John W. Winkelman

Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: Updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria - history, rationale, description, and significance

BACKGROUND In 2003, following a workshop at the National Institutes of Health, the International Restless Legs Syndrome Study Group (IRLSSG) developed updated diagnostic criteria for restless legs syndrome/Willis-Ekbom disease (RLS/WED). These criteria were integral to major advances in research, notably in epidemiology, biology, and treatment of RLS/WED. However, extensive review of accumulating literature based on the 2003 NIH/IRLSSG criteria led to efforts to improve the diagnostic criteria further. METHODS The clinical standards workshop, sponsored by the WED Foundation and IRLSSG in 2008, started a four-year process for updating the diagnostic criteria. That process included a rigorous review of research advances and input from clinical experts across multiple disciplines. After broad consensus was attained, the criteria were formally approved by the IRLSSG executive committee and membership. RESULTS Major changes are: (i) addition of a fifth essential criterion, differential diagnosis, to improve specificity by requiring that RLS/WED symptoms not be confused with similar symptoms from other conditions; (ii) addition of a specifier to delineate clinically significant RLS/WED; (iii) addition of course specifiers to classify RLS/WED as chronic-persistent or intermittent; and (iv) merging of the pediatric with the adult diagnostic criteria. Also discussed are supportive features and clinical aspects that are important in the diagnostic evaluation. CONCLUSIONS The IRLSSG consensus criteria for RLS/WED represent an international, interdisciplinary, and collaborative effort intended to improve clinical practice and promote further research.

Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study

Objective: We evaluated the cross-sectional association between restless legs syndrome (RLS) and prevalent cardiovascular disease (CVD) in a large community-based sample of middle-aged and elderly subjects. Methods: This is a cross-sectional observational study of 1,559 men and 1,874 women (mean age of 67.9 years) who were enrolled in the Sleep Heart Health Study, a community-based study of the cardiovascular consequences of sleep-disordered breathing. RLS was defined by positive responses on a self-administered questionnaire to the four diagnostic criteria, with symptoms occurring at least five times per month and associated with at least moderate distress. Coronary artery disease (CAD) was determined by self-report of doctor-diagnosed angina, myocardial infarction, or coronary revascularization procedure. Total CVD included CAD or history of physician-diagnosed stroke or heart failure. The relation of RLS to prevalent CAD and CVD was examined by multivariable logistic regression models Results: RLS was present in 6.8% of women (n = 128) and 3.3% of men (n = 51). After adjustment for age, sex, race, body mass index, diabetes mellitus, systolic blood pressure, antihypertensive medication use, total:high-density lipoprotein cholesterol ratio, and smoking history, the ORs for CAD were 2.05 (95% CI 1.38 to 3.04) and for CVD were 2.07 (1.43 to 3.00) for subjects with RLS compared to those without RLS. The associations of RLS with CAD and CVD were stronger in those with RLS symptoms at least 16 times per month and were stronger in those with severe than in those with moderately bothersome symptoms. Conclusions: Restless legs syndrome (RLS) is associated with prevalent coronary artery disease and cardiovascular disease. This association appears stronger in those with greater frequency or severity of RLS symptoms. GLOSSARY: AHI = apnea-hypopnea index; CAD = coronary artery disease; CVD = cardiovascular disease; DBP = diastolic blood pressure; ESRD = end-stage renal disease; HDL = high-density lipoprotein; IQR = interquartile range; LDL = low-density lipoprotein; OSA = obstructive sleep apnea; OSAH = obstructive sleep apnea/hypopnea; PLMS = periodic leg movements of sleep; RLS = restless legs syndrome; SBP = systolic blood pressure; SHHS = Sleep Heart Health Study.

Sleep Disturbance in Bipolar Disorder: Therapeutic Implications

In this review, the authors detail our current understanding of the crucial role that sleep and its disturbances play in bipolar disorder. Multiple lines of evidence suggest that impaired sleep can induce and predict manic episodes. Similarly, treatment of sleep disturbance may serve as both a target of treatment and a measure of response in mania. The depressive phase of bipolar illness is marked by sleep disturbance that may be amenable to somatic therapies that target sleep and circadian rhythms. Residual insomnia in the euthymic period may represent a vulnerability to affective relapse in susceptible patients. Given the importance of sleep in all phases of bipolar disorder, appropriate evaluation and management of sleep disturbance in patients with bipolar illness is further detailed.

Efficacy and safety of pramipexole in restless legs syndrome

Objective: To evaluate the efficacy and safety of pramipexole in patients with moderate to severe restless legs syndrome (RLS) Methods: The authors conducted a 12-week, double-blind, randomized, placebo-controlled trial of fixed doses of pramipexole (0.25, 0.50, and 0.75 mg/day). Patients (N = 344) were up-titrated to their randomized dose over 3 weeks. The primary efficacy endpoints were patient ratings of symptom severity on the International RLS Study Group Rating Scale (IRLS) and clinician ratings of improvement on the Clinical Global Impressions-Improvement (CGI-I) scale. Secondary efficacy endpoints included visual analogue ratings of sleep and quality of life (QOL) Results: By both primary measures, pramipexole was superior to placebo. For IRLS, the adjusted mean (SE) change from baseline to week 12 was −9.3 (1.0) for placebo, −12.8 (1.0) for 0.25 mg/day, −13.8 (1.0) for 0.50 mg/day, and −14.0 (1.0) for 0.75 mg/day (all p < 0.01). Similarly, pramipexole increased the percentage of patients with a CGI-I rating of “very much improved” or “much improved” at the end of the trial (51.2% for placebo and 74.7%, 67.9%, and 72.9% for pramipexole; all p < 0.05). Pramipexole significantly improved ratings of symptom severity, day and night, and also ratings of sleep satisfaction and QOL. Pramipexole was well tolerated: The most frequent adverse events with higher occurrence in the pramipexole group were nausea (19.0% vs 4.7%) and somnolence (10.1% vs 4.7%) Conclusion: As rated by patients and by clinicians, pramipexole was efficacious and safe in reducing the symptoms of restless legs syndrome.

Measuring sleep: Accuracy, sensitivity, and specificity of wrist actigraphy compared to polysomnography

OBJECTIVES We validated actigraphy for detecting sleep and wakefulness versus polysomnography (PSG). DESIGN Actigraphy and polysomnography were simultaneously collected during sleep laboratory admissions. All studies involved 8.5 h time in bed, except for sleep restriction studies. Epochs (30-sec; n = 232,849) were characterized for sensitivity (actigraphy = sleep when PSG = sleep), specificity (actigraphy = wake when PSG = wake), and accuracy (total proportion correct); the amount of wakefulness after sleep onset (WASO) was also assessed. A generalized estimating equation (GEE) model included age, gender, insomnia diagnosis, and daytime/nighttime sleep timing factors. SETTING Controlled sleep laboratory conditions. PARTICIPANTS Young and older adults, healthy or chronic primary insomniac (PI) patients, and daytime sleep of 23 night-workers (n = 77, age 35.0 ± 12.5, 30F, mean nights = 3.2). INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Overall, sensitivity (0.965) and accuracy (0.863) were high, whereas specificity (0.329) was low; each was only slightly modified by gender, insomnia, day/night sleep timing (magnitude of change < 0.04). Increasing age slightly reduced specificity. Mean WASO/night was 49.1 min by PSG compared to 36.8 min/night by actigraphy (β = 0.81; CI = 0.42, 1.21), unbiased when WASO < 30 min/night, and overestimated when WASO > 30 min/night. CONCLUSIONS This validation quantifies strengths and weaknesses of actigraphy as a tool measuring sleep in clinical and population studies. Overall, the participant-specific accuracy is relatively high, and for most participants, above 80%. We validate this finding across multiple nights and a variety of adults across much of the young to midlife years, in both men and women, in those with and without insomnia, and in 77 participants. We conclude that actigraphy is overall a useful and valid means for estimating total sleep time and wakefulness after sleep onset in field and workplace studies, with some limitations in specificity.

Antidepressants and Periodic Leg Movements of Sleep

BACKGROUND Frequent electroencephalographic arousals or awakenings associated with periodic leg movements (PLM) might be responsible in part for the complaints of sleep disturbances made by patients treated with antidepressants. Past studies, however, have determined the effects of only certain limited antidepressants, generally in small numbers of subjects, and never in a head-to-head study. METHODS A total of 274 consecutive patients taking antidepressants and 69 control subjects not taking antidepressants met criteria among patients referred for overnight diagnostic polysomnography. Periodic leg movements were visually counted and the PLM index (PLMI) was calculated. RESULTS The venlafaxine and selective serotonin reuptake inhibitor (SSRI) groups had significantly higher mean PLMIs than control and bupropion groups. Periodic leg movement indexes at thresholds considered to be of potential clinical significance were more statistically prevalent in the SSRI and venlafaxine groups compared with the control and bupropion groups. The odds ratio of having a PLMI greater than 20 was 5.15 for the SSRI group and 5.24 for the venlafaxine group compared with the control group. CONCLUSIONS Venlafaxine and SSRI-induced PLM are likely to be the result of enhanced serotonergic availability and secondarily decreased dopaminergic effects. The results of this study might assist in the selection of antidepressants, especially in patients with pronounced sleep complaints.

Human cerebral potentials associated with REM sleep rapid eye movements: links to PGO waves and waking potentials

Eye movement triggered averaging and topographic display techniques indicate the presence of parieto-occipital potentials that precede the rapid eye movements of human REM sleep. Since these potentials have strong similarities with PGO waves in animals, including lateralization according to eye movement (EM) direction, and with waking EM-antecedent potentials in man, this suggests that PGO-like activity both exists in man, and may be functionally related to EM-antecedent potentials in waking. The ability to detect such central potentials opens the possibility of studying REM sleep central physiological structure in a variety of normal and pathological conditions in humans.

National use of prescription medications for insomnia: NHANES 1999-2010.

STUDY OBJECTIVES To determine current patterns and predictors of use of prescription medications commonly used for insomnia (MCUFI) in the U.S. DESIGN Cross-sectional study. SETTING National Health and Nutrition Examination Survey, 1999-2010. PARTICIPANTS 32,328 noninstitutionalized community-dwelling U.S. adults. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS WE DEFINED MCUFI USE AS USE OF ANY OF THE FOLLOWING MEDICATIONS IN THE PRECEDING MONTH: benzodiazepine receptor agonists (eszopiclone, zaleplon, zolpidem, estazolam, flurazepam, quazepam, temazepam, triazolam), barbiturates (amobarbital, amobarbitalsecobarbital, chloral hydrate), doxepin, quetiapine, ramelteon, and trazodone. We estimated prevalence of MCUFI use and concurrent use of another sedating medication. We determined predictors of MCUFI use using multivariate logistic regression. Overall, 3% percent of adults used a MCUFI within the preceding month. Zolpidem and trazodone were used most commonly. Overall MCUFI use increased between 1999-2000 and 2009-2010 (P value for trend < 0.001). Concurrent use of other sedating medications was high, with 55% of MCUFI users taking at least one other sedating medication and 10% taking ≥ 3 other sedating medications. Concurrent use of MCUFIs with opioids (24.6%) and non-MCUFI benzodiazepines (19.5%) were most common. After adjustment, adults seeing a mental health provider (aOR 4.68, 95% C.I. 3.79, 5.77), using other sedating medications (aOR 4.18, 95% C.I. 3.36, 5.19), and age ≥ 80 years (aOR 2.55, 95% C.I. 1.63, 4.01) had highest likelihood of MCUFI use. CONCLUSION In this nationally representative sample, reported use of prescription medications commonly used for insomnia (MCUFIs) within the preceding month was common, particularly among older adults and those seeing a mental health provider, with high use of sedative polypharmacy among MCUFI users.

Treatment of nocturnal eating syndrome and sleep-related eating disorder with topiramate

BACKGROUND Sleep-related eating disorder (SRED) and nocturnal eating syndrome (NES) combine features of sleep disorders and eating disorders. Treatment of these nocturnal eating behaviors has been directed towards underlying identifiable sleep or eating disorders using dopaminergic or opioid agonists, as well as anorectic agents, at times with the addition of sedatives. METHODS Two patients with SRED and two with NES, who had failed multiple previous trials of pharmacotherapy and psychotherapy, were treated in a naturalistic, open-label fashion with topiramate at night. Reduction in nocturnal eating was graded based on self-report. Weight was computed at the outset of, and during, topiramate treatment. RESULTS One patient with NES had a complete elimination of nocturnal eating with topiramate, two patients (one with NES, one with SRED) had a marked response, and one patient (with SRED) had a moderate response. Mean dose was 218 mg, though three patients noted an improvement at 100 mg. Notable weight loss was observed in all patients (mean of 11.1 kg). Benefits of topiramate treatment have been maintained for a mean period of 8.5 months. CONCLUSIONS Topiramate may be of benefit for patients with NES or SRED in reducing nocturnal eating, improving nocturnal sleep, and producing weight loss.

Rotigotine Improves Restless Legs Syndrome: A 6-Month Randomized, Double-Blind, Placebo-Controlled Trial in the United States

This randomized, double‐blinded, placebo‐controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6‐month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score ≥ 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once‐daily transdermal patch (fixed‐dose regimen). The two co‐primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI‐1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were −4.5 (95% CI: −6.9, −2.2) for 2 mg/24 hr rotigotine, −5.2 (95% CI: −7.5, −2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 −0.65 (95% CI: −1.0, −0.3) and −0.9 (95% CI: −1.3, −0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6‐month double‐blind period.