Epilepsia, 46(11):18021809, 2005 Blackwell Publishing, Inc.

C 2005 International League Against Epilepsy

Vagus Nerve Stimulation Induces Concomitant Respiratory Alterations and a Decrease in SaO2 in Children
Boubker Zaaimi, Claire H berl , Patrick Berquin, Mickael Pruvost, Reinhard Grebe, e e and Fabrice Wallois
GRAMFC, Facult de M decine, D partement de P diatrie, CHU Nord, and Unit dExploration Fonctionnelles du Syst` me e e e e e e Nerveux P diatrique, CHU Nord, Amiens, France e

Summary: Purpose: To analyze respiratory alterations and effects on SaO2 caused by vagus nerve stimulation (VNS) in children with epilepsy. Methods: Polysomnographic recordings, including electroencephalography, thoracoabdominal distention, nasal airflow, SaO2 , and VNS artifact were evaluated in 10 children with pharmacoresistant epilepsy treated with VNS. Results: Each VNS caused a significant increase in respiratory frequency (p < 0.05) throughout the stimulation period and a decrease in thoracoabdominal-distention amplitude (p < 0.05),

especially at the beginning of the stimulation. These respiratory alterations induced a decrease in SaO2 from 1 to 5%. The effects of VNS on respiration differed significantly between rapid-eyemovement (REM) and non-REM (NREM) sleep states. Conclusions: VNS caused a pronounced change in respiration in children with epilepsy, and this induced a decrease in SaO2 . It is possible that VNS has a neuroprotective effect, and this possibility calls for further investigation. Key Words: EpilepsyVagus nerve stimulationRespiration NeuroprotectionSaO2 .

Vagus nerve stimulation (VNS), an adjunctive treatment for medication-resistant epilepsy, has been used in Europe since 1994. The antiepileptic effect of VNS was initially found in experiments with animal models (1,2) and has been confirmed in humans (35). An average seizure reduction of 44.7% after 6 months was reported (6) for 125 children who had a variety of seizure types. The vagus nerve carries most of the information from viscera to CNS, via various types of fibers (7). These afferents are engaged in physiologic regulation processes, such as those of the digestive and cardiorespiratory systems. An effect of VNS on respiration was first described by Breuer (8). Breuer demonstrated the role of the vagus nerve in shaping the different phases of respiration. Since then, numerous studies have been conducted in animals to elucidate the interaction between VNS afferents and brainstem and pontic respiratory neurons (9). In the Von Euler model, the vagus nerve afferents decrease the inspiratory-off-switch activation threshold, but little attention has been paid to respiratory/VNS interaction. The main discomfort reported by the patients receiving VNS is hoarseness and laryngeal irritation (10). Effects of VNS on respiration were expected,
Accepted June 25, 2005. Address correspondence and reprint requests to Dr. B. Zaaimi at GRAMFC Laboratoire de genie biophysique, Laboratoire de neurophysiologie, Facult de m decine, 3 rue des louvels, 80036 Amiens, France. e e E-mail : boubker.zaaimi@u-picardie.fr

but no major respiratory change due to VNS was detected in one study (11). However, hypopneicpolypneic episodes and hypocapnia were observed in one child (12), and others showed apneashypopneas (4,13) or increases in respiratory frequency with hypocapnia (14). VNS influences the interrelated network of respiration, epilepsy, and sleep. Sleep structure is modified by VNS (15,16) and by epilepsy (17,18). Modifications of sleep states are associated with changes in respiration (19), perhaps mediating some of the effects of VNS. We investigated the effect of VNS on the respiratory drive and related consequences including a possible change in SaO2 . We also analyzed the effect of VNS on respiration as a function of the sleep state. METHODS Data acquisition Overnight polysomnographic recording in clinical routine was used to investigate respiratory function in 10 children (six girls and four boys) with various types of refractory epilepsy, as described earlier (12). Respiratory effects due to VNS also were recorded during the awake state, but the qualitatively observable changes in respiratory variables were difficult to quantify because of the movement and unsteady behavior of the children. VNS (Cyberonics model 300, Webster, TX, U.S.A.) was applied 1802

VNS INDUCES RESPIRATORY AND SaO2 VARIATIONS through electrodes implanted around the left vagus nerve. Stimulation parameters were programmed by a stimulus generator implanted below the left clavicula (Cyberonics model NCP 100). The stimulus parameters (output current, stimulus frequency, pulse width, stimulus on-time, and stimulus off-time) and drug treatment were different for each child (Table 1). The output current was between 1.5 and 3 mA, the stimulus frequency was 30 Hz, and the pulse width was 500 s for all children. Stimulus on-time was 30 or 60 s, and stimulus off-time was between 1 and 3 minutes. Thoracic and abdominal piezoelectric sensors (1 cm diameter placed on the midline and fixed by belts over thorax and abdomen), a nasal thermistance, eight EEG derivations, electrocardiogram (ECG), and chin electromyogram (EMG) signals were used for polysomnographic recording. The SaO2 signal (Nelcor N200, Nellcor Puritan Bennett, Pleasanton, CA, U.S.A.) was acquired and evaluated for seven of these children (patients 2, 3, 4, 5, 6, 7, and 9). The VNS artifact was monitored by means of two EMG surface electrodes placed over the electrodes implanted for stimulation. These variables were recorded by a Deltamed coherence 3NT Device (sampling frequency, 256 Hz) and then converted to ASCII and imported into Spike 2 (Cambridge Electronic Design, Cambridge, U.K.) for further analysis. Data analysis Thoracic and/or abdominal-distention signals provide information concerning the respiratory cycle. The thoracic and the abdominal signals were integrated and then summed to determine the time course of the minute ventilation for the four children (patients 3, 5, 7, and 9) for whom both signals were recorded. Markers in the thoracic and abdominal-distention signal indicate for each respiratory cycle (RC) the beginning of inspiration, the beginning of expiration, and maximum and minimum of the amplitude. The RC was divided into different periods: T1 includes Ti (inspiratory time) with the peak inspiratory velocity (PIV) and nFP (no flow period: no thoracic or abdominal distention is perceived); T2 covers the time of expiration with the peak of expiratory velocity (PEV) (Fig. 1). A breath-by-breath analysis was performed to determine the time course of the respiratory variables (respiratory frequency and amplitude) before, during, and after stimulation. Respiratory variables are expressed relative to reference values (100%), determined from the 50 s directly before the onset of the stimulation. Stimulation periods free of artifacts and free of body movement during both rapid-eye-movement (REM) and non-REM (NREM) sleep were used for analysis. A mean was calculated from selected VNS periods for each respiratory variable. The number of VNS periods selected was different for every child, as shown in Table 1. The number of stimulations

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evaluated for each child was taken into account for the weighted mean curves. Students t test (test of conformity) was used to compare the weighted mean of each respiratory variable with its reference calculated from the mean. This test was performed for every second of a whole cycle, consisting of the reference time before stimulation, VNS time, and reference time after VNS. Parametric tests have limitations even though they are robust. In our application, the population is infinite and unknown, and it is only an assumption that the population is normally distributed, as required for Students t test. Therefore a nonparametric test (Wilcoxon sign-rank test) also was performed: it compared means of respiratory measures during VNS with means of the same measure over the same length of time directly preceding the stimulation. To investigate the effects of VNS during sleep, it is important to analyze respiratory effects according to the different sleep states. All the children in this study had cerebral diseases, and consequently, differentiation between sleep states was difficult even with the recording of electrooculograms (EOGs). Nevertheless, for child 10, periods of REM and NREM sleep were reliably identified on the basis of EEG, EMG, and EOG. For each sleep state, 10 periods of stimulation were selected and analyzed. For three children, the stimulation parameters were modified during sleep to set VNS parameters below the threshold above which life-threatening events may occur (12). We evaluated the data from these cases to elucidate the general relation between VNS parameters and the respiratory cycle. We studied evoked respiratory effects of VNS, but not apneahypopnea indexes (that could be measured by evaluating the VNS period). RESULTS Effect of VNS on respiratory amplitude In all children, each VNS decreased the amplitude of respiratory thoracoabdominal movement. Three phases can be distinguished. The maximal VNS effect was during the first 15 s of the stimulation period. This phase 1 included an abrupt and significant decrease in amplitude (22.7 15.8%; t = 3.67; p = 0.011). The decrease was maintained throughout the stimulation period in three children, and lasted only for the first 15 s after the start of VNS in seven children. Phase 2 lasted from the 15th second until the end of the VNS period, during which the thoracoabdominal-distention amplitude was lower than the mean, but not as low as during phase 1. Phase 3 showed a rebound effect, directly after the end of VNS; for four children, this involved a pronounced overshoot above baseline (Fig. 2A). The thoracic and abdominal signals for four children were integrated and summed to show the changes in minute ventilation. A maximal decrease of 47.2 17.1%
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TABLE 1.

B. ZAAIMI ET AL.
Clinical features of epileptic patients
Number of VNS periods selected for calculating means 10

Child 1

Age (years) 8

Sex F

Recording day 01/11/2001

Beginning of stimulation 04/1998

Stimulation parameters 1.75 mA 65 s 105 s 500 s 30 Hz 3 mA 35 s 175 s 500 s 30 Hz 2 mA 65 s 65 s 500 s 30 Hz 2 mA 35 s 173 s 500 s 30 Hz 2 mA 65 s 173 s 500 s 30 Hz 2 mA 65 s 65 s 500 s 30 Hz 2.5 mA 65s 175 s 500 s 20 Hz 2 mA 65 s 65 s 500 s 30 Hz 2 mA 65 s 65 s 500 s 30 Hz 2 mA 35 s 175 s 500 s 30 Hz

Type of epilepsy Symptomatic partial epilepsy CSWSS (PVLM)

Medication Felbamate

18

06/18/2003

11/2002

Symptomatic generalized epilepsy

Kepra Clobazam Topiramate Carbamazepine Phenytoine Topiramate Lamotrigine

11

08/23/2002

10/2001

10

Symptomatic generalized epilepsy LennoxGastaut

12

06/24/2003

10/2001

Symptomatic partial epilepsy

04/29/2004

09/2003

13

Cryptogenic partial epilepsy

Valproate Topiramate

06/26/2002

11/2000

24

Symptomatic generalized epilepsy LennoxGastaut

Valproate Clonaz pam e Lamotrigine Lamotrigine Clonaz pam e

16

05/19/2003

02/2002

Symptomatic partial epilepsy

10

05/21/2002

12/1999

15

Symptomatic partial epilepsy

Valproate Topiramate Phenobarbital Valproate Topiramate Clobazam Valproate Clonaz pam e Vigabatrin

13

11/22/2002

12/2000

14

Cryptogenic partial epilepsy

10

13

10/15/2003

01/2001

11

Symptomatic generalized epilepsy LennoxGastaut

(t = 5.6; p = 0.01) was noted during the first 15 s. The effect of VNS on the minute ventilation amplitude (Fig. 2B) was very similar to its effect on thoracic and abdominal distention amplitudes (Fig. 2A). Figure 2C shows the time course of relative amplitude for nasal airflow and thoracic and abdominal distentions (mean of the same 10 VNS periods). Obviously, the effect of VNS on thoracic and abdominal movement was greater than that on nasal airflow during all three phases.

Effects of VNS on the respiratory frequency During VNS, the respiratory frequency increased significantly for all children (t = 3.59; p = 0.011). This increase started and ended abruptly with VNS (Fig. 2D). During phase 1, the mean respiratory frequency increased to a maximum (121.5 18.1%), maintained during phase 2 (120.1 4.5%; maximum during phase 2 = 23.4 18.3%). In phase 3, the respiratory frequency decreased toward pre-VNS reference values.

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FIG. 1. A: A typical vagus nerve stimulation (VNS) period with signals of thoracic distention, nasal airow, SaO2 , and abdominal distention. VNS clearly affects thoracic and abdominal distention and results in a decrease in SaO2 .B: Characteristics of a respiratory cycle as determined from the thoracoabdominal distention signal.The solid vertical lines subdivide the respiratory cycle into period T1, consisting of inspiratory phase Ti and no-ow phase nFP, and period T2, the expiration phase. PIV, Peak of inspiratory ow; PEV, the peak of expiratory ow.

FIG. 2. Effect of vagus nerve stimulation (VNS) on the respiratory amplitude and frequency. The stimulation period starts at 0s. A: Individual and mean (bold curve) time courses of relative amplitudes of the respiratory movement for seven children. B: Individual and mean (bold curve) relative minute-ventilation amplitudes for four children. C: Individual thoracic and abdominal distentions and nasal-airow amplitudes. Three phases are distinguishable: phase 1: decrease of the amplitude to a minimum; phase 2: progressive increase of the amplitude until the end of VNS; phase 3: abrupt increase of the amplitude after the end of VNS (rebound effect). The decrease during phase 1 was signicant (p < 0.05). D: Relative respiratory frequencies for seven children and the mean (bold curve). The respiratory frequency increased abruptly during phase 1, remained stationary during phase 2, and decreased during phase 3. Throughout the stimulation period, the increase was significant.

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B. ZAAIMI ET AL. VNS (time constant, 3 s) (Fig. 4B). Child 6, during one period of stimulation, had apnea, with the SaO2 abruptly decreasing by 7%. No change in VNS parameters could explain this event. For two children (patients 2 and 7), the SaO2 remained stable during VNS. Interaction of VNS with sleep state EEG analysis failed to detect any microarousal induced by VNS. The effect of VNS on the respiratory frequency differed significantly (z = 2.67; p = 0.004) between REM and NREM sleep (Fig. 5A). For the respiratory amplitude, the difference was even more pronounced (z = 1.96; p = 0.004) (Fig. 5B). During the first phase of stimulation, VNS caused a bigger decrease in amplitude during NREM (maximum decrease, 56.4 6.4%) than during REM (maximum decrease, 30.2 11.3%) sleep. Thereafter, the respiratory amplitude progressively increased during the second phase for both sleep states. However, during REM, the amplitude increased more rapidly than during NREM. During the third phase, the respiratory amplitude increased abruptly, with a rebound effect of 69.84 13.14% (overshoot of 41.2 5.2% over baseline) during NREM and a rebound effect of 43.92 15.59% (overshoot of 40.6 6% over baseline) during REM sleep. Other findings It was necessary to adapt VNS parameters to the individual routinely, and this allowed acquisition of information about the effect of the VNS parameter current intensity on respiration. The intensity of the VNS current was clearly

The nonparametric test (Wilcoxon) confirmed the findings of the t test of conformity: The increase in frequency and the decrease in the amplitude during VNS were significant as compared with the reference time before stimulation. Effect of VNS on the expiratory pause One of the major effects of VNS on the respiratory cycle was a reduction in the time preceding the inspiration: the expiratory pause, nFP. As an example Fig. 3A shows for child 1 that the nFP vanished immediately after the beginning of VNS. The mean and standard deviation for thoracic-distention signals for 18 periods of 10 s before VNS (Fig. 3B), and 10 s starting with the onset of VNS (Fig. 3C) were calculated. The results clearly demonstrate the repeatability of the effect of VNS on the nFP. The nFP decreased significantly (t = 4.11; p < 0.001; z = 4.409; p < 0.01) by 54% between the two subsequent respiratory cycles directly before and after the onset of a VNS. These values were calculated from 31 different VNS periods gathered from all children (except patients 5 and 10, for whom the nFP could not be sufficiently well distinguished). Effect of VNS on the SaO2 A reduction of more than 1% in SaO2 was observed for 50% of the observed periods of stimulation for children 4, 5, and 6. For child 9, the SaO2 decreased by 1% systematically. For child 3, SaO2 decreased by >1% in 85% and >3% in 26% of the VNS periods (Fig. 4A). This decrease in SaO2 started 10 s after the beginning of the

FIG. 3. Beginning of a vagus nerve stimulation (VNS) period (A). Mean thoracicdistention signal before VNS (B) and during VNS (C); example for one child (1). Top: VNS signal and thoracic-distention signal. Before stimulation, the nFP is visible in each respiratory cycle, like a hook in the signal. From the beginning of VNS, the hook disappears, and nFP diminishes. Bottom: Mean (solid) and standard deviation (hatched) of 18 episodes of 10 s preceding VNS (left) and of the 10 s after the onset of 18 VNS periods.

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FIG. 4. Effect of vagus nerve stimulation (VNS) on SaO2 . A: SaO2 decreased by >1% during 43% of the VNS periods in seven children. B: Time course of the decrease in SaO2 during VNS. The decrease begins during the second phase of the stimulation. After the end of the stimulation, the SaO2 values increased toward the control values (child 9).

correlated to respiratory frequency and to thoracoabdominal distention: a stepwise increase of the stimulation current from 1 to 3 mA had a stepwise effect on the thoracic distension signal (Fig. 6). The effect on thoracic distention of the increase of VNS current was largest for the first three or four respiratory cycles (phase 1). DISCUSSION We studied the effects of VNS on respiration in children undergoing VNS for refractory epilepsy. For all children,

FIG. 6. Changes in the thoracic-distention signal according to the current used for vagus nerve stimulation (VNS) periods according to output current with the corresponding thoracic-distention signal. The higher the output current, the bigger the alteration of the thoracic signal.

the effect on respiratory frequency was significant during the whole stimulation period. The methods used, including a t test, allowed a further analysis of changes caused by VNS in respiration and visualized of the dynamics of these processes. It is generally believed that activity of afferent

FIG. 5. Effect of vagus nerve stimulation (VNS) on respiratory frequency (A) and on thoracoabdominal distention (B) during rapid eye movement (REM) and non-REM. The effect of VNS on thoracoabdominal distention was greater during NREM than during REM sleep states.

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vagal fibers and chemosensors are the major peripheral input to the bulbar respiratory network. Thus they contribute to the shape and duration of the various respiratory phases (9). Consequently, it is not surprising to observe respiratory impairment in patients treated with VNS. The effect of VNS on thoracoabdominal distention varies during the VNS period. The effect on thoracic distention was greater than that on abdominal distention, and nasal airflow showed the smallest effect. VNS induces a first phase of rapid, shallow breathing, with a decrease in tidal volume (this study, 20). Similar effects have been reported for vagotomized animals (21) and can be ascribed to the involvement of the afferent portion of the vagal fibers. These animal studies also showed that the rapid, shallow breathing was triggered in parallel to activation of c-fibers (21,22). Thus analysis of respiratory responses might indicate whether c-fibers are activated by VNS. Shortening of expiration (reduction of nFP) can thus be explained by inspiration switching. The threshold for the inspiratory on-switch progressively decreases during expiration and is consequently low toward the end (23). Our results suggest that VNS mimics the deflation reflex, which shortens expiration by triggering an earlier onset of inspiration (24). Such earlier inspiration is not specific to VNS and also is associated with stimulation of other afferents, including phrenic (25) and somatic afferents (26), and activation of brainstem structures in the rostral pons in absence of vagal feedback (27). Probably pontic structures also are involved, like the parabrachial nucleus and cortical structures where vagal afferents project directly. Limbic structures in rats receive vagal inputs. When these structures are stimulated, they induce similar shallow breathing (28). This type of response also is observed during hyperthermic ventilation, which involves the hypothalamus (29). C-fos expression (30), considered to be a marker of neuronal activation, and functional MRI (f MRI) (31) suggest that these structures might be involved in the response to standard clinical VNS. This kind of rapid shallow breathing induces hypoxemia (this study) and a decrease in PET CO2 (14). Phase 2 follows phase 1 and is not purely vagal, but constitutes an integration of respiratory responses to vagal and chemoreceptor stimulations of the respiratory network. Inhibitoryvagal and excitatory-hypoxic inputs compete in their effects on the central respiratory drive (32). The result of this, during phase 2, is the progressive return of the amplitude toward control values. The third phase constitutes a release from the two previous phases: respiration might be enhanced because of the persistent hypoxic stimulation while the restraining effect of the vagal afferent suddenly disappears. Thus it is becoming clear that the mechanisms by which VNS interacts with epilepsy are complex. VNS activates not only the vagal pathway but probably also chemosensitive pathways.
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FIG. 7. Network of interactions formed by respiration, sleep, epilepsy, and vagus nerve stimulation (VNS). Bold arrows, Potential VNS therapeutic pathway including hypoxic stimuli.

These loops are stimulated iteratively day after day. Such iterative hypoxichypocapnic stimulation, even weak, might trigger preconditioning with activation of neuroprotective mechanisms (33). Arterial gas tension strongly influences seizure duration. Indeed, hypoxichypocapnic and hyperoxichypercapnic challenges decrease seizure duration in dogs receiving electroconvulsive therapy (33,34). Neuroprotection associated with hypoxic preconditioning is observed under a wide variety of preconditioning hypoxic stimuli, provided that they are either iteratively presented (33,35) or weak (36). In our study, the chemosensitive stimulus was applied for 30 or 60 s, followed by an off-time of 1 to 3 min, which is probably sufficient, considering the number of conditioning stimuli presented. As a consequence, in the complex network involving respiration, sleep, epilepsy, and VNS mechanisms, we suggest that VNS therapy is partly dependent on intermittent and weak hypoxic stimuli. (Fig. 7) Neuronal hypoxic tolerance of brain and hippocampal neurons (33,37,38) is increased by mild or moderate hypoxic preconditioning challenge, and this might contribute to the benefits of VNS. Similarly, neuroprotection of preconditioning hypoxia attenuates the neurotoxicity and brain edema of kainic acid (39) and might prevent seizure-associated neuropathology (40). Many patients with intractable epilepsy have subcontinuous epileptic discharge, which interacts with normal brain function. A decrease in the side effects of epileptic discharge also might improve the epilepsy itself and the ability to perform cognitive tasks. The expression of immediate early genes (IEGs) and a variety of stress-related proteins are probably the key in hypoxia (41). Similarly, the purinergic system (adenosine, adenosine triphosphate, and guanosine monophosphate) is a possible intermediator involved in the respiratory response to hypoxia, trophic effects on neural cells, and prevention of seizures (42,43). It is thus possible the benefits to patients outweigh the risks of this weak desaturation, provided that all precautions are taken.

VNS INDUCES RESPIRATORY AND SaO2 VARIATIONS In conclusion, VNS induces a three-phase response in respiration and a related decrease in SaO2, which trigger chemosensory afferents. The antiepileptic effect of VNS might be associated with some kind of preconditioning involving both iterative vagus and hypoxic hypocapnic stimuli. Thus a better understanding of this putative chemosensitive neuroprotection mechanism associated with VNS is needed.
Acknowledgment: This study was supported by grants from Universit of Picardie Jules Verne, Amiens North University e Hospital, La Fondation de lAvenir (France), and Cyberonics @, EU. The excellent assistance of the Amiens North University Hospital technicians Mrs. Laurence Legrand, Chantal Ponthieux, Armelle Zuba, and Mr. Philippe Forget is gratefully acknowledged. We thank Mrs. Bev Moate for the manuscript grammatical corrections.

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