Abstract
Devinsky1 O, Friedman D, Duckro RB, Fountain NB, Gwinn RP, Leiphart JW, Murro AM, Van Ness PC. Epilepsia 2018;59:555–561. DOI: 10.1111/epi.13998
OBJECTIVE: To study the incidence and clinical features of sudden unexpected death in epilepsy (SUDEP) in patients treated with direct brain-responsive stimulation with the RNS System. METHODS: All deaths in patients treated in clinical trials (N = 256) or following U.S. Food and Drug Administration (FDA) approval (N = 451) through May 5, 2016, were adjudicated for SUDEP. RESULTS: There were 14 deaths among 707 patients (2208 postimplantation years), including 2 possible, 1 probable, and 4 definite SUDEP events. The rate of probable or definite SUDEP was 2.0/1000 (95% confidence interval [CI] 0.7–5.2) over 2036 patient stimulation years and 2.3/1000 (95% CI 0.9–5.4) over 2208 patient implant years. Stored electrocorticograms around the time of death were available for 4 patients with probable/definite SUDEP and revealed the following: frequent epileptiform activity ending abruptly (n = 2), no epileptiform activity or seizures (n = 1), and an electrographic and witnessed seizure with cessation of postictal electrocorticography (ECoG) activity associated with apnea and pulselessness (n = 1). SIGNIFICANCe: The SUDEP rate of 2.0/1000 patient stimulation years among patients treated with the RNS System is favorable relative to treatment-resistant epilepsy patients randomized to the placebo arm of add-on drug studies or with seizures after resective surgery. Our findings support that treatments that reduce seizures reduce SUDEP risk and that not all SUDEPs follow seizures.
Lacuey N, Zonjy B, Hampson JP, Sandhya Rani MR, Zaremba A, Sainju RK, Gehlbach BK, Schuele S, Friedman D, Devinsky O, Nei M, Harper MA, Dragon DN, Richerson SD. Epilepsia 2018;59:573–582. DOI: 10.1111/epi.14006.
OBJECTIVE: The aim of this study was to investigate periictal central apnea as a seizure semiological feature, its localizing value, and possible relationship with sudden unexpected death in epilepsy (SUDEP) pathomechanisms. METHODS: We prospectively studied polygraphic physiological responses, including inductance plethysmography, peripheral capillary oxygen saturation (SpO2), electrocardiography, and video electroencephalography (VEEG) in 473 patients in a multicenter study of SUDEP. Seizures were classified according to the International League Against Epilepsy (ILAE) 2017 seizure classification based on the most prominent clinical signs during VEEG. The putative epileptogenic zone was defined based on clinical history, seizure semiology, neuroimaging, and EEG. RESULTS: Complete datasets were available in 126 patients in 312 seizures. Ictal central apnea (ICA) occurred exclusively in focal epilepsy (51/109 patients [47%] and 103/312 seizures [36.5%]) (P < .001). ICA was the only clinical manifestation in 16/103 (16.5%) seizures, and preceded EEG seizure onset by 8 ± 4.9 s, in 56/103 (54.3%) seizures. ICA ≥60 s was associated with severe hypoxemia (SpO2 <75%). Focal onset impaired awareness (FOIA) motor onset with automatisms and FOA nonmotor onset semiologies were associated with ICA presence (P < .001), ICA duration (P = .002), and moderate/severe hypoxemia (P = .04). Temporal lobe epilepsy was highly associated with ICA in comparison to extratemporal epilepsy (P = .001) and frontal lobe epilepsy (P = .001). Isolated postictal central apnea was not seen; in 3/103 seizures (3%), ICA persisted into the postictal period. SIGNIFICANCE: ICA is a frequent, self-limiting semiological feature of focal epilepsy, often starting before surface EEG onset, and may be the only clinical manifestation of focal seizures. However, prolonged ICA (=60 s) is associated with severe hypoxemia and may be a potential SUDEP biomarker. ICA is more frequently seen in temporal than extratemporal seizures, and in typical temporal seizure semiologies. ICA rarely persists after seizure end. ICA agnosia is typical, and thus it may remain unrecognized without polygraphic measurements that include breathing parameters.
Middleton O, Atherton D, Bundock E, Donner E, Friedman D, Hesdorffer D, Jarrell H, McCrillis A, Mena OJ, Morey M, Thurman D, Tian N, Tomson T, Tseng Z, White S, Wright C, Devinsky O. Epilepsia 2018;59:530–543. DOI: 10.1111/epi.14030.
Sudden unexpected death of an individual with epilepsy can pose a challenge to death investigators, as most deaths are unwitnessed, and the individual is commonly found dead in bed. Anatomic findings (eg, tongue/lip bite) are commonly absent and of varying specificity, thereby limiting the evidence to implicate epilepsy as a cause of or contributor to death. Thus it is likely that death certificates significantly underrepresent the true number of deaths in which epilepsy was a factor. To address this, members of the National Association of Medical Examiners, North American SUDEP Registry, Epilepsy Foundation SUDEP Institute, American Epilepsy Society, and the Centers for Disease Control and Prevention constituted an expert panel to generate evidence-based recommendations for the practice of death investigation and autopsy, toxicological analysis, interpretation of autopsy and toxicology findings, and death certification to improve the precision of death certificate data available for public health surveillance of epilepsy-related deaths. The recommendations provided in this paper are intended to assist medical examiners, coroners, and death investigators when a sudden unexpected death in a person with epilepsy is encountered.
Ryvlin P, So EL, Gordon CM, Hesdorffer DC, Sperling MR, Devinsky O, Bunker MT, Olin B, Friedman D. Epilepsia 2018;59:562–572. DOI: 10.1111/epi.14002.
OBJECTIVE: Limited data are available regarding the evolution over time of the rate of sudden unexpected death in epilepsy patients (SUDEP) in drug-resistant epilepsy. The objective is to analyze a database of 40 443 patients with epilepsy implanted with vagus nerve stimulation (VNS) therapy in the United States (from 1988 to 2012) and assess whether SUDEP rates decrease during the postimplantation follow-up period. METHODS: Patient vital status was ascertained using the Centers for Disease Control and Prevention's National Death Index (NDI). An expert panel adjudicated classification of cause of deaths as SUDEP based on NDI data and available narrative descriptions of deaths. We tested the hypothesis that SUDEP rates decrease with time using the Mann-Kendall nonparametric trend test and by comparing SUDEP rates of the first 2 years of follow-up (years 1–2) to longer follow-up (years 3–10). RESULTS: Our cohort included 277 661 person-years of follow-up and 3689 deaths, including 632 SUDEP. Primary analysis demonstrated a significant decrease in age-adjusted SUDEP rate during follow-up (S = _27 P = .008), with rates of 2.47/1000 for years 1–2 and 1.68/1000 for years 3–10 (rate ratio 0.68; 95% confidence interval [CI] 0.53–0.87; P = .002). Sensitivity analyses confirm these findings. SIGNIFICANCE: Our data suggest that SUDEP risk significantly decreases during long-term follow-up of patients with refractory epilepsy receiving VNS Therapy. This finding might reflect several factors, including the natural long-term dynamic of SUDEP rate, attrition, and the impact of VNS Therapy. The role of each of these factors cannot be confirmed due to the limitations of the study.
Commentary
While volunteering at a church camp in a remote town, I received the dreaded message: one of my patients had died of probable sudden unexpected death in epilepsy patients (SUDEP). The child had been found prone in bed, less than 2 hours after being checked on by a parent. In that tearful phone call, I had no words of solace. I could not heal their child. It was the sweet parents who offered their words of encouragement to me. They knew their child had very refractory epilepsy. They knew this child was at increased risk of death due to seizures. We had discussed SUDEP, although SUDEP was conveyed as being a tragic but unlikely complication for a cognitively normal child with epilepsy. They knew how much I cared about their child. I had done everything I could.
Years later, I still think about this family. These kind parents who stated so confidently that they knew I had done my best. Yet, do I fully agree? As physicians, can we make this claim? How much do we really understand about the possible contribution of epilepsy in the death of any of our patients? Was I correct when I informed them that the risk of SUDEP was low? Could this have been prevented? Did the vagus nerve stimulator (VNS) placed in this child, on my recommendation, contribute to death? Recent publications, including the March 2018 issue of Epilepsia help answer these questions.
We must admit that we still do not understand all the mechanisms or risk factors contributing to SUDEP. To improve our understanding of SUDEP we need to gather more information. Unfortunately, not all epilepsy-related deaths are recognized as such due to considerable variability in investigations and certification of deaths. Therefore, the frequency of epilepsy-related deaths may be underestimated. To address this concern, the National Association of Medical Examiners has made recommendations for appropriate investigation and certification of deaths in people with epilepsy. Not only is autopsy with extended brain examination important but scene investigation, toxicology and histology studies, and examination of the epilepsy history must also be completed. This is essential, not just for those who die of presumed SUDEP but also to determine the role epilepsy may play in other deaths, such as drowning in a bathtub. It is not until we can better identify these patients that we can finally make progress in identifying ways to stop this catastrophic epilepsy complication.
Given how much we don't understand, did I provide the appropriate risk counseling? A population-based study of children with epilepsy showed that mortality rate due to epilepsy alone was similar to the expected mortality rate in the general population (1). The American Academy of Neurology recently published a practice guideline summary for the incidence rates and risk factors for SUDEP. They found that SUDEP occurs in 1 in 4500 children and 1 in 1000 adults with epilepsy per year (2). The recommendation was to discuss SUDEP as a possible event but to remind parents that each year 4499 of 4500 children with epilepsy will not be affected (2). Even with a low risk, it is important that this discussion occurs (3). Families want to know the risks and will seek answers.
What are the possible risk factors for SUDEP? The biggest risk factor is having bilateral convulsive (generalized tonic clonic) seizures, and the risk increases as the frequency of convulsive seizures increases. For those with frequent generalized tonic clonic, the risk of SUDEP increases to 18 per 1000 patient-years (4). By contrast, Lacuey et al. recently found that ictal central apnea occurred most often in focal onset impaired awareness seizures of temporal region onset. This further demonstrates how much we do not understand about the pathophysiology of SUDEP. In patients with treatment-resistant epilepsy and in epilepsy surgery candidates, the risk of SUDEP is also increased at 3.2 to 5.9 and 6.3 to 9.3 per 1000 person-years (PY), respectively (5, 6), but this is still a low risk, especially in children. Therefore, I likely provided the correct counseling.
Could this death have been prevented? The recommendation was to actively manage epilepsy therapies and consider having another person older than age 10 years in the bedroom (2). This child was treated with multiple antiseizure medications, and VNS that reduced seizure frequency by >50 percent. Seizure control was improved in the preceding months. The child had nighttime seizure monitoring and shared a bedroom with an older sibling. The parents and I had provided appropriate treatment and monitoring.
What about the VNS? The parents were informed by well-meaning friends that the VNS could have contributed to the death. Intraoperative bradycardia and asystole at the time of VNS placement, as well as delayed arrhythmias have been reported (7). Furthermore, ictal EKG frequently demonstrates tachycardia, but ictal bradycardia is also reported. Furthermore, QTc lengthening and shortening can also be seen, possibly leading to cardiac arrhythmias and SUDEP (8). Could VNS complicate these ictal cardiac rhythm changes?
The recent article by Ryvlin et al. provides excellent support that VNS does not increase risk of SUDEP and that that risk significantly decreases with long-term follow-up in those receiving VNS therapy. Using the VNS Therapy Device Tracking Database, they analyzed patients implanted with a VNS over a 24-year period for deaths and SUDEP, yielding a standardized mortality rate due to any cause of 13.3 per 1000 PY and a SUDEP rate during the first 2 years of 2.47 per 1000 PY and 1.68 per 1000 PY in years 3 to 10. These findings were previously noted in the American Academy of Neurology evidence-based guideline update on VNS in epilepsy (9). Similarly, the recent article by Devinsky and colleagues demonstrates that the standardized mortality rate due to SUDEP for patients with brain-responsive neurostimulation was 2.0 per 1000 PY over 2036 patient stimulation years. The decrease in SUDEP in these patients is likely due to improved seizure control. I can reassure these parents, and myself, that VNS did not contribute to the death of this child.
Upon review of the available literature, including the most recent findings of Lacuey, Ryvlin, Devinsky and colleagues, as well as the recommendations from the National Association of Medical Examiners, I am forced to recognize the humility we must have to work with this unpredictable disease. While my patient had some increased risk for SUDEP due to refractory seizures convulsive, the risk was still considered to be low. I followed all of the guidelines and recommendations for treatment and counseling. The parents followed all of the recommendations for seizure safety and monitoring. The child still died. Let this be a call to arms that we must have further research to better understand and be able to prevent SUDEP before this nightmare becomes the reality for another family.