Sex differences in seizure effects on social anxiety in persons with epilepsy.

PURPOSE: We investigated sex differences in the effect of seizures on social anxiety in persons with epilepsy. METHOD: In this cross-sectional multicenter study, social anxiety was measured using the short forms of the Social Phobia Scale (SPS-6) and Social Interaction Anxiety Scale (SIAS-6). SPS-6 scores ≥ 9 and SIAS-6 scores ≥ 12 were considered to indicate social phobia and social interaction anxiety, respectively. The Patient Health Questionnaire-9, Stigma Scale-Revised, and Family Adaptation-Partnership-Growth-Affection-Resolve scale were also completed. A logistic regression analysis with an interaction term was used to analyze the data. RESULTS: Out of 285 participants, a SPS-6 score ≥ 9 and a SIAS-6 score ≥ 12 were noted in 62 (21.8%) and 36 (12.6%) of participants, respectively. There was no difference in the prevalence of social anxiety between men and women. Intractable seizures and lack of seizure freedom were associated with a SPS-6 score ≥ 9 and a SIAS-6 score ≥ 12, but statistical significance was lost in the adjusted models. However, intractable seizures and lack of seizure freedom significantly interacted with sex for a SPS-6 score ≥ 9 (p = 0.018) and a SIAS-6 score ≥ 12 (p = 0.048) in both the separate and adjusted models. Specifically, intractable seizures tended to be positively associated with SPS-6 scores ≥ 9 than non-intractable seizures in men only (odds ratio = 2.602, p = 0.068), whereas lack of seizure freedom tended to be negatively associated with SIAS-6 scores ≥ 12 than seizure freedom in women only (odds ratio = 4.804, p = 0.053). CONCLUSION: We found significant sex differences in seizure effects on social anxiety. Intractable seizures were associated with social phobia in men, whereas lack of seizure freedom in the last year was associated with social interaction anxiety in women.

Cerebral Infarction Observed on Brain MRI in Unconscious Out-of-Hospital Cardiac Arrest Survivors: A Pilot Study.

BACKGROUND: Cumulative evidence regarding the use of brain magnetic resonance imaging (MRI) for predicting prognosis of unconscious out-of-hospital cardiac arrest (OHCA) survivors treated with targeted temperature management (TTM) is available. Theoretically, these patients are at a high risk of developing cerebral infarction. However, there is a paucity of reports regarding the characteristics of cerebral infarction in this population. Thus, we performed a pilot study to identify the characteristics and risk factors of cerebral infarction and to evaluate whether this infarction is associated with clinical outcomes. METHODS: A single-center, retrospective, registry-based cohort study was conducted at Severance Hospital, a tertiary center. Unconscious OHCA survivors were registered and treated with TTM between September 2011 and December 2015. We included patients who underwent brain MRI in the first week after the return of spontaneous circulation. We excluded patients who underwent any endovascular interventions to focus on "procedure-unrelated" cerebral infarctions. We assessed hypoxic-ischemic encephalopathy (HIE) and procedure-unrelated cerebral infarction separately on MRI. Patients were categorized into the following groups based on MRI findings: HIE (-)/infarction (-), infarction-only, and HIE (+) groups. Conventional vascular risk factors showing p < 0.05 in univariate analyses were entered into multivariate logistic regression. We also evaluated if the presence of this procedure-unrelated cerebral infarction lesion or HIE was associated with a poor clinical outcome at discharge, defined as a cerebral performance category of 3-5. RESULTS: Among 71 unconscious OHCA survivors who completed TTM, underwent MRI, and who did not undergo endovascular interventions, 14 (19.7%) patients had procedure-unrelated cerebral infarction based on MRI. Advancing age [odds ratio (OR) 1.11] and atrial fibrillation (OR 5.78) were independently associated with the occurrence of procedure-unrelated cerebral infarction (both p < 0.05). There were more patients with poor clinical outcomes at discharge in the HIE (+) group (88.1%) than in the infarction-only (30.0%) or HIE (-)/infarction (-) group (15.8%) (p < 0.001). HIE (+) (OR 38.69, p < 0.001) was independently associated with poor clinical outcomes at discharge, whereas infarction-only was not (p > 0.05), compared to HIE (-)/infarction (-). CONCLUSIONS: In this pilot study, procedure-unrelated cerebral infarction was noted in approximately one-fifth of unconscious OHCA survivors who were treated with TTM and underwent MRI. Older age and atrial fibrillation might be associated with the occurrence of procedure-unrelated cerebral infarction, and cerebral infarction was not considered to be associated with clinical outcomes at discharge. Considering that the strict exclusion criteria in this pilot study resulted in a highly selected sample with a relatively small size, further work is needed to verify our findings.

Family cohesion is differently associated with felt stigma depending on enacted stigma in adults with epilepsy.

PURPOSE: There have been little researches examining the role of family functioning on psychological outcomes in the field of adult epilepsy. We determined whether family functioning is correlated with felt stigma in adults with epilepsy. METHODS: In this cross-sectional study, adults with epilepsy and their caregivers were recruited. Data were collected using the Family Adaptability and Cohesion Evaluation Scale (FACES) III, the Family adaptation, partnership, growth, affection, and resolve (APGAR) questionnaire, the Stigma Scale for Epilepsy (SS-E), the modified questionnaire for episodes of discrimination, and the Beck Depression Inventory. Family functioning was measured by the caregivers. RESULTS: A total of 273 adult patients and their primary caregivers were included. Multivariate logistic analyses showed that family cohesion and excellent family functioning were negatively correlated with felt stigma after controlling for confounding variables. Enacted stigma, depressive symptoms, and university education were also significant. Interaction between enacted stigma and family cohesion on felt stigma was significant (p = 0.049). Family cohesion was negatively correlated with felt stigma only in the patients with enacted stigma (p = 0.011). CONCLUSIONS: Family functioning especially family cohesion may have protective effects against development of felt stigma in adults with epilepsy. Such protecting effects against felt stigma may be different according to enacted stigma. This understanding is helpful for developing effective psychosocial interventions to reduce felt stigma in patients with epilepsy.

Factors associated with stigma and depressive symptoms in family members of patients with epilepsy.

PURPOSE: Literature regarding family stigma related to epilepsy is scarce. This study investigated the prevalence of family stigma and depressive symptoms and the associated factors among the family members of patients with epilepsy. METHODS: In a cross-sectional study, Stigma Scale-Revised score ≥ 4 and Patient Health Questionnaire-9 score ≥ 10 were considered indicative of moderate-to-severe stigma and depressive symptoms, respectively. Stepwise logistic regression analyses were performed. RESULTS: Of the 482 family members, a mean age was 47.1 ±â€¯9.4 years, and 73.4% were female. Of the patients, a mean age was 25.5 ±â€¯16.7 years, and 45.0% were female. Idiopathic generalized epilepsy and focal epilepsy were noted in 22.4% and 65.6% of patients, respectively. Family stigma and depressive symptoms were noted in 10.0% and 11.2% of family members, respectively. Family stigma was significantly associated with high seizure frequency and being a sibling or offspring of a patient independent of their depressive symptoms. By contrast, depressive symptoms in family members were significantly associated with polytherapy, being parents of a patient, and neurological comorbidities independent of family stigma. In a subset of patients and their family, patients had higher proportion of stigma and depressive symptoms than their family. Depressive symptoms and stigma among patients were significantly correlated with those among parents, but not spouse. CONCLUSION: Family stigma is common in families with epilepsy and is closely related to depressive symptoms. Frequent seizures, polytherapy, neurological comorbidities, and the relationship to a patient may be factors that are independently associated with family stigma and depressive symptoms in family members.

Does the new Korean term for epilepsy reduce the stigma for Korean adults with epilepsy?

PURPOSE: The purpose of this study was to evaluate differences in stigma, disclosure management of epilepsy, and knowledge about epilepsy between patients with epilepsy who recognized and did not recognize the new Korean term for epilepsy. METHODS: This was a cross-sectional, multicenter study. The Stigma Scale-Revised, the Disclosure Management Scale, the Patient Health Questionnaire-9, and a questionnaire assessing knowledge about epilepsy were used. The set of questionnaires had two versions, using either the old or new name for epilepsy. Multivariate logistic regression analyses were used. RESULTS: A total of 341 patients with epilepsy and 509 family members were recruited. Approximately 62% of patients felt some degree of epilepsy-related stigma. Mild stigma, severe concealment of epilepsy diagnosis, and increased knowledge about epilepsy were independently identified as factors associated with recognition of the new term in patients. Recognition of the new term was more prevalent in patients and family members with higher education, female family members, and family members having patients with younger age at seizure onset and shorter duration of epilepsy. There were no significant differences between the two types of questionnaires. About 81% of patients and 93% of family members had a positive attitude about renaming epilepsy. CONCLUSION: The use of the new Korean term for epilepsy (cerebroelectric disorder) increased knowledge about epilepsy but did not reduce stigma and concealment of epilepsy diagnosis in Korean adults with epilepsy. Higher education may be an important factor for knowing the new term in patients and family members.

Factors associated with social anxiety in South Korean adults with epilepsy.

PURPOSE: The aim of this study was to examine social anxiety in South Korean adults with epilepsy and to identify associated factors. METHOD: This was a cross-sectional, multicenter study in South Korea. Social anxiety was assessed using short forms of the Social Phobia Scale (SPS-6) and Social Interaction Anxiety Scale (SIAS-6). The SPS-6 scores ≥9 and SIAS-6 scores ≥12 were considered indicative of social phobia and social interaction anxiety, respectively. The Patient Health Questionnaire-9 (PHQ-9); Stigma Scale-Revised (SS-R); Disclosure Management Scale; Family Adaptation, Partnership, Growth, Affection, Resolve (F-APGAR) scale; and a questionnaire assessing knowledge about epilepsy were also used. RESULTS: Of a total of 219 patients with epilepsy, 21% and 11% had SPS-6 scores ≥9 and SIAS-6 scores ≥12, respectively. In logistic regression analysis, SPS-6 scores ≥9 were independently associated with SS-R scores of 4-9 (odds ratio [OR]: 8.626, 95% confidence interval [CI]: 2.515-29.587, p = .001), SS-R scores 1-3 (OR: 5.496, 95% CI: 1.757-17.197, p = .003), and PHQ-9 scores ≥10 (OR: 4.092, 95% CI: 1.823-9.185, p = .001). In contrast, SIAS-6 scores ≥12 were related only to PHQ-9 scores ≥10 (OR: 8.740, 95% CI: 3.237-23.599, p < .001). Belonging to a dysfunctional family and lack of knowledge about epilepsy tended to be associated with social phobia (p = .071) and social interaction anxiety (p = .090), respectively. Epilepsy-related variables were not related to social anxiety. CONCLUSION: Social anxiety is not rare in patients with epilepsy. In this study, social phobia was associated with perceived stigma and depressive symptoms, whereas social interaction anxiety was related only to depressive symptoms in patients with epilepsy.

Effects of continuous positive airway pressure therapy on left ventricular diastolic function: a randomised, sham-controlled clinical trial.

Continuous positive airway pressure (CPAP) therapy may decrease left ventricular (LV) loads and improve myocardial oxygenation. In this study, we investigated the effect of CPAP on LV diastolic function compared with sham treatment in patients with severe obstructive sleep apnoea (OSA).This 3-month prospective single-centre randomised sham-controlled trial analysed 52 patients with severe OSA. Patients were randomly assigned (1:1) to receive either CPAP or sham treatment for 3 months. The main investigator and patients were masked to the trial randomisation. The primary end-point was change of early diastolic mitral annular (e') velocity over the 3-month period. Secondary end-points were pulse wave velocity (PWV), 24-h ambulatory blood pressure (BP) and variables of ventricular-vascular coupling at 3 months.After 3 months of follow-up, CPAP treatment significantly increased the e' velocity, and was greater than the sham treatment (0.65±1.70 versus -0.61±1.85 cm·s-1, p=0.014). The PWV, 24-h mean diastolic BP, night-time diastolic BP, arterial elastance index and ventricular-vascular coupling index after 3 months of follow-up decreased significantly in the CPAP group.In patients with severe OSA, CPAP treatment for 3 months improved LV diastolic function more than sham treatment, and was accompanied by improvements in arterial stiffness and ventricular-vascular coupling.

Increased Superoxide Dismutase 2 by Allopregnanolone Ameliorates ROS-Mediated Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus.

Excessive production of reactive oxygen species (ROS), along with dysfunction of the antioxidant defense system, such as that involving superoxide dismutase (SOD), may play a major role in neuronal death following status epilepticus (SE). Neurosteroids, which are allosteric modulators of the GABAA receptor in cerebral metabolism, have been suggested as being neuroprotective in various animal models; however, their effect to preventing ROS has not been examined. Herein, we investigate the neuroprotective role of allopregnanolone, the prototypical neurosteroid in the brain, in relation to the ROS-mediated neuronal injury. Adult male C57BL/6 mice were subjected to SE and treated with allopregnanolone. Hippocampal cell death was assessed by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and ROS production was investigated by in situ detection of oxidized hydroethidine. SOD2 expression was analyzed by both western blot and immunofluorescent staining in the hippocampal subfields. In mice treated with allopregnanolone after SE, hippocampal cell death, DNA fragmentation, oxidative DNA damage, and ROS production were reduced significantly compared to mice subjected to vehicle treatment after SE. Hippocampal SOD2 expression was significantly increased by allopregnanolone. These finding suggest that allopregnanolone plays a neuroprotective role, with not only anticonvulsant but also antioxidant effects, by increasing SOD2 in pilocarpine-induced SE model.

Atrophy of the pedunculopontine nucleus region in patients with sleep-predominant seizures: A voxel-based morphometry study.

Non-rapid eye movement (NREM) sleep increases interictal epileptiform discharges and frequency of seizures, whereas REM sleep suppresses them. The pedunculopontine nucleus (PPN), one of the REM sleep-modulating structures, is postulated to have a potent antiepileptogenic role. We asked if patients with sleep-predominant seizures (SPS) show volume changes in the region of the PPN compared to those with seizures occurring during awake state only (nSPS). The volume of the PPN region was assessed in patients with SPS, those with nSPS, and healthy volunteers, through voxel-based morphometry and automated, nonbiased region of interest (ROI) analysis of T1 magnetic resonance (MR) images. The volume of PPN region was statistically smaller in patients with SPS (n = 33) than in those with nSPS (n = 40) and healthy controls (n = 30) after controlling for covariates. These results suggest that a structural change in the PPN may be associated with sleep-predominant timing of seizure occurrence. Our findings might help understand the intervening pathomechanism that lies between the human sleep-wake cycle and epilepsy.

EGT022, an RGD-containing recombinant disintegrin, inhibits the VEGF-induced angiogenic process by targeting integrin ß3 in endothelial cells.

OBJECTIVES: EGT022, an RGD-containing recombinant disintegrin from human ADAM metallopeptidase domain 15 (ADAM15), has been reported to stimulate vascular maturation of retinal blood vessels with promotion of pericyte coverage through binding to integrin αIIbß3. Previous studies have reported that angiogenesis can be inhibited by several RGD motif-containing disintegrins; however, the effect of EGT022 on Vascular endothelial growth factor (VEGF)-induced angiogenesis has not yet been determined. This study was conducted in order to evaluate the anti-angiogenic function of EGT022 in VEGF-induced endothelial cells. METHODS: A proliferation and migration assay was performed using human umbilical vein endothelial cells (HUVEC) cells stimulated with VEGF to determine whether the angiogenic process was suppressed by EGT022. An in vitro trans-well assay and Mile's permeability assay were performed to determine the effect of EGT022 on permeability. Western blot was performed in order to further determine whether EGT022 can inhibit phosphorylation of VEGF receptor-2 (VEGFR2) and Phospholipase C gamma1 (PLC-γ1). An integrin binding assay and luciferase assay were performed for identification of the integrin target of EGT022. RESULTS: Angiogenesis including proliferation, migration, tube formation, and permeability was significantly inhibited by EGT022 in HUVEC cells. Our findings also demonstrated that EGT022 binds directly to integrin αvß3, induces dephosphorylation of integrin ß3, and inhibits phosphorylation of VEGFR2. In addition, phosphorylation of PLC-γ1 and activation of Nuclear Factor of Activated T-cell (NFAT), a downstream pathway of VEGF, are inhibited by EGT022 in HUVEC cells. CONCLUSION: These results clearly demonstrate the anti-angiogenic role played by EGT022 as a potent antagonist of integrin ß3 in endothelial cells.

Plant-expressed Zika virus envelope protein elicited protective immunity against the Zika virus in immunocompetent mice.

Zika virus infection causes multiple clinical issues, including Guillain-Barré syndrome and neonatal malformation. Vaccination is considered as the only strategy for the prevention of ZIKV-induced clinical issues. This study developed a plant-based recombinant vaccine that transiently expressed the ZIKV envelope protein (ZikaEnv:aghFc) in Nicotiana benthamiana and evaluated the protective immunity afforded by it in immunocompetent mice. ZikaEnv:aghFc induced both humoral and cellular immunity at a low dose (1-5 µg). This immune-inducing potential was enhanced further when adjuvanted CIA09A. In addition, antigen-specific antibodies and neutralizing antibodies were vertically transferred from immunized females to their progeny and afforded both protective immunity to ZIKV and cross-protection to Dengue virus infection. These results suggest that our plant-based ZIKV vaccine provides a safe and efficient protective strategy with a competitive edge.

An international pilot study of an Internet-based platform to facilitate clinical research in epilepsy: the EpiNet project.

PURPOSE: We created an epilepsy patient database that can be accessed via the Internet by neurologists from anywhere in the world. The database was designed to enroll and follow large cohorts of patients with specific epilepsy syndromes, and to facilitate recruitment of patients for investigator-initiated clinical trials. METHODS: The EpiNet database records physician-derived information regarding seizure type and frequency, epilepsy syndrome, etiology, drug history, and investigations. It can be accessed from any country by approved investigators via a secure, password-protected Website. All data are encrypted. The database is for both research and clinical purposes. Investigators were invited to register any patient with epilepsy, but were particularly encouraged to register patients when uncertain of the optimal management. Participation required approval from investigators' ethics committees and institutional review boards, and all patients or their caregiver provided written informed consent. Patients were not enrolled in clinical trials in this pilot study. KEY FINDINGS: The international pilot study recruited patients from September 2010 to November 2011. Sixty-four investigators or research assistants from 25 centers in 13 countries registered 1,050 patients. Patients with a wide range of epilepsy syndromes and etiologies were registered. Patients' ages ranged from 2 weeks to 90 years. SIGNIFICANCE: The Website was successfully used by doctors working in different health systems. The pilot study confirmed that this low-cost, collaborative approach to research has great potential. Large, multicenter cohort studies will commence in 2012, and randomized clinical trials are being planned. All epileptologists are invited to join this project.

Nasopharyngeal electrodes in temporal lobe epilepsy: A reappraisal of their diagnostic utility.

OBJECTIVE: To compare electroencephalography (EEG) recordings with nasopharyngeal electrodes (NPEs) plus anterior temporal electrodes (ATEs) (NPE recordings) and those with only ATEs (non-NPE recordings) for the detection of interictal epileptiform discharges (IEDs) in patients with suspected temporal lobe epilepsy (TLE). METHODS: We retrospectively analyzed the initial EEGs of 229 patients that were recorded simultaneously with ATEs and NPEs in addition to the electrodes of the 10-20 system of electrode placement. Two data sets of NPE and non-NPE recordings were reviewed independently by three interpreters with differing degrees of experience. Discordant findings in the interpretation among the three interpreters were resolved by a consensus to yield final results. RESULTS: IEDs were detected in 76.4% of patients with NPE recordings compared to 55.5% with non-NPE recordings (p < 0.01). Bilateral independent IEDs were found in 26.2% and 11.4% of EEGs with NPE and non-NPE recordings (p < 0.01). The degree of agreement for the detection of IEDs among the three interpreters was higher with the NPE than with non-NPE recordings (κappa score, 0.70 vs. 0.54). The increased diagnostic yield of NPE recordings for the detection of IEDs was particularly prominent in patients with mesial and non-lesional TLEs. CONCLUSIONS: EEG recordings using NPEs are useful to improve the sensitivity and level of agreement among interpreters for the detection of IEDs in patients with TLE. SIGNIFICANCE: NPE recordings may be recommended in routine EEGs for the evaluation of patients with suspected TLE.

A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy.

OBJECTIVES: Multidrug resistance protein 2 (MRP2, ABCC2) is involved in the transport of antiepileptic drugs and is upregulated in the brain tissues of patients with epilepsy. Therefore, genetic variations in the MRP2 gene may affect individual drug responses to the antiepileptic agent carbamazepine. METHODS: Associations between MRP2 polymorphisms and the adverse drug reactions (ADRs) of carbamazepine were analyzed using an integrated population genetics and molecular functional approach. In the initial case-control study, five tag single nucleotide polymorphisms in the MRP2 gene were analyzed in 146 patients with epilepsy. Patients were divided into two groups: those who experienced ADRs of the central nervous system and those who did not. An independent replication study was performed using DNA samples from 279 patients. RESULTS: A nonsynonymous polymorphism, c.1249G>A (p.V417I, rs2273697), showed a strong association with the neurological ADR caused by carbamazepine (P=0.005). Logistic regression analysis with multiple clinical variables indicated that the presence of A allele at the MRP2 c.1249G>A locus was an independent determinant of central nervous system ADR caused by carbamazepine. Moreover, the positive association of c.1249A was reproduced in the replication study (P=0.042, joint P value of the replication=0.001). The functional study using ATPase assay and FACScan flow cytometer indicated that carbamazepine was a substrate of MRP2 and that the 417I variation selectively reduced carbamazepine transport across the cell membrane. CONCLUSION: These results strongly suggest that the A-allele of the MRP2 single nucleotide polymorphism c.1247G>A is associated with adverse neurological drug reactions to carbamazepine.

The role of MMP-9 in integrin-mediated hippocampal cell death after pilocarpine-induced status epilepticus.

Recent studies demonstrate that matrix metalloproteinase-9 (MMP-9) is closely involved in the pathogenesis of epilepsy. This study investigated the role of MMP-9 in hippocampal cell death after pilocarpine-induced status epilepticus (SE). We showed that MMP-9 expression and activity significantly increased and beta1-integrin levels decreased on day 3 after SE. beta1-integrin degradation was also observed in hippocampal ex vivo extracts incubated with recombinant active MMP-9. Treatment with a selective MMP-9 inhibitor attenuated MMP-9 up-regulation, beta1-integrin degradation, the reduction of ILK activity and Akt phosphorylation, and subsequent hippocampal damage after SE. However, co-treatment with anti-beta1-integrin antibody almost completely blocked the protective effects of the MMP-9 inhibitor on both integrin-mediated survival signaling and hippocampal cell death. Our study demonstrates that MMP-9 induces apoptotic hippocampal cell death by interrupting integrin-mediated survival signaling after SE and suggests that MMP-9 may be a promising target for a neuroprotective approach to preventing seizure-induced hippocampal damage.

Palilalia, echolalia, and echopraxia-palipraxia as ictal manifestations in a patient with left frontal lobe epilepsy.

Palilalia is a relatively rare pathologic speech behavior and has been reported in various neurologic and psychiatric disorders. We encountered a case of palilalia, echolalia, and echopraxia-palipraxia as ictal phenomena of left frontal lobe epilepsy. A 55-year-old, right-handed man was admitted because of frequent episodes of rapid reiteration of syllables. Video-electroencephalography monitoring revealed stereotypical episodes of palilalia accompanied by rhythmic head nodding and right-arm posturing with ictal discharges over the left frontocentral area. He also displayed echolalia or echopraxia-palipraxia, partially responding to an examiner's stimulus. Magnetic resonance imaging revealed encephalomalacia on the left superior frontal gyrus and ictal single photon emission computed tomography showed hyperperfusion just above the lesion, corresponding to the left supplementary motor area (SMA), and subcortical nuclei. This result suggests that the neuroanatomic substrate involved in the generation of these behaviors as ictal phenomena might exist in the SMA of the left frontal lobe.

Long-term efficacy and tolerability of topiramate as add-on therapy in refractory partial epilepsy: an observational study.

PURPOSE: To evaluate the long-term efficacy and tolerability of topiramate (TPM) as add-on therapy in patients with refractory partial epilepsy. METHODS: This is a retrospective, single-center, long-term observational study. Patients fulfilling the criteria of medical intractability proposed by Berg et al. were entered into the study if they were newly prescribed TPM as add-on therapy between January 2000 and June 2002. The usual starting dosage of TPM was 50 mg/day and optimal-dose adjustments were made according to individual clinical responses. Efficacy and tolerability were analyzed every year during 5-year follow-up in the "intention-to-treat (ITT) population." Retention rate was estimated by Kaplan-Meyer analysis. RESULTS: A total of 125 patients were included in the study and 107 patients (85.6%) were followed for 5 years. Retention rate was 87.2% at 1 year and 64% at 5 years. At the end of 5 years, the median seizure frequency reduction rate was 69.0% and responder rate was 43.2% in the ITT population. Cumulative seizure-free rate (SFR) was 30.4% and the terminal 1-year SFR was 12.8% in the ITT population (20.0% in completers) at 5-year follow-up. Adverse events (AEs) occurred in 39.2% of patients, including significant AEs leading to antiepileptic drug (AED) withdrawal in 14.4%. The most common AEs were anorexia (16.0%), weight loss (10.4%), and gastrointestinal symptoms (8.8%). Concomitant AEDs were reduced in 25.0% of the completers. DISCUSSION: Low-dose and slow-dose escalation of TPM in add-on therapy for patients with refractory partial epilepsy is effective and well tolerated in long-term, individualized clinical practice.

Continuous Positive Airway Pressure Therapy Restores Cardiac Mechanical Function in Patients With Severe Obstructive Sleep Apnea: A Randomized, Sham-Controlled Study.

BACKGROUND: Continuous positive airway pressure (CPAP) therapy might decrease left ventricular (LV) and right ventricular (RV) loads and improve cardiac mechanical function in patients with obstructive sleep apnea (OSA). However, the benefits of CPAP therapy for cardiac mechanical function in patients with OSA have not previously been proved in a randomized, sham-controlled clinical trial. This study therefore investigated the effects of CPAP therapy on LV and RV mechanical function in patients with severe OSA and compared them with the effects of a sham intervention. METHODS: In this randomized sham-controlled trial, we analyzed LV and RV function by conventional and speckle-tracking echocardiography before and after 3 months of treatment in 52 patients with severe OSA. Patients were randomly assigned (1:1) to receive either CPAP or sham treatment for 3 months. The main investigator and patients were masked to the trial randomization. RESULTS: After 3 months, CPAP treatment significantly improved LV global longitudinal strain (GLS) compared with the sham treatment (-20.0% ± 2.1% vs -18.0% ± 2.5%; P = .004), although there were no differences in LV dimension or ejection fraction. CPAP treatment reduced RV size and improved the fractional area change (51.3% ± 7.9% vs 46.9% ± 6.7%; P = .038) compared with the sham treatment. CPAP treatment did not ameliorate the RV GLS compared with the sham treatment. CONCLUSIONS: In patients with severe OSA, CPAP treatment for 3 months improved LV and RV function compared with sham treatment. LV mechanical function assessed by speckle-tracking echocardiography and RV fractional area change assessed by two-dimensional echocardiography were significantly improved by CPAP treatment.

Efficient induction of cell-mediated immunity to varicella-zoster virus glycoprotein E co-lyophilized with a cationic liposome-based adjuvant in mice.

Varicella zoster virus (VZV) is a neurotropic and lymphotropic alpha herpesvirus that causes varicella and herpes zoster (HZ). At a primary infection, VZV causes varicella in young children. Reactivation of latent VZV in sensory ganglia causes painful HZ in elderly people, occasionally leading to a serious complication, postherpetic neuralgia (PHN). A live attenuated VZV vaccine, the first vaccine licensed for the prevention of HZ and PHN is not very effective, while a recombinant subunit vaccine provides higher and longer protection against HZ. In the present study, we developed a new adjuvant system CIA09A, which is composed of cationic liposomes, the Toll-like receptor 4 (TLR4) agonist de-O-acylated lipooligosaccharide, and Quillaja saponin fraction QS-21. We then determined its adjuvant activity for recombinant VZV glycoprotein E (gE) in mice. Co-lyophilization of the liposomal adjuvant formulation with gE did not abolish the immune-stimulating activity. In fact, the CIA09A-adjuvanted gE vaccine was highly effective in eliciting both humoral and cellular immune responses to the recombinant gE protein and VZV in a VZV-primed mouse model. Furthermore, the frequency of gE-specific polyfunctional CD4+ T cells expressing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-2 was significantly increased in mice immunized with the adjuvanted vaccine. These data indicate that co-lyophilization of protein antigens with CIA09A enables development of a liposome-adjuvanted vaccine in a single vial to induce strong cell-mediated immunity required for vaccine efficacy. Thus, the CIA09A-adjuvanted gE vaccine warrants further development as a new prophylactic vaccine against HZ.

Enhancement of the immune responses of mice to Bacillus anthracis protective antigen by CIA07 combined with alum.

Anthrax is an acute zoonotic disease caused by infection with Bacillus anthracis. B. anthracis spores are highly resistant to environmental degradation and are used as a biological weapon. In this study, we investigated the adjuvant activity of CIA07 to anthrax protective antigen (PA). A/J mice were immunized intraperitoneally once, or twice with a 4-week interval, with recombinant PA alone or combined with alum, CpG1826, or CIA07 as adjuvant, and serum anti-PA IgG antibody responses were measured 4 weeks after each immunization. All three adjuvants significantly enhanced anti-PA IgG antibody titer 4 weeks after the priming and boosting immunizations, and alum gave the highest titer. In order to evaluate the adjuvant activity of CIA07 in the presence of alum, Balb/c mice were immunized 3 times at 1-week intervals with PA in combination with alum, CIA07 or alum plus CIA07, and the immune responses were assessed 2 weeks after the third immunization. The serum anti-PA IgG antibody titer of the CIA07-treated group was 14-fold higher than the group given PA alone, and the coadministration of CIA07 with alum further increased the titer 3.5-fold (P < 0.05). The toxin neutralizing activity of the sera from the mice given the combination of CIA07 and alum was 109-times higher than the animals given PA alone. The mice given CIA07 plus alum also showed a marked increase in the number of IFN-gamma-, IL-2-, and IL-4-producing CD4(+) T cells among their splenocytes. These data suggest the potential of CIA07 in combination with alum as an adjuvant for the development of a potent anthrax vaccine.