Nocturnal aspects of narcolepsy with cataplexy

ARTICLE IN PRESS Sleep Medicine Reviews (2008) 12, 109–128

www.elsevier.com/locate/smrv

CLINICAL REVIEW

Nocturnal aspects of narcolepsy with cataplexy Giuseppe Plazzia,, Leonardo Serraa,b, Raffaele Ferric a

Department of Neurological Sciences, University of Bologna, Bologna, Italy Sleep Medicine Center, Pontifice Catholic University of Chile, Santiago, Chile c Department of Neurology IC, Oasi Institute (IRCSS), Troina, Italy b

KEYWORDS Narcolepsy; Sleep; REM sleep behaviour disorder; Sleep paralysis; Hypnagogic hallucinations; Cyclic alternating pattern; Periodic limb movements; Sleep apnea; Parasomnias; Treatment

Summary Even though the most impressive manifestation of narcolepsy is excessive sleepiness, paradoxically a significant number of patients have trouble sleeping at night. A wide array of alterations can affect the night-time sleep of a narcoleptic patient, and the aim of this review is to increase awareness on this issue, thereby enhancing the care of narcoleptic patients by more specific approaches to their disturbed night sleep. This review covers a broad variety of nocturnal sleep features in narcolepsy. Starting from animal models and the clinical features of patients, the paper then discusses the many comorbid conditions found in narcolepsy at night, the most advanced methods of analysis and the few recent advances in the specific treatment of night sleep in narcoleptic patients. & 2007 Elsevier Ltd. All rights reserved.

Introduction and historical review The first clinical description of narcolepsy in the medical literature can be attributed to Sir Thomas Willis,1 200 years before Ge´lineau coined the term ‘‘Narcolepsie’’ in 1880,2 from the Greek ‘‘narke’’ (na´rkZ): numbness, stupor; and ‘‘lepsis’’ (lZcı´s): attack, seizure. Narcolepsy therefore means ‘‘sleep attacks’’. In 1957, Yoss and Daly3 published their criteria for the diagnosis of the narcoleptic syndrome, with a description of the classic ‘‘narcoleptic tetrad’’ comprising the four main symptoms Corresponding author. Tel.: +39 51 2092926;

fax: +39 51 2092963. E-mail address: [email protected] (G. Plazzi).

of narcolepsy: excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic/hypnopompic hallucinations. Less well known though, are the night sleep disturbances that affect patients with narcolepsy that can be as devastating as daytime symptoms or exacerbate them. Unfortunately, Ge´lineau’s patient did not have any trouble sleeping at night, otherwise night sleep alteration in narcolepsy could have become part of the core symptoms. Nevertheless, the first unequivocal case report by Westphal published in 1877 stated that ‘‘persistent night-time sleeplessness must be noted’’, finding that his patient slept only a very small portion of the night.4,5 After the First International Symposium on Narcolepsy held in France 1975, it was proposed

1087-0792/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.smrv.2007.08.010

ARTICLE IN PRESS 110

G. Plazzi et al.

Nomenclature BMI CAP CNS CPAP CSF EDS EEG ESS GHB hcrt HH ICSD IH MSLT MWT NCAP NES NREM

body mass index; cyclic alternating pattern; central nervous system; continuous positive airway pressure; cerebrospinal fluid; excessive daytime sleepiness; electroencephalogram; Epworth sleepiness scale; gamma-hydroxybutyrate or sodium oxybate; hypocretin/orexin; hypnagogic/hypnopompic hallucinations; International classification of sleep disorders; idiopathic hypersomnia; multiple sleep latency test; maintenance of wakefulness test; non-CAP; nocturnal eating syndrome; non-rapid eye movement;

to add disturbed nocturnal sleep as a fifth symptom characteristic of this disease (‘‘narcoleptic pentad’’). Even though it is not necessary to establish the diagnosis, the latest version of the ICSD6 includes disturbed nocturnal sleep in the description of narcolepsy. Disrupted sleep, like cataplexy, is considered a core symptom of the disease, even more important than sleep paralysis or hypnagogic/ hypnopompic hallucinations.7 A wide array of alterations can affect the nighttime sleep of a narcoleptic patient, and there is no difference in nocturnal sleep symptoms across ethnic groups.8 This review is designed to increase awareness of this issue thereby enhancing the care of narcoleptic patients by more specific approaches to each aspect of their disturbed night sleep.

Animal models Animal models have been fundamental in understanding the pathophysiology of narcolepsy, namely the role of the hypocretinergic/orexinergic system, but also for the involvement of monoaminergic and cholinergic mechanisms. Less studied have been the ‘‘nocturnal’’ aspects of animal sleep (light period in rodents). Total waking and sleep time are preserved in canine models, but narcoleptic poodles do present less REM sleep, with normal light sleep and SWS.9 Waking and NREM sleep are very fragmented in Dobermans, with altered state

OSAS obstructive sleep apnoea syndrome; PLM periodic limb movements; PLMD periodic limb movement disorder; PLMS periodic limb movement syndrome; PLMW periodic limb movement of wakefulness; QoL quality of life; RBD REM-sleep behaviour disorder; REM rapid eye movement; RLS restless legs syndrome; RWA REM sleep without atonia; SDB sleep disordered breathing; SE sleep efficiency; SOREMPsleep-onset REM period; SP sleep paralysis; SRED sleep-related eating disorder; SSRI selective serotonin reuptake inhibitors; SWA slow wave activity; SWS slow wave sleep, stages III-IV; TCA tricyclic antidepressants; TST total sleep time; WASO waking time after sleep onset.

transitions into and from waking and other sleep stages (i.e., skipped stages, more frequent transitions, shorter mean duration of episodes).10 The circadian aspect is preserved at all levels (retinal input, cytoarchitecture, circadian rhythm of melatonin), with normal ultradian generation of REM sleep cyclicity as well.10,11 In a primate model, hypocretin-1 (hcrt-1) in cerebrospinal fluid (CSF) peaks at the latter third of the day, suggesting its role in wakefulness maintenance; it also remains elevated during prolonged wakefulness, indicating a circadian-independent component.12 On the other hand, systemic administration of hcrt-1 in narcoleptic dogs produces an increase in activity level, longer waking periods, a decrease in REM sleep without change in NREM sleep, reduced sleep fragmentation and a dose dependent reduction in cataplexy,13 though similar results have not been achieved by other groups.14 Narcolepsy murine models display sleep state patterns characterized by high similarity to the wild-type pattern during the light period, except for shorter REM sleep latency; with REM sleep times and episodes of longer duration, and decreased intervals between successive REM sleep periods; decreased NREM sleep and awake times (decrease in awake episode duration, with inability to maintain consolidated wakefulness). The main differences though are related to the marked fragmentation of wake and sleep episodes and the presence of REM sleep at sleep onset, with direct

ARTICLE IN PRESS Nocturnal aspects of narcolepsy with cataplexy transitions from wakefulness to REM, and pre-REM spindles at sleep onset. These patterns mirroring sleep and wake patterns in human narcoleptics are present in models of orexin receptors type 2 knockout mice, prepro-orexin knockout mice and in orexin/ataxin-3 mice (transgenic mice expressing an abnormal ataxin protein only in orexincontaining neurons, inducing their apoptosis).15–17 The first model differs from the others only because these mice are mildly affected with cataplexy, whereas interestingly orexin/ataxin-3 mice also display late-onset obesity, despite being hypophagic. This suggests a role for Hcrt-1 not only in the regulation of feeding behaviour, but also in energy homeostasis.16 In support of these findings, Mochizuki et al.18 recently found that besides severe sleep–wake fragmentation, Hcrt-1 knockout mice had markedly reduced ultradian rhythm of core body temperature, locomotor activity and wakefulness, with normal diurnal temperature variations. This blunted fall of core body temperature during the sleep period can be interpreted as an inadequate activation of the heat loss mechanisms or sustained activity of heat generating systems, due to the lack of Hcrt-1. Since sleep onset in humans is linked to the first phase of temperature decline, usually after its zenith or acrophase in the late evening (after 18:00–21:00 p.m.; 12–14 h after waking) and the peak in sleep propensity coincides with the nocturnal minimum of body temperature (4:00–6:00 a.m., about 3 h prior to waking), it is plausible that this altered thermoregulation may, at least in part, be responsible for the disturbed sleep of narcoleptics at night. Furthermore, increased distal-proximal skin temperature gradient, which normally correlates with sleep propensity, is higher among narcoleptic patients, even while awake, and parallels shorter sleep latencies at the MSLT compared to controls.19 Normal sleep and wake bouts in infant humans and rats are highly fragmented, characterized by rapid transitions between short-duration states; these gradually consolidate their ultradian rhythm and strengthen the circadian pattern during the first months of life in the humans and in the first three weeks in rats. Sleep–wake patterns of newborn rats do not differ between wild-type and Hcrt-1 knockout animals, up to the third week of age, when the knockout rats lag behind in terms of developmental consolidation, maintaining similar mean sleep-bout duration during the light and dark periods, while the wild-type rodents increase the bouts duration during the light period. Further divergence is then noted due to night time increase in the mean wake-bout duration in wild-types.

111 Therefore, Hcrt-1 deficiency (i.e., narcolepsy) does not imply a retaining or reversion to an infantile sleep pattern, but a regression back to a fragmented pattern of sleep and wakefulness. Sleep and wake can consolidate in the absence of a functional Hcrt-1 system, which in turn would later give stability beyond that attained during early infancy.20 Finally, probably one of the most important contributions of animal models is the demonstration that fragmented wakefulness in Hcrt-1 knockout mice is not the result of abnormal sleep homeostasis, poor circadian control, or a defective arousal system, but is rather a consequence of a low threshold for transition between states or ‘‘behavioural state instability’’.21 This agrees with the theory that narcolepsy’s pathophysiology resides in the sleep–wake state boundary control system.22

Clinical aspects Sleep pattern The normal sleep pattern of a young adult is characterized by 4–5 cycles of NREM–REM sleep of approximately 90–110 min each, for a total of approximately 7–8 h; entering into sleep through NREM-sleep, and presenting the first REM episode not until 80 min or longer after sleep onset. However, sleep cycles are not evenly distributed throughout the night, with REM sleep episodes becoming longer across the night, and slow-wave sleep (SWS, sleep stages 3 and 4) being prominent in the first cycles and tending to disappear at the end of the night. A few brief episodes of wakefulness tend to intrude in the later part of the night, usually near REM sleep transitions.23 Narcoleptic patients present a different sleep pattern, with longer NREM/REM cycles, longer intervals between REM episodes, and an attenuated progression of REM sleep (i.e., long episodes of REM at the beginning of the night that do not become much longer, subsequently).24,25 Without a doubt, the most important sleep abnormality characterizing narcolepsy is the occurrence of a REM sleep period at sleep onset (SOREMP)26 (Figure 1). In our experience, it is useful to explore SOREMPs clinically when suspecting narcolepsy by asking patients if they remember dreaming upon falling asleep or during naps (given that dreaming is much more frequent during REM than in NREM sleep). Not only do narcoleptics have a different sleep pattern, but their sleep is greatly disturbed by a

ARTICLE IN PRESS 112

G. Plazzi et al.

Figure 1 Transition from wakefulness to REM at sleep onset in a patient with narcolepsy; four 30–second epochs of polysomnographic recording, notice the immediate transition from waking (alpha frequency, high muscle tone) to REM sleep (appearance of ‘‘saw-tooth’’ theta waves, rapid eye movements and the disappearance of muscle tone).

large variety of phenomena. Up to 95% of patients report altered nocturnal sleep, clinically significant in 60% of them: vivid frightening dreams (61%), objective worsening of night sleep by naps (40%),24 inability to sleep without awakening (71%), getting up to eat at night (31%), early awakenings (83%), unrefreshed feeling upon awakening in the morning (50%),27 besides comorbidity with periodic leg movements (PLM), obstructive sleep apnea (OSAS) and REM sleep behaviour disorder (RBD).7 Furthermore, coincident sleep apnoea can lead to a delayed diagnosis, especially in older patients (over 40).28 In a cohort of 20 narcoleptic patients (EDS+cataplexy+SOREMP during nap recordings), 15% of patients reported that these sleep disturbances even preceded EDS and cataplexy at disease onset.24 In another series, sleep disturbance had its onset at the same time as EDS in 17 patients and after EDS in 18, whereas 17 patients could not accurately trace the onset and 15 never presented sleep problems at night.29 Merlotti et al.30 calculated that the age at onset for EDS was 20.4711.8 years, while the mean onset age for night sleep problems was 31.7714.8 years, finding also that the prevalence of sleep disturbances increased with age. This is also the only publication that addressed the evolution of the symptom, showing that for 21% of patients there was an improvement, 45% remained unchanged and 34% of patients worsened their night sleep over the years. Two of the four classic symptoms of narcolepsy are related directly to night sleep: sleep paralysis and hypnagogic/hypnopompic hallucinations.

These manifestations can also occur in normal individuals, usually in the setting of sleep deprivation, and a higher incidence has been reported in patients with idiopathic hypersomnia, mild sleepdisordered breathing or excessive sleepiness of uncertain cause.31

Sleep paralysis Sleep paralysis, the term introduced by Wilson in 1925 and first described by Mitchell in 1876,32 is a brief episode during which the patient upon falling asleep or awakening, more frequently in the morning but also in the middle of the night, is unable to perform voluntary movements, speak and sometimes even open the eyes. Usually the whole body is involved, but invariably respiratory and extraocular muscles are spared. The patient is fully aware of this state and able to recall the event which usually lasts around 120 s (ranging from a few seconds to a few minutes). Sleep paralysis is uncommon when in uncomfortable sleep positions, so patients may learn to sleep sitting to avoid them.33 Sleep paralysis episodes end spontaneously or, sometimes, after sensory stimulation (being lightly touched or spoken to), or after intense effort of the patient to ‘‘break’’ the paralysis.32 The prevalence of sleep paralysis in the general population is between 2.3% and 40%, with 1–10% of multiple episode occurrence;34 higher rates are seen in patients with sleep-related conditions.27 Fifty percent of the episodes can be associated

ARTICLE IN PRESS Nocturnal aspects of narcolepsy with cataplexy with hypnagogic/hypnopompic hallucinations.32 They were first associated with narcolepsy by Adie in 1926,35 and their prevalence in narcoleptic patients is around 25% (17 66%).3,32,33,36 Sleep paralysis episodes are more common in the first two hours of sleep and tend to occur more often again in the morning hours,34 arising more frequently from REM sleep.33,34 These peaks coincide with SOREMPs and the longer REM in the morning hours. Though brief, SOREMPs represent a lighter state of consciousness (compared to later REM episodes) with profound muscle inhibition, which may facilitate the phenomena.33 Eightyeight percent of narcoleptic patients can present them upon awakening, and 85% at falling asleep; 64% have sleep paralysis during the night sleep and naps, 27% during night-sleep only and 9% only during naps.36

Hypnagogic/hypnopompic hallucinations Described by Maury 30 years before narcolepsy in 1848, hypnagogic/hypnopompic hallucinations were only linked with the disease by Lhermitte and Tournay in 1927.37 Hypnagogic hallucinations occur while one is drifting into sleep, hypnopompic hallucinations occur upon awakening; they are thought to represent dream-like experiences intruding into wakefulness. Hypnagogic/hypnopompic hallucinations are present in up to 36% of healthy controls38 and in 20–65% of narcoleptic patients.27,37 Hypnagogic hallucinations are more frequent (89%) than the hypnopompic ones (41%), and up to a third of narcoleptic patients present both types,36 but hypnopompic hallucinations may be a better indicator of narcolepsy in subjects reporting excessive daytime sleepiness.39 They can arise at night-sleep only (22%), during naps only (18%) or both (59%).36 Hypnagogic/hypnopompic hallucinations are exacerbated by fatigue and emotion, hindered by uncomfortable settings, associated or not with sleep paralysis or cataplexy, and tend to diminish with age.37 As with sleep paralysis, hypnagogic/ hypnopompic hallucinations can be posture-dependent and tend to occur more frequently in the supine position.38 Vivid hallucinations have also led to misdiagnosis as schizophrenia.40

Periodic limb movements (PLM) PLM are stereotyped repetitive movements of the limbs, usually involving the lower extremities (similar to the triple flexion reflex), sometimes

113 interrupting sleep continuity.41,42 Their clinical relevance remains controversial, because they are highly prevalent also in the general population (4–11%), increase with age, and are also found in various medical and neurological disorders that do not primarily affect sleep.43 Nevertheless, a PLM index (number of PLM per hour of sleep) above 5 has been found in 25–70% of the narcoleptic population,44–46 and increased PLM have also been recorded during wakefulness (PLMW).47 Although PLM associated with arousals or awakenings in narcoleptics do not differ from those of patients with central nervous system (CNS) hypersomnia,44 interestingly, leg motor activity periodicity is significantly lower in narcoleptics compared to patients with restless legs syndrome (RLS).45 Since PLM are functionally interrelated to the cyclic alternating pattern,48,49 which is also reduced in narcoleptics,50,51 they have been hypothesized to represent a marker of decreased arousal fluctuation in this condition. The role of PLM as a separate neurological entity is questioned, except in patients with otherwise unexplained insomnia or hypersomnia in whom a therapeutic attempt is granted (PLM disorder or PLMD).6 In disorders related to dopaminergic dysfunction, PLM are considered to be a symptom of the disease, as they can be in narcolepsy, because there is some evidence of dopaminergic dysfunction in its pathophysiology.52 However, PLM in narcolepsy are associated with poorer sleep (increased awakening and arousal indexes, increased amount of sleep stage 1, lower sleep efficiency and higher sleepiness at the MSLT and MWT).46,53 It is important to emphasize that RLS or PLM in narcoleptic patients are frequently secondary to the use of antidepressant medication, particularly tricyclics and selective serotonin reuptake inhibitors, that are used in the treatment of cataplexy, sleep paralysis and hypnagogic/hypnopompic hallucinations. All tricyclics and selective serotonin reuptake inhibitors except for bupropion, even venlafaxine, have been reported to induce or worsen RLS and PLM.43 There are no data in literature of comorbidity of RLS and narcolepsy, independent of PLM, or secondary to medication. In our opinion and personal experience, comorbidity of RLS and narcolepsy does not exceed what would be expected in the general population. This is further supported by the different periodicity of PLM between these entities45 and an olfactory disturbance in narcoleptics (with or without RBD)54 that is not present in patients with RLS.55 However, RLS has been recently reported in 2 out of 9 patients

ARTICLE IN PRESS 114 with narcolepsy (22.2%), recruited in a study on the prevalence of RLS in a large cohort of patients with neurological diseases56 and a case report on RLS with the use of sodium oxybate (gamma-hydroxybutyrate, GHB) has also been published.57 Finally, very recently a genetic risk factor for PLM in sleep has been identified58 representing an additional factor to take into consideration in the complex relationship between PLM and narcolepsy.

Sleep-disordered breathing OSAS has also been found to have an increased incidence among narcoleptics, with values ranging 9.8–19% in polysomnographic studies.44,53,59 Some authors postulate that OSAS ‘‘occurs coincidentally in the middle-aged and aged male narcoleptic population’’.44 However, caution is necessary because narcoleptics with OSAS have higher number of awakenings, waking time after sleep onset, amount of sleep stage 1, less total sleep time,60 less SWS and are sleepier at the Epworth sleepiness scale than narcoleptics without OSAS.53 Furthermore, there is an intrinsic tendency to gain weight, especially at disease onset, in narcoleptic children61 and these patients have been found to have significantly greater body mass index (BMI) across various ethnic groups and cultural backgrounds,8 with up to one third of patients being obese (BMI 430)62 which in turn is a major risk/causative factor for sleep apnea. Since excessive daytime sleepiness is one of the primary symptoms of OSAS, thorough differential diagnosis by polysomnography is mandatory especially when there are no auxiliary symptoms (sleep paralysis, hypnagogic/hypnopompic hallucinations or clear-cut cataplexy). To further complicate matters, SOREMPs, considered a hallmark in the diagnosis of narcolepsy with the MSLT, can also occur in patients with OSAS, and in up to 3.9% of the general population, especially in shift workers, young adults, sleep–wake schedule abnormalities, and certain diseases such as Prader–Willi syndrome, Kleine–Levin syndrome, Parkinson’s disease, PLMD, drug withdrawal, REM sleep deprivation, alcoholism and major depression.63 OSAS patients can also have moderately diminished values of CSF hcrt (110–200 pg/ml),64 but not lower than 110 pg/ml or 30% of the mean control value suggested as the cutoff point for narcolepsy6 (reference values may vary between different laboratories).65 However, other authors have reported normal hcrt levels in OSAS patients.66 Although they cannot be reliably measured, plasma levels of Orexin-A-like immunoreactivity have been found decreased in OSAS and

G. Plazzi et al. are correlated to its severity and to the magnitude of sleep fragmentation.67 Nevertheless, there is a sub-group of OSAS patients who, despite adequate compliance with CPAP therapy, remain sleepy during the daytime. These patients may respond to stimulant medication (e.g., modafinil).68 Whether this represents a comorbidity is unknown: only two patients of a series of treated apnoeic patients have been reported as ‘‘narcolepticlike’’69 and, to our knowledge, no specific studies of hcrt-1 levels have been carried out in this subset of patients. OSAS in narcoleptics should not be treated differently from the general population.70

REM sleep behaviour disorder RBD was described as a separate entity in 1986 by Schenck et al.,71 but it was reported in narcoleptic patients earlier as ‘‘ambiguous sleep’’,72 characterized by ‘‘low phasic atonia with an extreme abundance of twitches and muscular discharges’’. Unlike PLM and OSAS, there is general agreement on the high prevalence of RBD in the narcoleptic population, ranging from 12% to 36%.73,74 RBD is a parasomnia related to REM sleep, characterized by a loss of the normal muscle atonia present during this sleep stage, allowing the patient to ‘‘act-out’’ usually violent dreams, with consequences of self or bed partner injuries; polygraphically, tonic and phasic electromyographic activity is evident during REM sleep that, when not symptomatic, is called REM without atonia (RWA). Narcoleptics without RBD frequently present this increased electromyographic activity during REM sleep,75 and have been shown to have higher prevalence of RWA, phasic EMG activity and REM density than controls. Instead, patients with idiopathic RBD have a higher prevalence of RWA than narcoleptics and controls (88%, 50% and 19%, respectively) have less than 80% of preserved REM atonia, but with smaller REM density.47 RBD in narcoleptics differs from the idiopathic form because of its much earlier age of onset, but there is disagreement in the sex preponderance (in the idiopathic form, RBD affects mostly men).73,74 Recent data suggest that idiopathic RBD and narcolepsy also share the olfactory dysfunction, but this disturbance might be intrinsic to narcolepsy, independent from the RBD comorbidity.54 Patients with narcolepsy-cataplexy are more frequently affected than those without cataplexy74 and, in many patients, RBD can be induced or aggravated by treatment (antidepressants).73

ARTICLE IN PRESS Nocturnal aspects of narcolepsy with cataplexy A differential diagnosis should be made with somnambulism and nocturnal frontal lobe epilepsy,76 patients with narcolepsy and RBD have a higher frequency of parasomnias in their history;75 polysomnographic studies are helpful in these cases and sometimes prolonged video-EEG monitoring may be necessary.

Non-REM sleep parasomnias Sleep-related eating disorder (SRED)/Nocturnal Eating Syndrome (NES) Feeding behaviour in narcoleptics has several peculiarities: 71% of narcoleptics report excessive postprandial drowsiness, sleepiness or sleep attacks, even during meals, versus 9% of controls; narcoleptics also have frequent chronic gastrointestinal problems (indigestion, heartburn, diarrhoea, constipation)77 and are significantly more overweight, with body mass indexes (BMI) approximately 10%–20% higher than that of matched healthy control subjects.77–79 This weight increase does not seem to result from a higher caloric intake, but a lower basal metabolism and changes in eating behaviour.79 Snacking is common, with up to 80% of patients eating bedtime snacks, and 32% having them in the middle of the night; mainly with a craving for sweets (82%), but also for animal proteins (60%) and fruit or vegetables (33%).77 Sleep-related eating disorder is common in young females,80 rarely associated with diurnal eating disorders (i.e., anorexia nervosa, bulimia), but with frequent psychiatric comorbidity.80,81 To our knowledge, it is not clear how many narcoleptics are also affected by NES/SRED,6 but narcolepsy has been found in some (small) cohorts of NES patients, mainly associated with sleepwalking, PLMD and hypnotic abuse, but also described in association with somniloquy, RLS and narcolepsy.80–82 Schenck and Hurwitz80 reported 2 patients with a clinical diagnosis of narcolepsy among 19 subjects with NES and Spaggiari et al.81 found one patient with narcolepsy among a group of 10 patients with NES evaluated clinically and polysomnographically. NES, which seems to have an underlying dopaminergic disturbance, shares with narcolepsy a response to stimulants,81,82 and interestingly firstdegree relatives of narcoleptic subjects are at greater risk for nocturnal eating (odds ratio 5.7);83 hcrt-1 is thought to regulate not only sleep but also metabolism and appetite, possibly explaining the association with nocturnal eating.84 Partly, increased appetite can be attributed to a secondary effect of medications (mainly tricyclic antidepressants), but also ingestion of carbohy-

115 drates during the night has been postulated as a mechanism by which narcoleptics use them as a sleep inducer to help themselves.77 A higher sensitivity for glucose ingestion facilitated sleepiness has been demonstrated in narcoleptics (with wake time decrease, reduction of sleep latency and increased sleepiness).85 On the other hand, Lammers et al.,86 in a small cohort of 12 narcoleptics, found that measuring spontaneous food intake, they ingested fewer calories than control subjects, mainly because they consumed fewer carbohydrates, an observation in line with previous findings of narcoleptic patients being more prone to the sleepiness inducing properties of carbohydrates. Dream-disturbed sleep Another frequent symptom that disturbs sleep in narcoleptic patients is the occurrence of vivid frightening dreams, that can appear in up to two thirds of them.24 These vivid terrifying dreams are very common, especially in patients also suffering from cataplexy and sleep paralysis. They are more frequent during night sleep, and arise mainly from REM sleep. Narcoleptics report dreaming in 97% of REM episodes, 80% of which are vivid, but also from SWS in 34%, with only 10% being vivid.87 Nightmares occur in up to 54% of patients, and emotional content is reported in up to 85% of dreams, mainly negative emotions (sorrow, anger, fear, guilt, disgust and disdain).27 Dream-disturbed sleep is also a component of chronic insomnia; poor sleepers have higher frequency of dreaming than good sleepers.88 Vivid dreams are reported more frequently during periods with high REM density, and more fragmented REM is characteristic of individuals with nightmares, but although narcoleptics have abundant REM phasic activity and fragmentation, few correlations between dream characteristics and REM parameters can be made, therefore dream recall mechanisms of insomniacs may be different from narcoleptics.89 Other parasomnias Scant data are available in the medical literature on parasomnias associated with narcolepsy. Mayer and Meier-Ewert75 reported 6 diagnoses of parasomnias in 13 narcoleptics without RBD (nightmares, bruxism, somnambulism under gamma-hydroxybutyrate therapy, and 3 with sleep talking), with only two of them with more than one parasomnia. Differently, narcoleptics with RBD had a much higher frequency of parasomnia history (38 parasomnias identified in 14 patients, with multiple parasomnias in 11 of them), either persisting since childhood or often with an asymptomatic interval of several years until the appearance of RBD, which

ARTICLE IN PRESS 116 seems to be the last parasomnia to occur. Nightmares, enuresis, bruxism, night terrors, somnambulism and sleep talking were reported. Other authors reported a history of parasomnia in 52% of a group of 25 narcoleptics, with bruxism (5 patients), enuresis (5 patients), and sleepwalking (4 patients) being the most common.90 Only one case of parasomnia overlap disorder has been reported in literature associated with narcolepsy (injurious sleepwalking, sleep terrors and RBD).91 Curiously, a not so uncommon entity, giggle incontinence or enuresis risoria (different from nocturnal enuresis) has been suspected to be linked to the narcoleptic syndrome, because of the similarity of muscle tone change and consequent total bladder voiding in response to laughter with the cataplectic phenomena; and also because of its positive response to methylphenidate in a difficult to treat entity.92 However, cataplectic attacks are not usually associated with incontinence, although this symptom was mentioned by Ge ´lineau in two out of 57 patients of one series and another case published in the medical literature.27,93 In addition, 35% of sleepwalkers have been found to be DQB1 positive (for the allele DQB1*0501), which taken together with allele studies of narcolepsy and RBD suggests that DQB1 genes are implicated in disorders of motor control during sleep.94 Depression Insomnia and depression are common comorbid conditions, to the point that it is often difficult to discern which is cause and which the consequence. Furthermore they may even share common pathological processes, specifically hyperactivation of the hypothalamic-pituitary-adrenal axis.95 Mood disturbances are present in 30–50% of narcoleptic patients,40 and can contribute to night sleep disturbance, e.g., up to 93% of depressed inpatients complain of insomnia.96 Sleep disturbance in depressed patients has some characteristic features, like decreased sleep continuity (increased sleep latency, multiple awakenings, early morning awakening), decreased SWS, shorter latency for the first REM period and increased amount of REM sleep, early in the first half of the night.96 Some of these features are also characteristic of narcoleptic patients, particularly REM sleep alterations and multiple awakenings, but it is not clear if these common neurophysiologic manifestations represent a shared final pathway of monoaminergic dysfunction underlying the sleepdisturbed phenotype. In a study directly comparing the sleep of narcoleptic and depressed outpatients, NREM sleep

G. Plazzi et al. differences (increased amount of stage 1 in narcoleptics) and sleep continuity measures (shorter sleep latency and greater WASO in narcoleptics) were the characteristics that reliably distinguished the two groups, regardless of age or SOREMP positivity.90 It must be borne in mind that mood disorders may also be masked by antidepressant therapy used to treat auxiliary symptoms of the disease (cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations), that usually respond to low doses,70 which may not be sufficient to achieve optimal levels of mood control.

Subjective complaints and sleep measurement from questionnaires The significant impact of narcolepsy on the patients’ quality of life is well established97 as is its impact on patients’ physical, mental and social health.98 However, few studies have addressed the weight of each symptom on such an impact, least of all night sleep disturbance. One study showed that even a seemingly benign symptom such as hypnagogic/hypnopompic hallucinations may greatly affect the quality of life of some patients,98 but there was no analysis of the overall significance of disturbed night sleep. Subjective night symptoms, in fact, do have a physiological correlate, as pointed out in another study in which narcoleptic patients who complained of sleep disturbance in a questionnaire did have objective evidence of it, while patients with no documented polysomnographic disturbances had no subjective complaints.30 Bruck99 found that night sleep disruption (nocturnal sleep disturbance/sleep paralysis/nightmares) correlated as well as daytime symptoms with the measured quality of life indexes, except in the domains of ‘‘vocational environment’’ and ‘‘sexual relationship’’ in which its impact was not as great as in the domains of ‘‘domestic environment’’, ‘‘extended family relationships’’, ‘‘social environment’’ and ‘‘psychological distress’’ (i.e., night symptoms correlated with a perception of the affected patient and the familiy’s adaptation to the illness, quality of family and extended family relationships and communication, current interests and participation in social and leisure activities, presence of dysphoric thoughts and feelings-anxiety, depression, irritability, worry over illness, selfesteem, body image and inappropriate guilt, etc.). More recently, another survey reported that the only clinical variables to affect the Health Related

ARTICLE IN PRESS Nocturnal aspects of narcolepsy with cataplexy QoL in narcoleptic individuals were the irresistible sleep episodes and the sleep disturbance.100 A questionnaire for the identification of features that would allow a clinical diagnosis of narcolepsy disclosed that patients, compared to controls, reported higher insomnia scores, shorter sleep latencies, shorter estimated total sleep time and approximately three times as many episodes of sleep paralysis, other motor parasomnias and arousals.101

Circadian rhythms in narcolepsy Several studies have addressed the involvement of the circadian processes in the pathogenesis or as a consequence of narcolepsy. In general, it can be stated that all major circadian and semicircadian sleep rhythms appear to be relatively maintained (sleep propensity pattern, ‘‘forbidden zones’’), with persistence of a definite circadian pattern with most sleep being restricted to the night period, peak of REM sleep at the 8th hour after sleep onset and interval between major nocturnal and diurnal SWS pulses of 14 h, identical to their occurrence in extended sleep in normal adults.102 Some authors have found a normally functioning circadian clock in narcoleptics (with SOREMPs and cataplexy), with normal core temperature rhythm,103 but a decreased amplitude with a phase advance of the circadian temperature rhythm has also been observed, displaying higher nocturnal temperatures and a nadir (the lowest temperature) only 1 hour after sleep onset in narcoleptics with SOREMPs, instead of the normal 4–5 h in controls.104 This last finding agrees with recent studies on animal models (see above). Not only temperature rhythm can be altered in narcolepsy: an 120–hour actigraphic study disclosed that the amplitude of the circadian rhythm of motor activity and immobility is also reduced, due to the excessive daytime sleepiness and the frequent nocturnal awakenings, with a significantly elevated and fragmented motor pattern during the night and more sustained immobility during the daytime. Consequently narcoleptics show a more scattered distributed motor pattern across the 24-h period. Interestingly there was a lack of day-to-day and night-to-night variability of activity monitor measures.105 On the other hand, evidence of strong ultradian rhythms show that NREM/REM cycles last about 120 min, significantly longer than in normal subjects and, during the daytime, REM episodes occur with the same periodicity (120 min), but the NREM

117 period (slow wave activity (SWA) pulses) is doubled (240 min).106 Sleep of narcoleptics is polyphasic, with overwhelming sleep episodes during the daytime and numerous awakenings fragmenting nocturnal sleep.107,108 Finally, homeostatic regulation of sleep is normal in narcoleptics,103,108,109 even with normal or stronger responses to sleep deprivation (with an overall enhancement of slow wave activity, even during REM sleep).106,109 Nevertheless, a disequilibrium between homeostatic regulation and sleep– wake regulatory mechanisms is suspected on the basis of an enhanced probability of sleep-onset REM, longer NREM/REM cycles and a less progressive increase in REM duration throughout the night.108 Another recent theory postulated an insufficient NREM sleep intensity that would explain nonconsolidated sleep in narcolepsy. From this point of view, the inability to consolidate sleep manifests when NREM sleep intensity decays below a certain threshold (impaired build-up of SWA in the second NREM cycle), resulting in reduced SWA and facilitating sleep interruption by more frequent and longer waking episodes.110

Polysomnographic findings Sleep architecture Though ICDS-2 states that diagnosis of narcolepsy can be made on purely clinical grounds, it also strongly suggests that whenever possible (especially in absence of cataplexy), patients should be studied with MSLT, preceded by a night of polysomnographic recording, also stressed as a Standardlevel recommendation in the most recent guidelines.6,111,112 Polysomnography the night before will allow not only differential diagnosis or comorbidity diagnosis, but can also reveal a seemingly characteristic pattern of night sleep in patients with narcolepsy. Narcolepsy patients present TST similar to controls,50,113,114 but with reduced sleep efficiency,7,50,102,107,114,115 shortened sleep latency,24,50,107,113,114,116,117 and shorter latency to the first REM episode.7,50,53,102,107,113,116,117 Nighttime sleep in narcolepsy is highly fragmented, interrupted by numerous awakenings24,50,53,116–118 and larger amounts of waking time after sleep onset.7,50,102,113,114,116 (Figure 2) This leads to a lighter sleep, with an increased amount of sleep stage 17,24,50,107,113,115,116,118 at the expense mainly

ARTICLE IN PRESS 118 of sleep stage 2, which is reduced.50,107,114–116,118 SWS can be preserved or reduced24,50,114–116,118 and the amount of REM sleep is comparable to that of the normal population.19,87,95,97,98,100,101 Surprisingly, if diurnal naps are prevented in narcoleptics, they may show even less TST than controls during the night, meaning that there is a disturbed sleep regulation, when sleep is confined to a specific part of the day, even after sleep deprivation.107 No significant night-to-night variability in activity monitor measures was described in an actigraphic study,105 but, polysomnographically, a first night effect has been documented53,90 with an increased sleep efficiency, decreased WASO and stage 2, decreased REM latency and increased REM and SWS percentage in the second night of the recordings, with PLM also increasing in the second night.

G. Plazzi et al. However, other authors found apparently contrasting findings (decreased sleep efficiency and marginally increased REM latency on the second night) but not reaching statistical significance.119 Daytime sleep represents about 10% of TST in narcoleptics, and this remains true despite subjectively satisfactory stimulant therapy.114 Polysomnographic values, in particular REM variables (SOREMPs, amount of REM sleep, number of REM periods), do not change with therapy. This lack of influence of chronic drug treatment on REM variables may be due to an action confined to daytime manifestations rather than the underlying disturbance, or because of tolerance.116 Daytime sleep in narcoleptics is also different, presenting higher amounts of stage 1, SWS and REM sleep, longer duration, and is accompanied by a less

Figure 2 Hypnogram and course of the EEG delta band power throughout the night in a patient with narcolepsy and in a normal control, the ‘‘typical’’ narcoleptic hypnogram presents a sleep onset REM period, numerous and prolonged awakenings and the loss of the normal sleep architecture.

ARTICLE IN PRESS Nocturnal aspects of narcolepsy with cataplexy

119

Figure 3 Example of ‘‘ambiguous sleep’’ in a patient with narcolepsy during REM sleep, with abnormally persisting elevated submentalis muscle tone (lack of atonia) and high phasic muscle activity over the chin and both tibialis anterior muscles (twitching).

active wakefulness. However, night and daytime sleep have a wide inter-individual variability.102 Undoubtedly, the presence of REM periods at sleep onset is the polygraphic hallmark of narcolepsy.25,26,113,120 SOREMPs, first described by Vogel in 1960,121 are defined as a REM period beginning within 15 min from sleep onset and are present in approximately 45% of recordings,24,59,87,115,116 at night or during daytime naps.26 Therefore, REM at sleep onset is as frequent as NREM.118 SOREMPs occur with higher probability in the morning, and their incidence is greater with several daytime naps or long sleep deprivation.24 SOREMPs do not occur in uncomfortable positions (as sitting on a chair or stool)122 and they also tend to diminish with age.123 REM sleep in narcoleptics is generally preceded by stages 1 or 2, instead of SWS as normal.24 Also, differences are found because of the attenuated progression of REM sleep and the longer interval between REM periods, that is linked to longer NREM/REM cycles.24,25,113 The distribution of REM latency is bimodal, with a first peak between 0 and 10 min after sleep onset (corresponding to SOREMPS) and a second peak at 80–90 min.59,116,124,125 One investigation described a tri-modal distribution, considering a late peak of prolonged REM latency after 150 min in 20% of their sample, associated with lower sleep efficiency, less REM

sleep, and more awakenings, stage 1 and WASO, which all correlated with higher comorbidity, namely PLMD and OSAS.59 The same authors also found higher comorbidity among the patients presenting with SOREMPs. As many as 9% of narcoleptics can have both OSAS and PLMD.53 Another striking feature of sleep in narcolepsy is the presence of ‘‘intermediate or dissociated sleep’’, difficult to score with the classic Reschtstaffen and Kales criteria because mixed features of one sleep stage in another can be seen (e.g., atonia during sleep stage 2 or persisting tone during REM sleep)24 (Figures 3 and 4). Also called ‘‘ambiguous sleep’’, ‘‘mixed NREM/REM sleep’’ or ‘‘Sleep 1–REM’’ was reported to represent between 0 and 14% of sleep time in narcoleptics.118 Probably this phenomenon is part of a spectrum of motor and state boundary dyscontrol starting with REM sleep without atonia, which is viewed by some as a probable lengthy prodrome of motor dyscontrol,73 and continues up to the most extreme forms involving prolonged behavioural release with a complete loss of recognizable sleep–wake state markers, by polygraphic monitoring, in the socalled status dissociatus. The nocturnal sleep pattern of narcolepsy is specific and correlations may exist between some aspects of nocturnal sleep and daytime symptomatology (REM sleep fragmentation and cataplexy).24

ARTICLE IN PRESS 120

G. Plazzi et al.

Figure 4 Example of ‘‘ambiguous sleep’’ in a patient with narcolepsy during NREM sleep, with low submentalis muscle tone and excessive amount of twitching evident over the tibialis anterior muscles.

In fact, patients with cataplexy have poorer sleep: shorter REM latencies, lower sleep efficiency, more awakenings, stage 1 and more important sleepiness (as measured by the Epworth sleepiness scale, MSLT and MWT).53 Conversely, patients without cataplexy are less sleepy and have less sleep disruption, sleep paralysis and sleep-related hallucinations.28 Nocturnal sleep disturbance may also be useful for more subtle differential diagnosis, as patients with idiopathic hypersomnia (formerly CNS hypersomnia or NREM hypersomnia) have normal or high sleep efficiency, fewer awakenings, less WASO, more TST (sleep longer) and, in particular, do not show REM sleep abnormalities.126 Recently a direct comparison of patients with narcolepsy-cataplexy, narcolepsy without cataplexy and idiopathic hypersomnia diagnosed according to ICSD-2 criteria by MartinezRodriguez127 found that the only significant neurophysiologic variables for distinguishing between those disorders were the mean sleep latency and the number and latency of SOREMs at the MSLT. Nevertheless there was a gradient for sleep efficiency and arousal index across the three disorders (more altered in narcolepsy-cataplexy, and less abnormal in idiopathic hypersomnia (IH)). Clinically, patients with narcolepsy with cataplexy acknowledge more night sleep fragmentation, automatic behaviours and short refreshing naps. DQB1*0602 positive patients with narcolepsy/ cataplexy have more altered sleep than DQB1*0602 negative patients,7,8 with a twofold shorter REM latency, twice the number of SOREMPs, more stage 1 and WASO, reduced sleep efficiency, more PLM

and more altered MSLTs (shorter latency and increased SOREMPs).7 Furthermore, DQB1*0602 positive normal controls also have reduced REM latency, but without SOREMPs and with increased sleep efficiency, increased stage 1 and less WASO, without changes in sleepiness (Epworth sleepiness scale and MSLT). Thus, HLA DQ polymorphism seems to modulate sleep tendency in humans.128 The effects of age on nocturnal sleep of narcoleptics have been found to parallel the pattern of normal ageing (i.e., reduced sleep efficiency, reduced TST, increased awakenings, increased WASO and reduction in SWS and REM sleep).29,129 The increased fragmentation and sleep loss correlate with increased daytime somnolence in controls, but there is no additional sleepiness in narcoleptics. Despite their age-related decrease of sleep quality, elderly narcoleptics are less sleepy and less likely to show REM sleep dyscontrol and manifest no age effects on mean sleep onset latency, REM sleep latency and frequency of REM onset.28,129 Controversy has existed as to how far the night sleep disturbances of narcoleptics are responsible for their excessive daytime sleepiness. In general, narcoleptic patients with longer and higher quality sleep have less sleepiness as measured by Epworth sleepiness scale, MSLT and MWT.53 Greater average sleepiness tends to correlate (weakly) with shorter sleep times, greater sleep disturbance and shorter nocturnal REM latency. Yet even patients with the least nocturnal disturbed sleep have severe daytime sleepiness.53 Night sleep is more disturbed in patients who continue to present daytime sleep

ARTICLE IN PRESS Nocturnal aspects of narcolepsy with cataplexy despite stimulant medication (i.e., in whom stimulant medication does not fully control daytime sleepiness),114 probably reflecting a more severe disease. Daytime sleep is not predictable on the basis of nocturnal total sleep time. Consolidating fragmented sleep of narcoleptics with reduction or elimination of sleep disruption by benzodiazepines or even GHB (at relatively low doses, 50 mg/Kg) may improve their quality of night sleep, but generally does not lead to improved daytime levels of sleep or sleepiness.114,130,131 This is further supported by the lack of worsening of sleepiness, despite an agerelated increase in sleep fragmentation.129 On the other hand, limited data are available to refute or validate patient perceptions that daytime napping interferes with night-time sleep. Narcoleptics who take daytime naps show slightly decreased sleep efficiency, SWS and slightly increased sleep stage 1, body movements, SOREMPs and REM fragmentation.114 Finally, the altered architecture of nocturnal sleep of narcoleptic patients has recently been demonstrated to play a role in the organization and consolidation of information (i.e., semantic memory) during sleep.132

Sleep microstructure Besides the analysis of the classical sleep stages (tonic aspects of sleep) in narcolepsy, few literature studies have addressed the transient (phasic) events of sleep which constitute the so-called sleep microstructure, such as saw-tooth waves, rapid eye movements, and muscle twitches, in REM sleep and short arousals, K-complexes, or sleep spindles in NREM sleep. Rapid eye movements and mentalis muscle twitches densities during REM sleep have been reported to be significantly higher in narcoleptics than in controls, with an altered distribution pattern.133 These authors concluded that the phasic activity of REM sleep in narcoleptics is disinhibited and they also reported that the REM periods of the patients contained 3 times as many waking epochs as those of the controls. A more recent study has confirmed these findings.134 On the other hand, sleep spindles and Kcomplexes constitute the physiological markers of stage 2 NREM sleep. Sleep spindle density was found to be higher in narcoleptic patients than in normal controls and this finding was interpreted as the expression of an increased power of the gate control exerted by thalamic structures during NREM sleep in patients with narcolepsy and, in particular, with idiopathic hypersomnia.135 K-complexes were

121 the focus of another study which showed that patients with narcolepsy had significantly less welldefined K-complexes than normal controls.136 In addition, a significant but very low correlation coefficient was found between the number of Kcomplexes observed during stage 2 NREM sleep and the time spent during that stage for the narcoleptic patients.136 As a conclusion, these findings seem to support the hypothesis that a K-complex has a sleep protective function. In recent years a new method to quantify and analyse NREM sleep microstructure has been utilized in a growing number of studies, taking into consideration a wide range of phasic sleep EEG events and addressed them all together in a comprehensive view. The so-called cyclic alternating pattern (CAP)48,49 is composed of different transient events indicated as subtypes A1, A2 and A3,137 organized in sequences in which the return to baseline is indicated as B phase. Among the different subtypes of the CAP A phases, the most common is the A1 characterized by sequences of K-complexes or delta bursts in NREM sleep stages, associated with mild or trivial polygraphic variations and activation of somatic and autonomic systems.137,138 Conversely, A2 and A3 subtypes of CAP seem to correspond to the traditional arousals.139–142 Narcoleptic patients have been found to display reduced total CAP rate (amount of NREM sleep occupied by CAP) with a selective reduction in the number of A1 subtypes/hour.50,51 These alterations of NREM sleep point to the possibility that a particular condition of decreased sleep instability is present in narcolepsy, with a lower amount of sleep-protective transient events (A1 subtypes). This microstructure alteration of sleep is probably able to influence other sleep-related phenomena in narcolepsy, such as PLM45 and might also influence the important cognitive processes which are believed to take place during this sleep stage.50,143,144 However, these speculations have only received preliminary experimental support.

EEG spectral analysis Spectral analysis of sleep EEG frequency bands has shed light on some additional interesting features of sleep in narcoleptics. Slow-wave activity power spectra are supposed to reflect the homeostatic recovery process (‘‘process S’’ in Borbely’s twoprocess model),145 the pressure of which interacts, in turn, with circadian and ultradian modulators of sleep, leading to the cyclic alternation of NREM/ REM sleep.108 In narcoleptics, slow-wave activity spectral analysis (0.5–4.5 Hz or Delta band) has

ARTICLE IN PRESS 122 shown that the only significant difference was an enhanced strength of the REM-ON oscillator, with respect to controls, which also accounts for the SOREMPs, the longer NREM/REM cycle duration and the less progressive increase in REM duration throughout the night, being also independent of the homeostatic pressure (sleep deprivation).108 This enhancement of the REM-ON/REM-OFF coupling parameters may be due to a weakened monoaminergic inhibition of REM-ON cholinergic cells which, in turn, reflects the lack of orexinergic input to the tuberomammilary nucleus, locus coeruleus and the raphe nuclei. Slow-wave activity analysis has also shown normal duration and decaying trend, with an increase in the delta power during NREM sleep.109,113 Some authors have also found an increased sigma power in NREM, and increased delta and beta power in REM,109 while others have noticed a decreased EEG beta power during REM and NREM that was interpreted as a decrease in central arousal mechanisms and a disturbance of sleep maintenance mechanisms.113 More recently, power spectra of narcoleptic patients were shown to be significantly higher mostly for frequencies between 19.5 and 25.0 in SWS, while during REM sleep, power spectra of narcoleptic patients showed significantly higher power density for frequency bins 0.5–1.5, 8.5–9.5, and 17.5–25 Hz. This suggests a ‘‘leakage’’ of EEG frequencies typical of normal REM sleep into NREM sleep in narcoleptic patients, in addition to the abnormally higher power in a larger spectral band during REM sleep.50 This intrusion of fast EEG frequencies was clear and significant during both CAP and NCAP NREM sleep and might indicate the intrusion of neurophysiological mechanisms typical of REM sleep during these stages in narcoleptic patients,50 adding further evidence to a state boundary dyscontrol theory. Nocturnal wakefulness in narcoleptics appears to be distributed in an oscillatory manner, with a pattern similar to the periodicity of daytime vigilance in normal controls, as assessed by EEG analysis (i.e., the normal fluctuations of vigilance seen in daytime are also present in narcoleptics during their nocturnal sleep).116 This has been hypothesized to be a reflection of an overall weakening of circadian control over sleep–wakefulness rhythms. This final finding in narcoleptics may help to understand the neuropsychological impairments of these patients, that may include attention and executive function deficits146 due to possible alterations in cognitive preattentive and attentive processing associated with altered functioning of the prefrontal cortex.147 Slow-wave activity during

G. Plazzi et al. NREM sleep has been indicated as a crucial component of the recently hypothesized synaptic downscaling during sleep, probably important for cognitive processing. Disturbed sleep microstructure, as shown by the CAP changes, probably contributes, together with the impaired diurnal functioning related to excessive somnolence and impaired attentive capabilities, to determine the cognitive alterations found in narcoleptic patients.50

Treatment The need for treatment of disturbed nocturnal sleep in narcolepsy is controversial and evidence supporting its utility is scant.70 Overall, several patients report an amelioration of sleep consolidation with modafinil, from the first days of treatment. This noteworthy effect has been documented by a moderate improvement in sleep efficiency.148 For this reason it is recommended to wait for such an effect before considering additional treatment of the patient’s disturbed nocturnal sleep. Like all patients with night sleep disturbances, narcoleptics should follow the rules of good sleep hygiene, namely avoiding caffeine and alcohol in the late afternoon. Smoking should be strongly discouraged since nicotine could worsen narcolepsy-cataplexy as a result of the cholinergic hypersensitivity that accompanies the disease.40 Probably, the only exception to sleep hygiene rules regards napping, that has not been objectively demonstrated to worsen night sleep, but by itself (short programmed naps) or associated with stimulant therapy, is an important pillar of EDS treatment. Lastly, sustained or slow-release formulations of stimulants are sometimes used to avoid rebound hypersomnolence, and when taken in too high or too late doses, can contribute to a later sleep onset or sleep fragmentation. No evidence-based recommendations can be made for sleep paralysis and hallucinations, because of the lack of studies in the literature. Sleep paralysis and hallucinations are usually treated as REM-associated phenomena, so that the therapeutic recommendations are the same as for cataplexy. Recent guidelines suggest GHB as first-line pharmacological treatment of cataplexy, at a starting dose of 4.5 g/night divided into two equal doses of 2.25 g (the first dose should be taken at bedtime and the second dose 2.5–4 h after the first). The dose may be increased to a maximum dosage of 9 g/night, divided into two equal doses of 4.5 g, by increments

ARTICLE IN PRESS Nocturnal aspects of narcolepsy with cataplexy of 1.5 g. Optimal response at any given dose may take as long as 8–12 weeks, therefore adjustments should be made with at least 2–week intervals. Second-line pharmacological treatments are antidepressants. Tricyclic antidepressants are the most potent, particularly clomipramine (10–75 mg), starting with the lowest dose possible. SSRIs are slightly less active but have fewer adverse effects. Venlafaxine, a norepinephrine/serotonine reuptake inhibitor, and reboxetine and atomotexine, norepinephrine reuptake inhibitors, lack published clinical evidence, but are widely used.70 PLM are also increased in narcoleptic patients, compared to the general population, but no studies have documented either the efficacy or the benefit of treating this disorder. When necessary L-dopa, GHB and bromocriptine have proved effective, but there is no documented effect on excessive daytime sleepiness.70 If SRED/NES is present, treatment consists in controlling the underlying sleep disorder, usually associating clonazepam, stimulants (e.g., d-fenfluramine) or dopaminergic agents (bromocriptine, carbidopa/L-dopa or pramipexole).80,81,149 Treatment of other sleep-related symptoms may improve sleep quality and EDS, but no dedicated guidelines are currently available. It is not proved, for example, that the treatment of RBD, a very common finding in narcolepsy, may ameliorate EDS. The need to treat RBD in narcolepsy is often confined to people presenting very frequent violent RBD episodes and, up to now, no medications other than the conventional drug of choice (clonazepam) have been tried in narcoleptics.40 If indicated, management of RBD consists first of all in warning the patient and bed-partner of potential injury and increasing the safety of the sleeping environment. The pharmacological therapy of choice is clonazepam 0.5–2.0 mg at bedtime, with tolerance being infrequent.150 Clonazepam suppresses the clinical motor manifestations of the disorder, but is ineffective in approximately 10% of patients.150 In patients unresponsive to or with contraindications for clonazepam (i.e., OSAS), melatonin 3–12 mg may restore RBD-related desynchronization of the circadian rhythm and possibly produce a direct restoration of the mechanisms producing REM-sleep muscle atonia.150 Pramipexole may also be an alternative treatment. OSAS is also more common in narcoleptic patients than in the general population, and the use of continuous positive airway pressure (CPAP) treatment can be difficult to apply due to their already disturbed nocturnal sleep. Moreover, no available trials confirm the utility of CPAP in these patients in terms of EDS amelioration.

123 Sleep-consolidating agents have probably been widely used in the past, but their effects have seldom been monitored. Only one controlled study assessed the tolerability and efficacy of triazolam on nocturnal sleep of narcoleptics, but no effects on EDS were recorded, with a very short follow-up.151 The recently re-introduced GHB might become the drug of choice in improving nocturnal sleep for it also reduces cataplexy and EDS.152,153 Gammahydroxybutyrate has been shown to facilitate sleep, consolidate REM sleep, improve cataplexy for up to 83% of patients and reduce EDS in 39%126 (e.g., a 2.25 g dose at bedtime decreases REM latency and fragmentation, increases the number of SOREMPs and REM efficiency, and in the first third of the night increases the amount of REM and SWS, reducing WASO and sleep stage 1). The effect of GHB on daytime sleepiness seems not to be by sleep consolidation, since smaller doses improve night sleep without major effects on EDS,131 but with higher doses (6.0–9.0 g/day) significant objective and subjective improvement is achieved (ESS and MWT, but not MSLT).152,154,155 No studies have tested the efficacy of behavioural and alternative therapies in ameliorating nocturnal sleep. In our personal experience until GHB is more widely available, though there is no evidence in literature (only an animal model of cataplexy and a single case report),156,157 it may be useful to try a sedative antidepressant at a night time dose to help patients with their sleep complaints, as well as with cataplexy, SP and HH (e.g., amitriptyline, trazodone or mirtazapine).

Summary and conclusions Even though nocturnal sleep disturbances are not yet among the classic symptoms of narcolepsy, they are as frequent and disturbing for the patient as can be daytime somnolence and cataplectic attacks. Clinically these disturbances are characterized by numerous awakenings, vivid and frightening dreams, SP and HH, parasomnias and a higher frequency of other sleep disorders (OSA, RBD, PLMD). Narcoleptic patients display a polyphasic sleep, with homeostatic sleep regulation and major circadian rhythms generally preserved, but with a longer NREM/REM ultradian cycle. Sleep/wake state fragmentation seems not to be the result of abnormal sleep homeostasis, poor circadian control, or a defective arousal system, but rather a consequence of a low threshold for transition

ARTICLE IN PRESS 124 between states (‘‘behavioural state instability’’). Up to a point, disturbed night sleep per se is not responsible for the EDS. Polygraphic studies characteristically show normal TST with reduced sleep efficiency (SE), shortened sleep and REM latencies, a higher number of awakenings and WASO, and increased sleep stage 1 with preserved REM and SWS. Microstructural changes have also been described (e.g., reduced total CAP rate). Therapeutically, patients with narcolepsy also benefit from following the rules of good sleep hygiene, with the exception of napping. Comorbid conditions (OSA, RBD, PLMD, parasomnias, etc.) should be addressed on a patient-to-patient basis. At the moment, the drug of choice for narcoleptic patients with altered nocturnal sleep should be GHB, as it also improves cataplexy and EDS.

Practice points (1) Narcoleptics should be asked not only about their daytime symptoms, but also about their night sleep because its disturbances may contribute to daytime symptoms and negatively influence their QoL. Issues that must be addressed are the presence of sleep paralysis, hallucinations, vivid dreams, nocturnal eating and depression. (2) Specific questions on possible comorbid conditions known to be frequent in narcolepsy should be posed, i.e., OSAS, PLMD and RBD. If a suspicion exists, proceed with an adequate polysomnographic study. (3) Night-sleep polysomnographic features of narcoleptics may contribute to the differential diagnosis with other disorders characterized by excessive daytime sleepiness. (4) There is no sleep facilitation in narcolepsy (neither REM nor NREM), which is not an exclusively REM-related disorder, but it rather comprises, as essential phenomena: strong enhancement of phasic REM mechanisms, lower central arousability and inability to sustain a specific neural state for relatively long periods. (5) Circadian rhythmicity and homeostatic processes are preserved in narcolepsy. (6) When potentially beneficial for the patient, specific therapy should be considered for night sleep disturbances and/or comorbidities. In the absence of comorbidities, the drug of choice seems to be sodium oxybate.

G. Plazzi et al.

Research agenda (1) Future pharmacological studies should also focus on disturbed nocturnal sleep, as part of the side effects and as an outcome for newer therapies (e.g., hypocretin replacement therapy) (2) Studies on behavioural and alternative therapies for ameliorating nocturnal sleep are needed. (3) Research on the microstructure abnormalities of sleep architecture in narcolepsy and its comorbidities can give clues on their role as markers for the disease, might help the arrangement of improved protocols for the diagnosis or for therapy followup and might help a better understanding of the disease pathophysiology. (4) Follow-up studies are mandatory in order to clarify the temporal sequence in the appearance of night sleep-related disorders.

Acknowledgements Dr. Serra’s participation has been supported by the Alban Programme, the European Union Programme of High Level Scholarships for Latin America, scholarship no. E06E100484CL.

References 1. Pearce JM. Willis on narcolepsy. J Neurol Neurosurg Psychiatry 2003;74(1):76. 2. Ge´lineau JBE. De la Narcolepsie. Gazette des Ho ˆpitaux 1880;53:626–8. 3. Yoss RE, Daly DD. Criteria for the diagnosis of the narcoleptic syndrome. Mayo Clin Proc 1957;32:320–8. 4. Westphal C. Eigentu ¨mliche mit Einschlafen verbundene Anfa ¨lle. Arch Psychiatr Nervenkr 1877;7:631–5. 5. Schenck CH, Bassetti CL, Arnulf I, et al. English translations of the first clinical reports on narcolepsy and cataplexy by Westphal and Ge ´lineau in the late 19th century, with commentary. J Clin Sleep Med 2007;3(3): 301–11. 6. American Academy of Sleep Medicine, eds. International Classification of Sleep Disorders, 2nd ed.: Diagnostic and Coding Manual. Westchester, IL: American Academy of Sleep Medicine; 2005. 7. Hong SC, Hayduk R, Lim J, et al. Clinical and polysomnographic features in DQB*10602 positive and negative narcolepsy patients: results from the modafinil clinical trial. Sleep Med 2000;1(1):33–9.

ARTICLE IN PRESS Nocturnal aspects of narcolepsy with cataplexy 8. Okun ML, Lin L, Pelin Z, et al. Clinical aspects of narcolepsy-cataplexy across ethnic groups. Sleep 2002; 25(1):27–35. 9. Mitler MM, Dement WC. Sleep studies on canine narcolepsy: pattern and cycle comparisons between affected and normal dogs. Electroencephalogr Clin Neurophysiol 1977;43(5):691–9. 10. Nishino S, Riehl J, Hong J, et al. Is narcolepsy a REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans. Neurosci Res 2000;38(4):437–46. 11. Schwartz WJ, Morton MT, Williams RS, et al. Circadian timekeeping in narcoleptic dogs. Sleep 1986;9(1 Pt 2): 120–5. 12. Zeitzer JM, Buckmaster CL, Parker KJ, et al. Circadian and homeostatic regulation of hypocretin in a primate model: implications for the consolidation of wakefulness. J Neurosci 2003;23(8):3555–60. 13. John J, Wu MF, Siegel JM. Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online 2000;3(1):23–8. 14. Fujiki N, Yoshida Y, Ripley B, et al. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog. Sleep 2003;26(8):953–9. 15. Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron 2003;38(5): 715–30. 16. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001;30(2):345–54. 17. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; %20;98(4): 437–51. 18. Mochizuki T, Klerman EB, Sakurai T, et al. Elevated body temperature during sleep in orexin knockout mice. Am J Physiol Regul Integr Comp Physiol 2006;291(3):R533–40. 19. Fronczek R, Overeem S, Lammers GJ, et al. Altered skintemperature regulation in narcolepsy relates to sleep propensity 30. Sleep 2006;29(11):1444–9. 20. Blumberg MS, Coleman CM, Johnson ED, et al. Developmental divergence of sleep–wake patterns in orexin knockout and wild-type mice. Eur J Neurosci 2007;25(2): 512–8. 21. Mochizuki T, Crocker A, McCormack S, et al. Behavioral state instability in orexin knock-out mice. J Neurosci 2004;24(28):6291–300. 22. Broughton R, Valley V, Aguirre M, et al. Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy: a laboratory perspective. Sleep 1986;9(1 Pt 2): 205–15. 23. Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. Philadelphia: Elsevier Saunders; 2005. *24. Montplaisir J. Disturbed nocturnal sleep.. Guilleminault C, Dement WC, Passouant P, editors. Narcolepsy. Proceedings of the first international symposium on narcolepsy, vol. 1976. Montpellier, France, New York: Spectrum publications; 1975 p. 43–56. The most important references are denoted by an asterisk.

125 25. Nobili L, Beelke M, Besset A, et al. Nocturnal sleep features in narcolepsy: a model-based approach. Rev Neurol (Paris) 2001;157(11 Pt 2):S82–6. *26. Tafti M, Villemin E, Carlander B, et al. Sleep onset rapideye-movement episodes in narcolepsy: REM sleep pressure or nonREM–REM sleep dysregulation? J Sleep Res 1992; 1(4):245–50. 27. Sturzenegger C, Bassetti CL. The clinical spectrum of narcolepsy with cataplexy: a reappraisal. J Sleep Res 2004; 13(4):395–406. 28. Rye DB, Dihenia B, Weissman JD, et al. Presentation of narcolepsy after 40. Neurology 1998;50(2):459–65. 29. Billiard M, Besset A, Cadilhac J. The clinical and polygraphic development of narcolepsy. In: Guilleminault C, Lugaresi E, editors. Sleep/wake disorders: natural history, epidemiology and long-term evolution. New York: Raven Press; 1983. p. 187–99. 30. Merlotti L, Roehrs T, Young D. Symptom patterns of narcolepsy patients: a questionnaire study. Sleep Res 1987; 16:391. 31. Aldrich MS. The clinical spectrum of narcolepsy and idiopathic hypersomnia. Neurology 1996;46(2):393–401. 32. Goode GB. Sleep paralysis. Arch Neurol 1962;6:228–34. *33. Hishikawa Y. Sleep paralysis.. Guilleminault C, Dement WC, Passouant P, editors. Narcolepsy. Proceedings of the first international symposium on narcolepsy, vol. 1976. Montpellier, France, New York: Spectrum Publications; 1975 p. 97–123. 34. Girard TA, Cheyne JA. Timing of spontaneous sleepparalysis episodes. J Sleep Res 2006;15(2):222–9. 35. Adie WJ. Idiopathic narcolepsy: A disease sui generis: with remarks on the mechanism of sleep. Brain 1926;49:257–306. 36. Kales A, Cadieux RJ, Soldatos CR, et al. Narcolepsycataplexy. I. Clinical and electrophysiologic characteristics. Arch Neurol 1982;39(3):164–8. *37. Ribstein M. Hypnagogic hallucinations. In: Guilleminault C, Dement WC, Passouant P, editors. Narcolepsy. Proceedings of the first international symposium on narcolepsy, July 1975. Montpellier, France, New York: Spectrum Publications; 1976 p. 145–60. 38. Dahmen N, Kasten M, Muller MJ, et al. Frequency and dependence on body posture of hallucinations and sleep paralysis in a community sample. J Sleep Res 2002;11(2): 179–80. 39. Ohayon MM, Priest RG, Caulet M, et al. Hypnagogic and hypnopompic hallucinations: pathological phenomena? Br J Psychiatry 1996;169(4):459–67. *40. Chokroverty SS, Rye DB. Narcolepsy in the older adult: epidemiology, diagnosis and management. Drugs Aging 2003;20(5):361–76. 41. Zucconi M, Ferri R, Allen R, et al. The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med 2006;7(2): 175–83. 42. American Sleep Disorders Association. Recording and scoring leg movements. The Atlas task force. Sleep 1993;16(8):748–59. 43. Hornyak M, Feige B, Riemann D, et al. Periodic leg movements in sleep and periodic limb movement disorder: prevalence, clinical significance and treatment. Sleep Med Rev 2006;10(3):169–77. 44. Baker TL, Guilleminault C, Nino-Murcia G, et al. Comparative polysomnographic study of narcolepsy and idiopathic

ARTICLE IN PRESS 126

45.

46.

47.

48.

49.

*50.

51.

52.

53.

54.

55. 56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

G. Plazzi et al. central nervous system hypersomnia. Sleep 1986;9(1 Pt 2): 232–42. Ferri R, Zucconi M, Manconi M, et al. Different periodicity and time structure of leg movements during sleep in narcolepsy/cataplexy and restless legs syndrome. Sleep 2006;29(12):1587–94. Bahammam A. Periodic leg movements in narcolepsy patients: impact on sleep architecture. Acta Neurol Scand 2007;115(5):351–5. Dauvilliers Y, Rompre S, Gagnon JF, et al. REM sleep characteristics in narcolepsy and REM sleep behavior disorder. Sleep 2007;30:844–9. Terzano MG, Mancia D, Salati MR, et al. The cyclic alternating pattern as a physiologic component of normal NREM sleep. Sleep 1985;8(2):137–45. Terzano MG, Parrino L, Spaggiari MC. The cyclic alternating pattern sequences in the dynamic organization of sleep. Electroencephalogr Clin Neurophysiol 1988;69(5):437–47. Ferri R, Miano S, Bruni O, et al. NREM sleep alterations in narcolepsy/cataplexy. Clin Neurophysiol 2005;116(11): 2675–84. Terzano MG, Smerieri A, Del Felice A, et al. Cyclic alternating pattern (CAP) alterations in narcolepsy. Sleep Med 2006;7(8):619–26. Boivin DB, Montplaisir J. The effects of L-dopa on excessive daytime sleepiness in narcolepsy. Neurology 1991;41(8):1267–9. Harsh J, Peszka J, Hartwig G, et al. Night-time sleep and daytime sleepiness in narcolepsy. J Sleep Res 2000;9(3): 309–16. Stiasny-Kolster K, Clever SC, Moller JC, et al. Olfactory dysfunction in patients with narcolepsy with and without REM sleep behaviour disorder. Brain 2007;130(Pt 2):442–9. Adler CH, Gwinn KA, Newman S. Olfactory function in restless legs syndrome. Mov Disord 1998;13(3):563–5. Ferri R, Lanuzza B, Cosentino FII, et al. A single question for the rapid screening of Restless Legs Syndrome in the neurological clinical practice. Eur J Neurol 2007;14(9): 1016–21. Abril B, Carlander B, Touchon J, et al. Restless legs syndrome in narcolepsy: a side effect of sodium oxybate? Sleep Med 2007;8(2):181–3. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007; 357(7):639–47. Mosko SS, Shampain DS, Sassin JF. Nocturnal REM latency and sleep disturbance in narcolepsy. Sleep 1984;7(2): 115–25. Wittig R, Zorick F, Piccione P, et al. Narcolepsy and disturbed nocturnal sleep. Clin Electroencephalogr 1983; 14(3):130–4. Kotagal S, Krahn LE, Slocumb N. A putative link between childhood narcolepsy and obesity. Sleep Med 2004;5(2): 147–50. Overeem S, Scammell TE, Lammers GJ. Hypocretin/orexin and sleep: implications for the pathophysiology and diagnosis of narcolepsy. Curr Opin Neurol 2002;15(6): 739–45. Singh M, Drake CL, Roth T. The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep 2006;29(7):890–5. Kanbayashi T, Inoue Y, Kawanishi K, et al. CSF hypocretin measures in patients with obstructive sleep apnea. J Sleep Res 2003;12(4):339–41. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007;369(9560):499–511.

66. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59(10):1553–62. 67. Nishijima T, Sakurai S, Arihara Z, et al. Plasma orexin-Alike immunoreactivity in patients with sleep apnea hypopnea syndrome. Peptides 2003;24(3):407–11. 68. Black JE, Hirshkowitz M. Modafinil for treatment of residual excessive sleepiness in nasal continuous positive airway pressure-treated obstructive sleep apnea/hypopnea syndrome. Sleep 2005;28(4):464–71. 69. Guilleminault C, Philip P. Tiredness and somnolence despite initial treatment of obstructive sleep apnea syndrome (what to do when an OSAS patient stays hypersomnolent despite treatment). Sleep 1996;19 (9 Suppl):S117–22. *70. Billiard M, Bassetti C, Dauvilliers Y, et al. EFNS guidelines on management of narcolepsy. Eur J Neurol 2006;13(10): 1035–48. 71. Schenck CH, Bundlie SR, Ettinger MG, et al. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep 1986;9(2):293–308. 72. de Barros-Ferreira M, Lairy GC, Ambiguous sleep in narcolepsy. In: Guilleminault C, Dement WC, Passouant P, editors. Narcolepsy. Proceedings of the First International Symposium on Narcolepsy, July 1975, Montpellier, France. New York: Spectrum Publications; 1976. p. 57–75. 73. Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Ann Neurol 1992;32(1): 3–10. 74. Nightingale S, Orgill JC, Ebrahim IO, et al. The association between narcolepsy and REM behavior disorder (RBD). Sleep Med 2005;6(3):253–8. 75. Mayer G, Meier-Ewert K. Motor dyscontrol in sleep of narcoleptic patients (a lifelong development?). J Sleep Res 1993;2(3):143–8. 76. Plazzi G, Vetrugno R, Provini F, et al. Sleepwalking and other ambulatory behaviours during sleep. Neurol Sci 2005;26(Suppl 3):s193–8. 77. Bell IR. Diet histories in Narcolepsy. In: Guilleminault C, Dement WC, Passouant P, editors. Narcolepsy. Proceedings of the First International Symposium on Narcolepsy, July 1975. Montpellier, France. New York: Spectrum publications; 1976. p. 221–7. 78. Overeem S, Mignot E, van Dijk JG, et al. Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol 2001;18(2):78–105. 79. Chabas D, Foulon C, Gonzalez J, et al. Eating disorder and metabolism in narcoleptic patients. Sleep 2007; in press. 80. Schenck CH, Hurwitz TD, Bundlie SR, et al. Sleep-related eating disorders: polysomnographic correlates of a heterogeneous syndrome distinct from daytime eating disorders. Sleep 1991;14(5):419–31. 81. Spaggiari MC, Granella F, Parrino L, et al. Nocturnal eating syndrome in adults. Sleep 1994;17(4):339–44. 82. Vetrugno R, Manconi M, Ferini-Strambi L, et al. Nocturnal eating: sleep-related eating disorder or night eating syndrome? A videopolysomnographic study. Sleep 2006; 29(7):949–54. 83. Ohayon MM, Okun ML. Occurrence of sleep disorders in the families of narcoleptic patients. Neurology 2006;67(4): 703–5. 84. Sakurai T. Roles of orexins and orexin receptors in central regulation of feeding behavior and energy homeostasis. CNS Neurol Disord Drug Targets 2006;5(3):313–25.

ARTICLE IN PRESS Nocturnal aspects of narcolepsy with cataplexy 85. Bruck D, Armstrong S, Coleman G. Sleepiness after glucose in narcolepsy. J Sleep Res 1994;3(3):171–9. 86. Lammers GJ, Pijl H, Iestra J, et al. Spontaneous food choice in narcolepsy. Sleep 1996;19(1):75–6. 87. Roth B, Bruhova S, Lehovsky M. REM sleep and NREM sleep in narcolepsy and hypersomnia. Electroencephalogr Clin Neurophysiol 1969;26(2):176–82. 88. Lugaresi E, Cirignotta F, Zucconi M, et al. Good and poor sleepers: an epidemiological survey of the San Marino population. In: Guilleminault C, editor. Sleep/wake disorders: natural history, epidemiology, and long term evolution. 1st ed. New York: Raven Press; 1983. p. 1–12. 89. Lee JH, Bliwise DL, Lebret-Bories E, et al. Dream-disturbed sleep in insomnia and narcolepsy. J Nerv Ment Dis 1993;181(5):320–4. 90. Reynolds III CF, Christiansen CL, Taska LS, et al. Sleep in narcolepsy and depression. Does it all look alike? J Nerv Ment Dis 1983;171(5):290–5. 91. Schenck CH, Boyd JL, Mahowald MW. A parasomnia overlap disorder involving sleepwalking, sleep terrors, and REM sleep behavior disorder in 33 polysomnographically confirmed cases. Sleep 1997;20(11):972–81. 92. Sher PK, Reinberg Y. Successful treatment of giggle incontinence with methylphenidate. J Urol 1996;156 (2 Pt 2):656–8. 93. Vgontzas AN, Sollenberger SE, Kales A, et al. Narcolepsycataplexy and loss of sphincter control. Postgrad Med J 1996;72(850):493–4. 94. Lecendreux M, Bassetti C, Dauvilliers Y, et al. HLA and genetic susceptibility to sleepwalking. Mol Psychiatry 2003;8(1):114–7. 95. Roth T, Roehrs T, Pies R. Insomnia: pathophysiology and implications for treatment. Sleep Med Rev 2007;11(1): 71–9. 96. Szelenberger W, Soldatos C. Sleep disorders in psychiatric practice. World Psychiatry 2005;4(3):186–90. 97. Broughton WA, Broughton RJ. Psychosocial impact of narcolepsy. Sleep 1994;17(8 Suppl):S45–9. 98. Goswami M. The influence of clinical symptoms on quality of life in patients with narcolepsy. Neurology 1998;50 (2 Suppl 1):S31–6. 99. Bruck D. The impact of narcolepsy on psychological health and role behaviours: negative effects and comparisons with other illness groups. Sleep Med 2001;2(5):437–46. 100. Dodel R, Peter H, Spottke A, et al. Health-related quality of life in patients with narcolepsy. Sleep Med 2007. 101. Parkes JD, Chen SY, Clift SJ, et al. The clinical diagnosis of the narcoleptic syndrome. J Sleep Res 1998;7(1):41–52. 102. Broughton R, Dunham W, Newman J, et al. Ambulatory 24 h sleep–wake monitoring in narcolepsy-cataplexy compared to matched controls. Electroencephalogr Clin Neurophysiol 1988;70(6):473–81. 103. Dantz B, Edgar DM, Dement WC. Circadian rhythms in narcolepsy: studies on a 90 min day. Electroencephalogr Clin Neurophysiol 1994;90(1):24–35. 104. Mosko SS, Holowach JB, Sassin JF. The 24-hour rhythm of core temperature in narcolepsy. Sleep 1983;6(2):137–46. 105. Middelkoop HA, Lammers GJ, Van Hilten BJ, et al. Circadian distribution of motor activity and immobility in narcolepsy: assessment with continuous motor activity monitoring. Psychophysiology 1995;32(3):286–91. *106. Nobili L, Ferrillo F, Besset A, et al. Ultradian aspects of sleep in narcolepsy. Neurophysiol Clin 1996;26(1):51–9. *107. Tafti M, Villemin E, Carlander B, et al. Sleep in human narcolepsy revisited with special reference to prior wakefulness duration. Sleep 1992;15(4):344–51.

127 *108. Ferrillo F, Donadio S, De Carli F, et al. A model-based approach to homeostatic and ultradian aspects of nocturnal sleep structure in narcolepsy. Sleep 2007;30(2): 157–65. 109. Tafti M, Rondouin G, Besset A, et al. Sleep deprivation in narcoleptic subjects: effect on sleep stages and EEG power density. Electroencephalogr Clin Neurophysiol 1992;83(6): 339–49. 110. Khatami R, Landolt HP, Achermann P, et al. Insufficient nonREM sleep intensity in narcolepsy-cataplexy. Sleep 2007; in press. 111. Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep 2005; 28(4):499–521. 112. Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test 290. Sleep 2005;28(1): 113–21. 113. Mukai J, Uchida S, Miyazaki S, et al. Spectral analysis of all-night human sleep EEG in narcoleptic patients and normal subjects. J Sleep Res 2003;12(1):63–71. 114. Rogers AE, Aldrich MS, Caruso CC. Patterns of sleep and wakefulness in treated narcoleptic subjects. Sleep 1994; 17(7):590–7. 115. Zorick F, Roehrs T, Wittig R, et al. Sleep–wake abnormalities in narcolepsy. Sleep 1986;9(1 Pt 2):189–93. 116. Bixler EO, Kales A, Vela-Bueno A, et al. Narcolepsy/ cataplexy. III: Nocturnal sleep and wakefulness patterns. Int J Neurosci 1986;29(3-4):305–16. 117. Browman CP, Gujavarty KS, Yolles SF, et al. Forty-eighthour polysomnographic evaluation of narcolepsy. Sleep 1986;9(1 Pt 2):183–8. 118. Hishikawa Y, Wakamatsu H, Furuya E, et al. Sleep satiation in narcoleptic patients. Electroencephalogr Clin Neurophysiol 1976;41(1):1–18. 119. Billiard M, Salva MQ, De Koninck J, et al. Daytime sleep characteristics and their relationships with night sleep in the narcoleptic patient. Sleep 1986;9(1 Pt 2):167–74. 120. Rechtschaffen A, Wolpert EA, Dement WC, et al. Nocturnal sleep of narcoleptics. Electroencephalogr Clin Neurophysiol 1963;15:599–609. 121. Vogel G. Studies in psychophysiology of dreams. III. The dream of narcolepsy. Arch Gen Psychiatry 1960;3:421–8. 122. Hishikawa Y, Shimizu T. Physiology of REM sleep, cataplexy and sleep paralysis. In: Fahn S, Hallett M, Luders HO, Marsden CD, editors. Negative motor phenomena: advances in neurology. Philadelphia: Lippincott-Raven; 1995. p. 245–71. 123. Gosselin A, Montplaisir J, Lesperance P, et al. The effect of age on the MSLT in 137 patients with narcolepsy. Sleep Res 1997;26:368. 124. Montplaisir J, Billiard M, Takahashi S, et al. Twenty-fourhour recording in REM-narcoleptics with special reference to nocturnal sleep disruption. Biol Psychiatry 1978;13(1): 73–89. 125. Mitler MM, van den HJ, Carskadon MA, et al. REM sleep episodes during the Multple Sleep Latency Test in narcoleptic patients. Electroencephalogr Clin Neurophysiol 1979;46(4):479–81. 126. Montplaisir J, Godbout R. Nocturnal sleep of narcoleptic patients: revisited. Sleep 1986;9(1 Pt 2):159–61. 127. Martinez-Rodriguez JE, Iranzo A, Casamitjana R, et al. Analisis comparativo de un grupo de pacientes con narcolepsia-cataplejia, narcolepsia sin cataplejia e hipersomnia idiopatica. Med Clin (Barc ) 2007;128(10):361–4.

ARTICLE IN PRESS 128 128. Mignot E, Young T, Lin L, et al. Nocturnal sleep and daytime sleepiness in normal subjects with HLADQB1*0602. Sleep 1999;22(3):347–52. 129. Lamphere J, Young D, Roehrs T, et al. Fragmented sleep, daytime somnolence and age in narcolepsy. Clin Electroencephalogr 1989;20(1):49–54. 130. Broughton R, Dunham W, Weisskopf M, et al. Night sleep does not predict day sleep in narcolepsy. Electroencephalogr Clin Neurophysiol 1994;91(1):67–70. 131. Scrima L, Hartman PG, Johnson Jr. FH, et al. Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: double-blind subjective measures 867. Biol Psychiatry 1989;26(4):331–43. 132. Mazzetti M, Campi C, Mattarozzi K, et al. Semantic priming effect during REM-sleep inertia in patients with narcolepsy. Brain Res Bull 2006;71(1–3):270–8. 133. Geisler P, Meier-Ewert K, Matsubayshi K. Rapid eye movements, muscle twitches and sawtooth waves in the sleep of narcoleptic patients and controls. Electroencephalogr Clin Neurophysiol 1987;67(6):499–507. 134. Vankova J, Nevsimalova S, Sonka K, et al. Increased REM density in narcolepsy-cataplexy and the polysymptomatic form of idiopathic hypersomnia. Sleep 2001;24(6):707–11. 135. Bove A, Culebras A, Moore JT, et al. Relationship between sleep spindles and hypersomnia. Sleep 1994;17(5):449–55. 136. Wauquier A, Aloe L, Declerck A. K-complexes: are they signs of arousal or sleep protective? J Sleep Res 1995;4(3):138–43. 137. Terzano MG, Parrino L, Smerieri A, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med 2001;2:537–53. 138. Ferri R, Parrino L, Smerieri A, et al. Cyclic alternating pattern and spectral analysis of heart rate variability during normal sleep. J Sleep Res 2000;9(1):13–8. 139. Parrino L, Smerieri A, Rossi M, et al. Relationship of slow and rapid EEG components of CAP to ASDA arousals in normal sleep. Sleep 2001;24(8):881–5. 140. American Sleep Disorders Association. EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep 1992;15(2):173–84. 141. Ferri R, Bruni O, Miano S, et al. All-night EEG power spectral analysis of the cyclic alternating pattern components in young adult subjects. Clin Neurophysiol 2005;116(10):2429–40. 142. Ferri R, Bruni O, Miano S, et al. Topographic mapping of the spectral components of the cyclic alternating pattern (CAP). Sleep Med 2005;6(1):29–36.

G. Plazzi et al. 143. Ferri R, Rundo F, Bruni O, et al. Regional scalp EEG slowwave synchronization during sleep cyclic alternating pattern A1 subtypes. Neurosci Lett 2006;404(3):352–7. 144. Ferri R, Rundo F, Bruni O, et al. Small-world network organization of functional connectivity of EEG slow-wave activity during sleep. Clin Neurophysiol 2007;118(2): 449–56. 145. Borbely AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms 1999;14(6):557–68. 146. Naumann A, Bellebaum C, Daum I. Cognitive deficits in narcolepsy. J Sleep Res 2006;15(3):329–38. 147. Thomas RJ. Fatigue in the executive cortical network demonstrated in narcoleptics using functional magnetic resonance imaging—a preliminary study. Sleep Med 2005; 6(5):399–406. 148. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol 1998; 43(1):88–97. 149. Provini F, Albani F, Vetrugno R, et al. A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleeprelated eating disorder. Eur J Neurol 2005;12(6):432–6. 150. Gagnon JF, Postuma RB, Montplaisir J. Update on the pharmacology of REM sleep behavior disorder. Neurology 2006;67(5):742–7. 151. Thorpy MJ, Snyder M, Aloe FS, et al. Short-term triazolam use improves nocturnal sleep of narcoleptics. Sleep 1992;15(3):212–6. 152. Xyrem International Study Group. Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Med 2005;6(5):415–21. 153. Xyrem International Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med 2004;5(2):119–23. 154. Mamelak M, Black J, Montplaisir J, et al. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy 316. Sleep 2004;27(7): 1327–34. 155. Lammers GJ, Arends J, Declerck AC, et al. Gammahydroxybutyrate and narcolepsy: a double-blind placebo-controlled study 649. Sleep 1993;16(3):216–20. 156. Foutz AS, Delashaw Jr. JB, Guilleminault C, et al. Monoaminergic mechanisms and experimental cataplexy. Ann Neurol 1981;10(4):369–76. 157. Sandyk R. Efficacy of trazodone in narcolepsy. Eur Neurol 1985;24(5):335–7.