Long-term efficacy and safety of cannabidiol in patients with treatment-resistant epilepsies: Four-year results from the expanded access program.

OBJECTIVE: Cannabidiol (CBD) expanded access program, initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsies (TREs) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019. METHODS: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/ml oral solution), increasing from 2 to 10 mg/kg/day to tolerance or maximum 25-50 mg/kg/day dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit. RESULTS: Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (range = 0-74.5), and patients were taking a median of three (range = 0-10) antiseizure medications (ASMs) at baseline; the most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/day; median exposure duration was 694 days. Median percentage reduction from baseline ranged 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) ranged 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. The most common AEs (≥20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%). SIGNIFICANCE: Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of TREs.

Adaptive Remote Sensing Paradigm for Real-Time Alerting of Convulsive Epileptic Seizures.

Epilepsy is a debilitating neurological condition characterized by intermittent paroxysmal states called fits or seizures. Especially, the major motor seizures of a convulsive nature, such as tonic-clonic seizures, can cause aggravating consequences. Timely alerting for these convulsive epileptic states can therefore prevent numerous complications, during, or following the fit. Based on our previous research, a non-contact method using automated video camera observation and optical flow analysis underwent field trials in clinical settings. Here, we propose a novel adaptive learning paradigm for optimization of the seizure detection algorithm in each individual application. The main objective of the study was to minimize the false detection rate while avoiding undetected seizures. The system continuously updated detection parameters retrospectively using the data from the generated alerts. The system can be used under supervision or, alternatively, through autonomous validation of the alerts. In the latter case, the system achieved self-adaptive, unsupervised learning functionality. The method showed improvement of the detector performance due to the learning algorithm. This functionality provided a personalized seizure alerting device that adapted to the specific patient and environment. The system can operate in a fully automated mode, still allowing human observer to monitor and override the decision process while the algorithm provides suggestions as an expert system.

Effect of morphine administration after status epilepticus on epileptogenesis in rats.

INTRODUCTION: Morphine is widely used in patients and has been reported to alter seizure threshold, but its role in the development of epilepsy is unknown. In this study, role of morphine administration in the development of epilepsy using the status epilepticus (SE) model was determined in rats. METHODS: Rats experiencing SE with lithium-pilocarpine (LiP) were randomized into four groups- saline, morphine low dose (5 mg/kg, s.c.), morphine high dose (5-20 mg/kg, s.c.), and naloxone (1 mg/kg, s.c.). Treatments were started 90 min after termination of SE and repeated twice daily for next three days. Rats were video monitored daily for 21 days to determine onset and frequency of spontaneous convulsive seizures (SS). RESULTS: Morphine in low doses increased frequency of SS (1.51 ± 0.15 vs LiP 0.60 ± 0.12 seizures/rat/day, p-value = 0.0026) and seizures occurred during handling (SDH) (0.08 ± 0.02 vs LiP control 0.01 ± 0.01) (p-value = 0.0018). In high doses, no significant change in SS and SDH was found as compared to LiP. No effect of morphine on the onset of SS and percentage of rats experienced SS was found. No effect of naloxone per se was found on SS. CONCLUSION: Morphine administration after SE does not affect epileptogenesis as no change in the onset of SS and percentage of rats experiencing SS was found. However, it might alter the susceptibility and frequency of SS. As no other study is available with a similar finding, it needs further evaluation.

Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials.

OBJECTIVE: We conducted a post hoc analysis of two randomized controlled trials, GWPCARE1 (NCT02091375) and GWPCARE2 (NCT02224703), to estimate the time to onset of cannabidiol (CBD) treatment effects (seizure reduction and adverse events [AEs]) in patients with Dravet syndrome (DS). METHODS: Patients received either plant-derived highly purified CBD (Epidiolex in the United States; 100 mg/ml oral solution) 10 mg/kg/day (CBD10; GWPCARE2) or 20 mg/kg/day (CBD20; GWPCARE1&2), or matching placebo for 14 weeks. Treatment started at 2.5 mg/kg/day, reached 10 mg/kg/day on Day 7, and went up to 20 mg/kg/day on Day 11 during the 14-day titration period. Percentage change from baseline in convulsive seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were also evaluated. RESULTS: Overall, 124 patients received placebo and 194 received CBD (CBD10, n = 64; CBD20, n = 130). Mean age was 9.5 years (range = 2.2-18.9). Patients had discontinued a median of four antiepileptic drugs (range = 0-26) and were currently taking a median of three (range = 1-5). Differences in convulsive seizure reduction between placebo and CBD emerged during titration and became nominally significant by Day 12 for CBD20 (p = .02) and Day 13 for CBD10 (p = .03). Additionally, differences in the 50% responder rate between placebo and CBD became apparent during titration. Onset of the first reported AE occurred during the titration period in 48.4% of placebo patients and 54.1% of CBD patients. The three most common AEs of somnolence, decreased appetite, and diarrhea resolved within 4 weeks of onset in the majority of CBD-treated patients (56.3%-72.9%). SIGNIFICANCE: The therapeutic effect of CBD in DS may start within 2 weeks of treatment in some patients. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week study period.

Add-on cannabidiol in patients with Dravet syndrome: Results of a long-term open-label extension trial.

OBJECTIVE: Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. METHODS: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day. RESULTS: Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444 days (range = 18-1535), with a mean modal dose of 22 mg/kg/day; patients received a median of three concomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations >3 × upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%-74% for convulsive seizures and 49%-84% for total seizures. Across all visit windows, ≥83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition. SIGNIFICANCE: We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: Compassionate use program in Germany.

OBJECTIVE: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). METHODS: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between .13 and .7 mg/kg/day. RESULTS: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1-46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31-572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic-clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range = .5-30) to 3.0 (range = 0-30) in the 3-month period before and after FFA treatment (p < .001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p = .005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. SIGNIFICANCE: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.

Influence of titration of antiseizure medications on treatment selection: Results of an online survey with clinicians in the United States.

INTRODUCTION: Most antiseizure medications (ASM) need to be titrated before the optimal dose is achieved. Titration can last several weeks to months. We assessed the impact titration schedules have on ASM treatment-related decisions in the United States (US). METHODS: An online survey was conducted with different healthcare providers (HCPs) in the US involved in the treatment and management of patients with epilepsy. The survey contained three sections: the first section with screening questions; the second on key factors that influence a HCP's decision-making when selecting treatments for different types of seizures and different treatment lines; and the third on the HCP's knowledge and perceptions regarding ASM titration for the treatment of patients with epilepsy. RESULTS: One-hundred and fifty HCPs (63% neurologists) completed the survey. Most HCPs considered titration schedule to be important, with only 1-3% of HCPs, depending on type of seizure, considering the titration schedule to be "not important at all" when prescribing therapy. Healthcare providers' acceptance of titration increased with shorter durations (≥50% accepted titration periods of ≤2 weeks), and lower number of tablets/capsules per dose (≥50% accepted ≤3 tablets/capsules per dose), doses (≥50% accepted ≤2 doses/day), and steps (≥50% accepted ≤3 steps/dose change). Most HCPs (68-91% depending on type of seizure) considered a titration duration of 6 or more weeks only somewhat acceptable or somewhat or highly unacceptable. Almost all HCPs selected "somewhat familiar", "familiar", or "very familiar" as the attribute that best defines their knowledge level of titration, with only 4% selecting "a little familiar". While 87% of HCPs agreed or strongly agreed that they could easily understand titration schedules, only 27% of them agreed or strongly agreed that patients could easily understand titration schedules and 58% of HCPs considered that adhering to the titration schedule was difficult for patients. Most HCPs agreed or strongly agreed that a complex or long titration schedule renders it difficult to achieve their treatment objectives. CONCLUSIONS: Healthcare providers take into account the duration and complexity of the titration period in their ASM prescribing decision-making and prefer shorter and simpler titration schedules, particularly for patients who are experiencing convulsive seizures and starting monotherapy. There was a clear difference between the HCP's belief in their own ability to understand a titration schedule, and their belief that the patient would be able to follow the titration schedule appropriately.

Anti-seizure medications and efficacy against focal to bilateral tonic-clonic seizures: A systematic review with relevance for SUDEP prevention.

We conducted a systematic review of anti-seizure medications (ASMs) and their efficacy for the control of focal to bilateral tonic-clonic seizures (FBTCS). FBTCS, especially when nocturnal, are recognized as one of the major risk factors for Sudden Unexpected Death in Epilepsy (SUDEP). We searched different online databases for all the randomized, double-blinded, and placebo-controlled clinical trials of ASMs that were FDA-approved after 1990 and that reported specifically on the reduction in FBTCS; when possible, this was compared to reduction in focal impaired awareness (FIA) seizures. The ASMs that yielded the most data (3 or more studies) were topiramate (TPM), followed by tiagabine (TGB), brivaracetam (BRV), and lamotrigine (LTG). TPM trials showed a reduction in FBTCS of 44.8% to 100% (4.5-99% over placebo); TGB 21.8% to 46.7% (21.8-61% over placebo); BRV 33.9% to 82.1% (11.6-57.4% over placebo); and LTG 55.2% (20.3-52% over placebo). Promising results, but with data from only one or two studies, were seen with cenobamate (18-59% efficacy above placebo), lacosamide (45.1-78.7%), levetiracetam (40.1-60.3%), oxcarbazepine (58.5-81.5%), and gabapentin (50-53.8%). Higher responses were often seen at higher doses, including at doses above those currently approved by the FDA. Results specific to nocturnal FBTCS were never reported for any ASM. Moreover, complete freedom from FBTCS specifically was very rarely reported, despite its relevance for SUDEP prevention. In conclusion, there are few data specifically comparing the efficacy of ASMs for prevention of FBTCS despite the known strong association of BTCS with SUDEP. This review was our attempt at filling a gap in the literature and calling for universal reporting of data specific to BTC seizure reduction in all future studies, preferably including specific reporting on nocturnal BTCS. This will help enable rational ASM selection to minimize BTC seizures and thereby decrease the risk of SUDEP.

The Efficacy and Safety Profile of Generic Intravenous Levetiracetam in a Real-World Setting.

BACKGROUND: There are 3 main epileptic conditions in hospital settings that may require intravenous antiepileptic treatment: status epilepticus, acute repetitive convulsive seizures, and postoperative seizures. Generic intravenous levetiracetam (IV LEV) (Focale; Great Eastern Drug Co, Bangkok, Thailand), has been reported to have comparable efficacy to original IV LEV for treating status epilepticus and acute repetitive convulsive seizures in a randomized controlled trial. At present, there are limited data on the efficacy and tolerability of generic intravenous LEV in real-world situations. OBJECTIVE: This study aimed to evaluate the clinical outcomes of generic IV LEV in a real-world setting. METHODS: A retrospective study and analyses were conducted. All adult patients who used IV LEV at University Hospital, Khon Kaen University, Thailand from June 1, 2019, until February 15, 2020, were included. Data were analyzed and reported in terms of the efficacy and tolerability of generic IV LEV. RESULTS: Ninety-three patients received IV LEV by 3 indications: status epilepticus, acute repetitive convulsive seizures, and postoperative seizures. The proportions of these 3 indications were 41.94% (39 patients), 9.67% (9 patients), and 48.39% (45 patients), respectively. The average seizure control rate at 24 hours was 89.25%. The seizure control rate was significantly higher in the acute repetitive convulsive seizures and postoperative seizure groups than in the status epilepticus group when generic IV LEV was given as the first-line treatment (75.00%; 88.37% vs 50.00%; P 0.035). The average length of hospital stay was 18.24 (25.40) days. There was no significant discharge status among the 3 groups (P = 0.348). Moreover, the average mortality rate was 5.38%. Side effects were reported in 14 patients (15.05%). The 2 most common side effects were vomiting and bronchospasm (3 patients; 3.22%). There were 10 patients with uncontrolled seizures at 24 hours (10.75%). The only factor associated with uncontrolled seizures at 24 hours was a history of epilepsy. The uncontrolled seizure group had a higher proportion of epilepsy patients than the seizure-controlled group (70.00% vs 33.73%; P = 0.037). Poor discharge status (not improved/death) was 18.28% (17 patients). There was no significant factor between those with an improved or poor discharge status. CONCLUSIONS: Generic IV LEV was effective and relatively well tolerated in the 3 clinical settings (ie, status epilepticus, acute repetitive convulsive seizures, and postoperative seizures). Further clinical data are still required to confirm the results of this study.(Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

Seizure detection using heart rate variability: A prospective validation study.

Although several validated seizure detection algorithms are available for convulsive seizures, detection of nonconvulsive seizures remains challenging. In this phase 2 study, we have validated a predefined seizure detection algorithm based on heart rate variability (HRV) using patient-specific cutoff values. The validation data set was independent from the previously published data set. Electrocardiography (ECG) was recorded using a wearable device (ePatch) in prospectively recruited patients. The diagnostic gold standard was inferred from video-EEG monitoring. Because HRV-based seizure detection is suitable only for patients with marked ictal autonomic changes, we defined responders as the patients who had a>50 beats/min ictal change in heart rate. Eleven of the 19 included patients with seizures (57.9%) fulfilled this criterion. In this group, the algorithm detected 20 of the 23 seizures (sensitivity: 87.0%). The algorithm detected all but one of the 10 recorded convulsive seizures and all of the 8 focal impaired awareness seizures, and it missed 2 of the 4 focal aware seizures. The median sensitivity per patient was 100% (in nine patients all seizures were detected). The false alarm rate was 0.9/24 h (0.22/night). Our results suggest that HRV-based seizure detection has high performance in patients with marked autonomic changes.

Post-ictal accelerometer silence as a marker of post-ictal immobility.

OBJECTIVE: Movement-based wearable sensors are used for detection of convulsive seizures. The identification of the absence of motion following a seizure, known as post-ictal immobility (PI), may represent a potential additional application of wearables. PI has been associated with potentially life-threatening complications and with sudden unexpected death in epilepsy (SUDEP). We aimed to assess whether wearable accelerometers (ACCs) could be used as a digital marker of PI. METHOD: Devices with embedded ACCs were worn by patients admitted to an epilepsy monitoring unit. Participants presenting with convulsive seizures were included in the study. PI presence and duration were assessed by experts reviewing video recordings. An algorithm for the automatic detection of post-ictal ACC silence and its duration was developed and the linear pairwise relationship between the automatically detected duration of post-ictal ACC silence and the duration of the expert-labeled PI was analyzed. RESULTS: Twenty-two convulsive seizures were recorded from 18 study participants. Twenty were followed by PI and two by agitation. The automated estimation of post-ictal ACC silence identified all the 20 expert-labeled PI. The regression showed that the duration of the post-ictal ACC silence was correlated with the duration of PI (Pearson r = .92; P < .001), with the age of study participants (Pearson r = .78; P < .001), and with the duration of post-ictal generalized electroencephalography suppression (PGES; Pearson r = .4; P = .033). SIGNIFICANCE: We highlight a novel application of wearables as a way to record post-ictal manifestations associated with an increased risk of SUDEP. The occurrence of a fatal seizure is unpredictable and the continuous, non-invasive, long-term identification of risk factors associated with each individual seizure may assume a great clinical importance.

Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.

OBJECTIVE: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. METHODS: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. RESULTS: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. SIGNIFICANCE: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Health-related quality of life and the burden of prolonged seizures in noninstitutionalized children with epilepsy.

OBJECTIVE: This study aimed to provide information on the burden of illness and health-related quality of life (HRQoL) in children with epilepsy who experience prolonged acute convulsive seizures (PACS) in the community setting, and to investigate factors that may predict poor HRQoL in this population. METHODS: Noninstitutionalized children (aged 3-16 years) who had experienced at least one PACS within the past year and had currently prescribed PACS rescue medication were enrolled in a cross-sectional study in Germany, Italy, Spain, and the United Kingdom (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3 [PERFECT-3]). Clinicians, parents/guardians, and patients completed web-based questionnaires regarding clinical characteristics, PACS frequency, and day-to-day impairment. Patients' HRQoL was rated by clinicians, parents/guardians, and patients themselves using the 5-dimension EuroQol questionnaire (EQ-5D) and summarized as a utility score. Potential predictors of poor HRQoL were tested in individual univariate generalized linear models and a global multivariable model. RESULTS: Enrolled children (N = 286) had experienced 1-400 PACS (median: 4) in the past year. Clinicians reported that 216/281 patients (76.9%) had learning disabilities of varying severity. Mean EQ-5D utility scores rated by clinicians (n = 279), parents (n = 277), and patients (n = 85) were 0.52 (standard deviation: 0.41), 0.51 (0.39), and 0.74 (0.29), respectively. Increasing PACS frequency, increasing severity of learning disability, and specialist school attendance were significantly associated with decreasing EQ-5D utility score. In the multivariable model, having learning disabilities was the best predictor of poor HRQoL. SIGNIFICANCE: Health-related quality of life was very poor in many children with epilepsy whose PACS were managed with rescue medication in the community, with learning disability being the most powerful predictor of patients' HRQoL. Mean EQ-5D utility scores were lower (worse) than published values for many other chronic disorders, indicating that optimal treatment should involve helping children and their families to manage learning disabilities and day-to-day impairments, in addition to preventing seizures.

Autonomic dysregulation in children with epilepsy with postictal generalized EEG suppression following generalized convulsive seizures.

OBJECTIVE: Postictal generalized electroencephalographic suppression (PGES) has been associated with sudden unexpected death in epilepsy (SUDEP) in adults. Decreased heart rate variability (HRV) is one clinical marker of SUDEP in adults with epilepsy. The objective of this study was to analyze the characteristics of HRV associated with generalized convulsive seizures (GCS) ±â€¯PGES in children. METHODS: Nine hundred and seventy-seven consecutive children who underwent prolonged scalp video-EEG (vEEG) and 1-lead electrocardiogram (ECG) monitoring at the Hospital for Sick Children, Toronto, Ontario, Canada were reviewed retrospectively from 2009 to 2011. Thirty-five children had GCS captured during their vEEG with or without PGES and met inclusion criteria. Children were subdivided into three age groups and compared with age-matched controls: 3-6 years; 7-12 years; and 13-18 years. Interictal HRV was measured at 5 min during N2 sleep. Preictal HRV was measured at 1 h prior to GCS onset, and postictal HRV was measured at 3 min post-GCS cessation. Low frequency (LF: ms2, 0.04-0.15 Hz) and high frequency (HF: ms2, 0.15-0.4 Hz) bands of heart rate oscillations were analyzed during the interictal and preictal periods. The root mean square of successive differences (RMSSDs) was analyzed during the following time points: interictal; preictal; and postictal. RESULTS: Thirty-five children had GCS: 18 children with PGES [3-6 years (n = 2); 7-12 years (n = 6); 13-18 years (n = 10)] and 17 children without PGES [3-6 years (n = 6); 7-12 years (n = 5); 13-18 years (n = 6)]. Seventeen additional age-matched controls were identified [3-6 years (n = 3); 7-12 years (n = 5); 13-18 years (n = 9)]. Seventy-four GCS were captured consisting of 36 GCS + PGES and 38 GCS - PGES. There was no difference of interictal HRV among children with GCS ±â€¯PGES and controls. The preictal LF and HF in 36 GCS + PGES were significantly higher compared with 38 GCS - PGES (p < 0.01). The postictal RMSSD in 36 GCS + PGES was significantly higher compared with 38 GCS - PGES (p < 0.01). The pre- to postictal RMSSD change was significantly lower in children with GCS + PGES than in those with GCS - PGES (p = 0.035). CONCLUSIONS: In summary, the preictal HRV in GCS + PGES was significantly higher than in children with GCS - PGES. The higher remaining postictal RMSSD in children with GCS + PGES is a potential indicator of autonomic dysregulation. In certain children with epilepsy, autonomic dysregulation may contribute to poor recovery from a GCS with subsequent PGES, thereby contributing to SUDEP. Heart rate variability and autonomic regulation in children with epilepsy should be further studied prospectively in order to better understand the mechanism by which PGES may lead to SUDEP.

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.

Novel features for capturing temporal variations of rhythmic limb movement to distinguish convulsive epileptic and psychogenic nonepileptic seizures.

OBJECTIVE: To investigate the characteristics of motor manifestation during convulsive epileptic and psychogenic nonepileptic seizures (PNES), captured using a wrist-worn accelerometer (ACM) device. The main goal was to find quantitative ACM features that can differentiate between convulsive epileptic and convulsive PNES. METHODS: In this study, motor data were recorded using wrist-worn ACM-based devices. A total of 83 clinical events were recorded: 39 generalized tonic-clonic seizures (GTCS) from 12 patients with epilepsy, and 44 convulsive PNES from 7 patients (one patient had both GTCS and PNES). The temporal variations in the ACM traces corresponding to 39 GTCS and 44 convulsive PNES events were extracted using Poincaré maps. Two new indices-tonic index (TI) and dispersion decay index (DDI)-were used to quantify the Poincaré-derived temporal variations for every GTCS and convulsive PNES event. RESULTS: The TI and DDI of Poincaré-derived temporal variations for GTCS events were higher in comparison to convulsive PNES events (P < 0.001). The onset and the subsiding patterns captured by TI and DDI differentiated between epileptic and convulsive nonepileptic seizures. An automated classifier built using TI and DDI of Poincaré-derived temporal variations could correctly differentiate 42 (sensitivity: 95.45%) of 44 convulsive PNES events and 37 (specificity: 94.87%) of 39 GTCS events. A blinded review of the Poincaré-derived temporal variations in GTCS and convulsive PNES by epileptologists differentiated 26 (sensitivity: 70.27%) of 44 PNES events and 33 (specificity: 86.84%) of 39 GTCS events correctly. SIGNIFICANCE: In addition to quantifying the motor manifestation mechanism of GTCS and convulsive PNES, the proposed approach also has diagnostic significance. The new ACM features incorporate clinical characteristics of GTCS and PNES, thus providing an accurate, low-cost, and practical alternative to differential diagnosis of PNES.

Cardiac stress after electroconvulsive therapy and spontaneous generalized convulsive seizures: A prospective echocardiographic and blood biomarker study.

AIM: Knowledge about cardiac stress related to seizures in electroconvulsive therapy (ECT) and spontaneously occurring generalized convulsive seizures (GCS) is limited. The aim of the present study was to analyze cardiac function and circulating markers of cardiac stress in the early postictal period after ECT and GCS. METHODS: Patients undergoing ECT in the Department of Psychiatry, Psychotherapy and Psychosomatics and patients undergoing diagnostic video-EEG monitoring (VEM) in the Department of Neurology were prospectively enrolled between November 2017 and November 2018. Cardiac function was examined twice using transthoracic echocardiography within 60 min and >4 h after ECT or GCS. Established blood markers (troponin T high-sensitive, N-terminal pro brain natriuretic peptide) of cardiac stress or injury were collected within 30 min, 4 to 6 h, and 24 h after ECT or GCS. In the ECT group, the troponin T values were also correlated with periprocedural heart rate and blood pressure values. Because of organizational or technical reasons, the measurement was not performed in all patients. RESULTS: Twenty patients undergoing ECT and 6 patients with epilepsy with a GCS during VEM were included. Postictal echocardiography showed no wall motion disorders and no change in left ventricular and right ventricular functions. Four of 17 patients displayed a transient increase in high-sensitive cardiac troponin T 4-6 h after the seizure (3 patients with ECT-induced seizure). None of these 4 patients had signs of an acute cardiac event, and periprocedural blood pressure or heart rate peaks during ECT did not significantly differ in patients with and without troponin T elevation. CONCLUSIONS: Signs of mild cardiac stress can occur in some patients following ECT or GCS without clinical complications, probably related to excessive catecholamine release during the seizure.

Neurogenic pulmonary edema following seizures: A retrospective computed tomography study.

INTRODUCTION: Data on the frequency and clinical relevance of neurogenic pulmonary edema (NPE) following epileptic seizures are limited. The aim of the present study was to analyze computed tomography (CT) examinations in patients with previous seizures. METHOD: Incidence of NPE and related clinical factors were retrospectively assessed in patients admitted because of epileptic seizures who underwent thoracic CT imaging as part of emergency diagnostics. RESULTS: Between January 2010 and January 2016, we included all patients admitted with the International Classification of Diseases (ICD) diagnosis code of epileptic seizure or epilepsy and who underwent CT imaging, including visualization of the lungs, as part of emergency diagnostics. Of the 47 included patients, 26 patients had suffered from generalized convulsive seizures (GCS), 17 patients had focal seizures with impaired and 4 without impaired consciousness. Signs of NPE were present in 5 out of 47 patients; all 5 patients had GCS prior to thoracic CT scan (i.e., 19% of patients with GCS). In four out of five cases, a single seizure was described; in one case, the seizure was only partially witnessed, but the indirect clinical signs strongly suggested a GCS. Related factors such as the initial respiratory rate or the initial pCO2 value were not significantly different in patients with and without signs of NPE. CONCLUSIONS: The highly selected and biased patient group warrants caution in the interpretation of the study results. Our data, however, confirm that signs of NPE appear to be rather frequent in patients with GCS. Its clinical significance as regards morbidity and sudden death in epilepsy is discussed.

Effect of gabapentin on sleep patterns disturbed by epilepsy.

For a long time, numerous sleep alterations induced by nocturnal epilepsy have been described. Such alterations include sleep fragmentation, decrement of sleep efficiency, increment of the wake time after sleep onset (WASO), increment of light sleep, and decrement of sleep depth. On the other hand, gabapentin (GBP), an antiepileptic drug analog of γ-aminobutyric acid (GABA) used as adjunctive and eventually, as a monotherapeutic treatment, induces a significant improvement in patients with both focal and secondarily generalized partial seizures. In experimental epilepsy models, this drug protects against pentylenetetrazol (PTZ)-induced convulsions. In consideration of such GBP properties, the aim of this work was to investigate its efficacy to protect against sleep disturbances provoked by convulsive seizures induced by the administration of PTZ. Nine-hour (9-hour) polygraphic studies were carried out in chronically implanted male adult Wistar rats separated into 4 different groups of 6 individuals. Control recordings in each group were done after saline administration. One group received a SC Subcutaneous (SC) injection of 50 mg/kg of PTZ alone while the other three groups were injected with either 15, 30, or 60 mg/kg IP Intraperitoneal (IP) of GBP 30 min prior to PTZ (50 mg/kg SC) administration. Animals displayed the whole range of electrophysiological and behavioral manifestations of the disease during the epileptic episodes induced by PTZ administration, and the states of vigilance were significantly altered. Insomnia occurred immediately after PTZ injection preceding the appearance of the first epileptic symptoms. Thus, both slow wave sleep (SWS) and rapid eye movement sleep (REM sleep) were completely inhibited during a relatively long period of time. The disturbing effects of epilepsy on sleep decreased when animals were under GBP treatment. Improvement of sleep was dependent on the administered dose of this antiepileptic drug.

Continuous EEG monitoring after brain tumor surgery.

BACKGROUND: Prolonged seizures generate cerebral hypoxia and increased intracranial pressure, resulting in an increased risk of neurological deterioration, increased long-term morbidity, and shorter survival. Seizures should be recognized early and treated promptly. The aim of the study was to investigate the occurrence of postoperative seizures in patients undergoing craniotomy for primary brain tumors and to determine if non-convulsive seizures could explain some of the postoperative neurological deterioration that may occur after surgery. METHODS: A single-center prospective study of 100 patients with suspected glioma. Participants were studied with EEG and video recording for at least 24 h after surgery. RESULTS: Seven patients (7%) displayed seizure activity on EEG recording within 24 h after surgery and another two patients (2%) developed late seizures. One of the patients with early seizures also developed late seizures. In five patients (5%), there were non-convulsive seizures. Four of these patients had a combination of clinically overt and non-convulsive seizures and in one patient, all seizures were non-convulsive. The non-convulsive seizures accounted for the majority of total seizure time in those patients. Non-convulsive seizures could not explain six cases of unexpected postoperative neurological deterioration. Postoperative ischemic lesions were more common in patients with early postoperative seizures. CONCLUSIONS: Early seizures, including non-convulsive, occurred in 7% of our patients. Within this group, non-convulsive seizure activity had longer durations than clinically overt seizures, but only 1% of patients had exclusively non-convulsive seizures. Seizures were not associated with unexpected neurological deterioration.