No abstract

Generalized absence seizures are neurophysiologically, pharmacologically, and developmentally unique and comprise the primary seizure type in a number of different absence epilepsy syndromes. Over the last 10 years, the availability of a number of animal models of generalized absence seizures and of sophisticated in vitro electrophysiological techniques that allow investigation of cortical and thalamic networks has begun to shed light on the pathogenesis of this disorder. The basic underlying mechanism appears to involve thalamocortical circuitry and the generation of abnormal oscillatory rhythms from that particular neuronal network. Biochemical mechanisms operative within thalamocortical circuitry during this neuronal oscillation seem to entail phase-locked gamma-aminobutyric acid (GABA)B-mediated inhibition alternating with glutamate-mediated excitation. The basic cellular mechanism operative within this tension between excitation and inhibition appears to involve the T-type calcium current. Local circuitry within the thalamus may influence these oscillatory rhythms by GABAA-mediated inhibition. Pharmacological factors at play external to thalamocortical circuitry include cholinergic, dopaminergic, and noradrenergic mechanisms. Pathways that utilize these various neurotransmitters project onto the thalamus and/or cortex from sites distant to those structures and may modulate the process either up or down. Perturbation of one or more of these neuronal networks may lead to abnormal neuronal oscillatory rhythms within thalamocortical circuitry, with a resultant generation of bilaterally synchronous spike wave discharges that characterize generalized absence seizures. Our increasing understanding of the basic mechanisms that underlie generalized absence seizures promises to allow, for the first time, a rational design of drug treatment for a seizure disorder based on the pathogenesis of that disorder.

The neuroanatomical substrate of seizures induced by picomolar amounts of corticotropinreleasing hormone in infant rats was investigated. Electrographic and behavioral phenomena were monitored in 42 rat pups aged 5 to 22 days. Rat pups carried bipolar electrodes implanted in subcortical limbic structures, as well as cortical electrodes and intracerebroventricular cannulae. The administration of corticotropin-releasing hormone produced age-specific seizures within minutes, which correlated with rhythmic amygdala discharges. Paroxysmal hippocampal and cortical discharges developed subsequently in some rats. Corticotropin-releasing hormone-induced electrographic and behavioral seizures originate in the amygdala.Corticotropin-releasing hormone (CRH) is a 41-amino acid neuropeptide, isolated originally from the mammalian hypothalamus [1], It has since been shown to be distributed nonrandomly in the central nervous system, and to perform roles other than the control of secretion of ACTH and endorphins from the anterior pituitary [2]. Specifically, central transduction of stress, anxiety, depression, and anorexia have been demonstrated [2,3].CRH activates neurons both in vivo and in vitro [4][5][6][7][8][9]. The peptide increases both spontaneous and evoked spike discharge from locus ceruleus neurons in vivo [4], CRH induces neuronal depolarization in CA1 and CA3 hippocampal pyramidal cells in the slice preparation in vitro [5]. CRH administered into the cerebral ventricles of adult rats causes epileptiform discharges in the amygdala after a 1-to 3-hour delay, which spread to the dorsal hippocampus [6]. These discharges progress over 3 to 7 hours to behavioral and electrographic seizures. The doses needed for frank seizure generation in adult rats axe 1-5 to 3-75 × 10 −9 mol (0.75-1.88 × 10 −9 mol/gm of brain weight) [6][7][8].We have previously shown that CRH is a far more rapid and potent convulsant in the neonatal rat [10]. Seizures occur with a latency of as little as 2 minutes and with CRH doses as low as 7.5 × 10 −12 mo! or 0.05 × 10 −9 mol/gm of brain weight [10]. The present study was designed to define the neurobiological matrix of the behavioral and electrographic effects of the neuropeptide. We used infant rats, starting on postnatal day 5. Materials and Methods AnimalsTimed-pregnancy Sprague-Dawley-derived rats were obtained from Zivic-Miller (Zelionplc, PA). They were housed under a 12-hour light/dark cycle and fed ad libitum. Copyright © 1992 Delivery times were monitored and were accurate to within 12 hours. The day of birth was considered day zero. The pups were kept with the mothers, and litters were culled to 12 pups. Infant rats were subjected to surgery 24 hours before recording and returned to their mothers. CRH was always administered between 9 and 10:30 AM, to minimize diurnal variations in seizure susceptibility [11] and in endogenous CRH levels [12]. Surgical ProcedureElectrodes were implanted under halothane anesthesia, using an infant rat stereotaxic apparatus as previously describe...

This case series represents the largest series of sudden unexplained death in children with epilepsy. At least two previously described risk factors for SUDEP in adults, low serum AED levels at time of death and AED polytherapy, do not appear to be significant in children.

We conducted a retrospective single-blind study assessing the value of MRI in 44 children surgically treated for partial epilepsy, and correlated the MRI findings with the pathology in all cases. MRI revealed abnormalities in concordance with the clinical and electroencephalographic data in 84% of patients. Developmental neuronal migration pathology was present in 25% of patients and was relatively more common in the sensorimotor cortex. There was hippocampal sclerosis in 50% of patients with temporal lobe resection; however, only two of the 10 children with hippocampal sclerosis were below the age of 12 years. Similarly, ganglio-glial tumors were more common than astrocytomas in children below age 12. These results indicate that MRI is sensitive in the detection of pathologic abnormalities in most pediatric candidates for epilepsy surgery, and that the distribution and type of pathology appear to be age related in this population.

Summary:It is well documented that children with autistic spectrum disorder (ASD) have an increased prevalence of seizures; however, studies have not been done to evaluate the prevalence of ASD in children with epilepsy. This comorbidity is important to define as early diagnosis and intervention in some children with ASD has been shown to improve outcome.Method: Children with epilepsy seen in a tertiary care epilepsy clinic were evaluated using validated autism screening questionnaires (ASQ). In addition, questions about sleep-related disorders, behavior, seizure characteristics, antiepileptic agents, and body mass index (BMI) were requested. An attempt was then made to determine if there was a correlation between the factors identified and ASD.Results: Of the 107 questionnaires returned, 97 ASQ's were properly completed and used in this study. Approximately 32% of children fit the ASQ criteria for having ASD. Most children had not been previously diagnosed. Worst behavior and daytime sleepiness was seen in those at greater risk (p < 0.01). Seizures also occurred earlier (approximately 2 years) in children at risk of having ASD.Conclusion: Though confirmatory diagnostic evaluations are needed, this questionnaire-based study suggests that children with epilepsy are at greater risk of having ASD, and illustrates the need for more clinical vigilance. Behavioral difficulties and daytime sleepiness identified in these children could potentially affect their ability to learn. It is of interest that the age of seizure onset identified in those at greater risk corresponds with the approximate age of regression identified in some children with ASD.

␥-Hydroxybutyric acid (GHB) is a naturally occurring metabolite of GABA that has been postulated to exert ubiquitous neuropharmacological effects through GABA B receptor (GABA B R)-mediated mechanisms. The alternative hypothesis that GHB acts via a GHB-specific, G protein-coupled presynaptic receptor that is different from the GABA B R was tested. The effect of GHB on regional and subcellular brain adenylyl cyclase in adult and developing rats was determined and compared with that of the GABA B R agonist (Ϫ)-baclofen. Also, using guanosine 5Ј-O-(3-[ 35 S]thiotriphosphate) ([ 35 S]GTP␥S) binding and low-K m GTPase activity as markers the effects of GHB and (Ϫ)-baclofen on G protein activity in the brain were determined. Neither GHB nor baclofen had an effect on basal cyclic AMP (cAMP) levels. GHB significantly decreased forskolin-stimulated cAMP levels by 40 -50% in cortex and hippocampus but not thalamus or cerebellum, whereas (Ϫ)-baclofen had an effect throughout the brain. The effect of GHB on adenylyl cyclase was observed in presynaptic and not postsynaptic subcellular tissue preparations, but the effect of baclofen was observed in both subcellular preparations. The GHB-induced alteration in forskolin-induced cAMP formation was blocked by a specific GHB antagonist but not a specific GABA B R antagonist. The (Ϫ)-baclofen-induced alteration in forskolin-induced cAMP formation was blocked by a specific GABA B R antagonist but not a specific GHB antagonist. The negative coupling of GHB to adenylyl cyclase appeared at postnatal day 21, a developmental time point that is concordant with the developmental appearance of [ 3 H]GHB binding in cerebral cortex, but the effects of (Ϫ)-baclofen were present by postnatal day 14. GHB and baclofen both stimulated [ 35 S]GTP␥S binding and low-K m GTPase activity by 40 -50%. The GHB-induced effect was blocked by GHB antagonists but not by GABA B R antagonists and was seen only in cortex and hippocampus. The (Ϫ)-baclofen-induced effect was blocked by GABA B R antagonists but not by GHB antagonists and was observed throughout the brain. These data support the hypothesis that GHB induces a G protein-mediated decrease in adenylyl cyclase via a GHB-specific G protein-coupled presynaptic receptor that is different from the GABA B R.

Summary:Purpose: To identify the predictors of postsurgical seizure freedom in children with refractory epilepsy and normal or nonfocal MRI findings.Methods: We analyzed 22 children with normal or subtle and nonfocal MRI findings, who underwent surgery for intractable epilepsy following extraoperative intracranial EEG. We compared clinical profiles, neurophysiological data (scalp EEG, magnetoencephalography (MEG) and intracranial EEG), completeness of surgical resection and pathology to postoperative seizure outcomes.Results: Seventeen children (77%) had a good postsurgical outcome (defined as Engel class IIIA or better), which included eight (36%) seizure-free children. All children with postsurgical seizure freedom had an MEG cluster in the final resection area. Postsurgical seizure freedom was obtained in none of the children who had bilateral MEG dipole clusters (3) or only scattered dipoles (1). All five children in whom ictal onset zones were confined to ≤5 adjacent intracranial electrodes achieved seizure freedom compared to three of 17 children with ictal onset zones that extended over >5 electrodes (p = 0.002). None of six children with more than one type of seizure became seizurefree, compared to eight of 16 children with a single seizure type (p = 0.04). Complete resection of the preoperatively localized epileptogenic zone resulted in seizure remission in 63% (5/8) and incomplete resections, in 21% (3/14) (p = 0.06). Age of onset, duration of epilepsy, number of lobes involved in resection, and pathology failed to correlate with seizure freedom.Conclusions: Surgery for intractable epilepsy in children with normal MRI findings provided good postsurgical outcomes in the majority of our patients. As well, restricted ictal onset zone predicted postoperative seizure freedom. Postoperative seizure freedom was less likely to occur in children with bilateral MEG dipole clusters or only scattered dipoles, multiple seizure types and incomplete resection of the proposed epileptogenic zone. Seizure freedom was most likely to occur when there was concordance between EEG and MEG localization and least likely to occur when these results were divergent.