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Background and Purpose Epidemiologic data suggest that cluster headache (CH) is significantly associated with cigarette smoking. The aim of this study was to determine differences in features between patients with a smoking history and those who are never-smokers, using data from a prospective multicenter registry. Methods Data used in this study were obtained from the Korean Cluster Headache Registry that collected data from consecutive patients diagnosed with CH. We compared clinical and demographic features between ever-smokers (current or former smokers) and never-smokers. Results This study enrolled 250 patients who were diagnosed with CH, of which 152 (60.8%) were ever-smokers and 98 (39.2%) were never-smokers. The age at CH onset was significantly lower in the never-smoker group than in the ever-smoker group [27.1±12.9 years vs. 30.6±10.9 years (mean±standard deviation), p=0.024]. Seasonal rhythmicity (58.1% vs. 44.7%, p=0.038) and triptan responsiveness (100% vs. 85.1%, p=0.001) were higher in never-smokers, while other clinical features such as pain severity, duration, attack frequency, and associated autonomic symptoms did not differ significantly between the groups. The male-to-female ratio was markedly higher in ever-smokers (29.4:1) than in never-smokers (1.7:1). Conclusions Most of the clinical features did not differ significantly between patients with a smoking history and never-smokers. However, the age at CH onset, sex ratio, and seasonal rhythmicity were significantly associated with smoking history.

Background Previous studies have reported notable differences in demographic and clinical features of cluster headache between Western and Asian populations, including lower prevalence of the chronic type and in women. Recently, prodromal symptoms of migraine and pre-attack symptoms of cluster headache have drawn attention regarding their potential pathophysiological implications and pre-emptive treatment. However, pre-attack symptoms of cluster headache have not been studied in the Asian population. Methods A total of 136 patients with cluster headache (21 first-onset, 110 episodic, and five chronic cases) were recruited in this multi-center study between October 2018 and December 2019. We evaluated the characteristics of pre-attack symptoms in a current bout using a structured questionnaire. Univariable and multivariable logistic regression analyses were performed to evaluate the factors associated with presence of pre-attack symptoms. Results Pre-attack symptoms were reported in 71.3% of our patients with cluster headache. When present, pre-attack symptoms occurred at a median of 20 minutes (range 1–120) before the attack. The prevalence of local and painful, local and painless sensory, autonomic, and general symptoms was 58.8%, 14.7%, 11.0%, and 30.1%, respectively. Multivariable logistic regression analysis revealed that higher number of bouts was associated with higher prevalence of pre-attack symptoms (OR = 1.464, p = 0.044). Conclusions Pre-attack symptoms were frequently observed in Korean patients with cluster headache, which was consistent with previous Western studies.

Background: Although cranial autonomic symptoms are typical in cluster headache, some individuals with cluster headache show no cranial autonomic symptoms during their headache attacks. Probable cluster headache is a subtype of cluster headache that fulfils all but one of the five criteria for cluster headache. This study aimed to investigate the frequency and clinical features of cluster headache and probable cluster headache without cranial autonomic symptoms in comparison to those with cranial autonomic symptoms.Methods: We analysed data from the Korea Cluster Headache Registry, a prospective multicentre registry involving data from 16 hospitals.Results: Of the 216 participants with cluster headache and 26 with probable cluster headache, 19 (8.8%) and 7 (26.9%), respectively, did not have cranial autonomic symptoms. Participants with cluster headache without cranial autonomic symptoms exhibited less severe anxiety (General Anxiety Disorder-7 score, median [interquartile range], 2.0 [1.0-6.0] vs 8.0 [3.0-12.0], p = 0.001) and depression (Patient Health Questionnaire-9 score, 3.0 [1.0-7.0] vs 7.0 [3.0-11.0], p = 0.042) than those with cranial autonomic symptoms. Other clinical features, including headache intensity, daily headache frequency, attack duration, bout duration, and location of the pain, did not differ between participants with cluster headache with and without cranial autonomic symptoms. Headache intensity was less severe in participants with probable cluster headache without cranial autonomic symptoms than in those with cranial autonomic symptoms (numeric rating scale, 8.0 [7.0-8.0] vs 9.5 [8.0-10.0], p = 0.015).Conclusions: A significant proportion of participants with cluster headache and probable cluster headache did not have cranial autonomic symptoms. Some clinical features of cluster headache and probable cluster headache differed based on the presence of cranial autonomic symptoms.

Background and purpose There have been few reports on recent trends in the occurrence of epilepsy. The aim of this study was to estimate the incidence and prevalence of epilepsy and analyze their annual trends in Korea over the period 2009-2017. Methods This nationwide population-based study was carried out using the National Health Insurance Service of Korea database. A prevalent case was defined as one of a patient receiving a prescription of anticonvulsants under the diagnostic codes for epilepsy or seizure. An incident case was ascertained by confirming the absence of any epilepsy-related diagnostic codes and anticonvulsant prescription for 2 years or more before the operational definition for a prevalent case was met. Alternative operational definitions for epilepsy were tested. The temporal trends of the incidence and prevalence of epilepsy were analyzed using a Poisson regression model, and are expressed as average annual percentage changes (AAPCs). Results The incidence of epilepsy increased from 28.7/100,000 persons in 2009 to 35.4/100,000 persons in 2017. The prevalence increased gradually from 3.4/1,000 persons in 2009 to 4.8/1,000 persons in 2017. These increasing trends were more evident among elderly subjects aged ≥75 years and in those who had codes for epilepsy or seizure as an additional diagnosis. Age standardization revealed a less prominent but still increasing trend in both incidence (AAPC=0.48%) and prevalence (AAPC=3.11%). Conclusions There have been increasing trends in both the prevalence and incidence of epilepsy in Korea between 2009 and 2017. This finding appears to be related to societal aging and the high incidence of symptomatic epilepsy in the elderly population.

Background Our aim was to investigate the relationship between coexisting cluster headache (CH) and migraine with anxiety and depression during active cluster bouts, and how symptoms change during remission. Methods We analyzed data from 222 consecutive CH patients and 99 age- and sex-matched controls using a prospective multicenter registry. Anxiety or depression was evaluated using the Generalized Anxiety Disorder-7 (GAD-7) or Patient Health Questionnaire-9 (PHQ-9), respectively. Moderate-to-severe anxiety or depression was defined as a score of ≥10 at baseline (during a cluster bout). We assessed for changes in anxiety and depression during CH remission periods. Results Among the CH patients, the prevalence of moderate-to-severe anxiety and depression was seen in 38.2% and 34.6%, respectively. Compared with controls, CH patients were associated with moderate-to-severe anxiety and depression (multivariable-adjusted odds ratio [aOR] = 7.32, 95% confidence intervals [CI] = 3.35–15.99 and aOR = 4.95, 95% CI = 2.32–10.57, respectively). CH patients with migraine were significantly more likely to have moderate-to-severe anxiety and depression (aOR = 32.53, 95% CI = 6.63–159.64 and aOR = 16.88, 95% CI = 4.16–68.38, respectively), compared to controls without migraine. The GAD-7 and PHQ-9 scores were significantly reduced between cluster bout and remission periods (from 6.8 ± 5.6 to 1.6 ± 2.8; P P Conclusions Our results indicate that CH patients are at increased risk of anxiety and depression, especially in the presence of coexisting migraine. However, the anxiety and depression can improve during remission periods.

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

Objective The aim of this study was to gather the expert opinions of Korean epileptologists regarding the treatment of adult patients with epilepsy. Methods A total of 42 neurologists who specialized in epilepsy were surveyed. They completed an online questionnaire describing multiple patient scenarios. Using these scenarios, they evaluated treatment strategies and gave their preference for specific antiepileptic drugs (AEDs) used to treat genetically mediated generalized epilepsy and focal epilepsy. Results Initial AED monotherapy, followed by a second form of alternative monotherapy or an add-on combination therapy, was the preferred treatment strategy. The experts reached consensus for 87.2% of the items. The most commonly selected AEDs for the initial monotherapy for patients with generalized epilepsy were levetiracetam or valproate. For those with focal epilepsy, levetiracetam, oxcarbazepine, or lamotrigine were the most popular selections. Ethosuximide was the treatment of choice only for patients with generalized epilepsy with prominent absence seizures. Levetiracetam was preferred as an add-on therapy for both generalized and focal epilepsy. For special populations of patients, such as elderly adults or those with comorbid diseases, levetiracetam or lamotrigine was selected as the treatment of choice. Conclusion Most of the survey results were in accordance with the US expert opinion survey published in 2016. This survey can assist clinicians in making clinical decisions when treating individual adult patients with epilepsy.

Purpose To compare controlled-release carbamazepine monotherapy (CBZ-CR) with lamotrigine and valproate combination therapy (LTG + VPA) in equivalent total drug load, as initial drug regimen in untreated patients with partial and/or generalized tonic-clonic seizures (GTCS). Methods This unblinded, randomized, 60-week superiority trial recruited patients having two or more unprovoked seizures with at least one seizure during previous three months. After randomization into CBZ-CR or LTG + VPA, patients entered into eight-week titration phase (TP), followed by 52-week maintenance phase (MP). Median doses of CBZ-CR and LTG + VPA were 600 mg/day and 75 mg/day + 500 mg/day, respectively. Primary outcome measure was completion rate (CR), a proportion of patients who have completed the 60-week study as planned. Secondary efficacy measures included seizure-free rate (SFR) for 52-week of MP and time to first seizure (TTFS) during MP. Results Among 207 randomized patients, 202 underwent outcome analysis (104 in CBZ-CR, 98 in LTG + VPA). CR was 62.5% in CBZ-CR and 65.3% in LTG + VPA (p = 0.678). SFR during MP was higher in LTG + VPA (64.1%) than CBZ-CR (47.8%) (P = 0.034). TTFS was shorter with CBZ-CR (p = 0.041). Incidence of adverse effects (AEs) were 57.7% in CBZ-CR and 60.2% in LTG + VPA and premature drug withdrawal rates due to AEs were 12.5% and 7.1%, respectively, which were not significantly different. Conclusion CR was comparable between LTG + VPA and CBZ-CR, however, both SFR for 52-week MP and TTFS during MP were in favor of LTG + VPA than CBZ-CR. The study suggested that LTG + VPA can be an option as initial drug regimen for untreated patients with partial seizures and/or GTCS except for women of reproductive age.

The criterion for the remission period of chronic cluster headache (CCH) was recently revised from < 1 month to < 3 months in the third edition of the International Classification of Headache Disorders (ICHD-3). However, information on the clinical features of CCH based on the ICHD-3 criteria is currently limited. The present study aimed to investigate the clinical features of CCH based on ICHD-3 using data from the Korean Cluster Headache Registry (KCHR). The KCHR is a multicentre prospective registry of patients with cluster headache (CH) from 15 hospitals. Among the 250 participants with CH, 12 and 176 participants were classified as having CCH and episodic cluster headache (ECH), respectively. Among 12 participants with CCH, 6 (50%) had remission periods of < 1 month, and the remaining 6 (50%) had a remission period of 1-3 months. Six participants had CCH from the time of onset of CH, and in the other 6 participants, CCH evolved from ECH. CCH subjects had later age of onset of CH, developed the condition after a longer interval after CH onset, and had more migraine and less nasal congestion and/or rhinorrhoea than ECH subjects. Clinical features of CCH with remission periods < 1 month were not significantly different from those of CCH with remission periods of 1-3 months, except for the total number of bouts. More current smoking and less diurnal rhythmicity were observed in participants with CCH evolved from ECH compared to those with ECH. In conclusion, the number of subjects with CCH doubled when the revised ICHD-3 criteria were used. Most of clinical characteristics of CCH did not differ when the previous and current version of ICHD was applied and compared. Some clinical features of CCH were different from those of ECH, and smoking may have a role in CH chronification.

Background and purpose Cluster headache (CH) can present with migrainous symptoms such as nausea, photophobia, and phonophobia. In addition, an overlap between CH and migraine has been reported. This study aimed to determine the differences in the characteristics of CH according to the presence of comorbid migraine. Methods This study was performed using data from a prospective multicenter registry study of CH involving 16 headache clinics. CH and migraine were diagnosed by headache specialists at each hospital based on third edition of the International Classification of Headache Disorders (ICHD-3). We interviewed patients with comorbid migraine to obtain detailed information about migraine. The characteristics and psychological comorbidities of CH were compared between patients with and without comorbid migraine. Results Thirty (15.6%) of 192 patients with CH had comorbid migraine, comprising 18 with migraine without aura, 1 with migraine with aura, 3 with chronic migraine, and 8 with probable migraine. Compared to patients with CH without migraine, patients with CH with comorbid migraine had a shorter duration of CH after the first episode [5.4±7.4 vs. 9.0±8.2 years (mean±standard deviation), p=0.008], a lower frequency of episodic CH (50.0% vs. 73.5%, p=0.010), and a higher frequency of chronic CH (13.3% vs. 3.7%, p=0.033). Psychiatric comorbidities did not differ between patients with and without comorbid migraine. The headaches experienced by patients could be distinguished based on their trigeminal autonomic symptoms, pulsating character, severity, and pain location. Conclusions Distinct characteristics of CH remained unchanged in patients with comorbid migraine with the exception of an increased frequency of chronic CH. The most appropriate management of CH requires clinicians to check the history of preceding migraine, particularly in cases of chronic CH.

Status epilepticus (SE) is one of the most serious neurologic emergencies. SE is a condition that encompasses a broad range of semiologic subtypes and heterogeneous etiologies. The treatment of SE primarily involves the management of the underlying etiology and the use of antiepileptic drug therapy to rapidly terminate seizure activities. The Drug Committee of the Korean Epilepsy Society performed a review of existing guidelines and literature with the aim of providing practical recommendations for antiepileptic drug therapy. This article is one of a series of review articles by the Drug Committee and it summarizes staged antiepileptic drug therapy for SE. While evidence of good quality supports the use of benzodiazepines as the first-line treatment of SE, such evidence informing the administration of second- or third-line treatments is lacking; hence, the recommendations presented herein concerning the treatment of established and refractory SE are based on case series and expert opinions. The choice of antiepileptic drugs in each stage should consider the characteristics and circumstances of each patient, as well as their estimated benefit and risk to them. In tandem with the antiepileptic drug therapy, careful searching for and treatment of the underlying etiology are required.

Objectives This study aimed to determine the characteristics and significance of a probable diagnostic entity for primary headache disorder (PHD). Background A diagnosis of probable primary headache disorder (PPHD) is given when a patient's headache fulfills all but one criteria of the third beta edition of the international classification of headache disorder (ICHD-3β). Despite the uncertainty regarding this diagnosis, the inclusion of a probable diagnosis entity in this manual may aid in the accurate classification of headache disorders and allow effective treatment strategies to be started at the patient's initial visit. Methods This cross-sectional multicenter registry study assessed first-visit patients with complaints of headaches who presented at the outpatient clinics of 11 neurologists in Korea. The classification of a headache disorder was made according to the criteria of the ICHD-3β by each investigator based on the initial evaluation of the patient or by a consensus meeting for uncertain cases. The rates of a probable diagnosis among PPHD patients were assessed and the clinical characteristics of these patients were compared with those of patients with a diagnosis of definite primary headache disorder (DPHD). Results A total of 1429 patients were diagnosed with PHD, and 305 (21.3%) of these patients had PPHD. The proportions of PPHD differed among the subtypes of DPHD as follows: migraines (16.1%), tension-type headaches (TTH; 33%), trigeminal autonomic cephalalgia (TAC; 40.9%), and other PHD (14%, P

The purpose of this study was to test the feasibility and usefulness of the International Classification of Headache Disorders, third edition, beta version (ICHD-3β), and compare the differences with the International Classification of Headache Disorders, second edition (ICHD-2). Consecutive first-visit patients were recruited from 11 headache clinics in Korea. Headache classification was performed in accordance with ICHD-3β. The characteristics of headaches were analyzed and the feasibility and usefulness of this version was assessed by the proportion of unclassified headache disorders compared with ICHD-2. A total of 1,627 patients were enrolled (mean age, 47.4±14.7 yr; 62.8% female). Classification by ICHD-3β was achieved in 97.8% of headache patients, whereas 90.0% could be classified by ICHD-2. Primary headaches (n=1,429, 87.8%) were classified as follows: 697 migraines, 445 tension-type headaches, 22 cluster headaches, and 265 other primary headache disorders. Secondary headache or painful cranial neuropathies/other facial pains were diagnosed in 163 patients (10.0%). Only 2.2% were not classified by ICHD-3β. The main reasons for missing classifications were insufficient information (1.6%) or absence of suitable classification (0.6%). The diagnoses differed from those using ICHD-2 in 243 patients (14.9%). Among them, 165 patients were newly classified from unclassified with ICHD-2 because of the relaxation of the previous strict criteria or the introduction of a new diagnostic category. ICHD-3β would yield a higher classification rate than its previous version, ICHD-2. ICHD-3β is applicable in clinical practice for first-visit headache patients of a referral hospital., Graphical Abstract

Background and purpose Deciding whether or not to perform neuroimaging in primary headache is a dilemma for headache physicians. The aim of this study was to identify clinical predictors of incidental neuroimaging abnormalities in new patients with primary headache disorders. Methods This cross-sectional study was based on a prospective multicenter headache registry, and it classified 1,627 consecutive first-visit headache patients according to the third edition (beta version) of the International Classification of Headache Disorders (ICHD-3β). Primary headache patients who underwent neuroimaging were finally enrolled in the analysis. Serious intracranial pathology was defined as serious neuroimaging abnormalities with a high degree of medical urgency. Univariable and multivariable logistic regression analyses were conducted to identify factors associated with incidental neuroimaging abnormalities. Results Neuroimaging abnormalities were present in 170 (18.3%) of 927 eligible patients. In multivariable analysis, age ≥40 years [multivariable-adjusted odds ratio (aOR)=3.37, 95% CI=2.07-6.83], male sex (aOR=1.61, 95% CI=1.12-2.32), and age ≥50 years at headache onset (aOR=1.86, 95% CI=1.24-2.78) were associated with neuroimaging abnormalities. In univariable analyses, age ≥40 years was the only independent variable associated with serious neuroimaging abnormalities (OR=3.37, 95% CI=1.17-9.66), which were found in 34 patients (3.6%). These associations did not change after further adjustment for neuroimaging modality. Conclusions Incidental neuroimaging abnormalities were common and varied in a primary headache diagnosis. A small proportion of the patients incidentally had serious neuroimaging abnormalities, and they were predicted by age ≥40 years. These findings can be used to guide the performing of neuroimaging in primary headache disorders.

Background: Periodic lateralized epileptiform discharges (PLEDs) are associated with altered consciousness in 75% of patients. Major controversy about PLEDs is whether they are ictal or interictal phenomenon. Diagnosis of non-convulsive status epilepticus is often guided by response to benzodiazepine. We conducted a study to evaluate quantitative differences of EEG activity with PLEDs according to their response to acute benzodiazepine trial. Methods: Nineteen patients with altered consciousness (stupor or coma) for whom the electroencephalography (EEG) recording with acute benzodiazepine trial was undertaken within 24 hours of onset of altered consciousness were retrospectively enrolled. Morphology of PLEDs including amplitude, frequency, and variability of the frequency was analyzed. Quantitative analysis of EEGs includes spectral power, spectral coherence, and graph theory analysis. Results of the analyses were compared between patients whose PLEDs were abolished by benzodiazepine (BDZ-R group) and those whose PLEDs persisted (BDZ-NR group). Results: Morphologic variables were not different between two groups. In BDZ-R group, alpha-1 activity was increased in both frontopolar areas. Beta activity was also increased in both frontal areas while delta activity was reduced. In BDZ-R group, alpha-1 and beta activities were more coherent between bilateral hemispheres in frontal, anterior temporal, and central areas. Coherence line topographic map also revealed more bilaterally symmetric pattern in BDZ-R group. Network characteristics revealed by graph theory analysis did not differ between the two groups. Conclusions: Greater higher frequency activity (alpha-1 and beta) and lesser lower frequency activity (delta) in frontal areas, and more coherent activity in higher frequency band between hemispheres were associated with benzodiazepine responsiveness. J Korean Neurol Assoc 33(4):288-296, 2015

Head impulse test (HIT) is helpful to understanding high-frequency vestibulo-ocular reflex in patients with dizziness and imbalance. There are some reports on abnormal HITs in cerebellar disorder. To our knowledge, there was no report of transient bilateral positive head impulse related to antiepileptic drugs. A 65-year-old woman developed dizziness and imbalance after treatment with pregabalin for pain control of radiation cystitis. Neurological examination exhibited positive bilateral HIT results, in addition to ataxia and gaze-evoked rebound nystagmus. Pregabalin intoxication can evoke transient positive horizontal head impulse test as another indicator of cerebellar dysfunction.

Autoimmune and unknown/cryptogenic encephalitis have been increasingly noted in the inflammatory etiology of new-onset status epilepticus (SE). We aimed to investigate clinical characteristics and the potential role of immunotherapy in encephalitis-related adult SE through our multicenter prospective SE registry. Among the 274 patients with SE, 35 (12.8%) patients demonstrated an inflammatory etiology and 19 out of 35 (54.3%) patients demonstrated unknown/cryptogenic cause. Patients with autoimmune and unknown/cryptogenic encephalitis shared similar clinical features. In unknown/cryptogenic encephalitis, the proportion of favorable outcomes (mRS 0-3) showed a different propensity at 3-6months after discharge between patients receiving active immunotherapy and not receiving any immunotherapy, although it was not statistically significant (at admission 28.6% vs 20%, p=0.603; at discharge 57.1% vs 60%, p=0.570; at 3-6months after discharge 90% vs 60%, p=0.214 in patients treated with active immunotherapy or without immunotherapy, respectively). Extensive autoantibody screening should be carried out and empirical immunotherapy may be potentially helpful even in patients without antibodies, although longer term and multi-national studies may be necessary to make a stronger recommendation.

This paper described the development of equalizing spacer for minimization of voltage drop according to DC feeder extension. Power consumption is increased as shorter interval of train driving time and transportation capacity increase in urban subway. Therefore we investigated voltage drop of catenary at a point in case of traction driving of a train in parallel to the DC power supply system. Based on it`s result, equalizing spacer is designed and fabrication to minimize the voltage drop in accordance with the power supply line arranged in three rows, and then its performance was confirmed that the stress distribution of main body and the distributed load are satisfied through the body structure modeling.

BACKGROUND AND PURPOSE Chronic daily headache (CDH) is a commonly reported reason for visiting hospital neurology departments, but its prevalence, clinical characteristics, and management have not been well documented in Korea. The objective of this study was to characterize the 1-year prevalence, clinical characteristics, medical consultations, and treatment for CDH in Korea. METHODS The Korean Headache Survey (KHS) is a nationwide descriptive survey of 1507 Korean adults aged between 19 and 69 years. The KHS investigated headache characteristics, sociodemographics, and headache-related disability using a structured interview. We used the KHS data for this study. RESULTS The 1-year prevalence of CDH was 1.8% (95% confidence interval, 1.1-2.5%), and 25.7% of the subjects with CDH met the criteria for medication overuse. Two-thirds (66.7%) of CDH subjects were classified as having chronic migraine, and approximately half of the CDH subjects (48.1%) reported that their headaches either substantially or severely affected their quality of life. Less than half (40.7%) of the subjects with CDH reported having consulted a doctor for their headaches and 40.7% had not received treatment for their headaches during the previous year. CONCLUSIONS The prevalence of CDH was 1.8% and medication overuse was associated with one-quarter of CDH cases in Korea. Many subjects with CDH do not seek medical consultation and do not receive appropriate treatment for their headaches.

Overproduction and accumulation of melanin in the skin can lead to pigmentation disorders, such as freckles and melasma. Many researchers are studying the regulation of melanogenesis in the skin with the aim of developing whitening cosmetics. In this study, bioactivity-guided separation of the hexane fraction of Schisandra chinensis (Turcz.) Baillon extract yielded five major compounds, β-chamigrenal, α-ylangenol, gomisin N, gomisin A, and schisandrin. The structures were identified by using 1H-NMR and 13C-NMR spectroscopy and comparing the spectral data with published data. Melanogenesis inhibitory activity assay in alpha-melanocyte-stimulating hormone (α-MSH)-induced B16F10 mouse melanoma cells revealed that gomisin N was the active component and significantly inhibited melanin synthesis in a concentration-dependent manner. Thus, we evaluated the mechanism underlying its anti-melanogenic effect. Gomisin N inhibited the expression of tyrosinase and microphthalmia-associated transcription factor (MITF) in B16F10 cells, while it did not affect cAMP response element binding protein (CREB) phosphorylation. Additionally, gomisin N activated AKT phosphorylation, which inhibits MITF expression. Thus, our results strongly suggest that the active compound, gomisin N, has potential for use in cosmetics to reduce hyperpigmentation.

Although anxiety and depression have been classified as distinct traits of affective disorders, previous studies have reported their co-occurrence in subjects with migraine. However, few reports are available on the clinical implications of this comorbidity. This study is to assess the comorbidity of anxiety and depression in subjects with migraine and its clinical implications in a population-based sample from Korea.We selected Korean subjects aged 19-69 years by the stratified random sampling method, and evaluated them using a semi-structured interview, designed to identify headache type, anxiety, and depression. We used Goldberg Anxiety Scale questions and Patient Health Questionnnaire-9 for the diagnosis of anxiety and depression, respectively.Of the 2,762 participants who completed the interview, 147 subjects (5.4%) were classified as having a migraine during the previous year. Among these 147 subjects, 17 (11.6%) had anxiety and depression, 28 (19.0%) had anxiety alone, 9 (6.1%) had depression alone, and 93 (63.3%) had neither anxiety nor depression. Headache frequency per month was remarkably higher in subjects having migraine with anxiety and depression (median [25-75 percentile values], 8.0 [2.5-21.0]) than in those having migraine with anxiety alone (2.0 [1.0-5.0], p = 0.003), migraine with depression alone (1.0 [0.3-4.0], p = 0.001), and migraine without anxiety or depression (1.0 [0.3-3.0], p 0.001). The migraine with anxiety alone (7.0 [6.0-8.0], p = 0.011) group and migraine with anxiety and depression (7.0 [5.0-9.0], p = 0.018) group showed higher Visual Analogue Scale scores for pain intensity compare to migraine without anxiety or depression (6.0 [5.0-7.0]) group.Approximately 1/3 of migraineurs with anxiety had depression and 2/3 of migraineurs with depression had anxiety. Combination of anxiety and depression was associated with an increased headache frequency. Anxiety was associated with exacerbation of headache intensity.

Background We conducted the study to examine accuracy of the magnetoencephalography (MEG) spike source localization in presurgical evaluation of patients with medically refractory focal epilepsy. Methods Ten consecutive patients with refractory focal epilepsy who were candidates for two-stage surgery with long-term intracranial electroencephalography (ICEEG) monitoring were enrolled. Interictal MEG recordings with simultaneous scalp EEG were obtained within 7 days before the ICEEG electrode implantation. The location of each MEG spike source was quantitatively compared with ICEEG spike foci (focal area of interictal spikes) and ICEEG ictal foci (earliest cortical origin of seizures). Gyral-width concordance and sublobar concordance were also determined for all MEG spike sources. Gyral-width concordance was defined by distance of 15 mm or less between MEG spike sources and ICEEG spike foci or ICEEG ictal foci. Results Visual analyses of the MEG traces of all 10 patients revealed 292 spikes (29.2 ± 24.0 per patient). Spike yield of the MEG was similar to the simultaneously recorded scalp EEG. MEG spike sources were closely located with ICEEG spike foci (distance: 9.3 ± 10.8 mm). Clustered MEG spike sources were even closer to ICEEG spike foci (distance: 7.3 ± 6.4 mm). MEG spike sources, even clustered ones, were less concordant with ICEEG ictal foci and had significant longer distance from ICEEG ictal foci (distance: 21.5 ± 15.6 mm for all sources, 19.7 ± 13.7 mm for clustered sources). Gyral-width concordance rate and sublobar concordance rate were also higher with ICEEG interictal spike foci than with ICEEG ictal foci. On the other hand, 53.4% of interictal spike foci from ICEEG were not detected by interictal MEG recordings. Conclusions MEG spike sources, especially clustered ones, from interictal recording could localize the irritative zone of ICEEG with a high accuracy. However, MEG spike sources have relatively poor correlation with seizure onset zone and lower sensitivity in identifying all irritative zones of ICEEG. This limitation should be considered in the interpretation of MEG results.

BACKGROUND:Various stimuli can trigger migraines in susceptible individuals. We examined migraine trigger factors by using a smartphone headache diary application. METHOD:Episodic migraineurs who agreed to participate in our study downloaded smartphone headache diary application, which was designed to capture the details regarding headache trigger factors and characteristics for 3 months. The participants were asked to access the smartphone headache diary application daily and to confirm the presence of a headache and input the types of trigger factors. RESULTS:Sixty-two participants kept diary entries until the end of the study. The diary data for 4,579 days were analyzed. In this data set, 1,099 headache days (336 migraines, 763 non-migraine headaches) were recorded; of these, 772 headache events had with trigger factors, and 327 events did not have trigger factors. The common trigger factors that were present on headache days included stress, fatigue, sleep deprivation, hormonal changes, and weather changes. The likelihood of a headache trigger was 57.7% for stress, 55.1% for sleep deprivation, 48.5% for fatigue, and 46.5% for any trigger. The headaches with trigger factors were associated with greater pain intensity (p

Previous studies have demonstrated an association of osteopenia/osteoporosis with idiopathic benign paroxysmal positional vertigo (BPPV). Since vitamin D takes part in the regulation of calcium and phosphorus found in the body and plays an important role in maintaining proper bone structure, decreased bone mineral density in patients with BPPV may be related to decreased serum vitamin D. We measured the serum levels of 25-hydroxyvitamin D in 100 patients (63 women and 37 men, mean age ± SD = 61.8 ± 11.6) with idiopathic BPPV and compared the data with those of 192 controls (101 women and 91 men, mean age ± SD = 60.3 ± 11.3) who had lived in the same community without dizziness or imbalance during the preceding year. The selection of the controls and acquisition of clinical information were done using the data from the Fourth Korean National Health and Nutrition Examination Survey, 2008. The serum level of 25-hydroxyvitamin D was lower in the patients with BPPV than in the controls (mean ± SD = 14.4 ± 8.4 versus 19.1 ± 6.8 ng/ml, p = 0.001). Furthermore, patients with BPPV showed a higher prevalence of decreased serum vitamin D (

Background and purpose New-onset headache in elderly patients is generally suggestive of a high probability of secondary headache, and the subtypes of primary headache diagnoses are still unclear in the elderly. This study investigated the characteristics of headache with an older age at onset (≥65 years) and compared the characteristics between younger and older age groups. Methods We prospectively collected demographic and clinical data of 1,627 patients who first visited 11 tertiary hospitals in Korea due to headache between August 2014 and February 2015. Headache subtype was categorized according to the International Classification of Headache Disorders, Third Edition Beta Version. Results In total, 152 patients (9.3%, 106 women and 46 men) experienced headache that began from 65 years of age [elderly-onset group (EOG)], while the remaining 1,475 patients who first experienced headache before the age of 65 years were classified as the younger-age-at-onset group (YOG). Among the primary headache types, tension-type headache (55.6% vs. 28.8%) and other primary headache disorders (OPH, 31.0% vs. 17.3%) were more common in the EOG than in the YOG, while migraine was less frequent (13.5% vs. 52.2%) (p=0.001) in the EOG. Among OPH, primary stabbing headache (87.2%) was more frequent in the EOG than in the YOG (p=0.032). The pain was significantly less severe (p=0.026) and the frequency of medication overuse headache was higher in EOG than in YOG (23.5% vs. 7.6%, p=0.040). Conclusions Tension-type headache and OPH headaches, primarily stabbing headache, were more common in EOG patients than in YOG patients. The pain intensity, distribution of headache diagnoses, and frequency of medication overuse differed according to the age at headache onset.

We sought to investigate the peripheral nerve excitability property of early diabetic neuropathy (DN) and provide a logical hypothesis regarding the pathophysiology of subclinical/early stage of DN. The automated nerve excitability test (NET) utilizing the threshold tracking technique (TTT) was performed to measure multiple excitability indices in 30 early DN and 30 normal subjects. Early DN was defined as N0 or N1 stage of Dyck's staging method. The protocols calculated strength-duration time constant (SDTC) from duration–charge curve, parameters of threshold electrotonus (TE) and current–threshold relationship (CTR) from sequential sub-threshold current, and recovery cycle (RC) from double supra-threshold stimulation. Each parameter of test was co-analyzed with clinical and laboratory data including age, sex, BMI, HgbA1c, lipid profile, and estimated glomerular filtration rate (eGFR). Compared to normal or N0 groups, N1 group had ‘fanning-in’ phenomenon in TE, increased refractory period, and decreased supernormality/subnormality. Linear regression showed that parameters associated with vascular factor were significantly related with STDC: absolute TG values were positively associated with STDC, whereas eGFR values were inversely related with STDC. Nerve excitability can be altered even in the early mild DN. The pattern of alteration suggests depolarizing nerve or nerve ischemia in pathophysiology of subclinical/early DN.

Summary Purpose: To evaluate the efficacy and safety of pregabalin (PGB) as adjunctive therapy, using a flexible-dosing schedule in Korean patients with refractory partial-onset seizures. Methods: This randomized, double-blind (DB), placebo-controlled trial consists of a 6-week baseline, a 12-week DB treatment, and a 1-week taper phase. Patients having recurrent partial seizures (≥4 seizures during baseline phase) under adequate pharmacotherapy were recruited to be randomized to PGB or placebo (PLC) in a 2 to 1 ratio. Starting dose was 150 mg/day, increased every 2 weeks by 150-mg/day increments up to maximum dose of 600 mg/day. The primary efficacy parameter was response ratio (RRatio) for all partial seizures. Results: A total of 178 patients (119 in PGB, 59 in PLC) were assigned to the study. Median daily doses of PGB and PLC were 367 and 420 mg/day, respectively. RRatio least squares (LS) mean was −35.8 in the PGB group and −23.2 in the PLC group, with estimated difference in RRatios being −12.6 [95% confidence interval (CI): −22.7 to −2.5, p = 0.015] in the intent-to-treat (ITT) population. Analysis of secondary efficacy measures showed a general trend favoring PGB over PLC. Seventy-seven patients (64.7%) in the PGB group and 18 patients (30.5%) in the PLC group developed adverse events (AEs) related to the study drug. Seven patients (5.9%) in the PGB group discontinued the study prematurely because of AEs. In the post hoc analysis, a significant weight gain (≥7% of baseline body weight) was found in 24.8% of patients taking PGB, which was more frequent in patients with a lower body mass index (BMI ≤20). Discussion: PGB was effective and easily tolerable as add-on treatment in an Asian population with refractory partial-onset seizures.

Objective Increased arterial stiffness is an independent predictor of cardiovascular diseases in hypertensive patients. Hypertension and aging can cause similar damage to small vessel walls. The objective of this study was to determine relationship between arterial stiffness measured by brachial–ankle pulse wave velocity (baPWV) and the risk of cerebral small vessel disease (SVD) in elderly people with hypertension. Methods We studied 196 elderly subjects with hypertension (≥50 years of age) who had neither large vessel stroke nor cardiac embolism. These patients were divided into three groups based on the results of brain MRI: (1) those with first-ever small vessel stroke; (2) those with asymptomatic subcortical ischemia; and (3) a control group with hypertension. Results The baPWV was significantly increased in the patients with first-ever small vessel stroke or asymptomatic subcortical infarction when compared to the control group, after adjusting for systolic blood pressure (SBP), pulse pressure (PP), and hs-CRP (p = 0.005). Among subjects with SVD on MRI, the number of lacunar infarcts (LIs) ≥ 5 was significantly related to a higher baPWV (p = 0.02). The relationship between the severity of periventricular white matter hyperintensities (PWMH) and the degree of baPWV became insignificant after adjustment for age. Conclusion Increased baPWV was significantly associated with the risk of SVD in elderly persons with hypertension. Therefore, the measurement of baPWV could be used to predict SVD.

Background A “Probable headache disorder” is diagnosed when a patient’s headache fulfills all but one criterion of a headache disorder in the 3rd beta edition of the International Classification of Headache Disorder (ICHD-3β). We investigated diagnostic changes in probable headache disorders in first-visit patients after at least 3 months of follow-up. Methods This was a longitudinal study using a prospective headache registry from nine headache clinics of referral hospitals. The diagnostic change of probable headache disorders at baseline was assessed at least 3 months after the initial visit using ICHD-3β. Results Of 216 patients with probable headache disorders at baseline, the initial probable diagnosis remained unchanged for 162 (75.0 %) patients, while it progressed to a definite diagnosis within the same headache subtype for 45 (20.8 %) by fulfilling the criteria during a median follow-up period of 6.5 months. Significant difference on the proportions of constant diagnosis was not found between headache subtypes (P 3 and ≤ 6 months vs. > 6 and ≤ 10 months) in probable migraine, probable TTH, and probable OPHD, respectively. Conclusions In this study, a probable headache diagnosis, based on ICHD-3β, remained in approximately three-quarters of the outpatients; however, diagnostic stability could differ by headache recurrence and subtype. Probable headache management might have to consider these differences.

Background Recent studies have shown an association between migraine and restless legs syndrome (RLS). However, migraine prevalence peaks from the 20s to 40s whereas RLS prevalence peaks after the 50s. Despite this, reports on how migraine and RLS may be associated by age is limited. Therefore, the purpose of this study is to investigate the comorbidity between migraine and RLS according to age. Methods We selected a stratified random population sample of Koreans aged 19 to 69 years and evaluated them with a 60-item semi-structured interview designed to identify RLS, headache type, and clinical characteristics of migraine. To assess the association between migraine and RLS according to age, we divided participants into 5 age groups (19–29, 30–39, 40–49, 50–59, and 60–69 years) and analysed each group. Results Subjects with migraine showed an increased RLS prevalence in the 19–29 (Odds ratio [OR] = 6.6, 95 % confidence interval [CI] = 1.2–36.8) and 40–49 (OR = 6.7, 95 % CI = 1.5–33.5) age groups compared to non-headache controls but failed to showed a significant association in the 50–59 (OR = 1.1, 95 % CI = 0.2–5.6) and 60–69 (OR = 0.4, 95 % CI = 0.1–4.0) age groups. Migraineurs with 1–10 (12.5 %, OR = 2.0, 95 % CI = 1.3–3.2, p = 0.003) and >10 (12.5 %, OR = 2.5, 95 % CI = 1.0–5.6, p = 0.038) attacks per month showed an increased RLS prevalence compared to migraineurs with

Background Vestibular migraine (VM), the common term for recurrent vestibular symptoms with migraine features, has been recognized in the appendix criteria of the third beta edition of the International Classification of Headache Disorders (ICHD-3β). We applied the criteria for VM in a prospective, multicenter headache registry study. Methods Nine neurologists enrolled consecutive patients visiting outpatient clinics for headache. The presenting headache disorder and additional VM diagnoses were classified according to the ICHD-3β. The rates of patients diagnosed with VM and probable VM using consensus criteria were assessed. Results A total of 1414 patients were enrolled. Of 631 migraineurs, 65 were classified with VM (10.3%) and 16 with probable VM (2.5%). Accompanying migraine subtypes in VM were migraine without aura (66.2%), chronic migraine (29.2%), and migraine with aura (4.6%). Probable migraine (75%) was common in those with probable VM. The most common vestibular symptom was head motion-induced dizziness with nausea in VM and spontaneous vertigo in probable VM. The clinical characteristics of VM did not differ from those of migraine without VM. Conclusion We diagnosed VM in 10.3% of first-visit migraineurs in neurology clinics using the ICHD-3β. Applying the diagnosis of probable VM can increase the identification of VM.

Background Although anxiety and depression have been classified as distinct traits of affective disorders, previous studies have reported their co-occurrence in subjects with migraine. However, few reports are available on the clinical implications of this comorbidity. This study is to assess the comorbidity of anxiety and depression in subjects with migraine and its clinical implications in a population-based sample from Korea. Methods We selected Korean subjects aged 19–69 years by the stratified random sampling method, and evaluated them using a semi-structured interview, designed to identify headache type, anxiety, and depression. We used Goldberg Anxiety Scale questions and Patient Health Questionnnaire-9 for the diagnosis of anxiety and depression, respectively. Results Of the 2,762 participants who completed the interview, 147 subjects (5.4%) were classified as having a migraine during the previous year. Among these 147 subjects, 17 (11.6%) had anxiety and depression, 28 (19.0%) had anxiety alone, 9 (6.1%) had depression alone, and 93 (63.3%) had neither anxiety nor depression. Headache frequency per month was remarkably higher in subjects having migraine with anxiety and depression (median [25–75 percentile values], 8.0 [2.5–21.0]) than in those having migraine with anxiety alone (2.0 [1.0–5.0], p = 0.003), migraine with depression alone (1.0 [0.3–4.0], p = 0.001), and migraine without anxiety or depression (1.0 [0.3–3.0], p

Objective : To differentiate between primary and secondary bilateral synchrony (PBS and SBS, respectively) in generalized spike-and-wave discharges (GSWD), we applied independent component analysis (ICA) to GSWD, and analyzed the characteristic patterns of independent components. Methods : EEGs from 19 patients with GSWD (9 PBS patients, 10 SBS patients) were studied. Thirty GSWD epochs were selected and concatenated to construct an EEG data matrix that was subjected to ICA. Selected independent components were localized by mapping them on a spherical model of the head by means of brain electrical source analysis (BESA) to define dipole sources. Results : Epileptic components of GSWD were clearly separated by the ICA algorithm in all patients. Between one and three components per patient were responsible for GSWD. In PBS patients, 70.6% of the independent components had dipole sources within the dorsolateral frontal region, and 56.5% of the independent components in SBS patients were within the medial frontal region ( P =0.012). The orientation of all of the independent components in PBS patients was radial, whereas 47.8% of the independent components in SBS patients were tangential; this difference was statistically significant ( P =0.001). Conclusions : Spatiotemporal decomposition of GSWD by using ICA might be helpful for differentiating SBS from PBS. Significance : The localization of the dipole sources of the independent components may provide insight into the pathophysiological origins of GSWD.

Trochleitis is an uncommon disorder that is defined as inflammation of the superior oblique tendon trochlea apparatus and is characterized by pain, point tenderness over the trochlea, and/or localized swelling [1, 2]. In absence of clear findings suggestive of inflammation on blood test and radiology, this characteristic orbital pain around the trochlea with tenderness and exacerbation during upward gaze is called a primary trochlear headache or trochleodynia [3, 4]. In addition to the characteristic pain, trochleodynia can be accompanied by migrainous headache, ptosis, and conjunctival injection [2–4]. However, trochleodynia presenting with diplopia is rare. Herein, we report a patient with fourth nerve palsy associated with primary trochlear headache. A 29-year-old man presented with binocular vertical diplopia and left-side periocular pain for 4 days, which occurred after 1 day of migrainous headache. The migraine disappeared spontaneously with supportive care. However, the concurrent dull headache, periocular pain, and diplopia were not improved by analgesics or triptans. He denied diurnal variation of these symptoms. The periocular pain was exacerbated by eye movements, especially elevation. Examination of external eye did not show abnormal findings such as conjunctival injection, chemosis, proptosis, and periorbital edema. Painful tenderness was evoked by compression over the trochlear area (a score of 8 on the visual analogue scale; Fig. 1a). He had no medical history of hypertension or diabetes mellitus. He also denied any head trauma or ocular operation history. The vital signs were stable. His head was tilted rightward (Fig. 2) and hypertropia of the left eye (2 prism diopter, PD) was increased on adduction (3 PD), depression (3 PD), and leftward head tilt (4 PD; Fig. 2). The fundus photography shows no abnormal ocular torsion. These findings were most consistent with left trochlear nerve palsy. Other findings of neurological and neuro-ophthalmological examinations were normal. The results of laboratory evaluations, including autoimmune disease and vasculitis, were normal. There were also no remarkable findings that could explain his neurological deficits on MRI of the brain and orbit (Fig. 3). We diagnosed him as having primary trochlear headache with trochlear nerve palsy. The patient was injected with 3 mg of dexamethasone and 3 mg of methylprednisolone (final volume, 1 ml) targeted to the symptomatic trochlea (Fig. 1b). Periocular pain and tenderness were resolved within 48 h, and the diplopia gradually improved over several days. Our patient showed trochlear nerve palsy with focal tenderness in the trochlea, which was responsive to local steroid injection. Trochleodynia is a pain originating in the trochlear region that is felt in the upper-inner angle of the orbit and typically exacerbates upon elevation or palpation [4, 5]. Trochleitis is a syndrome of inflammatory K. J. Lee S.-H. Jeong (&) A. Y. Lee J.-M. Kim Department of Neurology, Chungnam National University Hospital, 640, Daesa-dong, Joong-ku, Daejeon 301-721, Korea e-mail: mseaj@hanmail.net

Cytochrome P4502C9(CYP2C9) is largely responsible for terminating anticoagulant effect by hydroxylation of S-warfarin to inactive metabolites. Mutations in the CYP2C9 gene result in the expression of allelic variants, CYP2C9*2 and CYP2C9*3 with reduced enzyme activity compared to wild type CYP2C9*1. The aim of this study was to assess relationship between requirement of warfarin dose and polymorphism in CYP2C9 in Korean population. Patients on warfarin therapy for longer than 1 year were included from July 1999 to December 2000 and categorized as one of four groups; regular dose non-bleeding, regular dose bleeding, low dose non-bleeding and low dose bleeding. Low dose was defined as less than 10 mg/week for 3 consecutive monthly follow-ups. Bleeding complications included minor and major bleedings. Blood samples were processed for DNA extraction, genotyping and sequencing to detect polymorphism in CYP2C9. Demographic data, warfarin dose per week, prothrombin time (INR), indications and co-morbid diseases were assessed for each group. Total 90 patients on warfarin were evaluated; The low dose group has taken warfarin 7.6 +/- 1.7 mg/week, which was significantly lower than 31.4 +/- 0.9 mg/week in the regular dose group (p0.0001). The measured INR in the low dose group was similar to that of the regular dose group (2.3 +/- 0.7 vs. 2.3 +/- 0.6, p=0.9). Even though there was a higher possibility of CYP2C9 variation in the low dose group, no polymorphism in CYP2C9 was detected. All patients were homozygous C416 in exon 3 for CYP2C9*2 and A1061 in exon 7 for CYP2C9*3. The DNA sequencing data confirmed the homozygous C416 and A1061 alleles. In conclusion, polymorphism in CYP2C9 is not a critical factor for assessing warfarin dose requirement and risk of bleeding complications in a Korean population.