Faculty Bibliography

Awareness and research on epilepsy-related deaths (ERD), in particular Sudden Unexpected Death in Epilepsy (SUDEP), have exponentially increased over the last two decades. Most publications have focused on guidelines that inform clinicians dealing with these deaths, educating patients, potential risk factors and mechanisms. There is a relative paucity of information available for pathologists who conduct these autopsies regarding appropriate post mortem practice and investigations. As we move from recognizing SUDEP as the most common form of ERD toward in-depth investigations into its causes and prevention, health professionals involved with these autopsies and post mortem procedure must remain fully informed. Systematizing a more comprehensive and consistent practice of examining these cases will facilitate (i) more precise determination of cause of death, (ii) identification of SUDEP for improved epidemiological surveillance (the first step for an intervention study), and (iii) biobanking and cell-based research. This article reviews how pathologists and healthcare professionals have approached ERD, current practices, logistical problems and areas to improve and harmonize. The main neuropathology, cardiac and genetic findings in SUDEP are outlined, providing a framework for best practices, integration of clinical, pathological and molecular genetic investigations in SUDEP, and ultimately prevention.

It has come to our attention that we did not specify whether the stimulation magnitudes we report in this Article are peak amplitudes or peak-to-peak. All references to intensity given in mA in the manuscript refer to peak-to-peak amplitudes, except in Fig. 2, where the model is calibrated to 1 mA peak amplitude, as stated. In the original version of the paper we incorrectly calibrated the computational models to 1 mA peak-to-peak, rather than 1 mA peak amplitude. This means that we divided by a value twice as large as we should have. The correct estimated fields are therefore twice as large as shown in the original Fig. 2 and Supplementary Figure 11. The corrected figures are now properly calibrated to 1 mA peak amplitude. Furthermore, the sentence in the first paragraph of the Results section 'Intensity ranged from 0.5 to 2.5 mA (current density 0.125-0.625 mA mA/cm²), which is stronger than in previous reports', should have read 'Intensity ranged from 0.5 to 2.5 mA peak to peak (peak current density 0.0625-0.3125 mA/cm²), which is stronger than in previous reports.' These errors do not affect any of the Article's conclusions.

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.

Sleep spindles are a cardinal feature in human NREM sleep and may be important for memory consolidation. We studied the intracortical organization of spindles in men and women by recording spontaneous sleep spindles from different cortical layers using linear microelectrode arrays. Two patterns of spindle generation were identified using visual inspection, and confirmed with factor analysis. Spindles (10-16Hz) were largest and most common in upper and middle channels, with limited involvement of deep channels. Many spindles were observed in only upper or only middle channels, but about half occurred in both. In spindles involving both middle and upper channels, the spindle envelope onset in middle channels led upper by ∼25-50ms on average. The phase relationship between spindle waves in upper and middle channels varied dynamically within spindle epochs, and across individuals. Current source density analysis demonstrated that upper and middle channel spindles were both generated by an excitatory supragranular current sink while an additional deep source was present for middle channel spindles only. Only middle channel spindles were accompanied by deep low (25-50Hz) and high (70-170Hz) gamma activity. These results suggest that upper channel spindles are generated by supragranular pyramids, and middle channel by infragranular. Possibly, middle channel spindles are generated by core thalamocortical afferents, and upper channel by matrix. The concurrence of these patterns could reflect engagement of cortical circuits in the integration of more focal (core) and distributed (matrix) aspects of memory. These results demonstrate that at least two distinct intracortical systems generate human sleep spindles.SIGNIFICANCE STATEMENTBursts of ∼14Hz oscillations, lasting about a second, have been recognized for over 80 years as cardinal features of mammalian sleep. Recent findings suggest that they play a key role in organizing cortical activity during memory consolidation. We used linear microelectrode arrays to study their intracortical organization in humans. We found that spindles could be divided into two types. One mainly engages upper layers of the cortex, which are considered to be specialized for associative activity. The other engages both upper and middle layers, including those devoted to sensory input. The interaction of these two spindle types may help organize the interaction of sensory and associative aspects of memory consolidation.

The neocortex is composed of six anatomically and physiologically specialized layers. It has been proposed that integration of activity across cortical areas is mediated anatomically by associative connections terminating in superficial layers, and physiologically by slow cortical rhythms. However, the means through which neocortical anatomy and physiology interact to coordinate neural activity remains obscure. Using laminar microelectrode arrays in 19 human participants, we found that most EEG activity is below 10-Hz (delta/theta) and generated by superficial cortical layers during both wakefulness and sleep. Cortical surface grid, grid-laminar, and dual-laminar recordings demonstrate that these slow rhythms are synchronous within upper layers across broad cortical areas. The phase of this superficial slow activity is reset by infrequent stimuli and coupled to the amplitude of faster oscillations and neuronal firing across all layers. These findings support a primary role of superficial slow rhythms in generating the EEG and integrating cortical activity.

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

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/CONCLUSIONS: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.

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/CONCLUSIONS: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.

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/CONCLUSIONS: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.