Elevated CK-MB mass and plasma brain-type natriuretic peptide concentrations following convulsive seizures in children and adolescents: Possible evidence of subtle cardiac dysfunction

Purpose:   To evaluate the presence of myocardial injury during convulsive seizures in children and adolescents by determining serum concentrations of cardiac troponin I (cTnI), creatine kinase-MB mass (CK-MB mass), and plasma brain-type natriuretic peptide (BNP).
Methods:   Thirty-one children (20 boys; mean age, 6.6 ± 5.34 years) with convulsive seizures and 50 healthy children were enrolled. Serum cTnI, CK-MB mass, and plasma BNP concentrations were analyzed 12 h after the seizure and repeated 7 days thereafter in the patient group and obtained one time in the control group.
Results:   The difference between serum concentrations of cTnI obtained 12 h and 7 days after the seizure was not statistically significant. cTnI levels 12 h postictal and those in control subjects also were not significantly different. CK-MB mass and BNP at the 12th h were higher than those obtained on the 7th day (p  <  0 . 05 and p  <  0 . 001, respectively). Children with seizures had increased levels of CK-MB mass and BNP 12 h after seizure than control subjects (p  <  0 . 05 and p  <  0 . 001, respectively). The results of electrocardiography (ECG) recordings, which were obtained up to 30 min after seizure activity, were completely normal in patients with seizure.
Conclusion:   Normal cTnI levels are not indicative of overt myocardial necrosis in patients with seizures. However, markedly elevated BNP concentrations together with elevated CK-MB mass levels do suggest subtle cardiac dysfunction in patients with seizure, and further large-scale studies are warranted.     

Automated video-based detection of nocturnal motor seizures in children

Seizure detection devices can improve epilepsy care, but wearables are not always tolerated. We previously demonstrated good performance of a real-time video-based algorithm for detection of nocturnal convulsive seizures in adults with learning disabilities. The algorithm calculates the relative frequency content based on the group velocity reconstruction from video-sequence optical flow. We aim to validate the video algorithm on nocturnal motor seizures in a pediatric population. We retrospectively analyzed the algorithm performance on a database including 1661 full recorded nights of 22 children (age = 3-17 years) with refractory epilepsy at home or in a residential care setting. The algorithm detected 118 of 125 convulsions (median sensitivity per participant = 100%, overall sensitivity = 94%, 95% confidence interval = 61%-100%) and identified all 135 hyperkinetic seizures. Most children had no false alarms; 81 false alarms occurred in six children (median false alarm rate [FAR] per participant per night = 0 [range = 0-0.47], overall FAR = 0.05 per night). Most false alarms (62%) were behavior-related (eg, awake and playing in bed). Our noncontact detection algorithm reliably detects nocturnal epileptic events with only a limited number of false alarms and is suitable for real-time use.     

Severe postictal laryngospasm as a potential mechanism for sudden unexpected death in epilepsy: a near-miss in an EMU

A 42-year-old man with refractory epilepsy experienced a 1-min generalized tonic-clonic seizure followed by persistent inspiratory stridor and cyanosis while being monitored in our epilepsy monitoring unit (EMU). Although his cardiac parameters remained stable throughout the event, the patient's respiratory status rapidly declined, despite the urgent administration of oxygen via bag-valve-mask. He was subsequently intubated by the emergency code team, who noted severe laryngospasm while trying to insert the endotracheal tube. The patient was successfully resuscitated. This monitored case demonstrates that postictal laryngospasm may represent another potential cause of sudden unexpected death in epilepsy (SUDEP).     

Repeated amygdala-kindled seizures induce ictal rebound tachycardia in rats

It is thought that cardiovascular changes may contribute to sudden death in patients with epilepsy. To examine cardiovascular alterations that occur during epileptogenesis, we measured the heart rate of rats submitted to the electrical amygdala kindling model. Heart rate was recorded before, during, and after the induced seizures. Resting heart rate was increased in stages 1, 3, and 5 as compared with the unstimulated control condition. In the initial one third of the seizures, we observed bradycardia, which increased in intensity with increasing stage and was blocked by injecting methyl atropine. During stage 5 seizures, a rebound tachycardia was observed that also increased in intensity with increasing number of seizures. This study demonstrated the influence of seizure frequency on cardiac autonomic modulation, providing a basis for discussion of potential mechanisms that cause patients with epilepsy to die suddenly.     

Severe pulmonary congestion in a near miss at the first seizure: Further evidence for respiratory dysfunction in sudden unexpected death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) is the most important direct seizure-related cause of death, and most cases usually occur in patients with intractable, longstanding epilepsy.Suspected mechanisms for SUDEP include central and obstructive apnea, cardiac arrhythmia, postictal respiratory arrest, and primary cessation of brain activity. We report a patient who experienced a near SUDEP following his first prolonged tonic–clonic seizure requiring intubation. Chest X-ray examination showed severe bilateral congestion of the middle and superior pulmonary fields and an enlarged heart. Observations of pulmonary compromise in near-miss patients are extremely rare. Our patient showed marked cyanosis and respiratory distress after the index seizure, in agreement with the view that respiratory distress was the primary etiology in this case. Moreover, this observation confirms that SUDEP is not exclusively an issue for patients with chronic, uncontrolled epilepsy.     

Anoxia–ischemia: A mechanism of seizure termination in ictal asystole

Cerebral anoxia–ischemia (CAI) is a potent inhibitor of cerebral hyperactivity and a potential mechanism of seizure self-termination. Prolonged ictal asystole (IA) invariably leads to CAI and has been implicated as a potential cause of sudden unexplained death in epilepsy (SUDEP). IA was seen in eight consecutive patients (0.12% of all patients monitored). Ten of their seizures with IA had evidence of CAI on electroencephalography (EEG), manifested by bilateral hypersynchronous slowing (BHS), and were compared to 18 seizures without signs of CAI. The ictal EEG pattern resolved in all 10 CAI events with onset of the BHS. The period from IA onset to seizure end was reduced in events with BHS compared to events without BHS (10.5 s vs. 28.3 s, respectively; p = 0.005), and the total seizure duration tended to be shorter. Anoxia–ischemia as a result of IA may represent an effective endogenous mechanism for seizure termination and may explain why the hearts of patients with ictal asystole reported to date in the literature resumed beating spontaneously.     

Sudden unexpected death in epilepsy: people with nocturnal seizures may be at highest risk

Purpose: Most people with epilepsy who die suddenly and whose death is attributed to sudden unexpected death in epilepsy (SUDEP) are found in or by the bed for unknown reasons. We assessed whether those with sleep‐related SUDEP were more likely to have nocturnal seizures, and whether seizure patterns (diurnal vs. nocturnal) differed from people dying suddenly and living controls with epilepsy. Methods: Seizure patterns in a cohort of 154 people with epilepsy who died suddenly and after autopsy conformed to the definition of SUDEP and 616 controls living with epilepsy were classified as having “exclusively diurnal” or “nocturnal seizures.” Comparisons were made between the groups. SUDEP was classified as sleep‐related or non–sleep‐related based on eyewitness accounts and the circumstances surrounding death. Key Findings: SUDEP was primarily a sleep‐related (58%) and unwitnessed (86%) event. If sleep‐related, SUDEP was more likely to be unwitnessed [odds ratio (OR) 4.4, 95% confidence interval (CI) 1.6–12]. Those with sleep‐related SUDEP were more likely to have a history of nocturnal seizures than those who had non–sleep‐related SUDEP (OR 3.6, 95% CI 1.4–9.4). Those who died were more likely to have a history of nocturnal seizures than living controls (OR 3.9, 95% CI 2.5–6.0). After correction for previously established SUDEP risk factors ( Langan et al., 2005 ), the presence of nocturnal seizures remained significant (OR 2.6, 95% CI 1.3–5.0). Significance: Nocturnal seizures seem to be an independent risk factor for SUDEP. These findings underscore the importance of preventive measures, which may include night supervision.     

Respiratory changes with seizures in localization‐related epilepsy: Analysis of periictal hypercapnia and airflow patterns

Purpose: The rate of sudden unexpected death in epilepsy (SUDEP) approaches 9 per 1,000 patient‐years in patients with refractory epilepsy. Respiratory causes are implicated in SUDEP. We reported that ictal hypoxemia occurs in one‐third of seizures in localization‐related epilepsy. We now report on respiratory changes in the ictal/postictal period including changes in end‐tidal CO₂ (ETCO₂) that correlate directly with alveolar CO₂, allowing a precise evaluation of seizure‐related respiratory disturbances. Methods: One hundred eighty‐seven seizures were recorded in 33 patients with localization‐related epilepsy, with or without secondarily generalized convulsions, undergoing video‐electroencephalography (EEG) telemetry with recording of respiratory data. Results: The ictal/postictal ETCO₂ increase from baseline was 14 ± 11 mm Hg (11, ?1 to 50) [mean ± standard deviation (SD) (median, range)]. ETCO₂ peak was at or above 50 mm Hg with 35 of 94 seizures, 60 mm Hg with 15, and 70 mm Hg with five seizures. Eleven of the 33 patients had seizures with ETCO₂ elevation above 50 mm Hg. The duration of ictal/postictal ETCO₂ increase above baseline was 424 ± 807 s (154, 4 to 6225). The duration of ictal apnea was 49 ± 46 s (31, 6–222); most ictal apneic events were central. Oxygen desaturation to 60% or less occurred with 10 seizures, including five that did not progress to generalized convulsions. Respiratory rate and amplitude increased postictally. The peak ictal ETCO₂ change and duration of change were not associated with apnea duration or seizure duration. Peak ETCO₂ change was significantly associated with contralateral seizure spread. Conclusions: Severe and prolonged increases in ETCO₂ occur with seizures. Postictally, respiratory effort is not impaired. Ictally triggered ventilation–perfusion inequality from pulmonary shunting or transient neurogenic pulmonary edema may account for these findings.     

Increased risk of sudden unexpected death in epilepsy in females using lamotrigine: a nested, case-control study

Purpose: To estimate the incidence of sudden unexpected death in epilepsy (SUDEP) in Rogaland County, Norway, in the period August 1 1995–July 31 2005, and to investigate whether use of lamotrigine (LTG) was associated with increased risk in female patients or other subgroups. Methods: SUDEP victims were identified from autopsy reports and data from the Norwegian Cause of Death Registry. In all cases where SUDEP was considered as a possible cause of death, the hospital records were also reviewed. For each deceased, at least three living patients with epilepsy were randomly selected as controls. The market share in defined daily doses was collected for each year to estimate the number of patient‐years at risk on each antiepileptic drug. Key Findings: We identified 26 cases of SUDEP: 16 definite, 3 probable, and 7 possible; 15 patients were female and 11 were male. Of these, 10 patients (38.5%) were treated with LTG: 9 of these patients were female. The incidence of SUDEP was estimated as 1.0 per 1,000 patient‐years when all cases were included, and 0.7 per 1,000 patient‐years for definite and probable SUDEP. Seven of 12 (58.3%) of female patients with definite and probable SUDEP and 10 of 41 (24.4%) of controls matched on age and gender were on LTG (p = 0.038). The incidence of definite and probable SUDEP in women on LTG, was estimated as 2.5 per 1,000 patient‐years and 0.5 per 1,000 patient‐years in female who were not taking LTG (p = 0.007). Significance: The incidence of SUDEP was significantly higher among female patients with epilepsy who were being treated with LTG than among female patients with epilepsy who were not taking LTG, and a significantly higher proportion of female SUDEP cases than controls were taking LTG. Our findings may have implications for treatment of epilepsy in female patients.     

Significant postictal hypotension: Expanding the spectrum of seizure‐induced autonomic dysregulation

Periictal autonomic dysregulation is best studied using a “polygraphic” approach: electroencephalography ([EEG]), 3‐channel electrocardiography [ECG], pulse oximetry, respiration, and continuous noninvasive blood pressure [BP]), which may help elucidate agonal pathophysiologic mechanisms leading to sudden unexpected death in epilepsy (SUDEP). A number of autonomic phenomena have been described in generalized tonic–clonic seizures (GTCS), the most common seizure type associated with SUDEP, including decreased heart rate variability, cardiac arrhythmias, and changes in skin conductance. Postictal generalized EEG suppression (PGES) has been identified as a potential risk marker of SUDEP, and PGES has been found to correlate with post‐GTCS autonomic dysregulation in some patients. Herein, we describe a patient with a GTCS in whom polygraphic measurements were obtained, including continuous noninvasive blood pressure recordings. Significant postictal hypotension lasting >60 s was found, which closely correlated with PGES duration. Similar EEG changes are well described in hypotensive patients with vasovagal syncope and a similar vasodepressor phenomenon, and consequent cerebral hypoperfusion may account for the PGES observed in some patients after a GTCS. This further raises the possibility that profound, prolonged, and irrecoverable hypotension may comprise one potential SUDEP mechanism.     

Impact of periictal interventions on respiratory dysfunction,postictal EEG suppression,and postictal immobility

Purpose: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy‐related mortality. Seizure‐related respiratory dysfunction (RD), the duration of postictal generalized electroencephalography (EEG) suppression (PGES), and duration of postictal immobility (PI) may be important in the pathophysiology of SUDEP. Periictal interventions may reduce the risk of SUDEP. Methods: We assessed the impact of periictal nursing interventions on RD, PGES, and PI duration in patients with localization‐related epilepsy and secondarily generalized convulsions (GCs) recorded during video‐EEG telemetry in the epilepsy monitoring unit. Video‐EEG data were retrospectively reviewed. Interventions including administration of supplemental oxygen, oropharyngeal suction, and patient repositioning were evaluated. Interventions were performed based on nursing clinical judgment at the bedside and were not randomized. The two‐sided Wilcoxon rank‐sum test was used to compare GCs with and those without intervention. Robust simple linear regression was used to assess the association between timing of intervention and duration of hypoxemia (SaO₂ < 90%), PGES, and PI using data from only the first GC for each patient. Key Findings: Data from 39 patients with 105 GCs were analyzed. PGES >2 s occurred following 31 GCs in 16 patients. There were 21 GCs with no intervention (NOINT) and 84 GC with interventions (INT). In the INT group, the duration of hypoxemia was shorter (p = 0.0014) when intervention occurred before hypoxemia onset (mean duration 53.1 s) than when intervention was delayed (mean duration 132.42 s). Linear regression indicated that in GCs with nursing interventions, earlier intervention was associated with shorter duration of hypoxemia (p < 0.0001) and shorter duration of PGES (p = 0.0012). Seizure duration (p < 0.0001) and convulsion duration (p = 0.0457) were shorter with earlier intervention. PI duration was longer for GCs with PGES than GCs without PGES (p < 0.0001). The mean delay to first active nonrespiratory movement following GCs with PGES was 251.96 s and for GC without PGES was 66.06 s. The duration of PI was positively associated with lower SaO₂ nadir (p = 0.003) and longer duration of oxygen desaturation (p = 0.0026). There was no association between PI duration and seizure duration (p = 0.773), between PI duration and PGES duration (p = 0.758), or between PI duration and the timing of first intervention relative to seizure onset (p = 0.823). PGES did not occur in the NOINT group. The mean duration of desaturation was longer (110.9 vs. 49.9 s) (p < 0.0001), mean SaO₂ nadir was lower (72.8% vs. 79.7%) (p = 0.0086), and mean end‐tidal CO₂ was higher (58.6 vs. 50.3 mmHg) (p = 0.0359) in the INT group compared with the NOINT group. The duration of the seizure or of the convulsive component was not significantly different between the INT and NOINT groups. Significance: Early periictal nursing intervention was associated with reduced duration of RD and reduced duration of PGES. These findings suggest the possibility that such interventions may be effective in reducing the risk of SUDEP in the outpatient setting. Validation of these preliminary data with a prospective study is needed before definitive conclusions can be reached regarding the efficacy of periictal interventions in reducing the risk of SUDEP.     

Knowing the risk of SUDEP: Two family's perspectives and The Danny Did Foundation

There is much debate in the epilepsy community about whether neurologists should discuss the risk of sudden unexpected death in epilepsy (SUDEP) with their patients and family members. Those in favor purport that patients have a right to know about SUDEP. Opponents say the risk is so low that discussions only worry patients and families, especially if there is nothing that can be done to prevent SUDEP. North American surveys show that the epilepsy community knows little about SUDEP and neurologists are unlikely to talk about it. However, surveys of those bereaved by SUDEP show that an overwhelming majority of the parents, spouses, and family members want to be told about SUDEP immediately after the diagnosis of epilepsy. This article is written by two families bereaved by SUDEP and their strong belief that neurologists should have the discussion about the risk of SUDEP soon after the diagnosis of epilepsy.     

Effects of seizure severity and seizure repetition on postictal cardiac arrhythmia following maximal electroshock

Convulsive seizures triggered by maximal electroshock (MES) induce profound abnormalities in neural regulation of cardiac rhythm that are manifested by a period of marked cardiac arrhythmia in the immediate postictal state. It is not known whether seizure severity or seizure experience may influence the duration of cardiac arrhythmia in the postictal state. We varied the duration of MES administered to rats to vary seizure severity, as measured by the extensor to flexion (E/F) ratio. In separate experiments, rats were subjected to daily MES. Finally, we pretreated rats with ketamine prior to MES to block seizures hindlimb extension. In all animals, the R-R interval was plotted on the tachogram, and the duration of the arrhythmia was measured. Increases in MES duration increased significantly the E/F ratio and prolonged significantly the postictal cardiac arrhythmia. Repetition of MES caused a kindling effect with respect to seizure severity resulting in a significant increase of the E/F ratio and significant increases in the duration of postictal arrhythmia. Blocking of the hindlimb extension by ketamine abolished arrhythmia suggesting that the arrhythmia is not caused directly by MES. Severity of tonic convulsive seizures is a determinant of disordered cardiac autonomic regulation and directly influences the duration of cardiac arrhythmia during the immediate postictal state following MES. Seizure repetition also increases abnormalities of postictal neural regulation of the heart, but further studies are needed to determine whether this effect is independent of seizure severity increases.     

Sudden Unexpected Death in Epilepsy: Terminology and Definitions

Summary: Inconsistent and inaccurate death certification, lack of agreed definitions, different terminology, and different understanding of the same terminology hamper research into mortality in epilepsy and result in national statistics that are difficult to interpret. A consensus in death certification and in classification of epilepsy-related deaths, including sudden unexpected death in epilepsy (SUDEP), is needed. Guidelines for classifying cases as SUDEP are proposed. Their aim is to allow uniformity and comparability between studies. These guidelines take into account the limits of the information usually available in this setting even when these deaths are investigated. The guidelines are complemented by those dealing with identified deaths in epidemiologic studies where data are lacking.     

Heart rate dynamics in temporal lobe epilepsy-A long-term follow-up study

The aim of the present study was to prospectively evaluate long-term changes in interictal heart rate variability (HRV) in patients with temporal lobe epilepsy (TLE). A 24-h ECG was recorded at baseline and after a mean follow-up of 6.1 years in 18 patients with refractory TLE and 18 patients with well-controlled TLE. After the follow-up, the Poincaré components SD(1) (p=0.039) and SD(2) (p=0.001) were decreased in patients with refractory TLE compared to baseline, whereas in patients with well-controlled TLE no changes (p>0.05) in HR variability were observed. The reduction in HRV seems to be progressive in patients with chronic refractory TLE with recurrent seizures.