Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis.

STUDY OBJECTIVES: Periodic limb movements during sleep (PLMS) are a frequent finding in restless legs syndrome, but their impact on sleep is still debated, as well the indication for treatment. We systematically reviewed the available literature to describe which drug categories are effective in suppressing PLMS, assessing their efficacy through a meta-analysis, when this was possible. METHODS: The review protocol was preregistered on PROSPERO (CRD42021175848), and the systematic search was conducted on and EMBASE (last searched on March 2020). We included original human studies, which assessed PLMS modification on drug treatment with a full-night polysomnography, through surface electrodes on each tibialis anterior muscle. When at least 4 studies were available on the same drug or drug category, we performed a random-effect model meta-analysis. RESULTS: Dopamine agonists like pramipexole and ropinirole resulted the most effective, followed by l-dopa and other dopamine agonists. Alpha2delta ligands are moderately effective as well opioids, despite available data on these drugs are much more limited than those on dopaminergic agents. Valproate and carbamazepine did not show a significant effect on PLMS. Clonazepam showed contradictory results. Perampanel and dypiridamole showed promising but still insufficient data. The same applies to iron supplementation. CONCLUSIONS: Dopaminergic agents are the most powerful suppressors of PLMS. However, most therapeutic trials in restless legs syndrome do not report objective polysomnographic findings, there is a lack of uniformity in presenting results on PLMS. Longitudinal polysomnographic interventional studies, using well-defined and unanimous scoring criteria and endpoints on PLMS are needed. CITATION: Riccardi S, Ferri R, Garbazza C, Miano S, Manconi M. Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis. J Clin Sleep Med. 2023;19(4):811-822.

High-density EEG power topography and connectivity during confusional arousal.

Confusional arousal is the milder expression of a family of disorders known as Disorders of Arousal (DOA) from non-REM sleep. These disorders are characterized by recurrent abnormal behaviors that occur in a state of reduced awareness for the external environment. Despite frequent amnesia for the nocturnal events, when actively probed, patients are able to report vivid hallucinatory/dream-like mental imagery. Traditional (low-density) scalp and stereo-electroencephalographic (EEG) recordings previously showed a pathological admixture of slow oscillations typical of NREM sleep and wake-like fast-mixed frequencies during these phenomena. However, our knowledge about the specific neural EEG dynamics over the entire brain is limited. We collected 2 consecutive in-laboratory sleep recordings using high-density (hd)-EEG (256 vertex-referenced geodesic system) coupled with standard video-polysomnography (v-PSG) from a 12-year-old drug-naïve and otherwise healthy child with a long-lasting history of sleepwalking. Source power topography and functional connectivity were computed during 20 selected confusional arousal episodes (from -6 to +18 sec after motor onset), and during baseline slow wave sleep preceding each episode (from - 3 to -2 min before onset). We found a widespread increase in slow wave activity (SWA) theta, alpha, beta, gamma power, associated with a parallel decrease in the sigma range during behavioral episodes compared to baseline sleep. Bilateral Broadman area 7 and right Broadman areas 39 and 40 were relatively spared by the massive increase in SWA power. Functional SWA connectivity analysis revealed a drastic increase in the number and complexity of connections from baseline sleep to full-blown episodes, that mainly involved an increased out-flow from bilateral fronto-medial prefrontal cortex and left temporal lobe to other cortical regions. These effects could be appreciated in the 6 sec window preceding behavioral onset. Overall, our results support the idea that DOA are the expression of peculiar brain states, compatible with a partial re-emergence of consciousness.

Sustained remission from perinatal depression after bright light therapy: A pilot randomised, placebo-controlled trial.

OBJECTIVE: Perinatal depression (PND) is a severe complication of pregnancy, affecting both mothers and newborns. Bright light therapy (BLT) has only been tested in a few studies for treating either antenatal or postnatal depression. We conducted a pilot trial to investigate the efficacy and safety of BLT for PND occurring at any time across the perinatal period. METHODS: A single-blind RCT was carried out in women with an EPDS >12 from the 2nd gestational trimester until 9 months postpartum. Participants received either 30-minutes morning BLT (10'000 lux) or dim red light (DRL, 19 lux) for 6 weeks. RESULTS: Twenty-two women were randomised to BLT (n = 11) or DRL (n = 11). Among those receiving BLT, 73% achieved remission (improvement ≥50%, EPDS score ≤ 12), in contrast to 27% in the DRL group (p = 0.04). A significant influence of time on EPDS score and group-time interaction emerged, with a greater reduction in the BLT-group across the follow-up period. No women in either group reported major side effects. CONCLUSION: Morning BLT induced a significant remission from PND as compared to DRL and this effect was maintained across the perinatal period. BLT showed an excellent safety profile and was well-tolerated, thus representing a valid therapeutic strategy in this vulnerable perinatal population.

Iron deficiency in pregnancy: Influence on sleep, behavior, and molecular markers of adult male offspring.

Iron restriction during pregnancy can lead to iron deficiency and changes in the dopaminergic system in the adulthood of offspring, and restless legs syndrome (RLS) is closely related to these changes. Objectives: Analyze whether iron restriction during pregnancy would cause changes in the behavior, sleep, and dopaminergic system of the male offspring. In addition, we aimed to assess whether exercise would be able to modulate these variables. The pregnant rats (Wistar) were divided into four groups with different concentrations of iron in the diet: standard (St), supplementation (Su), restriction since weaning (R1), and restriction only during pregnancy (R2). After birth, the offspring were assigned to their respective groups according to the dams diet (St, Su, R1, and R2) and distributed into sedentary (SD) and exercised (EX) (for 8 weeks of training), reaching eight groups of offspring (O): OSt SD, OSt EX, OSu SD, OSu EX, OR1 SD, OR1 EX, OR2 SD, and OR2 EX. Sleep, behavior, and analysis of key genes of dopaminergic system (D2, DAT) were performed after 8 weeks. The results for trained offspring that the mother received supplementation diet were the most expressive, with increased freezing and the OR1 SD group showed an increase in DAT protein content. These changes may have been due to the association between the dams diet during pregnancy and the practice of exercise by the offspring. The different concentrations of iron during pregnancy caused changes in the offspring, however, they were not associated with fetal programming in the context of RLS.

The Management of Restless Legs Syndrome: An Updated Algorithm.

Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.

Mental Activity During Episodes of Sleepwalking, Night Terrors or Confusional Arousals: Differences Between Children and Adults.

OBJECTIVE/BACKGROUND: Night terrors, sleepwalking and confusional arousals are behavioral manifestations of incomplete awakenings from sleep. According to international diagnostic criteria, these behaviors occur in the absence of any mental experience, or in the presence of very limited cognition or dream imagery (eg, a single visual scene). The aim of this study was to systematically and retrospectively investigate the mental content associated with sleep terrors and/or sleepwalking in both children and adults. PATIENTS AND METHODS: Forty-five consecutive patients referred for a diagnosis of disorders of arousal (DOA) of all subtypes (sleepwalking/sleep terrors/confusional arousals) (25 adults: 30 ± 6 y, 15 females; 20 children: 10 ± 3 y, 6 females) underwent a detailed semi-structured interview about the mental content associated with their nocturnal episodes. The interview was comprehensive of specific questions about their subjective recall rate, several content details (characters, emotions, actions and setting/context), and hallucinatory or dissociative experiences during clinical episodes. Patients' reports were classified for complexity (Orlinsky scale) and content (Hall and Van de Castle categories). RESULTS: More than two-third of the children (n = 14) could not recall any mental activity associated with their episodes, whereas more than two-third (n = 16) of the adults recalled at least one mental experience. Half of the adult patients (n = 8) estimated that a specific mental content was subjectively present around 50% or more of the times. Seven adults and one child described clear and vivid hallucinatory experiences of "dreamed" objects or characters projected onto their real home environment, in the absence of any reality testing. Five adults and two children described one or more dissociative experiences. The content of the collected reports was dominated by dynamic actions acted out from a self-perspective, often with apprehension and in response to misfortune and danger, in a home-setting environment. CONCLUSION: These results suggest that current diagnostic criteria are tailored around the typical presentation of DOA in children, and do not always fit to adult patients with DOA. Furthermore, they support the concept that consciousness may reemerge in DOA patients during clinical episodes, in a peculiar dissociated, psychotic-like form.

Chronobiology, sleep-related risk factors and light therapy in perinatal depression: the "Life-ON" project.

BACKGROUND: Perinatal depression (PND) has an overall estimated prevalence of roughly 12 %. Untreated PND has significant negative consequences not only on the health of the mothers, but also on the physical, emotional and cognitive development of their children. No certain risk factors are known to predict PND and no completely safe drug treatments are available during pregnancy and breastfeeding. Sleep and depression are strongly related to each other because of a solid reciprocal causal relationship. Bright light therapy (BLT) is a well-tested and safe treatment, effective in both depression and circadian/sleep disorders. METHODS: In a 3-year longitudinal, observational, multicentre study, about 500 women will be recruited and followed-up from early pregnancy (10-15 gestational week) until 12 months after delivery. The primary aim of the present study is to systematically explore and characterize risk factors for PND by prospective sleep assessment (using wrist actigraphy, polysomnography and various sleep questionnaires) and bloodbased analysis of potential markers during the perinatal period (Life-ON study). Secondary aims are to explore the relationship between specific genetic polymorphisms and PND (substudy Life-ON1), to investigate the effectiveness of BLT in treating PND (substudy Life-ON2) and to test whether a short term trial of BLT during pregnancy can prevent PND (substudy Life-ON3). DISCUSSION: The characterization of specific predictive and risk factors for PND may substantially contribute to improve preventive medical and social strategies for the affected women. The study results are expected to promote a better understanding of the relationship between sleep disorders and the development of PND and to confirm, in a large sample of women, the safety and efficacy of BLT both in prevention and treatment of PND. TRIAL REGISTRATION: ClinicalTrials.gov NCT02664467 . Registered 13 January 2016.

Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation.

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) in conjunction with the European Restless Legs Syndrome Study Group (EURLSSG) and the RLS Foundation (RLS-F) to develop evidence-based and consensus-based recommendations for the prevention and treatment of long-term pharmacologic treatment of dopaminergic-induced augmentation in restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force made the following prevention and treatment recommendations: As a means to prevent augmentation, medications such as α2δ ligands may be considered for initial RLS/WED treatment; these drugs are effective and have little risk of augmentation. Alternatively, if dopaminergic drugs are elected as initial treatment, then the daily dose should be as low as possible and not exceed that recommended for RLS/WED treatment. However, the physician should be aware that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment by either medication should start only when symptoms have a significant impact on quality of life in terms of frequency and severity; intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can be continued by dividing or advancing the dose, or increasing the dose if there are breakthrough night-time symptoms. Alternatively, the patient can be switched to an α2δ ligand or rotigotine. For severe augmentation the patient can be switched either to an α2δ ligand or rotigotine, noting that rotigotine may also produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing α2δ ligands and rotigotine.

Sleep-Related Disorders in Children with Attention-Deficit Hyperactivity Disorder: Preliminary Results of a Full Sleep Assessment Study.

BACKGROUND AND METHODS: We present the preliminary results of a prospective case-control sleep study in children with a diagnosis of attention-deficit hyperactivity disorder (ADHD). A deep sleep assessment including sleep questionnaires, sleep habits, a video-polysomnographic recording with full high-density electroencephalography (EEG) and cardiorespiratory polygraphy, multiple sleep latency test, and 1-week actigraphic recording were performed to verify whether children with ADHD may be classified into one of the following five phenotypes: (1) hypoarousal state, resembling narcolepsy, which may be considered a "primary" form of ADHD; (2) delayed sleep onset insomnia; (3) sleep-disordered breathing; (4) restless legs syndrome and/or periodic limb movements; and (5) sleep epilepsy and/or EEG interictal epileptiform discharges. RESULTS: Fifteen consecutive outpatients with ADHD were recruited (two female, mean age 10.6 ± 2.2, age range 8-13.7 years) over 6 months. The narcolepsy-like sleep phenotype was observed in three children, the sleep onset insomnia phenotype was observed in one child, mild obstructive sleep apnea was observed in three children, sleep hyperkinesia and/or PLMs were observed in five children, while IEDs and or nocturnal epilepsy were observed in three children. Depending on the sleep phenotype, children received melatonin, iron supplementation, antiepileptic drugs, or stimulants. CONCLUSIONS: Our study further highlights the need to design an efficient sleep diagnostic algorithm for children with ADHD, thereby more accurately identifying cases in which a full sleep assessment is indicated.

Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation.

Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is common during pregnancy, affecting approximately one in five pregnant women in Western countries. Many report moderate or severe symptoms and negative impact on sleep. There is very little information in the medical literature for practitioners on the management of this condition during pregnancy. Accordingly, a task force was chosen by the International RLS Study Group (IRLSSG) to develop guidelines for the diagnosis and treatment of RLS/WED during pregnancy and lactation. A committee of nine experts in RLS/WED and/or obstetrics developed a set of 12 consensus questions, conducted a literature search, and extensively discussed potential guidelines. Recommendations were approved by the IRLSSG executive committee, reviewed by IRLSSG membership, and approved by the WED Foundation Medical Advisory Board. These guidelines address diagnosis, differential diagnosis, clinical course, and severity assessment of RLS/WED during pregnancy and lactation. Nonpharmacologic approaches, including reassurance, exercise and avoidance of exacerbating factors, are outlined. A rationale for iron supplementation is presented. Medications for RLS/WED are risk/benefit rated for use during pregnancy and lactation. A few are rated "may be considered" when RLS/WED is refractory to more conservative approaches. An algorithm summarizes the recommendations. These guidelines are intended to improve clinical practice and promote further research.

Pregnancy as a risk factor for restless legs syndrome.

Pregnant women have at least two or three times higher risk of experiencing restless legs syndrome (RLS) than the general population. These data come from few epidemiological studies finding an 11-27% prevalence of RLS during pregnancy. Women affected by pre-existing RLS often complain of worsening symptoms during pregnancy. This is usually a benign form of RLS, with the highest degree of severity in the third trimester and a tendency to disappear around delivery. The causes of the association between RLS and pregnancy are unknown. The most debated hypotheses are: metabolic alterations, with particular regard to iron and folate deficiency; hormonal influences related to the increase of prolactin, progesterone and estrogens during late pregnancy; and the changing motor habits and psychological state of pregnant women. The importance of folate and iron supplementation during pregnancy in preventing RLS is unclear. RLS in pregnant women is frequently unrecognized; they are often worried about the symptoms and do not receive an adequate explanation by doctors.