Large Muscle Group Movements during Sleep in Restless Leg Syndrome: Neurophysiological and Clinical Implications.

STUDY OBJECTIVES: Recently, criteria have been drawn up for Large Muscle group Movements during sleep (LMM), defined as movements lasting for 3-45 seconds in adults, which are often accompanied by changes in sleep stage, arousals, and increases in heart rate. The aim of this study was to characterize LMM in RLS, in order to better evaluate their impact on the neurophysiology of the disorder and, therefore, the possible clinical implications. METHODS: Consecutive, drug-free patients diagnosed with RLS and controls, aged 18 years or more, were retrospectively enrolled. Leg movement activity - short-interval (SILMS), periodic (PLMS) and isolated (ISOLMS) leg movements during sleep - and LMM were detected and scored. RESULTS: One-hundred patients and 67 controls were recruited. All movement measures were significantly higher in RLS. A significant positive correlation was found between LMM and ISOLMS index but not PLMS index in both groups. LMM index showed a significant negative correlation with total sleep time, sleep efficiency, and percentage of sleep stages N3 and R, as well as a significant positive correlation with number of awakenings, and percentage of sleep stages N1 and N2 only in patients with RLS. No significant correlation was found for either LMM or PLMS index and RLS severity. CONCLUSIONS: Different types of movements, including SILMS, ISOLMS, and LMM, play somewhat distinct roles in sleep neurophysiology in RLS. Notably, LMM, a newly recognized category of movements, demonstrate associations with sleep architecture instability and fragmentation, arousals, and awakenings, suggesting potential clinical implications.

Considering REM Sleep Behavior Disorder in the Management of Parkinson's Disease.

Rapid eye movement (REM) sleep behavior disorder (RBD) is the result of the loss of physiological inhibition of muscle tone during REM sleep, characterized by dream-enacting behavior and widely recognized as a prodromal manifestation of alpha-synucleinopathies. Indeed, patients with isolated RBD (iRBD) have an extremely high estimated risk to develop a neurodegenerative disease after a long follow up. Nevertheless, in comparison with PD patients without RBD (PDnoRBD), the occurrence of RBD in the context of PD (PDRBD) seems to identify a unique, more malignant phenotype, characterized by a more severe burden of disease in terms of both motor and non-motor symptoms and increased risk for cognitive decline. However, while some medications (eg, melatonin, clonazepam, etc.) and non-pharmacological options have been found to have some therapeutic benefits on RBD there is no available treatment able to modify the disease course or, at least, slow down the neurodegenerative process underlying phenoconversion. In this scenario, the long prodromal phase may allow an early therapeutic window and, therefore, the identification of multimodal biomarkers of disease onset and progression is becoming increasingly crucial. To date, several clinical (motor, cognitive, olfactory, visual, and autonomic features) neurophysiological, neuroimaging, biological (biofluids or tissue biopsy), and genetic biomarkers have been identified and proposed, also in combination, as possible diagnostic or prognostic markers, along with a potential role for some of them as outcome measures and index of treatment response. In this review, we provide an insight into the present knowledge on both existing and future biomarkers of iRBD and highlight the difference with PDRBD and PDnoRBD, including currently available treatment options.

Severity of REM sleep without atonia correlates with measures of cognitive impairment and depressive symptoms in REM sleep behaviour disorder.

This study aimed to correlate REM sleep without atonia (RSWA) and neuropsychological data in patients with idiopathic/isolated REM sleep behaviour disorder (iRBD) and those with RBD associated with Parkinson's disease (PDRBD), in order to assess whether higher degrees of RSWA are related to poorer cognitive performance. A total of 142 subjects were enrolled: 48 with iRBD, 55 with PDRBD, and 39 PD without RBD (PDnoRBD). All participants underwent video-polysomnographic recording, clinical and neuropsychological assessment. RSWA was quantified according to two manual scoring methods (Montréal, SINBAR) and one automated (REM atonia index, RAI). Mild cognitive impairment (MCI) was diagnosed according to diagnostic criteria for MCI in Parkinson's disease. The relationship between neuropsychological scores and RSWA metrics was explored by multiple linear regression analysis and logistic regression models. Patients with iRBD showed significantly lower visuospatial functions and working memory, compared with the others. More severe RSWA was associated with a higher risk of reduced visuospatial abilities (OR 0.15), working memory (OR 2.48), attention (OR 2.53), and semantic fluency (OR 0.15) in the iRBD. In the whole group, a greater RSWA was associated with an increased risk for depressive symptoms (OR 3.6). A total of 57(40%) MCI subjects were found (17 iRBD, 26 PDRBD, and 14 PDnoRBD). Preserved REM-atonia was associated with a reduced odds of multi-domain MCI in the whole study population (OR 0.54). In conclusion, a greater severity of RSWA was associated with an increased risk for poor cognitive performance and depressive mood in patients with RBD. Moreover, higher RAI was associated with a lower risk of multi-domain MCI.

Quantification of REM sleep without atonia: A review of study methods and meta-analysis of their performance for the diagnosis of RBD.

The present review focuses on REM sleep without atonia (RSWA) scoring methods. In consideration of the numerous papers published in the last decade, that used different methods for the quantification of RSWA, their systematic revision is an emerging need. We made a search using the PubMed, Embase, Scopus and Web of Science Databases, from 2010 until December 2021, combining the search term "RSWA" with "scoring methods", "IRBD", "alfasyn disease", and "neurodegenerative disease", and with each of the specific sleep disorders, diagnosed according to current criteria, with the identification of the references of interest for the topic. Furthermore, a Meta-analysis of the diagnostic performance of RSWA scoring methods, in terms of sensitivity and specificity, was carried out. The comparison of the hierarchical summary receiver-operating characteristic curves obtained for visual methods and that obtained for the automated REM sleep atonia index (RAI), shows substantially similar prediction areas indicating a comparable performance. This systematic review and meta-analysis support the validity of a series of visual methods and of the automated RAI in the quantification of RSWA with the purpose to guide clinicians in the interpretation of their results and their correct and efficient use within the diagnostic work-up for REM sleep behavior disorder.

Neuropsychological and Behavioral Profile in Sleep-Related Hypermotor Epilepsy (SHE) and Disorders of Arousal (DOA): A Multimodal Analysis.

STUDY OBJECTIVES: Disorder of arousal (DOA) and sleep-related hypermotor epilepsy (SHE) are complex, often bizarre, involuntary sleep behaviors, whose differential diagnosis may be challenging because they share some clinical features, such as sleep fragmentation. Mounting evidence highlights the critical role of sleep in cognitive functions. Controversial findings are raised about the cognitive profile in SHE; however, no studies have investigated the cognitive profile in DOA. This study aimed to assess whether sleep instability affects cognitive functions in patients with SHE or DOA. METHODS: This study analyzed 11 patients with DOA, 11 patients with SHE, and 22 healthy controls (HC). They underwent full-night video polysomnography (vPSG) and comprehensive neuropsychological and behavioral evaluation. Differences in the variables of interest among the SHE group, DOA group, and their respective control groups were evaluated. The auto-contractive map (auto-CM) system was used to evaluate the strength of association across the collected data. RESULTS: The SHE group had reduced sleep efficiency and increased wake after sleep onset (WASO); both the SHE and DOA groups showed increased % of N2 and REM sleep compared to the HC group. Neuropsychological and behavioral evaluations showed a different cognitive profile in the SHE group with respect to the HC group. The auto-CM showed that Pittsburgh Sleep Quality Index (PSQI), Beck depression inventory (BDI), MWCST_PE, Epworth sleepiness scale (ESS), WASO, N1, and % REM were strictly correlated with SHE, whereas the SE and arousal index (AI) were strictly related to DOA. CONCLUSIONS: Patients with SHE and DOA present different cognitive and psychiatric profiles, with subtle and selective cognitive impairments only in those with SHE, supporting the discriminative power of cognitive and psychiatric assessment in these two conditions.

Prevalence of sleep disruption and determinants of sleepiness in a cohort of Italian hospital physicians: The PRESOMO study.

Nightshift work can cause daytime somnolence and decreased alertness, and can increase risk of medical errors, occupational injuries and car accidents. We used a structured questionnaire, including the Epworth Sleepiness Scale (ESS), to assess the prevalence and the determinants of sleep disruption in 268 Italian University hospital physicians from Cagliari (N = 57), Milan (N = 180) and Pisa (N = 31), who participated in the multicentre study on the prevalence of sleep disturbance among hospital physicians (PRESOMO); 198 of them (74%) were engaged in nightshift work. We explored the association between history of nightshift work and poor sleep quality and daytime somnolence with multivariate logistic regression, adjusting by personal and lifestyle covariates. Age, female gender, taking medication interfering with sleep and an elevated ESS score were significant predictors of poor sleep quality and daytime somnolence. Nightshift work was associated with a higher prevalence of unrestful sleep (84% versus 70%; odds ratio [OR] = 2.4, 95% confidence interval [CI] 1.18-5.05) and daytime dozing (57% versus 35%; OR = 1.9, 95% CI 1.03-3.64), with an upward trend by years of engagement in nightshift work for both conditions (p = .043 and 0.017, respectively), and by number of nightshifts/year for unrestful sleep (p = .024). Such an association was not detected with the ESS scale. Our results suggest that nightshift work significantly affects sleep quality and daytime somnolence in hospital physicians, who might underestimate their daytime dozing problem, when asked to subjectively scale it.

Neurophysiological Aspects of REM Sleep Behavior Disorder (RBD): A Narrative Review.

REM sleep without atonia (RSWA) is the polysomnographic (PSG) hallmark of rapid eye movement (REM) sleep behavior disorder (RBD), a feature essential for the diagnosis of this condition. Several additional neurophysiological aspects of this complex disorder have also recently been investigated in depth, which constitute the focus of this narrative review, together with RSWA. First, we describe the complex neural network underlying REM sleep and its muscle atonia, focusing on the disordered mechanisms leading to RSWA. RSWA is then described in terms of its polysomnographic features, and the methods (visual and automatic) currently available for its scoring and quantification are exposed and discussed. Subsequently, more recent and advanced neurophysiological features of RBD are described, such as electroencephalography during wakefulness and sleep, transcranial magnetic stimulation, and vestibular evoked myogenic potentials. The role of the assessment of neurophysiological features in the study of RBD is then carefully discussed, highlighting their usefulness and sensitivity in detecting neurodegeneration in the early or prodromal stages of RBD, as well as their relationship with other proposed biomarkers for the diagnosis, prognosis, and monitoring of this condition. Finally, a future research agenda is proposed to help clarify the many still unclear aspects of RBD.

Artificial Neural Networks Analysis of polysomnographic and clinical features in Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): from sleep alteration to "Brain Fog".

STUDY OBJECTIVES: PANS (pediatric acute onset neuropsychiatric syndrome) is thought to be the result of several mechanisms and multiple etiologies, ranging from endocrine/metabolic causes to postinfectious autoimmune and neuroinflammatory disorders. Sleep disorders represent one of the most frequent manifestations of PANS, involving around 80% of patients. The present study describes the clinical and polysomnographic features in a group of PANS children identifying the relationships between sleep disorders and other PANS symptoms. METHODS: All participants underwent a clinical evaluation including comprehensive sleep history, polysomnography, cognitive assessment and blood chemistry examination. A data mining approach with fourth-generation artificial neural networks has been used in order to discover subtle trends and associations among variables. RESULTS: Polysomnography showed abnormality in 17 out of 23 recruited subjects (73.9%). In particular, 8/17 children (47%) had ineffective sleep, 10/17 (58.8%) fragmented sleep, 8/17 (47.1%) periodic limb movement disorder (PLMD) and 11/17 (64.7%) REM-sleep without atonia (RSWA). Most subjects presented more than one sleep disturbances. Notably, among the 19/23 patients diagnosed with Tic/Tourette disorder, 8/19 (42.1%) show PLMD and 10/19 (52.6%) RSWA. Artificial neural network methodology and the auto-contractive map exploited the links among the full spectrum of variables revealing the simultaneous connections among them, facing the complexity of PANS phenotype. CONCLUSION: Disordered sleep represents, for prevalence and impact on quality of life, a cardinal symptom in patients with PANS. Thus, considering the weight of sleep disturbances on diagnosis and prognosis of PANS, we could consider the possibility of including them among the major diagnostic criteria.

Association between dopaminergic medications and REM sleep behavior disorder in Parkinson's disease: a preliminary cohort study.

BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) is highly comorbid with Parkinson's disease (PD). Emerging evidence suggests that dopamine-replacement therapies (DRTs) for PD may modify the course of RBD, yet the nature of the association between DRTs and RBD remains unclear. To begin addressing this issue, we conducted a preliminary retrospective study to document whether DRTs are associated with the occurrence of RBD symptoms in PD patients. METHODS: The study included 250 PD patients who were screened for probable RBD via the RBD Screening Questionnaire (RBDSQ). For each patient, disease severity data were collected, in addition to their therapy and the associated levodopa equivalent daily dose (LEDD). The association between DRTs and RBDSQ scores was analyzed using logistic regression and correlation models. RESULTS: RBD scores were found to be associated with the LEDD of levodopa alone, but not of dopaminergic agonists (mainly D2/D3 receptor agonists) or their combination with levodopa. This association was not accounted for patient age or Hoehn and Yahr (H&Y) severity scores. CONCLUSIONS: Our study detected a significant association between doses of levodopa and RBD symptoms in PD patients. Future longitudinal studies are needed to establish what causal nexus may link these variables.

Sleep cardiac dysautonomia and EEG oscillations in amyotrophic lateral sclerosis.

STUDY OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to loss of motor neurons. However, the autonomic nervous system (ANS) can also be involved. The aim of this research was to assess the sleep macro- and microstructure, the cardiac ANS during sleep, and the relationships between sleep, autonomic features, and clinical parameters in a cohort of ALS patients. METHODS: Forty-two consecutive ALS patients underwent clinical evaluation and full-night video-polysomnography. Only 31 patients met inclusion criteria (absence of comorbidities, intake of cardioactive drugs, or recording artifacts) and were selected for assessment of sleep parameters, including cyclic alternating pattern (CAP) and heart rate variability (HRV). Subjective sleep quality and daytime vigilance were also assessed using specific questionnaires. RESULTS: Although sleep was subjectively perceived as satisfactory, compared with age- and sex-matched healthy controls, ALS patients showed significant sleep alteration: decreased total sleep time and sleep efficiency, increased nocturnal awakenings, inverted stage 1 (N1)/stage 3 (N3) ratio, reduced REM sleep, and decreased CAP rate, the latter supported by lower amounts of A phases with an inverted A1/A3 ratio. Moreover, a significant reduction in HRV parameters was observed during all sleep stages, indicative of impaired autonomic oscillations. CONCLUSION: Our results indicate that sleep is significantly disrupted in ALS patients despite its subjective perception. Moreover, electroencephalogram activity and autonomic functions are less reactive, as shown by a decreased CAP rate and a reduction in HRV features, reflecting an unbalanced autonomic modulation.

REM Sleep without atonia correlates with abnormal vestibular-evoked myogenic potentials in isolated REM sleep behavior disorder.

STUDY OBJECTIVES: The neurophysiological hallmark of REM sleep behavior disorder (RBD) is loss of atonia during REM sleep. Indeed, signs and symptoms of neurodegeneration can occur after years, even decades, from its beginning. This study aimed to measure neurophysiological alterations of the brainstem that potentially correlate with the severity of atonia loss, and determining whether a prodromal neurodegenerative disorder underlines this condition when it occurs as an isolated condition (iRBD). METHODS: Subjects with iRBD and matched healthy controls were recruited. The study included the recording of one-night polysomnography, vestibular-evoked myogenic potentials (VEMPs), and a [123I]-FP-CIT dopamine transporter (DAT) scan. The quantification of REM sleep without atonia (RSWA) was made according to two previously published manual methods and one automated method. RESULTS: The rate of alteration of VEMPs and VEMP score were significantly higher in iRBD patients than controls. Moreover, VEMP score was negatively correlated with the automated REM atonia index; a marginal statistical significance was also reached for the positive correlation with the visual tonic electromyographic parameter, while the other correlations, including that with DAT-scan score were not statistically significant. CONCLUSIONS: Brainstem neurophysiology in iRBD can be assessed by VEMPs and their alterations may possibly indicate an early expression of the neurodegenerative process underlying this disorder at the brainstem level, which awaits future longitudinal confirmation. The correlation between RSWA and VEMP alteration might also represent a prodromal aspect anticipating the possible evolution from iRBD to neurodegeneration, whereas DAT-scan abnormalities might represent a later step in this evolution.

Sleep in Parkinson's Disease with Impulse Control Disorder.

PURPOSE OF REVIEW: This paper aims to explore the relationship between impulse-control disorders (ICDs) and sleep problems in patients with Parkinson's disease (PD) among scientific literature. RECENT FINDINGS: Previously published results are controversial and sometimes inconclusive. ICDs and sleep disruption represent important non-motor features of Parkinson's disease, responsible for reducing quality of life and increasing burden of disease. The relationship between sleep problems and ICDs is complex and bidirectional. Indeed, sleep disturbances and fragmentation may play a crucial role in increasing susceptibility to impulsive behavior and may represent a risk factor for developing ICDs in PD patients. Moreover, REM sleep behavior disorder (RBD) and restless legs syndrome (RLS) have been indicated as independent risk factors for ICDs in PD patients. On the other hand, also ICDs may lead to sleep restriction and fragmentation, suggesting a bidirectional relationship. The association between sleep problems and ICDs in PD is far from being completely understood. Further studies are needed to confirm the nature of this relationship and its pathophysiology.

The Clinical Importance of Periodic Leg Movements in Sleep.

OPINION STATEMENT: Periodic leg movements during sleep (PLMS) are commonly found in patients with restless leg syndrome (RLS), but they may occur in other sleep disorders and several medical conditions. Their prevalence increases with age, but they can also be observed in children. During the last decades, very active research has been devoted to determine and understand the pathophysiology, associated events, and clinical significance of PLMS. This chapter tries to sum up the most relevant PLMS-related findings, focusing on the relationship between PLMS and the cardiovascular system, in order to understand the clinical implication of this complex motor phenomenon. PLMS have been associated with sympathetic overactivity, namely surges in nocturnal blood pressure and heart rate, without modification in global autonomic balance. Also, PLMS have been related to inflammatory cellular pathways, with elevated level of inflammatory markers, which are associated with cardiovascular risk. The PLMS-related modulation of the autonomic system and of inflammation may increase cardiovascular and cerebrovascular risk in subjects with frequent PLMS. Moreover, also, comorbidities associated with PLMS may play a synergic role in worsening the cardiovascular risk and the consequent mortality and morbidity. Furthermore, little is known about pathophysiological correlates in children with PLMS and their chronic implication on the cardiovascular and cerebrovascular systems. A few studies have suggested that treating PLMS with dopaminergic drugs may reduce their associated sympathetic overactivity and modify disease progression. Definitely, further research is needed to assess the clinical impact of PLMS, associated or not with RLS, and above all the long-term impact of treating PLMS on cardiovascular risk, morbidity, and mortality.

F-Wave Duration as a Specific and Sensitive Tool for the Diagnosis of Restless Legs Syndrome/Willis-Ekbom Disease.

STUDY OBJECTIVES: Restless legs syndrome, also known as Willis-Ekbom disease (RLS/WED), is a frequent condition, though its pathophysiology is not completely understood. The diagnosis of RLS/WED relies on clinical criteria, and the only instrumental tool, the suggested immobilization test, may lead to equivocal results. Recently, neurophysiological parameters related to F-wave duration have been proposed as a diagnostic aid. The aim of this study is to assess and compare the diagnostic values of these parameters in diagnosis of RLS/WED. METHODS: Fifteen women affected by primary RLS/WED and 17 age- and sex- matched healthy subjects. A complete electroneurographic evaluation, including nerve conduction studies (NCS), cutaneous silent period (CSP), and F-wave parameters, namely amplitude, F-wave duration (FWD), and the ratio between FWD and duration of the corresponding compound muscle action potential (FWD/CMAPD). RESULTS: No subject showed alterations of the NCS. However, FWD and FWD/CMAPD of both upper and lower limbs were significantly longer in patients than controls. Tibial FWD/CMAPD best discriminated RLS/WED patients from controls. A cutoff of 2.06 yielded a sensitivity of 69.2%, a specificity of 94.1%, a positive predictive power of 90%, and a negative predictive power of 80% (area under the curve = 0.817; 95% confidence interval = 0.674-0.959). The combination of ulnar or tibial FWD/CMAPD increases the sensitivity (85.7%) while slightly decreasing the specificity (87.5%, positive predictive value: 85.7%, negative predictive value: 87.5%). CONCLUSIONS: Lower limb FWD/CMAPD ratio may represent a supportive diagnostic tool, especially in cases of evening lower leg discomfort of unclear interpretation.

Isolated rapid eye movement sleep without atonia in amyotrophic lateral sclerosis.

OBJECTIVE: The aim of this study was to quantitatively analyze, with the most recent and advanced tools, the presence of periodic leg movements during sleep (PLMS) and/or rapid eye movement (REM) sleep without atonia (RSWA), in a group of patients with amyotrophic lateral sclerosis (ALS), and to assess their eventual correlation with the clinical severity of the disease. METHODS: Twenty-nine ALS patients were enrolled (mean age 63.6 years) along with 28 age-matched "normal" controls (mean age 63.8 years). Functional impairment due to ALS was evaluated using the ALS-Functional Rating Scale-Revised (ALS-FRS) and the ALS severity scale (ALSSS). Full video polysomnographic night recordings were obtained, and PLMS were analyzed by considering their number/hour of sleep and periodicity index, the distribution of intermovement intervals, and the distribution during the night. The characteristics of the chin electromyogram (EMG) amplitude during REM sleep were analyzed by means of the automatic atonia index and the number of chin EMG activations (movements). RESULTS: The ALS patients showed longer sleep latency than the controls, together with an increase in number of stage shifts, increased sleep stage 1, and decreased sleep stage 2. None of the leg PLMS parameters were different between the ALS patients and controls. The REM atonia index was significantly decreased in the ALS patients, and the number of chin movements/hour tended to increase. Both REM atonia index and number of chin movements/hour correlated significantly with the ALS-FRS; REM atonia was higher and chin movements were less in ALS patients with more preserved function (higher scores on the ALS-FRS). CONCLUSION: Abnormal REM sleep atonia seemed to be a genuine effect of ALS pathology per se and correlated with the clinical severity of the disease. It is unclear if this might constitute the basis of a possible risk for the development of REM sleep behavior disorder or represent a form of isolated RSWA in ALS.

Respiratory sleep disorders in Jeune syndrome: a case description.

PURPOSE: Jeune syndrome (JS, also described as asphyxiating thoracic dystrophy, ATD) is a rare autosomal recessive skeletal dysplasia characterized by a small, narrow chest and variable limb shortness with a considerable neonatal mortality as a result of respiratory distress. Significant life-threatening cervical spine abnormalities can be typical. METHOD: Here we describe the case of a male infant of Sardinian origin, who developed respiratory distress and feeding difficulties from the first months, correlated with muscle\skeletal dysmorphism prevalent on chest. Nocturnal respiratory sleep alterations were reported from parents. RESULTS: After clinical, genetics, radiographic and cervical MRI investigations, ATD diagnosis with C1 stenosis. A full-night video-polysomnographic study was performed in order to evaluate the sleep apnea condition. The study showed a condition of tachipnea\tachicardia, with several short respiratory events during sleep, both obstructive and central type with apneahypopnea index (AHI) 17/ h, mean duration 3.7 sec with longest 20 sec. CONCLUSION: It can be hypothesized that the combination of altered respiratory and cardiac frequency is related to central type of sleep respiratory disorders consequent to C1 compression, while the obstructive minor component is related to thoracic restrictive disorders. Full night lab-polygraphy is recommended in dysmorphic skeletal disorders like JS.