Distinct signatures of loss of consciousness in focal impaired awareness versus tonic-clonic seizures.

Loss of consciousness is a hallmark of many epileptic seizures and carries risks of serious injury and sudden death. While cortical sleep-like activities accompany loss of consciousness during focal impaired awareness seizures, the mechanisms of loss of consciousness during focal to bilateral tonic-clonic seizures remain unclear. Quantifying differences in markers of cortical activation and ictal recruitment between focal impaired awareness and focal to bilateral tonic-clonic seizures may also help us to understand their different consequences for clinical outcomes and to optimize neuromodulation therapies. We quantified clinical signs of loss of consciousness and intracranial EEG activity during 129 focal impaired awareness and 50 focal to bilateral tonic-clonic from 41 patients. We characterized intracranial EEG changes both in the seizure onset zone and in areas remote from the seizure onset zone with a total of 3386 electrodes distributed across brain areas. First, we compared the dynamics of intracranial EEG sleep-like activities: slow-wave activity (1-4 Hz) and beta/delta ratio (a validated marker of cortical activation) during focal impaired awareness versus focal to bilateral tonic-clonic. Second, we quantified differences between focal to bilateral tonic-clonic and focal impaired awareness for a marker validated to detect ictal cross-frequency coupling: phase-locked high gamma (high-gamma phased-locked to low frequencies) and a marker of ictal recruitment: the epileptogenicity index. Third, we assessed changes in intracranial EEG activity preceding and accompanying behavioural generalization onset and their correlation with electromyogram channels. In addition, we analysed human cortical multi-unit activity recorded with Utah arrays during three focal to bilateral tonic-clonic seizures. Compared to focal impaired awareness, focal to bilateral tonic-clonic seizures were characterized by deeper loss of consciousness, even before generalization occurred. Unlike during focal impaired awareness, early loss of consciousness before generalization was accompanied by paradoxical decreases in slow-wave activity and by increases in high-gamma activity in parieto-occipital and temporal cortex. After generalization, when all patients displayed loss of consciousness, stronger increases in slow-wave activity were observed in parieto-occipital cortex, while more widespread increases in cortical activation (beta/delta ratio), ictal cross-frequency coupling (phase-locked high gamma) and ictal recruitment (epileptogenicity index). Behavioural generalization coincided with a whole-brain increase in high-gamma activity, which was especially synchronous in deep sources and could not be explained by EMG. Similarly, multi-unit activity analysis of focal to bilateral tonic-clonic revealed sustained increases in cortical firing rates during and after generalization onset in areas remote from the seizure onset zone. Overall, these results indicate that unlike during focal impaired awareness, the neural signatures of loss of consciousness during focal to bilateral tonic-clonic consist of paradoxical increases in cortical activation and neuronal firing found most consistently in posterior brain regions. These findings suggest differences in the mechanisms of ictal loss of consciousness between focal impaired awareness and focal to bilateral tonic-clonic and may account for the more negative prognostic consequences of focal to bilateral tonic-clonic.

Neuronal Firing and Waveform Alterations through Ictal Recruitment in Humans.

Analyzing neuronal activity during human seizures is pivotal to understanding mechanisms of seizure onset and propagation. These analyses, however, invariably using extracellular recordings, are greatly hindered by various phenomena that are well established in animal studies: changes in local ionic concentration, changes in ionic conductance, and intense, hypersynchronous firing. The first two alter the action potential waveform, whereas the third increases the "noise"; all three factors confound attempts to detect and classify single neurons. To address these analytical difficulties, we developed a novel template-matching-based spike sorting method, which enabled identification of 1239 single neurons in 27 patients (13 female) with intractable focal epilepsy, that were tracked throughout multiple seizures. These new analyses showed continued neuronal firing with widespread intense activation and stereotyped action potential alterations in tissue that was invaded by the seizure: neurons displayed increased waveform duration (p < 0.001) and reduced amplitude (p < 0.001), consistent with prior animal studies. By contrast, neurons in "penumbral" regions (those receiving intense local synaptic drive from the seizure but without neuronal evidence of local seizure invasion) showed stable waveforms. All neurons returned to their preictal waveforms after seizure termination. We conclude that the distinction between "core" territories invaded by the seizure versus "penumbral" territories is evident at the level of single neurons. Furthermore, the increased waveform duration and decreased waveform amplitude are neuron-intrinsic hallmarks of seizure invasion that impede traditional spike sorting and could be used as defining characteristics of local recruitment.SIGNIFICANCE STATEMENT Animal studies consistently show marked changes in action potential waveform during epileptic discharges, but acquiring similar evidence in humans has proven difficult. Assessing neuronal involvement in ictal events is pivotal to understanding seizure dynamics and in defining clinical localization of epileptic pathology. Using a novel method to track neuronal firing, we analyzed microelectrode array recordings of spontaneously occurring human seizures, and here report two dichotomous activity patterns. In cortex that is recruited to the seizure, neuronal firing rates increase and waveforms become longer in duration and shorter in amplitude as the neurons are recruited to the seizure, while penumbral tissue shows stable action potentials, in keeping with the "dual territory" model of seizure dynamics.

Electrically stimulated auras as a potential biomarker of the epileptogenic zone.

Electrocortical stimulation mapping (ESM) is often performed in patients undergoing stereoelectroencephalography (SEEG) prior to epilepsy surgery, with the goal of identifying functional cortex and preserving it postoperatively. ESM may also evoke a patient's typical seizure semiology. The purpose of this study was to determine whether the sites at which typical auras are evoked during ESM are associated with other known clinical and electrophysiologic biomarkers of the epileptogenic zone: the seizure onset zone (SOZ), the early spread zone (ES), and high-frequency oscillations (HFOs). We found that the sites at which auras were provoked were not consistently associated with known biomarkers (p = 0.09). We conclude that evoked auras during ESM may reflect electrical spread rather than true epileptogenicity, and that a larger study is needed to assess their potential value as independent epileptic biomarkers.

Ex vivo multi-electrode analysis reveals spatiotemporal dynamics of ictal behavior at the infiltrated margin of glioma.

The purpose of this study is to develop a platform in which the cellular and molecular underpinnings of chronic focal neocortical lesional epilepsy can be explored and use it to characterize seizure-like events (SLEs) in an ex vivo model of infiltrating high-grade glioma. Microelectrode arrays were used to study electrophysiologic changes in ex vivo acute brain slices from a PTEN/p53 deleted, PDGF-B driven mouse model of high-grade glioma. Electrode locations were co-registered to the underlying histology to ascertain the influence of the varying histologic landscape on the observed electrophysiologic changes. Peritumoral, infiltrated, and tumor sites were sampled in tumor-bearing slices. Following the addition of zero Mg2+ solution, all three histologic regions in tumor-bearing slices showed significantly greater increases in firing rates when compared to the control sites. Tumor-bearing slices demonstrated increased proclivity for SLEs, with 40 events in tumor-bearing slices and 5 events in control slices (p-value = .0105). Observed SLEs were characterized by either low voltage fast (LVF) onset patterns or short bursts of repetitive widespread, high amplitude low frequency discharges. Seizure foci comprised areas from all three histologic regions. The onset electrode was found to be at the infiltrated margin in 50% of cases and in the peritumoral region in 36.9% of cases. These findings reveal a landscape of histopathologic and electrophysiologic alterations associated with ictogenesis and spread of tumor-associated seizures.

Using ICD-10 codes to identify elective epilepsy monitoring unit admissions from administrative billing data: A validation study.

Video-electroencephalogram (EEG) monitoring in the epilepsy monitoring unit (EMU) is essential for managing epilepsy and seizure mimics. Evaluation of care in the EMU would benefit from a validated code set capable of identifying EMU admissions from administrative databases comprised of large, diverse cohorts. We assessed the ability of code-based queries to parse EMU admissions from administrative billing records in a large academic medical center over a four-year period, 2016-2019. We applied prespecified queries for admissions coded as follows: 1) elective, 2) receiving video-EEG monitoring, and 3) including diagnoses typically required by major US healthcare payers for EMU admission. Sensitivity (Sn), specificity (Sp), and predictive value positive/negative (PVP, PVN) were determined. Two approaches were highly effective. Incorporating epilepsy, seizure, or seizure mimic codes as the admitting diagnosis (assigned at admission; Sn 96.3%, Sp 100.0%, PVP 98.3%, and PVN 100.0%) or the principal diagnosis (assigned after discharge; Sn 94.9%, Sp 100.0%, PVP 98.8%, and PVN 100.0%) identified elective adult EMU admissions with comparable reliability (p = 0.096). The addition of surgical procedure codes further separated EMU admissions for intracranial EEG monitoring. When applied to larger, more comprehensive datasets, these code-based queries should enhance our understanding of EMU utilization and access to care on a scalable basis.

All-cause mortality and SUDEP in a surgical epilepsy population.

Epilepsy surgery is considered to reduce the risk of epilepsy-related mortality, including sudden unexpected death in epilepsy (SUDEP), though data from existing surgical series are conflicting. We retrospectively examined all-cause mortality and SUDEP in a population of 590 epilepsy surgery patients and a comparison group of 122 patients with pharmacoresistant focal epilepsy who did not undergo surgery, treated at Columbia University Medical Center between 1977 and 2014. There were 34 deaths in the surgery group, including 14 cases of SUDEP. Standardized mortality ratio (SMR) for the surgery group was 1.6, and SUDEP rate was 1.9 per 1000 patient-years. There were 13 deaths in the comparison group, including 5 cases of SUDEP. Standardized mortality ratio for the comparison group was 3.6, and SUDEP rate was 4.6 per 1000 patient-years. Both were significantly greater than in the surgery group (p < 0.05). All but one of the surgical SUDEP cases, and all of the comparison group SUDEP cases, had a history of bilateral tonic-clonic seizures (BTCS). Of postoperative SUDEP cases, one was seizure-free, and two were free of BTCS at last clinical follow-up. Time to SUDEP in the surgery group was longer than in the comparison group (10.1 vs 5.9 years, p = 0.013), with 10 of the 14 cases occurring >10 years after surgery. All-cause mortality was reduced after epilepsy surgery relative to the comparison group. There was an early benefit of surgery on the occurrence of SUDEP, which was reduced after 10 years. A larger, multicenter study is needed to further investigate the time course of postsurgical SUDEP.

Multiscale recordings reveal the dynamic spatial structure of human seizures.

The cellular activity underlying human focal seizures, and its relationship to key signatures in the EEG recordings used for therapeutic purposes, has not been well characterized despite many years of investigation both in laboratory and clinical settings. The increasing use of microelectrodes in epilepsy surgery patients has made it possible to apply principles derived from laboratory research to the problem of mapping the spatiotemporal structure of human focal seizures, and characterizing the corresponding EEG signatures. In this review, we describe results from human microelectrode studies, discuss some data interpretation pitfalls, and explain the current understanding of the key mechanisms of ictogenesis and seizure spread.

Postictal clinical and electroencephalographic activity following intracranially recorded bilateral tonic-clonic seizures.

OBJECTIVE: The dynamics of the postictal period, which may demonstrate such dramatic clinical phenomena as focal neurological deficits, prolonged coma and immobility, and even sudden death, are poorly understood. We sought to classify and characterize postictal phases of bilateral tonic-clonic seizures based on electroencephalographic (EEG) criteria and associated clinical features. METHODS: We performed a detailed electroclinical evaluation of the postictal period in a series of 31 bilateral tonic-clonic seizures in 16 patients undergoing epilepsy surgery evaluations for focal pharmacoresistant epilepsy with intracranial electrodes and time-locked video. RESULTS: The postictal EEG demonstrated three clearly differentiated phases as follows: attenuation, a burst-attenuation pattern, and a return to continuous background, with abrupt, synchronized transitions between phases. Postictal attenuation was common, occurring in 84% of seizures in 94% of patients in this study. There was increased power in gamma frequencies (>25 Hz) during postictal attenuation periods relative to preictal baseline in 88% of seizures demonstrating the attenuation pattern (n = 25 seizures, P < 0.002). Such increases were seen in >90% of channels in 13 seizures (52%) and <10% of channels in three seizures (12%). Postictal immobility was seen in 87% of seizures, with either a flaccid (58%) or rigid/dystonic (29%) appearance. Clinical motor manifestations, including focal dystonic posturing, automatisms, head and eye deviation, and myoclonic jerking, continued or emerged within the first minute following seizure termination in 48% of seizures, regardless of EEG appearance. SIGNIFICANCE: Intracranial postictal attenuation, which may be diffuse or focal, is so common that it should be regarded as a ubiquitous feature of bilateral tonic-clonic seizures, rather than an unusual event. The prominence of high-frequency activity coupled with emerging clinical features, including rigid immobility and semiologies such as automatisms, during the postictal period supports the presence of ongoing seizure-related neuronal activity in unrecorded brain regions.

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

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.

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

Observations in witnessed Sudden Unexpected Death in Epilepsy (SUDEP) suggest that a fatal breakdown of the central autonomic control could play a major role in SUDEP. A previous MR study found volume losses in the mesencephalon in focal epilepsy that were more severe and extended into the lower brainstem in two patients who later died of SUDEP. The aims of this study were to demonstrate an association (1) between brainstem volume loss and impaired autonomic control (reduced heart rate variability [HRV]); (2) between brainstem damage and time to SUDEP in patients who later died of SUDEP. Two populations were studied: (1) Autonomic system function population (ASF, 18 patients with focal epilepsy, 11 controls) with HRV measurements and standardized 3 T MR exams. (2) SUDEP population (26 SUDEP epilepsy patients) with clinical MRI 1-10 years before SUDEP. Deformation-based morphometry of the brainstem was used to generate profile similarity maps from the resulting Jacobian determinant maps that were further characterized by graph analysis to identify regions with excessive expansion indicating significant volume loss or atrophy. The total number of regions with excessive expansion in ASF was negatively correlated with HRV (r = -.37, p = .03), excessive volume loss in periaqueductal gray/medulla oblongata autonomic nuclei explained most of the HRV associated variation (r/r2 = -.82/.67, p < .001). The total number of regions with excessive expansion in SUDEP was negatively correlated with time to SUDEP (r = -.39, p = .03), excessive volume loss in the raphe/medulla oblongata at the obex level explained most of the variation of the time between MRI to SUDEP (r/r2 = -.60/.35,p = .001). Epilepsy is associated with brainstem atrophy that impairs autonomic control and can increase the risk for SUDEP if it expands into the mesencephalon.

Sudden unexpected death in epilepsy, periictal physiology, and the SUDEP-7 Inventory.

Sudden unexpected death in epilepsy (SUDEP) is a significant public health burden. Epidemiological studies have identified clinical SUDEP risk factors across large populations, but the means to apply this information to individual patients are lacking. The SUDEP-7 Inventory was developed as a marker of clinical SUDEP risk and has been used in studies of potential SUDEP biomarkers. We retrospectively reviewed clinical data from 16 patients dying of SUDEP and 48 matched living epilepsy controls to determine whether individuals succumbing to SUDEP could be distinguished from living epilepsy controls using the revised SUDEP-7 Inventory, the absolute number of clinical risk factors as identified by an International League Against Epilepsy meta-analysis (ILAE score), and physiological characteristics previously associated with SUDEP risk. Mean revised SUDEP-7 Inventory score was 3.3 ± 2.0 in SUDEP cases and 3.8 ± 2.3 in controls (P = 0.39). Mean ILAE score was 2.4 ± 1.1 in SUDEP cases and 2.6 ± 1.4 in controls (P = 0.62). There were no significant differences in interictal heart rate variability (measured by the root mean square of differences of successive RR intervals), periictal cardiorespiratory dysfunction, and postictal generalized electroencephalographic suppression between the groups. This demonstrates that a reliable instrument for individual SUDEP risk stratification is lacking and highlights the need for improved understanding of SUDEP pathophysiology and individual risk determination.

Laser ablation is effective for temporal lobe epilepsy with and without mesial temporal sclerosis if hippocampal seizure onsets are localized by stereoelectroencephalography.

OBJECTIVE: Selective laser amygdalohippocampotomy (SLAH) using magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is emerging as a treatment option for drug-resistant mesial temporal lobe epilepsy (MTLE). SLAH is less invasive than open resection, but there are limited series reporting its safety and efficacy, particularly in patients without clear evidence of mesial temporal sclerosis (MTS). METHODS: We report seizure outcomes and complications in our first 30 patients who underwent SLAH for drug-resistant MTLE between January 2013 and December 2016. We compare patients who required stereoelectroencephalography (SEEG) to confirm mesial temporal onset with those treated based on imaging evidence of MTS. RESULTS: Twelve patients with SEEG-confirmed, non-MTS MTLE and 18 patients with MRI-confirmed MTS underwent SLAH. MTS patients were older (median age 50 vs 30 years) and had longer standing epilepsy (median 40.5 vs 5.5 years) than non-MTS patients. Engel class I seizure freedom was achieved in 7 of 12 non-MTS patients (58%, 95% confidence interval [CI] 30%-86%) and 10 of 18 MTS patients (56%, 95% CI 33%-79%), with no significant difference between groups (odds ratio [OR] 1.12, 95% CI 0.26-4.91, P = .88). Length of stay was 1 day for most patients (range 0-3 days). Procedural complications were rare and without long-term sequelae. SIGNIFICANCE: We report similar rates of seizure freedom following SLAH in patients with MTS and SEEG-confirmed, non-MTS MTLE. Consistent with early literature, these rates are slightly lower than typically observed with surgical resection (60%-80%). However, SLAH is less invasive than open surgery, with shorter hospital stays and recovery, and severe procedural complications are rare. SLAH may be a reasonable first-line surgical option for patients with both MTS and SEEG confirmed, non-MTS MTLE.

Serum serotonin levels in patients with epileptic seizures.

Profound cardiovascular and/or respiratory dysfunction is part of the terminal cascade in sudden unexpected death in epilepsy (SUDEP). Central control of ventilation is mediated by brainstem rhythm generators, which are influenced by a variety of inputs, many of which use the modulatory neurotransmitter serotonin to mediate important inputs for breathing. The aim of this study was to investigate epileptic seizure-induced changes in serum serotonin levels and whether there are potential implications for SUDEP. Forty-one epileptic patients were pooled into 2 groups based on seizure type as (1) generalized tonic-clonic seizures (GTCS) of genetic generalized epilepsy and focal to bilateral tonic-clonic seizures (FBTCS; n = 19) and (2) focal seizures (n = 26) based on clinical signs using surface video-electroencephalography. Postictal serotonin levels were statistically significantly higher after GTCS and FBTCS compared to interictal levels (P = .002) but not focal seizures (P = .941). The change in serotonin (postictal-interictal) was inversely associated with a shorter duration of tonic phase of generalized seizures. The interictal serotonin level was inversely associated with a shorter period of postictal generalized electroencephalographic suppression. These data suggest that peripheral serum serotonin levels may play a role in seizure features and earlier postseizure recovery; these findings merit further study.

The incidence and significance of periictal apnea in epileptic seizures.

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.

Addition of a hospital bedside sitter during intracranial stereotactic EEG monitoring improves safety and seizure responses in an adult epilepsy monitoring unit.

Expert consensus statements recommend continuous observation for patients undergoing intracranial electroencephalography (EEG), but this practice is neither universal nor specific regarding the type of observation. We compared outcomes for patients who underwent intracranial stereotactic EEG (SEEG) before and after the adoption of continuous monitoring by a staff bedside sitter. We retrospectively studied 26 consecutive adult patients who underwent SEEG placement at our center over a three-year period. Thirteen patients were monitored with usual protocol (no-sitter group), and 13 patients had a full-time hospital-employed sitter at bedside (sitter group). We analyzed nursing responses for all electroclinical seizures and characterized seizure-related adverse events. More seizures went unrecognized without a sitter (33.3% versus 15.0% of all seizures; p = 0.03). Two unrecognized focal to bilateral tonic-clonic seizures occurred only in the no-sitter group. Nursing response was significantly faster in the sitter group in relation to both electrographic seizure onset (12.0 s, p = 0.04) and clinical seizure onset (13.5 s, p = 0.02). Two patients in the no-sitter group pulled their electrodes out periictally while none did so in the sitter group. The addition of a full-time staff bedside sitter improved nursing response times and lowered the rate of unrecognized seizures in patients with SEEG monitoring. Sitters also helped to eliminate inadvertent major electrode displacement.

Sleep-disordered breathing, neuroendocrine function, and clinical SUDEP risk in patients with epilepsy.

INTRODUCTION: Sudden unexpected death in epilepsy (SUDEP) is a major contributor to epilepsy-related mortality. It is associated with nocturnal seizures and centrally mediated postictal cardiorespiratory dysfunction (CRD), but mechanisms and contributors remain poorly understood. METHODS: We performed a prospective, cross-sectional, observational pilot study in the Columbia University Medical Center (CUMC) adult epilepsy monitoring unit (EMU) to explore relationships between periictal CRD, sleep-disordered breathing (SDB), neuroendocrine function, and clinical SUDEP risk. Thirty patients (twenty women, ten men) underwent video-electroencephalogram (EEG) with electrocardiogram (EKG) and digital pulse oximetry, inpatient or outpatient polysomnography (PSG), and comprehensive laboratory evaluation of sex steroid hormones. Sudden unexpected death in epilepsy risk was defined as Low (0-2) or High (≥3) using the revised SUDEP-7 Inventory. Sleep-disordered breathing was defined using standard criteria. Neuroendocrine dysfunction was defined as ≥1 laboratory abnormality. RESULTS: Cardiorespiratory dysfunction occurred more frequently in high-risk patients (60% vs. 27%, p = 0.018). Endocrine dysfunction was seen in 35% of patients, more in men (p = 0.018). Sleep-disordered breathing was found in 88% of fully scoreable PSGs. CONCLUSIONS: There was no significant relationship between CRD, SDB, and neuroendocrine status, though all PSGs in those with high SUDEP risk or neuroendocrine dysfunction revealed SDB. Larger studies are needed to further elucidate relationships between CRD, SDB, neuroendocrine factors, and SUDEP.

From unwitnessed fatality to witnessed rescue: Nonpharmacologic interventions in sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) risk reduction remains a critical aim in epilepsy care. To date, only aggressive medical and surgical efforts to control seizures have been demonstrated to be of benefit. Incomplete understanding of SUDEP mechanisms limits the development of more specific interventions. Periictal cardiorespiratory dysfunction is implicated in SUDEP; postictal electroencephalography (EEG) suppression, coma, and immobility may also play a role. Nocturnal supervision is protective against SUDEP, presumably by permitting intervention in the case of a life-threatening event. Resuscitative efforts were implemented promptly in near-SUDEP cases but delayed in SUDEP deaths in the Mortality in Epilepsy Monitoring Unit Study (MORTEMUS) study. Nursing interventions--including repositioning, oral suctioning, and oxygen administration--reduce seizure duration, respiratory dysfunction, and EEG suppression in the epilepsy monitoring unit (EMU), but have not been studied in outpatients. Cardiac pacemakers or cardioverter-defibrillator devices may be of benefit in a few select individuals. A role for implantable neurostimulators has not yet been established. Seizure detection devices, including those that monitor generalized tonic-clonic seizure-associated movements or cardiorespiratory parameters, may provide a means to permit timely periictal intervention. However, these and other devices, such as antisuffocation pillows, have not been adequately investigated with respect to SUDEP prevention.

Single unit action potentials in humans and the effect of seizure activity.

Spike-sorting algorithms have been used to identify the firing patterns of isolated neurons ('single units') from implanted electrode recordings in patients undergoing assessment for epilepsy surgery, but we do not know their potential for providing helpful clinical information. It is important therefore to characterize both the stability of these recordings and also their context. A critical consideration is where the units are located with respect to the focus of the pathology. Recent analyses of neuronal spiking activity, recorded over extended spatial areas using microelectrode arrays, have demonstrated the importance of considering seizure activity in terms of two distinct spatial territories: the ictal core and penumbral territories. The pathological information in these two areas, however, is likely to be very different. We investigated, therefore, whether units could be followed reliably over prolonged periods of times in these two areas, including during seizure epochs. We isolated unit recordings from several hundred neurons from four patients undergoing video-telemetry monitoring for surgical evaluation of focal neocortical epilepsies. Unit stability could last in excess of 40 h, and across multiple seizures. A key finding was that in the penumbra, spike stereotypy was maintained even during the seizure. There was a net tendency towards increased penumbral firing during the seizure, although only a minority of units (10-20%) showed significant changes over the baseline period, and notably, these also included neurons showing significant reductions in firing. In contrast, within the ictal core territories, regions characterized by intense hypersynchronous multi-unit firing, our spike sorting algorithms failed as the units were incorporated into the seizure activity. No spike sorting was possible from that moment until the end of the seizure, but recovery of the spike shape was rapid following seizure termination: some units reappeared within tens of seconds of the end of the seizure, and over 80% reappeared within 3 min (τrecov = 104 ± 22 s). The recovery of the mean firing rate was close to pre-ictal levels also within this time frame, suggesting that the more protracted post-ictal state cannot be explained by persistent cellular neurophysiological dysfunction in either the penumbral or the core territories. These studies lay the foundation for future investigations of how these recordings may inform clinical practice.See Kimchi and Cash (doi:10.1093/awv264) for a scientific commentary on this article.