Influence of Long-Term Anti-Seizure Medications on Redox Parameters in Human Blood.

BACKGROUND: Epilepsy is a chronic brain disease affecting millions of people worldwide, but little is known about the impact of anti-seizure medications on redox homeostasis. METHODS: This study aimed to compare the effects of the long-term use of oral anti-seizure medications in monotherapy (lamotrigine, carbamazepine, and valproate) on antioxidant enzymes: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, haemoglobin, and methaemoglobin content in erythrocytes, and concentrations of total proteins and thiols, nitrites, lipid peroxides and total glutathione in the plasma of epilepsy patients and drug-naïve patients. RESULTS: The results showed that lamotrigine therapy led to lower superoxide dismutase activity (p < 0.005) and lower concentrations of total thiols (p < 0.01) and lipid peroxides (p < 0.01) compared to controls. On the other hand, therapy with carbamazepine increased nitrite levels (p < 0.01) but reduced superoxide dismutase activity (p < 0.005). In the valproate group, only a decrease in catalase activity was observed (p < 0.005). Canonical discriminant analysis showed that the composition of antioxidant enzymes in erythrocytes was different for both the lamotrigine and carbamazepine groups, while the controls were separated from all others. CONCLUSIONS: Monotherapy with anti-seizure medications discretely alters redox homeostasis, followed by distinct relationships between antioxidant components.

Psychometric evaluation of the Serbian version of the Stigma Scale of Epilepsy (SSE).

OBJECTIVE: To evaluate the psychometric properties of the Serbian-language version of the Stigma Scale of Epilepsy (SSE). METHODS: The sample consisted of 108 patients with epilepsy (PWE) (60.2 % were female, age range: 19-67 years) and 102 students (86.3 % were female, age range: 18-47 years). The study encompassed two phases: (1) translation of the SSE into Serbian using the back-translation technique, and (2) evaluation of reliability and construct validity of the Serbian-language version of SSE. In addition to the SSE, the PWE filled out a Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), Patient Health Questionnaire-9 (PHQ-9), and Generalized Anxiety Disorder-7 (GAD-7). The socio-demographic and clinical variables were noted for each patient by the semistructured interview. Besides completing the SSE, the students were asked if they knew anyone with epilepsy. The reliability of the questionnaire was tested by assessing the internal consistency of the scale (Cronbach's α), while construct validity was assessed by factor analysis, method of known-groups validation, and correlation analysis. RESULTS: SSE demonstrates a satisfactory level of reliability in both samples, with Cronbach's α of 0.86 in the PWE sample and 0.90 in the student sample. Using exploratory factor analysis, four factors were identified in both samples, corresponding relatively well with the scale domains originally produced, with a few exceptions described. Adverse effects (AEs) of antiseizure medications (ASMs) and driving ability significantly influenced SSE scores, but there were no significant effects of other socio-demographic and clinical variables on epilepsy-related stigma in the PWE sample. In addition, depression severity significantly influenced SSE scores (based on NDDI-E cut-off score), with the SSE showing a positive association with PHQ-9 (r = 0.42, p < .001) and GAD-7 (r = 0.35, p < .001) as well. Regarding the student sample, the effects of personal knowledge of someone with epilepsy on SSE scores were found to be significant. Besides, students (M = 46.28, SD = 16.43) reported higher epilepsy-related stigma than patients (M = 40.66, SD = 17.01), t(208) = 2.43, p < .05, d = 0.34. CONCLUSION: The Serbian version of the SSE has good psychometric properties and represents a useful tool for assessing epilepsy-related stigma in both patients and the general population.

Stigma and its association with health-related quality of life in adults with epilepsy.

OBJECTIVE: To explore the presence of felt and enacted stigma in people with epilepsy (PWE), members of a self-governing epilepsy organization and to evaluate the influence of both types of stigma on health-related quality of life (HRQoL) in PWE. METHODS: Participants were 55 PWE (age range: 18-53 years), members of a non-governmental organization (further "NGO"). The sociodemographic and epilepsy-related variables were collected through structured interviews designed for the purpose of the study. Felt stigma was assessed with the Epilepsy Stigma Scale (ESS) and enacted stigma with the Questionnaire for episodes of discrimination against PWE. Quality of Life in Epilepsy Inventory (QOLIE-31) (Serbian version) was used for the evaluation of HRQoL. RESULTS: The mean ESS score was 33.93 ± 14.50. Felt stigma was significantly associated with the male gender and the number of antiepileptic drugs (AEDs). Participants' mean score on the Questionnaire for episodes of discrimination was 2.80 ± 2.78. Enacted stigma was significantly correlated with male gender and number of AEDs, as well as with older age/longer duration of the disorder. Felt stigma scores were positively correlated with enacted stigma scores (p < 0.001), but only felt stigma scores were negatively related to QOLIE-31 overall score (p = 0.01). The combination of AEDs, seizure frequency, and felt stigma best explained the HRQoL in PWE (p < 0.001). CONCLUSION: Felt and enacted stigma are moderately related, but only felt stigma appears to be a significant predictor of the deteriorating HRQoL in this sample. Interventions targeting felt stigma should be considered a part of comprehensive epilepsy care as well as educating the wider community about epilepsy.

Electroencephalography in Assessment of Autism Spectrum Disorders: A Review.

Electroencephalography (EEG) can further out our understanding of autistic spectrum disorders (ASD) neurophysiology. Epilepsy and ASD comorbidity range between 5 and 46%, but its temporal relationship, causal mechanisms and interplay with intellectual disability are still unknown. Epileptiform discharges with or without seizures go as high as 60%, and associate with epileptic encephalopathies, conceptual term suggesting that epileptic activity can lead to cognitive and behavioral impairment beyond the underlying pathology. Seizures and ASD may be the result of similar mechanisms, such as abnormalities in GABAergic fibers or GABA receptor function. Epilepsy and ASD are caused by a number of genetic disorders and variations that induce such dysregulation. Similarly, initial epilepsy may influence synaptic plasticity and cortical connection, predisposing a growing brain to cognitive delays and behavioral abnormalities. The quantitative EEG techniques could be a useful tool in detecting and possibly measuring dysfunctions in specific brain regions and neuronal regulation in ASD. Power spectra analysis reveals a U-shaped pattern of power abnormalities, with excess power in the low and high frequency bands. These might be the consequence of a complicated network of neurochemical changes affecting the inhibitory GABAergic interneurons and their regulation of excitatory activity in pyramidal cells. EEG coherence studies of functional connectivity found general local over-connectivity and long-range under-connectivity between different brain areas. GABAergic interneuron growth and connections are presumably impaired in the prefrontal and temporal cortices in ASD, which is important for excitatory/inhibitory balance. Recent advances in quantitative EEG data analysis and well-known epilepsy ASD co-morbidity consistently indicate a role of aberrant GABAergic transmission that has consequences on neuronal organization and connectivity especially in the frontal cortex.

Anxiety and depression in patients with vocal fold nodules, edema and polyps.

PURPOSE: To compare the prevalence and severity of depression and anxiety among patients with vocal fold (VF) nodules, polyps and edema. At the same time the aim was to analyse association between severity of distress and the level of vocal handicap as well as to identify other factors related to severity of depression and anxiety in these patients. METHODS: To all participants were given five questionnaires: (1) questionnaire on socio-demographic and some other characteristics of patient; (2) Beck's Depression Inventory (BDI); (3) State-Trait Anxiety Inventory (STAI) 1 (State Anxiety); (4) STAI 2 (Trait Anxiety); and (5) Voice Handicap Index (VHI)-10. RESULTS: A total of 205 patients were included in this study. Mild-to-severe depression, according to BDI was present in 79 (38.6%) patients. Mild-to-severe state anxiety and trait anxiety were present in 199 (97.1%) and 200 (97.6%) patients, respectively. Only 10 patients had VHI-10 score ≤ 11. Multivariate analyses showed that there were no significant differences in the level of depression and anxiety between patients with VF nodules, polyps and edema. The VHI-10 score was significantly higher in patients with VF edema in comparison with VF nodule patients (p = 0.001), as well as in comparison with VF polyp patients (p = 0.001). CONCLUSION: The present study identified a high prevalence of psychological and vocal distress among patients with vocal disorders. Severity of depression and anxiety did not differ between patients with VF nodules, polyps and edema, and it was not related to the level of vocal handicap.

Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial.

BACKGROUND: More than a third of patients with epilepsy are treatment resistant, and thus new, more effective therapies to achieve seizure freedom are needed. Cenobamate (YKP3089), an investigational antiepileptic drug, has shown broad-spectrum anticonvulsant activity in preclinical studies and seizure models. We aimed to evaluate the safety, efficacy, and tolerability of adjunctive cenobamate in patients with uncontrolled focal (partial)-onset epilepsy. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled, dose-response study at 107 epilepsy and neurology centres in 16 countries. Adult patients (aged 18-70 years) with focal seizures despite treatment with 1-3 antiepileptic drugs were randomly assigned (1:1:1:1) via an interactive web response system, by block sizes of 4 within each country, to adjuvant once daily oral cenobamate at dose groups of 100 mg, 200 mg, or 400 mg, or placebo following an 8-week baseline assessment. Patients, investigators, and study personnel were masked to treatment assignment. The study included a 6-week titration phase and 12-week maintenance phase. The primary efficacy outcomes were percentage change in 28-day focal seizure frequency (focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizures) from baseline analysed in the modified intention-to-treat population (≥1 dose and any post-baseline seizure data) and responder rates (≥50% reduction) analysed in the maintenance phase population (≥1 dose in the maintenance phase and any maintenance phase seizure data). The primary efficacy outcomes were analysed using a hierarchal step-down procedure comparing 200 mg versus placebo, 400 mg versus placebo, then 100 mg versus placebo. Safety and tolerability were compared descriptively across treatment groups for all randomised patients. This study is registered with ClinicalTrials.gov, number NCT01866111. FINDINGS: Between July 31, 2013, and June 22, 2015, 437 patients were randomly assigned to either placebo (n=108) or cenobamate 100 mg (n=108), 200 mg (n=110), or 400 mg (n=111). Of these patients, 434 (106 [98%] in placebo group, 108 [100%] in 100 mg group, 109 [99%] in 200 mg group, and 111 [100%] in 400 mg group) were included in the modified intention-to-treat population, and 397 (102 [94%] in placebo group, 102 [94%] in 100 mg group, 98 [89%] in 200 mg group, and 95 [86%] in 400 mg group) were included in the modified intention-to-treat maintenance phase population. Median percentage changes in seizure frequency were -24·0% (IQR -45·0 to -7·0%) for the placebo group compared with -35·5% (-62·5 to -15·0%; p=0·0071) for the 100 mg dose group, -55·0% (-73·0 to -23·0%; p<0·0001) for the 200 mg dose group, and -55·0% (-85·0 to -28·0%; p<0·0001) for the 400 mg dose group. Responder rates during the maintenance phase were 25% (26 of 102 patients) for the placebo group compared with 40% (41 of 102; odds ratio 1·97, 95% CI 1·08-3·56; p=0·0365) for the 100 mg dose group, 56% (55 of 98; 3·74, 2·06-6·80; p<0·0001) for the 200 mg dose group, and 64% (61 of 95; 5·24, 2·84-9·67; p<0·0001) for the 400 mg dose group. Treatment-emergent adverse events occurred in 76 (70%) of 108 patients in the placebo group, 70 (65%) of 108 in the 100 mg group, 84 (76%) of 110 in the 200 mg group, and 100 (90%) of 111 in the 400 mg group. Treatment-emergent adverse events led to discontinuation in five (5%) patients in the placebo group, 11 (10%) in the 100 mg dose group, 15 (14%) in the 200 mg dose group, and 22 (20%) in the 400 mg dose group. One serious case of drug reaction with eosinophilia and systemic symptoms occurred in the 200 mg cenobamate group. No deaths were reported. INTERPRETATION: Adjunctive cenobamate reduced focal (partial)-onset seizure frequency, in a dose-related fashion. Treatment-emergent adverse events were most frequent in the highest dose group. Cenobamate appears to be an effective treatment option in patients with uncontrolled focal seizures. FUNDING: SK Life Science.

Epilepsy and interictal epileptiform activity in patients with autism spectrum disorders.

PURPOSE: The purpose of this study was to determine the prevalence of epilepsy and subclinical epileptiform abnormalities in children with autism spectrum disorder (ASD), and to investigate its effects on core autistic symptoms and adaptive behavior skills. METHODS: Patients with diagnosis of ASD who met full criteria on Autism Diagnostic Interview-Revised (ADI-R) were included in the study. Adaptive behavior skills were assessed by Vineland Adaptive Behavior Scale-II (VABS-II). Clinical assessment for epilepsy and video electroencephalography (EEG) (v-EEG) examinations during wakefulness and/or sleep were prospectively performed in all patients. RESULTS: A total of 112 patients with diagnosis of ASD of mean age 6.58 ±â€¯3.72 were included in the study. Based on clinical and v-EEG assessments, three groups of patients were defined: 1) patients with epilepsy (n = 17; 15.2%); 2) patients with epileptiform discharges in absence of clinical seizures (n = 14; 12.5%); 3) patients without epilepsy and without epileptiform discharges (n = 81; 72.3%). There were no significant differences between three groups of patients on ADI-R subscores. Speech development was also not significantly related to epilepsy. There was a slight tendency of the VABS-II motor skills score to be higher in the group of patients with autism without clinical diagnosis of epilepsy and without subclinical epileptiform discharges (p < 0.05) in comparison with the two other groups. According to this tendency, we might claim that patients with higher scores on motor skills could have 0.88 times lower odds for having epileptiform EEG activity. CONCLUSIONS: According to our results, we were not able to detect differences in the ADI-R between the three populations with ASD, all with unknown etiology. Epilepsy, as well as subclinical epileptic discharges, showed small effects on Motor Skills in patients with autism, and had no effect on adaptive behavior Communication/Socialization/Daily Living Skills.

Analysis of EEG Characteristics and Coherence in Patients Diagnosed as Borderline Personality.

Borderline personality disorder is a clinically important psychiatric diagnosis that is distinct from major depressive, bipolar and posttraumatic stress disorders, despite the overlapping symptoms. The diagnosis is mainly clinical and must follow the DMS 5 (or ICD 10) characteristics. The most common age at first presentation is in late adolescence, but the disorder frequently can be stay as misdiagnosed. Our study is concerned to QEEG characteristics, as well as coherence in borderline patients compared with healthy group, matched by number, gender and age and selected randomly. Our obtained results showed that electrophysiological characteristics for borderlines are fairly without statistical differences, except in low bands (delta and theta), which showed significantly lower frequencies and coherence compared to a healthy group. Future research in this filed with more patients is highly recommended.

Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients.

To determine the relationship between alterations in the activity of the enzymes participating in antioxidative defense system and neurological soft signs (NSS) in schizophrenic patients with the first episode psychosis (SFE, n = 19), patients in relapse (SR, n = 46), and healthy controls (HC, n = 20). NSS intensity and enzymatic plasma activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were compared between SFE, SR and HC subjects and a follow-up correlation analyses between the enzyme activities and NSS intensity was performed. NSS intensity was increased four times in schizophrenic patients compared with healthy controls. Activities of SOD and CAT were 40% decreased in SFE and these reductions were ameliorated by antipsychotic treatment. GPX activity was 20% decreased in both patient groups compared with controls. A negative correlation between NSS intensity and GPX activity was specifically found in the SFE patients. The data in this report argue that a reduction of GPX activity might be one of the causes for the emergence of NSS at the onset of schizophrenia, and provide the evidence that antipsychotic therapy can attenuate activity reductions of SOD and CAT, but not the activity reduction of GPX and the intensity of NSS.

Cerebellar cognitive affective syndrome presented as severe borderline personality disorder.

An increasing number of findings confirm the significance of cerebellum in affecting regulation and early learning. Most consistent findings refer to association of congenital vermis anomalies with deficits in nonmotor functions of cerebellum. In this paper we presented a young woman who was treated since sixteen years of age for polysubstance abuse, affective instability, and self-harming who was later diagnosed with borderline personality disorder. Since the neurological and neuropsychological reports pointed to signs of cerebellar dysfunction and dysexecutive syndrome, we performed magnetic resonance imaging of brain which demonstrated partially developed vermis and rhombencephalosynapsis. These findings match the description of cerebellar cognitive affective syndrome and show an overlap with clinical manifestations of borderline personality disorder.

Determinants of quality of life in people with epilepsy in Serbia.

PURPOSE: This study aimed at finding determinants of quality of life in people with epilepsy (PWE) living in Belgrade, Serbia. METHOD: In this study, we recruited consecutive adults with epilepsy attending our outpatient department. Adult patients (age range: 18-65years) of normal intelligence and without any progressive neurological disease or psychiatric disorder were included in the study. They completed the following questionnaires: QOLIE-31 Inventory (Serbian version), Beck's Depression Inventory-II, Beck's Anxiety Inventory, Symptom Check List-90, and Neurotoxicity Scale-II. Hierarchical multiple regression analysis was performed to assess the predictive effects of some factors on QOLIE-31 Inventory. RESULTS: The mean QOLIE-31 score of 203 patients who completed the questionnaires was 70.64±17.74. Sociodemographic factors (age, sex, education, and employment) did not significantly predict QOLIE-31 score. Significant determinants of quality of life were clinical characteristics - seizure severity and etiology of epilepsy - accounting for 30.9% of the variance, depressive and anxiety symptoms accounting for 42.8% of the variance, and cognitive effects of antiepileptic drugs, accounting for 1.5% above other variables. CONCLUSIONS: The results suggest that seizure severity and etiology of epilepsy, depressive and anxiety symptoms, and cognitive adverse medication effects are main determinants of quality of life in this population of PWE.

Epileptic seizures provoked by bathing with water at room temperature.

We report two Caucasian boys with seizures induced by bathing in lukewarm water. Different mechanisms of provocation were observed; in one boy a complex partial seizure was provoked by pouring water over the body, while in the other boy, a complex partial seizure with secondary generalisation was provoked by immersion. Since the water was not hot in either of the cases, the pathophysiological mechanism was not clear and the seizures could not be explained as hyperthermic-related events. We suggest that in the ILAE classification of epilepsies and epileptic seizures, bathing epilepsy should be added as a separate category, distinct from "hot-water epilepsy".

Psychometric evaluation of the Serbian version of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31).

PURPOSE: To evaluate the psychometric properties of the Serbian-language version of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31). METHODS: After undergoing a translation and cultural adaptation of its items in order to create a Serbian-language version of QOLIE-31, we assessed its psychometric properties-reliability, construct validity and criterion validity. The sample consisted of 203 adults with epilepsy. Reliability was tested both by assessing the internal consistency and by the test-retest method. Construct validity was assessed by factor analysis, multitrait-scaling analysis and method of known-groups validation. This was achieved by assessing the relationship between scales and external measures (socio-demographic characteristics, seizure severity and etiology of epilepsy). Criterion validity was assessed by correlation analysis between QOLIE-31 and Short form 36 health survey (SF-36) and Neurotoxicity scale-II. RESULTS: The domains showed high internal consistency (Cronbach's α 0.94). Test-retest reliability for Overall test score was 0.83 (Pearson's coefficient) indicating temporal stability. Seizure severity and etiology of epilepsy significantly influenced all QOLIE-31 domains except the Medication effect domain, with lowest scores in high seizure severity and symptomatic etiology groups. Employment status significantly influenced Overall quality of life, Emotional well-being, Social function and Overall score. Educational level was related to the Emotional well-being domain, with highest scores for students. The QOLIE-31 was highly positively correlated with SF-36 (rho=0.898) and strongly negatively correlated with Neurotoxicity scale-II (rho=-0.783). CONCLUSION: Serbian adaptation of the QOLIE-31 questionnaire is reliable and valid for assessing the quality of life in patients with epilepsy.

Prevalence of primary headaches in children from Belgrade, Serbia.

The aim of our study is to estimate the prevalence of migraine and tension-type headaches in 7-12-year-old school children from Belgrade. The sample was drawn from a total of 1259 school children from randomly selected primary schools. The diagnosis was made on the basis of a clinical interview combined with the neurological examination. The prevalence of migraine increases with age from 0.5% at the age of seven, to 6.8% at the age of 12. Female to male ratio inverts with age: males predominate at age 7-9, but females predominate at age 10-12. The estimated prevalence of tension-type headache increases with age from 0.5% in 7-year olds to 2.4% in 12-year olds. Statistically, the onset of migraine occurs significantly earlier than that of tension-type headache. Migraine and tension-type headache are frequent headache types and have different demographic characteristics among children.

[Comorbidity of migraine and somatic diseases].

INTRODUCTION: A 5-year prospective follow-up study was performed at the Institute of Mental Health in Belgrade, and it included adult patients diagnosed with migraine. MATERIAL AND METHODS: A protocol for prospective follow-up of comorbiditiy of migraine and somatic diseases was designed, whereas data were analyzed using standard statistical methods. RESULTS: The study comprised 381 patients, mean age 35.8 (range 19-60) years, 60 (15.8%) males and 321 (84.2%) females. The mean duration of migraine history before the first visit to the doctor was 7.7 (0-36) years. There was no concomitant disease in 50.5% of examinees. The most common concomitant diseases in the study population were: spondylosis (15.9%), head injury (12.9%), gynecological disorders (11.6% of female subgroup), hypotension (8.8%), hypertension (8.5%), allergy and asthma (5.8%), various cardiovascular diseases (4%) and epilepsy (3%). The incidence of the majority of diseases is in accordance with known epidemiological data for general population (except for head injury and epilepsy). In the subgroup of patients with comorbidity, almost 70% of patients reported more than one migraine attack per month, compared to 35% of patients without concomitant diseases, and about 60% of them had a higher intensity of headache in comparison with 35% of those without comorbidity. CONCLUSION: Present results indicate an increased severity of migraine attacks in patients with comorbidity. Therefore, it is necessary to assess how good management of comorbid diseases can alleviate the course and intensity of migraine headaches.

Antiepileptic, behavioral, and antidepressant effects of adjuvant lamotrigine therapy in drug-resistant epilepsy.

AIM: To evaluate the behavioral effects of lamotrigine as add-on therapy in treatment-resistant epilepsy. METHODS: An open, prospective, long-term study of lamotrigine as adjuvant therapy was performed in 56 patients with drug-resistant epilepsy (female/male ratio 35/21, age range 16-51 years). All the patients kept seizure diaries, and electroencephalograms were recorded at baseline and during 24 months of the treatment. Quality of life questionnaire, Hamilton depression scale (HMD), Beck depression scale (BDI), and Hamilton anxiety scale (HMA) were used before and during lamotrigine therapy. Comparative assessments were made in an age- and sex-matched control group treated with other antiepileptic drugs. RESULTS: Overall, seizure control was improved in 55.3% of the patients, remained unchanged in 39.3%, and deteriorated in 5.4%. Improvement in some quality of life measures occurred in 50% of the patients. The HMD subscales and BDI scale showed significant improvement in lamotrigine treated patients compared to the control group (ANOVA, p < 0.01). Negative behavioral effects occurred in 10.7% of the patients. CONCLUSION: Lamotrigine demonstrated significant antiepileptic long-term efficacy, and its positive effects on the mood and quality of life, which surpassed the negative behavioral effects, and contributed highly to the favorable treatment outcome.