Functional Impairment in Adult Sleepwalkers: A Case-Control Study

Abstract

Study Objectives:

To investigate the restorative quality of sleep and daytime functioning in sleepwalking adult patients in comparison with controls.

Design:

Prospective case-control study.

Setting:

Data were collected at the Sleep Disorders Center, Hôpital-Gui-de Chauliac, Montpellier, France between June 2007 and January 2011.

Participants:

There were 140 adult sleepwalkers (100 (median age 30 y, 55% male) in whom primary SW was diagnosed) who underwent 1 night of video polysomnography. All patients participated in a standardized clinical interview and completed a battery of questionnaires to assess clinical characteristics of parasomnia, daytime sleepiness, fatigue, insomnia, depressive and anxiety symptoms, and health-related quality of life. Results were compared with those of 100 sex- and age-matched normal controls.

Interventions:

N/A.

Measurements and Results:

Of the sleepwalkers, 22.3% presented with daily episodes and 43.5% presented with weekly episodes. Median age at sleepwalking onset was 9 y. Familial history of sleepwalking was reported in 56.6% of sleepwalkers and violent sleep related behaviors in 57.9%, including injuries requiring medical care for at least one episode in 17%. Significant associations were found between sleepwalking and daytime sleepiness, fatigue, insomnia, depressive and anxiety symptoms, and altered quality of life. Early-onset sleepwalkers had higher frequency of violent behaviors and injuries. Sleepwalkers with violent behaviors had higher frequency of sleep terrors and triggering factors, with greater alteration in health-related quality of life.

Conclusion:

Adult sleepwalking is a potentially serious condition that may induce violent behaviors, self-injury or injury to bed partners, sleep disruption, excessive daytime sleepiness, fatigue, and psychological distress, all of which affect health-related quality of life.

Citation:

Lopez R; Jaussent I; Scholz S; Bayard S; Montplaisir J; Dauvilliers Y. Functional impairment in adult sleepwalkers: a case-control study. SLEEP 2013;36(3):345-351.

INTRODUCTION

Sleepwalking (SW) is a common nonrapid eye movement (NREM) sleep parasomnia characterized by behaviors usually initiated during arousals from slow wave sleep (SWS).¹ Clinical presentation varies greatly, from a benign disease with simple, infrequent episodes to a severe disease with complex, injurious sleep related behaviors. SW can occur at any age, with an estimated 2-4% prevalence in adults that decreases with age.^2,3

Unlike rapid eye movement (REM) sleep behavior disorder, NREM parasomnias (confusional arousals, sleep terrors, and SW) have received little attention from researchers. NREM sleep arousal disorders were recently classified into primary NREM parasomnias, or sleep state disorders per se, and secondary parasomnias, or disorders of specific organ systems that also manifest during sleep.⁴ The pathophysiology of NREM sleep parasomnias remains unclear. The brain is partially awake, resulting in behavioral manifestations, and partially in NREM sleep, with no conscious awareness of actions.^5,6 Previous studies on SW reported increased awakenings from SWS that interfere with normal slow wave activity buildup.^7–9 Both NREM sleep instability and altered sleep homeostatic regulation may impair restorative sleep and daytime functioning in SW. However, associations between SW and excessive daytime sleepiness (EDS), fatigue, nighttime sleep problems, psychological distress, and health-related quality of life have been understudied. One clinical study reported EDS anecdotally in half of SW patients,¹⁰ which was recently confirmed in a small study that objectively measured sleepiness.¹¹ A recent large epidemio-logic study in the US adult general population also revealed an association between excessive sleepiness and having at least one SW episode in the previous year.²

Large case-control studies on adult sleepwalkers seen in clinic that consider both nighttime and daytime symptoms and psychological assessments are lacking. We conducted a clinically-based prospective case-control study aiming to (1) measure nighttime and daytime functioning, psychological health, and health-related quality of life using face-to-face interviews and standardized questionnaires in a large adult sample of primary SW patients compared with sex- and age-matched normal controls, and (2) determine relationships between the frequency and severity of parasomnia episodes, age at onset, familial history, and clinical characteristics of SW.

METHODS

Participants

From June 2007 to January 2011, SW was diagnosed in 140 consecutive adults at the Sleep Disorders Clinic, Mont-pellier-France. Inclusion criteria were (1) a primary complaint of typical clinical history of SW characterized by behavioral manifestations, misperception of the environment, impaired judgment, and frequent retrograde amnesia¹² (assessed by the patient and bed partner or parent) with no traumatic, neurological, or medication-induced origin according to the guidelines⁴; (2) at least one SW episode annually; (3) at least one episode in the past 6 months. Exclusion criteria were a positive clinical history of neurological disease (including epilepsy, REM sleep behavior disorder, and parkinsonism), psychosis, or concomitant sleep disorder assessed by semistructured clinical interview (mainly behavioral-induced insufficient sleep syndrome, narcolepsy, idiopathic hypersomnia and restless leg syndrome; more than two complaints/week), excepting reports of associated NREM parasomnias (nocturnal terrors, sleeptalking). None of the patients finally included had a bizarre phenotype with complex repetitive stereotyped behaviors suggestive of epileptic seizures, and none of them had a family history of epilepsy.

Polysomnography

All patients underwent 1 night of audio-video polysomnography (PSG) recording in the sleep laboratory. None were taking any medication known to influence sleep or motor activity for at least 1 month prior to PSG. Sleep recording included electroencephalogram leads (C3/A2, Fp1/T1, T1/O1, O1/C3, C4/A1, Fp2/T2, T2/O2, O2/C4), two electrooculograms, one chin electromyogram, and an electrocardiogram. Respiration was monitored with a nasal cannula/pressure transducer, mouth thermistor, chest and abdominal bands, and pulse oximeter. Sleep stage as well as microarousals and respiratory events were measured manually according to standard American Academy of Sleep Medicine (AASM) criteria.¹³ Obstructive sleep apneas were defined as > 10 sec complete airflow cessation associated with thoracoabdominal movements and hypopneas as ≥ 50% reduction in airflow plus ≥ 3% drop in SaO₂ and/or a micro-arousal based on AASM criteria.¹³ Surface electromyogram electrodes on anterior tibialis muscles recorded periodic limb movements during sleep (PLMS).¹⁴ Subjects with REM sleep parasomnias, nocturnal seizures, an apnea-hyponea event index > 10/h, PLMS index > 10/h, and > 20% loss of chin muscle atonia in REM sleep were excluded.

Forty sleepwalkers were excluded for infrequent episodes (n = 1), neurological comorbidities (epilepsy, n = 4; rapid eye movement sleep behavior disorder, n = 3), restless leg syndrome more than twice a week (n = 14), PLMS index > 10/h (n = 9), and apnea-hypopnea index > 10/h (n = 9). The final sample included 100 patients with primary SW (55 males, 45 females; age 18 to 58 y; median age 30 y). Investigating SW with audio-visual PSG monitoring is often difficult because episodes rarely occur in the sleep laboratory. However, we noted in 97 patients during the PSG either a typical parasomniac episode arising from SWS or one hypersynchronous delta wave arousal (defined as the occurrence of continuous hypersynchronous high-voltage [> 150 microvolts] delta waves [0.5-4 Hz])¹⁵ associated with an abnormal motor behavior on video or with a sustained increased muscle activity during SWS. Although neither totally sensitive nor specific to SW, these findings are supportive PSG criteria in the clinical context of parasomnia.^15,16

Results were compared for SW patients and 100 controls, who were community-dwelling adult volunteers recruited from local association networks (Montpellier, France). Controls were matched for age and sex (55 males, 45 females age 18 to 58 y; median age 27.5 y). The same exclusion criteria were used for controls and none reported any current or past symptoms of arousal disorders. None of the controls underwent a PSG recording.

All subjects gave their informed consent to participate in the study, which was approved by the local Institutional Review Board.

Clinical Evaluation

Patients and controls participated in face-to-face standardized clinical interviews to ascertain demographic and socioeconomic features, characteristics of parasomnia episodes, and normal general physical condition. Participants completed a battery of standardized questionnaires. None of the participants were taking any medication at least 1 month prior to evaluation.

Characteristics of SW Episodes

Age at onset, frequency of episodes at disease onset and at time of study, SW history in first- and second-degree relatives, and potential associated parasomnias (sleep terrors, sleeptalking) were assessed. Sleep related violent behaviors (physically aggressive or potentially dangerous behaviors for patients and cosleepers) were investigated in 95 patients together with potential associations with injuries defined as moderate to severe when they required medical care. Triggering factors for SW episodes were assessed by reports of strong positive emotions (such as unusual exciting leisure activity), stressful events, sleep deprivation, evening physical activity, drug intake, and alcohol use.

Nighttime Sleep Problems and Daytime Functioning

EDS was evaluated with the Epworth Sleepiness Scale (ESS).¹⁷ A total score of 10 or more indicates EDS. Fatigue symptoms were assessed with the Chalder Fatigue Scale (CFS), a self-rated measure of fatigue severity for physical (eight questions) and mental symptoms (six questions).¹⁸ A cutoff score of four or higher indicates fatigue. Insomnia was assessed by the Insomnia Severity Index (ISI), a seven-item self-report scale assessing subjective insomnia symptoms, including the degree of resultant distress.¹⁹ A cutoff score of 14 indicates insomnia; 21 indicates severe insomnia.

Psychologic Health and Health-Related Quality of Life

Depressive symptoms were assessed using the Beck Depression Inventory (BDI), a 21-item self-assessment tool, with higher scores indicating severe depressive symptoms (14-19 = moderate and > 19 = severe).²⁰ Anxiety symptoms were assessed using the State-Trait Anxiety Inventory Form Y (STAI); scores ≤ 60 indicate abnormal levels.²¹ Health-related quality of life was assessed using the 36-item Short Form Health Survey (SF-36).²²

Statistical Analysis

The sample is described using percentages for categorical variables and median and range for quantitative variables (e.g., age, disease duration, evolution), whereas the Shapiro-Wilk test revealed skewed distribution. Continuous variables were grouped into clinical thresholds. Sleepwalkers and controls were subjected to univariate comparisons using logistic regression analysis to evaluate the relationships between SW and social, clinical, and sleep characteristics. Associations were quantified with odds ratios (OR) and 95% confidence intervals (CI). Finally, logistic regressions were run to examine, in sleep-walkers, the univariate relationships between clinical characteristics and early-onset SW; history of violent behavior; familial NREM parasomnia; and frequency of SW episodes. Significance was set at P < 0.05. Statistical analyses were performed with SAS 9.2 (SAS Institute Inc., Cary, North Carolina).

RESULTS

Demographic parameters, including age (31.3 ± 9.3 for patients versus 31.1 ± 10.1 for controls), sex (55 male patients versus 55 male controls), body mass index (≥ 30 kg/m² in 3.1% of patients and 7.9% of controls), education, and socioprofessional characteristics, were not statistically different between SW patients and controls.

Clinical Features of SW Episodes

Table 1 shows that 22.8% of SW patients had daily episodes at the time of study, with 43.5% having at least one episode per week. Fifteen patients (16.3%) only had SW episodes either several nights per year or just 1 night per year (Table 1); however, they came to the sleep clinic due to the intensity of episodes with violent behaviors leading to severe injuries. Figure 1 shows the age distribution at SW onset, with more than half below 10 y, and only 16.9% adult onset. Median age at onset was 9 y (range 3-49), and median duration of evolution at time of study was 19 y (range 0-53). Only 22.3% of patients reported spontaneous improvement in episode frequency since onset, and frequency increased with age in 23.9%. Of the patients, 59.6% reported triggering factors that increased episode frequency and severity, mostly related to psychological stress, strong positive emotions, and sleep deprivation, and less frequently to alcohol or intense evening physical activity (Table 1). Only one subject reported medication (zolpidem) as a precipitating factor, and none reported fever. Night terrors were reported by 63.6% and sleeptalking by 91.9% of SW patients, but no controls, except for occasional sleeptalking by 41.0%. Occurrence of sleep related eating or sexual behaviors were not systematically assessed in our population but four patients reported spontaneous occurrence of sleep related eating and none reported sexsomnia.

Table 1.

Clinical features of sleepwalking patients (n = 100)

Figure 1.

Age at first episode in adult patients with sleepwalking.

A positive history of violent or dangerous sleep related behaviors were reported by 57.9% overall, with 31.2% of patients themselves and 45.8% of bed partners (Table 1). Violent behaviors with moderate to severe injuries occurring at least once per lifetime and requiring medical care for the patient himself were reported in 10.6% (10 patients including eight males). For example, one patient jumped out a third-floor window and sustained multiple fractures and serious head trauma. Another was hospitalized for months for lower limb and back fractures after a stairway fall. Others reported traumatic injuries with bruises, nose bleeding, fractures, abrasions, head contusions due to striking bedside tables, breaking walls, or jumping down stairs, leading to medical care. For six patients (6.4% of the population, five males), violent behaviors occurred toward bed partners who needed medical care after being attacked.

Positive familial history of SW was reported in 56.6% of patients, affecting first-degree relatives in 76.4%. Among familial cases, two SW adult members (including the proband) were reported in 58.9%, with 28.5% having three affected relatives and 12.6% having at least four affected relatives.

Daytime Functioning and Nighttime Sleep Problems

Table 2 presents the crude associations between daytime functioning, nighttime sleep problems, and SW. EDS (defined as ESS > 10) was reported in 42.2% of SW patients, significantly higher than the 11.0% in controls (OR = 5.96; 95% CI = 2.84-12.5; P < 0.001). Severe EDS (ESS > 15) was reported in 11.1% of SW patients and 1.0% in controls (P < 0.001). The association between SW and EDS (defined as a continuous variable) was confirmed (OR = 1.58; 95% CI = 1.33-1.87, for a two-point increase), with significant results even after adjusting for ISI, BDI, and fatigue scores (OR = 1.35; 95% CI = 1.07-1.70). A greater proportion of SW patients presented with moderate fatigue symptoms (CFS > 4) than controls (47% versus 14%; P < 0.001), with a reported association between SW and fatigue (defined as a continuous variable) (OR = 1.90; 95% CI = 1.54-2.35, for a two-point increase), which disappears after adjusting for ISI, BDI, and ESS scores.

Table 2.

Daytime functioning, nighttime sleep problems, and psychologic health in sleepwalking patients and in normal controls

Nighttime sleep disturbances were frequently reported in SW patients. More frequent insomnia symptoms (ISI > 14) were found in SW patients than in controls (43.4% versus 3.0%; P < 0.0001). Insomnia symptoms (defined as a continuous variable) were significantly associated with SW (OR = 2.00; 95% CI = 1.67-2.40, for a two-point increase), even after adjusting for BDI, fatigue, and ESS scores (OR = 1.92; 95% CI = 1.56-2.35). More precisely, our results showed significantly higher insomnia complaints for all ISI subcomponents in SW, with most complaints concerning the nonrestorative sleep profile (Table 2). However, only 5% of SW patients reported severe insomnia symptoms (ISI > 21), and 1% in control.

Psychologic Assessment and Health-Related Quality of Life

Table 2 presents the crude associations between psychological assessment, health-related quality of life assessed on the SF-36 scale, and SW. Note that depressive symptoms (BDI > 13) were more frequent in SW patients than in controls (20% versus 7.0%; P < 0.035). SW was significantly associated with BDI (OR = 1.26; 95% CI = 1.12-1.41), but this association does not remain significant after adjusting for ESS, fatigue, and insomnia scores. State anxiety level > 60 (OR = 2.95; 95% CI = 1.34-6.57) and trait anxiety level > 60 (OR = 1.05; 95% CI = 1.02-1.08) were associated with SW (Table 2). Alterations in health-related quality of life were greater for SW patients than controls for the entire SF-36 scale (Figure 2).

Figure 2.

Spidergrams showing the median values for SF-36 domain scores and OR (95% confidence interval) in sleepwalkers (n = 100) versus control patients (n = 100), for a five-point decrease. Scores range from 0 to 100, where 0 represents the worst possible health and 100 is perfect health. Mean scores for the individual SF-36 domains (PF, Physical Functioning; SF, Social Functioning; RP, Physical Role; BP, Bodily Pain; GH, General Health; MH, Mental Health; RE, Emotional Role; VT, Vitality) were significantly lower in SW patients compared with controls. OR, odds ratio.

Correlates of Clinical Characteristics of SW

We further analyzed the frequency of SW episodes, associated parasomnias, the time course of sleep episodes, violent and injury phenotypes, the familial component, daytime (EDS and fatigue) and nighttime symptoms (insomnia), psychological assessment (depressive and anxiety symptoms), and health-related quality of life in relation to clinical SW characteristics using logistic regression models. Compared with late-onset SW (patients older than 9 y, n = 44), early-onset SW in patients of similar age at time of study showed more frequent violent behaviors (OR = 2.63; 95% CI = 1.09-6.67) and injury (OR = 2.56; 95% CI = 1.05-6.25). In contrast, late-onset SW more frequently resulted in a worsening in the time course evolution than early-onset SW (OR = 5.65; 95% CI = 1.60-19.90). Compared with patients with no history of violent behavior (n = 40), patients with violent behavior (n = 55) had more frequent sleep terrors (81.8% versus 38.5%; OR = 7.20; 95% CI = 2.81-18.5) and triggering factors (74.1% versus 42.5%; OR = 3.87; 95% CI = 1.61-9.26), particularly alcohol intake, with no significant association with depressive and anxiety symptoms or mental health-related quality of life alterations.

In comparison with patients who had frequent somnambulism episodes (weekly to daily, n = 61), patients with infrequent episodes (less than weekly, n = 31) more frequently experienced improvement in SW evolution (10% versus 48%; OR = 6.10; 95% CI = 1.93-19.28), and unexpectedly, more frequent daytime sleepiness (ESS > 10) (31.7% versus 58.1%; OR = 2.99; 95% CI = 1.22-7.33). Similar comparisons between patients with familial NREM parasomnia and sporadic cases revealed no significant differences. Except for a larger occurrence of violent behaviors with injuries in males, no other sex difference was found in SW characteristics.

DISCUSSION

This is the largest prospective cohort study on adult sleepwalkers seen in clinic, using face-to-face clinical interviews, standardized questionnaires, and PSG assessments, to investigate the clinical characteristics, consequences, and comorbidities of SW. We found greater sleepiness, fatigue, insomnia, depressive and anxiety symptoms, and altered quality of life in adult SW patients compared with age- and sex-matched controls. However, we may acknowledge that SW patients referred to a sleep clinic may not reflect those from the general population.

SW is usually classified as an arousal disorder because complex behaviors occur during sudden arousals from SWS, commonly culminating in walking with an altered state of consciousness and impaired judgment.¹² Because SW patients often have little or no memory of their behaviors, diagnosis is based primarily on a positive clinical history from the patient, and importantly, corroboration by bed partner or parent. Sleep laboratory analyses are useful for ruling out differential diagnoses and associated conditions and for identifying potential triggers.^23,24 Because numerous conditions may mimic arousal disorders, especially in adults, a video-PSG was performed to exclude REM sleep parasomnias, nocturnal seizures,²⁵ sleep apnea syndrome, and PLMS.^23,24 We excluded patients for comorbid neurologic diseases and associated factors that may trigger parasomnia episodes, such as PLMS or obstructive sleep apnea syndrome indexes above 10/h that induce frequent arousals. Thus, one-third of patients were excluded, leaving a sample of adults with persistent primary NREM parasomnia.

Although SW may be a benign disease when episodes are simple and infrequent, most adult sleepwalkers who consulted the sleep clinic presented with a history of aggressive and/or injurious behaviors during sleep, causing problems with bed partners.^26,27 In the current study, more than half of SW adult patients had weekly somnambulism episodes, with violent behaviors in 57.9% and moderate to severe injuries requiring medical care for at least one lifetime episode in 17%. Patients with violent behaviors had more frequent associated sleep terrors and reports of triggering factors, including alcohol intake. Triggering factors that increased both the frequency and severity of episodes were reported in 59%, related mainly to stressful events, strong positive emotions, sleep deprivation, and less frequently to drug or alcohol intake or intense evening physical activity, all conditions promoting increased SWS and NREM sleep instability.^7–9 A recent epidemiologic study also highlighted the presence of alcohol intake, psychotropic medication, and sleep restriction as triggering factors for SW episodes.²

Previous studies showed SW onset mainly in childhood. Median age at SW onset in our population (with persistent parasomnias at adulthood) was 9 y old, a common finding with episodes tending to diminish with age.²⁸ However, a relatively large percentage (16.9%) of SW episodes began in adulthood in our population. Patients with early-onset SW had more frequent violent behaviors and injuries than those with late-onset SW. There were 22.7% of patients who reported less frequent SW episodes with age, but unexpectedly we reported that the frequency of SW episodes increased with age in 23.9%, with a significant worsening in the time course evolution in late-onset SW. SW is known to run in families, with both genetic and environmental factors playing key pathogenic roles.^29–33 We found a positive familial history of SW in 56.6%, with first-degree relatives affected in 76.4%. However, no sociodemographic or clinical characteristics distinguished patients with familial and sporadic SW. No sex effect was found on clinical SW characteristics except for the dangerous sleep related behaviors with moderate to severe injuries being more frequently reported in male sleepwalkers (81% of males) that confirmed earlier findings.²⁶

Adults with persistent SW showed higher sleep disruption, EDS, fatigue, and psychological distress than age-matched controls. Compared with most other sleep disorders (narcolepsy,³⁴ restless leg syndrome,³⁵ and sleep apnea syndrome³⁶), little is known about the effect of NREM parasomnia on daily functioning, psychological distress, or health-related quality of life.³⁷ EDS was reported in 42.2% of patients and severe in 11.1%, significantly higher than in controls, with similar results for fatigue. Our findings on association between SW and EDS are consistent with previous studies conducted in small clinic samples and a large epidemiologic population.^2,10,11 Unexpectedly in our study and for unclear reasons, patients with frequent SW episodes had less frequent EDS than patients with rare episodes. Hence, we were unable to establish a direct relationship between the number of parasomnia episodes and daytime consequences, even if no objective assessment of sleepiness was available. We also showed a significant association between insomnia symptoms and SW, with most symptoms being related to a nonrestorative sleep profile. Even without clinically defined episodes recorded by video-PSGs, lower slow wave activity in early night cycles, and more awakenings in SWS have been reported in SW patients.^7–9 Unfortunately, the current study does not help in the understanding of the mechanism of arousal from SWS. We may, however, hypothesize that NREM sleep disruption combined with an impaired sleep homeostatic mechanism is responsible for altered daytime functioning and restorative sleep in SW.

We observed more frequent depressive and anxiety symptoms in adult SW patients than in normal controls. Previous studies proposed that SW may be a nocturnal expression of a mental disorder,^38,39 together with a recent large epidemiologic study showing frequent associations between major depressive disorder, obsessive-compulsive disorder, and frequent episodes of SW.² However, based on studies on SW subjects seen in clinic this conclusion remained controversial.^39–41 We suggest instead a serious effect of persistent SW in adults on both psychological outcomes and quality of life, which were altered in most domains of the SF-36 scale.

The current study has some limitations. Adult SW patients who consult a sleep laboratory may not well represent SW patients in the general population. At our clinic, we see patients whose SW is the most frequent and severe, with more serious outcomes and comorbidities. The violent nature of SW behaviors varies from one patient to another and from one episode to another for a single patient, leading to difficulty in assessing the risk of injury to self or bed partner with potential forensic implications. Some patients were unable to report age at onset, the frequency and intensity of episodes, the presence and type of triggering factors, or disease evolution. This clinical study did not report on nighttime polysomnographic and daytime multiple sleep latency test patterns to link symptoms to objective measurements. Based on both clinical interview (with primary complaint of persistent SW at adulthood, frequent nighttime awakenings, and absence of long nighttime sleep, sleep inertia, cataplexy, hypnagogic hallucination and sleep paralysis), and PSG assessments (with frequent microarousals during SWS, frequent hypersynchronous delta wave arousals, low sleep efficiency and absence of REM sleep dysregulation), we may assume that almost none of these patients met criteria for hypersomnia of central origin, namely narcolepsy and idiopathic hypersomnia. However, potential mechanisms linking the presence of SW to the complaint of EDS (especially in patients with severe EDS, n = 11) remained unclear and required further investigations using objective daytime multiple sleep latency test measurements. Finally, we cannot exclude that some SW patients in our study also presented with mild sleep disordered breathing (apnea-hyponea ndex below 10/h) or an upper airway resistance syndrome²⁴ that may trigger parasomniac episodes but also fatigue and EDS.²

In summary, although usually considered a benign condition, adult SW is a potentially serious condition that can induce violent behaviors, with injury to self or bed partner, sleep disruption, excessive daytime sleepiness, fatigue, psychological distress, and altered quality of life. Further nighttime and daytime polysomnographic studies are needed to determine whether daytime functional impairment was linked SWS disruption, and whether they can be reversed through management of the disease per se.

DISCLOSURE STATEMENT

This was not an industry supported study. Dr. Montplaisir received research grants/support from Boehringer-Ingelheim and Sanofi-Aventis, served as an advisor for Boehringer-Ingelheim, Merck and Servier, and received honoraria for speaking engagements from Valeant Pharmaceutical, Boehringer-Ingelheim, Sanofi-Aventis and GlaxoSmithKline. Dr. Dauvilliers has received speaker's honoraria and funding for travel to conferences from UCB Pharma, Cephalon, Novartis, and Bioprojet. Prof. Dauvilliers has participated in advisory boards of UCB and Bioprojet. The other authors have indicated no financial conflicts of interest.