Challenges and future directions of SUDEP models.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among patients with epilepsy, causing a global public health burden. The underlying mechanisms of SUDEP remain elusive, and effective prevention or treatment strategies require further investigation. A major challenge in current SUDEP research is the lack of an ideal model that maximally mimics the human condition. Animal models are important for revealing the potential pathogenesis of SUDEP and preventing its occurrence; however, they have potential limitations due to species differences that prevent them from precisely replicating the intricate physiological and pathological processes of human disease. This Review provides a comprehensive overview of several available SUDEP animal models, highlighting their pros and cons. More importantly, we further propose the establishment of an ideal model based on brain-computer interfaces and artificial intelligence, hoping to offer new insights into potential advancements in SUDEP research. In doing so, we hope to provide valuable information for SUDEP researchers, offer new insights into the pathogenesis of SUDEP and open new avenues for the development of strategies to prevent SUDEP.

Antiseizure Medications and Sudden Unexpected Death in Epilepsy: An Updated Review.

Sudden unexpected death in epilepsy (SUDEP) is responsible for most epilepsy-related deaths. It is mainly related to unwitnessed nocturnal convulsions, either focal to bilateral or generalised tonic-clonic seizures (TCS). Targeted preventive strategies are currently lacking as underlying mechanisms are largely unknown. Antiseizure medications (ASMs) modulate SUDEP risk through seizure reduction, but it is yet undetermined whether individual ASMs or other medications could also influence the internal SUDEP cascade. Seizure detection devices (SDD) may offer an alternative strategy by preventing TCS from being unwitnessed. Here, we critically evaluated the current evidence on the influence of ASMs, non-epilepsy concomitant drugs and SDD on SUDEP occurrence. We found no robust evidence for the effect of starting ASMs on SUDEP beyond TCS control, but we found some indications of a protective effect for polytherapy. We found no signs that specific ASMs exert a risk for SUDEP. One study suggested a possible protective effect of levetiracetam requiring further investigation. Only a few small studies addressed the association between non-epilepsy concomitant drugs and SUDEP, with no consistent effect for psychotropic medications and one more extensive study suggesting a lower risk among statin users. We only found indirect evidence indicating a protective effect for enhancing nocturnal supervision without explicitly addressing the impact of SDD on SUDEP occurrence. Further work is needed to explore the potential of ASMs and other interventions to modulate SUDEP risk, and they should accurately account for TCS frequency, polypharmacy and markers of non-adherence.

The influence of risk factors, biomarkers and care settings on SUDEP counseling.

Although sudden unexpected death in epilepsy (SUDEP) is the most feared epilepsy outcome, there is a dearth of SUDEP counseling provided by neurologists. This may reflect limited time, as well as the lack of guidance on the timing and structure for counseling. We evaluated records from SUDEP cases to examine frequency of inpatient and outpatient SUDEP counseling, and whether counseling practices were influenced by risk factors and biomarkers, such as post-ictal generalized EEG suppression (PGES). We found a striking lack of SUDEP counseling despite modifiable SUDEP risk factors; counseling was limited to outpatients despite many patients having inpatient visits within a year of SUDEP. PGES was inconsistently documented and was never included in counseling. There is an opportunity to greatly improve SUDEP counseling by utilizing inpatient settings and prompting algorithms incorporating risk factors and biomarkers.

Enhancing the action of serotonin by three different mechanisms prevents spontaneous seizure-induced mortality in Dravet mice.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic neurotransmission suppresses seizure-induced sudden death in evoked seizure models. However, it is unclear whether elevated serotonin (5-HT) function will prevent spontaneous seizure-induced mortality (SSIM), which is characteristic of human SUDEP. We examined the effects of 5-HT-enhancing agents that act by three different pharmacological mechanisms on SSIM in Dravet mice, which exhibit a high incidence of SUDEP, modeling human Dravet syndrome. METHODS: Dravet mice of both sexes were evaluated for spontaneous seizure characterization and changes in SSIM incidence induced by agents that enhance 5-HT-mediated neurotransmission. Fluoxetine (a selective 5-HT reuptake inhibitor), fenfluramine (a 5-HT releaser and agonist), SR 57227 (a specific 5-HT3 receptor agonist), or saline (vehicle) was intraperitoneally administered over an 8-day period in Dravet mice, and the effect of these treatments on SSIM was examined. RESULTS: Spontaneous seizures in Dravet mice generally progressed from wild running to tonic seizures with or without SSIM. Fluoxetine at 30 mg/kg, but not at 20 or 5 mg/kg, significantly reduced SSIM compared with the vehicle control. Fenfluramine at 1-10 mg/kg, but not .2 mg/kg, fully protected Dravet mice from SSIM, with all mice surviving. Compared with the vehicle control, SR 57227 at 20 mg/kg, but not at 10 or 5 mg/kg, significantly lowered SSIM. The effect of these drugs on SSIM was independent of sex. SIGNIFICANCE: Our data demonstrate that elevating serotonergic function by fluoxetine, fenfluramine, or SR 57227 significantly reduces or eliminates SSIM in Dravet mice in a sex-independent manner. These findings suggest that deficits in serotonergic neurotransmission likely play an important role in the pathogenesis of SSIM, and fluoxetine and fenfluramine, which are US Food and Drug Administration-approved medications, may potentially prevent SUDEP in at-risk patients.

Minimum clinical utility standards for wearable seizure detectors: A simulation study.

OBJECTIVE: Epilepsy management employs self-reported seizure diaries, despite evidence of seizure underreporting. Wearable and implantable seizure detection devices are now becoming more widely available. There are no clear guidelines about what levels of accuracy are sufficient. This study aimed to simulate clinical use cases and identify the necessary level of accuracy for each. METHODS: Using a realistic seizure simulator (CHOCOLATES), a ground truth was produced, which was then sampled to generate signals from simulated seizure detectors of various capabilities. Five use cases were evaluated: (1) randomized clinical trials (RCTs), (2) medication adjustment in clinic, (3) injury prevention, (4) sudden unexpected death in epilepsy (SUDEP) prevention, and (5) treatment of seizure clusters. We considered sensitivity (0%-100%), false alarm rate (FAR; 0-2/day), and device type (external wearable vs. implant) in each scenario. RESULTS: The RCT case was efficient for a wide range of wearable parameters, though implantable devices were preferred. Lower accuracy wearables resulted in subtle changes in the distribution of patients enrolled in RCTs, and therefore higher sensitivity and lower FAR values were preferred. In the clinic case, a wide range of sensitivity, FAR, and device type yielded similar results. For injury prevention, SUDEP prevention, and seizure cluster treatment, each scenario required high sensitivity and yet was minimally influenced by FAR. SIGNIFICANCE: The choice of use case is paramount in determining acceptable accuracy levels for a wearable seizure detection device. We offer simulation results for determining and verifying utility for specific use case and specific wearable parameters.

Protocol for modulating the noradrenergic pathway from locus coeruleus to heart to prevent sudden unexpected death in epilepsy in mouse models.

The locus coeruleus (LC) and noradrenergic neurotransmission are involved in the regulation of sudden unexpected death in epilepsy (SUDEP). Here, we present a protocol for modulating the noradrenergic pathway from LC to heart to prevent SUDEP in acoustic and pentylenetetrazole-induced DBA/1 mouse models of SUDEP. We describe steps for constructing SUDEP models, calcium signal recording, and electrocardiogram monitoring. We then detail measurement of tyrosine hydroxylase content and activity, ß1 and p-ß1-AR content, and destruction of LCNE neurons. For complete details on the use and execution of this protocol, please refer to Lian et al.1.

Protocol for modulation of the serotonergic DR-PBC neural circuit to prevent SUDEP in the acoustic and PTZ-induced DBA/1 mouse models of SUDEP.

The dorsal raphe nucleus (DR) and the pre-Bötzinger complex (PBC) may play an important role in regulating seizure-induced respiratory arrest (S-IRA), the main contributor to sudden unexpected death in epilepsy. Here, we describe pharmacological, optogenetic, and retrograde labeling approaches to specifically modulate the DR to PBC serotonergic pathway. We detail steps for implanting optical fibers and viral infusion into DR and PBC regions and optogenetic techniques for exploring the role of 5-hydroxytryptophan (5-HT) neural circuit of DR-PBC in S-IRA. For complete details on the use and execution of this protocol, please refer to Ma et al. (2022).1.

Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia.

Epilepsy is at times a fatal disease. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in people with intractable epilepsy and is defined by exclusion; non-accidental, non-toxicologic, and non-anatomic causes of death. While SUDEP often follows a bilateral tonic-clonic seizure, the mechanisms that ultimately lead to terminal apnea and then asystole remain elusive and there is a lack of preventative treatments. Based on the observation that discrete seizures lead to local and postictal vasoconstriction, resulting in hypoperfusion, hypoxia and behavioural disturbances in the forebrain we reasoned those similar mechanisms may play a role in SUDEP when seizures invade the brainstem. Here we tested this neurovascular-based hypothesis of SUDEP in awake non-anesthetized mice by pharmacologically preventing seizure-induced vasoconstriction, with cyclooxygenase-2 or L-type calcium channel antagonists. In both acute and chronic mouse models of seizure-induced premature mortality, ibuprofen and nicardipine extended life while systemic drug levels remained high enough to be effective. We also examined the potential role of spreading depolarization in the acute model of seizure-induced premature mortality. These data provide a proof-of-principle for the neurovascular hypothesis of SUDEP rather than spreading depolarization and the use of currently available drugs to prevent it.

A unified hypothesis of SUDEP: Seizure-induced respiratory depression induced by adenosine may lead to SUDEP but can be prevented by autoresuscitation and other restorative respiratory response mechanisms mediated by the action of serotonin on the periaqueductal gray.

Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in people with epilepsy (PWE). Postictal apnea leading to cardiac arrest is the most common sequence of terminal events in witnessed cases of SUDEP, and postconvulsive central apnea has been proposed as a potential biomarker of SUDEP susceptibility. Research in SUDEP animal models has led to the serotonin and adenosine hypotheses of SUDEP. These neurotransmitters influence respiration, seizures, and lethality in animal models of SUDEP, and are implicated in human SUDEP cases. Adenosine released during seizures is proposed to be an important seizure termination mechanism. However, adenosine also depresses respiration, and this effect is mediated, in part, by inhibition of neuronal activity in subcortical structures that modulate respiration, including the periaqueductal gray (PAG). Drugs that enhance the action of adenosine increase postictal death in SUDEP models. Serotonin is also released during seizures, but enhances respiration in response to an elevated carbon dioxide level, which often occurs postictally. This effect of serotonin can potentially compensate, in part, for the adenosine-mediated respiratory depression, acting to facilitate autoresuscitation and other restorative respiratory response mechanisms. A number of drugs that enhance the action of serotonin prevent postictal death in several SUDEP models and reduce postictal respiratory depression in PWE. This effect of serotonergic drugs may be mediated, in part, by actions on brainstem sites that modulate respiration, including the PAG. Enhanced activity in the PAG increases respiration in response to hypoxia and other exigent conditions and can be activated by electrical stimulation. Thus, we propose the unifying hypothesis that seizure-induced adenosine release leads to respiratory depression. This can be reversed by serotonergic action on autoresuscitation and other restorative respiratory responses acting, in part, via the PAG. Therefore, we hypothesize that serotonergic or direct activation of this brainstem site may be a useful approach for SUDEP prevention.

Sudden Unexpected Death in Epilepsy: Pathogenesis, Risk Factors, and Prevention.

Sudden unexpected death in epilepsy (SUDEP) is a tragic and unexpected cause of death in patients with a known diagnosis of epilepsy. It occurs in up to 6.3 to 9.3/1,000 patients with drug-resistant epilepsy. The main three risk factors associated with SUDEP are the presence of generalized tonic-clonic seizures, the presence of a seizure in the past year, and an intellectual disability. There are several mechanisms that can result in SUDEP. The most likely sequence of events appears to be a convulsive seizure, overactivation of the autonomic nervous system, cardiorespiratory dysfunction, and death. While the risk of SUDEP is relatively high in patients with drug-resistant epilepsy, studies indicate that more than 50% of patients and caregivers are unaware of the diagnosis. Counseling about the diagnosis and preventative measures at the time of diagnosis is important. There are numerous interventions that may reduce the risk of SUDEP, including conservative measures such as nocturnal surveillance with a bed partner (where applicable) and automated devices. Optimizing seizure control with antiseizure medications and surgical interventions can result in a reduced risk of SUDEP.

Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome.

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells.

Cardiorespiratory findings in epilepsy: A recent review on outcomes and pathophysiology.

Epilepsy is a debilitating disorder of uncontrollable recurrent seizures that occurs as a result of imbalances in the brain excitatory and inhibitory neuronal signals, that could stem from a range of functional and structural neuronal impairments. Globally, nearly 70 million people are negatively impacted by epilepsy and its comorbidities. One such comorbidity is the effect epilepsy has on the autonomic nervous system (ANS), which plays a role in the control of blood circulation, respiration and gastrointestinal function. These epilepsy-induced impairments in the circulatory and respiratory systems may contribute toward sudden unexpected death in epilepsy (SUDEP). Although, various hypotheses have been proposed regarding the role of epilepsy on ANS, the linking pathological mechanism still remains unclear. Channelopathies and seizure-induced damages in ANS-control brain structures were some of the causal/pathological candidates of cardiorespiratory comorbidities in epilepsy patients, especially in those who were drug resistant. However, emerging preclinical research suggest that neurotransmitter/receptor dysfunction and synaptic changes in the ANS may also contribute to the epilepsy-related autonomic disorders. Thus, pathological mechanisms of cardiorespiratory dysfunction should be elucidated by considering the modifications in anatomy and physiology of the autonomic system caused by seizures. In this regard, we present a comprehensive review of the current literature, both clinical and preclinical animal studies, on the cardiorespiratory findings in epilepsy and elucidate the possible pathological mechanisms of these findings, in hopes to prevent SUDEP especially in patients who are drug resistant.

Near-sudden unexpected death in a patient with epilepsy undergoing hemodialysis: a case report.

Sudden unexpected death in epilepsy (SUDEP) has been defined as a sudden/unexpected, witnessed/unwitnessed, nontraumatic, and nondrowning death in epileptic patients with/without seizure evidence and documented status epilepticus. Identified as the leading cause of epilepsy-related deaths, SUDEP cases are highly unrecognized and underreported due to diagnostic difficulty. We report a case of a successfully revived hemodialysis patient who developed cardiopulmonary arrest after a witnessed convulsive seizure. Electroencephalogram revealed epileptic abnormalities. Therefore, this case could be seizure-induced cardiopulmonary arrest and near-SUDEP. Hence, the possibility of SUDEP should be considered even in hemodialysis patients having conventional coronary risk factors for sudden cardiac death.

The brain-heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention.

The influence of the central nervous system and autonomic system on cardiac activity is being intensively studied, as it contributes to the high rate of cardiologic comorbidities observed in people with epilepsy. Indeed, neuroanatomic connections between the brain and the heart provide links that allow cardiac arrhythmias to occur in response to brain activation, have been shown to produce arrhythmia both experimentally and clinically. Moreover, seizures may induce a variety of transient cardiac effects, which include changes in heart rate, heart rate variability, arrhythmias, asystole, and other ECG abnormalities, and can trigger the development of Takotsubo syndrome. People with epilepsy are at a higher risk of death than the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Although the cause of SUDEP is still unknown, cardiac abnormalities during and between seizures could play a significant role in its pathogenesis, as highlighted by studies on animal models of SUDEP and registration of SUDEP events. Recently, genetic mutations in genes co-expressed in the heart and brain, which may result in epilepsy and cardiac comorbidity/increased risk for SUDEP, have been described. Recognition and a better understanding of brain-heart interactions, together with new advances in sequencing techniques, may provide new insights into future novel therapies and help in the prevention of cardiac dysfunction and sudden death in epileptic individuals.

Risk estimation of SUDEP during COVID-19 pandemic era in a tertiary referral center.

OBJECTIVE: No data exist regarding the impact of the lockdown due to the COVID-19 pandemic on the risk factors of sudden unexpected death in epilepsy (SUDEP). This study aimed to stratify risk factors of SUDEP in relation to COVID-19 lockdown, among patients with epilepsy (PWE) in Cairo University epilepsy unit (CUEU). Therefore, we can detect risk factors and mitigate such factors in the second wave of the virus. METHODS: an observational, cross-sectional study carried on 340 Egyptian patients with active epilepsy. Individual risk identification and stratification was done by using The SUDEP and seizure Safety Checklist, after which sharing risk knowledge to PWE and their caregivers was undertaken. RESULTS: The mean age of patients was 29.72 ± 12.12. The median of the static factors was 4 (IQR 3-5) whereas, the median of the modifiable factors was 2 (IQR 1-3). Epilepsy emergencies (serial seizures or status epilepticus) were reported in 24.1 % of patients, for which non-compliance was the commonest cause, followed by deferral of epilepsy surgery for patients with drug resistant epilepsy (DRE). Stepwise logistic regression analysis showed that use of anxiolytic medications, non-compliance, keeping patients with DRE on dual anti-seizure medications (ASMs), or adding third medication increased the odds of increased seizure frequency by 2.7, 3.5, 16.6 and 6.1 times, respectively. CONCLUSION: Some COVID-19 related issues had influenced the risk of seizure worsening including postponing epilepsy surgery for patients with DRE, non-compliance, and psychiatric comorbidities. Special attention should be paid to these issues to mitigate the risk of SUDEP.

Prevención de la muerte súbita en la epilepsia fármaco resistente: investigaciones de enfermería / Prevention of sudden death in drug-resistant epilepsy: nursing research

Introducción: Una muerte súbita en epilepsia (SUDEP) ocurre cada diez minutos en todo el mundo. El 30 por ciento de los pacientes epilépticos padecen de epilepsia fármaco resistente (EFR), no logran el control de sus crisis y esto aumenta el riesgo de SUDEP. Muchos aún desconocen los factores de riesgo SUDEP y cómo prevenirlos. Los tratamientos para evitarla aún son insuficientes. Las investigaciones enfermeras aportan resultados positivos en el manejo de la enfermedad. Objetivo: Revisar el estado sobre mortalidad, autogestión de epilepsia e investigaciones enfermeras para prevenir la SUDEP en adolescentes y adultos con EFR. Material y Métodos: Revisión sistemática y búsqueda bibliográfica en las bases de datos PubMed SciELO, SCOPUS, ElSEVIER, MEDES, Organización Panamericana de la Salud (OPS), INFOMED y Google académico. Los criterios de selección: trabajos de la última década en adolescentes y adultos publicados en Cuba y el mundo, enfatizando en las investigaciones enfermeras. Búsqueda de palabras claves en español e inglés, sin restricciones de idioma. Desarrollo: Entre los tratamientos para evitar la SUDEP, destacan los dispositivos de detección de crisis y programas de ayuda online, pero aún son necesarias nuevas opciones. En los factores de riesgo, destacan aquellos relacionados con el sueño. Otros factores de riesgo SUDEP pudieran ser modificables con programas educativos. A pesar de que aún se debaten las formas más adecuadas de ofrecer información sobre SUDEP, los programas educativos enfermeros han evidenciado mayor autogestión, conocimiento de la enfermedad y apego al tratamiento. Conclusiones: El enfermero es el potencial humano ideal, para implementar acciones de autocuidado en las personas con EFR, y empoderarlas con habilidades para el manejo de su enfermedad y prevención de SUDEP(AU)

Introduction: A sudden death in epilepsy (SUDEP) occurs every ten minutes worldwide. Also, 30 percent of epileptic patients who suffer from drug-resistant epilepsy (DRE) fail to control their seizures, so the risk of SUDEP increases. Many epileptic patients are unaware of the risk factors for SUDEP and the ways to prevent it. Treatments to avoid SUDEP are still insufficient. Nursing research provide positive results in the management of the disease. Objective: To review the mortality status, self-management of epilepsy and nursing research to prevent SUDEP in adolescents and adults with DRE. Material and Methods: A systematic review and bibliographic search was carried out in the PubMed SciELO, SCOPUS, ELSEVIER, MEDES, Pan American Health Organization (PAHO), INFOMED and Google Scholar databases. Selection criteria included studies on nursing research conducted in adolescents and adults during the last decade that have been published in Cuba and other countries of the world. Keywords in Spanish and English without language restrictions were used to carry out the search. Development: Crisis detection devices and online help programs stand out among the treatments to avoid SUDEP, but new options are still necessary. Among the risk factors for SUDEP, those related to sleep are highlighted. Other risk factors for SUDEP could be modified with educational programs. Despite the most appropriate ways of offering information about SUDEP are still debated, nursing educational programs have shown greater self-management, knowledge of the disease, and adherence to treatment. Conclusions: The Nurse is the ideal human potential to implement self-care actions in people with EFR. These actions aim to learn new skills for managing their disease and preventing SUDEP(AU)

Near SUDEP during bilateral stereo-EEG monitoring characterized by diffuse postictal EEG suppression.

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. The pathophysiology of SUDEP is unknown. Postictal phenomena such as postconvulsive immobility (PI), postictal generalized electroencephalography (EEG) suppression (PGES), arousal deficits, cardiac arrhythmias, central apneas, and obstructive apneas due to laryngospasms have been suggested to contribute to SUDEP. We present, to our knowledge, the first case of a near-SUDEP event in a patient undergoing intracranial, stereotactic EEG (sEEG) monitoring. This case spotlights potential mediators of SUDEP, most notably the striking PGES and postictal apnea. The nature of the sEEG investigation illustrates the extent of cortical and subcortical postictal EEG suppression and showcases a transient return of cerebral activity likely to be missed on scalp-EEG recording. Critically, this case emphasizes the importance of continuous cardiorespiratory monitoring and underscores the importance of postictal arousal as a pathophysiological mechanism in SUDEP.