Use of Fluoxetine to Augment the Inter-Ictal Hypercapnic Ventilatory Response in Patients with Epilepsy: A Pilot Study.

Background: Severe peri-ictal respiratory dysfunction is a potential biomarker for high SUDEP risk and correlates with an attenuated hypercapnic ventilatory response (HCVR). Prior studies suggest a potential role for selective serotonergic reuptake inhibitors in modifying the HCVR, but this approach has not been studied in the epilepsy population. Objectives: To assess the feasibility of using fluoxetine to augment HCVR in epilepsy patients. Methods and Material: An inter-ictal HCVR was measured using a CO2 rebreathing technique in patients with epilepsy aged 18-75 years. Eligible participants were randomized to fluoxetine or placebo, and the HCVR was repeated at the end of week 4. Primary outcomes were recruitment and retention rate. Results: Of the 30 subjects enrolled, 22 were randomized (mean: 3.8 subjects/3 months), with a retention rate of 100% in fluoxetine and 95% in placebo. Conclusions: Our results demonstrate feasibility for a larger definitive future study to assess the efficacy of fluoxetine in augmenting HCVR.

Hypercapnic ventilatory response in epilepsy patients treated with VNS: A case-control study.

OBJECTIVE: Central CO2 chemoreception (CCR), a major chemical drive for breathing, can be quantified with a CO2 re-breathing test to measure the hypercapnic ventilatory response (HCVR). An attenuated HCVR correlates with the severity of respiratory dysfunction after generalized convulsive seizures and is a potential biomarker for sudden unexpected death in epilepsy (SUDEP) risk. Vagus nerve stimulation (VNS) may reduce SUDEP risk, but for unclear reasons the risk remains higher during the first 2 years after implantation. The vagus nerve has widespread connections in the brainstem, including key areas related to CCR. Here we examined whether chronic electrical stimulation of the vagus nerve induces changes in CCR. METHODS: We compared the HCVR in epilepsy patients with or without an active VNS in a sex- and age-matched case-control study. Eligible subjects were selected from a cohort of patients who previously underwent HCVR testing. The HCVR slope, change in minute ventilation (VE) with respect to change in end tidal (ET) CO2 (∆ VE/ ∆ ETCO2) during the test was calculated for each subject. Key variables were compared between the two groups. Univariate and multivariate analyses were carried out for HCVR slope as dependent variable. RESULTS: A total of 86 subjects were in the study. HCVR slope was significantly lower in the cases compared to the controls. Cases had longer duration of epilepsy and higher number of anti-epileptic drugs (AEDs) tried during lifetime. Having active VNS and ETCO2 were associated with a low HCVR slope while high BMI was associated with high HCVR slope in both univariate and multivariate analyses. DISCUSSION: We found having an active VNS was associated with relatively attenuated HCVR slope. Although duration of epilepsy and number of AEDs tried during lifetime was significantly different between the groups, they were not predictors of HCVR slope in subsequent analysis. CONCLUSION: Chronic electrical stimulation of the vagus nerve by VNS may be associated with an attenuated CCR [Correction added on 24 November 2021, after first online publication: The preceding sentence has been revised from "Chronic electrical stimulation of VNS nerve by VNS…"]. A larger prospective study may help to establish the time course of this effect in relation to the time of VNS implantation, whether there is a causal relationship, and determine how it affects SUDEP risk.

Ventilatory response to CO2 in patients with epilepsy.

OBJECTIVE: Severe periictal respiratory depression is thought to be linked to risk of sudden unexpected death in epilepsy (SUDEP) but its determinants are largely unknown. Interindividual differences in the interictal ventilatory response to CO2 (hypercapnic ventilatory response [HCVR] or central respiratory CO2 chemosensitivity) may identify patients who are at increased risk for severe periictal hypoventilation. HCVR has not been studied previously in patients with epilepsy; therefore we evaluated a method to measure it at bedside in an epilepsy monitoring unit (EMU) and examined its relationship to postictal hypercapnia following generalized convulsive seizures (GCSs). METHODS: Interictal HCVR was measured by a respiratory gas analyzer using a modified rebreathing technique. Minute ventilation (VE ), tidal volume, respiratory rate, end tidal (ET) CO2 and O2 were recorded continuously. Dyspnea during the test was assessed using a validated scale. The HCVR slope (ΔVE /ΔETCO2 ) for each subject was determined by linear regression. During the video-electroencephalography (EEG) study, subjects underwent continuous respiratory monitoring, including measurement of chest and abdominal movement, oronasal airflow, transcutaneous (tc) CO2 , and capillary oxygen saturation (SPO2 ). RESULTS: Sixty-eight subjects completed HCVR testing in 151 ± (standard deviation) 58 seconds, without any serious adverse events. HCVR slope ranged from -0.94 to 5.39 (median 1.71) L/min/mm Hg. HCVR slope correlated with the degree of unpleasantness and intensity of dyspnea and was inversely related to baseline ETCO2 . Both the duration and magnitude of postictal tcCO2 rise following GCSs were inversely correlated with HCVR slope. SIGNIFICANCE: Measurement of the HCVR is well tolerated and can be performed rapidly and safely at the bedside in the EMU. A subset of individuals has a very low sensitivity to CO2 , and this group is more likely to have a prolonged increase in postictal CO2 after GCS. Low interictal HCVR may increase the risk of severe respiratory depression and SUDEP after GCS and warrants further study.

Utility and safety of depth electrodes within the supratemporal plane for intracranial EEG.

OBJECTIVE: The epileptogenic zones in some patients with temporal lobe epilepsy (TLE) involve regions outside the typical extent of anterior temporal lobectomy (i.e., "temporal plus epilepsy"), including portions of the supratemporal plane (STP). Failure to identify this subset of patients and adjust the surgical plan accordingly results in suboptimum surgical outcomes. There are unique technical challenges associated with obtaining recordings from the STP. The authors sought to examine the clinical utility and safety of placing depth electrodes within the STP in patients with TLE. METHODS: This study is a retrospective review and analysis of all cases in which patients underwent intracranial electroencephalography (iEEG) with use of at least one STP depth electrode over the 10 years from January 2006 through December 2015 at University of Iowa Hospitals and Clinics. Basic clinical information was collected, including the presence of ictal auditory symptoms, electrode coverage, monitoring results, resection extent, outcomes, and complications. Additionally, cases in which the temporal lobe was primarily or secondarily involved in seizure onset and propagation were categorized based upon how rapidly epileptic activity was observed within the STP following seizure onsets: within 1 second, between 1 and 15 seconds, after 15 seconds, and not involved. RESULTS: Fifty-two patients underwent iEEG with STP coverage, with 1 STP electrode used in 45 (86.5%) cases and 2 STP electrodes in the other cases. There were no complications related to STP electrode placement. Of 42 cases in which the temporal lobe was primarily or secondarily involved, seizure activity was recorded from the STP in 36 cases (85.7%): in 5 cases (11.9%) within 1 second, in 5 (11.9%) between 1 and 15 seconds, and in 26 (61.9%) more than 15 seconds following seizure onset. Seizure outcomes inversely correlated with rapid ictal involvement of the STP (Engel class I achieved in 25%, 67%, and 82% of patients in the above categories, respectively). All patients without ictal STP involvement achieved seizure freedom. Only 4 (11.1%) patients with STP ictal involvement reported auditory symptoms. CONCLUSIONS: Ictal involvement of the STP is common even in the absence of auditory symptoms and can be effectively detected by the STP electrodes. These electrodes are safe to implant and provide useful prognostic information.

Drug-resistant epilepsy development following stem cell transplant and cyclosporine neurotoxicity induced seizures: Case report in an adult and analysis of reported cases in the literature.

INTRODUCTION: Drug-resistant epilepsy (DRE) occurs in 20-30% of all patients who develop epilepsy and can occur from diverse causes. Cyclosporine-A (CSA) is an immunosuppressive drug utilized to prevent graft-versus-host disease (GvHD) in transplant patients and is known to cause neurotoxicity, including seizures. In some cases, however, patients can develop DRE. Only a limited number of cases have been reported in which DRE has developed after CSA exposure - all in children. Here we present a rare case of an adult developing DRE after post-transplant CSA neurotoxicity. In addition, we provide a comprehensive review and analysis of all reported cases in the literature. CASE REPORT: A 29-year-old man with Non-Hodgkin's Lymphoma underwent an allogenic hematopoietic stem cell transplant and experienced a CSA-induced seizure at 7.5 months' post-transplant. The patient was discontinued on CSA and began a low dose tacrolimus regimen. At 33 months' post-transplant, he had seizure recurrence and developed DRE. Imaging revealed right mesial temporal sclerosis (MTS) and video EEG localized ictal activity to the right anterior temporal lobe. He was successfully treated with a right anterior temporal lobectomy and amygdalohippocampectomy. LITERATURE REVIEW: Seven peer-reviewed studies described 15 patients who underwent transplantation with post-transplant CSA administration and subsequently developed DRE following an initial CSA-induced seizure. All 15 patients were children suggesting that young age is a risk factor for DRE after CSA-induced seizures. Initial CSA-induced seizures occurred at an average of 1.6 ± 1.1 months after transplant and seizure recurrence 9.2 ± 8.0 months after transplant. All reported CSA routes of administration (n = 6) were intravenous and 7 of 9 (78%) reported CSA blood levels above the therapeutic range. The incidence of MTS (40%) in these 15 patients was significantly higher than the incidence in the general DRE population (24%) and was most effectively treated via epilepsy surgery. CONCLUSIONS: The use of cyclosporine for GvHD prophylaxis and treatment following transplantation may cause seizures and be associated with DRE. Although discontinuation and dose decrease of CSA often reverse adverse neurological events, initial CSA-induced seizures may be associated with MTS that and subsequent greater risk of DRE development.

Tolerability of a comprehensive cardiorespiratory monitoring protocol in an epilepsy monitoring unit.

BACKGROUND: Recent reports of fatal or near-fatal events in epilepsy monitoring units (EMUs) and an increasing awareness of the effects of seizures on breathing have stimulated interest in cardiorespiratory monitoring for patients undergoing video-electroencephalography (EEG) recording. Patient and provider acceptance of these extra recording devices has not previously been studied and may represent a barrier to widespread adoption. METHODS: We queried EMU subjects regarding their experiences with a monitoring protocol that included the continuous measurement of oral/nasal airflow, respiratory effort (chest and abdominal respiratory inductance plethysmography), oxygen saturation, and transcutaneous CO2. Surveys were returned by 71.4% (100/140) of eligible subjects. RESULTS: Overall, 73% of participants reported being moderately to highly satisfied with the monitoring, and 82% reported moderate to strong agreement that advance knowledge of the monitoring would not have changed their decision to proceed with the video-EEG study. Except for nasal airflow, none of the additional monitoring devices caused more discomfort than EEG electrodes. CONCLUSION: Patient acceptance of an EMU comprehensive cardiorespiratory monitoring protocol is high. The information obtained from "multimodality recording" should help clinicians and investigators understand the effect of seizures on both cardiac and respiratory physiology, may enhance safety in the EMU, and may aid in the identification of biomarkers for sudden unexpected death in epilepsy (SUDEP).

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.

Breathing Inhibited When Seizures Spread to the Amygdala and upon Amygdala Stimulation.

Sudden unexpected death in epilepsy (SUDEP) is increasingly recognized as a common and devastating problem. Because impaired breathing is thought to play a critical role in these deaths, we sought to identify forebrain sites underlying seizure-evoked hypoventilation in humans. We took advantage of an extraordinary clinical opportunity to study a research participant with medically intractable epilepsy who had extensive bilateral frontotemporal electrode coverage while breathing was monitored during seizures recorded by intracranial electrodes and mapped by high-resolution brain imaging. We found that central apnea and O2 desaturation occurred when seizures spread to the amygdala. In the same patient, localized electrical stimulation of the amygdala reproduced the apnea and O2 desaturation. Similar effects of amygdala stimulation were observed in two additional subjects, including one without a seizure disorder. The participants were completely unaware of the apnea evoked by stimulation and expressed no dyspnea, despite being awake and vigilant. In contrast, voluntary breath holding of similar duration caused severe dyspnea. These findings suggest a functional connection between the amygdala and medullary respiratory network in humans. Moreover, they suggest that seizure spread to the amygdala may cause loss of spontaneous breathing of which patients are unaware, and thus has potential to contribute to SUDEP. SIGNIFICANCE STATEMENT: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with chronic refractory epilepsy. Impaired breathing during and after seizures is common and suspected to play a role in SUDEP. Understanding the cause of this peri-ictal hypoventilation may lead to preventative strategies. In epilepsy patients, we found that seizure invasion of the amygdala co-occurred with apnea and oxygen desaturation, and electrical stimulation of the amygdala reproduced these respiratory findings. Strikingly, the subjects were unaware of the apnea. These findings indicate a functional connection between the amygdala and brainstem respiratory network in humans and suggest that amygdala seizures may cause loss of spontaneous breathing of which patients are unaware-a combination that could be deadly.

Mapping the temporal pole with a specialized electrode array: technique and preliminary results.

Temporopolar cortex plays a crucial role in the pathogenesis of temporal lobe epilepsy and subserves important cognitive functions. Because of its shape and position in the middle cranial fossa, complete electrode coverage of the temporal pole (TP) is difficult to achieve using existing devices. We designed a novel TP electrode array that conforms to the surface of temporopolar cortex and achieves dense electrode coverage of this important brain region. A multi-pronged electrode array was designed that can be placed over the surface of the TP using a straightforward insertion technique. Twelve patients with medically intractable epilepsy were implanted with the TP electrode array for purposes of seizure localization. Select patients underwent cognitive mapping by electrocorticographic (ECoG) recording from the TP during a naming task. Use of the array resulted in excellent TP electrode coverage in all patients. High quality ECoG data were consistently obtained for purposes of delineating seizure activity and functional mapping. During a naming task, significant increases in ECoG power were observed within localized subregions of the TP. One patient developed a transient neurological deficit thought to be related to the mass effect of multiple intracranial recording arrays, including the TP array. This deficit resolved following removal of all electrodes. The TP electrode array overcomes limitations of existing devices and enables clinicians and researchers to obtain optimal multi-site recordings from this important brain region.

Sudden unexpected death in epilepsy: fatal post-ictal respiratory and arousal mechanisms.

Sudden unexplained death in epilepsy (SUDEP) is the cause of premature death of up to 17% of all patients with epilepsy and as many as 50% with chronic refractory epilepsy. However, SUDEP is not widely recognized to exist. The etiology of SUDEP remains unclear, but growing evidence points to peri-ictal respiratory, cardiac, or autonomic nervous system dysfunction. How seizures affect these systems remains uncertain. Here we focus on respiratory mechanisms believed to underlie SUDEP. We highlight clinical evidence that indicates peri-ictal hypoxemia occurs in a large percentage of patients due to central apnea, and identify the proposed anatomical regions of the brain governing these responses. In addition, we discuss animal models used to study peri-ictal respiratory depression. We highlight the role 5-HT neurons play in respiratory control, chemoreception, and arousal. Finally, we discuss the evidence that 5-HT deficits contribute to SUDEP and sudden infant death syndrome and the striking similarities between the two.

Vagus nerve stimulation after lead revision.

OBJECT: Vagus nerve stimulation (VNS) has demonstrated benefit in patients with medically intractable partial epilepsy. As in other therapies with mechanical devices, hardware failure occurs, most notably within the VNS lead, requiring replacement. However, the spiral-designed lead electrodes wrapped around the vagus nerve are often encased in dense scar tissue hampering dissection and removal. The objective in this study was to characterize VNS lead failure and lead revision surgery and to examine VNS efficacy after placement of a new electrode on the previously used segment of vagus nerve. METHODS: The authors reviewed all VNS lead revisions performed between October 2001 and August 2011 at the University of Iowa Hospitals and Clinics. Twenty-four patients underwent 25 lead revisions. In all cases, the helical electrodes were removed, and a new lead was placed on the previously used segment of vagus nerve. All inpatient and outpatient records of the 25 lead revisions were retrospectively reviewed. RESULTS: Four cases were second lead revisions, and 21 cases were first lead revisions. The average time to any revision was 5 years (range 1.8-11.1 years), with essentially no difference between a first and second lead revision. The most common reason for a revision was intrinsic lead failure resulting in high impedance (64%), and the most common symptom was increased seizure frequency (72%). The average duration of surgery for the initial implantation in the 15 patients whose VNS system was initially implanted at the authors' institution was much shorter (94 minutes) than the average duration of lead revision surgery (173 minutes). However, there was a significant trend toward shorter surgical times as more revision surgeries were performed. Sixteen of the 25 cases of lead revision were followed up for more than 3 months. In 15 of these 16 cases, the revision was as effective as the previous VNS lead. In most of these cases, both the severity and frequency of seizures were decreased to levels similar to those following the previous implantation procedure. Only 1 complication occurred, and there were no postoperative infections. CONCLUSIONS: Lead revision surgery involving the placement of a new electrode at the previously used segment of vagus nerve is effective at decreasing the seizure burden to an extent similar to that obtained following the initial VNS implantation. Even with multiple lead revisions, patients can obtain VNS efficacy similar to that following the initial lead implantation. There is a learning curve with revision surgery, and overall the duration of surgery is longer than for the initial implantation. Note, however, that complications and infection are rare.

A systematic review of validated methods for identifying seizures, convulsions, or epilepsy using administrative and claims data.

PURPOSE: To systematically review algorithms to identify seizure, convulsion, or epilepsy cases in administrative and claims data, with a focus on studies that have examined the validity of the algorithms. METHODS: A literature search was conducted using PubMed and the Iowa Drug Information Service database. Reviews were conducted by two investigators to identify studies using data sources from the USA or Canada because these data sources were most likely to reflect the coding practices of Mini-Sentinel data partners. RESULTS: Eleven studies that validated seizure, convulsion, or epilepsy cases were identified. All algorithms included International Classification of Diseases, Ninth Revision, Clinical Modification code 345.X (epilepsy) and either code 780.3 (convulsions) or code 780.39 (other convulsions). Six studies included 333.2 (myoclonus). In populations that included children, 779.0 (convulsions in newborn) was also fairly common. Positive predictive values (PPVs) ranged from 21% to 98%. Studies that used nonspecific indicators such as presence of an electroencephalogram or anti-epileptic drug (AED) level monitoring had lower PPVs. In studies focusing exclusively on epilepsy as opposed to isolated seizure events, sensitivity ranged from 70% to 99%. CONCLUSIONS: Algorithm performance was highly variable, so it is difficult to draw any strong conclusions. However, the PPVs were generally best in studies where epilepsy diagnoses were required. Using procedure codes for electroencephalograms or prescription claims for drugs possibly used for epilepsy or convulsions in the absence of a diagnostic code is not recommended. Many newer AEDs require no drug level monitoring, so requiring an AED level monitoring procedure in algorithms to identify epilepsy is not recommended.

Bimodal ultradian seizure periodicity in human mesial temporal lobe epilepsy.

BACKGROUND: Mesial temporal lobe epilepsy (mTLE) has been suggested to follow a circadian rhythm. Previous research found an afternoon peak in mTLE seizure occurrence. We evaluated the pattern of seizure occurrence in patients with well-localized mTLE and hypothesized that peak seizure frequency would occur in the afternoon, and that this pattern would not be altered by age, gender, or seizure focus. METHODS: We retrospectively identified consecutive mTLE patients with a seizure-free outcome following anterior temporal lobectomy from 1993 to 2004 with video-EEG captured seizures. We recorded and plotted the 24-h clock time for each seizure and performed cosinor analysis. SAS Proc GLIMMIX was used to fit the linearized transform of the cosinor model. Negative binomial regression fitted by the generalized estimating equations (GEE) method was also performed to estimate and compare the mean seizure rates over a 24-h day. RESULTS: Sixty mTLE patients monitored between 2 and 16 days were analyzed. Mean (standard deviation), median number of seizures per subject were 10.47(7.86), 9.00. Cosinor plots indicated that the function had two modes: 7-8 a.m. and 4-5 p.m. GEE analysis was consistent with peak seizure frequency occurrence at 6-8 a.m. (p<0.0001) and 3-5 p.m. (p<0.01). CONCLUSIONS: We found a bimodal pattern of seizure occurrence in human mTLE, with peak seizure frequencies occurring between 6-8 a.m. and 3-5 p.m. confirming an afternoon peak, as well as a previously unsuspected morning peak in seizure occurrence that provides rationale for future investigations of antiepileptic drug chronopharmacology and informs patient counseling regarding patterns of seizure occurrence.

The effects of vagus nerve stimulation on decision-making.

Subcortical and brainstem structures are increasingly becoming recognized as important contributors to higher cognitive functioning. Decision-making is one such function, particularly as viewed within the framework of the somatic marker hypothesis (SMH). The SMH views the participation in decision-making by the body proper as integral to emotional biasing and hence key to choosing in an advantageous manner. This study focuses on the vagus nerves as a possible conduit for somatic afferent signals pertinent to decision-making. We tested eight epileptic patients with implanted left vagus nerve stimulators. To assess decision-making we used the gambling task, which is sensitive to real-life decision-making deficits. Using a counterbalanced design, each participant performed the gambling task under a condition in which low-level vagus nerve stimulation (VNS) was covertly delivered, and another condition in which no VNS was delivered. Participants showed improved performance, that is, made more advantageous choices, in the stimulated relative to the unstimulated condition. Although these results should be viewed as preliminary, they suggest that the vagus nerve is a conduit for afferent somatic signals that can influence decision-making.