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Study Objectives The pathomechanism of restless legs syndrome (RLS) is related to brain iron deficiency and iron therapy is effective for RLS, however, the effect of iron therapy on human brain iron state has never been studied with magnetic resonance imaging. This study aimed to investigate the change of brain iron concentrations in patients with RLS after intravenous iron therapy using quantitative susceptibility mapping (QSM). Methods We enrolled 31 RLS patients and 20 healthy controls. All participants underwent initial baseline (t0) assessment using brain magnetic resonance imaging, serum iron status, and sleep questionnaires including international RLS Study Group rating scale (IRLS). RLS patients underwent follow-up tests at 6 and 24 weeks (t1 and t2) after receiving 1000 mg ferric carboxymaltose. Iron content of region-of-interest on QSM images was measured for 13 neural substrates using the fixed-shaped method. Results RLS symptoms evaluated using IRLS were significantly improved after iron treatment (t0: 29.7±6.5, t1: 19.5±8.5, t2: 21.3±10.1; p Conclusions Intravenous iron treatment results in changes in brain iron content which correlate to reductions in RLS severity. This suggests a connection between symptom improvement and the associated specific brain regions constituting the sensorimotor network.

Study Objectives We conducted a prospective study to quantify motor activity during sleep measured by actigraphy before and after 3 months of treatment with clonazepam in patients with video-polysomnography (vPSG) confirmed isolated rapid eye movement (REM) sleep behavior disorder (iRBD). Methods The motor activity amount (MAA) and the motor activity block (MAB) during sleep were obtained from actigraphy. Then, we compared quantitative actigraphic measures with the results of the REM sleep behavior disorder questionnaire for the previous 3-month period (RBDQ-3M) and of the Clinical Global Impression-Improvement scale (CGI-I), and analyzed correlations between baseline vPSG measures and actigraphic measures. Results Twenty-three iRBD patients were included in the study. After medication treatment, large activity MAA dropped in 39% of patients, and the number of MABs decreased in 30% of patients when applying 50% reduction criteria. 52% of patients showed more than 50% improvement in either one. On the other hand, 43% of patients answered “much or very much improved” on the CGI-I, and RBDQ-3M was reduced by more than half in 35% of patients. However, there was no significant association between the subjective and objective measures. Phasic submental muscle activity during REM sleep was highly correlated with small activity MAA (Spearman’s rho = 0.78, p < .001) while proximal and axial movements during REM sleep correlated with large activity MAA (rho = 0.47, p = .030 for proximal movements, rho = 0.47, p = .032 for axial movements). Conclusions Our findings imply that quantifying motor activity during sleep using actigraphy can objectively assess therapeutic response in drug trials in patients with iRBD.

Several medications are approved to treat coronavirus disease 2019 (COVID-19) in Korea including nirmatrelvir/ritonavir, remdesivir, and regdanvimab. There is potential drug-drug interaction between antiepileptic drugs (AEDs) and the medications used to treat COVID-19. Several AEDs such as phenytoin, carbamazepine, phenobarbital, and primidone are strong cytochrome P450 inducers and can inhibit the drugs used for COVID-19. Particularly, these drugs are contraindicated with nirmatrelvir/ritonavir (Paxlovid®). There is a weaker drug-drug interaction between the AEDs and remdesivir. No significant interaction has been reported between the AEDs and molnupiravir. Pharmacokinetic interactions of the AEDs are important in effective management of COVID-19 in patients with epilepsy.

Objective Mild cognitive impairment (MCI) was found in 30 - 50% of the isolated REM sleep behavior disorder (iRBD) patients. Furthermore, it is known that patients with Parkinson’s Disease have attention network defects. Given that iRBD is known to be the prodromal disease of α -synucleinopathies, our aim was to investigate whether there are attention network dysfunctions in iRBD patients following the presence of MCI. Methods 14 healthy controls, 48 iRBD patients, 24 with MCI and 24 without MCI, were included in this study. Attention network task (ANT) was used to assess alerting, orienting, and executive control networks. Event-related potentials (ERPs) and behavioral performances were recorded during the ANT. Parietal N1 and P3 components were analyzed to find effects of the three attention networks. Results IRBD patients without MCI showed neuropsychological, behavioral, and ERP results similar to those of healthy controls. On the other hand, iRBD patients with MCI showed a general decline in cognitive domains with no alerting effect (controls, p = 0.043; iRBD-noMCI, p = 0.014; iRBD-MCI, p = 0.130) while preserving orienting and executive control effect. Furthermore, iRBD patients with MCI had impairments in executive function and verbal memory domains, compared to iRBD patients without MCI. Conclusions Our findings indicate that when cognition is reduced to MCI levels in iRBD patients, the attention network, especially the alerting component, is impaired. The attention network and cognition, on the other hand, can be preserved in iRBD patients due to the compensatory mechanism.

Introduction Recurrent arousals in obstructive sleep apnea (OSA) may lead to alteration in functional connection involving in the ascending reticular activating system (ARAS). We aimed to evaluate resting-state functional connectivity (FC) between eight ARAS nuclei and 105 cortical/subcortical regions in OSA patients and matched controls. Methods Total of 50 patients with moderate to severe OSA and 20 controls without OSA underwent overnight polysomnography (PSG) and resting-state functional magnetic resonance imaging in the following morning. Seed to voxel analysis of ARAS-cortical FC was compared between the patients and controls. The ARAS nuclei included dorsal and median raphe nucleus, locus coeruleus (LC), laterodorsal tegmental nucleus (LDTg), pedunculopontine tegmental nucleus, pontine nucleus oralis, parabrachial complex, and ventral tegmental area (VTA). Correlations between average FC values of significant clusters and PSG parameters were calculated in the patients. Results FC values in the three of the ARAS nuclei (LC, LDTg, and VTA) were significantly different between the group. The FC value between the LC and the precuneus cortex, posterior cingulate gyrus, and right lateral occipital cortex (LOC) was increased in OSA patients compared to the controls. The FC value between the LDTg and right LOC was enhanced, but the FC one between the VTA and right LOC was reduced in the patients. The average LC-cortical FC values positively correlated with the arousal index(r=0.282, p=0.047), apnea index(r=0.325, p=0.021), or apnea-hypopnea index (r=0.302, p=0.033) in OSA patients. Conclusion The results of this study support alteration in ARAS-cortical FC in OSA patients. Degree of the noradrenergic LC-cortical FC may be related to arousal or OSA severity in the patients. Support (if any)

Background: Obesity, obstructive sleep apnea (OSA), and excessive daytime sleepiness (EDS) are common conditions and are interrelated. Obesity is a risk factor for OSA and independently associated with EDS. We aimed to evaluate frequency of EDS in morbid obese patients with OSA and to identify contribution factor for EDS.Methods: This was a retrospective cross-sectional study in single sleep center. Consecutive patients with OSA (with apnea-hypopnea index 5/h or more) with morbid obesity (body mass index over 35 kg/m2) was enrolled. EDS were defined as Epworth Sleepiness Scale of 10 points or more. Clinical and polysomnographic variables were compared between those with and without EDS.Results: Total 110 morbid obese patients with OSA were enrolled, and 34 (31%) of them had EDS. Those with EDS had higher subjective symptom of insomnia and depression. Rapid eye movement sleep latency was shorter and minimum saturation was lower for those with EDS. Multivariate logistic regression analysis identified insomnia severity (odds ratio, 1.117) and minimum saturation (odds ratio, 0.952) as independent contribution factor for EDS.Conclusions: Result of this study suggest that 31.4% of morbid obese patients with OSA have EDS, and it can be affected by insomnia severity and desaturation during sleep.

Jin-Sun Jun1 &ast;, Jun-Sang Sunwoo2 &ast;, Jung-Ick Byun,3 Jung-Won Shin,4 Tae-Joon Kim,5 Carlos H Schenck,6 Ki-Young Jung7 1Department of Neurology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea; 2Department of Neurology, Kangbuk Samsung Hospital, Seoul, Republic of Korea; 3Department of Neurology, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea; 4Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea; 5Department of Neurology, Ajou University School of Medicine, Suwon, Republic of Korea; 6Minnesota Regional Sleep Disorders Center, and Department of Psychiatry, Hennepin County Medical Center and University of Minnesota Medical School, Minneapolis, MN, USA; 7Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Ki-Young Jung, Department of Neurology, Seoul National University Hospital, Neuroscience Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea, Tel +82-2-2072-4988, Fax +82-2-3672-7553, Email jungky@snu.ac.krObjective: To identify emotional and environmental factors that aggravate dream enactment behaviors (DEBs) in isolated rapid eye movement (REM) sleep behavior disorder (iRBD).Methods: In this cross-sectional study, a total of 96 polysomnography-confirmed iRBD patients (mean age, 68.5 years; men, 68%) and their caregivers completed questionnaires regarding potential aggravating factors related to DEBs, including emotion/feelings (stress, anger, anxiety, depressive mood, fatigue, pain), food (alcohol, caffeine, overeating in the evening, fasting/hunger), activities and sleep patterns (strenuous exercise, sex before bed, conflict/fighting, sleep deprivation, oversleeping, sleeping away from home, watching TV before bed), weather/environmental factors (cloudy or rainy weather, heat, cold, noise) and medication (skipping medication, taking hypnotics).Results: The patients reported that stress (61%) was the most aggravating factor for DEBs, followed by anxiety (56%), anger (51%), fatigue (49%), and watching TV before bed (46%). Similarly, the caregivers reported that these factors were most relevant to the aggravation of DEBs in the patients, although some factors were ranked differently. In the subgroup analyses, aggravating factors for DEBs did not differ by RBD symptom severity. Interestingly, the proportion of patients experiencing DEB aggravation by stress, anxiety and depressive mood was significantly higher in women than in men. Furthermore, depressed patients reported that stress and cloudy or rainy weather made DEBs worse than nondepressed patients.Conclusion: Our results suggest that DEBs in iRBD patients may be mainly aggravated by emotional factors. These negative effects appeared to be more prominent in female and depressed patients.Keywords: REM sleep behavior disorder, dream enactment behavior, precipitating factors

Purpose Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance. Any deficiency or dysfunction of the Tregs can influence the pathogenesis of autoimmune disease. This study aimed to assess the role of Tregs among patients with autoimmune encephalitis (AE) with different autoantibody types and to evaluate their association with clinical features. Methods This was a cross-sectional observational study involving 29 patients with AE. Peripheral blood was sampled from each patient for flow cytometric analysis. Proportions of CD4+CD25+ and CD4+CD25+Foxp3+ Tregs were calculated and compared between the antibody types (synaptic, paraneoplastic, and undetermined). Associations between the proportion of Tregs and clinical features were also evaluated. Results Five patients had synaptic autoantibodies, five had paraneoplastic autoantibodies, and the others were of an undetermined type. The proportion of CD4+CD25+ Tregs tended to be higher in those with paraneoplastic antibodies than in those with synaptic antibodies (post-hoc p = 0.028) and undetermined antibody status (post-hoc p = 0.043). A significant negative correlation was found between the proportion of Tregs and the initial modified Rankin score (r = −0.391, p = 0.036). Those who received intravenous immunoglobulin had lower proportions of Tregs than those who did not. Conclusion The results of the present study suggest that Tregs may play different roles according to the type of AE and may be linked to disease severity.

Study Objectives Rapid eye movement (REM) sleep without atonia (RWA) is essential for diagnosing REM sleep behavior disorder (RBD). Manual and automatic quantifications of RWA that use different criteria have been validated. This study compared the RWA quantification methods for diagnosing RBD. Methods The PubMed, EMBASE, Web of Science, and Cochrane Library databases were systemically searched for studies published from inception to December 2021. The inclusion criteria were cohort, cross-sectional, and case-control studies assessing the sensitivity and specificity of RWA quantification methods. Pooled estimates of the sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were determined. Risk of bias and certainty of evidence was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool and the Grading of Recommendations, Assessment, Development, and Evaluations framework, respectively. Results Fourteen articles including 402 patients with RBD met the inclusion criteria. Manual methods evaluating any chin and phasic flexor digitorum superficialis (FDS) activity had the highest DOR (138.8, 95% CI = 21.8% to 881.7%) and AUC (0.9686). The automatic REM atonia index (RAI) showed similar or higher sensitivity (89.1%, 95% CI = 84.6% to 92.7%) but a lower specificity (73.5%), DOR (43.1), and AUC (0.9369) than the manual techniques. Conclusions In this meta-analysis, manual RWA quantification that employed chin or phasic FDS activity had the best RBD diagnostic performance. The automatic RAI method may be useful for screening patients with RBD. The results should be interpreted carefully because of the high risk of bias in patient selection and significant heterogeneity among the studies. PROSPERO Registration number CRD42021276445.

Rapid eye movement sleep behavior disorder (RBD) is a parasomnia that is characterized by dream-enactment behavior, which can often result in sleep related injury. RBD is strongly associated with neurodegenerative disease especially with alpha-synucleinopathy. More than 70% of the patients convert to neurodegenerative disease including Parkinson’s disease or diffuse Lewy body dementia with a median period of 7.5 years. Treatment for RBD is currently focused on symptomatic treatment to prevent the injury. First step is establishing safe sleep environment to avoid injury. Clonazepam and melatonin are most commonly used medication for symptomatic treatment for RBD, however, well-designed randomized clinical trials are lacking. Prognostic counselling with longitudinal follow-up is also crucial in managing patients with RBD, which should be individualized for each patient with regular systematic follow-up evaluation.

STUDY OBJECTIVES: Restless legs syndrome (RLS) is known to be a risk factor for cardiovascular disease. However, there are no electrophysiological biomarkers to assess this risk. This study aimed to evaluate heart rate variability (HRV) and cardiovascular reflexes in the supine and standing positions during wakefulness in patients with RLS. METHODS: Fourteen drug-naïve patients with RLS (12 women and 2 men, mean age, 42.14 ± 7.81 years) and 10 healthy control patients underwent tests for blood pressure, heart rate when in the supine and standing positions, and deep breathing and handgrip tests in controlled laboratory conditions. Data on 5-minute R-R intervals at each position were collected and analyzed for HRV. RESULTS: Expected cardiovascular reflexes were within the normal range and were similar between the 2 groups. In HRV analysis, the normalized unit of the low-frequency component and the low-frequency/high-frequency ratio during standing were lower in patients with RLS than in the control patients. The low-frequency/high-frequency ratio responses during the change from the supine to the standing position were significantly reduced in patients with RLS (mean ± standard deviation, 2.94 ± 3.11; control patients: 7.51 ± 5.58; P = .042.) On Spearman rank correlation, questionnaires related to sleep problems were associated with the parameters of HRV. CONCLUSIONS: Patients with RLS showed reduced sympatho-vagal responses during the change from the supine to the upright position during wakefulness, and RLS-related sleep disturbance was a contributing factor for autonomic nervous system dysfunction. This case-control study showed a difference in HRV response to position change in a considerably small group of patients with RLS. The relevance of this finding is uncertain, but it may be worthy of further investigation in longitudinal studies on RLS and cardiovascular disease. CITATION: Shin J-W, Sunwoo J-S, Byun J-I, et al. Reduced sympatho-vagal responses to orthostatic stress in drug-naïve idiopathic restless legs syndrome. J Clin Sleep Med. 2021;17(5):957–963.

Introduction More than 80% of patients of isolated rapid eye movement (REM) sleep behavior disorder (iRBD), a prodromal disease of α-synucleinopathies, progress to neurological disease like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Resting-state EEG measurements taken at baseline have been related to the phenoconversion. The timing of the conversion and the disease to which it will convert are crucial issues in iRBD. This work used baseline EEG in iRBD to create a prediction model for the phenoconversion time and subtype of α-synucleinopathy. Methods Resting-state EEG and neurological assessments were performed at baseline on patients with iRBD. EEG spectral power, Shannon entropy and weighted phase lag index were employed as features. Four models were used to predict subtypes for the PD-MSA and DLB groups, and three models were used to predict survival. External validation was also performed. Results 29 patients out of 143 who were followed up to nine years (mean 3.4 years) later developed α-synucleinopathies (14 PD, 9 DLB, 6 MSA). With a concordance index of 0.8130 and an integrated Brier score of 0.0921, the random survival forest was the best model for predicting survival. For the subtype prediction analysis, the model with the highest accuracy, extreme gradient boosting, had an accuracy of 86.52%. Both models indicated a high importance on EEG slowing related features. Conclusion It is possible to predict the timing and subtype of phenoconversion in iRBD using machine learning models of using EEG biomarkers. To confirm our findings, further study is required, including large sample data from various countries. Support (if any)

Objective/Background We performed bioinformatic analysis of proteomic data to identify the biomarkers of restless legs syndrome (RLS) and provide insights into the putative pathomechanisms, including iron deficiency, inflammation, and hypoxic pathways. Patients/methods Patients with drug-naive idiopathic RLS were recruited at a university hospital from June 2017 to February 2018. Serum samples from patients with RLS (n = 7) and healthy sex- and age-matched controls (n = 6) were evaluated by proteomic analysis. For differentially expressed proteins (DEPs) in patients with RLS, compared to those in controls, the expression profiles and protein–protein interaction (PPI) network were characterized between dysregulated proteins and extracted proteins involved in iron deficiency, hypoxia, and inflammation responses using the String database (http://string-DB.org). The PPI network was visualized by Cytoscape ver. 3. 7. 1. Statistical analyses of the validation Western blot assays were performed using a Student's t-test. Results Interactome network analysis revealed a relationship among the eight proteins, their associated genes, and 150, 47, and 11 proteins related to iron deficiency, inflammation, and hypoxic pathways, respectively. All DEPs were well associated with inflammation, and complement 3, complement C4A, alpha-2 HS glycoprotein, and alpha-2 macroglobulin precursor were found to be in hub positions of networks involved in PPIs including iron deficiency, hypoxia pathway, and inflammation. C3 and C4A were verified using western blotting. Conclusions We identified key molecules that represent the selected cellular pathways as protein biomarkers by PPI network analysis. Changes in inflammation can mediate or affect the pathomechanism of RLS and can thus act as systemic biomarkers.

Background Electroconvulsive therapy (ECT) has strong efficacy in patients with treatment refractory schizophrenia. However, access to ECT has been limited by high costs, professional labor, treatment duration, and significant adverse effects. To provide support for the decision to perform ECT, we aimed to predict individual responses to ECT among patients with schizophrenia using machine learning analysis of resting-state electroencephalography (EEG). Methods Forty-seven patients diagnosed with schizophrenia or schizoaffective disorder with EEG recordings before the course of ECT were treated at Seoul National University Hospital. Among these patients, 29 were responders who showed scores of 3 or less on the Clinical Global Impression Severity scale after the course of ECT. Transfer entropy (TE), which represents information flow, was extracted from baseline EEG data and used as a feature. Feature selection was performed with four methods, including Random Subset Feature Selection (RSFS). The random forest classifier was used to predict individual ECT responses. Results The averaged TE, especially in frontal regions, was higher in ECT responders than in nonresponders. A predictive model using the RSFS method classified ECT responders and nonresponders with 85.3% balanced accuracy, 85.2% accuracy, 88.7% sensitivity, and 81.8% specificity. The positive predictive value was 82.6%, and the negative predictive value was 88.2%. Conclusions The results of the current study suggest that higher effective connectivity in frontal areas may be associated with a favorable ECT response. Furthermore, personalized decisions to perform ECT in clinical practice could be augmented by resting-state EEG biomarkers of the ECT response in schizophrenia patients.

When isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is combined with obstructive sleep apnea (OSA), the pattern of temporal association between REM without atonia (RWA) and apnea-hypopnea events may be related to improvements in RBD symptoms after positive airway pressure (PAP) treatment. We evaluated the frequency of improvement in RBD symptoms after PAP and the relationship of the degree of co-occurrence between RWA and apnea-hypopnea events to RBD symptom improvement after PAP treatment.In an institutional cohort with sleep disorders, 31 patients with video-polysomnography confirmed iRBD and concomitant OSA with an apnea-hypopnea index (AHI) of ≥15/h who received PAP treatment were included. Along with gross video-polysomnography parameters such as AHI and electromyography activity index during REM sleep, a mini-epoch-based parameter apnea-hypopnea-electromyography activity ratio (AH EMG activity ratio) was used to evaluate the co-occurrence between RWA and apnea-hypopnea events. Improvement in RBD symptoms after PAP treatment was designated as a clinical global impression-improvement (CGI-I) score of 0-3 at three-month.Twenty-three (74.2%) patients exhibited improvement in RBD symptoms after PAP treatment. No patient was taking an antidepressant medication. An AH EMG activity ratio of ≥15% (Odds ratio [OR] 10.146, 95% CI 1.302-79.032, P = 0.027) was significantly associated with clinical improvement after PAP treatment in a regression model adjusted for age, sex, AHI, and electromyography activity index during REM.Treatment of concomitant OSA with PAP can improve symptoms of iRBD. Respiratory events that co-occur with RWA may predict improvement in RBD symptoms after PAP treatment.

This paper presents an automatic algorithm for the detection of respiratory events in patients using electrocardiogram (ECG) and respiratory signals. The proposed method was developed using data of polysomnogram (PSG) and those recorded from a patch-type device. In total, data of 1,285 subjects were used for algorithm development and evaluation. The proposed method involved respiratory event detection and apnea-hypopnea index (AHI) estimation. Handcrafted features from the ECG and respiratory signals were applied to machine learning algorithms including linear discriminant analysis, quadratic discriminant analysis, random forest, multi-layer perceptron, and the support vector machine (SVM). High performance was demonstrated when using SVM, where the overall accuracy achieved was 83% and the Cohen's kappa was 0.53 for the minute-by-minute respiratory event detection. The correlation coefficient between the reference AHI obtained using the PSG and estimated AHI as per the proposed method was 0.87. Furthermore, patient classification based on an AHI cutoff of 15 showed an accuracy of 87% and a Cohen's kappa of 0.72. The proposed method increases performance result, as it records the ECG and respiratory signals simultaneously. Overall, it can be used to lower the development cost of commercial software owing to the use of open datasets.

We analyzed 136 patients (age, 67.5 ± 6.9 years; men, 59.6%) with idiopathic rapid eye movement sleep behavior disorder (iRBD). The results of the neuropsychological tests were not significantly different between APOE e4 carriers and noncarriers, suggesting that the APOE e4 allele was not associated with cognitive impairment in iRBD.

Background and Objective We used the Symptom Checklist 90-Revised (SCL-90-R) to compare the psychosomatic symptom profiles between periodic limb movement disorder (PLMD) and restless legs syndrome (RLS) patients. Methods Twenty consecutive drug-naïve RLS patients, 20 age- and sex-matched patients with PLMD and healthy controls were enrolled. Questionnaires evaluating sleep (Pittsburgh Sleep Quality Index, and Insomnia Severity Index), depression (Beck Depression Inventory II), and psychosomatic symptoms (SCL-90-R) were administered. Polysomnography was performed in the patients with PLMD or RLS. Results The mean age of the subjects was 57.5 ± 10.9 years, and half of the subjects were male. Compared with the patients with RLS, the patients with PLMD exhibited a reduced total sleep time (276.6 ± 41.3 vs. 322.4 ± 42.9, p = 0.04) and a decreased proportion of REM sleep (12.5 ± 6.6 vs. 17.8 ± 7.8, p = 0.009). The patients with RLS exhibited higher SCL-90-R T-scores on the somatization (post hoc p < 0.001), obsessive-compulsive (post hoc p < 0.001), interpersonal sensitivity (post hoc p = 0.003), anxiety (post hoc p = 0.005), and psychoticism (post hoc p = 0.004) domains than the controls. Compared to the controls, the patients with PLMD exhibited higher SCL-90-R scores only in hostility (post hoc p = 0.016). Somatization in the RLS patients was significantly worse than that in the PLMD patients (post hoc p = 0.003). Conclusions The results of our study demonstrate that psychosomatic distress is greater in RLS patients and lesser in PLMD patients. Somatization was a distinguishing symptom between RLS and PLMD.

Objective We investigated the effects of prolonged‐release melatonin (PRM) on idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). Methods In this 4‐week, randomized, double–blind, placebo–controlled pilot study, 30 participants with polysomnography–confirmed iRBD were assigned to receive PRM 2 mg per day, PRM 6 mg per day, or placebo. Medication was administered orally 30 min before bedtime. Primary outcomes included scores from the Clinical Global Impression‐Improvement (CGI‐I) and the Korean version of the RBD questionnaire‐Hong Kong (RBDQ‐KR). The secondary outcomes included RBDQ‐KR factor 1 and factor 2 subscores, the Pittsburgh Sleep Quality Index score, the Epworth Sleepiness Scale score, the Short Form Health Survey version 2 score, and the frequency of dream–enacting behaviors assessed using a sleep diary. Results After 4 weeks, there were no differences in the proportions of patients with a CGI‐I score of much improved or very much improved among the study groups. In addition, RBDQ‐KR scores and secondary outcomes were not improved in all groups at 4 weeks, and there were no differences between the groups. Conclusion Our findings suggest that PRM may not be effective in treating RBD–related symptoms within the dose range used in this study. Further studies using doses higher than 6 mg per day are warranted.

OBJECTIVE There is no scale for rating the severity of autoimmune encephalitis (AE). In this study, we aimed to develop a novel scale for rating severity in patients with diverse AE syndromes and to verify the reliability and validity of the developed scale. METHODS The key items were generated by a panel of experts and selected according to content validity ratios. The developed scale was initially applied to 50 patients with AE (development cohort) to evaluate its acceptability, reproducibility, internal consistency, and construct validity. Then, the scale was applied to another independent cohort (validation cohort, n = 38). RESULTS A new scale consisting of 9 items (seizure, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness) was developed. Each item was assigned a value of up to 3 points. The total score could therefore range from 0 to 27. We named the scale the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The new scale showed excellent interobserver (intraclass correlation coefficient [ICC] = 0.97) and intraobserver (ICC = 0.96) reliability for total scores, was highly correlated with modified Rankin scale (r = 0.86, p

Restless legs syndrome (RLS) is associated with dopaminergic dysfunction, and iron deficiency, manifesting as low ferritin. However, ferritin levels do not correlate well with demographic data. Based on the hypothesis that very low ferritin can accurately reflect clinical information, we herein described characteristics and treatment efficacy of RLS patients with ferritin levels under 15 ng/mL. We retrospectively reviewed 196 patients and collected clinical data. Twenty-one patients had ferritin levels under 15 ng/mL and were compared with those having ferritin levels over 15 ng/mL. The patients with very low ferritin levels were predominantly female, had earlier onset of symptoms, and showed a superior response to iron therapy. In conclusion, RLS patients with ferritin levels under 15 ng/mL showed distinct demographic features and treatment efficacy. Further studies on more patients with long-term follow-up are warranted to support this observation.

Background and Purpose: Individualized anti-epileptic drug (AED) selection in patient with epilepsy is crucial. However, there is no unified opinion in treating patients with drug resistant epilepsy (DRE). This survey aimed to make a consolidate consensus with epileptologists’ perspectives of the treatment for Korean DRE patients by survey responses.Methods: The survey was conducted with Korean epilepsy experts who have experience prescribing AEDs via e-mail. Survey questionnaires consisted of six items regarding prescription patterns and practical questions in treating patients with DRE in Korea. The research period was from February 2021 to March 2021.Results: The survey response rate was 83.3% (90/108). Most (77.8%) of the responders are neurologists. The proportion of patients whose seizures were not controlled by the second AED was 26.9%. The proportion of patients who had taken five or more AEDs is 13.9%, and those who are currently taking five or more AEDs are 7.3%, of which 54.5% and 37.9% reported positive effects on additional AED, respectively. The majority (91.1%) of respondents answered that the mechanism of action was the top priority factor when adding AED. Regarding data priority, responders considered that expert opinion should have the top priority, followed by clinical experiences, reimbursement guidelines and clinical evidence. Responders gave 64.9 points (range from 0 to 100) about overall satisfaction on reimbursement system of Health Insurance Review and Assessment Service for AED.Conclusions: This study on AED therapy for DRE patients is the first nationwide trial in Korean epilepsy experts. In five drug failure, the top priorities on AED selection are mechanism of action and expert opinion. These findings might help to achieve consensus and recognize the insight on optimal therapy of AED in DRE.

Cognitive impairment, particularly prefrontal function, has been reported in patients with restless legs syndrome. However, working memory performance in patients with restless legs syndrome remains uncertain. The present study aimed to examine working memory performance in patients with restless legs syndrome by investigating electroencephalography theta‐band oscillations within task‐relevant brain regions and the synchronization among oscillations during a working memory task. Twelve female idiopathic patients with restless legs syndrome and 12 female healthy controls participated in this study. Nineteen‐channel electroencephalography data were recorded while participants performed a Sternberg working memory task. We analysed event‐related theta‐band activity and interregional theta‐band phase synchrony during the memory retrieval phase. The spatial pattern of theta‐band phase synchrony was quantified using graph theory measures, including the clustering coefficient, characteristic path length, and small‐world propensity. Considerable increases in theta‐band activity and theta‐band phase synchrony were observed at 600–700 ms in controls and at 650–750 ms in restless legs syndrome subjects after the probe item was presented. During this period, induced theta‐band activity showed lower with borderline significance in the restless legs syndrome subjects than in the controls regardless of channel location (F 4,88 = 3.92, p = .06). Theta‐band phase synchrony between the frontal and posterior regions was significantly reduced in the restless legs syndrome subjects. Inefficiency in both global and local networks in the restless legs syndrome subjects was revealed by the decreased small‐world propensity (t 22 = 2.26, p = .03). Small‐world propensity was negatively correlated with restless legs syndrome severity (r = −.65, p = .02). Our findings suggest that patients with restless legs syndrome have multiple deficits in cognitive processes, including attentional allocation, evaluation of incoming stimuli, and memory manipulation of encoded information during a working memory task. Abnormal local theta‐band neural synchrony and global theta‐band neural synchrony may underlie the neurophysiological mechanism of the working memory dysfunction associated with restless legs syndrome.

Obstructive sleep apnea (OSA) has a bidirectional relationship with insulin resistance conditions; however, the mechanism remains unclear. This study aimed to compare dynamic nocturnal glucose changes among patients with OSA of varying levels of severity and evaluate temporal changes associated with the cardinal features of OSA (sympathetic hyperactivation, intermittent hypoxemia, and sleep fragmentation) in nondiabetic subjects. Nocturnal glucose was measured with a continuous glucose monitoring device every 5 min during polysomnography (PSG). The OSA features were evaluated using heart rate variability (HRV), minimum saturation, and electroencephalography. Eleven subjects with moderate to severe OSA and 12 subjects with no or mild OSA were evaluated. Those with moderate to severe OSA showed an increasing trend in blood glucose levels after sleep onset, whereas those without or with mild OSA showed a decreasing trend (F = 8.933, p p = 0.009), and minimum saturation remained lower in the moderate to severe OSA group than in the no or mild OSA group. High degrees of coupling between nocturnal glucose levels and each OSA feature were observed. Altered trends in nocturnal glucose in moderate to severe OSA may reflect glucose intolerance and result in metabolic consequences. Managing the features of sleep-related OSA may have implications for metabolic management in the future.

Objective Functional connectivity (FC) changes can occur prior to structural changes. This study aimed to evaluate data-driven whole-brain FC associated with isolated rapid eye movement sleep behavior disorder (iRBD) using multivariate pattern analysis (MVPA). Methods This was a cross-sectional study of 50 polysomnography-confirmed iRBD patients and 20 age- and sex-matched controls. We used MVPA implemented in the connectome-MVPA CONN toolbox to identify data-driven seed regions for post hoc seed-to-voxel connectivity analysis. The association between FC changes and clinical characteristics, including cognition, depression, autonomic function, and daytime sleepiness, was evaluated. Results MVPA revealed one significant cluster located in the left posterior insular cortex. Seed-to-voxel FC analysis using the cluster as a seed showed significantly reduced FC with two clusters located in the precuneus in iRBD patients compared to the controls. The degree of FC was associated with the Montreal Cognitive Assessment-Korean version scores (r = 0.317, p = 0.025). Conclusion This study emphasizes the insula as an important neural correlate associated with iRBD that was associated with cognitive function.

Background and purpose The aim of this study was to survey the expert opinions on treatments for convulsive status epilepticus (CSE) and nonconvulsive status epilepticus (NCSE) in adults. Methods Forty-two South Korean epileptologists participated in this survey. They completed an online questionnaire regarding various patient scenarios and evaluated the appropriateness of medications used to treat CSE and NCSE. Results Initial treatment with a benzodiazepine (BZD) followed by either a second BZD or an antiepileptic drug (AED) monotherapy was the preferred treatment strategy. More than two-thirds of the experts used a second BZD when the first one failed, and consensus was reached for 84.8% of the survey items. The preferred BZD was intravenous (IV) lorazepam for the initial treatment of status epilepticus. IV fosphenytoin and IV levetiracetam were chosen for AED monotherapy after the failure of BZD. The treatments for NCSE were similar to those for CSE. Continuous IV midazolam infusion was the treatment of choice for iatrogenic coma in refractory CSE, but other AEDs were preferred over iatrogenic coma in refractory NCSE. Conclusions The results of this survey are consistent with previous guidelines, and can be cautiously applied in clinical practice when treating patients with CSE or NCSE.