Abstract

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of premature mortality among young adults with refractory seizures. A sharp increase in clinical and forensic awareness over the last decade has accelerated the search to identify predictive risk biomarkers, clarify underlying cellular mechanisms, and develop effective interventions. In monitored nocturnal cases, available evidence points to a consistent pattern of postictal bradycardia with rapid collapse of brainstem cardiorespiratory pacemaking within minutes following termination of a generalized tonic-clonic seizure. Single gene discovery leading to SUDEP phenotypes in humans and mouse models now promises to speed the validation of candidate SUDEP genetic biomarkers and pinpoint malignant cellular excitability defects. The diverse biology and shared expression in brainstem pathways delineate distinct survival trajectories and molecular targets to mitigate SUDEP risk. Conditional deletion models confirm that SUDEP is a neurogenic, not cardiogenic, event and that brainstem involvement is both necessary and sufficient. SUDEP gene mutations lower the threshold for spreading depolarization (SD), a slow, self-regenerative pathological wave that silences neurons in critical brainstem networks. SD can occur independently of seizures, but can also be tightly coupled to their co-occurrence, offering molecular insight into a latent excitability threshold mechanism, a “second hit” that can explain why only some tonic-clonic seizures are lethal. While the role of brainstem SD awaits human confirmation, gene mutations that lower SD threshold in mice are found in clinical populations with elevated SUDEP risk. More research on modulating brainstem SD threshold could lead to lifesaving interventions in individuals at risk.

Introduction

Sudden unexpected death in epilepsy (SUDEP) is recognized as the most common cause of premature mortality among young adults with refractory seizures and diagnosed by exclusion of any other coexisting medical or forensic explanation (Nashef et al. 2012). While overall incidence is rare, SUDEP population risk is substantially elevated in certain epilepsy subgroups defined by age, seizure type, and genotype. However, even within these select groups, risk rarely exceeds 20%, and neither the peak age range (child to young adult), extent of seizure history, seizure type, nor degree of pharmacoresistance offers sufficient evidence to confidently identify a specific individual at inordinate risk or predict whether the next seizure could be the last. At present, there is still little firm evidence to guide the selection of optimal antiseizure medicine (Sveinsson et al. 2020; Cutillo, Tolba, and Hirsch 2021), or specific advances in postictal cardiopulmonary resuscitation protocols (Maguire et al. 2020). A clearer understanding of candidate biological mechanisms and validated biomarkers underlying SUDEP risk is critical to preventing this tragic epilepsy comorbidity.

The MORTEMUS Study Defines a Common Temporal Framework for Nocturnal Sudden Death

While the timing of an unprovoked seizure, lethal or not, is rarely predictable, the timing of SUDEP is not. The collaborative “MORTEMUS” study provided a landmark analysis of hospital-monitored cases that captured and clarified salient physiological events leading to nocturnal SUDEP, namely a consistent collapse of heartbeat and breathing initiated after the seizure has ended (Ryvlin et al. 2013). The study revealed that in all nine cases, terminal respiratory or cardiac arrest does not occur during seizure activity, but rather 3–15 minutes following its termination (Fig. 63–1).

Figure 63–1.

The MORTEMUS timetable of postictal cardiorespiratory activity in nine monitored SUDEP cases. All patients were alive at T = 0 (end of EEG seizure) and showed tachycardia and tachypnea for up to 3 minutes, followed by variable patterns of transient apneas (more...)

It is worth noting that during the postictal period in a slight majority of these cases, it is the heartbeat, showing bradycardia and asystoles, rather than respiration that fails first. Ictal and postictal sinus bradycardia was the only consistent premonitory sign of imminent collapse; however, in all cases, the final heartbeat invariably follows terminal respiratory arrest. No cases were free of asystoles, and only one death showed sudden respiratory arrest without postictal apneas. If there is a uniform pattern evident in this small dataset, it is that SUDEP is characterized by early postictal sinus bradycardia, accompanied by variable periods of cardiorespiratory rhythm failure, respiratory arrest, and cardiac standstill.

The MORTEMUS Pattern and Timetable Have Mechanistic Implications

Despite the limited sample cohort and unavoidable technical limitations, this profile narrows the potential pathophysiology of nocturnal SUDEP and offers consistent evidence for five mechanistic points. First, SUDEP is a postictal process triggered from 3 to 15 minutes following the termination of ictal activity. Second, once the cortical seizure ends, all cases but one showed a brief period of rebound tachycardia and breathing, evidence that bradycardia and apneas arising during the ictal event are still reversible. Third, in all cases, respiratory arrest precedes the final heartbeat, signifying primary neurogenic rather than cardiogenic collapse. Fourth, in all cases, death occurred following a solitary nocturnal generalized tonic-clonic seizure (GTCS) and in over half of these cases, the final seizure was the first GTCS witnessed in that individual, consistent with both innate as well as progressively acquired neural vulnerability. Fifth, postictal asphyxiation might contribute but cannot fully explain all SUDEP cases, since not all individuals found prone had airway obstruction, consistent with forensic findings of in-home pediatric and adult SUDEP (Craig et al. 2021).

These points confirm that nocturnal SUDEP begins minutes after the conclusion of a forebrain seizure and is not associated with ictal or postictal ventricular fibrillation, indicating a clear distinction between SUDEP and sudden cardiogenic death. Instead, the pattern of postictal cardiac failure is consistent with neurogenic, vagally mediated sinus bradycardia, occurring in tandem with, and facilitated by, intermittent interruptions and terminal silencing of breathing, quickly followed by cardiac arrest. The postictal apneas and asystoles indicate a progressive failure of intrinsic brainstem reflex escape pathways aggravated in part by hypercapnia and hypoxia. Since both heartbeat and respiration only transiently inactivate during the seizure and the irreversible decline begins afterward, clinical studies have focused appropriately on whether these severe ictal events are biomarkers that predict SUDEP.

Ictal Asystoles, Ictal Apneas, and Postictal Cortical EEG Suppression Are Unreliable SUDEP Biomarkers

Atypical SUDEP Patterns: Parallels with SCD, SIDS, and SUDY

The MORTEMUS study involved un-genotyped adult refractory epilepsy patients whose death followed a nocturnal seizure, and extrapolating a common network mechanism from this mixed cohort to younger ages or specific gene mutations may be premature. The consistent pattern of vagal collapse in the minutes following a tonic seizure is replicated in multiple genetically defined SUDEP mouse models, but it has not been carefully monitored in nonepileptic sudden death models. Sudden death in individuals with epilepsy may also occur during daytime and, rarely, in the absence of a witnessed seizure in an ill patient (Stecker et al. 2013; Lhatoo et al. 2016). The prerequisite of at least one premortem seizure delineates the forensic borderland between SUDEP and other sudden death syndromes, for example, sudden cardiac death (SCD), sudden infant death (SIDS), and sudden death in the young (SUDY) (Stiles et al. 2021). Some cases among these syndromes may actually share overlapping gene errors and mechanisms, and their forensic diagnosis could be confounded by inadequate antemortem clinical information, such as in SIDS infants SIDS infants or even individuals with syncopy who die before a subtle clinical seizure is detected. In fact, postmortem analysis has identified SCN1A variants (Brownstein et al. 2018) and hippocampal pathology suggestive of temporal lobe epilepsy in a significant fraction of SIDS cases (Kinney et al. 2015). Potential SIDS biomarkers include various cardiac channel and inflammatory genes, along with evidence supporting the serotonin hypoventilation hypothesis and environmental risk factors (Mehboob et al. 2021).

Monogenic SUDEP Risk

Ultimately, individual SUDEP risk is multifactorial, but like other rare disorders, the discovery of a monogenic basis for this phenotype opened the door to a new understanding of its genetic architecture. Whether the primary functional defect destabilizes cortical, cardiac, or respiratory pathways, the risk could be coincidental, that is, the chance combination of several gene mutations in these pathways in a person with acquired epilepsy. Alternatively, a single pleiotrophic gene might give rise to all three, which has now been clearly shown for several SUDEP risk genes.

The Neurocardiac Gene Hypothesis for SUDEP

The simultaneous presence of seizures and autonomic defects in individuals with epilepsy led to a general recognition, now widely appreciated, of cardiac arrhythmia as a comorbidity of epilepsy genes coexpressed in heart and brain. Single genes underlying long QT interval (LQT) cardiac arrhythmias, syncopy, and sudden cardiac death, of which the Brugada syndrome was an outstanding example, were the first to suggest a monogenic SUDEP mechanism. This syndrome, a fatal nocturnal cardiac arrhythmia due to mutation of the sodium channel subunit gene SCN5A, served as an attractive example of pleiotropic single gene risk shared by sudden cardiac death and epilepsy. The link might have been established earlier, if not for the widespread belief that this “cardiac” sodium channel was absent in brain (Wang et al. 1995). However, restricted expression was then identified in specific limbic regions of rat brain, supporting the hypothesis that sudden nocturnal death might result from single genes responsible for arrhythmias of heart and brain (Hartmann et al. 1999). SCN5A channels were later identified in both sleep and cardiorespiratory-relevant pontomedullary brainstem nuclei and in human brain (Donahue et al. 2000). SCN5A mutations have subsequently been reported in SUDEP cases (Parisi et al. 2013).

Potassium Channels

KCNQ1

The first experimental validation of the monogenic SUDEP hypothesis involved human cardiac LQT mutations engineered into mouse models that showed a dual heart/brain phenotype of electrophysiological LQT and lethal seizures with a pattern of postictal bradycardia and asystoles mirroring that is seen in MORTEMUS cases (Goldman et al. 2009). The mutations were in KCNQ1, the potassium channel responsible for KvLQT1, the most common human cardiac LQT arrhythmia gene, and also believed absent from brain. However, the channel is actually diffusely expressed in both adult human and mouse brain. In dorsal medulla, there is intense expression surrounding the nucleus tractus solitarius, which receives vagal afferent input from the lungs and heart and projects to both pontine respiratory and vagal brainstem nuclei, mediating postictal bradycardia and asystoles (Fig. 63–2). A retrospective clinical analysis revealed epilepsy in approximately 25%–50% of LQT patients with KvLQT1 mutations as well as other common cardiac LQT genes associated with sudden death, affirming that these genes are strong human SUDEP gene candidates (Johnson et al. 2009).

Figure 63–2.

(Left) KvLQT1 is widely expressed in forebrain and brainstem cardiorespiratory pathways in dorsal medulla surrounding the nucleus Tractus solitarius (nTS), dorsal vagal motor nucleus (DMX), and nucleus ambiguous (nA); the latter projects efferent preganglionic (more...)

Sodium Channels

Ryanodine Receptor

SUDEP Gene Diversity

Since the reports of these pioneering models, the number of candidate SUDEP genes has grown steadily, including those nominated either by molecular autopsy of SUDEP cases (Bagnall et al. 2016; Chahal et al. 2021), or more directly by video-EEG screening of SUDEP phenotypes in defined monogenic mouse mutants; many of these candidates await experimental or clinical validation. It is worth noting that in a recent blinded reappraisal of 17 cardiac genes reported in CLINGEN over 25 years as causative for long QT syndrome, only 3 (KCNQ1, KCNH2, and SCN5A) were curated as definitive disease-causing genes, while the remainder were either strong candidates for atypical syndromes or only moderately associated (Adler et al. 2020). Thus, critical analysis of a large number of human SUDEP cases will be necessary to arrive at the level of precision demanded for prospective clinically actionable genetics of SUDEP.

Similar to the LQT syndrome, distinct comorbid syndromes discovered in individuals without primary seizure disorders have also pointed to unexpected SUDEP genes and mechanisms. Three genes for migraine with hemiplegic aura (FHM1-3) identify a distinctive clinical subset at risk for SUDEP and share the spreading depolarization phenotype later found in other mouse models. Individuals with gain-of-function mutations in P/Q calcium channels encoded by CACNA1A (FHM1) (Indelicato and Boesch 2021), ATP1A2-3 (FHM2) (Balestrini et al. 2020), and SCN1A (FHM3)(Gargus and Tournay 2007) exhibit a distinctive familial phenotype of migraine with a hemiplegic aura, and epilepsy is reported in a subset of these gene carriers. The aura is linked to a low threshold for spreading depolarization as found in mice with engineered mutations as described below.

Other SUDEP gene candidates include the hyperpolarization-activated cyclic nucleotide channel HCN1 (Tu et al. 2011); FHF1 (FGF12), a gene for epileptic encephalopathy and cardiac arrhythmias (Veliskova et al. 2021); GABA A gamma2 receptor subunit mutations (Xia et al. 2016; Qu et al. 2021); and several genes within the MTOR signaling pathway mediating cell growth and cortical dysplasia, including DEPDC5 (Yuskaitis et al. 2018), GATOR1 (Baldassari et al. 2019), and PRICKLE1, a gene for a progressive myoclonus epilepsy syndrome (Hata, Yoshida, and Nishida 2019).

Monogenic Neurorespiratory Syndromes

For most SUDEP syndromes, gene discovery began with an episodic phenotype such as cardiac syncopy, which then expanded as new variants in patients and models revealed comorbid seizures. For example, the first human mutation of KCNA1 was identified in a patient with myokymia and episodic ataxia (Browne et al. 1994), and only later described as a gene for epilepsy in mice (Smart et al. 1998) and human (Zuberi et al. 1999). Since mutation of genes that primarily afflict respiration are generally lethal at the newborn stage, few have been identified that give rise to epilepsy phenotypes, but defects in brainstem inhibitory pathways have been identified in mouse models of central hypoventilation such as Rett syndrome (Chen et al. 2018).

An interesting exception is found in the serotonin pathway, an important modulator of central respiratory function and brain excitability. Of the 15 serotonin receptors, 5HTRA is essential for CO₂-triggered arousal (Buchanan et al. 2015) in the dorsal raphe (Kaur et al. 2020), but it is not linked to epileptogenesis. Optogenetic activation of 5HT neurons in dorsal raphe brainstem neurons is both anticonvulsant and suppresses respiratory arrest in the DBA/1 audiogenic seizure model of SUDEP (Zhang et al. 2018). 5HTR2C is linked to obesity, anxiety, sleep disturbance, and audiogenic seizures in mice (Tecott et al. 1995). We recently found that deletion of this X-linked metabotropic serotonin receptor leads to an even more complex epilepsy phenotype with multiple spontaneous late-onset seizure types and male-predominant SUDEP (Massey et al. 2021). This receptor is expressed primarily in interneurons, and activation leads to increased inhibitory GABAergic signaling; however, when 5HTR2c was selectively deleted only in excitatory neurons, the seizures and SUDEP risk remained, suggesting a complex neuromodulation of disinhibition in brain networks.

Although each of the existing monogenic SUDEP models requires deeper analysis, the biological diversity of these candidates has dramatically expanded our insight into sudden death mechanisms and illustrates how genetic biomarkers can define clinical SUDEP subsets with distinct premorbid phenotypes and temporal risk profiles. In addition, each model provides an invaluable biological test system to define the critical pathway and reverse the lethal phenotype.

Gene-Specific Longevity Profiles: SD50

The striking contribution of single genes to premature mortality is clearly evident in Kaplan-Meyer survival plots of defined monogenic mouse SUDEP models. The impact of each of these genes is also influenced by the genetic background of the host inbred strain, raising major implications for human genetic counseling. Nevertheless, comparisons of their distinctive survival curves provide intriguing insight into gene-specific longevity (Fig. 63–3). Inspection of these profiles reveals that inherited age of onset and lifetime risk are remarkably heterogeneous, showing a wide variation in gene-linked age-dependent penetrance, with cohort survival rates ranging from 10% to 100%. However, even within a single isogenic litter, some offspring die early and other littermates survive for many months, providing further evidence of a multifactorial mechanism where each risk gene interacts with still unknown factors affecting postictal vulnerability. A novel metric is applied here for each gene, namely, “SD50,” a measure of population half-life or the age at which 50% of affected mice succumb to sudden death, by analogy with the lethal dose LD50 in toxicology nomenclature. This metric may simplify future preclinical comparisons of the effect of drugs and interventions on SUDEP risk. For example, a very early-onset SD50 (10 days) arises from deletion of Sptan2, the α2 spectrin intracellular scaffolding protein that tethers multiple axonal membrane ion channels; a very delayed-onset SD25 (120 days in males) is due to loss of the 5HT2C serotonin receptor that induces late-onset convulsive seizures in mice; 5HT2C receptor variants are found in both adult human SUDEP and infantile SIDS cases (Massey et al. 2021). Further analysis of the temporal onset and penetrance of each mutation on survival may provide important clues into the plasticity of homeostatic rescue pathways available for each gene.

Figure 63–3.

Broad gene-specific differences in age of onset and rate of SUDEP penetrance. Kaplan-Meyer survival analysis demonstrates gene-specific survival curves in mouse SUDEP models as studied on their particular inbred lines, which could differ according to (more...)

Epistatic Interactions among SUDEP Genes Impact Survival

Multigenic interactions are major determinants of survival curves on inbred lines, and genetic crosses to obtain specific digenic combinations clearly show the decisive influence of even one additional mutant gene on the survival of monogenic mouse SUDEP models. This is particularly important when considering how common multiplex ion channel mutations are found in pharmacoresistant epilepsy cohorts, where the risk of epilepsy depended more on the specific pattern of mutations, rather than their numerical load (Klassen et al. 2011). In mouse models, some digenic combinations are destructive while others are protective. For example, the addition of a deficient Cacna1a PQ channel allele to a Kv1.1 null model increases survival by fourfold (Glasscock et al. 2007). Deletion of Mapt1 (tau) extends survival of Kcna1 (Holth et al. 2013) and Scn1a (Gheyara et al. 2014) loss-of-function mutants to a similar degree. Tau is of interest because it is protective in some, but not all ion channel SUDEP models; neither Scn8a- nor Scnb1-deficient models were protected by Mapt1 deletion (C. Chen et al. 2018). There are other interesting examples, some paradoxical, in the literature (Hawkins et al. 2011, 2016, 2021). The identity and spectrum of potential oligogenic interactors for each SUDEP gene are difficult to predict and add to the complexity of prospective clinical genetic risk counseling.

Conditional Genetic Dissection of Critical SUDEP Pathways

Progressive Central and Cardiac Pathology and SUDEP Risk

Diurnal Rhythm and SUDEP

The nocturnal predominance of SUDEP implicates still poorly understood circadian influences on mechanisms of seizure initiation, cardiac arrhythmias, apneas, postictal arousal, and autoresuscitation. Sleep exerts profound effects on both focal and generalized seizure cycles (Leguia et al. 2021), as well as on synchronization of cardiac tone and respiratory reflexes (Dergacheva et al. 2014). The exact mechanisms modulating diurnal control of these reflexes have long puzzled cardiac and respiratory physiologists, and extend from endocrine hormone effects on intrinsic membrane excitability to rhythmic fluctuations at the transcriptional level regulated by gene control over ion current density in heart (Jeyaraj et al. 2012) and metabolic modulation of persistent sodium (Paul et al. 2016) and fast potassium (Bano-Otalora et al. 2021) currents. Of all major tissues, brain shows a strong dark phase of metabolic transcriptional regulation, highly distinct from heart, and although complex, the circadian differences between gene expression in mouse and primate brain are not all shifted by 12 hours, as expected by daily activity patterns (Mure et al. 2018).

In SUDEP mouse models, time of day and stage of sleep may be important biomarkers. In a healthy rodent model, seizures evoked by electroshock during REM sleep were uniformly lethal (Benton S. Purnell, Hajek, and Buchanan 2017)(Purnell et al. 2021), perhaps because REM is linked to skeletal muscle (but not diaphragmatic) atonia. Scn1a mutant mice show NREM sleep defects (Kalume et al. 2015), and SUDEP mortality in this (Teran et al. 2019), and the Kv1.1 model (Moore et al. 2014), shows a striking nocturnal predominance.

Brainstem Spreading Depolarization

While the monogenic path from an ion channel defect to network hypersynchronization and lethal seizures is clearly established, membrane hyperexcitability alone does not provide a sufficient explanation for why every seizure is not uniformly lethal. As the mortality data indicate, most generalized tonic-clonic seizures, even in those with potent risk alleles, are survivable. The difference, as captured by the MORTEMUS study, is the remarkably consistent pattern of postictal events that distinguish a SUDEP from a near-SUDEP seizure, namely, a period of cardiorespiratory instability leading to terminal collapse 3–15 minutes after the seizure ends. A key to decipher the mechanism underlying this risk is to identify a pathogenic process that begins shortly after a seizure has stopped and slowly progresses for at least 15 minutes. Based purely on experimental models, this “second hit” likely involves the phenomenon of brainstem spreading depolarization (SD), which follows this timeline precisely and is supported by direct electrophysiological, imaging and genetic evidence.

SD is an ultraslow, 2–5 mm/min, self-propagating wave of depolarization linked to tissue hypoxia and a reversible collapse of neuronal excitability (see Chapter 62, this volume). During this wave, there is inactivation of neuronal spike generation, a massive efflux of potassium and glutamate, neurovascular changes, and extracellular edema with a slow recovery of neural transmission lasting minutes to hours. SD propagates in grey matter but does not breach heavily myelinated boundaries; in the brainstem this favors key cardiorespiratory centers: the dorsal cellular areas of pons and medulla such as the parabrachial nuclei, pre-Botzinger complex, and nucleus of the tractus solitarius. The SD-SUDEP hypothesis posits that a wave of SD arises after seizure termination and invades these brainstem areas, unleashing a cascade of central apnea, asystoles, and ultimately silencing cardiorespiratory activity.

Brainstem SD Is Linked to Postictal Cardiorespiratory Collapse in Mouse SUDEP Models

To test this hypothesis in a mouse SUDEP model, cortical seizures were triggered by focal 4AP application under urethane anesthesia while recording extracellularly from the dorsal medullary surface (Fig. 63–4). Following a cortical seizure in Kcna1^–/– mice, SD arose in the dorsal medulla in 11 mutants and all died, while SD never occurred in 8 wild-type mice and all survived. A similar pattern occurred in Scn1a mutants (Aiba and Noebels 2015). The timing of postictal brainstem depolarization and cardiorespiratory collapse revealed that death is tightly linked to the initiation of SD, not to the end of the seizure.

Figure 63–4.

Brainstem SD is linked to postictal cardiorespiratory collapse in SUDEP Kv1.1 KO mice and timing is consistent with MORTEMUS data. (Upper left) Cortical seizures were evoked by topical application of 4-aminopyridine while DC recordings from the medulla (more...)

Examples capturing the lethal postictal progression display two extremes of brainstem SD onset (red arrows). At left, the earliest delay until SD initiation was 1 minute following the end of the eighth seizure. At right, the longest delay was 15 minutes following a single prolonged seizure. In the latter, sustained hypopnea began during the seizure itself and continued postictally; the final respiratory arrest preceded ECG arrest (arrowhead). In both cases, lethality occurs within 1–2 minutes of brainstem SD onset.

SD can be evoked by multiple stimuli in brain, and the threshold for each region can be measured in vitro by the latency of the SD wave following application of increasing concentrations of potassium chloride or solutions deficient in oxygen and glucose (OGD). Analysis of brain slices reveals that these thresholds are lower in SUDEP mouse models, indicating that the genes directly impact neural tissue independent of possible vascular involvement following a seizure.

In Vivo SD Imaging

Diffusion-weighted imaging (DWI) identifies dynamic vascular glucose/oxygen uptake in brain tissue, reveals the pattern of intracerebral spread, and provides confirmatory evidence correlating brainstem depolarization preceding sudden death. The Cacna1a S218L gain-of-function mutant model of familial hemiplegic migraine (FHM1) enhances synaptic glutamate release, leading to convulsive seizures that resemble audiogenic episodes without cortical EEG activation, and show cortical spreading depolarization (Maagdenberg et al. 2010). DWI imaging during a cortically evoked seizure in anesthetized Cacna1a S218L mutant mice showed a wave of enhancement that descended subcortically; in some cases SD invaded the brainstem, triggering respiratory and cardiac arrest. Mice that died showed brainstem involvement, while those without brainstem involvement all survived (Loonen et al. 2019). SD thresholds are strongly regional in various syndromes, as evidenced by complex migraineurs with purely visual or hemiplegic auras. While SD in this particular FHM1 model originated in neocortex with variable subcortical spread, other gene mutations might facilitate alternate or multifocal SD origins, allowing different SUDEP and near SUDEP patterns. Interestingly, pregabalin blocked SD propagation into the hippocampus, but not brainstem regions in this model, indicating regional therapeutic sensitivity (Cain et al. 2017). More recent evidence in this model implicates inefficient glutamate reuptake following synaptic release as a potential contributor to SD dynamics (Parker et al. 2021).

Along with Scn1a, Kcna1, Ryr2, and Kcnq2, two other monogenic SUDEP mouse models of familial hemiplegic migraine, FHM2 (Kros, Lykke-Hartmann, and Khodakhah 2018), and FHM3 (Jansen et al. 2020) both show lowered thresholds for spontaneous cortical SD. In addition, brainstem hyperactivity and SD have been identified in acute focal forebrain convulsant seizure models with a pattern of lethal collapse distinct from the MORTEMUS pattern, potentially revealing recruitment of different pathways (Salam et al. 2017; Lovick and Jefferys 2021).

Seizure-SD Coupling

Spontaneous EEG seizures and SD have independent and region-specific thresholds reflecting diverse homeostatic mechanisms linked to neural connectivity and tissue metabolism (see Chapter 62, this volume), and the relationship between triggers of both phenomena remain to be elucidated. Triggers for human cortical seizures are usually unknown. Triggers for cortical SD in human complex migraine with aura syndromes involve a wide range of idiosyncratic provocative stimuli, including stress, exercise, hypoglycemia, and hyperadrenergic states. In neocortex, seizures typically terminate at a ceiling level of 7–14 mM [K+] out, below the lower range required to trigger SD in healthy tissue. An intervention that widens the gap between these thresholds could play an important role in the prevention of SUDEP.

Little is known about molecular excitability determinants that prevent seizures from triggering SD. A recent study identified Kcnq2, the potassium channel modulating M current, as the first example of a protective “rheostat” controlling the seizure-SD threshold (Aiba and Noebels 2021). Conditional deletion of Kcnq2 in excitatory neurons of Kv1.1 null mice (Kcnq2-cre-EMX) increased the occurrence of both spontaneous cortical seizures and SD waves, and dramatically elevated the appearance of coupled seizure-SD complexes, where a cortical seizure is reliably followed in less than 1 minute by an SD wave (Fig. 63–5). Interestingly, these coupled events showed a clear nocturnal predominance. In addition, there was a striking reduction of the intrinsic SD threshold, since unlike healthy mice, where SD spread is only unilateral and never crosses the midline, cortical SD waves in Kcnq2^–/– cre-EMX/Kcna1^–/– mice arose simultaneously in both hemispheres and showed a distinct diurnal cycle. A Kcnq2-activating drug delayed and at higher doses suppressed the onset of SD, while the inhibitor reproduced the SD phenotype in Kcna1^–/– mice. Further studies may determine whether modifying Kcnq2 current is unique to this model or more widely effective. Neurotransmitters may also contribute indirectly to SD threshold (see Chapter 62, this volume).

Figure 63–5.

Bihemispheric appearance of spontaneous cortical seizure-SD complexes in mice with Kcna1/Kcnq2 cre-EMX mutations. (Left upper) spontaneous bilateral seizure triggering unilateral SD in Kcna1 KO mutant. Isolated spontaneous SD could also appear unilaterally. (more...)

In summary, current experimental evidence for the hypothesis that SD is a sufficient mechanism for postictal demise in SUDEP mouse models includes the following: (1) SD arises in brainstem 1–15 minutes after a spontaneous (or audiogenic evoked) seizure, similar to the postictal vulnerable period in MORTEMUS cases, causing death within 1–2 minutes. (2) Once the brainstem SD is detected, the timing and pattern of postictal bradycardia, apneas, and final cardiorespiratory arrest replicate human MORTEMUS data. (3) While brainstem SD is always lethal, cortical seizures are not lethal unless brainstem SD is triggered, explaining why some seizures are not lethal. (4) Mutations in SUDEP genes lower SD threshold (both in vivo and in vitro) across multiple mouse models. (5) Three of these genes also generate episodic seizures, SD phenotypes, and SUDEP risk in human migraine with aura syndromes.

The Perilous Genetic Landscape of SUDEP

The emerging genetic landscape of SUDEP risk parallels the biological diversity of all epilepsy genes. The complexity reflects the unexpectedly broad phenotypic spectrum of single ion channelopathy variants, and the probability that in any individual, SUDEP risk reflects the sum of multiple degenerate gene errors, that is, an oligogenic profile (Klassen et al. 2011). As an example of the former, ECG monitoring of 547 seizures in 59 genotyped cases of Dravet syndrome failed to reveal peri-ictal cardiac arrhythmias in a majority of DS cases (Shmuely et al. 2020). As an example of oligogenic complexity, a high-resolution molecular autopsy analysis of over 100 ion channel genes screened in a single SCN1A Dravet syndrome/SUDEP individual identified structural variants in six additional candidate SUDEP genes (KCNH2, HCN2, CACANA1A, KCNE1, RYR2, SCN5A), along with significant respiratory pathway candidates (HTR3C-3D) (Klassen et al. 2014).

Epistatic complexity is a major challenge confronting the objectives of genetic counseling, in view of the evidence that multiple gene mutations can strongly favor or mask SUDEP risk, necessitating a comprehensive mutational profile. These factors raise concern regarding both the accuracy of clinical risk prediction and the selection of appropriate gene-guided therapeutic interventions. Until more is known, we need to not only maintain surveillance of the rapidly emerging candidate genes and awareness of their distinct mechanisms, but also to accept our current inability to predict with certainty their degree of penetrance in de novo cases with variants of unknown significance in the absence of supportive functional biomarkers (Goldman et al. 2016).

SUDEP: Gene-Guided Research and Interventions

Summary

SUDEP risk is strongly influenced by mono- and oligogenic impairment of central neurogenic autoresuscitation mechanisms invoked by a seizure upon invading the brainstem. In experimental mouse models, mutations of SUDEP genes alter network excitability throughout forebrain, respiratory, and central autonomic pathways and lower the intrinsic tissue threshold for SD. In brainstem, an SD wave mortally silences central cardiorespiratory pacemaking. Although this inactivation mechanism has yet to be confirmed in human SUDEP, the SD hypothesis is supported by strong physiological and genetic evidence in mouse models and conforms with the temporal sequence of events leading to mortality described by the MORTEMUS study. The SD hypothesis of brainstem-mediated collapse also offers insight into the failure of resuscitative efforts in the immediate aftermath of SUDEP, since brainstem rhythmicity cannot be restored until recovery of homeostatic imbalance in this critical region, which could last hours. Outstanding basic and clinical questions for future research include further discovery of the molecular and diurnal mechanisms that couple seizures to brainstem SD threshold and the development of accessible clinical surrogate physiological biomarkers that reflect SUDEP risk. More research on prophylactic and abortive interventions to stabilize brainstem respiratory circuitry is needed. If brainstem SD proves to be a final common path to postictal SUDEP risk, raising this threshold to block or attenuate the spread of the depolarizing wave may be an effective strategy to prevent SUDEP regardless of the molecular pathogenic etiology of epilepsy.

Acknowledgments

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