The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023.

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

Periodic limb movements in sleep are linked to decreased hippocampus and amygdala volumes in the population-based BiDirect Study.

STUDY OBJECTIVES: Even though numerous studies indicate that sleep disorders are associated with altered brain morphology, MRI studies focusing on periodic limb movements in sleep (PLMS) are scarce. Our aim was to investigate the association of PLMS with global and regional gray matter volumes as well as white matter hyperintensity (WMH) volume. METHODS: One hundred and eighty-nine subjects (57.0 ± 7.8 years, women: 50.5%) of the population-based BiDirect Study underwent a single-night polysomnography (PSG). Standard criteria of the American Academy of Sleep Medicine were applied to evaluate sleep characteristics and calculate the PLMS index (PLMSI). T1w and FLAIR images were acquired with cerebral MRI at 3 Tesla. Voxel-based morphometry was performed to determine the total gray matter volume as well as the volume of cortical segments and subcortical gray matter areas using SPM12 and CAT12. The WMH volume was quantified with the Brain Intensity AbNormality Classification Algorithm. The independent relationship between MRI markers and PLMSI was analyzed using multivariable linear regression with adjustment for age, sex, body mass index, intracranial volume, PSG scorer, PSG device, sleep apnea, and the use of antidepressants. RESULTS: PLMSI was not significantly related to global gray matter volume and WMH volume. However, significant inverse associations of the PLMSI with the volume of the hippocampus (left and right hemisphere) and left amygdala were observed. CONCLUSIONS: A significant relationship between a higher PLMSI and lower volumes of the hippocampus and amygdala was found among the participants of the BiDirect Study. Since these associations are based on exploratory analyses, further replications are required before drawing firm conclusions.

The relationship between Alzheimer's-related brain atrophy patterns and sleep macro-architecture.

Introduction: Sleep is increasingly recognized as a major risk factor for neurodegenerative disorders such as Alzheimer's disease (AD). Methods: Using an magnetic resonance imaging (MRI)-based AD score based on clinical data from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) case-control cohort, we investigated the associations between polysomnography-based sleep macro-architecture and AD-related brain atrophy patterns in 712 pre-symptomatic, healthy subjects from the population-based Study of Health in Pomerania. Results: We identified a robust inverse association between slow-wave sleep and the AD marker (estimate: -0.019; 95% confidence interval: -0.03 to -0.0076; false discovery rate [FDR] = 0.0041), as well as with gray matter (GM) thicknesses in typical individual cortical AD-signature regions. No effects were identified regarding rapid eye movement or non-rapid eye movement (NREM) stage 2 sleep, and NREM stage 1 was positively associated with GM thickness, mainly in the prefrontal cortical regions. Discussion: There is a cross-sectional relationship between AD-related neurodegenerative patterns and the proportion of sleep spent in slow-wave sleep.

Association Between Obstructive Sleep Apnea and Brain White Matter Hyperintensities in a Population-Based Cohort in Germany.

Importance: Underlying pathomechanisms of brain white matter hyperintensities (WMHs), commonly observed in older individuals and significantly associated with Alzheimer disease and brain aging, have not yet been fully elucidated. One potential contributing factor to WMH burden is chronic obstructive sleep apnea (OSA), a disorder highly prevalent in the general population with readily available treatment options. Objective: To investigate potential associations between OSA and WMH burden. Design, Setting, and Participants: Analyses were conducted in 529 study participants of the Study of Health in Pomerania-Trend baseline (SHIP-Trend-0) study with complete WMH, OSA, and important clinical data available. SHIP-Trend-0 is a general population-based, cross-sectional, observational study to facilitate the investigation of a large spectrum of common risk factors, subclinical disorders, and clinical diseases and their relationships among each other with patient recruitment from Western Pomerania, Germany, starting on September 1, 2008, with data collected until December 31, 2012. Data analysis was performed from February 1, 2019, to January 31, 2021. Exposures: The apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) were assessed during a single-night, laboratory-based polysomnography measurement. Main Outcomes and Measures: The primary outcome was WMH data automatically segmented from 1.5-T magnetic resonance images. Results: Of 529 study participants (mean [SD] age, 52.15 [13.58] years; 282 female [53%]), a total of 209 (40%) or 102 (19%) individuals were diagnosed with OSA according to AHI or ODI criteria (mean [SD] AHI, 7.98 [12.55] events per hour; mean [SD] ODI, 3.75 [8.43] events per hour). Both AHI (ß = 0.024; 95% CI, 0.011-0.037; P <.001) and ODI (ß = 0.033; 95% CI, 0.014-0.051; P <. 001) were significantly associated with brain WMH volumes. These associations remained even in the presence of additional vascular, metabolic, and lifestyle WMH risk factors. Region-specific WMH analyses found the strongest associations between periventricular frontal WMH volumes and both AHI (ß = 0.0275; 95% CI, 0.013-0.042, P < .001) and ODI (ß = 0.0381; 95% CI, 0.016-0.060, P < .001) as well as periventricular dorsal WMH volumes and AHI (ß = 0.0165; 95% CI, 0.004-0.029, P = .008). Conclusions and Relevance: This study found significant associations between OSA and brain WMHs, indicating a novel, potentially treatable WMH pathomechanism.

Interrater sleep stage scoring reliability between manual scoring from two European sleep centers and automatic scoring performed by the artificial intelligence-based Stanford-STAGES algorithm.

STUDY OBJECTIVES: The objective of this study was to evaluate interrater reliability between manual sleep stage scoring performed in 2 European sleep centers and automatic sleep stage scoring performed by the previously validated artificial intelligence-based Stanford-STAGES algorithm. METHODS: Full night polysomnographies of 1,066 participants were included. Sleep stages were manually scored in Berlin and Innsbruck sleep centers and automatically scored with the Stanford-STAGES algorithm. For each participant, we compared (1) Innsbruck to Berlin scorings (INN vs BER); (2) Innsbruck to automatic scorings (INN vs AUTO); (3) Berlin to automatic scorings (BER vs AUTO); (4) epochs where scorers from Innsbruck and Berlin had consensus to automatic scoring (CONS vs AUTO); and (5) both Innsbruck and Berlin manual scorings (MAN) to the automatic ones (MAN vs AUTO). Interrater reliability was evaluated with several measures, including overall and sleep stage-specific Cohen's κ. RESULTS: Overall agreement across participants was substantial for INN vs BER (κ = 0.66 ± 0.13), INN vs AUTO (κ = 0.68 ± 0.14), CONS vs AUTO (κ = 0.73 ± 0.14), and MAN vs AUTO (κ = 0.61 ± 0.14), and moderate for BER vs AUTO (κ = 0.55 ± 0.15). Human scorers had the highest disagreement for N1 sleep (κN1 = 0.40 ± 0.16 for INN vs BER). Automatic scoring had lowest agreement with manual scorings for N1 and N3 sleep (κN1 = 0.25 ± 0.14 and κN3 = 0.42 ± 0.32 for MAN vs AUTO). CONCLUSIONS: Interrater reliability for sleep stage scoring between human scorers was in line with previous findings, and the algorithm achieved an overall substantial agreement with manual scoring. In this cohort, the Stanford-STAGES algorithm showed similar performances to the ones achieved in the original study, suggesting that it is generalizable to new cohorts. Before its integration in clinical practice, future independent studies should further evaluate it in other cohorts.

Associations between sleep apnea and advanced brain aging in a large-scale population study.

Advanced brain aging is commonly regarded as a risk factor for neurodegenerative diseases, for example, Alzheimer's dementia, and it was suggested that sleep disorders such as obstructive sleep apnea (OSA) are significantly contributing factors to these neurodegenerative processes. To determine the association between OSA and advanced brain aging, we investigated the specific effect of two indices quantifying OSA, namely the apnea-hypopnea index (AHI) and the oxygen desaturation index (ODI), on brain age, a score quantifying age-related brain patterns in 169 brain regions, using magnetic resonance imaging and overnight polysomnography data from 690 participants (48.8% women, mean age 52.5 ± 13.4 years) of the Study of Health in Pomerania. We additionally investigated the mediating effect of subclinical inflammation parameters on these associations via a causal mediation analysis. AHI and ODI were both positively associated with brain age (AHI std. effect [95% CI]: 0.07 [0.03; 0.12], p-value: 0.002; ODI std. effect [95% CI]: 0.09 [0.04; 0.13], p-value: < 0.0003). The effects remained stable in the presence of various confounders such as diabetes and were partially mediated by the white blood cell count, indicating a subclinical inflammation process. Our results reveal an association between OSA and brain age, indicating subtle but widespread age-related changes in regional brain structures, in one of the largest general population studies to date, warranting further examination of OSA in the prevention of neurodegenerative diseases.

Sleep characteristics, cognitive performance, and gray matter volume: findings from the BiDirect Study.

STUDY OBJECTIVES: Sleep is essential for restorative metabolic changes and its physiological correlates can be examined using overnight polysomnography. However, the association between physiological sleep characteristics and brain structure is not well understood. We aimed to investigate gray matter volume and cognitive performance related to physiological sleep characteristics. METHODS: Polysomnographic recordings from 190 community-dwelling participants were analyzed with a principal component analysis in order to identify and aggregate shared variance into principal components. The relationship between aggregated sleep components and gray matter volume was then analyzed using voxel-based morphometry. In addition, we explored how cognitive flexibility, selective attention, and semantic fluency were related to aggregated sleep components and gray matter volume. RESULTS: Three principal components were identified from the polysomnographic recordings. The first component, primarily described by apnea events and cortical arousal, was significantly associated with lower gray matter volume in the left frontal pole. This apnea-related component was furthermore associated with lower cognitive flexibility and lower selective attention. CONCLUSIONS: Sleep disrupted by cortical arousal and breathing disturbances is paralleled by lower gray matter volume in the frontal pole, a proposed hub for the integration of cognitive processes. The observed effects provide new insights on the interplay between disrupted sleep, particularly breathing disturbances and arousal, and the brain.

A Biased Diffusion Approach to Sleep Dynamics Reveals Neuronal Characteristics.

We propose a biased diffusion model of accumulated subthreshold voltage fluctuations in wake-promoting neurons to account for stochasticity in sleep dynamics and to explain the occurrence of brief arousals during sleep. Utilizing this model, we derive four neurophysiological parameters related to neuronal noise level, excitability threshold, deep-sleep threshold, and sleep inertia. We provide the first analytic expressions for these parameters, and we show that there is good agreement between empirical findings from sleep recordings and our model simulation results. Our work suggests that these four parameters can be of clinical importance because we find them to be significantly altered in elderly subjects and in children with autism.

Prevalence and associated risk factors of periodic limb movement in sleep in two German population-based studies.

STUDY OBJECTIVES: Periodic limb movements in sleep (PLMS) are frequent motor phenomena; however, population-based data are scarce. We assessed the prevalence of PLMS and factors associated with PLMS within two German population-based cohorts, the SHIP-TREND and BiDirect. METHODS: Single-night polysomnography was performed on 1107 subjects recruited from the general population (mean age: 52.9 years, 54.1% men) in the SHIP-TREND and on 247 participants (mean age: 57.6 years, 50.6% men) in the BiDirect. PLMS were evaluated using the standard criteria of the American Academy of Sleep Medicine. Sociodemographic data, behavioral variables, medical history, current medication, and other sleep disorders were assessed. RESULTS: The prevalence of PLMS index (PLMSI) >15/hour was 32.4% (SHIP-TREND) and 36.4% (BiDirect). In multivariable models, age (odds ratio [OR] = 1.05 per +1 year), male gender (OR = 2.20), restless legs syndrome (OR = 2.32), physical inactivity (OR = 1.52), current smoking (OR = 1.49), diabetes (OR = 2.13), antidepressant use (OR = 2.27), lower serum magnesium (OR per -0.1 mmol/L = 1.27) showed a positive, and the intake of beta-blockers an inverse association with PLMSI >15/hour in SHIP-TREND. In BiDirect, age (OR = 1.13 per +1 year), body mass index (OR = 1.11 per +1 kg/m2), and restless legs syndrome (OR = 8.77) were significantly associated with PLMSI >15/hour. CONCLUSIONS: A high PLMSI is frequent in the German population. Age, male gender, restless legs syndrome, physical inactivity, current smoking, obesity, diabetes, antidepressant use, and lower magnesium were independently associated with PLMSI >15/hour in at least one of the cohorts.

Lack of Association Between Shape and Volume of Subcortical Brain Structures and Restless Legs Syndrome.

OBJECTIVE: Previous studies on patients with restless legs syndrome (RLS) yielded inconclusive results in the magnetic resonance imaging (MRI)-based analyses of alterations of subcortical structures in the brain. The aim of this study was to compare volumes as well as shapes of subcortical structures and the hippocampus between RLS cases and controls. Additionally, the associations between the genetic risks for RLS and subcortical volumes were investigated. METHODS: We compared volumetric as well as shape differences assessed by 3 T MRI in the caudate nucleus, hippocampus, globus pallidus, putamen, and thalamus in 39 RLS cases versus 117 controls, nested within a population-based sample. In a subsample, we explored associations between known genetic risk markers for RLS and the volumes of the subcortical structures and the hippocampus. RESULTS: No significant differences between RLS cases and controls in subcortical and hippocampal shapes and volumes were observed. Furthermore, the genetic risk for RLS was unrelated to any alterations of subcortical and hippocampal gray matter volume. INTERPRETATION: We conclude that neither RLS nor the genetic risk for the disease give rise to changes in hippocampal and subcortical shapes and gray matter volumes.

Insomnia-perchance a dream? Results from a NREM/REM sleep awakening study in good sleepers and patients with insomnia.

Study Objectives: Insomnia disorder (ID) is a frequent sleep disorder coupled with increased risks for somatic and mental illness. Although subjective complaints are severe, polysomnography (PSG) parameters show only modest differences between groups. Rapid eye movement (REM) sleep as the most aroused sleep state may be especially vulnerable to be perceived as wake. To directly assess possible differences, we determined auditory waking thresholds and sleep perception in patients with ID and healthy control participants (good sleeper controls [GSC]) in N2 and REM sleep. Methods: In case-control study, 27 patients with ID and 27 age- and gender-matched controls were included. Four consecutive nights were assessed in the sleep laboratory, with nights 3 and 4 each containing three awakenings either from stable N2 or REM sleep. Awakening thresholds in patients with ID did not differ from GSC, but decreased over the course of the night. Patients with ID indicated significantly more frequently than GSC having been awake when woken from REM sleep but not from N2 and were less sure when indicating they had been asleep. Additionally, participants with ID rated their REM sleep mentation as more emotionally negative compared with GSC. Conclusions: This study presents direct evidence that the subjective experience of insomnia might be specifically coupled to the REM sleep state. Assuming chronic hyperarousal as a central pathophysiologically relevant pathway for insomnia, this might become especially evident during REM sleep, thus reflecting a hybrid sleep state in insomnia being coupled with altered sleep perception.

Association of symptoms of insomnia and sleep parameters among kidney transplant recipients.

OBJECTIVE: Insomnia complaints are frequent among kidney transplant (kTx) recipients and are associated with fatigue, depression, lower quality of life and increased morbidity. However, it is not known if subjective insomnia symptoms are associated with objective parameters of sleep architecture. Thus, we analyze the association between sleep macrostructure and EEG activity versus insomnia symptoms among kTx recipients. METHODS: Participants (n1=100) were selected from prevalent adult transplant recipients (n0=1214) followed at a single institution. Insomnia symptoms were assessed by the Athens Insomnia Scale (AIS) and standard overnight polysomnography was performed. In a subgroup of patients (n2=56) sleep microstructure was also analyzed with power spectral analysis. RESULTS: In univariable analysis AIS score was not associated with sleep macrostructure parameters (sleep latency, total sleep time, slow wave sleep, wake after sleep onset), nor with NREM and REM beta or delta activity in sleep microstructure. In multivariable analysis after controlling for covariables AIS score was independently associated with the proportion of slow wave sleep (ß=0.263; CI: 0.026-0.500) and REM beta activity (ß=0.323; CI=0.041-0.606) (p<0.05 for both associations). CONCLUSIONS: Among kTx recipients the severity of insomnia symptoms is independently associated with higher proportion of slow wave sleep and increased beta activity during REM sleep but not with other parameters sleep architecture. The results suggest a potential compensatory sleep protective mechanism and a sign of REM sleep instability associated with insomnia symptoms among this population.

Reduced fractional anisotropy in patients with major depressive disorder and associations with vascular stiffness.

Previous studies revealed several alterations of the cerebral white matter in patients with major depressive disorder. However, it is unknown if these alterations are associated with vascular changes in the brain and other body parts. We compared diffusion tensor imaging derived fractional anisotropy in a well characterized sample of middle-aged patients with major depressive disorder (n = 290) and never-depressed controls (n = 346) by the method of tract-based spatial statistics. Subsequently, the potential role of pulse wave velocity as a mediator of depression- and age-related changes in extracted estimates of fractional anisotropy were analyzed. The results of the tract-based analysis revealed significantly reduced fractional anisotropy in the left posterior thalamic radiation associated with depression. Analyses of extracted data indicated additional reductions of fractional anisotropy bilaterally in the posterior thalamic radiation and in the left sagittal stratum. The analyses of indirect effects did not show any significant mediation of depression-related effects on fractional anisotropy via pulse wave velocity. However, age-related effects on fractional anisotropy were partially mediated by pulse wave velocity. In conclusion, major depressive disorder is associated with detrimental effects on cerebral white matter microstructure properties which are independent of vascular changes, as measured by pulse wave velocity. However, a portion of age-related detrimental effects on white matter is explained by vascular changes. Longitudinal studies are required for investigating changes in white matter and vascular parameters over time and their association with incident depression.

Depressive Symptoms Are Associated With Objectively Measured Sleep Parameters in Kidney Transplant Recipients.

STUDY OBJECTIVES: Both depression and sleep complaints are very prevalent among kidney transplant (kTx) recipients. However, details of the complex relationship between sleep and depression in this population are not well documented. Thus, we investigated the association between depressive symptoms and sleep macrostructure parameters among prevalent kTx recipients. METHODS: Ninety-five kTx recipients participated in the study (54 males, mean ± standard devation age 51 ± 13 years, body mass index 26 ± 4 kg/m2, estimated glomerular filtration rate 53 ± 19 ml/min/1.73 m2). Symptoms of depression were assessed by the Center for Epidemiologic Studies - Depression Scale (CES-D). After 1-night polysomnography each recording was visually scored and sleep macrostructure was analyzed. RESULTS: The CES-D score was significantly associated with the amount of stage 2 sleep (r = 0.20, P < .05), rapid eye movement (REM) latency (r = 0.21, P < .05) and REM percentage (r = -0.24, P < .05), but not with the amount of slow wave sleep (r = -0.12, P > .05). In multivariable linear regression models the CES-D score was independently associated with the amount of stage 2 sleep (ß: 0.205; confidence interval: 0.001-0.409; P = .05) and REM latency (ß: 0.234; confidence interval: 0.001-0.468; P = .05) after adjustment for potential confounders. CONCLUSIONS: Depressive symptoms among kTx recipients are associated with increased amount of stage 2 sleep and prolonged REM latency. Further studies are needed to confirm our findings and understand potential clinical implications.

Lack of Association between Genetic Risk Loci for Restless Legs Syndrome and Multimorbidity.

STUDY OBJECTIVES: Multimorbidity is a risk factor for incident restless legs syndrome (RLS). In this relationship, the potential role of known genetic risk loci for RLS has not been studied. Our aim was to evaluate whether carriers of specific RLS risk alleles have higher comorbidity burden than noncarriers. METHODS: The Dortmund Health Study (DHS) and the Study of Health in Pomerania (SHIP) are two independent cohort studies in Germany based on age-stratified, random samples drawn from the respective population registers. DHS included 1,312 subjects and SHIP included 4,308 subjects. RLS status was assessed according to the RLS standard minimal criteria. A comorbidity index was calculated by summing the scores of the following conditions: diabetes, hypertension, myocardial infarction, obesity, stroke, cancer, renal disease, anemia, depression, thyroid disease, and migraine. Thirteen single nucleotide polymorphisms (SNP) previously associated with elevated risk of RLS were genotyped. Analyses were carried out on the pooled sample of the two studies. RESULTS: The mean age was 50.4 ± 15.9 y, and the proportion of women was 51.4%. The mean number of comorbid conditions was 1.5 ± 1.3. In multivariable regression, the mean number of comorbidities was not significantly different between carriers of any of the RLS risk alleles and noncarriers either in the total pooled sample or in those having RLS symptoms. CONCLUSIONS: Based on these results it is unlikely that known genetic risk factors for RLS would lead to increased multimorbidity.

Association between lunar phase and sleep characteristics.

OBJECTIVES: Popular belief holds that the lunar cycle affects human physiology, behavior, and health, including sleep. To date, only a few and conflicting analyses have been published about the association between lunar phases and sleep. Our aim was to analyze the relationship between lunar phases and sleep characteristics. METHODS: In this retrospective, cross-sectional analysis, data from 319 patients who had been referred for sleep study were included. Individuals with apnea-hypopnea index ≥ 15/h were excluded. Socio-demographic parameters were recorded. All participants underwent one-night standard polysomnography. Associations between lunar cycle (new moon, full moon and alternate moon) and sleep parameters were examined in unadjusted and adjusted models. RESULTS: Fifty-seven percent of patients were males. Mean age for men was 45 ± 14 years and 51 ± 12 years for women. In total, 224 persons had their sleep study done during alternate moon, 47 during full moon, and 48 during new moon. Full moon was associated with lower sleep efficiency [median (%) (IQR): new moon 82 (18), full moon 74 (19), alternate moon 82 (15); P < 0.001], less deep sleep [median (%) (IQR): new moon 9 (9), full moon 6 (4), alternate moon 11 (9); P < 0.001], and increased REM latency [median (min) (IQR): new moon 98 (74), full moon 137 (152), alternate moon 97 (76); P < 0.001], even after adjustment for several covariables. CONCLUSION: The results are consistent with a recent report and the widely held belief that sleep characteristics may be associated with the full moon.

Multimorbidity and the risk of restless legs syndrome in 2 prospective cohort studies.

OBJECTIVE: Our aim was to evaluate the association between the cumulative effect of comorbidity and the risk of restless legs syndrome (RLS) in 2 population-based German cohort studies. METHODS: The Dortmund Health Study (DHS) (n = 1,312; median follow-up time: 2.1 years) and the Study of Health in Pomerania (SHIP) (n = 4,308; median follow-up time: 5.0 years) were used for the analyses. RLS was assessed at baseline and follow-up according to the RLS minimal criteria. A comorbidity index was calculated as a sum of the following conditions: diabetes, hypertension, myocardial infarction, obesity, stroke, cancer, renal disease, anemia, depression, thyroid disease, and migraine. The relationship between comorbidity and incident RLS was analyzed with multivariate logistic regression models. RESULTS: An increase in the number of comorbid conditions at baseline predicted prevalent RLS (DHS: trend odds ratio [OR] = 1.24, 95% confidence interval [CI] 0.99-1.56; SHIP: trend OR = 1.34, 95% CI 1.18-1.52) and incident RLS (DHS: trend OR = 1.32, 95% CI 1.04-1.68; SHIP: trend OR = 1.59, 95% CI 1.37-1.85) after adjustment for several covariates. The ORs for incident RLS associated with 3 or more comorbid diseases (DHS: OR = 2.51, 95% CI 1.18-5.34; SHIP: OR = 4.30, 95% CI 2.60-7.11) were higher than the ORs for any single disease. CONCLUSIONS: Multimorbidity was a strong risk factor for RLS in these 2 population-based cohort studies. The results support the hypothesis that cumulative disease burden is more important than the presence of a specific single disease in the pathophysiology of RLS.

The relationship between depressive symptoms and restless legs syndrome in two prospective cohort studies.

OBJECTIVE: Cross-sectional studies suggest a strong association between depression and restless legs syndrome (RLS); however, the temporal relationship between the two disorders remains unknown. We tested whether the presence of clinically relevant depressive symptoms (CRDS) is a risk factor for subsequent RLS in the general population. The relationship between prevalent RLS and incident CRDS was also examined. METHODS: Two independent, prospective cohort studies with representative, age-stratified random samples, the Dortmund Health Study (DHS; n = 1312/1122 [baseline/follow-up], median follow-up time = 2.1 years) and the Study of Health in Pomerania (SHIP; n = 4308/3300, median follow-up time = 5.0 years) were analyzed. RLS was assessed in both studies according to the RLS minimal criteria, at baseline and at follow-up. CRDS were assessed by the Center for Epidemiologic Studies-Depression scale (a score of ≥16) in DHS only at baseline and by the Munich-Composite International Diagnostic-Screener in SHIP at baseline and at follow-up. RESULTS: Clinically relevant depressive symptoms at baseline were associated new-onset RLS in both studies (DHS: odds ratio [OR] = 1.94, 95% confidence interval [CI] = 1.09-3.44; SHIP: OR = 2.37, 95% CI = 1.65-3.40) after adjustment for age, sex, education, body mass index, smoking, physical activity, and the presence of various comorbidities. RLS at baseline was an independent risk factor of incident CRDS in SHIP (OR = 1.82, 95% CI = 1.10-3.00). CONCLUSIONS: The presence of CRDS may be a risk factor for subsequent RLS. The relationship between the two disorders might be bidirectional because RLS also predicts incident depressive symptoms.

A time sequence analysis of the relationship between cardiovascular risk factors, vascular diseases and restless legs syndrome in the general population.

Previous cross-sectional studies regarding the association of restless legs syndrome (RLS) with cardiovascular morbidity are controversial. Our aim was to evaluate prospectively the relationship of cardiovascular risk factors and vascular diseases with incident RLS in the general population. The results are from two prospective population-based cohort studies: the Dortmund Health Study (n = 1312, median follow-up of 2.1 years) and the Study of Health in Pomerania (n = 4308, median follow-up of 5.0 years). RLS status was assessed twice according to the minimal criteria. Diabetes, hypertension, myocardial infarction and stroke, as well as currently taken medications, were assessed as self-reports. Body mass index and serum total cholesterol were also measured. The independent risks associated with each outcome were estimated by multivariable logistic regression models adjusted for comorbidities and behavioural factors. Obesity was an independent risk factor of incident RLS in the Dortmund Health Study, and higher body mass index was an independent risk factor in both studies. Diabetes, hypertension and hypercholesterolaemia were independent predictors of incident RLS in the Study of Health in Pomerania. The vascular comorbidity index, defined by the number of concurrent cardiovascular risk factors and vascular diseases, showed a positive association with incident RLS in both studies. RLS at baseline was not a significant predictor of any subsequent cardiovascular risk factors and/or vascular diseases in any of the studies. Cardiovascular risk factors and diseases predict the subsequent development of RLS in the general population. The presence of RLS is not a significant risk factor of cardiovascular morbidity.