A survey-based approach on restless legs syndrome: practices and perspectives among Italian neurologists.

INTRODUCTION: Restless Legs Syndrome (RLS) is a widely prevalent and complex neurological disorder. Despite notable advancements in managing RLS, the disorder continues to face challenges related to its recognition and management. OBJECTIVE: This study seeks to gain comprehensive insights into the knowledge and clinical practices among Italian neurologists regarding RLS diagnosis, management, and treatment, comparing approaches among general neurologists, movement disorder specialists, and sleep experts. METHODS: Members of the Italian Society of Neurology, the Italian Society of Parkinson and Movement Disorders, and the Italian Association of Sleep Medicine were invited to participate in a 19-question online survey. RESULTS: Among the 343 surveyed neurologists, 60% categorized RLS as a "sleep-related movement disorder." Forty% indicated managing 5-15 RLS patients annually, with sleep specialists handling the highest patient volume. Of note, only 34% adhered strictly to all five essential diagnostic criteria. The majority (69%) favored low-dosage dopamine agonists as their first-line treatment, with movement disorder specialists predominantly endorsing this approach, while sleep experts preferred iron supplementation. Regular screening for iron levels was widespread (91%), with supplementation typically guided by serum iron alterations. In cases of ineffective initial treatments, escalating dopamine agonist dosage was the preferred strategy (40%). CONCLUSIONS: These findings underscore a lack of a clear conceptualization of RLS, with a widespread misconception of the disorder as solely a movement disorder significantly influencing treatment approaches. Disparities in RLS understanding across neurology subspecialties underscore the necessity for improved diagnostic accuracy, targeted educational initiatives, and management guidelines to ensure consistent and effective RLS management.

Non-pharmacological and melatonin interventions for pediatric sleep initiation and maintenance problems: A systematic review and network meta-analysis.

Sleep initiation and maintenance problems are common in the pediatric population and while behavioral interventions are recommended, their efficacy remains to be evaluated in clinical trials. We conducted a systematic review and network meta-analysis to assess the efficacy of non-pharmacological treatments and melatonin for sleep initiation and maintenance problems in healthy pediatric populations. We included 30 studies in the systematic review and 15 in the meta-analysis. Three network meta-analyses were conducted for sleep onset latency (SOL), wake after sleep onset (WASO), and total sleep time (TST). For SOL variable, the results support greater effectiveness of light therapy and melatonin than evidence-based psychological interventions, whether implemented in combination with light therapy or not. Regarding WASO variable, evidence-based psychological interventions and a combination of those techniques plus light treatment were the most efficacious. Finally, for TST variable, a larger effect was shown for the combined treatment of evidence-based psychological intervention with light therapy in comparison to other interventions. In conclusion, we found a high variability between study protocols likely impacting the results of the meta-analysis. Future randomized control trials studies, stratified by pediatric age classes, are needed in order to provide clear suggestions in clinical settings.

Sleep counts! Role and impact of sleep in the multimodal management of multiple sclerosis.

BACKGROUND: In the last years, research on pharmacotherapy and non-pharmacological approaches to Multiple Sclerosis (MS) has significantly increased, along with a greater attention to sleep as a clinical outcome measure. This review aims to update the state of the art on the effects of MS treatments on sleep, but above all to evaluate the role of sleep and its management within the current and future therapeutic perspectives for MS patients. METHOD: A comprehensive MEDLINE (PubMed)-based bibliographic search was conducted. This review includes the 34 papers that met the selection criteria. RESULTS: First-line disease modifying therapies (especially the interferon-beta) seem to have a negative impact on sleep, assessed subjectively or objectively, while second-line treatments (in particular, natalizumab) do not seem to lead to the onset of daytime sleepiness (also evaluated objectively) and, in some cases, an improvement in sleep quality has been observed as well. Management of sleep is considered a major factor in modifying disease progression in pediatric MS; however, probably because only fingolimod has recently been approved in children, information is still scarce in this group of patients. CONCLUSIONS: Studies on the effect of drugs and non-pharmacological treatments for MS on sleep are still insufficient and there is a lack of investigations on the most recent therapies. However, there is preliminary evidence that melatonin, chronotherapy, cognitive-behavioral therapy, and non-invasive brain stimulation techniques might be further assessed as adjuvant therapies, thus representing a promising field of research.

Sleeping with time in mind? A literature review and a proposal for a screening questionnaire on self-awakening.

Some people report being able to spontaneously "time" the end of their sleep. This ability to self-awaken challenges the idea of sleep as a passive cognitive state. Yet, current evidence on this phenomenon is limited, partly because of the varied definitions of self-awakening and experimental approaches used to study it. Here, we provide a review of the literature on self-awakening. Our aim is to i) contextualise the phenomenon, ii) propose an operating definition, and iii) summarise the scientific approaches used so far. The literature review identified 17 studies on self-awakening. Most of them adopted an objective sleep evaluation (76%), targeted nocturnal sleep (76%), and used a single criterion to define the success of awakening (82%); for most studies, this corresponded to awakening occurring in a time window of 30 minutes around the expected awakening time. Out of 715 total participants, 125 (17%) reported to be self-awakeners, with an average age of 23.24 years and a slight predominance of males compared to females. These results reveal self-awakening as a relatively rare phenomenon. To facilitate the study of self-awakening, and based on the results of the literature review, we propose a quick paper-and-pencil screening questionnaire for self-awakeners and provide an initial validation for it. Taken together, the combined results of the literature review and the proposed questionnaire help in characterising a theoretical framework for self-awakenings, while providing a useful tool and empirical suggestions for future experimental studies, which should ideally employ objective measurements.

Predictive risk factors of phenoconversion in idiopathic REM sleep behavior disorder: the Italian study "FARPRESTO".

Most patients with idiopathic REM sleep behavior disorder (iRBD) will develop an overt α-synucleinopathy over time, with a rate of phenoconversion of 73.5% after 12 years from diagnosis. Several markers of phenoconversion were identified; however, most studies investigated biomarkers separately, with retrospective study designs, in small cohorts or without standardized data collection methods. The risk FActoRs PREdictive of phenoconversion in idiopathic REM sleep behavior disorder: the Italian STudy (FARPRESTO) is a multicentric longitudinal retrospective and prospective study with a cohort of incident (prospective recruitment) and prevalent (retrospective recruitment) iRBD patients, whose primary aim is to stratify the risk of phenoconversion, through the systematic collection by means of electronic case report forms of different biomarkers. Secondary aims are to (1) describe the sociodemographic and clinical characteristics of patients with iRBD; (2) collect longitudinal data about the development of α-synucleinopathies; (3) monitor the impact of iRBD on quality of life and sleep quality; (4) assess the correlation between phenoconversion, cognitive performance, and loss of normal muscle atony during REM sleep; (5) identify RBD phenotypes through evaluating clinical, biological, neurophysiological, neuropsychological, and imaging biomarkers; and (6) validate vPSG criteria for RBD diagnosis. The FARPRESTO study will collect a large and harmonized dataset, assessing the role of different biomarkers providing a unique opportunity for a holistic, multidimensional, and personalized approach to iRBD, with several possible application and impact at different levels, from basic to clinical research, and from prevention to management. The FARPRESTO has been registered at clinicaltrials.gov (NCT05262543).

Herbal Remedies and Their Possible Effect on the GABAergic System and Sleep.

Sleep is an essential component of physical and emotional well-being, and lack, or disruption, of sleep due to insomnia is a highly prevalent problem. The interest in complementary and alternative medicines for treating or preventing insomnia has increased recently. Centuries-old herbal treatments, popular for their safety and effectiveness, include valerian, passionflower, lemon balm, lavender, and Californian poppy. These herbal medicines have been shown to reduce sleep latency and increase subjective and objective measures of sleep quality. Research into their molecular components revealed that their sedative and sleep-promoting properties rely on interactions with various neurotransmitter systems in the brain. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that plays a major role in controlling different vigilance states. GABA receptors are the targets of many pharmacological treatments for insomnia, such as benzodiazepines. Here, we perform a systematic analysis of studies assessing the mechanisms of action of various herbal medicines on different subtypes of GABA receptors in the context of sleep control. Currently available evidence suggests that herbal extracts may exert some of their hypnotic and anxiolytic activity through interacting with GABA receptors and modulating GABAergic signaling in the brain, but their mechanism of action in the treatment of insomnia is not completely understood.

Therapy for Insomnia and Circadian Rhythm Disorder in Alzheimer Disease.

PURPOSE OF THE REVIEW: There is strong evidence for a bidirectional association between sleep disorders and Alzheimer's disease (AD). In particular, insomnia may be a potentially modifiable risk factor for AD. The present review summarizes recent advances in treatment of sleep disorders in AD. RECENT FINDINGS: Some studies investigated the efficacy and safety of hypnotic agents as ramelteon and mirtazapine to treat sleep disorders in AD but no significant therapeutic effects have been observed. Benzodiazepines are the most frequently used medication for treatment of insomnia but they may cause significant side effects in old subjects. Suvorexant, an orexin receptor antagonist, showed a positive effect on AD insomnia. Recent report suggests an association between trazodone use and delayed cognitive decline in AD. With respect to circadian rhythm disorders, non-pharmacological treatments, especially bright light therapy, could be useful and safe options for treatment in AD. Some pharmacological and non-pharmacological treatments might have benefits in AD patients with sleep disturbances, but further well-designed controlled trials are needed.

An update on the treatment of Restless Legs Syndrome/Willis-Ekbom Disease: prospects and challenges.

INTRODUCTION: Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sleep disorder characterized by an urge to move the legs, frequently associated or triggered by unpleasant sensations in the lower limbs that affects approximately 2.5% of adults. Therapy and management of RLS/WED require long-term interventions, since the typical manifestation of this disorder is chronic. Areas covered: In this review, we provide an update regarding the treatment of RLS/WED with particular attention to future challenges for its management. We reviewed a large variety of treatments studied in clinical trials and supported by the most updated guidelines. Alongside with first-line interventions other pharmacological options including opioids, benzodiazepines, iron therapy, and newly studied drugs are discussed. Furthermore, due to the occurrence of augmentation and worsening of symptoms we also reviewed the development of non-pharmacologic alternatives. Expert commentary: The management of RLS/WED is a challenge because of different long-term issues. Several complications, such as loss of the therapeutic effect of dopaminergic or non-dopaminergic agents and augmentation, are still unsolved concerns. However, the development of new drugs acting on adenosinergic and glutamatergic neurotransmission seems promising. Randomized controlled trials are needed in order to recognize effectiveness of new drugs or non-pharmacological treatment strategies.

A general population twin study of conduct problems and the auditory P300 waveform.

Reduced amplitude of the P300 event-related potential has been consistently associated with a variety of externalising problems, including conduct disorder. The few available genetically-informative studies of these relationships, however, were conducted among adolescents/adults (i.e., at an age when conduct disorder has typically already become manifest). Among 200 general population twins with a mean age of 9 years (range 6-14 years), we studied the relationship between the P300 waveform elicited by an auditory oddball task and the DSM-oriented conduct problems scale of the Child Behavior Checklist 6-18. Conduct problems scores were negatively and significantly correlated (r = -0.19, p = 0.01) with P300 amplitude; correlations between P300 amplitude and the other DSM-oriented Child Behavior Checklist scales were non-significant, except for oppositional defiant problems (p = 0.01). We found moderate heritability estimates for both P300 amplitude (0.58, CI:0.37;0.73) and conduct problems (0.52, CI:0.25;0.70). Bivariate twin analyses indicated that the covariation between these two phenotypes can be explained by additive genetic factors only, with a genetic correlation of -0.33. An association between reduced P300 amplitude and conduct problems can be substantiated already in childhood, at an age that precedes the most typical onset of conduct disorder. This relationship appears to be genetic in nature. Reduced P300 amplitude can represent a valuable marker for conduct problems, and can contribute to the early identification of children at high-risk for conduct disorder.

Functional characterization of a CRH missense mutation identified in an ADNFLE family.

Nocturnal frontal lobe epilepsy has been historically considered a channelopathy caused by mutations in subunits of the neuronal nicotinic acetylcholine receptor or in a recently reported potassium channel. However, these mutations account for only a minority of patients, and the existence of at least a new locus for the disease has been demonstrated. In 2005, we detected two nucleotide variations in the promoter of the CRH gene coding for the corticotropin releasing hormone in 7 patients. These variations cosegregated with the disease and were demonstrated to alter the cellular levels of this hormone. Here, we report the identification in an Italian affected family of a novel missense mutation (hpreproCRH p.Pro30Arg) located in the region of the CRH coding for the protein pro-sequence. The mutation was detected in heterozygosity in the two affected individuals. In vitro assays demonstrated that this mutation results in reduced levels of protein secretion in the short time thus suggesting that mutated people could present an altered capability to respond immediately to stress agents.

Left thalamomegaly in a patient with partial epilepsy.

Temporal lobe epilepsy (TLE) is associated with modification in thalamic structure and function. In particular, thalamic atrophy and hypometabolism can occur, affecting ipsilateral, contralateral thalami or both. We describe a 28-year-old epileptic woman, who presented peculiar neuroimaging findings, with enlargement of the thalamus contralateral to the epileptic focus. The patient was born from dystocic delivery, she presented partial motor seizures in the left side of the body, followed by generalisation, and the EEG showed a right temporal epileptic focus. Serial CT and MRI scan, performed along 11 years, showed a non-evolutive left thalamomegaly. 18-FDG PET showed reduced metabolic activity in the upper right temporal gyrus and in the ipsilateral thalamus. Thalamic asymmetry in our patient could be an occasional finding.