Neuroinflammation in Pathogenesis of Audiogenic Epilepsy: Altered Proinflammatory Cytokine Levels in the Rats of Krushinsky-Molodkina Seizure-Prone Strain.

Neuroinflammation plays an important role in epileptogenesis, however, most studies are performed using pharmacological models of epilepsy, while there are only few data available for non-invasive, including genetic, models. The levels of a number of pro-inflammatory cytokines were examined in the Krushinsky-Molodkina (KM) rat strain with high audiogenic epilepsy (AE) proneness (intense tonic seizure fit in response to loud sound) and in the control strain "0" (not predisposed to AE) using multiplex immunofluorescence magnetic assay (MILLIPLEX map Kit). Cytokine levels were determined in the dorsal striatum tissue and in the brain stem. Background levels of IL-1ß, IL-6, and TNF-α in the dorsal striatum of the KM rats were significantly lower than in the rats "0" (by 32.31, 27.84, and 38.87%, respectively, p < 0.05, 0.05, and 0.01), whereas no inter-strain differences in the levels of these metabolites were detected in the brain stem in the "background" state. Four hours after sound exposure, the TNF-α level in the dorsal striatum of the KM rats was significantly lower (by 38.34%, p < 0.01) than in the "0" rats. In the KM rats, the dorsal striatal levels of IL-1ß and IL-6 were significantly higher after the sound exposure and subsequent seizure fit, compared to the background (35.29 and 50.21% increase, p < 0.05, 0.01, respectively). In the background state the IL-2 level in the KM rats was not detected, whereas after audiogenic seizures its level was 14.01 pg/ml (significant difference, p < 0.01). In the KM rats the brain stem levels of IL-1ß and TNF-α after audiogenic seizures were significantly lower than in the background (13.23 and 23.44% decrease, respectively, p < 0.05). In the rats of the "0" strain, the levels of cytokines in the dorsal striatum after the action of sound (which did not induce AE seizures) were not different from those of the background, while in the brain stem of the "0" strain the levels of IL-1ß were lower than in the background (40.28%, p < 0.01). Thus, the differences between the background levels of cytokines and those after the action of sound were different in the rats with different proneness to AE. These data suggest involvement of the analyzed cytokines in pathophysiology of the seizure state, namely in AE seizures.

Predictors of hyperkinetic seizures.

OBJECTIVE: To identify predisposing factors for hyperkinetic seizure occurrence in a representative cohort of surgically treated patients with drug-resistant focal epilepsy. METHODS: We retrospectively recruited all seizure-free patients after epilepsy surgery with a postoperative follow-up ≥12 months. Patients were classified as presenting with hyperkinetic seizures if at least 2 episodes occurred during their disease history, based on clear-cut anamnestic description and/or video-EEG/stereo-EEG recordings. We performed univariable and multivariable logistic regression models to study the association between the occurrence of hyperkinetic seizures and some predictors. RESULTS: From a pool of 1758 consecutive patients who underwent surgery from 1996 to 2017, we identified 974 seizure-free cases. Considering at least 1-year follow-up, 937 cases were included (511 males, 91 patients with hyperkinetic seizures). Variables significantly associated with an increased risk of hyperkinetic seizure occurrence were (1) presence of epilepsy with sleep-related seizures (SRE) (P < 0.001); (2) histological diagnosis of type II focal cortical dysplasia (FCD) (P < 0.001); (3) resection including the frontal lobe (P = 0.002) (4) duration of epilepsy at surgery (P < 0.001) and (5) high seizure frequency at surgery (weekly: P = 0.02 - daily: P = 0.05). A resection including the occipital lobe reduced the risk of hyperkinetic seizures (P = 0.05). About 63% of patients had hyperkinetic seizure onset before 12 years and it was rarely reported before 5 years of age. SIGNIFICANCE: Our findings underlie the role of SRE, type II FCD and frontal epileptogenic zone as predictors of hyperkinetic seizure occurrence and highlight an age-dependent effect in favoring hyperkinetic manifestations.

Focal cortical dysplasia links to sleep-related epilepsy in symptomatic focal epilepsy.

OBJECTIVE: In sleep-related epilepsy (SRE), epileptic seizures predominantly occur during sleep, but the clinical characteristics of SRE remain elusive. We aimed to identify the clinical features associated with the occurrence of SRE in a large cohort of symptomatic focal epilepsy. METHODS: We retrospectively included patients with four etiologies, including focal cortical dysplasia (FCD), low-grade tumors (LGT), temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), and encephalomalacia. SRE was defined as more than 70% of seizures occurring during sleep according to the seizure diary. The correlation between SRE and other clinical variables, such as etiology of epilepsy, pharmacoresistance, seizure frequency, history of bilateral tonic-clonic seizures, and seizure localization was analyzed. RESULTS: A total of 376 patients were included. Among them 95 (25.3%) were classified as SRE and the other 281(74.7%) as non-SRE. The incidence of SRE was 53.5% in the FCD group, which was significantly higher than the other three groups (LGT: 19.0%; TLE-HS: 9.9%; encephalomalacia: 16.7%; P < 0.001). The etiology of FCD (p < 0.001) was significantly associated with SRE (OR: 9.71, 95% CI: 3.35-28.14) as an independent risk factor. In addition, small lesion size (p = 0.009) of FCD further increased the risk of SRE (OR: 3.18, 95% CI: 1.33-7.62) in the FCD group. SIGNIFICANCE: Our data highlight that FCD markedly increased the risk of sleep-related epilepsy independently of seizure localization. A small lesion of FCD further increased the risk of sleep-related epilepsy by 2.18 times in the FCD group.

Evaluation of Maternal Reproductive Outcomes and Biochemical Analysis from Wistar Audiogenic Rats (WAR) and Repercussions in Their Offspring.

The objective of the present study was to evaluate maternal reproductive performance, body weight, and frequency of external and internal anomalies of newborns of Wistar Audiogenic Rat (WAR) females as compared with Wistar rats. The adult WAR and Wistar rats were mated within their respective strains. After confirming the pregnancy, the body weights were weekly evaluated. On day 21 of pregnancy, the female rats were anesthetized and sacrificed to evaluate the maternal reproductive outcomes and biochemical profile, newborn weight, and external and internal anomalies. The WAR strain gained less weight during the pregnancy and presented hyperproteinemia, hypertriglyceridemia, and embryonic losses concerning Wistar rats, suggesting an inadequate intrauterine condition for embryonic development and fetal viability. WAR also presented a higher percentage of newborns classified as small for gestational age related to intrauterine growth restriction, which was confirmed by the lower number of ossification centers. There was a higher percentage of skeletal anomalies compared with fetuses of the Wistar dams, confirming their greater susceptibility during the formation and development of their skeletal system. Thus, the WAR presents physiological alterations compromising the viability of their embryos and fetuses, leading to impaired development of the newborns.

Lovastatin, not Simvastatin, Corrects Core Phenotypes in the Fragile X Mouse Model.

The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability (ID). The therapeutic efficacy of lovastatin is being tested in clinical trials for FX; however, the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in Fmr1-/y mice versus WT littermates: excessive hippocampal protein synthesis and susceptibility to audiogenic seizures (AGSs). We find that simvastatin does not correct excessive hippocampal protein synthesis in the Fmr1-/y hippocampus at any dose tested. In fact, simvastatin significantly increases protein synthesis in both Fmr1-/y and WT. Moreover, injection of simvastatin does not reduce AGS in the Fmr1-/y mouse, while lovastatin significantly reduces AGS incidence and severity versus vehicle-treated animals. These results show that unlike lovastatin, simvastatin does not correct core phenotypes in the Fmr1-/y mouse model.

Acute ischemic stroke following water immersion seizure: a case report.

Sing Rana K, Goswami JN, Sareen N. Acute ischemic stroke following water immersion seizure: a case report. Turk J Pediatr 2019; 61: 453-455. Water immersion epilepsy or bathing epilepsy is a rare form of reflex epilepsy. We report a 4-year-old child with water immersion epilepsy who manifested with an unusual presentation in the form of acute onset right hemiparesis triggered by sudden splashing of water on his face. The case is an attempt to sensitize clinicians about this entity. It also highlights the role of meticulous history-taking, examination, relevant investigations and management plan in such scenarios.

The electroclinical features of idiopathic generalized epilepsy patients presenting with fixation-off sensitivity.

To determine the electroclinical features of fixation-off sensitivity (FOS) in patients with idiopathic generalized epilepsy (IGE). We searched the EEG database using the terms "fixation-off sensitivity" and "idiopathic generalized epilepsy" over a four-year period from March 2014 to April 2018 in the Xijing Hospital, Xi'an, China. FOS was evaluated according to the technique proposed by Panayiotopoulos. Photic stimulation procedure and neuropsychological testing were performed during video-EEG monitoring. FOS was observed in eight patients with several different IGE syndromes, including four with eyelid myoclonia/Jeavons syndrome, two with juvenile myoclonic epilepsy, one with photosensitivity epilepsy, and one with epilepsy with generalized tonic-clonic seizures only. FOS was associated with seizures in five patients manifesting with eyelid myoclonic, myoclonic, and myoclonic-tonic-clonic seizures, and eyelid myoclonic status. FOS coexisted with photosensitivity in six patients as independent EEG features. Neuropsychological testing revealed transitory cognitive impairments associated with FOS. FOS is associated with several different IGE syndromes and may coexist with photosensitivity in the same patient as independent EEG features. FOS may be associated with both clinical seizures and cognitive impairments. Intermittent photic stimulation and registration of different eye conditions with and without fixation will aid the study of the dynamics of the visual system in epilepsy patients. [Published with video sequences on www.epilepticdisorders.com].

Clinical, neuroradiological, and electroencephalographic findings of reflex epilepsies

Background/aim: Reflex seizures are defined as epilepsies with seizures induced by a specific afferent stimulus or patient activity alone or in combination with spontaneous seizures, and/or accompanied by photoparoxysmal response on electroencephalogram (EEG). The aim of this study is to review and analyze clinical, neuroradiological, and EEG findings in reflex epilepsies. Materials and methods: The records of 1598 follow-up patients out of 2237 patients who had been examined between July 1995 and August 2017 were analyzed retrospectively. Results: Eighty of 1598 patients had reflex epilepsy and 72 of those patients had seizures induced by visual stimuli. Considering the somatosensory stimuli, in one patient it was associated with eating while in 7 patients it was associated with hot water. The results of neurological examination were normal in 90% while cranial imaging was normal in 82.5% of the patients. Only 53 of 80 patients' EEGs revealed pathological EEG findings. Furthermore, in 43 patients, the most frequently prescribed drug was valproate. Conclusion: In this hospital-based study, reflex epilepsy frequency was 5% and cranial imaging was mostly found to be normal, as stated in the literature. However, patient histories revealed an unexpectedly high rate of head trauma before seizure onset and a family history of epilepsy.

Deficient post-ictal cardiorespiratory compensatory mechanisms mediated by the periaqueductal gray may lead to death in a mouse model of SUDEP.

Post-ictal cardiorespiratory failure is implicated as a major cause of sudden unexpected death in epilepsy (SUDEP) in patients. The DBA/1 mouse model of SUDEP is abnormally susceptible to fatal seizure-induced cardiorespiratory failure (S-CRF) induced by convulsant drug, hyperthermia, electroshock, and acoustic stimulation. Clinical and pre-clinical studies have implicated periaqueductal gray (PAG) abnormalities in SUDEP. Recent functional neuroimaging studies observed that S-CRF resulted in selective changes in PAG neuronal activity in DBA/1 mice. The PAG plays a critical compensatory role for respiratory distress caused by numerous physiological challenges in non-epileptic individuals. These observations suggest that abnormalities in PAG-mediated cardiorespiratory modulation may contribute to S-CRF in DBA/1 mice. To evaluate this, electrical stimulation (20 Hz, 20-100 µA, 10 s) was presented in the PAG of anesthetized DBA/1 and C57BL/6 (non-epileptic) control mice, and post-stimulus changes in respiration [inter-breath interval (IBI)] and heart rate variability (HRV) were examined. The post-stimulus period was considered analogous to the post-ictal period when S-CRF occurred in previous DBA/1 mouse studies. PAG stimulation caused significant intensity-related decreases in IBI in both mouse strains. However, this effect was significantly reduced in DBA/1 vis-a-vis C57BL/6 mice. These changes began immediately following cessation of stimulation and remained significant for 10 s. This time period is critical for initiating resuscitation to successfully prevent seizure-induced death in previous DBA/1 mouse experiments. Significant post-stimulus increases in HRV were also seen at ≥60 µA in the PAG in C57BL/6 mice, which were absent in DBA/1 mice. These data along with previous neuroimaging findings suggest that compensatory cardiorespiratory modulation mediated by PAG is deficient, which may be important to the susceptibility of DBA/1 mice to S-CRF. These observations suggest that correcting this deficit pharmacologically or by electrical stimulation may help to prevent S-CRF. These findings further support the potential importance of PAG abnormalities to human SUDEP.

Clinical and electrophysiological findings in patients with phenylketonuria and epilepsy: Reflex features.

OBJECTIVE: Phenylketonuria (PKU) is the most common form of amino acid metabolism disorders with autosomal recessive inheritance. The brain damage can be prevented by early diagnosis and a phenylalanine-restricted diet. Untreated or late-treated patients may show mental retardation and other cognitive dysfunctions, as well as motor disability and/or epilepsy. METHODS: Three patients with PKU and epilepsy were recognized to have reflex epileptic features, and there were ten consecutive adult patients with PKU and epilepsy who were evaluated retrospectively. Medical history, ages at diagnosis and therapy onset, age at seizure onset, seizure types and reflex features, neurological findings, cranial imaging, electroencephalography (EEG) findings, and final clinical condition were evaluated. Reflex epilepsy features were examined in detail. RESULTS: The cases (6 females, 4 males) were diagnosed at ages between 3.5months and 12years. All patients had various degrees of mental-motor retardation and focal or generalized seizures with age at seizure onset varied between neonatal period and 15years. Three patients had febrile seizure, 3 patients had myoclonia, and 3 patients had status epilepticus. All patients had abnormal EEG findings except one. There was a slowing of background activity, and generalized discharges were observed in 7 patients; 3 of them had asymmetrical discharges. One patient had right hippocampal sclerosis (HS), and another patient had hypointensities in the basal ganglia and corpus callosum. Reflex features were clinically observed in 3 of the patients; however, EEG results did not show any related findings. One patient had reflex seizures triggered by photic stimuli, hot water, and startling; one by photic stimuli; and the other one by startling. CONCLUSION: Reports on the clinical and electrophysiological features of adult patients with PKU were scant. We emphasized that reflex clinical features may be observed in this metabolic disease, and focal epileptiform abnormalities and asymmetry may be present in electrophysiological evaluation besides the rare association with HS.

Juvenile myoclonic epilepsy and sleep.

Juvenile myoclonic epilepsy (JME) is a sleep-related epilepsy syndrome, and only a few studies have addressed the relationship between JME and sleep disorders. In this review, the sleep characteristics of patients with JME were summarized based on the features of circadian rhythm, the possible cause of the early morning seizures, the common subjective and objective sleep disorders, the alterations in sleep architecture, and the effect of sleep deprivation and sodium valproate (VPA). The aims of this study were to summarize the interaction between JME and sleep, to reveal JME sleep characteristics, to encourage clinicians to focus on JME and sleep, to heighten the positive diagnosis rate, to guide the treatment, to improve the prognosis, and to enhance the daily life quality of patients with JME. At the same time, this study aimed to present existing controversies, in order to necessitate further studies.

Intractable ictal vomiting: a new form of reflex epilepsy?

In this description of the clinical course of a young female with persistent and protracted vomiting along with occasional loss of consciousness and subtle motor manifestations, the differential diagnosis is debated. The epileptic origin of her symptoms was substantiated by the presence of interictal epileptiform discharges and dramatic response to valproate monotherapy. Possible lobar localizations are discussed with the support of existing literature on this rare ictal manifestation [Published with video sequence on www.epilepticdisorders.com].

Erectile Dysfunction in Wistar Audiogenic Rats Is Associated With Increased Cavernosal Contraction and Decreased Neuronal Nitric Oxide Synthase Protein Expression.

OBJECTIVE: To test the hypothesis that naive Wistar audiogenic rats (WARs) display erectile dysfunction (ED), which is associated with increased sympathetic-mediated contractile tone and decreased nitric oxide-mediated relaxation responses of the cavernous tissue. METHODS: Changes in the ratio of the maximal intracavernosal pressure-mean arterial pressure after the electrical stimulation of the right major pelvic ganglion were determined in vivo. Cavernosal contractility was induced by electrical field stimulation and phenylephrine. In addition, nonadrenergic-noncholinergic (NANC)-induced relaxation was determined. Rho-kinase (ROCK) pathway proteins, neuronal nitric oxide synthase (nNOS) protein expression, and endothelial nitric oxide synthase (eNOS) and extracellular signal-regulated kinase 1/2 activities were determined by Western blot. RESULTS: WARs display a significant decrease in maximal intracavernosal pressure-mean arterial pressure responses suggesting ED in this strain. Sympathetic-mediated contractile responses were increased in WARs and contractile responses to phenylephrine were not changed. The increased sympathetic-mediated contractile responses were not associated with changes in the ROCK pathway. On the other hand, NANC-mediated relaxation responses were significantly reduced in WARs. This functional response was accompanied by decreased nNOS and total eNOS protein expressions, augmented phosphorylated eNOS, and decreased extracellular signal-regulated kinase 1/2 phosphorylation levels. CONCLUSION: Our data have demonstrated that naive WARs display ED in vivo that is associated with increased sympathetic-mediated contractile responses and decreased NANC-mediated relaxation responses. The increase in contractile responses is independent of the ROCK pathway, and the changes in relaxation responses are associated with a decrease in nNOS protein expression, which may activate compensatory mechanisms in the cavernous tissue.

Genetic background contributes to the co-morbidity of anxiety and depression with audiogenic seizure propensity and responses to fluoxetine treatment.

BACKGROUND: Anxiety and depression are the most frequent comorbidities of different types of convulsive and non-convulsive epilepsies. Increased anxiety and depression-like phenotype have been described in the genetic absence epilepsy models as well as in models of limbic epilepsy and acquired seizure models, suggesting a neurobiological connection. However, whether anxiety and/or depression are comorbid to audiogenic epilepsy remains unclear. The aim of this study was to investigate whether anxiety or depression-like behavior can be found in rat strains with different susceptibility to audiogenic seizures (AS) and whether chronic fluoxetine treatment affects this co-morbidity. METHODS: Behavior in the elevated plus-maze and the forced swimming test was studied in four strains: Wistar rats non-susceptible to AS; Krushinsky-Molodkina (KM) strain, selectively bred for AS propensity from outbred Wistar rats; and a selection lines bred for maximal AS expression (strain "4") and for a lack of AS (strain "0") from KM×Wistar F2 hybrids. Effects of chronic antidepressant treatment on AS and behavior were also evaluated. RESULTS: Anxiety and depression levels were higher in KM rats (with AS) compared with Wistar rats (without AS), indicating the comorbidity with AS. However, in strains "4" and "0" with contrasting AS expression, but with a genetic background close to KM rats, anxiety and depression were not as divergent as in KMs versus Wistars. Fluoxetine treatment exerted an antidepressant effect in all rat strains irrespective of its effect on AS. CONCLUSIONS: Genetic background contributes substantively to the co-morbidity of anxiety and depression with AS propensity.

Alcohol withdrawal in epileptic rats - Effects on postictal depression, respiration, and death.

Patients with epilepsy are at risk of sudden unexpected death in epilepsy (SUDEP). The most common series of events in witnessed cases of SUDEP is a generalized convulsive seizure followed by terminal apnea. Risk factors for SUDEP include prolonged postictal depression (PID), as well as alcohol abuse. The present study examined these issues in a genetic epilepsy model that exhibits generalized convulsive audiogenic seizures (AGSz) but rarely exhibits seizure-induced death, the genetically epilepsy-prone rats (GEPR-9s). We evaluated the effect of ethanol withdrawal (ETX) in GEPR-9s on respiration patterns, duration of PID, and the incidence of seizure-induced death. Audiogenic seizures were induced in GEPR-9s and in normal Sprague-Dawley rats, which were subjected to a 4-day binge ethanol protocol, 18-24h after the last ethanol dose. Following the tonic seizures, all GEPR-9s exhibited PID, characterized by loss of the righting reflex and respiratory distress (RD), which were absent during ETX seizures in the normal rats. During ETX, GEPR-9s exhibited significant increases in the duration of PID and RD, compared with vehicle-treated GEPR-9s. A significant increase in the incidence of death following seizure in GEPR-9s subjected to ETX was observed, compared with that in vehicle-treated GEPR-9s and normal rats subjected to ETX. Death in GEPR-9s was preceded by prolonged seizures because, in part, of the emergence of post-tonic generalized clonus. These results indicate that ETX induced significant increases in the duration of PID and RD, which contributed to the greater incidence of mortality in GEPR-9s compared with that in vehicle-treated GEPR-9s and normal rats. These experiments observed an elevated risk of sudden death associated with alcohol withdrawal in a genetic epilepsy model that had previously been identified as a risk factor in human SUDEP.

Cognitive performance in juvenile myoclonic epilepsy patients with specific endophenotypes.

PURPOSE: Juvenile myoclonic epilepsy (JME) is a heterogeneous syndrome in which seizures can be precipitated not only by non-specific factors, such as sleep deprivation and stress, but also by specific stimuli, such as photic stimuli, eye-closure, praxis, and language. The presence of these reflex traits may indicate the hyperexcitability of different cortical areas, which may be reflected in patients' neuropsychological deficit profile. The objective of our study is to investigate the possible relations between JME endophenotypes and patients' cognitive performance. METHODS: 61 JME patients were divided into four groups: no reflex traits (group 1, 20 patients); praxis induction (group 2, 13); eye-closure and/or photosensitivity (group 3, 17); and a combination of different reflex traits (group 4, 11). Neuropsychological performance was compared between JME subgroups. 60 healthy controls were used to calculate z-scores. Patients also underwent psychiatric assessment. We controlled the clinical variables, e.g. age at epilepsy onset, frequency of myoclonic seizures, total and sedative drug load, setting them as covariables for the ANOVA analysis. RESULTS: Praxis induction was more common in males (p=0.018) and groups with reflex traits (2, 3, and 4) presented higher rates of persistent myoclonia, polytherapy, clonazepam use (group 3), and more frequent psychiatric comorbidities. Group 4 patients performed worse in Trail Making Test B than the patients in group 1. These findings were independent of clinical variables. CONCLUSION: JME patients with a combination of praxis induction and eye-closure/photosensitivity had greater executive dysfunction, revealing an association between reflex ictogenic mechanisms and cognitive performance.

Optical coherence tomography parameters in patients with photosensitive juvenile myoclonic epilepsy.

PURPOSE: Juvenile myoclonic epilepsy (JME) is commonly associated with photoparoxysmal response (PPR) with a reported prevalence of 25-42%. In this study, we aim to explore the relationship between the PPR and Optical Coherence Tomography (OCT) parameters in order to determine whether optic nerve fiber layer or other structural differences have a pathophysiological role of photosensitivity in patients with JME. METHODS: We studied 53 consecutive patients with Juvenile myoclonic epilepsy (JME) at our outpatient department. The interictal electroencephalogram (EEG) findings for each patient were analyzed for the presence of photoparoxysmal features. The peripapillary Retina Nerve Fiber Layer (RNFL) thickness, ganglion cell thickness, macular thickness and choroid thickness levels were analyzed using OCT. RESULTS: We classified the patients into two groups as those with PPR (Group 1) and those without PPR (Group 2). There were statistically significant differences in the average RNFL thickness values of the left eye between the two groups (p<0.001). Although the RNFL thickness of the right eye was higher in Group 1, no statistically significant difference was observed between the two groups. The RFNL thickness of the superior quadrants both in the right and the left eyes was significantly higher in Group 1 patients (p<0.001). Macular thickness of the right and left eyes were significantly thinner in Group 1 patients (p<0.001). Choroid thickness of the left eye was significantly higher in Group 1 than in Group 2 patients (p<0.001). Although the choroid thickness of the right eye was higher in Group 1 patients, no statistically significant difference was observed between the two groups. CONCLUSION: This is the first study to our knowledge which has investigated the relation between the OCT parameters and photosensitivity in patients with JME. We concluded that these microstructural features may be related to photosensitivity in patients with JME.

Evaluation of Cardiovascular Risk Factors in the Wistar Audiogenic Rat (WAR) Strain.

INTRODUCTION: Risk factors for life-threatening cardiovascular events were evaluated in an experimental model of epilepsy, the Wistar Audiogenic Rat (WAR) strain. METHODS: We used long-term ECG recordings in conscious, one year old, WAR and Wistar control counterparts to evaluate spontaneous arrhythmias and heart rate variability, a tool to assess autonomic cardiac control. Ventricular function was also evaluated using the pressure-volume conductance system in anesthetized rats. RESULTS: Basal RR interval (RRi) was similar between WAR and Wistar rats (188 ± 5 vs 199 ± 6 ms). RRi variability strongly suggests that WAR present an autonomic imbalance with sympathetic overactivity, which is an isolated risk factor for cardiovascular events. Anesthetized WAR showed lower arterial pressure (92 ± 3 vs 115 ± 5 mmHg) and exhibited indices of systolic dysfunction, such as higher ventricle end-diastolic pressure (9.2 ± 0.6 vs 5.6 ± 1 mmHg) and volume (137 ± 9 vs 68 ± 9 µL) as well as lower rate of increase in ventricular pressure (5266 ± 602 vs 7320 ± 538 mmHg.s-1). Indices of diastolic cardiac function, such as lower rate of decrease in ventricular pressure (-5014 ± 780 vs -7766 ± 998 mmHg.s-1) and a higher slope of the linear relationship between end-diastolic pressure and volume (0.078 ± 0.011 vs 0.036 ± 0.011 mmHg.µL), were also found in WAR as compared to Wistar control rats. Moreover, Wistar rats had 3 to 6 ventricular ectopic beats, whereas WAR showed 15 to 30 ectopic beats out of the 20,000 beats analyzed in each rat. CONCLUSIONS: The autonomic imbalance observed previously at younger age is also present in aged WAR and, additionally, a cardiac dysfunction was also observed in the rats. These findings make this experimental model of epilepsy a valuable tool to study risk factors for cardiovascular events in epilepsy.