, a growth factor-regulated protein kinase. Haplotype: A group of alleles of different genes on the same chromosome that are closely linked to be usually inherited as a single unit. Leptin: A protein hormone that is produced by fat cells and plays a role in the regulation of body weight. Leptin acts on the brain to suppress appetite and burn fat stored in fat
Introduction The ‘Hypersomnia of Central Origin’ category of the International Classification of Sleep Disorders, 2nd edn. (ICSD-2) includes those disorders in which the primary complaint is daytime sleepiness. By definition, conditions in this category are not due to disturbed sleep or misaligned circadian rhythms. Compared with hypersomnias related to other conditions, such as sleep-disordered breathing, the hypersomnias of central origin are rare causes of excessive daytime sleepiness (EDS). This article reviews and discusses the risk factors for these uncommon disorders.
Narcolepsy With and Without Cataplexy Narcolepsy is characterized by EDS and usually cataplexy, which is the most specific sign of the disease. Other symptoms include sleep-related hallucinations, sleep paralysis, frequent movement and awakening during sleep, and weight gain. Polysomnography and the multiple sleep latency test (MSLT) demonstrate characteristic electrophysiological findings. Narcolepsy with cataplexy is thought to be caused by a loss of hypocretin cells in the hypothalamus and is hypothesized to be an autoimmune-mediated disorder. Narcolepsy without cataplexy is a new subcategory of narcolepsy. In this condition, patients show all narcoleptic symptoms but cataplexy, and meet identical polysomnography and MSLT criteria to those with cataplexy. Hypocretin deficiency and human leukocyte antigen (HLA)
Encyclopedia of Sleep
http://dx.doi.org/10.1016/B978-0-12-378610-4.00218-7
cells. Mice with elevated levels of leptin are leaner than mice with lower levels of leptin. Moebius syndrome: A rare congenital neurological condition involving bilateral paresis of the facial muscles and other neurological symptoms. Myotonic dystrophy type 1: A multisystem disorder with myotonia, muscle weakness, cataracts, endocrine dysfunction, and intellectual impairment. It is caused by a CTG triplet expansion in the 3Lˇ-untranslated region of the DMPK gene on 19q13. Niemann–Pick disease type C: A rare inherited cholesterol metabolic disorder associated with seizures, mental retardation, and hepatosplenomegaly. Norrie’s disease: A rare X-linked recessive disorder causing ocular atrophy, intellectual disability, mental retardation, deafness, and dysmorphic features. Prader–Willi syndrome: A complex genetic disorder characterised by hypotonia, short stature, hypogonadism, intellectual disability, mental retardation, behavioral disturbances, and hyperphagia that results in excessive obesity.
positivity are less frequent in patients with narcolepsy without cataplexy. Although the specific causes of narcolepsy remain unknown, it appears that there are both genetic and environmental factors that contribute to the development of the disease.
Genetic Risk Factors About 90% of patients with narcolepsy with cataplexy have a specific haplotype – HLA-DQB1*0602. Only 40–60% of patients with narcolepsy without cataplexy carry this haplotype. Homozygosity for this allele at least doubles the risk of narcolepsy. However, this is of limited diagnostic value given the fact that about 12–38% of the general population has the HLA-DQB1*0602 haplotype and only 0.02% of the population actually has narcolepsy. In addition, some patients with narcolepsy have been found to not have this haplotype. Therefore, the DQB1*0602 haplotype is neither necessary nor sufficient for the development of narcolepsy. In heterozygotes, other HLA alleles have been postulated to confer susceptibility (DQB1*0301) or a protective effect (DQB1*0501 and DQB1*0601) with regard to the development of narcolepsy. Aside from HLA alleles, other genes have been implicated in the genetics of narcolepsy. The T cell receptor alpha gene is thought to be strongly implicated. Furthermore, several independent studies have found that some patients with narcolepsy have elevated levels of antibodies against a protein known as Tribbles homolog 2 (TRIB2), which is produced in hypocretin neurons; this work may prove to be the strongest evidence yet
391
392
Features, Factors, and Characteristics of Hypersomnias | Risk Factors for Hypersomnias
for an autoimmune cause of narcolepsy. However, TRIB2 antibodies are also neither strictly necessary nor sufficient for the development of narcolepsy. Other investigators have suggested a link between narcolepsy and immune-related genes, such as the tumor necrosis factor alpha gene and the receptor 2 gene. Numerous other susceptibility genes have also been postulated to be involved in the pathogenesis of narcolepsy, and this continues to be an area of active investigation. While most cases of narcolepsy are sporadic, there are multiple reports of familial narcolepsy. A genome-wide mapping study suggested potential linkage to chromosome 4p13-q21 in several Japanese families affected by narcolepsy with cataplexy. Genome-wide linkage analysis of a large French family with members who had narcolepsy with cataplexy and others with isolated recurrent naps suggested linkage to chromosome 21q. In monozygotic twins with narcolepsy, concordance is low (about 35%). First-degree relatives have an estimated 1–2% chance of developing narcolepsy; although small, this is 20–40 times the prevalence seen in the general population. Such findings support a multifactorial model for the development of narcolepsy, with a strong influence from environmental factors acting in combination with genetic factors, possibly triggering an autoimmune attack against the hypocretin system.
in people born in the month of March and a lower incidence among those born in September. This finding was only seen when cataplexy was moderate or severe. Thus sunlight exposure – possibly related to vitamin D, or another unknown environmental factor (e.g., infection early in life), may play a role. Several studies have revealed that obesity may be present from the early stages of the disease, even in cases with an onset in childhood. Whether obesity precedes the onset of the disease is not known. It is also unclear whether obesity in narcolepsy provides clues about the etiology of the disease, particularly in relation to the well-recognized hypocretin/orexin deficiency and its interaction with leptin; paradoxically, orexin increases foodcraving, and a deficiency in the protein would make one’s desire for food less. Alternatively, obesity may simply be a manifestation of narcolepsy. Taken together, these lines of evidence suggest that environmental events, particularly those early in life, can affect the probability of developing the disease.
Environmental Factors
The symptoms of narcolepsy can occur during the course of other neurological symptoms (i.e., ‘symptomatic narcolepsy’). Inherited conditions, brain tumors, and head trauma are the most common causes for symptomatic narcolepsy, and these will be described in detail below. Symptomatic narcolepsy has also been described in multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), neurosarcoidosis, vascular disorders, encephalitis, and neurodegenerative conditions. Of particular interest is the fact that patients with Parkinson’s disease may also have EDS, acute sleep attacks, sleep-onset rapid eye movement periods (SOREMPs), rapid eye movement (REM) sleep behavior disorder, and hallucinations, all of which are features similar to those seen in narcolepsy.
Several lines of evidence support an environmental influence for the pathogenesis of narcolepsy with cataplexy. First of all, the disease is not present at birth, but rather begins later in life, typically during the second decade of life with a smaller peak occurring in the fourth decade of life. In addition, patients with narcolepsy report a higher incidence of stressful life events in the year preceding the onset of narcolepsy compared to control subjects. Such events include psychosocial stress, surgery, minor head trauma, pregnancy/childbirth, menarche, overexertion, and an abrupt change in the reported sleep– wake cycle. In keeping with the postulated importance of early triggers, total stressors before the age of 10 years has been shown to be associated with the development of narcolepsy. Interestingly, low-to-undetectable cerebrospinal fluid hypocretin-1 concentration, which is the same biochemical abnormality seen in narcolepsy, has been found in many patients with acute brain trauma. In some cases, infections such as strep throat and the flu are implicated as triggering events for the development of narcolepsy. Higher rates of diagnosed strep infections and elevated antistreptococcal antibodies around the time of disease onset have been described. In addition, H1N1 infections and the H1N1 vaccine have been rarely associated with disease onset. Vitamin D has also been speculated to be involved in the pathogenesis of narcolepsy. Vitamin D has been proposed as a key environmental factor for several autoimmune diseases, including multiple sclerosis. A study from France found a higher incidence of vitamin D deficiency in patients with narcolepsy with cataplexy compared to gender- and age-matched normal controls. Unfortunately, no research exists at this time to support vitamin D as a protective measure or treatment for narcolepsy. A month-of-birth pattern is also present in narcolepsy. Several studies have shown a higher incidence of narcolepsy
Narcolepsy-Like Symptoms Due to Other Neurological Conditions
Genetic Syndromes and Features of Narcolepsy Several rare inherited conditions, such as Niemann–Pick disease type C, Coffin–Lowry syndrome, and Norrie’s disease (ND), have been reported to cause cataplexy. Patients with Niemann–Pick disease type C, which is a lipid storage disease, can experience cataplexy and, rarely, it can be one of the presenting features of the disease. Miglustat, a reversible inhibitor of the enzyme glucosylceramide synthase, has been reported to be effective in managing cataplexy and some of the other neurological symptoms seen in the condition. In Coffin– Lowry syndrome, up to 10% of patients experience characteristic paroxysmal drop attacks characterized by the sudden loss of muscle tone triggered by unexpected tactile or auditory stimuli. These cataplexy-like events have been demonstrated to respond to sodium oxybate, much like in narcolepsy. Patients with ND have deficiencies in monoamine (MOA) type-A and type-B activity. These patients also experience cataplexy as well as inappropriate periods of REM sleep during wakefulness. As a result of the clinical and biochemical features seen in ND,
Features, Factors, and Characteristics of Hypersomnias | Risk Factors for Hypersomnias
it has been postulated that an analogous MOA defect may play a role in narcolepsy. Aside from cataplexy, prominent EDS has also been described in several genetic conditions. In myotonic dystrophy type 1, patients often experience EDS, as well as short sleep latencies and SOREMPs during the MSLT (features typically seen in narcolepsy). EDS is a common and disabling symptom seen in Prader–Willi syndrome (PWS). It has been suggested that the sleepiness in PWS is caused by a central hypothalamic disturbance, and not by obstructive sleep apnea secondary to the characteristic obese body habitus seen in the disease. In addition to EDS, a narcolepsy-like condition has been described in PWS, in which food or excitement causes a momentary drop attack. Finally, several sleep disorders have been described in relation to the Moebius syndrome, including parasomnias, EDS, and laughter-induced atonia resembling cataplexy.
Brain Tumors Giving Rise to Features of Narcolepsy Brain neoplasms have been reported to cause symptoms characteristic of narcolepsy. In a large series, the most common locations for these tumors were the hypothalamus, pituitary gland, optic chiasm, suprasellar region, third ventricle and, less commonly, the midbrain. The pathologies of these tumors varied, and included craniopharyngioma, adenoma, astrocytoma, angioma, medulloblastoma, choroid plexus carcinoma, lymphoma, and subependymoma, in addition to several other tumor types. All patients exhibited EDS, most had SOREMPs on the MSLT, and about 55% exhibited cataplexy. Because the majority of cases described were HLA DR2 negative, the authors concluded that narcolepsy associated with brain tumors does exist as a distinct clinical entity and that typical cases were likely to share common pathophysiological mechanisms with idiopathic narcolepsy with cataplexy. In addition, the view that involvement of hypothalamic structures is important in the development of EDS, cataplexy, and other REM sleep abnormalities coincides with the notion that impairment of the hypothalamic–hypocretin system underlies the pathophysiology of most idiopathic cases of narcolepsy with cataplexy.
Posttraumatic Narcolepsy As described above, head trauma is a recognized risk factor for narcolepsy. However, in contrast to tumor cases, it is often difficult to determine the precise structure(s) impaired. The same case series described above failed to uncover specific brain structures implicated in posttraumatic narcolepsy. It is important to keep in mind that most patients with hypersomnia following head trauma do not have narcolepsy. In addition, issues related to compensation and legal concerns often confound the clinical scenario.
Recurrent Hypersomnia
393
B) Episodes recur at least once a year. C) The patient has normal alertness, cognitive functioning, and behavior between attacks. D) The hypersomnia is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder. Several forms of RH are reported in the literature, and these include (i) Kleine–Levin syndrome (KLS), (ii) menstrualrelated hypersomnia, and (iii) RH with comorbidity. We review the risk factors for these entities below.
Kleine–Levin Syndrome KLS is a rare disease characterized by recurrent episodes of hypersomnia and, to varying degrees, compulsive eating, cognitive changes, depression, irritability, and hypersexuality. It mainly afflicts teenage males. Some authors have described KLS with and without compulsive eating as distinct entities. A comprehensive review on KLS revealed that precipitating factors were present in 61% of patients. The most frequently reported was a minor infection such as a nonspecific fever, flulike illness, upper respiratory tract infection, or tonsillitis. Less commonly cited was summer gastroenteritis or a more severe infection. Urinary tract or eye infections were never reported. Infectious agents were rarely identified, but when detected included Epstein–Barr virus, varicella-zoster virus, enterovirus, posttyphoid vaccine, scarlet fever, and Streptococcus in the context of sepsis. Other reported triggers include alcohol consumption, marijuana use, head trauma (e.g., knock-out during boxing), physical exertion, and psychological distress. In addition, surgery with general or local (dental) anesthesia, lactation, and menses have also been reported at KLS onset. Personal or familial psychiatric history has been detected in only a small number of cases. Events that trigger subsequent episodes are less commonly described, but include a high proportion of infections, as well as surgery with anaesthesia, physical or mental effort, sunstroke, alcohol, jet lag, and attacks of hemiplegic migraine. No definite genetic predisposing factors have been uncovered in KLS. HLA-DQB1 typing performed in more than 100 patients with KLS did not differ between cases and control subjects in the HLA DR and DQ alleles. Several familial cases of KLS have been reported (about 4% of cases); however, these cases did not differ from sporadic cases in their features. At the time of writing this article, genome-wide mapping studies had not been performed in KLS, and no twin cases of KLS were reported in the literature.
Menstrual-Related Hypersomnia In menstrual-related hypersomnia, the triggers include menarche, menstruation alone or with an additional trigger (e.g., an infection, Girl Scout outing, exposure to alcohol, etc.) and puerperium. Each episode tends to be preceded by a triggering event; however, events do not occur with each menstruation or puerperium.
According to the ICSD-2, the diagnostic criteria of recurrent hypersomnia (RH) are as follows:
Recurrent Hypersomnia with Comorbidity
A) The patient experiences recurrent episodes of excessive sleepiness of two days’ to four weeks’ duration.
Recurrent hypersomnia has also been described in the context of numerous medical conditions. Associated conditions include
394
Features, Factors, and Characteristics of Hypersomnias | Risk Factors for Hypersomnias
metabolic encephalopathy, flu-like illness, upper airway infection, head trauma, acute viral encephalitis, stroke, brain tumor, paraneoplastic syndrome, genetic conditions (e.g., PWS and incontinentia pigmenti), and pervasive developmental disorders such as autism or Asperger’s disease.
Idiopathic Hypersomnia Idiopathic hypersomnia (IH) is less common and more poorly defined than narcolepsy. IH remains a diagnosis of exclusion, and polysomnography is needed to rule out other causes of hypersomnia. The current ICSD-2 definition distinguishes IH with and without long sleep time. In the former, patients have EDS despite at least 10 hours of sleep per night. They rarely awaken from sleep, have difficulty with arousal, and sleep (including naps) is not refreshing; ‘sleep drunkenness’ is prominent. In contrast, patients with IH without long sleep time have less prominent sleep drunkenness and sleep fewer than 10 hours per night. A review of 77 cases of IH reported that approximately one-third of patients with this condition had a family history of similar problems. Of the patients who underwent haplotype analysis, only 18% (7/39) were positive for the HLADQB1*0602 antigen, compared to 98% (61/62) of the patients with narcolepsy. There was a carrier frequency of 10% (4/39) for the Cw2 antigen in the patients with IH. No clear genetic marker was identified. The same review noted that there was no precipitant in the majority of cases of IH, with only 4% (3/77) of patients reporting a transient viral illness at the time of symptoms. An earlier review also noted the onset of symptoms with a viral illness, as well as with head trauma and prominent psychiatric symptoms. Once again, triggers were noted in only a minority of cases.
Behaviorally Induced Insufficient Sleep Syndrome Behaviorally Induced Insufficient sleep syndrome is the most common cause of EDS in the general population. Those who may be at particular risk include young adults, parents of children under the age of 18 years, shift workers, healthcare professionals, and those in transportation jobs. Other reported risk factors for insufficient sleep include smoking, the consumption of tobacco in a smokeless fashion, and secondhand smoke exposure. Among adolescents, extrinsic factors play a major role, including social interactions with friends, videogame use, extracurricular activities, early start times for classes, and poor sleep hygiene. Intrinsic factors may also play a role; for example, during puberty, the timing of melatonin release has been shown to change, shifting the adolescent’s circadian rhythm so that they feel sleepy later in the evening compared to earlier in life.
Hypersomnia Due to Medication The use of many drugs is associated with EDS. These include benzodiazepines, barbiturates, antidepressants, antipsychotics, and antihistaminergic medications. Limited research has
investigated the role of genetic influences on medicationinduced hypersomnia; however, genetic susceptibility has been reported with some medications. For example, a Japanese study demonstrated that the CYP2D6*10 allele was a risk factor for adverse events caused by H1 antihistamines. In addition, the occurrence of hypersomnia increased as the number of CYP2D6 mutant alleles increased. Another study reported an increased incidence of hypersomnolence during clozapine therapy in patients with a CLOCK (circadian locomotor output cycles kaput) gene polymorphism (3111T/C substitution). The effects of drug interactions can also be mediated by genetic factors. For example, in a patient with ultrahigh activity of CYP2C9, the addition of fluconazole, which is a potent inhibitor of CYP2C9, caused phenytoin intoxication despite use of the patient’s usual dose. Finally, the treatment of the EDS seen in narcolepsy is also modulated by genetic influences. For example, the functional polymorphism of the catechol-O-methyltransferase (COMT) gene is critically involved in the severity of narcolepsy and in the response to the stimulant modafinil.
Hypersomnia Due to a Medical Condition Several studies have examined the genetic factors implicated in the ‘sleep attacks’ and hypersomnia seen in Parkinson’s disease. The dopamine D2 receptor gene polymorphism Taq IA and the variant allele T of the (909T/C) preprohypocretin polymorphism have both been reported to be more commonly found in patients with Parkinson’s disease who experience sleep attacks. In patients experiencing sleep attacks without warning signs, an association has been reported with the dopamine receptor D4*2 (short) allele. Of note, the initially described association between daytime sleepiness and the COMT val158met polymorphism (rs4680) could not be confirmed in a larger study. Risk factors for the development of disease-induced hypersomnia have only been studied in a few other conditions. In cognitively normal apolipoprotein E e4 homozygotes, chronic daytime sleepiness has been reported in association with a distinctive decline in verbal memory. In patients with Sjogren’s syndrome, the dose of the þ49A;CT60G haplotype of the cytotoxic T lymphocyte-associated antigen 4 gene has been reported to be associated with the severity of daytime sleepiness. Finally, in a population-based sample of more than 5000 elderly male twins, EDS and depressive symptoms were found to have a significant genetic correlation; however, after covariate adjustment, the majority of individual variation in daytime sleepiness and depressive symptoms was attributable to individual-specific environmental factors.
See also: Descriptions of Hypersomnias: Behaviorally Induced Insufficient Sleep Syndrome; Hypersomnia Due to Drug or Substance; Idiopathic Hypersomnia with Long Sleep Time; Idiopathic Hypersomnia without Long Sleep Time; Narcolepsy due to a Medical Condition; Narcolepsy with Cataplexy; Narcolepsy without Cataplexy; Recurrent Hypersomnia; Features, Factors, and Characteristics of Hypersomnias: Epidemiology of Hypersomnia; Familial and Genetic
Features, Factors, and Characteristics of Hypersomnias | Risk Factors for Hypersomnias
Factors of Narcolepsy; Instrumentation and Methodology: Multiple Sleep Latency Test (MSLT); Sleep Loss in Disease States: Sleep Loss Associated with Medical Conditions and Diseases; Special Conditions, Disorders, and Clinical Issues for Hypersomnias: Medications and Sleep.
Further Reading American Academy of Sleep Medicine (2005) International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. Westchester, IL: American Academy of Sleep Medicine. Anderson KN, Pilsworth S, Sharples LD, Smith IE, and Shneerson JM (2007) Idiopathic hypersomnia: A study of 77 cases. Sleep 30: 1274–1281. Aran A, Lin L, Nevsimalova S, et al. (2009) Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 32: 979–983. Arnulf I, Zeitzer JM, File J, Farber N, and Mignot E (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. Billiard M, Jaussent I, Dauvilliers Y, and Besset A (2011) Recurrent hypersomnia: A review of 339 cases. Sleep Medicine Reviews 15: 247–257. Boulos MI and Murray BJ (2010) Current evaluation and management of excessive daytime sleepiness. Canadian Journal of Neurological Sciences 37: 167–176. Bourgin P, Zeitzer JM, and Mignot E (2008) CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurology 7: 649–662. Cvetkovic-Lopes V, Bayer L, Dorsaz S, et al. (2010) Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. The Journal of Clinical Investigation 120: 713–719. Dauvilliers Y, Arnulf I, and Mignot E (2007) Narcolepsy with cataplexy. The Lancet 369: 499–511. Dauvilliers Y, Montplaisir J, Cochen V, et al. (2010) Post-H1N1 narcolepsy-cataplexy. Sleep 33: 1428–1430.
395
Frenette E and Kushida CA (2009) Primary hypersomnias of central origin. Seminars in Neurology 29: 354–367. Hallmayer J, Faraco J, Lin L, et al. (2009) Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature Genetics 41: 708–711. Havaligi N, Matadeen-Ali C, Khurana DS, Marks H, and Kothare SV (2007) Treatment of drop attacks in Coffin–Lowry syndrome with the use of sodium oxybate. Pediatric Neurology 37: 373–374. Lattuada E, Cavallaro R, Benedetti F, Cocchi F, Lorenzi C, and Smeraldi E (2004) Genetic dissection of drug effects in clinical practice: CLOCK gene and clozapine-induced diurnal sleepiness. Neuroscience Letters 367: 152–155. Longstreth WT Jr., Koepsell TD, Ton TG, Hendrickson AF, and van Belle G (2007) The epidemiology of narcolepsy. Sleep 30: 13–26. Mignot E, Lin X, Arrigoni J, et al. (1994) DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans. Sleep 17(Suppl 8): S60–S67. Nishino S and Kanbayashi T (2005) Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Medicine Reviews 9: 269–310. Parkes JD (1999) Genetic factors in human sleep disorders with special reference to Norrie disease, Prader–Willi syndrome and Moebius syndrome. Journal of Sleep Research 8(Suppl 1): S14–S22. Saruwatari J, Matsunaga M, Ikeda K, et al. (2006) Impact of CYP2D6*10 on H1-antihistamine-induced hypersomnia. European Journal of Clinical Pharmacology 62: 995–1001. Sehgal A and Mignot E (2011) Genetics of sleep and sleep disorders. Cell 146: 194–207. Smit LS, Lammers GJ, and Catsman-Berrevoets CE (2006) Cataplexy leading to the diagnosis of Niemann–Pick disease type C. Pediatric Neurology 35: 82–84. Tafti M and Dauvilliers Y (2003) Pharmacogenomics in the treatment of narcolepsy. Pharmacogenomics 4: 23–33. Vossler DG, Wyler AR, Wilkus RJ, Gardner-Walker G, and Vlcek BW (1996) Cataplexy and monoamine oxidase deficiency in Norrie disease. Neurology 46: 1258–1261. Young TJ and Silber MH (2006) Hypersomnias of central origin. Chest 130: 913–920.
Glossary Allele: Any of the alternative forms of a gene. Different alleles can result in different traits or diseases. At other times, different alleles will result in the same expression of a gene. Cataplexy: A sudden and transient loss of generalized muscle tone triggered by strong emotions, such as laughter. Coffin–Lowry syndrome: A rare X-linked disorder typically associated with moderate to severe intellectual disability, mental retardation, characteristic facial features, skeletal deformities, and tapering fingers in males. Females are much more mildly and variably affected. The gene locus has been mapped to Xp22.2, and mutations have been identified in affected patients in the RSK-2 gene, a growth factor-regulated protein kinase. Haplotype: A group of alleles of different genes on the same chromosome that are closely linked to be usually inherited as a single unit. Leptin: A protein hormone that is produced by fat cells and plays a role in the regulation of body weight. Leptin acts on the brain to suppress appetite and burn fat stored in fat
Introduction The ‘Hypersomnia of Central Origin’ category of the International Classification of Sleep Disorders, 2nd edn. (ICSD-2) includes those disorders in which the primary complaint is daytime sleepiness. By definition, conditions in this category are not due to disturbed sleep or misaligned circadian rhythms. Compared with hypersomnias related to other conditions, such as sleep-disordered breathing, the hypersomnias of central origin are rare causes of excessive daytime sleepiness (EDS). This article reviews and discusses the risk factors for these uncommon disorders.
Narcolepsy With and Without Cataplexy Narcolepsy is characterized by EDS and usually cataplexy, which is the most specific sign of the disease. Other symptoms include sleep-related hallucinations, sleep paralysis, frequent movement and awakening during sleep, and weight gain. Polysomnography and the multiple sleep latency test (MSLT) demonstrate characteristic electrophysiological findings. Narcolepsy with cataplexy is thought to be caused by a loss of hypocretin cells in the hypothalamus and is hypothesized to be an autoimmune-mediated disorder. Narcolepsy without cataplexy is a new subcategory of narcolepsy. In this condition, patients show all narcoleptic symptoms but cataplexy, and meet identical polysomnography and MSLT criteria to those with cataplexy. Hypocretin deficiency and human leukocyte antigen (HLA)
Encyclopedia of Sleep
http://dx.doi.org/10.1016/B978-0-12-378610-4.00218-7
cells. Mice with elevated levels of leptin are leaner than mice with lower levels of leptin. Moebius syndrome: A rare congenital neurological condition involving bilateral paresis of the facial muscles and other neurological symptoms. Myotonic dystrophy type 1: A multisystem disorder with myotonia, muscle weakness, cataracts, endocrine dysfunction, and intellectual impairment. It is caused by a CTG triplet expansion in the 3Lˇ-untranslated region of the DMPK gene on 19q13. Niemann–Pick disease type C: A rare inherited cholesterol metabolic disorder associated with seizures, mental retardation, and hepatosplenomegaly. Norrie’s disease: A rare X-linked recessive disorder causing ocular atrophy, intellectual disability, mental retardation, deafness, and dysmorphic features. Prader–Willi syndrome: A complex genetic disorder characterised by hypotonia, short stature, hypogonadism, intellectual disability, mental retardation, behavioral disturbances, and hyperphagia that results in excessive obesity.
positivity are less frequent in patients with narcolepsy without cataplexy. Although the specific causes of narcolepsy remain unknown, it appears that there are both genetic and environmental factors that contribute to the development of the disease.
Genetic Risk Factors About 90% of patients with narcolepsy with cataplexy have a specific haplotype – HLA-DQB1*0602. Only 40–60% of patients with narcolepsy without cataplexy carry this haplotype. Homozygosity for this allele at least doubles the risk of narcolepsy. However, this is of limited diagnostic value given the fact that about 12–38% of the general population has the HLA-DQB1*0602 haplotype and only 0.02% of the population actually has narcolepsy. In addition, some patients with narcolepsy have been found to not have this haplotype. Therefore, the DQB1*0602 haplotype is neither necessary nor sufficient for the development of narcolepsy. In heterozygotes, other HLA alleles have been postulated to confer susceptibility (DQB1*0301) or a protective effect (DQB1*0501 and DQB1*0601) with regard to the development of narcolepsy. Aside from HLA alleles, other genes have been implicated in the genetics of narcolepsy. The T cell receptor alpha gene is thought to be strongly implicated. Furthermore, several independent studies have found that some patients with narcolepsy have elevated levels of antibodies against a protein known as Tribbles homolog 2 (TRIB2), which is produced in hypocretin neurons; this work may prove to be the strongest evidence yet
391
392
Features, Factors, and Characteristics of Hypersomnias | Risk Factors for Hypersomnias
for an autoimmune cause of narcolepsy. However, TRIB2 antibodies are also neither strictly necessary nor sufficient for the development of narcolepsy. Other investigators have suggested a link between narcolepsy and immune-related genes, such as the tumor necrosis factor alpha gene and the receptor 2 gene. Numerous other susceptibility genes have also been postulated to be involved in the pathogenesis of narcolepsy, and this continues to be an area of active investigation. While most cases of narcolepsy are sporadic, there are multiple reports of familial narcolepsy. A genome-wide mapping study suggested potential linkage to chromosome 4p13-q21 in several Japanese families affected by narcolepsy with cataplexy. Genome-wide linkage analysis of a large French family with members who had narcolepsy with cataplexy and others with isolated recurrent naps suggested linkage to chromosome 21q. In monozygotic twins with narcolepsy, concordance is low (about 35%). First-degree relatives have an estimated 1–2% chance of developing narcolepsy; although small, this is 20–40 times the prevalence seen in the general population. Such findings support a multifactorial model for the development of narcolepsy, with a strong influence from environmental factors acting in combination with genetic factors, possibly triggering an autoimmune attack against the hypocretin system.
in people born in the month of March and a lower incidence among those born in September. This finding was only seen when cataplexy was moderate or severe. Thus sunlight exposure – possibly related to vitamin D, or another unknown environmental factor (e.g., infection early in life), may play a role. Several studies have revealed that obesity may be present from the early stages of the disease, even in cases with an onset in childhood. Whether obesity precedes the onset of the disease is not known. It is also unclear whether obesity in narcolepsy provides clues about the etiology of the disease, particularly in relation to the well-recognized hypocretin/orexin deficiency and its interaction with leptin; paradoxically, orexin increases foodcraving, and a deficiency in the protein would make one’s desire for food less. Alternatively, obesity may simply be a manifestation of narcolepsy. Taken together, these lines of evidence suggest that environmental events, particularly those early in life, can affect the probability of developing the disease.
Environmental Factors
The symptoms of narcolepsy can occur during the course of other neurological symptoms (i.e., ‘symptomatic narcolepsy’). Inherited conditions, brain tumors, and head trauma are the most common causes for symptomatic narcolepsy, and these will be described in detail below. Symptomatic narcolepsy has also been described in multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), neurosarcoidosis, vascular disorders, encephalitis, and neurodegenerative conditions. Of particular interest is the fact that patients with Parkinson’s disease may also have EDS, acute sleep attacks, sleep-onset rapid eye movement periods (SOREMPs), rapid eye movement (REM) sleep behavior disorder, and hallucinations, all of which are features similar to those seen in narcolepsy.
Several lines of evidence support an environmental influence for the pathogenesis of narcolepsy with cataplexy. First of all, the disease is not present at birth, but rather begins later in life, typically during the second decade of life with a smaller peak occurring in the fourth decade of life. In addition, patients with narcolepsy report a higher incidence of stressful life events in the year preceding the onset of narcolepsy compared to control subjects. Such events include psychosocial stress, surgery, minor head trauma, pregnancy/childbirth, menarche, overexertion, and an abrupt change in the reported sleep– wake cycle. In keeping with the postulated importance of early triggers, total stressors before the age of 10 years has been shown to be associated with the development of narcolepsy. Interestingly, low-to-undetectable cerebrospinal fluid hypocretin-1 concentration, which is the same biochemical abnormality seen in narcolepsy, has been found in many patients with acute brain trauma. In some cases, infections such as strep throat and the flu are implicated as triggering events for the development of narcolepsy. Higher rates of diagnosed strep infections and elevated antistreptococcal antibodies around the time of disease onset have been described. In addition, H1N1 infections and the H1N1 vaccine have been rarely associated with disease onset. Vitamin D has also been speculated to be involved in the pathogenesis of narcolepsy. Vitamin D has been proposed as a key environmental factor for several autoimmune diseases, including multiple sclerosis. A study from France found a higher incidence of vitamin D deficiency in patients with narcolepsy with cataplexy compared to gender- and age-matched normal controls. Unfortunately, no research exists at this time to support vitamin D as a protective measure or treatment for narcolepsy. A month-of-birth pattern is also present in narcolepsy. Several studies have shown a higher incidence of narcolepsy
Narcolepsy-Like Symptoms Due to Other Neurological Conditions
Genetic Syndromes and Features of Narcolepsy Several rare inherited conditions, such as Niemann–Pick disease type C, Coffin–Lowry syndrome, and Norrie’s disease (ND), have been reported to cause cataplexy. Patients with Niemann–Pick disease type C, which is a lipid storage disease, can experience cataplexy and, rarely, it can be one of the presenting features of the disease. Miglustat, a reversible inhibitor of the enzyme glucosylceramide synthase, has been reported to be effective in managing cataplexy and some of the other neurological symptoms seen in the condition. In Coffin– Lowry syndrome, up to 10% of patients experience characteristic paroxysmal drop attacks characterized by the sudden loss of muscle tone triggered by unexpected tactile or auditory stimuli. These cataplexy-like events have been demonstrated to respond to sodium oxybate, much like in narcolepsy. Patients with ND have deficiencies in monoamine (MOA) type-A and type-B activity. These patients also experience cataplexy as well as inappropriate periods of REM sleep during wakefulness. As a result of the clinical and biochemical features seen in ND,
Features, Factors, and Characteristics of Hypersomnias | Risk Factors for Hypersomnias
it has been postulated that an analogous MOA defect may play a role in narcolepsy. Aside from cataplexy, prominent EDS has also been described in several genetic conditions. In myotonic dystrophy type 1, patients often experience EDS, as well as short sleep latencies and SOREMPs during the MSLT (features typically seen in narcolepsy). EDS is a common and disabling symptom seen in Prader–Willi syndrome (PWS). It has been suggested that the sleepiness in PWS is caused by a central hypothalamic disturbance, and not by obstructive sleep apnea secondary to the characteristic obese body habitus seen in the disease. In addition to EDS, a narcolepsy-like condition has been described in PWS, in which food or excitement causes a momentary drop attack. Finally, several sleep disorders have been described in relation to the Moebius syndrome, including parasomnias, EDS, and laughter-induced atonia resembling cataplexy.
Brain Tumors Giving Rise to Features of Narcolepsy Brain neoplasms have been reported to cause symptoms characteristic of narcolepsy. In a large series, the most common locations for these tumors were the hypothalamus, pituitary gland, optic chiasm, suprasellar region, third ventricle and, less commonly, the midbrain. The pathologies of these tumors varied, and included craniopharyngioma, adenoma, astrocytoma, angioma, medulloblastoma, choroid plexus carcinoma, lymphoma, and subependymoma, in addition to several other tumor types. All patients exhibited EDS, most had SOREMPs on the MSLT, and about 55% exhibited cataplexy. Because the majority of cases described were HLA DR2 negative, the authors concluded that narcolepsy associated with brain tumors does exist as a distinct clinical entity and that typical cases were likely to share common pathophysiological mechanisms with idiopathic narcolepsy with cataplexy. In addition, the view that involvement of hypothalamic structures is important in the development of EDS, cataplexy, and other REM sleep abnormalities coincides with the notion that impairment of the hypothalamic–hypocretin system underlies the pathophysiology of most idiopathic cases of narcolepsy with cataplexy.
Posttraumatic Narcolepsy As described above, head trauma is a recognized risk factor for narcolepsy. However, in contrast to tumor cases, it is often difficult to determine the precise structure(s) impaired. The same case series described above failed to uncover specific brain structures implicated in posttraumatic narcolepsy. It is important to keep in mind that most patients with hypersomnia following head trauma do not have narcolepsy. In addition, issues related to compensation and legal concerns often confound the clinical scenario.
Recurrent Hypersomnia
393
B) Episodes recur at least once a year. C) The patient has normal alertness, cognitive functioning, and behavior between attacks. D) The hypersomnia is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder. Several forms of RH are reported in the literature, and these include (i) Kleine–Levin syndrome (KLS), (ii) menstrualrelated hypersomnia, and (iii) RH with comorbidity. We review the risk factors for these entities below.
Kleine–Levin Syndrome KLS is a rare disease characterized by recurrent episodes of hypersomnia and, to varying degrees, compulsive eating, cognitive changes, depression, irritability, and hypersexuality. It mainly afflicts teenage males. Some authors have described KLS with and without compulsive eating as distinct entities. A comprehensive review on KLS revealed that precipitating factors were present in 61% of patients. The most frequently reported was a minor infection such as a nonspecific fever, flulike illness, upper respiratory tract infection, or tonsillitis. Less commonly cited was summer gastroenteritis or a more severe infection. Urinary tract or eye infections were never reported. Infectious agents were rarely identified, but when detected included Epstein–Barr virus, varicella-zoster virus, enterovirus, posttyphoid vaccine, scarlet fever, and Streptococcus in the context of sepsis. Other reported triggers include alcohol consumption, marijuana use, head trauma (e.g., knock-out during boxing), physical exertion, and psychological distress. In addition, surgery with general or local (dental) anesthesia, lactation, and menses have also been reported at KLS onset. Personal or familial psychiatric history has been detected in only a small number of cases. Events that trigger subsequent episodes are less commonly described, but include a high proportion of infections, as well as surgery with anaesthesia, physical or mental effort, sunstroke, alcohol, jet lag, and attacks of hemiplegic migraine. No definite genetic predisposing factors have been uncovered in KLS. HLA-DQB1 typing performed in more than 100 patients with KLS did not differ between cases and control subjects in the HLA DR and DQ alleles. Several familial cases of KLS have been reported (about 4% of cases); however, these cases did not differ from sporadic cases in their features. At the time of writing this article, genome-wide mapping studies had not been performed in KLS, and no twin cases of KLS were reported in the literature.
Menstrual-Related Hypersomnia In menstrual-related hypersomnia, the triggers include menarche, menstruation alone or with an additional trigger (e.g., an infection, Girl Scout outing, exposure to alcohol, etc.) and puerperium. Each episode tends to be preceded by a triggering event; however, events do not occur with each menstruation or puerperium.
According to the ICSD-2, the diagnostic criteria of recurrent hypersomnia (RH) are as follows:
Recurrent Hypersomnia with Comorbidity
A) The patient experiences recurrent episodes of excessive sleepiness of two days’ to four weeks’ duration.
Recurrent hypersomnia has also been described in the context of numerous medical conditions. Associated conditions include
394
Features, Factors, and Characteristics of Hypersomnias | Risk Factors for Hypersomnias
metabolic encephalopathy, flu-like illness, upper airway infection, head trauma, acute viral encephalitis, stroke, brain tumor, paraneoplastic syndrome, genetic conditions (e.g., PWS and incontinentia pigmenti), and pervasive developmental disorders such as autism or Asperger’s disease.
Idiopathic Hypersomnia Idiopathic hypersomnia (IH) is less common and more poorly defined than narcolepsy. IH remains a diagnosis of exclusion, and polysomnography is needed to rule out other causes of hypersomnia. The current ICSD-2 definition distinguishes IH with and without long sleep time. In the former, patients have EDS despite at least 10 hours of sleep per night. They rarely awaken from sleep, have difficulty with arousal, and sleep (including naps) is not refreshing; ‘sleep drunkenness’ is prominent. In contrast, patients with IH without long sleep time have less prominent sleep drunkenness and sleep fewer than 10 hours per night. A review of 77 cases of IH reported that approximately one-third of patients with this condition had a family history of similar problems. Of the patients who underwent haplotype analysis, only 18% (7/39) were positive for the HLADQB1*0602 antigen, compared to 98% (61/62) of the patients with narcolepsy. There was a carrier frequency of 10% (4/39) for the Cw2 antigen in the patients with IH. No clear genetic marker was identified. The same review noted that there was no precipitant in the majority of cases of IH, with only 4% (3/77) of patients reporting a transient viral illness at the time of symptoms. An earlier review also noted the onset of symptoms with a viral illness, as well as with head trauma and prominent psychiatric symptoms. Once again, triggers were noted in only a minority of cases.
Behaviorally Induced Insufficient Sleep Syndrome Behaviorally Induced Insufficient sleep syndrome is the most common cause of EDS in the general population. Those who may be at particular risk include young adults, parents of children under the age of 18 years, shift workers, healthcare professionals, and those in transportation jobs. Other reported risk factors for insufficient sleep include smoking, the consumption of tobacco in a smokeless fashion, and secondhand smoke exposure. Among adolescents, extrinsic factors play a major role, including social interactions with friends, videogame use, extracurricular activities, early start times for classes, and poor sleep hygiene. Intrinsic factors may also play a role; for example, during puberty, the timing of melatonin release has been shown to change, shifting the adolescent’s circadian rhythm so that they feel sleepy later in the evening compared to earlier in life.
Hypersomnia Due to Medication The use of many drugs is associated with EDS. These include benzodiazepines, barbiturates, antidepressants, antipsychotics, and antihistaminergic medications. Limited research has
investigated the role of genetic influences on medicationinduced hypersomnia; however, genetic susceptibility has been reported with some medications. For example, a Japanese study demonstrated that the CYP2D6*10 allele was a risk factor for adverse events caused by H1 antihistamines. In addition, the occurrence of hypersomnia increased as the number of CYP2D6 mutant alleles increased. Another study reported an increased incidence of hypersomnolence during clozapine therapy in patients with a CLOCK (circadian locomotor output cycles kaput) gene polymorphism (3111T/C substitution). The effects of drug interactions can also be mediated by genetic factors. For example, in a patient with ultrahigh activity of CYP2C9, the addition of fluconazole, which is a potent inhibitor of CYP2C9, caused phenytoin intoxication despite use of the patient’s usual dose. Finally, the treatment of the EDS seen in narcolepsy is also modulated by genetic influences. For example, the functional polymorphism of the catechol-O-methyltransferase (COMT) gene is critically involved in the severity of narcolepsy and in the response to the stimulant modafinil.
Hypersomnia Due to a Medical Condition Several studies have examined the genetic factors implicated in the ‘sleep attacks’ and hypersomnia seen in Parkinson’s disease. The dopamine D2 receptor gene polymorphism Taq IA and the variant allele T of the (909T/C) preprohypocretin polymorphism have both been reported to be more commonly found in patients with Parkinson’s disease who experience sleep attacks. In patients experiencing sleep attacks without warning signs, an association has been reported with the dopamine receptor D4*2 (short) allele. Of note, the initially described association between daytime sleepiness and the COMT val158met polymorphism (rs4680) could not be confirmed in a larger study. Risk factors for the development of disease-induced hypersomnia have only been studied in a few other conditions. In cognitively normal apolipoprotein E e4 homozygotes, chronic daytime sleepiness has been reported in association with a distinctive decline in verbal memory. In patients with Sjogren’s syndrome, the dose of the þ49A;CT60G haplotype of the cytotoxic T lymphocyte-associated antigen 4 gene has been reported to be associated with the severity of daytime sleepiness. Finally, in a population-based sample of more than 5000 elderly male twins, EDS and depressive symptoms were found to have a significant genetic correlation; however, after covariate adjustment, the majority of individual variation in daytime sleepiness and depressive symptoms was attributable to individual-specific environmental factors.
See also: Descriptions of Hypersomnias: Behaviorally Induced Insufficient Sleep Syndrome; Hypersomnia Due to Drug or Substance; Idiopathic Hypersomnia with Long Sleep Time; Idiopathic Hypersomnia without Long Sleep Time; Narcolepsy due to a Medical Condition; Narcolepsy with Cataplexy; Narcolepsy without Cataplexy; Recurrent Hypersomnia; Features, Factors, and Characteristics of Hypersomnias: Epidemiology of Hypersomnia; Familial and Genetic
Features, Factors, and Characteristics of Hypersomnias | Risk Factors for Hypersomnias
Factors of Narcolepsy; Instrumentation and Methodology: Multiple Sleep Latency Test (MSLT); Sleep Loss in Disease States: Sleep Loss Associated with Medical Conditions and Diseases; Special Conditions, Disorders, and Clinical Issues for Hypersomnias: Medications and Sleep.
Further Reading American Academy of Sleep Medicine (2005) International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. Westchester, IL: American Academy of Sleep Medicine. Anderson KN, Pilsworth S, Sharples LD, Smith IE, and Shneerson JM (2007) Idiopathic hypersomnia: A study of 77 cases. Sleep 30: 1274–1281. Aran A, Lin L, Nevsimalova S, et al. (2009) Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 32: 979–983. Arnulf I, Zeitzer JM, File J, Farber N, and Mignot E (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. Billiard M, Jaussent I, Dauvilliers Y, and Besset A (2011) Recurrent hypersomnia: A review of 339 cases. Sleep Medicine Reviews 15: 247–257. Boulos MI and Murray BJ (2010) Current evaluation and management of excessive daytime sleepiness. Canadian Journal of Neurological Sciences 37: 167–176. Bourgin P, Zeitzer JM, and Mignot E (2008) CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurology 7: 649–662. Cvetkovic-Lopes V, Bayer L, Dorsaz S, et al. (2010) Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. The Journal of Clinical Investigation 120: 713–719. Dauvilliers Y, Arnulf I, and Mignot E (2007) Narcolepsy with cataplexy. The Lancet 369: 499–511. Dauvilliers Y, Montplaisir J, Cochen V, et al. (2010) Post-H1N1 narcolepsy-cataplexy. Sleep 33: 1428–1430.
395
Frenette E and Kushida CA (2009) Primary hypersomnias of central origin. Seminars in Neurology 29: 354–367. Hallmayer J, Faraco J, Lin L, et al. (2009) Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature Genetics 41: 708–711. Havaligi N, Matadeen-Ali C, Khurana DS, Marks H, and Kothare SV (2007) Treatment of drop attacks in Coffin–Lowry syndrome with the use of sodium oxybate. Pediatric Neurology 37: 373–374. Lattuada E, Cavallaro R, Benedetti F, Cocchi F, Lorenzi C, and Smeraldi E (2004) Genetic dissection of drug effects in clinical practice: CLOCK gene and clozapine-induced diurnal sleepiness. Neuroscience Letters 367: 152–155. Longstreth WT Jr., Koepsell TD, Ton TG, Hendrickson AF, and van Belle G (2007) The epidemiology of narcolepsy. Sleep 30: 13–26. Mignot E, Lin X, Arrigoni J, et al. (1994) DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans. Sleep 17(Suppl 8): S60–S67. Nishino S and Kanbayashi T (2005) Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Medicine Reviews 9: 269–310. Parkes JD (1999) Genetic factors in human sleep disorders with special reference to Norrie disease, Prader–Willi syndrome and Moebius syndrome. Journal of Sleep Research 8(Suppl 1): S14–S22. Saruwatari J, Matsunaga M, Ikeda K, et al. (2006) Impact of CYP2D6*10 on H1-antihistamine-induced hypersomnia. European Journal of Clinical Pharmacology 62: 995–1001. Sehgal A and Mignot E (2011) Genetics of sleep and sleep disorders. Cell 146: 194–207. Smit LS, Lammers GJ, and Catsman-Berrevoets CE (2006) Cataplexy leading to the diagnosis of Niemann–Pick disease type C. Pediatric Neurology 35: 82–84. Tafti M and Dauvilliers Y (2003) Pharmacogenomics in the treatment of narcolepsy. Pharmacogenomics 4: 23–33. Vossler DG, Wyler AR, Wilkus RJ, Gardner-Walker G, and Vlcek BW (1996) Cataplexy and monoamine oxidase deficiency in Norrie disease. Neurology 46: 1258–1261. Young TJ and Silber MH (2006) Hypersomnias of central origin. Chest 130: 913–920.