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This study investigated the respiratory activity in adult Wistar rats across different behavioral seizure severity induced by pentylenetetrazole (PTZ). Animals underwent surgery for electrodes implantation, allowing simultaneous EEG and diaphragm EMG (DIAEMG) recordings and the respiratory frequency and DIAEMG amplitude were measured. Seizures were acutely induced through PTZ injection and classified based on a pre-established score, with absence-like seizures (spike wave discharge (SWD) events on EEG) representing the lowest score. The respiratory activity was grouped into the different seizure severities. During absence-like and myoclonic jerk seizures, the breathing frequency decreased significantly (∼50% decrease) compared to pre- and post-ictal periods. Pronounced changes occurred with more severe seizures (clonic and tonic) with periods of apnea, especially during tonic seizures. Apnea duration was significantly higher in tonic compared to clonic seizures. Notably, during PTZ-induced tonic seizures the apnea events were marked by tonic DIAEMG contraction (tonic-phase apnea). In the majority of animals (5 out of 7) this was a fatal event in which the seizure-induced respiratory arrest preceded the asystole. In conclusion, we provide an assessment of the respiratory activity in the PTZ-induced acute seizures and showed that breathing dysfunction is more pronounced in seizures with higher severity.

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OBJECTIVE: The authors investigated changes in vascular reactivity in rats following pilocarpine-induced status epilepticus. METHOD: Male Wistar rats weighing between 250g and 300g were used. Status epilepticus was induced using 385 mg/kg i.p. pilocarpine. After 40 days the thoracic aorta was dissected and divided into 4 mm rings and the vascular smooth muscle reactivity to phenylephrine was evaluated. RESULTS: Epilepsy decreased the contractile responses of the aortic rings to phenylephrine (0.1 nM-300 mM). To investigate if this reduction was induced by increasing NO production with/or hydrogen peroxide L-NAME and Catalase were used. L-NAME (N-nitro-L arginine methyl ester) increased vascular reactivity but the contractile response to phenylephrine increased in the epileptic group. Catalase administration decreased the contractile responses only in the rings of rats with epilepsy. CONCLUSIONS: Our findings demonstrated for the first time that epilepsy is capable of causing a reduction of vascular reactivity in rat aortas. These results suggest that vascular reactivity reduction is associated with increased production of Nitric Oxide (NO) as an organic attempt to avoid hypertension produced by excessive sympathetic activation.

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OBJECTIVE: Amygdala has been demonstrated as one of the brain sites involved in the control of cardiorespiratory functioning. The structural and physiological alterations induced by epileptic activity are also present in the amygdala and reflect functional changes that may be directly associated with a sudden unexpected death. Seizures are always associated with neuronal damage and changes in the expression of cation-chloride cotransporters and Na/K pumps. In this study, the authors aimed to investigate if these changes are present in the amygdala after induction of status epilepticus with pilocarpine, which may be directly correlated with Sudden Unexpected Death in Epilepsy (SUDEP). METHODS: Pilocarpine-treated wistar rats 60 days after Status Epilepticus (SE) were compared with control rats. Amygdala nuclei of brain slices immunostained for NKCC1, KCC2 and α1-Na+/K+-ATPase, were quantified by optical densitometry. RESULTS: The amygdaloid complex of the animals submitted to SE had no significant difference in the NKCC1 immunoreactivity, but KCC2 immunoreactivity reduced drastically in the peri-somatic sites and in the dendritic-like processes. The α1-Na+/K+-ATPase peri-somatic immunoreactivity was intense in the rats submitted to pilocarpine SE when compared with control rats. The pilocarpine SE also promoted intense GFAP staining, specifically in the basolateral and baso-medial nuclei with astrogliosis and cellular debris deposition. INTERPRETATION: The findings revealed that SE induces lesion changes in the expression of KCC2 and α1-Na+/K+-ATPase meaning intense change in the chloride regulation in the amygdaloid complex. These changes may contribute to cardiorespiratory dysfunction leading to SUDEP.

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Abstract Objective: The authors investigated changes in vascular reactivity in rats following pilocarpine-induced status epilepticus. Method: Male Wistar rats weighing between 250g and 300g were used. Status epilepticus was induced using 385 mg/kg i.p. pilocarpine. After 40 days the thoracic aorta was dissected and divided into 4 mm rings and the vascular smooth muscle reactivity to phenylephrine was evaluated. Results: Epilepsy decreased the contractile responses of the aortic rings to phenylephrine (0.1 nM-300 mM). To investigate if this reduction was induced by increasing NO production with/or hydrogen peroxide L-NAME and Catalase were used. L-NAME (N-nitro-L arginine methyl ester) increased vascular reactivity but the contractile response to phenylephrine increased in the epileptic group. Catalase administration decreased the contractile responses only in the rings of rats with epilepsy. Conclusions: Our findings demonstrated for the first time that epilepsy is capable of causing a reduction of vascular reactivity in rat aortas. These results suggest that vascular reactivity reduction is associated with increased production of Nitric Oxide (NO) as an organic attempt to avoid hypertension produced by excessive sympathetic activation.

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Objective: Amygdala has been demonstrated as one of the brain sites involved in the control of cardiorespiratory functioning. The structural and physiological alterations induced by epileptic activity are also present in the amygdala and reflect functional changes that may be directly associated with a sudden unexpected death. Seizures are always associated with neuronal damage and changes in the expression of cation-chloride cotransporters and Na/K pumps. In this study, the authors aimed to investigate if these changes are present in the amygdala after induction of status epilepticus with pilocarpine, which may be directly correlated with Sudden Unexpected Death in Epilepsy (SUDEP). Methods: Pilocarpine-treated wistar rats 60 days after Status Epilepticus (SE) were compared with control rats. Amygdala nuclei of brain slices immunostained for NKCC1, KCC2 and α1-Na+/K+-ATPase, were quantified by optical densitometry. Results: The amygdaloid complex of the animals submitted to SE had no significant difference in the NKCC1 immunoreactivity, but KCC2 immunoreactivity reduced drastically in the peri-somatic sites and in the dendritic-like processes. The α1-Na+/K+-ATPase peri-somatic immunoreactivity was intense in the rats submitted to pilocarpine SE when compared with control rats. The pilocarpine SE also promoted intense GFAP staining, specifically in the basolateral and baso-medial nuclei with astrogliosis and cellular debris deposition. Interpretation: The findings revealed that SE induces lesion changes in the expression of KCC2 and α1-Na + /K + -ATPase meaning intense change in the chloride regulation in the amygdaloid complex. These changes may contribute to cardiorespiratory dysfunction leading to SUDEP.

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To explore the role of the interictal and ictal SPECT to identity functional neuroimaging biomarkers for SUDEP risk stratification in patients with drug-resistant focal epilepsy (DRFE). Twenty-nine interictal-ictal Single photon emission computed tomography (SPECT) scans were obtained from nine DRFE patients. A methodology for the relative quantification of cerebral blood flow of 74 cortical and sub-cortical structures was employed. The optimal number of clusters (K) was estimated using a modified v-fold cross-validation for the use of K means algorithm. The two regions of interest (ROIs) that represent the hypoperfused and hyperperfused areas were identified. To select the structures related to the SUDEP-7 inventory score, a data mining method that computes an automatic feature selection was used. During the interictal and ictal state, the hyperperfused ROIs in the largest part of patients were the bilateral rectus gyrus, putamen as well as globus pallidus ipsilateral to the seizure onset zone. The hypoperfused ROIs included the red nucleus, substantia nigra, medulla, and entorhinal area. The findings indicated that the nearly invariability in the perfusion pattern during the interictal to ictal transition observed in the ipsi-lateral putamen F = 12.60, p = 0.03, entorhinal area F = 25.80, p = 0.01, and temporal middle gyrus F = 12.60, p = 0.03 is a potential biomarker of SUDEP risk. The results presented in this paper allowed identifying hypo- and hyperperfused brain regions during the ictal and interictal state potentially related to SUDEP risk stratification.

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BACKGROUND: Focal epilepsies have been described as a network disease. Noninvasive investigative techniques have been used to characterize epileptogenic networks. OBJECTIVE: This study aimed to describe ictal and interictal cortical and subcortical perfusion patterns using single- photon emission computed tomography (SPECT) in patients with drug-resistant epilepsy (DRE). METHODS: Thirty-five interictal-ictal SPECT scans were obtained from 15 patients with DRE. A methodology was developed to get a relative perfusion index (PI) of 74 cortical and sub-cortical brain structures. K-means algorithm, together with modified v-fold cross-validation, was used to identify the two regions of interest (ROIs) that represent hypoperfused and hyperperfused areas. RESULTS: In common with the individual analysis, the statistical analysis evidenced that the hyperperfusion ROIs resulting from group analysis during interictal and ictal involved mainly the cingulate gyrus, cuneus, lingual gyrus, and gyrus rectus as well as the putamen. ROIs hypoperfused included the red nucleus, the substantia nigra, and the medulla. The medians of the group analysis of the hypoperfusion and hyperperfusion ROIs were 0.601-0.565 and 1.133-1.119 for the ictal and interictal states, correspondingly. A group of mostly cortical structures involved in the hyperperfused ROIs in both interictal and ictal states showed no change or negative change in the transition from interictal to ictal state (mean change of -0.002). On the other hand, the brain stem, basal ganglia, red nucleus, and thalamus revealed a mean global change of 0.19, indicating a mild increase in the PI. However, some of these structures (red nucleus, substantia nigra, and medulla oblongata) remained hypoperfused during the interictal to ictal transition. CONCLUSION: The methodology employed made it possible to identify common cortical and subcortical perfusion patterns not directly linked to epileptogenicity, for a better epileptogenic network and sudden unexpected death (SUDEP) mechanism in DRE.

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SUMMARY OBJECTIVE: This study aimed to evaluate the concept of health professionals affiliated with the Brazilian League of Epilepsy on whether or not to inform patients about the risk factors related to the occurrence of sudden unexpected death in epilepsy. METHODS: A descriptive research of inquiry was conducted with direct survey on the Brazilian neurologist's view, regarding medical behavior in the health area to report or not about the risk of sudden unexpected death in epilepsy. Data collection consisted of a structured questionnaire available online. RESULTS: The study population consisted of a sample of 44 Brazilian League of Epilepsy members who answered the questionnaire, of which 25 (56.8%) were men and 19 (43.2%) were women. Among the analyzed questionnaires, 79.5% reported that they were aware of the risk factors for sudden unexpected death in epilepsy and 18.2% admitted not knowing the potential risk factors for sudden unexpected death in epilepsy. Notably, 59.1% of these professionals thought that an early discussion with the patient about sudden unexpected death in epilepsy must be considered. The majority (70%) felt that the neurologist should do this, and 22% believed that the subject should be discussed with psychologists. It was noted that 84.1% of respondents did not discuss or discussed only with some of their patients about the risk factors for sudden unexpected death in epilepsy. CONCLUSIONS: There is a need for encouraging early discussion of sudden unexpected death in epilepsy with epilepsy patients if the patient asks about the risks related to epilepsy and its treatment, when treatment adherence is low, in cases of intractable epilepsy with strong indication for surgical treatment, and when polytherapy is needed.

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This study aimed to compare heart rate variability (HRV) in patients with drug-resistant mesial temporal lobe epilepsy (MTLE) with healthy controls and to analyze their clinical and sociodemographic variables predictive for HRV. Thirty-nine consecutive patients with drug-resistant MTLE were included in the study. The control group included twenty-seven healthy participants matched by age and gender. Seven HRV indices (HR, RR, rMSSD, SDNN, LF, HF, and LF/HF) were compared between patients and controls. The clinical and sociodemographic variables independently associated with the HRV indices were identified by multiple linear regression. In comparison with controls, the patients with MTLE showed a significant reduction in RR, rMSSD, SDNN, LF, HF, and LF/HF indices (t value 1.97-5.97, p < 0.05). Multiple regression models showed that disease duration predicted 11-22% of the analyzed HRV indices. Time domain indices showed higher association with disease duration than coefficients in frequency domain. Patients with drug-resistant MTLE present cardiac autonomic tone dysfunction, showing a significant reduction in their HRV indices (RR, SDNN, rMSSD, LF, HF, and LF/HF). Disease duration has a negative association with all HRV indices. This study contributes to understanding the relationship between MTLE and the cardiac autonomic tone, with possible implications for sudden unexpected death in epilepsy.

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The multidrug-resistance (MDR) phenotype is typically observed in patients with refractory epilepsy (RE) whose seizures are not controlled despite receiving several combinations of more than two antiseizure medications (ASMs) directed against different ion channels or neurotransmitter receptors. Since the use of bromide in 1860, more than 20 ASMs have been developed; however, historically ~30% of cases of RE with MDR phenotype remains unchanged. Irrespective of metabolic biotransformation, the biodistribution of ASMs and their metabolites depends on the functional expression of some ATP-binding cassette transporters (ABC-t) in different organs, such as the blood-brain barrier (BBB), bowel, liver, and kidney, among others. ABC-t, such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP-1), and breast cancer-resistance protein (BCRP), are mainly expressed in excretory organs and play a critical role in the pharmacokinetics (PK) of all drugs. The transporter hypothesis can explain pharmacoresistance to a broad spectrum of ASMs, even when administered simultaneously. Since ABC-t expression can be induced by hypoxia, inflammation, or seizures, a high frequency of uncontrolled seizures increases the risk of RE. These stimuli can induce ABC-t expression in excretory organs and in previously non-expressing (electrically responsive) cells, such as neurons or cardiomyocytes. In this regard, an alternative mechanism to the classical pumping function of P-gp indicates that P-gp activity can also produce a significant reduction in resting membrane potential (ΔΨ0 = -60 to -10 mV). P-gp expression in neurons and cardiomyocytes can produce membrane depolarization and participate in epileptogenesis, heart failure, and sudden unexpected death in epilepsy. On this basis, ABC-t play a peripheral role in controlling the PK of ASMs and their access to the brain and act at a central level, favoring neuronal depolarization by mechanisms independent of ion channels or neurotransmitters that current ASMs cannot control.

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The COVID-19 pandemic has had an unprecedented impact on people and healthcare services. The disruption to chronic illnesses, such as epilepsy, may relate to several factors ranging from direct infection to secondary effects from healthcare reorganization and social distancing measures. OBJECTIVES: As part of the COVID-19 and Epilepsy (COV-E) global study, we ascertained the effects of COVID-19 on people with epilepsy in Brazil, based on their perspectives and those of their caregivers. We also evaluated the impact of COVID-19 on the care delivered to people with epilepsy by healthcare workers. METHODS: We designed separate online surveys for people with epilepsy and their caregivers. A further survey for healthcare workers contained additional assessments of changes to working patterns, productivity, and concerns for those with epilepsy under their care. The Brazilian arm of COV-E initially collected data from May to November 2020 during the country's first wave. We also examined national data to identify the Brazilian states with the highest COVID-19 incidence and related mortality. Lastly, we applied this geographic grouping to our data to explore whether local disease burden played a direct role in difficulties faced by people with epilepsy. RESULTS: Two hundred and forty-one people returned the survey, 20% were individuals with epilepsy (n = 48); 22% were caregivers (n = 53), and 58% were healthcare workers (n = 140). Just under half (43%) of people with epilepsy reported health changes during the pandemic, including worsening seizure control, with specific issues related to stress and impaired mental health. Of respondents prescribed antiseizure medication, 11% reported difficulty taking medication on time due to problems acquiring prescriptions and delayed or canceled medical appointments. Only a small proportion of respondents reported discussing significant epilepsy-related risks in the previous 12 months. Analysis of national COVID-19 data showed a higher disease burden in the states of Sao Paulo and Rio de Janeiro compared to Brazil as a whole. There were, however, no geographic differences observed in survey responses despite variability in the incidence of COVID-19. CONCLUSION: Our findings suggest that Brazilians with epilepsy have been adversely affected by COVID-19 by factors beyond infection or mortality. Mental health issues and the importance of optimal communication are critical during these difficult times. Healthcare services need to find nuanced approaches and learn from shared international experiences to provide optimal care for people with epilepsy as the direct burden of COVID-19 improves in some countries. In contrast, others face resurgent waves of the pandemic.

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Autonomic dysfunction in epilepsy is well-described. Heart rate variability (HRV) is a useful method to evaluate autonomic cardiac tone. Cardiac dysfunction may be involved in sudden unexpected death in epilepsy (SUDEP). HRV is a promising biomarker to enlighten the heart-brain axis role in SUDEP, but the required duration for a proper HRV recording in clinical routine remains unknown. This study aimed to verify the reliability of ultra-short HRV indices to evaluate cardiac autonomic tone in patients with epilepsy (PWE). Thirty-nine patients with mesial temporal lobe epilepsy (MTLE) had electrocardiogram recordings during the first day of video-EEG. Pearson's correlations were performed to evaluate the association between ultra-short HRV indices (five 1-min and five 30-s epochs) with standard time recording (5-min) and ANOVA compared the differences between mean HRV indices across epochs. Time domain (TD) indices showed higher mean r values when compared to frequency domain (FD) indices in 1-min (TD: r 0.80-0.99, FD: r 0.61-0.95) and 30-s epochs (TD: r 0.69-0.99, only high frequency: mean r values of 0.96). ANOVA evidenced that standard deviation of RR intervals and very low frequency means had at least 3 epochs significantly different for 1-min and 30-s epochs. Root mean square of the successive differences of RR intervals (rMSSD) presented higher Pearson's coefficient values and lower percentage of variation at 1-min or 30-s epochs in comparison to other HRV indices. In conclusion, rMSSD is the most reliable ultra-short HRV index for cardiac autonomic tone assessment in MTLE. The prognostic value of ultra-short HRV for cardiovascular risk evaluation in epilepsy remains to be determined in future studies.

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Sudden unexpected death in epilepsy (SUDEP) is the major cause of death that affects patients with epilepsy. The risk of SUDEP increases according to the frequency and severity of uncontrolled seizures; therefore, SUDEP risk is higher in patients with refractory epilepsy (RE), in whom most antiepileptic drugs (AEDs) are ineffective for both seizure control and SUDEP prevention. Consequently, RE and SUDEP share a multidrug resistance (MDR) phenotype, which is mainly associated with brain overexpression of ABC-transporters such as P-glycoprotein (P-gp). The activity of P-gp can also contribute to membrane depolarization and affect the normal function of neurons and cardiomyocytes. Other molecular regulators of membrane potential are the inwardly rectifying potassium channels (Kir), whose genetic variants have been related to both epilepsy and heart dysfunctions. Although it has been suggested that dysfunctions of the cardiac, respiratory, and brainstem arousal systems are the causes of SUDEP, the molecular basis for explaining its dysfunctions remain unknown. In rats, repetitive seizures or status epilepticus induced high expression of P-gp and loss Kir expression in the brain and heart, and promoted membrane depolarization, malignant bradycardia, and the high rate of mortality. Here we reviewed clinical and experimental evidences suggesting that abnormal expression of depolarizing/repolarizing factors as P-gp and Kir could favor persistent depolarization of membranes without any rapid functional recovery capacity. This condition induced by convulsive stress could be the molecular mechanism leading to acquired severe bradycardia, as an ineffective heart response generating the appropriate scenario for SUDEP development. This article is part of the Special Issue "NEWroscience 2018".

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OBJECTIVES: Frontal lobe epilepsy (FLE) may impair autonomic heart rate modulation. Decreased heart rate variability (HRV) may enhance risk of sudden death. Our objective was to describe whole day and wakefulness/sleep HRV parameters from FLE patients in comparison with those of healthy controls and correlate HRV parameters to SUDEP-7 scores. METHODS: Ten patients with FLE and 15 healthy controls underwent a 24-hour electrocardiogram holter. The SUDEP-7 score was calculated for patients. Subgroups were identified according to active epilepsy, number of generalized seizures, cognitive deficit, medication load, and time-length of epilepsy. Time-domain SDNN, SDNNi, SDANN, rMSDD, and pNN50 and frequency-domain LF, HF, and LF/HF parameters were analyzed. Wilcoxon and Spearman correlation tests were used. A P < .05 was considered significant. RESULTS: Patients SDNN, SDNNi, rMSSD, and pNN50 were decreased in 24-hour recordings. Although a tendency for a protective effect of sleep was seen for both patients and controls, intragroup comparisons of sleeping/waking states revealed a significant increase in sleep rMSSD (P = .046) and pNN50 (P = .041) only for controls. All 24-hour time-domain parameters and LF were inversely and significantly correlated to SUDEP-7, particularly SDANN (ρ = -0.896, P = .00019), known to deteriorate with diminished physical activity and decreased in patients with more generalized seizures. Wakefulness parameters did not correlate to SUDEP-7, whereas correlations to sleep parameters were very strong, particularly with rMSSD (ρ = -0.945, P = .00012). Cognitive deficit was associated with decreased pNN50, sleep pNN50, and LH. CONCLUSION: HRV is impaired in patients with FLE. Low HRV scores are associated with increased risk for SUDEP as measured by the SUDEP-7 score.

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Sudden unexpected death in epilepsy (SUDEP), definida como la muerte brusca, inesperada, con o sin testigos, no traumática ni por ahogo, que ocurre en circunstancias benignas, en un individuo con epilepsia, con o sin evidencias de crisis, pero sin estado epiléptico. En general, afecta sobre todo a pacientes con epilepsia refractaria. La incidencia es de 4-7/1000 pacientes al año. En nuestra región, no contamos con muchos datos epidemiológicos de SUDEP, lo cual es un desafío a investigar, ya que sabemos que el 85% de los pacientes con epilepsia viven en países en desarrollo. Es muy importante que los pacientes y/o familiares conozcan sobre SUDEP, ya que ayuda a lograr mejor lo objetivos de tratamiento, promueve mejor el reporte médico-paciente, disminuye ansiedad, filtra la información inadecuada y creencias inapropiadas. Pero es necesario preguntarles a ellos, cuanto saben de SUDEP, cómo, que y cuando recibir esta información. Existen países y culturas donde está vedado hablar de SUDEP. Tampoco conocemos cómo los médicos manejamos el tema, cuando decirlo, que contar y cómo hacerlo. Por otro lado, hay controversias entre los epileptólogos, en qué momento tratar la temática. Por este motivo, se realiza una encuesta a pacientes con epilepsia y/o familiares, además de especialistas médicos. El objetivo es evaluar si los colegas especialistas están hablando del tema y por otro lado constatar los conocimientos de SUDEP en los pacientes y/o familiares. Los resultados de la encuesta, arrojan que la mayoría de los médicos no habla del tema y la mayor parte de los familiares de pacientes con epilepsia desea conocer la temática al inicio de la enfermedad, contada por el médico. Gran número de ellos se ha informado por redes sociales y creen que es prevenible.

Sudden unexpected death in epilepsy (SUDEP), is defined as sudden, unexpected death, with or without witnesses, neither traumatic nor by choking, occurring in benign circumstances in an individual with epilepsy, with or without evidence of crisis, but without epileptic status. In general, it mainly affects patients with refractory epilepsy. The incidence is 4-7/1000 patients per year. In our region, we do not have much epidemiological data about SUDEP, which is a challenge to investigate, as we know that 85% of epilepsy patients live in developing countries. It is important to ask patients and/or family members how much do they know about SUDEP and how as well as when to receive this information. It is important that parents and/or family members know about SUDEP, as it helps to better achieve treat ment goals, better promotes doctor-patient reporting, decreases anxiety, filters inadequate information and inappropriate beliefs. There are countries and cultures where it is forbidden to talk about SUDEP. We also do not know how doctors handle the subject, when to talk about it, what to tell and how to do it. On the other hand, there are controversies among epileptologists at which point to deal with this subject. For this reason, a survey is conducted on parents of children with epilepsy and/or family members, as well as medical specialists. The objective is to be able to evaluate how specialist colleagues are talking about the topic and on the other hand evaluate some parameters of SUDEP in parents and/or family members. Most doctors do not talk about it and most relatives of epilepsy patients want to know the topic of the onset of the disease form their doctor. Large numbers of them have gathered information on SUDEP through social networks and believe it is preventable.

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The most important activity of erythropoietin (EPO) is the regulation of erythrocyte production by activation of the erythropoietin receptor (EPO-R), which triggers the activation of anti-apoptotic and proliferative responses of erythroid progenitor cells. Additionally, to erythropoietic EPO activity, an antiapoptotic effect has been described in a wide spectrum of tissues. EPO low levels are found in the central nervous system (CNS), while EPO-R is expressed in most CNS cell types. In spite of EPO-R high levels expressed during the hypoxicischemic brain, insufficient production of endogenous cerebral EPO could be the cause of determined circuit alterations that lead to the loss of specific neuronal populations. In the heart, high EPO-R expression in cardiac progenitor cells appears to contribute to myocardial regeneration under EPO stimulation. Several lines of evidence have linked EPO to an antiapoptotic role in CNS and in heart tissue. In this review, an antiapoptotic role of EPO/EPO-R system in both brain and heart under hypoxic conditions, such as epilepsy and sudden death (SUDEP) has been resumed. Additionally, their protective effects could be a new field of research and a novel therapeutic strategy for the early treatment of these conditions and avoid SUDEP.

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Sudden unexpected death in epilepsy (SUDEP) is the major cause of death in those patients suffering from refractory epilepsy (RE), with a 24-fold higher risk relative to the normal population. SUDEP risk increases with seizure frequency and/or seizure-duration as in RE and Status Epilepticus (SE). P-glycoprotein (P-gp), the product of the multidrug resistant ABCB1-MDR-1 gene, is a detoxifying pump that extrudes drugs out of the cells and can confer pharmacoresistance to the expressing cells. Neurons and cardiomyocytes normally do not express P-gp, however, it is overexpressed in the brain of patients or in experimental models of RE and SE. P-gp was also detected after brain or cardiac hypoxia. We have previously demonstrated that repetitive pentylenetetrazole (PTZ)-induced seizures increase P-gp expression in the brain, which is associated with membrane depolarization in the hippocampus, and in the heart, which is associated with fatal SE. SE can produce hypoxic-ischemic altered cardiac rhythm (HIACR) and severe arrhythmias, and both are related with SUDEP. Here, we investigate whether SE induces the expression of hypoxia-inducible transcription factor (HIF)-1α and P-gp in cardiomyocytes, which is associated with altered heart rhythm, and if these changes are related with the spontaneous death rate. SE was induced in Wistar rats once a week for 3 weeks, by lithium-pilocarpine-paradigm. Electrocardiograms, HIF-1α, and P-gp expression in cardiomyocytes, were evaluated in basal conditions and 72 h after SE. All spontaneous deaths occurred 48 h after each SE was registered. We observed that repeated SE induced HIF-1α and P-gp expression in cardiomyocytes, electrocardiographic (ECG) changes, and a high rate of spontaneous death. Our results suggest that the highly accumulated burden of convulsive stress results in a hypoxic heart insult, where P-gp expression may play a depolarizing role in cardiomyocyte membranes and in the development of the ECG changes, such as QT interval prolongation, that could be related with SUDEP. We postulate that this mechanism could explain, in part, the higher SUDEP risk in patients with RE or SE.

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A survey of 146 pediatric care providers (PCPs) revealed that 75.3% were unaware that children with epilepsy were at risk of death, specifically from sudden unexpected (or unexplained) death in epilepsy (SUDEP). PCPs assume that the treating neurologist discusses these risks. Increasing PCPs' knowledge of SUDEP will help address the care gap related to informing families about SUDEP.

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