Quantitative Evaluation of Medial Temporal Lobe Morphology in Children with Febrile Status Epilepticus: Results of the FEBSTAT Study.

BACKGROUND AND PURPOSE: The pathogenesis of febrile status epilepticus is poorly understood, but prior studies have suggested an association with temporal lobe abnormalities, including hippocampal malrotation. We used a quantitative morphometric method to assess the association between temporal lobe morphology and febrile status epilepticus. MATERIALS AND METHODS: Brain MR imaging was performed in children presenting with febrile status epilepticus and control subjects as part of the Consequences of Prolonged Febrile Seizures in Childhood study. Medial temporal lobe morphologic parameters were measured manually, including the distance of the hippocampus from the midline, hippocampal height:width ratio, hippocampal angle, collateral sulcus angle, and width of the temporal horn. RESULTS: Temporal lobe morphologic parameters were correlated with the presence of visual hippocampal malrotation; the strongest association was with left temporal horn width (P < .001; adjusted OR, 10.59). Multiple morphologic parameters correlated with febrile status epilepticus, encompassing both the right and left sides. This association was statistically strongest in the right temporal lobe, whereas hippocampal malrotation was almost exclusively left-sided in this cohort. The association between temporal lobe measurements and febrile status epilepticus persisted when the analysis was restricted to cases with visually normal imaging findings without hippocampal malrotation or other visually apparent abnormalities. CONCLUSIONS: Several component morphologic features of hippocampal malrotation are independently associated with febrile status epilepticus, even when complete hippocampal malrotation is absent. Unexpectedly, this association predominantly involves the right temporal lobe. These findings suggest that a spectrum of bilateral temporal lobe anomalies are associated with febrile status epilepticus in children. Hippocampal malrotation may represent a visually apparent subset of this spectrum.

Age- and sex-related characteristics of tonic GABA currents in the rat substantia nigra pars reticulata.

Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4ß3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age- and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved.

The role of EEG in febrile status epilepticus (FSE).

Febrile status epilepticus is an important neurological emergency and a risk factor for later development of epilepsy. There are guidelines recommending against the use of EEG in the evaluation of simple febrile seizures but the role in febrile status epilepticus is not well established. This article reviews the literature on the role of EEG in the evaluation of the patient with prolonged febrile seizures, summarizes the findings, and concludes with some simple recommendations based upon the existing knowledge. At least 30-40% of EEGs obtained within one week of febrile status epilepticus will contain abnormalities including focal slowing. In some series focal slowing appears to be associated with development of a spike focus in the same location. Prospective series with large numbers of patients and follow-up are required to ascertain whether such abnormalities are associated with later development of epilepsy.

Age- and gender-related differences in GABAA receptor-mediated postsynaptic currents in GABAergic neurons of the substantia nigra reticulata in the rat.

The responsiveness of the rat anterior substantia nigra pars reticulata (SNR) GABAergic neurons to GABA(A)ergic drugs changes with age and gender, altering its role in seizure control. To determine whether maturational and gender-specific differences in the properties of spontaneous GABA(A)Rs-mediated inhibitory postsynaptic currents (sIPSCs) underlie these events, we studied sIPSCs at baseline and after application of the alpha1 GABA(A)Rs subunit selective agonist zolpidem, at postnatal days (PN) 5-9, PN12-15, and PN28-32. Results were correlated with the alpha1 and alpha 3 GABA(A)Rs subunit immunoreactivity (-ir) at PN5, PN15, and PN30, using immunochemistry. The mean frequency, amplitude and charge transfer increased whereas the 10-90% rise time and decay time accelerated with age in both genders. The faster sIPSC kinetics in older rats were paralleled by increased alpha1-ir and decreased alpha 3-ir. At PN5-9, males had more robust sIPSCs (frequency, amplitude, charge carried per event and charge transfer) than females. At PN28-32, males exhibited higher amplitudes and faster kinetics than females. The zolpidem-induced increase of decay times, amplitude and charge transfer and alpha1-ir expression were the lowest in PN5-9 males but increased with age, in both genders. Our findings demonstrate that alterations in GABA(A)Rs subunit expression partially underlie age- and gender-specific sIPSC changes in SNR neurons. However, the observation of gender differences in sIPSC kinetics that cannot be attributed to changes in perisomatic alpha1 expression suggests the existence of additional gender-specific factors that control the sIPSC kinetics in rat SNR.

Phenomenology of prolonged febrile seizures: results of the FEBSTAT study.

BACKGROUND: Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent mesial temporal sclerosis and temporal lobe epilepsy. However, little is known about the semiology of FSE. METHODS: A prospective, multicenter study of the consequences of FSE included children, aged 1 month through 5 years, presenting with a febrile seizure lasting 30 minutes or more. Procedures included neurologic history and examination and an MRI and EEG within 72 hours. All information related to seizure semiology was reviewed by three epileptologists blinded to MRI and EEG results and to subsequent outcome. Inter-rater reliability was assessed by the kappa statistic. RESULTS: Among 119 children, the median age was 1.3 years, the mean peak temperature was 103.2 degrees F, and seizures lasted a median of 68.0 minutes. Seizure duration followed a Weibull distribution with a shape parameter of 1.68. Seizures were continuous in 52% and behaviorally intermittent (without recovery in between) in 48%; most were partial (67%) and almost all (99%) were convulsive. In one third of cases, FSE was unrecognized in the emergency department. Of the 119 children, 86% had normal development, 24% had prior febrile seizures, and family history of febrile seizures in a first-degree relative was present in 25%. CONCLUSIONS: Febrile status epilepticus is usually focal and often not well recognized. It occurs in very young children and is usually the first febrile seizure. Seizures are typically very prolonged and the distribution of seizure durations suggests that the longer a seizure continues, the less likely it is to spontaneously stop.

Epileptogenesis and rational therapeutic strategies.

The understanding of neurobiological mechanisms of epileptogenesis is essential for rational approaches for a possible disease modification as well as treatment of underlying causes of the epilepsies. More effort is necessary to translate results from basic investigations into new approaches for clinical research and to better understand a relationship with findings from clinical studies. The following report is a condensed synapsis in which molecular mechanisms of epileptogenesis, pharmacological modulation of epileptogenesis, evidence based therapy, refractoriness and prediction of outcome is provided in order to stimulate further collaborative international research.

Epileptiform EEG abnormalities in children with language regression.

The authors examined the records of 149 children with language regression (LR) who had overnight EEG monitoring. Children with isolated LR had a higher frequency of epileptiform abnormalities (60%) than those with LR in the context of autistic regression (31%, p = 0.002) and also a higher rate of clinical seizures (33% vs 8%, p < 0.001). EEG abnormalities in the LR only group were also more prominent. This suggests two subtypes of language regression.

[Neurodevelopmental disorders and epilepsy]. / Trastornos del neurodesarrollo y epilepsia.

INTRODUCTION AND DEVELOPMENT: Neurodevelopmental disorders and the epilepsies share common etiologies and pathologies. The severity of impairment and the variety of symptoms associated with neurodevelopmental disorders or with particular epilepsy syndromes reflect focal or global, structural or functional dysfunction of neuronal networks. The complex relationship between neurodevelopmental disorders and epilepsy is secondary to common factors that include genetics, cognition, motor and language function. The epileptic encephalopathies are associated with regression or slowing of cognitive, language or behavior and the accepted working hypothesis is that this is a direct consequence of the seizures or of the interictal epileptiform activity, as opposed to the associated medical condition. The evidence that recurrent seizures or abnormal electrical activity can cause specific cognitive, language or behavioral abnormalities even in accepted epileptic encephalopathies is still controversial. Data from animal studies and the clinical experience from epileptic encephalopathies of early life imply that there are developmental time windows crucial to the type of epilepsy syndrome and to cognitive and behavioral outcome. CONCLUSION: The management of children in whom a neurodevelopmental disorder coexists with epilepsy is a difficult problem that requires a multidisciplinary approach that addresses both the epilepsy and the specific cognitive or behavioral problem and is tailored to the needs of the individual child.

State of training in child neurology 1997-2002.

OBJECTIVE: To track growth of child neurology training programs during the past 7 years and to assess changes in resident demographics, use of different pathways for completion of training, and chosen careers after residency. METHODS: Two surveys were sent: one in June 2000 (response rate = 92% of active programs) and one in May 2001 (response rate = 98%) to the directors of all Accreditation Council for Graduate Medical Education-listed child neurology programs. Fifty-eight programs were consistently active through the survey period. RESULTS: From 1997 through 2002 there was an average of 80 positions per year with a fill rate of 65% and an average of 1.4 positions per program. Fifty-five percent of programs completely filled their first-year positions. An average of 47% of residents were international medical graduates. In 2001 and 2002, 51.5% of trainees were men, and 48.5% were women. Sixteen percent entered their programs through an alternative pathway. An equal number of residents entered academic and fellowship positions after graduation (41%), and 18% of residents went into private practice. Twenty-three percent went into basic research. Residents wrote papers in 48% of the programs. CONCLUSIONS: The number of child neurology positions and trainees has been stable through recent years but may not meet the growing demand for services. The increasing number of international medical graduates and women in training programs predicts a change in the demographic characteristics of the future child neurology workforce. Many residents are pursuing academic careers, and continued support for programs that provide avenues for training in research is needed.

Temporal lobe epileptogenesis and epilepsy in the developing brain: bridging the gap between the laboratory and the clinic. Progression, but in what direction?

The origins of human mesial temporal lobe epilepsy and hippocampal sclerosis are still not well understood. Hippocampal sclerosis and temporal lobe epileptogenesis involve a series of pathologies including hippocampal neuronal loss and gliosis, axonal reorganization, and maybe hippocampal neoneurogenesis. However, the causality of these events is unclear as well as their relation to the factors that may precipitate epileptogenesis. Significant differences between temporal lobe epileptogenesis in the adult and immature brain may require differential approaches. Hereditary factors also may participate in some cases of hippocampal sclerosis. The key point is to identify the significance of these age-dependent changes and to design preventive treatments. Novel strategies for the prevention and treatment of mesial temporal lobe epilepsy and hippocampal sclerosis may include rational use of neuroprotective agents, hormonotherapy, immunizations, and immunotherapy.

Testosterone regulates androgen and estrogen receptor immunoreactivity in rat substantia nigra pars reticulata.

At postnatal day (PN)1, there are sex differences in gonadal receptor expression in the rat substantia nigra pars reticulata (SNR). Male pups have lower levels of androgen receptor (AR) and estrogen receptor (ER)beta immunoreactivity (IR) compared to female pups, while ERalpha IR is equally expressed in the two sexes. To test whether these differences are due to sex differences in testosterone exposure, we injected female pups with testosterone propionate (TP) on the day of birth and analyzed the levels of AR and ER IR at PN1. TP-treated females have lower levels of AR and ERbeta IR than control, while there are no differences in the levels of ERalpha IR. TP treatment did not affect the number of AR and ER expressing cells. The regulation of SNR AR and ERbeta IR by testosterone may be important for the development of sex-specific functional systems involved in motor control.

Sex differences in androgen and estrogen receptor expression in rat substantia nigra during development: an immunohistochemical study.

Gonadal hormones are important regulators of sexual differentiation of the CNS. Exposure to testosterone and estrogen during development causes permanent organizational differences between males and females. We previously described functional sex-related differences of the GABA(A)ergic circuits of the rat substantia nigra pars reticulata (SNR) involved in the control of flurothyl seizures. This sexual differentiation of the SNR is regulated by postnatal testosterone. To assess whether the organizing effects of testosterone in the SNR are mediated via the androgen receptor (AR) and/or estrogen receptors (ER), we used immunohistochemistry to study the ontogeny of AR, ERalpha and ERbeta expression in SNR and substantia nigra pars compacta (SNC) of male and female rats. Rats on the day of birth [postnatal day (PN) 0] and at PN1, PN5, PN15 and PN30 were used. AR- and ERbeta-immunopositive cells were present in SNR and SNC in both sexes and at all ages. ERalpha was not detected in male and female SNC at PN0-PN1. In both substantia nigra (SN) regions, there were developmentally regulated sex differences in AR, ERalpha and ERbeta immunoreactivity. In the SN, each receptor showed specific intracellular localization: AR was present in the nucleus, ERalpha and ERbeta were present both in nuclear and extranuclear compartments. ERalpha was detected also in processes. At PN0-PN1, quantitative analysis revealed sex and regional differences in the distribution of SN cells expressing AR and ERalpha, while ERbeta were equally present in both sexes. The presence of gonadal steroid receptors in the SN suggests that the biological effects of gonadal hormones in the CNS extend beyond reproduction-related functions and may affect and modify motor behaviors (including seizures) in a sex-specific manner. Based on the ontogeny of SNR ERbeta, we hypothesize that postnatal injections of testosterone may regulate the nigral GABA(A) system through the aromatization pathway and activation of ERbeta.

Role of subcortical structures in the pathogenesis of infantile spasms: what are possible subcortical mediators?

Infantile spasms present a constellation of symptoms and laboratory findings that suggest a role of subcortical circuits in the pathogenesis of this illness. The clinical features of spasms and the influence of subcortical circuits in the regulation of the electroencephologram, along with frequent abnormalities in subcortical structure and functional anatomy, brain stem electrophysiology, sleep regulation, and subcortical neurotransmitter levels, point to the importance of subcortical circuits in the generation of spasms. Furthermore, laboratory evidence shows that modulation of subcortical nuclei may attenuate and ameliorate seizures. We review clinical evidence indicating abnormal function in subcortical circuits and present a hypothesis that the development of infantile spasms requires dysfunction in both cortical and subcortical circuits. The confluence of evidence suggesting a role of subcortical structures in the origin of spasms and laboratory data indicating an anticonvulsant role on some subcortical nuclei raise the possibility of novel approaches to the treatment of infantile spasms.

Sexual dimorphism and developmental regulation of substantia nigra function.

The substantia nigra is an important brain nucleus involved in the expression of movement disorders and seizures. The two most common movement disorders affecting the substantia nigra, Parkinson's disease and Tourette syndrome, show gender differences and age-related onset. To assess the substrates for the gender and age specificity of substantia nigra-related disorders, we determined the functional properties of the substantia nigra gamma-aminobutyric acid (GABAA) system along its anterior-posterior axis, using localized microinfusions of muscimol (a GABAA agonist) and susceptibility to motor seizures in rats. In the substantia nigra, there are sex-specific differences in the topographic segregation and functionality of GABAA systems. In mature male rats there are two distinct regions mediating opposite effects on seizures; in female rats there is only one region that can affect seizures. In the neonatal period, the presence of circulating testosterone is essential for the development of a substantia nigra region that exerts proconvulsant effects throughout the rat's life, a unique feature of the male substantia nigra. The final maturation of the substantia nigra occurs in the peripubertal period, and is in part regulated by testosterone as well. The recognition of the existence of distinct sex- and age-specific substantia nigra features can be translated into new cures of disorders affecting the substantia nigra.

Anticonvulsant efficacy of gabapentin on kindling in the immature brain.

The anticonvulsant and motor effects of gabapentin (GBP) were evaluated in rat pups aged 16-17 days. Fourteen-day-old rat pups received an implanted stimulating electrode in the amygdala unilaterally. Kindled seizures were produced on day 16 of life by repeatedly applying an electrical current stimulus to the amygdala electrode. Animals received kindling stimulation until they achieved three consecutive generalized convulsions. On day 17, rat pups received one of four doses of GBP 10, 25, 50, or 100 mg/kg. After receiving GBP, rat pups again received electrical stimulation to the amygdala electrode to determine the extent to which GBP prevented the kindled seizure. Anticonvulsant effects were found at doses as low as 10 mg/kg. A separate group of naïve rats received GBP to determine the motor effects of each treatment dose. Impaired motor performance, quantified as time on a balance beam, occurred at doses of >or=50 mg/kg. In summary, our data indicate that in immature rats, GBP exerts an anticonvulsant effect against kindled seizures at doses that do not significantly impair motor performance.

How long do new-onset seizures in children last?

Although there are data on the duration of seizures in patients with refractory epilepsy, little is known about the duration of seizures in nonrefractory epilepsy populations. In a prospective study, seizure duration was determined in 407 children with a first unprovoked seizure using a structured interview and review of medical and ambulance records. Analysis focused on the distribution of seizure duration and on the conditional probability that a seizure would stop once it had already lasted for a specified time. Seizures lasted > or = 5 minutes in 50% of cases, > or = 10 minutes in 29%, > or = 20 minutes in 16%, and > or = 30 minutes in 12%. Seizure duration data were best fit as the sum of two exponential distributions, one with a mean of 3.6 minutes accounting for 76% of cases and the other with a mean of 31 minutes accounting for 24% of cases. The longer a seizure lasted, the less likely it was to stop within the next few minutes. In the 182 children with 2 or more seizures, the durations of the first and second seizures were highly correlated (r = 0.395, p < 0.0001). We conclude that the distribution of seizure duration in children with a first unprovoked seizure differs markedly from that observed in patients with refractory epilepsy. A subgroup of patients are predisposed to prolonged seizures. The data suggest that, once a seizure lasts for more than 5-10 minutes, it is unlikely to stop spontaneously within the next few minutes, and intervention is therefore indicated. These findings also support the continued use of the current definition of status epilepticus as a seizure lasting for 30 minutes or longer for epidemiologic studies.

Genome scan of idiopathic generalized epilepsy: evidence for major susceptibility gene and modifying genes influencing the seizure type.

Idiopathic generalized epilepsy (IGE) is a common, complex disease with an almost exclusively genetic etiology but with variable phenotypes. Clinically, IGE can be divided into different syndromes. Varying lines of evidence point to the involvement of several interacting genes in the etiology of IGE. We performed a genome scan in 91 families ascertained through a proband with adolescent-onset IGE. The IGEs included juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic clonic seizures (EGTCS). Our linkage results support an oligogenic model for IGE, with strong evidence for a locus common to most IGEs on chromosome 18 (lod score 4.4/5.2 multipoint/two-point) and other loci that may influence specific seizure phenotypes for different IGEs: a previously identified locus on chromosome 6 for JME (lod score 2.5/4.2), a locus on chromosome 8 influencing non-JME forms of IGE (lod score 3.8/2.5), and, more tentatively, two newly discovered loci for absence seizures on chromosome 5 (lod scores 3.8/2.8 and 3.4/1.9). Our data also suggest that the genetic classification of different forms of IGE is likely to cut across the clinical classification of these subforms of IGE. We hypothesize that interactions of different combinations of these loci produce the related heterogeneous phenotypes seen in IGE families.

Neuroimaging abnormalities in children with an apparent first unprovoked seizure.

OBJECTIVE: To determine the incidence and type of neuroimaging abnormalities in children presenting with a first seizure. METHODS: In a prospective observational study, 411 children with a first afebrile seizure were seen between 1983 and 1992. Imaging studies were performed in 218 (53%). For this analysis we examined the most sensitive neuroimaging study performed which included 159 computed tomography scans and 59 magnetic resonance imagings (MRI). RESULTS: Four children were found to have lesions requiring intervention (brain tumor in two, neurocysticercosis in two). The remaining 407 were enrolled in a follow-up study of children with a first unprovoked seizure. After a mean follow-up of >10 years, none have developed clinical evidence of a tumor. In these 411 children, 45 (21%) of 218 imaging studies were abnormal. The most common abnormalities were focal encephalomalacia (n=16) and cerebral dysgenesis (n=11). Although children with partial seizures were more likely to be imaged (64%) than children with generalized seizures (43%) (P<0.001), the fraction of abnormal imaging studies was similar in both groups. Six children with a normal neurological examination who were initially classified as cryptogenic were subsequently found to have errors of cerebral migration on MRI. The incidence of lesions requiring acute intervention in children presenting with a first seizure is low. A significant proportion will have neuroimaging abnormalities particularly on MRI. CONCLUSIONS: Neuroimaging should be considered in any child with a first seizure who does not have an idiopathic form of epilepsy.

Short-term outcomes of children with febrile status epilepticus.

Febrile status epilepticus (SE) represents the extreme end of the complex febrile seizure spectrum. If there are significant sequelae to febrile seizures, they should be more common in this group. We have prospectively identified 180 children aged 1 month to 10 years who presented with febrile SE over a 10-year period in Bronx, New York, and Richmond, Virginia. They were compared with 244 children who presented with their first febrile seizure (not SE) in a prospective study done in the Bronx. The mean age of the children with febrile SE was 1.92 years, and of the comparison group, 1.85 years. Duration of SE was 30-59 min in 103 (58%), 60-119 min in 43 (24%), and > or =120 min in 34 (18%). Focal features were present in 64 (35%) of cases. There were no deaths and no cases of new cognitive or motor handicap. Children with febrile SE were more likely to be neurologically abnormal (20% vs. 5%; p < 0.001), to have a history of neonatal seizures (3% vs. 0; p = 0.006) and a family history of epilepsy (11% vs. 5%; p = 0.05) and less likely to have a family history of febrile seizures (15% vs. 27%; p = 0.01) than were children in the comparison group. The short-term morbidity and mortality of febrile SE are low. There are differences in the types of children who have febrile SE compared with those who experience briefer febrile seizures. Long-term follow-up of this cohort may provide insight into the relationship of prolonged febrile seizures and subsequent mesial temporal sclerosis.