Narcolepsy and cataplexy

Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 48

Narcolepsy and cataplexy 1

SEIJI NISHINO 1, 2 * AND EMMANUEL MIGNOT 1 Stanford University School of Medicine and Center for Narcolepsy, Stanford Sleep Research Center, Palo Alto, CA, USA 2

Circadian Neurobiology Laboratory, Palo Alto, CA, USA

INTRODUCTION Narcolepsy is a syndrome characterized by “excessive daytime sleepiness (EDS) that is typically associated with cataplexy and other REM sleep phenomena such as sleep paralysis and hypnagogic hallucinations” (American Academy of Sleep Medicine, 2005). Cataplexy, the sudden occurrence of muscle weakness in association with emotions such as laughing, joking, or anger, has long been considered a pathognomonic symptom of the syndrome (Guilleminault, 1994; Aldrich, 1996; Nishino and Mignot, 1997; Anic-Labat et al., 1999; Overeem et al., 2001a; Dauvilliers et al., 2003a). A broader definition of narcolepsy includes patients with sleepiness and abnormal rapid eye movement (REM) sleep, such as sleep-onset REM periods (SOREMPs) during the Multiple Sleep Latency Test (MSLT), sleep paralysis, or hypnagogic hallucinations (American Academy of Sleep Medicine, 2005). Disturbed nocturnal sleep is also central to the syndrome (Guilleminault, 1994; Aldrich, 1996; Nishino and Mignot, 1997; Anic-Labat et al., 1999; Overeem et al., 2001a; Dauvilliers et al., 2003a). The definition of narcolepsy was revised recently, owing to recent scientific advances. In most patients with cataplexy, a deficiency in the neuropeptide system hypocretin is involved in the pathophysiology of human narcolepsy (Nishino et al., 2000b, 2001b; Peyron et al., 2000; Thannickal et al., 2000; Kanbayashi et al., 2002; Krahn et al., 2002; Mignot et al., 2002). A tight association with the human leukocyte antigen (HLA) DQB1*0602 is also usually found in patients with cataplexy (Mignot et al., 1997a, 2001). In contrast, most patients with narcolepsy without cataplexy are

HLA-DQB1*0602 negative and do not have hypocretin deficiency, as measured in the cerebrospinal fluid (CSF) (Kanbayashi et al., 2002; Mignot et al., 2002; Dauvilliers et al., 2003b). Hypocretin deficiency is likely to be due to postnatal hypocretin cell loss, possibly through autoimmune mechanisms, but the etiology involved in this process has not been elucidated. Based on the pathophysiological differences, narcolepsy with and without cataplexy has been separated in the most recent revision of the International Classification of Sleep Disorders, second edition (ICSD-2) (see Table 48.1) (American Academy of Sleep Medicine, 2005). Since hypocretin deficiency can be clinically assessed by measuring hypocretin-1 in the CSF, CSF hypocretin-1 evaluations are now included as one of the possible diagnostic criteria for narcolepsy–cataplexy in the ICSD-2 (American Academy of Sleep Medicine, 2005). Narcolepsy is currently treated with amfetaminelike central nervous system (CNS) stimulants (for EDS) and antidepressants (for cataplexy). Some other classes of compounds, such as modafinil (a nonamfetamine wake-promoting compound for EDS) and g-hydroxybutyrate (GHB, a short-acting sedative for EDS/fragmented nighttime sleep and cataplexy, given at night), are also employed. Hypocretin replacement is also likely to be a new therapeutic option for patients with hypocretin-deficient narcolepsy, but this is still not available for use in humans. The development of small-molecule synthetic hypocretin agonists is likely required for this option to become viable. In this chapter, the clinical, pathophysiological, and pharmacological aspects of narcolepsy are discussed.

*Correspondence to: Seiji Nishino MD, PhD, Stanford University, Sleep and Circadian Neurobiology Laboratory and Center for Narcolepsy, 1201 Welch Road RM213, Palo Alto, CA 94304-5489, USA. Tel: (650) 723-3724, Fax: (650) 723-5873, E-mail: [email protected]

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EPIDEMIOLOGY The prevalence of narcolepsy The prevalence of narcolepsy has been investigated in multiple ethnic groups and countries. One of the most sophisticated prevalence studies was performed using a Finnish cohort consisting of 11,354 twin individuals (Hublin et al., 1994b). All subjects who responded to a questionnaire with answers suggestive of narcolepsy were contacted by telephone. Clinical interviews were performed and polysomnographic (PSG) recordings conducted in five subjects considered likely to have narcolepsy–cataplexy. Sleep monitoring finally identified three narcoleptic subjects with cataplexy, thus leading to a prevalence of 0.026% (Hublin et al., 1994b). All three subjects were dizygotic twins: cotwins were not affected. Other prevalence studies have led to similar prevalence values (0.02–0.067%) in Great Britain (Ohayon et al., 1996), France (Ondze´ et al., 1999), the Czech Republic (Roth, 1980), five European countries (Ohayon et al., 2002), and the USA (Dement et al., 1973; Silber et al., 2002). A study performed in 1945 in African American navy recruits also showed a prevalence of 0.02% in this ethnic group for narcolepsy–cataplexy (Solomon, 1945). Narcolepsy–cataplexy may be more frequent in Japan and less frequent in Israel. Two populationbased prevalence studies led to 0.16% and 0.18% prevalence figures in Japan (Honda, 1979; Tashiro et al., 1994). However, these studies used only questionnaires and interviews, but not polysomnography, to confirm the diagnosis. In Israel, only a few narcoleptic patients have been identified from the large population of subjects recruited into sleep clinics (Lavie and Peled, 1987). This has led to the suggestion that the prevalence of narcolepsy could be as low as 0.002% in this country/ ethnic group. It is notable to notice that the carrier frequency of DQB1*0602 is lowest in Israel (6%), followed by Japan and Korea (12%), North American and northern European Caucasians (25%), and African Americans (32%). Onset is variable in terms of age and may appear as either progressive or sudden. Age of onset distribution covers the entire age range from early childhood to 50 years of age (Okun et al., 2002). Two peaks, a larger one occurring at around 15 years of age and a smaller peak at approximately 36 years, have been reported (Dauvilliers et al., 2001b). Similar results were found in two different populations, although the reasons for this bimodal distribution remain obscure. The incidence of the disease was reported to be 1.37/100 000 per year (1.72 for men and 1.05 for women) in Olmsted County in Minnesota, and the incidence rate was highest in the second decade, followed in descending order by the third, fourth, and first decade (Silber et al., 2002).

Genetic versus environmental factors A familial tendency for narcolepsy has been recognized since its description in the late 19th century (Westphal, 1877). Starting in the 1940s, several studies were published that investigated the familial history of small cohorts of narcoleptic probands (Krabbe and Magnussen, 1942; Yoss and Daly, 1960; NevsimalovaBruhova and Roth, 1972; Baraitser and Parkes, 1978; Kessler et al., 1979; Honda et al., 1983). Using standard diagnostic criteria, more recent studies have shown rates of familial cases as 4.3% in Japan (Honda, 1988), 6% in the USA (Guilleminault et al., 1989), 7.6% in France (Dauvilliers et al., 2001b), and 9.9% in Canada (Dauvilliers et al., 2001b). In addition to subjects who fulfill all diagnostic criteria for narcolepsy– cataplexy, other relatives may report isolated recurrent sleep episodes and unexplained EDS; these subjects may suffer from an incomplete and milder form of the disorder (Billiard et al., 1994). Studies also revealed that the risk of a first-degree relative developing narcolepsy–cataplexy is 1–2.0%, 10 to 40 times higher than the risk in the general population (Billiard et al., 1994; Hublin et al., 1994a; Mignot, 1998). A limited number of twin cases studies have been published. Of 16 monozygotic (MZ) twin pairs with at least one affected twin, only four (or five depending on the criteria used for concordance) were concordant (Mignot, 1998). Although genetic predisposition is likely to be involved in the development of narcolepsy, the relatively low rate of concordance in narcoleptic MZ twins indicates that environmental factors also play a role in the development of the disorder. The nature of the possible environmental factors involved is not known. Frequently cited factors are head trauma (Lankford et al., 1994), sudden change in sleep/wake habits (Orellana et al., 1994), and various infections (Roth, 1980). Although these factors may be involved, there are no documented studies demonstrating increased frequency when compared to multiple control groups. Methodological issues such as bias recall or, in the case of changes in sleep–wake habits, the possibility of an early narcolepsy symptom have not been excluded.

SYMPTOMS OF NARCOLEPSY Sleepiness or excessive daytime sleepiness (EDS) EDS and cataplexy are considered the two primary symptoms of narcolepsy. EDS most typically mimics the feeling that people experience when they are severely sleep deprived. It may, however, also manifest as a chronic tiredness or fatigue. Narcoleptic subjects

NARCOLEPSY AND CATAPLEXY generally experience a permanent background of baseline sleepiness that easily leads to actual sleep episodes in monotonous sedentary situations. This feeling is most often relieved by short naps (15–30 minutes), but in most cases the refreshed sensation lasts for only a short time after awaking (Table 48.1). The refreshing value of short naps is of diagnostic value. Sleepiness also occurs in irresistible waves in these patients, a phenomenon best described as “sleep attacks”. Sleep attacks may occur in very unusual circumstances, such as in the middle of a meal or conversation, or while riding a bicycle. These attacks are often accompanied by microsleep episodes (Guilleminault, 1987) where the patient “blanks out”. The patient may then continue his or her activity in a semiconscious manner (writing incoherent phrases in a letter, speaking incoherently on the phone, etc.), a phenomenon called automatic behavior (Broughton and Ghanem, 1976; Dement, 1976; Guilleminault, 1987). Learning problems and impaired concentration are frequently associated (Broughton and Ghanem, 1976; Dement, 1976; Guilleminault, 1987; Cohen and Smith, 1989; Rogers and Rosenberg, 1990), but psychophysiological testing is generally normal. Sleepiness is usually the first symptom to appear, followed by cataplexy, sleep paralysis, and hypnagogic hallucinations (Yoss and Daly, 1957; Parkes et al., 1975; Roth, 1980; Billiard et al., 1983; Honda, 1988). Cataplexy onset occurs within 5 years after the occurrence of daytime somnolence in approximately two-thirds of cases (Roth, 1980; Honda, 1988). Less frequently, cataplexy appears many years after the onset of sleepiness. The mean age of onset of sleep paralysis and hypnagogic hallucinations is 2–7 years later than that of sleepiness (Kales et al., 1982; Billiard et al., 1983). In most cases, EDS and irresistible sleep episodes persist throughout the lifetime, although they often improve after retirement (possibly due to better management of activities, daytime napping, and adjustment of nighttime sleep).

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emotions (such as laughter, having a good hand at a card game, the pull of the fishing rod with a biting fish, the perfect hit at a baseball game) and less frequently by negative emotions (most typically anger or frustration). All antigravity muscles can be affected, leading to a progressive collapse of the subject. Respiration is not affected, although a feeling of oppression may be reported. The patient is typically awake at the onset of the attack but may experience blurred vision or ptosis. The attack is almost always bilateral and usually lasts for a few seconds to a minute. Neurological examination performed at the time of an attack shows a suppression of the patellar reflex and sometimes Babinski’s sign. Cataplexy is an extremely variable clinical symptom (Gelb et al., 1994). Most often, it is mild and occurs as a simple buckling of the knees, head dropping, facial muscle flickering, sagging of the jaw, or weakness in the arms. Slurred speech or mutism is also frequently associated. It is often imperceptible to the observer and may even be only a subjective feeling, such as a feeling of warmth or that somehow time is suspended (Wilson, 1927; Gelb et al., 1994). In other cases, it escalates to actual episodes of muscle paralysis that may last for up to several minutes. Falls and injury are rare, and most often the patient will have time to find support or to sit down while the attack is occurring. Long episodes occasionally blend into sleep and may rarely be associated with hypnagogic hallucinations. Patients may also experience “status cataplecticus”. This rare manifestation of narcolepsy is characterized by cataplexy that lasts several hours per day and confines the subject to bed. It can occur spontaneously or more often upon withdrawal from anticataplectic drugs (Passouant et al., 1970; Parkes et al., 1975; Hishikawa and Shimizu, 1995). Cataplexy often improves with advancing age. In rare cases, it disappears completely but in most patients it is better controlled (probably after the patient has learned to control his or her emotions) (Billiard et al., 1983; Rosenthal et al., 1990).

Cataplexy Cataplexy is distinct from EDS and pathognomonic of the disease (Guilleminault et al., 1974). The importance of cataplexy for the diagnosis of narcolepsy has been recognized since its description (Lo¨wenfeld, 1902; Henneberg, 1916) and in subsequent reviews on narcolepsy (Wilson, 1927; Daniels, 1934). Most authors now recognize patients with recurring sleepiness and cataplectic attacks as representing a homogeneous clinical entity; this has not been substantiated by the tight association with DQB1*0602 and hypocretin deficiency (see section on Pathophysiology). Cataplexy is defined as a sudden episode of muscle weakness triggered by emotional factors, most often in the context of positive

Sleep paralysis Sleep paralysis is present in 20–50% of all narcoleptic subjects (Yoss and Daly, 1960; Parkes et al., 1974; Hishikawa, 1976; Roth, 1980). It is often associated with hypnagogic hallucinations. Sleep paralysis is best described as a brief inability to perform voluntary movements at the onset of sleep, upon awakening during the night, or in the morning. Contrary to simple fatigue or locomotion inhibition, the patient is unable to perform even a small movement, such as lifting a finger. Sleep paralysis may last a few minutes and is often finally interrupted by noise or other external stimuli. The symptom is occasionally bothersome in

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Table 48.1 Clinical characteristics of narcolepsy–cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia Daytime sleepiness

Duration

Without long sleep time

Short (<30 min) Short (<30 min) Variable

(þ) (þ) ()

Long (>30 min)

()

Variable

()

SOREMPs

HLA-DQB1*0602 positivity

8 min*

2

>90%

8 min*

2

40–50%

8 min*

2

Not studied systematically

8 min*

1

No consistent results

Normal

8 min*

1

No consistent results

Normal

Other symptoms Cataplexy REM sleep-related symptoms Cataplexy () REM sleep-related symptoms With and without cataplexy REM sleep-related symptoms

Cataplexy () Prolonged nighttime sleep (10 h) Autonomic nervous system dysfunction Cataplexy () No prolonged nighttime sleep (<10 h) Autonomic nervous system dysfunction

Low CSF hypocretin-1 level (<110 pg/ml)

Sleep latency

85–90% >90% in HLA positive 10–20% (all HLA positive) Most cases studied{

*As per International Classification of Sleep Disorders, second edition (ICSD-2); previous ICSD classifications suggested 5 min. {CSF hypocretin-1 measurements have been studied in a limited number of cases of secondary narcolepsy. CSF, lumbar sac cerebrospinal fluid; HLA, human leukocyte antigen; MSLT, Multiple Sleep Latency Test; SOREMPs, sleep-onset rapid eye movement sleep periods.

S. NISHINO AND E. MIGNOT

Narcolepsy– cataplexy Narcolepsy without cataplexy Secondary narcolepsy (due to the medical condition) Idiopathic hypersomnia With long sleep time

Awaken refreshed

MSLT

NARCOLEPSY AND CATAPLEXY narcoleptic subjects, especially when associated with frightening hallucinations (Rosenthal, 1939). Whereas EDS and cataplexy are cardinal symptoms of narcolepsy, sleep paralysis occurs frequently as an isolated phenomenon, affecting 5–40% of the general population (Goode, 1962; Fukuda et al., 1987; Dahlitz and Parkes, 1993). Occasional episodes of sleep paralysis are often seen in adolescence and after sleep deprivation, and the prevalence is therefore high for single-episode occurrences.

Hypnagogic and hypnopompic hallucinations Abnormal visual (most often) or auditory perceptions that occur while falling asleep (hypnagogic) or upon waking up (hypnopompic) are frequently observed in narcoleptic subjects (Ribstein, 1976). These hallucinations are often unpleasant and typically associated with a feeling of fear or threat (Rosenthal, 1939; Hishikawa, 1976). Polygraphic studies indicate that these hallucinations occur most often during REM sleep (Hishikawa, 1976; Chetrit et al., 1994). These episodes are often difficult to distinguish from nightmares or unpleasant dreams, which also occur frequently in narcolepsy. Hypnagogic hallucinations are most often associated with sleep attacks. Importantly, unlike in schizophrenia, the hallucinatory content is well recognized by the patient. The hallucinations are most often complex, vivid, dream-like experiences (“half sleep” hallucinations) and may follow episodes of cataplexy or sleep paralysis, a feature that is not uncommon in severely affected patients. These hallucinations are usually easy to distinguish from hallucinations observed in schizophrenia, but the two conditions can coexist.

Other important associated symptoms One of the most frequently associated symptoms is insomnia, best characterized as a difficulty in maintaining nighttime sleep. Typically, narcoleptic patients fall asleep easily, only to wake up after a short time unable to fall asleep again for an hour or so. Narcoleptic patients do not usually sleep more than normal individuals over the 24-hour cycle (Hishikawa et al., 1976; Montplaisir et al., 1978; Broughton et al., 1988b) but frequently have a very disrupted nighttime sleep (Hishikawa et al., 1976; Montplaisir et al., 1978; Broughton et al., 1988b). This symptom often develops later in life and can be very disabling. Other frequently associated sleep problems include periodic leg movements (Mosko et al., 1984; Godbout and Montplaisir, 1985), REM behavior disorder, other parasomnias (Schenck and Mahowald, 1992; Mayer et al., 1993),

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and obstructive sleep apnea (Guilleminault et al., 1976; Mosko et al., 1984; Chokroverty, 1986). Narcolepsy is also associated with changes in energy homeostasis regulation. Narcoleptic patients are frequently obese (Honda et al., 1986; Schuld et al., 2000), have insulin-resistant diabetes mellitus more frequently (Honda et al., 1986), exhibit reduced food intake (Lammers et al., 1996), and have lower blood pressure and temperature (Sachs and Kaisjer, 1980; Mayer et al., 1997). These findings have not received much attention, as they have long been believed to be secondary to sleepiness or inactivity. More recently, however, it was shown that these metabolic changes are specific to hypocretin-deficient patients (Hara et al., 2001; Nishino et al., 2001b), suggesting a more direct pathophysiological link. Additional research in this area is warranted to clarify this association. Plazzi et al. (2006) recently reported on two children (aged 7 years) with narcolepsy–cataplexy associated with obesity and precocious puberty. These subjects were HLA-DQB1*0602 positive and had low CSF levels of hypocretin-1. Although it is not known whether these symptoms are due to impaired hypocretin neurotransmission or broader hypothalamic abnormalities (e.g., in the context of an inflammatory process toward hypocretin cells), these cases are informative for understanding the pathophysiology of hypocretin cell death. The association with precocious puberty may be more common, because this symptom is noted only in early-onset cases. Narcolepsy is a very incapacitating disease. It interferes with every aspect of life. The negative social impact of narcolepsy has been studied extensively. Patients experience impairments in driving and a high prevalence of either car or machine-related accidents. Narcolepsy also interferes with professional performance, leading to unemployment, frequent changes of employment, working disability, or early retirement (Broughton et al., 1981; Aldrich, 1989; Alaila, 1992). Several subjects also develop symptoms of depression, although these symptoms are often masked by anticataplectic medications (Roth and Nevsimalova, 1975; Broughton and Ghanem, 1976; Broughton et al., 1981).

ANIMAL MODELS OF NARCOLEPSY Canine narcolepsy models In the past 20 years, narcolepsy research has been facilitated by the existence of a unique animal model, canine narcolepsy. Canine narcolepsy was first reported in the early 1970s in two small breeds by Knecht et al. (1973) and Mitler et al. (1974). Early attempts to establish genetic transmission were unsuccessful, suggesting a

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nongenetic etiology in most cases of canine narcolepsy. In 1975, two narcoleptic Dobermans were reported in a single litter (Baker et al., 1982). The breeding of these animals led the demonstration that narcolepsy was transmitted as a single autosomal recessive gene with full penetrance in this breed. A narcoleptic colony of Doberman Pinschers was then established and maintained at Stanford University for more than 20 years. Familial canine narcolepsy was also reported in Labrador Retrievers and Dachshunds (Baker et al., 1982; Hungs et al., 2001). Interestingly, experiments indicate that animals heterozygous for the canine narcolepsy gene have subclinical abnormalities such as increased daytime sleepiness. In heterozygous animals, the administration of drugs that increase cholinergic and reduce monoaminergic transmissions (manipulations known to promote REM sleep) has been shown to induce cataplexy at specific developmental times (Mignot et al., 1993b). The parallel between human and canine narcolepsy is striking. In MSLT-like procedures, narcoleptic canines have short sleep and short REM latencies (Nishino et al., 2000c). Twenty-four-hour recording studies show sleep fragmentation and more daytime sleep than in control animals (Kaitin et al., 1986). Finally, as in human narcolepsy, sudden episodes of muscle weakness akin to cataplexy can be observed in association with strong positive emotions, most typically during the presentation of appetizing food or while at play. These episodes usually last a few seconds and preferentially affect hind legs, neck, or face. Cataplexy may also escalate into complete muscle paralysis with abolition of tendon reflexes. During these episodes, the animal is conscious and able visually to track nearby movement (for a video, see: http://www. med.stanford.edu/school/Psychiatry/narcolepsy/). Polygraphic recording indicates a desynchronized, wakelike EEG pattern at the onset of cataplexy, followed by increased theta activity and genuine REM sleep in long-lasting episodes (Kushida et al., 1985). Sequential pictures of cataplectic attacks in a narcoleptic Doberman are presented in Figure 48.1. The cause of autosomal recessive canine narcolepsy was identified through positional cloning (Lin et al., 1999; Hungs et al., 2001). Three mutations causing a complete dysfunction of a receptor for the newly identified neuropeptide system hypocretin (the hypocretin receptor 2 or Hcrtr2) were identified in Doberman, Labrador, and Dachshund pedigrees (Lin et al., 1999; Hungs et al., 2001) (Figure 48.2, Table 48.2). Sporadic cases of canine narcolepsy were later shown to be associated with low CSF and brain hypocretin levels (Ripley et al., 2001a), as found in human narcolepsy (Nishino et al., 2000b; Peyron et al., 2000; Thannickal

et al., 2000; Mignot et al., 2002) (see Table 48.2) (see section on Hypocretin deficiency in human narcolepsy and Figure 47.3 in Chapter 47).

Rodent narcolepsy models Several rodent models of narcolepsy are now also available (see Table 48.2). In one model, Chemelli et al. (1999) knocked out the preprohypocretin gene. The resulting model has fragmented sleep, transitions from wakefulness into REM sleep, and episodes of behavioral arrests akin to cataplexy or sleep-onset paralysis (Chemelli et al., 1999). In another model, a toxic transgene derived from an ataxin-3 human gene mutation (from a patient with Machado–Joseph disease), was driven by the preprohypocretin promoter, resulting in narcoleptic mice lacking hypocretin-containing cells (Hara et al., 2001). Rodents lacking either of the two hypocretin receptors, Hcrtr1 or Hcrtr2, are also available (Kisanuki et al., 2000; Willie et al., 2003). In these models, only Hcrtr2 receptor knockout animals experience behavioral arrest episodes similar to cataplexy. Interestingly, however, Hcrtr1 knockout animals have fragmented sleep but no behavioral arrest episodes (Kisanuki et al., 2000; Willie et al., 2003). It is also suggested that Hcrtr2 receptor knockout animals are less affected than hypocretin peptide knockout animals, suggesting a role for Hcrtr1 in increasing the severity of the phenotype (Willie et al., 2003). The rodent models are revolutionizing research in the area. Importantly, however, it is difficult to differentiate cataplexy from REM sleep onset or sleep paralysis in these models. The link between behavioral arrest and positive emotions is unclear and a systematic pharmacological characterization has not been performed (see the pharmacology section below).

NARCOLEPSY EVALUATION Diagnostic criteria for narcolepsy with and without cataplexy The clinical diagnosis of narcolepsy with cataplexy is based on the presence of EDS and/or sudden onsets of sleep occurring almost daily during a period of at least 3 months and on the presence of a clear clinical history of cataplexy (American Academy of Sleep Medicine, 2005). The EDS is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication, or substance use disorder (American Academy of Sleep Medicine, 2005). In the ISCD-2, it is described that the diagnosis of narcolepsy with cataplexy should, whenever possible, be confirmed by nocturnal polysomnography followed by a MSLT; in narcolepsy, MSLT mean sleep

NARCOLEPSY AND CATAPLEXY

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Fig. 48.1. Cataplectic attacks in Doberman pinschers. Emotional excitations, appetizing food, or playing readily elicit multiple cataplectic attacks in these animals, mostly bilateral (97.9%). Atonia initiated partially in the hind legs (79.8%), front legs (7.8%), neck/face (6.2%), or whole body/complete attacks (6.2%). Progression of attacks was also seen (49% of all attacks) (Fujiki et al., 2002).

latency is 8 minutes or less and more than two SOREMPs are observed despite sufficient nocturnal sleep prior to the test (American Academy of Sleep Medicine, 2005) (see Table 48.1). The MSLT is, however, not mandatory, and a clear history of typical and frequent cataplexy is most relevant to the diagnosis of narcolepsy with cataplexy (American Academy of Sleep Medicine, 2005). In contrast, the diagnosis of narcolepsy without cataplexy is mostly made by polygraphic findings and EDS (almost daily for a period of at least 3 months). REM sleep-related abnormalities (SOREMPs) should be confirmed by nocturnal

polysomnography followed by a MSLT (American Academy of Sleep Medicine, 2005). The regular MSLT consists of five naps, scheduled at 2-hour intervals starting between 9 and 10 a.m. (Richardson et al., 1978; Carskadon et al., 1986; Chervin et al., 1995). The test is terminated after a sleep period of 15 minutes, or after 20 minutes if the patient did not fall asleep. SOREMPs are defined as the occurrence of REM sleep within 15 minutes after sleep onset. Alternatively to the MSLT findings, CSF hypocretin measures can be applied; hypocretin-1 levels in the CSF are 110 pg/ml or less, or one-third of mean normal control

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Fig. 48.2. Genomic organization of the canine Hcrtr2 locus. The Hcrtr2 gene is encoded by seven exons. Sequence of the exon–intron boundary at the site for deletion of the transcript revealed that the canine short interspersed nucleotide element (SINE) was inserted 35 base pairs (bp) upstream of the 50 splice donor site of the fourth encoded exon in narcoleptic Doberman Pinschers. This insertion falls within the 50 flanking intronic region needed for pre-mRNA Lariat formation and proper splicing, causing exon 3 to be spliced directly to exon 5, and exon 4 to be omitted. This mRNA potentially encodes a nonfunctional protein with 38 amino acids deleted within the fifth transmembrane domain, followed by a frameshift and a premature stop codon at position 932 in the encoded RNA. In narcoleptic Labradors, the insertion was found 5 bp downstream of the 30 splice site of the fifth exon, and exon 5 is spliced directly to exon 7, omitting exon 6.

values. Low CSF hypocretin-1 levels are found in over 90% of patients with narcolepsy with cataplexy, and almost never in controls or rarely in other pathologies (see section on CSF hypocretin-1 levels). A nocturnal polysomnogram is useful for eliminating other possible causes of EDS such as periodic leg movements and obstructive sleep apnea prior to the MSLT. The diagnosis of upper airway resistance syndrome must also be considered very carefully. Sleep efficiency during nocturnal polysomnography may be normal or low. The diagnostic value of the MSLT for narcolepsy has been questioned by some authors (Lammers and Van Dijk, 1992; Moscovitch et al., 1993) on the basis of its specificity and sensitivity. First, approximately 15% of narcoleptic subjects with clearcut cataplexy do not have a short sleep latency and/or more than two SOREMPs during a single MSLT (Moscovitch et al., 1993; Mignot et al., 2002). Conversely, a small number

of patients with abnormal breathing may display typical narcolepsy-like MSLT results. As the prevalence of upper airway resistance syndrome and sleep apnea is 100 times greater than narcolepsy–cataplexy, false positives may be frequent if the test is interpreted without carefully excluding all other causes of EDS (Aldrich, 1993). A recent study in the general population also found that 3.6% of 556 adults had a MSLT finding consistent with narcolepsy (mean sleep latency 8 minutes or less, two or more SOREMPs) (Mignot et al., 2006), many without a clear complaint of EDS. In a number of countries, the MSLT is not commonly performed, especially if clearcut cataplexy is present. Some investigators rely on the presence of SOREMPs during a single night recording, an abnormality present in approximately half of narcoleptic patients with cataplexy. A single daytime nap study is also used by some to analyze for the presence of a

Table 48.2 Characterization of narcolepsy in human, dog, and mouse

Human Sporadic

DQB1*0602 (þ) (90–95%)

Hypocretin ligand deficiency (90%)

?

DQB1*0602 (þ) (75–80%)

Hypocretin ligand deficiency (75%)

De novo mutant (?), dominant

DQB1*0602 ()

Mutation in preprohypocretin gene Hypocretin ligand deficiency

?

()

Hypocretin ligand deficiency

Autosomal recessive, 100% of penetrance

()

Mutation in Hcrtr2 gene

Adolescence

EDS, cataplexy, SP, HH, SOREMPs, sleep fragmentation, obesity (þ) EDS, cataplexy, SP, HH, SOREMPs, sleep fragmentation, obesity (þ) EDS, severe cataplexy

Hypocretin mutant (only one case identified)

Extremely early onset (6 months)

Dog Sporadic (17 breeds)

7 weeks to 7 years

Familial (Dobermans, Labradors, Dachshunds) Mouse Hypocretin KO

Earlier than 6 months

Hypocretin cell death, hypocretin/ataxin-3 transgenic Hcrtr1 KO

6 weeks

4 weeks

Cataplexy, short sleep latency, SOREMPs Cataplexy, short sleep latency, SOREMPs Cataplexy, SOREMPs, short sleep latency, obesity (?) Cataplexy, SOREMPs, short sleep latency, obesity (þþ) Fragmented sleep, obesity (?) Cataplexy, SOREMPs, short sleep latency, obesity (?) Same sleep phenotype as preprohypocretin KO mice, obesity (?)

Autosomal recessive, 100% of penetrance

Hypocretin ligand deficiency

Autosomal dominant, 100% of penetrance

Hypocretin/dynorphin deficiency

NARCOLEPSY AND CATAPLEXY

?

Transmission

Earlier onset than sporadic cases

Double receptor KO

Abnormality in hypocretin system

Symptoms/phenotype

Familial

Hcrtr2 KO

Association with HLA/DLA

Onset

Absence of Hcrtr1 Autosomal recessive, 100% of penetrance

Absence of Hcrtr2

Recessive for each receptor gene

Absence of Hcrtr1 and 2

791

DLA, dog leukocyte antigen; EDS, excessive daytime sleepiness; HH, hypnagogic hallucinations; HLA, human leukocyte antigen; KO, knockout; SOREMPs, sleep-onset rapid eye movement sleep periods; SP, sleep paralysis.

792 S. NISHINO AND E. MIGNOT SOREMP or short sleep latency (Raynal, 1976; Roth of the third ventricle, suggestive of hypothalamic et al., 1986; Broughton et al., 1988a). Other groups have atrophy. Interestingly, some of these symptomatic advocated the use of continuous 24- or 36-hour PSG cases of narcolepsy are reported to be associated with recordings (Billiard et al., 1986) or ambulatory EEG a moderate decline in CSF hypocretin levels (Arii polygraphic recordings (Genton et al., 1995). Most inveset al., 2001; Melberg et al., 2001; Overeem et al., tigators have, however, found that the MSLT is more 2001b; Scammell et al., 2001) (see also pathophysiolpredictive than all of the above tests for diagnosing ogy section). narcolepsy, and is now the de facto “gold standard”. In the ICSD-2, narcolepsy with or without cataplexy Other polygraphic methods have been developed to associated with these conditions is classified under measure EDS in narcolepsy, most notably the mainte“narcolepsy due to a medical condition”, and a signifinance of wakefulness test (MWT) (Mitler et al., 1982). cant underlying medical or neurological disorder must The major difference between the MWT and the MSLT account for the EDS and/or cataplexy (American is the instruction given to the subject. In a MWT, the Academy of Sleep Medicine, 2005). The other diagnossubject is told to attempt to remain awake during the tic criteria (symptoms, polysomnographic and laborascheduled naps. MWTs are not used for diagnosis but tory findings) are the same as those for narcolepsy rather in the context of clinical trials to assess the effect with and without cataplexy. of treatment with psychostimulants (Mitler et al., 1998) or other drugs (e.g., modafinil and sodium oxybate, Differential diagnosis/Idiopathic also called GHB (g-hydroxybutyrate)) (US Modafinil in hypersomnia and other primary EDS Narcolepsy Multicenter Study Group, 2000; Mamelak Narcolepsy is often misdiagnosed as a psychiatric condiet al., 2004). In addition to these clinical and PSG tion (typically depression) or as epilepsy (especially in criteria, HLA typing showing the association with children). It may also be confounded with other forms HLA-DQB1*0602 is supportive of the diagnosis, but of hypersomnia, such as sleep apnea syndrome (SAS), the specificity of DQB1*0602 positivity is low (Mignot, idiopathic hypersomnia, or hypersomnia associated with 1998) (see pathophysiology section). depression. The presence of cataplexy is the key factor distinguishing narcolepsy from the other forms of Symptomatic narcolepsy hypersomnia. However, when cataplexy is predominant, Several cases of narcolepsy in association with brain narcolepsy can also be confused with syncope, drop tumors (most often localized in the posterior hypoattacks, atonic attacks, or attacks of histrionic nature. thalamus and the superior part of the brainstem) have Furthermore, some well informed individuals may been reported. Narcolepsy has also been reported in mimic the symptoms of narcolepsy in order to benefit patients with multiple sclerosis, encephalitis, cerebral from disability leave from work or to obtain a prescripischemia, cranial trauma, brain tumor, and cerebral tion of psychostimulants. degeneration (Aldrich and Naylor, 1989; Arii et al., Narcolepsy without cataplexy may overlap with 2001; Melberg et al., 2001; Scammell et al., 2001). idiopathic hypersomnia, a less common and heteroHypothalamic sarcoidosis has caused narcolepsy in geneous disorder with chronic sleepiness (Bassetti at least two patients, although neither had cataplexy and Aldrich, 1997; Black et al., 2004). By definition, (Aldrich and Naylor, 1989; Malik et al., 2001). Symppatients with idiopathic hypersomnia lack cataplexy tomatic narcolepsies are also present in children and have fewer than two SOREMPs on the MSLT. affected with Niemann–Pick type C disease (Challamel Some of these individuals have deep, excessively et al., 1994). The diagnosis of symptomatic narcolepsy long, periods of sleep, difficulty waking from sleep, requires that narcolepsy be developed in close temand long unrefreshing naps, but many have symptoms poral relationship with the neurological disorders, similar to those of narcolepsy (Aldrich, 1996; Bassetti because the association may be incidental rather and Aldrich, 1997) (see Table 48.1). than causal. A recent report described patients with Recurrent hypersomnia is another primary disorder paraneoplastic anti-Ma antibodies who had hypoof EDS. In these disorders, sleepiness occurs in epithalamic inflammation, sleepiness, and cataplexy, but sodes and not on a continuous basis. Kleine–Levin PSG findings were not reported (Overeem et al., syndrome, a pervasive functional disorder of the 2001b; Rosenfeld et al., 2001). Melberg et al. (2001) hypothalamus characterized by cognitive abnormaldescribed a Swedish family with autosomal dominant ities, hypersexuality, binge eating, and irritability cerebellar ataxia, deafness, and narcolepsy. Affected associated with periods of EDS and sleep periods as members gradually develop chronic sleepiness and long as 18–20 hours (Smolik and Roth, 1988; Billiard, cataplexy in young adulthood along with enlargement 1989) is the most typical variant.

NARCOLEPSY AND CATAPLEXY

PATHOPHYSIOLOGY OF NARCOLEPSY Pathophysiological consideration of narcolepsy–cataplexy In humans, the first REM sleep episode typically occurs approximately 90 minutes after sleep onset. Further REM sleep episodes reoccur every 90 minutes (every 30 minutes in dogs and cats) (Zepelin and Siegel, 2005). Four or five REM sleep episodes may occur during the night. Shortly after the discovery of REM sleep, it was found in narcolepsy that REM sleep often occurs at sleep onset (sleep-onset REM periods), even during short daytime naps (Jimbo et al., 1963; Rechtschaffen et al., 1963). Ever since, cataplexy, sleep paralysis, and hypnagogic hallucinations have been considered as disassociated manifestations of REM sleep. In this model, the occurrence of these symptoms is explained by an abnormal rapid transition to fullblown or partial REM sleep during active wake or sleep onset, and narcolepsy is regarded as a “disease of REM sleep” (Dement et al., 1966). This hypothesis may, however, be too simplistic. It does not explain the presence of sleepiness during the day and the short latency to both nonREM and REM sleep during nocturnal and nap recordings. Another complementary hypothesis is that narcolepsy results from vigilance and state boundary problems (Broughton et al., 1986). According to this hypothesis, a cataplectic attack represents an intrusion of REM sleep atonia during wakefulness, and the hypnagogic hallucinations appear as dream-like imagery taking place in the waking state, especially at sleep onset in patients who frequently have SOREMPs. During REM sleep, complete and “tonic” inhibition of muscle tone, together with “phasic” bursts of REM and swift muscle twitching, occurs physiologically. Electromyographic (typically monitored in neck or chin muscles combined with sleep EEG recordings) activity is at its lowest. Importantly, however, pyramidal tract motor cortex neuronal activity, which mediates limb movements, is as high during REM sleep as it is during active wake (Evarts, 1964, 1965). It is suggested that a tonic inhibitory signal originating in the dorsal pons overcomes the pyramidal motor activation system during REM sleep, resulting in complete muscle atonia during this sleep state (Siegel, 2005). This notion is supported by brain lesion studies in animals: when lesions are made in the dorsal pons, a phenomenon called “REM sleep without atonia” is observed, and the animals move their limbs during REM sleep (Hendricks et al., 1982). Similar phenomena (i.e., REM sleep behavior disorder) have been reported in humans associated with various neurological conditions (including stroke in the pons) (Kimura et al., 2000).

793

A number of experiments suggest that common pathways are shared in the mediation of cataplexy and REM sleep atonia. In narcoleptic Dobermans, a population of cell groups in the brainstem that is responsible for the loss of muscle tone during REM sleep is also active during cataplexy (Siegel et al., 1991). It has also recently been demonstrated that REM-off cells in the adrenergic locus coeruleus (LC) in the pons cease to discharge during cataplexy (Wu et al., 1999). Further, H-reflex activity (an electrically stimulated muscle response with monosynaptic latency due to excitation of Ia afferents in the spinal cord) profoundly diminishes or disappears during both REM sleep and cataplexy in humans (Guilleminault et al., 1974). Finally, the major mechanism of action of anticataplectics is thought to be the suppression of REM sleep by activating the central adrenergic system (Mignot et al., 1993a; Nishino et al., 1993). Therefore, the motor inhibitory components of REM sleep at the level of the lower brainstem and the spinal cord are also operative during cataplexy. In contrast, mechanisms of the induction of cataplexy are not well understood. Other experiments, however, point to differential mechanisms for the regulation of cataplexy and REM sleep. First, cataplexy in narcoleptic dogs can be elicited at any time by emotional excitation, whereas the occurrence of REM sleep in these animals is regulated by a normal 30-minute cyclicity (Nishino et al., 2000c). Second, injection of the cholinergic agonist carbachol in the basal forebrain (anterior hypothalamus) induces long-lasting cataplexy-like atonia in narcoleptic dogs, but this manipulation does not affect the 30-minute cyclicity of the occurrence of the phasic REM sleep phenomena (i.e., REMs) (Nishino et al., 1995, 2000c). Finally, dopamine D2/3 receptor agonists potently aggravate, and D2/3 receptor antagonists potently inhibit, cataplexy in narcoleptic dogs (see pharmacology section below) (Nishino et al., 1991), but these classes of compound have little effect on the occurrence of REM sleep (Okura et al., 2000). These experiments suggest that cataplexy and REM sleep atonia may share common executive systems, but are not identical. Cataplexy may be viewed as somewhat distinct from other REM-related symptoms such as sleep paralysis and hypnagogic hallucinations that can occur in normal individuals, and sleep paralysis and hypnago- gic hallucinations are not as predictive of hypocretin deficiency. The fact that patients with other sleep disorders, such as sleep apnea, and even healthy controls can manifest SOREMPs, hypnagogic hallucinations, and sleep paralysis when their sleep/wake patterns are sufficiently disturbed, yet these subjects never develop cataplexy, provides further support for the proposal that cataplexy may be distinct from other REM-associated symptoms (Fukuda et al., 1987;

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Bishop et al., 1996; Ohayon et al., 1996; Aldrich et al., 1997). The mechanisms explaining emotional triggering of cataplexy are also not well understood.

Deficiency in hypocretin (orexin) transmission in human narcolepsy MUTATION

SCREENING AND

CSF

HYPOCRETIN-1

MEASUREMENTS

Following on the cloning of the canine narcolepsy gene mutation, hypocretin-related genes were screened for mutations in human narcolepsy cases (Peyron et al., 2000). As expected from the observation that most cases of human narcolepsy are sporadic and not genetically transmitted (in contrast to the canine model), an extensive screening study did not identify preprohypocretin, Hcrtr1, or Hcrtr2 mutations in most human narcolepsy cases (Peyron et al., 2000; Hungs et al., 2001; Olafsdottir et al., 2001). Polymorphisms were observed but were not found to be associated with narcolepsy. Surprisingly, even familial cases of narcolepsy (some of which were HLA-DQB1*0602 negative) did not have any hypocretin mutations, suggesting heterogeneity in genetic cases (Peyron et al., 2000). Rather, only a single patient with a signal peptide mutation of the preprohypocretin gene was identified. This patient had an extremely early onset (6 months), severe narcolepsy–cataplexy, DQB1*0602 negativity, and undetectable CSF levels of hypocretin-1 (Peyron et al., 2000). This important observation indicates that hypocretin system gene mutations can cause narcolepsy in humans, as in animal models. Importantly, however, hypocretin gene polymorphisms or mutations do not contribute significantly to overall narcolepsy predisposition in the population. The hypocretin system is nonetheless functionally involved in the pathophysiology of narcolepsy, but not through genetic mutations in the hypocretin system. Most sporadic, HLA-DQB1*0602-positive narcoleptic patients with cataplexy have undetectable hypocretin-1 levels in the CSF (Nishino et al., 2000b, 2001b; Peyron et al., 2000; Kanbayashi et al., 2002; Mignot et al., 2002) (Figure 47.3 in Chapter 47). Follow-up neuropathological studies in 10 narcoleptic patients indicated dramatic loss of hypocretin-1, hypocretin-2, and preprohypocretin mRNA in the brain and hypothalamus of narcoleptic patients (Peyron et al., 2000; Thannickal et al., 2000) (see Figure 47.3 in Chapter 47). As mentioned above, these subjects have no hypocretin gene mutations (Peyron et al., 2000) and have a peripubertal or postpubertal disease onset as opposed to a 6-month onset in subjects with a preprohypocretin mutation (Peyron et al., 2000). Together with the tight HLA association (Mignot et al., 1997a, 2001), a likely pathophysiological mechanism in most

narcolepsy cases could thus involve an autoimmune alteration of hypocretin-containing cells in the CNS (see the autoimmune section). Furthermore, Dauvilliers et al. (2004b) recently reported a HLA-DQB1*0602-positive MZ twin pair discordant for narcolepsy and CSF hypocretin-1 (only the affected subject had a low hypocretin-1 level), suggesting that altered CSF hypocretin levels are state, and not trait, dependent and likely to be an acquired deficit. In other words, the genetic background is likely not sufficient to develop an abnormality in the hypocretin system. This finding is also complementary to the autoimmune hypothesis. The observation that CSF hypocretin-1 levels are decreased in patients with narcolepsy provides a new test to diagnose this disorder. Using a large sample of patients and controls, we determined that 110 pg/ml (30% of mean control values) was the most specific and sensitive cutoff value for diagnosing narcolepsy (Mignot et al., 2002) (Figure 48.3). Most samples had undetectable levels (< 40 pg/ml), and a few had detectable but very diminished levels. None of the patients with idiopathic hypersomnia, sleep apnea, restless legs syndrome, or insomnia had abnormal hypocretin levels.

DIAGNOSTIC

VALUE OF

CSF

HYPOCRETIN-1

MEASUREMENTS

Using the 110-pg/ml cutoff, CSF hypocretin-1 measurements are especially predictive in patients with definite cataplexy (99% specificity, 87% sensitivity). In these cases, sensitivity and specificity are higher than for the MSLT. In contrast, CSF hypocretin-1 measurements have a more limited predictive power in patients with atypical or absent cataplexy. Specificity is still extremely high (99%) but sensitivity is low (16%) (see Mignot et al., 2002, and Figure 48.3), with most patients having normal levels (Kanbayashi et al., 2002; Krahn et al., 2002; Mignot et al., 2002). This is clearly a dilemma for the clinician as there is more often a need for a definitive diagnosis in these atypical cases. The diagnostic value of the CSF hypocretin-1 test needs to be weighed against the trauma associated with obtaining CSF. Lumbar punctures (LPs) are well known to be safe, but post-LP headaches are often observed. The trauma associated with the LP must be balanced against the risk of mislabeling a patient with narcolepsy and possibly introducing lifelong treatment. In general, the MSLT is a more useful first step as it is more determinant to the diagnosis and treatment strategies. If a LP is still required, HLA typing could be useful as a first step, as almost all cases of narcolepsy with low CSF hypocretin-1 levels are also positive for the HLA-DQB1*0602 subtype (Dalal et al., 2001; Kanbayashi et al., 2002; Krahn et al., 2002; Mignot et al., 2002); only

NARCOLEPSY AND CATAPLEXY

795

800 Controls

Narcolepsy/Hypersomnia

Other Sleep Disorders

700

600

CSF Hypocretin-1 (pg/mL)

(17%)

500

(18%)

400 47

17

37 10 (56%) (31%)

194

32 38 (43%) (46%)

22 (22%)

9 (100%)

12 (20%)

12

16

12

300

200 30

100 13 (92%)

(100%) 129

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Fig. 48.3. Cerebrospinal fluid (CSF) hypocretin-1 concentrations in various control and sleep disorders. Each point represents the crude concentration of hypocretin-1 in a single person. The cutoffs for normal (>200 pg/ml) and low (110 pg/ml) hypocretin-1 concentrations are shown. Also noted is the total number of subjects in each range, and the percentage human leukocyte antigen (HLA)-DQB1*0602 positivity for a given group in a given range is noted parenthetically for certain disorders. Note that control carrier frequencies for DQB1*0602 are 17% to 22% in healthy control subjects and secondary narcolepsy, consistent with control values reported in Caucasians. In other patient groups, values are higher, with almost all hypocretin-deficient narcolepsy being HLA DQB1*0602 positive. The median value in each group is shown as a horizontal bar. (Updated from previously published data in Mignot et al., 2002.)

three exceptions have been reported (in several hundred patients with low hypocretin-1), including one case where cataplexy was very mild and atypical (Peyron et al., 2000; Dalal et al., 2001; Mignot et al., 2002). We estimate that the probability of observing low levels in HLA-negative cases without cataplexy to be far less than 1%. A rational argument can be made that neither the MSLT nor a CSF hypocretin-1 measurement will affect treatment plans in patients with cataplexy, and therefore such testing may be extraneous in such cases. In fact, in the ICSD-2, the MSLT is not required for the diagnosis of narcolepsy if clear, definite cataplexy is present. However, in many patients presenting with cataplexy, objective data are still recommended. In patients with cataplexy, CSF hypocretin-1 testing may be most helpful when the MSLT is difficult to conduct or interpret. In patients without cataplexy, most (but not all) cases with low CSF hypocretin-1 levels have been observed in

children who develop cataplexy later in the course of the disease (Mignot et al., 2002; Hecht et al., 2003; Kubota et al., 2003; Arii et al., 2004). Therefore, we generally advise that young children with EDS but without cataplexy undergo CSF hypocretin-1 testing, as well as patients in whom there is a suspicion that cataplexy is present but not clearly reported. Although the diagnostic value of low CSF hypocretin-1 (< 110 pg/ml) has been established, it is interesting to note that all healthy control values have been shown to be above 200 pg/ml (Mignot et al., 2002) (see Figure 48.3). In rare cases of narcolepsy and hypersomnia, we have found hypocretin-1 levels between these two values, raising the possibility of partial hypocretin deficiency in these patients (Mignot et al., 2002). Such values should, however, be interpreted cautiously, as in a large series of individuals with various neurological disorders we found that up to 15% had CSF

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S. NISHINO AND E. MIGNOT

hypocretin-1 values within this intermediate range (see Figure 48.3); most of these cases represented severe brain pathology, most notably head trauma, encephalitis, and subarachnoid hemorrhage (Ripley et al., 2001b; Dohi et al., 2005). Decreased hypocretin-1 levels in these cases may reflect damage to hypocretin transmission, or may be related to changes in CSF flow. Other authors have shown that CSF hypocretin-1 increases with locomotor activity and decreases with treatment with serotonin reuptake inhibitors (but never to near undetectable, narcolepsy-like levels) (Salomon et al., 2003). Therefore, the finding of hypocretin-1 levels in this intermediate range should alert the clinician to the possibility of underlying brain pathology, which may require additional clinical evaluation, laboratory testing, or imaging. Whether genuine hypocretin deficiency explains abnormal sleep in patients with these neurological disorders is in need of further investigation (see also next section). Although the etiology of hypocretin deficiency in humans still needs to be determined, the fact that a large majority of human narcolepsy–cataplexy subjects are hypocretin ligand deficient suggests that hypocretin agonists may be promising in the treatment of narcolepsy (see pharmacology section below).

HLA and narcolepsy NARCOLEPSY–CATAPLEXY Juji et al. (1984) were the first to report a tight association of HLA in narcolepsy. In this study, 100% of Japanese narcoleptics were found to be positive for HLA-DR2, in contrast to 25% of controls. The association was subsequently confirmed in Europe (Langdon et al., 1984; Billiard and Seignalet, 1985) and North America (Poirier et al., 1986). HLA is the general name for a group of genes located in the human major histocompatibility complex (MHC) region of human chromosome 6 (mouse chromosome 17). HLA genes encode cell-surface antigen-presenting proteins. The HLA region is divided into three subregions (Figure 48.4), HLA classes I, II, and III. HLA plays a key role in the recognition and processing of foreign antigens by the immune system. HLA-DR2 is implicated in several autoimmune diseases such as insulin-dependent diabetes mellitus and multiple sclerosis (see section on narcolepsy and the immune system). More specific antisera were used to characterize HLA-DR2 better, and it was shown that the serological haplotype, DR15-DQ6 (DR2-DQw1 subtype) was associated with narcolepsy (Honda and Matsuki, 1990). Furthermore, the amplification of the polymorphic exon (second exon) of the HLADQA and DQB genes by polymerase chain reaction has shown that all Caucasian narcoleptic subjects have the

same alleles, DRB1*1501, DQA1*0102, and DQB1*0602 (Kuwata et al., 1991). However, in African American narcoleptics the susceptibility to narcolepsy is more tightly associated with the DQ6 subtype than with the DR15. In fact, only 70% of African American narcoleptics are DR15 positive, whereas they are almost all positive for the DQ6 (Matsuki et al., 1992; Mignot et al., 1994b, 1997a, 1997b). The most specific marker of narcolepsy in a number of different ethnic groups studied to date is DQB1*0602, a HLA subtype found in 12% of Japanese, 25% of Caucasians, and 38% of African Americans (Mignot, 1998). HLA-DQB1*0602 is always associated with DQA1*0102, another HLA allele encoded by the nearby DQA1 gene, located less than 20 kilobases telomeric to DQB1 (see Figure 48.4). Interestingly, a significant reduction in REM sleep latency in normal subjects was also noted when they were DQB1*0602 positive (Mignot et al., 1998). Similarly, a recent study has found a weak DQB1*0602 association with MSLT SOREMPs in males drawn from the general population in the same sample (Mignot et al., 2006). Almost all patients with typical cataplexy carry HLA-DQB1*0602, and the DQB1 association is especially tight in subjects with hypocretin deficiency, as only four non-HLA-DQA1*0102-DQB1*0602-negative narcolepsy subjects with low or undetectable CSF hypocretin-1 levels have been identified to date (of several hundred subjects with CSF testing). The HLA association in narcolepsy is primary and not due to linkage disequilibrium with other loci (Mignot et al., 2001). Association studies across ethnic groups and the study of additional genetic markers in the region all indicate a primary DQ effect (Table 48.3). It is mostly due to DQA1*0102-DQB1*0602, but is not simply a dominant effect. Indeed, DQB1*0602 homozygotes have a 2–4fold higher risk than DQB1*0602/X heterozygotes (Pelin et al., 1998), and specific DQB1*0602 heterozygotes are at either increased (e.g., DQB1*0602/DQB1*0301) or decreased (e.g., DQB1*0602/DQB1*0601 or DQB1* 0602/DQB1*0501) risk (Mignot et al., 2001). Additional smaller effects have also been suggested for specific DRB1 alleles, another HLA locus located in the same region (see Figure 48.4 & Table 48.3). The complexity of the HLA allele association in narcolepsy (Mignot et al., 2001) mirrors that reported in various autoimmune diseases, such as type I diabetes.

HLA

AND OTHER GENETIC FACTORS IN

FAMILIAL NARCOLEPSY

Interestingly, the HLA association may be less tight in familial versus sporadic narcolepsy cases. Several of the concordant twin pairs that have been reported were HLA negative (Mignot, 1998). Approximately 25% of

NARCOLEPSY AND CATAPLEXY

797 Chromosome 6

Class II

Class III

C4 21A Bf C2 DP

DQ

Structure of Genes around HLA

TNF α,β BC

E

DQA1

A

DRA

Gemomic map of the DQ and DR resion

160 kb

DQ1-9

DR1-18 DR2

Serological typing

DQ1

DQB1*0601

GF

DRB1 85 kb

12 kb

DQ6

4000 kb

HSP40

DR

DQB1

Class I 3000

2000

1000

0

DQ5

DNA low resolution typing

DR15

DR16

DNA high resolution typing DQB1*0501

DQB1*0602 and DQA1*0102

DRB1*1502

DRB1*1501 (Caucasians and Asians) DRB1*1503 (African Americans)

Fig. 48.4. Major human leukocyte antigen (HLA) subtypes involved in narcolepsy susceptibility. The HLA genes are located on chromosome “6p21” and distributed over more than 4000 kilobases (kb). Antigen-presenting cells (macrophages and dendritic cells) have HLA class I (A, B, and C) and II (DQ, DR, and DP) protein, and the locations of genes enclosing these protein are shown. The HLA gene family is divided into two classes and located in major histocompatibility complex (MHC) class I (A, B, and C) and class II (DQ, DR, and DP) regions. Close to the HLA genes in the MHC class III region there are genes encoding complement 2 and 4, tumor necrosis factor (TNF), and heat shock protein (HSP40). The HLA DR and DQ genes are located very close to each other. HLA class II DR and DQ genes are heterodimers encoded by two genes each, one generating an a-chain, the other a b-chain. All of these genes are located within a small genetic distance, leading to extremely high linkage disequilibrium. Subtypes in bold increase susceptibility and underlined subtypes reduce predisposition to narcolepsy. DRA is nonpolymorphic and does not contribute significantly to HLA diversity, in contrast with DQA1, DQB1, and DRB1, which have several hundred possible alleles. The most important genetic factor in narcolepsy is HLA DQB1*0602, a subtype of DQ1 (DQ6). In Caucasians and Asians, the associated DR2 subtype DRB1*1501 is typically observed with DQB1*0602 (and DQA1*0102) in narcoleptic patients. In African Americans, either DRB1*1503, a DNA-based subtype of DR2, or DRB1*1101, a DNA-based subtype of DR5, is observed most frequently, together with DQB1*0602. DQB1*0602, a molecular subtype of the serologically defined DQ1 antigen is the most specific marker for narcolepsy across all ethnic groups.

the familial narcoleptic cases (including narcoleptic subjects and subjects presenting with only recurrent, isolated sleep episodes) are negative for DQB1*0602 (Mignot et al., 1996), supporting the existence of one or more genes with high penetrance not associated with

HLA. These genes could be located using systematic genome screening methods in extended families. Significant linkage was found at 4q13-q21 (logarithm of odds score 3.09) in eight small, multigenerational, HLA-positive families of narcoleptics, favoring the

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S. NISHINO AND E. MIGNOT

Table 48.3 Genotype distribution of DQB1 alleles in narcolepsy versus controls in three ethnic groups Caucasian

DQB1 allele 0602/0602 0602/0301 0602/other DQB1 0602/0501 0602/0601 Non-0602/ non-0602

African American

Japanese

Narcolepsy (n ¼ 238)

Control (n ¼ 146)

Odds ratio

Narcolepsy (n ¼ 77)

Control (n ¼ 243)

Odds ratio

Narcolepsy (n ¼ 105)

Control (n ¼ 698)

Odds ratio

18.1%{ 20.6%{ 45.8%{

2.10% 2.70% 17.10%

10.30 9.35 4.10

23.4%{ 15.6%{ 48.1%{

3.70% 3.30% 23.00%

7.95 5.42 3.10

15.2%{ 19.0%{ 56.0%{

0.70% 0.90% 7.70%

25.76 26.17 15.47

5.00% 0% 10.5%{

1.40% 0% 76.70%

3.71 – 0.00

6.5%* 0% 6.5%{

1.20% 0% 68.70%

5.72 – 0.03

1.90% 7.6%{ 0%*

0.70% 2.10% 87.80%

2.78 3.89 0.00

Allele groupings are ranked from the most predisposing to most protective combinations The highest risk is carried by subjects homozygous for DQB1*0602, followed by DQB1*0602/0301 heterozygotes. DQB1*0501, a subtype common in many ethnic groups, reduces susceptibility in Caucasian and Japanese subjects, even in the presence of DQB1*0602. DQB1*0601, a predominantly Asian subtype, is also relatively protective in the presence of DQB1*0602. Non-DQB1*0602 combinations confer a very high protective effect for narcolepsy–cataplexy. *P<0.05, {P<0.005 versus respective controls.

involvement of other genes such as the CLOCK gene and the g-aminobutyric acid (GABAA) receptor, subunit b1 (Gabrb1) gene in these families (Nakayama et al., 2000). In a large HLA-positive pedigree including 4 patients with and 10 without cataplexy, linkage to 21q was also reported (Dauvilliers et al., 2004c). The candidate gene strategy has also been used. Along this line, it has been reported that the tumor necrosis factor (TNF)-a gene with a thymine residue at position 857 in its promoter region (TNF-a(857T)) is associated with human HLA-DRB1*1501-positive (Hohjoh et al., 2001) and -negative narcolepsy (Wieczorek et al., 2003). In addition, a different distribution of the catechol-Omethyltransferase genotype, a key enzyme in dopaminergic and noradrenergic degradation, was found as well as a correlation between this phenotype and the severity of narcolepsy in female narcoleptic subjects (Dauvilliers et al., 2001a). Novel studies using genomewide associations are ongoing and likely to yield additional candidates.

HLA

IN NARCOLEPSY WITHOUT CATAPLEXY

Studies of HLA association were also conducted in narcoleptic subjects without cataplexy. An association with DQB1*0602 was found in only 40.9% of cases. This result clearly shows the close association between DQB1*0602 and the presence of cataplexy (Mignot et al., 1997a). This is also matched by a much lower percentage of patients without cataplexy who have low CSF hypocretin-1 levels (5–30% of patients, depending on the specific case series) (Mignot et al.,

2002). Some of these patients (approximately onethird) are children with recent onset (4 years or less) who are likely to develop cataplexy within a few years.

Narcolepsy and the immune system The strong association between HLA type and narcolepsy with cataplexy raises the possibility that narcolepsy is an autoimmune disease (Mignot et al., 1992). This hypothesis is also consistent with the peripubertal onset of the disease, but not the even sex ratio found in the disorder. The recent discovery of hypocretin-producing cells as a potential target has given further credence to the autoimmune hypothesis. Some earlier studies testing a variety of serological tests in narcoleptics yielded higher levels of antistreptolysine 0 and anti-DNase antibodies in narcoleptics than in controls (Billiard et al., 1989; Montplaisir et al., 1989). There is, however, not strong evidence for inflammatory processes or immune abnormalities associated with narcolepsy (Mignot et al., 1992), and studies have found no classical autoantibodies and no increase in oligoclonal CSF bands in narcoleptics (Frederickson et al., 1990). Typical autoimmune pathologies (erythrocyte sedimentation rate, serum immunoglobulin levels, C-reactive protein levels, complement levels, and lymphocyte subset ratios) are apparently normal in narcoleptic patients (Matsuki et al., 1988). Recent studies by Black et al. (2002) examined the presence of many neuron-specific and organ-specific autoantibodies, but no antibody association was found in patients with narcolepsy (HLA-DQB1*0602 positive and negative).

NARCOLEPSY AND CATAPLEXY 799 How HLA molecules in general, and HLA-DQ in of the same disease continuum, with similar pathophysparticular, predispose to autoimmune disorders is not iological effects on hypocretin transmission. Narcolepsy well understood. HLA-DQ is expressed on the surface with cataplexy is generally a more severe form of of B-cells, macrophages (including microglia), and the disease, most commonly associated with an almost activated T-cells. It is a heterodimer composed of an complete destruction of the hypocretin system. HLAa and a b chain, encoded by the polymorphic DQA1 DQB1*0602 may be a severity factor more likely to preand DQB1 genes, two genes in tight linkage disequilibdispose to complete hypocretin destruction. Only in rare rium (see Figure 48.4). HLA-DQ binds peptide fragcases of cataplexy would hypocretin cell loss be partial ments and can present the resulting complex to other but sufficient to produce normal levels of hypocretin cells of the immune system, as recognized by the T-cell and a narcolepsy phenotype. In these cases, compensareceptor complex. Autoimmune processes associated tion by the remaining hypocretin cells likely maintains with HLA probably involve the ability of some HLA CSF hypocretin-1 at normal levels. Projections with more alleles to bind and consequently present specific autoeffects on CSF hypocretin-1 but of less functional imporantigens to the rest of the immune system. In other tance for the phenotype (e.g., hypocretin afferents to HLA-associated diseases, however, antibodies directed the spinal cord) may also be more spared in patients with toward the potential target (e.g., islet cell antibodies in cataplexy and normal CSF levels. The observation that type I diabetes) or T-cell clones with primary responrare HLA-DQB1*0602-negative patients with cataplexy, siveness to target antigens (e.g., against myelin basic who have generally normal CSF hypocretin-1 levels, protein in multiple sclerosis) can be detected. In narcomay share a HLA genetic susceptibility with HLAlepsy, however, all attempts at demonstrating T-cell DQB1*0602-positive patients beyond DQB1*0602 – for reactivity against hypocretin peptides, or at detecting example, both groups have an increased frequency of autoantibodies directed at hypocretin-producing cells, DQB1*0301 – also supports this hypothesis (Mignot have failed (Black et al., 2005b). A recent report in et al., 2001) (see Table 48.3). mice suggested a possible functional antibody with In narcolepsy without cataplexy, cell loss would be indirect effects on cholinergic systems after passive less pronounced. The severity of the disease would be transfer, but this finding requires replication (Smith generally lower and the cell loss insufficient to result et al., 2004). Similarly, a possible reaction of CSF in low CSF hypocretin-1 levels. The HLA-DQB1*0602 immunoglobulin with hypothalamic extracts has been association with narcolepsy without cataplexy is weaker. reported recently (Black et al., 2005a). Only in rare cases might neuroanatomical destruction be These generally negative results do not necessarily pronounced, resulting in a low CSF hypocretin-1 concenexclude the possibility of an autoimmune mechanism, tration, but still sparing a select hypocretin cell subpopbut do raise the possibility of other, more complex, ulation projecting to cataplexy-triggering pathways. In neuroimmune mechanisms. Another possibility is an favor of this model is the study of Thanickal et al. infectious agent with particular tropism toward hypo(2000) reporting 14% remaining hypocretin cells in a cretin-producing cells, although HLA associations in patient without cataplexy, versus 4.4–9.4% remaining infectious diseases are usually not very tight or primarcells in five other subjects with cataplexy. However, ily to a single allele. Interest in the autoimmune arena lesion studies in rats also indicated a 50% decrease in has been recently rekindled by case reports that intraCSF hypocretin-1 with a 77% destruction of hypocretin venous immunoglobulin may reduce the development cells, suggesting that a substantial reduction in CSF of narcolepsy severity if administered within a year hypocretin-1 levels must be present in this patient withof onset (Dauvilliers et al., 2004a). Most of these studout cataplexy. ies are still preliminary or non-conclusive, but deserve The fact that HLA-DQB1*0602 is slightly increased to be developed further in order to strive towards prein frequency in patients without cataplexy but with norvention of the disease (Scammell, 2006). mal CSF hypocretin-1 concentration is also consistent with this hypothesis. This finding, however, remains to be confirmed in a population-based sample, as HLA Pathophysiological considerations for positivity may have been increased in clinical samples narcolepsy without cataplexy due to a bias in inclusion (some clinicians use HLA typAs up to 40% of narcoleptic subjects do not display ing to confirm the diagnosis of narcolepsy without catacataplexy, the pathophysiology of “narcolepsy without plexy). The model also predicts that a large number of cataplexy” holds clinical importance. Two possible, narcolepsy without cataplexy cases may exist in the gennonexclusive, pathophysiological models for narcoeral population but have a milder phenotype, consistent lepsy without cataplexy can be proposed. In the first with the observation of slightly decreased REM latency model, narcolepsy with and without cataplexy is part in normal population subjects with HLA-DQB1*0602

800 S. NISHINO AND E. MIGNOT (Mignot et al., 1998) and the finding of increased and the superior part of the brainstem) have been pubDQB1*0602 in subjects with multiple SOREMPs during lished. Narcolepsy has also been reported in patients MSLTs in the same sample (Mignot et al., 2006). Simiwith multiple sclerosis, encephalitis, cerebral ischemia, lar milder forms of the disease or long latent periods cranial trauma, brain tumor, and cerebral degeneration have been suggested for other autoimmune diseases (Aldrich and Naylor, 1989; Arii et al., 2001; Melberg such as DQ2-associated celiac disease, B27-associated et al., 2001; Scammell et al., 2001). Hypothalamic sarspondylarthropathies, and DR3/DR4-associated type I coidosis has caused narcolepsy in at least two patients, diabetes. In type I diabetes, for example, a larger numalthough neither had cataplexy (Aldrich and Naylor, ber of individuals, especially relatives of affected pro1989; Malik et al., 2001). Symptomatic narcolepsy is also bands, may be positive for islet cell antibodies without present in children affected with Niemann–Pick disease ever developing the disease. (Challamel et al., 1994). The diagnosis of symptomatic In the second model, the cause of cases without low narcolepsy requires that narcolepsy be developed in CSF hypocretin does not involve partial hypocretin cell close temporal relationship with the neurological disloss. Other systems downstream of hypocretin itself orders, as the association may be incidental rather may be involved, for example hypocretin receptors, than causal. histamine, or neuroanatomical systems unconnected In a recent meta-analysis, we collated 116 patients with hypocretin neurobiology. This pathophysiology with symptomatic secondary narcolepsy reported in may mirror that of those with hypocretin-nondeficient the literature; all met the ICSD criteria for secondary narcolepsy–cataplexy, which represent about 10% of narcolepsy (Nishino and Knbayashi, 2005). As several all narcolepsy–cataplexy subjects (see Figure 48.3). As authors have reported previously, inherited disorders the occurrence of cataplexy is tightly associated with (n ¼ 38), tumors (n ¼ 33), and head trauma (n ¼ 19) impairments of hypocretin neurotransmissions in were the three most frequent causes of symptomatic humans, canines, mice, and rats, it is likely that impairnarcolepsy. Of the 116 patients, 10 had multiple sclerosis ments of downstream hypocretin pathway are likely and one had acute disseminated encephalomyelitis. involved in these cases, although this cannot be tested Relatively rare cases were reported with vascular disordirectly at present. Minor degrees of impairment or a ders (n ¼ 6), encephalitis (n ¼ 4), neurodegeneration subset of pathways may also cause isolated EDS (i.e., (n ¼ 1), and heterodegenerative disorder (three cases narcolepsy without cataplexy). in one family). EDS without cataplexy or any REM Although two models are proposed, they may not be sleep abnormalities is also often associated with these entirely exclusive. A partial hypocretin cell loss may, for neurological conditions, and defined as symptomatic example, not be sufficient in itself to produce sympcases of EDS. toms but could lead to narcolepsy when associated with Although it is difficult to rule out comorbidity of additional defects downstream. A similar model, albeit idiopathic narcolepsy in some cases, review of the literspeculative, has been proposed in some obese-type ature reveals numerous unquestionable cases of sympdiabetic children where both type I and type II may tomatic narcolepsy (Nishino and Kanbayashi, 2005). coexist. In these cases, subjects with partially reduced These include patients with HLA negativity and/or late islet cell numbers may be asymptomatic when lean but onset, and patients in whom the occurrence of the nardevelop insulin resistance if obesity develops and the coleptic symptoms paralleled the rise and fall of the remaining islet population is unable to produce enough causative disease. Interestingly, a review of these insulin to keep up with increased tissue demand. patients (especially those with brain tumors) clearly To distinguish between these models, neuropathoindicated that the hypothalamus was involved most logical studies of patients with narcolepsy without catoften (Nishino and Kanbayashi, 2005). aplexy (as well as patients with hypocretin-nondeficient CSF hypocretin-1 levels were measured in a limited narcolepsy–cataplexy) are needed urgently. It is also number of symptomatic patients with narcolepsy and imperative to study narcolepsy without cataplexy not EDS of various etiologies; most had reduced levels. only in clinical samples but also in the general populaEDS in these patients is sometimes reversible, with an tion, as clinical cases may represent a more severe and improvement in the causative neurological disorder selected subpopulation. and in the hypocretin status. It has also been noted that in some symptomatic patients with EDS (with Parkinson’s disease and thalamic infarction), hypocretin staSymptomatic narcolepsy and EDS, and tus was in the normal range. In contrast to idiopathic the hypocretin system narcolepsy cases, the occurrence of cataplexy was not Several cases of narcoleptic patients with brain tumors as tightly associated with hypocretin ligand deficiency (most often localized in the posterior hypothalamus in symptomatic cases.

NARCOLEPSY AND CATAPLEXY 801 cataplexy)) are needed to reduce the symptoms of narcoHypocretin/orexin system and lepsy (Nishino and Mignot, 1997). sleep regulation Histamine is another monoamine implicated in the Hypocretins/orexins were discovered only in 1998, control of vigilance, and the histaminergic system is also 1 year before the cloning of the canine narcolepsy likely to mediate indirectly the wake-promoting effects gene. Two independent research groups made this disof hypocretin (Eriksson et al., 2001; Huang et al., covery. One group called the peptides “hypocretin”, 2001; Yamanaka et al., 2002). Interestingly, brain histabecause of their primary hypothalamic localization mine content is reduced dramatically in both Hcrtr2 and similarities with the hormone secretin (De Lecea gene-mutated and ligand-deficient narcoleptic dogs et al., 1998). The other group called the molecules (Nishino et al., 2002). The role of the histaminergic sys“orexin” after observing that central administration tem in the pathophysiology of narcolepsy, with possible of these peptides increased appetite in rats (Sakurai therapeutic applications, is a novel area worthy of inveset al., 1998). The precursor, preprohypocretin, is tigation (Shiba et al., 2004; Fujiki et al., 2006). cleaved to generate two active and related peptides, Many measurable behavioral activities and biochemhypocretin-1 (orexin A) and hypocretin-2 (orexin B). ical indices manifest rhythmic fluctuations over the Hypocretin-1 is a 33-residue peptide. It contains four 24-hour period. Whether hypocretin tone changes with cysteine forming two disulfide bonds. Hypocretin-2 conZeitgeber time was assessed by measuring extracellular sists of 28 amino acids and shares significant sequence hypocretin-1 levels in the rat brain CSF over 24 hours homology with hypocretin-1, especially at the C-terminal using in vivo dialysis (Fujiki et al., 2001; Yoshida end, but has no disulfide bonds (a linear peptide) et al., 2001; Zeitzer et al., 2003). The results demon(Sakurai et al., 1998) (Figure 47.4 in Chapter 47) (see strated the involvement of a slow diurnal pattern of also review in Sakurai, 2005). There are two G proteinhypocretin neurotransmission regulation (as in the coupled hypocretin receptors, Hcrtr1 and Hcrtr2), also homeostatic and/or circadian regulation of sleep). called orexin receptor 1 and 2 (OX1R and OX2R), with Hypocretin levels increase during the active periods a distinct distribution within the CNS (Sakurai et al., and are highest at the end of the active period, and 1998) (Figure 47.4 in Chapter 47). the levels decline with the onset of sleep. Furthermore, Hypocretin-1 and -2 are produced exclusively by a sleep deprivation increases hypocretin levels (Fujiki well-defined group of neurons localized in the lateral et al., 2001; Yoshida et al., 2001; Zeitzer et al., 2003). hypothalamus (Figure 47.4 in Chapter 47). The hypocreRecent electrophysiological studies have shown that tin neurons project to the olfactory bulb, cerebral cortex, hypocretin neurons are most active during wakefulthalamus, hypothalamus, and brainstem, particularly the ness, and reduce their activity during slow-wave and locus coeruleus and raphe nucleus, and to cholinergic REM sleep. Increased neuronal activity is associated nuclei and cholinoceptive sites (such as pontine reticular with body movements or phasic REM activity (Lee formation) thought to be important for sleep regulation et al., 2005; Mileykovskiy et al., 2005). In addition to (Peyron et al., 1998). this short-term change, our results of microdialysis A series of recent studies has shown that the hypoexperiments also suggest that basic hypocretin neurocretin system is a major excitatory system affecting transmission fluctuates over 24 hours and slowly the activity of monoaminergic (dopamine (DA), norepibuilds up during the active period. Adrenergic locus nephrine (NE), serotonin (5HT), and histamine) and chocoeruleus neurons are typical wake-active neurons linergic systems with major effects on vigilance states involved in vigilance control, and it has been demon(Willie et al., 2001; Taheri et al., 2002) (Figure 47.4 in strated recently that basic firing activity of wakeChapter 47). It is thus likely that a deficiency in hypoactive locus coeruleus neurons also significantly cretin neurotransmission induces an imbalance between fluctuates across various circadian intervals (Astonthese classical neurotransmitter systems, with primary Jones et al., 2001). effects on sleep-state organization and vigilance. Indeed, Several acute manipulations, such as exercise, low DA and/or NE contents have been reported to be high glucose utilization in the brain, and forced wakefulin several brain structures in narcoleptic Dobermans, ness, increase hypocretin levels (Willie et al., 2001; and in human narcolepsy brains examined post mortem Yoshida et al., 2001; Wu et al., 2002). It is therefore (Nishino and Mignot, 1997; Nishino et al., 2001a). These hypothesized that a buildup or acute increase of hypochanges are possibly due to compensatory mechanisms, cretin levels may counteract the homeostatic sleep because drugs that enhance dopaminergic neurotranspropensity that typically increases during the daytime mission (such as amfetamine-like stimulants and modaand during forced wakefulness (Yoshida et al., 2001). finil (for EDS)) and NE neurotransmission (such as Owing to the lack of increase in hypocretin tone, narnorepinephrine (noradrenaline) uptake blockers (for coleptic subjects may not be able to stay awake for

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prolonged periods and do not respond to various alerting stimuli. Conversely, reduction of the hypocretin tone at sleep onset may contribute to the profound deep sleep that normally inhibits REM sleep at sleep onset, and the lack of this system in narcolepsy may allow the occurrence of REM sleep at sleep onset.

TREATMENTS FOR NARCOLEPSY AND PHARMACOLOGICAL MECHANISMS Current treatments for human narcolepsy Nonpharmacological treatments (i.e., by behavioral modification) are often reported to be useful additions to the clinical management of patients with narcolepsy (Rogers, 1984; Roehrs et al., 1986; Thorpy and Goswami, 1990; Mullington and Broughton, 1993). Regular napping usually relieves sleepiness for 1–2 hours (Roehrs et al., 1986) and is the treatment of choice for some patients, but this often has negative social and professional consequences. Exercising to avoid obesity, keeping a regular sleep–wake schedule, and having a supportive social environment (e.g., patient group organizations and support groups) are also helpful. In almost all cases, however, pharmacological treatment

is needed: 94% of patients reported using medications in a recent survey by a patient group organization (American Narcolepsy Association, 1992). For EDS, amfetamine-like CNS stimulants or modafinil (nonamfetamine stimulant for which mechanisms of action are debated) are most often used (Table 48.4). These compounds possess wake-promoting effects in narcoleptic subjects as well as in control populations, but very high doses are required to normalize abnormal sleep tendency during daytime for narcolepsy (Mitler, 1994). For consolidating nighttime sleep, benzodiazepine hypnotics or GHB (also called sodium oxybate) are used occasionally, and nighttime administration of GHB reduces EDS and cataplexy during daytime (Scrima et al., 1989; Lammers et al., 1993). Occasional abuse in the context of rave parties has been reported, and prescription of the compound is highly supervised. Because slow-wave sleep is associated with growth hormone (GH) release, GHB also induces GH release and has been abused by athletes. GHB was classified as a schedule I controlled substance in 2000, but has recently been approved for the treatment of narcolepsy (schedule IV controlled substance). GHB, when administered at night, consolidates sleep and improves

Table 48.4 Current pharmacological treatments for excessive daytime sleepiness in human narcolepsy and related disorders Mode of action

Usual daily dose

Half-life (h)

Side-effects/notes

Irritability, mood changes, headaches, palpitations, tremors, excessive sweating, insomnia Same as amfetamines, less reduction of appetite or increase in blood pressure Less sympathomimetic effect, milder stimulant, slower onset of action, occasionally produces liver toxicity

Wake-promoting compounds for EDS Sympathomimetic stimulants D-Amfetamine sulfate Dopamine enhancer (dopamine release/ dopamine uptake inhibition) Methylphenidate HCl Dopamine enhancer

5–60 mg

16–30

10–60 mg

3

Pemoline*

20–115 mg

11–13

Nonamfetamine wake-promoting compounds Modafinil Unknown, inhibits dopamine uptake

100–400 mg

11–14

No peripheral sympathomimetic action, headaches, nausea

Short-acting hypnotics g-Hydroxybutyrate (GHB)

6–9 g (divided nightly)

2

Sedation, nausea

Dopamine enhancer

Unknown, may act on GABAB or specific GHB receptors, reduces dopamine release

*Potentially hepatotoxic – frequent liver function monitoring required.

NARCOLEPSY AND CATAPLEXY daytime functioning. Because of its short half-life, it must be administered twice a night. As amfetamine-like stimulants and modafinil have little effect on cataplexy, tricyclic antidepressants, such as imipramine or clomipramine, are used in addition to control cataplexy (Nishino and Mignot, 1997; Mignot, 2000; Nishino et al., 2000a) (Table 48.5). However, these compounds can cause a number of side-effects, such as dry mouth, constipation, or impotence. GHB is also used for the treatment of cataplexy. The antidepressants and GHB are also effective for the other REM sleep phenomena. Most of these compounds are known to act on the monoaminergic systems (Table 48.4). Most of the

803

compounds effective for EDS target the presynaptic enhancement of dopaminergic neurotransmission (DA release and DA uptake inhibition) (Nishino et al., 1998; Wisor et al., 2001), whereas anticataplectics are mediated mostly by enhancement of noradrenergic neurotransmission (Nishino et al., 1998). Animal data suggest that these compounds are effective for EDS and cataplexy, regardless of hypocretin receptor dysfunction and ligand deficiency (Babcock et al., 1976; Nishino and Mignot, 1997), and are likely to act on downstream pathways of hypocretin neurotransmission. A series of anatomical and functional findings suggested that these monoaminergic systems are likely to mediate effects of hypocretin on vigilance and

Table 48.5 Antidepressants currently used as anticataplectic agents Usual daily dose (mg)

Half-life (h)

Notes/side-effects

Tricyclics Imipramine Desipramine

10–100 25–200

5–30 10–30

Protriptyline

5–60

55–200

Clomipramine

10–150

15–60

Dry mouth, anorexia, sweating, constipation, drowsiness (NE >> 5HT > DA) A desmethyl metabolite of imipramine; effects and side-effects similar to those of imipramine (NE > 5HT > DA) Reported to improve vigilance measures; anticholinergic effects (5HT > NE >> DA) Digestive problems, dry mouth, sweating, tiredness, impotence. Anticholinergic effects. Desmethylclomipramine (NE >> 5HT > DA) is an active metabolite

SSRIs Fluoxetine

20–60

24–72

Fluvoxamine

50–300

15

NSRIs Venlafaxine

150–375

4

Milnacipran

30–50

8

NRI Atomoxetine

40–60*

5.2

No anticholinergic or antihistaminergic effects; good anticataplectic effect but less potent than clomipramine. Active metabolite norfluoxetine has more adrenergic effects No active metabolite; pharmacological profile similar to that of fluoxetine; less active than clomipramine; gastrointestinal side-effects New serotonergic and adrenergic uptake blocker; no anticholinergic effects; effective in cataplexy and sleepiness; nausea New serotonergic and adrenergic uptake blocker; no anticholinergic or antihistaminergic effects; effective in cataplexy Normally indicated for attention-deficit/hyperactivity disorder (ADHD)

SSRI, selective serotonin reuptake inhibitor; NSRI, norepinephrine/serotonin reuptake inhibitor; NRI, norepinephrine reuptake inhibitor. Reboxetine is another NRI, but is not available in the USA. *Dosage for ADHD treatment. It is suggested to start with smaller doses for anticataplectic treatment. g-Hydroxybutyric acid (GHB, sodium oxybate) is also reported to be effective in cataplexy and may act via GABAB or via specific GHB receptors. Reduces dopamine release. NE, norepinephrine; 5HT, 5-hydroxytriptamine; DA, dopamine. Selectivity of the compounds on these monoaminergic systems is indicated by >> (much greater) and > (greater), respectively.

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muscle tonus control (Peyron et al., 1998; Hagan et al., 1999; Horvath et al., 1999; Nambu et al., 1999; Yamanaka et al., 2002). In addition, the loss of hypocretin input would possibly induce monoaminergic dysfunction (Nishino et al., 2001a). Current pharmacological treatments are rather symptomatic, and are not satisfactory for many patients as they bring undesirable side-effects and drug tolerance. Furthermore, most patients need to take two different classes of compound to manage both EDS and cataplexy, creating a variety of complications (Nishino and Mignot, 1997; Mignot, 2000; Nishino et al., 2000a). For these reasons, people have awaited an ideal treatment that is more directly pathophysiologically oriented. Hypocretin/orexin peptides or its mimetics are, theoretically, the most promising agents. Unfortunately, however, large molecular peptides do not penetrate to the brain efficiently (Fujiki et al., 2003) and oral administration is not applicable for neuropeptides; nonpeptide agonists thus need to be developed. As hypocretin receptors are G protein-coupled, seven-transmembrane receptors (Figure 47.4 in Chapter 47), like most neuropeptide receptors, this deployment may be possible in the near future.

Pharmacological control of symptoms of narcolepsy ADRENERGIC

UPTAKE INHIBITION MEDIATES

THE ANTICATAPLECTIC EFFECTS OF CURRENTLY PRESCRIBED ANTIDEPRESSANT MEDICATIONS

In the past, the most commonly prescribed anticataplectic agents were tricyclic antidepressants. More recently, more selective monoaminergic reuptake inhibitors have become available. Antidepressants have a complex pharmacological profile that includes monoamine (serotonin, norepinephrine, epinephrine, and dopamine) uptake inhibition, and for older tricyclic antidepressants, cholinergic, histaminergic and a-adrenergic blocking properties (Mignot et al., 1993a; Nishino et al., 1993; Nishino and Mignot, 1997). In narcoleptic canines, inhibition of adrenergic, but not dopaminergic or serotonergic, uptake or other properties mediates the therapeutic efficacy of antidepressant compounds (Mignot et al., 1993a; Nishino et al., 1993). This observation fits well with available human pharmacological data (see Nishino and Mignot, 1997, and Table 48.5). Protriptyline, desipramine, viloxazine, and atomoxetine, four adrenergicspecific uptake blockers with no effect on serotonin transmission, are effective and potent anticataplectic agents (see Table 48.5). In contrast, fluoxetine and other serotonin-specific uptake inhibitors are active in cataplexy only at relatively high doses, an effect possibly mediated by the weak adrenergic uptake effects of these

compounds and their metabolites (Mignot et al., 1993a; Nishino et al., 1993). The observation that adrenergic uptake blockers are excellent anticataplectic agents correlates well with their potent inhibitory effects on REM sleep. Adrenergic transmission is reduced during REM sleep (for a review see Siegel, 2005). Firing rate in the locus coeruleus decreases during cataplexy in narcoleptic canines (Wu et al., 1999). Adrenergic uptake blockers might thus increase activity in projection sites involved in REM sleep regulation. The fact that serotonergic uptake blockers, also known to have inhibitory effects on REM sleep, have little or no effect on cataplexy is more surprising. Like adrenergic cells of the locus coeruleus, serotonergic cells of the raphe nuclei dramatically decrease their activity during REM sleep (Siegel, 2005). This discrepancy could be explained by a preferential effect of serotonergic projections on REM sleep features other than atonia, for example in the control of eye movements. In this model, adrenergic projections may be more important than serotonergic transmission in the regulation of REM sleep atonia and thus cataplexy (Mignot et al., 1993a). In favor of this hypothesis, a recent experiment has shown that serotonergic activity does not decrease during cataplexy in narcoleptic canines (Wu et al., 2004), in contrast with locus coeruleus activity (Wu et al., 1999).

INCREASED

DOPAMINERGIC TRANSMISSION MEDIATES

THE WAKE-PROMOTING EFFECTS OF CURRENTLY PRESCRIBED STIMULANT COMPOUNDS

The most commonly prescribed stimulants are amfetamine-like drugs, such as dextroamfetamine, methamfetamine, methylphenidate, pemoline, and the wake-promoting compound modafinil (see Table 48.4). Like tricyclic antidepressant compounds, amfetaminelike drugs are very nonspecific pharmacologically. Their main effect is to increase monoaminergic transmission globally, by stimulating monoamine release and blocking monoamine reuptake. Abuse and dose escalation can occur with amfetamine, especially in patients without cataplexy. Less abuse is reported with methylphenidate, and modafinil is believed not to be addictive. Recent studies have demonstrated that the wakepromoting effect of these compounds is secondary to dopamine release stimulation and dopamine reuptake inhibition (Nishino et al., 1998; Wisor et al., 2001). The mode of action of modafinil is debated, but this compound also selectively inhibits dopamine uptake (Mignot et al., 1994a). All of these compounds are ineffective in dopamine transporter knockout mice, suggesting a primary mediation of wake promotion via dopaminergic systems (Wisor et al., 2001). Interestingly,

NARCOLEPSY AND CATAPLEXY compounds selective for dopaminergic transmission have no effect on cataplexy, whereas amfetamine-like compounds with combined dopaminergic and adrenergic effects have some anticataplectic properties at high dosages (Mignot et al., 1993a; Kanbayashi et al., 2000). Adrenergic effects of amfetamine-like stimulants also correlate with the respective effects of these compounds on normal REM sleep (Nishino and Mignot, 1997; Kanbayashi et al., 2000). Dopaminergic specific uptake blockers have little effect on REM sleep when compared to adrenergic or serotonergic compounds (Nishino and Mignot, 1997). The most important effects of dopaminergic uptake blockers are to reduce total sleep time and slow-wave sleep (Nishino et al., 1998). This preferential effect of dopaminergic uptake blockers on nonREM sleep correlates with electrophysiological data. As opposed to adrenergic or serotonergic neurons, the firing rate of dopaminergic neurons is known to remain relatively constant during REM sleep (Miller et al., 1983; Steinfels et al., 1983). Interestingly, studies in both humans and narcoleptic canines have shown that large doses of stimulants are needed to “normalize” narcoleptic subjects polygraphically. In our narcoleptic Doberman population, amfetamine doses equivalent to 60 mg/day were needed to reduce daytime sleep to control levels (Shelton et al., 1995). In both control and narcoleptic animals, however, the dose–response curves for modafinil and amfetamine were parallel. This finding suggests that there is no difference in sensitivity to stimulants in narcoleptic animals; rather higher doses are needed in narcoleptic animals because of their extreme baseline sleepiness (Shelton et al., 1995).

OTHER

KNOWN MODULATORS OF NARCOLEPSY

SYMPTOMS

The effects of more than 200 compounds with various modes of action have been examined in human patients and narcoleptic canines (for a review see Nishino and Mignot, 1997). Almost all the compounds studied are monoaminergic and cholinergic modulators. These systems have been studied more intensively than others because selective pharmacological probes for these systems are more generally available. With cataplexy being easier to study than sleep in canines, most studies have also focused on cataplexy rather than sleepiness. For cataplexy, the findings were consistent with pharmacological studies of REM sleep. As is the case for REM sleep, the regulation of cataplexy is modulated positively by cholinergic systems and negatively by monoaminergic tone (Nishino and Mignot, 1997). Muscarinic M2 or M3 receptors mediate the cholinergic effects, whereas monoaminergic effects are modulated

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mostly by postsynaptic a1-adrenergic receptors and presynaptic D2/D3 dopaminergic autoreceptors (Nishino and Mignot, 1997). A number of studies have shown abnormal cholinergic and monoaminergic receptor density and neurotransmitter levels in human or canine narcolepsy brain and CSF samples (Faull et al., 1983; Mefford et al., 1983; Baker and Dement, 1985; Kilduff et al., 1986; Bowersox et al., 1987; Miller et al., 1990; Kish et al., 1992; Aldrich et al., 1994; Khan et al., 1994; Rinne et al., 1995; MacFarlane et al., 1997; Nishino and Mignot, 1997; Nishino et al., 2001a). Local injection studies in selected brain areas of narcoleptic canines have also shown functional relevance for some of these abnormalities (Reid et al., 1994, 1996; Nishino et al., 1995, 1997). Cholinergic hypersensitivity, dopaminergic abnormalities, and decreased histaminergic tone are likely to be critical downstream mediators of the expression of the hypocretin deficiency/narcolepsy symptomatology (Reid et al., 1994, 1996; Nishino et al., 1995, 1997, 2001a). The cholinergic/monoaminergic imbalances observed in narcolepsy are best illustrated by the finding that in asymptomatic animals heterozygotes for the hypocretin receptor-2 mutation, a combination of cholinergic agonists with an a1 blocker or a D2/D3 agonist can trigger cataplexy (Mignot et al., 1993b).

MODES

OF ACTION OF

GHB

The mode of action of GHB on sleep and narcolepsy is unclear. GHB has a major effect on dopamine transmission, reducing firing rate and raising brain content of dopamine (Maitre, 1997; Nishino and Mignot, 1997; Castelli et al., 2003). Other effects on opioid, glutamatergic, and acetylcholine transmission have been reported (Castelli et al., 2003). Specific GHB binding sites have been identified, but the compound is also a GABAB agonist (Castelli et al., 2003). Most studies to date suggest that the sedative hypnotic effect is mediated via GABAB agonist activity (Castelli et al., 2003; Queva et al., 2003). Whether this effect also mediates the anticataplectic effects after long-term administration is unknown. Human or animal studies using other GABAB agonists, for example high-dose baclofen, would be needed to answer these questions.

Future therapies Eventually, the treatment of narcolepsy is likely to involve hypocretin cell transplant or gene therapy technology (Table 48.6) (see Mignot and Nishino, 2005; Fujiki and Nishino, 2006). These therapies are, however, many years away, and the efficacy of exogenously administered hypocretin analogs (i.e., nonpeptide agonists) should be established first in humans. Meanwhile, more specific

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Table 48.6 Potential future narcolepsy therapies Type of compound

Description

Nonhypocretin-based therapy Novel monoamine reuptake inhibitors Novel SWS enhancers

Histaminergic H3 antagonists/inverse agonists Hypocretin-based therapy Hypocretin-1

Nonpeptide agonists Hypocretin cell transplant

Gene therapy Immune-based therapy Steroids IVIg Plasmapheresis

Anatomically targeted DA (stimulant) and NE (anticataplexy) reuptake inhibitors to reduce side-effects and abuse potential Novel GABAB agonists, such as a longer-acting GHB analogs; GABAA subtype-specific compounds (e.g., gaboxadol) or GABA reuptake inhibitors (e.g., tiagabine) may be effective Blockade of histamine autoreceptor is effective in sleepiness and cataplexy in animals models; effects in humans are still uncertain, but multiple compounds are in early human trials Disappointing effects after intravenous, intracisternal, and intranasal administration to date, but extremely high doses could still be effective; would likely be effective if could be delivered intracerebroventricularly High potential on a medium-term basis; peptide receptor agonists are, however, often difficult if not impossible to make May eventually provide a cure; results to date in other diseases are disappointing because of graft rejection, low survival rate of implant, and lack of supply for graft availability. All of these problems may be alleviated by improved stem cell technology. Likely to be more than 10 years away Promising in the future; potentially dangerous side-effects; could be combined with cell-based therapies Ineffective thus far; unlikely to be useful due to late clinical presentation of cell loss Equivocal results thus far; generally safe but occasional life-threatening side-effects Similar to IVIg but even fewer available data; more invasive than IVIg

DA, dopamine; GHB, g-hydroxybutyrate; H3, histamine receptor 3; IVIg, intravenous immunoglobulin; NE, norepinephrine; SWS, slowwave sleep.

targeting of the systems that interact closely with the hypocretin system or downstream effector mechanisms with increasingly refined pharmacological agents may be the best short-term solution for the symptomatic treatment of narcolepsy (Mignot and Nishino, 2005).

CONCLUSION Narcolepsy–cataplexy is most commonly caused by a loss of hypocretin-producing cells in the hypothalamus. Low CSF hypocretin-1 levels can be used to diagnose the condition. The disorder is tightly associated with HLA-DQB1*0602, suggesting that the cause in most patients may be autoimmune destruction of these cells. The hypocretin system sends strong excitatory projections on to monoaminergic cells. Studies in canine narcolepsy demonstrated that the loss of hypocretin neurotransmission creates a cholinergic–monoaminergic imbalance in narcolepsy. Abnormally sensitive cholinergic transmission, together with depressed dopaminergic

and histaminergic transmission, are believed to underlie abnormal REM sleep and daytime sleepiness in narcolepsy. Current treatments are symptomatically based and act downstream of the hypocretin abnormality. Presynaptic stimulation of dopaminergic transmission and adrenergic uptake inhibition mediate the wakepromoting and anticataplectic effects of stimulants and antidepressants respectively. GHB, a sedative compound, may act via GABAB receptors or specific GHB receptors. Whereas most cases of narcolepsy–cataplexy are caused by a hypocretin cell loss, some cases with cataplexy and most of those without cataplexy have normal CSF hypocretin-1 levels. This may reflect either disease heterogeneity or a partial loss of hypocretin neurons without significant CSF hypocretin-1 decrements. A critical area in need of further inquiry is the role of CSF hypocretin-1 testing in predicting therapeutic response to medications already in use to treat narcolepsy (Mignot et al., 2003). Developing an assay that could

NARCOLEPSY AND CATAPLEXY measure hypocretin-1 in plasma reliably may be possible and would also be useful when low levels were observed in narcolepsy (Nishino, 2006). The findings in animal models suggest that hypocretin replacement therapy is a promising new therapeutic option, and may improve both EDS and cataplexy (Mieda et al., 2004). However, the development of small molecular synthetic hypocretin receptor agonists is likely the next step for this therapeutic option in humans, because hypocretin peptides themselves do not penetrate to the brain effectively (Fujiki et al., 2003). If ligand replacement therapy is demonstrated to be effective in hypocretin-deficient narcolepsy, hypocretin cell transplant or gene therapy technology may also be applicable in the near future. These therapies are, however, many years away, and the efficacy of exogenously administered hypocretin analogs (nonpeptide agonists) in humans should be established first. Whether or not narcolepsy is an autoimmune disorder is still unclear, but highly suspected. Other possible explanations could involve an infectious agent, with participation of the immune system. Explaining the link between the HLA association and hypocretin deficiency must be a high priority. It may be possible to use CSF hypocretin-1 testing to evaluate the extent of hypocretin cell loss in early stages of the disease (e.g., in children), thus facilitating the development of treatments that may be able to arrest, or at least delay, disease progression. Similar strategies using immunosuppression have been used in other autoimmune diseases, such as type I diabetes mellitus. In one case, 2 months after an abrupt onset, high-dose prednisone was administered but no significant effects on symptoms and CSF hypocretin-1 levels were observed (Hecht et al., 2003); however, in this patients, levels of hypocretin-1 were already very low, suggesting the possibility that irreversible damage to cells had already occurred. In other cases with recent onset, intravenous immunoglobulin administration was reported to have positive effects (Lecendreux et al., 2003), suggesting the need for further studies. We anticipate that, in time, patients with narcolepsy will benefit from studies currently under way in sleep medicine as well as in other areas of medicine.

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