Ironing out the Links: Ferroptosis in epilepsy and SUDEP.

Iron is a crucial element for almost all organisms because it plays a vital role in oxygen transport, enzymatic processes, and energy generation due to its electron transfer capabilities. However, its dysregulation can lead to a form of programmed cell death known as ferroptosis, which is characterized by cellular iron accumulation, reactive oxygen species (ROS) production, and unrestricted lipid peroxidation. Both iron and ferroptosis have been identified as key players in the pathogenesis of various neurodegenerative diseases. While in epilepsy this phenomenon remains relatively understudied, seizures can be considered hypoxic-ischemic episodes resulting in increased ROS production, lipid peroxidation, membrane disorganization, and cell death. All of this is accompanied by elevated intracellular free Fe2+ concentration and hemosiderin precipitation, as existing reports suggest a significant accumulation of iron in the brain and heart associated with epilepsy. Generalized tonic-clonic seizures (GTCS), a primary risk factor for Sudden Unexpected Death in Epilepsy (SUDEP), not only have an impact on the brain but also lead to cardiogenic dysfunctions associated with "Iron Overload and Cardiomyopathy" (IOC) and "Epileptic heart" characterized by electrical and mechanical dysfunction and a high risk of malignant bradycardia. In line with this phenomenon, studies conducted by our research group have demonstrated that recurrent seizures induce hypoxia in cardiomyocytes, resulting in P-glycoprotein (P-gp) overexpression, prolonged Q-T interval, severe bradycardia, and hemosiderin precipitation, correlating with an elevated spontaneous death ratio. In this article, we explore the intricate connections among ferroptosis, epilepsy, and SUDEP. By synthesizing current knowledge and drawing insights from recent publications, this study provides a comprehensive understanding of the molecular underpinnings. Furthermore, this review offers insights into potential therapeutic avenues and outlines future research directions.

Reduced long-term mortality after successful resective epilepsy surgery: a population-based study.

BACKGROUND: We investigated all-cause and epilepsy-related mortality in patients operated with resective epilepsy surgery and in non-operated patients with drug-resistant epilepsy. Our hypothesis was that patients who proceed to surgery have lower mortality over time compared with non-operated patients. METHOD: Data from 1329 adults and children from the Swedish National Epilepsy Surgery Register and 666 patients with drug-resistant epilepsy who had undergone presurgical work-up but not been operated were analysed. The operated patients had follow-ups between 2 and 20 years. We used the Swedish Cause of Death Register to identify deaths. Autopsy reports were collected for patients with suspected sudden unexpected death in epilepsy (SUDEP). Kaplan-Meier and Cox regression analyses were performed to identify predictors for mortality and SUDEP. RESULTS: SUDEP accounted for 30% of all deaths. Surgery was associated with lower all-cause mortality (HR 0.7, 95% CI 0.5 to 0.9), also when adjusted for age, sex and tonic-clonic seizures at inclusion. The benefit of surgery seemed to persist and possibly even increase after 15 years of follow-up. Risk factors of mortality for operated patients were persisting seizures and living alone. Of the operated patients, 37% had seizures, and these had a higher risk of mortality (HR 2.1, 95% CI 1.4 to 3.0) and SUDEP (HR 3.5, 95% CI 1.7 to 7.3) compared with patients with seizure freedom at last follow-up. CONCLUSIONS: In this large population-based epilepsy surgery cohort, operated patients had a lower all-cause mortality compared with non-operated patients with drug-resistant epilepsy. Seizure freedom was the most important beneficial factor for both all-cause mortality and SUDEP among operated patients.

Clinical Perspective: EEG-Based Neuromodulation Technique for Epilepsy.

Epilepsy is the most common brain disorder around the world. The main treatments of epilepsy are through drug treatment or epilepsy surgery. However, examples of EEG-based neuromodulation treatments, such as Vagus nerve stimulation (VNS), thalamic deep brain stimulation (DBS), and responsive neuro-stimulation (RNS), are also promising therapeutic methods nowadays. The aim of the paper is to recognize the effectiveness and potential risks of the three techniques. By carrying out randomized multicenter double-blind trials, this research studied the effectiveness of VNS, RNS, and DBS by measuring the median seizure reduction rate, rate of the responder, and proportion of seizure-free patients; the sudden unexpected death in epilepsy (SUDEP) of the treated patients; and the possible side effects that each treatment may cause. This review paper discusses the classification of epilepsy, common treatment methods for epilepsy, previous studies related to the three techniques, and data collected from the randomized multicenter double-blind trials. All in all, the result suggested that for short-term treatment, DBS may be the most effective method, but for long-term treatment, RNS may be more recommended. As the SUDEP rates for all three methods are lower than the SUDEP rate for epilepsy surgery, EEG-based neuromodulation techniques may become the main treatment for epilepsy in the future.

Caffeine exacerbates seizure-induced death via postictal hypoxia.

Sudden unexpected death in epilepsy (SUDEP) is the leading epilepsy-related cause of premature mortality in people with intractable epilepsy, who are 27 times more likely to die than the general population. Impairment of the central control of breathing following a seizure has been identified as a putative cause of death, but the mechanisms underlying this seizure-induced breathing failure are largely unknown. Our laboratory has advanced a vascular theory of postictal behavioural dysfunction, including SUDEP. We have recently reported that seizure-induced death occurs after seizures invade brainstem breathing centres which then leads to local hypoxia causing breathing failure and death. Here we investigated the effects of caffeine and two adenosine receptors in two models of seizure-induced death. We recorded local oxygen levels in brainstem breathing centres as well as time to cessation of breathing and cardiac activity relative to seizure activity. The administration of the non-selective A1/A2A antagonist caffeine or the selective A1 agonist N6-cyclopentyladenosine reveals a detrimental effect on postictal hypoxia, providing support for caffeine modulating cerebral vasculature leading to brainstem hypoxia and cessation of breathing. Conversely, A2A activation with CGS-21680 was found to increase the lifespan of mice in both our models of seizure-induced death.

Long term outcome after surgical treatment for hypothalamic hamartoma.

PURPOSE: To determine long-term outcome for seizure control and clinical predictors for seizure freedom in patients undergoing surgical treatment for epilepsy associated with hypothalamic hamartoma (HH). METHODS: 155 patients underwent surgical treatment for HHs and treatment-resistant epilepsy at one center (Barrow Neurological Institute at St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA) between February 2003 and June 2010. Data collection included medical record review and direct follow-up interviews to determine seizure outcome. Statistical analysis included descriptive summaries of patient characteristics and time-to-event analysis for seizure freedom. RESULTS: Long-term survival with follow-up of at least five years since first surgical treatment was available for 108 patients (69.7% of the treatment cohort). The surgical approach for first HH intervention consisted of transventricular endoscopic resection (n = 57; 52.8%), transcallosal interforniceal resection (n = 35; 32.4%), pterional resection (n = 7; 6.5%), and gamma knife radiosurgery (n = 9; 8.3%). Multiple surgical procedures were required for 39 patients (36.1%). There were 10 known deaths from all causes in the treatment cohort (6.5%). Of these, one (0.6%) was related to immediate complications of HH surgery, three (1.9%) were attributed to Sudden Unexpected Death in Epileptic Persons (SUDEP), and one (0.6%) to complications of status epilepticus. For surviving patients with long-term follow-up, 55 (50.9%) were seizure-free for all seizure types. Univariable analysis showed that seizure-freedom was related to 1) absence of a pre-operative history for central precocious puberty (p = 0.01), and 2) higher percentage of HH lesion disconnection after surgery (p = 0.047). Kaplan-Meier survival analysis shows that long-term seizure outcome following HH surgery is comparable to short-term results. SUMMARY: These uncontrolled observational results show that long-term seizure control following HH surgical treatment is comparable to other forms of epilepsy surgery. Late relapse (at least one year after surgery) and SUDEP do occur, but in a relatively small number of treated patients. These results inform clinical practice and serve as a comparable benchmark for newer technologies for HH surgery, such as magnetic resonance imaging-guided laser interstitial thermal therapy, where long-term outcome results are not yet available.

Epilepsy-Related Mortality After Laser Interstitial Thermal Therapy in Patients With Drug-Resistant Epilepsy.

OBJECTIVES: The purpose of this report was to study the incidence of sudden unexpected death in epilepsy (SUDEP) after laser interstitial thermal therapy (LITT) for drug-resistant epilepsy (DRE). METHODS: A prospective observational study of consecutive patients treated with LITT between 2013 and 2021 was conducted. The primary outcome was the occurrence of SUDEP during postoperative follow-up. Surgical outcome was classified according to the Engel scale. RESULTS: There were 5 deaths, including 4 SUDEPs, among 135 patients with a median follow-up duration of 3.5 (range 0.1-9.0) years and a total of 501.3 person-years at risk. The estimated incidence of SUDEP was 8.0 (95% CI 2.2-20.4) per 1,000 person-years. Three SUDEPs occurred in patients with poor seizure outcomes, whereas 1 patient was seizure-free. Compared with pooled historical data, SUDEP occurred at a higher rate than in cohorts treated with resective surgery and at a rate similar to nonsurgical controls. DISCUSSION: SUDEP occurred early and late after mesial temporal LITT. The SUDEP rate was comparable with rates reported in epilepsy surgery candidates who did not receive intervention. These findings reinforce targeting seizure freedom to decrease SUDEP risk, including early consideration for further intervention. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that LITT is not effective in reducing SUDEP incidence in patients with DRE.

The amygdala lesioning due to status epilepticus - Changes in mechanisms controlling chloride homeostasis.

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.

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.

Advances in sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is the major cause of premature death in epilepsy patients, particularly those with refractory epilepsy. Sudden unexpected death in epilepsy is thought to be related to peri-ictal cardiac dysfunction, respiratory depression, and autonomic dysfunction, albeit the exact etiology is unknown. Sudden unexpected death in epilepsy prevention remains a huge challenge. The sole presence and frequency of generalized tonic-clonic seizures (GTCS) are the most important risk factors for SUDEP, and nocturnal monitoring may lower the risk with the use of remote listening devices. In addition, studies in animal models of SUDEP have discovered that multiple neurotransmitters, including serotonin (5-HT) and adenosine, may be involved in the pathophysiological mechanisms of SUDEP and that these neurotransmitters could be the targets of future pharmacological intervention for SUDEP. The latest research findings on the epidemiology, clinical risk factors, and probable causes of SUDEP are presented in this review.

Sudden Unexpected Death in Epilepsy: A Report of Three Commonly Encountered Anatomic Findings in the Forensic Setting With Recommendations for Best Practices.

ABSTRACT: Sudden unexplained death in epilepsy (SUDEP) is the most common cause of death in children and young adults with epilepsy with epileptic patients harboring a 27 times increased risk of death from SUDEP. Structural brain lesions are encountered in up to 50% of autopsy cases. In this case series, we report 3 previously undiagnosed structural causes of SUDEP discovered at autopsy at our institution including schizencephaly, ganglioglioma, and focal cortical dysplasia. Our major recommendation is in cases with suspected SUDEP, formal neuropathological examination and tissue sampling should be employed to identify and characterize specific potential anatomic etiologies.

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.

Epilepsy related multimorbidity, polypharmacy and risks in adults with intellectual disabilities: a national study.

BACKGROUND: A quarter of people with Intellectual Disability (ID) in the UK have epilepsy compared to 0.6% in the general population and die much younger. Epilepsy is associated with two-fifths of all deaths with related polypharmacy and multi-morbidity. Epilepsy research on this population has been poor. This study describes real-world clinical and risk characteristics of a large cohort across England and Wales. METHODS: A retrospective multi-centre cohort study was conducted. Information on seizure characteristics, ID severity, relevant co-morbidities, psychotropic and antiseizure drugs (ASDs), SUDEP and other risk factors was collected across a year. RESULTS: Of 904 adults across 10 centres (male:female, 1.5:1), 320 (35%) had mild ID and 584 (65%) moderate-profound (M/P) ID. The mean age was 39.9 years (SD 15.0). Seizures were more frequent in M/P ID (p < 0.001). Over 50% had physical health co-morbidities, more in mild ID (p < 0.01). A third had psychiatric co-morbidity and a fifth had an underlying genetic disorder. Autism Spectrum Disorder was seen in over a third (37%). Participants were on median two ASDs and overall, five medications. Over quarter were on anti-psychotics. Over 90% had an epilepsy review in the past year but 25% did not have an epilepsy care plan, particularly those with mild ID (p < 0.001). Only 61% had a documented discussion of SUDEP, again less likely with mild ID or their care stakeholders (p < 0.001). CONCLUSIONS: Significant levels of multi-morbidity, polypharmacy and a lack of systemised approach to treatment and risk exist. Addressing these concerns is essential to reduce premature mortality.

Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy.

OBJECTIVE: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP. METHODS: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5c/- ), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures. RESULTS: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic-ECG records on Depdc5c/- mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia. INTERPRETATION: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies. ANN NEUROL 2022;91:101-116.

Sudden unexpected death in epilepsy in persons younger than 50 years: A retrospective nationwide cohort study in Denmark.

OBJECTIVE: Persons with epilepsy have an increased mortality including a high risk of sudden unexplained death (SUD), also referred to as sudden unexpected death in epilepsy (SUDEP). We aimed to evaluate the risk of SUDEP in comparison to other causes of death and the risk of SUD in persons with and without epilepsy. METHODS: We undertook a retrospective population-based cohort study of all Danish citizens with and without epilepsy aged 1-49 years during 2007-2009. All deaths in the population were evaluated, and all cases of SUD identified. Primary causes of death in persons with epilepsy were evaluated independently by three neurologists and one neuropediatrician, using the unified SUDEP criteria. RESULTS: The three most frequent causes of death in persons with epilepsy were cancer (2.38 per 1000 person-years), SUDEP (1.65 per 1000 person-years), and pneumonia (1.09 per 1000 person-years) compared with cancer (.17 per 1000 person-years), accident-related deaths (.14 per 1000 person-years), and cardiovascular disease (.09 per 1000 person-years) in persons without epilepsy. Considering definite, definite plus, and probable cases, the SUDEP incidence was .27 per 1000 person-years (95% confidence interval [CI] = .11-.64) in children aged 1-17 years and 1.21 per 1000 person-years (95% CI = .96-1.51) in adults aged 18-49 years. Adjusted for age and sex, persons with epilepsy younger than 50 years had a 10.8-fold (95% CI = 9.97-11.64, p < .0001) increased all-cause mortality and a 34.4-fold (95% CI = 23.57-50.28, p < .0001) increased risk of SUD compared with persons without epilepsy. SUDEP accounted for 23.3% of all SUD. SIGNIFICANCE: This nationwide study of all deaths in persons with epilepsy younger than 50 years found a lower SUDEP risk in children compared with adults, and that epilepsy was a major risk factor for SUD in the background population. This underlines the importance of addressing risk factors for SUDEP to prevent premature death.

Review: Neuropathology findings in autonomic brain regions in SUDEP and future research directions.

Autonomic dysfunction is implicated from clinical, neuroimaging and experimental studies in sudden and unexpected death in epilepsy (SUDEP). Neuropathological analysis in SUDEP series enable exploration of acquired, seizure-related cellular adaptations in autonomic and brainstem autonomic centres of relevance to dysfunction in the peri-ictal period. Alterations in SUDEP compared to control groups have been identified in the ventrolateral medulla, amygdala, hippocampus and central autonomic regions. These involve neuropeptidergic, serotonergic and adenosine systems, as well as specific regional astroglial and microglial populations, as potential neuronal modulators, orchestrating autonomic dysfunction. Future research studies need to extend to clinically and genetically characterized epilepsies, to explore if common or distinct pathways of autonomic dysfunction mediate SUDEP. The ultimate objective of SUDEP research is the identification of disease biomarkers for at risk patients, to improve post-mortem recognition and disease categorisation, but ultimately, for exposing potential treatment targets of pharmacologically modifiable and reversible cellular alterations.

Mortality in tuberous sclerosis complex.

We studied mortality in tuberous sclerosis complex (TSC) by analyzing data from the Tuberous Sclerosis Alliance Natural History Database of 2233 patients from 18 United States TSC centers. Among 31 decedents with data; mean age of death was 29 years. Cause of death could be determined in 26 cases: 11 definitely related to TSC, 14 possibly related to TSC, and 1 unrelated to TSC. Causes of death included SUDEP in 11 (35.5%; Definite (5), Probable (4), Possible (2)), respiratory conditions in 6 (23.1%; lymphangiomyelomatosis in one), tumors in 3 (11.5%), suicide in 2 (7.7%), cardiopulmonary in 2 (7.7%), shunt malfunction in one, and drowning in one. For SUDEP cases, mean age of epilepsy onset was 7 months and 10/11 were treated with multiple anti-seizure medications (ASMs) at death; 7 had intractable epilepsy and 3 were controlled with ASMs. Patients with TSC and their families should be counseled about ASM adherence and lifestyle factors, and the potential role of nocturnal supervision or seizure detection devices to prevent SUDEP.

Improving prediction of sudden unexpected death in epilepsy: From SUDEP-7 to SUDEP-3.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality in epilepsy. The aim of this study is to evaluate the validity of the SUDEP-7 inventory and its components as tools for predicting SUDEP risk, and to develop and validate an improved inventory. METHODS: The study included 28 patients who underwent video-electroencephalography (EEG) monitoring and later died of SUDEP, and 56 age- and sex-matched control patients with epilepsy. The SUDEP-7 score, its individual components, and an alternative inventory were examined as predictors of SUDEP. RESULTS: SUDEP-7 scores were significantly higher among SUDEP patients compared with controls, both at time of admission (p = 0.024) and most recent follow-up (p = 0.016). SUDEP-7 scores declined only among controls, who demonstrated reduced seizure frequency. Seizure freedom after epilepsy surgery was also associated with survival. Several components of the SUDEP-7 inventory were independently associated with higher risk of SUDEP, including more than three generalized tonic-clonic (GTC) seizures (p = 0.002), one or more GTC seizures (p = 0.001), or one or more seizures of any type within the last year (p = 0.013), and intellectual disability (p = 0.031). In stepwise regression models, SUDEP-7 scores did not enhance the prediction of SUDEP over either GTC seizure frequency or seizure frequency alone. A novel SUDEP-3 inventory comprising GTC seizure frequency, seizure frequency, and intellectual disability (p < 0.001) outperformed the SUDEP-7 inventory (p = 0.010) in predicting SUDEP. SIGNIFICANCE: Our findings demonstrate the limitations of the SUDEP-7 inventory. We propose a new three-item SUDEP-3 inventory, which predicts SUDEP better than the SUDEP-7.

Early onset epilepsy and sudden unexpected death in epilepsy with cardiac arrhythmia in mice carrying the early infantile epileptic encephalopathy 47 gain-of-function FHF1(FGF12) missense mutation.

OBJECTIVE: Fibroblast growth factor homologous factors (FHFs) are brain and cardiac sodium channel-binding proteins that modulate channel density and inactivation gating. A recurrent de novo gain-of-function missense mutation in the FHF1(FGF12) gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the FHF1 missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice. METHODS: The Arg52His mutation was introduced into fertilized eggs by CRISPR (clustered regularly interspaced short palindromic repeats) editing to generate Fhf1R52H/F+ mice. Spontaneous epileptiform events in Fhf1R52H/+ mice were assessed by cortical electroencephalography (EEG) and video monitoring. Basal heart rhythm and seizure-induced arrhythmia were recorded by electrocardiography. Modulation of cardiac sodium channel inactivation by FHF1BR52H protein was assayed by voltage-clamp recordings of FHF-deficient mouse cardiomyocytes infected with adenoviruses expressing wild-type FHF1B or FHF1BR52H protein. RESULTS: All Fhf1R52H/+ mice experienced seizure or seizurelike episodes with lethal ending between 12 and 26 days of age. EEG recordings in 19-20-day-old mice confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures immediately preceding loss of brain activity and death. Within 2-53 s after lethal seizure onset, heart rate abruptly declined from 572 ± 16 bpm to 108 ± 15 bpm, suggesting a parasympathetic surge accompanying seizures that may have contributed to SUDEP. Although ectopic overexpression of FHF1BR52H in cardiomyocytes induced a 15-mV depolarizing shift in voltage of steady-state sodium channel inactivation and slowed the rate of channel inactivation, heart rhythm was normal in Fhf1R52H/+ mice prior to seizure. SIGNIFICANCE: The Fhf1 missense mutation p.Arg52His induces epileptic encephalopathy with full penetrance in mice. Both Fhf1 (p.Arg52His) and Scn8a (p.Asn1768Asp) missense mutations enhance sodium channel Nav 1.6 currents and induce SUDEP with bradycardia in mice, suggesting an FHF1/Nav 1.6 functional axis underlying altered brain sodium channel gating in epileptic encephalopathy.

The SANTÉ study at 10 years of follow-up: Effectiveness, safety, and sudden unexpected death in epilepsy.

OBJECTIVE: We evaluated the efficacy and safety of deep brain anterior thalamus stimulation after 7 and 10 years, and report the incidence of sudden unexpected death in epilepsy (SUDEP) and overall mortality in adults in the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTÉ) study. METHODS: After the 3-month blinded and 9-month unblinded phases, subjects continued to be assessed during long-term follow-up (LTFU) and later a continued therapy access phase (CAP), to further characterize adverse events and the incidence of SUDEP. Stimulus parameter and medication changes were allowed. RESULTS: One hundred ten implanted subjects accumulated a total of 938 device-years of experience (69 subjects during the LTFU phase and 61 subjects in the CAP phase). Prior to study closure, 57 active subjects continued therapy at 14 study centers, with follow-up of at least 10 (maximum 14) years. At 7 years, median seizure frequency percent reduction from baseline was 75% (p < .001), with no outcome differences related to prior vagus nerve stimulation or resective surgery. The most severe seizure type, focal to bilateral tonic-clonic, was reduced by 71%. Adding new antiseizure medications did not impact the pattern of seizure reduction over time. There were no unanticipated serious adverse events in the study. The definite-plus-probable SUDEP rate, based on SANTÉ study experience (two deaths in 938 years) and previous pilot studies (0 deaths in 76 years), indicated a rate of 2.0 deaths for 1000 person-years. Overall mortality was 6.9 deaths per 1000 person-years. SIGNIFICANCE: The long-term efficacy and safety profiles of the deep brain stimulation (DBS) system for epilepsy are favorable and demonstrate stable outcomes. Improvement in frequency of the most severe seizure type may reduce SUDEP risk. The SUDEP rate with DBS (2.0) is comparable to other neuromodulation treatments (i.e., vagus nerve stimulation, responsive neurostimulation) for drug-resistant focal epilepsy.

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.