Ictal Apnea Research Articles

Retrospective characterization of seizure semiology and treatment using continuous video‐EEG monitoring in neonatal encephalopathy in Uganda

AbstractObjectiveNeonatal encephalopathy (NE) is a leading cause of childhood death and disability, particularly in sub‐Saharan Africa. Detection of NE‐related seizures is challenging. We explored NE seizure semiology and management in Uganda.MethodsVideo‐EEG was recorded (days 1–5), seizure semiology reviewed according to ILAE classification and administration of antiseizure medication (ASM) evaluated. Clinicians treated seizures based on the clinical presentation alone.ResultsAmong 50 participants, 52% (26) had EEG‐confirmed seizures; 70% (18) combined electroclinical/electrographic; 4% (1) exclusively electroclinical; 22% (6) electrographic. Of those with electroclinical seizures (19), 42% displayed >1 semiology. Distribution of seizure semiology was; clonic 34% (11); autonomic 24% (8, of which 6 had prolonged ictal apnea); automatisms 18% (6); behavioral arrest 12% (4); and sequential 12% (4). ASM was administered to 64% (32/50). Of those with EEG‐confirmed seizures, only 62% (16/26) received ASM. In the non‐seizure group, 38% (9/24) received ASM during monitoring. ASM was administered 42 times, of which 45% (19) were considered appropriate.SignificanceIn this Ugandan NE population, incidence of seizures was high and clinical manifestations frequent. Clonic, autonomic and automatisms were most common. Clinical management was challenging, with both under and overtreatment evident. Respiratory impairment due to autonomic seizures frequently went unrecognized and is a prominent concern, particularly in settings without neonatal intensive care.

Ictal and Postictal Central Apnea in DEPDC5-Related Epilepsy.

DEPDC5-related epilepsy carries an increased risk of sudden unexpected death in epilepsy. We evaluated the occurrence and features of ictal central apnea (ICA) in patients with pathogenic sequence variant in DEPDC5. We reviewed data of 108 patients collected in 2 independent cohorts of patients with focal epilepsy who prospectively underwent long-term video-EEG monitoring (LTVM) with cardiorespiratory polygraphy. All patients underwent (1) at least an overnight polysomnography, (2) a high-field (3T) brain MRI study, and (3) CSF analysis when clinically indicated. Genetic testing (next-generation sequencing [NGS]) was offered for diagnostic purposes to patients with focal epilepsy of unknown etiology. In this cohort, NGS was finally performed in 29 patients, resulting in DEPDC5 pathogenic mutations in 5 patients. According to the presence of ictal apnea events, 5 of 14 patients with ICA showed pathogenic DEPDC5 variants (35%) while none of the 15 patients without ICA showed pathogenic mutation. Notably, DEPDC5 patients showed ICA in all recorded seizures (n = 15) with apnea duration ranging from 20 seconds to more than 1 minute. All seizures were characterized by motor arrest without overt automatic behaviors during ictal apnea. Scalp EEG showed the involvement of temporal lobe leads in all events. Severe oxygen desaturation was observed in 2 cases. In our cohort, ictal central apnea was a common finding in DEPDC5. These results support (1) the need for respiratory polygraphy during LTVM in DEPDC5-related epilepsy and (2) the potential relevance of genetic testing in patients with focal epilepsy of unknown etiology and ictal apnea.

High-Frequency Stimulation of the Centromedian Thalamic Nucleus Aborts Seizures and Ictal Apnea.

A 32-year-old right-handed woman presented with medically and surgically refractory left temporal neocortical epilepsy secondary to focal cortical dysplasia who underwent stereoelectroencephalography involving the centromedian nucleus of the thalamus. With the use of real-time stereoelectroencephalography monitoring, four electroclinical seizures were aborted by administering high-frequency stimulation at the centromedian nucleus at seizure onset. Seizures before stimulation were all associated with ictal apnea, while those with stimulation had no ictal apnea. This case demonstrates how providing high-frequency stimulation to the centromedian nucleus of the thalamus can abort electroclinical seizures and ictal apnea.

Seizures and Post-Ictal Respiratory Recovery in Kcnj16−/− Sprague-Dawley Rats

Epilepsy is a common neurological disorder (3.5 million in the US), of which ~1/3 continue to experience repeated seizures failing to benefit from anti-seizure medication. Poor seizure control puts patients with drug-resistant epilepsies at increased risk of Sudden Unexpected Death in Epilepsy (SUDEP), which is thought to result from severe post-ictal cardiorespiratory suppression. We’ve previously shown that Salt-Sensitive (SS) rats lacking 18 base pairs in the Kcnj16 gene (SS Kcnj16−/−), corresponding to a 6 amino acid (AA163-168) deletion in the second TM domain of Kir5.1, are susceptible to audiogenic seizures. Repeated seizures (1/day for 10 days) in this rat model resulted in ictal apnea, post-ictal respiratory suppression, diminished chemoreflexes, and high spontaneous mortality (PMID: 33232300). Here we generated additional Kcnj16−/− mutants on the outbred Sprague Dawley (SD Kcnj16−/−) genetic background to test the hypothesis that Kcnj16 mutations (T64I substitution; AA64-68 deletion (M7), and AA64-81 deletion (M8)) in the first TM domain of Kir5.1 causes: 1) audiogenic seizures, 2) progressive exacerbation of post-ictal ventilatory dysfunction, and 3) seizure-induced mortality. Ventilation (whole-body plethysmography) and seizure severity (Racine Score; HD video) were measured in male and female SD Kcnj16−/− rats for 20 minutes (min; baseline (BL)) before exposure to an auditory stimulus (2 min) and for 20 min of recovery. Mixed frequency white noise (WN) or a 10 kHz tone (85-95 dB) reproducibly elicited generalized tonic-clonic seizures (GTCSs) in all three SD mutants (T64I, M7, and M8). In SD Kcnj16−/− rats (T64I n=2, M7 n=3, M8 n=7, wild type n=2), 1 seizure/day for 10 days led to ictal apneas and transient post-ictal respiratory changes along with increases in body temperature (+1°C) following seizures, where breath frequency initially decreased (-25% of BL) before increasing (+40%) at 5 min post-stimulus and normalizing by 20 min. Tidal volume increased ~+80% from BL in the first 5 min and returned to BL by 20 min post-ictal. Minute ventilation was decreased (-10%) from BL within 1 min, increased to +60% by 5 minutes and returned to BL within 20 min post-stimulus. In contrast to previous SS Kcnj16−/− rat data, SD Kcnj16−/− rat post-ictal breathing patterns were unchanged across the 10-day seizure protocol, and we observed 100% survival. Our preliminary data suggests that Kcnj16 mutations at multiple sites can elicit the audiogenic seizure phenotype, but that SD Kcnj16−/− mutant rats appear resistant to repeated seizure-induced post-ictal ventilatory dysfunction and mortality — i.e. a potentially useful SUDEP-resistant model of repeated seizures. Funded by NIH HL122358. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Clinical spectrum, etiology, and treatment response in neonatal autonomic seizures: A case series

AbstractBackgroundNeonatal autonomic signs such as apnea, cyanosis, pallor, and desaturation rarely occur as isolated ictal phenomena and require a high degree of clinical suspicion in combination with continuous video electroencephalogram (vEEG) to establish a diagnosis.MethodsWe review the clinical profile, etiology, and treatment response in five neonates who presented with apnea as the primary seizure semiology.ResultsIctal apneic episodes were confirmed on continuous vEEG in all five infants within 24–48 h of symptom onset. Seizure etiologies included structural, infectious, and genetic, including a neonate with ANKRD11‐associated KBG syndrome, in which ictal apnea has not been previously described. Acute seizures resolved in all neonates following treatment with a single or combination of antiseizure medications.ConclusionsAbrupt onset and clustering episodes of apnea and oxygen desaturation in term infants should raise suspicion for epileptic seizures. Genetic testing should be considered as part of the diagnostic evaluation for autonomic seizures of unknown etiology. Early diagnosis and treatment of neonatal autonomic seizures may lead to excellent treatment response in the acute setting.

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5-Related Epilepsy.

DEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5-related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions. Depdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. Electroencephalogram (EEG), cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice. Depdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic-clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non-fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these mice developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole. Depdc5 deletion in excitatory neurons is sufficient to cause DEPDC5-related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5-related epilepsy and SUDEP. ANN NEUROL 2023;94:812-824.

Acute and chronic effects of seizures on cardiorespiratory control in the SSKcnj16-/- rat

Epilepsy is a common neurological disorder in which 1/3rd of patients experience repeated seizures, putting them at greater risk for Sudden Unexpected Death in Epilepsy (SUDEP). A leading hypothesis based on human data suggests severe post-ictal cardiorespiratory suppression precedes a SUDEP event. However, the pathophysiological consequences of repeated seizures on cardiorespiratory control/function remain unclear. Our lab has previously established a rat model harboring an 18 bp-mutation in the Kcnj16 gene (encoding Kir5.1 channel; SSKcnj16-/- rats), which is susceptible to sound-induced (audiogenic) seizures. In this model, repeated seizures (1/day for 10 days) lead to ictal apnea, post-ictal respiratory suppression, blunted chemoreflexes, and spontaneous mortality. While the respiratory effects of repeated seizures in our rat model have been established, the cardiorespiratory sequence of events leading to a SUDEP-like event remain unknown. Here we test the hypothesis that repeated seizures in SSKcnj16-/- rats result in cardiorespiratory dysfunction and lead to a sequence of pathological events accompanying human SUDEP. Male and female SSKcnj16-/- rats (n=5,6) were surgically implanted with radiotelemetry pressure devices and allowed >3 days to recover. The rats were then housed in a custom-made plethysmograph for long-term housing to measure breathing, blood pressure (BP), heart rate (HR), and behavior continuously for 10 days (d). The rats were exposed to a sound stimulus (2 min) to elicit a seizure once/d for 10d. As reported previously, audiogenic seizures caused ictal apneas and transient post-ictal respiratory frequency depression. However, for the first time, we also found ictal asystole and dramatic decreases in HR but increases in BP for ~20 min after seizures. These acute effects of seizures on breathing and HR/BP appear to be exaggerated with increasing numbers of seizures throughout the 10d protocol. In addition, we captured during the 10d protocol SUDEP-like events in six out of eleven SSKcnj16-/- rats studied. Unlike most experiments that showed recovery of cardiorespiratory measures within ~30 min, SSKcnj16-/- rats with a terminal event had reduced ventilation due to a reduced tidal volume, and BP steadily declined with minimal effects on HR in the 2-5 hours preceding death (n=4). Our preliminary data suggest repeated seizures induce acute cardiorespiratory disruptions which in some cases can lead to a SUDEP-like event in SSKcnj16-/- rats characterized by suppressed tidal volume, hypopnea and time-dependent hypotension. Funded by NIH HL122358 (MRH), DK126720 (OP), and HL135749 (AS). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Selective Serotonin Reuptake Inhibitors and 5-HT2 Receptor Agonists Have Distinct, Sleep-state Dependent Effects on Postictal Breathing in Amygdala Kindled Mice

Seizures can cause profound breathing disruptions. Seizures arising from sleep cause greater breathing impairment than those emerging from wakefulness and more often result in sudden unexpected death in epilepsy (SUDEP). The neurotransmitter serotonin (5-HT) plays a major role in respiration and sleep-wake regulation. 5-HT modulates seizure susceptibility and severity and is dysregulated by seizures. Thus, the impact of seizures on breathing dysregulation may be due to impaired 5-HT neurotransmission. We examined whether pharmacologically increasing 5-HT neurotransmission prior to seizures improves postictal breathing and how sleep-state during seizure induction contributes to these effects. We assessed breathing with whole-body plethysmography in 84 amygdala-kindled mice pre-treated with selective serotonin reuptake inhibitors (SSRI) or 5-HT2 receptor agonists. SSRIs and 5-HT2 agonists increased postictal breathing frequency (fR), tidal volume (VT), and minute ventilation (VE) at different timepoints following seizures induced during wakefulness. These effects were not observed following seizures induced during NREM sleep. SSRIs suppressed ictal and postictal apnea regardless of sleep state. The SSRI citalopram and the 5-HT2 agonists TCB-2 and MK-212 decreased breathing variability following wake-occurring seizures at different postictal timepoints. Only MK-212 decreased breathing variability when seizures were induced during NREM sleep. The 5-HT2A antagonist MDL-11939 reduced the effect of citalopram on fR, VT, and VE, and enhanced its effect on breathing variability in the initial period following a seizure. These results suggest that 5-HT mechanisms that are dependent on or independent from the 5-HT2 family of receptors impact breathing on different timescales during the recovery of eupnea, and that certain serotonergic treatments may be less effective at facilitating postictal breathing following seizures emerging from sleep.

Carotid body stimulation as a potential intervention in sudden death in epilepsy

ObjectiveTo investigate carotid body (CB) mechanisms related to sudden death during seizure. Ictal activation of oxygen-conserving reflexes (OCRs) can trigger fatal cardiorespiratory collapse in seizing rats, which presents like human sudden unexpected death in epilepsy (SUDEP). The CB is strongly implicated in OCR pathways; we hypothesize that modulating CB activity will provide insight into these mechanisms of death. MethodsLong-Evans rats were anesthetized with urethane. Recordings included: electrocorticography, electrocardiography, respiration via nasal thermocouple, and blood pressure (BP). The mammalian diving reflex (MDR) was activated by cold water delivered through a nasal cannula. Reflex and stimulation trials were repeated up to 16 times (4 pre-intervention, 12 post-intervention) or until death. In some animals, one or both carotid bodies were denervated. In some animals, the CB was electrically stimulated, both with and without MDR. Seizures were induced with kainic acid (KA). ResultsAnimals without seizure and with no CB modulation survived all reflexes. Non-seizing animals with CB denervation survived 7.1 ± 5.4 reflexes before death, and only 1 of 7 survived past the 12-trial threshold. Electrical CB stimulation without seizure and without reflex caused significant tachypnea and hypotension. Electrical CB stimulation with seizure and without reflex required higher amplitudes to replicate the physiological responses seen outside seizure. Seizing animals without CB intervention survived 3.2 ± 3.6 trials (per-reflex survival rate 42.0% ± 44.4%), and 0 of 7 survived past the 12-trial threshold. Seizing animals with electrical CB stimulation survived 10.5 ± 4.7 ictal trials (per-reflex survival rate 86.3% ± 35.0%), and 6 of 8 survived past the 12-trial threshold. SignificanceThese results suggest that, during seizure, the ability of the CB to stimulate a restart of respiration is impaired. The CB and its afferents may be relevant to fatal ictal apnea and SUDEP in humans, and CB stimulation may be a relevant intervention technique in these deaths.

Ictal apnea: A prospective monocentric study in patients with epilepsy.

Ictal respiratory disturbances have increasingly been reported, in both generalized and focal seizures, especially involving the temporal lobe. Recognition of ictal breathing impairment has gained importance for the risk of sudden unexpected death in epilepsy (SUDEP). The aim of this study was to evaluate the incidence of ictal apnea (IA) and related hypoxemia during seizures. We collected and analyzed electroclinical data from consecutive patients undergoing long-term video-electroencephalographic (video-EEG) monitoring with cardiorespiratory polygraphy. Patients were recruited at the epilepsy monitoring unit of the Civil Hospital of Baggiovara, Modena Academic Hospital, from April 2020 to February 2022. A total of 552 seizures were recorded in 63 patients. IA was observed in 57 of 552 (10.3%) seizures in 16 of 63 (25.4%) patients. Thirteen (81.2%) patients had focal seizures, and 11 of 16 patients showing IA had a diagnosis of temporal lobe epilepsy; two had a diagnosis of frontal lobe epilepsy and three of epileptic encephalopathy. Apnea agnosia was reported in all seizure types. Hypoxemia was observed in 25 of 57 (43.9%) seizures with IA, and the severity of hypoxemia was related to apnea duration. Apnea duration was significantly associated with epilepsy of unknown etiology (magnetic resonance imaging negative) and with older age at epilepsy onset (p< 0.001). Ictal respiratory changes are a frequent clinical phenomenon, more likely to occur in focal epilepsies, although detected even in patients with epileptic encephalopathy. Our findings emphasize the need for respiratory polygraphy during long-term video-EEG monitoring for diagnostic and prognostic purposes, as well as in relation to the potential link of ictal apnea with the SUDEP risk.

Opto‐ and Chemogenetic Dissection of Ictal Apnea Neural Circuitry

Sudden Unexpected Death in Epilepsy (SUDEP) is defined as the sudden, unexpected and unexplained death of a person with epilepsy and accounts for between 8 and 17% of epilepsy‐related deaths, rising to 50% for patients with refractory epilepsy. In a mouse model of SUDEP, we have recently shown that death is due to seizure‐induced respiratory arrest. In addition, apnea is initiated during the tonic phase and tonic respiratory muscle contraction is a possible mechanism of apnea. In the present study, we explore 1) whether tonic activity of the inspiratory rhythm generator in the brainstem and/or 2) upper motor neuron activity in the motor cortex drives ictal apnea.We recorded video, electrocorticogram (ECoG), electrocardiogram (ECG), and breathing via whole body plethysmography in adult mice carrying the human SCN8A encephalopathy mutation p.Asn1768Asp (N1768D; “D/+ mice”) during audiogenic seizures. This mutation was identified from a patient that died from SUDEP and D/+ mice have severe convulsive seizures with apnea and many suffer seizure‐induced death.To test the hypothesis that tonic activity from the inspiratory oscillator results in apnea, we implanted fiberoptic ferrules bilaterally into the Bötzinger Complex (BötC) of mice that express Channelrhodopsin2 (ChR2) under the vesicular GABA transporter (VGAT; “VGAT‐ChR2” mice) that were crossed with D/+ mice (Fig. 1A & B). The goal of the experiment is to photostimulate BötC during ictal apnea to inhibit tonic inspiratory activity and produce expiration (Fig. 1C). Seizures were evoked using a 15 kHz pure tone, as we have done before (Fig. 1D). Trains of light pulses (50 ms pulses, 5 mW of 473 nm light) were evoked repetitively during ictal apnea (Fig. 1E & F). However, this did not recover normal breathing rhythm and apnea duration was no different for any photostimulation paradigm versus control (p = 0.7892, F = 0.1747, One‐Way ANOVA; Fig. 1G). Although breathing was not affected during seizures, the effects on baseline breathing were substantial; for example, inspiration was inhibited for a full 10 second photostimulation train (Fig. 1H).To test the necessity of ictal activity from upper motor neurons in the motor cortex are required for generating ictal apnea, we expressed iDREADD receptors in cortical excitatory neurons of D/+ mice and injected CNO i.p. prior to inducing seizures with a 15 kHz pure tone (Fig. 2A). Under control conditions, seizures presented with the usual tonic phase apnea and spike wave discharges (SWDs) in the motor cortex (Fig. 2B). CNO was able to robustly inhibit the SWDs, but the tonic phase and apnea were not affected (Figs. 2C‐E). The effect of 3 mg/kg CNO on ECoG power was significantly greater than the effect on apnea (p = 0.0059, paired t‐test).In sum, we found that the core inspiratory oscillator circuitry in the brainstem is likely bypassed to create tonic inspiratory activity. Furthermore, inhibition of cortical upper motor neurons has no effect on apnea. Thus, our interpretation is that other pools of upper motor neurons must drive the tonic inspiratory activity and apnea.

Acute and Chronic Effects of Seizures on Cardiorespiratory Control in the SSKcnj16‐/‐Rat

Epilepsy is a common neurological disorder in which 1/3rd of patients experiences repeated seizures, which puts them at greater risk for Sudden Unexpected Death in Epilepsy (SUDEP). The pathophysiological consequences of repeated seizures resulting in SUDEP, including the effects of repeated seizures on cardiorespiratory function, remain unclear. We previously established a rat model (SSKcnj16‐/‐rats) in which 10 days of repeated daily audiogenic generalized tonic‐clonic seizures (GTCSs) lead to ictal apnea, post‐ictal respiratory suppression, blunted chemoreflexes and high spontaneous mortality (PMID: 33232300). Here we tested the hypotheses that a single GTCS is sufficient to blunt ventilatory chemoreflexes and that repeated seizures lead to progressively greater post‐ictal heart rate (HR) suppression and/or increases in blood pressure (BP). In our pilot experiment, a male SSKcnj16‐/‐rat was implanted with a pressure telemeter and placed in a chronic monitoring plethysmograph to measure breathing and BP/HR continuously for 10 days. The rat was exposed to a 10 kHz sound (2 mins) to elicit a seizure once/day for 10 days. We found that audiogenic seizures led to ictal apneas of variable lengths (4‐25 sec) and ictal asystole (~1‐2 sec), followed by a 31% increase in BP and 30% decrease in HR on days 1‐4. On days 9‐10, there was a 45% increase in BP and 50% decrease in HR, suggesting a progressive effect on HR and BP with repeated seizures. Ongoing studies aim to determine if the ventilatory responses to hypoxia (12% O2) or hypercapnia (7% CO2) are affected 1 hr after recovery from a single GTCS. Naïve SSKcnj16‐/‐rats (n=4, female) were subjected to pre‐ and post‐seizure hypercapnic chemoreflex testing. Relative to room air breathing, minute ventilation (expressed as % of control) increased during hypercapnia before (262% ± 12%) and 1 hr post‐seizure (240% ± 21%). However, breathing frequency responses to hypercapnia 1 hr post‐seizure were reduced (126% ± 6%) compared to before (164% ± 14%), and tidal volume increased to a greater amount post‐seizure (192% ± 13%) compared to before (168% ± 7%), suggesting a significant shift away from a frequency‐mediated to a tidal volume‐mediated chemoreflex response in the post‐ictal period. Our preliminary data suggest that like breathing, repeated seizures may have a progressively negative and acute effect on BP and HR, and that solitary seizures are sufficient to fundamentally alter the hypercapnic ventilatory responses in this rat model, which may have high relevance to human SUDEP.

Limbic system involvement in modulation of breathing during seizures and arousal

Automatic control of breathing is mediated by a neural network in the brainstem, modulated by central and peripheral inputs. A major source of this modulation comes from chemoreceptors from peripheral and central level. In addition, automatic control of breathing can be overridden by voluntary or conscious control. Pathways involved in this conscious control may be usurped by seizures, resulting in ictal apnea, at the same time that chemoreceptor drive is impaired. Here we studied mechanisms by which the limbic system might modulate breathing, and how this may lead to fatal apnea induced by a seizure. We used Scn1aR1407X/+ mice, a genetic mouse model of Dravet Syndrome (DS) and SUDEP, to study how activation of the Central Amygdala (CeA) can modify breathing and induce fatal apneas. Methods In DS mice (n=4), the CeA was stimulated under light anesthesia by injecting current with monopolar electrodes guided by a stereotaxic manipulator while measuring breathing using head-out plethysmography. The locations of the electrode were verified post hoc by electrolytic lesion and histology. A 3D map was generated of the portions of the CeA where breathing was modulated. In a separate group of DS (n=7) mice, whole-body plethysmography was used to assess baseline breathing, the hypercapnic ventilatory response (HCVR) and the hypoxic ventilatory response (HVR) before and after lesioning the CeA. In a third group of DS mice (n=11), electrolytic lesions were induced in the CeA. Mice were then instrumented with headmounts with EEG, ECG and EMG electrodes. After 5 days of recovery, headmounts were connected to a preamplifier and a commutator, and mice were placed in a plethysmography chamber to monitor breathing as well as EEG, ECG and EMG activity. Body temperature was increased with a heat lamp by 0.5°C per minute until a seizure was induced, or a maximum of 42.5°C was reached. Results CeA lesions did not affect baseline breathing, the HCVR or HVR, and did not prevent seizures in DS mice. Respiratory arrest and death occurred in control (sham-lesioned) DS mice following heat-induced seizures in 54.4% of cases (n=11). In contrast, only 9.1% of DS mice with CeA lesions showed ventilatory arrest and death after heat-induced seizures (n=11; p=0.016). Unilateral rostral amygdala lesions increased the survival rate from spontaneous seizures in DS mice (26.10% vs 49.12.5%, n=14 control, n=20 lesioned p=0.022). Stimulation of the rostral CeA produced apnea without causing seizures. Complete apnea could be induced for 1 minute without causing death in three animals, and for four minutes in one animal. Breathing returned immediately upon termination of amygdala stimulation in each case. There was also no reversal of anesthetic immobility, suggesting lack of an arousal response. Conclusions Our data suggest that the CeA modulates breathing and can induce complete apnea but is not directly involved in baseline respiratory rhythm generation or the ventilatory response to hypercapnia or hypoxia. Lesions of the CeA reduce the risk of apnea during seizures. We conclude that the CeA is a critical component of the neural pathway responsible for spread of seizures in the forebrain to key respiratory centers in the brainstem that elicits ventilatory arrest.

The Deep Breath Before the Plunge: Ictal Apnea and the Amygdala

A Human Amygdala Site That Inhibits Respiration and Elicits Apnea in Pediatric Epilepsy Rhone AE, Kovach CK, Harmata GIS, et al. JCI Insight. 2020;5(6):e134852. doi:10.1172/jci.insight.134852Background:Seizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown.Methods:We studied 8 pediatric patients with intractable epilepsy undergoing intracranial electroencephalography. We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine learning algorithm was used to delineate brain regions that inhibit respiration.Results:In 2 patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all 8 patients (3-17 years old). These effects did not depend on epilepsy type and were relatively specific to the amygdala, as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the amygdala inhibition of respiration (AIR) site, includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons.Conclusions:A focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target. Seizure-Related Apneas Have an Inconsistent Linkage to Amygdala Seizure Spread Park K, Kanth K, Bajwa S, et al. Epilepsia. 2020;61(6):1253-1260.Objective:Sudden unexpected death in epilepsy (SUDEP) is a frequent cause of death in epilepsy. Respiratory dysfunction is implicated as a critical factor in SUDEP pathophysiology. Human studies have shown that electrical stimulation of the amygdala resulted in apnea, indicating that the amygdala has a role in respiration control. Unilateral amygdala stimulation resulted in immediate onset of respiratory dysfunction occurring only during nose breathing. In small numbers of patients, some but not all spontaneous seizures resulted in apnea occurring shortly after seizure spread to the amygdala. With this study, we aimed to determine whether seizure onset or spread to the amygdala was necessary and sufficient to cause apnea.Methods:We investigated the temporal relationship between apnea/hypopnea (AH) onset and initial seizure involvement within the amygdala in patients with implanted depth electrodes.Results:Data from 17 patients (11 female) with 47 seizures were analyzed. With 7 seizures (3 patients), AH preceded amygdala seizure involvement by 2 to 55 seconds. There was no AH with 4 seizures (3 patients) that involved the amygdala. With 8 seizures (4 patients), AH occurred within 2 seconds following amygdala seizure onset. With 28 seizures, AH started >2 seconds after amygdala seizure onset (range: 3-158 seconds). Following seizure onset, there was a significant difference between AH onset time and amygdala seizure onset (P < .001). The mean ± standard deviation AH onset was 27.8 ± 41.06 seconds, and the mean time to amygdala involvement was 8.83 ± 20.19 seconds.Significance:There is a wide range of AH onset times relative to amygdala seizure involvement. With some seizures, amygdala seizure involvement occurs without AH. With other seizures, AH precedes amygdala seizures, suggesting that, with spontaneous seizures, involvement of the amygdala may not be crucial to induction of AH with all seizures. Other pathophysiology impacting brain stem respiratory networks may be of greater relevance to seizure-triggered apneas.

Causes and Effects Contributing to Sudden Death in Epilepsy and the Rationale for Prevention and Intervention.

Sudden unexpected death in epilepsy (SUDEP) claims the lives of one in every thousand epileptic patients each year. Autonomic, cardiac, and respiratory pieces to a mechanistic puzzle have not yet been completely assembled. We propose a single sequence of causes and effects that unifies disparate and competitive concepts into a single algorithm centered on ictal obstructive apnea. Based on detailed animal studies that are sometimes impossible in humans, and striking parallels with a growing body of clinical examples, this framework (1) accounts for the autonomic, cardiac, and respiratory data to date by showing the causal relationships between specific elements, and (2) highlights specific kinds of data that can be used to precisely classify various patient outcomes. The framework also justifies a “near miss” designation to be applied to any cases with evidence of obstructive apnea even, and perhaps especially, in individuals that do not require resuscitation. Lastly, the rationale for preventative oxygen therapy is demonstrated. With better mechanistic understanding of SUDEP, we suggest changes for detection and classification to increase survival rates and improve risk stratification.

Cardiorespiratory and autonomic function in epileptic seizures: A video-EEG monitoring study

PurposeSeizure-induced cardiorespiratory and autonomic dysfunction has long been recognized, and growing evidence points to its implication in sudden unexpected death in epilepsy (SUDEP). However, a comprehensive understanding of cardiorespiratory function in the preictal, ictal, and postictal periods are lacking. MethodsWe examined continuous cardiorespiratory and autonomic function in 157 seizures (18 convulsive and 139 nonconvulsive) from 70 consecutive patients who had a seizure captured on concurrent video-encephalogram (EEG) monitoring and polysomnography between February 1, 2012 and May 31, 2017. Heart and respiratory rates, heart rate variability (HRV), and oxygen saturation were assessed across four distinct periods: baseline (120 s), preictal (60 s), ictal, and postictal (300 s). Heart and respiratory rates were further followed for up to 60 min after seizure termination to assess return to baseline. ResultsIctal tachycardia occurred during both convulsive and nonconvulsive seizures, but the maximum rate was higher for convulsive seizures (mean: 138.8 beats/min, 95% confidence interval (CI): 125.3–152.4) compared with nonconvulsive seizures (mean: 105.4 beats/min, 95% CI: 101.2–109.6; p < 0.001). Convulsive seizures were associated with a lower ictal minimum respiratory rate (mean: 0 breaths/min, 95% CI: 0–0) compared with nonconvulsive seizures (mean: 11.0 breaths/min, 95% CI: 9.5–12.6; p < 0.001). Ictal obstructive apnea was associated with convulsive compared with nonconvulsive seizures. The low-frequency (LF) power band of ictal HRV was higher among convulsive seizures than nonconvulsive seizures (ratio of means (ROM): 2.97, 95% CI: 1.34–6.60; p = 0.008). Postictal tachycardia was substantially prolonged, characterized by a longer return to baseline for convulsive seizures (median: 60.0 min, interquartile range (IQR): 46.5–60.0) than nonconvulsive seizures (median: 0.26 min, IQR: 0.008–0.9; p < 0.001). For postictal hyperventilation, the return to baseline was longer in convulsive seizures (median: 25.3 min, IQR: 8.1–60) than nonconvulsive seizures (median: 1.0 min, IQR: 0.07–3.2; p < 0.001). The LF power band of postictal HRV was lower in convulsive seizures than nonconvulsive seizures (ROM: 0.33, 95% CI: 0.11–0.96; p = 0.043). Convulsive seizures with postictal generalized EEG suppression (PGES; n = 12) were associated with lower postictal heart and respiratory rate, and increased HRV, compared with those without (n = 6). ConclusionsProfound cardiorespiratory and autonomic dysfunction associated with convulsive seizures may explain why these seizures carry the greatest risk of SUDEP.

Reader response: Postconvulsive central apnea as a biomarker for sudden unexpected death in epilepsy (SUDEP).

It is generally thought, although probably not scientifically proven, that convulsive ictal apnea is secondary to diaphragm tonic contraction in conjunction with tonic limb muscular contraction.

The effect of seizure spread to the amygdala on respiration and onset of ictal central apnea.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death for patients with refractory epilepsy, and there is increasing evidence for a centrally mediated respiratory depression as a pathophysiological mechanism. The brain regions responsible for a seizure's inducing respiratory depression are unclear-the respiratory nuclei in the brainstem are thought to be involved, but involvement of forebrain structures is not yet understood. The aim of this study was to analyze intracranial EEGs in combination with the results of respiratory monitoring to investigate the relationship between seizure spread to specific mesial temporal brain regions and the onset of respiratory dysfunction and apnea. The authors reviewed all invasive electroencephalographic studies performed at Northwestern Memorial Hospital (Chicago) since 2010 to identify those cases in which 1) multiple mesial temporal electrodes (amygdala and hippocampal) were placed, 2) seizures were captured, and 3) patients' respiration was monitored. They identified 8 investigations meeting these criteria in patients with temporal lobe epilepsy, and these investigations yielded data on a total of 22 seizures for analysis. The onset of ictal apnea associated with each seizure was highly correlated with seizure spread to the amygdala. Onset of apnea occurred 2.7 ± 0.4 (mean ± SEM) seconds after the spread of the seizure to the amygdala, which was significantly earlier than after spread to the hippocampus (10.2 ± 0.7 seconds; p < 0.01). The findings suggest that activation of amygdalar networks is correlated with central apnea during seizures. This study builds on the authors' prior work that demonstrates a role for the amygdala in voluntary respiratory control and suggests a further role in dysfunctional breathing states seen during seizures, with implications for SUDEP pathophysiology.

Autonomic aspects of sudden unexpected death in epilepsy (SUDEP).

Sudden unexpected death in epilepsy (SUDEP) is a major cause of epilepsy-related mortality. SUDEP is highly linked to seizures, with most deaths occurring after convulsive seizures in sleep. In most cases of SUDEP, convulsive seizures appear to directly trigger catastrophic cardiorespiratory dysfunction leading to death. In the last few decades, many pathophysiological mechanisms have been proposed to explain the sequence of events leading to death. Patients with epilepsy often have underlying autonomic dysfunction, as measured by heart rate variability and other testing modalities. Additionally, seizures often trigger acute cardiac and respiratory dysfunction. While sinus tachycardia is the most common cardiac finding during seizures, asystole and malignant tachyarrhythmias may also occur. Seizures can also lead to respiratory dysfunction, including central ictal and obstructive apnea related to laryngospasm. Available data suggest that there could be underlying autonomic dysfunction, potentially related to genetic, medication, and other factors that might predispose individuals to sudden catastrophic cardio-respiratory dysfunction in the setting of a seizure, resulting in SUDEP. Further exploration of this possible link is needed. Patients with medically refractory epilepsy are at the highest risk, and adequate management via medical therapy to control convulsive seizures, or surgical intervention may decrease the SUDEP risk. Recently, many automated seizure detection systems have been developed to detect convulsive seizures, which may enable caregivers to more closely monitor individuals with epilepsy. Improved identification of seizures may be important for patients with refractory epilepsy as close supervision and timely intervention after a seizure could potentially reduce the risk of SUDEP.

Conscious control of breathing: A key to prevention of sudden unexpected death in epilepsy?

Conscious control of breathing: A key to prevention of sudden unexpected death in epilepsy?