Sex-based disparities in dopamine agonist response in patients with restless legs syndrome.

This study aimed to investigate sex-related differences in the response to ropinirole and pramipexole in patients with restless legs syndrome (RLS). By analysing clinical parameters and polysomnographic (PSG) findings, we sought to elucidate the potential factors related to sex disparities modulating treatment responses and sleep quality in RLS. A total of 41 drug-free patients with RLS, aged ≥18 years, underwent two consecutive nocturnal PSG recordings, without medication at baseline; before the second night, 26 patients received an oral dose of 0.25 mg pramipexole whereas 15 received 0.5 mg ropinirole. After each PSG recording, patients self-evaluated the severity of their previous night symptoms by means of an ad hoc visual analogue scale (VAS). At baseline, sleep efficiency and percentage of Stage N2 tended to be higher in females while wakefulness after sleep onset was significantly higher in males. After treatment, total leg movements during sleep (LMS), periodic LMS (PLMS), and periodicity indexes were significantly lower in females than in males. The VAS score was lower after treatment in all patients, without differences between the two sexes. This study demonstrates a higher acute responsiveness of PLMS to dopamine agonists (pramipexole and ropinirole) in females than in males with RLS. These findings might be explained by differential sex-related expression of dopamine receptors, especially D3, within the central nervous system. In addition, our findings provide translational hints toward a better tailored and sex-specific approach to the treatment of RLS associated with PLMS, with dopamine agonist possibly associated with a better outcome in females than in males.

Iron Deficiency and Sleep/Wake Behaviors: A Scoping Review of Clinical Practice Guidelines-How to Overcome the Current Conundrum?

Current evidence suggests that iron deficiency (ID) plays a key role in the pathogenesis of conditions presenting with restlessness such as attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS). In clinical practice, ID and iron supplementation are not routinely considered in the diagnostic work-up and/or as a treatment option in such conditions. Therefore, we conducted a scoping literature review of ID guidelines. Of the 58 guidelines included, only 9 included RLS, and 3 included ADHD. Ferritin was the most frequently cited biomarker, though cutoff values varied between guidelines and depending on additional factors such as age, sex, and comorbidities. Recommendations surrounding measurable iron biomarkers and cutoff values varied between guidelines; moreover, despite capturing the role of inflammation as a concept, most guidelines often did not include recommendations for how to assess this. This lack of harmonization on the interpretation of iron and inflammation biomarkers raises questions about the applicability of current guidelines in clinical practice. Further, the majority of ID guidelines in this review did not include the ID-associated disorders, ADHD and RLS. As ID can be associated with altered movement patterns, a novel consensus is needed for investigating and interpreting iron status in the context of different clinical phenotypes.

Gender medicine and sleep disorders: from basic science to clinical research.

Several pivotal differences in sleep and sleep disorders are recognized between women and men. This is not only due to changes in hormonal balance during women's reproductive life, such as in pregnancy and menopause. Women are more likely to report insomnia and non-specific symptoms of apneas, such as fatigue or mood disturbance, compared to men. Thus, it is important for clinicians and researchers to take sex and gender differences into account when addressing sleep disorders in order to acknowledge the biology unique to women. We present a narrative review that delves into the primary sleep disorders, starting from basic science, to explore the impact of gender differences on sleep and the current status of research on women's sleep health.

Sleep-Related Urologic Dysfunction.

This article reports on the epidemiology, prevalence, and physiopathology of sleep-related urinary dysfunction, a new syndromic category proposed by the recently revised ICSD-3-TR classification. Sleep enuresis, whether primary or secondary, monosymptomatic or plurisymptomatic, will be reviewed in terms of risk factors, comorbidity, and diagnostic and therapeutic indications. A definition of nocturia and its impact on patients' health, quality of life, and mortality will follow. Finally, the impact of urge incontinence on various medical and neurologic disorders will be discussed. Special emphasis will be placed on the possible association of this parasomnia with several sleep disorders and poor, fragmented sleep.

Hyperactivity in patients with narcolepsy and idiopathic hypersomnia: an exploratory study.

Introduction: Patients with either Idiopathic Hypersomnia or Narcolepsy demonstrate excessive daytime somnolence (EDS) with resultant inattention mimicking Attention Deficit Hyperactivity Disorder (ADHD). Patients with ADHD also often express sleep problems including EDS. Thus, patients with ADHD and patients with idiopathic hypersomnia or narcolepsy may share inattention and daytime drowsiness as common features. However, it is not known whether EDS patients with idiopathic hypersomnia or narcolepsy also have increased movement (hyperactivity) like ADHD patients, the determination of which is the purpose of this study. Methods: We studied 12 patients (7 Narcolepsy type 2 and 5 Idiopathic Hypersomnia) with EDS as shown by Multiple Sleep Latency Test which served as the gold standard for entry into the study. Twelve subjects without symptoms of EDS served as the control group. None of the participants had a previous history of ADHD. Each participant underwent a one-hour session laying at 45 degrees with surveys about the need to move and actigraphy as an objective measure of movement. Results: Sleep-disordered patients with EDS reported more symptoms of inattention and hyperactivity on the ADHD Self-Report Scale. At each of the time points patients with EDS had a clear trend to express the need to move more than controls on the Suggested Immobilization Test (SIT). For the total 60 minutes, a large effect size for the need to move during the SIT test was found between patients and controls (Cohen's d = 0.61, p=0.01). Patients with EDS did not express a need to move more to combat drowsiness than controls, nor did actigraphy show any difference in objective movement between patients and controls during the SIT. Conclusion: Patients with EDS express inattention and a need to move more than controls. However, hyperactivity was not verified by objective measurement, nor did the EDS patients express a need to move to combat drowsiness more than controls. Thus, a hypothesis to be further tested, is whether narcolepsy and idiopathic hypersomnia may be more a model of the inattentive form of ADHD rather than the combined or inattentive/hyperactive form of ADHD. Further studies are needed to explore the relationship between EDS and hyperactivity.

Vitamin D and Restless Legs Syndrome: A Review of Current Literature.

This review presents a detailed summary of the current literature regarding RLS and vitamin D deficiency. To our knowledge it is the first review of its kind. We review the prevalence of vitamin D deficiency in RLS as well as the evidence for the use of vitamin D supplementation in RLS management. We further examine the literature for proteomic and genetic evidence of a role for vitamin D in the pathogenesis of RLS. An alteration in vitamin D binding protein in RLS is one of the most consistent findings in the proteomic studies. Furthermore, we examine the interaction of vitamin D with calcium, phosphorus, and parathyroid hormone and the possible role of these connections in RLS. We also explore the possible nexus between RLS and vitamin D in renal disease, cardiovascular and cerebrovascular disease as well as inflammation. In addition, we review the potential interaction between vitamin D and RLS with iron, dopamine and other neurotransmitter systems including the endogenous opiate, serotoninergic, glutamatergic and adenosinergic systems. We also explore the role of vitamin D in RLS Augmentation (i.e., the paradoxical worsening of RLS symptoms when dopaminergic agents are used as a therapy for RLS). Although the literature is not entirely consistent in affirming vitamin D deficiency in RLS or the amelioration of RLS symptoms with vitamin D therapy, the collective studies overall indicate that vitamin D deficiency is common enough in RLS patients to suggest that RLS patients should have their vitamin D levels checked and any deficiency corrected as a standard of care. Highlights  Patients with Restless Legs Syndrome (RLS) may be deficient in vitamin D and therapy with vitamin D may ameliorate RLS. We present the first review dedicated solely to evaluating the relationship between RLS and vitamin D and present a case for the role of vitamin D in RLS pathogenesis.

Understanding patient characteristics and medication prescriptions in children with mental health and neurodevelopmental disorders referred to a sleep clinic-A quality improvement/quality assurance analysis.

Introduction: Motivated by challenges faced in outpatient sleep services for mental health and neurodevelopmental disorders (MHNDD) during the COVID-19 clinical shutdown, a pan-Canadian/international working group of clinicians and social scientists developed a concept for capturing challenging sleep and wake behaviours already at the referral stage in the community setting. Methods: In a quality improvement/quality assurance (QIQA) project, a visual logic model was the framework for identifying the multiple causes and possible interventions for sleep disturbances. Intake forms informed clinicians about situational experiences, goals/concerns, in addition to the questions from the Sleep Disturbances Scale for Children (SDSC), the ADHD Rating Scale-IV and medication history. Descriptive statistics were used to describe the sample. Results: 66% of the pilot study patients (n = 41) scored in the SDSC red domains (highest scoring) with highest sub-scores for insomnia (falling asleep 73%; staying asleep: 51%) and daytime somnolence (27%). A total of 90% of patients were taking at least one medication; 59% sleep initiation/sleep medications, 41% in combination with further non-stimulant medications, 9% with stimulants, 27% with antidepressants and 18% with antipsychotics. Polypharmacy was observed in 62% of all patients and in 73% of the ones medicated for sleep disturbances. Qualitative information supported individualisation of assessments. Conclusion: Our intake process enabled a comprehensive understanding of patients' sleep and wake profiles prior to assessment, at the referral stage. The high prevalence of insomnia in patients, combined with polypharmacy, requires special attention in the triaging process at the community level.

Behavioral sleep medicine-The need for harmonization of clinical best practice outcome measures in children and adolescents with intellectual or developmental disabilities and restless sleep.

In behavioral medicine, sleep disorders, insomnia in particular, may be considered comorbidities and precipitating factors to intellectual or developmental disabilities (IDD). Nevertheless, sleep alterations have often been neglected in favor of daytime features and symptoms, albeit simple behavioral nighttime observations may disclose hypermotor features that characterize restless sleep. The root of most hypermotor restlessness is linked to central iron deficiency. The latter is often exacerbated by vitamin D deficiency (VDD), which interferes with both dopaminergic and serotonergic mechanisms. In this way, an imbalance affecting daytime behavior and mood is created. Several sleep-related motor disorders such as bruxism, periodic and aperiodic leg movements, Restless Legs Syndrome (RLS), and Restless Sleep Disorder (RSD) are commonly seen in Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD). However, they are rarely diagnosed and often overlooked in affected children and adolescents. As a result, not only are these disorders not adequately addressed therapeutically, but their symptoms may be worsened by the side-effects of drugs used to contain disruptive daytime behavior, such as antipsychotics and antidepressants. In children with IDDs, obesity, inactivity and metabolic effects of antipsychotics often lead to Sleep Disordered Breathing (SDB), which is currently understood as an inflammatory state leading to "hyperactive" lethargy and further alterations of the hypoxic chain and vitamin D levels. Endorsing simple routine blood tests, including inflammatory markers such as C-reactive protein, ferritin, transferrin, and vitamin D levels, may favorably complement caregiver observations and ambulatory sleep recordings, leading to a sleep disorder diagnosis and consequent therapy. In fact, the treatment of SDB, RLS, and RSD has been copiously demonstrated to favorably impact vigilance, behavior, social competence, and academic skills in healthy and, to a greater extent, in IDD children. Thus, consulting and deliberating the root causes of functional and categorical diagnoses within a clinical framework may engender a more precise diagnosis and further benefit pediatric daytime and nighttime management of hyperactive behaviors.

Sleep and sleep-modifying factors in chronic migraine patients during the COVID-19 lockdown.

AIMS: The objective of the present study was to evaluate sleep features and sleep-modifying factors in patients with chronic migraine (CM) during the first Italian COVID-19 lockdown. MATERIAL AND METHODS: The study was based on an e-mail survey addressed to CM patients of our headache center. The survey investigated demographic, life-style, sleep, psychological, and migraine features during the first COVID-19 lockdown period and the month before. The outcomes were sleep quality (measured using PSQI) and variation in sleep quality, duration, and latency. RESULTS: Ninety-two patients were included. The mean PSQI was 11.96. Sleep quality was improved in 14.1%, stable in 47.8%, and worsened in 38.0%. Sleep latency was reduced in 5.4%, stable in 46.7%, and increased in 47.8%. Sleep duration was reduced in 29.3%, stable in 34.8%, and increased in 35.9%. Significant associations were found with age, work/study, remote working, job loss, meal quality change, smoking variation, COVID-19 province prevalence, home-inhabitant relationship, ratio of house size/number of people, stress, state anxiety, anxiety/depression variation, future concern variation, computer hours, internet hours, and television hours. CONCLUSION: The study described sleep features of chronic migraineurs during COVID-19 lockdown, pinpointing the main factors involved in sleep quality and sleep changes. Our findings revealed that migraineurs' sleep was closely linked with life-style and psychological features. Several modifiable factors came to light and they should be considered in order to develop an optimal management of CM. An appropriate and more aware treatment of sleep problems could be a way to improve migraineurs' life.

Chronic migraine in the first COVID-19 lockdown: the impact of sleep, remote working, and other life/psychological changes.

AIMS: The objective of this study was to evaluate the impact of the first Italian COVID-19 lockdown on patients with chronic migraine (CM). MATERIAL AND METHODS: The study was based on an e-mail survey addressed to CM patients of our headache center. The survey evaluated demographic, life style, sleep, psychological, and migraine features during the COVID-19 lockdown period and the month before. The outcomes were migraine impact on daily life and variation in attack frequency, attack duration, migraine pain intensity, migraine symptomatic drugs use per week, and efficacy. RESULTS: Ninety-two patients completed the survey. During the lockdown period, attack frequency was stable in 40,2%, increased in 33,7%, and reduced in 26,1% of patients; attack duration was stable in 55,4%, increased in 23,9%, and reduced in 20,7%. Migraine pain was stable or reduced in 65,2% and increased in 34,8%; number of symptomatic drugs per week was stable in 50%, reduced in 29,3%, and increased in 20,7%; migraine drug efficacy was stable in 73,9%, reduced in 17,4%, and increased in 8,7%. Patients had a HIT-6 score of 64,63 ± 8,81. Significant associations were found with remote working, smoke, education, discontinuation of the therapy performed within headache center, migraine familiarity, sleep, anxiety, perceived stress, concern about future, and COVID-19. CONCLUSION: During the lockdown, approximately half of the patients had a clinical stability, a quarter an improvement, and another quarter a worsening. We identified different migraine-influencing elements; in particular, the remote working could represent an easy way to ameliorate migraineurs' life.

Pediatric Restless Legs Syndrome.

Early-onset restless legs syndrome has a relatively high prevalence in pediatrics, is highly familial, and is often preceded by a diagnosis of periodic limb movement disorder or childhood insomnia. Diagnostic criteria are derived but not equal to those of the adult syndrome and are adapted according to children's age and linguistic competence. Diagnosis requires parents or caregivers to participate; video-polysomnographic nocturnal recording, although not mandatory, may help confirm dubious cases. The syndrome severely impacts children's sleep and cognitive-behavioral abilities. Iron supplementation is currently the most used and viable therapeutic option.

Restless Sleep Disorder.

Restless sleep disorder is (RSD) a condition characterized by frequent large movements during sleep associated with daytime impairment. RSD has been studied in children aged 6 to 18 years. Polysomnography is necessary for the diagnosis of RSD. The current diagnostic criteria include more than 5 large movements per hour of sleep documented by PSG. The pathophysiology is not known yet, but iron deficiency and sleep instability and increased sympathetic activation are suspected to play a role. Iron supplementation is the only treatment option studied so far.

Multicenter Study on Sleep and Circadian Alterations as Objective Markers of Mild Cognitive Impairment and Alzheimer's Disease Reveals Sex Differences.

BACKGROUND: Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention. OBJECTIVE: To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities. METHODS: Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status. RESULTS: Wake after sleep onset (WASO) was higher (p < 0.001) and sleep efficiency (SE) lower (p = 0.003) in MCI, and Sleep Regularity Index (SRI) was lower in AD patients compared to controls (p = 0.004). SE was lower in male AD compared to female AD (p = 0.038) and SRI lower in male AD compared to male controls (p = 0.008), male MCI (p = 0.047), but also female AD subjects (p = 0.046). Mesor was significantly lower in males in the overall population. Age reduced the dissimilarities for WASO and SE but demonstrated sex differences for amplitude (p = 0.009) in the overall population, controls (p = 0.005), and AD subjects (p = 0.034). The confusion-matrices showed good predictive power of actigraphic data. CONCLUSION: Actigraphic data could help identify disease or health status. Sex (possibly gender) differences could impact on neurodegeneration and disease trajectory with potential clinical applications.

Sleep disorders in pregnancy.

Anatomical, physiological, psychological and hormonal alterations affect sleep during pregnancy. Sleep appears tobe commonly impaired only after the first trimester. Albeit objective data regarding the reduction of sleep durationand efficiency are not univocal, poor sleep is reported by over half of pregnant women. The reasons underlyingthese complaints are multiple, including lower back pain, gastroesophageal reflux disorder (GERD), increasedmicturition and repositioning difficulties at night. Specific primary sleep disorders whose prevalence drasticallyincreases during pregnancy include obstructive sleep apnea (OSA) and restless legs syndrome (RLS), both relatedto gestational hypertension and gestational diabetes mellitus (GDM). Pre-eclampsia and labor complicationsleading to an increased number of cesarean sections and preterm births correlate with insomnia and OSA inparticular. Post-partum depression (PPD) and impairment of the mother-infant relationship may also be consideredas secondary effects deriving from poor sleep during pregnancy. Recognition and treatment of sleep disordersshould be encouraged in order to protect maternal and fetal health and prevent dire consequences at birth.