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STUDY OBJECTIVES: Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a harbinger of synuclein-mediated neurodegenerative diseases. It is unknown if this also applies to isolated REM sleep without atonia (RWA). We performed a long-term follow-up investigation of subjects with isolated RWA. METHODS: Participants were recruited from 50 subjects with isolated RWA who were identified at the sleep laboratory of the Department of Neurology at the Medical University of Innsbruck between 2003 and 2005. Eligible subjects underwent follow-up clinical examination, polysomnography, and assessment of neurodegenerative biomarkers (cognitive impairment, finger speed deficit, impaired color vision, olfactory dysfunction, orthostatic hypotension, and substantia nigra hyperechogenicity). RESULTS: After a mean of 8.6 ± 0.9 y, 1 of 14 participating subjects (7.3%) progressed to RBD. Ten of 14 RWA subjects (71.4%) were positive for at least one neurodegenerative biomarker. Substantia nigra hyperechogenicity and presence of mild cognitive impairment were both present in 4 of 14 subjects with isolated RWA. Electromyographic activity measures increased significantly from baseline to follow-up polysomnography ("any" mentalis and both anterior tibialis muscles: 32.5 ± 9.4 versus 52.2 ± 16.6%; p = 0.004). CONCLUSION: This study provides first evidence that isolated RWA is an early biomarker of synuclein-mediated neurodegeneration. These results will have to be replicated in larger studies with longer observational periods. If confirmed, these disease findings have implications for defining at-risk cohorts for Parkinson disease.

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STUDY OBJECTIVES: Video-polysomnography (v-PSG) is the gold standard for the diagnosis of sleep disorders. Quantitative assessment of type and distribution of physiological movements during sleep for the differentiation between physiological and pathological motor activity is lacking. We performed a systematic and detailed analysis of movements during physiological sleep using v-PSG technology. DESIGN: Prospective v-PSG investigation. SETTING: Academic referral center sleep laboratory. PARTICIPANTS: One hundred healthy sleepers aged 19-77 years recruited from a representative population sample after a two-step screening. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: All subjects underwent v-PSG. In all cases where electromyographic activity > 100 msec duration was visible during sleep in the mentalis, submentalis, flexor digitorum superficialis, or anterior tibialis muscles, the time-synchronized video was analyzed. Visible movements were classified according to movement type and topography, and movement rates were computed for the different sleep stages. A total of 9,790 movements (median 10.2/h, IQR 4.6-16.2) were analyzed: 99.7% were elementary, 0.3% complex. Movement indices were higher in men than women (men: median 13/h, interquartile range 7.1-29.3, women: median 7.9/h, interquartile range 3.4-14.5; P = 0.006). The majority of movements involved the extremities (87.9%) and were classified as focal (53.3%), distal (79.6%), and unilateral (71.5%); 15.3% of movements were associated with arousals. REM-related movements (median 0.8 sec, IQR 0.5-1.2) were shorter than NREM-related movements (median 1.1 sec, IQR 0.8-1.6; P = 0.001). Moreover, REM-related movements were predominantly myocloniform (86.6%), whereas NREM-related movements were more often non-myocloniform (59.1%, P < 0.001). CONCLUSION: Minor movements are frequent during physiological sleep, and are associated with low arousal rates. REM-related movements were predominantly myocloniform and shorter than NREM movements, indicating different influences on motor control during both sleep states.

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OBJECTIVE: Sleep disturbance is reported to be frequent in epilepsy. The role of comorbidity, which is frequently accompanied by sleep disturbance, has not been investigated. The present study assessed sleep disorders and circadian rhythm in patients with epilepsy, in whom relevant comorbidity was carefully excluded. METHODS: Two hundred patients with epilepsy (100 generalized, 100 partial), without relevant psychiatric, neurological or internal comorbidity, were compared with 100 matched controls. The questionnaire contained specifically tailored questions to address the association between epilepsy and sleep disturbance, and validated questionnaires aimed at sleep quality, excessive daytime sleepiness (EDS), circadian rhythm, sleep disorders, and quality of life. RESULTS: Forty-one percent of the participants reported on the acute effects of present or past seizures on sleep-wake rhythm, whereas chronic effects were not evident. Participants and controls did not differ in the rates of chronic sleep disturbance, EDS, and presence of sleep disorders (all p-values non-significant or n.s.). Apart from earlier sleep times on workdays (p = 0.001) in those with epilepsy, circadian variables were similarly distributed. Epilepsy was well controlled, with 75.9% being seizure free for ≥ 1 year. Longer durations of epilepsy showed a negative correlation with sleep quality (rho = -0.256, p < 0.001). Participants with generalized and partial epilepsies did not differ in rates of sleep disturbance, EDS, sleep disorders, and variables of circadian rhythm (all p-values n.s.). CONCLUSION: The present study demonstrated that chronic sleep disturbance is not increased in patients with well-controlled epilepsy without relevant comorbidity. This supports comorbidity and insufficient seizure control as major contributors of sleep disturbance in epilepsy.

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OBJECTIVE: Patients with narcolepsy often complain about attention deficits in everyday situations. In comparison with these subjective complaints, deficits in objective testing are subtler. The present study assessed the relationships between subjective complaints, objectively measured cognitive performance, disease-related variables, and mood. PATIENTS/METHODS: A total of 51 patients with narcolepsy and 35 healthy controls responded to questionnaires regarding subjectively perceived attention deficits, sleepiness, anxiety and depression. Moreover, they performed an extensive neuropsychological assessment tapping into attention, executive functions, and memory. RESULTS: Patients rated their level of attention in everyday situations to be relatively poor. In an objective assessment of cognitive functioning, they showed only slight attention and executive function deficits. The subjective ratings of attention deficits significantly correlated with ratings of momentary sleepiness, anxiety, and depression, but not with objectively measured cognitive performance. Momentary sleepiness and depression predicted almost 39% of the variance in the ratings of subjectively perceived attention deficits. CONCLUSION: The present study showed that sleepiness and depression, more than objective cognitive deficits, might play a role in the subjectively perceived attention deficits of patients with narcolepsy. The results suggested that when counselling and treating patients with narcolepsy, clinicians should pay attention to potential depression because subjective cognitive complaints may not relate to objective cognitive impairments.

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STUDY OBJECTIVES: Despite differences between American Academy of Sleep Medicine (AASM) and Rechtschaffen and Kales scoring criteria, normative values following the current AASM criteria are lacking. We investigated sleep and respiratory variables in healthy adults over the lifespan, and established polysomnographic normative values according to current standards. DESIGN: Prospective polysomnographic investigation. SETTING: Academic referral hospital sleep laboratory. PARTICIPANTS: One hundred healthy sleepers aged 19-77 y were selected from a representative population sample by a two-step screening. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: All subjects underwent one full-night polysomnography. Sleep and arousals were scored according to AASM standards. Respiration was scored according to AASM 2007 and 2012 criteria in order to compare both methods. Percentile curves showed age-related differences in sleep architecture: a decrease was found for sleep efficiency [≤ 30 y: 87.0 (71.9-94.1)% versus > 60 y: 79.7 (44.5-90.9)%], total sleep time [≤ 30 y: 413.5 (345.6-451.9) min versus > 60 y: 378.3 (216.0-440.0) min], the percentages of N3 [≤ 30 y 20.7 (15.2-37.5)% versus > 60 y: 14.9 (2.4-35.6)%] and rapid eye movement sleep [≤ 30 y 15.5 (7.5-23.6)% versus. > 60 y: 10.3 (1.9-21.9)%], whereas the percentage of wake time after sleep onset increased with age [≤ 30 y 6.0 (1.9-22.8)% versus > 60 y: 15.2 (6.3-48.7)%]. The apnea-hypopnea index (AHI) was higher when applying the AASM 2012 criteria [AHI AASM 2007 0.7 (0.0-21.5)/h versus 2012: 1.7 (0.0-25)/h; P < 0.001]. Eight percent of subjects had an AHI > 15/h. CONCLUSIONS: This study provides normative data on sleep macrostructure, microstructure, and respiration in adults following AASM standards. Furthermore, we demonstrated that respiration scoring according to AASM 2012 results in higher AHIs, and challenge the use of age-independent respiratory cutoff values.

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STUDY OBJECTIVES AND DESIGN: Rapid eye movement sleep without atonia (RWA) is the polysomnographic hallmark of REM sleep behavior disorder (RBD). To partially overcome the disadvantages of manual RWA scoring, which is time consuming but essential for the accurate diagnosis of RBD, we aimed to validate software specifically developed and integrated with polysomnography for RWA detection against the gold standard of manual RWA quantification. SETTING: Academic referral center sleep laboratory. PARTICIPANTS: Polysomnographic recordings of 20 patients with RBD and 60 healthy volunteers were analyzed. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Motor activity during REM sleep was quantified manually and computer assisted (with and without artifact detection) according to Sleep Innsbruck Barcelona (SINBAR) criteria for the mentalis ("any," phasic, tonic electromyographic [EMG] activity) and the flexor digitorum superficialis (FDS) muscle (phasic EMG activity). Computer-derived indices (with and without artifact correction) for "any," phasic, tonic mentalis EMG activity, phasic FDS EMG activity, and the SINBAR index ("any" mentalis + phasic FDS) correlated well with the manually derived indices (all Spearman rhos 0.66-0.98). In contrast with computerized scoring alone, computerized scoring plus manual artifact correction (median duration 5.4 min) led to a significant reduction of false positives for "any" mentalis (40%), phasic mentalis (40.6%), and the SINBAR index (41.2%). Quantification of tonic mentalis and phasic FDS EMG activity was not influenced by artifact correction. CONCLUSION: The computer algorithm used here appears to be a promising tool for REM sleep behavior disorder detection in both research and clinical routine. A short check for plausibility of automatic detection should be a basic prerequisite for this and all other available computer algorithms.

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OBJECTIVE: Augmentation of restless legs syndrome (RLS) is a potentially severe side-effect of dopaminergic treatment. Data on objective motor characteristics in augmentation are scarce. The aim of this study was to investigate in detail different variables of leg movements (LM) in untreated, treated, and augmented RLS patients. METHODS: Forty-five patients with idiopathic RLS [15 untreated, 15 treated (non-augmented), 15 augmented] underwent RLS severity assessment, one night of video-polysomnography with extended electromyographic montage, and a suggested immobilization test (SIT). RESULTS: Standard LM parameters as well as periodicity index (PI) and muscle recruitment pattern did not differ between the three groups. The ultradian distribution of periodic leg movements (PLM) in sleep during the night revealed significant differences only during the second hour of sleep (P <0.05). However, augmented patients scored highest on RLS severity scales (P <0.05) and were the only group with a substantial number of PLM during the SIT. CONCLUSION: This study demonstrates that polysomnography is of limited usefulness for the diagnosis and evaluation of RLS augmentation. In contrast, the SIT showed borderline differences in PLM, and differences on subjective scales were marked. According to these results, augmentation of RLS is a phenomenon that predominantly manifests in wakefulness.

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BACKGROUND: Despite several polysomnographic studies on periodic leg movements (PLM) in healthy sleep, data on the prevalence and characteristics of periodic arm movements (PAM) in normal subjects are lacking. We aimed to investigate PAM and their association with PLM during wakefulness and sleep in healthy subjects. METHODS: Ninety-one participants underwent video-polysomnography according to American Academy of Sleep Medicine 2007 criteria. In addition to standard electromyographic registration, data for both flexor digitorum superficialis muscles were recorded. RESULTS: Sixty-two subjects (68.1%) had a PAM index during wakefulness >5/h (median PAM index during wakefulness, 8.8/h; range, 0-77). Seven subjects (7.7%) had a PAM index >5/h during sleep (median PAM index during sleep, 0.7/h; range, 0-47.4). In 14% of cases, PAM during wakefulness were coincident with PLM during wakefulness. During sleep, this coincidence was not evident. The correlation between PAM and PLM was weak to moderate (during wakefulness: Spearman's ρ = 0.576, P < 0.001; during sleep: Spearman's ρ = 0.222, P = 0.036). CONCLUSION: In healthy subjects, PAM occur predominantly during wakefulness with no apparent true periodicity. In contrast to classical PLM, some PAM may not present a true periodic phenomenon, but rather random voluntary movements meeting the wide range of periodicity criteria for PLM.

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STUDY OBJECTIVES: Despite several polysomnographic normative studies and multiple surveys of sleep disorders in the general population, few data have been collected on healthy sleepers. We aimed to survey the characteristics of healthy sleep. METHODS: We prospectively investigated the sleep history of 100 subjects of a representative population sample who reported undisturbed sleep and in whom relevant sleep disorders were ruled out by a two-step screening procedure. Approximately four subjects had to be contacted for identifying 1 eligible subject who participated. RESULTS: The median reported time in bed was from 23:00 (21:30-02:00) to 07:00 (05:30-11:00). The total sleep duration was 7.3 h (5-10 h), varying from 7.5 h in the age group ≤ 30 years to 7 h in subjects aged 40-60 years and to 8 h in subjects > 60 years (p = 0.002). The median sleep efficiency was high (93.3%, range: 55.6% to 100%). Fifty-one subjects reported occasional snoring. Forty-five subjects reported sporadic non-bothersome sleep-related movement disorders (25 sleep-related leg cramps, 22 lifetime bruxism, 5 restless legs syndrome), and 36 had a history of sporadic non-bothersome parasomnias (27 nightmares, 12 sleepwalking, 1 sleep paralysis). CONCLUSION: In this population of healthy sleepers, snoring is the most common finding. Moreover, non-bothersome forms of recognizable sleep-related movement disorders and parasomnias are surprisingly common. These findings may suggest that diagnostic criteria of sleep disorders should not only be based on the presence of symptoms but also account for a minimum frequency or discomfort.

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BACKGROUND: Rapid eye movement (REM) sleep without atonia (RWA) is observed in some patients without a clinical history of REM sleep behavior disorder (RBD). It remains unknown whether these patients meet the refined quantitative electromyographic (EMG) criteria supporting a clinical RBD diagnosis. We quantitatively evaluated EMG activity and investigated its overnight distribution in patients with isolated qualitative RWA. METHODS: Fifty participants with an incidental polysomnographic finding of RWA (isolated qualitative RWA) were included. Tonic, phasic, and 'any' EMG activity during REM sleep on PSG were quantified retrospectively. RESULTS: Referring to the quantitative cut-off values for a polysomnographic diagnosis of RBD, 7/50 (14%) and 6/50 (12%) of the patients showed phasic and 'any' EMG activity in the mentalis muscle above the respective cut-off values. No patient was above the cut-off value for tonic EMG activity or phasic EMG activity in the anterior tibialis muscles. Patients with RWA above the cut-off value showed higher amounts of RWA during later REM sleep periods. CONCLUSIONS: This is the first study showing that some subjects with incidental RWA meet the refined quantitative EMG criteria for a diagnosis of RBD. Future longitudinal studies must investigate whether this subgroup with isolated qualitative RWA is at an increased risk of developing fully expressed RBD and/or neurodegenerative disease.

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STUDY OBJECTIVES: Many sleep disorders are characterized by increased motor activity during sleep. In contrast, studies on motor activity during physiological sleep are largely lacking. We quantitatively investigated a large range of motor phenomena during polysomnography in physiological sleep. DESIGN: Prospective polysomnographic investigation. SETTING: Academic referral sleep laboratory. PARTICIPANTS: One hundred healthy sleepers age 19-77 y were strictly selected from a representative population sample by a two-step screening procedure. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Polysomnography according to American Academy of Sleep Medicine (AASM) standards was performed, and quantitative normative values were established for periodic limb movements in sleep (PLMS), high frequency leg movements (HFLM), fragmentary myoclonus (FM), neck myoclonus (NM), and rapid eye movement (REM)-related electromyographic (EMG) activity. Thirty-six subjects had a PLMS index > 5/h, 18 had a PLMS index > 15/h (90th percentile: 24.8/h). Thirty-three subjects had HFLM (90th percentile: four sequences/night). All subjects had FM (90th percentile 143.7/h sleep). Nine subjects fulfilled AASM criteria for excessive FM. Thirty-five subjects had NM (90th percentile: 8.8/h REM sleep). For REM sleep, different EMG activity measures for the mentalis and flexor digitorum superficialis muscles were calculated: the 90th percentile for phasic mentalis EMG activity for 30-sec epochs according to AASM recommendation was 15.6%, and for tonic mentalis EMG activity 2.6%. Twenty-five subjects exceeded the recently proposed phasic mentalis cutoff of 11%. None of the subjects exceeded the tonic mentalis cutoff of 9.6%. CONCLUSION: Quantification of motor phenomena is a basic prerequisite to develop normative values, and is a first step toward a more precise description of the various motor phenomena present during sleep. Because rates of motor events were unexpectedly high even in physiological sleep, the future use of normative values for both research and clinical routine is essential.

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OBJECTIVE: This controlled study investigated associations between comorbidity and medication in patients with polysomnographically confirmed idiopathic REM sleep behavior disorder (iRBD), using a large multicenter clinic-based cohort. METHODS: Data of a self-administered questionnaire on comorbidity and medication use of 318 patients with iRBD and 318 matched controls were analyzed. Comparisons between cases and controls were made using logistic regression analysis. RESULTS: Patients with iRBD were more likely to report depression (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.3-2.9) and concomitant antidepressant use (OR 2.2, 95% CI 1.4-3.6). Subanalysis of antidepressant agents revealed that the increased use of antidepressants in iRBD was due to selective serotoninergic reuptake inhibitors (OR 3.6, 95% CI 1.8-7.0) and not due to other antidepressant classes. Patients with iRBD reported more lifetime antidepressant use than comorbid depression (antidepressant use: OR 1.9, 95% CI 1.1-3.3; depression: OR 1.6, 95% CI 1.0-2.5). Patients with iRBD reported more ischemic heart disease (OR 1.9, 95% CI 1.1-3.1). This association did not change substantially when adjusting for cardiovascular risk factors (OR 2.3, 95% CI 1.3-3.9). The use of inhaled glucocorticoids was higher in patients with iRBD compared to controls (OR 5.3, 95% CI 1.8-15.8), likely reflecting the higher smoking rate in iRBD (smoking: OR 15.3, 95% CI 2.0-118.8; nonsmoking: OR 2.4, 95% CI 0.4-13.2) and consequent pulmonary disease. CONCLUSIONS: This large study confirms the association between comorbid depression and antidepressant use in iRBD. In addition, there was an unexpected association of iRBD with ischemic heart disease that was not explained by cardiovascular risk factors.

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There has been no previous side-by-side comparison of the diagnostic criteria for restless legs syndrome (RLS) (Willis-Ekbom disease) and growing pains. In our review, we explore this comparison emphasizing overlaps and disconnects, summarize recent literature exploring the relationship between the 2 entities, and make suggestions for future research. There is considerable overlap in the diagnostic criteria for childhood RLS and growing pains. The literature also indicates that RLS and growing pains more commonly occur together than one would expect based on chance alone, and the family histories of RLS and growing pains often are overlapping. Leg rubbing to obtain relief from leg discomfort is common to both disorders, though walking to obtain relief seems unique to RLS. Childhood RLS also has been reported to be painful in up to 45% of cases. The development of standard diagnostic criteria is necessary to move forward in the field of growing pains research. A quantitative and validated rating scale for growing pains severity already exists. Because of the clinical and genetic similarity between RLS and growing pains, studies that parallel those previously performed in RLS patients are recommended for growing pains patients. For example, a genome wide association study in growing pains patients of all possible genes with particular attention to those identified as related to RLS and a therapeutic trial of medications known to be effective in RLS would be welcome. Abnormalities in vitamin D metabolism also may be common to both disorders.

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STUDY OBJECTIVES: Narcolepsy is reported to affect 26-56/100,000 in the general population. We aimed to describe clinical and polysomnographic features of a large narcolepsy cohort in order to comprehensively characterize the narcoleptic spectrum. METHODS: We performed a chart- and polysomnographybased review of all narcolepsy patients of the Innsbruck narcolepsy cohort. RESULTS: A total of 100 consecutive narcolepsy patients (87 with cataplexy [NC], 13 without cataplexy [N]) were included in the analysis. All subjects had either excessive daytime sleepiness or cataplexy as their initial presenting clinical feature. Age at symptom onset was 20 (6-69) years. Diagnostic delay was 6.5 (0-39) years. The complete narcolepsy tetrad was present in 36/100 patients; 28/100 patients had three cardinal symptoms; 29/100 had two; and 7/100 had only excessive daytime sleepiness. Severity varied broadly with respect to excessive daytime sleepiness (median Epworth Sleepiness Scale score: 18, range 10-24), cataplexy (8-point Likert scale: median 4.5, range 1-8), hypnagogic hallucinations (median 4.5, range 1-7), and sleep paralysis (median 3, range 1-7). Sleep comorbidity was highly prevalent and ranged from sleeprelated movement disorders (n = 55/100), parasomnias (n = 34/100), and sleeprelated breathing disorders (n = 24/100), to insomnia (n = 28/100). REM sleep without atonia or a periodic limb movement in sleep index > 5/h were present in most patients (90/100 and 75/100). A high percentage of narcoleptic patients in the present study had high frequency leg movements (35%) and excessive fragmentary myoclonus (22%). Of the narcolepsy patients with clinical features of REM sleep behavior disorder (RBD), 76.5% had EMG evidence for RBD on the multiple sleep latency test (MSLT), based on a standard cutoff of a minimum of 18% of 3-sec miniepochs. CONCLUSION: This study is one of the largest monocentric polysomnographic studies to date of patients with narcolepsy and confirms the frequent comorbidity of narcolepsy with many other sleep disorders. Our study is the first to evaluate the percentage of patients with high frequency leg movements and excessive fragmentary myoclonus in narcolepsy and is the first to demonstrate EMG evidence of RBD in the MSLT. These findings add to the growing body of literature suggesting that motor instability is a key feature of narcolepsy.

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A diagnosis of definite REM sleep behavior disorder requires both a positive history for REM sleep behavior disorder and polysomnographic demonstration of REM sleep without atonia. To improve and facilitate screening for REM sleep behavior disorder, there is a need for simple clinical tools with sufficient sensitivity and specificity for the identification of subjects with probable REM sleep behavior disorder. We developed a short REM sleep behavior disorder screening questionnaire with 7 REM sleep behavior disorder- and 2 non-REM sleep behavior disorder-specific control items and performed a validation study in 70 REM sleep behavior disorder subjects and 140 sleep disorder controls. Response patterns to all 7 REM sleep behavior disorder-specific items differed between REM sleep behavior disorder and non-REM sleep behavior disorder patients (all P < 0.05), whereas the 2 non-REM sleep behavior disorder-specific control items did not differentiate between REM sleep behavior disorder and non-REM sleep behavior disorder (all P > .05). In 5 of the 7 REM sleep behavior disorder-specific items, AUC was greater than 0.700. These 5 items were included in the Innsbruck REM sleep behavior disorder inventory. In this questionnaire, a cutoff of 0.25 (number of positive symptoms divided by number of answered questions) had a sensitivity of 0.914 and a specificity of 0.857 for both idiopathic and Parkinson's-related REM sleep behavior disorder (AUC, 0.886). The Innsbruck REM sleep behavior disorder inventory is a promising, easy-to-use, short screening tool for REM sleep behavior disorder with excellent sensitivity and specificity for both idiopathic and Parkinson's-related REM sleep behavior disorder.

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