Usefulness of saliva for perampanel therapeutic drug monitoring.

OBJECTIVE: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) helps optimize drug management for patients with epilepsy. Salivary testing is both noninvasive and easy, and has several other advantages. Due to technical advances, salivary TDM has become feasible for several drugs, including AEDs, and its value has been investigated. Until recently, saliva TDM of perampanel (PER) had not been reported. The purpose of our study was to confirm whether saliva is a biological substitute for plasma in PER TDM. METHODS: Adult patients diagnosed with epilepsy who received PER from August 2018 to March 2019 at Seoul National University Hospital were enrolled. Total and free PER were measured in simultaneously obtained plasma and saliva samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatographic (HPLC). We examined the correlations between saliva and plasma PER concentrations and whether the use of concomitant medications classified as cytochrome P450 (CYP)3A4 inducers affected the correlations. RESULTS: Thirty patients were enrolled, aged 16 to 60; 10 (33%) were women. Patients received 2 to 12 mg (mean, 6 mg) of PER. The average total and free concentrations of PER were 343.02 (46.6-818.0) and 1.53 (0.51-2.92) ng/mL in plasma and 9.74 (2.21-33.0) and 2.83 (1.01-6.8) ng/mL in saliva, respectively. A linear relationship was observed between the total PER concentrations in saliva and the total and free PER concentrations in plasma (both P < .001; r = .678 and r = .619, respectively). The change in the PER concentration caused by the CYP3A4 inducer did not affect the correlation between saliva and plasma concentrations (all P < .001). SIGNIFICANCE: The PER concentration in saliva was correlated with that in plasma. This correlation was not affected by CYP3A4 inducers. Our results demonstrate for the first time that PER is measurable in saliva and suggest the potential for the clinical application of the saliva PER TDM matrix.

Prognosis of spontaneous cervical artery dissection and transcranial Doppler findings associated with clinical outcomes.

OBJECTIVES: We categorised spontaneous cervical artery dissection (sCAD) by radiological features and investigated factors associated with favourable outcomes. METHODS: We retrospectively analysed 128 patients with sCAD with a median follow-up duration of 25 months. Twenty-nine constituted the aneurysm group, 52 the stenotic group, and 47 the occlusive group. Various relevant factors, including National Institute of Health Stroke Scale (NIHSS) scores, type of antithrombotic therapy, stroke progression in the first week, and transcranial Doppler (TCD) flow-waveforms (in the occlusive subgroup) were analysed. Favourable outcomes were defined as a 1-year modified Rankin-Scale score of 0-1. Favourable anatomical outcomes were defined as a reversal of dissection-associated stenosis during follow-up. RESULTS: The aneurysm and stenotic groups showed favourable outcomes, while the occlusive group outcomes were less favourable. In the stenotic group, anticoagulation, an NIHSS score ≥4, and stroke progression were inversely associated with favourable long-term outcomes. Remarkably, in the occlusive group, flow abnormality more severe than minimal flow was associated with stroke progression, unfavourable long-term outcome, and arterial irreversibility. CONCLUSIONS: The outcome of sCAD depends on its radiological subtype. In the occlusive subtype, which is associated with the worst outcome, TCD flow analysis may predict acute stroke progression and long-term outcome. KEY POINTS: • Outcomes in cervical artery dissection may be determined by radiological subtypes. • The aneurysm and stenotic groups had favourable outcomes. • The occlusive group had less favourable functional outcomes. • Flow-waveform analysis by TCD could predict functional and anatomical outcomes.

Leisure time physical activity in patients with epilepsy in Seoul, South Korea.

The aim of this study was to investigate the frequencies of and barriers to leisure time physical activity (LTPA) of people with epilepsy (PWE), and influencing factors, particularly those related to mood. Data were obtained from 178 PWE who visited the Seoul National University Hospital outpatient clinic in January and February 2007. Most PWE reported not being involved in LTPA as much as they wished. PWE reported hiking (n=32, 18%) and walking (n=25, 14%) as the most common LTPA. Many PWE identified epilepsy-specific barriers such as "the fear of experiencing seizures during activity" and "discouragement from activity by family and/or friends." In multiple logistic regression analysis, PWE who were on antiepileptic drug polytherapy (OR=2.49, 95% CI=1.22-5.08, P=0.01), had anxiety (OR=3.25, 95% CI=1.22-8.60, P=0.02), and had had previous seizure experiences during activities (OR=2.84, 95% CI=1.30-6.20, P=0.01) were significantly more likely to be inactive. Educational programs for reducing anxiety and misunderstanding about activity of PWE and guidelines for promoting LTPA among PWE are needed.

Effect of Number of Previous Antiseizure Medications on Efficacy and Tolerability of Adjunctive Brivaracetam for Uncontrolled Focal Seizures: Post Hoc Analysis.

INTRODUCTION: The aim was to evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with severely drug-resistant focal seizures versus adults with less drug-resistant disease. METHODS: Data were pooled from patients with focal seizures on 1-2 concomitant antiseizure medications (ASMs) randomized to BRV 50, 100, 200 mg/day, or placebo in 3 phase 3 trials (N01252 [NCT00490035], N01253 [NCT00464269], and N01358 [NCT01261325]) with a 12-week treatment period. Outcomes were assessed in patients with ≥ 5 and 0-4 previous ASMs (stopped before trial drug initiation). RESULTS: In ≥ 5 previous ASMs subgroup (BRV 50, 100, 200 mg/day: n = 26, n = 137, n = 120; placebo: n = 151), percentage reduction over placebo in 28-day adjusted focal seizure frequency was 13.0% for 50 mg/day (p = 0.38), 18.1% for 100 mg/day (p = 0.006), 19.8% for 200 mg/day (p = 0.004), and 17.0% for all BRV-treated patients (p = 0.001). The 50% responder rate was 26.9%, 29.9%, 30.0%, and 29.7% for BRV 50, 100, 200, and 50-200 mg/day, respectively (placebo: 13.2%); odds ratios versus placebo were statistically significant (p < 0.05) for BRV 100, 200, and 50-200 mg/day. In 0-4 previous ASMs subgroup (BRV 50, 100, 200 mg/day: n = 135, n = 195, n = 129; placebo: n = 267), all BRV dosages showed statistically significant (1) percentage reduction over placebo in 28-day adjusted focal seizure frequency (21.4-28.7%); (2) differences from placebo in median percentage reduction in 28-day adjusted focal seizure frequency from baseline (35.5-45.9%; placebo: 21.3%); and (3) odds ratios versus placebo (favoring BRV) for 50% responder rates. In BRV-treated patients, treatment-emergent adverse event (TEAE) incidence (73.8% [217/294] vs. 64.6% [329/509]) and discontinuation due to TEAEs (10.5% vs. 4.5%) were higher in the ≥ 5 versus 0-4 previous ASMs subgroup; serious TEAEs were rare in both subgroups (≥ 5 previous ASMs: 3.1%; 0-4 previous ASMs: 2.9%). CONCLUSION: Adjunctive BRV showed efficacy and was generally well tolerated in adults with focal seizures independent of the number of previous ASMs.

Changes in neuropsychological functioning following temporal lobectomy in patients with temporal lobe epilepsy.

PURPOSE: This study was conducted to evaluate the changes in neuropsychological functioning in patients with temporal lobe epilepsy (TLE) after temporal lobe resection. METHODS: Fifty-four TLE patients were evaluated before and after surgery using comprehensive neuropsychological tests to assess general intelligence, executive functioning, language, verbal and visual memory, working memory, visuo-spatial ability, attention and motor function. RESULTS: The patients with left TLE showed no impairment of neuropsychological functioning after surgery, with the exception of auditory immediate memory. Furthermore, they showed significant improvement in performance IQ, executive function, working memory, visual memory, attention and psychomotor speed. The patients with right TLE did not show any significant impairment in post-operative neuropsychological functioning. They showed improvements in intellectual and executive functions, language, visual memory, visuo-spatial ability, attention and motor function post-operatively. The patients with hippocampal sclerosis showed greater post-operative improvements than the patients without hippocampal sclerosis regardless of the side. Patients with better pre-operative neuropsychological function had a higher chance of successfully discontinuing all seizure medications after surgery. DISCUSSION: The results of this study suggest that temporal lobectomy does not harm the neuropsychological functioning of patients with intractable TLE and that it improves cognitive functions of the contralateral hemisphere.

Reliability of semiology description.

OBJECTIVE: Seizure semiology is important for classifying patients' epilepsy. Physicians usually get most of the seizure information from observers though there have been few reports on the reliability of the observers' description. This study aims at determining the reliability of observers' description of the semiology. METHODS: We included 92 patients who had their habitual seizures recorded during video-EEG monitoring. We compared the semiology described by the observers with that recorded on the videotape, and reviewed which characteristics of the observers affected the reliability of their reported data. RESULTS: The classification of seizures and the individual components of the semiology based only on the observer-description was somewhat discordant compared with the findings from the videotape (correct classification, 85%). The descriptions of some ictal behaviors such as oroalimentary automatism, tonic/dystonic limb posturing, and head versions were relatively accurate, but those of motionless staring and hand automatism were less accurate. The specified directions by the observers were relatively correct. The accuracy of the description was related to the educational level of the observers. CONCLUSIONS: Much of the information described by well-educated observers is reliable. However, every physician should keep in mind the limitations of this information and use this information cautiously.

Altered Network Characteristics of Spike-Wave Discharges in Juvenile Myoclonic Epilepsy.

Epilepsy is a disease marked by hypersynchronous bursts of neuronal activity; therefore, identifying the network characteristics of the epileptic brain is important. Juvenile myoclonic epilepsy (JME) represents a common, idiopathic generalized epileptic syndrome, characterized by spike-and-wave discharge (SWD) electroencephalographic (EEG) waveforms. We compare herein the network properties of periods of SWD and baseline activity using graph theory. EEG data were obtained from 11 patients with JME. Functional cortical networks during SWD and baseline periods were estimated by calculating the coherence between all possible electrode pairs in the delta, theta, alpha, beta and gamma bands. Graph theoretical measures, including nodal degree, characteristic path length, clustering coefficient, and small-world index were then used to evaluate the characteristics of epileptic networks in JME. We also assessed short- and long-range connections between SWD and baseline networks. Compared to baseline, increased coherence was observed during SWD in all frequency bands. The nodal degree of the SWD network, particularly in the frontal region, was significantly higher compared to the baseline network. The clustering coefficient and small-world index were significantly lower in the theta and beta bands of the SWD versus baseline network, but the characteristic path length did not differ among networks. Long-range connections were increased during SWD, particularly between frontal and posterior brain regions. Our study suggests that SWD in JME is associated with increased local (particularly in frontal region) connectivity. Furthermore, the SWD network was associated with increased long-range connections, and reduced small-worldness, which may impair information processing during SWD.

Outdoor artificial light at night, obesity, and sleep health: Cross-sectional analysis in the KoGES study.

Obesity is a common disorder with many complications. Although chronodisruption plays a role in obesity, few epidemiological studies have investigated the association between artificial light at night (ALAN) and obesity. Since sleep health is related to both obesity and ALAN, we investigated the association between outdoor ALAN and obesity after adjusting for sleep health. We also investigated the association between outdoor ALAN and sleep health. This cross-sectional survey included 8526 adults, 39-70 years of age, who participated in the Korean Genome and Epidemiology Study. Outdoor ALAN data were obtained from satellite images provided by the US Defense Meteorological Satellite Program. We obtained individual data regarding outdoor ALAN; body mass index; depression; and sleep health including sleep duration, mid-sleep time, and insomnia; and other demographic data including age, sex, educational level, type of residential building, monthly household income, alcohol consumption, smoking status and consumption of caffeine or alcohol before sleep. A logistic regression model was used to investigate the association between outdoor ALAN and obesity. The prevalence of obesity differed significantly according to sex (women 47% versus men 39%, p < 0.001) and outdoor ALAN (high 55% versus low 40%, p < 0.001). Univariate logistic regression analysis revealed a significant association between high outdoor ALAN and obesity (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.14-1.35, p < 0.001). Furthermore, multivariate logistic regression analyses showed that high outdoor ALAN was significantly associated with obesity after adjusting for age and sex (OR 1.25, 95% CI 1.14-1.37, p < 0.001) and even after controlling for various other confounding factors including age, sex, educational level, type of residential building, monthly household income, alcohol consumption, smoking, consumption of caffeine or alcohol before sleep, delayed sleep pattern, short sleep duration and habitual snoring (OR 1.20, 95% CI 1.06-1.36, p = 0.003). The findings of our study provide epidemiological evidence that outdoor ALAN is significantly related to obesity.

Recurrent syncope triggered by temporal lobe epilepsy: ictal bradycardia syndrome.

Ictal asystole is potentially lethal, and known to originate from the involvement of limbic autonomic regions. Appropriate treatment must include an antiepileptic drug and the implantation of a pacemaker. We report the case of a 54-year-old male with recurrent syncope secondary to ictal asystole triggered by temporal lobe epilepsy. This was confirmed by combined Holter and video-electroencephalogram monitoring.

Increased circulating endothelial microparticles and carotid atherosclerosis in obstructive sleep apnea.

BACKGROUND AND PURPOSE: Endothelial impairment is a linking mechanism between obstructive sleep apnea (OSA) and cardiovascular diseases. Profiles of endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) reflect the degree of endothelial impairment. The aims of this study were to measure the levels of EMPs and progenitor cells in OSA, determine the correlations between these factors and OSA severity and the degree of atherosclerosis, and document any changes in these factors after therapy. METHODS: Subjects with (n=82) and without (n=22) OSA were recruited prospectively. We measured the number of colony-forming units (CFU) in cell culture as the endothelial progenitor cell index, and the number of EMPs using flow cytometry with CD31 [platelet endothelial cell adhesion molecule (PECAM)], CD42 (platelet glycoprotein), annexin V, and CD62E (E-selectin) antibodies at baseline and after 4-6 weeks of continuous positive airway pressure (CPAP) therapy. Carotid intima-media thickness (IMT) was regarded as a marker of atherosclerosis. RESULTS: The levels of PECAM(+)CD42(-) (p<0.001), PECAM(+)annexin V(+) (p<0.001), and E-selectin(+) microparticles (p=0.001) were higher in OSA subjects than in non-OSA subjects. The number of CFU did not differ between the two groups. OSA severity independently predicted the levels of PECAM(+)CD42(-) (p=0.02) and PECAM(+)annexin V(+) (p=0.004). Carotid IMT was correlated with OSA severity (p<0.001), PECAM(+)CD42(-) (p=0.03), and PECAM(+)annexin V(+) (p=0.01). Neither OSA severity nor carotid IMT was correlated with either the number of CFU or E-selectin(+). CPAP therapy decreased the occurrence of E-selectin(+) (p<0.001) in 21 of the OSA subjects, but had no effect on the other microparticles of the number of CFU. CONCLUSIONS: OSA led to the overproduction of EMPs, which moderately correlated with OSA severity and the degree of atherosclerosis, and partly responded to therapy. The endothelial impairment might contribute to future cardiovascular events.

Clinico-electrical Characteristics of Lateral Temporal Lobe Epilepsy; Anterior and Posterior Lateral Temporal Lobe Epilepsy.

BACKGROUND AND PURPOSE: This study aimed to determine whether there are clinicoelectrical differences between anterior lateral temporal lobe epilepsy (ALTLE) and posterior lateral temporal lobe epilepsy (PLTLE), taking medial temporal lobe epilepsy (MTLE) as a reference. METHODS: We analyzed the historical information, ictal semiologies, and ictal EEGs of temporal lobe epilepsy patients with a documented favorable surgical outcome (Engel class I or II) at follow-up after more than one year. LTLE was defined when a discrete lesion on MRI or an ictal onset zone in invasive study was located outside the collateral sulcus. LTLE was further divided into ALTLE and PLTLE by reference to the line across the cerebral peduncle. Total 107 seizures of 13 ALTLE, 8 PLTLE and 21 MTLE patients were reviewed. RESULTS: Initial hypomotor symptom was frequently observed in PLTLE (P<0.001). Oroalimentary automatism (OAA) was not observed initially in PLTLE. Generalized tonic-clonic seizures occurred significantly earlier in PLTLE than in ALTLE or MTLE (P< 0.001). Ictal scalp EEG was not helpful in differentiating between ALTLE and PLTLE. CONCLUSIONS: Frequent hypomotor onset, the absence of initial oroalimentary automatism, and early generalization are characteristic findings of PLTLE, although they are insufficient to differentiate it from ALTLE or MTLE.