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


Address correspondence to Andre R. Brunoni, MD, Av. Prof. Lineu Prestes 2565, 3o andar, Centro de Pesquisas Clinicas, Hospital Universitário, Universidade de São Paulo, SP CEP 005508-000, Brazil. E-mail: brunoni@usp.br


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.