Female sex steroids and epilepsy: Part 2. A practical and human focus on catamenial epilepsy.

Catamenial epilepsy is the best described and most researched sex steroid-specific seizure exacerbation. Yet despite this there are no current evidence-based treatments, nor an accepted diagnostic tool. The best tool we currently have is tracking seizures over menstrual cycles; however, the reality of tracking seizures and menstrual cycles is fraught with challenges. In Part 1 of this two-part review, we outlined the often complex and reciprocal relationship between seizures and sex steroids. An adaptable means of tracking is required. In this review, we outline the extent and limitations of current knowledge on catamenial epilepsy. We use sample data to show how seizure exacerbations can be tracked in short/long and even irregular menstrual cycles. We describe how seizure severity, an often overlooked and underresearched form of catamenial seizure exacerbation, can also be tracked. Finally, given the lack of treatment options for females profoundly affected by catamenial epilepsy, Section 3 focuses on current methods and models for researching sex steroids and seizures as well as limitations and future directions. To permit more informative, mechanism-focused research in humans, the need for both a consistent classification of catamenial epilepsy and an objective biomarker is highlighted.

Catamenial epilepsy occurrence and patterns in a mixed population of women with epilepsy.

We evaluated the occurrence and distribution of patterns of catamenial epilepsy in a heterogenous cohort of women with epilepsy on no hormonal therapies, enrolled in a prospective, observational study. The primary aim of the study was pregnancy rate in women with epilepsy with no prior reproductive problems. In this analysis, we included women who recorded one or more menstrual cycles with one or more seizures. We measured progesterone concentrations for one to three cycles. We defined catamenial patterns as twofold or greater average daily seizure frequency around menstruation (C1), ovulation (C2), and for anovulatory cycles, from midcycle through menstruation (C3). Twenty-three of the 89 enrolled women with epilepsy were eligible for this analysis; 12 of 23 met criteria for catamenial epilepsy; five of 23 demonstrated only a C1 pattern, two of 23 only a C2 pattern, five of 23 a combined C1/C2 pattern, and the one woman with anovulatory cycles did not demonstrate a C3 pattern. There were no differences in likelihood of demonstrating a catamenial pattern between those who reported a prior catamenial pattern and those who did not (p = .855). This analysis demonstrates the utility of app-based tracking to determine a catamenial pattern. Larger prospective studies could confirm these findings and inform potential therapeutic trial designs for catamenial epilepsy.

Management of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: There are limited data about the treatment and management of epilepsy with eyelid myoclonia (EEM). The objective of this study was to determine areas of consensus among an international panel of experts for the management of EEM (formerly known as Jeavons syndrome). METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the treatment, other areas of management, and prognosis for EEM. RESULTS: There was a strong consensus for valproic acid as the first-line treatment, with levetiracetam or lamotrigine as preferable alternatives for women of childbearing age. There was a moderate consensus that ethosuximide and clobazam are also efficacious. There was a strong consensus to avoid sodium channel-blocking medications, except for lamotrigine, as they may worsen seizure control. There was consensus that seizures typically persist into adulthood, with remission occurring in <50% of patients. There was less agreement about other areas of management, including dietary therapy, lens therapy, candidacy for driving, and outcome. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the optimal management of EEM. These areas of consensus may inform clinical practice to improve the management of EEM. In addition, multiple areas with less agreement were identified, which highlight topics for further research.

Follow-up to low-dose fenfluramine for Sunflower syndrome: A non-randomized controlled trial.

AIM: This study reports on the long-term results for an initial cohort of patients with Sunflower syndrome who enrolled in an open-label study of low-dose fenfluramine as well as the short-term results of a second cohort. METHOD: We conducted a single-center, open-label study at the Massachusetts General Hospital. We analyzed the effect of fenfluramine on handwaving seizure frequency at monthly intervals during a 4-month core study period for the second patient cohort, and we evaluated the long-term (>2 years) effect of fenfluramine for the initial patient cohort. RESULTS: Eight of the 10 patients from the second cohort provided analyzable seizure data. These patients experienced a 33% median reduction in seizure frequency during the core study, as compared to the previously reported 79% for the initial cohort (n = 9). Of the seven patients from the first cohort who remain on fenfluramine in the extension study, five continue to experience benefit. Fenfluramine was overall well tolerated with minimal side effects, reduced appetite and fatigue being the primary adverse events, and no evidence of cardiac valvulopathy or pulmonary hypertension. INTERPRETATION: This study suggests fenfluramine can be an effective, durable, and well-tolerated antiseizure medication option for patients with Sunflower syndrome.

Anticonvulsant Effect of Asparagus racemosus Willd. in a Mouse Model of Catamenial Epilepsy.

Asparagus racemosus Willd. (Family Liliaceae), also known as female reproductive tonic, is traditionally used across the Sub-Himalayan region in Uttarakhand, India for treatment of epilepsy and disorders of female reproductive system. Therefore, in this study, we investigated the anticonvulsant effect of A. racemosus in a mouse model of catamenial epilepsy. We artificially increased progesterone and neurosteroid levels (a state of pseudo-pregnancy) in adult Swiss albino female mice by injecting pregnant mares' serum gonadotropin (PMSG) (5 IU s.c.), followed by human chorionic gonadotropin (HCG) (5 IU s.c.) after 46 h. In the following 10 days, A. racemosus treatment was given along with measurement of progesterone, estradiol, and corticosterone levels in the blood. Neurosteroid withdrawal was induced by finasteride (50 mg/kg, i.p.) on treatment day 9. Twenty-four hours after finasteride administration (day 10 of treatment), seizure susceptibility was evaluated with the sub-convulsant pentylenetetrazole (PTZ) dose (40 mg/kg i.p.). Four hours after PTZ, animals were assessed for depression like phenotypes followed by euthanasia and separation of brain parts (cortex and hippocampus). The results showed that PMSG and HCG treatment elevated progesterone and estradiol levels. Treatment with finasteride increased seizure susceptibility and depression due to decreased progesterone and elevated estrogen levels coupled with decreased monoamine and elevated corticosterone levels. A. racemosus treatment, on the other hand, significantly decreased seizure susceptibility and depression like behaviors, possibly because of increased progesterone, restored estradiol, corticosterone, and monoamine levels. We concluded that herbal formulations using A. racemosus root extracts may be used as monotherapy or adjuvant therapy along with available AEDs for the better and safe management of catamenial epilepsy as well as comorbid depression.

[Self-induced epileptic seizures: Prevalence, Causes and Treatment]. / Selbstinduzierte epileptische Anfälle Prävalenz, Ursachen und Behandlung.

Self-induced seizures were first described in 1827. A majority of authors found that in unselected patients with epilepsy, the prevalence rate of these seizures was 1%. In patients with photosensitive epilepsy, there was roughly a 25% prevalence. Apart from visual stimulation, many other mechanisms of self-induction have been described. A feeling of pleasure or relaxation during seizures may be a reason for self-inductive behaviour. But often the procedure of self-induction is experienced as involuntary. Treatment is always difficult. Behavioral therapy has been proven effective in some patients. In patients with photosensitive epilepsy, sunglasses are recommended. Fenfluramine, clonazepam and valproate seem to be a bit more effective than other drugs. After all, the treatment effect depends on the motivation of the patient to change the condition.

Sunflower syndrome: a poorly understood photosensitive epilepsy.

Sunflower syndrome is a rare photosensitive epilepsy which has received little attention in recent medical literature. The historical cases documenting the epilepsy's stereotyped handwaving motion in front of light characterized the behavior as self-inducing seizures via mimic of stroboscopic effect. However, the relationship between handwaving episodes and attendant generalized electroencephalogram abnormalities, and an appreciation of the compulsive attraction the sun and other light sources hold for these patients, suggest the handwaving motion may be a part of the seizure rather than a mechanism of self-induction. The lack of awareness of Sunflower syndrome often leads to misdiagnosis. The seizures are often refractory to traditional anticonvulsant medication, and patients resort to behavioral intervention, such as hats and sunglasses, to reduce handwaving episodes. Further study is required to determine the syndrome's natural history and to identify more effective treatment options. WHAT THIS PAPER ADDS: Sunflower syndrome is a rare condition that is often misdiagnosed. Awareness of the clinical and electroencephalogram characteristics of Sunflower syndromemay reduce the prevalence of misdiagnosis.

Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects.

Focal epileptic seizures can in some patients be managed by inhibiting γ-aminobutyric acid (GABA) uptake via the GABA transporter 1 (GAT1) using tiagabine (Gabitril®). Synergistic anti-seizure effects achieved by inhibition of both GAT1 and the betaine/GABA transporter (BGT1) by tiagabine and EF1502, compared to tiagabine alone, suggest BGT1 as a target in epilepsy. Yet, selective BGT1 inhibitors are needed for validation of this hypothesis. In that search, a series of BGT1 inhibitors typified by (1R,2S)-2-((4,4-bis(3-methylthiophen-2-yl)but-3-en-yl)(methyl)amino)cyclohexanecarboxylic acid (SBV2-114) was developed. A thorough pharmacological characterization of SBV2-114 using a cell-based [3H]GABA uptake assay at heterologously expressed BGT1, revealed an elusive biphasic inhibition profile with two IC50 values (4.7 and 556 µM). The biphasic profile was common for this structural class of compounds, including EF1502, and was confirmed in the MDCK II cell line endogenously expressing BGT1. The possibility of two binding sites for SBV2-114 at BGT1 was assessed by computational docking studies and examined by mutational studies. These investigations confirmed that the conserved residue Q299 in BGT1 is involved in, but not solely responsible for the biphasic inhibition profile of SBV2-114. Animal studies revealed anti-seizure effects of SBV2-114 in two mouse models, supporting a function of BGT1 in epilepsy. However, as SBV2-114 is apparent to be rather non-selective for BGT1, the translational relevance of this observation is unknown. Nevertheless, SBV2-114 constitutes a valuable tool compound to study the molecular mechanism of an emerging biphasic profile of BGT1-mediated GABA transport and the putative involvement of two binding sites for this class of compounds.

Reflex Epilepsy with Hot Water: Clinical and EEG Findings, Treatment, and Prognosis in Childhood.

Hot water epilepsy (HWE) is a subtype of reflex epilepsy in which seizures are triggered by the head being immersed in hot water. Hot water or bathing epilepsy is the type of reflex epilepsy most frequently encountered in our clinic. We describe our patients with HWE and also discuss the clinical features, therapeutic approaches, and prognosis. Eleven patients (10 boys, 1 girl), aged 12 months to 13 years, admitted to the pediatric neurology clinic between January 2018 and August 2019, and diagnosed with HWE or bathing epilepsy based on International League Against Epilepsy (ILAE)-2017, were followed up prospectively for ∼18 months. Patients' clinical and electroencephalography (EEG) findings and treatment details were noted. All 11 patients' seizures were triggered by hot water. Age at first seizure was between 2 months and 12 years. Seizure types were generalized motor seizures, absence, and atonic. EEG was normal in two patients, but nine patients had epileptiform discharges. Magnetic resonance imaging of the brain was performed and reported as normal (except in one case). Histories of prematurity were present in two patients, unprovoked seizures in one, and low birth weight and depressed birth in the other. Patients with HWE have normal neuromuscular development and neurological examination results, together with prophylaxis or seizure control with a single antiepileptic drug, suggesting that it is a self-limited reflex epilepsy.

Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy.

OBJECTIVE: Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is characterized by hypermotor seizures and may be caused by gain-of-function mutations affecting the nicotinic acetylcholine receptor (nAChR). Benefit from nicotine consumption has been reported in adult patients with this disorder. For the first time, the effect of transdermal nicotine is evaluated in children. METHODS: Transdermal nicotine was applied to three boys, two aged 10 years (7 mg/24 h) and one six years (3.5 mg/24 h). Autosomal dominant sleep-related hypermotor epilepsy was caused by the p.S280F-CHRNA4 (cholinergic receptor, nicotinic, alpha polypeptide 4) mutation. The children suffered from frequent, persistent nocturnal seizures and had developed educational and psychosocial problems. Seizure frequency and cognitive and behavioral parameters were assessed before and after treatment. RESULTS: A striking seizure reduction was reported soon after treatment onset. Hypermotor seizures disappeared; only sporadic arousals, sometimes with minor motor elements, were observed. Psychometric testing documented improvement in cognitive domains such as visuospatial ability, processing speed, memory, and some areas of executive functions. SIGNIFICANCE: Nicotine appears to be a mechanistic treatment for this specific disorder, probably because of desensitization of the mutated receptors. It may control seizures resistant to conventional drugs for epilepsy and impact socioeducational function in children. This mode of precision therapy should receive more attention and should be available to more patients with uncontrolled CHRNA4-related ADSHE across the age span.

Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants.

OBJECTIVE: Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. METHODS: Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. RESULTS: Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. SIGNIFICANCE: This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice.

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.

Down-Regulation of Astrocytic Kir4.1 Channels during the Audiogenic Epileptogenesis in Leucine-Rich Glioma-Inactivated 1 (Lgi1) Mutant Rats.

The dysfunction of astrocytic inwardly rectifying potassium (Kir) 4.1 channels, which mediate the spatial potassium-buffering function of astrocytes, is known to be involved in the development of epilepsy. Here, we analyzed the Kir4.1 expressional changes in Leucine-Rich Glioma-Inactivated 1 (Lgi1) mutant rats, which is a model of autosomal dominant lateral temporal lobe epilepsy in humans, to clarify the role of astrocytic Kir4.1 channels in Lgi1-related epileptogenesis. Priming acoustic stimulation (at postnatal day 16) conferred seizure susceptibility on Lgi1 mutant rats, which evoked audiogenic seizures with test stimulation at eight weeks. In the seizure-susceptible Lgi1 mutant rats (before test stimulation), astrocytic Kir4.1 expression was down-regulated region-specifically in the cerebral cortex, hippocampus, and amygdala. In addition, prophylactic treatments of Lgi1 mutant rats with valproic acid (VPA, 30 mg/kg and 200 mg/kg) for two weeks prevented both the development of seizure susceptibility and the down-regulation of Kir4.1 expression in astrocytes. The present study demonstrated for the first time that the astrocytic Kir4.1 expression was reduced in the Lgi1-related seizure model, suggesting that the down-regulation of Kir4.1 channels in astrocytes is involved in audiogenic epileptogenesis caused by Lgi1 mutation. In addition, VPA seemed to have a prophylactic effect on Lgi1-related seizures.

Effect of Ethosuximide on Audiogenic Epilepsy in Krushinsky-Molodkina Rats.

The anticonvulsant effect of ethosuximide (T-type calcium channel blocker) was evaluated in Krushinsky-Molodkina rats predisposed to audiogenic epilepsy. Ethosuximide given with drinking water (300 mg/kg/day) over 45 days slightly reduced proneness to audiogenic epilepsy and increased locomotor activity of the animals at the periphery of the open field. Neonatal administration of ethosuximide (3-4 mg per animal, from 2 to 10 days of life) insignificantly modulated the parameters of audiogenic epilepsy in these animals at the age of 1.5 months and reduced manifestation of audiogenic myoclonic convulsion that developed after long daily sound presentation started at the age of 3 months. The findings attested to a weak anticonvulsant effect of ethosuximide on tonic convulsions with its predominant effect on convulsions with forebrain focus location.

Study of Uridine Effect on the Development of Audiogenic Tonic Seizures in Krushinsky-Molodkina Strain Rats.

The latency of tonic seizure in response to loud sound (in rats of the Krushinsky-Molodkina strain with audiogenic epilepsy) had been slightly (although statistically significantly) longer after chronic uridine injections (100 mg/kg, i.p., three times a day during 9 or 12 days). The recovery time from the tonic seizure was shorter after 12 days of injections in comparison to the 9-day injection period. At the same time, the intensity of tonic seizures provoked by loud sound did not change after chronic uridine injections. The lack of uridine anticonvulsive effect demonstrated in the audiogenic epilepsy model contradicts the anticonvulsant effects of uridine in experiments with other seizure models, in which the epileptic foci were localized in the forebrain structures.

Recurrence of Epileptic Spasms as Reflex Seizures Induced by Eating: A Case Report and Literature Review.

Background Eating epilepsy (EE) is a rare form of reflex epilepsy in which seizures are induced by eating. It is known that most patients with eating seizures, in fact, suffer from symptomatic temporal lobe epilepsy (TLE), whereas only a few patients with epileptic spasms induced by eating (E-ES) have been reported. Patient Description The patient was an 8-year-old girl whose magnetic resonance imaging (MRI) of the head detected dysgenesis of the corpus callosum, cerebellar hypogenesis, marked cerebral asymmetry, broad polymicrogyria, periventricular heterotopia, and closed lip-type schizencephaly. She experienced E-ES as the second form of recurrent seizures after the first recurrence of spontaneous ES. After E-ES occurred, the EEG findings in the right hemisphere, predominantly over the right centrotemporal region, were clearly exacerbated, although the interictal EEG originally showed left-side-dominant asymmetric hypsarrhythmia. The ictal EEG of the E-ES showed diffuse large triphasic (negative-positive-negative) potentials, predominantly over the right centrotemporoparietal region. Conclusions This is a unique case because the E-ES were recurrent ES, although the previous ES were spontaneous, which may provide insight into the mechanism of E-ES.

Photosensitivity in generalized epilepsies.

Photosensitivity, which is the hallmark of photosensitive epilepsy (PSE), is described as an abnormal EEG response to visual stimuli known as a photoparoxysmal response (PPR). The PPR is a well-recognized phenomenon, occurring in 2-14% of patients with epilepsy but its pathophysiology is not clearly understood. PPR is electrographically described as 2-5Hz spike, spike-wave, or slow wave complexes with frontal and paracentral prevalence. Diagnosis of PPR is confirmed using intermittent photic stimulation (IPS) as well as video monitoring. The PPR can be elicited by certain types of visual stimuli including flicker, high contrast gratings, moving patterns, and rapidly modulating luminance patterns which may be encountered during e.g., watching television, playing video games, or attending discotheques. Photosensitivity may present in different idiopathic (genetic) epilepsy syndromes e.g. juvenile myoclonic epilepsy (JME) as well as non-IGE syndromes e.g. severe myoclonic epilepsy of infancy. Consequently, PPR is present in patients with diverse seizure types including absence, myoclonic, and generalized tonic-clonic (GTC) seizures. Across syndromes, abnormalities in structural connectivity, functional connectivity, cortical excitability, cortical morphology, and behavioral and neuropsychological function have been reported. Treatment of photosensitivity includes antiepileptic drug administration, and the use of non-pharmacological agents, e.g. tinted or polarizing glasses, as well as occupational measures, e.g. avoidance of certain stimuli.

Genetically epilepsy-prone rats (GEPRs) and DBA/2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs.

This review summarizes the current knowledge about DBA/2 mice and genetically epilepsy-prone rats (GEPRs) and discusses the contribution of such animal models on the investigation of possible new therapeutic targets and new anticonvulsant compounds for the treatment of epilepsy. Also, possible chemical or physical agents acting as proconvulsant agents are described. Abnormal activities of enzymes involved in catecholamine and serotonin synthesis and metabolism were reported in these models, and as a result of all these abnormalities, seizure susceptibility in both animals is greatly affected by pharmacological manipulations of the brain levels of monoamines and, prevalently, serotonin. In addition, both genetic epileptic models permit the evaluation of pharmacodynamic and pharmacokinetic interactions among several drugs measuring plasma and/or brain level of each compound. Audiogenic models of epilepsy have been used not only for reflex epilepsy studies, but also as animal models of epileptogenesis. The seizure predisposition (epileptiform response to sound stimulation) and substantial characterization of behavioral, cellular, and molecular alterations in both acute and chronic (kindling) protocols potentiate the usefulness of these models in elucidating ictogenesis, epileptogenesis, and their mechanisms. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

Overexpression of the immediate-early genes Egr1, Egr2, and Egr3 in two strains of rodents susceptible to audiogenic seizures.

Genetic animal models of epilepsy are an important tool for further understanding the basic cellular mechanisms underlying epileptogenesis and for developing novel antiepileptic drugs. We conducted a comparative study of gene expression in the inferior colliculus, a nucleus that triggers audiogenic seizures, using two animal models, the Wistar audiogenic rat (WAR) and the genetic audiogenic seizure hamster (GASH:Sal). For this purpose, both models were exposed to high intensity auditory stimulation, and 60min later, the inferior colliculi were collected. As controls, intact Wistar rats and Syrian hamsters were subjected to stimulation and tissue preparation protocols identical to those performed on the experimental animals. Ribonucleic acid was isolated, and microarray analysis comparing the stimulated Wistar and WAR rats showed that the genomic profile of these animals displayed significant (fold change, |FC|≥2.0 and p<0.05) upregulation of 38 genes and downregulation of 47 genes. Comparison of gene expression profiles between stimulated control hamsters and stimulated GASH:Sal revealed the upregulation of 10 genes and the downregulation of 5 genes. Among the common genes that were altered in both models, we identified the zinc finger immediate-early growth response gene Egr3. The Egr3 protein is a transcription factor that is induced by distinct stress-elicited factors. Based on immunohistochemistry, this protein was expressed in the cochlear nucleus complex, the inferior colliculus, and the hippocampus of both animal models as well as in lymphoma tumors of the GASH:Sal. Our results support that the overexpression of the Egr3 gene in both models might contribute to neuronal viability and development of lymphoma in response to stress associated with audiogenic seizures. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

Pharmacological and neuroethological study of the acute and chronic effects of lamotrigine in the genetic audiogenic seizure hamster (GASH:Sal).

The present study aimed to investigate the behavioral and anticonvulsant effects of lamotrigine (LTG) on the genetic audiogenic seizure hamster (GASH:Sal), an animal model of audiogenic seizure that is in the validation process. To evaluate the efficiency of acute and chronic treatments with LTG, GASH:Sals were treated with LTG either acutely via intraperitoneal injection (5-20mg/kg) or chronically via oral administration (20-25mg/kg/day). Their behavior was assessed via neuroethological analysis, and the anticonvulsant effect of LTG was evaluated based on the appearance and the severity of seizures. The results showed that acute administration of LTG exerts an anticonvulsant effect at the lowest dose tested (5mg/kg) and that chronic oral LTG treatment exerts an anticonvulsant effect at a dose of 20-25mg/kg/day. Furthermore, LTG treatment induced a low rate of secondary adverse effects. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".