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

Vilella, Laura; Lacuey, Nuria; Hampson, Johnson P.; Rani, M.R. Sandhya; Loparo, Kenneth A.; Sainju, Rup K.; Friedman, Daniel; Nei, Maromi; Strohl, Kingman P.; Allen, Luke; Scott, Catherine; Gehlbach, Brian K.; Zonjy, Bilal; Hupp, Norma J.; Zaremba, Anita; Shafiabadi, Nassim; Zhao, Xiuhe; Reick-Mitrisin, Victoria; Schuele, Stephan; Ogren, Jennifer A.; Harper, Ronald M.; Diehl, Beate; Bateman, Lisa M.; Devinsky, Orrin; Tanner, Adriana; Tatsuoka, Curtis; Lhatoo, Samden D.

doi:10.3389/fneur.2019.00166

Cited by 71 publications

(112 citation statements)

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“…The number of patients with postictally reduced oxygen saturation is similar or rather low when compared with results of dedicated studies on the effect of seizures on breathing. Bateman et al demonstrated that pulse oximetry will show oxygen desaturations below 90% in 33.2% of all seizures, and such data was well demonstrated in several recent studies, pointing especially at GTCS that lead to a temporary decline in breathing efforts and reduced peripheral oxygenation [32][33][34][35][36][37][38][39]. Overall, postictal respiratory depression may be caused by multiple reasons not limited to anticonvulsive treatment [9].…”

Section: Discussionmentioning

confidence: 90%

Efficacy, Tolerability, and Safety of Concentrated Intranasal Midazolam Spray as Emergency Medication in Epilepsy Patients During Video-EEG Monitoring

et al. 2020

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Background An efficient, well tolerated, and safe emergency treatment with a rapid onset of action is needed to prevent seizure clusters and to terminate prolonged seizures and status epilepticus. Objectives This study aimed to examine the efficacy, tolerability, and safety of intranasal midazolam (in-MDZ) spray in clinical practice. Methods In this retrospective, multicenter observational study, we evaluated all patients with peri-ictal application of in-MDZ during video-EEG monitoring at the epilepsy centers in Frankfurt and Marburg between 2014 and 2017. For every patient, we analyzed the recurrence of any seizure or generalized tonic-clonic seizures after index seizures with and without in-MDZ administration. Treatment-emergent adverse events (TEAEs) were also evaluated. Results In-MDZ was used in 243 patients with epilepsy (mean age 35.5 years; range 5-76 years; 46.5% female) for treatment of 459 seizures. A median dose of in-MDZ 5 mg (i.e., two puffs; range 2.5-15 mg) was administered within a median time from EEG seizure onset until in-MDZ application of 1.18 min [interquartile range (IQR) 1.27], while median time from clinical seizure onset until in-MDZ administration was 1.08 min (IQR 1.19). In-MDZ was given within 1 min after EEG seizure onset in 171 seizures. An intraindividual comparison of seizures with and without application of in-MDZ was feasible in 171 patients, demonstrating that in-MDZ reduced the occurrence of any (Cox proportional-hazard model p < 0.001) and generalized tonic-clonic seizure (Cox proportional-hazard model p = 0.0167) over a period of 24 h. The seizure-free timespan was doubled from a median of 5.0 h in controls to a median of 10.67 h after in-MDZ administration. We additionally clustered in-MDZ administrations for the 119 patients who received in-MDZ more than once, comparing them with the index cases without in-MDZ. Even when considering subsequent seizures with in-MDZ administration, a patient receiving in-MDZ is still half as likely to incur another seizure in the upcoming 24 h as compared with when the same patient does not receive in-MDZ (hazard ratio 0.50; 95% CI 0.42-0.60; p < 0.01). In-MDZ was well tolerated without major adverse events. The most common side effects were irritation of the nasal mucosa [37 cases (8.1%)], prolonged sedation [26 cases (5.7%)], and nausea and vomiting [12 cases (2.6%)]. A decline in oxygen saturation was measured after 78 seizures (17%). Conclusion We conclude that in-MDZ is a safe and efficient treatment option to prevent short-term recurrence of seizures. In-MDZ can be administered very quickly by trained staff within 1-2 min after seizure onset. No major cardiocirculatory or respiratory adverse events were observed.

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Section: Discussionmentioning

confidence: 90%

Efficacy, Tolerability, and Safety of Concentrated Intranasal Midazolam Spray as Emergency Medication in Epilepsy Patients During Video-EEG Monitoring

et al. 2020

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“…In our study, we found no effect of either class of drug on PCCA, suggesting that PCCA may have a higher threshold for prevention effects than ICA or else, the number of PCCA seizures was too small for an effect to be seen. A recent study with a larger number of seizures (558 in 218 patients) found that longer ICA duration was related to PCCA presence [27], and therefore, preventing ICA may have relevance in the prevention of PCCA.…”

Section: Discussionmentioning

confidence: 98%

“…We prospectively studied 476 seizures in 204 patients. Of these, 312 seizures were part of a study of ICA incidence [6]; 148 generalized clonic seizures (GCS) were reported in another partially overlapping study that analyzed ICA and PCCA incidences [27,28]. All were consented participants in the National Institute of Neurological Disorders and Stroke (NINDS) Center for SUDEP Research's Autonomic and Imaging Biomarkers of SUDEP multicenter project (U01-NS090407) and its precursor, the Prevention and Risk Identification of SUDEP Mortality (PRISM) Project (P20NS076965).…”

Section: Patients and Clinical Settingsmentioning

confidence: 99%

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

Lacuey

Martins

Vilella³

et al. 2019

Epilepsy & Behavior

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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.

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“…In a study of electroencephalography (EEG), oxygen saturation levels, thoracoabdominal excursions, and electro-cardiography (ECG) with epilepsy patients, central apneas occurred during generalized convulsive seizures and post-ictal periods [4]. In a larger cohort of patients with focal epilepsy, central apneas were reported during and after 37% of seizures [5]. In a heart-monitoring study of implantable loop recorders in epilepsy patients over 24 months, peri-ictal cardiac arrhythmias were observed.…”

Section: Introductionmentioning

confidence: 99%

Directed Connectivity Analysis of the Neuro-Cardio- and Respiratory Systems Reveals Novel Biomarkers of Susceptibility to SUDEP

Hutson

Rezaei

Gautier

et al. 2020

IEEE Open J. Eng. Med. Biol.

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The paper describes the results from a unique experimental and analytical study in a well-controlled animal model of Sudden Unexpected Death in Epilepsy (SUDEP). As the name implies, SUDEP is difficult to impossible to study in humans due to the uncertainty in the timing of death occurrence over years. It is much easier to do this with animals as they also have much shorter life span. The animal model we employed is one of two most prominent animal models of SUDEP. Our aim was to elucidate potential impairments in the functional connectivity between the brain, heart and lungs that could contribute to our better understanding of the underlying causes of SUDEP. This is the first study of its kind in SUDEP and, as far as we know, the first multivariate study between the heart, brain and lungs, part of the emerging field of organomics. In this contribution, we report for the first time results from tri-organ analysis of concurrent electroencephalographic, electrocardiographic and plethysmographic recordings in a control group (wild-type healthy mice) and a group of mice genetically predisposed to SUDEP and epileptic seizures. We were able to produce strong statistical evidence (p<0.001) that SUDEP-prone animals exhibit statistically significant inter-organ (brain, heart and lungs) abnormalities in specific functional afferent and efferent interactions. The graphic abstract is a schematic representation of the statistically significant (a) decreased and (b) increased neuro-cardio-respiratory network interactions of the KO compared to WT mice averaged over frequencies of 1-200 Hz. The thickness of arrows corresponds to the magnitude, and the (+) or (-) sign above the arrows to the signs of the difference of the ssGPDC values of KO from the ones of WT animals for each interaction. We also show the impact of epileptic seizures on the dynamics of these functional connectivities. These results suggest that the novel measures of neuro-cardio-respiratory connectivity we developed from network analysis in the frequency domain do shed light on potential pathophysiological mechanisms of SUDEP and ictogenesis, could be utilized as biomarkers of susceptibility to SUDEP and seizures, as well as in the assessment and improvement of the efficacy of current and future intervention strategies for treatment of seizures and risk to SUDEP.

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

Cited by 71 publications

References 53 publications

Efficacy, Tolerability, and Safety of Concentrated Intranasal Midazolam Spray as Emergency Medication in Epilepsy Patients During Video-EEG Monitoring

Efficacy, Tolerability, and Safety of Concentrated Intranasal Midazolam Spray as Emergency Medication in Epilepsy Patients During Video-EEG Monitoring

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

Directed Connectivity Analysis of the Neuro-Cardio- and Respiratory Systems Reveals Novel Biomarkers of Susceptibility to SUDEP

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