Heart rate variability during sleep in children with partial epilepsy

Heart rate variability during sleep in children with partial

epilepsy

R A F F A E L E F E R R I 1 , 2 , L I L I A C U R Z I - D A S C A L O V A 3 , 4 ,

A L E X I S A R Z I M A N O G L O U 3 , 5 , M A R I E B O U R G E O I S 4 ,

C H R I S T I N E B E A U D 4 , M A G D A L A H O R G U E N U N E S 6 , M A U R I Z I O E L I A 2 ,

S E B A S T I A N O A . M U S U M E C I 2 and M A R I A N G E L A T R I P O D I 2

1Sleep Research Center, 2Department of Neurology, Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy,3INSERM, 4Laboratoire de Physiologie-EF and 5Service de Neuropediatrie, Hopital Robert Debre, Paris, France and 6Division of Neurology,

Hospital Sao Lucas, School of Medicine, Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre-RS, Brazil

Accepted in revised form 18 December 2001; received 11 September 2001

Correspondence: Dr Raffaele Ferri, Sleep Research Center, Oasi Institute, Via Conte Ruggero 73, 94018 Troina, Italy. Tel.: +39 0935 936111;

fax: +39 0935 653327; e-mail: [email protected]

J. Sleep Res. (2002) 11, 153–160

SUMMARY Alterations in autonomic control of cardiac activity in epileptic patients have been

reported by several studies in the past, and both ictal and interictal modifications of

heart rate regulation have been described. Alterations of autonomic control of cardiac

activity can play an important role in sudden unexplained death in patients with

epilepsy (SUDEP). However, the presence of specific changes in heart rate variability

(HRV) during sleep, not correlated with seizures, has not been assessed in children with

epilepsy; for this reason, we evaluated features of cardiac autonomic function during

sleep without ictal epileptiform electroencephalogram (EEG) activity in a group of

children with partial epilepsy. Eleven patients (five males and six females; mean age

11.5 years, SD: 3.65 years) affected by partial epilepsy were admitted to this study; 11

normal subjects (five males and six females; mean age 12.9 years, SD: 2.72 years) served

as a control group. All subjects slept in the laboratory for two consecutive nights. The

data were analyzed during the second night. Sleep was polygraphically recorded

[including one electrocardiography (ECG) channel] and signals were digitally stored. A

series of 5-min ECG epochs were chosen from each sleep stage, during periods without

evident ictal epileptiform activity in the EEG. Electrocardiography signals were

analyzed for automatic detection of R-waves and, subsequently, a series of time- and

frequency-domain measures were calculated. Epileptic subjects tended to show an

overall lower HRV in both time- and frequency-domain parameters, principally during

rapid eye movement (REM) sleep and, to a lesser extent, during sleep stage 2. Among

the different bands, this decrease was most evident for the high-frequency band (HF)

absolute power. For this reason, the ratio between the low-frequency band (LF) and

HF was always higher in epileptic patients than in normal controls and the difference

was statistically significant during sleep stages 3 and/or 4 and REM sleep. Our results

indicate that during sleep, a particular condition of basal modification in autonomic

characteristics occurs (mostly during REM sleep) in partial epilepsy patients. This

finding might represent an important factor contributing to the complex mechanism of

SUDEP which takes place most often during sleep and supports the need of studying

HRV specifically during this state in subjects with seizures.

KEYWORDS autonomic function, heart rate variability, partial epilepsy, sleep,

spectral analysis

� 2002 European Sleep Research Society 153

INTRODUCTION

Alterations of autonomic control of cardiac activity in

epileptic patients has been reported by several studies in the

past (Van Buren 1958; Van Buren and Ajmone-Marsan 1960);

both ictal and interictal modifications of heart rate regulation

have been described almost exclusively in adult subjects. In

particular, seizures can be accompanied frequently by a

significant increase in heart rate (Blumhardt et al. 1986;

Frysinger and Harper 1990; Galimberti et al. 1996, 2000;

Kuroiwa et al. 1994) and, more rarely, by bradycardia

(Blumhardt et al. 1986; Coulter 1984; Galimberti et al. 1996;

Goodman et al. 1990). Interictally, only few studies were able

to show alterations of the heart rhythm; Drake et al (1993)

reported that subjects at risk for sudden unexplained death in

patients with epilepsy (SUDEP) were likely to present abnor-

mal electrocardiogram (ECG) with increased heart rate.

Heart rate is under the control of efferent sympathetic and

vagal activities directed to the sinus node which are modulated

by central brainstem and peripheral oscillators (Malliani et al.

1991). Spectral analysis of heart rate variability (HRV) is a

quantitative reliable method for analyzing the modulatory

effects of neural mechanisms on the sinus node (Task Force of

the European Society of Cardiology and the North American

Society of Pacing and Electrophysiology 1996) and two main

components are currently considered: high frequency (HF) and

low frequency (LF). Vagal activity is the major contributor to

the HF component, while the LF component is considered by

some authors as a marker of sympathetic modulation and by

others as a parameter including both vagal and sympathetic

influences.

There are several conditions in which an alteration of

autonomic control of heart rate has been demonstrated;

among these, some are particularly interesting: (a) infants at

risk for the sudden infant death syndrome show a significant

reduction in HRV during sleep (Cauchemez et al. 1991; Curzi-

Dascalova et al. 1994, 1996; Eiselt et al. 1993; Harper et al.

1978; Schechtman et al. 1989; Spassov et al. 1994); (b) children

with Down’s syndrome (without epilepsy) present obstructive

and central sleep apnea and a significant decrease in HRV

(Ferri et al. 1997, 1998); (c) the decrease in HRV is considered

as an important risk factor in different neurological patholo-

gies (Smirne et al. 1990) such as Parkinson’s disease, as an

example (Ferini-Strambi et al. 1992).

Spectral analysis of HRV has also been applied to the study of

cardiac function in adult patients with epilepsy (Messenheimer

et al. 1990; Vaughn et al. 1996) and subjects with temporal lobe

epilepsy have been reported to show a decreased total HRV and

LF/HF ratio (Massetani et al. 1997; Tomson et al. 1998).

It is known that SUDEP occurs most frequently during

sleep (Jallon 1999; Kloster and Engelskjon 1999; Opeskin et al.

2000) and that among its risk factors, prone position and

central apnea can be strictly correlated with sleep itself. It has

also been reported that there exists a peculiar characteristic in

autonomic control of HRV during normal sleep. The

low-frequency band shows a decrease, reaching minimal values

during slow wave sleep (SWS). On the contrary, rapid eye

movement (REM) sleep is accompanied by elevated LF values,

similar to those of wakefulness, both in children (Baharav

et al. 1995) and young adults (Vaughn et al. 1995). In children,

the opposite is true for HF which increases with sleep onset

and reaches the highest values during SWS (Baharav et al.

1995); in young adults, HF has been reported to be maximal

during sleep stage 2 (S2) (Vaughn et al. 1995). The ratio

between these two components of HRV (LF/HF) shows

changes similar to those of LF (Baharav et al. 1995). Thus,

spectral analysis of HRV has been considered as being a

reliable noninvasive method to quantify changes in the

sustained tonic autonomic influences on the heart during sleep.

However, the eventual presence of specific changes in HRV

during sleep, not correlated with seizures, has not been

assessed in children with epilepsy; for this reason, the aim of

the present study is to evaluate features of the cardiac

autonomic function during sleep without ictal epileptiform

electroencephalogram (EEG) activity in a group of subjects

with partial epilepsy and to compare the results with those

obtained from a group of normal controls. The occurrence of

generalized tonic–clonic seizures has been reported to be a risk

factor for SUDEP (Ficker 2000); however, our aim was also to

test the hypothesis that subtle but significant changes in HRV

during sleep exist also in patients with partial epilepsy.

SUBJECTS AND METHODS

Subjects

Eleven patients (five males and six females; mean age

11.5 years, SD: 3.65 years) affected by partial epilepsy were

admitted to this study. All patients were under antiepileptic

drug therapy (one or more anticonvulsivants) and their clinical

characteristics are reported, in detail, in Table 1. In all cases,

EEG and neuroimaging studies were performed which con-

firmed the diagnosis reported in Table 1. In particular,

interictal EEG recordings were obtained in all subjects which

showed focal spikes and/or spike-and-wave complexes over

different scalp areas, the location of which was in agreement

with the abnormalities found by neuroimaging. All diagnoses

were made after careful analysis of clinical history, repeated

EEG recordings and neuroimaging studies.

Eleven other normal subjects (five males and six females;

mean age 12.9 years, SD: 2.72 years) were also included and

served as a control group. All these subjects were neurolog-

ically and cardiologically normal.

Recordings

All subjects slept in the laboratory for two consecutive nights.

The data were analyzed during the second night. For deter-

mination of sleep stages, the EEG, electrooculogram (EOG),

and electromyogram (EMG) of the submentalis muscle were

recorded; other physiological variables such as ECG (CM4

derivation: anode in position V4 and cathode attached to the

154 R. Ferri et al.

� 2002 European Sleep Research Society, J. Sleep Res., 11, 153–160

manubrium of the sternum), peripheral oxygen saturation and

chest wall movement by thoracic impedance were also recor-

ded. All signals were digitally recorded (sampled at a rate of

128 Hz) and also reproduced on paper by means of a

polygraph.

Sleep and HRV analysis

Sleep staging was accomplished following standard criteria

(Rechtschaffen and Kales 1968). In particular, sleep staging

was carried out by visually analyzing the EEG (C3-right

earlobe derivation), the EOG (left and right outer canthi

referred to the left earlobe), and the EMG (submentalis

muscle). Body position was also assessed by means of a video

camera; during all epochs chosen for HRV analysis patients

rested in supine or lateral position.

In order to study sleep stage-related HRV, a series of 5-min

epochs was chosen from the following sleep stages: S2, SWS and

REM sleep. For each subject, at least nine epochs were selected

(three epochs fromS2, three epochs from SWS, and three epochs

from REM). All epochs were carefully chosen during periods

without evident ictal epileptiform activity in the EEG.

In order to avoid gross effects on HRV, only periods

without transient activation phases (Schieber et al. 1971) or

arousal (American Sleep Disorders Association 1992) were

selected. Moreover, because of the age range of our subjects,

children and adolescents, a low incidence of arousals was

expected; in fact, the number of arousal events shows a linear

increase with age (Boselli et al. 1998; Mathur and Douglas

1995). Finally, the eventual presence of apneas and hypopneas

was carefully controlled so that the epochs selected for analysis

were free from potentially interfering respiratory events.

In each 5-min epoch, ECG signals were analyzed for

automatic detection of R-waves with a computer program

utilizing a simple threshold plus first and second derivative

algorithm. In order to overcome the problem of the low

sampling rate of our recorders (128 Hz), which might have

caused a bias in the estimation of the R-wave fiducial point

(Task Force of the European Society of Cardiology and the

North American Society of Pacing and Electrophysiology

1996) and a consequent alteration of the spectrum, a parabolic

interpolation was used to refine its evaluation (Bianchi et al.

1993; Merri et al. 1990). The first 256 R–R intervals from each

epoch were utilized for all subsequent analysis steps.

First of all, a series of time-domain measures was calculated:

(a) mean R–R-value, SDNN (SD of all R–R intervals);

(b) RMSSD (the square root of the mean of the sum of the

squares of differences between adjacent R–R intervals);

(c) NN50 (number of pairs of adjacent R–R intervals differing

by more than 50 ms in the entire epoch);

(d) pNN50 (percentage of NN50 among the total R–R

intervals).

The raw (noninterpolated) R–R interval tachograms were also

processed by means of a fast Fourier transform (FFT)

algorithm and the following spectral parameters were obtained:

(a) VLF (power in very low frequency range, <0.04 Hz);

(b) LF (power in low-frequency range, 0.04–0.15 Hz);

(c) HF (power in high-frequency range, 0.15–0.4 Hz);

(d) total power (VLF + LF + HF);

(e) LF% (LF power in normalized units: LF/(total power –

VLF) · 100);

(f) HF% (HF power in normalized units: HF/(total power –

VLF) · 100);

(g) LF/HF (ratio LF/HF);

(h) VLF peak (frequency of highest peak in the VLF range);

(i) LF peak (frequency of highest peak in the LF range);

(j) HF peak (frequency of highest peak in the HF range).

Statistical analysis

In all patient and normal control subjects, individual average

values were obtained for each parameter, in each sleep stage.

Table 1 Clinical characteristics of the patients admitted to the study

Age/sex

(years)

Epilepsy

typeaSeizure

typebAge at

onset (years)

Seizure

frequency Drugs

Therapy duration

(months)

Psychomotor

development

Side of EEG and/or

neuroimaging anomalies

4.9/F L1 CPS 2.7 4–11/year CBZ 2 Normal Right

6.3/M L2 CPS 0.5 4–10/day VPA, LTG, TGB 50 Questionable Right

8.5/M L2 CPS 0.1 1–3/month CBZ 104 Normal Left

10.0/M L1 PSSG 5.6 Seizure free VPA 52 Questionable Right

12.0/M L2 CPS 1.5 1–3/day CBZ, PHT 12 Normal Right

12.7/F L2 CPS 8.8 1–3/day PHT, GBP 46 Questionable Bilateral

13.1/F L2 CPS 3 days 1–3/month CBZ, VPA, LTG 136 Normal Right

13.2/M L2 CPS 9.0 1–3/day VPA, LTG 48 Normal Left

14.7/F L2 CPS 1.0 1–3/day CBZ, PBT 168 Normal Left

14.9/F L2 SPSS 10.5 1–3/month CBZ, LTG 54 Normal Right

16.2/F L1 SPMS 2.0 1–3/day CBZ, VPA >6 Questionable Left

L1, localization-related epilepsies and syndromes: idiopathic; L2, localization-related epilepsies and syndromes: symptomatic; CPS, complex partial

seizures; PSSG, partial seizure secondarily generalized; SPSS, simple partial seizure with somatosensory or special sensory symptoms; SPMS,

simple partial seizure with motor symptoms; CBZ, carbamazepine; VPA, valproate; LTG, lamotrigine; TGB, tiagabine; PHT, phenytoin; GBP,

gabapentin; PBT, phenobarbital.aCommission ILAE (1989).bCommission ILAE (1981).

Heart rate variability during sleep in epilepsy 155


Subsequently, the group comparison between HRV parame-

ters obtained during each sleep stage considered in this study,

was performed by means of the Mann–Whitney nonparametric

test for independent data sets (Siegel 1956).

RESULTS

All subjects included in this study slept for at least 8 h, and in

all cases a clear differentiation between S2, SWS and REM

during successive sleep cycles was evident.

Table 2 shows the comparison between the time-domain HR

findings in partial epilepsy patients and normal controls during

the different sleep stages. Overall, in this table, there is a lower

HRV in epileptic patients than in normal controls. During

S2, there is a tendency towards statistical significance

(0.1 > P > 0.05) for the difference between RMSSD which is

lower in patients than in normal controls. During SWS, none of

the comparisons shows a statistically significant difference

between the two groups. On the contrary, during REM sleep,

the difference between the values of RMSSD obtained in the two

groups is statistically significant and also SDNN, NN50 and

pNN50 almost reach statistical significance (0.1 > P > 0.05).

Figure 1 shows, as an example, the spectral analysis of HRV

during slow-wave sleep in an epileptic patient (left) and in a

normal control (right). The top graphs show the entire time

series formed by 256 consecutive R–R intervals. The bottom

graphs show the spectra obtained by FFT of the same data.

Figure 2 shows the results of the spectral analysis of HRV

during sleep in both groups. The absolute power of VLF seems

to be not different in the two groups; on the contrary, LF and,

mostly, HF show lower values in the patients than in normal

controls. The statistical analysis was significant for the compar-

ison between the values of HF obtained in the two groups,

during REM sleep. Also, the total power was lower in epileptic

patients than in normal controls with a tendency towards

statistical significance for the comparisons during S2 and REM.

Figure 3 shows the comparison between the relative per-

centage of LF and HF, during the different sleep stages. Low-

frequency percentage was always higher in epileptic patients

than in normal control and the difference was statistically

significant during SWS and REM; HF% was always lower in

epileptic patients than in normal control and, again, the

difference was significant during SWS and REM. In the same

figure, the comparison between the values of the LF/HF ratio

obtained from the two groups during the different sleep stages

is also shown. This ratio was always higher in epileptic patients

than in normal control and the difference was statistically

significant during SWS and REM.

DISCUSSION

Spectral analysis of HRV has been used to study fluctuations in

the autonomic nervous system activity during sleep. With this

technique, LF shows a decrease during sleep, reaching minimal

values during SWS; on the contrary, REM sleep is accompan-

ied by elevated LF values, similar to those of wakefulness, both

in children (Baharav et al. 1995) and young adults (Vaughn

et al. 1995). In children, the opposite is true for HF, which

increases with sleep onset and reaches the highest values during

SWS (Baharav et al. 1995); in young adults, HF has been

Normal controls

(n = 11)

Epileptic patients

(n = 11)

Mean SD Mean SD Wilcoxon P<

Sleep stage 2

Mean R–R-value (s) 0.879 0.211 0.825 0.116 NS

SDNN 0.087 0.049 0.053 0.021 NS

RMSSD 0.092 0.069 0.048 0.024 0.1 > P > 0.05

NN50 97.636 65.080 57.793 48.854 NS

pNN50 38.289 25.522 22.659 18.370 NS

Slow-wave sleep

Mean R–R-value (s) 0.867 0.210 0.842 0.119 NS

SDNN 0.069 0.054 0.046 0.017 NS

RMSSD 0.084 0.080 0.046 0.024 NS

NN50 94.591 69.904 61.009 53.036 NS

pNN50 37.094 27.413 23.917 20.805 NS

REM sleep

Mean R–R-value (s) 0.856 0.194 0.782 0.094 NS

SDNN 0.094 0.053 0.058 0.030 0.1 > P > 0.05

RMSSD 0.093 0.079 0.042 0.027 0.05

NN50 81.727 58.343 39.373 34.834 0.1 > P > 0.05

pNN50 32.050 22.878 15.445 13.657 0.1 > P > 0.05

SDNN, standard deviation of all R–R intervals; RMSSD, square root of the mean of the sum

of the squares of differences between adjacent R–R intervals; NN50, number of pairs of adjacent

R–R intervals differing by more than 50 ms in the entire epoch; pNN50, NN50%.

Table 2 Comparison between HR findings

in epileptic patients and normal controls

during sleep stage 2

156 R. Ferri et al.


reported to be maximal during S2 (Vaughn et al. 1995). The

ratio between these two components of HRV (LF/HF) shows

changes similar to those of LF (Baharav et al. 1995).

Thus, spectral analysis of HRV has been considered as being

a reliable noninvasive method to quantify changes in the

sustained tonic autonomic influences on the heart during sleep.

The results obtained from the present study in normal controls

show good agreement with the findings of previous reports

(Baharav et al. 1995; Vaughn et al. 1995).

The main results of the present study can be synthesized as

follows: epileptic subjects tended to show an overall lower

HRV in both time- and frequency-domain parameters, mostly

during REM sleep and, to a lesser extent, during S2. Among the

different bands, this decrease was most evident for HF absolute

power. For this reason, the LF/HF ratio was always higher in

epileptic patients than in normal controls and the difference

was statistically significant during SWS and REM sleep.

In the past, interictal autonomic control of heart rate has

almost exclusively been studied during wakefulness in epileptic

patients (Frysinger et al. 1993; Massetani et al. 1997; Messen-

heimer et al. 1990; Vaughn et al. 1996) or during wakefulness

and sleep but without separating these states between them

(Tomson et al. 1998). In these studies, decreased total HRV

and LF/HF ratio have been reported and interpreted as signs

of decreased sympathetic activity. Particular attention was also

focused on the possible explanations for the changes observed

and the most important factors considered were: type of

epilepsy (temporal lobe epilepsy, juvenile myoclonic epilepsy),

side of the EEG focus, and type of medication.

Often, the study of patients with epilepsy is influenced by their

treatment with different and variously associated drugs, lasting

for years. Our patients were all under antiepileptic drug therapy

(Table 1); thus, we cannot exclude that some role can be played

by these factors. In this regard, it is not yet clear whether or not

these substances are able to modify HRV in a significant way.

Quint et al (1990) found no consistent effect after phenytoin

acute administration to normal subjects; on the contrary, the

same authors reported a significant decrease inHRVpower after

carbamazepine administration. These results were confirmed by

Tomson et al (1998), who could demonstrate decreased SD of

R–R intervals and lower LF power, suggesting a decreased

sympathetic tone, in patients treated with carbamazepine. On

Figure 1. Example of spectral analysis of heart rate variability (HRV) during slow-wave sleep in an epileptic patient (left) and in a normal control

(right). The top graphs show the entire time series formed by 256 consecutive R–R intervals. The bottom graphs show the spectra obtained by fast

Fourier transform of the same data. Power is expressed in s2/beat.



the contrary, Devinsky et al (1994) suggested that carbamaze-

pine might be responsible, at least in part, for the greater HRV

found in their patients with partial epilepsy. Finally, Massetani

et al (1997) were unable to demonstrate any correlation between

spectral analysis of HRV and drug therapy.

It seems that there is a better agreement on the effects of the

side of the EEG focus in the previous studies (Massetani et al.

1997; Tomson et al. 1998; Vaughn et al. 1996) which reported

more impaired parameters (reduced total variability, reduced

LF and LF/HF ratio) in patients with a right EEG focus than

in the others. This was explained with a possible asymmetric

central autonomic control on the cardiac function (Lane et al.

1992). We could not separate the effects of the right EEG

abnormalities vs. those over the left side because of the size of

our patient group; however, our epileptic subjects presented

EEG abnormalities more often over the right side than over

the left (Table 1).

In our patients, all affected by partial epilepsy and under

different antiepileptic drug therapy, we demonstrated that,

during sleep and in supine position, a lower HRV can be

detected, which occurs mostly during REM sleep and, to a

lesser degree, during SWS. This decreased HRV is accompan-

ied by an imbalance between the sympathetic and vagal

systems with a preponderance of the first determined, mostly,

by a clear reduction in the HF band, related to the respiratory

sinus arrhythmia and parasympathetic activity (Akselrod et al.

1981; Task Force of the European Society of Cardiology and

the North American Society of Pacing and Electrophysiology

1996).

Apparently, these results seem to be in partial disagreement

with the studies not considering HRV specifically during sleep

(Frysinger et al. 1993; Massetani et al. 1997; Messenheimer

et al. 1990; Tomson et al. 1998; Vaughn et al. 1996); however,

it must be noted that a recent work by Galimberti et al (2000)

reported that, when occurring during sleep, partial seizures can

modify heart rate to a much greater extent than those taking

place during wakefulness and that this effect might be because

of the different basal autonomic conditions during this state.

Figure 2. Spectral analysis of heart rate vari-

ability (HRV) during sleep. Top left: absolute

power of very low-frequency band (VLF).

Top right: absolute power of LF. Bottom left:

absolute power of high-frequency band (HF).

Bottom right: total absolute power. Values

are shown as mean + SE of the mean.

158 R. Ferri et al.


It is surprising that the autonomic status of epileptic patients

has not been studied specifically during sleep in detail because

the relationship between sleep and epilepsy is well known and

has been carefully studied in the past.

More interestingly, it is also well known that SUDEP occurs

most frequently during sleep (Jallon 1999; Kloster and

Engelskjon 1999; Opeskin et al. 2000) and that among its risk

factors, prone position and central apnea can be strictly

correlated with sleep itself.

CONCLUSION

Our results indicate that during sleep a particular condition of

basal modification in autonomic asset occurs (mostly during

REM sleep) in partial epilepsy patients; this finding might

represent an important factor contributing to the complex

mechanism of SUDEP which takes place most often during

sleep and supports the need of studying HRV specifically

during this state in subjects with seizures.

ACKNOWLEDGEMENT

This work was partially supported by the international grant

CNPq-INSERM 910173/98-2 to one of the authors (M.L.N.).

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Heart rate variability during sleep in children with partial epilepsy

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