Lack of causal association between epilepsy and dementia: A Mendelian randomization analysis.

OBJECTIVE: Epidemiological studies have reported an association between epilepsy and dementia. However, the causal relationship between epilepsy and the risk of dementia is not clear. We aimed to inspect the causal effect of epilepsy on memory loss and dementia. METHODS: We analyzed summary data of epilepsy, memory loss, and dementia from the genome-wide association study (GWAS) using the two-sample Mendelian randomization (MR) method. We used the estimated odds ratio of memory loss and dementia associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures: all epilepsy, focal epilepsy (including focal epilepsy with hippocampal sclerosis, lesion-negative focal epilepsy, and focal epilepsy with other lesions), and genetic generalized epilepsy (including childhood absence epilepsy, generalized tonic-clonic seizures alone, Juvenile absence epilepsy, and Juvenile myoclonic epilepsy). RESULTS: According to the result of MR using the inverse variance weighted method (IVW), we found that genetically predicted epilepsy did not causally increase the risk of memory loss and dementia (p > 0.05). Results of the MR-Egger and weighted median method were consistent with the IVW method. CONCLUSIONS: No evidence has been found to support the notion that epilepsy can result in memory loss and dementia. The associations observed in epidemiological studies could be attributed, in part, to confounding or nongenetic determinants.

Idiopathic generalized epilepsy with phantom absences, absence status, and generalized tonic-clonic seizures: A case report.

RATIONALE: Phantom absences refer to mild and short-lasting absence seizures, which are usually accompanied by infrequent generalized tonic-clonic seizures and absence status. Generally, phantom absences do not impair the individual neurological functions. Herein, we report the case of a young woman with idiopathic generalized epilepsy, phantom absences, absence status, and generalized tonic-clonic seizures. PATIENT CONCERNS: A 31-year-old woman presented with a 16-year history of paroxysmal convulsions. DIAGNOSES: Electroencephalogram (EEG) showed recurrent universal and synchronized 3~4 Hz spike waves and spike-slow waves in the interictal phase with normal background activity. During the ictal phases, EEG revealed bursts of 3~4 Hz spike waves and spike-slow waves that were universal, synchronized, and symmetrical. Additionally, there was 1 seizure episode induced by a 3-Hz flash in the current case. Based on these findings, a diagnosis of idiopathic generalized epilepsy was made. INTERVENTIONS: The patient was treated with oral sodium valproate, and the epileptic seizures were controlled. OUTCOMES: The frequency of absence seizures was significantly reduced and there were no generalized tonic-clonic seizures. LESSONS: Idiopathic generalized epilepsy with phantom absences, absence status, and generalized tonic-clonic seizures is an extremely rare condition. EEG is the exclusive method for diagnosis. Antiepileptic drugs are effective for controlling epileptic seizures in this disease.

Childhood absence epilepsy patients with cognitive impairment have decreased sleep spindle density.

OBJECTIVE: To explore the differences in sleep spindle (SS) characteristics during stage N2 sleep between children with childhood absence epilepsy and healthy controls, and between children with childhood absence epilepsy with or without cognitive impairment. METHODS: We recruited 29 children (14 females, 15 males, mean age: 8 (2.5) years) with childhood absence epilepsy who did not undergone antiseizure treatments previously and 30 age-matched controls (14 females, 16 males, mean age: 9 (3.0) years). For all patients, data on medical history were collected. Each child was monitored overnight by long-term video electroencephalography and was evaluated by the Wechsler Intelligence Scale for Children-Fourth Edition. Next, we compared anterior SS characteristics, including density, frequency, cycle length, duration, amplitude, and percentage of sleep stages. RESULTS: The childhood absence epilepsy group exhibited lower spindle density and duration in the first 37.5 min of stage N2 sleep than the control group (P < 0.01). A decrease in spindle density could be observed in the childhood absence epilepsy group with aggravated cognition impairment. The spindle density was substantially lower in the cognitively impaired group than in the cognitively unimpaired group (P < 0.01). No significant differences were observed in SS amplitude, SS frequency, SS cycle length, and the distribution of sleep stages. CONCLUSIONS: Reduction in spindle density and duration is associated with the mechanisms underlying childhood absence epilepsy. The deficit in SS density is related with impaired cognition. This deficiency in SSs may be a useful predictive indicator of cognitive impairment in children with absence epilepsy, indicating that SSs may become a useful biomarker and potential adjuvant anti-seizure target for cognitive impairment caused by childhood absence epilepsy.

Sleep quality and circadian rhythm profile of persons with juvenile myoclonic epilepsy in a tertiary epilepsy center: A case-control study.

PURPOSE: This study evaluated sleep quality, chronotype, and excessive diurnal somnolence in persons with Juvenile Myoclonic Epilepsy (JME) and their possible association with clinical variables. METHODS: This cross-sectional controlled study evaluated 49 consecutive patients (65% females, mean age 27.53 years) with an electroclinical diagnosis of JME and 49 healthy controls (55% females, mean age 28.55 years). The Pittsburgh Sleep Quality Inventory (PSQI) was used to assess sleep quality and the Epworth Sleepiness Scale (ESS) to evaluate excessive daytime sleepiness. The patients' chronotype was evaluated by the Morningness-Eveningness Questionnaire (MEQ). Epilepsy-related factors gathered from the medical chart and personal interview were epilepsy duration, age at onset, frequency of myoclonic (Mcl), generalized tonic-clonic (GTC) and absence (ABS) seizures, pharmacoresponse, and current antiseizure medication (ASM). RESULTS: Persons with JME did not differ from the control group regarding daytime sleepiness (p=0.840); however, the JME group had worse sleep quality (p=0.01) than the controls. Persons with JME presented a more evening chronotype than controls (p = 0.003). The age at onset, epilepsy duration, frequency of Mcl seizure, frequency of GTC seizure, frequency of ABS seizure, and drug response did not predict ESS and MEQ scales. Pharmacoresponsive patients had lower PSQI scores compared with pharmacoresistant patients (p=0.036). CONCLUSION: Persons with JME have worse sleep quality and a more evening chronotype. Notably, pharmacoresistant patients present a worse sleep quality that deserves attention and special care due to the relationship between sleep deprivation and seizure worsening.

STAG2 microduplication in a patient with eyelid myoclonia and absences and a review of EMA-related reported genes.

Xq25 microduplication involving exclusively STAG2 is a new distinctive cohesinopathy including mild to moderate intellectual disability, speech delay and facial dysmorphism. Seizures seem to be scarce, but detailed seizure type descriptions are missing. We report the case of an 8-year-old boy with mild intellectual disability and eyelid myoclonia with onset at age of 3 years, initially misinterpreted as tics. An ictal VIDEO-EEG documented eye closure elicited generalized 3 Hz spike-waves or polyspike-waves concomitant to eyelid myoclonia, sometimes associated to brief clinically observable absences. Intermittent photic stimulation revealed a photoparoxysmal response. Array CGH identified a 199 kb copy number gain in Xq25 including the whole STAG2 gene, inherited from his asymptomatic mother. To the best of our knowledge, this is the first case of STAG2 encephalopathy fulfilling all electroclinical criteria for epilepsy with eyelid myoclonia and absences (EMA), formally named Jeavons syndrome (JS). As for other Genetic Generalized Epilepsy syndromes, EMA/JS usually occurs in normally developing children. Intellectual disability of variable degree is occasionally reported. On the background of other genes responsible for Developmental and Epileptic Encephalopathies, linked to specific generalized seizure types or seizure combinations, we discuss the contribution of pathogenic variants in CHD2, SYNGAP1 and some other genes as, RORB, NEXMIF and KCNB1 to this peculiar EMA phenotype.

N-acetylcysteine aggravates seizures while improving depressive-like and cognitive impairment comorbidities in the WAG/Rij rat model of absence epilepsy.

N-acetylcysteine (NAC) is an antioxidant with some demonstrated efficacy in a range of neuropsychiatric disorders. NAC has shown anticonvulsant effects in animal models. NAC effects on absence seizures are still not uncovered, and considering its clinical use as a mucolytic in patients with lung diseases, people with epilepsy are also likely to be exposed to the drug. Therefore, we aimed to study the effects of NAC on absence seizures in the WAG/Rij rat model of absence epilepsy with neuropsychiatric comorbidities. The effects of NAC chronic treatment in WAG/Rij rats were evaluated on: absence seizures at 15 and 30 days by EEG recordings and animal behaviour at 30 days on neuropsychiatric comorbidities. Furthermore, the mechanism of action of NAC was evaluated by analysing brain expression levels of some possible key targets: the excitatory amino acid transporter 2, cystine-glutamate antiporter, metabotropic glutamate receptor 2, the mechanistic target of rapamycin and p70S6K as well as levels of total glutathione. Our results demonstrate that in WAG/Rij rats, NAC treatment significantly increased the number and duration of SWDs, aggravating absence epilepsy while ameliorating neuropsychiatric comorbidities. NAC treatment was linked to an increase in brain mGlu2 receptor expression with this being likely responsible for the observed absence seizure-promoting effects. In conclusion, while confirming the positive effects on animal behaviour induced by NAC also in epileptic animals, we report the aggravating effects of NAC on absence seizures which could have some serious consequences for epilepsy patients with the possible wider use of NAC in clinical therapeutics.

Eyelid myoclonia with absences related to epileptic negative myoclonus.

Eyelid myoclonia with absences (EMA) is an epileptic syndrome characterised by eyelid myoclonia with or without absences, eye closure-induced paroxysms, and photosensitivity. The relationship between EMA and epileptic negative myoclonus has not previously been reported. Herein, we describe a case of a 10-year-old girl who presented with eyelid myoclonia, eye closure-induced paroxysms, and photosensitivity, which was compatible with the diagnosis of EMA. Ictal EEG depicted an eye closure-induced diffuse 3.0-4.5-Hz polyspike-and-wave complex, which was accompanied by eye fluttering (eyelid myoclonia). EMG disclosed a brief interruption (60-140 mseconds) of tonic contraction of the orbicularis oculi muscle, which was associated with the polyspike-and-wave complex on EEG. The findings led to the diagnosis of epileptic negative myoclonus. Eye closure-induced eyelid epileptic negative myoclonus, demonstrated in this patient, may be an atypical seizure type of EMA that represents an intermediate between eyelid myoclonia and epileptic negative myoclonus.

Etanercept rescues cognitive deficits, depression-like symptoms, and spike-wave discharge incidence in WAG/Rij rat model of absence epilepsy.

Pro-inflammatory cytokines have been shown to be associated with the development of seizures in the WAG/Rij rat model of absence epilepsy. Importantly, WAG/Rij rats also exhibit cognitive deficits and depression-like behaviors. It is possible that pro-inflammatory cytokines mediate these comorbid conditions of absence epilepsy given their well-established effects on cognition and affective responses. The current study investigated the potential therapeutic effect of etanercept (tumor necrosis factor inhibitor) on cognitive impairment, depression-like behavior, and spike-wave discharges (SWDs) typically observed in the WAG/Rij rats. Eight-month-old male WAG/Rij rats and Wistar controls were tested in Morris water maze (MWM), passive avoidance (PA), forced swimming, sucrose preference, and locomotor activity tests, and electroencephalogram (EEG) recordings were taken from a separate group of WAG/Rij rats after 8 weeks of etanercept or vehicle treatment. Consistent with earlier work, WAG/Rij rats exhibited cognitive deficits and depression-like behavior. From these, the cognitive deficits and despair-like behavior were rescued by etanercept administration, which also reduced the frequency of SWDs without affecting their duration. Our results support the hypothesis that pro-inflammatory cytokines mediate the absence seizures and comorbid symptoms of absence epilepsy.

Towards a Better Understanding of Cognitive Deficits in Absence Epilepsy: a Systematic Review and Meta-Analysis.

Cognition in absence epilepsy (AE) is generally considered undisturbed. However, reports on cognitive deficits in AE in recent years have suggested otherwise. This review systematically assesses current literature on cognitive performance in children with AE. A systematic literature search was performed in Pubmed, Embase, Cochrane and Web of Science. All studies reporting on cognitive performance in children with AE were considered. In total 33 studies were eligible for inclusion. Neuropsychological tests were classified into the following domains: intelligence; executive function; attention; language; motor & sensory-perceptual examinations; visuoperceptual/visuospatial/visuoconstructional function; memory and learning; achievement. Random-effect meta-analyses were conducted by estimating the pooled mean and/or pooling the mean difference in case-control studies. Full-scale IQ in children with AE was estimated at 96.78 (95%CI:94.46-99.10) across all available studies and in case-control studies IQ was on average 8.03 (95%CI:-10.45- -5.61) lower. Verbal IQ was estimated at 97.98 (95%CI:95.80-100.16) for all studies and 9.01 (95%CI:12.11- -5.90) points lower in case-control studies. Performance IQ was estimated at 97.23 (93.24-101.22) for all available studies and 5.32 (95%CI:-8.27-2.36) points lower in case-control studies. Lower performance was most often reported in executive function (cognitive flexibility, planning, and verbal fluency) and attention (sustained, selective and divided attention). Reports on school difficulties, neurodevelopmental problems, and attentional problems were high. In conclusion, in contrast to common beliefs, lower than average neurocognitive performance was noted in multiple cognitive domains, which may influence academic and psychosocial development.

Eyelid myoclonia with absences: Electroclinical features and prognostic factors.

OBJECTIVE: Eyelid myoclonia with absences (EMA) is a syndrome characterized by eyelid myoclonia with or without absences, eye closure-induced generalized electroencephalographic (EEG) paroxysms and photosensitivity. Few data are available about the prognostic factors of this syndrome. The main objectives of our study were to describe the clinical and EEG features of a group of patients with EMA and to evaluate the presence of prognostic factors. METHODS: We retrospectively selected a cohort of patients with diagnosis of EMA evaluated in the epilepsy service of the Neurological Clinic of Catania, in the Neurology and Clinical Neurophysiopathology Unit of Oasi Research Institute, Troina and in the Regional Epilepsy Centre of Bianchi-Melacrino-Morelli Hospital of Reggio Calabria. We considered the features of the patients during the first year of disease, and at the last follow-up visit. We stratified the patients into two groups: "seizure-free", defined as the absence of seizures for at least 2 years, and "not seizure-free" and we evaluated the evolution of their characteristics and the presence of factors associated with outcome. RESULTS: We enrolled 51 patients (40 women (78%); mean age: 30.8 years ± 15.5 [range 10-79]). The mean follow-up time was 8.7 ± 5.8 years. Eleven patients (21.6%) achieved the condition of seizure-free. Family history of epilepsy was associated with the condition of seizure-free (P = 0.05). At the last follow-up visit, EEG photosensitivity and eye closure sensitivity were significantly associated with the condition of "not seizure-free". SIGNIFICANCE: The results of our study revealed that a positive family history of epilepsy might be associated with a better outcome in EMA. Furthermore, the persistence of photosensitivity and eye closure sensitivity might indicate persistence of seizures, offering an aid in therapeutic management.

Cognitive profile and academic achievement of children with absence epilepsy.

The main aim of this study was to examine the cognitive profile and academic achievement of children with absence epilepsy. It is investigated whether all scale intelligence score, intelligence subscale scores, and academic achievement of the children with absence epilepsy differed from healthy peers and Turkish norm values. Nineteen children with absence epilepsy and 19 healthy children participate in the study. The Wechsler Intelligence Scale for Children-IV (WISC-IV) is used to measure their intelligence scores. A teacher assessment form (Teacher's Report Form (TRF)) is obtained from the participants' teachers for the measurement of academic achievement, and the students' report cards are collected as an additional measure of it. Participants with absence epilepsy have significantly lower scores of total intelligence score (Mean (M) = 76.68, Standard Deviation (SD) = 25.18), verbal comprehension score (M = 81.68, SD = 25.29), perceptual reasoning score (M = 85.47, SD = 20.61), processing speed score (M = 77.95, SD = 18.61), and working memory (M = 83.74, SD = 19.04), which are measured by WISC-IV, than healthy peers (respectively M = 105.84, SD = 16.20; M = 105.47, SD = 18.12; M = 103.63, SD = 12.88; M = 104.05, SD = 12.98; M = 104.74, SD = 18.97) and norm values (M = 100, SD = 10). No difference is observed between the subscale scores of WISC-IV for within group with absence epilepsy. Moreover, they have lower Turkish language (M = 73.65, SD = 19.19) and mathematics (M = 76.26, SD = 22.29) grade report scores than healthy peers (respectively M = 90.76, SD = 12.01; M = 88.64, SD = 15.93). There is no difference between the two groups in terms of the academic achievement obtained from the TRF. It is necessary to support children with absence epilepsy academically. We analyzed whether the current pattern has changed by comparing the intelligent scores and academic achievement of children with absence epilepsy who have recovered after treatment with their healthy peers. In fact, there is no difference between the children with absence epilepsy who have recovered after treatment and their healthy peers in terms of total intelligence score and its subscale scores. Similarly, there is no difference between them in terms of mathematics score on their report. Only the difference in the score of Turkish language continues in the same direction.

Childhood Absence Epilepsy evolving to Eyelid Myoclonia with Absence Epilepsy.

PURPOSE: Children with Childhood Absence Epilepsy (CAE) may develop generalized tonic-clonic seizure or juvenile myoclonic epilepsy. A possible evolution to Eyelid Myoclonia with Absence Epilepsy (EMA) hasn't been documented yet. We report the electroclinical features of a case series of children with CAE that evolved to EMA after therapy withdrawal. METHOD: Of 108 patients with CAE referred at our Epilepsy Center in the last ten years, 5 satisfied the inclusion criteria: CAE diagnosis, a minimum of 3 years follow-up, a progression to EMA after therapy withdrawal. RESULTS: All the six subjects were females. CAE was characterized by typical absences induced by hyperventilation; intermittent photic stimulation (IPS) was negative. All subjects were treated successfully with valproate. After drug withdrawal, all the six girls presented EMA. EMA was characterized by eyelid myoclonia with or without brief absences related to generalized spike/polyspike-waves discharges induced by IPS and less frequently by eye-closure. CONCLUSIONS: Our study documented another possible evolution of CAE into EMA. These results support the hypothesis that these two epileptic conditions are dynamic processes evolving into one another. CAE and EMA could be considered "system epilepsy" characterized by a high susceptibility to changes in the brain networks during specific life periods such as childhood and puberty.

Pharmacology of epileptogenesis and related comorbidities in the WAG/Rij rat model of genetic absence epilepsy.

Animal studies currently represent the best source of information also in the field of epileptogenesis research. Many animal models have been proposed and studied so far both from the pathophysiological and pharmacological point of view. Furthermore, they are widely used for the identification of potentially clinically valuable biomarkers. The WAG/Rij rat model, similarly to other genetic animal strains, represents a suitable animal model of absence epileptogenesis accompanied by depressive-like and cognitive comorbidities. Generally, animal models of epileptogenesis are characterized by an identifiable initial insult (e.g. traumatic brain injury), a latent phase lasting up to the appearance of the first spontaneous seizure and a chronic phase characterized by recurrent spontaneous seizures. In most of genetic models: the initial insult should be defined as the mutation causing epilepsy, which is not clearly defined in the WAG/Rij rat model; the latent phase ends at the appearance of the first spontaneous seizure, which is about 2-3 months of age in WAG/Rij rats and thereafter the chronic phase. WAG/Rij rats also display depressive-like comorbidity around the age of 4 months, which is apparently linked to the development of absence seizures considering both its ontogeny and the fact that drugs affecting absence seizures development also block the development of depressive-like behavior. Finally, WAG/Rij rats also display cognitive impairment in some memory tasks, however, this has not been yet definitively linked to absence seizures development and may represent an epiphenomenon. This review is focused on the effects of pharmacological treatments against epileptogenesis and their effects on comorbidities.

Ongoing Photosensitivity in An Elderly Patient With Jeavons Sydrome.

INTRODUCTION: Photosensitivity, which is a main feature of Jeavons syndrome, can be seen in other types of idiopathic or genetic epilepsies with focal or generalized seizures and tends to disappear spontaneously usually in the second decade. Although it responds well to antiepileptic treatment, especially to valproic acid, it may continue into adulthood in rare cases. CASE REPORT: We describe a 63-year-old male patient with eyelid myoclonia with absences, generalized tonic-clonic seizures, and severe photosensitivity accompanied by eyelid myoclonia. Seizures were treated with antiepileptic treatment, whereas photosensitivity still continued on electroencephalogram without clinical findings. CONCLUSION: Our elderly patient with Jeavons syndrome with ongoing remarkable photosensitivity demonstrated that it may continue to older ages, although it is uncommon.

Attention profiles in childhood absence epilepsy compared with attention-deficit/hyperactivity disorder.

OBJECTIVE: This study aimed to compare the attention profiles of subjects with childhood absence epilepsy (CAE) to those of children with attention-deficit/hyperactivity disorder (ADHD) and controls. METHOD: We retrospectively reviewed the medical records of 20 children (age 7.2 ±â€¯1.6 years, 5 boys) in whom CAE was diagnosed at the Department of Pediatric Neurology of Asan Medical Center, Seoul, Korea. ADHD and control subjects were selected from children who visited the Department of Pediatric Psychiatry and were confirmed as having or not having ADHD based on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). The 20 children with CAE, 20 with ADHD and 20 controls completed the Advanced Test of Attention (ATA), which is a computerized continuous performance task. RESULTS: The CAE subjects without ADHD showed increased Omission errors (p=.013) on the visual ATA and Response time (p=0.044) on the auditory ATA than the controls, although these differences did not remain significant after multiple comparison correction. The CAE subjects without ADHD had significantly decreased Response time variability on the visual ATA than the ADHD group (p<0.001). The CAE subjects with comorbid ADHD showed increased Commission errors (p=0.020) and Response time variability (p=0.016) on the visual ATA and increased Commission errors (p=0.022) on the auditory ATA than the CAE subjects without ADHD, although statistical significance disappeared after multiple comparison adjustments. CONCLUSION: These findings suggest that selective attention is impaired in children with CAE and comorbid ADHD contributes to further impairment of sustained attention and response inhibition.

Pretreatment behavior and subsequent medication effects in childhood absence epilepsy.

OBJECTIVE: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE). METHODS: The Child Behavior Checklist (CBCL) was administered at baseline, week 16-20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure. RESULTS: A total of 382 participants at baseline, 310 participants at the week 16-20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%-11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16-20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6-54.7]), externalizing problems (51.4 [98.3% CI 48.5-54.3]), attention problems (57.8 [98.3% CI 55.6-60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1-57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4-49.6]; 45.8 [98.3% CI 42.9-48.7]; 54.6 [98.3% CI 52.4-56.9]; 53.0 [98.3% CI 51.3-54.8]). Lack of seizure freedom and elevated week 16-20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6-60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1-56.9]). CONCLUSIONS: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE. CLINICALTRIALSGOV IDENTIFIER: NCT00088452. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.

Sociability impairments in Genetic Absence Epilepsy Rats from Strasbourg: Reversal by the T-type calcium channel antagonist Z944.

Childhood absence epilepsy (CAE) is associated with interictal co-morbid symptoms including abnormalities in social behaviour. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a model of CAE that exhibits physiological and behavioural alterations characteristic of the human disorder. However, it is unknown if GAERS display the social deficits often observed in CAE. Sociability in rodents is thought to be mediated by neural circuits densely populated with T-type calcium channels and GAERS contain a missense mutation in the Cav3.2 T-type calcium channel gene. Thus, the objective of this study was to examine the effects of the clinical stage pan-T-type calcium channel blocker, Z944, on sociability behaviour in male and female GAERS and non-epileptic control (NEC) animals. Female GAERS showed reduced sociability in a three-chamber sociability task whereas male GAERS, male NECs, and female NECs all showed a preference for the chamber containing a stranger rat. In drug trials, pre-treatment with 5mg/kg of Z944 normalized sociability in female GAERS. In contrast, female NECs showed impaired sociability following Z944 treatment. Dose-dependent decreases in locomotor activity were noted following Z944 treatment in both strains. Treatment with 10mg/kg of Z944 altered exploration such that only 8 of the 16 rats tested explored both sides of the testing chamber. In those that explored the chamber, significant preference for the stranger rat was observed in GAERS but not NECs. Overall, the data suggest that T-type calcium channels are critical in regulating sociability in both GAERS and NEC animals. Future research should focus on T-type calcium channels in the treatment of sociability deficits observed in disorders such as CAE.

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model.

One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in 2 different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early long-term treatment with fingolimod (1 mg/kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in WAG/Rij rats. However, these effects were transitory, as 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control levels. Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced phosphorylated mammalian target of rapamycin and phosphorylated p70S6k levels, and by increased phosphorylated Akt in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic effects of fingolimod. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of lysine 8 of histone H4 (at both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects of fingolimod. However, the antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline.