NARCOLEPSY WITH CATAPLEXY AND NOCTURNAL COMPULSIVE BEHAVIORS doi: 10.5665/sleep.1280
Narcolepsy with Cataplexy Associated with Nocturnal Compulsive Behaviors: A Case-Control Study
Vincenzo Palaia, MD1; Francesca Poli, MD, PhD1; Fabio Pizza, MD1; Elena Antelmi, MD1; Christian Franceschini, PsyD, PhD1; Keivan Kaveh Moghadam, MD1; Frederica Provini, MD, PhD1; Uberto Pagotto, MD2; Pasquale Montagna, MD1†; Carlos H. Schenck, MD3; Emmanuel Mignot, MD4; Giuseppe Plazzi, MD1 1 Department of Neurological Sciences University of Bologna, Bologna, Italy; 2Endocrinology Unit and Centre of Applied Biomedical Research, Department of Clinical Medicine, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, Italy; 3Minnesota Regional Sleep Disorders Center, Department of Psychiatry, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, MN; 4Center for Narcolepsy, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA
Study Objectives: To assess the prevalence of sleep related-eating disorder (SRED) and nocturnal smoking (NS) in patients with narcolepsy with cataplexy (NC). Design: Case-control study. Setting: University hospital. Patients or Participants: 65 consecutive adult NC patients (33 men; mean age 43.9 ± 19.2 years) and 65 age-, sex-, and geographical originmatched controls. Interventions: Validated questionnaires were used to investigate SRED, NS, restless legs syndrome (RLS), and psychopathological traits (using Eating Disorder Inventory-2 [EDI-2]; Maudsley Obsessive-Compulsive Inventory [MOCI]; and Beck Depression Inventory [BDI]). Measurements and Results: NC patients showed a higher prevalence of SRED (32% vs 3%, P = 0.00001), NS (21% vs 0%, P = 0.00006), and RLS (18% vs 5%, P = 0.013) than controls. Moreover, NC patients presented more frequently with an eating-related pathological profile on the EDI-2 (80% vs 46%, P = 0.00006) and had a higher prevalence of depressed mood on the BDI (41% vs 18%, P = 0.004). In comparison to patients without SRED, NC patients with SRED were more frequently women (71% vs 39%, P = 0.013), had higher “bulimic” (29% vs 2%, P = 0.004) and “social insecurity” (48% vs 18%, P = 0.013) traits on the EDI-2, had higher obsessive-compulsiveness on the MOCI (29% vs 4%, P = 0.009), and were more depressed on the BDI (67% vs 29%, P = 0.005). NC patients with NS showed more frequent pathological profiles on the EDI-2 (100% vs 75%, P = 0.035), including the “bulimic” (29% vs 6%, P = 0.015), “perfectionism” (43% vs 14%, P = 0.016), and “social insecurity” (50% vs 22, P = 0.035) profiles. Conclusion: Our study shows a strong association of the compulsive nocturnal behaviors SRED and NS with adult NC. Keywords: Narcolepsy with cataplexy, nocturnal compulsive behaviors, case-control study, sleep related-eating disorder, nocturnal smoking. Citation: Palaia V; Poli F; Pizza F; Antelmi E; Franceschini C; Moghadam KK; Provini F; Pagotto U; Montagna P; Schenck CH; Mignot E; Plazzi G. Narcolepsy with cataplexy associated with nocturnal compulsive behaviors: a case-control study. SLEEP 2011;34(10):1365-1371.
INTRODUCTION Narcolepsy with cataplexy (NC) is a central nervous system hypersomnia, characterized by excessive daytime sleepiness (EDS), cataplexy (transient loss of muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep.1 It is caused by the selective loss of hypothalamic neurons2 producing hypocretin-1 and 2 (or orexin-A and B),3,4 two related peptides involved in regulation of sleep-wake transition, energy homeostasis, feeding behavior, and reward systems.5 Accordingly, low/undetectable cerebrospinal (CSF) hypocretin-1 (hrct-1) is observed in almost all cases of NC. Sleep-related eating disorder (SRED) is a NREM parasomnia, characterized by recurrent episodes of involuntary eating and drinking during arousals from the main sleep period. It involves nocturnal consumption of food or toxic substances, dis†
ruption of nocturnal sleep, and increased risk for sleep-related injuries including those derived from food seeking/cooking, morning anorexia, or other medical consequences.1 SRED has been found associated with various sleep disorders in case series: sleepwalking (SW), periodic limb movements during sleep (PLMS), narcolepsy, restless legs syndrome (RLS), and obstructive sleep apnea (OSA).6,7 The high rate of PLMS and rhythmic masticatory muscle activity in SRED patients,8 together with the high prevalence of SRED (33%) in idiopathic RLS,9 suggests a pathophysiological derangement of the dopaminergic system. Besides SRED, other compulsive behaviors can arise from nocturnal sleep, such as nocturnal smoking (NS). NS is an “out of control” smoking behavior during nocturnal awakenings characterized by an inner desire to smoke associated or not associated with eating. NS has also been reported in RLS patients,10 a frequent and possibly confounding condition in NC.11 Finally, NC has been associated with excessive weight gain and obesity via unclear mechanisms.12-18 Some studies have suggested a common genetic predisposition,19 while other authors have found that increased BMI is intrinsic to the NC phenotype.18 In this context, weight gain occurs despite paradoxically lowered daytime caloric intake, suggesting decreased energy expenditure.18 Given the frequent association of SRED with other sleep disorders and the recent report of food craving-behaviors in NC,20,21 our study aimed at assessing the prevalence of SRED and NS in
Dr. Montagna died December 9, 2010.
Submitted for publication December, 2010 Submitted in final revised form May, 2011 Accepted for publication May, 2011 Address correspondence to: Giuseppe Plazzi, Dipartimento di Scienze Neurologiche dell’Università di Bologna, via Ugo Foscolo, 7, 40123 Bologna, Italy; Tel: +390512092926; Fax: +390512092963; E-mail: giuseppe.
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adult NC patients. We hypothesized that these abnormalities could contribute to obesity in NC. PATIENTS AND METHODS Patients Sixty-five consecutive patients with a clinical and polysomnographic diagnosis of NC according to the International Classification of Sleep Disorders (ICSD-2)1 were enrolled in this study. These subjects were consecutive patients routinely followed at the Outpatient Clinic for Narcolepsy, Department of Neurological Sciences, University of Bologna between January 2008 and April 2009. Each patient was asked to indicate an acquaintance (not relative) of the same sex, age (± 3 years), and geographical area of origin (Northern, Central, or Southern Italy) who was willing to complete the same questionnaires. The institutional review board of the Department of Neurological Sciences, University of Bologna approved the study project, and all subjects signed a written informed consent.
Table 1—NC patients vs Controls Number of subjects (N) Demographic Data Age (y) mean ± SD Female Sex Area (Italy) North Centre South BMI (kg/m2) mean ± SD Smoking Cigarette (n. per day) mean ± SD Alcohol drinkers Coffee drinkers Cola drinkers Systemic hypertension Cardiovascular diseases Endocrinological diseases Other internal diseases Drugs (except NC) NC Features ESS mean score ± SD Cataplexy Hallucinations Sleep paralysis MSLT sleep latency (min) mean ± SD MSLT SOREMPs mean ± SD CSF hcrt-1 (pg/mL) mean ± SD
NC
Controls
p-value
65
65
43.9 ± 19.2 49.2%
43.8 ± 19.3 49.2%
ns ns
71% 18% 11% 27.6 ± 5.5 46.2% 17.4 ± 8.6 29.2% 87.7% 38.5 21.5% 7.7% 21.5% 20% 30.8%
71% 18% 11% 24.4 ± 4.7 21.5% 13.8 ± 8.1 40% 83.1% 21.5 15.4% 6.2% 9.2% 12.3% 24.6%
ns ns ns 0.0002 0.003 ns ns ns 0.035 ns ns ns ns ns
16.5 ± 4.9 100% 69.2% 67.7% 4±3 3.9 ± 1.3 31.6 ± 48.8 (N 26/65) 100% 60% 29.2% 18.5%
5.6 ± 2.9 0% 9.2% 6.2% na na na
< 0.000001 < 0.000001 < 0.000001 < 0.000001
Methods Each subject (patients and controls) underwent a semi-structured interview HLADQB1*0602 na collecting demographic data (age, Modafinil use 0% < 0.000001 body mass index [BMI], smoking Venlafaxine use 0% < 0.000001 status, and habitual consumption of Sodium oxybate use 0% < 0.000001 caffeinated beverages), employment, general health status and comorbidiSD, standard deviation; BMI, body mass index; NC, narcolepsy with cataplexy; ESS, Epworth Sleepiness ties (arterial hypertension, cardioScale; MSLT, multiple sleep latency test; SOREMP, sleep onset REM period; CSF, cerebrospinal fluid; vascular diseases, endocrinological, HCRT1, hypocretin-1; SRED, sleep-related eating disorder; NS, nocturnal smoking; RLS, restless and internal medicine disorders— legs syndrome; IRLSS, International Restless Legs Syndrome Study rating scale; MOCI, Maudsley i.e.gastroenterological, respiratory, Obsessive-Compulsive Inventory; BDI, Beck Depression Inventory; EDI-2, Eating Disorder Inventory and urological diseases), subjective (second edition); DT, “Drive for Thinness”; BU, “Bulimia”; BD, “Body Dissatisfaction”; I, “Ineffectiveness”; sleep characteristics (self-reported P, “Perfectionism”; ID, “Interpersonal Distrust”; IA, “Interoceptive Awareness”; MF, “Maturity Fears”; ASC, “Asceticism”; IR, “Impulse Regulation”; SI, “Social Insecurity.” sleep latency, total sleep time, and Table 1 continues on the following page nocturnal awakenings), use of psychotropic medications, dopaminergic tiveness” – I; “Perfectionism” – P; “Interpersonal Distrust” agents, and other current medications. Previously validated – ID; “Interoceptive Awareness” – IA; “Maturity Fears” questionnaires9 assessing current (last 3 months) and lifetime presence of the following sleep disorders were administered: – MF; “Asceticism” – ASC; “Impulse Regulation” – IR; (a) SRED (Italian translation of the 7 questions of the in“Social Insecurity” – SI), commonly associated with eating ternational criteria1); (b) RLS (International criteria for didisorders24; (b) the Maudsley Obsessive-Compulsive Inven22 agnosis of RLS ); (c) RLS severity (International Restless tory (MOCI)25 for obsessive-compulsive traits; (c) the Beck 23 Legs Syndrome Study Rating Scale [IRLSS] ); and (d) NS Depression Inventory (BDI)26; and (d) the Epworth Sleepi10 (Smoking Disorder Questionnaire ). All subjects also comness Scale (ESS).27 Definite obsessive-compulsiveness was pleted the following self-administered questionnaires/scales: considered with MOCI score ≥ 17,25,28,29 and depressed mood (a) the Eating Disorder Inventory-2 (EDI-2), exploring 11 with BDI score ≥ 10.30,31 Clinical records were reviewed to psychopathological profiles (namely: “Drive for Thinness” – collect MSLT, HLA-DQB1*0602 data of all NC patients, DT; “Bulimia” – BU; “Body Dissatisfaction” – BD; “Ineffecand CSF hcrt-1, when available. Moreover, information on SLEEP, Vol. 34, No. 10, 2011
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Table 1 (continued)—NC patients vs Controls Sleep Disorders SRED NS RLS IRLSS mean ± SD Subjective nocturnal total sleep time 1-2 h 3-4 h 5-6 h ≥7h Subjective nocturnal sleep latency ≤ 15 min 16-30 min ≥ 30 min Unknown Subjective difficulties in falling asleep Complaint of nocturnal awakenings Hypnotic use Psychological Features MOCI Pathological scores (≥ 17) Borderline Normal Mean score ± SD BDI Pathological scores (≥ 10) Mean score ± SD EDI-2 Pathological DT BU BD I P ID IA MF ASC IR SI
NC
Controls
p-value
32.3% 21.5% 18.5% 20.0 ± 10.8
3.1% 0% 4.6% 10.3 ± 4.5
0.00001 0.00006 0.013 ns ns
0% 7.7% 33.8% 58.5%
0% 0% 30.8% 69.2%
98.5% 1.5% 0% 0% 27.7% 100% 1.5%
61.5% 27.7% 9.2% 1.5% 32.3% 70.8% 9.2%
12.3% 23.1% 64.6% 10.5 ± 4.9
7.7% 16.9% 75.4% 8.6 ± 4.8
0.015
41.5% 10.1 ± 8.3
18.5% 5.4 ± 5.4
0.004 0.0002
80% 33.8% 10.8% 40% 27.7% 20% 38.5% 20% 38.5% 20% 10.8% 27.7%
46.2% 12.3% 3.1% 23.1% 9.2% 12.3% 20% 6.2% 18.5% 7.7% 4.6% 10.8%
0.00006 0.004 ns 0.038 0.007 ns 0.021 0.019 0.012 0.042 ns 0.014
0.000004
RESULTS ns 0.000002 ns ns
SD, standard deviation; BMI, body mass index; NC, narcolepsy with cataplexy; ESS, Epworth Sleepiness Scale; MSLT, multiple sleep latency test; SOREMP, sleep onset REM period; CSF, cerebrospinal fluid; HCRT1, hypocretin-1; SRED, sleep-related eating disorder; NS, nocturnal smoking; RLS, restless legs syndrome; IRLSS, International Restless Legs Syndrome Study rating scale; MOCI, Maudsley Obsessive-Compulsive Inventory; BDI, Beck Depression Inventory; EDI-2, Eating Disorder Inventory (second edition); DT, “Drive for Thinness”; BU, “Bulimia”; BD, “Body Dissatisfaction”; I, “Ineffectiveness”; P, “Perfectionism”; ID, “Interpersonal Distrust”; IA, “Interoceptive Awareness”; MF, “Maturity Fears”; ASC, “Asceticism”; IR, “Impulse Regulation”; SI, “Social Insecurity.”
NC Patients and Controls Sixty-five (33 males and 32 females) NC patients (43.9 ± 19.2 years old, BMI = 27.6 ± 5.5 kg/m2), entered in the study. Patients mainly lived in Northern Italy (71%), with 18% and 11% of subjects coming from Central and Southern Italy, respectively. NC symptoms included excessive daytime sleepiness and cataplexy (100%), hypnagogic hallucinations (69%), and sleep paralysis (67%). NC patients had a mean ESS score of 16.5 ± 4.9, a mean CSF hcrt1 level of 31.6 ± 48.7 pg/mL (available in 26 subjects), and HLA DQB1*0602 genotype (all subjects). At 5-opportunity multiple sleep latency test (MSLT),32 a mean sleep latency of 4.0 ± 3.0 min, with 3.9 ± 1.3 sleep onset REM periods was shown. At the time of this study, 71% (n = 46) of the NC patients were under stable pharmacological treatment with various combinations: 60% modafinil, 29% venlafaxine, and 19% sodium oxybate. Detailed clinical and demographic characteristics of patients and controls are reported in Table 1.
Clinical Features in NC vs Controls NC patients had a higher BMI than controls (27.6 ± 5.5 vs 24.4 ± 4.7, P = 0.0002), were more frequently smokers (46% vs 21%, P = 0.003), and more frequent drinking of caffeinated cola (38% vs 21%, P = 0.035). As expected, NC patients had higher ESS values and more cataplexy, hypnagogic hallucinations, and sleep paralysis (all p-values < 0.000001). Additionally, NC patients reported more nocturnal awakenings and had shorter subjective nocturnal sleep latency (Table 1).
current NC pharmacological treatment, history of substance abuse, and of comorbid sleep disorders (OSA, SW and other NREM sleep parasomnias, REM sleep behavior disorder) were collected. SLEEP, Vol. 34, No. 10, 2011
Statistical Analyses Clinical, demographic, and sleep disorders data are presented as means ± standard deviation or frequencies for continuous versus categorical variables, respectively. Statistical differences of demographic, clinical, sleep disorders, and psychometric variables were first tested between NC patients versus controls, then in subgroups of NC patients with and without SRED, RLS, or NS. A p-value < 0.05 was considered significant. As appropriate, χ2 or Fisher exact test were used for categorical data, and Mann-Whitney U test for continuous variables.
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In addition to the above, NC patients suffered more frequently from the following sleep disorders in comparison to controls: SRED 32% vs 3% (P = 0.00001), RLS 18% vs 5% (P = 0.013), and NS 21% vs 0% (P = 0.00006). NC patients also had significantly higher MOCI scores (P = 0.015) (without reaching statistical significance for definite obsessive-compulsiveness), and higher BDI scores with significant recurrence of depressed mood (41% vs 18%, P = 0.004), when compared to controls. Finally, patients were found to score more frequently in the pathological range for the various EDI-2 traits (80% vs 46%, P = 0.00006), with higher prevalence of the following profiles: DT (34% vs 12%, P = 0.004), BD (40% vs 23%, P = 0.038), I (28% vs 9%, P = 0.007), ID (38% vs 20%, P = 0.021), IA (20% vs 6%, P = 0.019), MF (38% vs 18%, P = 0.012), ASC (20% vs 8%, P = 0.042), and SI (28% vs 11%, P = 0.014) (Table 1).
Table 2—NC patients with and without SRED Number of subjects (N) Demographical Data Age (y) mean ± SD Female Sex Area (Italy) North Center South BMI (kg/m2) mean ± SD Smoking Cigarette (n. per day) mean ± SD Alcohol drinkers Coffee drinkers Cola drinkers Systemic hypertension Cardiovascular diseases Endocrinological diseases Other internal diseases Drugs (except NC)
NC-SRED 21
NC-no SRED 44
p-value
41.2 ± 16.4 71.4%
45.3 ± 20.4 38.6%
ns 0.013 ns
76.2% 9.5% 14.3% 27.5 ± 5.6 61.9% 14.4 ± 5.8 33.3% 95.2% 57.1 14.3% 9.5% 23.8% 9.5% 19%
68.2% 22.7% 9.1% 27.6 ± 5.5 38.6% 19.7 ± 9.9 27.3% 84.1% 29.5 25% 6.8% 20.5% 25% 36.4%
ns ns ns ns ns 0.032 ns ns ns ns ns
NC Features
Clinical Features in NC vs BMI-Matched ESS mean score ± SD 17.1 ± 5.1 16.2 ± 4.8 ns Controls Cataplexy 100% 100% ns To investigate whether higher BMI in Hallucinations 66.7% 70.5% ns narcolepsy was a primary driver of the Sleep paralysis 71.4% 65.9% ns effect of narcolepsy on SRED, we comMSLT sleep latency (min) mean ± SD 4.1 ± 2.9 4 ± 3.1 ns pared a subgroup of 36 NC with 36 conMSLT SOREMPs mean ± SD 3.5 ± 1.6 4 ± 1.1 ns trols matched for sex, age, and BMI (± 3 CSF hcrt-1 (pg/mL) mean ± SD 59.3 ± 67.8 28 ± 37.1 ns kg/m2). In this comparison, NC patients (N 10/21) (N 13/44) reported a higher rate of internal medicine Modafinil use 61.9% 59.1% ns comorbidities (25% vs 6%, P = 0.022), Venlafaxine use 33.3% 27.3% ns a higher frequency of smoking (42% vs Sodium oxybate use 19% 18.2% ns 14%, P = 0.009), and higher cola consumpHypnotics 0% 2.3% ns tion (44% vs 22%, P = 0.046) than matched Dopaminergic agents 4.8% 2.3% ns controls. More importantly, NC patients had more nocturnal awakenings, a signifiOSA, obstructive sleep apnea; CPAP, continuous positive air pressure device. cantly shorter subjective nocturnal sleep Table 2 continues on the following page latency, and a higher frequency of SRED (25% vs 6%, P = 0.022) and NS (19% vs 0%, P = 0.011). BDI scores were more frequently in the clear-cut depressed mood range (42% vs 19%, and both subgroups had equivalent levels of comorbid nocturP = 0.041), while EDI-2 traits were more often pathological (83% nal sleep disturbances. vs 56%, P = 0.011), without displaying any specific profile (see NC patients with NS (21%, n = 14) were more frequently Supplemental Table S1). employed (P = 0.041) than other NC patients (both daytime smokers and nonsmokers). NC patients with NS were all dayDemographic Features, Sleep Comorbidity, and Psychological time smokers (100% vs 31%, P = 0.000001), and had higher Traits in NC Patients with and without SRED, NS, and RLS cigarette consumption (≥ 20) per day (57% vs 16%, P < 0.005). NC patients with SRED (32%, n = 21) were more freNS in NC was significantly associated with presence of a pathoquently women (71% vs 39%, P = 0.013) and cola drinkers logical profile at EDI-2 (100% vs 74%, P = 0.035), most nota(57% vs 29%, P = 0.032) than the 44 NC patients without bly BU (29% vs 6%, P = 0.015), P (43% vs 14%, P = 0.016), SRED. SRED in NC was significantly associated with defiand SI (50% vs 22%, P = 0.035) (Table S2). nite obsessive-compulsiveness on the MOCI (P = 0.009), with Twelve NC patients had RLS (18%). These patients were depressed mood on the BDI (67% vs 29%, P = 0.005), and significantly older (mean age of 55 vs 42 years, P = 0.03) than with the BU (29% vs 2%, P = 0.004) and SI (48% vs 18%, NC patients without RLS. Finally, RLS in NC was signifiP = 0.013) profiles on the EDI-2 (Table 2). The other clinical cantly associated with obsessive-compulsiveness on the MOCI features, most notably BMI, where not associated with SRED, (P = 0.037) and with the P (42% vs 15%, P = 0.038) profile on SLEEP, Vol. 34, No. 10, 2011
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previously reported associations of NC with overweight/obesity,12-18,20,21 with NC-SRED NC-no SRED p-value RLS,11 and depressed mood.33-36 Nocturnal eating has been anecdotally Sleep Disorders reported in narcoleptic patients,6,37 but had NS 33.3% 15.9% ns never been systematically assessed. These RLS 23.8% 15.9% ns associations were not related to the presIRLSS mean ± SD 24.4 ± 12.7 16.9 ± 8.7 ns ence of other sleep disorders nor to curMild untreated OSA 9.5% 11.4% ns rent pharmacological treatment, although OSA treated with CPAP 9.5% 11.4% ns we cannot rule out an effect of the NC All OSA 19% 22.7% ns medications. Previous studies, however, REM sleep behavior disorder 38.1% 34.1% ns have shown that modafinil, venlafaxine, NREM sleep parasomnias 14.3% 13.6% ns and sodium oxybate decrease food intake/ Subjective nocturnal total sleep time ns craving,38-40 suggesting that these treat1-2 h 0% 0% ments could have mitigated these abnor3-4 h 9.5% 6.8% mal nocturnal behaviors. 5-6 h 38.1% 31.8% As with SRED overall in case series ≥7h 52.4% 61.4% (66% to 83%), SRED in NC mostly affectSubjective nocturnal sleep latency ns ed women (71%).1 Unlike in the general ≤ 15 min 95.2% 100% population,1,41 however, SRED in narco16-30 min 4.8% 0% lepsy was not associated with increased ≥ 30 min 0% 0% BMI, weight gain, or nocturnal awakenUnknown 0% 0% ings, suggesting a possible primary effect Subjective difficulties in falling asleep 28.6% 27.3% ns of hypocretin deficiency. Interestingly, Complaint of nocturnal awakenings 100% 100% ns NC patients with nocturnal feeding also rated higher in the areas of obsessivePsychological Features compulsiveness, bulimic profile, and deMOCI 0.009 pressed mood, suggesting a compulsive Pathological scores (≥ 17) 28.6% 4.5% personality in NC-SRED patients when Borderline 28.6% 20.5% compared to other NC subjects. Given the Normal 42.9% 75% cross-sectional nature of our study, howMean score ± SD 12.8 ± 5.7 9.3 ± 4 0.032 ever, we cannot determine whether these BDI personality traits contribute to, co-occur Pathological scores (≥ 10) 66.7% 29.5% 0.005 with, or result from nocturnal eating epiMean score ± SD 13.9 ± 9.1 8.3 ± 7.4 0.010 sodes. Compulsiveness of SRED in NC EDI-2 patients could reflect an “out of control” Pathological 90.5% 75% ns context in NC in which SRED arises.1,9 In DT 38.1% 31.8% ns a previous study,20 increased bulimia was BU 28.6% 2.3% 0.004 reported in NC, but was strictly confined BD 47.6% 36.4% ns to NC patients with SRED. Further, deI 42.9% 20.5% ns pressed mood was overall more frequent P 19% 20.5% ns in NC patients versus controls, especially ID 42.9% 36.4% ns in those with SRED. Our finding thus IA 23.8% 18.2% ns confirms available data on depressive disMF 42.9% 36.4% ns orders in narcolepsy,33-36 and further suggests a vicious cycle of SRED and mood ASC 33.3% 13.6% ns disturbance within NC. IR 9.5% 11.4% ns In our sample, a high prevalence of SI 47.6% 18.2% 0.013 smoking was found, and many patients were also found to exhibit NS. As smoking OSA, obstructive sleep apnea; CPAP, continuous positive air pressure device. has a proven nicotinic dopamine-stimulating effect,42 with positive effect on sleepithe EDI-2 (Table S3). RLS was not significantly associated with ness and possibly cataplexy,43 it could represent an attempt at SRED or NS in NC patients. self-therapy. Interestingly, NC patients with NS presented more frequently with psychopathological traits such as “bulimia” and DISCUSSION “social insecurity” (similar to NC patients with SRED versus Using validated tools and a carefully designed control group, NC patients without SRED), and “perfectionism.” Additionwe found a strong association of NC with SRED and NS, two ally, our results linking compulsiveness and depressed mood to compulsive nocturnal behaviors. Our results are in line with daytime and nocturnal nicotine addiction in NC may be related Table 2 (continued)—NC patients with and without SRED
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to recent findings pinpointing the paradoxical anxiolytic effect of nicotine in an experimental animal model of NC.44 Although SRED and NS were not reciprocally associated in our NC sample, the overlap of abnormal EDI-2 traits in NC with SRED and with NS may suggest a common underlying mechanism for these behaviors. Surprisingly, RLS was not associated with nocturnal compulsive eating/smoking, which differs from prior reports in idiopathic RLS.9,10 This finding is in favor of different pathophysiological mechanisms underlying RLS in NC.11 We might speculate that hypocretin deficiency impairs impulse control through its effects on dopaminergic systems, resulting in NS and SRED. In healthy subjects, feeding is confined to wakefulness, and hypocretins promote both wake and locomotor activity/food seeking45 during the day. Hypocretinproducing neurons have widespread afferent and efferent projections46-50 and play a complex role in cortical arousal, appetite regulation, in the cephalic phase of digestion (namely the preparatory phase of feeding), in stress/reward mechanisms, and in regulating motor and emotional arousal.45 Further, the loss of hypocretinergic neurons that characterizes NC creates a state of sleep-wake boundary abnormality,51 which could favor the occurrence of abnormal nocturnal behaviors. The close interactions of the hypocretin neurons with the dopaminergic system further corroborate the hypothesis of a dopaminergic system impairment underlying SRED and NS pathophysiology, as confirmed by their improvement under dopaminergic treatment.52,53 The high recurrence of nocturnal compulsive eating and smoking behaviors in NC also calls for wider care on the nocturnal complaints of these patients and for future studies assessing the efficacy of targeted pharmacological treatments on the burden of symptoms of narcolepsy.
6. Schenck CH, Hurwitz TD, Bundlie SR, Mahowald MW. Sleep-related eating disorders: polysomnographic correlates of a heterogeneous syndrome distinct from daytime eating disorders. Sleep 1991;14:419-31. 7. Schenck CH, Mahowald MW. Review of nocturnal sleep-related eating disorders. Int J Eat Disord 1994;15:343-56. 8. Vetrugno R, Manconi M, Ferini-Strambi L, Provini F, Plazzi G, Montagna P. Nocturnal eating: sleep-related eating disorder or night eating syndrome? A videopolysomnographic study. Sleep 2006;29:949-54. 9. Provini F, Antelmi E, Vignatelli L, et al. Association of restless legs syndrome with nocturnal eating: a case-control study. Mov Disord 2009;24:871-7. 10. Provini F, Antelmi E, Vignatelli L, et al. Increased prevalence of nocturnal smoking in restless legs syndrome (RLS). Sleep Med 2010;11:218-20. 11. Plazzi G, Ferri R, Antelmi E, et al. Restless legs syndrome is frequent in narcolepsy with cataplexy patients. Sleep 2010;33:689-94. 12. Daniels L. Narcolepsy. Medicine 1934;13:1-122. 13. Kotagal S, Hartse KM, Walsh JK. Characteristics of narcolepsy in preteenaged children. Pediatrics 1990;85:205-9. 14. Challamel MJ, Mazzola ME, Nevsimalova S, Cannard C, Louis J, Revol M. Narcolepsy in children. Sleep 1994;17(8 Suppl):S17-20. 15. Schuld A, Hebebrand J, Geller F, Pollmacher T. Increased body-mass index in patients with narcolepsy. Lancet 2000;355:39-40. 16. Dahmen N, Bierbrauer J, Kasten M. Increased prevalence of obesity in narcoleptic patients and relatives. Eur Arch Psychiatry Clin Neurosci 2001;251:85-9. 17. Kotagal S, Krahn LE, Slocumb N. A putative link between childhood narcolepsy and obesity. Sleep Med 2004;5:147-50. 18. Poli F, Plazzi G, Di Dalmazi G, et al. Body mass index-independent metabolic alterations in narcolepsy with cataplexy. Sleep 2009;32:1491-7. 19. Okun ML, Lin L, Pelin Z, Hong S, Mignot E. Clinical aspects of narcolepsy/cataplexy across ethnic groups. Sleep 2002;25:27-35. 20. Chabas D, Foulon C, Gonzalez J, et al. Eating disorder and metabolism in narcoleptic patients. Sleep 2007;30:1267-73. 21. Fortuyn HA, Swinkels S, Buitelaar J, et al. High prevalence of eating disorders in narcolepsy with cataplexy: a case-control study. Sleep 2008;31:335-41. 22. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4:101-19. 23. Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4:121-32. 24. Garner DM. Eating disorders inventory-2: professional manual. Odessa, FL: Psychological Assessment Resources, 1991. 25. Hodgson RJ, Rachman S. Obsessional-compulsive complaints. Behav Res Ther 1977;15:389-95. 26. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561-71. 27. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-5. 28. Chan DW. The Maudsley Obsessional-Compulsive Inventory: a psychometric investigation on Chinese normal subjects. Behav Res Ther 1990;28:413-20. 29. Støylen IJ, Larsen S, Kvale G. The Maudsley Obsessional-Compulsive Inventory and OCD in a Norwegian nonclinical sample. Scand J Psychol 2000;41:283-6. 30. Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck depression inventory: Twenty five years of evalutation. Clin Psychol Rev 1988;8:77-100. 31. Leach C, Lucock M, Barkham M, Stiles WB, Noble R, Iveson S. Transforming between Beck Depression Inventory and CORE-OM scores in routine clinical practice. Br J Clin Psychol 2006;45:153-66. 32. 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. Sleep 2005;28:113-21. 33. Roth B, Nevsimalova S. Depression in narcolepsy and hypersomnia. Schweiz Arch Neurol Neurochir Psychiatr 1975;116:291-300. 34. Daniels E, King MA, Smith IE, Shneerson JM. Health-related quality of life in narcolepsy. J Sleep Res 2001;10:75-81. 35. Dauvilliers Y, Paquereau J, Bastuji H, Drouot X, Weil JS, Viot-Blanc V. Psychological health in central hypersomnias: the French Harmony study. J Neurol Neurosurg Psychiatry 2009;80:636-41.
ACKNOWLEDGMENTS Institution where this work was performed: Department of Neurological Sciences, University of Bologna, Bologna, Italy. This study was supported by MIUR PRIN 2008 prot. 2008HB385M (grant to Giuseppe Plazzi). DISCLOSURE STATEMENT This was not an industry supported study. Dr Plazzi has consulted for Cephalon and UCB-Pharma. Dr. Mignot has consulted for Jazz, Actelion, Roche, and Cephalon; is on the advisory board of Eli Lilly; has participated in lectures for Roche; has received research support from Jazz; and has financial interests in Resmed. The other authors have indicated no financial conflicts of interest. REFERENCES
1. American Academy of Sleep Medicine. The international classification of sleep disorders, 2nd ed: diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine, 2005. 2. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000;27:469-74. 3. de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamusspecific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998;95:322-7. 4. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998;92:1 page following 696. 5. Tsujino N, Sakurai T. Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 2009;61:162-76.
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Nocturnal Compulsive Behaviors in Narcolepsy—Palaia et al
36. Vignatelli L, Plazzi G, Peschechera F, Delaj L, D’Alessandro R. A 5-year prospective cohort study on health-related quality of life in patients with narcolepsy. Sleep Med 2010. 37. Spaggiari MC, Granella F, Parrino L, Marchesi C, Melli I, Terzano MG. Nocturnal eating syndrome in adults. Sleep 1994;17:339-44. 38. Perez GA, Haney M, Foltin RW, Hart CL. Modafinil decreases food intake in humans subjected to simulated shift work. Pharmacol Biochem Behav 2008;90:717-22. 39. Malhotra S, King KH, Welge JA, Brusman-Lovins L, McElroy SL. Venlafaxine treatment of binge-eating disorder associated with obesity: a series of 35 patients. J Clin Psychiatry 2002;63:802-6. 40. McElroy SL, Guerdjikova AI, Winstanley EL, et al. Sodium oxybate in the treatment of binge eating disorder: An open-label, prospective study. Int J Eat Disord 2011;44:262-8. 41. Winkelman JW. Clinical and polysomnographic features of sleep-related eating disorder. J Clin Psychiatry 1998;59:14-9. 42. Corrigall WA, Coen KM, Adamson KL. Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 1994;653:278-284. 43. Krahn LE, Martin KA, Silber MH. Narcoleptic patients’ perceptions of nicotine. J Clin Sleep Med 2009;5:390. 44. Plaza-Zabala A, Martín-García E, de Lecea L, Maldonado R, Berrendero F. Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior. J Neurosci 2010;30:2300-10. 45. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 2001;24:429-58.
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46. Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998;18:999610015. 47. Date Y, Ueta Y, Yamashita H, et al. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci U S A 1999;96:748-53. 48. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K. Distribution of orexin neurons in the adult rat brain. Brain Res 1999;827:243-60. 49. Elias CF, Saper CB, Maratos-Flier E, et al. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 1998;402:442-59. 50. Yoshida K, McCormack S, España RA, Crocker A, Scammell TE. Afferents to the orexin neurons of the rat brain. J Comp Neurol 2006;494:845-61. 51. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001;24:726-31. 52. Schenck CH, Hurwitz TD, O’Connor KA, Mahowald MW. Additional categories of sleep-related eating disorders and the current status of treatment. Sleep 1993;16:457-66. 53. Provini F, Albani F, Vetrugno R, et al. A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleep-related eating disorder. Eur J Neurol 2005;12:432-6.
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Table S1—NC patients vs BMI-matched controls Number of subjects (N) Demographical Data Age (y) mean ± SD Female Sex Area (Italy) North Centre South BMI (kg/m2) mean ± SD Smoking Cigarette (N per day) mean ± SD Alcohol drinkers Coffee drinkers Cola drinkers Systemic hypertension Cardiovascular diseases Endocrinological diseases Other internal diseases Drugs (except NC) NC Features ESS mean score ± SD Cataplexy Hallucinations Sleep paralysis MSLT sleep latency (min) mean ± SD MSLT SOREMPs mean ± SD CSF hcrt-1 (pg/mL) mean ± SD HLADQB1*0602 Modafinil use Venlafaxine use Sodium oxybate use Sleep Disorders SRED NS RLS IRLSS mean ± SD Subjective nocturnal total sleep time 1-2 h 3-4 h 5-6 h ≥7h Subjective nocturnal sleep latency ≤ 15 min 16-30 min ≥ 30 min Unknown Subjective difficulties in falling asleep Complaint of nocturnal awakenings Hypnotic use
NC 36
BMI ± 3 matched Controls 36
41.4 ± 19.5 47.2%
41.7 ± 19.2 47.2%
69.4% 22.2% 8.3% 25.5 ± 4 41.7% 15.8 ± 10.3 30.6% 88.9% 44.4 19.4% 8.3% 22.2% 25% 27.8%
66.7% 16.7% 16.7% 24.9 ± 3.6 13.9% 12.6 ± 5.3 38.9% 83.3% 22.2 13.9% 8.3% 13.9% 5.6% 22.2%
ns 0.009 ns ns ns 0.046 ns ns ns 0.022 ns
17.3 ± 4.6 100% 69.4% 69.4% 3.9 ± 3 3.9 ± 1.3 26.1 ± 48.4 (N 12/36) 100% 63.9% 33.3% 16.7%
5.4 ± 3.1 0% 13.9% 11.1% na na na
< 0.000001 < 0.000001 < 0.000001 < 0.000001
na 0% 0% 0%
< 0.000001 0.0002 0.025
25% 19.4% 16.7% 22 ± 12.3
5.6% 0% 2.8% 15 (N 1)
0.022 0.011 ns ns ns
0% 5.6% 19.4% 75%
0% 0% 27.8% 72.2%
100% 0% 0% 0% 30.6% 100% 0%
63.9% 27.8% 8.3% 0% 30.6% 66.7% 5.6%
P-value ns ns ns
0.0004
ns 0.0002 ns
Table S1 continues on the following page SLEEP, Vol. 34, No. 10, 2011
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Table S1 (continued)—NC patients vs BMI-matched controls Psychological Features MOCI Pathological scores (≥ 17) Borderline Normal Mean score ± SD BDI Pathological scores (≥ 10) Mean score ± SD EDI-2 Pathological DT BU BD I P ID IA MF ASC IR SI
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NC
BMI ± 3 matched Controls
8.3% 25% 66.7% 10 ± 4.5
13.9% 13.9% 72.2% 9.2 ± 5.5
ns
41.7% 9.6 ± 8.4
19.4% 5.7 ± 6
0.041 0.018
83.3% 19.45 5.6% 25% 22.2% 19.4% 25% 16.7% 38.9% 25% 16.7% 25%
55.6% 13.9% 5.6% 30.6% 8.3% 13.9% 22.2% 5.6% 27.8% 11.1% 5.6% 11.1%
0.011 ns ns ns ns ns ns ns ns ns ns ns
1371B
P-value ns
Nocturnal Compulsive Behaviors in Narcolepsy—Palaia et al
Table S2—NC patients with and without NS Number of subjects (N) Demographical Data Age (y) mean ± SD Female Sex Area (Italy) North Center South BMI (kg/m2) mean ± SD Smoking Smoking > 20 cig/day Cigarette (N per day) mean ± SD Alcohol drinkers Coffee drinkers Cola drinkers Systemic hypertension Cardiovascular diseases Endocrinological diseases Other internal diseases Drugs (except NC) NC Features ESS mean score ± SD Cataplexy Hallucinations Sleep paralysis MSLT sleep latency (min) mean ± SD MSLT SOREMPs mean ± SD CSF hcrt-1 (pg/mL) mean ± SD Modafinil use Venlafaxine use Sodium oxybate use Hypnotics Dopaminergic agents
NC-NS+ 14
NC-NS51
P-value
41.5 ± 13.9 35.7%
44.7 ± 20.5 52.9%
ns ns ns
78.6% 7.1% 14.3% 26.8 ± 4.7 100% 57% 18.9 ± 8.8 21.4% 92.9% 42.9 28.6% 14.3% 14.3% 21.4% 28.6%
68.6% 21.6% 9.8% 27.8 ± 5.7 31.4% 16% 16.1 ± 8.6 31.4% 86.3% 37.3 19.6% 5.9% 23.5% 19.6% 31.4%
17.5 ± 5.8 100% 64.3% 78.6% 3.7 ± 1.7 3.7 ± 1.4 31.2 ± 30 (N 7/14) 64.3% 50% 7.1% 0% 0%
16.2 ± 4.6 100% 70.6% 64.7% 4.1 ± 3.3 3.9 ± 1.3 31.8 ± 54.8 (N 19/51) 58.8% 23.5% 21.6% 2% 4%
ns 0.000001 < 0.005 ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns ns
Table S2 continues on the following page
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Table S2 (continued)—NC patients with and without NS Sleep Disorders SRED RLS IRLSS mean ± SD Mild untreated OSA OSA treated with CPAP All OSA REM sleep behaviour disorder NREM sleep parasomnias Subjective nocturnal total sleep time 1-2 h 3-4 h 5-6 h ≥7h Subjective nocturnal sleep latency ≤ 15 min 16-30 min ≥ 30 min Unknown Subjective difficulties in falling asleep Complaint of nocturnal awakenings Psychological Features MOCI Pathological scores (≥ 17) Borderline Normal Mean score ± SD BDI Pathological scores (≥ 10) Mean score ± SD EDI-2 Pathological DT BU BD I P ID IA MF ASC IR SI
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NC-NS+
NC-NS-
P-value
50% 14.3% 21.5 ± 6.4 7% 21% 28% 50% 21%
27.5% 19.6% 19.8 ± 11.4 12% 8% 20% 31% 12%
ns ns ns ns ns ns ns ns ns
0% 0% 35.7% 64.3%
0% 9.8% 33.3% 56.9%
100% 0% 0% 0% 7.1% 100%
98% 2% 0% 0% 33.3% 100%
21.4% 14.3% 64.3% 10.6 ± 6
9.8% 25.5% 64.7% 10.4 ± 4.6
ns
57.1% 12.7 ± 9 100%
37.3% 9.4 ± 8.1 74.5%
ns ns 0.035
50% 28.6% 42.9% 28.6% 42.9% 57.1% 35.7% 35.7% 35.7% 7.1% 50%
29.4% 5.9% 39.2% 27.5% 13.7% 33.3% 15.7% 39.2% 15.7% 11.8% 21.6%
ns 0.015 ns ns 0.016 ns ns ns ns ns 0.035
ns
1371D
ns ns
Nocturnal Compulsive Behaviors in Narcolepsy—Palaia et al
Table S3—NC patients with and without RLS NC-RLS 12
NC-no RLS 53
P-value
Demographical Data Age (y) mean ± SD Female Sex Area (Italy) North Center South BMI (kg/m2) mean ± SD Smoking Cigarette (N per day) mean ± SD Alcohol drinkers Coffee drinkers Cola drinkers Systemic hypertension Cardiovascular diseases Endocrinological diseases Other internal diseases Drugs (except NC)
55.1 ± 19.3 66.7%
41.5 ± 18.4 45.3%
0.030 ns ns
75% 16.7% 8.3% 29.0 ± 5.2 41.7% 13.6 ± 5.9 16.7% 91.7% 41.7 41.7% 33.3% 41.7% 41.7% 50%
69.8% 18.9% 11.3% 27.3 ± 5.5 47.2% 18.2 ± 9 32.1% 86.8% 37.7 17% 1.9% 17% 15.1% 26.4%
NC Features ESS mean score ± SD Cataplexy Hallucinations Sleep paralysis MSLT sleep latency (min) mean ± SD MSLT SOREMPs mean ± SD CSF hcrt-1 (pg/mL) mean ± SD
17.2 ± 3.8 100% 75% 75% 5.8 ± 5 3.7 ± 1.3 0±0 (Nº 2/12) 66.7% 16.7% 25%
16.3 ± 5.1 100% 67.9% 66% 3.7 ± 2.3 3.9 ± 1.3 34.2 ± 49.9 (Nº 24/53) 58.5% 32.1% 17%
41.7% 16.7% 22.2 ± 9.9
30.2% 22.6% na
0% 16.7% 50% 33.3%
0% 5.7% 30.2% 64.2%
91.7% 8.3% 0% 0% 33.3% 100% 8.3%
100% 0% 0% 0% 26.4% 100% 0%
Number of subjects (N)
Modafinil use Venlafaxine use Sodium oxybate use Sleep Disorders SRED NS IRLSS mean ± SD Subjective nocturnal total sleep time 1-2 h 3-4 h 5-6 h ≥7h Subjective nocturnal sleep latency ≤ 15 min 16-30 min ≥ 30 min Unknown Subjective difficulties in falling asleep Complaint of nocturnal awakenings Hypnotic use
ns ns ns ns ns ns ns 0.003 ns 0.038 ns ns ns ns ns ns ns ns ns ns ns ns ns ns
ns
ns ns ns
Table S3 continues on the following page
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Table S3 (continued)—NC patients with and without RLS Psychological Features MOCI Pathological scores (≥ 17) Borderline Normal Mean score ± SD BDI Pathological scores (≥10) Mean score ± SD EDI-2 Pathological DT BU BD I P ID IA MF ASC IR SI
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NC-RLS
NC-no RLS
P-value
0.029
16.7% 50% 33.3% 13.1 ± 4.8%
11.3% 17% 71.7% 9.9 ± 4.7%
0.037
50% 14.9 ± 11.9
39.6% 9±7
ns ns
75% 33.3% 8.3% 50% 25% 41.7% 33.3% 25% 16.7% 8.3% 25% 25%
81.1% 34% 11.3% 37.7% 28.3% 15.1% 39.6% 18.9% 43.4% 22.6% 7.5% 28.3%
ns ns ns ns ns 0.038 ns ns ns ns ns ns
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Nocturnal Compulsive Behaviors in Narcolepsy—Palaia et al
