Vagus nerve stimulator-induced apneas and hypopneas in a child with
refractory seizures
Running title: Vagal nerve stimulators and apneas
Fuzhan Parhizgar a, Karen Rogers b, Daniel Hurst b, Kenneth Nugent a and Rishi Raj a,*
a
Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock,
TX, USA
b
Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX, USA
*
Corresponding author: Rishi Raj, M.D.
Department of Internal Medicine,
Texas Tech University Health Sciences Center,
3601 4th Street, Stop 9410, Lubbock,
Texas 79430, USA
Tel.: +1 806 743 3155; Fax: +1 806 743 3148;
E-mail: rishi.raj@ttuhsc.edu.
Received: 29 March 2011
Revised: 13 May 2011
Accepted: 7 July 2011
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Abstract. Vagal nerve stimulators (VNS) can decrease seizure frequency in pediatric patients
with refractory seizure disorders. However, vagal nerve stimulation can cause apneas and
hypopneas during sleep, especially in patients with undiagnosed obstructive sleep apnea. We
currently care for a young boy with cerebral palsy and refractory seizures. His mother noted
intermittent noisy breathing and pauses in breathing at night following VNS implantation. An
overnight sleep study revealed very abnormal sleep architecture and an apnea-hypopnea event
rate of nine per h (18 per h when supine). After a review of the management options, the VNS
was disabled. A repeat sleep study demonstrated improved sleep architecture and a reduced
number of apneas and hypopneas (overall and supine event rate 1.7 per h). Management
options in these patients include changing the VNS parameters, the use of positive airway
pressure therapy, and discontinuing the VNS device.
Keywords: Vagal nerve stimulator, apnea, hypopnea, seizures
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1. Introduction
Vagal nerve stimulators (VNS) can reduce the frequency of seizures to varying
degrees in patients with epilepsy [1]. Patients implanted younger than 12 yr, patients with
tuberous sclerosis, and Lennox-Gastaut patients may have better outcomes with VNS
treatment [1]. However, VNS can change the respiratory pattern in patients and can induce or
aggravate sleep apnea. We report a patient who had an increase in apneas and hypopneas after
VNS implantation and discuss the management options.
2. Case report
The patient, a 5-year-old boy with cerebral palsy, started having seizures at 20 mo of
age. He was developmentally delayed and had a vocabulary span of five words at 20 mo.
Electroencephalography done during these seizure episodes showed generalized, frontal and
central spike and spike wave activity. The seizure frequency increased to 20 times per day.
Eventually his seizures were refractory to combination medical therapy. No other etiology for
his seizures was uncovered despite an extensive evaluation, including multiple genetic and
metabolic tests. The patient was finally treated with zonisamide, valproate, and clorazepate
and had a VNS implanted. This therapeutic regimen improved seizure control, but he
continued to have seizures at the rate of one event every one to two weeks. On a follow up
visit, the mother reported intermittent noisy breathing and pauses in breathing during the
night. These symptoms were new and were not present before the VNS was placed. No
excessive daytime somnolence or behavioral changes were reported by the mother. Physical
examination was unremarkable except for findings consistent with his underlying diagnosis of
cerebral palsy. No stridor or difficulty breathing were noted during the physical examination.
The patient was referred for a diagnostic polysomnography for suspected obstructive sleep
apnea (OSA). The montage employed consisted of electroencephalography (F4-M1, C4-M1,
F3-M2, C3-M2, O2-M1, O1-M2), electro-oculography (E1-M2, E2-M2), electromyography
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(EMG) (submental, mental), snoring (microphone), nasal and oral airflow (thermistor), chest
and abdominal respiratory effort, pulse oximetry, single lead electrocardiography, limb EMG,
and body position (manual). Computerized polysomnography recording equipment (BioLogic Sleep Scan V. 2.03.05. Natus, San Carlos, CA) was used to record the
polysomnography. The study was scored per the criteria set forward by the American
Academy of Sleep Medicine in 2007 [2]. This sleep study demonstrated OSA/hypopnea with
an overall apnea-hypopnea index (AHI) of 9.0 and a supine AHI of 18.0. Sleep efficiency was
63%. Sleep stage distribution for the night was 37% stage W (wakefulness), 1.5% stage N1
(non-rapid eye movement [NREM] 1), 17.5% stage N2 (NREM 2), 44.0% stage N3 (NREM
3) and 0% stage R (rapid eye movement [REM]). Sleep onset latency was prolonged at 92
min. Hypopnea events coincided with VNS impulses, which could clearly be seen on the
EMG channel (Fig. 1). The sleep technician reported “stridorous vocalizations” which
coincided with the vagal nerve stimulations. The VNS impulses occurred approximately every
150 sec and lasted approximately 35 sec. Subtle decrease in airflow was noted during
wakefulness, but during sleep every single VNS impulse was associated with significant
decrease in flow without any change in thoracic or abdominal movements. Most impulses
were not associated with arousals or desaturation. No apnea/hypopnea events independent of
the VNS impulses were noted. These events (mostly hypopneas) were more severe in the
supine position and were partially relieved when the patient was placed in a lateral position.
Various therapeutic options were considered for treating the patient’s OSA. Positive
airway pressure therapy was considered less than an ideal solution because of behavioral and
compliance issues. The patient had already had a tonsillectomy and adenoidectomy in the past
for non-sleep related issues, and other surgical therapy was considered too invasive. It was
decided to cautiously discontinue the VNS and closely monitor the patient for recurrent
seizure activity. The VNS was disabled, and the patient was scheduled for another sleep
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study. The mother reported disappearance of the apnea events and near complete
disappearance of the noisy breathing during the night. Repeat diagnostic polysomnography
revealed snoring but no “stridorous vocalizations”. Sleep onset and REM onset were within
normal limits. Sleep efficiency had increased to 96.4%. Sleep stage distribution for this repeat
sleep study was 3.6% stage W (wakefulness), 0% stage N1 (NREM 1), 33.2% stage N2
(NREM 2), 47.0% stage N3 (NREM 3) and 16.2% stage R (REM). The AHI was 1.7 with one
central, five obstructive, and seven hypopneic events. The patient spent the entire night in
supine position, and the supine AHI was 1.7 as well. The patient’s seizure frequency and
severity did not change after discontinuing the VNS, but seizure control has been incomplete
during the last 2 yr, even with the addition of lacosamide.
3. Discussion
VNS therapy can induce apneas and hypopneas in patients without OSA and can
increase the number in patients with OSA. However, information on the frequency and
severity of these sleep disordered breathing events is limited. Hsieh et al. [3] studied nine
epileptic pediatric patients (13.9 ± 4.6 yr old) with VNS using polysomnography during their
sleep. Sleep efficiency was reduced, and sleep latency and REM latency were increased. The
average apnea-hypopnea index was 14.4 ± 19.4 per h, and the arousal index was 31.8 ± 39.4
per h. The mean oxygen saturation was 96.7% ± 1.1%, and they had 10 ± 9 desaturation
episodes per h. Eight patients had snoring or loud breathing during sleep. Six patients had an
AHI ≥ 5; these patients had 8.3 ± 11.3 central apneas per h, 73.3 ± 61.5 obstructive hypopneas
per h, and 18.8 ± 26.9 obstructive apneas per h. One patient had a high event rate when supine
(180 events per h), and one had a high event rate when in REM sleep (15 per h). There was no
correlation between the respiratory event rate and body mass index. This study reports the
highest AHI observed in these patients and demonstrates that children can have clinically
significant OSA associated with VNS therapy. One of these patients had an AHI of 37 after
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VNS placement. Repeat polysomnography in this patient with the VNS turned off showed
that her AHI had decreased from 37 to 10 [3].
Treatment options for these patients include changing the VNS parameters, positive
airway pressure therapy, and turning off the VNS device. VNS operational parameters can
influence the AHI in patients with VNSs. A cycling time of 300 sec is a common but not
universal setting for most VNS [4]. Since most obstructive events are related to vagal
stimulation in these patients and more severe sleep-disordered breathing is associated with the
shorter cycling time, increasing the cycling time to 300 sec in patients with shorter cycling
times will likely improve the sleep-disordered breathing in these patients [4,5]. Stimulation
frequency also affects the severity of airflow obstruction and can be adjusted in patients with
OSA/hypopnea related to VNS. Airflow obstruction and obstructive events related to VNS are
highest at a device setting of 30 Hz, are less at 20 Hz, and are virtually non-existent at 10 Hz
[6]. Both lowering the frequency and increasing the cycle time have been recommended by
the manufacturer to potentially prevent worsening of OSA during VNS therapy. In patients
with severe sleep-disordered breathing related to VNS in whom other therapeutic options are
either ineffective or not tolerated, taping the magnet over the stimulator during sleep might be
an alternative to deactivating the stimulator completely. The authors are unaware of any
published literature on the effectiveness of the VNS when it is on only for a portion of the
day, but it seems reasonable to speculate that vagal nerve stimulation for approximately 16 h
in a 24-h period is more effective than no stimulation at all. VNS related sleep-disordered
breathing events also depend on patient related factors. The AHI is often higher in the supine
position and positional therapy could be used as an adjunct in these patients [4]. Hsieh et al.
[3] and Marzec et al. [4] reported that continuous positive airway pressure (CPAP) was
effective in treating sleep disordered breathing events in two patients with VNS. However,
Ebben et al. [7] noted that CPAP titration with the device turned on was difficult and that
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CPAP decreased but did not eliminate sleep disordered breathing events. This patient had an
AHI of 82.3 during diagnostic polysomnography with the VNS on; the AHI was 0.4 with the
VNS off and 13 with CPAP and the VNS on [7]. The patient reported by Hsieh had an AHI of
37 after VNS placement [3]. This AHI dropped to 10 after switching off the VNS and to 0.8
with CPAP and the VNS on [3].
In summary, VNS frequently can cause sleep apnea or exacerbate sleep apnea in
patients with a preexisting diagnosis. These patients should routinely be checked for signs and
symptoms of sleep disturbance before and after implantation of VNS, followed by a sleep
study if clinically indicated. Treatment should be individualized, and therapeutic options
consist of continuous positive airway pressure therapy, adjusting the VNS parameters and
discontinuation of VNS.
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Figure Legend
Fig. 1. A 300 sec representative epoch from the first polysomnography. Chin
electromyography (green) shows artifacts corresponding to the vagal nerve stimulator (VNS)
stimulation (labeled “VNS On”). Hypopnea events corresponded precisely with the periods of
VNS activation and comprised nearly all sleep disordered breathing events during this study.
These disappeared after the VNS was inactivated.