Eliza Yumi de Freitas Sonoda

Preventing tomorrow's sudden cardiac death in epilepsy today: what should physicians know about this?

Approximately 1% of the population has epilepsy, the most common neurological disorder. Moreover, people with epilepsy are more likely to die prematurely than those without epilepsy, and the most common epilepsy-related category of death is sudden unexpected death in epilepsy (SUDEP). Information concerning risk factors for SUDEP is conflicting, but potential risk factors include: age, early onset of epilepsy, duration of epilepsy, uncontrolled seizures, seizure frequency, number of antiepileptic drugs and winter temperatures. Additionally, the cause of SUDEP is still unknown; however, the most commonly suggested mechanisms are cardiac abnormalities during and between seizures. This review discusses the epidemiology, risk factors, etiology, and preventative measures in the management of SUDEP.

Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats

It is thought that cardiovascular changes may contribute to sudden death in patients with epilepsy. To examine cardiovascular alterations that occur during epileptogenesis, we measured the heart rate of rats submitted to the electrical amygdala kindling model. Heart rate was recorded before, during, and after the induced seizures. Resting heart rate was increased in stages 1, 3, and 5 as compared with the unstimulated control condition. In the initial one third of the seizures, we observed bradycardia, which increased in intensity with increasing stage and was blocked by injecting methyl atropine. During stage 5 seizures, a rebound tachycardia was observed that also increased in intensity with increasing number of seizures. This study demonstrated the influence of seizure frequency on cardiac autonomic modulation, providing a basis for discussion of potential mechanisms that cause patients with epilepsy to die suddenly.

Impairment of Sexual Function in Rats with Epilepsy

INTRODUCTION Epilepsy is a chronic disease that affects men and women of all ages, with different levels of severity. Many individuals with epilepsy also suffer from impairments in sexual function. However, it is difficult to differentiate between the impact of the disease and the impact of antiepileptic drugs on sexual function in human subjects. AIMS To evaluate sexual behavior in adult male rats submitted to chronic pilocarpine-induced epilepsy. METHODS First, non-epileptic rats were exposed to nine training sessions to acquire sexual experience, and their baseline sexual performance was evaluated. Then, the same rats were given pilocarpine to induce status epilepticus followed by chronic epilepsy. Once the animals had developed spontaneous recurrent seizures, their sexual behavior was evaluated during three sessions. MAIN OUTCOME MEASURES Examine changes in latencies to first mount, intromission, and ejaculation, and the total number of mounts, intromissions, and ejaculations. RESULTS All outcome measures related to sexual motivation and sexual performance were markedly impaired during chronic epilepsy compared with the baseline and the control group. CONCLUSION These findings will aid in understanding the interaction between sexual behavior and epilepsy, as well as encouraging further experimental studies in human patients with epilepsy suffering from sexual dysfunction.

IS COLD THE NEW HOT IN SUDDEN UNEXPECTED DEATH IN EPILEPSY? Effect of low temperature on heart rate of rats with epilepsy

Sudden unexpected death in epilepsy (SUDEP) is the commonest cause of seizure-related mortality in people with refractory epilepsy. Several risk factors for SUDEP are described; however, the importance of including low temperatures as risk factor for SUDEP was never explored. Based on this, the aim of this study was to evaluate the heart rate of rats with epilepsy during low temperature exposure. Our results showed that low temperature clearly increased the heart rate of rats with epilepsy. Taken together, we concluded that exposure to low temperatures could be considered important risk factors from cardiovascular abnormalities and hence sudden cardiac death in epilepsy.

To sushi or not to sushi: can people with epilepsy have sushi from time to time?

To the Editor: Epilepsy is one of the most prevalent neurological conditions and knows no age, racial, social class, geographic, or national boundaries [1]. Unfortunately, sudden unexpected death in epilepsy (SUDEP) is the commonest cause of death directly related to epilepsy, occurring frequently in people with chronic epilepsy [2]. The main risk factors for SUDEP are associated with poorly controlled seizures, suggesting that most cases of SUDEP are seizure-related events [2]. Although potential pathomechanisms for SUDEP remain unknown, cardiac abnormalities during and between seizures might contribute to SUDEP [2,3]. Progress continues to be made in relation to medical management of epilepsy, but the antiepileptic drugs are still limited in clinical efficacy. Following this reasoning, there is currently a paucity of credible evidence to support the use of complementary and alternative medical therapies in patients with epilepsy [4]. Omega-3 fatty acid has an interesting role in this scenario. With respect to epilepsy, the first randomized, placebo-controlled, parallel group study of omega-3 supplementation in patients with chronic epilepsy showed only a transient effect on seizure frequency that was not confirmed by other research groups, but additional trials are required [5,6]. These results did not totally confirm that omega-3 fatty acids reduce the frequency of epileptic seizures in patients with intractable epilepsy; however, they supported the safety of omega-3 supplementation in people with epilepsy [5]. It is very important to emphasize that nutritional therapy (e.g., omega-3 supplementation) is not a substitute for anticonvulsant medications. From an experimental point of view, our research was the first to demonstrate that chronic treatment with omega-3 promotes neuroprotection and increases the number of parvalbumin-positive neurons in the hippocampus of rats with epilepsy, suggesting that omega-3 promotes positive plastic changes in the brain [7]. Quite interestingly, there is now great interest in omega-3 fatty acids for the prevention of SUDEP [5,8]. As omega-3 fatty acids per se have been shown to reduce cardiac arrhythmias and sudden cardiac deaths, it was proposed that omega-3 fatty acid supplementation in patients with refractory seizures may reduce seizures, seizure-associated cardiac arrhythmias, and hence SUDEP [5,8,9]. Based on all these facts and considering the potential heart/ brain benefits of omega-3, an interesting question could be evaluated: Should epileptologists be concerned with the omega-3 origin? Yes, they should be. For that, some arguments might be put forward. As we know, the human body cannot synthesize omega-3 fatty acids; hence, these nutrients must be obtained from food. In the brain, intake of long-chain omega-3 fatty acids, commonly found in fish and fish oil, not only contributes to central nervous system

Activation and involvement of the lateral–posterior nucleus of the thalamus after a single generalized tonic–clonic seizure

The lateral-posterior thalamic nuclei (LP) have been shown to play an important role in controlling epileptic activity. In addition, thalamic atrophy and neuronal loss have been observed in epilepsy. The objective of this study was to investigate whether lateral-posterior neuronal activation may be observed shortly after a single generalized seizure in rats submitted to the pilocarpine model of epilepsy. The results showed an increased lateral-posterior activation as soon as the seizure occurred, suggesting that neuronal loss in the thalamus is not only the consequence of chronic epilepsy.

Carbamazepine does not alter the intrinsic cardiac function in rats with epilepsy

Among the causes for sudden unexpected death (SUDEP) in epilepsy, the effects of antiepileptic drugs on the heart have been poorly explored. Based on this, the aim of our study was to evaluate the heart rate (in vivo and isolated ex vivo) and ventricular pressure (isolated ex vivo) of rats with and without epilepsy treated with carbamazepine. Four groups of adult, male Wistar rats (200-250 g) were studied: [A] control rats (n=8), received neither pilocarpine nor carbamazepine [B] carbamazepine-treated rats (n=8), received a daily dose of 120 mg/Kg, i.p. of carbamazepine for two weeks; [C] rats with epilepsy that received just saline solution (n=8); [D] rats with epilepsy that received a daily dose of 120 mg/Kg, i.p. of carbamazepine for two weeks (n=8). Our results showed significant increase in heart rate in animals with epilepsy (with and without the use of carbamazepine) when compared to the control groups in vivo. In contrast, we did not find differences during isolated ex vivo experiments comparing animals with and without epilepsy and despite the use of carbamazepine. Our results suggest that, in isolation, carbamazepine may not be a potential risk factor for sudden unexpected death in epilepsy.

Is there something special about cardiovascular abnormalities and sudden unexpected death in epilepsy among patients with chronic renal insufficiency in regular hemodialysis program

Of the many risk factors suggested for sudden unexpected death in epilepsy (SUDEP), higher frequency of seizures is a very consistent issue. Following this reasoning, it has been established that hemodialysis-associated seizure is a complication of dialysis procedure. Based on these facts, this study investigated a possible association between cardiovascular abnormalities and SUDEP among patients with chronic renal insufficiency in regular hemodialysis program. For that, a retrospective medical history of 209 patients was reviewed to investigate the occurrence of convulsive seizures and EKG abnormalities during dialytic program. Three patients presented generalized tonic-clonic seizures, one had partial seizure with secondary generalization, and one presented unclassified seizure. Any EKG abnormalities and SUDEP event were found in all patients evaluated. In conclusion, the present findings demonstrated uncommon the occurrence of seizures and also SUDEP. Probably, the main justification to not allow us to demonstrated a direct relation between SUDEP and cardiovascular diseases in hemodialysis are the reduced number of cases examined.

Premature ventricular complexes: How benign are they in epilepsy?

Clinical and experimental studies make it clear that SUDEP is a phenomenon resulting from several factors, which can act both individually and together [1–3]. In this sense, there are a growing number of studies demonstrating an increased prevalence of markers for sudden cardiac arrest in refractory epilepsy [4]. In brief, people with refractory epilepsy have high prevalence of severe QTc prolongation and early repolarization pattern and higher resting heart rate when comparedwith healthy people [3]. In 2005, our research group was the first to demonstrate that the resting heart rate of rats with uncontrolled epilepsy was higher compared with animals without epilepsy [5]. Likewise, Damasceno and colleagues [6] showed that Wistar Audiogenic Rats (WAR) also exhibited high resting heart rate and QTc prolongation compared to animals without audiogenic seizures. Additionally, they also demonstrated that the isolated heart of WAR is more susceptible to arrhythmias induced by ischemia/reperfusion [6]. Moreover, Naggar and colleagues [7] reported cardiac hypertrophy in rats submitted to a kainic acid model of epilepsy; however, they verified decreased ventricular fibrillation susceptibility despite a higher QTc dispersion [7]. Furthermore, Fazan and coworkers [8] showed that WAR have reduced heart rate variability, and a higher frequency of premature ventricular complexes (PVCs) when compared to the control group. Thus, the studies carried out until now brought us to evaluate the interictal ECGs of pilocarpine-treated rats. For that, five Wistar rats with 2 months of

080 — (TOB0037) Evaluation of neurodevelopmental profile in rats following early-life seizures

Rationale: Neonatal seizures are the most common manifestation of neurological dysfunction in the neonate. Animal data indicate that seizures during development are associated with a high probability of long-term adverse effects such as learning and memory impairment and behavioral changes, but the mechanisms underlying those effects are not completely understood. This study quantified the expression of proteins involved in synaptic transmission (PSD-95, KCC2, and GABAT-1). Methods: The experimental group (EXP) received pilocarpine (380 mg/kg, i.p.), and the control group (CTR) received saline at postnatal day 9. At postnatal day 100, the animals (n= 4 per group) were euthanized, and the hippocampi were dissected for Western blot analysis. The results were analyzed using the Mann–Whitney test. Results: The immunoblot data showed an increase in GABT1, PSD-95, and KCC2 in the experimental group as compared with control rats. Discussion/conclusions: The enhanced expression of PSD-95 suggested a facilitation of the excitatory synaptic transmission, which could be counterbalanced by an increase in both KCC2 expression and GABAT-1 expression, a potential strategy to protect the brain from a new insult. These data raise the interesting possibility that neonatal seizures lead to an imbalance between excitatory neurotransmission and inhibitory neurotransmission.