Ictal Central Apnea Is Predictive of Mesial Temporal Seizure Onset: An Intracranial Investigation.

OBJECTIVE: Ictal central apnea (ICA) is a semiological sign of focal epilepsy, associated with temporal and frontal lobe seizures. In this study, using qualitative and quantitative approaches, we aimed to assess the localizational value of ICA. We also aimed to compare ICA clinical utility in relation to other seizure semiological features of focal epilepsy. METHODS: We analyzed seizures in patients with medically refractory focal epilepsy undergoing intracranial stereotactic electroencephalographic (SEEG) evaluations with simultaneous multimodal cardiorespiratory monitoring. A total of 179 seizures in 72 patients with reliable artifact-free respiratory signal were analyzed. RESULTS: ICA was seen in 55 of 179 (30.7%) seizures. Presence of ICA predicted a mesial temporal seizure onset compared to those without ICA (odds ratio = 3.8, 95% confidence interval = 1.3-11.6, p = 0.01). ICA specificity was 0.82. ICA onset was correlated with increased high-frequency broadband gamma (60-150Hz) activity in specific mesial or basal temporal regions, including amygdala, hippocampus, and fusiform and lingual gyri. Based on our results, ICA has an almost 4-fold greater association with mesial temporal seizure onset zones compared to those without ICA and is highly specific for mesial temporal seizure onset zones. As evidence of symptomatogenic areas, onset-synchronous increase in high gamma activity in mesial or basal temporal structures was seen in early onset ICA, likely representing anatomical substrates for ICA generation. INTERPRETATION: ICA recognition may help anatomoelectroclinical localization of clinical seizure onset to specific mesial and basal temporal brain regions, and the inclusion of these regions in SEEG evaluations may help accurately pinpoint seizure onset zones for resection. ANN NEUROL 2024;95:998-1008.

Stimulation-induced respiratory enhancement in corticothalamic regions.

OBJECTIVE: We aimed to identify corticothalamic areas and electrical stimulation paradigms that optimally enhance breathing. METHODS: Twenty-nine patients with medically intractable epilepsy were prospectively recruited in an epilepsy monitoring unit while undergoing stereoelectroencephalographic evaluation. Direct electrical stimulation in cortical and thalamic regions was carried out using low (<1 Hz) and high (≥10 Hz) frequencies, and low (<5 mA) and high (≥5 mA) current intensities, with pulse width of .1 ms. Electrocardiography, arterial oxygen saturation (SpO2 ), end-tidal carbon dioxide (ETCO2 ), oronasal airflow, and abdominal and thoracic plethysmography were monitored continuously during stimulations. Airflow signal was used to estimate breathing rate, tidal volume, and minute ventilation (MV) changes during stimulation, compared to baseline. RESULTS: Electrical stimulation increased MV in the amygdala, anterior cingulate, anterior insula, temporal pole, and thalamus, with an average increase in MV of 20.8% ± 28.9% (range = 0.2%-165.6%) in 19 patients. MV changes were associated with SpO2 and ETCO2 changes (p < .001). Effects on respiration were parameter and site dependent. Within amygdala, low-frequency stimulation of the medial region produced 78.49% greater MV change (p < .001) compared to high-frequency stimulation. Longer stimulation produced greater MV changes (an increase of 4.47% in MV for every additional 10 s, p = .04). SIGNIFICANCE: Stimulation of amygdala, anterior cingulate gyrus, anterior insula, temporal pole, and thalamus, using certain stimulation paradigms, enhances respiration. Among tested paradigms, low-frequency, low-intensity, long-duration stimulation of the medial amygdala is the most effective breathing enhancement stimulation strategy. Such approaches may pave the way for the future development of neuromodulatory techniques that aid rescue from seizure-related apnea, potentially as a targeted sudden unexpected death in epilepsy prevention method.

Protocols for multimodal polygraphy for cardiorespiratory monitoring in the epilepsy monitoring unit. Part I: Clinical acquisition.

Multimodal polygraphy including cardiorespiratory monitoring in the Epilepsy Monitoring is becoming increasingly important. In addition to simultaneous recording of video and EEG, the combination of these techniques not only improves seizure detection, it enhances patient safety and provides information on autonomic clinical symptoms, which may be contributory to localization of seizure foci. However, there are currently no consensus guidelines, nor adequate information on devices available for multimodal polygraphy for cardiorespiratory monitoring in the Epilepsy Monitoring Unit. Our purpose here is to provide protocols and information on devices for such monitoring. Suggested parameters include respiratory inductance plethysmography (thoraco-abdominal belts for respiratory rate), pulse oximetry and four-lead electrocardiography. Detailed knowledge of devices, their operability and acquisition optimization enables accurate interpretation of signal and differentiation of abnormalities from artifacts. Multimodal polygraphy brings new opportunities for identification of peri-ictal cardiorespiratory abnormalities, and may identify high SUDEP risk individuals.

Protocols for multimodal polygraphy for cardiorespiratory monitoring in the epilepsy monitoring unit. Part II - Research acquisition.

Multimodal polygraphy including cardiorespiratory monitoring is a valuable tool for epilepsy and sudden unexpected death in epilepsy (SUDEP) research. Broader applications in research into stress, anxiety, mood and other domains exist. Polygraphy techniques used during video electroencephalogram (EEG) recordings provide information on cardiac and respiratory changes in the peri-ictal period. In addition, such monitoring in brain mapping during chronic intracranial EEG evaluations has helped the understanding of pathomechanisms that lead to seizure induced cardiorespiratory dysfunction. Our aim here is to provide protocols and information on devices that may be used in the Epilepsy Monitoring Unit, in addition to proposed standard of care data acquisition. These devices include oronasal thermistors, oronasal pressure transducers, capnography, transcutaneous CO2 sensors, and continuous noninvasive blood pressure monitoring. Standard protocols for cardiorespiratory monitoring simultaneously with video EEG recording, may be useful in the study of cardiorespiratory phenomena in persons with epilepsy.

Limbic and paralimbic respiratory modulation: From inhibition to enhancement.

OBJECTIVE: Increased understanding of the role of cortical structures in respiratory control may help the understanding of seizure-induced respiratory dysfunction that leads to sudden unexpected death in epilepsy (SUDEP). The aim of this study was to characterize respiratory responses to electrical stimulation (ES), including inhibition and enhancement of respiration. METHODS: We prospectively recruited 19 consecutive patients with intractable epilepsy undergoing stereotactic electroencephalography (EEG) evaluation from June 2015 to June 2018. Inclusion criteria were patients ≥18 years in whom ES was indicated for clinical mapping of ictal onset or eloquent cortex as part of the presurgical evaluation. ES was carried out at 50 Hz, 0.2 msec, and 1-10 mA current intensity. Common brain regions sampled across all patients were amygdala (AMY), hippocampus (HG), anterior cingulate gyrus (CING), orbitofrontal cortex (OrbF), temporal neocortex (TNC), temporal pole (TP), and entorhinal cortex (ERC). Seven hundred fifty-five stimulations were conducted. Quantitative analysis of breathing signal, that is, changes in breathing rate (BR), depth (TV), and minute ventilation (MV), was carried out during ES using the BreathMetrics breathing waveform analysis toolbox. Electrocardiography, arterial oxygen saturation, end-tidal and transcutaneous carbon dioxide, nasal airflow, and abdominal and thoracic plethysmography were monitored continuously during stimulations. RESULTS: Electrical stimulation of TP and CING (at lower current strengths <3 mA) increased TV and MV. At >7-10 mA, CING decreased TV and MV. On the other hand, decreased TV and MV occurred with stimulation of mesial temporal structures such as AMY and HG. Breathing changes were dependent on stimulation intensity. Lateral temporal, entorhinal, and orbitofrontal cortices did not affect breathing either way. SIGNIFICANCE: These findings suggest that breathing responses other than apnea can be induced by ES. Identification of two regions-the temporal pole and anterior cingulate gyrus-for enhancement of breathing may be important in paving the way to future development of strategies for prevention of SUDEP.

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.

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.

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.

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

OBJECTIVE: To characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy. METHODS: This was a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of sudden unexpected death in epilepsy (SUDEP) in patients ≥18 years old with intractable epilepsy and monitored GCS. Video-EEG, thoracoabdominal excursions, nasal airflow, capillary oxygen saturation, and ECG were analyzed. RESULTS: We studied 148 GCS in 87 patients. Nineteen patients had generalized epilepsy; 65 had focal epilepsy; 1 had both; and the epileptogenic zone was unknown in 2. Ictal central apnea (ICA) preceded GCS in 49 of 121 (40.4%) seizures in 23 patients, all with focal epilepsy. Postconvulsive central apnea (PCCA) occurred in 31 of 140 (22.1%) seizures in 22 patients, with generalized, focal, or unknown epileptogenic zones. In 2 patients, PCCA occurred concurrently with asystole (near-SUDEP), with an incidence rate of 10.2 per 1,000 patient-years. One patient with PCCA died of probable SUDEP during follow-up, suggesting a SUDEP incidence rate 5.1 per 1,000 patient-years. No cases of laryngospasm were detected. Rhythmic muscle artifact synchronous with breathing was present in 75 of 147 seizures and related to stertorous breathing (odds ratio 3.856, 95% confidence interval 1.395-10.663, p = 0.009). CONCLUSIONS: PCCA occurred in both focal and generalized epilepsies, suggesting a different pathophysiology from ICA, which occurred only in focal epilepsy. PCCA was seen in 2 near-SUDEP cases and 1 probable SUDEP case, suggesting that this phenomenon may serve as a clinical biomarker of SUDEP. Larger studies are needed to validate this observation. Rhythmic postictal muscle artifact is suggestive of post-GCS breathing effort rather than a specific biomarker of laryngospasm.

Cortical Structures Associated With Human Blood Pressure Control.

Importance: A better understanding of the role of cortical structures in blood pressure control may help us understand cardiovascular collapse that may lead to sudden unexpected death in epilepsy (SUDEP). Objective: To identify cortical control sites for human blood pressure regulation. Design, Setting, and Participants: Patients with intractable epilepsy undergoing intracranial electrode implantation as a prelude to epilepsy surgery in the Epilepsy Monitoring Unit at University Hospitals Cleveland Medical Center were potential candidates for this study. Inclusion criteria were patients 18 years or older who had electrodes implanted in one or more of the regions of interest and in whom deep brain electrical stimulation was indicated for mapping of ictal onset or eloquent cortex as a part of the presurgical evaluation. Twelve consecutive patients were included in this prospective case series from June 1, 2015, to February 28, 2017. Main Outcomes and Measures: Changes in continuous, noninvasive, beat-by-beat blood pressure parameter responses from amygdala, hippocampal, insular, orbitofrontal, temporal, cingulate, and subcallosal stimulation. Electrocardiogram, arterial oxygen saturation, end-tidal carbon dioxide, nasal airflow, and abdominal and thoracic plethysmography were monitored. Results: Among 12 patients (7 female; mean [SD] age, 44.25 [12.55] years), 9 electrodes (7 left and 2 right) all in Brodmann area 25 (subcallosal neocortex) in 4 patients produced striking systolic hypotensive changes. Well-maintained diastolic arterial blood pressure and narrowed pulse pressure indicated stimulation-induced reduction in sympathetic drive and consequent probable reduction in cardiac output rather than bradycardia or peripheral vasodilation-induced hypotension. Frequency-domain analysis of heart rate and blood pressure variability showed a mixed picture. No other stimulated structure produced significant blood pressure changes. Conclusions and Relevance: These findings suggest that Brodmann area 25 has a role in lowering systolic blood pressure in humans. It is a potential symptomatogenic zone for peri-ictal hypotension in patients with epilepsy.