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Jung-Ick Byun,1 Tae-Won Yang,2– 4 Jun-Sang Sunwoo,5 Won Chul Shin,1,6 Oh-Young Kwon,2,4,7,* Ki-Young Jung8,* 1Department of Neurology, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Republic of Korea; 2Department of Neurology, Gyeongsang National University College of Medicine, Jinju, Republic of Korea; 3Department of Neurology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea; 4Institute of Science, Gyeongsang National University College of Medicine, Jinju, Republic of Korea; 5Department of Neurology, Kangbuk Samsung Hospital, Seoul, Republic of Korea; 6Department of Medicine, AgeTech-service Convergence Major, Kyung Hee University, Seoul, Republic of Korea; 7Department of Neurology, Gyeongsang National University Hospital, Jinju, Republic of Korea; 8Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea*These authors contributed equally to this workCorrespondence: Oh-Young Kwon, Department of Neurology, Gyeongsang National University College of Medicine, 15, Jinjudae-ro 816beon-gil, Jinju, 52727, Republic of Korea, Tel +82-55-750-8288, Email oykwon@gnu.ac.kr 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, 110-744, Republic of Korea, Tel +82-2-920-6649, Email jungky@snu.ac.krPurpose: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by REM sleep without atonia (RWA) and is regarded as the prodromal stage of α-synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). RWA is also associated with neurodegeneration driven by α-synucleinopathy. However, the level of RWA across the α-synucleinopathy spectrum remains elusive. We aimed to rate the percentage of RWA across the α-synucleinopathy spectrum, encompassing prodromal and overt phenotypes.Methods: A systematic search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases. We included cohort, cross-sectional, and case–control studies comparing the RWA percentage during REM sleep evaluated by tonic chin activity (RWA%-T) or by phasic chin activity (RWA%-P) across the α-synucleinopathy spectrum. Bayesian network meta-analysis was used to combine both direct and indirect evidence regarding the group differences in the RWA%-T and RWA%-P. The surface under the cumulative ranking curve was used to estimate the ranked probability.Results: Fifteen articles met the inclusion criteria. The investigations included 204 iRBD, 295 PD with RBD (PDwtRBD), 187 PD without RBD (PDwoRBD), 42 MSAwtRBD, 9 DLBwtRBD patients, and 246 controls. MSAwtRBD ranked first in RWA%-T, whereas iRBD ranked first in RWA%-P. RWA% in PDwoRBD patients was comparable to that in the controls and was lower than that in PDwtRBD patients.Conclusion: Overt phenotypes such as MSAwtRBD and PDwtRBD ranked high in RWA%-T, whereas iRBD, a prodromal type, ranked highest in RWA%-P. Taken together, our data suggest that the percentage of neurodegeneration in RBD patients may be associated with RWA%-T rather than RWA%-P.Prospero Registration Number: CRD42021276445.Keywords: REM sleep behavior disorder, α-synucleinopathy, REM sleep without atonia, network meta-analysis

Jin-Sun Jun1 *, Jun-Sang Sunwoo2 *, 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*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

Background: Cryptogenic new-onset refractory status epilepticus (cNORSE) currently lacks comprehensive knowledge regarding its clinical dynamics, prognostic factors and treatment guidance. Here we present the longitudinal clinical profiles, predictive factors for outcomes and the optimal duration of immunotherapy in patients with cNORSE., Methods: This retrospective secondary endpoint analysis investigated patients with cNORSE identified from a prospective autoimmune encephalitis cohort at a national referral centre in Korea. The main outcomes included longitudinal functional scales, seizure frequency and the number of antiseizure medications. Measures encompassed NORSE-related clinical parameters such as the duration of unconsciousness, immunotherapy profiles, cytokine/chemokine analysis, and serial MRI scans., Results: A total of 74 patients with cNORSE were finally analysed (mean age: 38.0±18.2; 36 (48.6%) male). All patients received first-line immunotherapy, and 91.9% (68/74) received second-line immunotherapy. A total of 83.8% (62/74) regained consciousness within a median duration of 30 days (14-56), and 50% (31/62) achieved good outcome (mRS ≤2) at 2 years. Poor 1-year outcomes (mRS ≥3) were predicted by the presence of mesial temporal lobe (mTL) and extra-mTL lesions at 3-month MRI, and prolonged unconsciousness (≥60 days). Those with mTL atrophy exhibited a higher seizure burden post-NORSE. The optimal duration of immunotherapy appeared to be between 18 weeks and 1-year post-NORSE onset., Conclusions: This study elucidates longitudinal clinical dynamics, functional outcomes, prognostic factors and immunotherapy response in patients with cNORSE. These findings might contribute to a more standardised understanding and clinical decision-making for cNORSE., Competing Interests: Competing interests: Dr S-TL reports personal fees from Roche/Genentech (steering committee) and Advanced Neural Technologies (advisory board), and grants from GC Pharma and Celltrion, outside the submitted work. Dr DD reports consultant fees (paid to institution) from UCB, Immunovant, Argenx, Arialys and Astellas Pharmaceuticals. Dr DD has patents pending for LUZP4-IgG, cavin-4-IgG and SKOR2 IgG as markers of neurological autoimmunity, and patents licensed for KLHL11 IgG., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Among patients with epilepsy, 30-40% experience recurrent seizures even after adequate antiseizure medications therapies, making them refractory. The early identification of refractory epilepsy is important to provide timely surgical treatment for these patients. In this study, we analyze interictal electroencephalography (EEG) data to predict drug refractoriness in patients with temporal lobe epilepsy (TLE) who were treated with monotherapy at the time of the first EEG acquisition. Various EEG features were extracted, including statistical measurements and interchannel coherence. Feature selection was performed to identify the optimal features, and classification was conducted using different classifiers. Functional connectivity and graph theory measurements were calculated to identify characteristics of refractory TLE. Among the 48 participants, 34 (70.8%) were responsive, while 14 (29.2%) were refractory over a mean follow-up duration of 38.5 months. Coherence feature within the gamma frequency band exhibited the most favorable performance. The light gradient boosting model, employing the mutual information filter-based feature selection method, demonstrated the highest performance (AUROC = 0.821). Compared to the responsive group, interchannel coherence displayed higher values in the refractory group. Interestingly, graph theory measurements using EEG coherence exhibited higher values in the refractory group than in the responsive group. Our study has demonstrated a promising method for the early identification of refractory TLE utilizing machine learning algorithms., (© 2024. The Author(s).)

Study Objectives: Isolated rapid-eye movement behavior disorder (iRBD) is a prodromal synucleinopathy, but its conversion rate and subtypes can vary among different cohorts. We report the clinical characteristics and phenoconversion rate of the large single-center iRBD cohort in Korea and compared it to the Montreal cohort., Methods: This prospective cohort study examined 238 patients with polysomnography confirmed iRBD from Seoul National University Hospital (SNUH) who completed at least one follow-up evaluation. We compared the baseline and phenoconversion data of the SNUH cohort to those of 242 iRBD patients in the Montreal cohort., Results: In the SNUH cohort, age at RBD diagnosis was similar (66.4±7.8 vs 65.6±8.4, p=0.265), but the proportion of men was lower (63.0% vs. 74.0%, p=0.001), and the duration of follow-up was shorter than that in the Montreal cohort (3.7±2.0 vs. 4.8±3.6 years, p<0.001). During follow-up, 34 (11.8%) patients in the SNUH cohort converted to neurodegenerative disease: 18 (52.9%) to Parkinson's disease, 9 (26.5%) to dementia with Lewy bodies (DLB), and 7 (20.6%) to multiple system atrophy. The conversion rate in the SNUH cohort was 15% after 3 years, 22% after 5 years, and 32% after 7 years, which was significantly lower than that of the Montreal cohort (log-rank test, p=0.002). Among phenoconversion subtype, fewer subjects in the SNUH group than in the Montreal group converted to DLB (Gray's test p=0.001)., Conclusions: Through a comparative analysis between the SNUH and Montreal cohorts, we identified a significant difference in phenoconversion rates, particularly for DLB patients. These findings underscore the importance of further research into the underlying factors, such as racial and geographical factors contributing to such disparities., (© 2024 American Academy of Sleep Medicine.)

Objective: Restless legs syndrome (RLS) is a common sleep disorder among adolescents. This study aimed to investigate the lifestyle factors and sleep disturbances associated with the symptoms suggestive of RLS in Korean adolescents., Methods: In this cross-sectional study, we investigated a total of 25,789 adolescents (mean age, 15.8 ± 1.7 years; male, 48.5 %). The presence of symptoms suggestive of RLS was assessed with a single question about RLS in the Global Sleep Assessment Questionnaire. We performed multiple logistic regression analysis to estimate the odds ratios (ORs) and 95 % confidence intervals (CIs) of lifestyle factors and sleep disturbances that were independently associated with adolescent RLS., Results: The prevalence of RLS-suggestive symptoms was 5.1 % among adolescents. After adjustment, lifestyle factors associated with symptoms suggestive of RLS were occasional alcohol consumption (OR, 1.245; 95 % CI, 1.006-1.540) and proneness to Internet addiction (OR, 1.027; 95 % CI, 1.021-1.033). Bedtime behaviors associated with RLS-suggestive symptoms were sleeping with a doll or pet (OR, 1.194; 95 % CI, 1.032-1.381) and sleeping with a TV or radio on (OR, 1.366; 95 % CI, 1.156-1.614). Male sex, frequent snoring and witnessed apnea, perceived sleep insufficiency, excessive daytime sleepiness were also associated with RLS-suggestive symptoms in adolescents., Conclusions: Adolescents with symptoms suggestive of RLS were associated with different lifestyle factors compared to adults with RLS. Further research is needed to determine the clinical implications of lifestyle factors in adolescent RLS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Study Objectives: Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies and eventually phenoconverts to overt neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Associations of baseline resting-state electroencephalography (EEG) with phenoconversion have been reported. In this study, we aimed to develop machine learning models to predict phenoconversion time and subtype using baseline EEG features in patients with iRBD., Methods: At baseline, resting-state EEG and neurological assessments were performed on patients with iRBD. Calculated EEG features included spectral power, weighted phase lag index, and Shannon entropy. Three models were used for survival prediction, and four models were used for α-synucleinopathy subtype prediction. The models were externally validated using data from a different institution., Results: A total of 236 iRBD patients were followed up for up to 8 years (mean 3.5 years), and 31 patients converted to α-synucleinopathies (16 PD, 9 DLB, 6 MSA). The best model for survival prediction was the random survival forest model with an integrated Brier score of 0.114 and a concordance index of 0.775. The K-nearest neighbor model was the best model for subtype prediction with an area under the receiver operating characteristic curve of 0.901. Slowing of the EEG was an important feature for both models., Conclusions: Machine learning models using baseline EEG features can be used to predict phenoconversion time and its subtype in patients with iRBD. Further research including large sample data from many countries is needed to make a more robust model., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective/background: This study investigated fatigue and excessive daytime sleepiness to determine which was more closely related to depression in the general population., Patients/methods: Participants were investigated across 15 South Korean districts. Excessive daytime sleepiness, fatigue, and depression were evaluated using the Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), and Patient Health Questionnaire-9 (PHQ-9), respectively. Depression was defined as PHQ-9 ≥ 10. The authors classified the combination of excessive daytime sleepiness and fatigue as excessive daytime sleepiness with fatigue (E + F + , ESS ≥ 11, FSS ≥ 36), fatigue without excessive daytime sleepiness (E - F + , ESS < 11, FSS ≥ 36), excessive daytime sleepiness without fatigue (E + F - , ESS ≥ 11, FSS < 36), and no fatigue and excessive daytime sleepiness (E - F - , ESS < 11, FSS < 36)., Results: Among 2,493 participants (1,257 women), mean age was 47.9 ± 0.3 years. The prevalence of depression, fatigue, and excessive daytime sleepiness was 8.4% (n = 210), 30.8% (n = 767), and 15.3% (n = 382), respectively. The frequency of the four categories with depression (vs. controls) was as follows.: E + F + (n = 67, 31.9% vs. 7.3%) (P < 0.001), E - F + (n = 71, 33.8% vs. 20.3%) (P < 0.001), E + F - ( n = 16, 7.6% vs. 5.8%) (P = 0.294), and E - F - (n = 56, 26.7% vs. 66.6%) (P < 0.001). After adjusting for covariates, depression was associated with E + F + (odds ratio, OR 8.804, 95% confidence interval (CI) 5.818-13.132), E - F + (OR 3.942, 95% CI 2.704-5.747), E + F - (OR 2.812, 95% CI 1.542-5.131), and E - F - (reference). Additionally, we performed logistic regression according to two categories. There was no significant difference in the association of depression between E + F - (reference) and E - F + (OR 1.399, 95% CI 0.760-2.575)., Conclusion: Although fatigue and excessive daytime sleepiness were associated with depression regardless of the presence of each other, we could not clarify which was more closely related to depression., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Several neurological manifestations shortly after a receipt of coronavirus infectious disease 2019 (COVID-19) vaccine have been described in the recent case reports. Among those, we sought to evaluate the risk of encephalitis and meningitis after COVID-19 vaccination in the entire South Korean population., Methods: We conducted self-controlled case series (SCCS) analysis using the COVID-19 immunization record data from the Korea Disease Control Agency between February 2021 and March 2022, linked with the National Health Insurance Database between January 2021 and October 2022. We retrieved all medical claims of adults aged 18 years or older who received at least one dose of COVID-19 vaccines (BNT162b2, mRNA-1273, ChAdOx1-S, or Ad26.COV2.S), and included only those who had a diagnosis record for encephalitis or meningitis within the 240-day post-vaccination period. With day 0 defined as the date of vaccination, risk window was defined as days 1-28 and the control window as the remainder period excluding the risk windows within the 240-day period. We used conditional Poisson regression to estimate the incidence rate ratios (IRR) with 95% confidence intervals (CI), stratified by dose and vaccine type., Results: From 129,956,027 COVID-19 vaccine doses administered to 44,564,345 individuals, there were 251 and 398 cases of encephalitis and meningitis during the risk window, corresponding to 1.9 and 3.1 cases per 1 million doses, respectively. Overall, there was an increased risk of encephalitis in the first 28 days of COVID-19 vaccination (IRR 1.26; 95% CI 1.08-1.47), which was only significant after a receipt of ChAdOx1-S (1.49; 1.03-2.15). For meningitis, no increased risk was observed after any dose of COVID-19 vaccine (IRR 1.03; 95% CI 0.91-1.16)., Conclusions: Our findings suggest an overall increased risk of encephalitis after COVID-19 vaccination. However, the absolute risk was small and should not impede COVID-19 vaccine confidence. No significant association was found between the risk of meningitis and COVID-19 vaccination., (© 2024. The Author(s).)

Introduction: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia., Methods: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing., Results: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes., Discussion: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion., Highlights: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 < .001). There was no significant difference in susceptibility values between the controls and RLS patients at t0. In the caudate nucleus, putamen, and pulvinar thalamus of RLS patients, the QSM values differed significantly for three timepoints (p = .035, .048, and .032, respectively). The post-hoc analysis revealed that the QSM values increased at t1 in the caudate nucleus (66.8 ± 18.0 vs 76.4 ± 16.6, p = .037) and decreased from t1 to t2 in the putamen (69.4 ± 16.3 vs 62.5 ± 13.6, p = .025). Changes in the QSM values for the pulvinar and caudate nuclei at t1 were positively and negatively correlated with symptomatic improvement, respectively (r = 0.361 and -0.466, respectively)., 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objective: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of neurodegeneration and is associated with cortical dysfunction. The purpose of this study was to investigate the spatiotemporal characteristics of cortical activities underlying impaired visuospatial attention in iRBD patients using an explainable machine-learning approach., Methods: An algorithm based on a convolutional neural network (CNN) was devised to discriminate cortical current source activities of iRBD patients due to single-trial event-related potentials (ERPs), from those of normal controls. The ERPs from 16 iRBD patients and 19 age- and sex-matched normal controls were recorded while the subjects were performing visuospatial attentional task, and converted to two-dimensional images representing current source densities on flattened cortical surface. The CNN classifier was trained based on overall data, and then, a transfer learning approach was applied for the fine-tuning to each patient., Results: The trained classifier yielded high classification accuracy. The critical features for the classification were determined by layer-wise relevance propagation, so that the spatiotemporal characteristics of cortical activities that were most relevant to cognitive impairment in iRBD were revealed., Conclusions: These results suggest that the recognized dysfunction in visuospatial attention of iRBD patients originates from neural activity impairment in relevant cortical regions and may contribute to the development of useful iRBD biomarkers based on neural activity., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in this study, (Copyright © 2023. Published by Elsevier B.V.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Cognitive impairments are common in isolated rapid-eye-movement sleep behavior disorder (iRBD), in which the cholinergic system may play an important role. This study aimed to characterize the cortical cholinergic activity using resting-state functional connectivity (FC) of the nucleus basalis of Meynert (NBM) according to the cognitive status of iRBD patients., Methods: In this cross-sectional study, 33 patients with polysomnography-confirmed iRBD and 20 controls underwent neuropsychological evaluations and resting-state functional magnetic resonance imaging. Thirteen of the iRBD patients had mild cognitive impairment (iRBD-MCI), and the others were age-matched patients with normal cognition (iRBD-NC). The seed-to-voxel NBM-cortical FC was compared among the patients with iRBD-MCI, patients with iRBD-NC, and controls. Correlations between average values of significant clusters and cognitive function scores were calculated in the patients with iRBD., Results: There were group differences in the FC of the NBM with the left lateral occipital cortex and lingual gyrus (adjusted for age, sex, and education level). The strength of FC was lower in the iRBD-MCI group than in the iRBD-NC and control groups (each post-hoc p <0.001). The average NBM-lateral occipital cortex FC was positively correlated with the memory-domain score in iRBD patients., Conclusions: The results obtained in this study support that cortical cholinergic activity is impaired in iRBD patients with MCI. FC between NBM and posterior regions may play a central role in the cognitive function of these patients., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2022 Korean Neurological Association.)

Purpose: This study aimed to investigate sleep problems and comorbid conditions associated with fatigue in the general population., Methods: The data were obtained from a nationwide cross-sectional survey conducted in 2018. The Fatigue Severity Scale was used to assess fatigue. We examined sleep habits, such as workday sleep duration, chronotype, and free-day catch-up sleep, excessive daytime sleepiness (EDS), depression, and other comorbid conditions. We conducted multiple logistic regression analysis with the presence of fatigue as a dependent variable., Results: Of 2,493 adults aged 19 to 92 years, 50% men, mean age was 47.9 ± 16.4 years. The average workday sleep duration was 7.1 ± 1.1 h, and the prevalence of fatigue was 31%. After adjusting for potential confounders, fatigue was associated with EDS (odds ratio [OR] 3.751, 95% confidence interval [CI] 2.928-4.805), depression (OR 3.736, 95% CI 2.701-5.169), perceived insufficient sleep (OR 1.516, 95% CI 1.249-1.839), free-day catch-up sleep (OR 1.123, 95% CI 1.020-1.235), less alcohol intake (OR 0.570, 95% CI 0.432-0.752), and physical inactivity (OR 0.737, 95% CI 0.573-0.948). On subgroup analysis, fatigue was additionally associated with short workday sleep duration (OR 0.899, 95% CI 0.810-0.997) in individuals without EDS. However, among those with EDS, only depression (OR 2.842, 95% CI 1.511-5.343) and less alcohol intake (OR 0.476, 95% CI 0.247-0.915) were associated with fatigue., Conclusion: Fatigue was significantly associated with depression independent of EDS. Further research is warranted to better understand the pathophysiological relationship between fatigue, depression, and sleep., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Although periodic limb movement during sleep (PLMS) and restless legs syndrome (RLS) are common in children and adolescents, they are relatively overlooked as a target of treatment. PLMS has been evaluated as having a lower clinical significance than RLS. This study examined the relationship of socio-behavioral factors of PLMS in Korean adolescents and checked whether PLMS is associated with excessive daytime sleepiness (EDS), depending on whether restless legs symptoms accompany it. In a cross-sectional study, 25,789 adolescents between 12 and 18 years of age (15.76 ± 1.73 years; female 51.49%) were evaluated using an online survey. Various self-report questionnaires were used to assess PLMS and RLS symptoms, EDS, sleep habits, and various socio-behavioral factors. The prevalence of self-perceived PLMS and restless legs symptoms were 903 (3.50%) and 1311 (5.08%), respectively. Of the 1311 participants, 399 had self-perceived PLMS. The odds ratios (ORs) for self-perceived PLMS in participants with restless legs symptoms were: males (OR = 1.528; 95% CI: 1.145-2.040), usually/always experienced apnea apnea (OR, 3.006; 95% CI, 1.954-4.624), increased proneness to Internet addiction (OR = 1.013; 95% CI: 1.001-1.025), sometimes/often consuming coffee (OR = 1.312; 95% CI: 1.015-1.695), EDS (OR = 0.826; 95% CI: 0.488-1.398), and perceived insufficient sleep (OR = 1.143; 95% CI: 0.835-1.565). The male gender, witness apnea, consuming coffee, and being prone to Internet addiction were identified as factors significantly associated with self-perceived PLMS in participants with restless legs symptoms. However, EDS and insufficient sleep were associated with self-perceived PLMS in the absence of restless legs symptoms.

Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective/background: 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., Patients/methods: 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., Results: 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., Conclusions: 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Epstein-Barr virus (EBV) is implicated in various neurological conditions. However, the relationship between EBV DNA in cerebrospinal fluid (CSF) and central nervous system (CNS) infection is unclear. We evaluated the clinical manifestation of patients with EBV DNA detected in CSF., Methods: We reviewed the medical records of patients admitted to Seoul National University Hospital from January 2000 to March 2021 who underwent EBV polymerase chain reaction (PCR) tests in CSF. The subjects were divided into positive and negative groups depending on the presence of EBV DNA, and further clinical information was obtained from positive patients., Results: CSF EBV PCR tests were performed in 807 patients, and 57 (7.1%) tested positive. Pleocytosis was common (81.1%) in CSF samples with EBV DNA detected, and the proportion was significantly higher than that in samples that were EBV PCR negative (44.5%, p < 0.0001). Among 57 patients with EBV DNA detected in CSF, 51 (89.5%) were diagnosed with CNS infection or inflammatory disorders. Of the 51 patients, 31 (60.8%) had possible etiologies other than EBV. Follow-up evaluation was conducted in 19 of 20 patients, and 63.2% showed a favorable outcome., Conclusion: Positive EBV PCR in CSF is mostly nonspecific and should be interpreted with caution. A comprehensive workup is needed to identify other etiologies before considering EBV as the sole culprit., Competing Interests: Conflicts of Interest Kon Chu and Sang Kun Lee have been on the editorial board of encephalitis since October 2020. They were not involved in the review process of this article. No other potential conflict of interest relevant to this article was reported., (Copyright © 2022 Korean Encephalitis and Neuroinflammation Society.)

Objective: White matter (WM) tract-specific changes may precede gray matter loss in isolated rapid eye movement sleep behavior disorder (iRBD). We aimed to evaluate tract-specific WM changes using tract-specific statistical analysis (TSSA) and their correlation with clinical variables in iRBD patients., Methods: This was a cross-sectional single-center study of 50 polysomnography-confirmed iRBD patients and 20 age- and sex-matched controls. We used TSSA to identify tract-specific fractional anisotropy (FA) and mean diffusivity (MD) in fourteen major fiber tracts and analyzed between-group differences in these values. Correlations between FA or MD values and clinical variables, including RBD symptom severity, depression and cognition, were evaluated., Results: Patients with iRBD showed lower FA in the right anterior thalamic radiation (ATR) and higher MD in the bilateral ATR and right inferior fronto-occipital fasciculus (IF-OF) than controls after adjusting for age, sex, and years of education. MD values in the IF-OF positively correlated with scores on the Korean version of the Rapid Eye Movement Sleep Behavior Disorder Questionnaire-Hong Kong (RBDQ-KR, p = 0.042) and the Korean version of the geriatric depression scale (GDS-K, p = 0.002) in iRBD patients. Only GDS-K scores independently correlated with IF-OF MD values after adjusting for RBDQ-KR scores (adjusted p = 0.026)., Conclusion: This study suggests WM microstructural disruption in the bilateral ATR and right IF-OF in patients with iRBD and that alterations in the IF-OF may contribute to depressive symptoms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2021 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Background and Purpose: Japanese encephalitis (JE) is caused by the JE virus of the Flaviviridae family and is spread by mosquito bites, and no specific antiviral treatment for it exists. Here we describe the clinical presentations, laboratory findings, clinical outcomes, and adverse events after combination treatment of immunoglobulin, ribavirin, and interferon-α2b administered to patients with JE., Methods: Data were collected and reviewed from a prospective cohort of encephalitis patients admitted to Seoul National University Hospital between August 1, 2010 and October 31, 2019. We reviewed the medical records of the patients diagnosed with JE and treated either with supportive care only or with combination treatment of intravenous immunoglobulin, oral ribavirin, and subcutaneous interferon-α2b., Results: Eleven patients were diagnosed with laboratory-confirmed JE based on the diagnosis criteria of JE. The median age was 61 years, and five patients were male. Eight patients were treated with the combination therapy, while three patients received supportive management only. Four of the eight patients (50%) treated with the combination therapy showed partial recovery, while one patient (12.5%) showed complete recovery. Two patients experienced hemolytic anemia related to ribavirin and febrile reaction to immunoglobulin, respectively. Among the three patients who received supportive management only, one (33.3%) showed partial recovery and the other two (67.7%) did not show improvement., Conclusions: Combination treatment of immunoglobulin, ribavirin, and interferon-α2b was found to be tolerable in JE in this study. Further studies of appropriate designs and involving larger numbers of patients are warranted to explore the efficacy of this combination therapy., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2021 Korean Neurological Association.)

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., Competing Interests: Conflict of Interest The authors declare that they have no conflicts of interest., (Copyright © 2021 Korean Epilepsy Society.)

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., (© 2021 American Academy of Sleep Medicine.)

Narcolepsy is a rare neurological disorder characterized by excessive daytime sleepiness (EDS) with or without cataplexy. A main pathophysiology of narcolepsy is hypocretin deficiency in the central nervous system resulting from a selective loss of hypocretin neurons in the lateral hypothalamus. To date, the pathogenesis of hypocretin neuron loss in narcolepsy is the most commonly accepted autoimmune hypothesis which is supported by genetic risk factors for narcolepsy such as HLA‑DQB1*06:02 allele and T-cell receptor alpha polymorphisms. Other evidence supporting the immune-mediated mechanisms include the presence of anti-Tribbles homolog 2 (TRIB2) and anti-streptococcal antibodies in patients with narcolepsy, seasonal patterns of narcolepsy onset, and increased incidence of narcolepsy after the H1N1 pandemic influenza A infections and vaccinations. Among several types of vaccines, the AS03-adjuvanted vaccine Pandemrix (GlaxoSmithKline) was the only vaccine found to increase the risk of narcolepsy. However, the comprehensive results of several epidemiological studies indicate the adjuvant AS03 alone cannot cause the disease. The genetic predisposition, environmental triggers, molecular mimicry of specific H1N1 antigens, and bystander immune activation caused by the adjuvant AS03 may have combined to contribute to autoimmunity against hypocretin neurons and development of narcolepsy., Competing Interests: Conflicts of Interest No potential conflict of interest relevant to this article was reported., (Copyright © 2021 Korean Encephalitis and Neuroinflammation Society.)

Bacterial meningitis is a neurological emergency with high morbidity and mortality. We herein investigated clinical features, etiology, antimicrobial susceptibility profiles, and prognosis of bacterial meningitis in adults from a single tertiary center. We retrospectively reviewed medical records of patients with laboratory-confirmed bacterial meningitis from 2007 to 2016. Patients with recent neurosurgery, head trauma, or indwelling neurosurgical devices were classified as having healthcare-related meningitis. Causative microorganisms were identified by analyzing cerebrospinal fluid (CSF) and blood cultures, and antimicrobial susceptibility profiles were evaluated. We performed multiple logistic regression analysis to identify factors associated with unfavorable outcomes. We identified 161 cases (age, 55.9 ± 15.5 years; male, 50.9%), of which 43 had community-acquired and 118 had healthcare-related meningitis. CSF and blood culture positivity rates were 91.3% and 30.4%, respectively. In community-acquired meningitis patients, Klebsiella pneumoniae (25.6%) was the most common isolate, followed by Streptococcus pneumoniae (18.6%) and Listeria monocytogenes (11.6%). The susceptibility rates of K. pneumoniae to ceftriaxone, cefepime, and meropenem were 85.7%, 81.3%, and 100%, respectively. Among healthcare-related meningitis patients, the most common bacterial isolates were coagulase-negative staphylococci (28.0%), followed by Staphylococcus aureus (16.1%) and Enterobacter spp. (13.6%). Neurological complications occurred in 39.1% of the patients and the 3-month mortality rate was 14.8%. After adjusting for covariates, unfavorable outcome was significantly associated with old age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00-1.06), neurological complications (OR 4.53, 95% CI 1.57-13.05), and initial Glasgow coma scale ≤ 8 (OR 19.71, 95% CI 4.35-89.40). Understanding bacterial pathogens and their antibiotic susceptibility may help optimize antimicrobial therapy in adult bacterial meningitis.

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Study Objectives: We investigated electroencephalographic (EEG) slow oscillations (SOs), sleep spindles (SSs), and their temporal coordination during nonrapid eye movement (NREM) sleep in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD)., Methods: We analyzed 16 patients with video-polysomnography-confirmed iRBD (age, 65.4 ± 6.6 years; male, 87.5%) and 10 controls (age, 62.3 ± 7.5 years; male, 70%). SSs and SOs were automatically detected during stage N2 and N3. We analyzed their characteristics, including density, frequency, duration, and amplitude. We additionally identified SO-locked spindles and examined their phase distribution and phase locking with the corresponding SO. For inter-group comparisons, we used the independent samples t-test or Wilcoxon rank-sum test, as appropriate., Results: The SOs of iRBD patients had significantly lower amplitude, longer duration (p = 0.005 for both), and shallower slope (p < 0.001) than those of controls. The SS power of iRBD patients was significantly lower than that of controls (p = 0.002), although spindle density did not differ significantly. Furthermore, SO-locked spindles of iRBD patients prematurely occurred during the down-to-up-state transition of SOs, whereas those of controls occurred at the up-state peak of SOs (p = 0.009). The phase of SO-locked spindles showed a positive correlation with delayed recall subscores (p = 0.005) but not with tonic or phasic electromyography activity during REM sleep., Conclusions: In this study, we found abnormal EEG oscillations during NREM sleep in patients with iRBD. The impaired temporal coupling between SOs and SSs may reflect early neurodegenerative changes in iRBD., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Antiepileptic drugs are well known for their effects on cognition and electrophysiologic changes. However, perampanel is yet to be evaluated for its effects on cognitive function and electroencephalography (EEG). The purpose of the present study was to identify the effect of perampanel on neuropsychological (NP) tests and quantitative EEG (QEEG) and their relationship with the level of the drug in blood. Seventeen patients with epilepsy were enrolled in the study. Electroencephalographic recordings were obtained, and NP tests were conducted before perampanel intake and 6 months after treatment. The relative frequency band power, peak alpha frequency, and NP test scores were compared before and after drug administration. The serum concentration of perampanel was correlated with the QEEG changes. Delayed recall of the Rey Complex Figure showed significant improvement (20.03 vs. 22.94; P = 0.004) following perampanel administration. Other cognitive function tests showed no significant differences before and after drug administration. Theta frequency band power increased in all brain regions (P = 0.001-0.01), and alpha frequency power decreased in all brain regions (P = 0.006-0.03). The theta/alpha ratio, which represents background EEG slowing, increased in all brain areas (P = 0.003-0.02). The peak frequency of the alpha rhythm decreased after perampanel intake (t = 2.45, P = 0.03). Difference of relative alpha power in the central region positively correlated with the blood level of perampanel (r = 0.53, P = 0.03). Perampanel induced electrophysiological slowing, but cognitive decline was not observed. Because the controls were not compared in the study, the results of cognitive function tests should be interpreted conservatively. Background EEG slowing correlated with the serum concentration of perampanel. Our results show the effect of perampanel on cognitive function and background EEG in adult patients with epilepsy., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The present study aimed to examine the association between morningness-eveningness preferences, sleep duration, weekend catch-up sleep duration and depression among Korean high-school students. A total of 8,655 high-school students participated from 15 districts in South Korea and completed an online self-report questionnaire. The following sleep characteristics were assessed: weekday and weekend sleep duration, weekend catch-up sleep duration, morningness-eveningness preference, perceived sufficiency of sleep, self-reported snoring and sleep apnea, daytime sleepiness, and sleep environment. Age, gender, body mass index, number of private classes, proneness to internet addiction, and depressive mood were also evaluated. A logistic regression analysis was conducted to compute odds ratios for the association between depression and sleep characteristics, after controlling for relevant covariates. Eveningness preference was a significant predictor of depressive mood (adjusted OR, 1.71; 95% CI, 1.47-1.99). Weekend CUS durations that were ≥2 hr and enrollment in numerous private classes were associated with a lower risk for depression (0.68, 0.55-0.85; 0.76, 0.60-0.95; respectively). Female gender, underweight and obese body weight, short weekday sleep durations, excessive daytime sleepiness, perceived excessiveness and insufficiency of sleep, self-reported snoring and sleep apnea, proneness to internet addiction and a non-optimal sleep environment were associated with an increased risk for depression. Eveningness preference and insufficient weekday sleep duration were associated with an increased risk for depression. Weekend CUS duration ≥2 hr reduced the risk for depression. Diverse aspects, including sleeping habits and sleep-related environmental factors, should be considered to reduce depressive symptoms in late adolescents., (© 2020 European Sleep Research Society.)

Purpose: Respiratory viruses (RVs) are pathogens that can cause central nervous system (CNS) infection, but previous research has been limited to a pediatric population. In recent years, several cases of adult RV meningoencephalitis have begun to be reported. We decided to research the CNS infection of RV in the entire neuroinfection registry., Methods: We retrospectively reviewed the neurologic infection registry of Seoul National University (Seoul, Korea). Among a total of 661 patients in the registry, 10 adult patients were diagnosed with RV-related meningoencephalitis on RV multiplex polymerase chain reaction (PCR) screening test. We analyzed the clinical presentation, laboratory findings, and clinical course of the 10 patients., Results: Three patients were definite RV meningoencephalitis who had positive PCR results from cerebrospinal fluid. The other seven patients were diagnosed with probable RV meningoencephalitis if they had positive PCR results in the sputum and negative results in other extensive workup., Conclusion: RV-related meningoencephalitis should be considered a possible etiology in adult meningoencephalitis patients. To diagnose these viruses, screening test of RV PCR is recommended even in patients without upper respiratory infection symptoms., Competing Interests: Conflicts of Interest Jangsup Moon, Soon-Tae Lee, Kyung-Il Park, Keun-Hwa Jung, Sang Kun Lee, Kon Chu have been editorial board of encephalitis since October 2020. They were not involved in the review process of this original article. No other potential conflict of interest relevant to this article was reported., (Copyright © 2021 Korean Encephalitis and Neuroinflammation Society.)

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-naïve 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Isolated rapid eye movement sleep behavior disorder (iRBD) patients are at risk of cognitive impairments, however the underlying mechanism is still unclear. This study aimed to evaluate thalamo-cortical functional connectivity (FC) using resting-state functional magnetic resonance imaging (fMRI) and its correlation with cognitive dysfunction in patients with iRBD., Methods: A total 37 polysomnographies (PSGs) confirmed iRBD patients and 15 age-sex matched controls underwent resting-state fMRI and comprehensive neuropsychological assessment. Thalamo-cortical FC was evaluated by using seed-to voxel analysis and was compared between the iRBD and controls. Correlation between the average value of significant clusters and cognitive function scores in iRBD were calculated., Results: Compared to the control subjects, patients with iRBD patients showed cognitive decline in word list recognition (p = 0.016), and constructional recall (p = 0.044). The FC analysis showed increased FC between the left thalamus and occipital regions including the right cuneal cortex, left fusiform gyrus and lingual gyrus (cluster level p < 0.05, corrected for false discovery rate). The averaged thalamo-fusiform FC value positively correlated with word list recognition after adjusting for age and sex (adjusted r = 0.347, p = 0.041)., Conclusion: Thalamic resting state FC is altered in iRBD patients and is associated with the cognitive function. Enhancement of the thalamo-occipital FC may reflect a compensatory mechanism for cognitive impairment in iRBD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Purpose: The first-line medications for the symptomatic treatment of rapid eye movement sleep behavior disorder (RBD) are clonazepam and melatonin taken at bedtime. We aimed to identify the association between depression and treatment response in patients with idiopathic RBD (iRBD)., Methods: We reviewed the medical records of 123 consecutive patients (76 males; age, 66.0±7.7 years; and symptom duration, 4.1±4.0 years) with iRBD who were treated with clonazepam and/or melatonin. Clonazepam and melatonin were initially administered at 0.25-0.50 and 2 mg/day, respectively, at bedtime, and the doses were subsequently titrated according to the response of individual patients. Treatment response was defined according to the presence or absence of any improvement in dream-enacting behaviors or unpleasant dreams after treatment., Results: Forty (32.5%) patients were treated with clonazepam, 56 (45.5%) with melatonin, and 27 (22.0%) with combination therapy. The doses of clonazepam and melatonin at followup were 0.5±0.3 and 2.3±0.7 mg, respectively. Ninety-six (78.0%) patients reported improvement in their RBD symptoms during a mean follow-up period of 17.7 months. After adjusting for potential confounders, depression was significantly associated with a negative treatment response (odds ratio=3.76, 95% confidence interval=1.15-12.32, p =0.029)., Conclusions: We found that comorbid depression is significantly associated with a negative response to clonazepam and/or melatonin in patients with iRBD. Further research with larger numbers of patients is needed to verify our observations and to determine the clinical implications of comorbid depression in the pathophysiology of iRBD., Competing Interests: Carlos H. Schenck is a consultant for Axovant Sciences, Inc. The other authors have no potential conflicts of interest to disclose., (Copyright © 2020 Korean Neurological Association.)

Objective: In this study, we investigated differences in sleep patterns between obese and non-obese adolescents, and determined which sleep-related parameters were associated with a risk of adolescent obesity., Methods: In this cross-sectional study, we evaluated 22,906 adolescents between 12 and 18 years of age (mean 15.2 ± 1.7 years; male 50.9%). Self-report questionnaires were used to assess body mass index (BMI) and sleep habits. Obesity was defined as a BMI-for-age ≥ 95th percentile. Weekend catch-up sleep (CUS) duration was calculated as the sleep duration on free days minus sleep duration on school days. We estimated mid-sleep time on free days corrected for oversleep on free days (MSFsc) and social jet lag. Then, we performed multivariate analysis for adolescent obesity and BMI, respectively., Results: The prevalence of obesity was 6.0%. The average sleep duration (P = 0.017) and weekend CUS duration (P < 0.001) of obese adolescents were shorter than those of non-obese adolescents. However, there was no significant difference in MSFsc or social jet lag by the obesity status. After adjustment, obesity was significantly associated with short average sleep duration (odds ratio [OR] 0.91, 95% confidence interval [CI] 0.86-0.96) and short weekend CUS duration (OR 0.92, 95% CI 0.89-0.95). Similarly, BMI was inversely correlated with average sleep duration (B = -0.15, 95% CI -0.19 to -0.11) and weekend CUS duration (B = -0.09, 95% CI -0.11 to -0.06)., Conclusions: Our observations suggest that short sleep duration, rather than late MSFsc or social jet lag, was associated with adolescent obesity., (Copyright © 2020. Published by Elsevier B.V.)

Study Objectives: To characterize emotion regulation strategies in patients with idiopathic REM sleep behavior disorder (iRBD) and to explore whether these strategies are associated with clinical symptoms., Methods: In this cross-sectional multicenter study, a total of 94 polysomnography-confirmed iRBD patients (mean age, 67.6 years; men, 56%) and 50 healthy controls (mean age, 65.4 years; men, 48%) completed the Cognitive Emotion Regulation Questionnaire (CERQ), the Korean version of the RBD questionnaire-Hong Kong (RBDQ-KR), the Buss-Durkee Hostility Inventory (BDHI), the second edition of the Beck Depression Inventory (BDI-II), and the Korean version of the Montreal Cognitive Assessment (MoCA-K)., Results: The iRBD group had lower CERQ adaptive scores than the control group, whereas the CERQ maladaptive scores were not significantly different between the groups. Among the CERQ adaptive subscales, the scores for positive refocusing, refocusing on planning, and positive reappraisal were significantly lower in the iRBD group than in the control group. Higher CERQ adaptive scores were correlated with lower scores on RBDQ-KR factor 1 (dream-related) and the BDI-II and higher MoCA-K scores but were not correlated with RBDQ-KR factor 2 (behavioral manifestation) or BDHI scores. Among the dream content-related items of RBDQ-KR factor 1, the CERQ adaptive score was associated only with frequent nightmares. No correlation was found between CERQ maladaptive scores and any variable except for a positive correlation with BDI-II scores., Conclusions: Our results provide evidence of emotion regulation deficits in iRBD patients. Furthermore, these results were linked to dream-related factors, especially nightmares, along with depressive symptoms and cognitive impairment., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Objectives: Thalamocortical abnormalities have been implicated in the pathophysiology of restless legs syndrome (RLS). We hypothesized that sleep spindle and slow oscillation (SO) activity is impaired in RLS, and that this dysfunction may contribute to sleep disturbance in these patients. To address this issue, we characterized sleep spindle and SO activity in RLS., Methods: Fifteen drug-naive, idiopathic RLS patients (13 female and 2 male) and 15 female healthy controls participated in this study. Nineteen-channel electroencephalograms were obtained during polysomnographic (PSG) recordings. An automated sleep spindle and SO detection algorithm was used to detect sleep spindle (12-16 Hz) and SO (<1 Hz) activity. The quantitative characteristics of sleep spindle and SO activity were investigated., Results: Compared with the healthy controls, in RLS patients, we observed density and power reduction in sleep spindles. In SOs, density reduction and duration increment were shown in RLS patients. In addition, SO-spindle coordination was deficient in RLS as revealed by reduced SO locked spindle power, dispersed and delayed spindle phase, and decreased SO-spindle coupling. Although sleep spindle power was negatively correlated with wake after sleep onset (WASO) time, SO duration was positively correlated with the arousal index in RLS., Conclusions: Our study suggests that sleep disturbances may be mediated by a combined deficit in spindle and SO activity and SO-spindle coordination. The abnormal SO and spindle activity observed in RLS support the notion that thalamocortical abnormalities underlie this condition and may promote disturbed sleep integrity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The neural substrates related to periodic leg movements during sleep (PLMS) remain uncertain, and the specific brain regions involved in PLMS have not been evaluated. We investigated the brain regions associated with PLMS and their severity using the electroencephalographic (EEG) source localization method. Polysomnographic data, including electromyographic, electrocardiographic, and 19-channel EEG signals, of 15 patients with restless legs syndrome were analyzed. We first identified the source locations of delta-band (2-4 Hz) spectral power prior to the onset of PLMS using a standardized low-resolution brain electromagnetic tomography method. Next, correlation analysis was conducted between current densities and PLMS index. Delta power initially and most prominently increased before leg movement (LM) onset in the PLMS series. Sources of delta power at -4~-3 seconds were located in the right pericentral, bilateral dorsolateral prefrontal, and cingulate regions. PLMS index was correlated with current densities at the right inferior parietal, temporoparietal junction, and middle frontal regions. In conclusion, our results suggest that the brain regions activated before periodic LM onset or associated with their severity are the large-scale motor network and provide insight into the cortical contribution of PLMS pathomechanism.

Objective: The efficacy and safety of 1-month atomoxetine and midodrine therapies were compared. Three-month atomoxetine and combination therapies were investigated for additional benefits., Methods: This prospective open-label randomized trial included 50 patients with symptomatic neurogenic orthostatic hypotension (nOH). The patients received either atomoxetine 18 mg daily or midodrine 5 mg twice daily and were evaluated 1 and 3 months later. Those who still met the criteria for nOH at 1 month received both midodrine and atomoxetine for an additional 2 months, and if not, they continued their initial medication. The primary outcome was an improvement in orthostatic blood pressure (BP) drop (maximum BP change from supine to 3 min after standing) at 1 month. The secondary endpoints were symptom scores, percentage of patients with nOH at 1 and 3 months., Results: Patients with midodrine or atomoxetine treatment showed comparative improvement in the orthostatic BP drop, and overall only 26.2% of the patients had nOH at 1 month, which was similar between the treatment groups. Only atomoxetine resulted in significant symptomatic improvements at 1 month. For those without nOH at 1 month, there was additional symptomatic improvement at 3 months with their initial medication. For those with nOH at 1 month, the combination treatment resulted in no additional improvement. Mild-to-moderate adverse events were reported by 11.6% of the patients., Interpretation: One-month atomoxetine treatment was effective and safe in nOH patients. Atomoxetine improved orthostatic BP changes as much as midodrine and was better in terms of ameliorating nOH symptoms., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Background: Although previous research provides insight into the role of neuroinflammation in idiopathic REM sleep behavior disorder, the association of this disorder with peripheral blood inflammatory markers remains unclear., Objective: To investigate inflammatory cytokines in plasma samples in patients with idiopathic rapid eye movement sleep behavior disorder and to explore whether these markers are associated with prodromal symptoms of α-synucleinopathies., Methods: We collected plasma from patients with polysomnographically confirmed idiopathic rapid eye movement sleep behavior disorder without parkinsonism or dementia (n = 54) and from healthy controls (n = 56). The following cytokines were measured: interleukin-1β, interleukin-2, interleukin-6, interleukin-10, and tumor necrosis factor-α. The idiopathic REM sleep behavior disorder patients underwent sleep, motor, cognitive, olfactory, and autonomic testing., Results: The anti-inflammatory cytokine, interleukin-10, levels in the idiopathic rapid eye movement sleep behavior disorder group were significantly upregulated compared to the control group (P = 0.022), but this difference did not withstand Bonferroni correction. The other proinflammatory cytokine levels did not differ between the groups. No correlation was found between the cytokine levels and any clinical variable., Conclusions: Our data do not provide evidence supporting the role of peripheral inflammation in idiopathic rapid eye movement sleep behavior disorder. However, considering the limited statistical power because of the small sample size, further large-scale longitudinal studies with a broader spectrum of cytokines are needed to clarify this issue. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objectives: Idiopathic REM sleep behavior disorder (iRBD) patients are susceptible to cognitive deficits, especially attention dysfunction. The objective of this study is to elucidate the neural mechanism of the dysfunction in attention known as 'inhibition of return' (IOR) in iRBD patients based on an analysis of oscillatory cortical activity during a selective attention task., Methods: Event-related potentials (ERPs) were recorded from iRBD patients and normal control subjects while performing a Posner task. The differences in N1 ERP and theta- and beta-bands event-related spectral perturbations (ERSPs) between valid and invalid stimuli were compared between groups., Results: The N1 amplitude was significantly higher for the invalid stimuli in controls, while the valid-invalid difference was not significant in iRBD patients. The valid-invalid differences in ERSPs were prominent in controls at ∼100-400 ms for the theta-band and ∼200-400 ms for the beta-band, and the valid-invalid differences in ERSPs were not significant in the iRBD patients., Conclusion: The results demonstrated that valid-invalid differences in neural activity were absent in iRBD patients, and these neural findings were in accord with the behavioral results., Significance: Our findings imply impairment in sensory-perceptual processing mediated by attentional control and response inhibition in early-stage iRBD before clinical neurodegeneration., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)