A library of quantitative markers of seizure severity

Objective

Understanding fluctuations in seizure severity within individuals is important for determining treatment outcomes and responses to therapy, as well as assessing novel treatments for epilepsy. Current methods for grading seizure severity rely on qualitative interpretations from patients and clinicians. Quantitative measures of seizure severity would complement existing approaches to electroencephalographic (EEG) monitoring, outcome monitoring, and seizure prediction. Therefore, we developed a library of quantitative EEG markers that assess the spread and intensity of abnormal electrical activity during and after seizures.

Methods

We analyzed intracranial EEG (iEEG) recordings of 1009 seizures from 63 patients. For each seizure, we computed 16 markers of seizure severity that capture the signal magnitude, spread, duration, and postictal suppression of seizures.

Results

Quantitative EEG markers of seizure severity distinguished focal versus subclinical seizures across patients. In individual patients, 53% had a moderate to large difference (rank sum $r>.3$, $p<.05$) between focal and subclinical seizures in three or more markers. Circadian and longer term changes in severity were found for the majority of patients.

Significance

We demonstrate the feasibility of using quantitative iEEG markers to measure seizure severity. Our quantitative markers distinguish between seizure types and are therefore sensitive to established qualitative differences in seizure severity. Our results also suggest that seizure severity is modulated over different timescales. We envisage that our proposed seizure severity library will be expanded and updated in collaboration with the epilepsy research community to include more measures and modalities.     

Human heart rate variability and sleep stages

With the aim of better understanding the dynamic changes in sympatho-vagal tone occurring during the night, human heart rate variability (HRV) during the various sleep stages was evaluated by means of autoregressive spectral analysis.Each recording consisted of an electroencephalogram, an electrooculogram, and electromyogram, an electrocardiogram, and a spirometry trace. All of the data were sampled and stored in digital form.Sleep was analysed visually, but HRV was analysed off-line by means of original software using Burg's algorithm to calculate the LF/HF ratio (LF: 0.04–0.12 Hz; HF: 0.15–0.35 Hz) for each sleep stage.Seven healthy subjects (four males; mean age 35 years) were enrolled in the study.Our findings show a progressive and significant reduction in the LF/HF ratio through sleep stages S1–S4, as a result of an increase in the HF component; this indicates the prevalence of parasympathetic activity during slow-wave sleep. During wakefulness, S1 and REM, the LF/HF values were similar and close to 1.

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Sommario Allo scopo di comprendere meglio le modificazioni del tono del sistema nervoso autonomo durante la notte, è stata valutata la variabilità del ritmo cardiaco (HRV) negli stadi del sonno, impiegando una metodica autoregressiva di analisi spettrale.Ciascuna registrazione consisteva di elettroencefalogramma, elettro-oculogramma, elettromiografia, spirometria ed elettrocardiogramma, campionati e registrati in forma digitale.L'ipnogramma è stato ottenuto ispettivamente, mentre l'analisi dell'HRV è stata eseguita con un software dedicato, utilizzando l'algoritmo di Burg e calcolando il rapporto LF/HF (LF: 0.04–0.12 Hz; HF: 0.15–0.35 Hz) per ciascuno stadio del sonno.Sono stati arruolati nello studio 7 soggetti sani (4 maschi, età media 35 anni). I nostri risultati mostrano una progressiva e significativa diminuzione di LF/HF dallo stadio 1 al 4, imputabile ad un aumento del tono del parasimpatico (aumento della componente HF), mentre il valore del rapporto durante veglia, REM e fase 1 è risultato simile (circa 1).

     

强迫症患者治疗前后心率变异性的频谱分析

目的 观察强迫症患者治疗前后心率变异性的改变.方法 符合CCMD-3强迫症诊断标准的68例患者口服马来酸氟伏沙明治疗,治疗前后进行心率变异性检查.结果 强迫症组治疗前的心率变异性总功率(TP)、高频功率(HF)指标均低于正常对照组,差异有统计学意义(P＜0.01),低频功率/高频功率强迫症组治疗前高于正常对照组,差异具...     

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.     

No apparent effect of surgery for temporal lobe epilepsy on heart rate variability

BACKGROUND: Impaired cardiac autonomic function may contribute to the risk of sudden unexpected death in epilepsy (SUDEP). Clinical observations indicate that successful epilepsy surgery is associated with a reduced risk of SUDEP. However, in a previous study we found impaired cardiac control pre-surgically in patients with poor outcome of surgery, indicating an a priori lower risk in responders to epilepsy surgery. We have now examined the effect of surgery on cardiac autonomic control in the same patients. METHODS: We used 24 h EKG recordings to assess heart rate variability (HRV) by spectral analysis in 21 consecutive patients after temporal lobe epilepsy surgery. The HRV was compared with healthy controls, with pre-surgical HRV in the same patients, and analyzed in relation to seizure control 1 year after surgery. RESULTS: The patients with poor outcome after surgery had significantly lower SD of RR-intervals, total power, very low frequency power and low frequency power than matched healthy controls. The patients with favorable outcome did not differ from the controls, and the postoperative HRV was not different from HRV before surgery in any of the patient groups. CONCLUSION: We could not demonstrate any effect on HRV of temporal lobe epilepsy surgery in these patients. The observed lower HRV in the poor outcome group was present already before epilepsy surgery as previously reported. Although our results need confirmation in a larger study, the observations suggest that the increased risk of SUDEP in patients failing epilepsy surgery may be due to a common factor predisposing to surgical failure, impaired HRV as well as to an increased risk of SUDEP.     

A systematic review and meta-analysis of heart rate variability in epilepsy and antiepileptic drugs

Purpose: Epilepsy is associated with near‐fatal and fatal arrhythmias, and sudden unexpected death in epilepsy (SUDEP) is partly related to cardiac events. Dysfunction of the autonomous nervous system causes arrhythmias and, although previous studies have investigated the effects of epilepsy on the autonomic control of the heart, the results are still mixed regarding whether imbalance of sympathetic, vagal, or both systems is present in epilepsy, and also the importance of anticonvulsant treatment on the autonomic system. Therefore, we aimed to investigate epilepsy and its treatment impact on heart rate variability (HRV), assessed by sympathetic and parasympathetic activity expressed as low‐frequency (LF) and high‐frequency (HF) power spectrum, respectively. Method: We performed a systematic review from the first date available to July 2011 in Medline and other databases; key search terms were “epilepsy”; “anticonvulsants”; “heart rate variability”; “vagal”; and “autonomous nervous system.” Original studies that reported data and/or statistics of at least one HRV value were included, with data being extracted by two independent authors. We used a random‐effects model with Hedges’s g as the measurement of effect size to perform two main meta‐analyses comparing LF and HF HRV values in (1) epilepsy patients versus controls; (2) patients receiving versus not receiving treatment; and (3) well‐controlled versus refractory patients. Secondary analyses assessed other time‐ and frequency‐domain measurements (nonlinear methods were not analyzed due to lack of sufficient data sets). Quality assessment of each study was verified and also meta‐analytic techniques to identify and control bias. Meta‐regression for age and gender was performed. Key Findings: Initially, 366 references were identified. According to our eligibility criteria, 30 references (39 studies) were included in our analysis. Regarding HF, epilepsy patients presented lower values (g ?0.69) than controls, with the 95% confidence interval (CI) ranging from ?1.05 to ?0.33. No significant differences were observed for LF (g ?0.18; 95% CI ?0.71 to 0.35). Patients receiving treatment presented HF values to those not receiving treatment (g ?0.05; 95% CI ?0.37 to 0.27), with a trend for having higher LF values (g 0.1; 95% CI ?0.13 to 0.33), which was more pronounced in those receiving antiepileptic drugs (vs. vagus nerve stimulation). No differences were observed for well‐controlled versus refractory patients, possibly due to the low number of studies. Regression for age and gender did not influence the results. Finally, secondary time‐domain analyses also showed lower HRV and lower vagal activity in patients with epilepsy, as shown by the standard deviation of normal‐to‐normal interval (SDNN) and the root mean square of successive differences (RMSSD) indexes, respectively. Significance: We confirmed and extended the hypothesis of sympathovagal imbalance in epilepsy, as showed by lower HF, SDNN, and RMSSD values when compared to controls. In addition, there was a trend for higher LF values in patients receiving pharmacotherapy. As lower vagal (HF) and higher sympathetic (LF) tone are predictors of morbidity and mortality in cardiovascular samples, our findings highlight the importance of investigating autonomic function in patients with epilepsy in clinical practice. Assessing HRV might also be useful when planning therapeutic interventions, as some antiepileptic drugs can show hazardous effects in cardiac excitability, potentially leading to cardiac arrhythmia.     

Stability over time of short-term heart rate variability

Abstract Heart rate variability (HRV) is a widely used method to assess cardiac autonomic control. However, the reproducibility of especially short-term HRV has not been properly evaluated. Therefore, we assessed the stability of short-term HRV over a three to four month period. We had seven consecutive electrocardiographic (ECG) recordings from 89 subjects with stable coronary artery disease obtained during a large multicenter study. The HRV assessments were performed from these 40-minute ECG-recordings simulating normal daily activities, i. e., recordings consisting of 5 to 10 minute periods of rest, paced breathing, standing, submaximal exercise and recovery. Both time and frequency domain HRV analyses were conducted from the whole 40-minute recordings and from the 5-minute periods of rest and paced breathing. The coefficient of variation (CV) varied between 5.1–16.7% for the 40-minute and 6.0–37.1% for the 5-minute time domain and 4.4–11.0 % for the 40-minute and 7.2–16.5 % for the 5-minute frequency domain measurements. The mean of the RR intervals and the total power showed the highest stability over time. The most unstable measure was the standard deviation of all NN intervals (SDNN). In conclusion, most short-term HRV measures were highly stable over time indicating low physiological variation. However, the SDNN showed large variability in consecutive recordings. Sources of support: EU Environment and Climate Research Program, contract NV4-CT97–0568.     

The relationship between heart rate variability and measures of body habitus

There is a well-recognized relationship between autonomic nervous system function and body habitus although few studies have addressed the role of the parasympathetic nervous system. A decrease in parasympathetic nervous-system-mediated heart rate variability in obesity may in part explain the mortality and morbidity that are associated with the obese state. We used multiple linear regression techniques to explore the relationship between measures of heart rate variability and anthropometric indices in 597 male participants in the Normative Aging Study. After adjustment for age and log₁₀ heart rate, weight and body mass index were significant predictors of both the expiratory to inspiratory ratio (E/I ratio) and the difference between maximum and minimum heart rate (HR_Max-Min). The abdomen-to-hip ratio and percentage body fat were not significant predictors of measures of heart rate variability. A one standard deviation change in the anthropometric index (weight, body mass index) resulted in a decrease in the E/I ratio of 0.010–0.014 and a decrease in the HR_Max-Min of 0.486–0.715 beats/min. A change in the anthropometric index across the distribution (5–95 percentile) resulted in a decrease in the E/I ratio of 0.032–0.037 and a decrease in the HR_Max-Min of 1.56–2.39 beats/min. These results indicate that heart rate variability and overall body size are correlated. This association could in part explain the mortality and morbidity that is associated with the obese state.     

The effect of depression on heart rate variability during pregnancy

Depression during pregnancy has been associated with a number of adverse outcomes, but the underlying physiological mechanisms involved remain unclear. The purpose of this study was to examine the effects of maternal depression during pregnancy on the autonomic modulation of heart rate, in a naturalistic setting. Eighty-one pregnant women were studied between 25 and 31 weeks of gestation and were identified as either Depressed (n = 46), or healthy, Control (n = 35), based on depression scores and lifetime psychiatric history. Subjects wore a 24-h Holter recorder to measure time-domain and frequency-domain of heart rate variability (HRV). Pregnant women in the Depressed Group had significantly reduced time-domain measures: standard deviation of all 24-h NN intervals (SDNN) and the standard deviation of the averages of NN intervals in all 5-min segments of the entire recording (SDANN) (P = 0.013, 0.016, respectively), as well as higher heart rates while asleep (P = 0.028), compared to Controls, after controlling for age, smoking, and antidepressant (AD) medication. The low frequency/high frequency (LF/HF) ratio during the sleeping hours was associated with higher depression scores (R = 0.24; P = 0.041). HRV measures improved in women taking AD medication. The autonomic nervous system may be affected in women experiencing depression during pregnancy, indicating a possible decreased parasympathetic (vagal) influence. Women taking AD medication showed some improvement in HRV measures. These data suggest that psychophysiological changes occur in women experiencing depression during pregnancy.     

Effects of caffeine on heart rate and QT variability during sleep

Administration of caffeine in the evening produces poor sleep. Patients with insomnia have characteristic electrocardiogram (ECG) changes, including increased heart rate (HR), increased sympathetic activity, and decreased parasympathetic activity. Fifteen young adult normal subjects slept in the laboratory for several nights prior to randomization into a caffeine protocol where subjects received caffeine 400 mg 30 min prior to one night of sleep and placebo randomly prior to another night. ECG was sampled at a rate of 500 Hz and recorded onto a PC. Data samples of 256-s periods of the ECG trace were taken from wake (before sleep), stage II, and REM for placebo and caffeine conditions. A peak detection algorithm was used to identify the R-R intervals (in milliseconds) from the ECG. A common QT variability algorithm was used to find the QT interval for each beat using the time-stretch model. The powers for HR and QT series were integrated in the bands of LF (low frequency: 0.04-0.15 Hz) and HF (high frequency: 0.15-0.5 Hz) bands. There was a significant caffeine by sleep stage interaction for LF/HF ratios (F = 4.0; df = 2, 18; P = .04). LF/HF ratios were significantly higher during REM following caffeine administration. There was also a significant caffeine by sleep stage interaction for QTvi (QT variability normalized for mean QT interval divided by HR variability normalized for mean HR; F = 5.6; df = 2, 12; P = .02). QTvi was also significantly higher during REM following caffeine administration. The higher LF/HF ratios and QTvi during REM are most likely due to the sympathetic effects of caffeine. These findings suggest that excessive caffeine intake may result in adverse cardiovascular events in vulnerable subjects.     

The beat of social cognition: Exploring the role of heart rate variability as marker of mentalizing abilities

There is a long-standing debate on the influence of physiological signals on social behavior. Recent studies suggested that heart rate variability (HRV) may be a marker of social cognitive processes. However, this evidence is preliminary and limited to laboratory studies. In this study, 25 participants were assessed with a social cognition battery and asked to wear a wearable device measuring HRV for 6 consecutive days. The results showed that reduced HRV correlated with higher hostility attribution bias. However, no relationship was found between HRV and other social cognitive measures including facial emotion recognition, theory of mind or emotional intelligence. These results suggest that HRV may be linked to specific social cognitive processes requiring online emotional processing, in particular those related to social threat. These findings are discussed in the context of the neurovisceral integration model.     

Electroconvulsive therapy: A comparison of seizure duration as monitored with electroencephalograph and electromyograph

EEG and EMG were monitored simultaneously at 72 ECT sessions in 18 patients. When EMG was recorded from the leg the duration of EMG curve convulsions varied between 43 and 89 % of the EEG recorded seizure duration of the same fit. The EMG/EEG seizure ratio varied widely among different patients as well as within the single patient during a series of ECT sessions. EMG recording from the masseter muscles showed EMG seizure duration to be more in accordance with the EEG seizure duration than EMG recordings from the leg. The EMG/EEG seizure ratio (masseter) varied from 65 to 100 %, which was significantly higher than the EMG/EEG seizure ratio obtained with EMG recorded from the calf muscles. The use of EEG monitoring of ECT is advocated in order to obtain the most precise evaluation of the cerebral seizure activity. If EEG monitoring is not available EMG recorded from the masseter muscles provides a reasonably accurate and easily applicable method of monitoring the presence and duration of the ECT-induced seizure.     

Reproducibility of heart rate variability and blood pressure variability in individuals with spinal cord injury

Abstract Individuals with spinal cord injury (SCI) are prone to orthostatic intolerance and an increased risk of cardiovascular disease. The use of heart rate variability (HRV) and blood pressure variability (BPV) as indices of cardiovascular regulation would be valuable in this population; however, their reproducibility has yet to be tested in those with SCI. The purpose of this study was to examine the day-to-day reproducibility of resting HRV and BPV in individuals with SCI. Ten individuals (age 35.9±13.2 yrs) with chronic (5.4±7.7 years post injury) SCI (C4-T12; ASIA A-C) participated. On two occasions within a two-week period, 10-minute supine electrocardiogram and Finapres blood pressure recordings were obtained during spontaneous breathing. Computer software calculated frequency domain measures of HRV and BPV (Low frequency (LF) power, High frequency (HF) power, and LF:HF ratio). Intraclass correlations coefficients (R) were used as an index of day-to-day reproducibility, and analyses were conducted on all participants and only those with tetraplegia. For HRV, measures of heart rate, LF, and LF:HF were found to be highly reproducible (R=0.82–0.88); however, the reproducibility of HF was found to be poor (all participants: R=0.53, tetraplegia: R=0.66). Measures of blood pressure as well as systolic BPV also showed high reproducibility (R=0.72–0.93). Measures of diastolic BPV were less reproducible but still acceptable (R=0.71–0.89) with the exception of LF:HF_DBP (R=0.51). In conclusion, despite the autonomic dysfunction associated with SCI, measures of HRV and BPV may still be used as reproducible indices of autonomic cardiovascular regulation in this population.     

Reproducibility of heart rate and blood pressure variability in patients with chronic obstructive pulmonary disease

Abstract. Wide variations in respiratory rate and hypoxic stimulation of chemoreceptors may produce unreliable autonomic results in patients with COPD. We studied the reproducibility of two consecutive measurements of heart rate variability (HRV) and blood pressure variability (BPV) by time frequency analysis in patients with COPD while controlling respiratory rate and oxygen hemoglobin saturation (SaO₂). Reproducibility was assessed by paired t-tests and correlation analyses between repeated measures. Correlation analyses of the log transformed low (LF) and high frequency (HF) HRV were 11.5 ± 1.1 in measurement A and 11.5 ± 1.0 in measurement B (r = 0.89, p < 0.0001), and 10.5 ± 1.1 in measurement A and 10.6 ± 1.1 in measurement B (r = 0.89, p < 0.0001) respectively. The log transformed LF and HF BPV were 4.9 ± 1.3 in measurement A and 5.3 ± 0.9 in measurement B (r = 0.70, p < 0.0002), and 6.4 ± 1.3 in measurement A and 6.6 ± 1.2 in measurement B (R = 0.71 p < 0.0001) respectively. In conclusion, time frequency analysis of HRV and BPV is reproducible and reliable in patients with COPD while controlling their respiratory rate and oxygen hemoglobin saturation. Reproducibility of these measurements may allow for a non-invasive evaluation of autonomic tone in response to treatments in COPD patients.     

Relationship between frequency spectrum of heart rate variability and autonomic nervous activities during sleep in newborns

Introduction

We analyzed the frequency spectrum of two neonatal sleep stages, namely active sleep and quiet sleep, and the relationship between these sleep stages and autonomic nervous activity in 74 newborns and 16 adults as a comparison.

Comparison of changes in heart rate variability and blood pressure during nitroglycerin administration and head-up tilt testing

Objective  To compare the changes in heart rate variability (HRV) and blood pressure (BP) between standard head-up tilt test (HUT) and nitroglycerin administration. Methods  Eighteen healthy men and women aged 23–58 years participated. HRV was assessed using standard methods at rest and during both tests. Heart rate and BP data were collected during a standard HUT (maximal tilt = 70° for 10 minutes) and following administration of 0.4 mg of nitroglycerin during supine rest. Test order was randomized. Repeated measure ANOVA was used to determine if changes in HRV and BP were significantly different between treatments. Paired t tests were used to examine the change from baseline to treatment for each variable. Results  As compared to HUT, the change in diastolic blood pressure and HRV measures was significantly (P < 0.05) less after nitroglycerin administration. However, no significant differences (P > 0.05) in HRV variables were found between nitroglycerin administration and HUT during the 5th and 6th minutes of each test. Interpretation  Nitroglycerin administration and HUT caused significantly different changes in HRV over a ten-minute average. However nitroglycerin produced its maximal effect on HRV during the 5th and 6th minutes, which was similar to the effect caused by HUT at the same time. When using nitroglycerin administration to assess changes in HRV indices, the fifth and sixth minutes of testing will provide information similar to that of a HUT protocol. Supported by: GCRC: M01-RR00400, General Clinical Research Center Program, NCRR/NIH.     

Effects of light and sleep stages on heart rate variability in humans.

Effects of light intensity and sleep stages on heart rate variability (HRV) were investigated in young healthy subjects. The low-frequency (LF)/high-frequency (HF) ratio was significantly increased by exposing either to bright lights of 10 000 lx or to extreme darkness (< 0.01 lx), while HF and LF components of HRV were not changed, when compared with those under dim light (100 lx). However, LF was significantly increased at REM sleep, when compared with that at the pre-sleep wake. In contrast, HF was increased at all stages of sleep, and the LF/HF ratio was decreased at slow wave sleep during the baseline night.     

The effects of acetylic salicylic acid on heart rate variability in healthy subjects

In this placebo controlled double blind cross over study multiple daily dosing with 500 mg acetylic salicylic acid did not influence heart rate variability in 16 healthy male volunteers aged 25 (22–28) years (median; range) to a relevant extent (p > 0.05). M. Siepmann and R. Rauh contributed equally to this work