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An explanation for sudden death in epilepsy (SUDEP)

An explanation for sudden death in epilepsy (SUDEP) This review traces the examination of autonomic, cardiovascular, and respiratory derangements associated with seizure activity in the clinical and preclinical literature generally, and in the author’s animal model specifically, and concludes with the author’s views on the potential mechanisms for sudden death in epilepsy (SUDEP). An animal model that employs kainic acid-induced seizures on a background of urethane anesthesia has permitted unprecedented access to the behavior of autonomic, cardiovascular, and respiratory systems during seizure activity. The result is a detailed description of the major causes of death and how this animal model can be used to develop and test preventative and interventional strategies. A critical translational step was taken when the rat data were shown to directly parallel data from definite SUDEP cases in the clinical literature. The reasons why ventricular fibrillation as a cause of death is so rarely reported and tools for verifying that seizure-associated laryngospasm can induce obstructive apnea as a cause of death are discussed in detail. Many details of the specific kinetics of activation of brainstem neurons serving autonomic and respiratory function remain to be elucidated, but the boundary conditions described in this review provide an excellent framework for more focused studies. A number of studies conducted in animal models of seizure activity and in epilepsy patients have contributed information on the auto- nomic, cardiovascular, and respiratory consequences of seizure activity spreading through hypothalamus and brainstem to the periphery. The result is detailed information on the systemic impact of seizure spread and the development of an under- standing of the essential mechanistic features of sudden unexpected death in epilepsy (SUDEP). This review summarizes translation of data obtained from animal models to biomarkers that are useful in evaluating data from epilepsy patients. Keywords Seizure · Laryngospasm · Ventricular fibrillation · Obstructive apnea Definition of SUDEP of key cardiopulmonary events that contribute to an overall pattern ending with death [3]. Sudden unexpected death in epilepsy (SUDEP) is the sud- Qualifiers of “definite”, “probable”, and “possible” den, unexpected death of someone with epilepsy, who was depend on the availability of autopsy or direct observations/ otherwise healthy. Attention to the condition in the last recordings of terminal event and the presence or absence of decade has resulted in refinements in the definition (“… a a competing cause of death. “Definite” is used when com - non-traumatic, non-drowning death that occurs in benign peting causes of death are ruled out by autopsy or having circumstances in an individual with epilepsy…” see e.g., [1, directly observed/recorded the terminal event. “Probable” 2]), more detailed calculations of incidence (from about 1–9 is used in the absence of autopsy data or likely alternative deaths per 1000 patient years) [2–4], and the identification cause of death and confidence that the circumstances sur - rounding the death were otherwise benign. “Possible” is used when a competing cause of death exists and autopsy data are unavailable. A “plus” designation attached to the * Mark Stewart mark.stewart@downstate.edu “definite” or “probable” definitions is used “when a con - comitant condition other than epilepsy is identified before or Department of Physiology and Pharmacology, State after death, if the death may have been due to the combined University of New York Downstate Medical Center, 450 effect of both conditions, and if autopsy or direct observa - Clarkson Avenue, Brooklyn, NY 11203, USA tions/recordings of terminal event did not prove the con- Department of Neurology, State University of New York comitant condition to be the cause of death” [1]. Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA Vol.:(0123456789) 1 3 308 The Journal of Physiological Sciences (2018) 68:307–320 While the incidence of sudden deaths is < 10/1000 [2–4], remarkably, motor convulsions were absent [17, 18]. This the highest risk occurs in patients whose seizures are poorly preparation has permitted an extraordinary range of record- controlled, and SUDEP is the leading cause of death in ings during seizure activity [19]. Some recordings, in fact, young adults with uncontrolled seizures. With an estimated such as continuous and direct visualization of the larynx 65 million people worldwide currently living with epilepsy, during seizure activity, have not been possible previously and hundreds of thousands of new diagnoses annually, [20]. The seizure activity induced by kainic acid is of limbic SUDEP is a significant concern—especially if preventative cortical origin, thus resembling temporal lobe seizures, and or interventional strategies could be made available. follows a similar pattern to that seen when administered to unanesthetized animals, namely a period of seizure activ- ity that can be long lasting enough to meet the definition Utility of animal models for SUDEP studies of status epilepticus, followed by much briefer discrete sei- zures over. The pronounced metabolic derangements associ- A wide range of animal models has been used to explore ated with status epilepticus are also not present, due to the cardiac and/or respiratory derangements due to or associ- absence of motor convulsions (e.g., [21, 22]). ated with seizure activity that may contribute to an individ- ual’s death (for wide-ranging reviews: [5, 6]). For example, research employing transgenic mouse models has suggested Panautonomic activation during limbic critical contributions from genetic mutations impacting cortical seizure activity serotonergic neurotransmission and function in brainstem respiratory centers [2, 7–9]. However, over a dozen mouse Access to autonomic premotor and preganglionic neurons strains show audiogenic seizures [10]. from limbic cortical regions is relatively direct, with pro- Complicating the development and accepted value of jections from subiculum into paraventricular nucleus of the animal models is that what is known and what is unknown hypothalamus (PVN; there are also projections where limbic about the circumstances of each human death has been used cortical and insular cortical outputs are relayed through the to question the appropriateness of particular animal models amygdala) [23–26], and projections from PVN into med- for the study of SUDEP. As examples, because of data that ullary areas for both sympathetic premotor and parasym- the majority of deaths occur at night (suggesting a circadian pathetic preganglionic activation. Projections also engage variance in some parameter) and when the individual was in respiratory rhythm generation and motor areas (e.g., [7, 8, bed (suggesting that, as with some infants, the airway might 11]). Many of these projections are reviewed in [27, 28] and become obstructed by bedding) (reviewed in [2]), data from highly schematized in Fig. 1. animal models not specifically incorporating these details Clinical reports and experimental studies have demon- are often dismissed as incomplete. Identification of linkages strated changes in cardiac, respiratory, gastrointestinal, and between the animal model and human pathophysiology has genitourinary function before, during, and after a seizure been challenging. (see e.g., [29–41]). Significant autonomic effects of sei- In audiogenic seizure-prone mice, death typically accom- zures more commonly occur in association with generalized panies an extreme tonic phase that includes hindlimb exten- tonic–clonic seizures or partial seizures originating in the sion (e.g., [8, 11–15]). The parallels of this convulsive activ- temporal lobe [31, 42, 43] than in association with absence ity to aspects of human motor convulsions and the systemic seizures or focal seizures that minimally impact limbic or physiological impact of this seizure type have not been fully insular cortices. With a starting view that a seizure that established, but the audiogenic seizure phenotype has been causes death must do so by spreading to autonomic brain extremely valuable in epilepsy research. regions to ultimately impact cardiovascular or respiratory Our approach to the SUDEP mechanism has been differ - function, we began by looking for such spread in recordings ent. Having used urethane as an anesthetic for work on hip- from autonomic peripheral nerves. pocampal theta rhythm, one of the best-studied EEG signals Each seizure was able to increase parasympathetic activ- reflecting synchrony in the limbic system [16], we found ity by about tenfold and sympathetic tone by nearly as much that seizure activity could be induced under urethane, but [36]. Although both divisions of the autonomic nervous 1 3 The Journal of Physiological Sciences (2018) 68:307–320 309 have been noted during seizures, including premature atrial and ventricular contractions [44] and ST-segment changes indicating cardiac ischemia [49, 50]. The main finding from many of the clinical and animal studies was that seizure- induced autonomic changes were transient: when the seizure abated, ANS activity reverted to normal pre-seizure levels. Although less common, bradyarrhythmias, includ- ing periods of asystole, have been reported in epilepsy patients [51–58]. In our animal studies of seizure-induced bradyarrhythmia, extremes significantly impacted cardiac output and we showed in physiological simulations that the resulting decrease in brain blood flow would termi- nate any ongoing seizure activity (Fig. 3) [59, 60]. Simi- lar examples of seizure termination have been reported in the clinical literature [61, 62]. The resulting conclusion with regard to a mechanism of sudden death was that it may not be possible for severe autonomic derangements to be lethal. If the seizure was the stimulus for increased vagal tone and bradyarrhythmia, terminating the seizure would end the stimulus and permit a return to baseline conditions. A seizure-induced overdrive of the vagal out- put to the heart might never be lethal because it would be self-terminating. Fig. 1 Simplified schematic of pathways from cortical regions to the brainstem to influence autonomic outflow. Adapted from [105] with permission. Lines denote bidirectional connections, and arrows Ventricular fibrillation denote monodirectional projections. The key point is that pathways exist for seizure spread from limbic cortical areas (via subiculum) to Cardiac fibrosis and hypertrophy, increased QT interval hypothalamus (including paraventricular nucleus, PVN) and to brain- lengths and dispersion, evidence for increased sympathetic stem regions serving as parasympathetic motor and sympathetic pre- motor functions. Relayed projections through the amygdala are even tone and decreased parasympathetic tone, and the commonly more prominent. Projections from neocortical regions, including acknowledged observations of ictal tachycardia all raise insular cortex, have their own access to the hypothalamus and brain- the question of whether ventricular fibrillation (VF) may stem nuclei. The result is a multitude of pathways for seizure spread be a cause of SUDEP (e.g., [63], see also [64]). Generally, to impact autonomic and respiratory brainstem regions. NTS nucleus of the tractus solitarius, RVLM rostral ventrolateral medulla decreased vagal protection increases the risk for ventricu- lar fibrillation (VF; [65]). To date, four cases of VF arising from seizures [66, 67], plus one case of VF in relation to seizure-induced takotsubo cardiomyopathy [68] have been system showed significant increases in activity, the result- documented. In addition, epilepsy has been shown to be a ing change in heart rate and rhythm, which could be either risk factor for sudden cardiac arrest ending in ventricular brady- or tachy-arrhythmia, depended upon the relative fibrillation [69, 70]. levels in each division and the baseline conditions (Fig. 2). We looked at conditions that might favor ventricular Multiple studies have sought to define the extent to which fibrillation, a condition which when initiated would be seizures alter cardiac rhythm (e.g., [43–45]). Seizures that lethal whether a precipitating seizure continued or not. produce sinus arrhythmias provoke tachycardia in up to 99% Briefly, we found that entry into ventricular tachycardia of cases [46], with HR increases to 120–150 bpm [45, 47, and ventricular fibrillation could occur spontaneously 48]. Episodes of ictal bradycardia to a HR of 20–40 bpm under narrow conditions of moderate, but not severe have been reported [48]. Other changes to cardiac rhythm hypoxia, sympathetic overdrive, and minimal vagal activity 1 3 310 The Journal of Physiological Sciences (2018) 68:307–320 Fig. 2 Recordings from peripheral autonomic nerve and ganglion to to-peak amplitude of seizure EEG (black) tended to be larger when demonstrate seizure-induced increases in both divisions of the ANS. seizures were associated with bradycardia in ECG (green). Parasym- a Increases in vagus nerve activity during a single discrete seizure pathetic (blue) and sympathetic (red) activity was always increased, (shown divided into for sequential segments where each segment but the relative levels of the sympathetic and parasympathetic activ- shows arterial blood pressure, hippocampal EEG, and vagus nerve ity changes (and the starting heart rate—not shown) contribute to multi-unit activity). Note that the massive vagal activity increases the final condition of bradycardia or tachycardia. Adapted from the by the second and third segments. b Increases in multi-unit activity doctoral thesis of Isaac Naggar with permission (Stewart, mentor). d recorded in superior cervical ganglion, even during a very brief sei- Portion of a schematic diagram (full diagram is shown in Fig.  9) to zure. a and b were taken from [36] with permission. c Percent change emphasize the sequence of events: seizure activity changes autonomic in mean activity (EEG autonomic peripheral nerve or ganglion) and activity; seizure ends; autonomic activity returns to pre-seizure levels. hear rate from the beginning of bradycardic and tachycardic sei- EEG electroencephalogram, ECG electrocardiogram zures to the peak autonomic activity during the seizure. The peak- (Fig. 4) [64, 71]. Even small amounts of vagal activity were increasing ventricular cavity size and not increasing ven- protective. Most interesting was the finding that repeated tricular wall thickness is eccentric hypertrophy, and this seizure activity in rats led to cardiac dilatation that actually increases the path length for conduction within the ventric- lowered the already small risk for ventricular fibrillation ular myocardium. The longer path length might explain the [72]. Enlargement of the overall dimension of the heart by increased difficulty in initiating ventricular fibrillation in 1 3 The Journal of Physiological Sciences (2018) 68:307–320 311 Fig. 3 Simulation of seizure-induced asystole and demonstration flow, stopping the seizure. Seizure activity resumed after the stimu- of impact on seizure activity. a–e Taken from [60] with permis- lation because the chemical convulsant is still present. Phentolamine sion. After complete vagal transection, vagal afferent (stimulation infusion (e) for peripheral vasodilation to decrease systemic blood of the central segment of the vagus) or vagal efferent (stimulation of pressure had similar effects to the vagus nerve stimulation-induced the peripheral segment of the vagus) stimulation was tested at 10 or asystole. To the right is another segment of the full schematic shown 50  Hz. Neither 10-Hz (a) nor 50-Hz (b) afferent vagal stimulation in Fig.  9. This segment emphasizes a different sequence of events: had an impact on heart rate (red sweep in each panel) or kainic acid- seizure activity changes autonomic activity; asystole occurs; asystole induced seizure activity (top green sweep in each panel). Efferent causes the seizure activity to end; autonomic activity returns to pre- vagal stimulation at 10  Hz (c) slowed the heart, but did not signifi- seizure levels. The main point to emphasize is that the evidence indi- cantly alter brain blood flow (blue and middle green sweeps). Efferent cates that seizure-induced asystole will be self-terminating because vagal stimulation at 50  Hz (d) produced asystole, a significant drop these episodes terminate the seizures that underlie the autonomic in systemic blood pressure and significant decreases in brain blood derangement dilated hearts, i.e., a lower incidence of reentrant arrhyth- Whereas the most common cause of VF in humans is mias. Protection by the vagus and the very specific condi- regional cardiac ischemia in the setting of myocardial tions necessary for destabilizing the ventricular conduction infarction, global hypoxemia has been implicated in some pathways suggested that seizure-induced ventricular fibril- conditions to produce arrhythmias (e.g., obstructive apnea; lation was not the most likely cause of sudden death due [73], cf. [74]). The closest we came to triggering a run of to seizure activity. VF with a “vagal storm” supports the notion that global 1 3 312 The Journal of Physiological Sciences (2018) 68:307–320 Fig. 4 Ventricular fibrillation as a possible seizure-induced condition were greater than the doses that caused maximal increases in heart that cannot self-terminate. a Segment of the full schematic shown in rate and thus may have been producing local effects, including vasos- Fig.  9. b Spontaneous entry into ventricular fibrillation (VF) with a pasm, in the heart. e The contributions of dead space conditions and combination of bilateral vagal transection, isoproterenol, and sys- isoproterenol dose when added to bilateral vagotomy illustrating the temic hypoxemia as a result of breathing with an extended dead space very narrow range of conditions favoring VF. f The rate and extent of of 4 ml. c Segment from a period of asystole caused by 50-Hz vagal hypoxemia were critical for VF (red). Too small a change (black) or stimulation where a short spontaneous run of ventricular tachycar- too great a change (blue) produced either sinus or non-sinus bradycar- dia developed, but did not persist or devolve to VF because the vagal dia, respectively, but never VF. From [71] with permission stimulation continued. d Isoproterenol doses needed to enable VF hypoxemia can destabilize the conduction pathways of the Airway occlusion by laryngospasm heart: a 50-Hz vagal stimulus train initiated a run of ven- tricular tachycardia in our rat model, but this was relatively As the conditions for VF are highly constrained and appear quickly suppressed by the continuation of the vagal stimulus to disfavor VF with repeated seizures, we sought a more train (Fig. 4c). We suspect that periods of severe bradyar- likely explanation for sudden death. Seizure activity signifi- rhythmia or asystole may disable some regions of the intrin- cantly alters respiratory rhythm, causing an irregular, but sic conduction system or ventricular myocardium thereby increased respiratory rate and an irregular, but decreased disrupting the normal sequential activation of myocytes and tidal volume, leaving a relatively unchanged minute ventila- favoring VF. tion [20]. 1 3 The Journal of Physiological Sciences (2018) 68:307–320 313 Fig. 5 Comparison of seizure-induced obstructive apnea due to laryn- from laryngoscope). The EEG in the top panel shows termination of gospasm and seizure-induced central apnea. Taken from [20] with seizure activity and non-seizure “events” that are due to the heart beat permission. Each panel consists of a head-out plethysmogram, ECG, late in the trace. The bottom panel shows an example of a period of and EEG records. In the top panel, airflow can be seen to get reduced central apnea ending with an exaggerated breath (gasp), but no sig- to a minimum as bradyarrhythmia with ST segment changes (indi- nificant changes in ECG or EEG. Note, too, that the airway remained cating cardiac hypoxia) by a completely closed airway (top snapshot in a motionless open position during the central apneic period Respiratory changes during seizures can be significant We found during seizure activity that episodes of central (reviewed in [2, 7, 75]). Reports of ictal tachypnea, bradyp- apnea (defined as periods of no airflow and no evidence of nea, and apnea (e.g., [3, 20, 76–82]) all point to an impact of respiratory effort) and obstructive apnea (defined as peri - seizure activity on respiratory rhythm generation and thereby ods of no airflow with evidence of inspiratory effort) were a role in oxygen desaturation during seizures [77, 80]. both observed [20, 88], but only the periods of obstructive Animal studies involving rats [18, 20, 36], mice [11, apnea were associated with severe systemic consequences 83], cats [84, 85], and sheep [86, 87] have all contributed and death (Fig. 5). The basis for the airway obstruction was to a demonstration of the importance of ictal hypoxemia in demonstrated to be seizure-induced laryngospasm [20]. This seizure-induced death. was sufficient to completely prevent airflow and precipitated Laryngospasm sufficient to produce partial airway rapid desaturation, ischemic cardiac rhythm and functional occlusion was also typical [20]. High-frequency “convul- changes, respiratory arrest, cardiac arrest, and finally death. sive” activity of the vocal folds was described as a feature Other, indirect evidence has supported laryngospasm, most of seizure activity, but occasionally, the spasm of laryngeal significantly, pulmonary edema (e.g., [14, 89–91]). musculature was such that complete airway occlusion with Central apneic episodes were associated with smaller obstructive apnea occurred [20]. changes in oxygen saturation (e.g., Fig. 6) and were argued Interestingly, in our experiments, animals with a protected to result from seizure-triggered activation of the diving airway (tracheal implant, endotracheal tube, or tracheal win- reflex [88], a “normal” response that results from co-acti- dow) never died during seizure activity, but animals with- vation of both divisions of the autonomic nervous system out airway protection died more than 20% of the time [20]. (Fig. 7) [92–96]. 1 3 314 The Journal of Physiological Sciences (2018) 68:307–320 Fig. 6 Illustration of the active laryngeal states for both obstructive tion and slowing during obstructive apnea and the uniform PQRST apnea due to laryngospasm and the seizure-associated periods of cen- complexes during central apnea. The asterisks above the ECG record- tral apnea. Each panel shows a segment of EEG, multi-unit recurrent ing mark the times of the high-resolution sweeps shown to the right laryngeal nerve activity (RLN), and ECG. The RLN, which carries (also marked with asterisks). The recording illustrating obstructive motor output for both laryngeal abductors and adductors, is active apnea is taken from the end of a seizure; seizure activity is present during both types of apnea. Note the significant slowing and ST from the beginning of the illustrated data and an estimate of seizure changes associated with obstructive apnea, but no ECG changes asso- offset (based on a complete flatlining of EEG) is marked by an arrow. ciated with central apnea. Shown to the right are three ECG sweeps Calibrations on the figure. Taken from [20] with permission for each type of apnea to illustrate the pronounced ST segment eleva- The mammalian diving response is an extremely powerful response that comes during attempts to breathe against a reflex response to nasopharyngeal stimulation that results in closed airway or during asphyxiation (e.g., [100–102]). apnea, bradycardia, and increased systemic blood pressure, The sympathetic response to airway occlusion is severe highlighting the integration of these systems. The strong- (e.g., [101]). We also find that seizure activity drives sym- est evidence that the diving reflex is not the mechanism for pathetic outflow to the adrenal gland (Nobuhiro Watanabe airflow cessation during seizure-induced periods of central and Mark Stewart, unpublished), amplifying the sympathetic apnea is the fact that the HR changed in our animals by impact of hypoxia during seizure activity. In fact, the sympa- less than 10% [88], whereas other studies have reported thetic activity is critical for many of the cardiac performance HR changes over 50% in rats (e.g., [97–99]). In fact, we changes (e.g., [59]). initially compared seizure-induced central apneic episodes to breath holding [20] because periods of seizure-induced central apnea were relatively free of the intense autonomic 1 3 The Journal of Physiological Sciences (2018) 68:307–320 315 Fig. 7 Illustration of respiratory rhythm reset and evidence that sei- tered), plethysmograph, ECG, and two EEG recordings, one from zure-associated central apneic episodes result from a partial activa- each hemisphere over dorsal hippocampus. The pronounced arti- tion of the diving reflex brainstem circuitry. Taken from [88] with facts evident on the filtered EEG trace are associated with the central permission. Raw data record shows two events, the first associ- apneic episode lasting about 1.5  s (onset indicated by arrow), and a ated with a flat head-out plethysmogram and the second showing later event that does not include cessation of airflow. High-frequency a small ripple present in the plethysmogram. Both events are simi- events are evident in the full bandpass EEG records. Segment of raw larly associated with brief bursts in the EEG that can be isolated by data is taken from a longer seizure episode; the onset and offset of high-pass filtering (top sweep). When non-flat plethysmogram peri- the seizure itself are not illustrated. Calibrations are 0.025  mV fil- ods are superimposed using the brief bursts to align the records, the tered EEG, 0.2  ml plethysmograph, 0.05  mV ECG, and 0.2  mV for plethysmograms superimpose, indicating a reset of the respiratory both EEG channels. Time calibration is 2 s. b Twenty superimposed rhythm with each burst. The periods of no air movement are consist- sequential non-apneic events from a single animal to highlight the ent with activation of the diving reflex efferent pathways and resem- complete alignment of the pre- and post-artifact plethysmograph ble responses induced by actual activation of the diving reflex with records. This alignment, given the broader range of phases leading up nasopharyngeal mist or irrigation with water (data not shown). a to the event onset, indicates a resetting of the respiratory rhythm, but Example record of two events, one event that includes complete ces- the rhythm after about 1–1.5 s becomes highly variable. Calibrations sation of breathing effort as evidenced by flatline plethysmograph, are 0.05 mV filtered EEG and 0.2 ml plethysmograph. Time calibra- and a later event where respiratory effort did not stop. Records from tion is 1 s top to bottom are high-pass filtered EEG (top EEG channel was fil- epilepsy patients? Translation to the bedside The detailed publication of results from the MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) [3] pre- As detailed as our studies have been, how could it be pos- sented a sequence of events between seizure and death that sible to translate results from rats, which are anesthetized, included the onset of “terminal apnea” followed by cardiac and induced to have seizures with a chemical convulsant to 1 3 316 The Journal of Physiological Sciences (2018) 68:307–320 Fig. 8 Biomarkers to translate the laryngospasm evidence in our rat of airway obstruction. This second biomarker is the development of model to human subjects. Taken from [103, 104] with permission. A significant RR interval variability due to both the bradycardia and critical of finding during simulated laryngospasm was thoracic EMG conduction block as well as the development of very short intervals bursts associated with attempts to inspire against the closed airway (c–e). EMG electromyogram, RR interval time interval between suc- could be easily seen in ECG and even EEG records, especially when cessive R-wave peaks in the PQRST sequence of each heart beat, high-pass filtered (a). The presence of this extra effort clearly her - SDNN standard deviation of the mean interval between successive alded the obstructive apnea period and steadily increased until stop- R-waves in an ECG recording, PIP peak inspiratory pressure devel- ping completely (a, b), which was the point of respiratory arrest. A oped inside the closed respiratory system by inspiratory effort against second biomarker is also available, particularly late during the period the closed airway arrest. A supplement to the paper showed raw data from the In fact, two complementary biomarkers can be derived key cases that led to this overall sequence. In analyzing our from ECG records (Fig. 8). The first is the EMG-based sig- data, we found that during inspiratory attempts against an nal descried above and the second biomarker is an abrupt occluded airway, EMG signals from the effort mixed with increase in RR interval variance with the particular appear- the ECG recordings [20, 103]. The MORTEMUS paper ance of very short intervals associated with attempts to interpreted these signals as evidence of actual breathing, and inspire during obstruction. We believe that this linkage we could show with certainty that these events also reflected between our model and the clinical data argues strongly effort during airway occlusion and, further, that the ampli- for airway obstruction in the human cases and that seizure- tude of these signals correlated with the effort [103, 104]. induced laryngospasm may link the ictal state to postictal terminal events. Further, we argue that these biomarkers can 1 3 The Journal of Physiological Sciences (2018) 68:307–320 317 Fig. 9 Summary schematic of possible outcomes mediated by auto- poor ejection fraction will lead to decreased brain blood flow and ter - nomic overactivity associated with seizures. As described in Fig.  2, minate the seizure). Once the point of respiratory arrest is reached, the majority of seizures will terminate on their own and permit a relaxation of the laryngospasm or artificially opening the airway will spontaneous recovery of autonomic derangements. As highlighted in not be sufficient for resuscitation. There is clearly a window of oppor - Fig. 3, asystole will terminate the seizure and lead to the same kind of tunity for cardiopulmonary resuscitation (CPR) to resuscitate patients recovery once the seizure ends. Ventricular fibrillation is one path to at this point, but resuscitation depends on how quickly CPR can be death (Fig.  4), but this is a difficult condition to achieve and actually applied [3]. As a preventative measure, the best prevention remains gets harder as the heart dilates with repeated seizures [72]. The cause good control of seizures. As interventions, the opportunity for resus- of death that we believe is the most likely, given that laryngospasm citation after VF or laryngospasm is short. Attention to differentiating is a feature of every convulsive seizure, is seizure-induced laryngo- between these two possibilities will save additional time. Critically, spasm sufficient to cause obstructive apnea. The apneic condition access to an animal model such as ours will permit the exploration of can persist beyond the end of the seizure (the severe bradycardia and additional preventative or interventional approaches be applied to past cases to subclassify possible causes of resuscitation interventions, and approaches that can lead to death and used to monitor patients to improve outcomes by prevention. signaling times of airway obstruction. Acknowledgements The author is grateful to his sponsor, Dr. Harumi Hotta of the Tokyo Metropolitan Institute of Gerontology, and for the support of the Japan Society for the Promotion of Science. The research Prevention and intervention itself was supported with philanthropic contributions, university sup- port, and other sources. 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Proc Natl Acad Sci USA 113:7272– org/10.1016/j.nbd.2017.01.008 7277. https ://doi.org/10.1073/pnas.15182 02113 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Physiological Sciences Springer Journals

An explanation for sudden death in epilepsy (SUDEP)

Stewart, Mark
The Journal of Physiological Sciences , Volume 68 (4) – Mar 14, 2018
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Springer Journals
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Copyright © 2018 by The Physiological Society of Japan and Springer Japan KK, part of Springer Nature
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Biomedicine; Human Physiology; Neurosciences; Animal Biochemistry; Animal Physiology; Cell Physiology; Neurobiology
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1880-6546
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1880-6562
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10.1007/s12576-018-0602-z
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29542031
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Abstract

This review traces the examination of autonomic, cardiovascular, and respiratory derangements associated with seizure activity in the clinical and preclinical literature generally, and in the author’s animal model specifically, and concludes with the author’s views on the potential mechanisms for sudden death in epilepsy (SUDEP). An animal model that employs kainic acid-induced seizures on a background of urethane anesthesia has permitted unprecedented access to the behavior of autonomic, cardiovascular, and respiratory systems during seizure activity. The result is a detailed description of the major causes of death and how this animal model can be used to develop and test preventative and interventional strategies. A critical translational step was taken when the rat data were shown to directly parallel data from definite SUDEP cases in the clinical literature. The reasons why ventricular fibrillation as a cause of death is so rarely reported and tools for verifying that seizure-associated laryngospasm can induce obstructive apnea as a cause of death are discussed in detail. Many details of the specific kinetics of activation of brainstem neurons serving autonomic and respiratory function remain to be elucidated, but the boundary conditions described in this review provide an excellent framework for more focused studies. A number of studies conducted in animal models of seizure activity and in epilepsy patients have contributed information on the auto- nomic, cardiovascular, and respiratory consequences of seizure activity spreading through hypothalamus and brainstem to the periphery. The result is detailed information on the systemic impact of seizure spread and the development of an under- standing of the essential mechanistic features of sudden unexpected death in epilepsy (SUDEP). This review summarizes translation of data obtained from animal models to biomarkers that are useful in evaluating data from epilepsy patients. Keywords Seizure · Laryngospasm · Ventricular fibrillation · Obstructive apnea Definition of SUDEP of key cardiopulmonary events that contribute to an overall pattern ending with death [3]. Sudden unexpected death in epilepsy (SUDEP) is the sud- Qualifiers of “definite”, “probable”, and “possible” den, unexpected death of someone with epilepsy, who was depend on the availability of autopsy or direct observations/ otherwise healthy. Attention to the condition in the last recordings of terminal event and the presence or absence of decade has resulted in refinements in the definition (“… a a competing cause of death. “Definite” is used when com - non-traumatic, non-drowning death that occurs in benign peting causes of death are ruled out by autopsy or having circumstances in an individual with epilepsy…” see e.g., [1, directly observed/recorded the terminal event. “Probable” 2]), more detailed calculations of incidence (from about 1–9 is used in the absence of autopsy data or likely alternative deaths per 1000 patient years) [2–4], and the identification cause of death and confidence that the circumstances sur - rounding the death were otherwise benign. “Possible” is used when a competing cause of death exists and autopsy data are unavailable. A “plus” designation attached to the * Mark Stewart mark.stewart@downstate.edu “definite” or “probable” definitions is used “when a con - comitant condition other than epilepsy is identified before or Department of Physiology and Pharmacology, State after death, if the death may have been due to the combined University of New York Downstate Medical Center, 450 effect of both conditions, and if autopsy or direct observa - Clarkson Avenue, Brooklyn, NY 11203, USA tions/recordings of terminal event did not prove the con- Department of Neurology, State University of New York comitant condition to be the cause of death” [1]. Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA Vol.:(0123456789) 1 3 308 The Journal of Physiological Sciences (2018) 68:307–320 While the incidence of sudden deaths is < 10/1000 [2–4], remarkably, motor convulsions were absent [17, 18]. This the highest risk occurs in patients whose seizures are poorly preparation has permitted an extraordinary range of record- controlled, and SUDEP is the leading cause of death in ings during seizure activity [19]. Some recordings, in fact, young adults with uncontrolled seizures. With an estimated such as continuous and direct visualization of the larynx 65 million people worldwide currently living with epilepsy, during seizure activity, have not been possible previously and hundreds of thousands of new diagnoses annually, [20]. The seizure activity induced by kainic acid is of limbic SUDEP is a significant concern—especially if preventative cortical origin, thus resembling temporal lobe seizures, and or interventional strategies could be made available. follows a similar pattern to that seen when administered to unanesthetized animals, namely a period of seizure activ- ity that can be long lasting enough to meet the definition Utility of animal models for SUDEP studies of status epilepticus, followed by much briefer discrete sei- zures over. The pronounced metabolic derangements associ- A wide range of animal models has been used to explore ated with status epilepticus are also not present, due to the cardiac and/or respiratory derangements due to or associ- absence of motor convulsions (e.g., [21, 22]). ated with seizure activity that may contribute to an individ- ual’s death (for wide-ranging reviews: [5, 6]). For example, research employing transgenic mouse models has suggested Panautonomic activation during limbic critical contributions from genetic mutations impacting cortical seizure activity serotonergic neurotransmission and function in brainstem respiratory centers [2, 7–9]. However, over a dozen mouse Access to autonomic premotor and preganglionic neurons strains show audiogenic seizures [10]. from limbic cortical regions is relatively direct, with pro- Complicating the development and accepted value of jections from subiculum into paraventricular nucleus of the animal models is that what is known and what is unknown hypothalamus (PVN; there are also projections where limbic about the circumstances of each human death has been used cortical and insular cortical outputs are relayed through the to question the appropriateness of particular animal models amygdala) [23–26], and projections from PVN into med- for the study of SUDEP. As examples, because of data that ullary areas for both sympathetic premotor and parasym- the majority of deaths occur at night (suggesting a circadian pathetic preganglionic activation. Projections also engage variance in some parameter) and when the individual was in respiratory rhythm generation and motor areas (e.g., [7, 8, bed (suggesting that, as with some infants, the airway might 11]). Many of these projections are reviewed in [27, 28] and become obstructed by bedding) (reviewed in [2]), data from highly schematized in Fig. 1. animal models not specifically incorporating these details Clinical reports and experimental studies have demon- are often dismissed as incomplete. Identification of linkages strated changes in cardiac, respiratory, gastrointestinal, and between the animal model and human pathophysiology has genitourinary function before, during, and after a seizure been challenging. (see e.g., [29–41]). Significant autonomic effects of sei- In audiogenic seizure-prone mice, death typically accom- zures more commonly occur in association with generalized panies an extreme tonic phase that includes hindlimb exten- tonic–clonic seizures or partial seizures originating in the sion (e.g., [8, 11–15]). The parallels of this convulsive activ- temporal lobe [31, 42, 43] than in association with absence ity to aspects of human motor convulsions and the systemic seizures or focal seizures that minimally impact limbic or physiological impact of this seizure type have not been fully insular cortices. With a starting view that a seizure that established, but the audiogenic seizure phenotype has been causes death must do so by spreading to autonomic brain extremely valuable in epilepsy research. regions to ultimately impact cardiovascular or respiratory Our approach to the SUDEP mechanism has been differ - function, we began by looking for such spread in recordings ent. Having used urethane as an anesthetic for work on hip- from autonomic peripheral nerves. pocampal theta rhythm, one of the best-studied EEG signals Each seizure was able to increase parasympathetic activ- reflecting synchrony in the limbic system [16], we found ity by about tenfold and sympathetic tone by nearly as much that seizure activity could be induced under urethane, but [36]. Although both divisions of the autonomic nervous 1 3 The Journal of Physiological Sciences (2018) 68:307–320 309 have been noted during seizures, including premature atrial and ventricular contractions [44] and ST-segment changes indicating cardiac ischemia [49, 50]. The main finding from many of the clinical and animal studies was that seizure- induced autonomic changes were transient: when the seizure abated, ANS activity reverted to normal pre-seizure levels. Although less common, bradyarrhythmias, includ- ing periods of asystole, have been reported in epilepsy patients [51–58]. In our animal studies of seizure-induced bradyarrhythmia, extremes significantly impacted cardiac output and we showed in physiological simulations that the resulting decrease in brain blood flow would termi- nate any ongoing seizure activity (Fig. 3) [59, 60]. Simi- lar examples of seizure termination have been reported in the clinical literature [61, 62]. The resulting conclusion with regard to a mechanism of sudden death was that it may not be possible for severe autonomic derangements to be lethal. If the seizure was the stimulus for increased vagal tone and bradyarrhythmia, terminating the seizure would end the stimulus and permit a return to baseline conditions. A seizure-induced overdrive of the vagal out- put to the heart might never be lethal because it would be self-terminating. Fig. 1 Simplified schematic of pathways from cortical regions to the brainstem to influence autonomic outflow. Adapted from [105] with permission. Lines denote bidirectional connections, and arrows Ventricular fibrillation denote monodirectional projections. The key point is that pathways exist for seizure spread from limbic cortical areas (via subiculum) to Cardiac fibrosis and hypertrophy, increased QT interval hypothalamus (including paraventricular nucleus, PVN) and to brain- lengths and dispersion, evidence for increased sympathetic stem regions serving as parasympathetic motor and sympathetic pre- motor functions. Relayed projections through the amygdala are even tone and decreased parasympathetic tone, and the commonly more prominent. Projections from neocortical regions, including acknowledged observations of ictal tachycardia all raise insular cortex, have their own access to the hypothalamus and brain- the question of whether ventricular fibrillation (VF) may stem nuclei. The result is a multitude of pathways for seizure spread be a cause of SUDEP (e.g., [63], see also [64]). Generally, to impact autonomic and respiratory brainstem regions. NTS nucleus of the tractus solitarius, RVLM rostral ventrolateral medulla decreased vagal protection increases the risk for ventricu- lar fibrillation (VF; [65]). To date, four cases of VF arising from seizures [66, 67], plus one case of VF in relation to seizure-induced takotsubo cardiomyopathy [68] have been system showed significant increases in activity, the result- documented. In addition, epilepsy has been shown to be a ing change in heart rate and rhythm, which could be either risk factor for sudden cardiac arrest ending in ventricular brady- or tachy-arrhythmia, depended upon the relative fibrillation [69, 70]. levels in each division and the baseline conditions (Fig. 2). We looked at conditions that might favor ventricular Multiple studies have sought to define the extent to which fibrillation, a condition which when initiated would be seizures alter cardiac rhythm (e.g., [43–45]). Seizures that lethal whether a precipitating seizure continued or not. produce sinus arrhythmias provoke tachycardia in up to 99% Briefly, we found that entry into ventricular tachycardia of cases [46], with HR increases to 120–150 bpm [45, 47, and ventricular fibrillation could occur spontaneously 48]. Episodes of ictal bradycardia to a HR of 20–40 bpm under narrow conditions of moderate, but not severe have been reported [48]. Other changes to cardiac rhythm hypoxia, sympathetic overdrive, and minimal vagal activity 1 3 310 The Journal of Physiological Sciences (2018) 68:307–320 Fig. 2 Recordings from peripheral autonomic nerve and ganglion to to-peak amplitude of seizure EEG (black) tended to be larger when demonstrate seizure-induced increases in both divisions of the ANS. seizures were associated with bradycardia in ECG (green). Parasym- a Increases in vagus nerve activity during a single discrete seizure pathetic (blue) and sympathetic (red) activity was always increased, (shown divided into for sequential segments where each segment but the relative levels of the sympathetic and parasympathetic activ- shows arterial blood pressure, hippocampal EEG, and vagus nerve ity changes (and the starting heart rate—not shown) contribute to multi-unit activity). Note that the massive vagal activity increases the final condition of bradycardia or tachycardia. Adapted from the by the second and third segments. b Increases in multi-unit activity doctoral thesis of Isaac Naggar with permission (Stewart, mentor). d recorded in superior cervical ganglion, even during a very brief sei- Portion of a schematic diagram (full diagram is shown in Fig.  9) to zure. a and b were taken from [36] with permission. c Percent change emphasize the sequence of events: seizure activity changes autonomic in mean activity (EEG autonomic peripheral nerve or ganglion) and activity; seizure ends; autonomic activity returns to pre-seizure levels. hear rate from the beginning of bradycardic and tachycardic sei- EEG electroencephalogram, ECG electrocardiogram zures to the peak autonomic activity during the seizure. The peak- (Fig. 4) [64, 71]. Even small amounts of vagal activity were increasing ventricular cavity size and not increasing ven- protective. Most interesting was the finding that repeated tricular wall thickness is eccentric hypertrophy, and this seizure activity in rats led to cardiac dilatation that actually increases the path length for conduction within the ventric- lowered the already small risk for ventricular fibrillation ular myocardium. The longer path length might explain the [72]. Enlargement of the overall dimension of the heart by increased difficulty in initiating ventricular fibrillation in 1 3 The Journal of Physiological Sciences (2018) 68:307–320 311 Fig. 3 Simulation of seizure-induced asystole and demonstration flow, stopping the seizure. Seizure activity resumed after the stimu- of impact on seizure activity. a–e Taken from [60] with permis- lation because the chemical convulsant is still present. Phentolamine sion. After complete vagal transection, vagal afferent (stimulation infusion (e) for peripheral vasodilation to decrease systemic blood of the central segment of the vagus) or vagal efferent (stimulation of pressure had similar effects to the vagus nerve stimulation-induced the peripheral segment of the vagus) stimulation was tested at 10 or asystole. To the right is another segment of the full schematic shown 50  Hz. Neither 10-Hz (a) nor 50-Hz (b) afferent vagal stimulation in Fig.  9. This segment emphasizes a different sequence of events: had an impact on heart rate (red sweep in each panel) or kainic acid- seizure activity changes autonomic activity; asystole occurs; asystole induced seizure activity (top green sweep in each panel). Efferent causes the seizure activity to end; autonomic activity returns to pre- vagal stimulation at 10  Hz (c) slowed the heart, but did not signifi- seizure levels. The main point to emphasize is that the evidence indi- cantly alter brain blood flow (blue and middle green sweeps). Efferent cates that seizure-induced asystole will be self-terminating because vagal stimulation at 50  Hz (d) produced asystole, a significant drop these episodes terminate the seizures that underlie the autonomic in systemic blood pressure and significant decreases in brain blood derangement dilated hearts, i.e., a lower incidence of reentrant arrhyth- Whereas the most common cause of VF in humans is mias. Protection by the vagus and the very specific condi- regional cardiac ischemia in the setting of myocardial tions necessary for destabilizing the ventricular conduction infarction, global hypoxemia has been implicated in some pathways suggested that seizure-induced ventricular fibril- conditions to produce arrhythmias (e.g., obstructive apnea; lation was not the most likely cause of sudden death due [73], cf. [74]). The closest we came to triggering a run of to seizure activity. VF with a “vagal storm” supports the notion that global 1 3 312 The Journal of Physiological Sciences (2018) 68:307–320 Fig. 4 Ventricular fibrillation as a possible seizure-induced condition were greater than the doses that caused maximal increases in heart that cannot self-terminate. a Segment of the full schematic shown in rate and thus may have been producing local effects, including vasos- Fig.  9. b Spontaneous entry into ventricular fibrillation (VF) with a pasm, in the heart. e The contributions of dead space conditions and combination of bilateral vagal transection, isoproterenol, and sys- isoproterenol dose when added to bilateral vagotomy illustrating the temic hypoxemia as a result of breathing with an extended dead space very narrow range of conditions favoring VF. f The rate and extent of of 4 ml. c Segment from a period of asystole caused by 50-Hz vagal hypoxemia were critical for VF (red). Too small a change (black) or stimulation where a short spontaneous run of ventricular tachycar- too great a change (blue) produced either sinus or non-sinus bradycar- dia developed, but did not persist or devolve to VF because the vagal dia, respectively, but never VF. From [71] with permission stimulation continued. d Isoproterenol doses needed to enable VF hypoxemia can destabilize the conduction pathways of the Airway occlusion by laryngospasm heart: a 50-Hz vagal stimulus train initiated a run of ven- tricular tachycardia in our rat model, but this was relatively As the conditions for VF are highly constrained and appear quickly suppressed by the continuation of the vagal stimulus to disfavor VF with repeated seizures, we sought a more train (Fig. 4c). We suspect that periods of severe bradyar- likely explanation for sudden death. Seizure activity signifi- rhythmia or asystole may disable some regions of the intrin- cantly alters respiratory rhythm, causing an irregular, but sic conduction system or ventricular myocardium thereby increased respiratory rate and an irregular, but decreased disrupting the normal sequential activation of myocytes and tidal volume, leaving a relatively unchanged minute ventila- favoring VF. tion [20]. 1 3 The Journal of Physiological Sciences (2018) 68:307–320 313 Fig. 5 Comparison of seizure-induced obstructive apnea due to laryn- from laryngoscope). The EEG in the top panel shows termination of gospasm and seizure-induced central apnea. Taken from [20] with seizure activity and non-seizure “events” that are due to the heart beat permission. Each panel consists of a head-out plethysmogram, ECG, late in the trace. The bottom panel shows an example of a period of and EEG records. In the top panel, airflow can be seen to get reduced central apnea ending with an exaggerated breath (gasp), but no sig- to a minimum as bradyarrhythmia with ST segment changes (indi- nificant changes in ECG or EEG. Note, too, that the airway remained cating cardiac hypoxia) by a completely closed airway (top snapshot in a motionless open position during the central apneic period Respiratory changes during seizures can be significant We found during seizure activity that episodes of central (reviewed in [2, 7, 75]). Reports of ictal tachypnea, bradyp- apnea (defined as periods of no airflow and no evidence of nea, and apnea (e.g., [3, 20, 76–82]) all point to an impact of respiratory effort) and obstructive apnea (defined as peri - seizure activity on respiratory rhythm generation and thereby ods of no airflow with evidence of inspiratory effort) were a role in oxygen desaturation during seizures [77, 80]. both observed [20, 88], but only the periods of obstructive Animal studies involving rats [18, 20, 36], mice [11, apnea were associated with severe systemic consequences 83], cats [84, 85], and sheep [86, 87] have all contributed and death (Fig. 5). The basis for the airway obstruction was to a demonstration of the importance of ictal hypoxemia in demonstrated to be seizure-induced laryngospasm [20]. This seizure-induced death. was sufficient to completely prevent airflow and precipitated Laryngospasm sufficient to produce partial airway rapid desaturation, ischemic cardiac rhythm and functional occlusion was also typical [20]. High-frequency “convul- changes, respiratory arrest, cardiac arrest, and finally death. sive” activity of the vocal folds was described as a feature Other, indirect evidence has supported laryngospasm, most of seizure activity, but occasionally, the spasm of laryngeal significantly, pulmonary edema (e.g., [14, 89–91]). musculature was such that complete airway occlusion with Central apneic episodes were associated with smaller obstructive apnea occurred [20]. changes in oxygen saturation (e.g., Fig. 6) and were argued Interestingly, in our experiments, animals with a protected to result from seizure-triggered activation of the diving airway (tracheal implant, endotracheal tube, or tracheal win- reflex [88], a “normal” response that results from co-acti- dow) never died during seizure activity, but animals with- vation of both divisions of the autonomic nervous system out airway protection died more than 20% of the time [20]. (Fig. 7) [92–96]. 1 3 314 The Journal of Physiological Sciences (2018) 68:307–320 Fig. 6 Illustration of the active laryngeal states for both obstructive tion and slowing during obstructive apnea and the uniform PQRST apnea due to laryngospasm and the seizure-associated periods of cen- complexes during central apnea. The asterisks above the ECG record- tral apnea. Each panel shows a segment of EEG, multi-unit recurrent ing mark the times of the high-resolution sweeps shown to the right laryngeal nerve activity (RLN), and ECG. The RLN, which carries (also marked with asterisks). The recording illustrating obstructive motor output for both laryngeal abductors and adductors, is active apnea is taken from the end of a seizure; seizure activity is present during both types of apnea. Note the significant slowing and ST from the beginning of the illustrated data and an estimate of seizure changes associated with obstructive apnea, but no ECG changes asso- offset (based on a complete flatlining of EEG) is marked by an arrow. ciated with central apnea. Shown to the right are three ECG sweeps Calibrations on the figure. Taken from [20] with permission for each type of apnea to illustrate the pronounced ST segment eleva- The mammalian diving response is an extremely powerful response that comes during attempts to breathe against a reflex response to nasopharyngeal stimulation that results in closed airway or during asphyxiation (e.g., [100–102]). apnea, bradycardia, and increased systemic blood pressure, The sympathetic response to airway occlusion is severe highlighting the integration of these systems. The strong- (e.g., [101]). We also find that seizure activity drives sym- est evidence that the diving reflex is not the mechanism for pathetic outflow to the adrenal gland (Nobuhiro Watanabe airflow cessation during seizure-induced periods of central and Mark Stewart, unpublished), amplifying the sympathetic apnea is the fact that the HR changed in our animals by impact of hypoxia during seizure activity. In fact, the sympa- less than 10% [88], whereas other studies have reported thetic activity is critical for many of the cardiac performance HR changes over 50% in rats (e.g., [97–99]). In fact, we changes (e.g., [59]). initially compared seizure-induced central apneic episodes to breath holding [20] because periods of seizure-induced central apnea were relatively free of the intense autonomic 1 3 The Journal of Physiological Sciences (2018) 68:307–320 315 Fig. 7 Illustration of respiratory rhythm reset and evidence that sei- tered), plethysmograph, ECG, and two EEG recordings, one from zure-associated central apneic episodes result from a partial activa- each hemisphere over dorsal hippocampus. The pronounced arti- tion of the diving reflex brainstem circuitry. Taken from [88] with facts evident on the filtered EEG trace are associated with the central permission. Raw data record shows two events, the first associ- apneic episode lasting about 1.5  s (onset indicated by arrow), and a ated with a flat head-out plethysmogram and the second showing later event that does not include cessation of airflow. High-frequency a small ripple present in the plethysmogram. Both events are simi- events are evident in the full bandpass EEG records. Segment of raw larly associated with brief bursts in the EEG that can be isolated by data is taken from a longer seizure episode; the onset and offset of high-pass filtering (top sweep). When non-flat plethysmogram peri- the seizure itself are not illustrated. Calibrations are 0.025  mV fil- ods are superimposed using the brief bursts to align the records, the tered EEG, 0.2  ml plethysmograph, 0.05  mV ECG, and 0.2  mV for plethysmograms superimpose, indicating a reset of the respiratory both EEG channels. Time calibration is 2 s. b Twenty superimposed rhythm with each burst. The periods of no air movement are consist- sequential non-apneic events from a single animal to highlight the ent with activation of the diving reflex efferent pathways and resem- complete alignment of the pre- and post-artifact plethysmograph ble responses induced by actual activation of the diving reflex with records. This alignment, given the broader range of phases leading up nasopharyngeal mist or irrigation with water (data not shown). a to the event onset, indicates a resetting of the respiratory rhythm, but Example record of two events, one event that includes complete ces- the rhythm after about 1–1.5 s becomes highly variable. Calibrations sation of breathing effort as evidenced by flatline plethysmograph, are 0.05 mV filtered EEG and 0.2 ml plethysmograph. Time calibra- and a later event where respiratory effort did not stop. Records from tion is 1 s top to bottom are high-pass filtered EEG (top EEG channel was fil- epilepsy patients? Translation to the bedside The detailed publication of results from the MORTality in Epilepsy Monitoring Unit Study (MORTEMUS) [3] pre- As detailed as our studies have been, how could it be pos- sented a sequence of events between seizure and death that sible to translate results from rats, which are anesthetized, included the onset of “terminal apnea” followed by cardiac and induced to have seizures with a chemical convulsant to 1 3 316 The Journal of Physiological Sciences (2018) 68:307–320 Fig. 8 Biomarkers to translate the laryngospasm evidence in our rat of airway obstruction. This second biomarker is the development of model to human subjects. Taken from [103, 104] with permission. A significant RR interval variability due to both the bradycardia and critical of finding during simulated laryngospasm was thoracic EMG conduction block as well as the development of very short intervals bursts associated with attempts to inspire against the closed airway (c–e). EMG electromyogram, RR interval time interval between suc- could be easily seen in ECG and even EEG records, especially when cessive R-wave peaks in the PQRST sequence of each heart beat, high-pass filtered (a). The presence of this extra effort clearly her - SDNN standard deviation of the mean interval between successive alded the obstructive apnea period and steadily increased until stop- R-waves in an ECG recording, PIP peak inspiratory pressure devel- ping completely (a, b), which was the point of respiratory arrest. A oped inside the closed respiratory system by inspiratory effort against second biomarker is also available, particularly late during the period the closed airway arrest. A supplement to the paper showed raw data from the In fact, two complementary biomarkers can be derived key cases that led to this overall sequence. In analyzing our from ECG records (Fig. 8). The first is the EMG-based sig- data, we found that during inspiratory attempts against an nal descried above and the second biomarker is an abrupt occluded airway, EMG signals from the effort mixed with increase in RR interval variance with the particular appear- the ECG recordings [20, 103]. The MORTEMUS paper ance of very short intervals associated with attempts to interpreted these signals as evidence of actual breathing, and inspire during obstruction. We believe that this linkage we could show with certainty that these events also reflected between our model and the clinical data argues strongly effort during airway occlusion and, further, that the ampli- for airway obstruction in the human cases and that seizure- tude of these signals correlated with the effort [103, 104]. induced laryngospasm may link the ictal state to postictal terminal events. Further, we argue that these biomarkers can 1 3 The Journal of Physiological Sciences (2018) 68:307–320 317 Fig. 9 Summary schematic of possible outcomes mediated by auto- poor ejection fraction will lead to decreased brain blood flow and ter - nomic overactivity associated with seizures. As described in Fig.  2, minate the seizure). Once the point of respiratory arrest is reached, the majority of seizures will terminate on their own and permit a relaxation of the laryngospasm or artificially opening the airway will spontaneous recovery of autonomic derangements. As highlighted in not be sufficient for resuscitation. There is clearly a window of oppor - Fig. 3, asystole will terminate the seizure and lead to the same kind of tunity for cardiopulmonary resuscitation (CPR) to resuscitate patients recovery once the seizure ends. Ventricular fibrillation is one path to at this point, but resuscitation depends on how quickly CPR can be death (Fig.  4), but this is a difficult condition to achieve and actually applied [3]. As a preventative measure, the best prevention remains gets harder as the heart dilates with repeated seizures [72]. The cause good control of seizures. As interventions, the opportunity for resus- of death that we believe is the most likely, given that laryngospasm citation after VF or laryngospasm is short. Attention to differentiating is a feature of every convulsive seizure, is seizure-induced laryngo- between these two possibilities will save additional time. Critically, spasm sufficient to cause obstructive apnea. The apneic condition access to an animal model such as ours will permit the exploration of can persist beyond the end of the seizure (the severe bradycardia and additional preventative or interventional approaches be applied to past cases to subclassify possible causes of resuscitation interventions, and approaches that can lead to death and used to monitor patients to improve outcomes by prevention. signaling times of airway obstruction. Acknowledgements The author is grateful to his sponsor, Dr. Harumi Hotta of the Tokyo Metropolitan Institute of Gerontology, and for the support of the Japan Society for the Promotion of Science. The research Prevention and intervention itself was supported with philanthropic contributions, university sup- port, and other sources. 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The Journal of Physiological Sciences – Springer Journals

Published: Mar 14, 2018

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