Seizures and early onset dementia: D2HGA1 inborn error of metabolism in adults.

D-2-hydroxyglutaric aciduria type 1 (D2HGA1) is a rare inherited metabolic disorder usually manifesting in infancy/early childhood with seizures and significant central nervous system involvement. We report two siblings with D2HGA1 presenting with mild intellectual disability, and the onset of seizures in adulthood. One of them was misdiagnosed as tuberous sclerosis due to her presentation and the presence of subependymal nodules on brain imaging. Both further developed early onset dementia. This report expands the phenotype of D2HGA1 to include late-onset seizures and early onset dementia in adults.

Detection of de novo del(18)(q22.2) and a familial of 15q13.2-q13.3 microduplication in a fetus with congenital heart defects.

OBJECTIVE: We present detection of de novo del(18)(q22.2) and a familial 15q13.2-q13.3 microduplication in a fetus with congenital heart defects (CHD). CASE REPORT: A 27-year-old, primigravid woman was referred for genetic counseling because of fetal CHD. Prenatal ultrasound at 17 weeks of gestation revealed pericardial effusion, cardiomegaly and a large ventricular septal defect. The pregnancy was subsequently terminated at 18 weeks of gestation, and a 192-g female fetus was delivered with facial dysmorphism. Cytogenetic analysis of the umbilical cord revealed a karyotype of 46,XX,del(18)(q22.2). The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) of the placental tissue revealed a 2.08-Mb 15q13.2-q13.3 microduplication encompassing KLF13 and CHRNA7, and a 10.74-Mb 18q22.2-q23 deletion encompassing NFATC1. The phenotypically normal father carried the same 2.08-Mb 15q13.2-q13.3 microduplication. Polymorphic DNA marker analysis confirmed a paternal origin of the distal 18q deletion. CONCLUSION: Prenatal diagnosis of CHD should include a complete genetic study of the embryonic tissues, and the acquired information is useful for genetic counseling.

Transplacental lidocaine intoxication.

Neonatal seizures are frequent in neonatal intensive care and the most common cause is perinatal asphyxia. Among other causes, toxin exposure is rare.We present a boy with an uneventful vaginal birth, who presented one hour after birth with apnea, hypotonia, mydriasis, tongue fasciculation, and tonic seizures. There was no hypoxic ischemic encephalopathy and brain imaging was normal. Toxicology screening revealed a toxic concentration of lidocaine in his blood. The intoxication was transplacental, as a cord blood sample confirmed the toxic level. This was probably due to maternal perineal nerve block with lidocaine.Perineal local infiltration of lidocaine is not without risk for the newborn. Toxicology screen remains an important tool in the work-up of neonatal seizures and sudden unexpected postnatal collapse.

Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice.

Epilepsy is a neurological disorder often associated with seizure that affects ∼0.7% of pregnant women. During pregnancy, most epileptic patients are prescribed antiepileptic drugs (AEDs) such as valproic acid (VPA) to control seizure activity. Here, we show that prenatal exposure to VPA in mice increases seizure susceptibility in adult offspring through mislocalization of newborn neurons in the hippocampus. We confirmed that neurons newly generated from neural stem/progenitor cells (NS/PCs) are integrated into the granular cell layer in the adult hippocampus; however, prenatal VPA treatment altered the expression in NS/PCs of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), consequently increasing the ectopic localization of newborn neurons in the hilus. We also found that voluntary exercise in a running wheel suppressed this ectopic neurogenesis and countered the enhanced seizure susceptibility caused by prenatal VPA exposure, probably by normalizing the VPA-disrupted expression of multiple genes including Cxcr4 in adult NS/PCs. Replenishing Cxcr4 expression alone in NS/PCs was sufficient to overcome the aberrant migration of newborn neurons and increased seizure susceptibility in VPA-exposed mice. Thus, prenatal exposure to an AED, VPA, has a long-term effect on the behavior of NS/PCs in offspring, but this effect can be counteracted by a simple physical activity. Our findings offer a step to developing strategies for managing detrimental effects in offspring exposed to VPA in utero.

Adenosine receptor antagonists including caffeine alter fetal brain development in mice.

Consumption of certain substances during pregnancy can interfere with brain development, leading to deleterious long-term neurological and cognitive impairments in offspring. To test whether modulators of adenosine receptors affect neural development, we exposed mouse dams to a subtype-selective adenosine type 2A receptor (A2AR) antagonist or to caffeine, a naturally occurring adenosine receptor antagonist, during pregnancy and lactation. We observed delayed migration and insertion of γ-aminobutyric acid (GABA) neurons into the hippocampal circuitry during the first postnatal week in offspring of dams treated with the A2AR antagonist or caffeine. This was associated with increased neuronal network excitability and increased susceptibility to seizures in response to a seizure-inducing agent. Adult offspring of mouse dams exposed to A2AR antagonists during pregnancy and lactation displayed loss of hippocampal GABA neurons and some cognitive deficits. These results demonstrate that exposure to A2AR antagonists including caffeine during pregnancy and lactation in rodents may have adverse effects on the neural development of their offspring.

Administration of docosahexaenoic acid before birth and until aging decreases kainate-induced seizures in adult zebrafish.

Docosahexaeonic acid (DHA) is the final compound in the omega-3 polyunsaturated fatty acids (PUFA) synthetic pathway and the most abundant PUFA found in the brain. DHA plays an essential role in the development of the brain, and the intakes in pregnancy and early life affect growth and cognitive performance later in childhood. Recently, it has been proposed that dietary intake of DHA could be a non-pharmacological interventional strategy for the treatment of seizures in humans. However, to date, the experimental approaches to study the antiepileptic effect of DHA have been exclusively restricted to rodent models during short-to-medium periods of treatment. The purpose of the present study was to test the chronic anticonvulsivant effects of DHA supplementation in zebrafish from the pre-spawning stage to aging, taking advantage of our recently described kainate-induced seizure model using this animal. To that end, two groups of adult female zebrafish were fed with standard or 200mg/kg DHA-enriched diets during 1 month previous to the spawning, and offspring subdivided in two categories, and subsequently fed with standard or DHA diets, generating 4 groups of animals that were aged until 20 months. Afterward, KA was intraperitoneally administered and epileptic score determined. All the DHA-enriched groups presented antiepileptic effects compared to the control group, showing that DHA presents an anticonvulsant potential. Among the studied groups, zebrafish fed with DHA from the pre-spawning stage to aging presented the best antiepileptic profile. These results show a neuroprotective benefit in zebrafish fed with DHA-enriched diet before birth and during the whole life.

Loss of zebrafish lgi1b leads to hydrocephalus and sensitization to pentylenetetrazol induced seizure-like behavior.

Mutations in the LGI1 gene predispose to a hereditary epilepsy syndrome and is the first gene associated with this disease which does not encode an ion channel protein. In zebrafish, there are two paralogs of the LGI1 gene, lgi1a and lgi1b. Knockdown of lgi1a results in a seizure-like hyperactivity phenotype with associated developmental abnormalities characterized by cellular loss in the eyes and brain. We have now generated knockdown morphants for the lgi1b gene which also show developmental abnormalities but do not show a seizure-like behavior. Instead, the most striking phenotype involves significant enlargement of the ventricles (hydrocephalus). As shown for the lgi1a morphants, however, lgi1b morphants are also sensitized to PTZ-induced hyperactivity. The different phenotypes between the two lgi1 morphants support a subfunctionalization model for the two paralogs.

Toluene exposure during the brain growth spurt reduced behavioral responses to nicotine in young adult rats: a potential role for nicotinic acetylcholine receptors in fetal solvent syndrome.

Toluene, an industrial organic solvent, is voluntarily inhaled as drug of abuse. Toluene has been shown to inhibit the nicotinic acetylcholine receptors. Nicotinic receptors play an important role in brain development during brain growth spurt and early adolescence. The long-term effects of neonatal and adolescent toluene exposure on behavioral responses to nicotine in early adulthood were compared. Sprague-Dawley male and female rats were treated with toluene (500 mg/kg, ip) or corn oil daily over postnatal day (PN) 4-9 or 25-30. Nicotine-induced hypothermia, antinociception, and seizure activity were examined during PN 56-60. Toluene exposure during the brain growth spurt, but not adolescence, reduced the behavioral responses to nicotine in young adult rats. However, the levels of alpha4, alpha7, and beta2 nicotinic receptors were not altered in the frontal cortex, striatum, thalamus, hippocampus, and cerebellum by neonatal toluene exposure. These results indicate that toluene exposure during the brain growth spurt produces long-term changes in nicotine sensitivity, which may be unrelated to the total expression levels of alpha4, alpha7, and beta2 nicotinic receptors. The alterations in nicotine sensitivity may be related to the neurobehavioral disturbance associated with fetal solvent syndrome.

Neurodevelopment in seizure-prone and seizure-resistant rat strains: recognizing conflicts in management.

Cytoarchitectural alterations during central nervous system (CNS) development are believed to underlie aberrations in brain morphology that lead to epilepsy. We have recently reported marked reductions in hippocampal and white matter volumes along with relative ventriculomegaly in a rat strain bred to be seizure-prone (FAST) compared to a strain bred to be seizure-resistant (SLOW) (Gilby et al., 2002, American Epilepsy Society 56th Annual Meeting). This study was designed to investigate deviations in gene expression during late-phase embryogenesis within the brains of FAST and SLOW rats. In this way, we hoped to identify molecular mechanisms operating differentially during neurodevelopment that might ultimately create the observed differences in brain morphology and/or seizure susceptibility. Using Superarray technology, we compared the expression level of 112 genes, known to play a role in neurodevelopment, within whole brains of embryonic day 21 (E21) FAST and SLOW rats. Results revealed that while most genes investigated showed near equivalent expression levels, both Apolipoprotein E (APOE) and the beta2 subunit of the voltage-gated sodium channel (SCN2beta) were significantly underexpressed in brains of the seizure-prone embryos. Currently, these transcripts have no known interactions during embryogenesis; however, they have both been independently linked to seizure disposition and/or neurodevelopmental aberrations leading to epilepsy. Thus, alterations in the timing and/or degree of expression for APOE and SCN2beta may be important to developmental cascades that ultimately give rise to the differing brain morphologies, behaviors, and/or seizure vulnerabilities that characterize these strains.

Antiepileptogenic and antioxidant effects of Nigella sativa oil against pentylenetetrazol-induced kindling in mice.

Nigella sativa oil (NSO), a herbaceous plant, has been used for thousands of years for culinary and medical purposes. This study aimed to investigate the anticonvulsant and antioxidant activities of NSO on pentylenetetrazol (PTZ) kindling seizures in mice. Nigella sativa oil was tested for its ability (i) to suppress the convulsive and lethal effects of PTZ in kindled mice (anti-epileptogenic effect), (ii) to attenuate the PTZ-induced oxidative injury in the brain tissue (antioxidant effect) when given as a pretreatment prior to each PTZ injection during kindling acquisition. Valproate, a major antiepileptic drug, was also tested for comparison. Both substances studied significantly decreased oxidative injury in the mouse brain tissue in comparison with the PTZ-kindling group. Nigella sativa oil was found to be the most effective in preventing PTZ-induced seizures relative to valproate. Nigella sativa oil showed anti-epileptogenic properties as it reduced the sensitivity of kindled mice to the convulsive and lethal effects of PTZ; valproate was ineffective in preventing development of any of these effects. The data obtained support the hypothesis that neuroprotective action of NSO may correlate with its ability to inhibit not only excessive reactive oxygen species (ROS) formation but also seizure generation.

The type B brevetoxin (PbTx-3) adversely affects development, cardiovascular function, and survival in Medaka (Oryzias latipes) embryos.

Brevetoxins are produced by the red tide dinoflagellate Karenia brevis. The toxins are lipophilic polyether toxins that elicit a myriad of effects depending on the route of exposure and the target organism. Brevetoxins are therefore broadly toxic to marine and estuarine animals. By mimicking the maternal route of exposure to the oocytes in finfish, we characterized the adverse effects of the type B brevetoxin brevetoxin-3 (PbTx-3) on embryonic fish development and survival. The Japanese rice fish, medaka (Oryzias latipes), was used as the experimental model in which individual eggs were exposed via microinjection to various known concentrations of PbTx-3 dissolved in an oil vehicle. Embryos injected with doses exceeding 1.0 ng/egg displayed tachycardia, hyperkinetic twitches in the form of sustained convulsions, spinal curvature, clumping of the erythrocytes, and decreased hatching success. Furthermore, fish dosed with toxin were often unable to hatch in the classic tail-first fashion and emerged head first, which resulted in partial hatches and death. We determined that the LD(50) (dose that is lethal to 50% of the fish) for an injected dose of PbTx-3 is 4.0 ng/egg. The results of this study complement previous studies of the developmental toxicity of the type A brevetoxin brevetoxin-1 (PbTx-1), by illustrating in vivo the differing affinities of the two congeners for cardiac sodium channels. Consequently, we observed differing cardiovascular responses in the embryos, wherein embryos exposed to PbTx-3 exhibited persistent tachycardia, whereas embryos exposed to PbTx-1 displayed bradycardia, the onset of which was delayed.

Nitric oxide synthase inhibition and delayed cerebral injury after severe cerebral ischemia in fetal sheep.

After transient cerebral ischemia in fetal sheep, delayed disruptions in cerebral energetics are represented by a delayed increase in cortical impedance, a progressive decrease in the concentration of oxidized cytochrome oxidase as measured by near-infrared spectroscopy, and cortical seizures. Because the production of nitric oxide (NO), a potent mediator of neuronal death, is increased during this phase, the present study investigated whether inhibition of NO synthesis could ameliorate the delayed disruption in cerebral energetics. Eleven late gestation fetal sheep were subjected to 30 min of transient cerebral ischemia in utero. Two hours later, the treatment group (n = 5) received a continuous infusion of N(G)-nitro-L-arginine, a competitive inhibitor of NO synthase, whereas the control group (n = 6) received PBS. Changes in concentration of oxidized cytochrome oxidase, cortical impedance, and electrocortical activity were observed for 3 d. A delayed increase in cortical impedance of similar magnitude and duration commenced at 14+/-4 h in the control and at 15+/-3 h in the treatment groups. The progressive decrease in oxidized cytochrome oxidase signal, by -2.2+/-0.2 micromol/L in the control and -2.0+/-0.4 micromol/L in the treatment group at 72 h postischemia, was similar in both groups. In both groups, delayed cortical seizures were indicated by intense low-frequency electrocortical activity. In the treatment group, duration of cortical seizures was increased and the intensity of the final electrocortical activity was more depressed (-19+/-1 dB versus -10+/-2 dB). The results indicate that after cerebral ischemia in fetal sheep, NO synthase inhibition does not ameliorate the delayed disruptions in cerebral energetics. However, the effect of NO synthase inhibition on delayed cortical seizures may improve our understanding of the role of NO during this phase.

Perinatal observations in forty-eight neurologically impaired term infants.

OBJECTIVE: Our goal was to review the perinatal characteristics of 48 singleton term infants with central nervous system neurologic impairment. STUDY DESIGN: Medical records were retrospectively reviewed for maternal characteristics, prenatal and intrapartum care patterns, neonatal course, and long-term outcome. Those patients without evidence of an obvious acute asphyxial event, traumatic delivery, or preterm birth were excluded. The study population was then subclassified according to the admission fetal heart rate pattern. RESULTS: Of these 48 term infants the admission fetal heart rate pattern was nonreactive in 33 (69%) and reactive in 15 (31%). Maternal characteristics, prenatal care, and long-term outcome were statistically similar between the two groups. However, the nonreactive group exhibited significantly more characteristics consistent with a prior asphyxial event: thick "old" meconium, "fixed" nonreactive baseline fetal heart rate, meconium-stained skin, and meconium aspiration syndrome. In contrast, in the reactive group a fetal heart rate pattern developed that was consistent with Hon's theory for intrapartum asphyxia and manifested by a prolonged tachycardia in association with persistent nonreactivity, diminished fetal heart rate variability, and fetal heart rate decelerations. CONCLUSIONS: Among fetuses later found to be neurologically impaired, a persistent nonreactive fetal heart rate tracing obtained from admission to delivery appears to be evidence of prior neurologic injury.

Antenatal and intrapartum factors associated with the occurrence of seizures in term infant.

To identify antenatal and intrapartum risk factors associated with seizures in term newborns, 40 infants who had seizures within 72 hours of birth were compared with 400 controls using logistic regression analysis. The risk of seizure in the term newborn was approximately one per 1000 in the population studied. The logistic regression model identified a group of infants in whom the risk of seizure was approximately one per 100. The risk factors included in the model were antepartum anemia, antepartum bleeding, asthma, meconium-stained amniotic fluid, presentation other than occiput anterior, fetal distress, and shoulder dystocia. Consistent with other studies, our analysis confirmed a strong association between seizures and factors that increase the risk of fetal asphyxia.