Effects of Vagal Nerve Stimulation on Cognition and Quality of Life in Epilepsy

Epilepsy & Behavior 2, 46 –53 (2001) doi:10.1006/ebeh.2000.0148, available online at http://www.idealibrary.com on

Effects of Vagal Nerve Stimulation on Cognition and Quality of Life in Epilepsy 1 Carl B. Dodrill, Ph.D.* ,2 and George L. Morris † *Regional Epilepsy Center, Departments of Neurology and Neurological Surgery, University of Washington School of Medicine, Seattle, Washington 98104; and † Department of Neurology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, Wisconsin Received July 25, 2000; revised December 29, 2000; accepted for publication January 2, 2001

To evaluate the cognitive and quality-of-life (QOL) impacts of vagal nerve stimulation (VNS), 160 patients with uncontrolled partial seizures from 20 sites were enrolled in a double-blind study. Patients were randomly assigned to low (minimal) stimulation (n ⴝ 82) or high (now clinically used) stimulation (n ⴝ 78) conditions and given a group of cognitive and QOL tests before implantation and after 12–16 weeks of VNS treatment. Results showed no clear cognitive changes. However, fewer emotional and physical problems were reported by the High Group than the Low Group at the end of the study. The 32 patients who had at least 50% seizure relief showed slightly more improvement in QOL variables than those patients who did not demonstrate this degree of seizure reduction. Overall, a small number of favorable QOL but no cognitive changes were associated with levels of VNS stimulation that are now typically used clinically. © 2001 Academic Press Key Words: epilepsy; vagus nerve; stimulation; cognition; quality of life.

INTRODUCTION

liorating the symptoms (seizures) but leaving the patient with additional treatment-related difficulties does not provide an adequate outcome. Several preliminary reports of favorable cognitive and/or QOL changes with vagal nerve stimulation (VNS) now exist in the clinical literature (6, 10 –13). However, most of these observations are unblinded, anecdotal, and currently available only in abstract form. In only one case has a formal test or inventory been used (11). In the experimental literature, there is now some suggestion that enhanced recognition memory may occur in animals (14, 15) and in humans (16), providing that VNS is moderate in intensity and providing that it is delivered after the stimuli to be remembered have been presented and specifically during the period of memory consolidation. Unfortunately, this information was not available when we planned our study, and we therefore did not include memory measures in it. In summary, there are suggestions of positive QOL and perhaps cognitive effects of VNS in the literature, but these effects have not been well documented. In no instance have negative cognitive and QOL effects of VNS been reported. The current research presents the

The technique of stimulation of the left vagus nerve for relief from epileptic seizures has been well described including the method itself, the mechanism of action, and a summary of the animal literature (1). Several investigations in humans now provide support for relief from seizures as a consequence of using this procedure in adults (2– 4) as well as in children (5–7). Relief from seizures is typically incomplete (often 30 – 40% have at least a 50% reduction in attacks) although this relief may improve over time (8). Adverse quality-of-life (QOL) and cognitive changes secondary to treatments for seizures are recognized as substantial issues in epilepsy (9), and ame1 This research was supported by Cyberonics, Inc., the manufacturer of the NCP prosthetic device. The authors were paid consultants to Cyberonics during the course of this study. 2 To whom correspondence should be addressed Regional Epilepsy Center (Box 359745), Harborview Medical Center, 325 Ninth Avenue, Seattle, WA 98104-2499. Fax: (206) 731-4409. E-mail: [email protected].

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Cognitive/QOL Effects of Vagal Nerve Stimulation TABLE 1 Comparison of Patient Characteristics across Subject Groups Variable Age Mean SD Range Gender Female Male Race White Hispanic Other Etiology of seizures Known Unknown Total seizure frequency per day (baseline) Median Mean SD Years of seizure disorder Mean SD

Low group (n ⫽ 82)

High group (n ⫽ 78)

All patients (n ⫽ 160)

35.3 9.9 15–60

32.9 10.9 13–64

34.1 10.4 13–64

48 (58%) 34 (42%)

41 (53%) 37 (47%)

89 (56%) 77 (44%)

70 (86%) 6 (7%) 6 (7%)

73 (94%) 3 (4%) 2 (2%)

143 (89%) 9 (6%) 8 (5%)

26 (32%) 56 (68%)

25 (32%) 53 (69%)

51 (32%) 109 (58%)

.48 1.04 1.31

.53 1.47 2.93

.51 1.25 2.26

23.20 11.19

21.93 11.29

22.57 11.22

Note. No statistically significant (P ⬍ 0.05) differences were found across the groups for any variable. Also, no differences were found on any of the variables in comparison with the 198 patients in the clinical study (2).

results of a large, multisite, controlled trial where formal testing of cognition and QOL was accomplished under blinded conditions.

METHODS The protocol used in the clinical study from which the present data were obtained is described in detail elsewhere (2). Briefly, patients were required to have at least six partial-onset seizures involving alteration of consciousness over 30 days with no more than 21 days between attacks. All patients entered into a 12- to 16-week baseline phase during which they were evaluated at four clinic visits. Baseline seizure frequency was computed as the average of those reported during the four baseline visits. At the end of baseline, patients who continued to meet the protocol requirements were implanted with the vagus nerve stimulator (NeuroCybernetic Prosthesis, Cyberonics, Inc.). Two weeks were allowed for healing, patients were randomly assigned to either low stimulation or high stimulation conditions, and the treatment phase was begun at which point the device was turned on. A ramp-up procedure was undertaken by which pa-

tients in the Low Group were advanced to stimulation parameters that were barely detectable by the patient and not believed to be therapeutic. Patients in the High Group were ramped up to a just tolerable, higher level of stimulation which was believed to be effective and which is similar to that which is now used in clinical treatment. Details of the stimulation parameters are provided in the clinical report (2). Treatment continued for 12–16 weeks during which the blind was maintained and seizures were recorded. Subjects Of 194 subjects who finished the clinical study (2), 160 provided usable data on the cognitive tests for both baseline and treatment periods and these 160 individuals constitute the patient pool used in this study. Complete and usable test information was not available on the remaining 34 patients due to mental retardation too severe to permit testing, to postictal confusion following a recent seizure, or to scheduling problems. Of the 160 patients used in this study, 82 were randomly assigned to the Low Group and 78 to the High Group. Table 1 presents information on these subject groups and on the 160 patients as a whole. No Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

48 differences were found across the subject groups on any of these baseline variables. Furthermore, a comparison of the patient descriptive information given in this table with similar information given for the entire group in the clinical study (2) reveals no differences of either clinical or statistical significance. Thus, the current sample appears to be representative of the larger group used in the clinical study.

Cognitive Tests At the end of the baseline phase and at the end of the treatment phase, a battery of cognitive and QOL/ adjustment measures were scheduled. The following cognitive tests were attempted with every testable patient, and they rendered a total of nine variables. Wonderlic Personnel Test (17). This is a written test of mental abilities that renders results closely approximating those of the WAIS Full Scale IQ (18). It requires 12 minutes for completion and results in scores for the number of items correct and the number on which errors have been made. Parallel forms of this test were used in a counterbalanced fashion. Digit Cancellation. A page of random one-digit numbers is presented and the patient cancels with a single stroke as many as possible of two target digits in a 4-minute period. The variables resulting are number of items correct and number of items omitted. Form I (“0” and “7”) and Form II (“1” and “6”) were used in counterbalanced order. This test has been used in studies of the cognitive effects of antiepileptic drugs (19, 20). Stroop Test. A single color plate is used on which color names (“red”, “green”, “blue”, “orange”) are printed in incongruous colors (“red” is printed in blue print, “blue” is printed in orange print, “orange” is printed in green print, etc.). The same test is part of the Neuropsychological Battery for Epilepsy (21), except that only 8 of the 16 lines of 11 words per line are used. On the first (reading speed) part of the test, the patient reads the words as quickly as possible, ignoring the colors, and on the second part (interference) the colors of print are read, ignoring the words. Time (150- and 300-second maximums for the first and second parts, respectively) and errors for both parts are recorded. Two forms of the test were used, with the order counterbalanced for each patient. Symbol Digit Modalities Test (22). This is similar to the Digit Symbol subtest of the Wechsler Adult Intelligence Scale—Revised (WAIS-R) except that numbers rather than symbols are written. Only the written part Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

Dodrill and Morris

is used, and the number of items correct in 90 seconds is the score.

Tests of Adjustment and Mood The tests of adjustment and mood were administered at the same session as the cognitive measures. All of them were given when the patient obtained a score of at least 8 items correct on the Wonderlic Personnel Test, which corresponds to a WAIS-R Full Scale IQ score of approximately 75. When 4 to 7 items were correct on the Wonderlic, all of the tests of adjustment and mood were omitted except for the Washington Psychosocial Seizure Inventory (WPSI), which was given. When fewer than 4 items were correct on the Wonderlic Personnel Test (IQ estimate ⬍ 70), no measure of adjustment or mood was attempted. The tests of adjustment and mood were as follows. Quality of Life in Epilepsy Inventory (QOLIE)-31 (23). This is a 31-item questionnaire developed on the basis of factor analysis and including scales labeled Seizure Worry, Overall Quality of Life, Emotional Well-Being, Energy/fatigue, Cognitive, Medication Effects, Social Function, and Overall Score. A portion of the items in the QOLIE-31 came from existing QOL instruments, and a portion were created for this inventory by the authors of it (23). The inventory covers both general and epilepsy-related domains. SF-36 Health Survey (24). This is a generic health survey with no reference to epilepsy. The scales arising from the inventory include Physical Functioning, Role Physical (enhanced), Bodily Pain, General Health, Vitality, Social Function, Role Emotional (enhanced), and Mental Health. Medical Outcomes Study (MOS) (25). Two scales were selected for study here, the Mental Health Index and the Current Health Scale. These are generic health-related scales with no special reference to epilepsy. Health-Related Hardiness Scale (HRHS) (26). This is a general personality measure of felt ability to cope with health-related events. The scales include Control, Commitment, Challenge, and a total HRHS scale. Washington Psychosocial Seizure Inventory (27). This 132-item inventory of psychosocial adjustment in epilepsy provides indications of functioning in each of seven areas (Family Background, Emotional Adjustment, Interpersonal Adjustment, Vocational Adjustment, Financial Status, Adjustment to Seizures, Medicine and Medical Management). Each scale is empirically anchored in assessments of actual performance

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Cognitive/QOL Effects of Vagal Nerve Stimulation TABLE 2 Means (SD) of Baseline and Treatment Performance on Cognitive Tasks across the Low and High Stimulation Groups Low stimulation (n ⫽ 82) Test/variable Wonderlic Personnel Test Items correct Items wrong Digit Cancellation Number right Number omitted Stroop Test Reading speed(s) Reading speed (errors) Interference(s) Interference (errors) Symbol Digit Modalities Number right (written)

High stimulation (n ⫽ 78)

Baseline

Treatment

Baseline

Treatment

Significance: group ⫻ time interaction, P

14.12 (7.91) 7.18 (4.88)

14.11 (8.09) 7.94 (5.55)

12.96 (7.61) 7.70 (5.88)

12.19 (7.66) 8.14 (5.91)

0.2510 0.7206

139.74 (52.30) 6.74 (12.16)

142.94 (53.36) 5.40 (7.37)

134.24 (58.84) 6.33 (16.33)

130.76 (54.95) 5.32 (6.60)

0.1467 0.9697

56.56 (21.10) 1.04 (1.37) 120.82 (25.65) 4.95 (5.23)

56.64 (22.61) .68 (1.45) 117.86 (27.03) 4.08 (3.90)

68.18 (28.93) 1.08 (1.77) 126.62 (27.35) 5.25 (5.02)

69.17 (29.93) 1.01 (1.53) 124.24 (25.17) 4.26 (3.45)

0.2481 0.1033 0.4107 0.7414

42.55 (13.89)

43.25 (12.42)

38.06 (14.33)

37.84 (14.25)

0.551

Note. Significance levels are based on interaction effects of the high and low treatment groups using difference scores (treatment minus baseline). Initial levels of test scores and treatment sites were covaried out.

in everyday life. In addition, an index of overall adjustment is obtained as are two validity scales (Lie Scale, Rare Items Scale). The tests were administered in the following order: Wonderlic, Digit Cancellation, QOLIE-31, SF-36, MOS, HRHS, Symbol Digit Modalities, and WPSI. Examiners were psychometrists or psychologists who had attended a comprehensive training session where a test manual with detailed instructions was provided to facilitate uniformity in testing procedures.

Data Analysis The primary data analysis evaluated differential baseline-to-treatment changes across the Low and High Groups with consideration of each test variable (9 cognitive, 34 QOL) separately. These analyses were performed on difference scores (treatment minus baseline) with study site and initial level of test scores covaried out merely to be certain that these were not contaminating factors. In a secondary set of analyses, the baseline-to-treatment changes for each variable were computed for the Low Group and the High Group separately. Finally, differential baseline-totreatment changes for each test variable were sought out across patients divided according to whether a 50% or greater relief from seizures had been obtained during the course of the study regardless of placement in the Low Group or the High Group.

RESULTS For the primary analyses, the results of the baselineto-treatment period changes across the Low and High Groups are presented in Table 2 for the cognitive tests and in Table 3 for the QOL measures. Table 2 shows no statistically significant differences in the cognitive area. Thus, scores did not change differentially on these tests as a function of group placement. In the QOL area, however, Table 3 demonstrates that the SF-36 Role Physical and Role Emotional scales improved more during the course of the study in the High Group than in the Low Group. The same was true for the WPSI Financial Status Scale. The Low and High Groups were then considered separately in search of baseline-to-treatment changes in a series of secondary analyses. The Low Group showed improvement on two variables (reading error rate on the Stroop Test (P ⬍ 0.05) and fewer concerns on the Seizure Worry Scale of the QOLIE-31 (P ⬍ 0.05)). The High Group, however, showed improvement on 10 variables: better concentration on the high interference portion of the Stroop Test (P ⬍ 0.01); SF-36 Physical Function (P ⬍ 0.01) and Role Emotional (P ⬍ 0.05) better; QOLIE-31 Seizure Worry (P ⬍ 0.05), Cognitive Functioning (P ⬍ 0.01), Social Functioning (P ⬍ 0.05), and Overall score (P ⬍ 0.01) all better; WPSI Emotional Adjustment (P ⬍ 0.05), Interpersonal Adjustment (P ⬍ 0.05), Adjustment to Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

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Dodrill and Morris

TABLE 3 Means (SD) of Baseline and Treatment Performances on QOL Measures across the Low and High Stimulation Groups Low stimulation (n ⫽ 82) Test/variable Quality of Life in Epilepsy-31 Seizure Worry Overall QOL Emotional Well-Being Energy/Fatigue Cognitive Function Medication Effects Social Functioning Overall Score SF-36 Health Survey Physical Function Role Physical Bodily Pain General Health Vitality Social Function Role Emotional Mental Health Summary: Physical Summary: Emotional Medical Outcomes Study Mental health Current health Health-Related Hardiness Scale Control Commitment Challenge Total HRHS Washington Psychosocial Seizure Inventory Family Background Emotional Adjustment Interpersonal Adjustment Vocational Adjustment Financial Status Adjustment to Seizures Medicine and Medical Management Overall Psychosocial Functioning Lie Rare Items

High stimulation (n ⫽ 78)

Baseline

Treatment

Baseline

Treatment

Significance: group ⫻ time interaction, P

50.88 (25.16) 62.06 (15.34) 65.04 (19.29) 54.65 (19.65) 57.62 (21.90) 57.89 (29.53) 54.60 (21.95) 57.83 (14.34)

57.29 (22.26) 64.08 (15.33) 66.11 (19.51) 54.24 (17.66) 60.16 (19.90) 64.19 (28.44) 55.61 (24.50) 59.86 (14.73)

51.87 (26.80) 67.02 (14.73) 68.28 (17.28) 57.09 (19.18) 53.40 (23.16) 54.05 (31.24) 53.19 (24.59) 58.07 (15.01)

60.65 (23.65) 67.93 (13.42) 71.53 (16.25) 58.55 (18.85) 59.46 (21.94) 58.45 (30.15) 59.07 (23.96) 62.02 (14.14)

0.2612 0.9914 0.3156 0.3129 0.2789 0.9900 0.2825 0.2740

83.66 (18.36) 62.18 (33.04) 68.41 (24.99) 61.90 (21.46) 54.65 (19.65) 67.98 (21.26) 72.73 (32.01) 65.04 (19.29) 47.13 (6.84) 44.28 (10.75)

85.24 (18.91) 64.00 (33.20) 66.52 (25.04) 64.20 (20.16) 54.24 (17.66) 70.18 (25.74) 74.09 (33.32) 66.11 (19.51) 47.34 (8.21) 45.04 (10.27)

83.30 (17.08) 68.51 (34.32) 71.91 (22.42) 66.21 (19.34) 57.09 (19.18) 68.88 (27.20) 76.09 (27.36) 68.28 (17.28) 48.31 (9.39) 45.41 (10.11)

89.68 (11.72) 76.17 (27.23) 72.72 (21.00) 69.32 (16.31) 58.55 (18.85) 75.53 (19.67) 85.87 (21.51) 71.53 (16.25) 49.86 (6.84) 48.09 (9.12)

0.1051 0.0373 0.3764 0.4574 0.3129 0.4729 0.0256 0.3156 0.1272 0.2017

65.83 (17.75) 59.49 (25.42)

67.66 (18.43) 61.79 (23.74)

69.38 (16.58) 64.85 (22.36)

71.66 (15.83) 65.69 (19.80)

0.6087 0.9798

42.39 (8.78) 30.65 (7.63) 30.14 (8.04) 103.18 (20.00)

41.91 (9.01) 30.47 (8.45) 30.02 (8.66) 102.40 (23.37)

39.06 (9.34) 28.09 (7.43) 27.28 (8.38) 94.43 (20.54)

39.09 (10.58) 27.85 (9.09) 26.32 (9.08) 93.26 (25.61)

0.9275 0.5443 0.1432 0.5604

2.48 (2.48) 13.08 (6.14) 6.14 (4.28) 6.88 (3.18) 2.89 (2.11) 6.15 (3.67) 1.71 (1.41) 20.42 (9.83) 2.08 (1.67) 1.28 (1.26)

2.57 (2.44) 13.18 (6.30) 6.08 (4.76) 6.60 (3.39) 2.91 (2.07) 5.55 (3.33) 1.52 (1.32) 19.91 (10.23) 2.15 (1.82) 1.82 (1.09)

2.62 (1.92) 13.53 (6.06) 6.72 (3.85) 6.70 (2.76) 2.60 (2.22) 6.83 (3.50) 1.79 (1.28) 21.17 (8.73) 2.11 (1.96) 1.32 (1.37)

2.47 (2.26) 12.21 (5.88) 5.62 (4.08) 6.77 (2.75) 2.25 (2.06) 5.96 (3.61) 1.45 (1.34) 18.66 (8.64) 2.08 (1.90) 1.92 (1.66)

0.4057 0.1314 0.0947 0.5335 0.0315 0.9020 0.6225 0.1256 0.6489 0.8364

Note. Significance levels are based on interaction effects of the high and low treatment groups using difference scores (treatment minus baseline). Initial level of test scores and treatment sites were covaried out.

Seizures (P ⬍ 0.05), and Overall (P ⬍ 0.01) all better. Both groups also endorsed more rare items on the WPSI at the end of the study than during baseline (P ⬍ 0.01), a finding that is likely due to random responding on this inventory. It was the last test completed by the patients at the very end of the study. In the final set of analyses, a search was for differential changes across patients who had and who had not achieved at least a 50% reduction in seizures durCopyright © 2001 by Academic Press All rights of reproduction in any form reserved.

ing the treatment period in comparison with the baseline period. A total of 32 people (13 in the Low Group, 19 in the High Group) had achieved 50% relief from seizures, and 128 had not. No statistically significant differences between the patients who had and who had not achieved a 50% reduction in seizures were found on any cognitive variable, but on QOL variables, patients with at least a 50% reduction in seizures reported fewer complaints on the QOLIE-31 Cognitive

Cognitive/QOL Effects of Vagal Nerve Stimulation

Functioning Scale (P ⬍ 0.01) and improved adjustment in the area of medical care on the WPSI (P ⬍ 0.05) than did patients who had less than a 50% relief in seizures.

DISCUSSION This study shows a limited number of improvements in reported QOL with VNS and especially at intensity levels that are now customarily used in clinical practice (high stimulation such as found with the High Group). Patients reported somewhat fewer emotional, physical, and social concerns on the QOL measures after VNS stimulation. It is also noted that they commonly provided such reports to many of the investigators during the course of the study. Nevertheless, five important questions must be addressed in evaluating the findings of this study. First, the adequacy of blinding of the patients and the staff in regard to treatment condition must be reviewed. Extensive efforts were made to blind the patients as to the treatment group in which they were placed. Both groups of patients routinely felt the stimulation, but they were not given cues about the nature and frequency of the stimulation in the two treatment conditions. Furthermore, the protocol explicitly required that the patients be seen in such a manner that they did not have any contact with one another at their clinic visits. With regard to the staff, the stimulators were turned off during the clinic visits so that the staff did not have hints as to which group the patients were in. No doubt patients in both groups had hopes and expectations of seizure relief from the stimulator, but there is no evidence that one group had more expectations than the other group. Although exceptions may have occurred inadvertently, we believe that the extensive efforts made to maintain blinding of group placement were generally successful. Furthermore, since it was the difference across these two conditions that was the primary outcome of the study, a general placebo or nonspecific effect was at least minimized if not excluded altogether. Second, the question must be raised as to why there were not more statistically significant differences between the Low and High Groups. Relief from seizures in the Low Group was approximately 15% while relief in the High Group was 28%. While the difference between these figures is statistically significant (P ⬍ 0.05) (2), it is likely that it was not great enough to show differential changes across the groups on most test variables. Also, it appears that the Low Group

51 experienced some benefit from VNS, an effect of the active-control design of the study. Where an activecontrol positively affects patients, differences between the active-control and treatment groups are more difficult to demonstrate. These factors, and possibly others, are likely responsible for the relatively small number of differences found between the groups in Table 2. A third question pertains to why there were not more statistically significant differences between those patients who did and those who did not have 50% relief from seizures. Studies of new antiepileptic drugs provide some insight here as they routinely produce only a limited number of changes on tests such as those used in this study, even when 50% relief of seizures has been obtained (19, 28, 29). Indeed, in these three studies of vigabatrin and tiagabine, on only 6% of 111 test variables were statistically significant improvements found at the 0.05 level of confidence. The results of the present investigation are highly similar and it may be that relief from seizures by any of these therapeutic methods is simply not great enough in these patients with chronic and difficult-to-manage epilepsy to be reflected in clear changes in test scores. A fourth point worthy of attention pertains to the possibility of chance findings. Each of 43 variables had been evaluated on four occasions by statistical tests. Thus, a total of 172 statistical tests were run at the 0.05 level of confidence, and six or seven statistically significant findings may have emerged on the basis of chance alone. If the findings were primarily a function of chance, positive and negative results would be expected with approximately equal frequency. However, of 28 statistically significant findings produced by the study, 26 were positive and 2 were negative. The 2 negative findings were increased numbers of Rare Items on the WPSI from baseline to treatment for both the Low Group and the High Group. These findings were likely due to an increase in random responding on the WPSI as it was placed at the very end of the study for all patients. Patients may have hurried to complete the last of eight pages of questions, and at least some of them may not have taken the time to read the final questions carefully. If the results on the Rare Items Scale are set aside, there were 26 significant findings in the study overall, all of which favored VNS. Thus, although we cannot rule out the possibility that some findings may have been due to chance, the possibility should be considered that there may have been a mild positive QOL change with VNS therapy. Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.

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A final point worthy of attention is the lack of cognitive change documented by the results of our tests. While the Stroop Test rendered two positive findings, persuasive evidence for a general positive change was lacking. This was true even though some patients reported being more alert and feeling more cognitively able during VNS treatment. Such reports have also been recorded elsewhere (12, 13), but these patient reports may be reflecting an increased feeling of ability to cope rather than actually improved cognition. On the other hand, it is true that we did not evaluate the area of memory that has now been shown to be an area of potential positive change (14 –16), and therefore there may have been some positive patient reported changes that we missed. While the question of possibly improved memory with VNS therapy must be left to future research, it does appear safe to say that VNS was not associated with any negative impact on cognition. Overall, the data in this paper raise the possibility that VNS produces a mildly improved sense of wellbeing physically, emotionally, and socially. This sense of improvement is not clearly tied to relief from seizures, perhaps for the reasons specified above. A cognitive change could not be documented in this study although no tests of memory were included. Further studies of memory and also of the QOL effects of VNS apart from seizure relief are warranted to specify these effects and their causes with greater precision.

ACKNOWLEDGMENTS This investigation was supported by Cyberonics, Inc. Gratitude is expressed to the following investigators and to their sites who provided patients for the study: Stephen Collins, M.D., Ph.D. (Cleveland, OH); Christopher DeGiorgio, M.D. (Los Angeles, CA); Richard Gilmartin, M.D. (Wichita, KS); Adrian Handforth, M.D. (Los Angeles, CA); Thomas Henry, M.D. (Atlanta, GA); John Jones, M.D. (Madison, WI); Douglas Labar, M.D., Ph.D. (New York, NY); David Labiner, M.D. (Tucson, AZ); George Morris, M.D. (Milwaukee, WI); Jerome Murphy, M.D. (Kansas City, MO); Dean Naritoku, M.D. (Springfield, IL); Gershon Ney, M.D. (New Hyde Park, NY); Ivan Osorio, M.D. (Kansas City, KS); Ruzica Ristanovic, M.D. (Chicago, IL); Martin Salinsky, M.D. (Portland, OR); Steven Schachter, M.D. (Boston, MA); Evelyn Tecoma, M.D., Ph.D. (La Jolla, CA); Basim Uthman, M.D. (Gainesville, FL); Bradley Vaughn, M.D. (Chapel Hill, N.C.); James Wheless, M.D. (Houston, TX).

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