ABSTRACT
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.
Subject(s)
Arrhythmias, Cardiac , Electroencephalography , Humans , Female , Male , Adult , Arrhythmias, Cardiac/epidemiology , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/diagnosis , Incidence , Middle Aged , Prospective Studies , Sudden Unexpected Death in Epilepsy/epidemiology , Seizures/epidemiology , Seizures/physiopathology , Epilepsy, Generalized/epidemiology , Epilepsy, Generalized/physiopathology , Aged , Young Adult , Electrocardiography , AdolescentABSTRACT
Sudden unexpected death in epilepsy (SUDEP) is a tragic and unexpected cause of death in patients with a known diagnosis of epilepsy. It occurs in up to 6.3 to 9.3/1,000 patients with drug-resistant epilepsy. The main three risk factors associated with SUDEP are the presence of generalized tonic-clonic seizures, the presence of a seizure in the past year, and an intellectual disability. There are several mechanisms that can result in SUDEP. The most likely sequence of events appears to be a convulsive seizure, overactivation of the autonomic nervous system, cardiorespiratory dysfunction, and death. While the risk of SUDEP is relatively high in patients with drug-resistant epilepsy, studies indicate that more than 50% of patients and caregivers are unaware of the diagnosis. Counseling about the diagnosis and preventative measures at the time of diagnosis is important. There are numerous interventions that may reduce the risk of SUDEP, including conservative measures such as nocturnal surveillance with a bed partner (where applicable) and automated devices. Optimizing seizure control with antiseizure medications and surgical interventions can result in a reduced risk of SUDEP.
Subject(s)
Drug Resistant Epilepsy , Epilepsy , Sudden Unexpected Death in Epilepsy , Humans , Sudden Unexpected Death in Epilepsy/etiology , Sudden Unexpected Death in Epilepsy/prevention & control , Death, Sudden/epidemiology , Death, Sudden/etiology , Death, Sudden/prevention & control , Epilepsy/epidemiology , Seizures/drug therapy , Risk FactorsABSTRACT
OBJECTIVE: Prolonged postictal generalized electroencephalographic suppression (PGES) is a potential biomarker for sudden unexpected death in epilepsy (SUDEP), which may be associated with dysfunctional autonomic responses and serotonin signaling. To better understand molecular mechanisms, PGES duration was correlated to 5HT1A and 5HT2A receptor protein expression and RNAseq from resected hippocampus and temporal cortex of temporal lobe epilepsy patients with seizures recorded in preoperative evaluation. METHODS: Analyses included 36 cases (age = 14-64 years, age at epilepsy onset = 0-51 years, epilepsy duration = 2-53 years, PGES duration = 0-93 s), with 13 cases in all hippocampal analyses. 5HT1A and 5HT2A protein was evaluated by Western blot and histologically in hippocampus (n = 16) and temporal cortex (n = 9). We correlated PGES duration to our previous RNAseq dataset for serotonin receptor expression and signaling pathways, as well as weighted gene correlation network analysis (WGCNA) to identify correlated gene clusters. RESULTS: In hippocampus, 5HT2A protein by Western blot positively correlated with PGES duration (p = .0024, R2 = .52), but 5HT1A did not (p = .87, R2 = .0020). In temporal cortex, 5HT1A and 5HT2A had lower expression and did not correlate with PGES duration. Histologically, PGES duration did not correlate with 5HT1A or 5HT2A expression in hippocampal CA4, dentate gyrus, or temporal cortex. RNAseq identified two serotonin receptors with expression that correlated with PGES duration in an exploratory analysis: HTR3B negatively correlated (p = .043, R2 = .26) and HTR4 positively correlated (p = .049, R2 = .25). WGCNA identified four modules correlated with PGES duration, including positive correlation with synaptic transcripts (p = .040, Pearson correlation r = .52), particularly potassium channels (KCNA4, KCNC4, KCNH1, KCNIP4, KCNJ3, KCNJ6, KCNK1). No modules were associated with serotonin receptor signaling. SIGNIFICANCE: Higher hippocampal 5HT2A receptor protein and potassium channel transcripts may reflect underlying mechanisms contributing to or resulting from prolonged PGES. Future studies with larger cohorts should assess functional analyses and additional brain regions to elucidate mechanisms underlying PGES and SUDEP risk.
Subject(s)
Epilepsy, Temporal Lobe , Epilepsy , Sudden Unexpected Death in Epilepsy , Humans , Adolescent , Young Adult , Adult , Middle Aged , Infant, Newborn , Infant , Child, Preschool , Child , Serotonin , Epilepsy, Temporal Lobe/genetics , Epilepsy, Temporal Lobe/surgery , Electroencephalography/methods , Epilepsy/pathology , Temporal Lobe/pathology , Hippocampus/pathology , Receptors, Serotonin/geneticsSubject(s)
Epilepsy , Sudden Unexpected Death in Epilepsy , Death, Sudden , Epilepsy/diagnosis , Humans , Retrospective StudiesABSTRACT
Convulsive seizures are the most consistently reported risk factor for SUDEP. However, the precise mechanisms by which convulsive seizures trigger fatal cardiopulmonary changes are still unclear. Additionally, it is not clear why some seizures cause death when most do not. This article reviews the physiologic changes that occur during and after convulsive seizures and how these may contribute to SUDEP. Seizures activate specific cortical and subcortical regions that can cause potentially lethal cardiorespiratory changes. Clinical factors, including sleep state, medication treatment and withdrawal, positioning and posturing during seizures, and underlying structural or genetic conditions may also affect specific aspects of seizures that may contribute to SUDEP. While seizure control, either through medication or surgical treatment, is the primary intervention that reduces SUDEP risk, unfortunately, seizures cannot be fully controlled despite maximal treatment in a significant proportion of people with epilepsy. Thus specific interventions to prevent adverse seizure-related cardiopulmonary consequences are needed. The potential roles of repositioning/stimulation after seizures, oxygen supplementation, cardiopulmonary resuscitation and clinical treatment options in reducing SUDEP risk are explored. Ultimately, understanding of these factors may lead to interventions that could reduce or prevent SUDEP.
Subject(s)
Epilepsy , Sudden Unexpected Death in Epilepsy , Death, Sudden/etiology , Death, Sudden/prevention & control , Epilepsy/therapy , Humans , Risk Factors , Seizures , SleepABSTRACT
Agenesis of the corpus callosum is a brain malformation that can occur in isolation or in conjunction with other congenital or developmental defects. The clinical sequelae of this condition include epilepsy, cognitive deficits, developmental delay, and various neurological and psychiatric disorders. Here we present the case of a patient with congenital complete agenesis of the corpus callosum and medically refractory epilepsy who underwent stereoelectroencephalography. This identified a left frontal ictal focus and revealed that contralateral spread occurred though the anterior commissure, a rare and interesting occurrence. Left frontal resection resulted in significant improvement. This demonstrates the role of the anterior commissure in ictal spread and the potential for novel methods of seizure spread in patients with temporal lobe epilepsy that must be considered in a surgical approach.
ABSTRACT
OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality in epilepsy. The aim of this study is to evaluate the validity of the SUDEP-7 inventory and its components as tools for predicting SUDEP risk, and to develop and validate an improved inventory. METHODS: The study included 28 patients who underwent video-electroencephalography (EEG) monitoring and later died of SUDEP, and 56 age- and sex-matched control patients with epilepsy. The SUDEP-7 score, its individual components, and an alternative inventory were examined as predictors of SUDEP. RESULTS: SUDEP-7 scores were significantly higher among SUDEP patients compared with controls, both at time of admission (p = 0.024) and most recent follow-up (p = 0.016). SUDEP-7 scores declined only among controls, who demonstrated reduced seizure frequency. Seizure freedom after epilepsy surgery was also associated with survival. Several components of the SUDEP-7 inventory were independently associated with higher risk of SUDEP, including more than three generalized tonic-clonic (GTC) seizures (p = 0.002), one or more GTC seizures (p = 0.001), or one or more seizures of any type within the last year (p = 0.013), and intellectual disability (p = 0.031). In stepwise regression models, SUDEP-7 scores did not enhance the prediction of SUDEP over either GTC seizure frequency or seizure frequency alone. A novel SUDEP-3 inventory comprising GTC seizure frequency, seizure frequency, and intellectual disability (p < 0.001) outperformed the SUDEP-7 inventory (p = 0.010) in predicting SUDEP. SIGNIFICANCE: Our findings demonstrate the limitations of the SUDEP-7 inventory. We propose a new three-item SUDEP-3 inventory, which predicts SUDEP better than the SUDEP-7.
Subject(s)
Sudden Unexpected Death in Epilepsy , Adolescent , Adult , Electroencephalography , Epilepsy/diagnosis , Epilepsy/mortality , Epilepsy/surgery , Epilepsy, Generalized/mortality , Epilepsy, Tonic-Clonic/mortality , Female , Follow-Up Studies , Humans , Intellectual Disability/mortality , Male , Middle Aged , Predictive Value of Tests , Retrospective Studies , Seizures/mortality , Survival Analysis , Young AdultABSTRACT
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.
ABSTRACT
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.
ABSTRACT
OBJECTIVE: This study was undertaken to identify clinical factors associated with seizure freedom after magnetic resonance-guided laser interstitial thermal therapy (MRgLiTT) in temporal lobe epilepsy patients with unilateral mesial temporal sclerosis (MTS). METHODS: We identified 56 patients with magnetic resonance imaging-defined MTS who underwent MRgLiTT with at least 1 year of follow-up. Primary outcome was seizure freedom at 1 year. We examined the association of seizure freedom and the following clinical factors: age at surgery, gender, history of febrile seizures, history of focal to bilateral tonic-clonic seizures, duration of epilepsy at the time of surgery, frequency of interictal epileptiform discharges (IEDs), seizure frequency, and presence of bilateral IEDs. RESULTS: Thirty-five (62.5%) patients were seizure-free at 1 year. The presence of bilateral IEDs and age at surgery were associated with 1-year seizure freedom after MRgLiTT. The presence of bilateral IEDS was associated with lower odds of seizure freedom (odds ratio [OR] = .05, 95% confidence interval [CI] = .01-.46, p = .008), whereas increasing age at surgery was associated with increased odds of seizure freedom (OR = 1.10, 95% CI = 1.03-1.19, p = .009). SIGNIFICANCE: This study demonstrates associations between presence of bilateral IEDs and age at surgery and seizure freedom at 1 year after MRgLiTT.
Subject(s)
Epilepsy, Temporal Lobe/therapy , Laser Therapy/methods , Treatment Outcome , Adult , Drug Resistant Epilepsy/therapy , Female , Humans , Hyperthermia, Induced/methods , Magnetic Resonance Imaging , Male , Middle Aged , Retrospective Studies , Seizures/prevention & controlABSTRACT
OBJECTIVE: We compared long-term seizure outcome, neuropsychological outcome, and occupational outcome of anterior temporal lobectomy (ATL) with and without sparing of mesial structures to determine whether mesial sparing temporal lobectomy prevents memory decline and thus disability, with acceptable seizure outcome. METHODS: We studied patients (nâ¯=â¯21) and controls (nâ¯=â¯21) with no evidence of mesial temporal sclerosis (MTS) on MRI who had surgery to treat drug-resistant epilepsy. Demographic and pre- and postsurgical clinical characteristics were compared. Patients had neuropsychological assessment before and after surgery. Neuropsychological analyses were limited to patients with left-sided surgery and available data (nâ¯=â¯14 in each group) as they were at risk of verbal memory impairment. The California Verbal Learning Test II (CVLT-II) (sum of trials 1-5, delayed free recall) and the Logical Memory subtest of the Wechsler Memory Scale III or IV (WMS-III or WMS-IV) (learning and delayed recall of prose passages) were used to assess verbal episodic learning and memory. Seizure and occupational outcomes were assessed. RESULTS: The chance of attaining seizure freedom was similar in the two groups, so sparing mesial temporal structures did not lessen the chance of stopping seizures. Sparing mesial temporal structures mitigated the extent of postoperative verbal memory impairment, though some of these individuals suffered decline as a consequence of surgery. Occupational outcome was similar in both groups. SIGNIFICANCE: Mesial temporal sparing resections provide a similar seizure outcome as ATL, while producing a better memory outcome. Anterior temporal lobectomy including mesial structure resection did not increase the risk of postoperative disability.
Subject(s)
Drug Resistant Epilepsy , Epilepsy, Temporal Lobe , Anterior Temporal Lobectomy , Drug Resistant Epilepsy/surgery , Epilepsy, Temporal Lobe/surgery , Hippocampus/surgery , Humans , Neuropsychological Tests , Temporal Lobe/surgery , Treatment OutcomeABSTRACT
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.
Subject(s)
Brain Stem/physiopathology , Epilepsy, Generalized/physiopathology , Posture/physiology , Respiration , Seizures/physiopathology , Adolescent , Adult , Aged , Electroencephalography , Epilepsy, Generalized/diagnosis , Female , Humans , Male , Middle Aged , Seizures/diagnosis , Severity of Illness Index , Young AdultABSTRACT
In the appropriate clinical setting, the presence of interictal epileptiform abnormalities (IEAs) on EEG supports the diagnosis of epilepsy. However, the absence of epileptiform abnormalities on EEG cannot exclude a diagnosis of epilepsy. The goal of our study is to determine the prevalence of IEAs in patients with confirmed epilepsy, determined by having at least one epileptic seizure recorded during video-EEG monitoring. In addition, we aimed to analyze the time to recording IEAs and seizures in correlation with patient age, duration of epilepsy, and seizure focus localization. We retrospectively evaluate EEG data for all patients admitted to the epilepsy monitoring unit over a 2-year period. Of the 151 patients included, 129 (86%) patients had IEAs and 22 (14%) patients had no IEAs. Age and duration of epilepsy were not independent predictors of whether IEAs were present on EEG. The duration of EEG monitoring and time to first seizure did not influence IEA detection. In patients with IEAs, the mean time to the first IEA was 1.57â¯days. By day 5, IEAs were observed in 95% of the patients who had IEAs present on EEG (82% of total patients). The majority (75%) of patients also had their first seizure by day 5. We concluded that five days of EEG recording is optimal to detect IEAs and seizures, and that more prolonged recording has a low yield. Failure to detect IEAs should be interpreted with caution, and is not useful for diagnostic purposes.
Subject(s)
Electroencephalography , Epilepsy , Epilepsy/diagnosis , Humans , Monitoring, Physiologic , Retrospective Studies , Seizures/diagnosisABSTRACT
Progressive myoclonic epilepsy (PME) is characterized by prominent myoclonus and generalized or focal seizures. A recently described novel KCNC1 mutation is associated with a specific phenotype of progressive myoclonic epilepsy, which has been defined as myoclonic epilepsy and ataxia due to potassium channel mutation (MEAK). Our case illustrates a typical presentation of this disease and the potential for misdiagnosis as idiopathic generalized epilepsy during the early phase of the disease. Unique findings that may suggest an alternative diagnosis are a progressive myoclonus, prominent ataxia/dysmetria on examination, and abnormally high amplitude in the sensory evoked potential recording. We also report a brief review of the existing literature on MEAK. Early and accurate diagnosis with genetic testing may significantly help in counseling patients and families.
Subject(s)
Myoclonic Epilepsies, Progressive/diagnosis , Myoclonic Epilepsies, Progressive/physiopathology , Shaw Potassium Channels/genetics , Adolescent , Ataxia/diagnosis , Ataxia/genetics , Ataxia/physiopathology , Electroencephalography , Epilepsy, Generalized/diagnosis , Genetic Testing , Humans , Magnetic Resonance Imaging , Male , Myoclonic Epilepsies, Progressive/geneticsABSTRACT
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.
Subject(s)
Apnea/complications , Apnea/metabolism , Death, Sudden/etiology , Epilepsy/complications , Epilepsy/metabolism , Serotonin/metabolism , Adolescent , Adult , Aged , Apnea/physiopathology , Electroencephalography/methods , Epilepsy/physiopathology , Female , Humans , Male , Middle Aged , Seizures/complications , Seizures/physiopathologyABSTRACT
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 (pâ¯=â¯0.02). In the BZD group, ICA duration was significantly shorter than in the control group (pâ¯=â¯0.02), as was postictal generalized EEG suppression (PGES) duration (pâ¯=â¯0.021). Both SRI and BZD groups were associated with smaller seizure-associated oxygen desaturation (pâ¯=â¯0.009; pâ¯âªâ¯0.001). Neither presence nor duration of PCCA was significantly associated with SRI or BZD (pâ¯â«â¯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.
Subject(s)
Benzodiazepines/therapeutic use , Epilepsy/drug therapy , Hypoxia/drug therapy , Seizures/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sleep Apnea, Central/drug therapy , Adolescent , Adult , Aged , Cohort Studies , Electroencephalography/methods , Epilepsy/physiopathology , Female , Humans , Hypoxia/physiopathology , Male , Middle Aged , Oximetry/methods , Prospective Studies , Seizures/physiopathology , Sleep Apnea, Central/physiopathology , Sudden Unexpected Death in Epilepsy/prevention & control , Young AdultABSTRACT
BACKGROUND: MR Imaging has shown atrophy in brainstem regions that were linked to autonomic dysfunction in epilepsy patients. The brainstem projects to and modulates the activation state of several wide-spread cortical/subcortical regions. The goal was to investigate 1. Impact of brainstem atrophy on gray matter connectivity of cortical/subcortical structures and autonomic control. 2. Impact on the modulation of cortical/subcortical functional connectivity. METHODS: 11 controls and 18 patients with non-lesional focal epilepsy (FE) underwent heart rate variability (HRV) measurements and a 3â¯T MRI (T1 in all subjects, task-free fMRI in 7 controls/ 12 FE). The brainstem was extracted, and atrophy assessed using deformation-based-morphometry. The age-corrected z-scores of the mean Jacobian determinants were extracted from 71 5x5x5 mm grids placed in brainstem regions associated with autonomic function. Cortical and non-brainstem subcortical gray matter atrophy was assessed with voxel-based-morphometry and mean age corrected z-scores of the modulated gray matter volumes extracted from 380 cortical/subcortical rois. The profile similarity index was used to characterize the impact of brainstem atrophy on gray matter connectivity. The fMRI was preprocessed in SPM12/Conn17 and the BOLD signal extracted from 398 ROIs (16 brainstem). A dynamic task-free analysis approach was used to identify activation states. Connectivity HRV relationship were assessed with Spearman rank correlations. RESULTS: HRV was negatively correlated with reduced brainstem right hippocampus/parahippocampus gray matter connectivity in controls (pâ¯<â¯.05, FDR) and reduced brainstem to right parietal cortex, lingual gyrus, left hippocampus/amygdala, parahippocampus, temporal pole, and bilateral anterior thalamus connectivity in FE (pâ¯<â¯.05, FDR). Dynamic task-free fMRI analysis identified 22 states. The strength of the functional brainstem/cortical connectivity of state 15 was negatively associated with HRV (râ¯=â¯-0.5, pâ¯=â¯.03) and positively with decreased brainstem-cortical (0.49, pâ¯=â¯.03) gray matter connectivity. CONCLUSION: The findings of this small pilot study suggest that impaired brainstem-cortex gray matter connectivity in FE negatively affects the brainstem's ability to control cortical activation.
Subject(s)
Brain Stem/pathology , Brain Stem/physiopathology , Connectome , Epilepsies, Partial/pathology , Epilepsies, Partial/physiopathology , Gray Matter/pathology , Gray Matter/physiopathology , Heart Rate/physiology , Adult , Atrophy/pathology , Brain Stem/diagnostic imaging , Electrocardiography , Epilepsies, Partial/diagnostic imaging , Female , Gray Matter/diagnostic imaging , Humans , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
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.
ABSTRACT
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.