Chronic Epilepsy Research Articles

Tiagabine suppresses pentylenetetrazole-induced seizures in mice and improves behavioral and cognitive parameters by modulating BDNF/TrkB expression and neuroinflammatory markers

Tiagabine (Tia), a new-generation antiseizure drug that mimics the GABAergic signaling by inhibiting GABA transporter type-1, is the least studied molecule in chronic epilepsy models with comorbid neurobehavioral and neuroinflammatory parameters. Therefore, the current study investigated the effects of Tia in a real-time manner on electroencephalographic (EEG) activity, behavioral manifestations and mRNA expression in pentylenetetrazole (PTZ)-kindled mice. Male BALB/c mice were treated with tiagabine (0.5, 1 and 2 mg/kg) for 21 days with simultaneous PTZ (40 mg/kg) injection every other day for a total of 11 injections and monitored for seizure progression with synchronized validation through EEG recordings from cortical electrodes. The post-kindling protection from anxiety and memory deficit was verified by a battery of behavioral experiments. Isolated brains were evaluated for oxidative alterations and real-time changes in mRNA expression for BDNF/TrkB, GAT-1 and GAT-3 as well as neuroinflammatory markers. Experimental results revealed that Tia at the dose of 2 mg/kg maximally inhibited the development of full bloom seizure and reduced epileptic spike discharges from the cortex. Furthermore, Tia dose-dependently exerted the anxiolytic effects and protected from PTZ-evoked cognitive impairment. Tia reduced lipid peroxidation and increased superoxide dismutase and glutathione levels in the brain via augmentation of GABAergic modulation. PTZ-induced upregulated BDNF/TrkB signaling and pro-inflammatory cytokines were mitigated by Tia with upregulation of GAT-1 and GAT-3 transporters in whole brains. In conclusion, the observed effects of Tia might have resulted from reduced oxidative stress, BDNF/TrkB modulation and mitigated neuroinflammatory markers expression leading to reduced epileptogenesis and improved epilepsy-related neuropsychiatric effects.

Serum Markers of Neuronal Damage and Astrocyte Activity in Patients with Chronic Epilepsy: Elevated Levels of Glial Fibrillary Acidic Protein

Objectives. Blood-brain barrier (BBB) dysfunction is one of the key pathogenic mechanisms in the development of epilepsy. There is therefore an increasing need to identify BBB biomarkers as these will have prognostic and therapeutic implications. The purpose of this study was to assess the levels of the BBB permeability markers, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), S100B, and furin in patients with stable epilepsy compared with the levels in healthy controls. Materials and Methods. This cross-sectional study included 119 epilepsy patients and 80 healthy controls. Circulating levels of GFAP, NSE, S100B, and furin were measured and questionnaires regarding epilepsy, use of drugs, and comorbidities were completed by all participants. Results. GFAP levels were higher in epilepsy patients after adjustment for potential confounders (sex, age, and BMI) in linear regression ( p = 0.042 ). No significant differences were found in levels of S100B, NSE, or furin. None of the markers were significantly associated with epilepsy duration, seizure type or severity, or seizures in the preceding six months. The majority of the patients (79.7%) did not report seizures within the last 6 months. Conclusion. Our main finding is elevated serum levels of GFAP in epilepsy patients. The results may suggest the presence of astrocyte activation in our patient population with stable epilepsy. Future prospective studies focusing on the longitudinal relationship between epilepsy debut, seizures, and time of blood sampling for BBB markers, also within CSF, could provide valuable knowledge including regarding novel treatment options. The study registration number is 2011/1096, 2018/1437.

Specific profiles of new-onset vs. non-inaugural status epilepticus: From diagnosis to 1-year outcome.

While new-onset status epilepticus (NOSE) is a harbinger of chronic epilepsy, prospective medical data are sparse in terms of specifying whether the evolution of status epilepticus (SE) and seizure expression in NOSE resembles what occurs in patients who have already been diagnosed with epilepsy [non-inaugural SE (NISE)] in all aspects apart from its inaugural nature. The aim of this study was to compare the clinical, MRI, and EEG features that could distinguish NOSE from NISE. We conducted a prospective monocentric study in which all patients ≥18 years admitted for SE over a 6-month period were included. A total of 109 patients (63 NISE and 46 NOSE cases) were included. Despite similar modified Rankin scores before SE, several aspects of the clinical history distinguished NOSE from NISE patients. NOSE patients were older and frequently had neurological comorbidity and preexisting cognitive decline, but they had a similar prevalence of alcohol consumption to NISE patients. NOSE and NISE evolve in the same proportions as refractory SE (62.5% NOSE, 61% NISE) and share common features such as the same incidence (33% NOSE, 42% NISE, and p = 0.53) and volumes of peri-ictal abnormalities on MRI. However, in NOSE patients, we observed greater non-convulsive semiology (21.7% NOSE, 6% NISE, and p = 0.02), more periodic lateral discharges on EEG (p = 0.004), later diagnosis, and higher severity according to the STESS and EMSE scales (p < 0.0001). Mortality occurred in 32.6% of NOSE patients and 21% of NISE patients at 1 year (p = 0.19), but with different causes of death occurring at different time points: more early deaths directly linked to SE at 1 month occurred in the NOSE group, while there were more remote deaths linked to causal brain lesions in the NISE group at final follow-up. In survivors, 43.6% of the NOSE cases developed into epilepsy. Despite acute causal brain lesions, the novelty related to its inaugural nature is still too often associated with a delay in diagnosing SE and a poorer outcome, which justifies the need to more clearly specify the various types of SE to constantly raise awareness among clinicians. These results highlight the relevance of including novelty-related criteria, clinical history, and temporality of occurrence in the nosology of SE.

Neuroprotection impact of biochanin A against pentylenetetrazol-kindled mice: Targeting NLRP3 inflammasome/TXNIP pathway and autophagy modulation.

Recurrent seizures characterize epilepsy, a complicated and multifaceted neurological disease. Several neurological alterations, such as cell death and the growth of gorse fibers, have been linked to epilepsy. The dentate gyrus of the hippocampus is particularly vulnerable to neuronal loss and abnormal neuroplastic changes in the pentylenetetrazol (PTZ) kindling model. Biochanin A has potent anti-inflammatory and antioxidant properties, according to previous evidence and its possible impact in epilepsy has never previously been claimed. The current work aimed to investigate biochanin A's anti-epileptic potential in PTZ-induced kindling model in mice. Chronic epilepsy was established in mice by giving PTZ (35mg/kg, i.p) every other day for 21days. Biochanin A (20mg/kg) was given daily till the end of the experiment. Biochanin A pretreatment significantly reduced the severity of epileptogenesis by 51.7% and downregulated the histological changes in the CA3 region of the hippocampus by 42% along with displaying antioxidant/anti-inflammatory efficacy through upregulated hemeoxygenase-1 (HO-1) and, erythroid 2-related factor 2 (Nrf2) levels in the brain by 1.9-fold and 2-fold respectively, parallel to reduction of malondialdehyde (MDA), myeloperoxidase (MPO), glial fibrillary acidic protein (GFAP) and L-glutamate/IL-1β/TXNIB/NLRP3 axis. Moreover, biochanin A suppressed neuronal damage by reducing the astrocytes' activation and significantly attenuated the PTZ-induced increase in LC3 levels by 55.5%. Furthermore, molecular docking findings revealed that BIOCHANIN A has a higher affinity for phosphoinositide 3-kinase (PI3k), threonine kinase2 (AKT2), and mammalian target of rapamycin complex 1 (mTORC1) indicating the neuroprotective and anti-epileptic characteristics of biochanin A in the brain tissue of PTZ-kindled mice.

Abstract WMP26: Acute Left Superior Temporal Damage Results In Phonological Errors In Word Comprehension

Right hemisphere deactivation by right carotid injection of sodium amytal (Wada testing) in chronic epilepsy results in few phonological errors in word comprehension. Based on this finding, recent models of language processing indicate that speech sound and spoken word processing is bilateral, so that unilateral stroke should not affect distinguishing phonologically similar words (e.g. boat/note) for word comprehension. We tested the alternative hypothesis that acute left hemisphere stroke in superior temporal gyrus (STG) results in phonological errors in a word-picture verification task, which would support the proposal that the right hemisphere does not support speech sound processing and word comprehension before recovery through reorganization of structure/function relationships. Methods: A series of 218 participants were tested with a word-picture verification test with targets and phonologically similar words and had brain MRI within 4 days of stroke onset. We evaluated associations between any damage to left STG and phonological errors using chi square, and the correlation between degree of damage to STG and number of errors using Spearman Rho. Results: We found a very strong association between infarct in left STG and the production of phonological errors in word comprehension (chi squared= 31.2; p &lt;0.00001). Furthermore, the number of phonological errors was strongly correlated with the degree of infarct in left STG (rho=0.49; p&lt;0.00001). Results indicate that left STG, when acutely damaged, often results in phonological errors in word comprehension. These results indicate that the paucity of such errors in comprehension in studies of chronic left hemisphere stroke or Wada testing is a result of reorganization following chronic left temporal dysfunction. Patients with acute left STG stroke should be tested with sensitive tests for word comprehension deficits, including phonologically similar words, before giving verbal direction on exam or obtaining informed consent for procedures.

Investigating the mechanism of antiepileptogenic effect of apigenin in kainate temporal lobe epilepsy: possible role of mTOR.

Clarifying the underlying mechanisms of epileptogenesis is important in preventing the progression of chronic epilepsy. In epilepsy, the mTOR (mammalian target of rapamycin) pathway plays a critical role in mediating the mechanism of epileptogenesis. In this study, we investigate whether apigenin can exert antiepileptogenic effects through the inhibition of mTOR in the kainate model of epilepsy. For assessing the antiepileptogenic effect of apigenin in kainic acid (KA)-induced temporal lobe epilepsy (TLE) model, apigenin at a dose of 50mg/kg was administrated by gavage for 6days. An intracranial electroencephalogram (iEEG) was performed to confirm the establishment of status epilepticus. BrdU was used to detect neurogenesis in the CA3, and dentate gyrus and mossy fiber sproutings were assessed by Timm staining. The expression of mTOR was quantified via western blot. We found that apigenin-pretreatment had a significant inhibitory effect on neural cell death, spontaneous seizure spikes, aberrant neurogenesis, mTOR hyperactivity, and aberrant mossy fiber sprouting. Overall, these results suggest that apigenin has an antiepileptogenic effect and may be a useful target for inhibiting mTOR hyperactivity in epilepsy.

Long-term outcomes of classic and novel anti-seizure medication in a kainate-induced model of chronic epilepsy

ObjectiveIntrahippocampal injection of kainate (KA) is a reliable model of temporal lobe epilepsy (TLE) that replicates spontaneous recurrent seizures. Both electrographic seizures and electroclinical seizure (most generalized seizure) can be detected in KA model. Electrographic seizures such as high-voltage sharp waves (HVSWs) and hippocampal paroxysmal discharges (HPDs) are far more common and attracting much attention. A comprehensive study on the anticonvulsant effects of classic and novel antiseizure medications (ASMs) on spontaneous electroclinical seizures, especially during long-term treatment, is still lacking. Here, we evaluated the effects of six ASMs in this model on electroclinical seizures over eight weeks. MethodsUsing 24-hour continuous electroencephalographical (EEG) monitoring in free-moving mice, we tested the effectiveness of six ASMs (valproic acid, VPA; carbamazepine, CBZ; lamotrigine, LTG; perampanel, PER; brivaracetam, BRV; and everolimus, EVL) on the electroclinical seizures over eight weeks in the intrahippocampal kainate mouse model. ResultsVPA, CBZ, LTG, PER and BRV significantly suppressed electroclinical seizures in the early stages of treatment, but the mice gradually developed resistance to these drugs. Overall, the mean frequency of electroclinical seizures was not significantly lower during the 8-week treatment than that at baseline in any ASM-treated group. The individual responses to ASMs varied widely. ConclusionLong-term treatment with VPA, LTG, CBZ, PER, BRV and EVL did not relieve electroclinical seizures in this TLE model. Additionally, the window for screening new ASMs in this model should be set to at least 3 weeks to account for drug resistance.

Blood-Brain Barrier-Associated Proteins Are Elevated in Serum of Epilepsy Patients.

Blood-brain barrier (BBB) dysfunction emerges as one of the mechanisms underlying the induction of seizures and epileptogenesis. There is growing evidence that seizures also affect BBB, yet only scarce data is available regarding serum levels of BBB-associated proteins in chronic epilepsy. In this study, we aimed to assess serum levels of molecules associated with BBB in patients with epilepsy in the interictal period. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2, S100B, CCL-2, ICAM-1, P-selectin, and TSP-2 were examined in a group of 100 patients who were seizure-free for a minimum of seven days and analyzed by ELISA. The results were compared with an age- and sex-matched control group. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2 and S100B were higher in patients with epilepsy in comparison to control group (p < 0.0001; <0.0001; 0.001; <0.0001; <0.0001, respectively). Levels of CCL-2, ICAM-1, P-selectin and TSP-2 did not differ between the two groups. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2 and S100B are elevated in patients with epilepsy in the interictal period, which suggests chronic processes of BBB disruption and restoration. The pathological process initiating epilepsy, in addition to seizures, is probably the factor contributing to the elevation of serum levels of the examined molecules.

Peroxiredoxin 6 Regulates Glutathione Peroxidase 1-Medited Glutamine Synthase Preservation in the Hippocampus of Chronic Epilepsy Rats.

Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats, although the underlying mechanisms of its anti-convulsive effects are not fully understood. To elucidate this, the present study was designed to investigate whether NAC affects astroglial glutamine synthase (GS) expression mediated by GSH peroxidase 1 (GPx1) and/or peroxiredoxin 6 (Prdx6) in the epileptic hippocampus. As compared to control animals, GS and GPx1 expressions were upregulated in reactive CA1 astrocytes of chronic epilepsy rats, while their expressions were significantly decreased in clasmatodendritic CA1 astrocytes and reactive astrocytes within the molecular layer of the dentate gyrus. Prdx6 expression was increased in reactive CA1 astrocytes as well as clasmatodendritic CA1 astrocytes. In the molecular layer of the dentate gyrus, Prdx6 expression levels were similar to those in control animals. NAC ameliorated clasmatodendrosis through the increment of GS and GPx1 expressions, while it abolished Prdx6 upregulation. 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) alleviated clasmatodendrosis by enhancing GPx1 and GS expressions in clasmatodendritic CA1 astrocytes without changing the Prdx6 level. NAC or MJ33 did not affect GS, GPx1 and Prdx6 expression in astrocytes within the molecular layer of the dentate gyrus. These findings indicate that upregulated aiPLA2 activity of Prdx6 may abolish GPx1-mediated GS preservation and lead to clasmatodendrosis in CA1 astrocytes, which would extend spontaneous seizure duration due to impaired glutamate-glutamine conversion regulated by GS. Therefore, the present data suggest that aiPLA2 activity of Prdx6 in astrocytes may be one of the upstream effectors of seizure duration in the epileptic hippocampus.

Pharmacokinetics of cannabidiol following single oral and oral transmucosal administration in dogs.

In the last few years, different formulations containing cannabidiol (CBD) were tested with regard to its efficacy on chronic pain, refractory epilepsy, anxiety, aggressive behavior and atopic dermatitis in dogs. CBD is generally administered orally, but its low bioavailability, probably due to a first-pass metabolism, represents a great limitation. The aim of this study was to evaluate if CBD bioavailability increases after oral transmucosal administration (OTM) compared to oral treatment. Twelve dogs diagnosed with mild chronic pain were enrolled in the study and treated once orally or OTM (6 dogs/group) with a pure CBD in oil formulation at a dosing rate of 1 mg/kg b.w. At prefixed time points, blood samples were collected to define CBD plasma concentrations vs. time profiles, and the main pharmacokinetics parameters were obtained by non-compartmental model. CBD Cmax, Tmax, terminal half-life and AUC0 - t were 206.77 ± 167 and 200.33 ± 158.33 ng/mL, 2.17 ± 0.98 and 1.92 ± 1.11 h, 2.67 ± 0.53 and 2.62 ± 0.64 h, 647.51 ± 453.17, and 536.05 ± 370.21 h*ng/mL, following oral and OTM administration, respectively. No significant difference in pharmacokinetic parameters were observed between treatments. The OTM administration did not increase cannabidiol bioavailability compared to oral treatment. The almost perfectly superimposable mean plasma concentrations of cannabidiol following the two treatments suggests that CBD is not able to be adsorbed by the oral mucosa or that its absorption is very scarce, and that CBD is swallowed and absorbed in the gastrointestinal tract.

Synaptosome microRNAs: emerging synapse players in aging and Alzheimer's disease.

Synaptosome microRNAs: emerging synapse players in aging and Alzheimer's disease.

Attenuation of Seizures, Cognitive Deficits, and Brain Histopathology by Phytochemicals of Imperata cylindrica (L.) P. Beauv (Poaceae) in Acute and Chronic Mutant Drosophila melanogaster Epilepsy Models.

Imperata cylindrica is a globally distributed plant known for its antiepileptic attributes, but there is a scarcity of robust evidence for its efficacy. The study investigated neuroprotective attributes of Imperata cylindrica root extract on neuropathological features of epilepsy in a Drosophila melanogaster mutant model of epilepsy. It was conducted on 10-day-old (at the initiation of study) male post-eclosion bang-senseless paralytic Drosophila (parabss1) involved acute (1-3 h) and chronic (6-18 days) experiments; n = 50 flies per group (convulsions tests); n = 100 flies per group (learning/memory tests and histological examination). Administrations were done in 1 g standard fly food, per os. The mutant flies of study (parabss1) showed marked age-dependent progressive brain neurodegeneration and axonal degeneration, significant (P < 0.05) bang sensitivity and convulsions, and cognitive deficits due to up-regulation of the paralytic gene in our mutants. The neuropathological findings were significantly (P < 0.05) alleviated in dose and duration-dependent fashions to near normal/normal after acute and chronic treatment with extract similar to sodium valproate. Therefore, para is expressed in neurons of brain tissues in our mutant flies to bring about epilepsy phenotypes and behaviors of the current juvenile and old-adult mutant D. melanogaster models of epilepsy. The herb exerts neuroprotection by anticonvulsant and antiepileptogenic mechanisms in mutant D. melanogaster due to plant flavonoids, polyphenols, and chromones (1 and 2) which exert antioxidative and receptor or voltage-gated sodium ion channels' inhibitory properties, and thus causing reduced inflammation and apoptosis, increased tissue repair, and improved cell biology in the brain of mutant flies. The methanol root extract provides anticonvulsant and antiepileptogenic medicinal values which protect epileptic D. melanogaster. Therefore, the herb should be advanced for more experimental and clinical studies to confirm its efficacy in treating epilepsy.

5-Hydroxy Tryptamine Receptor 6 Inactivation Improves Cognitive Impairment in Pilocarpine-Induced Chronic Epilepsy through Modulating Metabolic Injury

5-Hydroxy Tryptamine Receptor 6 Inactivation Improves Cognitive Impairment in Pilocarpine-Induced Chronic Epilepsy through Modulating Metabolic Injury

ON THE ROLE OF TUMOR NECROSIS FACTOR-ALPHA (TNF-α) AND NUCLEAR FACTOR p-NF-κB IN THE PENTYLENETETRAZOLE KINDLING PATHOGENESIS

Determining the role of endogenous factors as markers of chronic epileptic activity allows pathogenetically justifying new approaches to treating epilepsy. The aim of the work was the immunohistochemical study of the expression of the tumor necrosis factor-alpha (TNF-α) and nuclear factor p-NF-κB in the tissue of the dorsal parts of the hippocampus in rats with kindling seizures. Kindling was produced in 15 rats by three-week i.p. pentylenetetrazole (PTZ, 35.0 mg/kg) administration. 20 control group rats were injected with 0.9% NaCl solution. The avidin-biotin-peroxidase method was used in 10 control group rats for staining. The rest ten rats composed the negative control group and stained using only secondary antibodies. The color intensity of the brain sections of the control and kindling groups was compared with the color of the brain sections of the negative control group using the "Image J" program. In rats with PTZ-kindling, the level of TNF-α was 17.86+0.83 relative units (RU) and exceeded the corresponding indicator in the control group (4.78+0.14 RU), (p&lt;0.001). The expression of p-NF-κB was 5.24+0.61 against 1.73+0.07 RU in control (p&lt;0.001). Determination of the expression of TNF-α and NF-κB in limbic structures can be used as markers of the effectiveness of experimental treatment methods for chronic epilepsy. Key words: seizures, cytokines, hypoxia, pentylenetetrazol, hippocamp

A Feature Extraction Method for Seizure Detection Based on Multi-Site Synchronous Changes and Edge Detection Algorithm.

Automatic detection of epileptic seizures is important in epilepsy control and treatment, and specific feature extraction assists in accurate detection. We developed a feature extraction method for seizure detection based on multi-site synchronous changes and an edge detection algorithm. We investigated five chronic temporal lobe epilepsy rats with 8- and 12-channel detection sites in the hippocampus and limbic system. Multi-site synchronous changes were selected as a specific feature and implemented as a seizure detection method. For preprocessing, we used magnitude-squared coherence maps and Canny edge detection algorithm to find the frequency band with the most significant change in synchronization and the important channel pairs. In detection, we used the maximal cross-correlation coefficient as an indicator of synchronization and the correlation coefficient curves' average value and standard deviation as two detection features. The method achieved high performance, with an average 96.60% detection rate, 2.63/h false alarm rate, and 1.25 s detection delay. The experimental results show that synchronization is an appropriate feature for seizure detection. The magnitude-squared coherence map can assist in selecting a specific frequency band and channel pairs to enhance the detection result. We found that individuals have a specific frequency band that reflects the most significant synchronization changes, and our method can individually adjust parameters and has good detection performance.

Synapse-specific changes in Arc and BDNF in rat hippocampus following chronic temporal lobe epilepsy

Expression of immediate early genes (IEGs) in the brain is important for synaptic plasticity, and probably also in neurodegenerative conditions. To understand the cellular mechanisms of the underlying neuropathophysiological processes in epilepsy, we need to pinpoint changes in concentration of synaptic plasticity-related proteins at subsynaptic levels. In this study, we examined changes in synaptic expression of Activity-regulated cytoskeleton-associated (Arc) and Brai Derived Neurotrophic Factor (BDNF) in a rat model of kainate-induced temporal lobe epilepsy (TLE). Western blotting showed reduced concentrations of Arc and increased concentrations of BDNF in hippocampal synaptosomes in chronic TLE rats. Then, using quantitative electron microscopy, we found corresponding changes in subsynaptic regions in the hippocampus. Specifically, we detected significant reductions in the concentrations of Arc in the presynaptic terminal of Schaffer collateral glutamatergic synapses in the stratum radiatum of the CA1 area in TLE, as well as in their adjacent postsynaptic spines. In CA3, there was a significant reduction of Arc only in the presynaptic terminal cytoplasm. Conversely, in CA3, there was a significant increase in the expression of BDNF in the presynaptic terminal, but not in the postsynaptic spine. Significant increase in BDNF concentration in the CA1 postsynaptic density was also obtained. We hypothesize that the observed changes in Arc and BDNF may contribute to both cognitive impairment and increased excitotoxic vulnerability in chronic epilepsy.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) as a novel presentation of CNS autoimmunity in a pediatric patient with Wiskott-Aldrich syndrome (WAS)

Objective Report a novel case of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) presenting as relapsing bilateral optic neuritis in a pediatric patient with Wiskott-Aldrich syndrome (WAS). Background WAS is a rare X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections, thrombocytopenia, eczema, malignancies, and autoimmunity. Known CNS autoimmune manifestations include cerebral vasculitis, but optic neuritis, CNS demyelination, and MOGAD have not been previously reported. Design/Methods Chart review Results A 5-year-old boy with a history of chronic immune thrombocytopenia, hypogammaglobulinemia, anemia, and focal epilepsy developed binocular vision loss. MRI of the brain demonstrated enlargement of bilateral optic nerves with marked enhancement of the nerve sheaths consistent with optic neuritis, as well as multiple small enhancing supratentorial lesions. He was treated with pulse methylprednisolone followed by oral steroid taper, and he returned to baseline with no reported residual visual deficits. Five months later, he experienced a relapse of bilateral vision loss, and repeat MRI re-demonstrated bilateral optic neuritis as well as resolution of prior brain lesions. He was treated with repeat course of steroids and experienced moderate improvement in his vision. Rituximab was then initiated to prevent further relapses of optic neuritis while treating his chronic suspected immune-mediated thrombocytopenia. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) via serum fluorescence-activated cell sorting assay was positive (titer 1:100), confirming a diagnosis of MOGAD. At age six, molecular panel testing for genes associated with primary immunodeficiency identified a missense WAS gene variant. He was subsequently found to have decreased WAS protein expression consistent with a diagnosis of WAS. Conclusions We describe a case of pediatric MOGAD presenting with multiphasic bilateral optic neuritis in a patient with WAS. This case expands the reported spectrum of CNS autoimmunity associated with WAS and may help to inform indications for therapeutic options such as bone marrow transplant.

Pentylenetetrazole kindling-induced epilepsy rat models: Insight on the severity state, a comparative study.

This study aimed to carry out a comparative study of the main models of chronic epilepsy induced by pentylenetetrazole (PTZ)-kindling method and to assess the efficacy of sodium valproate, one of the main antiepileptics, on the best epilepsy-inducing kindling model. Two sets of 24 animals were divided into 4 groups of 6 animals and treated as follow: Set 1 included: group 1, control; group 2, the classic kindling PTZ group (UKEOD); group 3, PTZ kindling every other day group with challenge (CKEOD); group 4, PTZ kindling every day group, with challenge (CKED); Set 2 included: group 1, control; group 2, CKEOD group; group 3 and 4, receiving either valproate 200mg/kg or valproate 300mg/kg +CKEOD procedure. Results show that CKEOD group significantly reduced the number of injections necessary to reach the fully-kindled state, increased the severity of seizures and improved the stability of seizures. In addition, the CKEOD group significantly increased the level of malondialdehyde and GABA transaminase, reduced the level of reduced glutathione, catalase and GABA. Furthermore, it had no impact on plasma levels of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT). Valproate 300mg/kg significantly protected animals against kindling induced by CKEOD. The kindling model with a challenge dose administered on day 1 (CKEOD) thus allows to induce more severe, more stable chronic epilepsy and in a shorter period of time, and could thus contribute to a better understanding of epilepsy, as well as its uses in drug discovery.

Protocol for an observational cohort study investigating biomarkers predicting seizure recurrence following a first unprovoked seizure in adults

IntroductionA first unprovoked seizure is a common presentation, reliably identifying those that will have recurrent seizures is a challenge. This study will be the first to explore the combined utility...

Targeting aberrant dendritic integration to treat cognitive comorbidities of epilepsy.

Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed a marked increase in the fraction of hippocampal first-order CA1 pyramidal cell dendrites capable of generating dendritic spikes in the kainate model of chronic epilepsy. Moreover, in epileptic mice dendritic spikes were generated with lower input synchrony, and with a lower threshold. The Nav1.3/1.1 selective Na+ channel blocker ICA-121431 reversed dendritic hyperexcitability in epileptic mice, while the Nav1.2/1.6 preferring anticonvulsant S-Lic did not. We used in vivo two-photon imaging to determine if aberrant dendritic excitability is associated with altered place-related firing of CA1 neurons. We show that ICA-121431 improves degraded hippocampal spatial representations in epileptic mice. Finally, behavioural experiments show that reversing aberrant dendritic excitability with ICA-121431 reverses hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.