Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy.

BACKGROUND: In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. METHODS: Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick. RESULTS: A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia. CONCLUSIONS: Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).

COVID-19 and epilepsy: How are people with epilepsy in Brazil?

PURPOSE: During COVID-19 pandemic the global population is facing an important psychosocial distress. The aim of this study was to evaluate how people with epilepsy (PWE) in Brazil is dealing with the pandemic, in relation to seizure frequency, access to antiseizure medicines (ASM), medical follow-up, and well-being. METHODS: An online questionnaire survey among PWE (group 1) and caregivers (group 2) was applied in the social networks of the Brazilian Association of Epilepsy, the official Brazilian chapter of the International Bureau for Epilepsy. The questionnaire was composed of 46 generic questions in four areas, namely, demographics and baseline clinical data as well as epilepsy and quality-of-life impact by COVID-19 pandemic based on the domains of the abbreviated World Health Organization Quality of Life (WHOQOL-BREF) instrument. RESULTS: The questionnaire was answered by 464 participants including 380 (81.9%) PWE (78.7% female; age 34.3 yrs.; ±9.76) and 84 (18.1%) caregivers (patients' age 14.1 yrs.; ±10.30). During the COVID-19 pandemic, 36.8% of PWE and 36.4% of caregivers reported difficulties in accessing the epilepsy healthcare provider, and visits occurred normally only in 29.7% of PWE and in 34.5% of the caregivers group. Telehealth was not provided for 66.6% of group 1 and for 58.5% of group 2. Lack of availability of ASM was reported by 21.9% of PWE and 28.0% of caregivers in public dispensing units and by 19.2% and 17.8%, respectively, in private pharmacies. Increase in seizures during pandemic was mentioned by 26.3% and 27.9% of groups 1 and 2, respectively. Patients who had increase in seizure frequency had more frequently reported problems with treatment and in quality-of-life concepts. Fear of having a more severe COVID-19 presentation because of epilepsy was reported by 74.5% of PWE and by 89.8% of caregivers. Dissatisfaction with current health status was reported by 36.7% and 38.1% in groups 1 and 2, respectively, and that the support from others has decreased (56.1% and 66.1%, in groups 1 and 2) during the pandemic. The factors with higher Odds Ratio of increase in seizure frequency during pandemic were age >41 yrs., treatment in public healthcare system, drug-resistant epilepsy, adversities in getting ASM in public dispensing units, difficulties with prescription renewals, current financial problems and belief that epilepsy or ASM are risk factors for contracting COVID-19. CONCLUSION: During COVID-19 pandemic in Brazil, PWE and caregivers reported increase in seizures in one-fourth of the patients and several difficulties, namely problems in accessing the healthcare system including ASM dispensation, telehealth, and fear of having a more severe COVID-19 because of epilepsy. There were also physical, psychological, and social concerns which affected quality-of-life-related aspects in this population. These facts may increase treatment gap in epilepsy in Brazil as well in other developing countries.

Validation of the Health-Related Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) for Brazilian Portuguese.

OBJECTIVE: The present study aimed to validate the 55-item Health-Related Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) in Brazilian Portuguese and evaluate the relation of its results with clinical data and caregiver burden. METHODS: The QOLCE-55 was submitted to translation, back-translation, and cultural adaptation in a pilot sample with 20 subjects. To ensure the psychometric properties of validation, the validation of the QOLCE-55 was carried out in a sample of 45 patients with epilepsy aged between 4 and 18 years and their parents or caregivers and compared with the results of other quality-of-life instruments, namely, the QVCE-50 and QOLIE-AD-48, as well as with the SDQ, abrief behavioral screeningquestionnaire. The WASI and SON-R 2½-7 [a] were used for evaluation of intelligence quotient (IQ) and the Burden Interview for the caregiver burden. RESULTS: Internal consistency measured by Cronbach's alpha coefficient was moderate (0.692; p = 0.264), and the test-retest reliability analyzed by the intraclass correlation coefficient was satisfactory when compared with the results by different examiners on the same day (0.951; p = 0.001) and at different times (0.778; p = 0.001). This version of the QOLCE-55 presented a strong correlation with the QVCE-50 (0.904; p < 0.001) and SDQ (-0.428; p = 0.004) but a low correlation with the QOLIE-AD-48 (0.094; p = 0.729). This version also presented a correlation with IQ (R = 0.456, p = 0.003) and an inverse correlation with the Burden Interview (-0.390; p = 0.012). Low quality of life was associated with the presence of tonic-clonic seizures (p = 0.005), polytherapy (p = 0.003), and low socioeconomic conditions (p = 0.005). CONCLUSIONS: The Brazilian Portuguese version of the QOLCE-55 was confirmed as a reliable and valid scale to assess quality of life in children and adolescents with epilepsy. Behavioral problems, caregiver burden, tonic-clonic seizures, polytherapy, and socioeconomic precariousness were associated with low quality-of-life values, while IQ was positively correlated with the quality of life in this population.

Dysfunctional personality beliefs and executive performance in patients with juvenile myoclonic epilepsy.

BACKGROUND: This article intends to verify the association of dysfunctional beliefs of personality disorders with the executive performance in people with juvenile myoclonic epilepsy (JME). METHODS: Fifty-two patients (35 women, 67.3%) with JME aged 18-50 yrs. (32.3 ±â€¯9.7) were evaluated between May 2017 and April 2018 and compared with controls. All subjects were submitted to the Personality Beliefs Questionnaire (PBQ) (Beck & Beck, 1991; Savoia et al., 2006), Dysexecutive Questionnaire (DQ; Wilson et al., 1996; Macuglia et al., 2016), estimated intelligence quotient (IQ) using Vocabulary and Block Design tests, attention and executive functions evaluation (Controlled Oral Word Association (COWA), Digit Span, Trail Making Tests (TMT) A and B, Stroop and Wisconsin Card Sorting Test (WCST)). The inclusion criteria were as follows: diagnosis of JME (ILAE, 1989); age ≥18 yrs., schooling ≥ 11 yrs. and IQ ≥70. The inclusion criteria for the control group were the same except diagnosis of epilepsy. RESULTS: Compared with controls, patients presented higher scores in PBQ for personality disorders, namely Narcissistic (z = -0.79; p < 0.001), Borderline (z = -0.58; p = 0.002), Paranoid (z = -0.43; p = 0.017), and Histrionic (z = -0.39; p = 0.041). Executive functions were impaired when compared with controls in TMT A (z = -0.97; p = 0.038), TMT B (z = -0.65; p = 0.023), and COWA (z = -0.51; p = 0.001). Patients showed higher WCST scores for Errors (z = -1.62; p ≤ 0.001), Perseverative Errors (z = -0.77; p = 0.001), Non-Perseverative Errors (z = -1.01; p = 0.001), Conceptual Level Response (z = -1.56; p ≤ 0.001), Completed Categories (z = -2.12; p = 0.002), and Failure to Maintain Context (z = -0.49; p = 0.015). Personality Beliefs Questionnaire results showed correlation with lower values in TMT A, Antisocial (r = -0.298; p = 0.032), Narcissistic (r = -0.303; p = 0.029), Schizoid (r = - 0.410; p = 0.003), Histrionic (r = -0.341; p = 0.013), Passive-aggressive (r = -0.341; p = 0.015), and Obsessive-compulsive (r = -0.319; p = 0.021); TMT B results showed a trend for Obsessive-compulsive traits (r = -0.261; p = 0.052); COWA was correlated to Dependent (r = 0.319; p = 0.021); and Digit Span to Passive-aggressive (r = 0.287; p = 0.039). On WCST, Failure to Maintain Context was correlated to Avoidant (r = 0.335; p = 0.017). The DQ was not correlated with PBQ. CONCLUSION: People with JME presented dysfunctional beliefs of personality disorder that were correlated with executive dysfunction. These findings reinforce the need for psychological rehabilitation in these patients.

Revisiting personality in epilepsy: Differentiation of personality in two epilepsies starting in adolescence.

PURPOSE: The purpose of this study was to investigate personality characteristics and clinical parameters in two well-defined epilepsies: mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE/HS) and juvenile myoclonic epilepsy (JME) through NEO Revised Personality Inventory (NEO-PI-R) and Neurobehavior Inventory (NBI) standardized instruments. METHODS: One hundred patients undergoing corticoamygdalohippocampectomy (CAH), 100 patients with JME, and 100 control subjects answered the personality measures. Clinical parameters such as psychiatric symptoms, seizure frequency, duration of epilepsy, and side of the lesion in MTLE/HS group were investigated. Statistical analysis consisted of the mean and standard deviation (SD) of each variable. Student's t-test or Fisher exact test were used according to the variable studied. RESULTS: The three groups were within the average range of NEO-PI-R and NBI, although 'tendencies' and differences were demonstrated. The MTLE/HS and control subjects had a similar profile: low scores in Neuroticism and high in Conscientiousness (r = -0.330; p < 0.001/r = -0.567; p < 0.001, respectively) in opposition to what occurred in JME, low in Conscientiousness and high in Neuroticism (r = -0.509; p = 0.005). The NBI 'sense of personal destiny' trait was higher (3.15; p = 0.003) in MTLE/HS than in JME and controls. The JME 'law and order' scores were lower than in other groups (p = 0.024). A tendency towards specific NBI traits differentiates MTLE/HS (Factor 3) from JME (Factor 1) groups. Psychiatric symptoms and seizure frequency were correlated with worse scores in NBI and, especially, in Neuroticism domain of NEO-PI-R. CONCLUSION: Specific personality features were linked to each epileptic disease. These findings highlight the importance of considering unique features linked to epilepsy conditions in daily clinical observation to develop support programmes.

EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality.

PURPOSE: EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. METHODS: We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/- KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. RESULTS: Nine variants were classified as "pathogenic," 14 as "likely pathogenic," 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. CONCLUSIONS: NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and "microdysgenesis" neuropathology of JME.Genet Med 19 2, 144-156.

ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.

The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.

Cerebal overinhibition could be the basis for the high prevalence of epilepsy in persons with Down syndrome.

Down syndrome (DS) is the most common cause of genetic intellectual disability, and the trisomy 21 is associated with more than 80 clinical traits, including higher risk for epilepsy. Several hypotheses have been put forward to explain the mechanisms underlying increased seizure susceptibility in DS: inherent structural brain abnormalities, abnormal cortical lamination, disruption of normal dendritic morphology, and underdeveloped synaptic profiles. A deficiency or loss of GABA inhibition is hypothesized to be one of the main alterations related to the epileptogenic process. Paradoxically, enhanced GABA inhibition has also been reported to promote seizures. One major functional abnormality observed in the brains of individuals and mouse models with DS appears to be an imbalance between excitatory and inhibitory neurotransmission, with excessive inhibitory brain function. This review discusses the GABAergic system in the human DS brain and the possible implication of the GABAergic network circuit in the epileptogenic process in individuals where the pathogenetic basis for epilepsy is unknown.

Cardiac autonomic modulation of children with Down syndrome.

The aim of this study is to analyze the autonomic modulation in children with Down syndrome (DS). The study was conducted with a convenience sample of children with DS and without heart disease, from the Genetics Clinic of the Hospital Infantil Darcy Vargas and APAE São Paulo, São Paulo, SP, Brazil. The control group was matched for sex and age. The analysis of autonomic modulation was performed using the indices of heart rate variability (HRV). The children remained in the supine position with spontaneous breathing for 20 min. Heart rate was recorded beat-to-beat. HRV analysis was performed in time and frequency domain. For data analysis, we used Student's t test: unpaired and Mann-Whitney. It was considered statistically significant at p < 0.05. From 75 children with DS, 50 were excluded, a total of 25 children [16 boys, 8.6 (1.4) years] participated in this study, and the control group also consisted of 25 children [16 boys, 9.0 (1.2) years] without the syndrome. The BMI of the volunteers with DS was higher than the controls [19.1 (2.9) vs. 15.8 (1.2), p < 0.0001]. There were differences between groups in the indices in frequency domain: LFms(2) [1242.1 (788.25) vs. 786.44 (481.90), p = 0.040], LFun [69.104 (11.247) vs. 57.348 (11.683), p = 0.0004], HFun [30.896 (11.247) vs. 42.520 (11.634), p = 0.0004] and LF/HF [2.594 (1.104) vs. 1.579 (0.9982), p = 0.0004]. No differences were observed in time domain indices. The results indicate increased indices representing the sympathetic branch of the autonomic nervous system and those that indicate the overall modulation in children with DS.

A controversial question: Can morphometry and clinical history be enough to diagnose hippocampal dysplasia?

The presence of dysmorphic neurons with strong cytoplasmatic accumulation of heavy non-phosphorylated neurofilament is crucial for the diagnostics of focal cortical dysplasia type II (FCDII). While ILAE's classification describes neocortical dysplasias, some groups have reported patients with mesial t abnormal neurons in the hippocampus of mesial temporal lobe epilepsy. Here we report a patient with such abnormal neurons in the hippocampus and compared it with previous reports of hippocampal dysplasia. Finally, we discuss the need for diagnostic criteria of hippocampal dysplasia.

Association between leisure time, physical activity, and mood disorder levels in individuals with epilepsy.

The aim of this study was to investigate the association between physical activity levels (occupational, sports, and leisure time activities), depression, anxiety, and epilepsy. The behavioral outcomes of individuals with epilepsy (E) were also compared with healthy control subjects (C). The sample included 31 individuals with epilepsy (12 with idiopathic generalized epilepsy and 19 with partial epilepsy) and 31 control subjects. Self-rating questionnaires were used to assess mood (State-Trait Anxiety Inventory and Beck Depression Inventory), anxiety, and depression as well as habitual physical activity. Patients with epilepsy were more severely impaired compared to control subjects in both mood questionnaires and presented higher levels of depression (35%), state anxiety (18%), and trait anxiety (12.6%) when compared to the C group. Although physical activity level did not differ significantly between groups, linear regression analyses showed that the physical activity leisure level predicted 31% of depression levels and 26% of anxiety levels in the E group. These data suggest that low levels of physical activity may be considered a risk factor for the development of depression and anxiety and can play an important role in the quality of life of individuals with epilepsy.

Minimum effective sodium valproate dose in genetic generalized epilepsies.

INTRODUCTION: Sodium valproate (VPA) is the most effective antiseizure medication (ASM) in genetic generalized epilepsies (GGEs). However, the frequent adverse effects and the high risk inflicted on the exposed offspring make it imperative to search for the lowest daily VPA dose able to control seizures for most patients. In the current published series, the VPA value of <1000 mg was the most adopted. OBJECTIVE: This study aims to provide a cutoff VPA value below which a given daily dose can be considered a low dose in patients with GGEs. METHODS: This retrospective, observational cohort study included patients with clinical and electroencephalographic diagnoses of GGEs based on the ILAE criteria. Patients were followed up for at least two years using VPA in mono- or polytherapy. Clinical data, VPA dose, and associated ASMs were analyzed. Adverse effects were also evaluated. We related seizure control to VPA doses through uni- and multivariate statistical analyses. RESULTS: From 225 patients, 169 (75%) had good seizure control, with most (60%) receiving monotherapy. The cutoff daily VPA dose capable of distinguishing these patients from those without seizure control was up to 1000 mg (p = 0.006) in univariate analyses and up to 700 mg in multivariate analyses. For patients in polytherapy, the cutoff was up to 1750 mg and 1800 mg in uni- and multivariate analyses, respectively. CONCLUSIONS: The lowest daily VPA dose in monotherapy able to control seizures for most GGE patients was up to 700 mg, a value that can be used as a low dose criterion in studies assessing the therapeutic VPA ranges. Patients using higher VPA doses or in polytherapy present a lower probability of seizure control.

Ketogenic therapy in childhood and adolescence: recommendations of the Brazilian experts group.

Ketogenic dietary therapies (KDTs) are a safe and effective treatment for pharmacoresistant epilepsy in children. There are four principal types of KDTs: the classic KD, the modified Atkins diet (MAD), the medium-chain triglyceride (MCT) diet, and the low glycemic index diet (LGID). The International Ketogenic Diet Study Group recommends managing KDTs in children with epilepsy. However, there are no guidelines that address the specific needs of the Brazilian population. Thus, the Brazilian Child Neurology Association elaborated on these recommendations with the goal of stimulating and expanding the use of the KD in Brazil.

As terapias dietéticas cetogênicas (TDC) são um tratamento seguro e eficaz para epilepsia farmacorresistente em crianças. Existem quatro tipos principais de TDCs: a dieta cetogênica (DC) clássica, a dieta de Atkins modificada (DAM), a dieta de triglicerídeos de cadeia média (DTCM) e a dieta de baixo índice glicêmico (DBIG). O Grupo Internacional de Estudos de Dietas Cetogênicas (International Ketogenic Diet Study Group) propõe recomendações para o manejo da DC em crianças com epilepsia. No entanto, faltam diretrizes que contemplem as necessidades específicas da população brasileira. Assim, a Associação Brasileira de Neurologia Infantil elaborou essas recomendações com o objetivo de estimular e expandir o uso da DC no Brasil.

Physiological and electroencephalographic responses to acute exhaustive physical exercise in people with juvenile myoclonic epilepsy.

Although the available evidence suggests that exercise may positively affect epilepsy, whether this effect is applicable to different types of epilepsy has not been established. Physiological responses during rest, acute physical effort, and a recovery period were studied by concomitant analysis of cerebral electric activity using EEGs in subjects with juvenile myoclonic epilepsy (JME) and healthy controls. In addition, level of habitual physical activity, body composition, and 1 week of actigraphy monitoring data were evaluated. Twenty-four subjects (12 with JME and 12 controls) participated in this study. Compared with the control group, the JME group had a significantly lower V˙O(2) at rest (13.3%) and resting metabolic rate (15.6%). The number of epileptiform discharges in the JME group was significantly reduced during the recovery period (72%) compared with the resting state. There were no significant differences between the JME and control groups in behavioral outcomes and sleep parameters evaluated by actigraphy monitoring. The positive findings of our study strengthen the evidence for the benefits of physical exercise for people with JME.

Neuropsychiatric Symptoms of Alzheimer's Disease in Down Syndrome and Its Impact on Caregiver Distress.

BACKGROUND: Neuropsychiatric symptoms (NPS) are non-cognitive manifestations common to dementia and other medical conditions, with important consequences for the patient, caregivers, and society. Studies investigating NPS in individuals with Down syndrome (DS) and dementia are scarce. OBJECTIVE: Characterize NPS and caregiver distress among adults with DS using the Neuropsychiatric Inventory (NPI). METHODS: We evaluated 92 individuals with DS (≥30 years of age), divided by clinical diagnosis: stable cognition, prodromal dementia, and AD. Diagnosis was determined by a psychiatrist using the Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities (CAMDEX-DS). NPS and caregiver distress were evaluated by an independent psychiatrist using the NPI, and participants underwent a neuropsychological assessment with Cambridge Cognitive Examination (CAMCOG-DS). RESULTS: Symptom severity differed between-groups for delusion, agitation, apathy, aberrant motor behavior, nighttime behavior disturbance, and total NPI scores, with NPS total score being found to be a predictor of AD in comparison to stable cognition (OR for one-point increase in the NPI = 1.342, p = 0.012). Agitation, apathy, nighttime behavior disturbances, and total NPI were associated with CAMCOG-DS, and 62% of caregivers of individuals with AD reported severe distress related to NPS. Caregiver distress was most impacted by symptoms of apathy followed by nighttime behavior, appetite/eating abnormalities, anxiety, irritability, disinhibition, and depression (R2 = 0.627, F(15,76) = 8.510, p < 0.001). CONCLUSION: NPS are frequent and severe in individuals with DS and AD, contributing to caregiver distress. NPS in DS must be considered of critical relevance demanding management and treatment. Further studies are warranted to understand the biological underpinnings of such symptoms.

Impulsiveness, personality traits and executive functioning in patients with juvenile myoclonic epilepsy.

PURPOSE: To evaluate impulsiveness in adult patients with JME and its relationship with personality traits and executive functioning. METHODS: Patients completed psychiatric evaluation (DSM IV), Barratt Impulsiveness Scale (BIS-11), Neo Revised Personality Inventory (NEO PI-R) and executive functioning evaluation comprising Controlled Oral Word Association (COWA), Digit Span, Trail Making Tests (TMT), Stroop Test (ST) and Wisconsin Card Sorting Test (WSCT). Healthy controls (63 % female, mean age 35.7 yrs. (±8.37)) were examined to allow calculation of z-scores. RESULTS: 50 patients (70 % female; mean age 32.5 yrs. (±9.2)) presented higher scores of Total (z=-0.37; p = 0.005) and Motor Impulsiveness (z=-0.79; p < 0.001) on BIS-11. Motor Impulsiveness was associated with higher rates of mild psychiatric disorders (depression and anxiety) (p = 0.035) and worse myoclonic seizure control (p = 0.007). NEO PI-R showed differences on Neuroticism (z=-0.60; p < 0.001), Openness (z = 0.38; p = 0.043), Agreeableness (z=-0.38; p = 0.033) and Conscientiousness (z=-0.53; p = 0.003). There were positive correlations between BIS-11 and Neuroticism with Total, Motor and Non-Planning Impulsiveness, on the other hand, Conscientiousness was negatively correlated with these as well as with Attentive Impulsiveness. Patients performance was worse than that of controls on COWA (z=-0.43; p = 0.009) and WCST's Total Number of Completed Categories (z=-2.08; p = 0.005), Trials Taken to Complete First Category (z=-1.56; p = 0.013), Percentage of Total Errors (z=-1.56; p < 0.001), Perseverative Errors (z=-0.73; p = 0.002), Non-Perseverative Errors (z=-1.05; p = 0.003) and Conceptual Level Responses (z=-1.52; p < 0.001). Non-Planning Impulsiveness correlated with Performance (ST and TMT). CONCLUSION: Patients with JME present with impulsive behavior, personality features and executive dysfunction which are linked and may lead to lack of commitment in treatment and affect other aspects of life.

Neuropsychological findings related to the presence of pre-surgical comorbid depression in Latin-American patients with mesial temporal lobe epilepsy and hippocampal sclerosis.

PURPOSE: To evaluate the neuropsychological findings related to the presence of pre-surgical comorbid depression in Latin-American patients with mesial temporal lobe epilepsy (MTLE) and unilateral hippocampal sclerosis (HS). METHOD: Patients with drug-resistant MTLE and unilateral, left (L-) or right (R-) HS were studied. To diagnose depression, psychiatrists with expertise in epilepsy applied a semi-structured interview based on DSM. The depression group (DG) included patients with a psychiatric diagnosis in addition to a Beck Depression Inventory (BDI) score >16 points, and the non-depression group (NDG) included those without this diagnosis and with a BDI score ≤16. We analysed two clusters of neuropsychological tests, which evaluated memory (Complex Rey Figure III, Logical Memory II and RAVLT VII) and attention plus executive functions (Stroop I/II/III and Trail Making A/B). Moreover, we calculated the z-scores (Zs) using a local control group. The DG was compared to the NDG, independently and according to the HS side, using non-parametrical analyses. Due to the multivariate analysis, the p-value was corrected by applyingpost hoc Bonferroni adjustment. RESULTS: We analysed 65 patients. The NDG included 51 (78.4 %) patients, and the DG included 14 (21.5 %) patients. Pre-surgical comorbid depression occurred in eight patients with L- (n = 29) and in six patients with R-MTLE-HS (n = 36). All of these groups had similar gender, age, IQs, and years of schooling. Compared to the healthy subjects, the L-MTLE-HS patients had lower Zs in verbal episodic memory tests [Logical Memory II (p < 0.001), and RAVLT VII (p < 0.001)], and the R-MTLE-HS patients had lower scores in visual episodic memory [Complex Rey Figure III (p < 0.001)]. In the analysis of the DGvs. NDG, there were no differences in the clusters of tests of memory or in those of attention and executive functions. Moreover, when we analysed the patients according to HS side, no neuropsychological difference was observed in the DG and NDG in terms of L- and R-MTLE-HS. CONCLUSIONS: The patients with MTLE and unilateral HS in this study showed no differences in memory, attention and executive functions in relation to the presence of pre-surgical comorbid depression and independently of HS side. In this series from Latin-America, this psychiatric comorbidity did not affect cognition more than epilepsy alone.

Magnetic resonance spectroscopy reveals an epileptic network in juvenile myoclonic epilepsy.

PURPOSE: To investigate the cerebral metabolic differences between patients with juvenile myoclonic epilepsy (JME) and normal controls and to evaluate to what extent these metabolic alterations reflect involvement of an epileptic network. METHODS: Sixty patients with JME were submitted to multi-voxel proton spectroscopy (1H-MRS) at 1.5 T over medial prefrontal cortex (MPC), primary motor cortex (PMC), thalamus, striatum, posterior cingulate gyrus (PCG), and insular, parietal, and occipital cortices. We determined ratios for integral values of N-acetyl-aspartate (NAA) and glutamate-glutamine (GLX) over creatine-phosphocreatine (Cr). The control group (CTL) consisted of 30 age- and sex-matched healthy volunteers. RESULTS: The NAA/Cr ratio, a measure of neuronal injury, was reduced in PMC, MPC, and thalamus among patients. In addition, they had an altered GLX/Cr ratio, which is involved in excitatory activity, on PMC, MPC, and PCG, where it was reduced, whereas it was increased on insula and striatum. Multiple regression analysis revealed the strongest correlation between thalamus and MPC, but the thalamus was also correlated with insula, occipital cortex, and striatum among patients. Lower NAA/Cr was observed with advancing age and duration of epilepsy, regardless of frequency of seizures and antiepileptic drug therapy in thalamus and frontal cortex. DISCUSSION: The identification of a specific network of neurochemical dysfunction in patients with JME, with diverse involvement of particular structures within the thalamocortical circuitry, suggests that cortical hyperexcitability in JME is not necessarily diffuse, supporting the knowledge that the focal/generalized distinction of epileptogenesis should be reconsidered. Furthermore, evidence is provided toward progressive neuronal dysfunction in JME.

Provocative and inhibitory effects of a video-EEG neuropsychologic protocol in juvenile myoclonic epilepsy.

PURPOSE: Studies suggest that higher cognitive functions could precipitate seizures in juvenile myoclonic epilepsy (JME). The present study aimed to analyze the effects of higher mental activity on epileptiform discharges and seizures in patients with JME and compare them to those of habitual methods of activation. METHODS: Seventy-six patients with JME (41 female) underwent a video-EEG (electroencephalography) neuropsychologic protocol (VNPP) and habitual methods of activation for 4-6 h. RESULTS: Twenty-nine of the 76 (38.2%) presented provocative effect, and inhibition was seen in 28 of 31 (90.3%). A mixed effect was observed in 11 (35.5%), and 30 patients (39.5%) suffered no effect of VNPP. Action-programming tasks were more effective than thinking in provoking epileptiform discharges (23.7% and 11.0% of patients, respectively, p = 0.03). Inhibitory effect was observed equally in the various categories of tasks, except in mental calculation, which had a higher inhibitory rate. Habitual methods of activation were more effective than VNPP in provoking discharges. Anxiety disorders were diagnosed in 24 of 58 patients (41.4%); anxious patients had greater discharge indexes and no significant inhibitory effect on VNPP. DISCUSSION: Praxis exerted the most remarkable provocative effect, in accordance with the motor circuitry hyperexcitability hypothesis in JME. Inhibitory effect, which had no such task specificity, might be mediated by a widespread cortical-thalamic pathway, possibly involving the parietal cortex. The frequent inhibitory effect found under cortical activation conditions, influenced by the presence of anxiety, supports nonpharmacologic therapeutic interventions in JME.

Are personality traits of juvenile myoclonic epilepsy related to frontal lobe dysfunctions? A proton MRS study.

PURPOSE: Personality traits characterized by emotional instability and immaturity, unsteadiness, lack of discipline, hedonism, frequent and rapid mood changes, and indifference toward one's disease have been associated with patients who have juvenile myoclonic epilepsy (JME). Literature data demonstrate worse seizure control and more psychosocial dysfunctions among patients with JME who have those traits. In this controlled study we performed a correlation analysis of psychiatric scores with magnetic resonance spectroscopy (MRS) values across JME patients, aiming to verify the existence of a possible relation between frontal lobe dysfunction and the prevalence of personality disorders (PDs) in JME. METHODS: Sixteen JME patients with cluster B PDs, 41 JME patients without any psychiatric disorder, and 30 healthy controls were submitted to a psychiatric evaluation and to a quantitative multivoxel MRS of thalamus; insula; cingulate gyrus; striatum; and frontal, parietal, and occipital lobes. Groups were homogeneous according to age, gender, and manual dominance. Psychiatric evaluation was performed through the Scheduled Clinical Interview for DSM-IV, Axis I and II (SCID I and II, respectively). RESULTS: A significant reduction of N-acetyl-aspartate over creatinine (NAA/Cr) ratio was observed mainly in the left frontal lobe in the JME and PD group. In addition, a significant increase in the glutamate-glutamine over creatinine GLX/Cr ratio was also observed in this referred region in the same group. DISCUSSION: These data support the hypothesis that PDs in JME could represent neuronal dysfunction and possibly a more severe form of this epileptic syndrome.