Heart rate variability during sleep in children with partial epilepsy
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Transcript of 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
� 2002 European Sleep Research Society, J. Sleep Res., 11, 153–160
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.
� 2002 European Sleep Research Society, J. Sleep Res., 11, 153–160
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.
Heart rate variability during sleep in epilepsy 157
� 2002 European Sleep Research Society, J. Sleep Res., 11, 153–160
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.
� 2002 European Sleep Research Society, J. Sleep Res., 11, 153–160
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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