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.

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.

Do Hippocampal Neurons Really Count for Comorbid Depression in Patients With Mesial Temporal Lobe Epilepsy and Hippocampal Sclerosis? A Histopathological Study.

Depression is the most frequent psychiatric comorbidity seen in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis (HS). Moreover, the HS is the most frequent pathological hallmark in MTLE-HS. Although there is a well-documented hippocampal volumetric reduction in imaging studies of patients with major depressive disorder, in epilepsy with comorbid depression, the true role of the hippocampus is not entirely understood. This study aimed to verify if patients with unilateral MTLE-HS and the co-occurrence of depression have differences in neuronal density of the hippocampal sectors CA1-CA4. For this purpose, we used a histopathological approach. This was a pioneering study with patients having both clinical disorders. However, we found no difference in hippocampal neuronal density when depression co-occurs in patients with epilepsy. In this series, CA1 had the lowest counting in both groups, and HS ILAE Type 1 was the most prevalent. More studies using histological assessments are needed to clarify the physiopathology of depression in MTLE-HS.

Efficacy and safety of levetiracetam as adjunctive therapy for refractory focal epilepsy.

BACKGROUND: Epilepsy affects about 50 million people worldwide and around 30% of these patients have refractory epilepsy, with potential consequences regarding quality of life, morbidity and premature mortality. OBJECTIVE: The aim of treatment with antiseizure medications (ASMs) is to allow patients to remain without seizures, with good tolerability. Levetiracetam is a broad-spectrum ASM with a unique mechanism of action that differs it from other ASMs. It has been shown to be effective and safe for treating adults and children with epilepsy. METHODS: This was a phase III, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of levetiracetam in children and adults (4-65 years) as an adjuvant treatment for focal-onset seizures. It was conducted among 114 patients undergoing treatment with up to three ASMs. The primary efficacy analysis was based on the proportion of patients who achieved a reduction of ≥ 50% in the mean number of focal seizures per week, over a 16-week treatment period. The patients were randomized to receive placebo or levetiracetam, titrated every two weeks from 20 mg/kg/day or 1,000 mg/day up to 60 mg/kg/day or 3,000 mg/day. RESULTS: Levetiracetam was significantly superior to placebo (p = 0.0031); 38.7% of the participants in the levetiracetam group and 14.3% in the control group shows reductions in focal seizures. Levetiracetam was seen to have a favorable safety profile and an adverse event rate similar to that of placebo. CONCLUSION: Corroborating the results in the literature, levetiracetam was shown to be effective and safe for children and adults with refractory focal-onset epilepsy.

Faux Pas Recognition Test: transcultural adaptation and evaluation of its psychometric properties in Brazil.

Introduction: Many neuropsychiatric and neurodegenerative disorders produce Theory of Mind impairment. We aimed to implement a Brazilian Portuguese version of the Faux Pas Recognition Test (FPRT) and evaluate its psychometric properties.Methods: We first completed an English-Brazilian Portuguese translation and adaptation to obtain an FPRT Brazilian Portuguese version. We performed a multicentric study with 153 healthy participants (68.6% women), mean age of 38.8 years (SD = 14.6) and 12.9 years of schooling (SD = 4.5). Linear regression analysis was performed to evaluate the association of social class, age, schooling, and FPRT scores. The psychometric analyses comprised item analysis, exploratory factor analysis, reliability, and validity analysis.Results: Normative data in a Brazilian population is presented. A positive correlation of scores with years of schooling, social class, and an inverse relation with age was found. The exploratory factorial analysis found a two-component structure, one component, consisting of questions 1 through 6 (Eigenvalue 5.325) and another component, consisting of questions 7 and 8 (Eigenvalue 1.09). Cronbach's alpha of the 20 stories was .72. All control stories had a poor discriminative index.Conclusion: The FPRT Brazilian Portuguese version demonstrated good internal consistency and, psychometric properties and is adequate for use even in lower educational contexts in Brazil.

Efficacy and safety of levetiracetam as adjunctive therapy for refractory focal epilepsy / Eficácia e segurança do levetiracetam como terapia adjunta na epilepsia focal refratária

ABSTRACT Background: Epilepsy affects about 50 million people worldwide and around 30% of these patients have refractory epilepsy, with potential consequences regarding quality of life, morbidity and premature mortality. Objective: The aim of treatment with antiseizure medications (ASMs) is to allow patients to remain without seizures, with good tolerability. Levetiracetam is a broad-spectrum ASM with a unique mechanism of action that differs it from other ASMs. It has been shown to be effective and safe for treating adults and children with epilepsy. Methods: This was a phase III, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of levetiracetam in children and adults (4-65 years) as an adjuvant treatment for focal-onset seizures. It was conducted among 114 patients undergoing treatment with up to three ASMs. The primary efficacy analysis was based on the proportion of patients who achieved a reduction of ≥ 50% in the mean number of focal seizures per week, over a 16-week treatment period. The patients were randomized to receive placebo or levetiracetam, titrated every two weeks from 20 mg/kg/day or 1,000 mg/day up to 60 mg/kg/day or 3,000 mg/day. Results: Levetiracetam was significantly superior to placebo (p = 0.0031); 38.7% of the participants in the levetiracetam group and 14.3% in the control group shows reductions in focal seizures. Levetiracetam was seen to have a favorable safety profile and an adverse event rate similar to that of placebo. Conclusion: Corroborating the results in the literature, levetiracetam was shown to be effective and safe for children and adults with refractory focal-onset epilepsy.

RESUMO Introdução: A epilepsia afeta cerca de 50 milhões de pessoas em todo o mundo e aproximadamente 30% desses pacientes apresentam epilepsia refratária, com possíveis consequências na qualidade de vida, morbidade e mortalidade prematura. Objetivo: O objetivo do tratamento com fármacos antiepilépticos (FAEs) é permitir que os pacientes permaneçam sem crises epilépticas com boa tolerabilidade. O levetiracetam (LEV) é um FAE de amplo espectro, com mecanismo de ação único, diferente dos demais e que demonstra ser eficaz e seguro no tratamento de adultos e crianças. Métodos: Estudo de fase III, multicêntrico, randomizado, duplo-cego e controlado por placebo avalia a eficácia e a segurança do LEV em crianças e adultos (4-65 anos) como tratamento adjuvante para crises de início focal em 114 pacientes já tratados com até três FAEs. A análise de eficácia primária foi baseada na proporção de pacientes que apresentaram redução ≥50% no número médio de crises epilépticas focais semanais, durante 16 semanas. Os pacientes foram randomizados para receber placebo ou LEV, titulado a cada duas semanas de 20 mg/kg/dia ou 1.000 mg/dia até 60 mg/kg/dia ou 3.000 mg/dia. Resultados: LEV foi significativamente superior ao placebo (p=0,0031), com 38,7% dos participantes no grupo LEV e 14,3% no grupo controle que apresentaram redução das crises focais. LEV apresenta bom perfil de segurança com eventos adversos semelhantes ao placebo. Conclusão: Corroborando com os resultados da literatura, o levetiracetam mostra-se eficaz e seguro para crianças e adultos com epilepsia focal refratária.

Neurocysticercosis and pharmacoresistant epilepsy: possible role of calcified lesions in epileptogenesis.

Neurocysticercosis is a neglected and usually poverty-related disease of high public importance. The mechanisms by which the calcified lesions cause epilepsy are not known, but have been attributed to residual perilesional gliosis or an inflammatory process. This case shows that an inflammatory response to a calcified granuloma may be associated with the development of epilepsy. The increase in glutamate and kinin B1 (pro-epileptogenic) receptors added by reduced expression of kinin B2 (anti-epileptogenic) receptors may explain the chronic epileptogenesis associated with the lesion, corroborating the hypothesis of inflammatory mechanisms involved in the pathophysiology of epilepsy in these patients.

Seizures in self-limited epilepsy with centrotemporal spikes: video-EEG documentation.

PURPOSE: Self-limited epilepsy with centrotemporal spikes, formerly called benign epilepsy with centrotemporal spikes, or rolandic epilepsy, is an age-related and well-defined epileptic syndrome. Since seizures associated with rolandic spikes are infrequent and usually occur during sleep, and repetitive or prolonged EEG recording for diagnostic purposes is not necessary for diagnosis, reports of ictal video-electroencephalographic seizures in this syndrome are rare. We aimed to show ictal video-EEG of typical rolandic seizures. METHODS: We report the ictal video-EEG recordings of two children with rolandic epilepsy who presented typical rolandic seizures during routine recording. RESULTS: Case 1: A 9-year-old boy, with normal development, had his first seizure at 8 years old, characterized by paresthesia in his left face, blocking of speech, and drooling. Carbamazepine was started with seizure control. Case 2: A 10-year-old boy, with normal development, started with focal seizures during sleep, characterized by eye and perioral deviation, and speech arrest at age of 7. He started using oxcarbazepine. Both patients underwent routine electroencephalography for electroclinical diagnosis and presented a seizure. CONCLUSION: Although self-limited epilepsy with centrotemporal spikes is a very common epileptic syndrome, seizure visualization is very difficult, and these videos may bring didactical information for recognition of this usual presentation of benign childhood focal epilepsy.

Effects of a brief psychotherapeutic intervention on resilience and behavior in patients with drug-resistant mesial temporal lobe epilepsy and late seizure recurrence after surgery.

Seizure recurrence (SR) after epilepsy surgery in patients with medically resistant temporal lobe epilepsy and mesial temporal sclerosis (TLE-MTS) can compromise medical treatment and quality of life (QOL). However, there is a scarcity of interventions specifically addressing this issue in the literature. We aimed to evaluate the impact of a four-week psychotherapeutic intervention on the levels of resilience, behavioral symptoms, and QOL of patients with drug-resistant TLE-MTS who underwent corticoamygdalohippocampectomy (CAH) and who presented with late SR. Fifty patients who had been diagnosed with TLE-TMS, undergone CAH, and presented with late SR were included. The study instruments included a clinical and sociodemographic questionnaire and the Brazilian versions of the Connor-Davidson Resilience Scale (CD-RISC-10), the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), the Interictal Dysphoric Disorder Inventory (IDDI), and the Quality of Life in Epilepsy Inventory (QOLIE-31). Significant reductions in the IDDI (p < 0.001) and NDDI-E (p < 0.001) scores, improvements in the CD-RISC-10 (p < 0.001) and QOLIE-31 (p < 0.001) scores, and positive correlations between resilience levels and QOL (p < 0.01), as well as a negative correlation between depressive symptoms and resilience (p < 0.01) and QOL (p < 0.01), were observed after the psychotherapeutic intervention. Improvements in the resilience levels and QOL, with concomitant reductions in depressive symptoms, were observed in patients with TLE-MTS and late SR after a brief psychotherapeutic intervention. Since there is a lack of studies that measured the impact of interventions in this patient subpopulation, these results may support the development of treatment strategies for this specific group.

Altered Proteins in the Hippocampus of Patients with Mesial Temporal Lobe Epilepsy.

Mesial temporal lobe epilepsy (MTLE) is usually associated with drug-resistant seizures and cognitive deficits. Efforts have been made to improve the understanding of the pathophysiology of MTLE for new therapies. In this study, we used proteomics to determine the differential expression of proteins in the hippocampus of patients with MTLE compared to control samples. By using the two-dimensional electrophoresis method (2-DE), the proteins were separated into spots and analyzed by LC-MS/MS. Spots that had different densitometric values for patients and controls were selected for the study. The following proteins were found to be up-regulated in patients: isoform 1 of serum albumin (ALB), proton ATPase catalytic subunit A (ATP6V1A), heat shock protein 70 (HSP70), dihydropyrimidinase-related protein 2 (DPYSL2), isoform 1 of myelin basic protein (MBP), and dihydrolipoamide S-acethyltransferase (DLAT). The protein isoform 3 of the spectrin alpha chain (SPTAN1) was down-regulated while glutathione S-transferase P (GSTP1) and protein DJ-1 (PARK7) were found only in the hippocampus of patients with MTLE. Interactome analysis of the nine proteins of interest revealed interactions with 20 other proteins, most of them involved with metabolic processes (37%), presenting catalytic activity (37%) and working as hydrolyses (25%), among others. Our results provide evidence supporting a direct link between synaptic plasticity, metabolic disturbance, oxidative stress with mitochondrial damage, the disruption of the blood⁻brain barrier and changes in CNS structural proteins with cell death and epileptogenesis in MTLE. Besides this, the presence of markers of cell survival indicated a compensatory mechanism. The over-expression of GSTP1 in MTLE could be related to drug-resistance.

Prognosis of Juvenile myoclonic epilepsy with eye-closure sensitivity.

PURPOSE: Eye closure sensitivity (ECS) has been described as a reflex trait in juvenile myoclonic epilepsy (JME). However, there is no consensus regarding its significance on prognosis. The aim of this study is to clarify the long-term impact of ECS documented by a clinical interview and a video-EEG neuropsychological protocol (VNPP) in a series of 133 JME patients. METHODS: Data from 22 JME patients with ECS confirmed by a VNPP (Group 1) were compared with those of 20 JME patients without any reflex traits (Group 2). They were followed for a mean of 8.21 years (SD=±5.044). The frequency of seizures was assessed using a diary. Except for photosensitivity (PS), any other reflex traits occurrence, drugs/alcohol abuse intake, noncompliance, and Jeavons syndrome, were considered exclusion criteria. RESULTS: Group 1 had a lower age at epilepsy onset (p = 0.028), higher incidence of febrile seizures (13.6%), and familial history of epilepsy (p = 0.023). Only 18.2% had self-perception of eyelid myoclonia (EM) (kappa coefficient = 0.193), which persisted in 77.3% of patients. Limb myoclonia, tonic-clonic seizures (TCS) and/or myoclonic-tonic-clonic seizures (MTCS), as well as absences were more frequent (p = 0.015; p = 0.013; p = 0.011, respectively) in Group 1. PS did not influenced frequency of EM (p = 1.0), absences (p = 0.648), or TCS/MTCS (p = 0.934). Psychiatric comorbidities were not different between groups. CONCLUSIONS: ECS is related to a worse outcome regarding control of all seizure types, persistence of EM, and higher frequency of limb myoclonia, as well as the total number of TCS and/or MTCS.

The impact of epilepsy duration in a series of patients with mesial temporal lobe epilepsy due to unilateral hippocampal sclerosis.

PURPOSE: To evaluate if the duration of epilepsy influences MRI volumes of the hippocampus, amygdala, parahippocampal gyrus, entorhinal cortex and temporal pole of both hemispheres and epileptogenic hippocampus neuronal cell density and dentate gyrus granular cells distribution in patients with refractory mesial temporal lobe epilepsy due to hippocampal sclerosis (MTLE/HS). METHODS: Seventy-seven patients with refractory MTLE/HS submitted to surgery were included. Histopathological analysis included: (1) quantitative: hippocampal subfields and total estimated hippocampal cell density (HCD), thickness of the dentate gyrus - normal, thinning or dispersion; (2) qualitative: type of HS and granule cells pathology in the dentate gyrus (normal, neuronal cell loss, dispersion and bilamination). Automated MRI-derived measurements from bilateral temporal structures (hippocampus, amygdala, parahippocampal gyrus, temporal pole, entorhinal cortex) were obtained for 58 subjects. Histopathological and imaging findings were compared with data from specimens obtained in autopsies of age-matched individuals and living controls, respectively, and the data were adjusted for the age at epilepsy onset and the frequency of focal impaired awareness seizures/month. RESULTS: Forty-two (54.5%) patients presented right HS. The greater the duration of epilepsy, the smaller the total estimated HCD (p = 0.025; r = -0.259). Patients with a normal distribution of the granular cells had a shorter epilepsy duration than those with dispersion (p = 0.018) or thinning (p = 0.031). A reduced ipsilateral hippocampal volume (r = -0.551, p = 0.017) and a smaller hippocampal asymmetry index (r = -0.414, p = 0.002) were correlated to a longer epilepsy duration. The estimated HCD was correlated to the volume of the ipsilateral hippocampus (r = 0.420, p = 0.001). CONCLUSION: Our study showed an increasing atrophy of the ipsilateral hippocampus in patients with a longer epilepsy duration. Our data suggest that this reduction in hippocampal volume is related to neuronal loss. Besides that, we also showed an increased probability of exhibiting an abnormal distribution of the granular cells in the dentate gyrus in patients with longer epilepsy duration.

Different patterns of epileptiform-like activity are generated in the sclerotic hippocampus from patients with drug-resistant temporal lobe epilepsy.

Human hippocampal slice preparations from patients with temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) are excellent material for the characterization of epileptiform-like activity. However, it is still unknown if hippocampal regions as cornu Ammonis (CA) 1, CA3 and CA4, generate population epileptiform-like activity. Here, we investigated epileptiform activities of the subiculum, CA1, CA2, CA3, CA4 (induced by elevation of extracellular potassium concentration) and the dentate gyrus (induced with hilar stimulation and elevation of potassium concentration) from sclerotic hippocampi of patients with drug-resistant TLE. Five types of epileptiform-like activity were observed: interictal-like events; periodic ictal spiking; seizure-like events; spreading depression-like events; tonic seizure-like events and no activity. Different susceptibilities to generate epileptiform activity among hippocampal regions were observed; the dentate gyrus was the most susceptible region followed by the subiculum, CA4, CA1, CA2 and CA3. The incidence of epileptiform activity pattern was associated with specific regions of the hippocampal formation. Moreover, it was observed that each region of the hippocampal formation exhibits frequency-specific ranges in each subfield of the sclerotic human tissue. In conclusion, this study demonstrates that epileptiform-like activity may be induced in different regions of the hippocampal formation, including regions that are severely affected by neuronal loss.

Morphometric MRI features and surgical outcome in patients with epilepsy related to hippocampal sclerosis and low intellectual quotient.

OBJECTIVE: The objectives of this study were to verify in a series of patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) if those with low intellectual quotient (IQ) levels have more extended areas of atrophy compared with those with higher IQ levels and to analyze whether IQ could be a variable implicated on a surgical outcome. MATERIAL AND METHODS: Patients (n=106) with refractory MTLE-HS submitted to corticoamygdalohippocampectomy (CAH) (57 left mesial temporal lobe epilepsy (MTLE); 45 males) were enrolled. To determine if the IQ was a predictor of seizure outcome, totally seizure-free (SF) versus nonseizure-free (NSF) patients were evaluated. FreeSurfer was used for cortical thickness and volume estimation, comparing groups with lower (<80) and higher IQ (90-109) levels. RESULTS: In the whole series, 42.45% of patients were SF (Engel Class 1a; n=45), and 57.54% were NSF (n=61). Total cortical volume was significantly reduced in the group with lower IQ (p=0.01). Significant reductions in the left hemisphere included the following: rostral middle frontal (p=0.001), insula (p=0.002), superior temporal gyrus (p=0.003), thalamus (p=0.004), and precentral gyrus (p=0.02); and those in the right hemisphere included the following: rostral middle frontal (p=0.003), pars orbitalis (p=0.01), and insula (p=0.02). Cortical thickness analysis also showed reductions in the right superior parietal gyrus in patients with lower IQ. No significant relationship between IQ and seizure outcome was found. CONCLUSIONS: This is the first study of a series of patients with pure MTLE-HS, including those with low IQ and their morphometric magnetic resonance imaging (MRI) features using FreeSurfer. Although patients with lower intellectual scores presented more areas of brain atrophy, IQ was not a predictor of surgical outcome. Therefore, when evaluating seizure follow-up, low IQ in patients with MTLE-HS might not contraindicate resective surgery.

Impact of hippocampal subfield histopathology in episodic memory impairment in mesial temporal lobe epilepsy and hippocampal sclerosis.

OBJECTIVE: The objective of the study was to analyze preoperative visual and verbal episodic memories in a homogeneous series of patients with mesial temporal lobe epilepsy (MTLE) and unilateral hippocampal sclerosis (HS) submitted to corticoamygdalohippocampectomy and its association with neuronal cell density of each hippocampal subfield. METHODS: The hippocampi of 72 right-handed patients were collected and prepared for histopathological examination. Hippocampal sclerosis patterns were determined, and neuronal cell density was calculated. Preoperatively, two verbal and two visual memory tests (immediate and delayed recalls) were applied, and patients were divided into two groups, left and right MTLE (36/36). RESULTS: There were no statistical differences between groups regarding demographic and clinical data. Cornu Ammonis 4 (CA4) neuronal density was significantly lower in the right hippocampus compared with the left (p=0.048). The groups with HS presented different memory performance - the right HS were worse in visual memory test [Complex Rey Figure, immediate (p=0.001) and delayed (p=0.009)], but better in one verbal task [RAVLT delayed (p=0.005)]. Multiple regression analysis suggested that the verbal memory performance of the group with left HS was explained by CA1 neuronal density since both tasks were significantly influenced by CA1 [Logical Memory immediate recall (p=0.050) and Logical Memory and RAVLT delayed recalls (p=0.004 and p=0.001, respectively)]. For patients with right HS, both CA1 subfield integrity (p=0.006) and epilepsy duration (p=0.012) explained Complex Rey Figure immediate recall performance. Ultimately, epilepsy duration also explained the performance in the Complex Rey Figure delayed recall (p<0.001). SIGNIFICANCE: Cornu Ammonis 1 (CA1) hippocampal subfield was related to immediate and delayed recalls of verbal memory tests in left HS, while CA1 and epilepsy duration were associated with visual memory performance in patients with right HS.

Efficacy and safety of a video-EEG protocol for genetic generalized epilepsies.

INTRODUCTION: Video-EEG has been used to characterize genetic generalized epilepsies (GGE). For best performance, sleep recording, photic stimulation, hyperventilation, and neuropsychological protocols are added to the monitoring. However, risks and benefits of these video-EEG protocols are not well established. The aim of this study was to analyze the efficacy and safety of a video-EEG neuropsychological protocol (VNPP) tailored for GGE and compare its value with that of routine EEG (R-EEG). METHODS: We reviewed the VNPP and R-EEG of patients with GGE. We considered confirmation of the clinical suspicion of a GGE syndrome and characterization of reflex traits as benefits; and falls, injuries, psychiatric and behavioral changes, generalized tonic-clonic (GTC) seizures, and status epilepticus (SE) as the main risks of the VNPP. RESULTS: The VNPPs of 113 patients were analyzed. The most common epileptic syndrome was juvenile myoclonic epilepsy (85.8%). The protocol confirmed a GGE syndrome in 97 patients and 62 had seizures. Sleep recording had a provocative effect in 51.2% of patients. The second task that showed highest efficacy was praxis (39.3%) followed by hyperventilation (31.3%). Among the risks, 1.8% had GTC seizures and another 1.8%, SE. Eighteen percent of patients had persistently normal R-EEG, 72.2% of them had discharges during VNPP. Generalized tonic-clonic seizures, myoclonic status epilepticus, and repeated seizures were the main risks of VNPP present in 6 (5.31%) patients while there were no complications during R-EEG. CONCLUSIONS: The VNPP in GGE is a useful tool in diagnosis and characterization of reflex traits, and is a safe procedure. Its use might preclude multiple R-EEG exams.

Cognitive performance in juvenile myoclonic epilepsy patients with specific endophenotypes.

PURPOSE: Juvenile myoclonic epilepsy (JME) is a heterogeneous syndrome in which seizures can be precipitated not only by non-specific factors, such as sleep deprivation and stress, but also by specific stimuli, such as photic stimuli, eye-closure, praxis, and language. The presence of these reflex traits may indicate the hyperexcitability of different cortical areas, which may be reflected in patients' neuropsychological deficit profile. The objective of our study is to investigate the possible relations between JME endophenotypes and patients' cognitive performance. METHODS: 61 JME patients were divided into four groups: no reflex traits (group 1, 20 patients); praxis induction (group 2, 13); eye-closure and/or photosensitivity (group 3, 17); and a combination of different reflex traits (group 4, 11). Neuropsychological performance was compared between JME subgroups. 60 healthy controls were used to calculate z-scores. Patients also underwent psychiatric assessment. We controlled the clinical variables, e.g. age at epilepsy onset, frequency of myoclonic seizures, total and sedative drug load, setting them as covariables for the ANOVA analysis. RESULTS: Praxis induction was more common in males (p=0.018) and groups with reflex traits (2, 3, and 4) presented higher rates of persistent myoclonia, polytherapy, clonazepam use (group 3), and more frequent psychiatric comorbidities. Group 4 patients performed worse in Trail Making Test B than the patients in group 1. These findings were independent of clinical variables. CONCLUSION: JME patients with a combination of praxis induction and eye-closure/photosensitivity had greater executive dysfunction, revealing an association between reflex ictogenic mechanisms and cognitive performance.

Phenotyping juvenile myoclonic epilepsy. Praxis induction as a biomarker of unfavorable prognosis.

PURPOSE: Juvenile myoclonic epilepsy (JME) is a heterogeneous syndrome with seizures presenting typical fluctuation in diurnal cycle and relation with awakening. Few publications have approached clinical expressions of praxis induction (PI) in the nosology of JME as well as its impact on outcome. The aim of this study is to characterize PI as the only reflex trait in JME and its relation with prognosis. METHOD: JME with PI reported on a questionnaire and confirmed by video-EEG testing (Group 1, 20 patients) were compared with JME without any reflex epileptic trait (Group 2, 25 patients) and followed for a mean of 7.82 years (SD=3.98). Circadian distribution and frequency of seizures were assessed in a diary. Patients also had psychiatric evaluation. RESULTS: Prevalence of PI was 20/133 (15%) JME patients, and was predominant in males (1.5 male: 1 female; OR 13; p=0.042). Among Group 1 patients, only 2/20 presented seizures exclusively in the morning (p=0.013), and none, exclusively on awakening (p<0.001). PI patients had worse prognosis regarding control of myocloni (p=0.02) and absences (p=0.01); only 7/20 (35.0%) could be treated with VPA in monotherapy (p=0.01). At the last follow-up, 2/20 (10.0%) of Group 1 and 10 (40.0%) of Group 2 patients were free of all three seizure types (p=0.02). Even though relative risk of stress as a precipitant of seizures increased 3.82 times in Group 1, psychiatric comorbidities were not different between groups. CONCLUSION: PI reflex trait in JME is related to seizures without preferential circadian occurrence and reduced response to antiepileptic drugs.

Expression and activity of thimet oligopeptidase (TOP) are modified in the hippocampus of subjects with temporal lobe epilepsy (TLE).

OBJECTIVE: Thimet oligopeptidase (TOP) is a metalloprotease that has been associated with peptide processing in several nervous system structures, and its substrates include several peptides such as bradykinin, amyloid beta (Aß), and major histocompatibility complex (MHC) class I molecules. As shown previously by our research group, patients with temporal lobe epilepsy (TLE) have a high level of kinin receptors as well as kallikrein, a kinin-releasing enzyme, in the hippocampus. METHODS: In this study, we evaluated the expression, distribution, and activity of TOP in the hippocampus of patients with TLE and autopsy-control tissues, through reverse-transcription polymerase chain reaction (RT-PCR), enzymatic activity, Western blot, and immunohistochemistry. In addition, hippocampi of rats were analyzed using the pilocarpine-induced epilepsy model. Animals were grouped according to the epilepsy phases defined in the model as acute, silent, and chronic. RESULTS: Increased TOP mRNA expression, decreased protein levels and enzymatic activity were observed in tissues of patients, compared to control samples. In addition, decreased TOP distribution was also visualized by immunohistochemistry. Similar results were observed in tissues of rats during the acute phase of epilepsy model. However, increased TOP mRNA expression and no changes in immunoreactivity were found in the silent phase, whereas increased TOP mRNA expression and increased enzymatic activity were observed in the chronic phase. SIGNIFICANCE: The results show that these alterations could be related to a failure in the mechanisms involved in clearance of inflammatory peptides in the hippocampus, suggesting an accumulation of potentially harmful substances in nervous tissue such as Aß, bradykinin, and antigenic peptides. These accumulations could be related to hippocampal inflammation observed in TLE subjects.