Jan Ulfberg

A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome†

Iron deficiency may exacerbate symptoms in the Restless Legs Syndrome (RLS). We investigated the effect of intravenous iron sucrose or placebo on symptoms in patients with RLS and mild to moderate iron deficit. Sixty patients with primary RLS (seven males, age 46 (9) years, S‐ferritin ≤45 μg/L) recruited from a cohort of 231 patients were randomly assigned in a 12‐months double‐blind, multi‐centre study of iron sucrose 1000 mg (n = 29) or saline (n = 31). The primary efficacy variable was the RLS severity scale (IRLS) score at week 11. Median IRLS score decreased from 24 to 7 (week 11) after iron sucrose and from 26 to 17 after placebo (P = 0.123, N.S. for between treatment comparison). The corresponding scores at week 7 were 12 and 20 in the two groups (P = 0.017). Drop out rate because of lack of efficacy at 12 months was 19/31 after placebo and 5/29 patients after iron sucrose (Kaplan–Meier estimate, log rank test P = 0.0006) suggesting an iron induced superior long term RLS symptom control. Iron sucrose was well tolerated. This study showed a lack of superiority of iron sucrose at 11 weeks but found evidence that iron sucrose reduced RLS symptoms both in the acute phase (7 weeks) and during long‐term follow up in patients with variable degree of iron deficiency. Further studies on target patient groups, dosing and dosing intervals are warranted before iron sucrose could be considered for treatment of iron deficient patients with RLS.

Restless legs syndrome among women: prevalence, co-morbidity and possible relationship to menopause

Objectives Restless legs syndrome (RLS) is a common neurological movement disorder with a female preponderance and an increasing prevalence with age. During the menopausal transition, sleep is affected. Prior studies suggest that female hormones are associated with the clinical manifestation of RLS. Methods A random sample of 5000 women aged 18–64 years was selected from the general Swedish population. They were sent questions on RLS, general health, sleep problems, reproductive health and menopausal state. Results The response rate was 70.3%; 15.7% of the women were diagnosed with RLS. Prevalence increased with age. RLS subjects more often had symptoms of affected sleep and depressed mood. Co-morbidity with heart disease was more common among RLS subjects, whereas hypertension and diabetes mellitus were not. There was a strong association between vasomotor symptoms and RLS but no statistical relationship between use of hormone replacement therapy, postmenopausal state and RLS. Conclusion The prevalence of RLS among Swedish women is high. RLS sufferers more often suffered from depression and heart disease, whereas no such associations were noted for diabetes or hypertension. We found an increased prevalence of RLS among women with vasomotor symptoms (night sweats) during the menopausal transition but not among women using hormone replacement therapy.

When gender matters: Restless legs syndrome. Report of the “RLS and woman” workshop endorsed by the European RLS Study Group

Sleep is an essential human behavior that shows prominent gender differences. Disturbed sleep, in particular, is much more prevalent in females than males. Restless legs syndrome (RLS) as one cause of disturbed sleep was observed to be somewhat more common among women than men in Ekboms 1945 seminal series of clinical cases with the disease. He, however, reported this gender difference mainly for those with more severe symptoms. Since then numerous studies have reported that women are affected by RLS about twice as often as males for mild as well as moderate to severe RLS. The present review focuses on RLS in females from the perspectives of both epidemiology and pathophysiology. RLS will generally become worse or might appear for the first time during pregnancy. Parity increases the risk of RLS later in life suggesting that pregnancy is a specific behavioral risk factor for developing RLS. Some evidence suggests that dysfunction in iron metabolism and high estrogen levels might contribute to RLS during pregnancy. But, menopause does not lower the incidence of RLS nor does hormone replacement therapy lead to an increase, suggesting a quite complex uncertain role of hormones in the pathophysiology of RLS. Therefore, further, preferably longitudinal studies are needed to unravel the factors causing RLS in women. These studies should include genetic, clinical and polysomnographic variables, as well as hormonal measures and variables assessing iron metabolism.

Sleep apnea and hormone replacement therapy: a pilot study and a literature review

Background.  Sleep apnea syndrome (SAS) is a common condition and a risk factor of cardiovascular and cerebrovascular diseases. The purpose of this pilot study was to investigate the effect of a gestagen (trimegeston) and estradiol hormone combination on perimenopausal and postmenopausal women with SAS.

Health-related quality of life and restless legs syndrome among women in Sweden

Aim:  Restless legs syndrome (RLS) is a common neurological movement disorder with a female preponderance, an increasing prevalence with age and comorbidity. Previous studies on the relationship between health‐related quality of life (HRQOL) and RLS are still sparse but knowledge is increasing. The aim of this study was to evaluate the unique impact of RLS on HRQOL in a population‐based sample.

Reduced daytime intramuscular blood flow in patients with restless legs syndrome/Willis–Ekbom disease

The aim of this study was to examine possible signs of impairment of the microcirculation in the lower extremities of female patients suffering from primary restless legs syndrome (RLS)/Willis–Ekbom disease.

Treatment of restless legs syndrome with a nitroglycerin patch

To the Editor: The data presented in the April issue, 2012, of Sleep Medicine by Baskol and collaborators is an important contribution to the literature on restless legs syndrome (RLS) as it illuminates a new way of thinking around the pathophysiology of RLS, a puzzling syndrome [1]. In this paper, it was reported that primary RLS patients had lower levels of nitric oxide (NO) than in healthy subjects indicating that RLS patients are under oxidative stress [1]. In our polyclinic a female patient, 67 years old, was prescribed nitroglycerin by a long acting transdermal patch (glyceryltrinitrat, 5 mg/24 h) because of her angina attacks. One month later, she stated that her symptoms from a known RLS were substantially reduced. She had discontinued treatment with dopaminergic agents. Two additional female patients, 48 and 60 years old, were prescribed nitroglycerin patch increasing the dose from 1.25 mg/ 24 h to 5 mg /24 h. They were suffering from very severe RLS, according to the International Restless Legs Syndrome Study Group (IRLSSG) severity scale since childhood [2]. The patients were instructed to use the patch between 6 PM and 6 AM in order to try to avoid tolerance to the drug. These two patients reported improvement in their RLS-symptoms one month later. Both of them had discontinued treatments with dopaminergic agents and codeine. Headache, a common side effect seen in patients treated with nitroglycerin, was experienced by all three patients, but the headache declined and disappeared in a few weeks. Ekbom who coined ‘‘restless legs’’ in his thesis in 1945, claimed that RLS was caused by a circulatory disturbance. He treated a few patients with short acting sublingual nitroglycerin tablets with a variable efficacy [3]. Nitroglycerin, used to treat angina attacks, is converted to nitric oxide (NO) in the body. Production of NO results in relaxation of vascular smooth muscle and NO also has a role as a messenger in the brain, such as a modifier of dopaminer-

Periodic Limb Movements are Associated with Vasomotor Symptoms

STUDY OBJECTIVES Periodic limb movements (PLMs) are characterized by involuntary movements of the lower extremity during sleep. The etiology of PLM has been suggested to involve the dopaminergic system which, in turn, can be modulated by estrogen. It is currently unknown whether PLMs are associated with the menopausal transition and/or concomitant vasomotor symptoms. The aim of the present study was to examine if objectively diagnosed PLMs (with and without arousals) are more common in postmenopausal women or in women with vasomotor symptoms. A secondary aim was to analyze the influence of PLMs on self-reported HRQoL. METHODS A community-based sample of 348 women underwent full-night polysomnography. PLMs (index > 15) and associated arousals (PLM arousal index > 5) were evaluated according to AASM scoring rules. Health-related quality of life was measured using the SF-36 questionnaire. The occurrence of peri- and postmenopausal symptoms were evaluated by a questionnaire and plasma levels of follicle stimulating hormone (FSH) were measured. RESULTS After adjusting for confounding factors, vasomotor symptoms remained a significant explanatory factor for the occurrence of PLMs (adj. OR 1.86, 95% CI 1.03-3.37). In women with PLM arousals, adjusted OR for vasomotor symptoms was 1.61, 95% CI 0.76-3.42. PLMs did not seem to affect HRQoL. CONCLUSION We found that clinically significant PLMs, but not PLM with arousals, were more common among women with vasomotor symptoms, even after controlling for confounding factors. Menopausal status per se, as evidenced by FSH in the postmenopausal range, was not associated with PLMs.

Time to improve awareness of restless legs syndrome.

Restless legs Syndrome (RLS) is a disorder that hardly receives the attention it should deserve. A study conducted in Europe and United States suggests that RLS is greatly under-diagnosed and under-treated.[1] The American patients’ organization, Restless Legs Syndrome Foundation has taken account of these observations and often reminds us that RLS is “the most common disorder you have never heard of” (www.rls.org).

Morning cortisol and fasting glucose are elevated in women with chronic widespread pain independent of comorbid restless legs syndrome

Abstract Background and aims: Chronic widespread pain (CWP) is associated with poor quality of sleep, but the detailed underlying mechanisms are still not fully understood. In this study we investigated the influence of CWP on morning cortisol and fasting glucose concentrations as well as sleep disordered breathing. Methods: In this case-control study, subjects with CWP (n=31) and a control group without CWP (n=23) were randomly selected from a population-based cohort of women. Current pain intensity, sleep quality, excessive daytime sleepiness [Epworth sleepiness scale (ESS)], psychiatric comorbidity and occurrence of restless legs syndrome (RLS) were assessed. Overnight polygraphy was applied to quantify sleep apnoea, airflow limitation and attenuations of finger pulse wave amplitude (>50%) as a surrogate marker for increased skin sympathetic activity. Morning cortisol and fasting glucose concentrations were determined. Generalised linear models were used for multivariate analyses. Results: CWP was associated with higher cortisol (464±141 vs. 366±111 nmol/L, p=0.011) and fasting glucose (6.0±0.8 vs. 5.4±0.7 mmol/L, p=0.007) compared with controls. The significance remained after adjustment for age, body mass index, RLS and anxiety status (β=122±47 nmol/L and 0.89±0.28 mmol/L, p=0.009 and 0.001, respectively). The duration of flow limitation in sleep was longer (35±22 vs. 21±34 min, p=0.022), and pulse wave attenuation was more frequent (11±8 vs. 6±2 events/h, p=0.048) in CWP subjects compared with controls. RLS was associated with higher ESS independent of CWP (β=3.1±1.3, p=0.018). Conclusions: Elevated morning cortisol, impaired fasting glucose concentration and increased skin sympathetic activity during sleep suggested an activated adrenal medullary system in subjects with CWP, which was not influenced by comorbid RLS. Implications: CWP is associated with activated stress markers that may deteriorate sleep.