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Keywords:

  • Heart-rate variability;
  • Refractory epilepsy;
  • Vagus nerve stimulation;
  • Circadian rhythm;
  • Autonomic nervous system

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Summary: Purpose: To elucidate possible effect of vagus nerve stimulation (VNS) therapy on interictal heart rate (HR) variability in patients with refractory epilepsy before and after 1-year VNS treatment.

Methods: A 24-hour electrocardiogram (ECG) was recorded at the baseline and after 12 months of VNS treatment in 14 patients with refractory epilepsy, and once in 28 healthy age- and sex-matched control subjects. Time and frequency domain measures, along with fractal and complexity measures of HR variability, were analyzed from the ECG recordings.

Results: The mean value of the RR interval (p = 0.008), standard deviation of N-N intervals (SDNN) (p < 0.001), very-low frequency (VLF) (p < 0.001), low-frequency (LF) (p = 0.001), and high-frequency (HF) (p = 0.002) spectral components of HR variability, and the Poincaré components SD1 (p = 0.005) and SD2 (p < 0.001) of the patients with refractory epilepsy were significantly lower than those of the control subjects before VNS implantation. The nocturnal increase in HR variability usually seen in the normal population was absent in patients with refractory epilepsy. VNS had no significant effects on any of the HR-variability indexes despite a significant reduction in the frequency of seizures.

Conclusions: HR variability was reduced, and the nocturnal increase in HR variability was not present in patients with refractory epilepsy. One-year treatment with VNS did not have a marked effect on HR variability, suggesting that impaired cardiovascular autonomic regulation is associated with the epileptic process itself rather than with recurrent seizures.

Partial and generalized epilepsies affect autonomic functions during ictal, postictal, and interictal states. During seizures, sympathetic activation often manifests itself as blood pressure and heart rate (HR) increase (1,2), although parasympathetic activation also may predominate during partial seizures. Some evidence indicates depression of autonomic respiratory reflexes postictally, and during the interictal state, the dysfunction of autonomic cardiovascular regulation is associated with diminished HR variability in patients with temporal lobe epilepsy (3). Although diminished nocturnal HR variability has recently been associated with sudden unexpected death in epilepsy (SUDEP) (4), the clinical significance of impaired HR variability in patients with epilepsy has remained unclear.

Vagus nerve stimulation (VNS; vagus nerve stimulation/stimulator) is a nonpharmacologic antiepileptic therapy for patients with refractory epilepsy who are not candidates for resective surgery or who have had resective surgery with unsatisfactory results. Prospective, randomized, and multicenter studies have shown that VNS treatment is safe, well tolerated, and effective in seizure reduction (5,6).

VNS is normally implanted below the left clavicle, and the electrodes are placed around the left vagus nerve (7) which has a wide range of afferent projections throughout the forebrain (8). Current information (9) suggests that the thalamus and other limbic structures are activated during stimulation. Despite the close interaction between VNS and the centers controlling cardiovascular functions, the effects of VNS on cardiovascular autonomic regulation in patients with refractory epilepsy have not been widely studied.

A previous prospective study in seven patients with epilepsy suggested that VNS treatment may have some effect on cardiac autonomic function during the night (10), but another study in 10 patients with epilepsy did not show any effects of VNS on cardiovascular regulation (11).

The aim of the present study was to evaluate the effect of VNS on cardiac autonomic control in patients with refractory epilepsy before and 1 year after the implantation of VNS, by recording various measures of HR variability with a 24-h ECG recording.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients and control subjects

The study was carried out in the Department of Neurology, the University Hospital of Oulu, Oulu, Finland, with the approval of the local ethics committee. All patients and control subjects gave their informed consent before their inclusion in the study.

The study group consisted of 14 consecutive patients with refractory epilepsy (eight male and six female patients; mean ± SD age at the first recording, 34.3 ± 9.3 years; range, 20–52 years), who received the implantation of a Neurocybernetic Prosthesis (NCP Generator Cyberonic, Webster, TX, U.S.A.). The clinical characteristics of the patients are presented in Table 1. A presurgical evaluation (MRI, 24-h video-EEG telemetry recording) was made for each subject before the decision about the implantation of VNS was made, and none of the patients was considered an eligible candidate for resective epileptic surgery after these evaluations. All patients had received different mono- and polytherapy treatment without achieving sufficient control of their seizures. All patients continued to have seizures before the VNS was implanted (mean number of seizures per month, 48.4; range, 15–150), despite the appropriate use of antiepileptic drugs (AEDs). One patient had previously undergone right partial temporal lobe resection, one patient had undergone two left lobe operations and radiation therapy, and a third patient had had corpus callosotomy. Despite surgical treatment, the patients continued to have seizures. Background AED doses were kept as constant as possible during the follow up.

Table 1. Clinical characteristics of patients with refractory epilepsy
Patients (no.)Age (yr)/ genderType of epilepsyEEG focusMRI/CTAEDs t0AEDs t1 (+/−)Reduction in seizure frequency (%)
  1. TLE, temporal lobe epilepsy; FLE, frontal lobe epilepsy; PME, progressive myoclonic epilepsy; MFE, multifocal epilepsy; CBZ, carbamazepine; BZD, benzodiazepine; ESM, ethosuximide; VPA, sodium valproate; GBP, gabapentin; LTG, lamotrigine; TPM, topiramate; OXC, oxcarbazepine; VGB, vigabatrin; LEV, levetiracetam; t0, AED at baseline; t1, AED at 1 year of VNS implantation.

152/MTLERight normalNormalCBZ, BDZ >50
229/FTLEUndeterminedGray-matter heterotopyESM, VPA, GBP, CBZ >50
338/MTLELeftMinor left HC atrophyLTG, TPM-LTG, - TPM>50
432/MMFEUndeterminedSchizencephalyCBZ, VPA, GBP >50
534/MFLELeftNormalGBP, LTG, VPA <50
626/MFLELeftLeft frontal atrophyVPA, LTG, CBZ, GBP >50
738/FFLELeftLeft hippocampal sclerosisCBZ, TPM >50
843/MPLEUndeterminedVenous malformationOXC, LTG, GBP >50
927/MFLELeftNormalCBZ, LTG <50
1044/FFLERightCerebellar atrophyBZD, OXC Unchanged
1125/FFLEUndeterminedNormalVGB, LTG, OXC >50
1227/FPMEUndeterminedNormalVPA, BZD+ TPMUnchanged
1345/FFLEMultifocalCortical atrophyOXC, VPA, BZD <50
1420/MFLEMultifocalNormalLEV, TPM, LTG >50

Patients were carefully interviewed and clinically examined. Their epilepsy and seizure type was classified according to the recommendations of the International League Against Epilepsy (ILAE) (12,13). Patient 2) had mental retardation, and patient 4 had West syndrome with mild mental retardation.

The results of laboratory tests (liver and renal functions, serum electrolytes, and basic hematologic indices) were normal. Blood samples for the laboratory tests were taken in the morning before the 24-h ECG recording. All patients had normal ECG at baseline.

The control group consisted of 28 healthy age- and sex-matched subjects (16 men and 12 women; mean ± SD age at the first recording, 34.4 ± 9.3 years; range, 20–53 years) picked from among healthy individuals participating in a study comparing the characteristics of hypertensive and normotensive subjects who in turn had been randomly selected by their personal social security numbers from the general population of Oulu. All were carefully examined and had no medication or diseases affecting the autonomic nervous system in their medical histories.

Methods

VNS (the model 100 Neurocybernetic prosthesis; Cyberonics, Pulse Generator, Houston, TX, U.S.A.) was implanted by using a previously described method (7) between February 1999 and September 2002. The starting level of stimulation was 0.25 mA; stimulation frequency, 30 Hz; pulse width, 500 ms; on time, 30 s; and off time, 5 min. Generally the output current was increased by 0.25 mA every 2 weeks. The output current was increased to a clinical response. If the patients experienced intolerable side effects, the output current was decreased, or the increase was delayed for another 2 weeks. The mean (range) stimulation output intensity 1 year after the VNS implantation was 2.9 (1.75–3.5) mA; stimulation frequency, 30 Hz; pulse width, 500 ms; on time, 30 s; and mean (range) off time, 4.7 (3.0–5.0) min.

Twenty-four-hour ECG recordings were performed twice with a portable two-channel tape recorder (Del Mar CardioCorder model 456A; Del Mar Medical, Irvine, CA, U.S.A.) in all the patients, before and 1 year after the VNS implantation. During the second 24-h ECG recording, the VNS stimulator was on. In the control subjects, the 24-h ECG recording was performed once. During the recordings, patients and control subjects were allowed to perform their daily activities. Patients documented possible seizures on a diary during the 24-h ECG recording.

The ECG data were sampled digitally and transferred from an Oxford Medilog scanner (Oxford Instruments, Oxford, U.K.) to a microcomputer for analysis of the HR variability. All the RR-interval time series were first edited automatically, and then careful manual editing was performed by visual inspection of the RR intervals. For detecting artefacts and premature beats, and deleting the filling gaps, each RR-interval time series was passed through a filter by using previously described methods (14).

In the final analysis, the 24-h HR-variability data were divided into segments of 3,600 s, and only segments with >85% sinus beats were included in the analysis. The mean duration of all the RR intervals and the standard deviation of all the NN intervals (SDNN) were computed as time domain measures.

An autoregressive model was used to estimate the power-spectrum densities of HR variability (15). Linear trends were abolished from the RR-interval data segments of 512 samples to make the data more stationary. The power spectra were quantified by measuring the area in three frequency bands: 0.005 to 0.04 Hz (very low frequency, VLF), 0.04 to 0.15 Hz (low frequency, LF), and 0.15 to 0.4 Hz (high frequency, HF). The HF fluctuation of the RR interval mainly reflects the cardiovagal modulation and the inspiratory inhibition of vagal tone, whereas the VLF and LF bands are thought to reflect sympathetic excitation (16), sympathovagal balance (17), and arterial pressure oscillations (18).

In addition to spectral analysis, the SD of continuous long-term RR-interval variability (SD2) and the instantaneous beat-to-beat RR-interval variability (SD1) were assessed by using quantitative two-dimensional vector analysis (Poincaré) (19,20). SD1 describes the magnitude of the beat-to-beat variability, reflecting vagal modulation of the HR variability, and has a relatively strong correlation with the HF spectral component, and SD2 describes the long-term RR-interval fluctuation and reflects the magnitude of the LF spectral component. One advantage of the Poincaré method over spectral-analysis techniques is that it is not sensitive to stationary irregularities and trends in the RR intervals, therefore being more suitable for HR-variability analyses with ambulatory ECG recordings (20).

For long-term HR-variability scaling analysis, the power-law slope β was calculated. This exponent reflects the distribution of the spectral characteristics of RR data in the region of the VLF band obtained from 24-h ECG recordings. The power law relation of RR-interval variability was calculated from the frequency range of 10−4 and 10−2 by a previously described method (21,22). The fractal correlation properties of the HR were quantified by using a detrended fluctuation-analysis technique, which is a modified root-mean-square analysis of random walk. The fractal property was defined for the short-term (<11 beats, α) correlation of RR-interval data (the short-term scaling exponent) (23).

Statistical analyses

The data were analyzed by using the SPSS software (SPSS 11.5; SPSS Inc., Chicago, IL, U.S.A.). Statistical analysis was performed by using the Mann–Whitney two-sample test to compare the values of the control subjects and those of the patients. The Wilcoxon signed-rank test was used to compare the values of the patients before VNS implantation and 1 year after the procedure. A value of p < 0.05 was considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

All patients completed 1-year follow-up. Seizure reduction of ≥50% was observed in nine patients (responders). Three patients had <50% seizure reduction, and two patients did not experience any change in seizure frequency during VNS treatment (nonresponders).

The mean values for the HR and the various measures of HR variability both in patients with refractory epilepsy before and 1 year after implantation of the VNS and in the control subjects are presented in Table 2. The mean value of the RR interval (p = 0.008), SDNN (p < 0.001), the spectral components VLF (p < 0.001), LF (p = 0.001), and HF (p = 0.002), and the Poincaré components SD1 (p = 0.005) and SD2 (p < 0.001) of the patients with refractory epilepsy were significantly lower than those of the control subjects before VNS implantation. Similarly, 1 year after the implantation of the VNS, the mean value of the RR interval (p = 0.002), SDNN (p < 0.001), the spectral components VLF (p < 0.001), LF (p < 0.001), and HF (p < 0.001), and the Poincaré components SD1 (p < 0.001) and SD2 (p < 0.001) were lower in the patients with refractory epilepsy than in the control subjects. No differences were found in any HR-variability measurements in patients with refractory epilepsy before and 1 year after the implantation of the VNS.

Table 2. Heart rate and measures of heart-rate variability in control subjects and in patients with refractory epilepsy before and 1 year after the implantation of vagus nerve stimulator
 Control subjects (n = 28)Epilepsy patients
Before VNS implantation (n = 14)One year after VNS implantation (n = 14)
  1. RRI, RR interval; SDNN, SD of all NN intervals; VLF, very low frequency; LF, low frequency; HF, high frequency; SD1, beat-to-beat variability measure from Poincaré; SD2, long-term variability measure from Poincaré; α, short-term fractal correlation parameter; slope β, long-term power-law slope. Values are presented as medians (interquartile range).

  2. ap < 0.01, bp < 0.001 compared with control subjects; the Mann–Whitney U test.

RRI (ms)854 (809–922)  785 (722-826)a  750 (670-830)a  
SDNN (ms)181 (150–214)  127 (100–157)b  116 (107–147)b  
VLF (ms × ms)3,296 (1,963–5,604)853 (609–1,214)b984 (509–1,918)b
LF (ms × ms)1,740 (1,123–3,275)456 (327–1,051)a474 (179–694)b  
HF (ms × ms)1,054 (315–2,291)  232 (189–610)a  215 (166–396)b  
SD134 (25–60)   21 (17–27)a   20 (17–26)b   
SD2143 (125–190)  94 (81–117)b  90 (74–124)b  
α1.24 (1.06–1.30) 1.15 (1.08–1.17)  1.18 (1.09–1.23)  
Slope β  −1.14 (−1.37 to −1.07)  −1.28 (−1.40 to −1.24)  −1.33 (−1.45 to −1.23)

None of the patients and control subjects had cardiac arrhythmias or other clinically significant ECG changes during the 24-h ECG recording.

Figure 1 shows the suppression of the circadian fluctuation of the HF and LF spectral components in patients with epilepsy before and 1 year after the implantation of the VNS, compared with that of the healthy control subjects. The HF and LF values of the patients were lower throughout the 24-h ECG recording time than were those of the control subjects. The nocturnal increase in the HF and LF spectral components that was seen in the control subjects could not be detected in the patients with refractory epilepsy before or 1 year after the implantation of the VNS.

imageimage

Figure 1. The 24-h circadian fluctuation of low-frequency (A) and high-frequency (B) components of HR variability (medians) in epilepsy patients before VNS implantation (circles), 1 year after (line) and in healthy control subjects (squares).

No differences were noted in any HR-variability measurements (p > 0.05), apart from SD1 Poincaré component (median, interquartile range) when responders (22, 22–44; p = 0.039) were compared with nonresponders (17,13–21) before VNS implantation. However, the mean value of the RR interval, SDNN, the spectral components VLF, LF, and HF, the Poincaré components SD1 and SD2 and the power–law slope β (p = 0.042) of the nonresponders (median, interquartile range: RR interval, 654, 626–760; p = 0.020; SDNN, 108, 91–114; p = 0.045; VLF, 360, 279–833; p = 0.014; LF, 201, 104–338; p = 0.014; HF, 173, 50–197; p = 0.014; SD1, 17, 9.3–18; p = 0.009; SD2, 67, 55–90; p = 0.028; power-law slope β, −1.47, −1.55 to −1.32; p = 0.042) were significantly lower than those of the responders (median, interquartile range: RR interval, 812, 731–877; SDNN, 130, 111–154; VLF, 1,592, 879–2,127; LF, 686, 474–990; HF, 351, 210–558; SD1, 22, 20–31; SD2, 113, 82–128; power-law slope β, −1.29, −1.34 to −1.17) after 1 year of VNS implantation.

The VNS therapy was well tolerated without major adverse effects. Eleven patients reported hoarseness during the stimulation; one patient reported coughing during the stimulation; four patients reported sensations on the left side of the neck; and one patient had occasional pain during the stimulation. One patient reported occasional shortness of breath. One of the patients had no side effects.

The high interindividual variability of documented seizures during the 24-h ECG recordings did not allow a meaningful statistical analysis of the effects of seizures on the HR variability.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In the present study, patients with refractory epilepsy had significantly lower HR variability than did the control subjects before implantation of VNS, and 1-year treatment with VNS did not have a significant impact on HR-variability measurements. In addition, the circadian HR fluctuation seen in healthy control subjects was not present in patients with refractory epilepsy, and VNS treatment did not seem to have an effect on circadian HR variability. Therefore the findings of the present study suggest that refractory epilepsy reduces HR variability, but that long-term VNS treatment has no marked effect on cardiac autonomic control.

Previous studies have reported diminished interictal HR variability in patients with epilepsy, mainly temporal lobe epilepsy, but it has remained unclear whether the observed reduction in cardiovascular responses is due to the epileptic process itself or to the AEDs (3,24–26). In the present study, patients with refractory epilepsy had significantly lower HR variability before the implantation of VNS, and after 1 year of VNS treatment, no changes were seen in HR-variability measurements. Patients with refractory epilepsy also had decreased circadian HR variability at the baseline of the study and no nocturnal increase in the HR variability. This is consistent with what has previously been reported in patients with temporal lobe epilepsy (27). One-year treatment with VNS did not change the circadian HR variability in these patients.

Interestingly, 1 year after the implantation of VNS, most of the present patients had experienced >50% seizure reduction, but this seizure reduction was not associated with changes in the HR variability in the patient group as a whole. This suggests that the epileptic process itself may be associated with reduced HR variability rather than recurrent seizures, which is in accordance with findings from previous studies (24,27). In addition, the HR variability was similar in responders and nonresponders before the VNS implantation. However, after 1 year of VNS treatment, HR variability increased in responders but decreased in nonresponders, suggesting that successful VNS with a marked reduction in seizure frequency may have a favorable effect on autonomic cardiac control and HR variability. However, the number of patients in the present study was small, and further studies in larger patient populations are needed to confirm this finding.

The vagus nerve is the main parasympathetic efferent nerve regulating autonomic functions such as HR and gastric tone. However, the vagus nerve is also a mixed nerve composed of ∼80% afferent sensory fibers carrying information arising from the head, neck, and abdomen to the brain. Despite the close interaction between the vagus nerve and the heart, only one study has tried to explore the long-term effects of VNS on cardiac vagal tone (10). In that study, long-term VNS therapy appeared to have some effects on cardiac autonomic function, with a reduction of the HF component during the night and a flattening of sympathovagal circadian changes. Conversely, short-term studies have suggested that VNS does not have an effect on the HR (11,28). During VNS, the left vagus nerve is stimulated below the cardiac branches of the vagus nerve, and this may explain why the cardiac function is unaffected by routine VNS.

AEDs have been associated with dysfunction of cardiovascular regulation, and particularly carbamazepine (CBZ) has been associated with diminished HR variability (3,25,29,30). One prospective study demonstrated that CBZ may suppress both sympathetic and parasympathetic functions in patients with newly diagnosed epilepsy (31). In that study, the circadian HR fluctuation appeared to be decreased even before the CBZ treatment, and after starting the CBZ treatment, the suppression of HR variability was even more pronounced during both the day and the night. This suggests that epilepsy itself is associated with cardiovagal dysregulation, which is suggested by other studies as well (24,27), but CBZ also appears to have an additive effect on HR variability. In the present study, all patients were receiving polytherapy with different AED dosages, and most of the patients were taking a voltage-dependent sodium channel blocker. Therefore the effect of different types of AEDs on suppressed HR variability is difficult to assess from the present observations.

Patients with epilepsy have an increased risk of sudden death (sudden unexpected death in epilepsy, SUDEP). SUDEP has been associated with generalized tonic–clonic seizures, young age, low AED levels, use of multiple AEDs, and refractory epilepsy (25,30,32,33), but healthy, compliant patients also may die unexpectedly (34,35). Therefore individual patients at high risk of SUDEP are difficult to identify. The suggested mechanisms of SUDEP include cardiac arrhythmia, neurogenic pulmonary edema, and postictal suppression of brainstem respiratory centers leading to central apnea (36–38). One study suggested that autonomic stimulation is increased in association with seizures in patients with a high risk of SUDEP, particularly in sleep (39). Another study suggested that nocturnal suppression of HR variability may contribute to the risk of SUDEP in patients with epilepsy (4), making the present findings of abnormalities of nocturnal HR variability associated with refractory epilepsy particularly interesting. It was recently reported that 2-year VNS therapy seemed to decrease SUDEP rate (40), which is consistent with the finding of improved autonomic cardiac control and normalization of HR variability after successful treatment with VNS in the present study.

In conclusion, HR variability was reduced, and the nocturnal increase in HR variability was not present in patients with refractory epilepsy. One-year treatment with VNS did not affect HR variability markedly despite a significant reduction in seizure frequency. Therefore the results of the present study suggest that long-term VNS treatment does not affect autonomic nervous system functions as reflected by HR variability, and they further suggest that the epileptic process itself may alter HR variability independent of recurrent seizures. Further studies are needed to explore the interrelations between structural brain lesions, chronic refractory epilepsy, VNS therapy, and autonomic cardiovascular dysregulation.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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