Promoting sleep health during pregnancy for enhancing women's health: a longitudinal randomized controlled trial combining biological, physiological and psychological measures, Maternal Outcome after THERapy for Sleep (MOTHERS).

BACKGROUND: Sleep is vital for maintaining individuals' physical and mental health and is particularly challenged during pregnancy. More than 70% of women during the gestational period report insomnia symptoms. Sleep dysfunction in the peripartum increases the risk for a cascade of negative health outcomes during late pregnancy, birth, and postpartum. While psychological interventions are considered the first line treatment for sleep difficulties, they are still scarcely offered during pregnancy and there is a lack of longitudinal research combining psychological and physiological indices. METHODS: The present protocol outlines a randomized controlled trial aimed at testing the long-term effectiveness of an automatized digitalized psychoeducational intervention for insomnia for expectant mothers complaining insomnia symptoms without comorbidity. Outcomes include physiological, hormonal, and subjective indices of maternal psychopathology, stress, and emotional processes, and sleep and wellbeing of the family system. The trial is part of a longitudinal study evaluating expectant mothers from early pregnancy (within the 15th gestational week) to 6-months postpartum through 6 observational phases: baseline (BSL), 6- and 12-weeks from BSL (FU1-FU2), 2-to-4 weeks after delivery (FU3), and 3- and 6-months after delivery (FU4-5). We plan to recruit 38 women without sleep difficulties (Group A) and 76 women with sleep difficulties (Group B). Group B will be randomly assigned to digital psychological control intervention (B1) or experimental psychoeducational intervention targeting insomnia (B2). At 3 time points, an ecological-momentary-assessment (EMA) design will be used to collect data on sleep and emotions (diaries), sleep-wake parameters (actigraphy) and stress reactivity (salivary cortisol). We will also test the DNA methylation of genes involved in the stress response as biomarkers of prenatal poor sleep. Information on partner's insomnia symptoms and new-borns' sleep will be collected at each stage. DISCUSSION: The proposed protocol aims at testing an easily accessible evidence-based psychoeducational intervention for expectant mothers to help them improving sleep, health, and wellbeing in the peripartum. The results could improve the understanding and management of sleep difficulties and peripartum depression. TRIAL REGISTRATION: The study protocol has been registered on 22 April 2024 with ClinicalTrials.gov Protocol Registration and Results System (PRS), ID: NCT06379074. PROTOCOL VERSION: April 23, 2024.

A machine learning model to predict the risk of perinatal depression: Psychosocial and sleep-related factors in the Life-ON study cohort.

Perinatal depression (PND) is a common complication of pregnancy associated with serious health consequences for both mothers and their babies. Identifying risk factors for PND is key to early detect women at increased risk of developing this condition. We applied a machine learning (ML) approach to data from a multicenter cohort study on sleep and mood changes during the perinatal period ("Life-ON") to derive models for PND risk prediction in a cross-validation setting. A wide range of sociodemographic variables, blood-based biomarkers, sleep, medical, and psychological data collected from 439 pregnant women, as well as polysomnographic parameters recorded from 353 women, were considered for model building. These covariates were correlated with the risk of future depression, as assessed by regularly administering the Edinburgh Postnatal Depression Scale across the perinatal period. The ML model indicated the mood status of pregnant women in the first trimester, previous depressive episodes and marital status, as the most important predictors of PND. Sleep quality, insomnia symptoms, age, previous miscarriages, and stressful life events also added to the model performance. Besides other predictors, sleep changes during early pregnancy should therefore assessed to identify women at higher risk of PND and support them with appropriate therapeutic strategies.

The parasomnia defense in sleep-related homicide: A systematic review and a critical analysis of the medical literature.

This review critically analyzes the forensic application of the Parasomnia Defense in homicidal incidents, drawing from medical literature on disorders of arousal (DOA) and rapid-eye-movement sleep behavior disorder (RBD). A systematic search of PubMed, Scopus, Embase, and Cochrane databases was conducted until October 16, 2022. We screened English-language articles in peer-reviewed journals discussing murders committed during sleep with a Parasomnia Defense. We followed PRISMA guidelines, extracting event details, diagnosis methods, factors influencing the acts, perpetrator behavior, timing, motives, concealment, mental experiences, victim demographics, and court verdicts. Three sleep experts evaluated each case. We selected ten homicides, four attempted homicides, and one homicide/attempted homicide that met inclusion/exclusion criteria. Most cases were suspected DOA as unanimously confirmed by experts. RBD cases were absent. Among aggressors, a minority reported dream-like experiences. Victims were primarily female family members killed in or near the bed by hands and/or with sharp objects. Objective sleep data and important crime scene details were often missing. Verdicts were ununiform. Homicides during DOA episodes, though rare, are documented, validating the Parasomnia Defense's use in forensics. RBD-related fatal aggression seems very uncommon. However, cases often lack diagnostic clarity. We propose updated guidelines to enhance future reporting and understanding of such incidents.

Role of sleep in neurodegeneration: the consensus report of the 5th Think Tank World Sleep Forum.

Sleep abnormalities may represent an independent risk factor for neurodegeneration. An international expert group convened in 2021 to discuss the state-of-the-science in this domain. The present article summarizes the presentations and discussions concerning the importance of a strategy for studying sleep- and circadian-related interventions for early detection and prevention of neurodegenerative diseases. An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years; discussed the current challenges in the field of relationships among sleep, sleep disorders, and neurodegeneration; and identified future priorities. Sleep efficiency and slow wave activity during non-rapid eye movement (NREM) sleep are decreased in cognitively normal middle-aged and older adults with Alzheimer's disease (AD) pathology. Sleep deprivation increases amyloid-ß (Aß) concentrations in the interstitial fluid of experimental animal models and in cerebrospinal fluid in humans, while increased sleep decreases Aß. Obstructive sleep apnea (OSA) is a risk factor for dementia. Studies indicate that positive airway pressure (PAP) treatment should be started in patients with mild cognitive impairment or AD and comorbid OSA. Identification of other measures of nocturnal hypoxia and sleep fragmentation could better clarify the role of OSA as a risk factor for neurodegeneration. Concerning REM sleep behavior disorder (RBD), it will be crucial to identify the subset of RBD patients who will convert to a specific neurodegenerative disorder. Circadian sleep-wake rhythm disorders (CSWRD) are strong predictors of caregiver stress and institutionalization, but the absence of recommendations or consensus statements must be considered. Future priorities include to develop and validate existing and novel comprehensive assessments of CSWRD in patients with/at risk for dementia. Strategies for studying sleep-circadian-related interventions for early detection/prevention of neurodegenerative diseases are required. CSWRD evaluation may help to identify additional biomarkers for phenotyping and personalizing treatment of neurodegeneration.

Sleep and sleep disorders during pregnancy and postpartum: The Life-ON study.

OBJECTIVE: to prospectively assess sleep and sleep disorders during pregnancy and postpartum in a large cohort of women. METHODS: multicenter prospective Life-ON study, recruiting consecutive pregnant women at a gestational age between 10 and 15 weeks, from the local gynecological departments. The study included home polysomnography performed between the 23rd and 25th week of pregnancy and sleep-related questionnaires at 9 points in time during pregnancy and 6 months postpartum. RESULTS: 439 pregnant women (mean age 33.7 ± 4.2 yrs) were enrolled. Poor quality of sleep was reported by 34% of women in the first trimester of pregnancy, by 46% of women in the third trimester, and by as many as 71% of women in the first month after delivery. A similar trend was seen for insomnia. Excessive daytime sleepiness peaked in the first trimester (30% of women), and decreased in the third trimester, to 22% of women. Prevalence of restless legs syndrome was 25%, with a peak in the third trimester of pregnancy. Polysomnographic data, available for 353 women, revealed that 24% of women slept less than 6 h, and 30.6% of women had a sleep efficiency below 80%. Sleep-disordered breathing (RDI≥5) had a prevalence of 4.2% and correlated positively with BMI. CONCLUSIONS: The Life-ON study provides the largest polysomnographic dataset coupled with longitudinal subjective assessments of sleep quality in pregnant women to date. Sleep disorders are highly frequent and distributed differently during pregnancy and postpartum. Routine assessment of sleep disturbances in the perinatal period is necessary to improve early detection and clinical management.

Optimal risk and diagnosis assessment strategies in perinatal depression: A machine learning approach from the life-ON study cohort.

This study aimed to assess the concordance of various psychometric scales in detecting Perinatal Depression (PND) risk and diagnosis. A cohort of 432 women was assessed at 10-15th and 23-25th gestational weeks, 33-40 days and 180-195 days after delivery using the Edinburgh Postnatal Depression Scale (EPDS), Visual Analogue Scale (VAS), Hamilton Depression Rating Scale (HDRS), Montgomery-Åsberg Depression Rating Scale (MADRS), and Mini International Neuropsychiatric Interview (MINI). Spearman's rank correlation coefficient was used to assess agreement across instruments, and multivariable classification models were developed to predict the values of a binary scale using the other scales. Moderate agreement was shown between the EPDS and VAS and between the HDRS and MADRS throughout the perinatal period. However, agreement between the EPDS and HDRS decreased postpartum. A well-performing model for the estimation of current depression risk (EPDS > 9) was obtained with the VAS and MADRS, and a less robust one for the estimation of current major depressive episode (MDE) diagnosis (MINI) with the VAS and HDRS. When the EPDS is not feasible, the VAS may be used for rapid and comprehensive postpartum screening with reliability. However, a thorough structured interview or clinical examination remains necessary to diagnose a MDE.

Spinal cord stimulation in severe pharmacoresistant restless legs syndrome-two case reports.

Restless legs syndrome is a prevalent, sleep-related sensorimotor disorder with relevant impact on the patients' quality of life. For patients suffering from severe, pharmacoresistant restless legs syndrome, few therapeutic options remain to alleviate symptoms. In this case series, two patients with severe, pharmacoresistant restless legs syndrome were treated with epidural spinal cord stimulation and repeatedly assessed with polysomnography, including sleep structure and periodic limb movements as objective biomarkers not subject to placebo effects, during a 6-month follow-up period. One of the patients experienced excellent short- and long-term efficacy on subjective symptom severity (International RLS Study group rating scale 1 vs. 34 points at 3 months) and objective sleep parameters such as sleep architecture and periodic limb movements during sleep, while the second patient only reported short-term benefits from spinal cord stimulation. Ultimately, both patients opted for removal of the device for inefficacy. Based on the complex pathophysiology of restless legs syndrome and presumed mechanism of action of spinal cord stimulation in chronic pain disorders, we provide a detailed hypothesis on the possible modulating effect of spinal cord stimulation on the key symptoms of restless legs syndrome. Apart from describing a new therapeutic option for pharmacoresistant restless legs syndrome, our findings might also provide further insights into the pathophysiology of the syndrome.

Clinical and instrumental features in 82 patients with insufficient sleep syndrome.

Insufficient sleep syndrome possibly represents the worldwide leading cause of daytime sleepiness, but remains poorly recognised and studied. The aim of this case series is to comprehensively describe a cohort of patients with insufficient sleep syndrome. Eighty-two patients were studied concerning demographic and socio-economic features, medical, psychiatric and sleep comorbidities, substance use, sleep symptoms, actigraphy, video-polysomnography, multiple sleep latency tests and treatment. The typical patient with insufficient sleep syndrome is a middle-aged adult (with no difference of gender), employed, who has a family, often carrying psychiatric and neurological comorbidities, in particular headache, anxiety and depression. Other sleep disorders, especially mild sleep apnea and bruxism, were common as well. Actigraphy was a valuable tool in the characterisation of insufficient sleep syndrome, showing a sleep restriction during weekdays, associated with a recovery rebound of night sleep during weekends and a high amount of daytime sleep. An over- or underestimation of sleeping was common, concerning both the duration of night sleep and daytime napping. The average daily sleep considering both daytime and night-time, weekdays and weekends corresponds to the recommended minimal normal duration, meaning that the burden of insufficient sleep syndrome could mainly depend on sleep fragmentation and low quality. Sleep efficiency was elevated both in actigraphy and video-polysomnography. Multiple sleep latency tests evidenced a tendency toward sleep-onset rapid eye movement periods. Our study offers a comprehensive characterisation of patients with insufficient sleep syndrome, and clarifies their sleeping pattern, opening avenues for management and treatment of the disorder. Current options seem not adapted, and in our opinion a cognitive-behavioural psychotherapy protocol should be developed.

Slow wave activity across sleep-night could predict levodopa-induced dyskinesia.

A disruption in the slow wave activity (SWA) mediated synaptic downscaling process features Parkinson's disease (PD) patients presenting levodopa-induced dyskinesia (LID). To corroborate the role of SWA in LID development, 15 PD patients with LID, who underwent a polysomnography before LID's appearance, were included. Slow wave sleep epochs were extracted, combined and segmented into early and late sleep. SWA power was calculated. A linear regression model established that the SWA overnight decrease could predict the time to the emergence of LID. Our finding supports the link between SWA-mediated synaptic downscaling and the development of LID. If confirmed, it could pave the way to the study of possible sleep targeted therapies able to protect PD patients from LID development.

Effectiveness of exercise and pramipexole in the treatment of restless leg syndrome: Implications on the dopaminergic system and PTPRD.

OBJECTIVE: Dopaminergic dysfunction, iron reduction and variations in the PTPRD gene (protein tyrosine phosphatase receptor type delta) may be associated with restless leg syndrome (RLS). Here, we evaluate the effect of pramipexole (PPX) and exercise on genes and proteins associated with RLS and on sleep patterns in spontaneously hypertensive rats (SHR). METHODS: Animals were distributed into 4 groups: 1) Control (CTRL); 2) Exercise (EX); 3) Exercise and pramipexole (EX + PPX); and 4) Pramipexole (PPX). PPX treatment was performed daily (0.125 mg/kg), while exercise was conducted over 5 sessions per week, both for 4 weeks. RESULTS: EX + PPX increased the protein levels of PTPRD, reduced the protein levels of the enzyme tyrosine hydroxylase (TH) and improved sleep parameters in both cycles; on the other hand, the use of PPX reduced mRNA and protein levels of PTPRD and TH but improved the sleep pattern in the light cycle. However, in the dark cycle, pramipexole caused the worsening of symptoms. CONCLUSIONS: We suggest that the improvement in sleep pattern by EX + PPX may be associated with the increased protein levels of PTPRD and that EX + PPX can reverse the negative effects of PPX.

A series of 7 cases of patients with narcolepsy with hypocretin deficiency without the HLA DQB1*06:02 allele.

STUDY OBJECTIVES: We report data collected from 2 reference European sleep centers on a series of patients with narcolepsy with hypocretin-1 deficiency and absence of the human leukocyte antigens (HLA) DQB1*06:02 allele. METHODS: Clinical data, HLA DQ markers, and cerebrospinal fluid assessments were collected retrospectively from Caucasian patients with a diagnosis of narcolepsy type 1 with cerebrospinal fluid hypocretin-1 deficiency (< 110 pg/ml) and absence of the HLA DQB1*06:02 allele, with follow-up with at least 1 visit within the last 4 years, consecutively admitted to 2 European sleep centers (Lugano, Switzerland and Montpellier, France). RESULTS: Seven patients (3 of 29 patients in Lugano and 4 of 328 in Montpellier) were diagnosed with narcolepsy with hypocretin-1 deficiency and absence of HLA DQB1*06:02 (ie, 2% of patients with narcolepsy type 1). Regarding the HLA-DQB1 genotyping, 4 cases were positive for HLA DQB1*03:01, 1 for DQB1*03:02, and 3 for DQB1*02:01. Three patients had atypical cataplexy and 1 had no cataplexy. Only 2 patients had both a mean sleep latency of less than 8 minutes and more than 2 sleep onset rapid eye movement periods on the Multiple Sleep Latency Test, indicative of a less severe condition. CONCLUSIONS: Although rare, this series of 7 cases confirms that hypocretin-deficient narcolepsy should not be excluded in the absence of HLA DQB1*06:02, especially if patients are carriers of other high-risk HLA-DQB1 alleles (DQB1*03:01, *03:02, *02:01). These data support the hypothesis that narcolepsy type 1 is a wider disease spectrum linked to the loss of hypocretin peptide. CITATION: Miano S, Barateau L, De Pieri M, et al. A series of 7 cases of patients with narcolepsy with hypocretin deficiency without the HLA DQB1*06:02 allele. J Clin Sleep Med. 2023;19(12):2053-2057.

Diagnosis and Management of NREM Sleep Parasomnias in Children and Adults.

Non-rapid eye movement (NREM) sleep parasomnias are recurrent abnormal behaviors emerging as incomplete arousals out of NREM sleep. Mounting evidence on NREM sleep parasomnias calls for an update of clinical and therapeutical strategies. In the current review, we summarize the state of the art and provide the necessary background to stimulate a critical revision of diagnostic criteria of disorders of arousal (DoA), the most common NREM sleep parasomnia. In particular, we highlight the poor sensitivity of the diagnostic items related to amnesia and absence of conscious experiences during DoA episodes, encourage the role of video-polysomnography and home-video recordings in the diagnostic and treatment work-up, and suggest three levels of diagnostic certainty based on clinical and objective findings. Furthermore, we highlight current gaps of knowledge that prevent the definition of standard guidelines and future research avenues.

Origin, synchronization, and propagation of sleep slow waves in children.

STUDY OBJECTIVES: Sleep slow wave activity, as measured using EEG delta power (<4 Hz), undergoes significant changes throughout development, mirroring changes in brain function and anatomy. Yet, age-dependent variations in the characteristics of individual slow waves have not been thoroughly investigated. Here we aimed at characterizing individual slow wave properties such as origin, synchronization, and cortical propagation at the transition between childhood and adulthood. METHODS: We analyzed overnight high-density (256 electrodes) EEG recordings of healthy typically developing children (N = 21, 10.3 ± 1.5 years old) and young healthy adults (N = 18, 31.1 ± 4.4 years old). All recordings were preprocessed to reduce artifacts, and NREM slow waves were detected and characterized using validated algorithms. The threshold for statistical significance was set at p = 0.05. RESULTS: The slow waves of children were larger and steeper, but less widespread than those of adults. Moreover, they tended to mainly originate from and spread over more posterior brain areas. Relative to those of adults, the slow waves of children also displayed a tendency to more strongly involve and originate from the right than the left hemisphere. The separate analysis of slow waves characterized by high and low synchronization efficiency showed that these waves undergo partially distinct maturation patterns, consistent with their possible dependence on different generation and synchronization mechanisms. CONCLUSIONS: Changes in slow wave origin, synchronization, and propagation at the transition between childhood and adulthood are consistent with known modifications in cortico-cortical and subcortico-cortical brain connectivity. In this light, changes in slow-wave properties may provide a valuable yardstick to assess, track, and interpret physiological and pathological development.

Automatic video analysis and classification of sleep-related hypermotor seizures and disorders of arousal.

OBJECTIVE: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy with seizures occurring mostly during sleep. SHE seizures present different motor characteristics ranging from dystonic posturing to hyperkinetic motor patterns, sometimes associated with affective symptoms and complex behaviors. Disorders of arousal (DOA) are sleep disorders with paroxysmal episodes that may present analogies with SHE seizures. Accurate interpretation of the different SHE patterns and their differentiation from DOA manifestations can be difficult and expensive, and can require highly skilled personnel not always available. Furthermore, it is operator dependent. METHODS: Common techniques for human motion analysis, such as wearable sensors (e.g., accelerometers) and motion capture systems, have been considered to overcome these problems. Unfortunately, these systems are cumbersome and they require trained personnel for marker and sensor positioning, limiting their use in the epilepsy domain. To overcome these problems, recently significant effort has been spent in studying automatic methods based on video analysis for the characterization of human motion. Systems based on computer vision and deep learning have been exploited in many fields, but epilepsy has received limited attention. RESULTS: In this paper, we present a pipeline composed of a set of three-dimensional convolutional neural networks that, starting from video recordings, reached an overall accuracy of 80% in the classification of different SHE semiology patterns and DOA. SIGNIFICANCE: The preliminary results obtained in this study highlight that our deep learning pipeline could be used by physicians as a tool to support them in the differential diagnosis of the different patterns of SHE and DOA, and encourage further investigation.

Multiple sleep-wake disturbances after stroke predict an increased risk of cardio-cerebrovascular events or death: A prospective cohort study.

BACKGROUND AND PURPOSE: Contradictory evidence on the impact of single sleep-wake-disturbances (SWD), such as sleep-disorderd breating (SDB) or insomnia, in patients with stroke, on the risk of subsequent cardio- and cerebrovascular events (CCE) and death, exists. Very recent studies in the general population suggest that the presence of multiple SWD increases cardio-cerebrovascular risk. Hence, the aim of this study was to asssess whether a novel score capturing the burden of multiple SWD, a so called "sleep burden index", is predictive for subsequent CCE including death in a prospectively followed cohort of stroke patients. METHODS: Patients with acute ischemic stroke or transient ischemic attack (TIA) were prospectively recruited. Four SWD were analyzed: (i) SDB with respirography; (ii) insomnia (defined using the insomnia severity index [ISI]); (iii) restless legs syndrome (RLS; defined using the International RLS Study Group rating scale); and (iv) self-estimated sleep duration at 1 and 3 months. A "sleep burden index", calculated using the mean of z-transformed values from assessments of these four SWD, was created. The occurrence of CCE was recorded over a mean ± standard deviation (SD) follow-up of 3.2 ± 0.3 years. RESULTS: We assessed 437 patients (87% ischemic stroke, 13% TIA, 64% males) with a mean ± SD age of 65.1 ± 13.0 years. SDB (respiratory event index ≥ 5/h) was present in 66.2% of these patients. Insomnia (ISI ≥ 10), RLS and extreme sleep duration affected 26.2%, 6.4% and 13.7% of the patients 3 months post-stroke. Seventy out of the 437 patients (16%) had at least one CCE during the follow-up. The sleep burden index was associated with a higher risk for subsequent CCE, including death (odds ratio 1.80 per index unit, 95% confidence interval 1.19-2.72; p = 0.0056). CONCLUSION: The presence of multiple SWDs constitutes a risk for subsequent CCE (including death) within the first 3 years following stroke. Larger systematic studies should assess the utility of the sleep burden index for patients' risk stratification in clinical practice.

Electrophysiological and Neuropsychological Indices of Cognitive Dysfunction in Patients with Chronic Insomnia and Severe Benzodiazepine Use Disorder.

Benzodiazepine (BDZ) misuse is a growing health problem, with 1-2% of patients under BDZ treatment meeting the criteria for use disorder or dependence. Although BDZ addiction potential has been known for decades, much remains unknown its effects on brain functions. The aim of this study was to assess the neuropsychological and neurophysiological profile of a group of chronic insomniacs taking long-term high doses of benzodiazepine. We recruited 17 consecutive patients admitted to our third-level Sleep Medicine Unit for drug discontinuation (7 males, mean age 49.2 ± 11.2 years, mean education 13.7 ± 3.9 years, mean daily diazepam-equivalent BDZ: 238.1 ± 84.5 mg) and 17 gender/age-matched healthy controls (7 males, mean age 46.8 ± 14.1 years, mean education 13.5 ± 4.5 years). We performed a full neuropsychological evaluation of all subjects and recorded their scalp event-related potentials (Mismatch-Passive Oddball-Paradigm and Active Oddball P300 Paradigm). Patients with chronic insomnia and BDZ use disorder showed a profound frontal lobe executive dysfunction with significant impairment in the cognitive flexibility domain, in face of a preserved working, short and long-term memory. In patients, P300 amplitude tended to be smaller, mainly over the frontal regions, compared to controls. BDZ use disorder has a severe cognitive impact on chronic insomnia patients. Long-term high-dose BDZ intake should be carefully evaluated and managed by clinicians in this specific patient population, especially in relation to risky activities.

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.

Putative Animal Models of Restless Legs Syndrome: A Systematic Review and Evaluation of Their Face and Construct Validity.

Restless legs syndrome (RLS) is a sensorimotor disorder that severely affects sleep. It is characterized by an urge to move the legs, which is often accompanied by periodic limb movements during sleep. RLS has a high prevalence in the population and is usually a life-long condition. While its origins remain unclear, RLS is initially highly responsive to treatment with dopaminergic agonists that target D2-like receptors, in particular D2 and D3, but the long-term response is often unsatisfactory. Over the years, several putative animal models for RLS have been developed, mainly based on the epidemiological and neurochemical link with iron deficiency, treatment efficacy of D2-like dopaminergic agonists, or genome-wide association studies that identified risk factors in the patient population. Here, we present the first systematic review of putative animal models of RLS, provide information about their face and construct validity, and report their role in deciphering the underlying pathophysiological mechanisms that may cause or contribute to RLS. We propose that identifying the causal links between genetic risk factors, altered organ functions, and changes to molecular pathways in neural circuitry will eventually lead to more effective new treatment options that bypass the side effects of the currently used therapeutics in RLS, especially for long-term therapy.

Frequency and evolution of sleep-wake disturbances after ischemic stroke: A 2-year prospective study of 437 patients.

OBJECTIVE: In the absence of systematic and longitudinal data, this study prospectively assessed both frequency and evolution of sleep-wake disturbances (SWD) after stroke. METHODS: In 437 consecutively recruited patients with ischemic stroke or transient ischemic attack (TIA), stroke characteristics and outcome were assessed within the 1st week and 3.2 ± 0.3 years (M±SD) after the acute event. SWD were assessed by interview and questionnaires at 1 and 3 months as well as 1 and 2 years after the acute event. Sleep disordered breathing (SDB) was assessed by respirography in the acute phase and repeated in one fifth of the participants 3 months and 1 year later. RESULTS: Patients (63.8% male, 87% ischemic stroke and mean age 65.1 ± 13.0 years) presented with mean NIHSS-score of 3.5 ± 4.5 at admission. In the acute phase, respiratory event index was >15/h in 34% and >30/h in 15% of patients. Over the entire observation period, the frequencies of excessive daytime sleepiness (EDS), fatigue and insomnia varied between 10-14%, 22-28% and 20-28%, respectively. Mean insomnia and EDS scores decreased from acute to chronic stroke, whereas restless legs syndrome (RLS) percentages (6-9%) and mean fatigue scores remained similar. Mean self-reported sleep duration was enhanced at acute stroke (month 1: 07:54 ± 01:27h) and decreased at chronic stage (year 2: 07:43 ± 01:20h). CONCLUSIONS: This study documents a high frequency of SDB, insomnia, fatigue and a prolonged sleep duration after stroke/TIA, which can persist for years. Considering the negative effects of SWD on physical, brain and mental health these data suggest the need for a systematic assessment and management of post-stroke SWD.