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Vagal nerve stimulation in children
Vagal Nerve Stimulation in Children Patricia K. Crumrine Vagal nerve stimulation is a new therapeutic option for patients with medically refractory epilepsy. The FDA approved the NeuroCybernetic Prosthesis (NCP) in July 1997 for use in adults and adolescents over the age of 12 years with medically refractory epilepsy. Most of the patients in the initial pilot studies and subsequent extended longitudinal and randomized controlled studies were adults. There were small numbers of children who received the NCP system. However, these were not part of controlled studies. As the system has had greater exposure in the United States and Europe, there are more children who are receiving vagal nerve stimulation (VNS). Initial data from open-label, uncontrolled studies suggest that VNS does have some efficacy and safety for those children with refractory epilepsy who have not responded to appropriate trials of antiepileptic drugs. The questions to be asked and answered are as follows: (1) When is a child medically refractory? (2) What are the criteria for selection for VNS? (3) Which seizure types or syndromes will benefit most from the treatment? and (4) What are the most effective and safe stimulation parameters, and do these vary depending on the seizure type?
Copyright 9 2000 by W.B. Saunders Company
qOR SOME CHILDREN epilepsy may be a chronic problem, uncontrolled by standard antiepileptic drugs (AEDs). Families and caregivers of these children are often desperate for therapies that will control the seizures. Prevalence figures for epilepsy cite figures of 5 to 9 per 1,0001 with about 5% to 10% of these patients being intractable. 2 Most of the intractable patients will have partial seizures. The time frame for establishing intractable epilepsy for most patients is about 2 years? For children with structural lesions (eg, migrational abnormalities) the time period to establish intractability may be shorter. For those children for whom AEDs are not helpful, other alternatives are needed. Ketogenic diet as well as hormonal and vitamin therapies have been considered as altematives with varying degrees of success reported. 4 Vagal nerve stimulation is a new therapeutic option for this refractory population. Clinical studies in adults cite both efficacy and safety. Small uncontrolled studies in children suggest similar results.
F
HISTORY
The vagus nerve is a complex nerve that provides information from the viscera of the abdomen to the brain via general visceral afferents. The origin of these fibers is in the abdominal viscera
From the Pediatric Epilepsy Program and the EEG and Pediatric Epilepsy Monitoring Unit, University of Pittsburgh School of Medicine, Pittsburgh, PA. Address reprint requests to Patricia K. Crumrine, MD, Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213-2583. Copyright 9 2000 by W.B. Saunders Company 1071-9091/00/0703-0009510.00/0 doi:10.105 3/spen.2000.9218 216
and the termination is in the nucleus of the solitary tract that extends throughout the medulla oblongata. From this nucleus there are projections to many areas of the brain, including thalamic and hypothalamic structures, amygdala, and possibly other subcortical structures. Early studies of vagal nerve stimulation in cats demonstrated both desynchronization and synchronization of the EEG. 5-7Whether synchronization or desynchronization of the EEG occurred depended on the stimulation parameters used. Because seizures often result from recruitment and synchronization of discharges within thalamocortical pathways, the thought was that desynchronization of these discharges might produce an antiepileptic effect. Studies in other laboratory animals, including strychnine-induced seizures in the dog 8 and pentylenetetrazol-induced and maximal electroshock seizures in the rat 9,1~ and monkey, 11 demonstrated similar findings on the EEG and evidence of an antiepileptic effect. McLachan 12 demonstrated that vagal stimulation decreased spike frequency in rats by 33% after topical application of penicillin to the cortex. Other EEG studies of vagal stimulation in experimental animals include synchronization at high frequencies (70 Hz), rapid eye movement (REM) sleep, or slow wave sleep. 7 The stimulation parameters used determined the type of EEG response. Stimulation at 20 to 50 Hz and 10 v produced desynchronization of the EEG via slow acting C fibers, whereas high-frequency stimulation led to synchronization. 13,14 Despite the desynchronization of the EEG following vagal nerve stimulation on the EEG in experimental animals, a similar effect has not been found in human clinical studies. 15-17 One of the initial concerns of vagal stimulation
Seminars in Pediatric Neurology, Vol 7, No 3 (September), 2000: pp 216-223
VAGAL NERVE STIMULATION IN CHILDREN
was what the effect would be on cardiac rhythms. Studies of vagal efferents demonstrate an asymmetric innervation of the heart with fibers from the right vagus going to the sinoatrial node and those from the left going to the atrioventricular node. Stimulation studies in dogs revealed a greater degree of cardiac slowing with right vagal stimulation compared with stimulation of the left vagus. 18 The effects from stimulation of the vagus nerve depend on the frequency and intensity of the stimulation with higher stimulation intensities producing little change in heart rate. 7 The mechanism of action for vagal nerve stimulation is unknown. Because stimulation of the vagus nerve results in afferents to the nucleus of the solitary tract, one hypothesis has been that the projections from this tract interrupt partial seizures via a limbic circuit. 7 Naritoku et al j9 demonstrated fos reactivity in the rat in amygdala and limbic cortex after vagal stimulation. Others have explored the effect of vagal nerve stimulation on the brainstem noradrenergic nuclei z~ and other neurotransmitter systems. 17 DEVICE AND TECHNIQUES
Using the NeuroCybernetic Prosthesis (NCP) System (Cyberonics, Inc, Houston, TX), the first vagal nerve stimulator was placed in a human in 1988. 21 The device was patented by Dr. Jacob Zabara and developed by Cyberonics, Houston, Texas. The neuroprosthesis system (NCP) consists of a pulse generator packaged in titanium case, helical bipolar leads that attach to the vagus nerve, a programming wand that communicates information between the pulse generator and a laptop computer with an IBM-compatible software package that permits adjustments in the stimulation parameters, and two handheld magnets. 22 There have been improvements in design and battery life of the pulse generator since the original NCP system was placed in 1988. The newer pulse generators are slimmer, smaller, and have batteries that may last up to 7 to 10 years depending on stimulation parameters and use. The Food and Drug Administration (FDA) approved the NeuroCybernetic Prosthesis System (NCP) for use as adjunct therapy in adults and children over the age of 12 years in July 1997. The NeuroCybernetic Prosthesis is implanted subcutaneously in the anterior chest wall or infraclavicular region in a surgical suite with the patient
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under general anesthesia. The infraclavicular placement is a good area for young women, asthenic children, and developmentally delayed children who might bother the device. The surgeon exposes the carotid sheath as for a carotid endarterectomy and the vagus nerve. Helical, flexible bipolar electrodes are attached to the vagus nerve and impedances for the electrodes are checked. Impedances should be between 400 and 3,000 ohms. 23 The leads are attached to the generator and the device then placed into the chest pocket. Timing for initiation of the NeuroCybernetics prosthesis NCP varies somewhat between centers. In the initial clinical studies, the device was "turned on" about 2 weeks after implantation, allowing time for healing of the incision. Some centers now turn the stimulation device on in the operation room at the conclusion of the implantation procedure. The initial output current is usually set at 0.25 mA and increased by 0.25 mA increments to settings that are tolerated by the patient. Parameter settings include constant output currents of 0 to 12 mA, signal frequencies of 1 to 145 Hz, pulse widths of 130 to 1,000 ~tsec. Pulse ON times of 7 to 270 seconds and Pulse OFF times of 0.2 to 180 minutes. Most of the pediatric studies have reported output currents of 1.00 to 1.75, with some at 2.0 to 2.5 mA. Higher output currents are less well tolerated. Initial settings during the compassionate use studies included output currents of 0.25 to 2.75, frequency of 30 Hz, pulse width of 500 lasec with device on times of 30 to 90 seconds and off times of 5 to 180 minutes. Currently, there are many variations of these settings in use. Changing the frequency to 20 Hz and the pulse width to 250 ~tsec may lengthen battery life. Many treating physicians are now using more rapid cycling paradigms by having the device go on and off every few seconds. There has not been a standard paradigm determined for a particular age or seizure type. The treating physician can set the parameters using the programming wand and a laptop computer with the programming software and IBM-compatible laptop computer. The intervals for changing the settings can be determined by the patient response. A suggested interval following implantation is every 2 weeks for the first 4 to 6 weeks. CLINICAL STUDIES IN HUMANS
The first humans received an NCP in 1988. There were 11 adults implanted between November 1988
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PATRICIA K. CRUMRINE
and September 1989.15 Penry and Dean 15 reported the results for 4 of these patients in 1990. Two of the patients with complex partial seizures became seizure-free and one third had a 40% reduction in seizures. Subsequent studies included two singleblind pilot studies of 14 patients with partial seizures, 2426 a randomized active-control trial using high stimulation with low stimulation in 254 patients27; a multicenter, randomized, longitudinal controlled trial of 114 patients, 28,29 open long-term evaluation of 64 patients3~ pilot study of 5 adults with symptomatic generalized epilepsy. In the early pilot studies, about 36% of patients achieved 50% or greater control of their seizures. In the multicenter, randomized high versus low stimulation study about one third of the patient in the high stimulation group achieved at least 50% decrease in their seizures. At an 18-month follow-up, 52% of patients achieved 50% decrease in seizures. By March 1999 more than 4,000 patients had received vagal nerve stimulation. 32 Studies in the pediatric population included 12 children between 4 and 16 years by Murphy et al, 33 60 children who were either in a compassionate use or active-control protocol, 34 16 children with refractory epilepsy 35 and 16 children with epileptic encephalopathies (Table 1). 36 In the initial pediatric studies there were 3 of 12 patients who reported >90% decrease in seizures. 33 In a follow-up study with added patients 46 of 60 children achieved 42% reduction in seizures 18 months after implantation. 34 Lundgren et a135 reported that 6 of 16
achieved >50% reduction about 12 months after implantation. Parker et a136 noted only a median 17% reduction in seizures in 15 children after 1 year and 42% reduction after 2 years. In the second year of the study the authors permitted changes in AEDs and doses that were not permitted during the first year of the study. Cyberonics, Inc., held a consensus conference on the vagal nerve stimulator (VNS) and adolescence March 4 through 7, 1999, in Orlando, Florida. Investigators from Children's Mercy Hospital in Kansas City (Murphy), University of Texas-Houston (Wheless), Boston Children's Hospital (Helmers), Minnesota Epilepsy Group (Frost), Pediatric Neurology of Idaho (Bettis), Seattle Children's Hospital (Sotero deMenezes), Children's Hospital of Wisconsin (Wilfong), University Hospital Charles Nicolle, Rouen, France (Parain), and Kings' College Hospital, London, UK (Robinson) reported the results of their pediatric patients in open studies. 37 There were no common protocols for the 309 patients at these various institutions, although 114 patients were part of pediatric VNS study group. Ages ranged from 3 years to about 18 years for most of the investigators. Some of the investigators had patients implanted for only about 3 to 6 months. The authors reported their results differently as noted in Table 1. In addition to published results of pediatric cases with VNS there are now many pediatric epilepsy centers implanting children. Many of the centers have at least 25 to 30 patients with NCP.
Table 1. Pediatric Studies With the Vagus Nerve Stimulation
Author
Patient No.
Age (years)
3 Months
6 Months
Murphy Wheless Helmers Frost* Bettis Sotero DeMenezes Wilfong Parain~ Robinson Lundgrent
60 59 80 25 15 10 25 20 15 16
3-18 5-18 3-median 12 years 8-16 Adolescence 5-18 6-18 NA Median 11 years 4-15
23% 37.5% -26%
31% 53.6%
Control 12 Months 34%
18 Months
24Months
42%
-59%
20%
19% NHS3
17% NHS3
43%
NOTE. Control is defined as median seizure control for the population as a whole. Abbreviation: NA, not available. *Frost reported that 70% had >50% reduction in seizures. tLundgren defined efficacy using the National Hospital Seizure Severity Scoring system (NHS). This showed decreases at 4 to 6 months and 12 months (3 children at 4 to 6 months and 2 more at 12 months). r reported that 75% had 50% reduction at 9 to 24 months.
VAGAL NERVE STIMULATION IN CHILDREN
PEDIATRIC INDICATIONS
In the United States, the FDA approval indicates that the NCP device can be used as adjunctive therapy for refractory partial seizures in adults and children over the age of 12 years. In the European community indications include both partial and generalized seizures, without an age restriction. Randomized, controlled studies in children are incomplete at this time. Indications in open and compassionate use trials in children have included refractory complex partial epilepsies, children with epileptic encephalopathies, Lennox-Gastaut syndrome (LGS), generalized tonic-cionic, and absence seizures. Part of the problem in the selection of the child for this procedure is deciding when the child is refractory and what the natural history of the epilepsy itself may be. Camfield and Camfield 37 defined intractability as failure to three AEDs. Huttenlocher reported a follow-up of 145 children with refractory seizures and noted that at 10 years after the diagnosis of their seizures 70% achieved at least a 5-year seizure-free period. Given this natural history, should children receive a VNS? If so, when in the course of their epilepsy should they undergo VNS? Should children who are being considered for complete corpus callosotomy receive a trial of the NCP device before surgery? Wheless et a138 cite the following indications for consideration of the device: (I) medically refractory epilepsy; (2) adequate trial of at least three AEDs; (3) exclusion of nonepileptic events; and (4) lack of surgery candidacy. There are certain contraindications to implantation of the NCP. Children who have had prior vagotomy, either unilateral or bilateral, should not receive the NCP device. Children with cardiac arrhythmias or conduction abnormalities should receive clearance from a cardiologist and should be followed carefully during and following implantation. Dyspnea may be a risk factor for those with chronic obstructive pulmonary disease. Because cervical magnetic resonance imaging may not be performed once the device is implanted, children with cervical masses should be excluded. OUTCOMES OF VNS IN CHILDREN
Most investigators note that very few patients actually become seizure-free following implantation of the VNS. The standard that most of the
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initial studies used to determine efficacy was a 50% or greater than reduction in seizures. Investigators note that much of the effect of the VNS comes several months after implantation, sometimes up to 12 months later. Most patients obtain about a 25% reduction in their seizures at a 3 month follow-up after implantation. In most published reports, the response to VNS has been noted for the group of patients as a whole, and not by seizure types. Parker et a136specified the results based on seizure types in a prospective study of children with epileptic encephalopathies that included severe myoclonic epilepsy of infancy, LGS, and myoclonic-astatic seizures. They noted median seizure reduction in those with LGS as 34%; 4 children with severe myoclonic epilepsy of infancy had an increase in seizures of 31%; those with myoclonic-astatic epilepsy had no response or 40% increase. Their patients did not have any changes in their AEDs or doses during the first year. At 2 years after implantation, median seizure reduction was 43% with changes in both AEDs and doses. Of the 15 children receiving VNS, I became seizure-free and 2 had >60% reduction in seizures. Ben-Menachem et al 3~ reported 8 patients with LGS and 9 patients with primary generalized epilepsy, including absence seizures. Five of eight patients with LGS had a response in all seizure types; generalized tonicclonic seizures responded best. Of the 9 patients reported with primary generalized epilepsy, 6 had typical absence and all responded with >50% reduction in seizures. Seven of the 16 patients reported by Lundgren et a135 had had prior epilepsy surgery. Ages of their patients ranged from 4 to 16 years at the time of implantation. There were 4 patients with LGS. The authors noted that no particular seizure type responded better or worse to VNS. Overall 6 of 16 children achieved >50% seizure reduction after 12 months; there was no further seizure reduction noted after 12 months. 35 Wheless et a139 presented the results of 12 patients with LGS aged 3.5 to 27 years who received the NCE Seven of these patients had prior callosotomies; 42% of the patients had >50% reduction in seizures using a rapid-cycle sequence, and none had exacerbation of seizures. Crumrine et al 4~ reported the results of implantation of 8 patients aged 9 to 24 years; 6 patients were children and 2 were young adults. Two of the patients had LGS. Of this group, 3 of 8 achieved 50% to 75%
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PATRICIA K. CRUMRINE
reduction in seizures. Overall, the studies in children indicate moderate to significant reduction in seizure frequency, and sometimes in intensity. The number of children who become seizure-free is small. COMPLICATIONS FROM VAGAL NERVE STIMULATION
The initial concerns of the procedure were related to the question of what the effect of chronic stimulation would have on the vagal nerve. The stimulating electrodes are designed as flexible helical coils that decrease the impact of stimulation. The stimulation protocols used to date have not resulted in any documented damage to the vagus nerve. 41,42 In a randomized high stimulation/ low stimulation study in adults, the major adverse effects were in the high stimulation group and consisted of hoarseness, throat pain, dyspnea, paresthesia, and muscle pain. 41 Monitoring of gastric acid and cardiac rhythms did not detect any adverse effects. 42 In the early pilot studies, transient left vocal cord paralysis and paralysis of the left facial nerve occurred; this has not been seen in more recent studies. Postoperative infections occur in about 3% of patients. 43 Schallert et a144investigated the swallowing function of 8 children following vagal nerve implantation. They noted that 4 of 8 children had laryngeal penetration of barium with barium swallow studies during therapeutic stimulation and 6 of 8 during maximum stimulation. None had evidence of aspiration. Three of the children had laryngeal penetration when they were not receiving vagal stimulation. Murphy et a144 reported side adverse events in children receiving the NCP system, noting that most adverse events were the hoarseness and coughing. Tatum et a145recently reported four adult patients who experienced ventricular asystole intraoperatively while the NCP was being implanted. There were no autonomic dysfunctions reported in the
early controlled studies, including changes in mean heart rate, variability of heart rate, or bradycardia. 7,27 Environmental exposure to properly functioning microwave ovens, airport metal detectors, cellular phones, electrical ignition systems, theftprevention devices, and power transmission lines should not affect the operation of the system. 46,47 Electromechanical devices that have a strong static or pulsing magnetic field could inadvertently activate the magnet. Patients should keep these at least 6 inches from the NCP pulse generator. 47 Hospital and medical risks include therapeutic radiation, external defbrillation, electrosurgical cautery, body MRI, and extracorporeal shockwave lithotripsy. Another initial question was whether it was safe to perform a head MRI. Head imaging with MR can be done using a transmit and receive head coil. The following recommendations are made by Cyberonics: (1) head coil type: transmit and receive only; (2) static magnetic field strength: -<2.0 tesla; (3) specific-rate absorption:
Table 2. Suggested Parameters for Vagus Nerve Stimulation
Output current (mA) Pulse width (psec) Frequency (Hz) Signal on time (seconds) Signal off time (minutes) Magnet current (mA) Magnet on time (seconds) Magnet pulse (psec)
0-2 Weeks
2-4 Weeks
4-8 Weeks
3 Months
0.25-0.5 500 (250) 20 (30) 30 5 (10) .5-.75 30 500 (250)
0.75-1.0 500 (250) 20 (30) <30 1-3 1.0-1.25 30 500 (250)
1.0-1.75 250 20 (30) <1 <1 1.25-2.0 30 500 (250)
1.5-2.75 (2.0) 250 20 (30) <1 <1 1.75-2.0 (2.25) 30 500 (250)
VAGAL NERVE STIMULATION IN CHILDREN
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was perceived improvement in the children receiving VNS. The improvements noted were independent of the degree of seizure control and were in areas of cognition and behavior. Parker et a136 and Ben-Menachem et a147 raise the question of whether this may be related to serotinergic modulation of the behavior and affect. The issue of cost-effectiveness of the NCP system is an important one in this day of managed health care. Cost of the device itself is about $10,000. Hospital and physician costs associated with the surgical implantation could include another $20,000 to $30,000. Approximately two thirds of state Medicaid programs provide some coverage for N C P implants; Health Care Finance Administration supports the program as does C H A M P U S , United MetraHealth, Kaiser, Blue Cross and Blue Shield Technology, as well as other private insurers and managed health care companies. 48 Begley et a149 looked at the cost of epilepsy in the United States based on population clinical and survey data. They reported that the average direct cost per case was $6,429 over a 6-year follow-up period after diagnosis. Boon et al 5~ did a cost-benefit analysis of medically refractory patients who received the NCP and found that epilepsy-related direct medical costs decreased from $8,330 before the VNS to $4,215 in the year after implantation and that hospitalization admission days decreased from 21 to 8 days. This is the first study that has looked at a cost-benefit effect of VNS. The authors noted that other studies comparing specific AEDs to VNS, and comparison of different stimulation parameters would also be helpful as one tries to decide if this is the most effective treatment decision to make. SUMMARY
Although controlled studies in children are not completed, the preliminary studies suggest the
VNS is a safe and effective treatment for children with medically refractory epilepsy. Although most of the studies to date have included children with refractory partial complex epilepsy and LGS, there are some studies that suggest that some of the generalized epilepsies may also respond to this treatment. What remains unknown currently are whether there are specific settings that work more effectively for one seizure type compared with another and whether combinations of Ads and VNS and various types of surgical procedures are also options. Suggestions are provided as criteria for selection of the child for VNS. However, decisions should be carefully presented and discussed with caregivers and patients. Most families and patients tolerate the NCP device; most report improvement in the behavior and performance o f the children that is independent of the decrease in seizures. Improved QOL for these children with refractory epilepsy is the goal.
APPENDIX: RESOURCES FOR FAMILIES AND CAREGIVERS
1. Videotapes and patient information on the NCP| System. This information is available to physicians, nurses, and patients: Cyberonics, Inc. 16511 Space Center Boulevard, Suite 600 Houston, Texas 77058 Phone: (800) 332-1375 FAX: (281) 218-9332 2. Epilepsy Foundation 4351 Garden City Drive Landover, MD 20785-2267 (301) 459-3700 website: www.efa.org 3. Articles: Lyne Bridget M: A new method in seizure management: Vagus nerve stimulation. Exceptional Parent May:84-90, 1999 Henry TR: Most commonly asked question about vagus nerve stimulation for epilepsy.The Neurologist 4:284-289, 1998
REFERENCES
1. Annegers JF: The epidemiology of epilepsy, in Wyllie E (ed): The Treatment of Epilepsy: Principles and Practice. Baltimore, MD, Williams & Wilkins, 1996, pp 165-172 2. Hauser WA, Hessdorfer DC: The natural history of seizures, in Wyllie E (ed): The Treatment of Epilepsy: Principles and Practice. Baltimore, MD, Williams & Wilkins, 1996, pp 173-178 3. Reynolds EH: Early treatment and prognosis of epilepsy. Epilepsia 28:97-106, 1987 4. Prasad AN, Stafstrom CF, Holmes GL: Alternative epi-
lepsy therapies: The ketogenic diet, immunoglobulins, and steroids. Epilepsia 37:$81-$95, 1996 (suppl 1) 5. Henry TR, Bakay RAE, Votaw JR: Brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: I. acute effects at high and low levels of stimulation. Epilepsia 39:983-989, 1998 6. The Vagus Nerve Stimulation Study Group: A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 45:224-230, 1995 7. Rutecki P: Anatomical, physiological, and theoretical
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basis for the antiepileptic effect of vagus nerve stimulation. Epilepsia 31 :S 1-$6, 1990 (suppl 2) 8. Zabara J: Inhibition of experimental seizures in canines by repetitive vagal stimulation. Epilepsia 33:1005-1012, 1992 9. Woodbury DM, Woodbury JW: Effects of vagal stimulation on experimentally induced seizures in rats. Epilepsia 31:$7-S19, 1990 (suppl 2) 10. Woodbury DM, Woodbury JW: Vagal stimulation reduces the severity of maximal electroshock seizures in intact rats: Use of a cuff electrode for stimulating and recording. PACE 14:94-107, 1991 11. Lockard JW, Congdon WC, Ducharme LL: Feasibility and safety of vagal stimulation in monkey model. Epilepsia 31:$20-$26, 1990 (suppl 2) 12. McLachan RS: Suppression of interictal spikes and seizures by stimulation of the vagus nerve. Epilepsia 34:918923, 1993 13. Chase MH, Nakamura Y: Cortical and subcortical EEG patterns of response to afferent abdominal vagal stimulation: Neurographic correlates. Physiol Behav 3:605-610, 1968 14. Chase MH, Nakamura Y, Clemente CD, et al: Afferent vagal stimulation: Neurographic correlates of induced EEG synchronization and desynchronization. Brain Res 5:236-249, 1967 15. Peury JK, Dean JC: Prevention of intractable partial seizures by intermittent vagal stimulation in humans: Preliminary results. Epilepsia 31 :$40-$43, 1990 (suppl 2) 16. Salinsky MC, Burchiel KJ: Vagus nerve stimulation has no effect on awake EEG rhythms in humans. Epilepsia 34:299304, 1993 17. Hammond EJ, Uthman BM, Wilder BJ, et al: Neurochemical effects of vagus nerve stimulation in humans. Brain Res 583:300-303, 1992 18. Randall WC, Ardell JL: Differential innervation of the heart, in Zipes D, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. New York, NY, Grune and Stratton, 1985 pp 137-144 19. Naritoku DK, Terry WJ, Helfert RH: Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res 22:53-62, 1995 20. Naritoku D, Terry WJ, Helfert RW: Intermittent vagus nerve stimulation activates brainstem noradrenergic nuclei. Epilepsia 35:3, 1994 (suppl 8) 21. Uthman BM, Wilder BJ, Hammond EJ, et al: Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures. Epilepsia 31 :$44-$50, 1990 (suppl 2) 22. Cyberonics: Physician's manual for the Model 100 NCP Pulse Generator. Houston, TX, Cyberonics, 1998. Ref Type: Pamphlet 23. Terry R, Tarver WB, Zabara J: An implantable neurocybernetic prosthesis system. Epilepsia 31 :$33-$37, 1990 (suppl 2) 24. Ramsay RE, Uthman BM, Augustinisson LE, et al: Vagus nerve stimulation for treatment of partial seizures: 2. safety, side effects, and tolerability. Epilepsia 35:627-636, 1994 25. Uthman BM, Wilder B J, Penry JK, et al: Treatment of epilepsy by stimulation of the vagus nerve. Neurology 43:13381345, 1993 26. Uthman BM, Wilder BJ, Hammond EJ, et al: Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures. Epilepsia 31:$44-$50, 1990 (suppl 2)
PATRICIA K. CRUMRINE
27. Handforth A, DeGigiorgio CM, Schacter SC, et al: Vagus nerve stimulation therapy for partial-onset seizures: A randomized active-control trial. Neurology 51:48-55, 1998 28. Ben-Menachem E, Mafion-Espaillat, Ristanovic R, et al: Vagus nerve stimulation for treatment of partial seizures. 1. A controlled study of effect on seizures. Epilepsia 35:616-626, 1994 29. The Vagus Nerve Stimulation Study Group: A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 45:224230, 1995 30. Ben-Menachem E, Hellstri3m K, Waldton C, et al: Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years. Neurology 52:1265-1267, 1999 31. George R, Salinsky M, Kuzniecky R, et al: Vagus nerve stimulation for treatment of partial seizures: 3. Long-term follow-up on first 67 patients exiting a controlled study. Epilepsia 35:637-643, 1994 32. VNS & Adolescence: A Consensus Conference. Orlando, Florida, March 4-7, Cyberonics 1999 33. Murphy JV, Hornig G, Schallert G: Left vagal nerve stimulation in children with refractory epilepsy: Preliminary observations. Arch Neuro152:886-889, 1995 34. Murphy JV: Left vagal nerve stimulation in children with medically refractory epilepsy. J Pediatr 134:563-566, 1999 35. Lundgren J, Amark P, Blennow G, et al: Vagus nerve stimulation in 16 children with refractory epilepsy. Epilepsia 39:809-813, 1998 36. Parker APJ, Polkey CE, Binnie CD, et al: Vagus nerve stimulation in epileptic encephalopathies. Pediatrics 103:778782, 1999 37. Camfield PR, Camfield CS: Antiepileptic drug therapy: When is epilepsy truly intractable? Epilepsia 37:$60-$65, 1996 (suppl 1) 38. Huttenlocher PR, Hapke RJ: A follow-up study of intractable seizures in childhood. Ann Neurol 28:699-765, 1990 39. Wheless JW, Venkatarman V, Baumgartner AB, et al: Vagus nerve stimulation as adjunctive therapy in LennoxGastaut Syndrome. Epilepsia 40:91, 1999 (suppl 2, abstr) 40. Crumrine PK, Foley CM, Adelson PD, et al: Vagal nerve stimulation in a pediatric population. Epilepsia 40:169, 1999 (suppl 2, abstr) 41. Schacter SC, Saper CB: Vagus nerve stimulation. Epilepsia 39:677-686, 1998 42. McLachlan RS: Vagus nerve stimulation for treatment of seizures? Maybe. Arch Neurol 55:232-233, 1998 43. Schallert G, Foster J, Lindquist N, et al: Chronic stimulation of the left vagal nerve in children: Effect on swallowing. Epilepsia 39:1113-1114, 1998 44. Murphy JV, Homig GW, Schallert GS, et al: Adverse events in children receiving intermittent left vagal nerve stimulation. Pediatr Neurol 19:42-44, 1998 45. Tatum WO, Moore DB, Stecker MM, et al: Ventricular asystole during vagus nerve stimulation for epilepsy in humans. Neurology 52:1267-1269, 1999 46. Cyberonics Inc. Physician Manual for the NCP | Generator Model 100. Houston, TX, Cyberonics, Inc, 1997 47. Ben-Menachem E, Hamberger A, Hedner T, etal: Effects of vagus nerve stimulation on amino acids and other metabolites
VAGAL NERVE STIMULATION IN CHILDREN
in the CSF of patients with partial seizures. Epilepsy Res 46:227, 1995 48. Second Annual Vagus Nerve Stimulation Symposium. Laguna Niguel, August 2-5, Cyberonics, 1998, p 21 49. Begley CE, Famulari M, Annegers JF, et al: The cost of
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epilepsy in the United States: An estimate from populationbased clinical and survey data. Epilepsia 41:342-351, 2000 50. Boon P, Vonck K, Vandekerckhove T, et al: Vagus nerve stimulation for medically refractory epilepsy; efficacy and cost-benefit analysis. Acta Neurochir (Wien) 141:447-453, 1999
Copyright 9 2000 by W.B. Saunders Company
qOR SOME CHILDREN epilepsy may be a chronic problem, uncontrolled by standard antiepileptic drugs (AEDs). Families and caregivers of these children are often desperate for therapies that will control the seizures. Prevalence figures for epilepsy cite figures of 5 to 9 per 1,0001 with about 5% to 10% of these patients being intractable. 2 Most of the intractable patients will have partial seizures. The time frame for establishing intractable epilepsy for most patients is about 2 years? For children with structural lesions (eg, migrational abnormalities) the time period to establish intractability may be shorter. For those children for whom AEDs are not helpful, other alternatives are needed. Ketogenic diet as well as hormonal and vitamin therapies have been considered as altematives with varying degrees of success reported. 4 Vagal nerve stimulation is a new therapeutic option for this refractory population. Clinical studies in adults cite both efficacy and safety. Small uncontrolled studies in children suggest similar results.
F
HISTORY
The vagus nerve is a complex nerve that provides information from the viscera of the abdomen to the brain via general visceral afferents. The origin of these fibers is in the abdominal viscera
From the Pediatric Epilepsy Program and the EEG and Pediatric Epilepsy Monitoring Unit, University of Pittsburgh School of Medicine, Pittsburgh, PA. Address reprint requests to Patricia K. Crumrine, MD, Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213-2583. Copyright 9 2000 by W.B. Saunders Company 1071-9091/00/0703-0009510.00/0 doi:10.105 3/spen.2000.9218 216
and the termination is in the nucleus of the solitary tract that extends throughout the medulla oblongata. From this nucleus there are projections to many areas of the brain, including thalamic and hypothalamic structures, amygdala, and possibly other subcortical structures. Early studies of vagal nerve stimulation in cats demonstrated both desynchronization and synchronization of the EEG. 5-7Whether synchronization or desynchronization of the EEG occurred depended on the stimulation parameters used. Because seizures often result from recruitment and synchronization of discharges within thalamocortical pathways, the thought was that desynchronization of these discharges might produce an antiepileptic effect. Studies in other laboratory animals, including strychnine-induced seizures in the dog 8 and pentylenetetrazol-induced and maximal electroshock seizures in the rat 9,1~ and monkey, 11 demonstrated similar findings on the EEG and evidence of an antiepileptic effect. McLachan 12 demonstrated that vagal stimulation decreased spike frequency in rats by 33% after topical application of penicillin to the cortex. Other EEG studies of vagal stimulation in experimental animals include synchronization at high frequencies (70 Hz), rapid eye movement (REM) sleep, or slow wave sleep. 7 The stimulation parameters used determined the type of EEG response. Stimulation at 20 to 50 Hz and 10 v produced desynchronization of the EEG via slow acting C fibers, whereas high-frequency stimulation led to synchronization. 13,14 Despite the desynchronization of the EEG following vagal nerve stimulation on the EEG in experimental animals, a similar effect has not been found in human clinical studies. 15-17 One of the initial concerns of vagal stimulation
Seminars in Pediatric Neurology, Vol 7, No 3 (September), 2000: pp 216-223
VAGAL NERVE STIMULATION IN CHILDREN
was what the effect would be on cardiac rhythms. Studies of vagal efferents demonstrate an asymmetric innervation of the heart with fibers from the right vagus going to the sinoatrial node and those from the left going to the atrioventricular node. Stimulation studies in dogs revealed a greater degree of cardiac slowing with right vagal stimulation compared with stimulation of the left vagus. 18 The effects from stimulation of the vagus nerve depend on the frequency and intensity of the stimulation with higher stimulation intensities producing little change in heart rate. 7 The mechanism of action for vagal nerve stimulation is unknown. Because stimulation of the vagus nerve results in afferents to the nucleus of the solitary tract, one hypothesis has been that the projections from this tract interrupt partial seizures via a limbic circuit. 7 Naritoku et al j9 demonstrated fos reactivity in the rat in amygdala and limbic cortex after vagal stimulation. Others have explored the effect of vagal nerve stimulation on the brainstem noradrenergic nuclei z~ and other neurotransmitter systems. 17 DEVICE AND TECHNIQUES
Using the NeuroCybernetic Prosthesis (NCP) System (Cyberonics, Inc, Houston, TX), the first vagal nerve stimulator was placed in a human in 1988. 21 The device was patented by Dr. Jacob Zabara and developed by Cyberonics, Houston, Texas. The neuroprosthesis system (NCP) consists of a pulse generator packaged in titanium case, helical bipolar leads that attach to the vagus nerve, a programming wand that communicates information between the pulse generator and a laptop computer with an IBM-compatible software package that permits adjustments in the stimulation parameters, and two handheld magnets. 22 There have been improvements in design and battery life of the pulse generator since the original NCP system was placed in 1988. The newer pulse generators are slimmer, smaller, and have batteries that may last up to 7 to 10 years depending on stimulation parameters and use. The Food and Drug Administration (FDA) approved the NeuroCybernetic Prosthesis System (NCP) for use as adjunct therapy in adults and children over the age of 12 years in July 1997. The NeuroCybernetic Prosthesis is implanted subcutaneously in the anterior chest wall or infraclavicular region in a surgical suite with the patient
217
under general anesthesia. The infraclavicular placement is a good area for young women, asthenic children, and developmentally delayed children who might bother the device. The surgeon exposes the carotid sheath as for a carotid endarterectomy and the vagus nerve. Helical, flexible bipolar electrodes are attached to the vagus nerve and impedances for the electrodes are checked. Impedances should be between 400 and 3,000 ohms. 23 The leads are attached to the generator and the device then placed into the chest pocket. Timing for initiation of the NeuroCybernetics prosthesis NCP varies somewhat between centers. In the initial clinical studies, the device was "turned on" about 2 weeks after implantation, allowing time for healing of the incision. Some centers now turn the stimulation device on in the operation room at the conclusion of the implantation procedure. The initial output current is usually set at 0.25 mA and increased by 0.25 mA increments to settings that are tolerated by the patient. Parameter settings include constant output currents of 0 to 12 mA, signal frequencies of 1 to 145 Hz, pulse widths of 130 to 1,000 ~tsec. Pulse ON times of 7 to 270 seconds and Pulse OFF times of 0.2 to 180 minutes. Most of the pediatric studies have reported output currents of 1.00 to 1.75, with some at 2.0 to 2.5 mA. Higher output currents are less well tolerated. Initial settings during the compassionate use studies included output currents of 0.25 to 2.75, frequency of 30 Hz, pulse width of 500 lasec with device on times of 30 to 90 seconds and off times of 5 to 180 minutes. Currently, there are many variations of these settings in use. Changing the frequency to 20 Hz and the pulse width to 250 ~tsec may lengthen battery life. Many treating physicians are now using more rapid cycling paradigms by having the device go on and off every few seconds. There has not been a standard paradigm determined for a particular age or seizure type. The treating physician can set the parameters using the programming wand and a laptop computer with the programming software and IBM-compatible laptop computer. The intervals for changing the settings can be determined by the patient response. A suggested interval following implantation is every 2 weeks for the first 4 to 6 weeks. CLINICAL STUDIES IN HUMANS
The first humans received an NCP in 1988. There were 11 adults implanted between November 1988
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PATRICIA K. CRUMRINE
and September 1989.15 Penry and Dean 15 reported the results for 4 of these patients in 1990. Two of the patients with complex partial seizures became seizure-free and one third had a 40% reduction in seizures. Subsequent studies included two singleblind pilot studies of 14 patients with partial seizures, 2426 a randomized active-control trial using high stimulation with low stimulation in 254 patients27; a multicenter, randomized, longitudinal controlled trial of 114 patients, 28,29 open long-term evaluation of 64 patients3~ pilot study of 5 adults with symptomatic generalized epilepsy. In the early pilot studies, about 36% of patients achieved 50% or greater control of their seizures. In the multicenter, randomized high versus low stimulation study about one third of the patient in the high stimulation group achieved at least 50% decrease in their seizures. At an 18-month follow-up, 52% of patients achieved 50% decrease in seizures. By March 1999 more than 4,000 patients had received vagal nerve stimulation. 32 Studies in the pediatric population included 12 children between 4 and 16 years by Murphy et al, 33 60 children who were either in a compassionate use or active-control protocol, 34 16 children with refractory epilepsy 35 and 16 children with epileptic encephalopathies (Table 1). 36 In the initial pediatric studies there were 3 of 12 patients who reported >90% decrease in seizures. 33 In a follow-up study with added patients 46 of 60 children achieved 42% reduction in seizures 18 months after implantation. 34 Lundgren et a135 reported that 6 of 16
achieved >50% reduction about 12 months after implantation. Parker et a136 noted only a median 17% reduction in seizures in 15 children after 1 year and 42% reduction after 2 years. In the second year of the study the authors permitted changes in AEDs and doses that were not permitted during the first year of the study. Cyberonics, Inc., held a consensus conference on the vagal nerve stimulator (VNS) and adolescence March 4 through 7, 1999, in Orlando, Florida. Investigators from Children's Mercy Hospital in Kansas City (Murphy), University of Texas-Houston (Wheless), Boston Children's Hospital (Helmers), Minnesota Epilepsy Group (Frost), Pediatric Neurology of Idaho (Bettis), Seattle Children's Hospital (Sotero deMenezes), Children's Hospital of Wisconsin (Wilfong), University Hospital Charles Nicolle, Rouen, France (Parain), and Kings' College Hospital, London, UK (Robinson) reported the results of their pediatric patients in open studies. 37 There were no common protocols for the 309 patients at these various institutions, although 114 patients were part of pediatric VNS study group. Ages ranged from 3 years to about 18 years for most of the investigators. Some of the investigators had patients implanted for only about 3 to 6 months. The authors reported their results differently as noted in Table 1. In addition to published results of pediatric cases with VNS there are now many pediatric epilepsy centers implanting children. Many of the centers have at least 25 to 30 patients with NCP.
Table 1. Pediatric Studies With the Vagus Nerve Stimulation
Author
Patient No.
Age (years)
3 Months
6 Months
Murphy Wheless Helmers Frost* Bettis Sotero DeMenezes Wilfong Parain~ Robinson Lundgrent
60 59 80 25 15 10 25 20 15 16
3-18 5-18 3-median 12 years 8-16 Adolescence 5-18 6-18 NA Median 11 years 4-15
23% 37.5% -26%
31% 53.6%
Control 12 Months 34%
18 Months
24Months
42%
-59%
20%
19% NHS3
17% NHS3
43%
NOTE. Control is defined as median seizure control for the population as a whole. Abbreviation: NA, not available. *Frost reported that 70% had >50% reduction in seizures. tLundgren defined efficacy using the National Hospital Seizure Severity Scoring system (NHS). This showed decreases at 4 to 6 months and 12 months (3 children at 4 to 6 months and 2 more at 12 months). r reported that 75% had 50% reduction at 9 to 24 months.
VAGAL NERVE STIMULATION IN CHILDREN
PEDIATRIC INDICATIONS
In the United States, the FDA approval indicates that the NCP device can be used as adjunctive therapy for refractory partial seizures in adults and children over the age of 12 years. In the European community indications include both partial and generalized seizures, without an age restriction. Randomized, controlled studies in children are incomplete at this time. Indications in open and compassionate use trials in children have included refractory complex partial epilepsies, children with epileptic encephalopathies, Lennox-Gastaut syndrome (LGS), generalized tonic-cionic, and absence seizures. Part of the problem in the selection of the child for this procedure is deciding when the child is refractory and what the natural history of the epilepsy itself may be. Camfield and Camfield 37 defined intractability as failure to three AEDs. Huttenlocher reported a follow-up of 145 children with refractory seizures and noted that at 10 years after the diagnosis of their seizures 70% achieved at least a 5-year seizure-free period. Given this natural history, should children receive a VNS? If so, when in the course of their epilepsy should they undergo VNS? Should children who are being considered for complete corpus callosotomy receive a trial of the NCP device before surgery? Wheless et a138 cite the following indications for consideration of the device: (I) medically refractory epilepsy; (2) adequate trial of at least three AEDs; (3) exclusion of nonepileptic events; and (4) lack of surgery candidacy. There are certain contraindications to implantation of the NCP. Children who have had prior vagotomy, either unilateral or bilateral, should not receive the NCP device. Children with cardiac arrhythmias or conduction abnormalities should receive clearance from a cardiologist and should be followed carefully during and following implantation. Dyspnea may be a risk factor for those with chronic obstructive pulmonary disease. Because cervical magnetic resonance imaging may not be performed once the device is implanted, children with cervical masses should be excluded. OUTCOMES OF VNS IN CHILDREN
Most investigators note that very few patients actually become seizure-free following implantation of the VNS. The standard that most of the
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initial studies used to determine efficacy was a 50% or greater than reduction in seizures. Investigators note that much of the effect of the VNS comes several months after implantation, sometimes up to 12 months later. Most patients obtain about a 25% reduction in their seizures at a 3 month follow-up after implantation. In most published reports, the response to VNS has been noted for the group of patients as a whole, and not by seizure types. Parker et a136specified the results based on seizure types in a prospective study of children with epileptic encephalopathies that included severe myoclonic epilepsy of infancy, LGS, and myoclonic-astatic seizures. They noted median seizure reduction in those with LGS as 34%; 4 children with severe myoclonic epilepsy of infancy had an increase in seizures of 31%; those with myoclonic-astatic epilepsy had no response or 40% increase. Their patients did not have any changes in their AEDs or doses during the first year. At 2 years after implantation, median seizure reduction was 43% with changes in both AEDs and doses. Of the 15 children receiving VNS, I became seizure-free and 2 had >60% reduction in seizures. Ben-Menachem et al 3~ reported 8 patients with LGS and 9 patients with primary generalized epilepsy, including absence seizures. Five of eight patients with LGS had a response in all seizure types; generalized tonicclonic seizures responded best. Of the 9 patients reported with primary generalized epilepsy, 6 had typical absence and all responded with >50% reduction in seizures. Seven of the 16 patients reported by Lundgren et a135 had had prior epilepsy surgery. Ages of their patients ranged from 4 to 16 years at the time of implantation. There were 4 patients with LGS. The authors noted that no particular seizure type responded better or worse to VNS. Overall 6 of 16 children achieved >50% seizure reduction after 12 months; there was no further seizure reduction noted after 12 months. 35 Wheless et a139 presented the results of 12 patients with LGS aged 3.5 to 27 years who received the NCE Seven of these patients had prior callosotomies; 42% of the patients had >50% reduction in seizures using a rapid-cycle sequence, and none had exacerbation of seizures. Crumrine et al 4~ reported the results of implantation of 8 patients aged 9 to 24 years; 6 patients were children and 2 were young adults. Two of the patients had LGS. Of this group, 3 of 8 achieved 50% to 75%
220
PATRICIA K. CRUMRINE
reduction in seizures. Overall, the studies in children indicate moderate to significant reduction in seizure frequency, and sometimes in intensity. The number of children who become seizure-free is small. COMPLICATIONS FROM VAGAL NERVE STIMULATION
The initial concerns of the procedure were related to the question of what the effect of chronic stimulation would have on the vagal nerve. The stimulating electrodes are designed as flexible helical coils that decrease the impact of stimulation. The stimulation protocols used to date have not resulted in any documented damage to the vagus nerve. 41,42 In a randomized high stimulation/ low stimulation study in adults, the major adverse effects were in the high stimulation group and consisted of hoarseness, throat pain, dyspnea, paresthesia, and muscle pain. 41 Monitoring of gastric acid and cardiac rhythms did not detect any adverse effects. 42 In the early pilot studies, transient left vocal cord paralysis and paralysis of the left facial nerve occurred; this has not been seen in more recent studies. Postoperative infections occur in about 3% of patients. 43 Schallert et a144investigated the swallowing function of 8 children following vagal nerve implantation. They noted that 4 of 8 children had laryngeal penetration of barium with barium swallow studies during therapeutic stimulation and 6 of 8 during maximum stimulation. None had evidence of aspiration. Three of the children had laryngeal penetration when they were not receiving vagal stimulation. Murphy et a144 reported side adverse events in children receiving the NCP system, noting that most adverse events were the hoarseness and coughing. Tatum et a145recently reported four adult patients who experienced ventricular asystole intraoperatively while the NCP was being implanted. There were no autonomic dysfunctions reported in the
early controlled studies, including changes in mean heart rate, variability of heart rate, or bradycardia. 7,27 Environmental exposure to properly functioning microwave ovens, airport metal detectors, cellular phones, electrical ignition systems, theftprevention devices, and power transmission lines should not affect the operation of the system. 46,47 Electromechanical devices that have a strong static or pulsing magnetic field could inadvertently activate the magnet. Patients should keep these at least 6 inches from the NCP pulse generator. 47 Hospital and medical risks include therapeutic radiation, external defbrillation, electrosurgical cautery, body MRI, and extracorporeal shockwave lithotripsy. Another initial question was whether it was safe to perform a head MRI. Head imaging with MR can be done using a transmit and receive head coil. The following recommendations are made by Cyberonics: (1) head coil type: transmit and receive only; (2) static magnetic field strength: -<2.0 tesla; (3) specific-rate absorption:
Table 2. Suggested Parameters for Vagus Nerve Stimulation
Output current (mA) Pulse width (psec) Frequency (Hz) Signal on time (seconds) Signal off time (minutes) Magnet current (mA) Magnet on time (seconds) Magnet pulse (psec)
0-2 Weeks
2-4 Weeks
4-8 Weeks
3 Months
0.25-0.5 500 (250) 20 (30) 30 5 (10) .5-.75 30 500 (250)
0.75-1.0 500 (250) 20 (30) <30 1-3 1.0-1.25 30 500 (250)
1.0-1.75 250 20 (30) <1 <1 1.25-2.0 30 500 (250)
1.5-2.75 (2.0) 250 20 (30) <1 <1 1.75-2.0 (2.25) 30 500 (250)
VAGAL NERVE STIMULATION IN CHILDREN
221
was perceived improvement in the children receiving VNS. The improvements noted were independent of the degree of seizure control and were in areas of cognition and behavior. Parker et a136 and Ben-Menachem et a147 raise the question of whether this may be related to serotinergic modulation of the behavior and affect. The issue of cost-effectiveness of the NCP system is an important one in this day of managed health care. Cost of the device itself is about $10,000. Hospital and physician costs associated with the surgical implantation could include another $20,000 to $30,000. Approximately two thirds of state Medicaid programs provide some coverage for N C P implants; Health Care Finance Administration supports the program as does C H A M P U S , United MetraHealth, Kaiser, Blue Cross and Blue Shield Technology, as well as other private insurers and managed health care companies. 48 Begley et a149 looked at the cost of epilepsy in the United States based on population clinical and survey data. They reported that the average direct cost per case was $6,429 over a 6-year follow-up period after diagnosis. Boon et al 5~ did a cost-benefit analysis of medically refractory patients who received the NCP and found that epilepsy-related direct medical costs decreased from $8,330 before the VNS to $4,215 in the year after implantation and that hospitalization admission days decreased from 21 to 8 days. This is the first study that has looked at a cost-benefit effect of VNS. The authors noted that other studies comparing specific AEDs to VNS, and comparison of different stimulation parameters would also be helpful as one tries to decide if this is the most effective treatment decision to make. SUMMARY
Although controlled studies in children are not completed, the preliminary studies suggest the
VNS is a safe and effective treatment for children with medically refractory epilepsy. Although most of the studies to date have included children with refractory partial complex epilepsy and LGS, there are some studies that suggest that some of the generalized epilepsies may also respond to this treatment. What remains unknown currently are whether there are specific settings that work more effectively for one seizure type compared with another and whether combinations of Ads and VNS and various types of surgical procedures are also options. Suggestions are provided as criteria for selection of the child for VNS. However, decisions should be carefully presented and discussed with caregivers and patients. Most families and patients tolerate the NCP device; most report improvement in the behavior and performance o f the children that is independent of the decrease in seizures. Improved QOL for these children with refractory epilepsy is the goal.
APPENDIX: RESOURCES FOR FAMILIES AND CAREGIVERS
1. Videotapes and patient information on the NCP| System. This information is available to physicians, nurses, and patients: Cyberonics, Inc. 16511 Space Center Boulevard, Suite 600 Houston, Texas 77058 Phone: (800) 332-1375 FAX: (281) 218-9332 2. Epilepsy Foundation 4351 Garden City Drive Landover, MD 20785-2267 (301) 459-3700 website: www.efa.org 3. Articles: Lyne Bridget M: A new method in seizure management: Vagus nerve stimulation. Exceptional Parent May:84-90, 1999 Henry TR: Most commonly asked question about vagus nerve stimulation for epilepsy.The Neurologist 4:284-289, 1998
REFERENCES
1. Annegers JF: The epidemiology of epilepsy, in Wyllie E (ed): The Treatment of Epilepsy: Principles and Practice. Baltimore, MD, Williams & Wilkins, 1996, pp 165-172 2. Hauser WA, Hessdorfer DC: The natural history of seizures, in Wyllie E (ed): The Treatment of Epilepsy: Principles and Practice. Baltimore, MD, Williams & Wilkins, 1996, pp 173-178 3. Reynolds EH: Early treatment and prognosis of epilepsy. Epilepsia 28:97-106, 1987 4. Prasad AN, Stafstrom CF, Holmes GL: Alternative epi-
lepsy therapies: The ketogenic diet, immunoglobulins, and steroids. Epilepsia 37:$81-$95, 1996 (suppl 1) 5. Henry TR, Bakay RAE, Votaw JR: Brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: I. acute effects at high and low levels of stimulation. Epilepsia 39:983-989, 1998 6. The Vagus Nerve Stimulation Study Group: A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 45:224-230, 1995 7. Rutecki P: Anatomical, physiological, and theoretical
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basis for the antiepileptic effect of vagus nerve stimulation. Epilepsia 31 :S 1-$6, 1990 (suppl 2) 8. Zabara J: Inhibition of experimental seizures in canines by repetitive vagal stimulation. Epilepsia 33:1005-1012, 1992 9. Woodbury DM, Woodbury JW: Effects of vagal stimulation on experimentally induced seizures in rats. Epilepsia 31:$7-S19, 1990 (suppl 2) 10. Woodbury DM, Woodbury JW: Vagal stimulation reduces the severity of maximal electroshock seizures in intact rats: Use of a cuff electrode for stimulating and recording. PACE 14:94-107, 1991 11. Lockard JW, Congdon WC, Ducharme LL: Feasibility and safety of vagal stimulation in monkey model. Epilepsia 31:$20-$26, 1990 (suppl 2) 12. McLachan RS: Suppression of interictal spikes and seizures by stimulation of the vagus nerve. Epilepsia 34:918923, 1993 13. Chase MH, Nakamura Y: Cortical and subcortical EEG patterns of response to afferent abdominal vagal stimulation: Neurographic correlates. Physiol Behav 3:605-610, 1968 14. Chase MH, Nakamura Y, Clemente CD, et al: Afferent vagal stimulation: Neurographic correlates of induced EEG synchronization and desynchronization. Brain Res 5:236-249, 1967 15. Peury JK, Dean JC: Prevention of intractable partial seizures by intermittent vagal stimulation in humans: Preliminary results. Epilepsia 31 :$40-$43, 1990 (suppl 2) 16. Salinsky MC, Burchiel KJ: Vagus nerve stimulation has no effect on awake EEG rhythms in humans. Epilepsia 34:299304, 1993 17. Hammond EJ, Uthman BM, Wilder BJ, et al: Neurochemical effects of vagus nerve stimulation in humans. Brain Res 583:300-303, 1992 18. Randall WC, Ardell JL: Differential innervation of the heart, in Zipes D, Jalife J (eds): Cardiac Electrophysiology and Arrhythmias. New York, NY, Grune and Stratton, 1985 pp 137-144 19. Naritoku DK, Terry WJ, Helfert RH: Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res 22:53-62, 1995 20. Naritoku D, Terry WJ, Helfert RW: Intermittent vagus nerve stimulation activates brainstem noradrenergic nuclei. Epilepsia 35:3, 1994 (suppl 8) 21. Uthman BM, Wilder BJ, Hammond EJ, et al: Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures. Epilepsia 31 :$44-$50, 1990 (suppl 2) 22. Cyberonics: Physician's manual for the Model 100 NCP Pulse Generator. Houston, TX, Cyberonics, 1998. Ref Type: Pamphlet 23. Terry R, Tarver WB, Zabara J: An implantable neurocybernetic prosthesis system. Epilepsia 31 :$33-$37, 1990 (suppl 2) 24. Ramsay RE, Uthman BM, Augustinisson LE, et al: Vagus nerve stimulation for treatment of partial seizures: 2. safety, side effects, and tolerability. Epilepsia 35:627-636, 1994 25. Uthman BM, Wilder B J, Penry JK, et al: Treatment of epilepsy by stimulation of the vagus nerve. Neurology 43:13381345, 1993 26. Uthman BM, Wilder BJ, Hammond EJ, et al: Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures. Epilepsia 31:$44-$50, 1990 (suppl 2)
PATRICIA K. CRUMRINE
27. Handforth A, DeGigiorgio CM, Schacter SC, et al: Vagus nerve stimulation therapy for partial-onset seizures: A randomized active-control trial. Neurology 51:48-55, 1998 28. Ben-Menachem E, Mafion-Espaillat, Ristanovic R, et al: Vagus nerve stimulation for treatment of partial seizures. 1. A controlled study of effect on seizures. Epilepsia 35:616-626, 1994 29. The Vagus Nerve Stimulation Study Group: A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 45:224230, 1995 30. Ben-Menachem E, Hellstri3m K, Waldton C, et al: Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years. Neurology 52:1265-1267, 1999 31. George R, Salinsky M, Kuzniecky R, et al: Vagus nerve stimulation for treatment of partial seizures: 3. Long-term follow-up on first 67 patients exiting a controlled study. Epilepsia 35:637-643, 1994 32. VNS & Adolescence: A Consensus Conference. Orlando, Florida, March 4-7, Cyberonics 1999 33. Murphy JV, Hornig G, Schallert G: Left vagal nerve stimulation in children with refractory epilepsy: Preliminary observations. Arch Neuro152:886-889, 1995 34. Murphy JV: Left vagal nerve stimulation in children with medically refractory epilepsy. J Pediatr 134:563-566, 1999 35. Lundgren J, Amark P, Blennow G, et al: Vagus nerve stimulation in 16 children with refractory epilepsy. Epilepsia 39:809-813, 1998 36. Parker APJ, Polkey CE, Binnie CD, et al: Vagus nerve stimulation in epileptic encephalopathies. Pediatrics 103:778782, 1999 37. Camfield PR, Camfield CS: Antiepileptic drug therapy: When is epilepsy truly intractable? Epilepsia 37:$60-$65, 1996 (suppl 1) 38. Huttenlocher PR, Hapke RJ: A follow-up study of intractable seizures in childhood. Ann Neurol 28:699-765, 1990 39. Wheless JW, Venkatarman V, Baumgartner AB, et al: Vagus nerve stimulation as adjunctive therapy in LennoxGastaut Syndrome. Epilepsia 40:91, 1999 (suppl 2, abstr) 40. Crumrine PK, Foley CM, Adelson PD, et al: Vagal nerve stimulation in a pediatric population. Epilepsia 40:169, 1999 (suppl 2, abstr) 41. Schacter SC, Saper CB: Vagus nerve stimulation. Epilepsia 39:677-686, 1998 42. McLachlan RS: Vagus nerve stimulation for treatment of seizures? Maybe. Arch Neurol 55:232-233, 1998 43. Schallert G, Foster J, Lindquist N, et al: Chronic stimulation of the left vagal nerve in children: Effect on swallowing. Epilepsia 39:1113-1114, 1998 44. Murphy JV, Homig GW, Schallert GS, et al: Adverse events in children receiving intermittent left vagal nerve stimulation. Pediatr Neurol 19:42-44, 1998 45. Tatum WO, Moore DB, Stecker MM, et al: Ventricular asystole during vagus nerve stimulation for epilepsy in humans. Neurology 52:1267-1269, 1999 46. Cyberonics Inc. Physician Manual for the NCP | Generator Model 100. Houston, TX, Cyberonics, Inc, 1997 47. Ben-Menachem E, Hamberger A, Hedner T, etal: Effects of vagus nerve stimulation on amino acids and other metabolites
VAGAL NERVE STIMULATION IN CHILDREN
in the CSF of patients with partial seizures. Epilepsy Res 46:227, 1995 48. Second Annual Vagus Nerve Stimulation Symposium. Laguna Niguel, August 2-5, Cyberonics, 1998, p 21 49. Begley CE, Famulari M, Annegers JF, et al: The cost of
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epilepsy in the United States: An estimate from populationbased clinical and survey data. Epilepsia 41:342-351, 2000 50. Boon P, Vonck K, Vandekerckhove T, et al: Vagus nerve stimulation for medically refractory epilepsy; efficacy and cost-benefit analysis. Acta Neurochir (Wien) 141:447-453, 1999