Adjustment in children with intractable epilepsy:importance of seizure duration and family factors

Seventy-five families of children with intractable epilepsy but without a severe learning disability (mean age 7 years 1 month, SD 2 years 6 months; range 2 to 12 years) who attended a regional paediatric neurology service, were surveyed. A postal questionnaire was used which included standardized measures of child and family adjustment; forty-eight families responded (64%; 31 males, 17 females). There was no significant difference between responders and non-responders in terms of age, sex, number of other chronic illnesses and disabilities, age at epilepsy diagnosis, seizure type, nor number of antiepileptic drugs currently prescribed (p > 0.05). The importance of including multidimensional measures of outcome was highlighted by the finding that epilepsy, pharmacological, and psychosocial factors were differentially associated with specific adjustment difficulties. Two factors appeared to be most pervasively implicated across a range of adjustment problems: frequency of rectal diazepam administration and family patterns of relating to each other (p <0.05). It appeared that duration of seizures (as indicated by frequency of rectal diazepam administration), rather than the frequency of seizures per se, was more pernicious in terms of poor adjustment. Intrafamilial relations (degree of conflict/cohesion and soon) were not only associated with adjustment difficulties in the child, but also with the frequency of seizures themselves. Implications for psychological interventions in intractable epilepsy in childhood are highlighted.

Memory in children with temporal lobe epilepsy is at least partially explained by executive dysfunction

An association between memory and executive dysfunction (ED) has been demonstrated in patients with mixed neurological disorders. We aimed to investigate the impact of ED in memory tasks of children with temporal lobe epilepsy (TLE). We evaluated 36 children with TLE and 28 controls with tests for memory, learning, attention, mental flexibility, and mental tracking. Data analysis was composed of comparison between patients and controls in memory and executive function; correlation between memory and executive function tests; and comparison between patients with mild and severe ED in memory tests. Children with TLE had worse performance in focused attention, immediate and delayed recall, phonological memory, mental tracking, planning, and abstraction. Planning, abstraction, and mental tracking were correlated with visual and verbal memory. Children with severe ED had worse performance in verbal and visual memory and learning tests. This study showed that ED was related to memory performance in children with TLE. (C) 2012 Elsevier Inc. All rights reserved.

Epileptologists probe vagus nerve stimulation in children with refractory epilepsy: a promise against sudden unexpected death in epilepsy

It is clear that sudden unexpected death in epilepsy (SUDEP) is mainly a problem for people with refractory epilepsy, but our understanding of the best way to its prevention is still incomplete. Although the pharmacological treatments available for epilepsies have expanded, some antiepileptic drugs are still limited in clinical efficacy. In the present paper, we described an experience with vagus nerve stimulation (VNS) treatment by opening space and providing the opportunity to implement effective preventative maps to reduce the incidence of SUDEP in children and adolescents with refractory epilepsy.

Language lateralization correlates with verbal memory performance in children with focal epilepsy

PURPOSE: Assessment of language dominance with functional magnetic resonance imaging (fMRI) and neuropsychological evaluation is often used prior to epilepsy surgery. This study explores whether language lateralization and cognitive performance are systematically related in young patients with focal epilepsy. METHODS: Language fMRI and neuropsychological data (language, visuospatial functions, and memory) of 40 patients (7-18 years of age) with unilateral, refractory focal epilepsy in temporal and/or frontal areas of the left (n = 23) or right hemisphere (n = 17) were analyzed. fMRI data of 18 healthy controls (7-18 years) served as a normative sample. A laterality index was computed to determine the lateralization of activation in three regions of interest (frontal, parietal, and temporal). RESULTS: Atypical language lateralization was demonstrated in 12 (30%) of 40 patients. A correlation between language lateralization and verbal memory performance occurred in patients with left-sided epilepsy over all three regions of interest, with bilateral or right-sided language lateralization being correlated with better verbal memory performance (Word Pairs Recall: frontal r = -0.4, p = 0.016; parietal r = -0.4, p = 0.043; temporal r = -0.4, p = 0.041). Verbal memory performance made the largest contribution to language lateralization, whereas handedness and side of seizures did not contribute to the variance in language lateralization. DISCUSSION: This finding reflects the association between neocortical language and hippocampal memory regions in patients with left-sided epilepsy. Atypical language lateralization is advantageous for verbal memory performance, presumably a result of transfer of verbal memory function. In children with focal epilepsy, verbal memory performance provides a better idea of language lateralization than handedness and side of epilepsy and lesion.

Duplication of the sodium channel gene cluster on 2q24 in children with early onset epilepsy

Sodium channel gene aberrations are associated with a wide range of seizure disorders, particularly Dravet syndrome. They usually consist of missense or truncating gene mutations or deletions. Duplications involving multiple genes encoding for different sodium channels are not widely known. This article summarizes the clinical, radiologic, and genetic features of patients with 2q24 duplication involving the sodium channel gene cluster.

Cognitive impairment and cortical reorganization in children with benign epilepsy with centrotemporal spikes

Benign epilepsy with centrotemporal spikes (BECTS) is associated with mild cognitive deficits, especially language impairment. This study aimed to clarify whether children with BECTS with left- or right-hemispheric, or bilateral focus have specific neuropsychological language deficits when compared to healthy controls, whether these deficits correlate functionally with language network organization (typical vs. atypical), and whether cofactors such as duration, handedness, and medication have a relevant impact on language reorganization processes.

Verbal emotional memory in children and adolescents with temporal lobe epilepsy: A first study

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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. © 2013 International League Against Epilepsy.
Key Words: Adherence, Epilepsy, Dried blood spots, MARS, Depressed mood.

LGI2 truncation causes a remitting focal epilepsy in dogs

One quadrillion synapses are laid in the first two years of postnatal construction of the human brain, which are then pruned until age 10 to 500 trillion synapses composing the final network. Genetic epilepsies are the most common neurological diseases with onset during pruning, affecting 0.5% of 2-10-year-old children, and these epilepsies are often characterized by spontaneous remission. We previously described a remitting epilepsy in the Lagotto romagnolo canine breed. Here, we identify the gene defect and affected neurochemical pathway. We reconstructed a large Lagotto pedigree of around 34 affected animals. Using genome-wide association in 11 discordant sib-pairs from this pedigree, we mapped the disease locus to a 1.7 Mb region of homozygosity in chromosome 3 where we identified a protein-truncating mutation in the Lgi2 gene, a homologue of the human epilepsy gene LGI1. We show that LGI2, like LGI1, is neuronally secreted and acts on metalloproteinase-lacking members of the ADAM family of neuronal receptors, which function in synapse remodeling, and that LGI2 truncation, like LGI1 truncations, prevents secretion and ADAM interaction. The resulting epilepsy onsets at around seven weeks (equivalent to human two years), and remits by four months (human eight years), versus onset after age eight in the majority of human patients with LGI1 mutations. Finally, we show that Lgi2 is expressed highly in the immediate post-natal period until halfway through pruning, unlike Lgi1, which is expressed in the latter part of pruning and beyond. LGI2 acts at least in part through the same ADAM receptors as LGI1, but earlier, ensuring electrical stability (absence of epilepsy) during pruning years, preceding this same function performed by LGI1 in later years. LGI2 should be considered a candidate gene for common remitting childhood epilepsies, and LGI2-to-LGI1 transition for mechanisms of childhood epilepsy remission.

Familial component of epilepsy in cleft lip and palate

It is well recognized that offspring of women with epilepsy who are taking anticonvulsant medications have an increased incidence of clefting abnormalities. This increase has been attributed to the teratogenic effects of anticonvulsant medications but an alternative explanation involving a genetic association of epilepsy and clefting has also been proposed. Five family studies attempting to resolve this controversy have been inconclusive either because of study design or analytic limitations. This family study was designed to determine whether epilepsy aggregates in families ascertained by an individual with a clefting disorder. The Mayo Clinic medical linkage registry was used to identify individuals with cleft lip with or without cleft palate and cleft palate in southeast Minnesota from 1935-1986. Only those cases who were 15 years or younger during this period were included in the study. The proband's parents and descendants of their parents, including the proband's sibs, children, grandchildren, niece/nephews, grandnieces/nephews, halfsibs and spouses were also identified and all of their medical records were reviewed for seizure disorders. The standardized morbidity ratios for epilepsy of 0.9 (95% CI 0.2-2.6) observed for first degree relatives (excluding parents) and 0.0 for second degree relatives were not increased. The SMRs ranged from 0.7-2.2 for the individual relative types (parents 1.5, sibs 0.7, children 2.2, probands 1.1, spouses 2.0) and were also not increased. These results do not support the suggestions of some that clefting and epilepsy aggregate together in families. ^

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.

Prenatal environmental exposure and neurodevelopmentally important gene expression in malformed brain tissue from pediatric intractable epilepsy patients

The primary objective of this proposal was to determine whether mitochondrial oxidative stress and variation in a particular mtDNA lineage contribute to the risk of developing cortical dysplasia and are potential contributing factors in epileptogenesis in children. The occurrence of epilepsy in children is highly associated with malformations of cortical development (MCD). It appears that MCD might arise from developmental errors due to environmental exposures in combination with inherited variation in response to environmental exposures and mitochondrial function. Therefore, it is postulated that variation in a particular mtDNA lineage of children contributes to the effects of mitochondrial DNA damage on MCD phenotype. Quantitative PCR and dot blot were used to examine mitochondrial oxidative damage and single nucleotide polymorphism (SNP) in the mitochondrial genome in brain tissue from 48 pediatric intractable epilepsy patients from Miami Children’s Hospital and 11 control samples from NICHD Brain and Tissue Bank for Developmental Disorders. Epilepsy patients showed higher mtDNA copy number compared to normal health subjects (controls). Oxidative mtDNA damage was lower in non-neoplastic but higher in neoplastic epilepsy patients compared to controls. There was a trend of lower mtDNA oxidative damage in the non-neoplastic (MCD) patients compared to controls, yet, the reverse was observed in neoplastic (MCD and Non-MCD) epilepsy patients. The presence of mtDNA SNP and haplogroups did not show any statistically significant relationships with epilepsy phenotypes. However, SNPs G9804A and G9952A were found in higher frequencies in epilepsy samples. Logistic regression analysis showed no relationship between mtDNA oxidative stress, mtDNA copy number, mitochondrial haplogroups and SNP variations with epilepsy in pediatric patients. The levels of mtDNA copy number and oxidative mtDNA damage and the SNPs G9952A and T10010C predicted neoplastic epilepsy, however, this was not significant due to a small sample size of pediatric subjects. Findings of this study indicate that an increase in mtDNA content may be compensatory mechanisms for defective mitochondria in intractable epilepsy and brain tumor. Further validation of these findings related to mitochondrial genotypes and mitochondrial dysfunction in pediatric epilepsy and MCD may lay the ground for the development of new therapies and prevention strategies during embryogenesis.