Abstract 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 4 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 LM 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 scoring of 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.
Background and purpose
Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviours during REM sleep. Several studies showed that iRBD is a prodromal stage ...of synucleinopathies. Therefore, identifying iRBD in the general population is of utmost importance. In this study, we explore whether the assessment of rest–activity rhythm features can distinguish patients with iRBD from patients with disorders characterized by other pathological motor activity during sleep and healthy controls.
Methods
Nineteen patients with video‐polysomnographic diagnosis of iRBD, 39 patients with other disorders with motor activity during sleep 19 with restless leg syndrome (RLS) and 20 with untreated sleep apnea syndrome (SAS) and 16 healthy controls underwent 2‐week actigraphy and video‐polysomnography, and completed REM sleep behavior disorder screening questionnaires. Non‐parametric analyses were applied to assess the rest–activity rhythm features.
Results
Patients with iRBD showed lower sleep efficiency, increased estimated wake after sleep onset and increased frequency of prolonged activity bouts compared to those with RLS and controls, while no difference emerged compared with SAS patients. Moreover, patients with iRBD presented increased occurrence of estimated nap in comparison to those with RLS, those with SAS and controls. The I < O, a 24‐h measure that expresses the relationship between nocturnal and diurnal motor activity intensity, distinguished patients with iRBD from those with RLS, those with SAS and controls, with an area under the curve greater than that of REM sleep behavior disorder screening questionnaires. An I < O of 98.32 shows the best balance between sensitivity (63.2%) and specificity (89.1%).
Discussion
The I < O index distinguished iRBD patients from those with other pathological motor activity during sleep and controls, confirming its use as an objective measure suitable to screen large at‐risk populations.
Background and purpose
Visualization of phosphorylated α‐synuclein at serine 129 (p‐syn) in skin nerves is a promising test for the in vivo diagnosis of synucleinopathies. Here the aim was to ...establish the intra‐ and inter‐laboratory reproducibility of measurement of intraneural p‐syn immunoreactivity in two laboratories with major expertise (Würzburg and Bologna).
Methods
In total, 43 patients affected by Parkinson's disease (PD 21 patients), dementia with Lewy bodies (DLB 1), rapid eye movement sleep behaviour disorder (RBD 11), multiple system atrophy (MSA‐P 4) and small fibre neuropathy (SFN 6) were enrolled. Skin biopsy was performed at the C7 paravertebral spine region and distal skin sites (thigh or leg). The analysis was standardized in both laboratories and carried out blinded on a single skin section double stained with antibodies to p‐syn and the pan‐axonal marker protein gene product 9.5. Fifty skin sections were randomly selected for the analysis: 25 from C7 and 25 from distal sites. Differently classified sections were re‐evaluated to understand the reasons for the discrepancy.
Results
The intra‐laboratory analysis showed an excellent reproducibility both in Würzburg (concordance of classification 100% of sections; K = 1; P < 0.001) and Bologna (96% of sections; K = 0.92; P < 0.001). Inter‐laboratory analysis showed reproducibility in 45 sections (90%; K = 0.8; P < 0.001) and a different classification in five sections, which was mainly due to fragmented skin samples or weak fluorescent signals.
Conclusions
Analysis of p‐syn showed excellent inter‐ and intra‐laboratory reproducibility supporting the reliability of this technique. The few ascertained discordances were important to further improve the standardization of this technique.
To compare the diagnostic accuracy of the immunofluorescence (IF) technique and aSyn-seed amplification assay (aSyn-SAA) of skin and cerebrospinal fluid (CSF) in disclosing pathological α-syn in ...idiopathic idiopathic REM sleep behavior disorder (iRBD) as early phase of a synucleinopathy. We prospectively recruited 41 patients with iRBD and 40 matched clinical controls including RBD associated with type 1 Narcolepsy (RBD-NT1, 21 patients), iatrogenic causes (2 pt) or OSAS (6 pt) and 11 patients with peripheral neuropathies. IF from samples taken by skin biopsy and aSyn-SAA from skin and CSF samples were analysed blinded to the clinical diagnosis. IF showed a good diagnostic accuracy (89%) that was lower in the case of skin and CSF-based aSyn-SAA (70% and 69%, respectively) because of a lower sensitivity and specificity. However, IF showed a significant agreement with CSF aSyn-SAA. In conclusion, our data may favor the use of skin biopsy and aSyn-SAA as diagnostic tools for a synucleinopathy in iRBD.
Abstract 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.
Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was ...recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017.
Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients.
Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.
•Dermal p-syn deposition is consistent over time in patients with RBD.•Only RBD patients with dermal p-syn deposition converted to manifest PD/DLB.•Dermal p-syn-positivity was observed in patients who still had a normal FP-CIT-SPECT at follow-up.
Purpose: Individuals with fibromyalgia and obesity experience significant impairment in physical functioning. Pain catastrophizing, kinesiophobia, and pain acceptance have all been identified as ...important factors associated with the level of disability. The objective of this study was to evaluate the role of pain catastrophizing, kinesiophobia, and pain acceptance as mediators of the association between perceived pain severity and physical functioning in individuals with fibromyalgia and obesity. Patients and Methods: In this cross-sectional study, 165 women with fibromyalgia and obesity completed self-report questionnaires of perceived pain severity (ie, Numeric Pain Rating Scale), pain catastrophizing (ie, Pain Catastrophizing Scale), kinesiophobia (ie Tampa Scale of Kinesiophobia), pain acceptance (ie, Chronic Pain Acceptance Questionnaire), and perceived physical functioning (ie, Physical Functioning subscale of the Fibromyalgia Impact Questionnaire). In addition, a performance-based test (ie, 6-minute walking test) was conducted to assess objective physical functioning. Two multiple mediation analyses were performed. Results: Pain acceptance and kinesiophobia mediated the relationship between pain severity and self-reported physical functioning. Pain catastrophizing and kinesiophobia mediated the relationship between pain severity and performance-based functioning. Conclusion: Pain acceptance, kinesiophobia, and pain catastrophizing should be addressed in rehabilitative intervention to improve physical functioning. Interestingly, the subjective and objective aspects of physical functioning are influenced by different factors. Therefore, interventions for women with fibromyalgia and obesity should focus on factors related to both subjective and performance-based physical functioning. Keywords: chronic pain, fear-avoidance model, fibromyalgia, functioning, obesity, psychological flexibility model
To ascertain abnormalities of sympathetic and cardiovascular reactivity during mental stress in patients with narcolepsy and cataplexy (NC). We studied 10 untreated patients with established criteria ...for NC and hypocretin deficiency, and 15 sex and age matched healthy subjects. Subjects underwent sitting microneurographic recording of muscle sympathetic activity (MSNA) from peroneal nerve, heart rate (HR) and blood pressure (BP) during resting state and mental stress (3-min of paced auditory serial arithmetic test -PASAT) and a cold test (two minutes immersion of a hand in ice water). The awake state was continuously monitored by an ambulatory polygraphic recorder. NC patients disclosed a tendency to show decreased MSNA and BP during resting state compared to controls although the difference was not significant. However during mental stress NC patients showed decreased MSNA, BP and HR compared to controls but no difference were found during cold test. Our data demonstrated a decreased sympathetic and cardiovascular reactivity during mental stress in NC patients suggesting a possible effect of hypocretin on autonomic reaction during mental activation as reported in animal models.
Background and purpose: The aim of this study was to evaluate the presence of abnormalities in the brain of patients with restless legs syndrome (RLS) using voxel‐based morphometry and diffusion ...tensor imaging (DTI).
Methods: Twenty patients and twenty controls were studied. Voxel‐based morphometry analysis was performed using statistical parametric mapping (SPM8) and FSL‐VBM software tools. For voxel‐wise analysis of DTI, tract‐based spatial statistics (TBSS) and SPM8 were used.
Results: Applying an appropriate threshold of probability, no significant results were found either in comparison or in correlation analyses.
Conclusions: Our data argue against clear structural or microstructural abnormalities in the brain of patients with idiopathic RLS, suggesting a prevalent role of functional or metabolic impairment.
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