Seizures Cause Prolonged Impairment of Ventilation, CO2 Chemoreception and Thermoregulation.

Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO2 chemoreception). We then studied Scn1a R1407X/+ (Dravet syndrome; DS) and Scn8a N1768D/+ (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system in mice. Depleting 5-HT with para-chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced postictal inhibition of the HCVR and hypothermia. These results are consistent with the previous observation that seizures cause transient impairment of serotonergic neuron function, which would be expected to inhibit the many aspects of respiratory control dependent on 5-HT, including baseline ventilation and the HCVR. These results provide a scientific rationale to investigate the interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing postictal 5-HT tone.SIGNIFICANCE STATEMENT There is increasing evidence that seizure-induced respiratory dysfunction contributes to the pathophysiology of sudden unexpected death in epilepsy (SUDEP). However, the cellular basis of this dysfunction has not been defined. Here, we show that seizures impair CO2 chemoreception in some epilepsy patients. In two mouse models of SUDEP we found that generalized convulsive seizures impaired CO2 chemoreception, and induced hypothermia, two effects reported with serotonergic neuron dysfunction. The defects in chemoreception and thermoregulation were exacerbated by chemical depletion of serotonin and reduced with fenfluramine, suggesting that seizure-induced respiratory dysfunction may be due to impairment of serotonin neuron function. These findings suggest that impaired chemoreception because of transient inhibition of serotonergic neurons may contribute to the pathophysiology of SUDEP.

Accuracy of patient-reported spell duration: A comparative study.

Clinicians rely heavily on patient histories to make medical diagnoses, most of which are inherently subjective and prone to inaccuracies. The aim of this study is to compare the subjective versus objective duration of spells through a retrospective chart review of patients admitted to the epilepsy monitoring unit at our tertiary care medical center. One hundred patients were analyzed. Differences in the accuracy of subjective estimations versus objective duration were compared by age, sex, focal versus generalized, location (frontal versus non-frontal), and spell type (focal aware versus impaired awareness and epileptic versus non-epileptic). Our data show that patients are poor subjective estimators, with 73% of patients overestimating the duration of their spells. We did not find differences in estimated duration by age, sex, seizure location or spell type. A notable exception was patients with generalized convulsive seizures, who accurately reported spell duration to within 17 s. This is likely because these seizures are stereotypical, and patients/family time them. Moreover, patients with non-epileptic spells were worse estimators of their spell duration than those with epileptic spells. In addition, although the prefrontal lobe plays a role in time estimation, we did not find that patients with frontal lobe seizures were worse estimators than those with non-frontal seizures, but invasive monitoring can more precisely localize seizures within areas of the frontal lobe responsible for time estimation. Our data emphasize the importance of not relying solely on patient-reported time estimation in diagnosing and developing treatment plans and instead instructing patients to time their spells.

Interictal respiratory variability predicts severity of hypoxemia after generalized convulsive seizures.

OBJECTIVE: Severe respiratory dysfunction induced by generalized convulsive seizures (GCS) is now thought to be a common mechanism for sudden unexpected death in epilepsy (SUDEP). In a mouse model of seizure-induced death, increased interictal respiratory variability was reported in mice that later died of respiratory arrest after GCS. We studied respiratory variability in epilepsy patients as a predictive tool for severity of postictal hypoxemia, a potential biomarker for SUDEP risk. We then explored the relationship between respiratory variability and central CO2 drive, measured by the hypercapnic ventilatory response (HCVR). METHODS: We reviewed clinical, video-electroencephalography, and respiratory (belts, airflow, pulse oximeter, and HCVR) data of epilepsy patients. Mean, SD, and coefficient of variation (CV) of interbreath interval (IBI) were calculated. Primary outcomes were: (1) nadir of capillary oxygen saturation (SpO2 ) and (2) duration of oxygen desaturation. Poincaré plots of IBI were created. Covariates were evaluated in univariate models, then, based on Akaike information criteria (AIC), multivariate regression models were created. RESULTS: Of 66 GCS recorded in 131 subjects, 30 had interpretable respiratory data. In the multivariate model with the lowest AIC value, duration of epilepsy was a significant predictor of duration of oxygen desaturation. Duration of tonic phase and CV of IBI during the third postictal minute correlated with SpO2 nadir, whereas CV of IBI during non-rapid eye movement sleep had a negative correlation. Poincaré plots showed that long-term variability was significantly greater in subjects with ≥200 s of postictal oxygen desaturation after GCS compared to those with <200 s desaturation. Finally, HCVR slope showed a negative correlation with measures of respiratory variability. SIGNIFICANCE: These results indicate that interictal respiratory variability predicts severity of postictal oxygen desaturation, suggesting its utility as a potential biomarker. They also suggest that interictal respiratory control may be abnormal in some patients with epilepsy.

Hypercapnic ventilatory response in epilepsy patients treated with VNS: A case-control study.

OBJECTIVE: Central CO2 chemoreception (CCR), a major chemical drive for breathing, can be quantified with a CO2 re-breathing test to measure the hypercapnic ventilatory response (HCVR). An attenuated HCVR correlates with the severity of respiratory dysfunction after generalized convulsive seizures and is a potential biomarker for sudden unexpected death in epilepsy (SUDEP) risk. Vagus nerve stimulation (VNS) may reduce SUDEP risk, but for unclear reasons the risk remains higher during the first 2 years after implantation. The vagus nerve has widespread connections in the brainstem, including key areas related to CCR. Here we examined whether chronic electrical stimulation of the vagus nerve induces changes in CCR. METHODS: We compared the HCVR in epilepsy patients with or without an active VNS in a sex- and age-matched case-control study. Eligible subjects were selected from a cohort of patients who previously underwent HCVR testing. The HCVR slope, change in minute ventilation (VE) with respect to change in end tidal (ET) CO2 (∆ VE/ ∆ ETCO2) during the test was calculated for each subject. Key variables were compared between the two groups. Univariate and multivariate analyses were carried out for HCVR slope as dependent variable. RESULTS: A total of 86 subjects were in the study. HCVR slope was significantly lower in the cases compared to the controls. Cases had longer duration of epilepsy and higher number of anti-epileptic drugs (AEDs) tried during lifetime. Having active VNS and ETCO2 were associated with a low HCVR slope while high BMI was associated with high HCVR slope in both univariate and multivariate analyses. DISCUSSION: We found having an active VNS was associated with relatively attenuated HCVR slope. Although duration of epilepsy and number of AEDs tried during lifetime was significantly different between the groups, they were not predictors of HCVR slope in subsequent analysis. CONCLUSION: Chronic electrical stimulation of the vagus nerve by VNS may be associated with an attenuated CCR [Correction added on 24 November 2021, after first online publication: The preceding sentence has been revised from "Chronic electrical stimulation of VNS nerve by VNS…"]. A larger prospective study may help to establish the time course of this effect in relation to the time of VNS implantation, whether there is a causal relationship, and determine how it affects SUDEP risk.

Ventilatory response to CO2 in patients with epilepsy.

OBJECTIVE: Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO2 (hypercapnic ventilatory response [HCVR] or central respiratory CO2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs). METHODS: Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (VE ), tidal volume, respiratory rate, end tidal (ET) CO2 and O2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope (ΔVE /ΔETCO2 ) for each subject was determined by linear regression. During the video-electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO2 , and capillary oxygen saturation (SPO2 ). RESULTS: Sixty-eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from -0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO2 . Both the duration and magnitude of postictal tcCO2 rise following GCSs were inversely correlated with HCVR slope. SIGNIFICANCE: Measurement of the HCVR is well tolerated and can be performed rapidly and safely at the bedside in the EMU. A subset of individuals has a very low sensitivity to CO2 , and this group is more likely to have a prolonged increase in postictal CO2 after GCS. Low interictal HCVR may increase the risk of severe respiratory depression and SUDEP after GCS and warrants further study.

The association of serotonin reuptake inhibitors and benzodiazepines with ictal central apnea.

OBJECTIVE: Ictal (ICA) and postconvulsive central apnea (PCCA) have been implicated in sudden unexpected death in epilepsy (SUDEP) pathomechanisms. Previous studies suggest that serotonin reuptake inhibitors (SRIs) and benzodiazepines (BZDs) may influence breathing. The aim of this study was to investigate if chronic use of these drugs alters central apnea occurrence in patients with epilepsy. METHODS: Patients with epilepsy admitted to epilepsy monitoring units (EMUs) in nine centers participating in a SUDEP study were consented. Polygraphic physiological parameters were analyzed, including video-electroencephalography (VEEG), thoracoabdominal excursions, and pulse oximetry. Outpatient medication details were collected. Patients and seizures were divided into SRI, BZD, and control (no SRI or BZD) groups. Ictal central apnea and PCCA, hypoxemia, and electroclinical features were assessed for each group. RESULTS: Four hundred and seventy-six seizures were analyzed (204 patients). The relative risk (RR) for ICA in the SRI group was half that of the control group (p = 0.02). In the BZD group, ICA duration was significantly shorter than in the control group (p = 0.02), as was postictal generalized EEG suppression (PGES) duration (p = 0.021). Both SRI and BZD groups were associated with smaller seizure-associated oxygen desaturation (p = 0.009; p ≪ 0.001). Neither presence nor duration of PCCA was significantly associated with SRI or BZD (p ≫ 0.05). CONCLUSIONS: Seizures in patients taking SRIs have lower occurrence of ICA, and patients on chronic treatment with BZDs have shorter ICA and PGES durations. Preventing or shortening ICA duration by using SRIs and/or BZD in patients with epilepsy may play a possible role in SUDEP risk reduction.

Amygdala enlargement in mesial temporal lobe epilepsy: an alternative imaging presentation of limbic epilepsy.

PURPOSE: To assess imaging, clinical, and pathological features of mesial temporal lobe epilepsy (mTLE) patients with amygdala enlargement (AE) in comparison with those with mesial temporal sclerosis (MTS). METHODS: Clinical, imaging, and pathologic features were retrospectively reviewed in 40 mTLE patients with postoperative follow-up (10 with AE and 30 with MTS). The volumes and signal intensity of the amygdala and hippocampus were assessed in 10 AE, 10 age- and sex-matched MTS patients, and 12 controls (HC). RESULTS: AE patients had a lower rate of concordant FDG PET (p < 0.05) and required more frequently intracerebral electrodes compared to MTS patients (p < 0.05). AE had larger ipsilateral amygdala (p < 0.0001) and hippocampus volumes (p < 0.0001) compared to MTS and to HC, with no significant differences for other brain structures. Normalized FLAIR signal was higher in the ipsilateral than contralateral amygdala in both AE and MTS (p < 0.001 and p < 0.05, respectively) and higher in the ipsilateral amygdala compared to HC (p < 0.05). In MTS, ADC in the ipsilateral amygdala (867 mm2/s) was higher compared to the contralateral one (804.8 × 10-6 mm2/s, p < 0.01), compared to HC (773 × 10-6 mm2/s, p < 0.01) and compared to the ipsilateral amygdala in AE (813.7 × 10-6 mm2/s, p < 0.05). AE patients had dysplasia (50%) or astrocytic gliosis (50%) of the amygdala extending to the hippocampus and temporal isocortex, and only 2/10 cases had pathologic findings of MTS. CONCLUSION: AE patients have distinct imaging and pathologic features compared to MTS, and require more extensive preoperative workup. Recognition of AE may improve preoperative assessment in TLE surgical candidates.

Serum serotonin levels in patients with epileptic seizures.

Profound cardiovascular and/or respiratory dysfunction is part of the terminal cascade in sudden unexpected death in epilepsy (SUDEP). Central control of ventilation is mediated by brainstem rhythm generators, which are influenced by a variety of inputs, many of which use the modulatory neurotransmitter serotonin to mediate important inputs for breathing. The aim of this study was to investigate epileptic seizure-induced changes in serum serotonin levels and whether there are potential implications for SUDEP. Forty-one epileptic patients were pooled into 2 groups based on seizure type as (1) generalized tonic-clonic seizures (GTCS) of genetic generalized epilepsy and focal to bilateral tonic-clonic seizures (FBTCS; n = 19) and (2) focal seizures (n = 26) based on clinical signs using surface video-electroencephalography. Postictal serotonin levels were statistically significantly higher after GTCS and FBTCS compared to interictal levels (P = .002) but not focal seizures (P = .941). The change in serotonin (postictal-interictal) was inversely associated with a shorter duration of tonic phase of generalized seizures. The interictal serotonin level was inversely associated with a shorter period of postictal generalized electroencephalographic suppression. These data suggest that peripheral serum serotonin levels may play a role in seizure features and earlier postseizure recovery; these findings merit further study.

The incidence and significance of periictal apnea in epileptic seizures.

OBJECTIVE: The aim of this study was to investigate periictal central apnea as a seizure semiological feature, its localizing value, and possible relationship with sudden unexpected death in epilepsy (SUDEP) pathomechanisms. METHODS: We prospectively studied polygraphic physiological responses, including inductance plethysmography, peripheral capillary oxygen saturation (SpO2 ), electrocardiography, and video electroencephalography (VEEG) in 473 patients in a multicenter study of SUDEP. Seizures were classified according to the International League Against Epilepsy (ILAE) 2017 seizure classification based on the most prominent clinical signs during VEEG. The putative epileptogenic zone was defined based on clinical history, seizure semiology, neuroimaging, and EEG. RESULTS: Complete datasets were available in 126 patients in 312 seizures. Ictal central apnea (ICA) occurred exclusively in focal epilepsy (51/109 patients [47%] and 103/312 seizures [36.5%]) (P < .001). ICA was the only clinical manifestation in 16/103 (16.5%) seizures, and preceded EEG seizure onset by 8 ± 4.9 s, in 56/103 (54.3%) seizures. ICA ≥60 s was associated with severe hypoxemia (SpO2 <75%). Focal onset impaired awareness (FOIA) motor onset with automatisms and FOA nonmotor onset semiologies were associated with ICA presence (P < .001), ICA duration (P = .002), and moderate/severe hypoxemia (P = .04). Temporal lobe epilepsy was highly associated with ICA in comparison to extratemporal epilepsy (P = .001) and frontal lobe epilepsy (P = .001). Isolated postictal central apnea was not seen; in 3/103 seizures (3%), ICA persisted into the postictal period. SIGNIFICANCE: ICA is a frequent, self-limiting semiological feature of focal epilepsy, often starting before surface EEG onset, and may be the only clinical manifestation of focal seizures. However, prolonged ICA (≥60 s) is associated with severe hypoxemia and may be a potential SUDEP biomarker. ICA is more frequently seen in temporal than extratemporal seizures, and in typical temporal seizure semiologies. ICA rarely persists after seizure end. ICA agnosia is typical, and thus it may remain unrecognized without polygraphic measurements that include breathing parameters.

Tolerability of a comprehensive cardiorespiratory monitoring protocol in an epilepsy monitoring unit.

BACKGROUND: Recent reports of fatal or near-fatal events in epilepsy monitoring units (EMUs) and an increasing awareness of the effects of seizures on breathing have stimulated interest in cardiorespiratory monitoring for patients undergoing video-electroencephalography (EEG) recording. Patient and provider acceptance of these extra recording devices has not previously been studied and may represent a barrier to widespread adoption. METHODS: We queried EMU subjects regarding their experiences with a monitoring protocol that included the continuous measurement of oral/nasal airflow, respiratory effort (chest and abdominal respiratory inductance plethysmography), oxygen saturation, and transcutaneous CO2. Surveys were returned by 71.4% (100/140) of eligible subjects. RESULTS: Overall, 73% of participants reported being moderately to highly satisfied with the monitoring, and 82% reported moderate to strong agreement that advance knowledge of the monitoring would not have changed their decision to proceed with the video-EEG study. Except for nasal airflow, none of the additional monitoring devices caused more discomfort than EEG electrodes. CONCLUSION: Patient acceptance of an EMU comprehensive cardiorespiratory monitoring protocol is high. The information obtained from "multimodality recording" should help clinicians and investigators understand the effect of seizures on both cardiac and respiratory physiology, may enhance safety in the EMU, and may aid in the identification of biomarkers for sudden unexpected death in epilepsy (SUDEP).

Incidence and Types of Cardiac Arrhythmias in the Peri-Ictal Period in Patients Having a Generalized Convulsive Seizure.

BACKGROUND AND OBJECTIVES: Generalized convulsive seizures (GCSs) are the main risk factor of sudden unexpected death in epilepsy (SUDEP), which is likely due to peri-ictal cardiorespiratory dysfunction. The incidence of GCS-induced cardiac arrhythmias, their relationship to seizure severity markers, and their role in SUDEP physiopathology are unknown. The aim of this study was to analyze the incidence of seizure-induced cardiac arrhythmias, their association with electroclinical features and seizure severity biomarkers, as well as their specific occurrences in SUDEP cases. METHODS: This is an observational, prospective, multicenter study of patients with epilepsy aged 18 years and older with recorded GCS during inpatient video-EEG monitoring for epilepsy evaluation. Exclusion criteria were status epilepticus and an obscured video recording. We analyzed semiologic and cardiorespiratory features through video-EEG (VEEG), electrocardiogram, thoracoabdominal bands, and pulse oximetry. We investigated the presence of bradycardia, asystole, supraventricular tachyarrhythmias (SVTs), premature atrial beats, premature ventricular beats, nonsustained ventricular tachycardia (NSVT), atrial fibrillation (Afib), ventricular fibrillation (VF), atrioventricular block (AVB), exaggerated sinus arrhythmia (ESA), and exaggerated sinus arrhythmia with bradycardia (ESAWB). A board-certified cardiac electrophysiologist diagnosed and classified the arrhythmia types. Bradycardia, asystole, SVT, NSVT, Afib, VF, AVB, and ESAWB were classified as arrhythmias of interest because these were of SUDEP pathophysiology value. The main outcome was the occurrence of seizure-induced arrhythmias of interest during inpatient VEEG monitoring. Moreover, yearly follow-up was conducted to identify SUDEP cases. Binary logistic generalized estimating equations were used to determine clinical-demographic and peri-ictal variables that were predictive of the presence of seizure-induced arrhythmias of interest. The z-score test for 2 population proportions was used to test whether the proportion of seizures and patients with postconvulsive ESAWB or bradycardia differed between SUDEP cases and survivors. RESULTS: This study includes data from 249 patients (mean age 37.2 ± 23.5 years, 55% female) who had 455 seizures. The most common arrhythmia was ESA, with an incidence of 137 of 382 seizures (35.9%) (106/224 patients [47.3%]). There were 50 of 352 seizure-induced arrhythmias of interest (14.2%) in 41 of 204 patients (20.1%). ESAWB was the commonest in 22 of 394 seizures (5.6%) (18/225 patients [8%]), followed by SVT in 18 of 397 seizures (4.5%) (17/228 patients [7.5%]). During follow-up (48.36 ± 31.34 months), 8 SUDEPs occurred. Seizure-induced bradycardia (3.8% vs 12.5%, z = -16.66, p < 0.01) and ESAWB (6.6% vs 25%; z = -3.03, p < 0.01) were over-represented in patients who later died of SUDEP. There was no association between arrhythmias of interest and seizure severity biomarkers (p > 0.05). DISCUSSION: Markers of seizure severity are not related to seizure-induced arrhythmias of interest, suggesting that other factors such as occult cardiac abnormalities may be relevant for their occurrence. Seizure-induced ESAWB and bradycardia were more frequent in SUDEP cases, although this observation was based on a very limited number of SUDEP patients. Further case-control studies are needed to evaluate the yield of arrhythmias of interest along with respiratory changes as potential SUDEP biomarkers.

Failure to breathe persists without air hunger or alarm following amygdala seizures.

Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To understand causes of postictal apnea, we used a multimodal approach to study brain mechanisms of breathing control in 20 patients (ranging from pediatric to adult) undergoing intracranial electroencephalography for intractable epilepsy. Our results indicate that amygdala seizures can cause postictal apnea. Moreover, we identified a distinct region within the amygdala where electrical stimulation was sufficient to reproduce prolonged breathing loss persisting well beyond the end of stimulation. The persistent apnea was resistant to rising CO2 levels, and air hunger failed to occur, suggesting impaired CO2 chemosensitivity. Using es-fMRI, a potentially novel approach combining electrical stimulation with functional MRI, we found that amygdala stimulation altered blood oxygen level-dependent (BOLD) activity in the pons/medulla and ventral insula. Together, these findings suggest that seizure activity in a focal subregion of the amygdala is sufficient to suppress breathing and air hunger for prolonged periods of time in the postictal period, likely via brainstem and insula sites involved in chemosensation and interoception. They further provide insights into SUDEP, may help identify those at greatest risk, and may lead to treatments to prevent SUDEP.

Use of Fluoxetine to Augment the Inter-Ictal Hypercapnic Ventilatory Response in Patients with Epilepsy: A Pilot Study.

Background: Severe peri-ictal respiratory dysfunction is a potential biomarker for high SUDEP risk and correlates with an attenuated hypercapnic ventilatory response (HCVR). Prior studies suggest a potential role for selective serotonergic reuptake inhibitors in modifying the HCVR, but this approach has not been studied in the epilepsy population. Objectives: To assess the feasibility of using fluoxetine to augment HCVR in epilepsy patients. Methods and Material: An inter-ictal HCVR was measured using a CO2 rebreathing technique in patients with epilepsy aged 18-75 years. Eligible participants were randomized to fluoxetine or placebo, and the HCVR was repeated at the end of week 4. Primary outcomes were recruitment and retention rate. Results: Of the 30 subjects enrolled, 22 were randomized (mean: 3.8 subjects/3 months), with a retention rate of 100% in fluoxetine and 95% in placebo. Conclusions: Our results demonstrate feasibility for a larger definitive future study to assess the efficacy of fluoxetine in augmenting HCVR.

Room tilt illusion in epilepsy.

Room tilt illusion is a rare phenomenon in which a person transiently perceives the surrounding environment as tilted to one side. Epilepsy is one of the presumed causes of room tilt illusion, but this has never been proven. We present a case of room tilt illusion that is epileptic in nature, documented by video- EEG monitoring. Our Patient is a 30-year-old woman with 11 years history of bi-monthly spells of sudden tilt of the whole environment counterclockwise for a duration of one to two seconds. These spells were initially diagnosed as psychogenic. She was then admitted to our video-EEG monitoring unit. She had three of her typical spells during monitoring, with corresponding changes of brief generalized spike-wave burst on EEG that coincided temporarily with her symptoms. The video otherwise did not reveal any sway or tilt of the patient herself. She was started on topiramate with resolution of her symptoms. She remained spell-free when seen during follow-up, six months later. This case illustrates a first example of room tilt illusion that is documented to be epileptic in nature. This case adds to the varied nature of how epilepsy can manifest in patients, which may support improved diagnosis and treatment of epileptic patients.

Automated Analysis of Risk Factors for Postictal Generalized EEG Suppression.

Rationale: Currently, there is some ambiguity over the role of postictal generalized electro-encephalographic suppression (PGES) as a biomarker in sudden unexpected death in epilepsy (SUDEP). Visual analysis of PGES, known to be subjective, may account for this. In this study, we set out to perform an analysis of PGES presence and duration using a validated signal processing tool, specifically to examine the association between PGES and seizure features previously reported to be associated with visually analyzed PGES. Methods: This is a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of SUDEP in adult patients with intractable epilepsy. We studied videoelectroencephalogram (vEEG) recordings of generalized convulsive seizures (GCS) in a cohort of patients in whom respiratory and vEEG recording were carried out during the evaluation in the epilepsy monitoring unit. A validated automated EEG suppression detection tool was used to determine presence and duration of PGES. Results: We studied 148 GCS in 87 patients. PGES occurred in 106/148 (71.6%) seizures in 70/87 (80.5%) of patients. PGES mean duration was 38.7 ± 23.7 (37; 1-169) seconds. Presence of tonic phase during GCS, including decerebration, decortication and hemi-decerebration, were 8.29 (CI 2.6-26.39, p = 0.0003), 7.17 (CI 1.29-39.76, p = 0.02), and 4.77 (CI 1.25-18.20, p = 0.02) times more likely to have PGES, respectively. In addition, presence of decerebration (p = 0.004) and decortication (p = 0.02), older age (p = 0.009), and hypoxemia duration (p = 0.03) were associated with longer PGES durations. Conclusions: In this study, we confirmed observations made with visual analysis, that presence of tonic phase during GCS, longer hypoxemia, and older age are reliably associated with PGES. We found that of the different types of tonic phase posturing, decerebration has the strongest association with PGES, followed by decortication, followed by hemi-decerebration. This suggests that these factors are likely indicative of seizure severity and may or may not be associated with SUDEP. An automated signal processing tool enables objective metrics, and may resolve apparent ambiguities in the role of PGES in SUDEP and seizure severity studies.

Seizure Clusters, Seizure Severity Markers, and SUDEP Risk.

Rationale: Seizure clusters may be related to Sudden Unexpected Death in Epilepsy (SUDEP). Two or more generalized convulsive seizures (GCS) were captured during video electroencephalography in 7/11 (64%) patients with monitored SUDEP in the MORTEMUS study. It follows that seizure clusters may be associated with epilepsy severity and possibly with SUDEP risk. We aimed to determine if electroclinical seizure features worsen from seizure to seizure within a cluster and possible associations between GCS clusters, markers of seizure severity, and SUDEP risk. Methods: Patients were consecutive, prospectively consented participants with drug-resistant epilepsy from a multi-center study. Seizure clusters were defined as two or more GCS in a 24-h period during the recording of prolonged video-electroencephalography in the Epilepsy monitoring unit (EMU). We measured heart rate variability (HRV), pulse oximetry, plethysmography, postictal generalized electroencephalographic suppression (PGES), and electroencephalography (EEG) recovery duration. A linear mixed effects model was used to study the difference between the first and subsequent seizures, with a level of significance set at p < 0.05. Results: We identified 112 GCS clusters in 105 patients with 285 seizures. GCS lasted on average 48.7 ± 19 s (mean 49, range 2-137). PGES emerged in 184 (64.6%) seizures and postconvulsive central apnea (PCCA) was present in 38 (13.3%) seizures. Changes in seizure features from seizure to seizure such as seizure and convulsive phase durations appeared random. In grouped analysis, some seizure features underwent significant deterioration, whereas others improved. Clonic phase and postconvulsive central apnea (PCCA) were significantly shorter in the fourth seizure compared to the first. By contrast, duration of decerebrate posturing and ictal central apnea were longer. Four SUDEP cases in the cluster cohort were reported on follow-up. Conclusion: Seizure clusters show variable changes from seizure to seizure. Although clusters may reflect epilepsy severity, they alone may be unrelated to SUDEP risk. We suggest a stochastic nature to SUDEP occurrence, where seizure clusters may be more likely to contribute to SUDEP if an underlying progressive tendency toward SUDEP has matured toward a critical SUDEP threshold.

Association of Peri-ictal Brainstem Posturing With Seizure Severity and Breathing Compromise in Patients With Generalized Convulsive Seizures.

OBJECTIVE: To analyze the association between peri-ictal brainstem posturing semiologies with postictal generalized electroencephalographic suppression (PGES) and breathing dysfunction in generalized convulsive seizures (GCS). METHODS: In this prospective, multicenter analysis of GCS, ictal brainstem semiology was classified as (1) decerebration (bilateral symmetric tonic arm extension), (2) decortication (bilateral symmetric tonic arm flexion only), (3) hemi-decerebration (unilateral tonic arm extension with contralateral flexion) and (4) absence of ictal tonic phase. Postictal posturing was also assessed. Respiration was monitored with thoracoabdominal belts, video, and pulse oximetry. RESULTS: Two hundred ninety-five seizures (180 patients) were analyzed. Ictal decerebration was observed in 122 of 295 (41.4%), decortication in 47 of 295 (15.9%), and hemi-decerebration in 28 of 295 (9.5%) seizures. Tonic phase was absent in 98 of 295 (33.2%) seizures. Postictal posturing occurred in 18 of 295 (6.1%) seizures. PGES risk increased with ictal decerebration (odds ratio [OR] 14.79, 95% confidence interval [CI] 6.18-35.39, p < 0.001), decortication (OR 11.26, 95% CI 2.96-42.93, p < 0.001), or hemi-decerebration (OR 48.56, 95% CI 6.07-388.78, p < 0.001). Ictal decerebration was associated with longer PGES (p = 0.011). Postictal posturing was associated with postconvulsive central apnea (PCCA) (p = 0.004), longer hypoxemia (p < 0.001), and Spo2 recovery (p = 0.035). CONCLUSIONS: Ictal brainstem semiology is associated with increased PGES risk. Ictal decerebration is associated with longer PGES. Postictal posturing is associated with a 6-fold increased risk of PCCA, longer hypoxemia, and Spo2 recovery. Peri-ictal brainstem posturing may be a surrogate biomarker for GCS severity identifiable without in-hospital monitoring. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that peri-ictal brainstem posturing is associated with the GCS with more prolonged PGES and more severe breathing dysfunction.

Effect of vagus nerve stimulation on blood glucose concentration in epilepsy patients - Importance of stimulation parameters.

In previous animal experiments, we demonstrated that cervical vagus nerve stimulation (VNS) inhibits pancreatic insulin secretion, thereby raises blood glucose levels, and impairs glucose tolerance through afferent signaling. However, there are no reports suggesting that similar effects occur in patients treated with chronic cervical VNS for epilepsy. In contrast to clinical VNS used for epilepsy, where the stimulation is intermittent with cycles of on and off periods, stimulation was continuous in our previous animal experiments. Thus, we hypothesized that the timing of the stimulation on/off cycles is critical to prevent impaired glucose tolerance in epilepsy patients chronically treated with cervical VNS. We conducted a retrospective analysis of medical records from patients with epilepsy. Blood glucose levels did not differ between patients treated with pharmacotherapy only (98 ± 4 mg/dL, n = 16) and patients treated with VNS plus pharmacotherapy (99 ± 3 mg/dL, n = 24, duration of VNS 4.5 ± 0.5 years). However, a multiple linear correlation analysis of patients with VNS demonstrated that during the follow-up period of 7.9 ± 0.7 years, blood glucose levels increased in patients with long on and short off periods, whereas blood glucose did not change or even decreased in patients that were stimulated with short on and long off periods. We conclude that chronic cervical VNS in patients with epilepsy is unlikely to induce glucose intolerance or hyperglycemia with commonly used stimulation parameters. However, stimulation on times of longer than 25 sec may bear a risk for hyperglycemia, especially if the stimulation off time is shorter than 200 sec.

Postictal serotonin levels are associated with peri-ictal apnea.

OBJECTIVE: To determine the relationship between serum serotonin (5-HT) levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA) in epileptic seizures. METHODS: We prospectively evaluated video EEG, plethysmography, capillary oxygen saturation (SpO2), and ECG for 49 patients (49 seizures) enrolled in a multicenter study of sudden unexpected death in epilepsy (SUDEP). Postictal and interictal venous blood samples were collected after a clinical seizure for measurement of serum 5-HT levels. Seizures were classified according to the International League Against Epilepsy 2017 seizure classification. We analyzed seizures with and without ICA (n = 49) and generalized convulsive seizures (GCS) with and without PCCA (n = 27). RESULTS: Postictal serum 5-HT levels were increased over interictal levels for seizures without ICA (p = 0.01), compared to seizures with ICA (p = 0.21). In patients with GCS without PCCA, serum 5-HT levels were increased postictally compared to interictal levels (p < 0.001), but not in patients with seizures with PCCA (p = 0.22). Postictal minus interictal 5-HT levels also differed between the 2 groups with and without PCCA (p = 0.03). Increased heart rate was accompanied by increased serum 5-HT levels (postictal minus interictal) after seizures without PCCA (p = 0.03) compared to those with PCCA (p = 0.42). CONCLUSIONS: The data suggest that significant seizure-related increases in serum 5-HT levels are associated with a lower incidence of seizure-related breathing dysfunction, and may reflect physiologic changes that confer a protective effect against deleterious phenomena leading to SUDEP. These results need to be confirmed with a larger sample size study.

Incidence, Recurrence, and Risk Factors for Peri-ictal Central Apnea and Sudden Unexpected Death in Epilepsy.

Introduction: Peri-ictal breathing dysfunction was proposed as a potential mechanism for SUDEP. We examined the incidence and risk factors for both ictal (ICA) and post-convulsive central apnea (PCCA) and their relationship with potential seizure severity biomarkers (i. e., post-ictal generalized EEG suppression (PGES) and recurrence. Methods: Prospective, multi-center seizure monitoring study of autonomic, and breathing biomarkers of SUDEP in adults with intractable epilepsy and monitored seizures. Video EEG, thoraco-abdominal excursions, capillary oxygen saturation, and electrocardiography were analyzed. A subgroup analysis determined the incidences of recurrent ICA and PCCA in patients with ≥2 recorded seizures. We excluded status epilepticus and obscured/unavailable video. Central apnea (absence of thoracic-abdominal breathing movements) was defined as ≥1 missed breath, and ≥5 s. ICA referred to apnea preceding or occurring along with non-convulsive seizures (NCS) or apnea before generalized convulsive seizures (GCS). Results: We analyzed 558 seizures in 218 patients (130 female); 321 seizures were NCS and 237 were GCS. ICA occurred in 180/487 (36.9%) seizures in 83/192 (43.2%) patients, all with focal epilepsy. Sleep state was related to presence of ICA [RR 1.33, CI 95% (1.08-1.64), p = 0.008] whereas extratemporal epilepsy was related to lower incidence of ICA [RR 0.58, CI 95% (0.37-0.90), p = 0.015]. ICA recurred in 45/60 (75%) patients. PCCA occurred in 41/228 (18%) of GCS in 30/134 (22.4%) patients, regardless of epilepsy type. Female sex [RR 11.30, CI 95% (4.50-28.34), p < 0.001] and ICA duration [RR 1.14 CI 95% (1.05-1.25), p = 0.001] were related to PCCA presence, whereas absence of PGES was related to absence of PCCA [0.27, CI 95% (0.16-0.47), p < 0.001]. PCCA duration was longer in males [HR 1.84, CI 95% (1.06-3.19), p = 0.003]. In 9/17 (52.9%) patients, PCCA was recurrent. Conclusion: ICA incidence is almost twice the incidence of PCCA and is only seen in focal epilepsies, as opposed to PCCA, suggesting different pathophysiologies. ICA is likely to be a recurrent semiological phenomenon of cortical seizure discharge, whereas PCCA may be a reflection of brainstem dysfunction after GCS. Prolonged ICA or PCCA may, respectively, contribute to SUDEP, as evidenced by two cases we report. Further prospective cohort studies are needed to validate these hypotheses.