World Association of Sleep Medicine (WASM) 2016 standards for recording and scoring leg movements in polysomnograms developed by a joint task force from the International and the European Restless Legs Syndrome Study Groups (IRLSSG and EURLSSG).

This report presents the results of the work by a joint task force of the International and European Restless Legs Syndrome Study Groups and World Association of Sleep Medicine that revised and updated the current standards for recording and scoring leg movements (LM) in polysomnographic recordings (PSG). First, the background of the decisions made and the explanations of the new rules are reported and then specific standard rules are presented for recording, detecting, scoring and reporting LM activity in PSG. Each standard rule has been classified with a level of evidence. At the end of the paper, Appendix 1 provides algorithms to aid implementation of these new standards in software tools. There are two main changes introduced by these new rules: 1) Candidate LM (CLM), are any monolateral LM 0.5-10 s long or bilateral LM 0.5-15 s long; 2) periodic LM (PLM) are now defined by runs of at least four consecutive CLM with an intermovement interval ≥10 and ≤ 90 s without any CLM preceded by an interval <10 s interrupting the PLM series. There are also new options defining CLM associated with respiratory events. The PLM rate may now first be determined for all CLM not excluding any related to respiration (providing a consistent number across studies regardless of the rules used to define association with respiration) and, subsequently, the PLM rate should also be calculated without considering the respiratory related events. Finally, special considerations for pediatric studies are provided. The expert visual scoringof LM has only been altered by the new standards to require accepting all LM > 0.5 s regardless of duration, otherwise the technician scores the LM as for the old standards. There is a new criterion for the morphology of LM that applies only to computerized LM detection to better match expert visual detection. Available automatic scoring programs will incorporate all the new rules so that the new standards should reduce technician burden for scoring PLMS.

Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group.

OBJECTIVES: We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. METHODS: The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). RESULTS: Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. CONCLUSIONS: The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

Environmental risk factors for REM sleep behavior disorder: a multicenter case-control study.

OBJECTIVE: Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder. METHODS: Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors. RESULTS: A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p < 0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008). CONCLUSIONS: Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

Absence of cardiovascular disease risk factors in restless legs syndrome.

OBJECTIVE: Restless legs syndrome (RLS) might represent a condition at risk of cardiovascular (and cerebrovascular) disease; the role of sleep periodic leg movements, sleep deprivation, and presence of common risk factors for heart disease in these patients remains to be determined. The aim of this study was to evaluate the eventual presence of risk factors for cerebrovascular disease in RLS. MATERIALS & METHODS: Eighty-seven consecutive patients affected by idiopathic RLS were included in this study together with 81 controls. Blood count, chemistry, and kidney function tests were obtained. We detected subjects suffering from diabetes mellitus, kidney diseases, heart diseases, disk herniation, neuropathy, blood diseases, liver diseases, artery diseases, dyslipidemia, or hypertension. Polysomnography was recorded in 66 patients, and cerebral neuroimaging was obtained in 59 patients with RLS. RESULTS: None of the differences in blood test parameters was statistically significant; however, hypertension was found to be more frequent in controls and dyslipidemia was more frequent in patients with RLS, but this was explained by its higher frequency in patients also affected by obstructive sleep apnea. A diagnosis of cerebrovascular disease was posed for 14 patients with RLS (16.1%), but no predictive factor for its presence was found at the binomial logistic regression. CONCLUSION: Our findings argue against the presence of an altered lipid metabolism as a risk factor for the development of cerebrovascular disease in patients with RLS, even if they do support the idea that cerebrovascular disease might be frequent in this condition.

Bruxism and nocturnal groaning.

Sleep bruxism (SB) is a sleep-related movement disorder, characterized by tooth grinding and/or clenching. The causes of SB range from psychosocial factors to an excessive sleep arousal response. Some studies showed that SB episodes during sleep are under the influences of transient activity of the brainstem arousal. Nocturnal groaning (NG) is a parasomnia characterized by an expiratory monotonous vocalization occurring during sleep, especially in REM sleep and during the second half of the night. The pathogenesis of NG remains still unclear and many hypotheses arose, ranging from the persistence of a vestigial ventilatory pattern rather than an expiratory upper airways' obstruction. Sleep microstructure fluctuation might modulate the NG, since the end of the NG episode usually is synchronized with a cortical arousal and an autonomic activation. Further studies should clarify the pathophysiology of SB and NG, especially when the two phenomena are associated.

Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome.

OBJECTIVE: A comparison between equivalent low doses of the D2 preferential agonist bromocriptine and the D3 preferential agonist pramipexole was performed in order to understand which dopamine agonist receptor subtype plays the main role in the treatment of restless legs syndrome (RLS) with periodic leg movements during sleep (PLMS). METHODS: A placebo-controlled, prospective, single-blind investigation was carried out on 45 drug-naive patients with idiopathic RLS. Each patient underwent 2 consecutive full night polysomnographic studies. The first night was performed without medication. Prior to the second night, one group received a single oral dose of 0.25 mg pramipexole while a second group received a single oral dose of 2.5 mg bromocriptine, and the remaining patients received placebo. Additionally, symptoms of restlessness were assessed. RESULTS: Subjective symptoms improved with both pramipexole and bromocriptine; however, the amelioration after pramipexole was scored higher. Only pramipexole induced an improvement in sleep efficiency and a reduction in wakefulness after sleep onset. Pramipexole was more effective than bromocriptine in reducing periodic leg movements, in particular in patients with a high baseline periodic leg movements index. Typical periodic leg movements, with an interval ranging between 10 and 40 seconds, disappeared completely after pramipexole treatment but persisted, even if reduced, after bromocriptine. CONCLUSIONS: Dopamine agonists targeting the dopamine D3 receptor subtype have a higher efficacy on periodic leg movements and RLS than a drug that preferentially targets the D2 receptor subtype. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with RLS pramipexole as compared to an estimated equivalent dose of bromocriptine results in greater improvement in some measures of RLS and PLMS severity after one night of treatment.

Effectiveness of maxillo-mandibular advancement in obstructive sleep apnea patients with and without skeletal anomalies.

This study evaluates the effectiveness of maxillo-mandibular advancement (MMA) in patients with obstructive sleep apnea syndrome (OSAS), even those without skeletal anomalies, indicating the possibility of extending this procedure to more patients. Two groups with different skeletal patterns were studied pre- and post-surgery. Group 1 (11 patients) had severe or moderate OSAS and maxillo-mandibular hypoplasia and/or mandibular deformities (SNA angle 78 degrees or less or SNA angle>78 degrees but with SNB<65 degrees and severe skeletal class II malocclusion). Group 2 (11 patients) had severe or moderate OSAS without maxillo-mandibular hypoplasia or deformity (SNA angle>80 degrees , dental class I occlusion). Analysis comprised: apnea hypopnea index (AHI), posterior airway space (PAS), SNA and SNB angles, Epworth sleepiness scale (ESS), body mass index (BMI), and a subjective standardized questionnaire about aesthetic appearance. All patients had increased PAS width and complete remission of objective and subjective OSAS symptoms evaluated by AHI and ESS. Results in both groups are comparable. Data were analysed using t-test; p<0.005 was statistically significant. All patients were satisfied with the functional and aesthetic results. MMA is effective in patients with severe or moderate OSAS, even in those without skeletal and/or occlusal anomalies and can be considered in more patients.

Periodic leg movements in Cheyne-Stokes respiration.

Periodic leg movements during sleep (PLMS) are repetitive jerks of the lower limbs. Their occurrence can be isolated or part of various sleep disorders, such as restless legs syndrome (RLS), narcolepsy and obstructive sleep apnoea. Dopamine agonists are very effective in suppressing PLMS in RLS from the first night of administration. PLMS are often associated with cortical and autonomic arousals and may contribute to sleep disruption. Herein, a case of association between PLMS, Cheyne-Stokes respiration (CSR) and severe insomnia is described. Repeated polysomnographic studies demonstrated a clear synchronisation between PLMS and hyperventilation episodes, and the complete recovery of CSR, sleep quality and PLMS during nocturnal ventilation. In the same patient, pharmacological treatment with a dopamine agonist was ineffective on both PLMS and CSR. These results suggest that periodic leg movements during sleep coupled with central breathing events, similar to those observed in conjunction with obstructive events, may have a different origin in terms of neurotransmitter and pathway implicated, compared with periodic leg movements during sleep in restless legs syndrome, and are resolved by treatment of the respiratory abnormalities.

A single question for the rapid screening of restless legs syndrome in the neurological clinical practice.

The purposes of this study were to validate the use of a single standard question for the rapid screening of restless legs syndrome (RLS) and to analyze the eventual effects of the presence of RLS on self-assessed daytime sleepiness, global clinical severity and cognitive functioning. We evaluated a group of 521 consecutive patients who accessed our neurology clinic for different reasons. Beside the answer to the single question and age, sex, and clinical diagnosis, the following items were collected from all patients and normal controls: the four criteria for RLS, the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Severity (CGI-S), and the Mini-Mental State evaluation. RLS was found in 112 patients (70 idiopathic). The single question had 100% sensitivity and 96.8% specificity for the diagnosis of RLS. ESS and CGI-S were significantly higher in both RLS patient groups than in normal controls. RLS severity was significantly higher in idiopathic than in associated/symptomatic RLS patients. RLS can be screened with high sensitivity and good reliability in large patient groups by means of the single question; however, the final diagnosis should always be confirmed by the diagnostic features of RLS and accompanied by a careful search for comorbid conditions.

Aetiopathogenesis of restless legs syndrome.

The pathogenesis of restless legs syndrome (RLS) is not yet completely understood. However, recent research addressed the hypothesis that dopaminergic pathways are involved in the mechanisms responsible for the syndrome both for sensory and motor symptoms. Different aspects of RLS physiopathogenesis are discussed: the genetic components indicating different chromosomes are responsible for the heterogeneity in the phenotypic expression of the familial forms of RLS; the neurophysiologic data showing the hyperexcitability of the cortico-motor efferents at supraspinal level, with spinal cord involvement leading to a definition of RLS as a syndrome of somatosensory misperception, disturbed gain regulation and/or a shifted threshold; the paucity of neuroimaging data, which do not definitively clarify the eventual dopaminergic dysfunction in RLS patients, at least at the basal ganglia level; an illustration of the iposideremic hypothesis starting from the therapeutic effect of iron, although not for all patients, and based on some neurophysiologic and neuropathologic results both in humans and animal models; and finally the role of the opioid system, suggesting an imbalance of dopamine-opiate system inputs to brain regions involved in motor responses and pain perception, and representing an aberrant behavioural response to sensory inputs. All these theories may have a final common pathway in the dopaminergic system, reinforcing the empirical results of benefit with dopamine or dopamine-agonist treatments in RLS.

On the pathway of an animal model for restless legs syndrome...

Restless legs syndrome (RLS) is a chronic sleep motor disorder that affects up to 10% of the general population. Except for periodic leg movements (PLM), which can be found in the great majority of RLS patients, no objective hematochimic or neurophysiological markers are available to prove the diagnosis, which is based on clinical standard criteria. Nowadays, the aetiopathogenesis of the syndrome is unknown. In a consistent sample of patients affected by the idiopathic form, the disease is inherited as an autosomal dominant trait related to an unidentified locus, while each symptomatic form is probably linked to a specific cause. Although of possible different origins, both the primary and secondary forms may share the same pathogenetic mechanism, which, even if unclear, could be characterised by a neurological dysfunction of the dopaminergic system. Several issues, including strong efficacy of dopamine-agonist treatments, support this theory, which is currently considered the main pathogenetic hypothesis. Most of the past studies tried to clarify the RLS mechanism using the neurophysiological, biochemical and neuroimaging techniques applied to the field of human research. Now the time has come to accept the challenge in creating an animal model of RLS, which may emerge as a decisive step in understanding RLS pathogenesis, and to develop and test new therapies. Even though there have been a few significant efforts, a valid animal model of RLS still does not exist. In past pioneering studies, the authors attempted to induce restless motor behaviour in animals by different strategies: antidopaminergic pharmacological interventions, spinal or cerebral lesions of specific regions involved in the motor control and in dopamine regulation, and selective deletion of genes coding for dopamine receptors. Rodents (mice and rats) were always chosen by the authors as the animals for their experiments. The current tendency in achieving an RLS model is generally represented by simulation of a symptomatic condition of RLS or by a direct interference of the dopaminergic system. In this regard, the pharmacological method had the intention to reproduce the neuroleptic-induced acathisia, the spinal lesional model was based on the hypothesis of myelopathic- related PLM, and the hypothalamic lesion tested the motor consequence of A11 dopaminergic neurons. Preliminary studies are underway to replicate the pregnancy-related form of RLS by using a hormonal intervention, and the iron-deficiency secondary form by using specific iron-free diets. Today, modern technologies are available to easily replicate in animals most of the symptomatic RLS conditions. In addition, more than a few well validated animal models of different diseases known to be related to RLS or PLM, for instance, Parkinson's disease, rheumatoid arthritis and renal failure, could also be exploited in addressing this topic. The real obstacle in achieving an RLS model is the absence of a certain diagnostic marker to recognise if the animal that underwent the different experimental procedures has developed the RLS condition or not. Concerning this issue, possible specific endpoints are represented by the increase in locomotor activity, which are ascertainable by different techniques, such as openfield or run-wheel activity, or by sleep fragmentation, in which the circadian shift can be verified by applying polysomnography on the animal. PLM are probably the only specific and reliable markers available to recognise and quantify experimentally induced RLS. Despite a few authors who reported the presence of limb-phasic, pseudoperiodic activity during sleep in old or in lesioned rats, the existence of spontaneous or provoked PLM in animals is still debated. Eventually, the PLM features in an animal could be markedly different compared to human ones. To recognise and characterise PLM in animals, three more essential steps are required: a method to record directly, as in humans, the activity of the tibialis anterior (TA) muscles, a consistent amount of normative control data on the TA activity in healthy animals, and reliable analysis to distinguish the generic phasic muscular activity to a possible unambiguous PLM pattern. This review includes a summary and a critical discussion of the previous tentative RLS models, proposals for other possible animal models, and firstly the preliminary normative data on TA activity during sleep in normal rodents.

REM sleep behaviour disorder.

REM sleep behaviour disorder (RBD) is a parasomnia characterised by nocturnal complex motor activity associated with dream mentation. RBD, which affects mainly older men, may be idiopathic or associated with other neurological disorders. A strong association between RBD and alpha-synucleinopathies has been recently observed, with the parasomnia often heralding the clinical onset of the neurodegenerative disease. The idiopathic form accounts for up to 60% of the cases reported in the three largest series of RBD patients. Follow-up studies in small samples revealed that a proportion of RBD patients will eventually develop Parkinson's disease and/or a dementia of Lewy bodies type in the years following the RBD diagnosis. Recently, neurophysiological and neuropsychological studies in idiopathic RBD have found evidence of central nervous system dysfunction. An impairment of cortical activity, specific neuropsychological deficits, signs of autonomic dysfunction and olfactory impairment have been observed in these patients, challenging the concept of idiopathic RBD. The detection of early markers of neurodegenerative disorders in idiopathic RBD, and the evaluation of their value by the combined application in prospective studies may be crucial for developing early intervention strategies.

EEG synchronisation during sleep-related epileptic seizures as a new tool to discriminate confusional arousals from paroxysmal arousals: preliminary findings.

Confusional arousals, paroxysmal arousals (as part of the nocturnal frontal lobe epilepsy) and normal arousals and awakenings from NREM sleep are frequently a challenge for differential diagnosis. In this article we describe the course of synchronisation between different EEG channels during nocturnal seizures in 3 patients with sleep-related epileptic seizures and in 1 patient with sleep terrors. The functional interactions between the different EEG channels during the nocturnal seizures were analysed by means of the so-called synchronisation likelihood (SL). SL is a measure of the dynamical (linear and nonlinear) interdependencies between a time series (EEG channel) and one or more other time series. The main results of our study are the confirmation of a significant increase in EEG synchronisation during sleep-related seizures and the indication that clinically similar ictal motor patterns might be generated by different neurophysiological mechanisms, characterised by different patterns of synchronisation involving multiple or single frequency bands. This new approach might be useful to differentiate motor seizures, emerging from NREM sleep, from parasomnias (arousal disorders) when both ictal and interictal EEGs are uninformative.

'Nocturnal groaning': just a sound or parasomnia?

We describe the clinical and polysomnographic characteristics of 12 patients complaining of expiratory groaning during sleep. Groaning occurred almost exclusively during rapid eye movement sleep. We reviewed all the literature cases, obtaining a total sample of 27 patients. There is no evident association with any predisposing factors or underlying disease. The results obtained from empirical treatment, including drugs and CPAP, are unsatisfactory. The origins of nocturnal groaning, as well as the long-term prognosis, remained unexplained.

Neuropsychological assessment in idiopathic REM sleep behavior disorder (RBD): does the idiopathic form of RBD really exist?

OBJECTIVE: To evaluate the cognitive performance of patients with idiopathic REM sleep behavior disorder (RBD). METHODS: The authors studied 17 consecutive patients with idiopathic RBD vs 17 age- and education-matched control subjects. Tests given to each patient and control included Mini-Mental State Examination, verbal and spatial short-term memory, visual selective attention, verbal fluency, prose memory, visuoconstructional abilities, spatial learning, and executive function tests. A self-administered depression rating scale was also used. RESULTS: RBD patients had significantly lower scores than control subjects in two tests: copy of Rey-Osterrieth Figure and Corsi Supraspan Learning. No correlation was found between the results of neuropsychological tests and RBD duration or with polysomnographic findings. CONCLUSIONS: Visuospatial constructional dysfunction and altered visuospatial learning may be present in idiopathic RBD. A neuropsychological assessment may be indicated in RBD patients.

The assessment of daytime sleep propensity: a comparison between the Epworth Sleepiness Scale and a newly developed Resistance to Sleepiness Scale.

INTRODUCTION: The Epworth sleepiness scale (ESS) is widely used as a way of measuring subjective sleep propensity in research and clinical practice. Psychometric studies do not rule out the presence of more than one latent dimension underlying the items. OBJECTIVE: Aims of the present study were to: (a) evaluate psychometric proprieties of the ESS by means of classic psychometric techniques; (b) compare them with those from a newly developed resistance to sleepiness scale (RSS); (c) evaluate, following the latent trait theory, whether the items of both ESS and RSS could be conceptualized as different levels of an interval variable representative of a single latent trait related to sleep propensity. METHODS: One hundred and forty-six inpatients suffering from different sleep disorders filled in both the RSS and ESS in a sleep disorder centre. RESULTS: Indexes of fit derived by the application of the extended logistic model are consistent with the idea that each ESS item can be conceptualized as different levels of an interval variable representative of a single latent trait. However, most of the ESS items are found to be located at the opposite extremes of this continuum. CONCLUSIONS: The under representation of situations characterized by an intermediate soporific nature in the ESS could limit ESS sensitivity to detect intermediate variations of sleep propensity.

Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP).

The aims of this study were to assess cognitive function in obstructive sleep apnea (OSA) patients and to evaluate the effect of short- and long-term treatment with continuous positive airway pressure treatment (CPAP). A battery of neuropsychological tests, the Epworth Sleepiness Scale (ESS), and the Beck Inventory Scale were administered to 23 patients with severe OSA (age: 56.5+/-6.13; AHI: 54.9+/-13.37) and to 23 age- and education-matched controls. The OSA patients were evaluated in a baseline condition and in two follow-up treatment sessions (after 15 days and 4 months of CPAP, respectively). At baseline, OSA patients had a significant impairment, compared to controls, in tests of sustained attention, visuospatial learning, executive function, motor performance, and constructional abilities. The longitudinal evaluation showed that after a 15-days CPAP treatment attentive, visuospatial learning, and motor performances returned to normal levels. A 4-months CPAP treatment did not result in any further improvement in cognitive tests. Performance on tests evaluating executive functions and constructional abilities was not affected by short- and long-term treatment with CPAP. The findings of this study confirm the hypothesis of partial reversibility of cognitive dysfunction in OSA patients after CPAP.