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 \u3c 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

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

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

Reduced Condensing and Ordering Effects by 7‑Ketocholesterol and 5β,6β-Epoxycholesterol on DPPC Monolayers

The exposure of organic-coated marine aerosols containing cholesterol (Chol) to radiation and/or an oxidizing atmosphere results in the formation of oxidized derivatives or oxysterols and will likely change aerosol surface properties. However, the intermolecular interactions between oxysterols and other lipid components and their influence on the surface properties of marine aerosols are not well-known. To address this question, the interfacial behavior and domain morphology of model Langmuir monolayers of two ring-substituted oxysterols, 7-ketocholesterol (7-KChol) and 5β,6β-epoxycholesterol (5,6β-EChol), mixed with 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phosphocholine (DPPC) were investigated by means of compression isotherms and Brewster angle microscopy (BAM) over a broad range of surface pressures and sterol molar ratios. Mixed DPPC/cholesterol (Chol) monolayers were also measured for comparison. The results of compression experiments showed that the condensing effect induced on mixed DPPC/sterol monolayers at low surface pressures and for intermediate molar ratios (0.3 ≤ <i>X</i>_sterol ≤ 0.7) was weaker for oxysterols than for Chol. Additionally, mixed DPPC/oxysterol monolayers exhibited markedly smaller (∼2–3-fold) interfacial rigidity. Examination of the excess free energy of mixing further revealed that DPPC monolayers containing 7-KChol and Chol were thermodynamically more stable at high surface pressures than those with 5,6β-EChol, indicating that the strength of interactions between DPPC and 5,6β-EChol was the smallest. Finally, BAM images in the LE–LC phase of DPPC revealed that in comparison to Chol the addition of small amounts of oxysterols results in larger and less numerous domains, showing that oxysterols are not as effective in fluidizing the condensed phase of DPPC. Taken together, these results suggest that the strength of van der Waals interactions of DPPC alkyl chains with sterols follows the sterol hydrophobicity, with Chol being the most hydrophobic and oxysterols more hydrophilic due to their ketone and epoxy moieties. The difference in the condensing ability and stability of 7-KChol and 5,6β-EChol on DPPC likely originates from the distinct molecular structure and position of oxidation on the steroid nucleus. As suggested by recent MD simulations, depending on the oxidation position, ring-substituted oxysterols have a broader angular distribution of orientation than Chol in bilayers, which could be responsible for the observed reduction in condensing ability

Data from: Postconvulsive central apnea as a biomarker for sudden unexpected death in epilepsy (SUDEP)

Objective: To characterize peri-ictal apnea and post-ictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy. Methods: Prospective, multi-center epilepsy monitoring study of autonomic and breathing biomarkers of SUDEP in patient’s ≥18 years old with intractable epilepsy and monitored GCS. Video EEG, thoraco-abdominal excursions, nasal airflow, capillary oxygen saturation and electrocardiography were analyzed. Results: We studied 148 GCS in 87 patients. Nineteen patients had generalized epilepsy, 65 had focal, one had both and in two, the epileptogenic zone was unknown. Ictal central apnea (ICA) preceded GCS in 49/121 (40.4%) seizures in 23 patients, all with focal epilepsy. Post-convulsive central apnea (PCCA) occurred in 31/140 (22.1%) seizures in 22 patients, with generalized, focal or unknown epileptogenic zones. In two patients, PCCA occurred concurrently with asystole (near-SUDEP), with an incidence rate of 10.2/1000 patient-years. One PCCA patient died of probable SUDEP during follow up, suggesting a SUDEP incidence rate 5.1 per 1000 patient-years. No cases of laryngospasm were detected. Rhythmical muscle artifact synchronous with breathing was present in 75/147 seizures, and related to stertorous breathing (OR 3.856, 95%CI 1.395-10.663, p=0.009). Conclusions: PCCA occurred in both focal and generalized epilepsies, suggesting a different pathophysiology from ICA, which only occurred in focal epilepsy. PCCA was seen in two near-SUDEP and one probable SUDEP case, suggesting that this phenomenon may serve as a clinical biomarker of SUDEP. Larger studies are needed to validate this observation. Rhythmical post-ictal muscle artifact is suggestive of post-GCS breathing effort, rather than a specific biomarker of laryngospasm

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

ObjectiveTo characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy.MethodsThis 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.ResultsWe 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).ConclusionsPCCA 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

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Near-SUDEP Event in Patient 1

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