Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities

Purpose: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotype-genotype correlations with SCN1A alterations. Methods: We included patients with SMEI including borderline SMEI (SMEB), GEFS+, febrile seizures (FS), or other seizure types precipitated by fever. We performed a clinical and genetic study focusing on SCN1A, using dHPLC, gene sequencing, and MLPA to detect genomic deletions/duplications on SMEI/SMEB patients. Results: We classified patients as: SMEI/SMEB = 55; GEFS+ = 26; and other phenotypes = 51. SCN1A analysis by dHPLC/sequencing revealed 40 mutations in 37 SMEI/SMEB (67%) and 3 GEFS+ (11.5%) probands. MLPA showed genomic deletions in 2 of 18 SMEI/SMEB. Most mutations were de novo (82%). SMEB patients carrying mutations (8) were more likely to have missense mutations (62.5%), conversely SMEI patients (31) had more truncating, splice site or genomic alterations (64.5%). SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS compared to those with missense mutations and without mutations (p = 0.00007, ANOVA test). None of the remaining patients with seizures precipitated by fever carried SCN1A mutations. Conclusion: We obtained a frequency of 71% SCN1A abnormalities in SMEI/SMEB and of 11.5% in GEFS+ probands. MLPA complements DNA sequencing of SCN1A increasing the mutation detection rate. SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS. This study confirms the high sensitivity of SCN1A for SMEI/SMEB phenotypes. © 2007 International League Against Epilepsy.

Interictal autonomic abnormalities in idiopathic Rolandic Epilepsy

We investigated 50 young patients with a diagnosis of Rolandic Epilepsy (RE) for the presence of abnormalities in autonomic tone compared with 50 young patients with idiopathic generalized epilepsy with absences and 50 typically developing children of comparable age. We analyzed time domain (N-N interval, pNN50) and frequency domain (High Frequency (HF), Low Frequency (LF) and LF/HF ratio) indices from ten-minute resting EKG activity. Patients with RE showed significantly higher HF and lower LF power and lower LF/HF ratio than controls, independent of the epilepsy group, and did not show significant differences in any other autonomic index with respect to the two control groups. In RE, we found a negative relationship between both seizure load and frequency of sleep interictal EEG abnormalities with parasympathetic drive levels. These changes might be the expression of adaptive mechanisms to prevent the excessive sympathetic drive seen in patients with refractory epilepsies. © 2012 Elsevier Inc.

Astrocytic GABA transporter GAT-1 dysfunction in experimental absence seizures

An enhanced tonic GABA-A inhibition in the thalamus plays a crucial role in experimental absence seizures, and has been attributed, on the basis of indirect evidence, to a dysfunction of the astrocytic GABA transporter-1 (GAT-1). Here, the GABA transporter current was directly investigated in thalamic astrocytes from a well-established genetic model of absence seizures, the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), and its non-epileptic control (NEC) strain. We also characterized the novel form of GABAergic and glutamatergic astrocyte-to-neuron signalling by recording slow outward currents (SOCs) and slow inward currents (SICs), respectively, in thalamocortical (TC) neurons of both strains. In patch-clamped astrocytes, the GABA transporter current was abolished by combined application of the selective GAT-1 and GAT-3 blocker, NO711 (30µM) and SNAP5114 (60µM), respectively, to GAERS and NEC thalamic slices. NO711 alone significantly reduced (41%) the transporter current in NEC, but had no effect in GAERS. SNAP5114 alone reduced by half the GABA transporter current in NEC, whilst it abolished it in GAERS. SIC properties did not differ between GAERS and NEC TC neurons, whilst moderate changes in SOC amplitude and kinetics were observed. These data provide the first direct demonstration of a malfunction of the astrocytic thalamic GAT-1 transporter in absence epilepsy and support an abnormal astrocytic modulation of thalamic ambient GABA levels. Moreover, while the glutamatergic astrocyte-neuron signalling is unaltered in the GAERS thalamus, the changes in some properties of the GABAergic astrocyte-neuron signaling in this epileptic strain may contribute to the generation of absence seizures.

Adherence to antiepileptic medicines in children:a multiple-methods assessment involving dried blood spot sampling

Purpose - To evaluate adherence to prescribed antiepileptic drugs (AEDs) in children with epilepsy using a combination of adherence-assessment methods. Methods - A total of 100 children with epilepsy (≤17 years old) were recruited. Medication adherence was determined via parental and child self-reporting (≥9 years old), medication refill data from general practitioner (GP) prescribing records, and via AED concentrations in dried blood spot (DBS) samples obtained from children at the clinic and via self- or parental-led sampling in children's own homes. The latter were assessed using population pharmacokinetic modeling. Patients were deemed nonadherent if any of these measures were indicative of nonadherence with the prescribed treatment. In addition, beliefs about medicines, parental confidence in seizure management, and the presence of depressed mood in parents were evaluated to examine their association with nonadherence in the participating children. Key Findings - The overall rate of nonadherence in children with epilepsy was 33%. Logistic regression analysis indicated that children with generalized epilepsy (vs. focal epilepsy) were more likely (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.37–15.81) to be classified as nonadherent as were children whose parents have depressed mood (OR 3.6, 95% CI 1.16–11.41). Significance - This is the first study to apply the novel methodology of determining adherence via AED concentrations in clinic and home DBS samples. The present findings show that the latter, with further development, could be a useful approach to adherence assessment when combined with other measures including parent and child self-reporting. Seizure type and parental depressed mood were strongly predictive of nonadherence.

Modelling the dynamics of genetic algorithms using statistical mechanics

A formalism for modelling the dynamics of Genetic Algorithms (GAs) using methods from statistical mechanics, originally due to Prugel-Bennett and Shapiro, is reviewed, generalized and improved upon. This formalism can be used to predict the averaged trajectory of macroscopic statistics describing the GA's population. These macroscopics are chosen to average well between runs, so that fluctuations from mean behaviour can often be neglected. Where necessary, non-trivial terms are determined by assuming maximum entropy with constraints on known macroscopics. Problems of realistic size are described in compact form and finite population effects are included, often proving to be of fundamental importance. The macroscopics used here are cumulants of an appropriate quantity within the population and the mean correlation (Hamming distance) within the population. Including the correlation as an explicit macroscopic provides a significant improvement over the original formulation. The formalism is applied to a number of simple optimization problems in order to determine its predictive power and to gain insight into GA dynamics. Problems which are most amenable to analysis come from the class where alleles within the genotype contribute additively to the phenotype. This class can be treated with some generality, including problems with inhomogeneous contributions from each site, non-linear or noisy fitness measures, simple diploid representations and temporally varying fitness. The results can also be applied to a simple learning problem, generalization in a binary perceptron, and a limit is identified for which the optimal training batch size can be determined for this problem. The theory is compared to averaged results from a real GA in each case, showing excellent agreement if the maximum entropy principle holds. Some situations where this approximation brakes down are identified. In order to fully test the formalism, an attempt is made on the strong sc np-hard problem of storing random patterns in a binary perceptron. Here, the relationship between the genotype and phenotype (training error) is strongly non-linear. Mutation is modelled under the assumption that perceptron configurations are typical of perceptrons with a given training error. Unfortunately, this assumption does not provide a good approximation in general. It is conjectured that perceptron configurations would have to be constrained by other statistics in order to accurately model mutation for this problem. Issues arising from this study are discussed in conclusion and some possible areas of further research are outlined.

Abnormal visual habituation in pediatric photosensitive epilepsy

Objective - To investigate visual habituation – a measure of visual cortical excitability – in photosensitive patients in pediatric age and compare the findings with a matched sample with idiopathic generalized epilepsies without photosensitivity and with normally developing children. Methods - We presented a full-field black-and-white checkerboard pattern, at 3 reversal/s with 100% contrast binocularly for 600 consecutive trials and measured the N75–P100 and P100–N145 pattern-reversal visual evoked potential inter-peak amplitudes and N75, P100, N145 latencies for the six blocks of 100 responses. As a measure of habituation we used the slope of the linear regression line of the N75–P100 and P100–N145 peak-to-peak amplitudes. The slope of the linear regression line of the N75–P100 and P100–N145 latencies was also analyzed. Results - Statistical analysis revealed significant differences between the three groups in the slope index of N75–P100 PR-VEP amplitude, with increased or constant amplitude in the PS group compare to the IGE and ND across the six blocks. Conclusions - Our results support the notion that photosensitivity is associated with altered control of excitatory and inhibitory cortical processes. The causal relationship between habituation deficit and photo-paroxysmal response needs to be further investigated with longitudinal studies. Significance This study supports the hypothesis that suppression of PR-VEP is a sensitive intermediate phenotype, which discriminates patients with photosensitivity from those with generalized epilepsies in pediatric age.

Clinical characteristics of patients with epilepsy in a specialist neuropsychiatry service

Neuropsychiatry services provide specialist input into the assessment and management of behavioral symptoms associated with a range of neurological conditions, including epilepsy. Despite the centrality of epilepsy to neuropsychiatry and the recent expansion of neuropsychiatry service provision, little is known about the clinical characteristics of patients with epilepsy who are routinely seen by a specialist neuropsychiatry service. This retrospective study filled this gap by retrospectively evaluating a naturalistic series of 60 consecutive patients with epilepsy referred to and assessed within a neuropsychiatry setting. Fifty-two patients (86.7%) had active epilepsy and were under the ongoing care of the referring neurologist for seizure management. The majority of patients (N = 42; 70.0%) had a diagnosis of localization-related epilepsy, with temporal lobe epilepsy as the most common epilepsy type (N = 37; 61.7%). Following clinical assessment, 39 patients (65.0%) fulfilled formal diagnostic criteria for at least one psychiatric disorder; nonepileptic attack disorder (N = 37; 61.7%), major depression (N = 23; 38.3%), and generalized anxiety disorder (N = 16; 26.7%) were the most commonly diagnosed comorbidities. The clinical characteristics of patients seen in specialist neuropsychiatry settings are in line with the results from previous studies in neurology clinics in terms of both epilepsy and psychiatric comorbidity. Our findings confirm the need for the development and implementation of structured care pathways for the neuropsychiatric aspects of epilepsy, with focus on comorbid nonepileptic attacks and affective and anxiety symptoms. This is of particular importance in consideration of the impact of behavioral symptoms on patients' health-related quality of life.