Risk of encephalitis and meningitis after COVID-19 vaccination in South Korea: a self-controlled case series analysis.

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.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

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.

Fatigue or excessive daytime sleepiness: which is more closely related to depression?

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.

Fatigue is associated with depression independent of excessive daytime sleepiness in the general population.

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.

Association between morningness-eveningness, sleep duration, weekend catch-up sleep and depression among Korean high-school students.

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.

Working memory deficits in patients with idiopathic restless legs syndrome are associated with abnormal theta-band neural synchrony.

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 (F4,88  = 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 (t22  = 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.

Effects of perampanel on cognition and quantitative electroencephalography in patients with epilepsy.

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.

Development of the clinical assessment scale in autoimmune encephalitis.

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 < 0.001), and had acceptable internal consistency (Cronbach α = 0.88). Additionally, in the validation cohort, the scale showed high interobserver reliability (ICC = 0.99) and internal consistency (Cronbach α = 0.92). INTERPRETATION: CASE is a novel clinical scale for AE with a high level of clinimetric properties. It would be suitable for application in clinical practice and might help overcome the limitations of current outcome scales for AE. ANN NEUROL 2019;85:352-358.

Peripheral Blood Inflammatory Cytokines in Idiopathic REM Sleep Behavior Disorder.

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-1ß, 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.

Lack of association between dopamine transporter loss and non-motor symptoms in patients with Parkinson's disease: a detailed PET analysis of 12 striatal subregions.

INTRODUCTION: Patients with Parkinson's disease (PD) present a variety of non-motor symptoms. However, it remains unclear whether dopamine depletion is related to non-motor symptoms, and which non-motor symptoms are significantly dependent on dopaminergic deficit. METHODS: Forty-one patients with PD who underwent positron emission tomography imaging of dopamine transporters (DATs) were recruited for this study. The striatum was divided into 12 subregions, and DAT activity, as striatal dopaminergic concentration, was calculated in each subregion. In addition to measuring motor symptoms using the Unified Parkinson's Disease Rating Scale-part III (UPDRS-III), various non-motor symptoms were assessed using the Montreal cognitive assessment, frontal assessment battery, Beck depression inventory (BDI), Beck anxiety inventory, PD sleep scale (PDSS), PD fatigue scale, and non-motor symptoms scale (NMSS) for PD. RESULTS: For simple linear regression analyses, dopaminergic depletion in all striatal subregions was negatively correlated with the UPDRS-III score. The most relevant non-motor symptom assessment related to dopaminergic loss in the 12 subregions was NMSS, followed by BDI and PDSS. However, following multiple linear regression analyses, dopaminergic depletion in the 12 striatal subregions was not related with any of the non-motor symptoms. Conversely, dopaminergic deficit in the right anterior and posterior putamen was associated with the UPDRS-III score. CONCLUSIONS: Striatal dopaminergic depletion was not significantly correlated with any of the various non-motor symptoms in PD. Our findings suggest that non-dopaminergic systems are significantly implicated in the pathogenesis of non-motor symptoms in patients with PD.

High risk of obstructive sleep apnea, insomnia, and daytime sleepiness among commercial motor vehicle drivers.

PURPOSE: We investigated the prevalence of sleep problems, such as obstructive sleep apnea (OSA), insomnia, and daytime sleepiness in commercial motor vehicle (CMV) drivers compared with that in the general population. METHODS: This is a cross-sectional study comparing sleep habits and sleep problems in 110 truck drivers with 1001 matched controls from the general population. The assessment was based on self-administered questionnaires that included the Berlin questionnaire, the insomnia severity index, and the Epworth sleepiness scale (ESS). Multivariate regression analysis was performed to determine whether CMV drivers were independently associated with these sleep problems compared with controls. RESULTS: The prevalence of a high risk of OSA and insomnia was 35.5% and 15.2%, respectively, in CMV drivers, which was significantly higher than in controls with a prevalence of 12.2% and 4.1%, respectively (P < 0.001 for both). Although CMV drivers showed higher ESS scores than controls, the prevalence of daytime sleepiness did not differ between the two groups (19.1% vs. 16.8%, P = 0.54). After adjusting for covariates, CMV drivers had 3.68 times higher odds (95% CI 2.29-5.84) of OSA and 2.97 times higher odds (95% CI, 1.46-6.06) of insomnia compared with controls. However, the degree of daytime sleepiness was not independently associated with CMV drivers. CONCLUSIONS: The prevalence of OSA and insomnia in CMV drivers was higher than that in the general population. Daytime sleepiness was associated with increased BMI, depression, OSA, and short sleep duration, regardless of CMV driving as an occupational factor.

Association between Restless Legs Syndrome Symptoms and Self-Reported Hypertension: a Nationwide Questionnaire Study in Korea.

BACKGROUND: The association between restless legs syndrome (RLS) and hypertension remains controversial. We investigated the relationship between RLS and hypertension in a nationwide sample of the Korean adult population. METHODS: This was a cross-sectional questionnaire-based study including 2,740 adults aged 19 years or more. Subjects who met the four essential International RLS Study Group criteria and reported symptoms occurring at least once a week were defined as the RLS group. The presence of hypertension was defined as a self-reported history of physician-diagnosed hypertension. We conducted multiple logistic regression analysis to determine the independent association between RLS symptoms and self-reported hypertension after adjusting for potential confounding factors. RESULTS: Among the 2,740 subjects, 68 (2.5%; 95% confidence interval [CI], 1.9%-3.1%) were found to have RLS with a symptom frequency of at least once a week. The prevalence of self-reported hypertension was 30.9% (95% CI, 20.5%-42.0%) in the RLS group, which was significantly higher than that in controls (12.4%; 95% CI, 11.2%-13.6%; P < 0.001). Multiple logistic regression analysis showed that the adjusted odds ratio for self-reported hypertension in the RLS group was 2.10 (95% CI, 1.12-3.93) compared to controls. In addition to RLS symptoms, old age, being overweight, low education level, diabetes mellitus, and short sleep duration were significantly associated with self-reported hypertension. CONCLUSION: RLS symptoms occurring at least once a week is independently associated with a higher prevalence of self-reported hypertension in the adult Korean population. Further research will confirm the clinical implication of the present results and the causal relationship between RLS and hypertension.

Anti-LGI1 encephalitis is associated with unique HLA subtypes.

OBJECTIVE: Autoimmune encephalitis (AE), represented by anti-leucine-rich glioma-inactivated 1 (anti-LGI1) and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, has increasing clinical significance based on recent discoveries of neuronal autoantibodies. However, its immunopathogenesis is not fully understood. Here, we investigated whether AE is associated with the human leukocyte antigen (HLA) subtypes. METHODS: We compared the HLA genotypes of 11 anti-LGI1 and 17 anti-NMDAR encephalitis patients to the control groups, which consisted of 210 epilepsy patients and 485 healthy Koreans. RESULTS: Anti-LGI1 encephalitis was associated with the DRB1*07:01-DQB1*02:02 haplotype (10 patients; 91%) in HLA class II genes, as well as with B*44:03 (8 patients; 73%) and C*07:06 (7 patients; 64%) in the HLA class I region. The prevalence of these alleles in anti-LGI1 encephalitis was significantly higher than that in the epilepsy controls or healthy controls. By contrast, anti-NMDAR encephalitis was not associated with HLA genotypes. Additional analysis using HLA-peptide binding prediction algorithms and computational docking underpinned the close relationship. INTERPRETATION: This finding suggests that most anti-LGI1 encephalitis develops in a population with specific HLA subtypes, providing insight into a novel disease mechanism. Ann Neurol 2017;81:183-192.

Clinical manifestations and treatment outcomes of parvovirus B19 encephalitis in immunocompetent adults.

Parvovirus B19 (PVB19) has rarely been identified as a cause of encephalitis in immunocompetent adults, in whom clinical information regarding PVB19 encephalitis has remained unclear. Herein, we report the clinical presentations, laboratory and imaging findings, and treatment outcomes of five immunocompetent adults with PVB19 encephalitis. Although none of the patients showed any distinctive features of PVB19 infection, they showed various clinical manifestations, including one instance of brainstem involvement. Additionally, immunotherapy can be considered an effective approach, especially in immunocompetent adults with PVB19 encephalitis who are resistant to the initial management.

Recently Uncontrolled Glycemia in Diabetic Patients Is Associated with the Severity of Intracranial Atherosclerosis.

BACKGROUND AND PURPOSE: Diabetes mellitus is a specific risk factor for intracranial atherosclerosis (ICAS) regardless of race. However, it is largely unknown whether poor glycemic control is associated with the severity of ICAS in diabetic patients. METHODS: We selected diabetic patients with acute ischemic stroke who were prospectively registered between March 2005 and December 2015. The patients who had a high-risk source of cardiogenic embolism were excluded. ICAS was graded from 0 to 3 by the number of significant (≥50%) stenoses on intracranial magnetic resonance angiography, and was divided into 4 types: unilateral anterior, bilateral anterior, posterior, and anterior plus posterior. Ordinal and multinomial regression tests were applied for the factors influencing the number and types of ICAS. RESULTS: A total of 774 patients with noncardioembolic acute ischemic stroke with diabetes were enrolled. The multiplicity of ICAS was independently associated with age (odds ratio [OR], 1.035 per 1 year, 1.018-1.052; P < .001), hypertension (OR, 1.992, 1.336-2.965; P = .001), and glycated hemoglobin (HbA1c; OR, 1.207 per 1%, 1.089-1.338; P < .001) in the ordinal regression model. In multinomial regression, bilateral anterior stenosis tended to be correlated with age (OR, 1.042, 1.008-1.077; P = .016) and HbA1c (OR, 1.201 per 1%, .991-1.520; P = .057). Both anterior and posterior stenoses were significantly associated with age (OR, 1.056, 1.029-1.084; P < .001), hypertension (OR, 2.584, 1.404-4.762; P = .002), and HbA1c (OR, 1.272, 1.070-1.511; P = .006). CONCLUSIONS: Age, concomitant hypertension, and HbA1c were factors associated with multiple intracranial stenoses. Further study is warranted to elucidate whether poor glycemic control facilitates ICAS in diabetic patients.

HLA-B*40:02 and DRB1*04:03 are risk factors for oxcarbazepine-induced maculopapular eruption.

OBJECTIVE: Oxcarbazepine (OXC) is a widely used antiepileptic drug for the treatment of partial seizures that was developed through structural variation of carbamazepine. Although OXC has a lower risk of cutaneous adverse drug reactions (cADRs) than carbamazepine, cADRs ranging from maculopapular eruption (MPE) to the more severe Stevens-Johnson syndrome and toxic epidermal necrolysis still limit the use of OXC in some patients. A few human leukocyte antigen (HLA)-related genetic risk factors for carbamazepine-induced cADRs have been identified. However, the HLA-related genetic risk factors associated with OXC-induced cADRs are unknown. METHODS: A total of 40 patients who experienced OXC-induced MPE and 70 patients who were tolerant to OXC treatment were included in the study. Genomic DNA was extracted from the peripheral blood of these patients, and high-resolution HLA genotyping was performed. RESULTS: The HLA-B*40:02 and HLA-DRB1*04:03 alleles were significantly associated with OXC-induced MPE compared with the OXC-tolerant group (odds ratio [OR] 4.33, p = 0.018 and OR 14.64, p = 0.003, respectively) and the general Korean population (OR 4.04, p = 0.001 and OR 3.11, p = 0.019, respectively). The HLA-B*15:01 genetic frequency was significantly lower in the OXC-MPE group compared to the OXC-tolerant group (OR 0.18, p = 0.016) and the Korean population (OR 0.22, p = 0.030). The allele frequencies of well-known HLA-related risk factors for carbamazepine-induced cADRs (HLA-B*15:02, A*31:01 and B*15:11) were not different among the three groups. SIGNIFICANCE: This study is the first to demonstrate an association of HLA-B*40:02 and HLA-DRB1*04:03 with OXC hypersensitivity using a large cohort of patients with OXC-induced MPE. These findings should be confirmed in future studies in different ethnic groups.

Headache as an Aura of Epilepsy: Video-EEG Monitoring Study.

BACKGROUND: Headache can be associated with epilepsy as a pre-ictal, ictal, or post-ictal phenomenon; however, studies of patients with headache as an epileptic aura are scarce. We performed the present study to investigate the incidence and characteristics of headache as an epileptic aura, via confirmation of electroencephalography (EEG) changes by video-EEG monitoring. METHODS: Data of aura and clinical seizure episodes of 831 consecutive patients who undertook video-EEG monitoring were analyzed retrospectively. For patients who had headache as an aura, information on the detailed features of headache was acquired, including location, nature, duration, and the presence of accompanying symptoms. Video-recorded clinical seizures, EEG findings, and neuroimaging data were used to determine the ictal onset areas in the patients. RESULTS: Six out of 831 (0.7%) patients experienced headache as aura (age range, 25-52 years), all of whom had partial seizures. The incidence of pre-ictal headache was 6.3% (25/831), and post-ictal headache was 30.9% (257/831). In patients with headache as aura, five patients described headache as the most frequent aura, and headache was the second most frequent aura in one patient. The characteristics of headache were hemicrania epileptica in two patients, tension-type headache in another two patients, and migraine-like headache in the remaining two patients. No patient met the diagnostic criteria of ictal epileptic headache or migraine aura-triggered seizure. CONCLUSION: Our study showed that headache as an aura is uncommon in adult patients with epilepsy, and that headache can present as diverse features, including hemicrania epileptica, tension-type headache, and migraine-like headache. Further studies are necessary to characterize the features of headache as an epileptic aura in adult patients with epilepsy.

Prediction of mortality and functional outcome from status epilepticus and independent external validation of STESS and EMSE scores.

BACKGROUND: Two clinical scoring systems, the status epilepticus severity score (STESS) and the epidemiology-based mortality score in status epilepticus (EMSE), are used to predict mortality in patients with status epilepticus (SE). The aim of this study was to compare the outcome-prediction function of the two scoring systems regarding in-hospital mortality using a multicenter large cohort of adult patients with SE. Moreover, we studied the potential role of these two scoring systems in predicting the functional outcome in patients with SE. METHODS: The SE cohort consisted of patients from the epilepsy centers of eight academic tertiary medical centers in South Korea. The clinical and electroencephalography data for all adult patients with SE from January 2013 to December 2014 were derived from a prospective SE database. The primary outcome variable was defined as in-hospital death. The secondary outcome variable was defined as a poor functional outcome, i.e., a score of 1-3 on the Glasgow Outcome Scale, at discharge. RESULTS: Among the 120 non-hypoxic patients with SE recruited into the study, 16 (13.3%) died in the hospital and 64 (53.3%) were discharged with a poor functional outcome. The receiver-operating characteristic (ROC) curve for prediction of in-hospital death based on the STESS had an area under the curve of 0.673 with an optimal cutoff value for discrimination (best match for both sensitivity (0.56) and specificity (0.70)) that was ≥ 4 points. The two combinations of elements of the EMSE system (EMSE-ALDEg and EMSE-ECLEg) predicted not only in-hospital mortality with the best match for sensitivity (more than 0.6) and specificity (more than 0.6), but also a poor functional outcome with the best match for both sensitivity (>0.7) and specificity (>0.6). STESS did not predict a poor functional outcome (area under the ROC, 0.581; P = 0.23). CONCLUSION: Although the EMSE is a clinical scoring system that focuses on individual mortality, we did not find differences between the EMSE and STESS in the prediction of in-hospital death. The EMSE was useful in predicting poor functional outcome, as it was significantly better than STESS.

Orthostatic intolerance symptoms are associated with depression and diminished quality of life in patients with postural tachycardia syndrome.

BACKGROUND: Patients with postural tachycardia syndrome often appear depressive and report diminished quality of life (QOL). In the current study, we first evaluated if the maximal heart rate (HR) increment after standing is associated with the clinical symptoms in patients with excessive orthostatic tachycardia (OT). Next, we investigated the correlations among the symptoms of orthostatic intolerance (OI), depression, and health-related QOL in these patients. Finally we assessed if patients with minimal OI symptoms suffer from depression or diminished QOL. METHODS: We performed a comprehensive questionnaire-based assessment of symptoms in 107 patients with excessive OT with a ≥ 30 beats/min heart rate increment (or ≥ 40 beats/min in individuals aged between 12 and 19) within 10 min after standing up. An existing orthostatic intolerance questionnaire (OIQ), the Beck depression inventory-II (BDI-II), and the 36 Item Short-Form Health Survey were completed prior to any treatment. Correlation analyses among the items of the questionnaires and other parameters were performed. Additionally, patients with minimal OI symptoms were analysed separately. RESULTS: The maximal orthostatic HR increment was not associated with the clinical symptoms. The OI symptoms were significantly correlated with depression and diminished QOL. The BDI-II score demonstrated a positive linear relationship with total OIQ score (r = 0.516), and both physical and mental component summary scales of SF-36 showed a negative linear relationship with total OIQ score (r = -0.542 and r = -0.440, respectively; all p <0.001). Some OI symptoms were more strongly associated with depression, and others were more strongly related to QOL. Chest discomfort and concentration difficulties were the most influential OI symptoms for depression, while nausea and concentration difficulties were the most influential symptoms for physical and mental QOL, respectively. Dizziness and headache were the two most common complaints in patients with mild to moderate OI symptoms. In addition, subjects with minimal OI symptoms also had considerable deterioration in QOL. CONCLUSION: The OI symptoms, but not the maximal HR increment, are significantly correlated with depression and diminished QOL in patients with excessive OT. Therefore, pervasive history taking is important when encountering patients with excessive OT.

Dysregulation of long non-coding RNAs in mouse models of localization-related epilepsy.

Genome-wide profiling has revealed that eukaryotic genomes are transcribed into numerous non-coding RNAs. In particular, long non-coding RNAs (lncRNAs) have been implicated in various human diseases due to their biochemical and functional diversity. Epileptic disorders have been characterized by dysregulation of epigenetic regulatory mechanisms, and recent studies have identified several lncRNAs involved in neural development and network function. However, comprehensive profiling of lncRNAs implicated in chronic epilepsy has been lacking. In this study, microarray analysis was performed to obtain the expression profile of lncRNAs dysregulated in pilocarpine and kainate models, two models of temporal lobe epilepsy commonly used for studying epileptic mechanisms. Total of 4622 lncRNAs were analyzed: 384 lncRNAs were significantly dysregulated in pilocarpine model, and 279 lncRNAs were significantly dysregulated in kainate model compared with control mice (≥3.0-fold, p < 0.05). Among these, 54 and 14 lncRNAs, respectively, had adjacent protein-coding genes whose expressions were also significantly dysregulated (≥2.0-fold, p < 0.05). Majority of these pairs of lncRNAs and adjacent genes shared the same direction of dysregulation. For the selected adjacent gene-lncRNA pairs, significant Gene Ontology terms were embryonic appendage morphogenesis and neuron differentiation. This was the first study to comprehensively identify dysregulated lncRNAs in two different models of chronic epilepsy and will likely provide a novel insight into developing lncRNA therapeutics.