Epilepsiu, 31(Suppl. 2):S44-S50, 1990 Raven Press, Ltd., New York 0 1990 International League Against Epilepsy
Efficacy and Safety of Vagus Nerve Stimulation in Patients With Complex Partial Seizures Basim M. Uthman, B. J. Wilder, Edward J. Hammond, and *Steven A. Reid Neurology Service, and *Neurological Surgery Section, Department of Veterans Affairs Medical Center, Gainesville, Florida, U.S.A.
~
Summary: A clinical trial of chronic intermittent vagal stimulation in five patients suggests that the procedure may be safe and effective as adjunctive treatment of medically intractable seizures of partial onset. Patients tolerated well the implantation of the neurocybernetic prosthesis and the vagal stimulation without serious physiological or lifestyle changes. Stimulation of the vagus nerve either reduced the seizure frequency or decreased the duration or intensity of seizures. Adverse side
effects were limited to a tingling sensation in the throat and hoarseness during stimulation. A major complication was mechanical interruption of the wire-electrode circuitry, with consequent cessation of stimulation. The small number of patients and the relatively short followup period make this a pilot study, but the results are promising. Key Words: Epilepsy-Seizures-Vagus nerveElectrical stimulation-Safety-Prognosis.
INTRODUCTION
encephalogram (EEG) (Magnes et al., 1961; Chase et al., 1967). In order to obtain antiepileptic effects, C fibers need to be stimulated, with all effects being graded with stimulus strength (Woodbury and Woodbury, 1990). Pentylenetetrazol-induced seizures are not altered by maximal A-fiber stimulation, and B-fiber stimulation has only little effect. We studied the effect of chronic intermittent stimulation of the vagus nerve in five patients with CPS, and the results are promising. Implantation of the neurocybernetic prosthesis (NCP), developed by Cyberonics, Inc., was performed at the Department of Veterans Affairs Medical Center and the University of Florida College of Medicine, Gainesville, Florida. Six more patients were studied at the Bowman Gray School of Medicine, Winston-Salem, North Carolina, and the University of Miami Medical Center, Miami, Florida. There appear to be no previous reports on the antiepileptic effects of vagal stimulation in humans.
As many as 3540% of patients with complex partial seizures (CPS) remain refractory to treatment with the currently available antiepileptic drugs. As active research on the development of safe and efficacious treatments for epilepsy continues, a new method involving stimulation of the vagus nerve has been developed. Intermittent stimulation of the vagus nerve with a multiprogrammable implant is being tested in clinical trials for the treatment of medically refractory CPS. Animal studies show that at certain electrical output parameters, vagus nerve stimulation may prevent or abort electrically and chemically induced seizures in rats (Woodbury and Woodbury, 1990). Physiologic studies in animals show that stimulation of the cervical vagus nerve may produce evoked potentials in the cerebral cortex (O'Brien et al., 1971; Caret al., 1975), the hippocampus (Serkov and Bratus, 1970), the cerebellum (Hennemann and Rubia, 1978), and the thalamus (Car et al., 1975). Furthermore, stimulation of the vagus nerve at certain current frequencies may produce desynchronization of the electro-
PATIENTS AND METHODS
We studied five patients (four men and one woman), aged 20-59 years, who had CPS. The seizures were refractory to treatment with antiepileptic drugs given alone or in various combinations. All patients met the following criteria: 1. average of more than six CPS per month doc-
~
Address correspondence and reprint requests to Dr. B. M. Uthman at Neurology Service (127), Department of Veterans Affairs Medical Center, Gainesville, FL 32602-1 197, U.S.A.
s44
EPILEPTIC COMPLEX PARTIAL SEIZURES
umented on a seizure calendar for 2 years with fewer than 14 consecutive seizure-free days; 2. CPS with or without simple partial seizures (SPS), as defined by the International Classification of Epileptic Seizures (Commission, 1981); 3. constant dosage of phenytoin or carbamazepine, or both, for at least 1 month before the study; 4. age 18-60 years; 5. good mental ability with IQ presumed to be >go; 6. etiology of seizures either not treatable or progressive; 7. no history of asthma, heart or lung disease, or other progressive systemic disorder; 8. no history of psychiatric disorder or recurrent episodes of depression; 9. no previous vagotomy procedures; 10. no history of insulin-dependent diabetes mellitus; 11. no history of gastritis, stress-induced ulcers, or gastric-duodenal ulcers. Patients who were deemed noncompliant with therapy or unable to keep an accurate seizure calendar were excluded. All patients gave written informed consent for participation in the study. Study design Each patient had physical and neurological examinations and baseline studies consisting of computed tomographic (CT) scan or magnetic resonance imaging (MRI) of the brain, EEG, gastric acid output analysis, complete blood-cell count, measurement of trough serum antiepileptic drug levels, serum electrolytes, calcium, phosphate, cholesterol, and triglycerides, and liver function tests. Patients were then admitted to the hospital for 2 or 3 days for implantation of the NCP. The implant consisted of a multiprogrammable pulse generator that delivers electrical signals to the left vagus nerve via bipolar electrodes wound around the nerve in the neck between the superior and inferior cardiac branches. The surgical technique has been described by Reid (1990). Patients were observed for 2 weeks after implantation of the device to establish a postsurgical baseline and to allow for wound healing and proper electrode fixation. Cervical and chest x-ray films were obtained to confirm placement of the device and the electrodes. Patients then entered a 2-week zero stimulation (placebo)period in which they were told that the device was on, although in actuality no stimulation was applied. At the beginning of postoperative week 5 , the NCP was programmed and acti-
s45
TABLE 1. Parameters of initial stimulation of the vagus nerve Parameters Output current Signal frequency ON time OFF time Pulse width Daily treatment time Magnet current
1mA 50 Hz
60s 60min 250 )LS 24 h OmA
vated utilizing the manufacturer’s softwear via a programming wand placed over the device. This procedure is done outside the body through the patient’s clothing and takes only a few minutes. The NCP and the program have been described by Terry et al. (1990). The parameters of the initial electrical stimulation to the vagus nerve are shown in Table 1. Patients were followed at 6, 8, 12, 16, 20, and 24 weeks after the implantation. Each follow-up visit included a physical examination, measurement of trough serum antiepileptic drug levels, and review of the seizure calendar. Proper function of the NCP system and any changes made to programmed settings were documented. At the beginning of weeks 9, 16, 20, and 24, stimulation was continued with the initial parameters, or the output current andor number of stimulation periods per hour were increased if the patient had not had at least a 25% reduction in seizure frequency. At the beginning of week 13, patients entered a Cweek placebo period, with the same conditions as in the first period. At the beginning of week 24, patients entered an openextension period in which they were seen at 2- to 3-month intervals. At the end of the second placebo period, patients were provided with a magnet carried in a holster pocket mounted on a belt at the waist. The magnet could be applied over the NCP for 2 s and removed to activate the system instantaneously at the beginning of a seizure with the hope of aborting it. Figure 1 summarizesthe study design. statistical analysis At each follow-up visit, seizure calendars were collected and the seizure history (time, date, duration, and type of seizure) was recorded and calculated as a ratio of seizures per day. The patient’s daily average total seizure count for 6 months before implantation of the NCP was compared with that of each stimulation and placebo period. The treatment was considered efficacious if there was at least a 50% reduction in seizure frequency. Reduction in the intensity or duration of seizures or postictal periods was considered a favorable effect. Epilrpsia, Vd. 31, Suppl. 2, 19Po
B. M. UTHMAN ET AL.
S46
MAGNET PROVIDED
IMPLANT
BASELINE
w
I
JPLACEBO 1
STIM. 1
4 WKS
4 WK8
STIM. 2
PLACEBO 2
STIM. 3
STIM. 4
-l-l-l-l-l-l52 WKS
4 WKS
4 WKS
4 WKS
4 WKS
FIG. 1. Study design for chronic intermittent vagal stimulation in patients with intractable complex partial seizures.
RESULTS
significant changes were observed during or immediately after stimulation (Fig. 2).
Effects on cardiac rhythm Distal to the stimulating electrodes, the left vagus nerve innervates the heart through the inferior cervical cardiac and thoracic branches. To identify possible cardiac side effects of chronic intermittent vagal stimulation, we monitored the heart with an electrocardiogram (ECG) and 24-h Holter monitor during baseline and after 8 weeks of stimulation and compared the results. There were no notable changes in the minimum, maximum, or average heart rates (Table 2). There were also no changes in benign dysrhythmias, except in one patient who had an asymptomatic increase in premature atrial contractions. This patient had probably been in and out of first-degree atrioventricular block, as a previous ECG showed a slightly prolonged PR interval. However, there was no notable change in his PR interval after stimulation (baseline PR = 0.25 s; poststimulation PR = 0.24 s). There was no appreciable change in ECG morphology in any of the patients. To test for acute effects of vagal stimulation on the ECG, we stimulated patients during ECG recording, using the following parameters: output current = 1 to 5 mA; signal frequency = 10 and 50 Hz; pulse width = 250 bs; ON time = 84 s. No
Gastrointestinal effects The left vagus nerve may influence gastric acid secretion via the anterior gastric vagus cord. Fasting acid output of the stomach was measured for 1 h during the baseline period for comparison with gastric acid output after 8 weeks of vagal stimulation. No chemical stimulation, such as pentagastrin, was utilized, and only basal acid output was measured. After the patient's throat was numbed, a rubber tube was introduced into the esophagus, and under fluoroscopy, the tip of the tube was placed in the area of the antrium. Gastric secretions were collected with a constant suction pump and titrated over two consecutive 30-min periods. The gastric acid output of all patients was within the normal range (0.1-3.8 mEq/h). No follow-up analysis of gastric acid output is currently available. However, none of the patients experienced gastrointestinal problems, such as nausea, vomiting, heartburn, hematemesis, melena, diarrhea, or constipation.
Safety
Other effects Patients tolerated the vagal stimulation well and none reported pain, discomfort, or significant changes in their daily activities, sleep habits, breathing, eating, swallowing, or appetite. In particular,
TALBE 2. Cardiac effects of chronic intermittent vagal stirnulation Heart rate (beatshin) Patient
Baseline min-max (av)
Arrhythmias (per 24 h)
FOIIOW-UP min-max (av)
FOIIOW-UD
Baseline ~
co1
61-135 (87)
55-128 (83)
c02 C03
50-1 10 (77) 54-147 (90)
51-112 (80) 50-140 (89)
C04
48-145 (69)
49-137 (76)
C05
NA
53-120 (76)
PAC = premature atrial contraction; PVC available. a Average per hour. Epilepsia, Vol. 31. Suppl. 2 , 1990
=
premature ventricular contraction; PR
PAC (4) PVC (0) PVC (1) PVC (6/h)" PAC (14) PAC (6) PR = 0.25 s NA =
~~~~~
~~
PAC ( 5 ) PVC ( I ) PVC (0) PVC (3/h)" PAC ( 5 ) PAC (3,011) PR = 0.24 s PVC (0) PR = 0.22 s
atriventricular conduction time: NA
=
not
EPlLEPTlC COMPLEX PARTIAL SElZURES
s47
FIG. 2. Electrocardiogram of a patient during vagal stimulation. Note the absence of an effect on the heart during or immediately after 30 s stimulation (. = stimulation off).
vagal stimulation did not arouse patients from their sleep, although the NCP would turn on as frequently as every 10 min. During waking hours, patients were aware of the stimulation, because they felt a tingling, beating, or vibrating sensation in the throat or were hoarse as they talked during stimulation. The awareness seemed to habituate with time, and patients may barely perceive the stimulus even though the system works perfectly. Even during a stimulation epoch of 30-80 s, the subjective feeling of stimulation intensity may fade shortly after the onset of stimulation. When a high intensity is selected, patients may cough briefly for 2-5 s as stimulation begins and only during the first few stimulation periods. Follow-up chest and cervical x-ray films at 2 and 20 weeks after implantation showed no significant displacement of the electrodes or the NCP. No rejection reaction was noted. There were no remarkable changes in the clinical laboratory tests. No appreciable weight loss or weight gain occurred. There was no notable change in the systolic or diastolic blood pressure. Electrophysiological studies Noncephalic reference recording of the left vagus-nerve-evoked potential showed a scalp negative component with latency at 12 ms with a very high amplitude (up to 60 pV) and widespread scalp distribution (Hammond et al., 1990). Field distribution studies indicated that this potential was generated in the neck, in the region of the stimulating electrodes. Intraoperative studies in one patient in-
dicated that this potential was myogenic, because it was abolished by a muscle-paralyzing agent. The pulse waveform of the electrical stimulus artifact recorded over the stimulating electrodes was monitored to confirm that the circuitry of the NCP system was intact. The patients’ subjective feelings of the tingling sensation and objective monitoring were helpful in ascertaining whether the system was functioning (Hammond et al., 1990). No effect of vagal stimulation was observed in the EEG of awake, anesthetized, or sleeping patients. There were no obvious acute effects on interictal epileptiform activity. In one patient, stimulation abruptly terminated the clinical and EEG seizure activity approximately 11 s after the onset of a CPS. For details and effects of vagal stimulation on other evoked potentials, see Hammond et al. (1990). Complications All patients tolerated well the general anesthesia and the surgical implantation of the NCP. Mild pain at the surgical sites lasted for 24-48 h or less. Patients were up and around the next day and were discharged home 2 or 3 days after the operation. About 10-20 weeks after implantation of the NCP, patients reported a rather sudden decrease id perception of the stimulus or stopped perceiving it. The diagnostics program incorporated into the stimulating device showed high impedance, indicating a break in the wire-electrode system. The electrical stimulus artifact recorded over the stimulating electrodes showed a differentiated pulse waveform (Hammond et al., 1990) in three patients, indicating Epileppsia. Vd.31. Suppl. 2 , 1990
S48
B. M . UTHMAN ET A L .
a break in one electrode, and no pulse at all in two patients, indicating a break in both electrodes. Replacement of the one broken electrode with a disc electrode at the site of the stimulating device was done in two patients with local anesthesia. Thus stimulation was changed from bipolar to unipolar mode. The other three patients had a revision operation at the neck and chest sites on the left side. After careful dissection of fibrous tissue, the electrodes were unwound from around the vagus nerve, removed, and replaced with a new electrode wire system that had better fatigue and corrosion properties. Because the break was around the electrodewire junction, a third Silastic spiral was wound around the vagus nerve 0.5-1 cm proximal to the two stimulating electrodes in order to anchor the two wires parallel to the vagus and absorb any torque tension from bending or rotating. All patients tolerated the revision operation well. Of importance, intraoperative findings showed only fibrosis around the electrode without any damage to the vagus nerve, even after 4 months of stimulation or 9 months after the implantation. Stimulation was resumed 2 weeks after the surgical repair.
Average Seizuresper Day
"
A
Epilepsia, Vol. 31. Suppl. 2 , 1990
,
.
.
.
R1
C1
S1
52
C2
X
X
XX
R2
S7
Period
Average Seizures per Day
I
0.4
0.3 0.2
0.1 0 BL
B
R1
C1
S1
C2
S2
53
X
S5
S6
57
Period
Average Seizures per Day
1.44 12 1 0.8 0.6 0.4 02
m=Y
Three patients (COI, C03, and C05) had a greater than 50% reduction in seizure frequency, which gradually returned to baseline after the electrode break. Two of these patients (C03 and C05) regained the same percentage decrease in seizures within 8 weeks after the repair, one with bipolar and one with unipolar stimulation (Table 3 and Fig. 3A, C,E). The third patient (CO1) had a 32% reduction in seizure frequency within 4 weeks of the revision (Table 3 and Fig. 3A). One patient (C02) showed no signifcant change in seizure frequency, but the seventy and duration of seizures, as well as the postictal period, were reduced compared with the baseline period. This effect was regained after electrode repair, and a 30% reduction in seizure frequency was obtained within 8 weeks after stimulation was resumed (Table 3 and Fig. 3B). Patient C04 had no reduction in seizure frequency, but reported less severe and briefer ictal and postictal periods (Table 3 and Fig. 3D). He was also more alert and socially active. Before stimulation, he had interrupted speech (several brief pauses before completion of a sentence or phrase) and great difficulty expressing himself. Baseline EEG showed frequent 1- to 3-s episodes (about once every 10 s) of bilaterally synchronous, high-amplitude, generalized, and frontally predominant activity. A few weeks after vagus stimulation, he became more conversant, speech became normal, and his
.
BL
I
1
0
EL
C
Rl
C1
S1
52
C2
s) XX
XX R2+M S7
Perkd
0.8
0.6
0.4 0.2
0
D
BL
R1
C1
S1
S2
C2 S3 Perkd
S4
X
R2
S7
Average Seizures per Day
I
BL
R1
S2
C2 X S4 s5 s6 S7 Period FIG. 3. Effect of vagal stimulation on the frequency of complex partial seizures in five patients (A-E; patients CO1-CO5, respectively). BL = 6-month baseline; R = surgical recovery; C = control (placebo) period of no stimulation; S = stimulation period; X = one broken lead; XX = two broken leads; * = lead problem first recognized; ** = lead problem repaired; M = magnetic activation. Stippled columns, stimulation periods; filled columns, no stimulation.
E
C1
S1
EPILEPTIC COMPLEX PARTIAL SEIZURES
s49
TABLE 3. Change in seizure frequency during each study period
Patient
co1 c02 C03 C04 C05
Seizure increase or decrease (%)
Baseline (seizureslday)
R
CI
S1
s2
c2
s3
s4
s5
S6
s7
0.32 0.24 1.19 0.41 0.70
-54.7 -54.0 -31.9 53.7 133.2
11.9 -4.6 -40.1 64.0 33.6
15.3 46.0 -38.2 18.7 13.0
-66.0 -27.0 -48.1 44.7 -3.3
-47.2 -71.9 -13.5 52.7 -59.3
-32.1 -11.4 -83.1 49.8 12.0
-45.7 -1.5 -46.3 68.3 -74.1
-31.3 25.3 -23.7 64.0 -26.1
-4.9 3.4 -59.3 70.3 -42.2
-32.1 -30.0 -90.3 80.4 -57.2
R = recovery period (no stimulation); C = control period (no stimulation); S = stimulation period.
EEG showed less frequent epileptiform activity. The increase in seizure frequency could be explained by more accurate reporting of the frequent brief seizures as the patient became more alert. In spite of the apparent seizure increase, the patient and his parents considered the effect of vagal stimulation favorable on the basis of shorter and less severe CPS and the absence of generalized tonicclonic seizures. Three patients reported abortion of seizures with manual activation of stimulation (via the magnet) early in the seizure. The best and most consistent results were obtained in a patient who had an aura lasting approximately 20 s before the onset of every CPS. He could abort the seizures by activating the stimulus at the onset of the aura. This patient had never reported an isolated aura before vagal stimulation was tried. In another patient, the clinical and EEG manifestations of CPS were stopped with activation of the stimulus approximately 11 s after the seizures began. This effect could be coincidental because seizures lasting 12-15 s were previously recorded with closed-circuit TV-EEG monitoring. DISCUSSION Stimulation of the vagus nerve is a novel method in its earliest phase of efficacy and safety studies in humans. The most tolerable stimulation parameters with the best antiepileptic properties are yet to be determined. Lower current frequencies (-20 Hz), higher tolerable current outputs (-2 mA), shorter off time (5-10 min), and pulse width of 250-500 ps seem to give the best results. Results are sometimes even better when patients activate the system with a magnet on demand at the onset of a seizure. The mechanisms by which intermittent vagal stimulation exerts an antiepileptic effect are unknown. Possible mechanisms are desynchronization of neuronal discharge, release of inhibitory neurotransmitters, stimulation of inhibitory pathways, or increase in the electrical threshold for seizures. The epileptogenic focus is said to be in an “isolated or anarchic”
state devoid of control inputs, and intermittent vagal stimulation may interrupt the “independent” activity of that focus. Vagal stimulation at random rather than regular intervals may have a better antiepileptic effect. The patient’s sense of being in control of the situation (when the manual activating magnet is provided) and the contribution of the placebo effect to the antiepileptic effect of vagal stimulation cannot be underestimated at this early stage of use. We observed in some of our patients that the antiepileptic effect, as manifested by a reduction in seizure frequency, duration, and intensity, lagged 4-8 weeks after both the initiation and the discontinuation of stimulation. This suggests that the antiepileptic properties are cumulative and lasting. This could explain the lack of a significant reduction in seizure frequency during the initial stimulation period and the absence of a return of seizure frequency to baseline during the second placebo period in some patients (e.g., CD2). The NCP (Cyberonics Model 100) and the bipolar vagal stimulation lead (Cyberonics Model 300) appear to be a reliable and state-of-the-art stimulation system that can be programmed with any IBM-compatible personal computer using programming software and a programming wand (Cyberonics Model 200). The software is user-friendly and simple to operate. The menu-driven operation, help, prompt, and message functions facilitate simple and rapid programming and keep the user fully informed of what is occurring step by step. Programming capabilities include revision of the NCP’s programmable parameters, device diagnostics testing, storage and retrieval of telemetered data, synchronization of the stimulus signal with an evoked-potential measuring apparatus, and resetting of the N C P s microprocessor. With the parameters used in this study, no significant adverse side effects were reported. Of importance, no gross damage to the vagus nerve was observed in three patients whose stimulating leads were replaced. Animal studies in the adult cat peroneal or sciatic nerves have shown that irreversible axonal injury Epilrpsio. Vol. 31, Suppl. 2 , 1990
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B. M . UTHMAN ET AL.
may result from sustained, continuous, and high frequency stimulation (Agnew and McCreery, 1990). However, intermittent stimulation of peripheral nerves with moderate frequencies was found to be effective and safe to the nerve. If chronic intermittent vagal stimulation turns out to be safe and efficacious for the treatment of intractable CPS, it may have advantages over current medical therapy. Improved seizure control, absence of the cognitive, systemic, and hypersensitivity side effects of antiepileptic drugs, and the obviation of expensive periodic blood studies are only a few of the potential benefits. The battery life of the current NCP is approximately 2 years, and the device can be easily changed by a minor surgical procedure. Modifications in the hardware of the device to prolong the battery life are in progress. The total cost of the NCP replacement is comparable to the cost of a 5-year supply of certain antiepileptic drugs. Additionally, vagal stimulation may offer another option of treatment before temporal lobectomy or other corticectomies are performed for the treatment of medically intractable CPS. In particular, those patients with bilateral, independent epileptogenic foci may have better seizure control with vagal stimulation than with temporal lobectomy. Among all patients with epilepsy, seizures are completely controlled in roughly 50%, partially controlled in 35%, and uncontrolled in 15%. At least 360,000 persons in the United States who have partial epilepsy have uncontrolled seizures, and at least 15% (54,000) may be good candidates for surgical therapy (Ward, 1983). Currently, however, probably no more than 400 operations for epilepsy are performed in North America each year. The only realistic hope of seizure control for the overwhelming majority of patients with intractable epilepsy is better use of the currently available drugs or the development of new and more effective drugs (Trei-
man, 1988). Until an ideal efficacious and nontoxic antiepileptic drug is found, efforts to develop other treatments should continue for these patients. REFERENCES Agnew WF, McCreery DB. Considerations for safety with chronically implanted nerve electrodes. Epilepsiu 1990;3I(suppl 2):S27-31 (this issue). Car A, Jean A, Roman C. A pontine primary relay for ascending projections of the superior laryngeal nerve. Exp Bruin Res 1975;22:197-201. Chase MH, Nakamura Y, Clements CD. Afferent vagal stimulation: Neurographic correlates ofinduced EEG synchronization and desynchronization. Bruin Res 1%7;5:236-49. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsiu 1981;22:489-501. Hammond EJ, Ramsay RE, Uthman BM, Reid SA, Wilder BJ. Vagus nerve stimulation in humans: neurophysiological studies and electrophysiological monitoring. Epilepsiu 1990; 3l(suppl 2):S51-9 (this issue). Hennemann HE, Rubia FJ. Vagal representation in the cerebellum of the cat. Pflugers Arch 1978;375:119-23. Magnes J, Moruzzi G, Pompeiano 0. Synchronization of the EEG produced by low frequency electrical stimulation of the region of the solitary tract. Arch Ztul Biol 1%1;99:33-67. O’Brien JH, Pimpaneau A, Albe-Fessard D. Evoked cortical responses to vagal, laryngeal and facial afferents in monkeys under chloralose anaesthesia. Electroencephulogr Clin Neurophysiol 1971;31:7-20. Reid SA. Surgical technique for implantation of neurocybernetic prosthesis. Epilepsiu 1990;31(suppl2):S38-9 (this issue). Serkov FN, Bratus NV. Electrical responses of the hippocampus to stimulation of the vagus nerve. In: Rusinow VS, ed. Electrophysiology of the central nervous system. New York: Plenum Press, 1970. Terry R, Tarver WB, Zabara J. An implantable neurocybernetic prosthesis system. Epilepsiu 1990;31(suppl 2):S33-7 (this issue). Treiman DM. Gamma vinyl GABA: Current role in the management of drug-resistant epilepsy. Epilepsiu 1989;3O(suppl 3):S3 1-5. Ward, AA Jr. Perspectives for surgical therapy of epilepsy. In: Ward AA Jr, Penry JK, Purpura DD, eds. Epilepsy. New York:Raven Press, 1983. Woodbury DM, Woodbury JW. Effects of vagal stimulation on experimentally induced seizures in rats. Epilepsiu 1990; 3l(suppl 2):S7-19 (this issue).
Efficacy and Safety of Vagus Nerve Stimulation in Patients With Complex Partial Seizures Basim M. Uthman, B. J. Wilder, Edward J. Hammond, and *Steven A. Reid Neurology Service, and *Neurological Surgery Section, Department of Veterans Affairs Medical Center, Gainesville, Florida, U.S.A.
~
Summary: A clinical trial of chronic intermittent vagal stimulation in five patients suggests that the procedure may be safe and effective as adjunctive treatment of medically intractable seizures of partial onset. Patients tolerated well the implantation of the neurocybernetic prosthesis and the vagal stimulation without serious physiological or lifestyle changes. Stimulation of the vagus nerve either reduced the seizure frequency or decreased the duration or intensity of seizures. Adverse side
effects were limited to a tingling sensation in the throat and hoarseness during stimulation. A major complication was mechanical interruption of the wire-electrode circuitry, with consequent cessation of stimulation. The small number of patients and the relatively short followup period make this a pilot study, but the results are promising. Key Words: Epilepsy-Seizures-Vagus nerveElectrical stimulation-Safety-Prognosis.
INTRODUCTION
encephalogram (EEG) (Magnes et al., 1961; Chase et al., 1967). In order to obtain antiepileptic effects, C fibers need to be stimulated, with all effects being graded with stimulus strength (Woodbury and Woodbury, 1990). Pentylenetetrazol-induced seizures are not altered by maximal A-fiber stimulation, and B-fiber stimulation has only little effect. We studied the effect of chronic intermittent stimulation of the vagus nerve in five patients with CPS, and the results are promising. Implantation of the neurocybernetic prosthesis (NCP), developed by Cyberonics, Inc., was performed at the Department of Veterans Affairs Medical Center and the University of Florida College of Medicine, Gainesville, Florida. Six more patients were studied at the Bowman Gray School of Medicine, Winston-Salem, North Carolina, and the University of Miami Medical Center, Miami, Florida. There appear to be no previous reports on the antiepileptic effects of vagal stimulation in humans.
As many as 3540% of patients with complex partial seizures (CPS) remain refractory to treatment with the currently available antiepileptic drugs. As active research on the development of safe and efficacious treatments for epilepsy continues, a new method involving stimulation of the vagus nerve has been developed. Intermittent stimulation of the vagus nerve with a multiprogrammable implant is being tested in clinical trials for the treatment of medically refractory CPS. Animal studies show that at certain electrical output parameters, vagus nerve stimulation may prevent or abort electrically and chemically induced seizures in rats (Woodbury and Woodbury, 1990). Physiologic studies in animals show that stimulation of the cervical vagus nerve may produce evoked potentials in the cerebral cortex (O'Brien et al., 1971; Caret al., 1975), the hippocampus (Serkov and Bratus, 1970), the cerebellum (Hennemann and Rubia, 1978), and the thalamus (Car et al., 1975). Furthermore, stimulation of the vagus nerve at certain current frequencies may produce desynchronization of the electro-
PATIENTS AND METHODS
We studied five patients (four men and one woman), aged 20-59 years, who had CPS. The seizures were refractory to treatment with antiepileptic drugs given alone or in various combinations. All patients met the following criteria: 1. average of more than six CPS per month doc-
~
Address correspondence and reprint requests to Dr. B. M. Uthman at Neurology Service (127), Department of Veterans Affairs Medical Center, Gainesville, FL 32602-1 197, U.S.A.
s44
EPILEPTIC COMPLEX PARTIAL SEIZURES
umented on a seizure calendar for 2 years with fewer than 14 consecutive seizure-free days; 2. CPS with or without simple partial seizures (SPS), as defined by the International Classification of Epileptic Seizures (Commission, 1981); 3. constant dosage of phenytoin or carbamazepine, or both, for at least 1 month before the study; 4. age 18-60 years; 5. good mental ability with IQ presumed to be >go; 6. etiology of seizures either not treatable or progressive; 7. no history of asthma, heart or lung disease, or other progressive systemic disorder; 8. no history of psychiatric disorder or recurrent episodes of depression; 9. no previous vagotomy procedures; 10. no history of insulin-dependent diabetes mellitus; 11. no history of gastritis, stress-induced ulcers, or gastric-duodenal ulcers. Patients who were deemed noncompliant with therapy or unable to keep an accurate seizure calendar were excluded. All patients gave written informed consent for participation in the study. Study design Each patient had physical and neurological examinations and baseline studies consisting of computed tomographic (CT) scan or magnetic resonance imaging (MRI) of the brain, EEG, gastric acid output analysis, complete blood-cell count, measurement of trough serum antiepileptic drug levels, serum electrolytes, calcium, phosphate, cholesterol, and triglycerides, and liver function tests. Patients were then admitted to the hospital for 2 or 3 days for implantation of the NCP. The implant consisted of a multiprogrammable pulse generator that delivers electrical signals to the left vagus nerve via bipolar electrodes wound around the nerve in the neck between the superior and inferior cardiac branches. The surgical technique has been described by Reid (1990). Patients were observed for 2 weeks after implantation of the device to establish a postsurgical baseline and to allow for wound healing and proper electrode fixation. Cervical and chest x-ray films were obtained to confirm placement of the device and the electrodes. Patients then entered a 2-week zero stimulation (placebo)period in which they were told that the device was on, although in actuality no stimulation was applied. At the beginning of postoperative week 5 , the NCP was programmed and acti-
s45
TABLE 1. Parameters of initial stimulation of the vagus nerve Parameters Output current Signal frequency ON time OFF time Pulse width Daily treatment time Magnet current
1mA 50 Hz
60s 60min 250 )LS 24 h OmA
vated utilizing the manufacturer’s softwear via a programming wand placed over the device. This procedure is done outside the body through the patient’s clothing and takes only a few minutes. The NCP and the program have been described by Terry et al. (1990). The parameters of the initial electrical stimulation to the vagus nerve are shown in Table 1. Patients were followed at 6, 8, 12, 16, 20, and 24 weeks after the implantation. Each follow-up visit included a physical examination, measurement of trough serum antiepileptic drug levels, and review of the seizure calendar. Proper function of the NCP system and any changes made to programmed settings were documented. At the beginning of weeks 9, 16, 20, and 24, stimulation was continued with the initial parameters, or the output current andor number of stimulation periods per hour were increased if the patient had not had at least a 25% reduction in seizure frequency. At the beginning of week 13, patients entered a Cweek placebo period, with the same conditions as in the first period. At the beginning of week 24, patients entered an openextension period in which they were seen at 2- to 3-month intervals. At the end of the second placebo period, patients were provided with a magnet carried in a holster pocket mounted on a belt at the waist. The magnet could be applied over the NCP for 2 s and removed to activate the system instantaneously at the beginning of a seizure with the hope of aborting it. Figure 1 summarizesthe study design. statistical analysis At each follow-up visit, seizure calendars were collected and the seizure history (time, date, duration, and type of seizure) was recorded and calculated as a ratio of seizures per day. The patient’s daily average total seizure count for 6 months before implantation of the NCP was compared with that of each stimulation and placebo period. The treatment was considered efficacious if there was at least a 50% reduction in seizure frequency. Reduction in the intensity or duration of seizures or postictal periods was considered a favorable effect. Epilrpsia, Vd. 31, Suppl. 2, 19Po
B. M. UTHMAN ET AL.
S46
MAGNET PROVIDED
IMPLANT
BASELINE
w
I
JPLACEBO 1
STIM. 1
4 WKS
4 WK8
STIM. 2
PLACEBO 2
STIM. 3
STIM. 4
-l-l-l-l-l-l52 WKS
4 WKS
4 WKS
4 WKS
4 WKS
FIG. 1. Study design for chronic intermittent vagal stimulation in patients with intractable complex partial seizures.
RESULTS
significant changes were observed during or immediately after stimulation (Fig. 2).
Effects on cardiac rhythm Distal to the stimulating electrodes, the left vagus nerve innervates the heart through the inferior cervical cardiac and thoracic branches. To identify possible cardiac side effects of chronic intermittent vagal stimulation, we monitored the heart with an electrocardiogram (ECG) and 24-h Holter monitor during baseline and after 8 weeks of stimulation and compared the results. There were no notable changes in the minimum, maximum, or average heart rates (Table 2). There were also no changes in benign dysrhythmias, except in one patient who had an asymptomatic increase in premature atrial contractions. This patient had probably been in and out of first-degree atrioventricular block, as a previous ECG showed a slightly prolonged PR interval. However, there was no notable change in his PR interval after stimulation (baseline PR = 0.25 s; poststimulation PR = 0.24 s). There was no appreciable change in ECG morphology in any of the patients. To test for acute effects of vagal stimulation on the ECG, we stimulated patients during ECG recording, using the following parameters: output current = 1 to 5 mA; signal frequency = 10 and 50 Hz; pulse width = 250 bs; ON time = 84 s. No
Gastrointestinal effects The left vagus nerve may influence gastric acid secretion via the anterior gastric vagus cord. Fasting acid output of the stomach was measured for 1 h during the baseline period for comparison with gastric acid output after 8 weeks of vagal stimulation. No chemical stimulation, such as pentagastrin, was utilized, and only basal acid output was measured. After the patient's throat was numbed, a rubber tube was introduced into the esophagus, and under fluoroscopy, the tip of the tube was placed in the area of the antrium. Gastric secretions were collected with a constant suction pump and titrated over two consecutive 30-min periods. The gastric acid output of all patients was within the normal range (0.1-3.8 mEq/h). No follow-up analysis of gastric acid output is currently available. However, none of the patients experienced gastrointestinal problems, such as nausea, vomiting, heartburn, hematemesis, melena, diarrhea, or constipation.
Safety
Other effects Patients tolerated the vagal stimulation well and none reported pain, discomfort, or significant changes in their daily activities, sleep habits, breathing, eating, swallowing, or appetite. In particular,
TALBE 2. Cardiac effects of chronic intermittent vagal stirnulation Heart rate (beatshin) Patient
Baseline min-max (av)
Arrhythmias (per 24 h)
FOIIOW-UP min-max (av)
FOIIOW-UD
Baseline ~
co1
61-135 (87)
55-128 (83)
c02 C03
50-1 10 (77) 54-147 (90)
51-112 (80) 50-140 (89)
C04
48-145 (69)
49-137 (76)
C05
NA
53-120 (76)
PAC = premature atrial contraction; PVC available. a Average per hour. Epilepsia, Vol. 31. Suppl. 2 , 1990
=
premature ventricular contraction; PR
PAC (4) PVC (0) PVC (1) PVC (6/h)" PAC (14) PAC (6) PR = 0.25 s NA =
~~~~~
~~
PAC ( 5 ) PVC ( I ) PVC (0) PVC (3/h)" PAC ( 5 ) PAC (3,011) PR = 0.24 s PVC (0) PR = 0.22 s
atriventricular conduction time: NA
=
not
EPlLEPTlC COMPLEX PARTIAL SElZURES
s47
FIG. 2. Electrocardiogram of a patient during vagal stimulation. Note the absence of an effect on the heart during or immediately after 30 s stimulation (. = stimulation off).
vagal stimulation did not arouse patients from their sleep, although the NCP would turn on as frequently as every 10 min. During waking hours, patients were aware of the stimulation, because they felt a tingling, beating, or vibrating sensation in the throat or were hoarse as they talked during stimulation. The awareness seemed to habituate with time, and patients may barely perceive the stimulus even though the system works perfectly. Even during a stimulation epoch of 30-80 s, the subjective feeling of stimulation intensity may fade shortly after the onset of stimulation. When a high intensity is selected, patients may cough briefly for 2-5 s as stimulation begins and only during the first few stimulation periods. Follow-up chest and cervical x-ray films at 2 and 20 weeks after implantation showed no significant displacement of the electrodes or the NCP. No rejection reaction was noted. There were no remarkable changes in the clinical laboratory tests. No appreciable weight loss or weight gain occurred. There was no notable change in the systolic or diastolic blood pressure. Electrophysiological studies Noncephalic reference recording of the left vagus-nerve-evoked potential showed a scalp negative component with latency at 12 ms with a very high amplitude (up to 60 pV) and widespread scalp distribution (Hammond et al., 1990). Field distribution studies indicated that this potential was generated in the neck, in the region of the stimulating electrodes. Intraoperative studies in one patient in-
dicated that this potential was myogenic, because it was abolished by a muscle-paralyzing agent. The pulse waveform of the electrical stimulus artifact recorded over the stimulating electrodes was monitored to confirm that the circuitry of the NCP system was intact. The patients’ subjective feelings of the tingling sensation and objective monitoring were helpful in ascertaining whether the system was functioning (Hammond et al., 1990). No effect of vagal stimulation was observed in the EEG of awake, anesthetized, or sleeping patients. There were no obvious acute effects on interictal epileptiform activity. In one patient, stimulation abruptly terminated the clinical and EEG seizure activity approximately 11 s after the onset of a CPS. For details and effects of vagal stimulation on other evoked potentials, see Hammond et al. (1990). Complications All patients tolerated well the general anesthesia and the surgical implantation of the NCP. Mild pain at the surgical sites lasted for 24-48 h or less. Patients were up and around the next day and were discharged home 2 or 3 days after the operation. About 10-20 weeks after implantation of the NCP, patients reported a rather sudden decrease id perception of the stimulus or stopped perceiving it. The diagnostics program incorporated into the stimulating device showed high impedance, indicating a break in the wire-electrode system. The electrical stimulus artifact recorded over the stimulating electrodes showed a differentiated pulse waveform (Hammond et al., 1990) in three patients, indicating Epileppsia. Vd.31. Suppl. 2 , 1990
S48
B. M . UTHMAN ET A L .
a break in one electrode, and no pulse at all in two patients, indicating a break in both electrodes. Replacement of the one broken electrode with a disc electrode at the site of the stimulating device was done in two patients with local anesthesia. Thus stimulation was changed from bipolar to unipolar mode. The other three patients had a revision operation at the neck and chest sites on the left side. After careful dissection of fibrous tissue, the electrodes were unwound from around the vagus nerve, removed, and replaced with a new electrode wire system that had better fatigue and corrosion properties. Because the break was around the electrodewire junction, a third Silastic spiral was wound around the vagus nerve 0.5-1 cm proximal to the two stimulating electrodes in order to anchor the two wires parallel to the vagus and absorb any torque tension from bending or rotating. All patients tolerated the revision operation well. Of importance, intraoperative findings showed only fibrosis around the electrode without any damage to the vagus nerve, even after 4 months of stimulation or 9 months after the implantation. Stimulation was resumed 2 weeks after the surgical repair.
Average Seizuresper Day
"
A
Epilepsia, Vol. 31. Suppl. 2 , 1990
,
.
.
.
R1
C1
S1
52
C2
X
X
XX
R2
S7
Period
Average Seizures per Day
I
0.4
0.3 0.2
0.1 0 BL
B
R1
C1
S1
C2
S2
53
X
S5
S6
57
Period
Average Seizures per Day
1.44 12 1 0.8 0.6 0.4 02
m=Y
Three patients (COI, C03, and C05) had a greater than 50% reduction in seizure frequency, which gradually returned to baseline after the electrode break. Two of these patients (C03 and C05) regained the same percentage decrease in seizures within 8 weeks after the repair, one with bipolar and one with unipolar stimulation (Table 3 and Fig. 3A, C,E). The third patient (CO1) had a 32% reduction in seizure frequency within 4 weeks of the revision (Table 3 and Fig. 3A). One patient (C02) showed no signifcant change in seizure frequency, but the seventy and duration of seizures, as well as the postictal period, were reduced compared with the baseline period. This effect was regained after electrode repair, and a 30% reduction in seizure frequency was obtained within 8 weeks after stimulation was resumed (Table 3 and Fig. 3B). Patient C04 had no reduction in seizure frequency, but reported less severe and briefer ictal and postictal periods (Table 3 and Fig. 3D). He was also more alert and socially active. Before stimulation, he had interrupted speech (several brief pauses before completion of a sentence or phrase) and great difficulty expressing himself. Baseline EEG showed frequent 1- to 3-s episodes (about once every 10 s) of bilaterally synchronous, high-amplitude, generalized, and frontally predominant activity. A few weeks after vagus stimulation, he became more conversant, speech became normal, and his
.
BL
I
1
0
EL
C
Rl
C1
S1
52
C2
s) XX
XX R2+M S7
Perkd
0.8
0.6
0.4 0.2
0
D
BL
R1
C1
S1
S2
C2 S3 Perkd
S4
X
R2
S7
Average Seizures per Day
I
BL
R1
S2
C2 X S4 s5 s6 S7 Period FIG. 3. Effect of vagal stimulation on the frequency of complex partial seizures in five patients (A-E; patients CO1-CO5, respectively). BL = 6-month baseline; R = surgical recovery; C = control (placebo) period of no stimulation; S = stimulation period; X = one broken lead; XX = two broken leads; * = lead problem first recognized; ** = lead problem repaired; M = magnetic activation. Stippled columns, stimulation periods; filled columns, no stimulation.
E
C1
S1
EPILEPTIC COMPLEX PARTIAL SEIZURES
s49
TABLE 3. Change in seizure frequency during each study period
Patient
co1 c02 C03 C04 C05
Seizure increase or decrease (%)
Baseline (seizureslday)
R
CI
S1
s2
c2
s3
s4
s5
S6
s7
0.32 0.24 1.19 0.41 0.70
-54.7 -54.0 -31.9 53.7 133.2
11.9 -4.6 -40.1 64.0 33.6
15.3 46.0 -38.2 18.7 13.0
-66.0 -27.0 -48.1 44.7 -3.3
-47.2 -71.9 -13.5 52.7 -59.3
-32.1 -11.4 -83.1 49.8 12.0
-45.7 -1.5 -46.3 68.3 -74.1
-31.3 25.3 -23.7 64.0 -26.1
-4.9 3.4 -59.3 70.3 -42.2
-32.1 -30.0 -90.3 80.4 -57.2
R = recovery period (no stimulation); C = control period (no stimulation); S = stimulation period.
EEG showed less frequent epileptiform activity. The increase in seizure frequency could be explained by more accurate reporting of the frequent brief seizures as the patient became more alert. In spite of the apparent seizure increase, the patient and his parents considered the effect of vagal stimulation favorable on the basis of shorter and less severe CPS and the absence of generalized tonicclonic seizures. Three patients reported abortion of seizures with manual activation of stimulation (via the magnet) early in the seizure. The best and most consistent results were obtained in a patient who had an aura lasting approximately 20 s before the onset of every CPS. He could abort the seizures by activating the stimulus at the onset of the aura. This patient had never reported an isolated aura before vagal stimulation was tried. In another patient, the clinical and EEG manifestations of CPS were stopped with activation of the stimulus approximately 11 s after the seizures began. This effect could be coincidental because seizures lasting 12-15 s were previously recorded with closed-circuit TV-EEG monitoring. DISCUSSION Stimulation of the vagus nerve is a novel method in its earliest phase of efficacy and safety studies in humans. The most tolerable stimulation parameters with the best antiepileptic properties are yet to be determined. Lower current frequencies (-20 Hz), higher tolerable current outputs (-2 mA), shorter off time (5-10 min), and pulse width of 250-500 ps seem to give the best results. Results are sometimes even better when patients activate the system with a magnet on demand at the onset of a seizure. The mechanisms by which intermittent vagal stimulation exerts an antiepileptic effect are unknown. Possible mechanisms are desynchronization of neuronal discharge, release of inhibitory neurotransmitters, stimulation of inhibitory pathways, or increase in the electrical threshold for seizures. The epileptogenic focus is said to be in an “isolated or anarchic”
state devoid of control inputs, and intermittent vagal stimulation may interrupt the “independent” activity of that focus. Vagal stimulation at random rather than regular intervals may have a better antiepileptic effect. The patient’s sense of being in control of the situation (when the manual activating magnet is provided) and the contribution of the placebo effect to the antiepileptic effect of vagal stimulation cannot be underestimated at this early stage of use. We observed in some of our patients that the antiepileptic effect, as manifested by a reduction in seizure frequency, duration, and intensity, lagged 4-8 weeks after both the initiation and the discontinuation of stimulation. This suggests that the antiepileptic properties are cumulative and lasting. This could explain the lack of a significant reduction in seizure frequency during the initial stimulation period and the absence of a return of seizure frequency to baseline during the second placebo period in some patients (e.g., CD2). The NCP (Cyberonics Model 100) and the bipolar vagal stimulation lead (Cyberonics Model 300) appear to be a reliable and state-of-the-art stimulation system that can be programmed with any IBM-compatible personal computer using programming software and a programming wand (Cyberonics Model 200). The software is user-friendly and simple to operate. The menu-driven operation, help, prompt, and message functions facilitate simple and rapid programming and keep the user fully informed of what is occurring step by step. Programming capabilities include revision of the NCP’s programmable parameters, device diagnostics testing, storage and retrieval of telemetered data, synchronization of the stimulus signal with an evoked-potential measuring apparatus, and resetting of the N C P s microprocessor. With the parameters used in this study, no significant adverse side effects were reported. Of importance, no gross damage to the vagus nerve was observed in three patients whose stimulating leads were replaced. Animal studies in the adult cat peroneal or sciatic nerves have shown that irreversible axonal injury Epilrpsio. Vol. 31, Suppl. 2 , 1990
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B. M . UTHMAN ET AL.
may result from sustained, continuous, and high frequency stimulation (Agnew and McCreery, 1990). However, intermittent stimulation of peripheral nerves with moderate frequencies was found to be effective and safe to the nerve. If chronic intermittent vagal stimulation turns out to be safe and efficacious for the treatment of intractable CPS, it may have advantages over current medical therapy. Improved seizure control, absence of the cognitive, systemic, and hypersensitivity side effects of antiepileptic drugs, and the obviation of expensive periodic blood studies are only a few of the potential benefits. The battery life of the current NCP is approximately 2 years, and the device can be easily changed by a minor surgical procedure. Modifications in the hardware of the device to prolong the battery life are in progress. The total cost of the NCP replacement is comparable to the cost of a 5-year supply of certain antiepileptic drugs. Additionally, vagal stimulation may offer another option of treatment before temporal lobectomy or other corticectomies are performed for the treatment of medically intractable CPS. In particular, those patients with bilateral, independent epileptogenic foci may have better seizure control with vagal stimulation than with temporal lobectomy. Among all patients with epilepsy, seizures are completely controlled in roughly 50%, partially controlled in 35%, and uncontrolled in 15%. At least 360,000 persons in the United States who have partial epilepsy have uncontrolled seizures, and at least 15% (54,000) may be good candidates for surgical therapy (Ward, 1983). Currently, however, probably no more than 400 operations for epilepsy are performed in North America each year. The only realistic hope of seizure control for the overwhelming majority of patients with intractable epilepsy is better use of the currently available drugs or the development of new and more effective drugs (Trei-
man, 1988). Until an ideal efficacious and nontoxic antiepileptic drug is found, efforts to develop other treatments should continue for these patients. REFERENCES Agnew WF, McCreery DB. Considerations for safety with chronically implanted nerve electrodes. Epilepsiu 1990;3I(suppl 2):S27-31 (this issue). Car A, Jean A, Roman C. A pontine primary relay for ascending projections of the superior laryngeal nerve. Exp Bruin Res 1975;22:197-201. Chase MH, Nakamura Y, Clements CD. Afferent vagal stimulation: Neurographic correlates ofinduced EEG synchronization and desynchronization. Bruin Res 1%7;5:236-49. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsiu 1981;22:489-501. Hammond EJ, Ramsay RE, Uthman BM, Reid SA, Wilder BJ. Vagus nerve stimulation in humans: neurophysiological studies and electrophysiological monitoring. Epilepsiu 1990; 3l(suppl 2):S51-9 (this issue). Hennemann HE, Rubia FJ. Vagal representation in the cerebellum of the cat. Pflugers Arch 1978;375:119-23. Magnes J, Moruzzi G, Pompeiano 0. Synchronization of the EEG produced by low frequency electrical stimulation of the region of the solitary tract. Arch Ztul Biol 1%1;99:33-67. O’Brien JH, Pimpaneau A, Albe-Fessard D. Evoked cortical responses to vagal, laryngeal and facial afferents in monkeys under chloralose anaesthesia. Electroencephulogr Clin Neurophysiol 1971;31:7-20. Reid SA. Surgical technique for implantation of neurocybernetic prosthesis. Epilepsiu 1990;31(suppl2):S38-9 (this issue). Serkov FN, Bratus NV. Electrical responses of the hippocampus to stimulation of the vagus nerve. In: Rusinow VS, ed. Electrophysiology of the central nervous system. New York: Plenum Press, 1970. Terry R, Tarver WB, Zabara J. An implantable neurocybernetic prosthesis system. Epilepsiu 1990;31(suppl 2):S33-7 (this issue). Treiman DM. Gamma vinyl GABA: Current role in the management of drug-resistant epilepsy. Epilepsiu 1989;3O(suppl 3):S3 1-5. Ward, AA Jr. Perspectives for surgical therapy of epilepsy. In: Ward AA Jr, Penry JK, Purpura DD, eds. Epilepsy. New York:Raven Press, 1983. Woodbury DM, Woodbury JW. Effects of vagal stimulation on experimentally induced seizures in rats. Epilepsiu 1990; 3l(suppl 2):S7-19 (this issue).
