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Increased understanding of the role of cortical structures in respiratory control may help the understanding of seizure-induced respiratory dysfunction that leads to sudden unexpected death in epilepsy (SUDEP). The aim of this study was to characterize respiratory responses to electrical stimulation (ES), including inhibition and enhancement of respiration.We prospectively recruited 19 consecutive patients with intractable epilepsy undergoing stereotactic electroencephalography (EEG) evaluation from June 2015 to June 2018. Inclusion criteria were patients ≥18 years in whom ES was indicated for clinical mapping of ictal onset or eloquent cortex as part of the presurgical evaluation. ES was carried out at 50 Hz, 0.2 msec, and 1-10 mA current intensity. Common brain regions sampled across all patients were amygdala (AMY), hippocampus (HG), anterior cingulate gyrus (CING), orbitofrontal cortex (OrbF), temporal neocortex (TNC), temporal pole (TP), and entorhinal cortex (ERC). Seven hundred fifty-five stimulations were conducted. Quantitative analysis of breathing signal, that is, changes in breathing rate (BR), depth (TV), and minute ventilation (MV), was carried out during ES using the BreathMetrics breathing waveform analysis toolbox. Electrocardiography, arterial oxygen saturation, end-tidal and transcutaneous carbon dioxide, nasal airflow, and abdominal and thoracic plethysmography were monitored continuously during stimulations.Electrical stimulation of TP and CING (at lower current strengths3 mA) increased TV and MV. At7-10 mA, CING decreased TV and MV. On the other hand, decreased TV and MV occurred with stimulation of mesial temporal structures such as AMY and HG. Breathing changes were dependent on stimulation intensity. Lateral temporal, entorhinal, and orbitofrontal cortices did not affect breathing either way.These findings suggest that breathing responses other than apnea can be induced by ES. Identification of two regions-the temporal pole and anterior cingulate gyrus-for enhancement of breathing may be important in paving the way to future development of strategies for prevention of SUDEP.

Objectives Hypoxia, or abnormally low blood‐oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. Methods We analyzed high‐resolution T1‐weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic‐clonic seizures (GTCS) recorded during long‐term video‐electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age‐ and sex‐matched healthy controls (n = 43). Subjects were sub‐divided into those with mild/moderate (GTCS‐hypox‐mild/moderate, n = 12) and severe (GTCS‐hypox‐severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2) during VEEG. Whole‐brain voxel‐based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. Results Morphometric and volumetric alterations appeared in association with peri‐GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. Significance Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".

Dr Fisher and colleagues have recently provided a commentary on our critique of the 2017 International League Against Epilepsy (ILAE) classification of epileptic seizures and epilepsies. The commentary was disappointing in that it did not depart from their original views and suggests a lack of engagement to consider an alternative framework that might improve the ILAE classifications of epileptic seizures and the epilepsies. Epileptologists actively dealing with people with epilepsy must provide feedback and express their views on any official ILAE position, as the latter would only be valid if it succeeds in striking a balance between the perspectives of any ILAE commission and that of the practitioners. It is evident that thoughtful critiques of ILAE position papers can only be forwarded once a text is published and their directions put into use, which is what we did in our critique, in an effort to achieve the best synthesis of accumulated knowledge that could result in a practical, useful, and forward-looking classification of epileptic seizures and the epilepsies.

ObjectivesSudden unexpected death in epilepsy (SUDEP) is a catastrophic epilepsy outcome for which there are no reliable premortem imaging biomarkers of risk. Percival respiratory depression is seen in monitored SUDEP and near SUDEP cases, and abnormal chemosensing of raised blood carbon dioxide (CO2) is thought to contribute. Damage to brainstem respiratory control and chemosensing structures has been demonstrated in structural imaging and neuropathological studies of SUDEP. We hypothesized that functional MRI (fMRI) correlates of abnormal chemosensing are detectable in brainstems of persons with epilepsy (PWE) and are different from healthy controls (HC).MethodsWe analyzed fMRI BOLD activation and brain connectivity in 10 PWE and 10 age- and sex-matched HCs during precisely metered iso-oxic, hypercapnic breathing challenges. Segmented brainstem responses were of particular interest, along with characterization of functional connectivity metrics between these structures. Regional BOLD activations during hypercapnic challenges were convolved with hemodynamic responses, and the resulting activation maps were passed on to group-level analyses. For the functional connectivity analysis, significant clusters from BOLD results were used as seeds. Each individual seed time-series activation map was extracted for bivariate correlation coefficient analyses to study changes in brain connectivity between PWE and HCs.Results(1) Greater brainstem BOLD activations in PWE were observed compared to HC during hypercapnic challenges in several structures with respiratory/chemosensing properties. Group comparison between PWE vs. HC showed significantly greater activation in the dorsal raphe among PWE (p < 0.05) compared to HCs. (2) PWE had significantly greater seed-seed connectivity and recruited more structures during hypercapnia compared to HC.SignificanceThe results of this study show that BOLD responses to hypercapnia in human brainstem are detectable and different in PWE compared to HC. Increased dorsal raphe BOLD activation in PWE and increased seed-seed connectivity between brainstem and adjacent subcortical areas may indicate abnormal chemosensing in these individuals. Imaging investigation of brainstem respiratory centers involved in respiratory regulation in PWE is an important step toward identifying suspected dysfunction of brainstem breathing control that culminates in SUDEP and deserve further study as potential imaging SUDEP biomarkers.

For the treatment of mesial temporal lobe epilepsy on the language-dominant side in patients at high risk of memory decline, we propose a minimally invasive diagnostic and treatment technique, adopting the principles of multiple hippocampal transections (MHT) using stereo-electroencephalography-guided radiofrequency (SEEG-guided-RF-MHT). This new technique allows targeting of the longitudinal fibers in the hippocampus critical for seizure spreading, while sparing the transverse circuits which are considered important for memory processing and avoiding discomfort and longer post-operatory recovery time associated with craniotomies. We report the efficacy and safety of this procedure in a preliminary observational study of cases. Five patients at high risk of memory decline, including three with non-lesional hippocampi on MRI, had temporal lobe epilepsy (TLE) necessitating depth electrode implantation. A new strategy of SEEG electrode placement was used to mimic MHT. After confirming hippocampal seizure onset, all the patients had three linear ablations perpendicular to the amigdalohippocampal complex. The procedure was performed at the patient's bedside with the patient awake during the full length of the procedure. Four out of five patients were seizure-free (average follow up: 14-18 months). There were no associated complications. Visual inspection of brain MRI of patients at six months following SEEG-guided RF-MHT showed significant hippocampal volume preservation. Subjects who received the procedure in the dominant side reported no subjective memory complaints in the follow-up clinic assessments at six months. Our preliminary seizure outcome seems very promising since the majority of our patients (four out of five patients) were seizure-free. Since no lesions are made outside the amygdalo-hippocampal complex using this technique and the temporal stem remains intact, more favorable memory and language outcome is expected in patients at high risk of memory decline.

The aim of this study was to determine if insular damage is associated with markers of autonomic dysfunction.We studied patients who underwent temporal lobe and/or insular resections for epilepsy surgery between April 2010 and June 2015 at University Hospitals Cleveland Medical Center (UHCMC). Presurgical T1-weighted MPRAGE, standard T1, T2 and FLAIR sequences were compared with postsurgical MRI by a neuroradiologist and classified as type 0 (no involvement of insula), type 1 (minimal involvement of insular margin), type 2 (insular involvement25%), and type 3 (insular involvement ≥25%). Analysis of heart rate variability (HRV) was carried out in pre- and postoperative video-electroencephalography (vEEG) recording. Time-domain parameters were calculated: (mean of the RR intervals (MNN), root mean square difference of successive RR intervals (RMSSD), standard deviation of the RR intervals (SDNN), and coefficient of variation (CV)). In addition, frequency-domain parameters were calculated: low frequency (LF), high frequency (HF), and low frequency/high frequency (LF/HF).Twenty-one patients (14 females) with mean age of 36.2 ± 14.4 years (30; 22-75) were studied. Insular involvement was classified as type 0 (4 patients [19%]), type 1 (9 [43%]), type 2 (7 [33%]), and type 3 (1 [5%]). Significant decrease in RMSSD (p = 0.025) and CV (p = 0.008) was seen in insular damage types 2 and 3 compared with no or minimal insular involvement (types 0 and 1). Right-sided resections were associated with increase in LF power (p = 0.010) and the LF/HF ratio (p = 0.017).This study indicates that insular resection may lead to autonomic function changes.

Multimodal polygraphy including cardiorespiratory monitoring in the Epilepsy Monitoring is becoming increasingly important. In addition to simultaneous recording of video and EEG, the combination of these techniques not only improves seizure detection, it enhances patient safety and provides information on autonomic clinical symptoms, which may be contributory to localization of seizure foci. However, there are currently no consensus guidelines, nor adequate information on devices available for multimodal polygraphy for cardiorespiratory monitoring in the Epilepsy Monitoring Unit. Our purpose here is to provide protocols and information on devices for such monitoring. Suggested parameters include respiratory inductance plethysmography (thoraco-abdominal belts for respiratory rate), pulse oximetry and four-lead electrocardiography. Detailed knowledge of devices, their operability and acquisition optimization enables accurate interpretation of signal and differentiation of abnormalities from artifacts. Multimodal polygraphy brings new opportunities for identification of peri-ictal cardiorespiratory abnormalities, and may identify high SUDEP risk individuals.

Multimodal polygraphy including cardiorespiratory monitoring is a valuable tool for epilepsy and sudden unexpected death in epilepsy (SUDEP) research. Broader applications in research into stress, anxiety, mood and other domains exist. Polygraphy techniques used during video electroencephalogram (EEG) recordings provide information on cardiac and respiratory changes in the peri-ictal period. In addition, such monitoring in brain mapping during chronic intracranial EEG evaluations has helped the understanding of pathomechanisms that lead to seizure induced cardiorespiratory dysfunction. Our aim here is to provide protocols and information on devices that may be used in the Epilepsy Monitoring Unit, in addition to proposed standard of care data acquisition. These devices include oronasal thermistors, oronasal pressure transducers, capnography, transcutaneous CO

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.

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.

Objective: Electrical stimulation (ES) potentially delineates epileptogenic cortex through induction of typical seizures. Although frequently employed, its value for epilepsy surgery remains controversial. Similarly, ES is used to identify symptomatogenic zones, but with greater success and a long-standing evidence base. Recent work points to new seizure symptoms such as ictal central apnea (ICA) that may enhance presurgical hypotheses. The aims of this review are 2-fold: to determine the value of ES-induced seizures (ESIS) in epilepsy surgery and to analyze current evidence on ICA as a new surrogate of symptomatogenic cortex.Methods: Three databases were searched for ESIS. Investigators independently selected studies according to pre-specified criteria. Studies reporting postoperative outcome in patients with ESIS were included in a meta-analysis. For ES-induced apnea, a thorough search was performed and reference list searching was employed.Results: Of 6,314 articles identified for ESIS, 25 were considered eligible to be reviewed in full text. Fourteen studies were included in the qualitative synthesis (1,069 patients); six studies were included in the meta-analysis (530 patients). The meta-analysis showed that favorable outcome is associated with ESIS prior to surgery (OR: 2.02; 95% CI: 1.332–3.08). In addition, the overall estimation of the occurrence of favorable outcome among cases with ESIS is 68.13% (95% CI: 56.62–78.7). On the other hand, recent studies have shown that stimulation of exclusively mesial temporal lobe structures elicits central apnea and represents symptomatogenic anatomic substrates of ICA. This is in variance with traditional teaching that mesial temporal ES is non-symptomatogenic.Conclusions: ES is a tool highly likely to aid in the delineation of the epileptogenic zone, since ESIS is associated with favorable postoperative outcomes (Engel I). There is an urgent need for prospective evaluation of this technique, including effective stimulation parameters and surgical outcomes, that will provide knowledge base for practice. In addition, ES-induced apnea studies suggest that ICA, especially when it is the first or only clinical sign, is an important semiological feature in localizing the symptomatogenic zone to mesial temporal lobe structures, which must be considered in SEEG explorations where this is planned, and in surgical resection strategies.

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.

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.

This article critiques the International League Against Epilepsy (ILAE) 2015-2017 classifications of epilepsy, epileptic seizures, and status epilepticus. It points out the following shortcomings of the ILAE classifications: (1) they mix semiological terms with epileptogenic zone terminology; (2) simple and widely accepted terminology has been replaced by complex terminology containing less information; (3) seizure evolution cannot be described in any detail; (4) in the four-level epilepsy classification, level two (epilepsy category) overlaps almost 100% with diagnostic level one (seizure type); and (5) the design of different classifications with distinct frameworks for newborns, adults, and patients in status epilepticus is confusing. The authors stress the importance of validating the new ILAE classifications and feel that the decision of Epilepsia to accept only manuscripts that use the ILAE classifications is premature and regrettable.

Introduction Ictal central apnea (ICA) occurs in up to 44% focal seizures (temporal > extratemporal) and precedes scalp electrographic (EEG) seizure onset in 54% of them. Central apnea can be elicited by electrical stimulation of mesial temporal structures (amygdala, hippocampus, and anteromesial parahippocampal and fusiform gyri), known symptomatogenic anatomical substrates for ICA. We aimed to analyze ICA value as an early semiological sign in invasive evaluation of suspected mesial temporal lobe epilepsy (MTLE). Methods We examined seizure records of intractable, suspected MTLE patients undergoing intracranial EEG (ICEEG) evaluations who had simultaneous respiratory belts with artifact-free signal. Results We analyzed 32 seizures (11 patients). ICA was seen in 22/32 (68.7%) seizures in 9 patients, was the first clinical manifestation in all of them, and the only clinical sign in 5/32 (15.6%). ICA onset occurred simultaneously or after ICEEG seizure onset in 20/22 (91%) seizures by 4.9 +4.6 [0-14] seconds. In one patient with bilateral amygdalar and hippocampal implantation, ICA occurred before ICEEG seizure onset, indicating seizure discharge in an untargeted, probably extra amygdalohippocampal, symptomatogenic location. Conclusions ICA incidence in mesial temporal lobe (MTL) seizures is 68.7%. ICA is often the first clinical sign and sometimes the only clinical manifestation in MTLE, but usually goes unrecognized. ICA recognition may help anatomo-electro-clinical localization of clinical seizure onset to known symptomatogenic areas. ICA preceding ICEEG onset may indicate inadequate putative epileptogenic zone coverage, and may impact surgical outcomes. Respiratory monitoring in surgical evaluations is of critical importance and should be carried out as standard of care.

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.

A 56-year-old man with refractory bitemporal epilepsy was monitored in the Epilepsy Monitoring Unit (EMU). In a video-EEG captured seizure, brief oroalimentary automatisms were followed by increased inspiratory effort, accompanied by prominent, visible tracheal movements and audible inspiratory stridor. The patient's oxygen saturation rapidly declined to 62%; persistent severe hypoxemia ended with spontaneous effective respiration commencing at seizure end. Subsequent seizures necessitated intensive care unit admission for respiratory distress, and ventilator support. This case suggests that ictal laryngospasm, a rare seizure manifestation, may represent another potential mechanism of sudden unexpected death in epilepsy (SUDEP). [Published with video sequence on www.epilepticdisorders.com].

Author(s): Lacuey, Nuria; Zonjy, Bilal; Hampson, Johnson P; Rani, MR Sandhya; Zaremba, Anita; Sainju, Rup K; Gehlbach, Brian K; Schuele, Stephan; Friedman, Daniel; Devinsky, Orrin; Nei, Maromi; Harper, Ronald M; Allen, Luke; Diehl, Beate; Millichap, John J; Bateman, Lisa; Granner, Mark A; Dragon, Deidre N; Richerson, George B; Lhatoo, Samden D | Abstract: 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 l .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 l75%). Focal onset impaired awareness (FOIA) motor onset with automatisms and FOA nonmotor onset semiologies were associated with ICA presence (P l .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.

MRI-negative anterior cingulate epilepsy is a rare entity. Herein, we describe a case of MRI and functional imaging-negative intractable frontal lobe epilepsy in which, initially, secondary bilateral syn- chrony of surface and intracranial EEG and non-lateralizing semiology rendered identification of the epileptogenic zone difficult. A staged bilat- eral stereotactic EEG exploration revealed a very focal, putative ictal onset zone in the right anterior cingulate gyrus, as evidenced by interictal and ictal high-frequency oscillations (at 250 Hz) and induction of seizures from the same electrode contacts by 50-Hz low-intensity cortical stimulation. This was subsequently confirmed by ILAE class 1 outcome following resec- tion of the ictal onset and irritative zones. Histopathological examination revealed focal cortical dysplasia type 1b (ILAE Commission, 2011) as the cause of epilepsy. The importance of anatomo-electro-clinical correlation is illustrated in this case in which semiological and electrophysiological fea- tures pointed to the anatomical localization of a challenging, MRI-negative epilepsy. (Published with video sequence)

The aim of this study is to investigate functional connectivity between right and left mesial temporal structures using cerebrocerebral evoked potentials. We studied seven patients with drug-resistant focal epilepsy who were explored with stereotactically implanted depth electrodes in bilateral hippocampi. In all patients cerebrocerebral evoked potentials evoked by stimulation of the fornix were evaluated as part of a research project assessing fornix stimulation for control of hippocampal seizures. Stimulation of the fornix elicited responses in the ipsilateral hippocampus in all patients with a mean latency of 4.6 ms (range 2-7 ms). Two patients (29 %) also had contralateral hippocampus responses with a mean latency of 7.5 ms (range 5-12 ms) and without involvement of the contralateral temporal neocortex or amygdala. This study confirms the existence of connections between bilateral mesial temporal structures in some patients and explains seizure discharge spreading between homotopic mesial temporal structures without neocortical involvement.

Objective The aim of this study was to determine if insular damage is associated with markers of autonomic dysfunction. Methods We studied patients who underwent temporal lobe and/or insular resections for epilepsy surgery between April 2010 and June 2015 at University Hospitals Cleveland Medical Center (UHCMC). Presurgical T1-weighted MPRAGE, standard T1, T2 and FLAIR sequences were compared with postsurgical MRI by a neuroradiologist and classified as type 0 (no involvement of insula), type 1 (minimal involvement of insular margin), type 2 (insular involvement Analysis of heart rate variability (HRV) was carried out in pre- and postoperative video-electroencephalography (vEEG) recording. Time-domain parameters were calculated: (mean of the RR intervals (MNN), root mean square difference of successive RR intervals (RMSSD), standard deviation of the RR intervals (SDNN), and coefficient of variation (CV)). In addition, frequency-domain parameters were calculated: low frequency (LF), high frequency (HF), and low frequency/high frequency (LF/HF). Results Twenty-one patients (14 females) with mean age of 36.2 ± 14.4 years (30; 22–75) were studied. Insular involvement was classified as type 0 (4 patients [19%]), type 1 (9 [43%]), type 2 (7 [33%]), and type 3 (1 [5%]). Significant decrease in RMSSD (p = 0.025) and CV (p = 0.008) was seen in insular damage types 2 and 3 compared with no or minimal insular involvement (types 0 and 1). Right-sided resections were associated with increase in LF power (p = 0.010) and the LF/HF ratio (p = 0.017). Conclusions This study indicates that insular resection may lead to autonomic function changes.

Objective The aim of this study is to determine outcome of resective epilepsy surgery in MRI-negative extratemporal lobe epilepsy (MNETLE) patients who underwent invasive evaluations and to determine factors governing outcome. Methods We studied 28 patients who underwent resective epilepsy surgery for MNETLE from August 2006 to November 2015, in whom complete follow-up information was available. Electro-clinical, pathological and surgical data were evaluated. 24 patients (82.8%) were explored with intracranial EEG (9 stereoelectroencephalography (SEEG), 7 subdural grids and 8 both). All patients were followed for at least 6 months. Results During a mean follow up period of 32 [6–113] months, 13 (46.4%) patients became seizure-free (ILAE 1) and 18 (64.3%) had a good (ILAE 1, 2, 3) outcome. 21 (75.0%) patients had focal cortical dysplasia (FCD). Univariate analysis showed that more restricted (regional) interictal and ictal epileptiform discharges in surface EEG were significantly associated with seizure freedom (P = 0.016 and P = 0.024). Multivariate analysis confirmed that having ≥120 electrode contacts in the evaluation is an independent variable predicting seizure freedom (HR = 4.283, 95% CI = 1.342–13.676, P = 0.014). Conclusion Invasive EEG is a powerful tool in the pre-surgical evaluation of patients with MNETLE. Invasive EEG implantation that include the irritative zone and EEG onset zone as indicated by surface EEG, as well as wider brain coverage predict seizure freedom, contingent upon a sound anatomo-electro-clinical hypothesis for implantation.

SummaryObjective To describe the phenomenology of monitored sudden unexpected death in epilepsy (SUDEP) occurring in the interictal period where death occurs without a seizure preceding it. Methods We report a case series of monitored definite and probable SUDEP where no electroclinical evidence of underlying seizures was found preceding death. Results Three patients (two definite and one probable) had SUDEP. They had a typical high SUDEP risk profile with longstanding intractable epilepsy and frequent generalized tonic–clonic seizures (GTCS). All patients had varying patterns of respiratory and bradyarrhythmic cardiac dysfunction with profound electroencephalography (EEG) suppression. In two patients, patterns of cardiorespiratory failure were similar to those seen in some patients in the Mortality in Epilepsy Monitoring Units Study (MORTEMUS). Significance SUDEP almost always occur postictally, after GTCS and less commonly after a partial seizure. Monitored SUDEP or near-SUDEP cases without a seizure have not yet been reported in literature. When nonmonitored SUDEP occurs in an ambulatory setting without an overt seizure, the absence of EEG information prevents the exclusion of a subtle seizure. These cases confirm the existence of nonseizure SUDEP; such deaths may not be prevented by seizure detection–based devices. SUDEP risk in patients with epilepsy may constitute a spectrum of susceptibility wherein some are relatively immune, death occurs in others with frequent GTCS with one episode of seizure ultimately proving fatal, while in others still, death may occur even in the absence of a seizure. We emphasize the heterogeneity of SUDEP phenomena.

Stereotactic electroencephalography is a method for the invasive study for the human epileptic brain as a prelude to epilepsy surgery. The discipline of stereotactic electroencephalography is underpinned by an anatomo-electro-clinical analysis of epileptic seizures of focal origin and goes beyond simple stereotactic placement of depth electrodes. Stringent analysis of semiological and electrophysiological features is coupled with an understanding of this information in 3D anatomical space. Stereotactic electroencephalography offers significant advantages over subdural grid implantations, allowing pinpoint accuracy access to sulcal areas and deep brain structures, such as the insula, cingulate, basal and mesial brain regions, while associated with lower complication rates. Recent times have seen an exponential growth in stereotactic electroencephalography interest, driven in part by increasing complexity of typical epilepsy surgery patients in epilepsy surgery centers. Such patients are much more likely to be magnetic resonance imaging negative, or reoperations, or to have multifocal or widespread areas of cortical abnormalities. Herein, we discuss the advantages of stereotactic electroencephalography, principles of patient selection, implantation, and interpretation.

We analyzed the only two sudden unexpected death in epilepsy (SUDEP) cases from 320 prospectively recruited patients in the three-year Prevention and Risk Identification of SUDEP Mortality (PRISM) project. Both patients had surgically refractory epilepsy, evidence of left insular damage following previous temporal/temporo-insular resections, and progressive changes in heart rate variability (HRV) in monitored evaluations prior to death. Insular damage is known to cause autonomic dysfunction and increased mortality in acute stroke. This report suggests a possible role for the insula in the pathogenesis of SUDEP. The presence of intrinsic insular lesions or acquired insular damage in patients with refractory epilepsy may be an additional risk factor for SUDEP.