Which diagnostic findings in disorders with excessive daytime sleepiness are really helpful? A retrospective study

J Sleep Res. (2016) 25, 307 313 Excessive daytime sleepiness Which diagnostic findings in disorders with excessive daytime sleepiness are really helpful? A retrospective study UTE KRETZSCHMAR 1,2, ESTHER WERTH 1, CHRISTIAN STURZENEGGER 3, RAMIN KHATAMI 4, CLAUDIO L. BASSETTI 5 and CHRISTIAN R. BAUMANN 1 1 University Hospital, Zurich, Switzerland; 2 Schulthess Clinic, Zurich, Switzerland; 3 Hohenklinik Wald, Wald, Switzerland; 4 Clinic Barmelweid, Barmelweid, Switzerland; 5 Insel Hospital, Berne, Switzerland Keywords actigraphy, biomarkers, diagnosis, polysomnography, sleepiness, vigilance tests Correspondence Prof. Dr. med. Christian R. Baumann Department of Neurology University Hospital Zurich 8091 Zurich Switzerland. Tel.: +41 44 255 5511; fax: +41 44 255 9201; e-mail: christian.baumann@usz.ch Accepted in revised form 13 November 2015; received 8 June 2015 DOI: 10.1111/jsr.12383 ABSTRACT Due to extensive clinical and electrophysiological overlaps, the correct diagnosis of disorders with excessive daytime sleepiness is often challenging. The aim of this study was to provide diagnostic measures that help discriminating such disorders, and to identify parameters, which don t. In this single-center study, we retrospectively identified consecutive treatment-na ıve patients who suffered from excessive daytime sleepiness, and analyzed clinical and electrophysiological measures in those patients in whom a doubtless final diagnosis could be made. Of 588 patients, 287 reported subjective excessive daytime sleepiness. Obstructive sleep apnea is the only disorder that could be identified by polysomnography alone. The diagnosis of insufficient sleep syndrome relies on actigraphy as patients underestimate their sleep need and the disorder shares several clinical and electrophysiological properties with both narcolepsy type 1 and idiopathic hypersomnia. Sleep stage sequencing on MSLT appears helpful to discriminate between insufficient sleep syndrome and narcolepsy. Sleep inertia is a strong indicator for idiopathic hypersomnia. There are no distinctive electrophysiological findings for the diagnosis of restless legs syndrome. Altogether, EDS disorders are common in neurological sleep laboratories, but usually cannot be diagnosed based on PSG and MSLT findings alone. The diagnostic value of actigraphy recordings can hardly be overestimated. INTRODUCTION In sleep laboratories run by neurologists, chronic excessive daytime sleepiness (EDS) belongs to the most common reasons for referral. EDS is characterized by an increased sleep pressure at daytime that may lead to involuntary naps and sleep attacks during the day (Bassetti and Gugger, 2000; Shen et al., 2006). The effects of EDS can be debilitating and even life-threatening: chronically sleepy patients often exhibit psychosocial distress, decreased work or school performance, and increased risk for accidents (Roth and Roehrs, 1996). EDS is a common medical problem it is a key symptom of a multitude of sleep-wake disturbances such as narcolepsy, idiopathic hypersomnia, or sleep apnea, but is also a frequent complication of other medical conditions. The estimated prevalence of EDS in a normal healthy population ranges from 2 to 16% (Akerstedt and Gillberg, 1990; Roth and Roehrs, 1996; Partinen and Hublin, 2000; Young, 2004; Ng and Tan, 2005; Mignot et al., 2006). This large variety of studied prevalences is due to different methological approaches and to different definitions of EDS. Questionnaires and standardized scales are useful to screen for subjective EDS. The most widely used scales are the Karolinska Sleepiness Scale, the Stanford Sleepiness Scale, and the Epworth Sleepiness Scale (ESS) (Hoddes et al., 1972; Johns, 1991; Gillberg et al., 1994). All these scales measure slightly different aspects of EDS. On the other hand, EDS can be measured more objectively by standardized tests in the sleep laboratory. For instance, the multiple sleep latency test (MSLT) has been designed to assess sleep pressure during daytime (Littner et al., 2005). Even for experienced sleep specialists, correctly diagnosing patients with EDS is sometimes challenging. Disorders with EDS are not always easy to distinguish from each other, particularly in the absence of pathognomonic symptoms or 307

308 U. Kretzschmar et al. other specific findings. This is particularly applying to illdefined disorders such as narcolepsy type 2 (formerly known as narcolepsy without cataplexy), idiopathic hypersomnia or insufficient sleep syndrome (formerly known as behaviourally induced insufficient sleep syndrome), but also for disorders with better diagnostic criteria (AASM, 2014; Baumann et al., 2014). With this study, we aimed at identifying discriminating diagnostic findings for well-identifiable disorders with EDS in consecutive treatment-na ıve patients who were examined in a neurological sleep laboratory over a defined period of time. METHODS Patients We retrospectively assessed data from all consecutive treatment-na ıve in- and outpatients who have been examined in our tertiary neurological sleep laboratory during the years 2005 2007. Patients were allocated by the general practitioner, a specialist, or by themselves. In this cohort, we identified and further analyzed those patients who suffered from subjective EDS as assessed with the ESS. In the same university hospital, pneumologists run another sleep laboratory focusing on sleep apnea. Patients from this sleep laboratory were not included, and study patients were excluded as well. The geographical area served by our institution is Zurich, the largest Swiss city, and the neighbouring metropolitan area (>1.5 million citizens). The retrospective analysis of the anonymized dataset was performed along the guidelines of the local ethical committee. Methods For the purpose of this study, we created a Filemakerdriven database. This database happened to be one of the main precursors of a European multicenter database on narcolepsy and related disorders (Luca et al., 2013). It contains 4 files for every patient: 1) symptoms as reported during structured interviews in our outpatient clinic, 2) scores from scales which are included in the Zurich Sleep Questionnaire (see below), 3) data from electrophysiological, laboratory, and radiological studies, and 4) the final diagnosis. The latter is classified according to the level of diagnostic certainty (definite versus uncertain). A single study doctor (U.K.) encoded the data in a computed registry. Prior to sleep laboratory examinations, all patients were interviewed and examined in our outpatient clinic. Furthermore, they completed the Zurich Sleep Questionnaire that includes validated scales such as the ESS, the Sleep Apnea Scale of the Sleep Disorders Questionnaire, the Ullanlinna Narcolepsy Scale, and the Swiss Narcolepsy Scale (Johns, 1991; Hublin et al., 1994; Weatherwax et al., 2003; Sturzenegger and Bassetti, 2004; ). Consecutive diagnostic procedures such as electrophysiological testings relied on findings and suspected diagnoses and were driven by international recommendations. Diagnoses were initially made according to the International Classification of Sleep Disorders, version 2 (ICSD-2) (American Academy of Sleep Medicine, 2005), and were in the meantime re-evaluated along the current version of these criteria (ICSD-3) (American Academy of Sleep Medicine, 2014). For the diagnosis of insufficient sleep syndrome (ISS), we required additional diagnostic procedures than proposed by the ICSD-3 criteria, i.e. the execution of 14 days ambulatory actigraphy to prove short sleep times and a clinically significant catching up of sleep during weekends and holidays, i.e. at least 2 h more sleep than during working days. Electrophysiological examinations included nocturnal video-polysomnography (PSG), MSLT, maintenance of wakefulness test (MWT), and actigraphy. Nocturnal PSG comprised a 16-channel recording system (MedCare A10). We used 4 electroencephalogram channels, 2 electrooculogram channels, 1 chin electromyogram channel, and channels for nasal flow, arterial oxyhemoglobin saturation, chest and abdominal wall excursions, heart rate, and 2 tibialis anterior EMG channels. PSG evaluation was performed along international criteria and included the quantitative assessment of sleep stages, sleep efficiency (defined as total sleep time/sleep period time), arousal index, sleep latency [time from light-off to the first epoch of non-rapid eye movement (NREM2)] and REM latency including sleep onset REM (SOREM) periods, periodic limb movements during sleep index (PLMI), apnea-hypopnea-index (AHI) and oxygen desaturation index (ODI) (Rechtschaffen and Kales, 1968; Iber et al., 2007). MSLT was performed on the day after nocturnal PSG and consisted of 4 5 nap opportunities during 20 min at 2-h intervals across the day following PSG, beginning 1.5 h after waking up (Littner et al., 2005). This test including preceding PSG were performed in all patients who complained of subjective EDS, i.e. who had pathologically increased values on the Epworth sleepiness scale, and in those in whom the conduction of these tests was relevant for other diagnostic, therapeutic or medicolegal reasons. On the other hand, MWT consisted of 4 epochs that lasted 40 min each, during which the patients tried to stay awake despite comfortable and nonstimulating conditions. This test was performed only in a subset of patients, particularly in those whose fitness to drive was evaluated, or when treatment effects were assessed. Mean sleep latency in MSLT and MWT were defined as the time from light off to the first epoch of NREM1 sleep or any other sleep stage. At MSLT, EDS was diagnosed when mean latency to any stage of sleep was 8 min. Furthermore, we searched for SOREM periods on MSLT and analyzed the sequence of sleep stages in naps with SOREM periods (Marti et al., 2009). Actigraphy studies to assess sleep times and activity levels were performed over the 14 days before PSG in a subset of patients and included both sleep logs and wrist actigraphy recordings (on the non-dominant wrist; light sensor data included, ActiWatch, Neurotechnology,

Discriminating disorders with sleepiness 309 Cambridge, United Kingdom) (King et al., 2005; Morgenthaler et al., 2007). Analyses of serum or cerebrospinal fluid parameters were performed in selected patients only and included the determination of levels of the hypothalamic wake-promoting neurotransmitter hypocretin (orexin) in the cerebrospinal fluid, and typing of human leukocyte antigen (HLA) alleles that are linked to narcolepsy (Mignot et al., 1994; Baumann et al., 2014). Analysis of EDS patients Because there is a large overlap between sleepiness and tiredness in the Swiss German language, we based the diagnosis of subjective EDS on the ESS >10 points). Treatment-na ıve patients with subjective EDS and a clearcut final diagnosis were further evaluated in this study (Fig. 1). Sleep laboratory examinations that have been performed to supervise treatment effects were not included for analyses. We grouped EDS patients according to their final diagnosis, and analyzed epidemiological, questionnaire, clinical, electrophysiological, and laboratory data. Data analyses include a synopsis of the demographic and clinical characteristics of our study population. Descriptive analysis of continuous variables is presented as mean standard deviation. Associations between continuous variables were calculated by ANOVA and post hoc two-sample t-tests, and Pearson correlation tests were performed as well. Nonparametric tests (u-test Mann Whitney, Kruskal Wallis test) were performed when necessary. Statistical analyses were performed with SPSS version 19. RESULTS General findings We collected the data of 735 patients. Of those, 147 patients had incomplete datasets and were therefore excluded these patients did not completely fill in the Zurich Sleep 735 consecu ve treatment-naïve sleep laboratory pa ents Dataset complete? No (n = 147) Yes (n = 588) Subjec ve EDS: ESS scores 10? No (n = 301) Yes (n = 287) Well-defined diagnosis? No (n = 91) Yes (n = 196) General analysis: Table 1 EDS discriminant analysis: Table 2 Figure 1. Flow diagram depicting the inclusion procedure in this retrospective study. Questionnaire including the ESS (Figure 1). Of the remaining 588 patients, 38% were female, and the mean age (SD) at time of examinations was 50 16 years (Table 1). PSG recordings were conducted in 376 patients (64%), MSLT in 304 patients (52%), and MWT in 91 patients (15%). Actigraphy recordings were available in 205 patients (35%). In 54 patients (9%), we performed HLA typing, and cerebrospinal fluid hypocretin-1 was determined in 43 patients (7%). During interviews, 367 of 588 patients reported sleepiness or tiredness as most disturbing symptom. Subjective EDS as assessed with ESS scores >10 was present in 287 patients (49%). Besides EDS, other common cardinal symptoms at admission included problems to fall asleep or to maintain sleep (139 patients, 24%), uncomfortable feelings in the lower legs, associated with an urge to move, particularly in the evening and at night (78 patients, 13%), and loud and habitual snoring with interrupted breathing (64 patients, 11%). Symptoms such as acting out of dreams, somnambulism, epileptic seizures at night, hypnic headache, and sleep paralysis were less commonly reported. Categorized diagnostic groups (according to ICSD-3) after completion of diagnostic procedures in 588 patients included hypersomnia disorders including narcolepsy type 1 and idiopathic hypersomnia (98 patients, 17% of 588), sleeprelated movement disorders (89 patients, 15%), sleep-related breathing disorders (94 patients, 16%), insomnia disorders (90 patients, 15%), insufficient sleep syndrome (62 patients, 11%), and parasomnia disorders (36 patients, 6%) (Table 1). In 38 patients (6%), no specific sleep-wake disorder was Table 1 Diagnoses in 588 Zurich patients. EDS: excessive daytime sleepiness, assessed with the Epworth Sleepiness Scale (>10). %: percentage of the population of 588 patients. Numbers in bold font add together the numbers within groups of sleep-wake disorders n % EDS in (%) Hypersomnia disorders 98 17 98 (100) Narcolepsy type 1 35 6 35 (100) Idiopathic hypersomnia 8 1 8 (100) Hypersomnia due to medical condition 42 7 42 (100) Hypersomnia due to substance abuse 7 1 7 (100) Sleep-related movement disorders 89 15 44 (49) Restless legs syndrome 72 13 42 (58) Sleep-related breathing disorders 94 16 52 (55) Obstructive/mixed sleep apnea syndrome 85 14 49 (58) Central sleep apnea syndrome 9 2 3 (33) Insomnia 90 15 15 (17) Insufficient sleep syndrome 62 11 62 (100) Parasomnia disorders 36 6 3 (8) REM sleep behaviour disorder 21 4 13 (62) Isolated symptoms 32 5 4 (13) Sleep related epilepsy 18 3 3 (17) Circadian rhythm sleep disorders 20 3 5 (25) Sleep related headaches 11 2 1 (9) No specific sleep-wake disorder 38 6 0 (0) Isolated fatigue 25 4 0 (0)

310 U. Kretzschmar et al. Table 2 Epidemiological, clinical, electrophysiological, and laboratory characteristics of patients with EDS (excessive daytime sleepiness) and well-defined diagnosis. Discriminative findings are underlined N1 IHS ISS OSAS RLS P n 35 8 62 49 42 Age (years)* 40 18 34 17 34 10 53 18 59 13 <0.001 Gender (% male) 45 17 75 83 35 <0.001 Family history of EDS (%) 0 0 10 4 33 Sleep duration by history (h/24 h)* 7.4 1.5 11.8 1.3 7.3 0.6 7.1 1.8 6.3 1.8 <0.001 Sleep inertia (%) 3 88 6 8 12 <0.001 ESS* 16.6 4.1 16.3 1.9 15.8 3.5 13.8 3.1 13.7 3.8 n.s. SA-SDQ* 28.7 7.4 19.0 3.0 27.8 6.4 39.7 7.7 30.1 7.4 <0.001 Ullanlinna Narcolepsy Scale* 23.9 5.7 11.7 6.7 12.8 2.5 10.1 4.5 7.7 3.9 <0.001 Swiss Narcolepsy Scale* 27.1 25.9 11.1 21.6 22.1 12.3 14.5 22.4 31.6 19.8 <0.001 PSG: sleep efficiency (%)* 86 13 94 5 94 5 84 10 86 8 0.007 PST: total sleep time (min) 411 69 453 35 449 32 398 52 402 47 0.027 PSG: NREM1 (%)* 16 10 6 1 8 5 20 15 10 8 0.009 PSG: NREM2 (%)* 37 12 55 5 50 16 47 18 50 8 0.006 PSG: NREM3/4 (%)* 13 8 11 10 14 10 4 8 7 8 0.001 PSG: REM (%)* 19 9 16 6 18 4 12 7 16 5 0.014 PSG: NREM2 latency (min)* 7.2 7.8 10.8 2.9 7.8 4.0 14.8 9.0 12.5 12.0 <0.001 PSG: REM latency (min)* 36.4 22.9 83.5 19.9 67.9 22.8 152.0 103.0 125.7 90.4 <0.001 PSG: AHI* 7.5 13.6 0.2 0.2 4.1 4.9 39.2 29.4 8.2 9.9 <0.001 PSG: ODI* 4.8 8.0 0.4 0.3 2.9 4.4 34.9 30.3 4.4 2.8 <0.001 PSG: PLMI* 17.3 23.2 2.3 4.7 1.5 4.9 19.6 32.5 21.5 14.5 n.s. MSLT: MSL (min)* 1.9 1.6 3.9 3.5 4.5 2.7 6.1 4.1 7.3 5.4 0.006 MSLT: 1 SOREM (%) 10 0 15 4 27 <0.001 MSLT: 2 SOREM s (%) 90 0 10 0 0 <0.001 MSLT: REM NREM (%) 74 13 0 4 >0.001 MWT: MSL (min)* (n) 8.3 5.4 (17) 18.3 2.2 (4) 13.1 5 (14) 14.2 1.8 (6) (0) 0.004 Actigraphy: sleep/24 h (h)* 7.9 1.4 11.3 1.2 6.5 0.7 6.9 2.2 6.8 1.4 <0.001 Actigraphy: sleep diff WE-WD 0.3 0.4 0.6 0.6 2.2 1.2 0.2 0.4 0.5 0.9 <0.001 (3) Hypocretin-1 (pg/ml)* 32 40 (20) 461 219 (4) 391 151 (8) (0) (0) <0.001 *Mean SD. Naps with WAKE REM NREM instead of WAKE NREM REM sequence, in % of all SOREM naps. Age, age at sleep lab examinations; AHI, apnea-hypopnea index; ESS, Epworth Sleepiness Scale; IHS, idiopathic hypersomnia; ISS, insufficient sleep syndrome; MSLT, multiple sleep latency test; MWT, maintenance of wakefulness test; N1, narcolepsy type 1; ODI, oxygen desaturation index; OSAS, obstructive sleep apnea syndrome; PLMI, periodic limb movements index; PSG, polysomnography; RLS, restless legs syndrome; SA-SDQ, Sleep Apnea Scale of the Sleep Disorders Questionnaire; SOREM, sleep-onset rapid eye movement sleep; WD, weekdays; WE, weekend and holidays. diagnosed. Most of these patients suffered from isolated fatigue (Fatigue severity scale 4.0, n = 25), some of restless legs-like syndrome (n = 7) (Baumann et al., 2007; Valko et al., 2008). EDS patients The 287 treatment-na ıve EDS patients with complete datasets were further analyzed: subjective EDS as assessed with the ESS was observed in all diagnostic groups (Tables 1 and 2). Detailed clinical and electrophysiological data of subjective EDS patients with well-defined diagnoses (narcolepsy type 1, idiopathic hypersomnia, insufficient sleep syndrome, obstructive sleep apnea syndrome, restless legs syndrome) are given in Table 2. ESS scores did not differ between groups. Patients with sleep-related movement or breathing disorders were older than the other subjects (P = 0.002). The portion of female patients was highest in idiopathic hypersomnia (P < 0.001). Discriminating parameters for specific EDS disorders Narcolepsy type 1 These patients were identified by the Ullanlinna Narcolepsy Scale (sensitivity 100%, specificity 64%) and by the Swiss Narcolepsy Scale (sensitivity 89%, specificity 85%). Post hoc analyses revealed that these values differed significantly from all other groups (both: P < 0.001). REM sleep latency on PSG was shorter (mean 36.4 min) than in all other disorders (P < 0.001). Apart from the shortest mean sleep latency (P = 0.009), MSLT revealed that multiple sleep-onset REM periods were more frequent than in other disorders (P < 0.001). Furthermore, the sequence WAKE REM NREM during MSLT naps is highly indicative of narcolepsy (P < 0.001). The ability to stay awake in non-stimulant conditions during maintenance of wakefulness tests was more impaired in narcolepsy patients than in other EDS patients (P = 0.004). Other factors discriminating narcolepsy

Discriminating disorders with sleepiness 311 from other EDS disorders could not be identified. Still, periodic limb movement indices were higher than in patients with idiopathic hypersomnia or insufficient sleep syndrome (17.3 versus 1.6), and similar to restless legs syndrome (RLS) patients. Idiopathic hypersomnia The absence of restorative properties of sleep (i.e. sleep inertia) was a strong indicator for idiopathic hypersomnia (P < 0.001). Furthermore, long sleep duration per 24 h was another parameter to discriminate patients with idiopathic hypersomnia from other EDS patients, both by history (P < 0.001) and by actigraphy (P = 0.006). Mean sleep latencies on MSLT and PSG sleep latencies were higher than in narcolepsy patients and did not significantly differ from other EDS patients. Together with insufficient sleep syndrome patients, subjects with idiopathic hypersomnia revealed highest sleep efficiencies and lowest percentages of NREM1 sleep on PSG. Daily sleep duration as assessed by history did not differ from sleep/24 h as assessed by actigraphy. Insufficient sleep syndrome Apart from the actigraphy finding of short rest times with sleep rebound on weekends of 2 h more sleep than during weekdays, no parameter was identified to discriminate insufficient sleep syndrome from other EDS disorders. Patients had lowest sleep durations on actigraphy recordings (ns), a finding that was in contrast to their reported sleep duration, the latter being similar to other patients groups. Insufficient sleep syndrome patients shared characteristics with both narcolepsy (low NREM2 and REM sleep latencies on PSG) and idiopathic hypersomnia (high sleep efficiency on PSG) patients. Notably, 10% of insufficient sleep syndrome patients had multiple sleep-onset REM periods on MSLT, but only rarely with the sequence WAKE REM NREM. Obstructive sleep apnea The Sleep Apnea Scale of the Sleep Disorders Questionnaire was not able to discriminate obstructive sleep apnea patients from other EDS patients, in contrast to increased apneahypopnea-indices and oxygen desaturation indices on PSG (both P < 0.001). Apnea patients had high proportions of NREM1 sleep (reflecting frequent arousals), and only little deep sleep (NREM3; mean 4%), but these parameters did not differ from other disorders. Restless legs syndrome In RLS patients, periodic limb movement indices did not discriminate from narcolepsy and obstructive sleep apnea patients. The only parameter that differed from all other groups was the high portion of patients with a positive family history of EDS. DISCUSSION EDS is a manifestation not only of hypersomnia disorders, but can complicate the course of literally all other sleep-wake disorders. Highest frequencies of EDS were found in hypersomnia disorders, sleep-related breathing disorders, and sleep-related movement disorders. We compared clinical and electrophysiological findings in patients with clear-cut diagnoses, i.e. narcolepsy type 1, idiopathic hypersomnia, insufficient sleep syndrome, obstructive sleep apnea, and restless legs syndrome patients, to better understand which measures might discriminate some of the disorders. ESS values appeared to be similar in all of these disorders. Therefore, a high ESS score is not necessarily indicative of narcolepsy. In fact, we found similarly high levels of subjective EDS in patients with idiopathic hypersomnia and in subjects with insufficient sleep syndrome. Obstructive sleep apnea was the only of the examined disorders that could be identified by the means of sleep laboratory findings alone, i.e. by high apnea-hypopnea indices and oxygen desaturation indices alone. This is in line with the current ICSD-3 criteria which recommend polysomnography for the diagnosis of obstructive sleep apnea (AASM, American Academy of Sleep Medicine, 2014). Narcolepsy type 1 reveals lowest mean sleep latencies and highest portions of patients with multiple sleep-onset REM periods and REM NREM sequences on MSLT, but shares several findings with insufficient sleep syndrome patients, including low mean sleep latencies on PSG and MSLT, and even multiple sleep-onset REM periods on MSLT (here: in 10% of chronically sleep-restricted patients) and short REM latencies on PSG. Although mean sleep latencies on MSLT were significantly lower in narcolepsy, there is still considerable overlap. In patients with doubtful cataplexy and without available hypocretin levels in the cerebrospinal fluid, therefore, MSLT should be repeated after actigraphy-controlled sleep extension. This conclusion is also in agreement with the recommendations of an international panel on the diagnosis of narcolepsy type 2 (Baumann et al., 2014). Even more, our findings suggest that maintenance of wakefulness tests which usually are used for monitoring of treatment effects and for the evaluation of driving capabilities may be helpful in the diagnosis of narcolepsy, for narcoleptic patients revealed significantly poorer performances than all other EDS patients. On the other hand, questionnaires such as the Ullanlinna Narcolepsy Scale, and the Swiss Narcolepsy Scale appear highly sensitive and specific and therefore likely to correctly identify most narcolepsy type 1 patients. The international diagnostic recommendations, however, require objective testing such as MSLT or hypocretin measurements (AASM, American Academy of Sleep Medicine, 2014). Given the therapeutic options in narcolepsy, with stimulant or sodium oxybate treatment, this strict requirement makes sense.

312 U. Kretzschmar et al. For the diagnosis of idiopathic hypersomnia, the assessment of sleep times per 24 h appears to be critical. Actigraphy provides a reliable measure, but in these patients, history-taking appears sufficient, as there is no underestimation of sleep times. On the other hand, the presence of sleep inertia as reported by the patients appears discriminating even more than polysomnography or MSLT measures. Sleep inertia is not a criterion in the ICSD-3, but should be evaluated for a future version (AASM, American Academy of Sleep Medicine, 2014). In patients with insufficient sleep syndrome, however, a systematic long-term assessment of sleep times per 24 h with actigraphy appears to be critical. Our findings suggest that insufficient sleep syndrome patients overestimate their sleep per 24 h, when asked by history. The only discriminating finding in this condition is the difference of sleep times during weekends and weekdays on actigraphy. The disorder presents with increased sleep efficiencies on PSG, similar to idiopathic hypersomnia. On MSLT, mean sleep latencies are low and multiple sleep onset REM periods may occur, which might lead to the false diagnosis of narcolepsy. Regarding MSLT results, the analysis of sleep stage sequencing can be helpful, with the predominant sequence WAKE REM NREM being more suggestive of narcolepsy. This MSLT measure is not yet enough validated, but might be included in future versions of the ICSD. For restless legs syndrome, there are no discriminatory electrophysiological findings, as periodic limb movement indices are similar in other sleep-wake disorders, particularly narcolepsy and obstructive sleep apnea. Therefore, the diagnosis must be based on the patients history and positive response to dopaminergic treatment, and a positive family history of EDS might be helpful as well. Polysomnographic recordings should be performed in doubtful cases, e.g. those without response to dopaminergic treatment (Baumann et al., 2007). The most significant limitation of this study is its retrospective single-center design. Because of this limitation, characteristics could be derived only for well-defined and common diagnoses: to find discriminative findings, a disorder must be diagnosed on solid grounds. The former diagnosis of idiopathic hypersomnia without long sleep time for instance is not only controversial among sleep clinicians, but also difficult to diagnose as there are no markers to prove it. As for narcolepsy type 2, there is also an ongoing discussion about the existence of such an entity, and the diagnosis is challenging (Baumann et al., 2014). When applying strict actigraphy criteria to rule of insufficient sleep syndrome as we do in Zurich, then narcolepsy type 2 becomes exceedingly rare. In Zurich, narcolepsy type 2 is about fifty times rarer than narcolepsy type 1. Larger multicenter studies with standardized examinations to better diagnose narcolepsy type 2 and other ill-defined disorders are necessary to provide further insights into less unambiguous and rarer sleep-wake disorders with EDS. In summary, EDS disorders appear to be common in sleep laboratories run by neurologists. Still, given the situation that our neurological sleep laboratory is surrounded by other sleep laboratories run by pulmonologists or psychiatrists, the portion of EDS patients might be lower in other sleep laboratories. Apart from sleep apnea, none of the examined disorders can be diagnosed based on PSG and MSLT findings alone. The assessment of sleep inertia is important for the diagnosis of idiopathic hypersomnia. Actigraphy recordings are critical for the distinction of the highly prevalent insufficient sleep syndrome and thus for treatment decisions. 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