Development Of Seizures Research Articles

Potassium and glutamate transport is impaired in scar-forming tumor-associated astrocytes

Unprovoked recurrent seizures are a serious comorbidity affecting most patients who suffer from glioma, a primary brain tumor composed of malignant glial cells. Cellular mechanisms contributing to the development of recurrent spontaneous seizures include the release of the excitatory neurotransmitter glutamate from glioma into extracellular space. Under physiological conditions, astrocytes express two high affinity glutamate transporters, Glt-1 and Glast, which are responsible for the removal of excess extracellular glutamate. In the context of neurological disease or brain injury, astrocytes become reactive which can negatively affect neuronal function, causing hyperexcitability and/or death. Using electrophysiology, immunohistochemistry, fluorescent in situ hybridization, and Western blot analysis in different orthotopic xenograft and allograft models of human and mouse gliomas, we find that peritumoral astrocytes exhibit astrocyte scar formation characterized by proliferation, cellular hypertrophy, process elongation, and increased GFAP and pSTAT3. Overall, peritumoral reactive astrocytes show a significant reduction in glutamate and potassium uptake, as well as decreased glutamine synthetase activity. A subset of peritumoral astrocytes displayed a depolarized resting membrane potential, further contributing to reduced potassium and glutamate homeostasis. These changes may contribute to the propagation of peritumoral neuronal hyperexcitability and excitotoxic death.

Physical Activity Reduces Epilepsy Incidence: a Retrospective Cohort Study in Swedish Cross-Country Skiers and an Experimental Study in Seizure-Prone Synapsin II Knockout Mice

BackgroundEpilepsy patients commonly exercise less than the general population. Animal studies indicate beneficial effects of physical activity in established epilepsy, while its effect on the development is currently less known.MethodsHere, we investigated the incidence of epilepsy during 20 years in a cohort of participants from the long-distance Swedish cross-country ski race Vasaloppet (n = 197,685) and compared it to the incidence of non-participating-matched controls included in the Swedish population register (n = 197,684). Individuals diagnosed with diseases such as stroke and epilepsy before entering the race were excluded from both groups. Experimentally, we also determined how physical activity could affect the development of epilepsy in epilepsy-prone synapsin II knockout mice (SynIIKO), with and without free access to a running wheel.ResultsWe identified up to 40–50% lower incidence of epilepsy in the Vasaloppet participants of all ages before retirement. A lower incidence of epilepsy in Vasaloppet participants was seen regardless of gender, education and occupation level compared to controls. The participants included both elite and recreational skiers, and in a previous survey, they have reported a higher exercise rate than the general Swedish population. Sub-analyses revealed a significantly lower incidence of epilepsy in participants with a faster compared to slower finishing time. Dividing participants according to specified epilepsy diagnoses revealed 40–50% decrease in focal and unspecified epilepsy, respectively, but no differences in generalized epilepsy. Voluntary exercise in seizure-prone SynIIKO mice for 1 month before predicted epilepsy development decreased seizure manifestation from > 70 to 40%. Brain tissue analyses following 1 month of exercise showed increased hippocampal neurogenesis (DCX-positive cells), while microglial (Iba1) and astrocytic activation (GFAP), neuronal Map2, brain-derived neurotrophic factor and its receptor tyrosine receptor kinase B intensity were unaltered. Continued exercise for additionally 2 months after predicted seizure onset in SynIIKO mice resulted in a 5-fold reduction in seizure manifestation (from 90 to 20%), while 2 months of exercise initiated at the time of predicted seizure development gave no seizure relief, suggesting exercise-induced anti-epileptogenic rather than anti-convulsive effect.ConclusionThe clinical study and the experimental findings in mice indicate that physical activity may prevent or delay the development of epilepsy.

Treatment with CCR2 antagonist is neuroprotective but does not alter epileptogenesis in the pilocarpine rat model of epilepsy

Neuroinflammation role on epileptogenesis has been the subject of increasing interest. Many studies showed elevation in cytokines and chemokines expression following seizures, such as, CCL2 protein (C-C motif ligand 2 chemokine) and its specific receptor, CCR2. In addition, recent studies manipulating the CCL2/CCR2 complex verified improved seizure outcome in different seizure models. In the present study, the effects of CCR2 antagonist was investigated using the pilocarpine rat model of epilepsy. Status epilepticus (SE) was induced by pilocarpine i.p. injection in adult rats. Daily oral treatment with CCR2 antagonist or vehicle was initiated 5 h following SE and lasted 5 or 10 days. Rats were euthanized 5 days after SE to evaluate neuronal damage and glial density or 30 days after SE to investigate spontaneous seizures development and seizure susceptibility to a second hit pentylenetetrazol (PTZ) test. Rats that received CCR2 antagonist presented less degenerating cells at hippocampal CA1 region. There was also a significant decrease in CA1 volume after SE that was not observed in treated rats. On the other hand, microglia cell density increased after SE regardless of CCR2 antagonist use. Treatment with CCR2 antagonist did not alter spontaneous seizure occurrence or later seizure susceptibility to PTZ in chronic rats. Additional rats were pretreated with CCR2 antagonist prior to SE induction, but this did not change SE progression. The data show that oral treatment with CCR2 antagonist is neuroprotective, but does not alter other epileptogenic factors, such as, neuroinflammation, or seizure development, after pilocarpine-induced SE in rats.

Micronized resveratrol shows promising effects in a seizure model in zebrafish and signalizes an important advance in epilepsy treatment

Resveratrol is a natural non-flavonoid polyphenolic that has been emerging in epilepsy treatment. Despite its pharmacological properties, the poor bioavailability of resveratrol has been an important barrier that hinders its application as an anticonvulsant. The aim of this work was to improve resveratrol’s anticonvulsant effects by micronizing this compound through supercritical fluid micronization technology, which promotes an increase of the particles' surface area and allows significantly reduced particle size to be obtained. We obtained commercial and micronized resveratrol and investigated the anticonvulsant effects of resveratrol as commercially found and micronized resveratrol in a pentylenetetrazole-induced seizure model in zebrafish (Danio rerio) larvae. Diazepam was used as the positive control. Also, animals had their locomotor and exploratory activity analyzed 24 h after the seizure occurrence. The occurrence of the tonic-clonic seizure stage was only prevented by diazepam and micronized resveratrol, unlike the non-processed compound. The seizure development was significantly slowed by diazepam and micronized resveratrol, while non-micronized resveratrol was not able to increase the latency of seizure stages. In addition, diazepam and micronized resveratrol prevented the deleterious effects of pentylenetetrazole-induced seizures on animals’ locomotor and exploratory behaviour. Obtained data demonstrates that the micronization process potentiates the anticonvulsant effect of resveratrol. Micronized resveratrol achieved a similar effect to the classical drug diazepam, with the benefit that it may be a safe drug candidate to be used during the neurodevelopmental stage.

Autism spectrum disorder in children and young people with non-epileptic seizures

PurposeNon-epileptic seizures are paroxysmal events which to an observer resemble epileptic seizures. Proposed risk factors incorporate biopsychosocial aspects including factors in the affected individual. Unexpectedly high rates of autism spectrum disorder (ASD) occurred in the clinical population reported here. Although elevated levels of psychiatric co-morbidity are known to be present in patients with NES, ASD has only been previously described in a single case report. MethodsThis case series captures rates of ASD in 59 children and young people who were referred to a specialist paediatric mental health service at Great Ormond Street Hospital, London, UK for assessment and treatment of non-epileptic seizures between 2012 and 2016. Results10/59 (16.9%) of the children and young people with non-epileptic seizures also had ASD, with 5/10 (50%) of these undiagnosed with ASD before referral. Children and young people with ASD were significantly more likely to have tics or attention-deficit hyperactivity disorder than those without ASD. ConclusionASD may be a common co-morbidity in non-epileptic seizures. Careful clinical assessment with consideration of ASD traits is therefore important in the non-epileptic seizures population. It is beneficial to diagnose ASD early as its presence is likely to require a modified approach to assessment and treatment of non-epileptic seizures. Study of the development of non-epileptic seizures in ASD may suggest hypotheses for the pathogenesis of non-epileptic seizures in the wider population.

Scalp EEG spikes predict impending epilepsy in TSC infants: A longitudinal observational study.

ObjectiveTo determine if routine electroencephalography (EEG) in seizure‐naive infants with tuberous sclerosis complex (TSC) can predict epilepsy and subsequent neurocognitive outcomes.MethodsForty infants 7 months of age or younger and meeting the genetic or clinical diagnostic criteria for tuberous sclerosis were enrolled. Exclusion criteria included prior history of seizures or treatment with antiseizure medications. At each visit, seizure history and 1‐hour awake and asleep video‐EEG, standardized across all sites, were obtained until 2 years of age. Developmental assessments (Mullen and Vineland‐II) were completed at 6, 12, and 24 months of age.ResultsOf 40 infants enrolled (mean age of 82.4 days), 32 completed the study. Two were lost to follow‐up and six were treated with antiepileptic drugs (AEDs) due to electrographic seizures and/or interictal epileptiform discharges (IEDs) on their EEG studies prior to the onset of clinical seizures. Seventeen of the 32 remaining children developed epilepsy at a mean age of 7.5 months (standard deviation [SD] = 4.4). Generalized/focal slowing, hypsarrhythmia, and generalized/focal attenuation were not predictive for the development of clinical seizures. Presence of IEDs had a 77.3% positive predictive value and absence a 70% negative predictive value for developing seizures by 2 years of age. IEDs preceded clinical seizure onset by 3.6 months (mean). Developmental testing showed significant decline, only in infants with ongoing seizures, but not infants who never developed seizures or whose seizures came under control.SignificanceIEDs identify impending epilepsy in the majority (77%) of seizure‐naive infants with TSC. The use of a 1‐hour awake and asleep EEG can be used as a biomarker for ongoing epileptogenesis in most, but not all, infants with TSC. Persistent seizures, but not history of interictal epileptiform activity or history of well‐controlled seizures, correlated with low scores on the Vineland and Mullen tests at 2 years of age.

Selective inhibition of mTORC1/2 or PI3K/mTORC1/2 signaling does not prevent or modify epilepsy in the intrahippocampal kainate mouse model

Dysregulation of the PI3K/Akt/mTOR pathway has been implicated in several brain disorders, including epilepsy. Rapamycin and similar compounds inhibit mTOR.complex 1 and have been reported to decrease seizures, delay seizure development, or prevent epileptogenesis in different animal models of genetic or acquired epilepsies. However, data for acquired epilepsy are inconsistent, which, at least in part, may be due to the poor brain penetration and long brain persistence of rapamycin and the fact that it blocks only one of the two cellular mTOR complexes. Here we examined the antiepileptogenic or disease-modifying effects of two novel, brain-permeable and well tolerated 1,3,5-triazine derivatives, the ATP-competitive mTORC1/2 inhibitor PQR620 and the dual pan-PI3K/mTORC1/2 inhibitor PQR530 in the intrahippocampal kainate mouse model, in which spontaneous seizures develop after status epilepticus (SE). Following kainate injection, the two compounds were administered over 2 weeks at doses previously been shown to block mTORC1/2 or PI3K/mTORC1/2 in the mouse brain. When spontaneous seizures were recorded by continuous (24/7) video-EEG recording starting 6 weeks after termination of treatment, no effects on incidence or frequency of seizures were observed. Drug treatment suppressed the epilepsy-induced activation of the PI3K/Akt/mTOR pathway in the hippocampus, but granule cell dispersion in the dentate gyrus was not prevented. When epilepsy-associated behavioral alterations were determined 12–14 weeks after kainate, mice pretreated with PQR620 or PQR530 exhibited reduced anxiety-related behavior in the light-dark box, indicating a disease-modifying effect. Overall, the data indicate that mTORC1/C2 or PI3K/mTORC1/C2 inhibition may not be an antiepileptogenic strategy for SE-induced epilepsy.

Early treatment with C1 esterase inhibitor improves weight but not memory deficits in a rat model of status epilepticus

BackgroundStatus epilepticus (SE) is a prolonged and continuous seizure that lasts for at least 5 min. An episode of SE in a healthy system can lead to the development of spontaneous seizures and cognitive deficits which may be accompanied by hippocampal injury and microgliosis. Although the direct mechanisms underlying the SE-induced pathophysiology remain unknown, a candidate mechanism is hyperactivation of the classical complement pathway (C1q-C3 signaling). We recently reported that SE triggered an increase in C1q-C3 signaling in the hippocampus that closely paralleled cognitive decline. Thus, we hypothesized that blocking activation of the classical complement pathway immediately after SE may prevent the development of SE-induced hippocampal-dependent learning and memory deficits. MethodsBecause C1 esterase inhibitor (C1-INH) negatively regulates activation of the classical complement pathway, we used this drug to test our hypothesis. Two groups of male rats were subjected to 1 hr of SE with pilocarpine (280–300 mg/kg, i.p.), and treated with either C1-INH (SE+C1-INH, 20 U/kg, s.c.) or vehicle (SE+veh) at 4, 24, and 48 h after SE. Control rats were treated with saline. Body weight was recorded for up to 23 days after SE. At two weeks post SE, recognition and spatial memory were determined using Novel Object Recognition (NOR) and Barnes maze (BM), respectively, as well as locomotion and anxiety-like behaviors using Open Field (OF). Histological and biochemical methods were used to measure hippocampal injury including cell death, microgliosis, and inflammation. ResultsOne day after SE, both SE groups had a significant loss of body weight compared to controls (p<0.05). By day 14, the weight of SE+C1-INH rats was significantly higher than SE+veh rats (p<0.05), and was not different from controls (p>0.05). At 14 days post-SE, SE+C1-INH rats displayed higher mobility (distance travelled and average speed, p<0.05) and had reduced anxiety-like behaviors (outer duration, p<0.05) than control or SE+veh rats. In NOR, control rats spent significantly more time exploring the novel object vs. the familiar (p<0.05), while rats in both SE groups spent similar amount of time exploring both objects. During days 1–4 of BM training, the escape latency of the control group significantly decreased over time (p<0.05), whereas that of the SE groups did not improve (p>0.05). Compared to vehicle-treated SE rats, SE+C1-INH rats had increased levels of C3 and microglia in the hippocampus, but lower levels of caspase-3 and synaptic markers. ConclusionsThese findings suggest that acute treatment with C1-INH after SE may have some protective, albeit limited, effects on the physiological recovery of rats’ weight and some anxiolytic effects, but does not attenuate SE-induced deficits in hippocampal-dependent learning and memory. Reduced levels of caspase-3 suggest that treatment with C1-INH may protect against cell death, perhaps by regulating inflammatory pathways and promoting phagocytic/clearance pathways.

P25 Magnetic resonance imaging findings in children with Parry Romberg syndrome and en coup de sabre

Poster presentation Tuesday 8 October Background En coup de sabre (ECDS) is a form of linear scleroderma characterised by skin induration followed by unilateral pigmentation dysregulation over the frontoparietal region with associated scarring. Parry Romberg syndrome (PRS) is a sporadic neurocutaneous disease characterised by slow and progressive hemifacial atrophy of the skin, muscles, and bony structures. Both conditions are associated with neurological symptoms such as headache and seizures. A wide variety of magnetic resonance findings associated with these conditions have been described. However, to date, attempts to identify predictors of MRI abnormalities have remained unsuccessful. The aim of this study was to: (i) describe the abnormalities seen on MRI in a large group of children with PRS/ECDS; and (ii) identify demographic, clinical, and laboratory predictors of MRI abnormalities. Methods This was a single centre (Great Ormond Street Hospital, London) retrospective case series of patients with PRS/ECDS seen from 2001-2018. We identified patients with cutaneous symptoms consistent with the clinical descriptions of PRS/ECDS: lateral forehead scleroderma with/without hemifacial atrophy. Presenting clinical, immunological, and MR brain findings are reported. Results are expressed as medians and ranges or frequencies and percentages. Fisher’s exact test was used to identify clinical associations with MRI abnormalities. Results A total of 17 patients were identified: 7 males and 10 females; median age 13 years (range 3 – 23). Non-cutaneous manifestations included seizures, headaches, stroke, cranial nerve dysfunction, anxiety, hypertension, hypermobility, Raynaud’s, myositis, and gastro-oesophageal reflux. The positive MR findings included ipsilateral enhanced white matter signalling, mineral deposition, lateral ventricle dilation, leptomeningeal enhancement, cavernomas, generalised atrophy, and loss of cortical gyration. The presence of seizures and the PRS phenotype were significantly associated with an abnormal MRI (p &lt; 0.05) and showed trends towards significance with ipsilateral enhanced white matter signalling (p = 0.09). Conclusion The development of seizures and the PRS phenotype predict abnormalities in MR brain imaging in childhood PRS/ECDS. Baseline and regular monitoring MR brain scans should be carried out in all patients with PRS/ECDS to identify abnormalities associated with the development of seizures. Conflicts of Interest The authors declare no conflicts of interest.

Prevention of post-ischemic seizure by rapamycin is associated with deactivation of mTOR and ERK1/2 pathways in hyperglycemic rats

Pre-ischemic hyperglycemia increases the occurrence of post-ischemic seizures both in experimental and clinical settings. The underlying mechanisms are not fully delineated; however, activation of mammalian target of rapamycin (mTOR) has been shown to be engaged in the pathogenesis of epilepsy, in which seizures are a regular occurrence. Therefore, we wanted to explore specifically the capacity of an mTOR inhibitor, rapamycin, in preventing post-ischemic seizures in hyperglycemic rats and to explore the underlying molecular mechanisms. The results showed that none of the rats in the sham control, EG ischemic, or within 3 h of I/R in hyperglycemic ischemic groups experienced seizures. Generalized tonic-clonic seizures were observed in all 8/8 of hyperglycemic ischemic rats at 16 h of I/R. Treatment with rapamycin successfully blocked post-ischemic seizures in 7/8 hyperglycemic ischemic animals. Rapamycin also lessened the neuronal death extraordinarily in hyperglycemic ischemic animals as revealed by histopathological studies. Protein analysis revealed that transient ischemia resulted in increases in p-mTOR and p-S6, especially in the hippocampi of the hyperglycemic ischemic rats. Rapamycin treatment completely blocked mTOR activation. Furthermore, hyperglycemic ischemia induced a much prominent rise of p-ERK1/2 both in the cortex and the hippocampi compared with EG counterparts; whereas rapamycin suppressed it. We conclude that the development of post-ischemic seizures in the hyperglycemic animals may be associated with activations of mTOR and ERK1/2 pathways and that rapamycin treatment inhibited the post-ischemic seizures effectively by suppressing the mTOR and ERK1/2 signaling.

Diagnostic significance of biomarkers of the epileptic seizures development in patients with arterial aneurysms

The aim of the study was to establish the diagnostic significance of biochemical parameters, considered as markers of epileptic seizures in patients with arterial aneurysms (AA). 82 patients with AA (50.4 ± 11.5 year-old) with epileptic seizures (35 persons) and without them (47 persons) were examined. Before treatment, the following biochemical parameters were determined in plasma of patients: lactate, pyruvate, products reacting with thiobarbituric acid (TBA-P), antioxidant activity of the serum, activity of superoxidedismutase and catalase, tumor necrosis factor-alpha (TNF-ά). To characterize the diagnostic significance of the results, the diagnostic sensitivity and the diagnostic efficacy were determined. The complex of biochemical tests with high diagnostic significance, consisting of lactate, lactate/pyruvateindex, catalase activity, TBA-P and TNF-α, was established in patients with AA with epileptic seizures. It allows considering these parameters as markers of epileptic seizures development in patients with AA. Among the most diagnostically significant tests for detection of epileptic seizures in patients with AA should be considered the concentration of TNF-ά with diagnostic sensitivity of 73%, the diagnostic specificity of 79% and the diagnostic efficacy of 75%.

Novel Optogenetic Approaches in Epilepsy Research.

Epilepsy is a major neurological disorder characterized by repeated seizures afflicting 1% of the global population. The emergence of seizures is associated with several comorbidities and severely decreases the quality of life of patients. Unfortunately, around 30% of patients do not respond to first-line treatment using anti-seizure drugs (ASDs). Furthermore, it is still unclear how seizures arise in the healthy brain. Therefore, it is critical to have well developed models where a causal understanding of epilepsy can be investigated. While the development of seizures has been studied in several animal models, using chemical or electrical induction, deciphering the results of such studies has been difficult due to the uncertainty of the cell population being targeted as well as potential confounds such as brain damage from the procedure itself. Here we describe novel approaches using combinations of optical and genetic methods for studying epileptogenesis. These approaches can circumvent some shortcomings associated with the classical animal models and may thus increase the likelihood of developing new treatment options.

Delayed audiogenic seizure development in a genetic rat model is associated with overactivation of ERK1/2 and disturbances in glutamatergic signaling

Krushinsky-Molodkina (KM) rats genetically prone to audiogenic seizure are characterized by age-dependent expression of audiogenic seizures (AGS). It is known that the critical period of enhanced seizure susceptibility in rodents occurs at 2nd–3rd weeks of postnatal development. However, KM rats do not express AGS at this time-point, but start to demonstrate a stable AGS only after the age of 3 months. We hypothesized that this delay in AGS susceptibility in KM rats is genetically determined and may depend on some alterations in the development of the hippocampal glutamatergic system during the early postnatal period. We analyzed the expression and activity of seizure-related proteins, such as vesicular glutamate transporter 2 (VGLUT2), extracellular signal-regulated kinases 1 and 2 (ERK1/2), synapsin I, and NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor (NR2B) in the hippocampus of KM rats during postnatal development. A significantly higher activity of ERK1/2 in KM rats was observed at 14th, 30th, and 60th days of postnatal development (P14, P30, P60) in comparison with control Wistar rats of the corresponding ages, while in adult (P120) KM rats it was at the same level with Wistar rats. Despite the increased activity of ERK1/2 at P14 and P30, the phosphorylation of synapsin I at Ser62/67 was significantly lower in the hippocampus of KM rats than in Wistar rats of the same ages; however, at P60 and P120, the phosphorylation of synapsin I was enhanced. Our data also revealed the increase of VGLUT2 and NR2B expression at P14, which dramatically decreased at the later stages. Our data indicate that a genetically determined increase in ERK1/2 kinase activity during postnatal ontogenesis in KM rats may be associated with the disturbances in synthesis and activity of the proteins, which are responsible for glutamatergic transmission in the KM rat hippocampus during the seizure susceptibility development.

Association between interleukin-6 gene polymorphisms and febrile seizure risk: A meta-analysis.

Background:The association between plasma interleukin-6 (IL-6) levels and the development of febrile seizures (FS) has been reported in multiple previous studies, which showed significantly higher serum IL-6 levels in FS patients than in control patients. However, the mechanism underlying this association remains unclear. One previous study indicated an increased frequency of the −174 GG and −597 GG genotypes in FS patients. Although IL-6 gene polymorphisms may be associated with FS risk, this association remains a matter of debate.ObjectiveConsidering the lack of meta-analyses addressing the possible association between IL-6 gene polymorphisms and the risk of FS, we aimed to perform a meta-analysis to determine the association of IL-6 gene polymorphisms (−572, −174, −597) with the risk of FS.MethodsWe conducted a systematic literature search in the PubMed, EMBASE, and WANFANG databases to collect eligible articles. The associations of IL-6 gene polymorphisms with FS risk were evaluated by calculating the pooled odds ratios and 95% confidence intervals. The dominant, recessive, heterozygous, homozygous, and allele genetic models were used to calculate the combined ORs.ResultsOur meta-analysis showed that IL-6 (−572, −174, −597) polymorphisms were significantly associated with susceptibility to FS.Conclusion:This study provided knowledge regarding the association of IL-6 (572, 174, 597) polymorphisms with susceptibility to FS. The T allele and TT genotype may be associated with an increased risk for FS.

Predictive value of acute EEG measurements for seizures and epilepsy after stroke using a dry cap electrode EEG system — Study design and proof of concept

The development of seizures is a common complication in patients with stroke. A recent study suggests that electroencephalography (EEG) could be useful to predict the occurrence of seizures after stroke. However, EEG is not routinely performed in the follow-up after stroke.We present the design and proof of concept of a large prospective cohort study in which we seek to evaluate the predictive usefulness of a single dry cap EEG measurement in the acute phase after stroke or transient ischemic attack (TIA) with respect to the development of poststroke epilepsy (PSE).In patients with ischemic stroke (IS), TIA, or intracerebral hemorrhage (ICH), an acute EEG measurement using a dry cap electrode EEG (dEEG) system is performed within 7 days of symptom onset. Electroencephalography data will be analyzed quantitatively and qualitatively looking for background asymmetry, different band power ratios, and epileptiform activity. The development of seizures will be assessed repeatedly during the first 2 years after stroke or TIA using a validated questionnaire.Results from the pilot phase of 11 patients showed that the dry cap EEG measurements in patients with acute stroke and TIA are feasible. In comparison with conventional EEG, a higher proportion of noise and artifacts was detected.This article is part of the Special Issue “Seizure & Stroke”

Risk of Seizures in Patients with Organophosphate Poisoning: A Nationwide Population-Based Study.

Objective: Previous research has demonstrated that patients with a history of organophosphate poisoning tend to have a higher risk of neurological disorder. However, research on the rate of seizure development in patients after organophosphate poisoning is lacking. This study examined whether individuals with organophosphate poisoning have an increased risk of seizures through several years of follow-up. Patients and Methods: We conducted a retrospective study on a cohort of 45,060 individuals (9012 patients with a history of organophosphate poisoning and 36,048 controls) selected from the Taiwan National Health Insurance Research Database. The individuals were observed for a maximum of 12 years to determine the rate of new-onset seizure disorder. We selected a comparison cohort from the general population that was randomly frequency-matched by age, sex, and index year and further analyzed the risk of seizures using a Cox regression model adjusted for sex, age, and comorbidities. Results: During the study period, the risk of seizure development was 3.57 times greater in patients with organophosphate poisoning compared with individuals without, after adjustments for age, sex, and comorbidities. The absolute incidence of seizures was highest in individuals aged 20 to 34 years in both cohorts (adjusted hazard ratio = 13.0, 95% confidence interval = 5.40−31.4). A significantly higher seizure risk was also observed in patients with organophosphate poisoning and comorbidities other than cirrhosis. Conclusions: This nationwide retrospective cohort study demonstrates that seizure risk is significantly increased in patients with organophosphate poisoning compared with the general population.

Evaluation of the effects of liraglutide on the development of epilepsy and behavioural alterations in two animal models of epileptogenesis

Liraglutide (LIR) is a novel long-lasting glucagon-like peptide-1 (GLP-1) analogue that facilitates insulin signalling and shows also neuroprotective properties in different brain disease models. In this study, we explored the potential antiepileptogenic effects of LIR in two different animal models; namely, the mouse intrahippocampal kainic acid (KA) model of temporal lobe epilepsy and the WAG/Rij rat model of absence epileptogenesis. Moreover, we evaluated LIR effects on comorbidities in various behavioural tests. Mice with kainate-induced epilepsy were treated with LIR (300 μg/kg/day s.c.) for 4 weeks after status epilepticus and then evaluated for drug effects on seizure development and behavioural alterations, whereas WAG/Rij rats were treated for 17 weeks (starting at 30 days of age, before seizure onset) with LIR (300 μg/kg/day s.c.) in order to investigate whether an early chronic treatment was able to reduce the development of absence seizures and related comorbidities. Our results indicate that LIR was effective in reducing the development of spontaneous seizures in kainate-induced epilepsy; moreover, in this model, it prevented memory impairment and related anxiety-like behaviour in the open field (OF) test while in the forced swimming test (FST), LIR displayed an apparent pro-depressant effect that was instead related to reduced endurance as confirmed by Rotarod test. In contrast, LIR was unable to modify the epileptogenic process underlying the development of absence seizures in WAG/Rij rats while being antidepressant in the FST in this strain. Our results indicate that LIR may represent a promising novel treatment to prevent and treat the epileptogenic process and its associated behavioural and cognitive alterations in some models of convulsive epilepsy characterized by neurodegeneration, since LIR effects are likely secondary to its recognized neuroprotective properties.

Serotonin abnormalities in Dravet syndrome mice before and after the age of seizure onset

Dravet syndrome (DS) is a genetic form of severe epilepsy often associated with mutation of the SCN1A gene encoding the voltage gated sodium channel Nav1.1. Typically refractive to conventional therapy, serotonin neurotransmission may be an innovative target for treatment. To further understand the role of serotonin in this disorder, in this study we examined the state of the endogenous serotonin system in an Scn1a+/– mouse model of DS. Examined at an age before seizures appear, we found the hypothermic effect of 5-HT1A receptor agonist administration was attenuated. HPLC analysis of brain monoamine content revealed modestly reduced serotonin levels in tissue samples of the midbrain that included the dorsal raphe nucleus but no changes elsewhere in the brain. The reduced sensitivity to 5-HT1A agonist administration seen at young ages reversed after the age of seizure development when mice showed an exaggerated hypothermic response. Likewise, adult DS mice showed a pronounced hypersensitivity to a 5-HT2A/2C agonist. As adults however monoamine levels were not detectably altered. Thus there are alterations in the endogenous serotonin system that both precede and follow the appearance of seizure in DS mice, most strikingly in the response to agonist administration.

A Feedforward Mechanism for Epileptogenesis Regulated by Lactate Dehydrogenase A

Abstract INTRODUCTION Despite the ketogenic diet's successful use since the 1920s, epilepsy as a disease of energy metabolism is a novel concept. We previously established that seizures deplete neuronal energy stores and reprogram neurons from aerobic to glycolytic metabolic phenotype, marked by upregulation of lactate dehydrogenase A (LDHA). LDHA has recently been shown to play a role in neuronal membrane depolarization and epileptogenesis. We show here that LDHA upregulation through HIF1a may lead to seizure formation. METHODS Resected tissue from 11 epileptic patients were probed for LDHA expression. To study the electrophysiological consequences of LDHA, we used a mixed rat cortical cell culture model on a microelectrode array (MEA). Furthermore, we developed a novel murine model of chronic focal cortical epilepsy to establish HIF1a's role in mediating LDHA expression and seizure formation. Finally, we used a lentivirus vector to directly upregulate LDHA in neurons cultured on an MEA to measure neuronal bursting. RESULTS We found LDHA increased significantly in epileptic tissue versus nonepileptic tissue. Induction of seizure activity in cultured neurons with low magnesium resulted in increased LDHA and subsequently increased baseline bursting over 10 d. Inhibition of LDHA activity with stiripentol and isosafrole decreased the overall burst frequency. Cells that were induced to upregulate LDHA via DMOG, an upstream HIF1a potentiator, showed a significant increase in baseline bursting activity. Furthermore, placement of cobalt, a HIF1a stabilizer, into the frontal cortex of mice caused chronic seizures emanating from perilesion cortex which showed increased LDHA. Finally, direct LDHA upregulation resulted in increased bursting activity confirming that LDHA may lead to seizure formation. CONCLUSION Overall, our data show that LDHA, regulated by HIF1a, can contribute to seizure development. These data suggest a novel molecular mechanism for the pathogenesis of epilepsy where seizures cause LDHA upregulation which then further drives seizures, leading to a cycle of epileptogenesis.

Seizures in Childhood: Aetiology, Diagnosis, Treatment, and What the Future May Hold

Seizures are one of the most common medical problems affecting children, and epilepsy is the most common chronic neurological condition in children. Childhood epilepsy syndromes include a wide spectrum of disorders ranging from benign to life threatening. While there are many known epilepsy syndromes, there are many factors, which may lead to the development of seizures in children including infection, traumatic brain injury, or structural abnormality. Up to 40% of childhood epilepsies are thought to have some component of genetic involvement. New genes, mutations, and variants involved in epilepsy are being identified continuously. Most of the genes which have been identified encode for neurotransmitter receptors, ion channels, molecules involved in intracellular signalling, or proteins involved in synaptic structure. As new candidate genes in epilepsy are identified, new technologies in genetic testing are becoming available and more accessible, making the molecular diagnosis of epilepsy increasingly relevant to researchers, physicians, patients, and their families. The standard of care and first-line treatment is the use of antiepileptic drugs. For those patients with medication-refractory epilepsy other available therapies include ketogenic diet, vagal nerve stimulator, or epilepsy surgery. The newest advancement in the treatment of paediatric epilepsies is based around the idea of targeted therapy. These therapies incorporate pharmacogenomics, the principle that an individual’s genetic background affects their response to specific drugs, as well as precision medicine, which identifies treatments for the damaged products resulting from specific gene mutations. Many of these therapies are still under research or in trial; however, there is much promise for the future of targeted medications.