Revisiting the clinical impact of variants in EFHC1 in patients with different phenotypes of genetic generalized epilepsy.

The most common form of genetic generalized epilepsy (GGE) is juvenile myoclonic epilepsy (JME), which accounts for 5 to 10% of all epilepsy cases. The gene EFHC1 has been implicated as a putative cause of JME. However, it remains debatable whether testing for EFHC1 mutations should be included in the diagnostic epilepsy gene panels. To investigate the clinical utility of EFHC1 testing, we studied 125 individuals: 100 with JME and 25 with other GGEs. We amplified and sequenced all EFHC1 coding exons. Then, we predicted the pathogenicity or benign impact of the variants using the analyses proposed by the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP). Mutation screening revealed 11 missense variants in 44 probands with JME (44%) and one of the seven individuals with generalized tonic-clonic seizures on awakening (14%). Six of the 11 variants (54%) were classified as 'benign,' and the remaining variants were considered variants of uncertain significance (VUS). There is currently a limitation to test for genes that predispose an individual to complex, nonmonogenic phenotypes. Thus, we show suggestive evidence that EFHC1 testing lacks a scientific foundation based on the disputed nature of the gene-disease relationship and should be currently limited to research purposes.

Investigation of the cingulate cortex in idiopathic generalized epilepsy.

OBJECTIVE: Studies using quantitative neuroimaging have shown subtle abnormalities in patients with idiopathic generalized epilepsy (IGE). These findings have several locations, but the midline parasagittal structures are most commonly implicated. The cingulate cortex is related and may be involved. The objective of the current investigation was to perform a comprehensive analysis of the cingulate cortex using multiple quantitative structural neuroimaging techniques. METHODS: Thirty-two patients (18 women, 30 ± 10 years) and 36 controls (18 women, 32 ± 11 years) were imaged by 3 Tesla magnetic resonance imaging (MRI). A volumetric three-dimensional (3D) sequence was acquired and used for this investigation. Regions-of-interest were selected and voxel-based morphometry (VBM) analyses compared the cingulate cortex of the two groups using Statistical Parametric Mapping (SPM8) and VBM8 software. Cortical analyses of the cingulate gyrus was performed using Freesurfer. Images were submitted to automatic processing using built-in routines and recommendations. Structural parameters were extracted for individual analyses, and comparisons between groups were restricted to the cingulate gyrus. Finally, shape analyses was performed on the anterior rostral, anterior caudal, posterior, and isthmus cingulate using spherical harmonic description (SPHARM). RESULTS: VBM analyses of cingulate gyrus showed areas of gray matter atrophy, mainly in the anterior cingulate gyrus (972 mm(3) ) and the isthmus (168 mm(3) ). Individual analyses of the cingulate cortex were similar between patients with IGE and controls. Surface-based comparisons revealed abnormalities located mainly in the posterior cingulate cortex (718.12 mm(2) ). Shape analyses demonstrated a predominance of anterior and posterior cingulate abnormalities. SIGNIFICANCE: This study suggests that patients with IGE have structural abnormalities in the cingulate gyrus mainly localized at the anterior and posterior portions. This finding is subtle and variable among patients.

Computational methods of EEG signals analysis for Alzheimer's disease classification.

Computational analysis of electroencephalographic (EEG) signals have shown promising results in detecting brain disorders, such as Alzheimer's disease (AD). AD is a progressive neurological illness that causes neuron cells degeneration, resulting in cognitive impairment. While there is no cure for AD, early diagnosis is critical to improving the quality of life of affected individuals. Here, we apply six computational time-series analysis methods (wavelet coherence, fractal dimension, quadratic entropy, wavelet energy, quantile graphs and visibility graphs) to EEG records from 160 AD patients and 24 healthy controls. Results from raw and wavelet-filtered (alpha, beta, theta and delta bands) EEG signals show that some of the time-series analysis methods tested here, such as wavelet coherence and quantile graphs, can robustly discriminate between AD patients from elderly healthy subjects. They represent a promising non-invasive and low-cost approach to the AD detection in elderly patients.

Structural abnormalities of the thalamus in juvenile myoclonic epilepsy.

Studies have suggested that the thalamus is a key structure in the pathophysiology of juvenile myoclonic epilepsy. The objective of the present investigation was to examine the thalami of patients with juvenile myoclonic epilepsy using a combination of multiple structural neuroimaging modalities. The association between these techniques may reveal the mechanisms underlying juvenile myoclonic epilepsy and help to identify the neuroanatomical structures involved. Twenty-one patients with juvenile myoclonic epilepsy (13 women, mean age=30±9 years) and a control group of 20 healthy individuals (10 women, mean age=31±8 years) underwent MRI in a 2-T scanner. The volumetric three-dimensional sequence was used for structural investigation. Evaluation of the thalamus comprised voxel-based morphometry, automatic volumetry, and shape analysis. Comparisons were performed between patient and control groups. Voxel-based morphometry analysis identified areas of atrophy located in the anterior portion of the thalamus. Post hoc analysis of automatic volumetry did not reveal significant differences between the groups. Shape analysis disclosed differences between patients and controls in the anterior and inferior portions of the right thalamus and in the anterior portion of the left thalamus. The present investigation confirms that thalami of patients with juvenile myoclonic epilepsy are structurally abnormal with impairments located mainly in the anterior and inferior sections.

Correlation between quantitative EEG and MRI in idiopathic generalized epilepsy.

The objective of this study was to investigate the relationship between the focal discharges sometimes observed in the electroencephalogram of patients with idiopathic generalized epilepsies and subtle structural magnetic resonance imaging abnormalities. The main hypothesis to be assessed is that focal discharges may arise from areas of structural abnormality which can be detected by quantitative neuroimaging. Focal discharges were used for quantitative electroencephalogram source detection. Neuroimaging investigations consisted of voxel-based morphometry and region of interest volumetry. For voxel-based morphometry, volumetric MRI were acquired and processed. The images of each patient were individually compared with a control group. Statistical analysis was used to detect differences in gray matter volumes. Region of interest-based morphometry was automatically performed and used essentially to confirm voxel-based morphometry findings. The localization of the focal discharges on the electroencephalogram was compared to the neuroimaging results. Twenty-two patients with idiopathic generalized epilepsies were evaluated. Gray matter abnormalities were detected by voxel-based morphometry analysis in 77% of the patients. There was a good concordance between EEG source detection and voxel-based morphometry. On average, the nearest voxels detected by these methods were 19 mm (mm) apart and the most statistically significant voxels were 34 mm apart. This study suggests that in some cases subtle gray matter abnormalities are associated with focal epileptiform discharges observed in the electroencephalograms of patients with idiopathic generalized epilepsies.

MRI and EEG as long-term seizure outcome predictors in familial mesial temporal lobe epilepsy.

OBJECTIVE: To evaluate the natural history and outcome predictors in familial mesial temporal lobe epilepsy (FMTLE). METHODS: We conducted a longitudinal study of 103 individuals from 17 FMTLE families (mean follow-up: 7.6 years). We divided subjects into 3 groups: FMTLE (n = 53), unclassified seizure (n = 18), and asymptomatics (n = 32). We divided FMTLE patients into 3 subgroups: seizure-free (n = 19), infrequent (n = 17) seizures, and frequent (n = 17) seizures and further reclassified them into favorable and poor outcome. We defined hippocampal atrophy (HA) by visual MRI analysis and performed volumetry in those who had 2 MRIs. RESULTS: FMTLE patients with infrequent seizures evolved to either frequent seizures (17.6%) or seizure freedom (23.5%). In the seizure-free group, most remained seizure-free and 21% developed infrequent seizures. All patients with frequent seizures remained in the same status or underwent surgery. Twelve percent of the asymptomatics and 22% of the unclassified-seizure group evolved to FMTLE with infrequent seizures. Predictive factors of poor outcome were presence of HA (p = 0.0192) and interictal epileptiform discharges (p = 0.0174). The relationship between initial precipitating incidents and clinical outcome was not significant although a tendency was observed (p = 0.055). Use of antiepileptic drugs and secondary generalized seizures during the patient's lifetime did not predict poor outcome. We observed progression of HA only in the group with frequent seizures. CONCLUSION: Most patients with FMTLE continued in the same clinical status. However, patients with frequent seizures had progression of HA and none improved except those who underwent surgery. Interictal epileptiform discharges and HA predicted poorer outcome in FMTLE, and there was a tendency in favor of initial precipitating incidents as outcome predictors.

Long term follow up of familial mesial temporal lobe epilepsy / Evolução da epilepsia de lobo temporal mesial familiar

OBJECTIVE: To analyze seizure outcome in individuals with familial mesial temporal lobe epilepsy (FMTLE). METHOD: We followed prospectively 64 individuals with FMTLE and 37 asymptomatic individuals belonging to 28 families. RESULTS: Patients with FMTLE had a mean follow up was 93.4 ± 15.8 months. At baseline they were divided in benign (n = 29), remission (n = 28) and refractory (n = 7). At last follow up visit 41.4 percent patients with benign FMTLE remained classified as benign, 20.7 percent became refractory and 37.9 percent were in remission. In the subgroup of FMTLE in remission 21 75 percent remained without seizures; 21.4 percent were classified as benign FMTLE, and one died (3.6 percent) from cause unrelated to epilepsy. All refractory patients remained refractory. From the asymptomatic group, 10.8 percent became symptomatic (FMTLE). The mean follow up was 76.0 ± 21.2 months. CONCLUSION: Prospective follow up of more than 7 years in patients with FMTLE revealed that it is unlikely to achieve seizure control in those with refractory seizures. Patients with diagnose of more benign forms of FMTLE for more than one year are likely to either remit or remain under well controlled seizures. The majority of patients who had achieved seizure remission remained seizure-free and none became refractory. Asymptomatic individuals had a greater probability to have seizures compared to the general population in a 6 year period of follow up.

OBJETIVOS: Analisar a evolução de famílias com epilepsia de lobo temporal mesial familiar (ELTMF). METODOLOGIA: Seguimento prospectivo de 64 pacientes com ELTMF e 37 membros assintomáticos pertencente a 28 famílias. RESULTADOS: A média de seguimento dos pacientes com ELTMF foi de 93,4 ± 15,8 meses. Na avaliação inicial os pacientes foram divididos em benignos (n = 29), remissão (n = 28) e refratários (n = 7). Na última visita disponível, 41,4 por cento dos pacientes com ELTMF benigna permaneceram classificados como benignos, 20,7 por cento tornaram-se refratários e 37,9 por cento entraram em remissão. No grupo em remissão, 75 por cento permaneceram livres de crise, 21,4 por cento foram classificados como benignos e um faleceu (3,6 por cento) de causa não relacionada à epilepsia. Todos pacientes refratários permaneceram refratários. Em relação aos assintomáticos 10,8 por cento evoluíram com crises. A média de seguimento dos assintomáticos foi de 76,0 ± 21,2 meses. CONCLUSÃO: O seguimento prospectivo de mais de 7 anos de pacientes com ELTMF revelou que é improvável ocorrer controle de crises no grupo refratário. No grupo benigno é muito provável que estes indivíduos entrem em remissão ou permaneçam com evolução benigna. A maioria dos pacientes do grupo em remissão permaneceu em remissão e nenhum se tornou refratário. Em relação aos assintomáticos a probabilidade de apresentar uma crise no decorrer de aproximadamente 6 anos foi maior que o observado na população geral.