Au t i s m spectrum disorders are characterized by social

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1 J Neurosurg Pediatrics 5: , 5: , 2010 Vagus nerve stimulation therapy in patients with autism spectrum disorder and intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry Clinical article Mi c h a e l L. Le v y, M.D., Ph.D., 1 Ka r e n M. Le v y, R.N., B.S.N., 1 Day n a Ho f f, M.B.A., 1 Ar u n Pa u l Am a r, M.D., 2 Min S. Pa r k, M.D., 1 Jo r d a n M. Co n k l i n, B.S., 1 Li s sa Ba i r d, M.D., 1 a n d Mi c h a e l L. J. Ap u z z o, M.D. 2 1 Division of Pediatric Neurosurgery, Children s Hospital of San Diego, University of California, San Diego; and 2 Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California Object. The purpose of this study was to determine the effectiveness of vagus nerve stimulation (VNS) therapy on quality-of-life (QOL) variables among patients with both autism spectrum disorder (ASD) and persistent or recurrent intractable epilepsy. Methods. Data were obtained from the VNS therapy patient outcome registry, which was established after US FDA approval of the VNS device in 1997 as a means of capturing open-label clinical data outside of protocol. The integrity of the systems for collecting and processing registry data was authenticated by an independent auditing agency. The effect of potential selection bias, however, remains uncertain. Results. Two cohorts were compared: 1) patients with epilepsy but without ASD (non-asd [NASD] Group, 315 patients) who were being tracked in the registry (this cohort, which was controlled for age, included patients 20 years of age or younger); and 2) patients with a diagnosis of ASD who underwent implantation of the VNS device (ASD Group, 77 patients). Differences between the ASD and NASD groups were noted in the following categories: sex (male preponderance in ASD); normal imaging results (MR imaging results normal in ASD); depression (less common in ASD); behavioral problems (more common in ASD); neurological deficit (more common in ASD); mental retardation (more common in ASD); and developmental delay. The only QOL difference between the ASD and NASD groups was noted in mood at 12 months postimplant (mood was improved in ASD) (p = 0.04). There were no other differences in the QOL variables. Conclusions. Patients with ASD and intractable epilepsy respond as favorably as all other patients receiving VNS therapy. In addition, they may experience a number of QOL improvements, some of which exceed those classically observed following placement of a VNS device. (DOI: / PEDS09153) Ke y Wo r d s epilepsy epilepsy surgery failed surgery autism autism spectrum disorder seizure vagus nerve stimulation Au t i s m spectrum disorders are characterized by social symptoms that may include a lack of interaction with other persons, avoidance of eye contact, delayed ability in understanding the thoughts or emotions of others, and problems with emotional control. Persons with autism usually have difficulty with communication and may exhibit repetitive behaviors. In addition, mental retardation and seizures are sometimes noted in persons Abbreviations used in this paper: AED = antiepileptic drug; ASD = autism spectrum disorder; NASD = non-asd; QOL = quality of life; VNS = vagus nerve stimulation. J Neurosurg: Pediatrics / Volume 5 / June 2010 with ASD. 19 An estimated 5 38% of children with autism also have epilepsy. 15 The same brain dysfunction associated with autism may also be associated with epilepsy, especially in children who have both autism and mental retardation. 7 In tuberous sclerosis, autism is associated with both the tuber location (temporal lobe) and the epileptic activity in those areas. 7 A study from Iceland suggested that ASD is more prevalent among children who experienced seizures during their 1st year of life than in the general population. 21 A Swedish study reported that a third of the adult patients with autism had experienced seizures since 595

2 M. L. Levy et al. they were children or adolescents. 5,6 To date, no potential surgical management has been suggested for patients with ASD. For patients with ASD and epilepsy, early diagnosis and intervention with physical therapy, occupational therapy, and speech therapy remain the mainstay of treatment and intervention. For patients within the more severe realm of ASD with epilepsy, additional therapies include medical management. The impact of VNS on the control of seizures in patients with medically refractory epilepsy has been well documented in adults 2,3,9,22,23 as well as in children. 4,10,11 The consideration of QOL issues in these patients has always been of importance. 8,25 Vagus nerve stimulation, which involves the surgical implantation of a pulse generator, lead, and electrodes to deliver chronic intermittent stimulation to the vagus nerve, has been approved by the US FDA as a treatment for medically refractory partial-onset seizures in patients 12 years of age and older. The comorbidity of autism and epilepsy led to the VNS epilepsy registry for a comparison of outcomes in epilepsy patients with autism and young epilepsy patients with no history of cranial surgery. A number of papers have discussed the positive QOL considerations as recorded in patients following placement of a VNS device ,16 Given the nature of QOL improvements generally noted, we sought to identify any potential differences between patients with ASD and epilepsy when compared with age-matched controls with epilepsy but without ASD. Given the prevalence of QOL benefits following placement of a VNS device, any further differences would potentially be of even greater benefit in patients with ASD. Methods Study Objective The objective of these analyses was to compare 2 groups of patients enrolled in the VNS epilepsy registry: 1) patients with no history of cranial surgery or autism, but with intractable epilepsy (control group); and 2) patients with a history of both autism and intractable epilepsy. In this exploratory analysis, the control group 1 was further restricted by the patient age parameter of 20 years or younger. The VNS Epilepsy Registry In 1998, shortly after the US FDA approved VNS for partial-onset seizures in patients 12 years of age and older, the manufacturer (Cyberonics, Inc.) established a patient registry. This registry affords the opportunity to identify patients with certain characteristics and comorbidities and to track aggregated outcomes at various intervals after implantation of the VNS device. Health care providers enrolling patients in the registry completed medical history forms at baseline. Diagnoses were made according to the physician s judgment; no criteria were provided for comorbidities. Follow-up forms recorded seizure frequency and QOL at 3, 6, 12, and 24 months after implantation. SYNERGOS, Inc., (a contract research organization) and the manufacturer conducted an audit that authenticated the integrity of the systems used to collect and process data in the registry. Study Groups The data for this paper were drawn from the VNS epilepsy registry in September 2002; the same data set as that analyzed in Amar et al., 1 who reported that approximately 40% of all patients receiving VNS were enrolled in the registry at that time. This comparison of outcomes included the following: 1) a control group consisting of patients with no history of cranial surgery, no history of autism, intractable epilepsy, and age 20 years or younger; and 2) patients with a history of autism, with or without a history of cranial surgery, with intractable epilepsy, and with no restrictions for age. The age restriction in the control group was chosen to provide a roughly age-matched comparison for the relatively young patients with autism. In patients in the study groups, complete medical histories and outcome data were obtained at both 3 and 12 months after implantation of the VNS device. Data points include the patients demographic data, cause of epilepsy, epilepsy syndrome, total number of seizures per unit of time (seizure burden), seizure summary information (longest seizure-free period, and so on), current AED therapy, MR imaging findings, medical history (including epilepsy surgery), categories of prior epilepsy surgery, and device settings. Patients designated within the ASD category had universally been diagnosed by their pediatricians and neurologists, and treatment had been initiated prior to placement of their VNS device. Standardized treatment protocols for patients with ASD have not been established to date. During follow-up visits at 3, 6, 12, 18, and 24 months, the following data were submitted: seizure burden, seizure summary information, magnet usage in the VNS unit, device settings, and AED changes. Analysis of Patient Characteristics For the analysis of continuous patient characteristics such as age, age at onset, duration of epilepsy, weight, and number of seizures per day preimplantation, summary statistics (number, mean, SD, minimum, median, and maximum) were computed for each patient group. Wilcoxon rank-sum tests were used to compare continuous variables between groups. For categorical variables such as sex, race, MR imaging status, cause of seizures, epilepsy syndrome, and number of AEDs prior to implant, the 2 patient groups were compared using chi-square or Fisher exact tests, as appropriate. The medical history form was revised on November 11, 1999, by adding depression, mental retardation, developmental delay, cerebral palsy, autism, Rhett syndrome, and tuberous sclerosis. With regard to patients enrolled in the registry before this date, these medical histories remained unmarked and were presumed unknown unless clear and specific comments regarding them were noted on the original version of the corresponding data collection form. The percent change in seizure frequency was computed within each patient. Lower and upper limits on the percent change in seizure frequency were set at 100% and 100%, respectively. Then, summary statistics (number, 596 J Neurosurg: Pediatrics / Volume 5 / June 2010

3 Vagus nerve stimulation therapy in patients with autism mean, SD, minimum, median, and maximum) were computed at each of the follow-up visits. The percent change in seizure frequency was compared between patient groups at each follow-up visit by using a Wilcoxon rank-sum test. In addition, the percentage of patients with a 50, 75, 90, or 100% reduction was compared between groups at each follow-up visit by using Fisher exact tests. The percentage of patients with any increase or more than a 25% increase in seizure frequency was also compared between patients at each follow-up visit by using Fisher exact tests. The change in QOL, including alertness, verbal communication, memory, school/professional achievements, mood changes, postictal state, and cluster seizures, was compared between the 2 groups at each follow-up visit by using chi-square tests. For each parameter of QOL, a comparison was made to the preimplantation state. One of 5 responses was selected for each parameter, including the following: 5, much better; 4, better; 3, no change; 2, worse; or 1, much worse. For this analysis, improvement was defined as a response of 4 or 5. In addition, patients evaluated in the registry were assessed using the Quality of Life in Epilepsy-10 questionnaire, which consists of questions designed to assess the patient s and/or the family s rating of patient memory, level of physical and mental well-being, energy, depression, worries about seizures and work, social limitations, and overall QOL on VNS treatment. It should be noted that the registry is selfreported and therefore has unknown (and unknowable) biases that may differ between ASD and other groups. Statistical Analysis Summary statistics (number, mean, SD, minimum, median, and maximum) were computed for the physician s global assessment at each of the follow-up visits. The physician s global score was compared between groups at each follow-up visit by using a Wilcoxon rank-sum test. All analyses were based on a constant cohort; only patients with a complete history as well as both 3- and 12-month follow-up visits. All analyses were performed using SAS version 8.2. Because this analysis was exploratory due to the large number of comparisons, no level of significance was established. Probability values are provided for informational purposes. Results A total of 393 patients were evaluated in the constant cohort; 315 patients age 20 years or younger with no history of cranial surgery, NASD, and intractable epilepsy, and 78 patients with a history of autism and intractable epilepsy. Patient Characteristics Table 1 lists patient demographic data and characteristics. More than 73% of the patients with autism were male, whereas nearly 54% of the patients with no history of cranial surgery were male (p = 0.002). More than 14% of the patients with autism were institutionalized, compared with almost 3% of the patients with no history of cranial surgery (p = ). Of the patients with autism, J Neurosurg: Pediatrics / Volume 5 / June % presented with normal results on MR imaging, and 47.3% of patients with no history of cranial surgery presented with normal MR imaging results (p = ). With regard to epilepsy syndrome, almost half (48.6%; p = ) of patients with no history of cranial surgery had localized seizures, whereas 37.2% (p = ) and 26.9% (p = ) of the patients with autism had generalized seizures or Lennox-Gastaut syndrome, respectively. Differences between groups were not as pronounced for age, age at onset, duration of epilepsy, race, weight, seizure origins, number of AEDs, or number of seizures preimplantation. Medical History In Table 2 we compare the medical histories of the 2 groups. With regard to intracranial surgery, 4.4% (p = ) and 2.9% (p = ) of the patients with autism had undergone a previous callosotomy and lobectomy, respectively, for epilepsy, compared with none of the patients without cranial surgery. More than 38% of the patients with autism had a history of psychosocial or psychiatric disorders, compared with only 16.3% of the patients with no history of cranial surgery (p = ). Nearly one-third (31.5%) of the patients with no history of cranial surgery had behavioral problems, compared with two-thirds (65.3%) of the patients with autism (p < ). Of the patients with no history of cranial surgery, 37.5% had neurological defects, compared with 55.4% of the patients with autism (p = ). More than 91% of the patients with autism were mentally retarded, compared with 63.3% of the comparison group (p < ). Similarly, 92% of the patients with autism were developmentally delayed, compared with 73.8% of the comparison group (p = ). Finally, nearly 11% of the patients with autism had a history of tuberous sclerosis, compared with only 1.9% of the patients with no history of cranial surgery (p = ). Seizure Frequency The upper panel of Fig. 1 shows the percent change in seizure frequency at the 3-month ( 46.9% control group, 47.1% autism group) and 12-month ( 55.6% control group, 62.5% autism group) follow-up visits. The lower panel of Fig. 1 shows the proportion of patients with 50, 75, or 90% reduction, or with no seizures reported at either visit (control group: 48.6, 28.3, 15.9, and 4.4% at 3 months; 55.9, 36.2, 21.6, and 4.8% at 12 months; autism group: 48.7, 29.5, 18, and 5.1% at 3 months; 61.5, 38.5, 21.8, and 7.7% at 12 months). The proportion of patients with any increase at 3 or 12 months (control group: 21.6 or 21.9%; autism group: 19.2 or 21.8%) or at least a 25% increase in seizure frequency (control group: 16.2 or 15.4%; autism group: 17.1 or 18%) was also similar between the 2 groups. Quality of Life At 3 months after implantation of the VNS device, the 2 groups were similar with respect to alertness, verbal communication, memory, school/professional achievements, mood changes, postictal state, or cluster seizures. At 12 months postimplantation, almost 62% of the patients 597

4 M. L. Levy et al. TABLE 1: Demographic data and characteristics of patients with autism and epilepsy treated surgically compared with patients 20 years of age or younger without cranial surgery, compiled from the VNS epilepsy registry* Characteristic Control Autism p Value Statistical Test no. of patients (total 393) age (yrs) median (range) 12 (1 20) 9.5 (4 37) Wilcoxon rank-sum test mean t-test, unequal variance age at onset (yrs) median (range) 1.5 (0 17.5) 1 (0 10.4) Wilcoxon rank-sum test mean t-test, unequal variance duration of epilepsy (yrs) median (range) 8 (0.5 20) 7.7 (1.5 35) Wilcoxon rank-sum test mean t-test, unequal variance sex M 169 (53.7%) 57 (73.1%) Fisher exact test F 146 (46.3%) 21 (26.9%) race white 263 (86.0%) 71 (96.0%) chi-square test black 18 (5.9%) 0 (0.0%) hispanic 17 (5.6%) 1 (1.3%) asian 4 (1.3%) 1 (1.3%) other 4 (1.3%) 1 (1.3%) unknown/missing data 9 4 weight (lbs) median (range) 80 (13 280) 71 (20 212) Wilcoxon rank-sum test mean t-test, unequal variance patients institutionalized 9 (2.9%) 11 (14.3%) Fisher exact test seizure origin known 116 (36.8%) 22 (28.2%) Fisher exact test MRI results normal 149 (47.3%) 44 (56.0%) Fisher exact test localized seizures 153 (48.6%) 26 (33.3%) Fisher exact test temporal 43 7 rt side 32 1 lt side 26 1 frontal 45 3 bilat unknown 29 7 generalized seizures 92 (29.2%) 29 (37.2%) Fisher exact test Lennox-Gastaut syndrome 55 (17.5%) 21 (26.9%) Fisher exact test rolandic seizures 0 (0.0%) 0 (0%) JME 1 (0.3%) 0 (0%) Fisher exact test other 14 (4.4%) 2 (2.6%) no. of AEDs preimplant median (range) 2 (0 5) 2 (0 5) Wilcoxon rank-sum test mean t-test, equal variance 0 6 (1.9%) 2 (2.6%) chi-square test 1 43 (13.7%) 10 (12.8%) (41.6%) 36 (46.2%) (33.6%) 20 (25.6%) 4 23 (7.3%) 8 (10.3%) 5 6 (1.9%) 2 (2.6%) (continued) 598 J Neurosurg: Pediatrics / Volume 5 / June 2010

5 Vagus nerve stimulation therapy in patients with autism TABLE 1: Demographic data and characteristics of patients with autism and epilepsy treated surgically compared with patients 20 years of age or younger without cranial surgery, compiled from the VNS epilepsy registry* (continued) Characteristic Control Autism p Value Statistical Test most common AEDs (no. of patients) VPA (108) VPA (37) LTG (107) LTG (31) TPM (105) TPM (29) CBZ (62) CBZ (12) PHT (50) CLZ (11) no. of seizures/day preimplant median (range) 2.14 ( ) 3.70 ( ) Wilcoxon rank-sum test mean t-test, unequal variance * CBZ = carbamazepine; CLZ = clobazam; JME = jacksonian motor epilepsy; LTG = lamotrigine; PHT = phenytoin; TPM = topiramate; VPA = valproic acid. A patient s seizures may have more than one focal point. A patient may have other seizures in addition to seizures of another type. However, patients are counted only for the primary type unless no primary was noted (and then the seizure was counted as other ). TABLE 2: Medical history of patients with autism and epilepsy treated surgically compared with patients 20 years of age or younger without cranial surgery, per data in the VNS epilepsy registry Medical History No. Control (%)* No. w/ Autism (%)* p Value congenital brain malformation 49 (16.3) 10 (14.5) meningitis/encephalitis 21 (6.8) 7 (9.5) vascular brain malformation 2 (0.7) 2 (2.8) evaluated for epilepsy op 133 (42.6) 34 (49.3) intracranial op previous callosotomy for epilepsy 0 (0.0) 3 (4.4) previous lobectomy for epilepsy 0 (0.0) 2 (2.9) other op; for epilepsy 0 (0.0) 1 (1.7) other; any intracranial op 12 (3.8) 0 (0.0) brain tumor 4 (1.3) 1 (1.4) head injury 9 (2.9) 2 (2.8) febrile seizures 50 (16.1) 7 (10.1) psychosocial/psychiatric disorders 49 (16.3) 26 (38.2) depression 34 (11.5) 1 (2.1) behavioral problems 95 (31.5) 47 (65.3) < neurological defect 114 (37.5) 36 (55.4) mental retardation 195 (63.3) 62 (91.2) < developmental delay 231 (73.8) 54 (91.5) cerebral palsy 56 (17.9) 9 (16.1) autism 0 (0.0) 78 (100.0) Rhett syndrome 0 (0.0) 0 (0.0) tuberous sclerosis 6 (1.9) 6 (10.7) major op procedures 38 (12.3) 7 (9.7) chronic illness 35 (11.5) 10 (14.3) other 68 (28.5) 14 (26.4) * The total number of patients in this analysis may not be 393 due to missing data. According to the Fisher exact test. Note that the medical history form was revised on November 11, 1999, by adding these factors to medical histories. Unless clear and specific comments regarding the medical histories were noted on the original version of the corresponding data collection form, medical histories remain unmarked and were subsequently presumed unknown. J Neurosurg: Pediatrics / Volume 5 / June

6 M. L. Levy et al. Fig. 1. Bar graphs. Upper: Percent change in seizure frequency at 3 and 12 months after implantation of a VNS device. Lower: Percentage of patients with categorical seizure reductions. in the autism group had improved mood, compared with 47% of the patients in the control group (p = ). At 3 months, no more than 9% of patients were reported as worse or much worse in any single QOL category, and at 21 months, the same applied to 7.7% of the patients (Fig. 2). Physician s Global Score The physician s median global score at both the 3- and 12-month follow-up visits (control group: 14 [ 25, 50] and 17 [ 50, 50]; autism group: 12 [ 21, 50] and 19 [ 35, 50]) was similar for the 2 groups. Discussion Children with developmental disabilities are more likely than developmentally normal children to have medically refractory epilepsy, are at increased risk for prolonged seizures, and are at increased risk for recurrent episodes of prolonged seizures. 12 A number of important QOL side effects of VNS may additionally contribute to enhanced outcomes as distinct from seizure control. In treatment of mentally retarded, developmentally delayed patients with epilepsy, 61% of the pediatric population with a VNS device had at least a 50% reduction in seizure frequency at 12 months. 12 Several investigators have reported on the outcomes of patients with autism who received VNS for medically refractory epilepsy. Of the 6 patients reported in a study of hypothalamic hamartomas, 4 had severe autistic behaviors, and 3 of them were mentally retarded. Changes in seizure frequency for the 4 autistic patients were 90%, 50%, and 25%, with 1 unchanged. 18 In a VNS outcome registry study of patients with Landau-Kleffner syndrome or autism, the 59 autistic patients had median reductions in seizure frequency of 40% after 3 months and 55% at 12 months. Improvements in QOL included alertness, which was 75% better at 3 months and 76% better at 12 months. At 12 months, more than 50% of the patients were reportedly better in achievement, mood, postictal period, and seizure clustering. 20 After 2 years of VNS in a prospective study, none of the 8 patients with ASD experienced a decrease in seizure frequency. The quality of social interactive abilities improved in 3 patients and worsened in 1, but most of the changes were considered minor. 5,6 A case study of a patient with Asperger syndrome (a form of ASD) and epilepsy reported a decrease of 68.8% in the number of seizures after 5 months of VNS. After 6 months of VNS, the duration of seizures decreased by 83%, and mood and achievements improved from poor to good. 24 Compared with the 37% median seizure reduction and 37% of patients with seizure reductions of 50% or more that were reported for patients after 1 year in the clinical trials of VNS (396 patients, Declining N sample), both groups in the present study showed a greater reduction in seizures (control group: 55.6% median seizure reduction, 55.9% with seizure reductions of 50% or more; autism group: 62.5 and 61.5%, respectively). 16 The reason for these differences is not known, but could be attributed to the experience with VNS attained by clinicians after its approval, or the possibility of bias from self-reported data. Fig. 2. Bar graph showing results in the QOL category: percentage of patients reported better or much better at 3 and 12 months after implantation of a VNS device. 600 J Neurosurg: Pediatrics / Volume 5 / June 2010

7 Vagus nerve stimulation therapy in patients with autism J Neurosurg: Pediatrics / Volume 5 / June 2010 This exploratory analysis comparing a constant cohort at 3 and 12 months after implantation of a VNS device found that changes in seizure frequency and QOL were not appreciably different between patients 20 years of age or younger without cranial surgery and those with autism. Some differences were noted in the percentages of patients with certain characteristics and medical history. The differences between groups in the percentage of patients with cranial surgery should be attributed to the control group selection criteria, which excluded a history of cranial surgery. Compared with the control group, a greater percentage of the patients with autism had many characteristics associated with autism: behavioral problems, neurological defects, mental retardation, developmental delay, tuberous sclerosis, and median age at onset of seizures of 1 year. 15,17,19 The difficulty in comparing patients with and those without ASD is based on the earlier onset of seizures in the former group and the earlier intervention and placement of the VNS device. In comparing the overall population of patients with intractable epilepsy and NASD and those with ASD, age becomes a significant confounding variable. Comparisons of these series have noted consistent differences in the variables age, age at onset, duration of epilepsy, sex, body weight, type of epilepsy syndrome, and the number of seizures per day preimplantation. A number of the variables evaluated were significantly related to the variable of age, including duration of epilepsy and greater weight. Additionally, 68% of the patients with autism were male. When controlling for age, significant differences included duration of epilepsy, sex, proportion institutionalized, and type of epilepsy syndrome. Patients with ASD also present most often with generalized seizures or Lennox-Gastaut syndrome, compared with localized seizures in the controls. Despite this difference, there was no significant difference in number of seizures preimplantation between patients with ASD and controls. In the current series, consistent differences in medical history for patients with ASD include behavioral problems, psychosocial or psychiatric disorders, neurological defects, mental retardation, and developmental delay. Numerous studies have documented that pediatric patients show improvements in QOL measures, including mood, alertness, verbal skills, memory, and school/professional achievements, although such improvements in QOL are not solely due to improved seizure control. 14 A 6-center, retrospective study evaluated the effectiveness of VNS therapy in patients with Lennox-Gastaut syndrome at 3 and 6 months. Fifty patients (median age 13 years) with medically refractory epilepsy underwent implantation of a VNS device, after which investigators noted that QOL improved. In an additional report of VNS of the 95 patients with follow-up data at 3 months, both responders and nonresponders analyzed in this study reported improvements in QOL. 13 In a single-center study of 38 children with medically refractory epilepsy, age range 11 months 16 years, follow-up more than 6 months later found that VNS was associated with statistically significant reductions in seizure frequency (p = 0.05) and higher QOL scores (p < 0.01). 16 At a median follow-up of 12 months, 29% of patients experienced a greater than 90% reduction in seizure frequency, and 86% were reported as having improved QOL. Quality-of-life scores in this group were higher among patients with a shorter duration of epilepsy (p = 0.08) and in those who had an onset of seizures after the age of 1 year (p = 0.05), when compared with those who had longer follow-up times (p = 0.003). Again, QOL does not correlate solely with seizure reduction. This is similar to previous QOL findings in patients receiving VNS therapy, in whom improvement in QOL did not correlate solely with seizure reduction. 17 In the current study, VNS had no significant impact on decreasing seizures between groups. The percent seizure frequency at all follow-up visits was not statistically different between the groups. Changes in QOL noted following VNS include alertness, which improved in more than 50% after both 3 and 6 months of treatment in one study. After 6 months, more than 25% showed improvement in verbal communication, school, work, postictal recovery, and seizure clustering. Improvements in memory, mood, and ambulation were noted in only a few patients. Decline was noted in the mood of 1 patient and the seizure clustering of 2 patients. The QOL was not based on the degree of seizure reduction or medication changes. Improvements in QOL were more important or life-affecting than seizure reduction. Problems with assessment of QOL in these patients include the fact that the scales are both simple and/or unvalidated. 16,17 In the current study, differences between the ASD and NASD groups were noted in the following categories: sex (male preponderance in ASD); normal imaging results (MR imaging results normal in ASD); depression (less common in ASD); behavioral problems (more common in ASD); neurological deficit (more common in ASD); mental retardation (more common in ASD); and developmental delay (Table 1). The only difference between the ASD and NASD groups was noted in mood, at 12 months postimplantation (mood was improved in the ASD group; p = 0.04). There were no other differences in the QOL variables. We found that patients with ASD respond as favorably as all other patients receiving VNS therapy. In addition, they improved with regard to the QOL. Problems with the study include the use of a standardized database as noted, in addition to the difficulties with the designation of children within the broad spectrum of autistic disorders. Further prospective work will be warranted to potentially evaluate the impact of VNS in patients with ASD and seizure disorders. Conclusions This study has some limitations; for example, unlike most prospective clinical trials, this registry study lacks randomization and masking. In addition, the reader should be aware of the bias that can be introduced with self-reported data. Data describing side effects and patient safety issues were not recorded in this registry, but were kept in a separate database as required by the US FDA. Furthermore, the number of statistical tests that were performed required that the analysis be considered 601

8 M. L. Levy et al. exploratory. Despite these limitations, the results of this study show that VNS provides the same benefits of seizure reduction and improved QOL to both patients with refractory epilepsy only, and those with refractory epilepsy and autism. Disclosure The authors received funding from the Autism Tree Project Foundation. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: ML Levy, KM Levy, AP Amar, D Hoff. Acquisition of data: ML Levy, AP Amar, MS Park, L Baird, D Hoff. Analysis and interpretation of data: ML Levy, MS Park, L Baird, JM Conklin. Drafting the article: ML Levy. Critically revising the article: ML Levy. Reviewed final version of the manuscript and approved it for submission: all authors. Statistical analysis: L Baird, JM Conklin. Administrative/technical/ material support: ML Levy, L Baird, D Hoff. Study supervision: MLJ Apuzzo. Acknowledgments The authors thank W. Brent Tarver, Susan Siefert (Cyberonics, Inc.), and colleagues for access to the VNS therapy patient outcome registry data, and Marcella Johnson, M.S., for assisting in the statistical analysis. They also thank the Autism Tree Project Foundation for the funding to pursue this project. References 1. Amar AP, Apuzzo ML, Liu CY: Vagus nerve stimulation therapy after failed cranial surgery for intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry. Neurosurgery 62 (Suppl 2): , Amar AP, Heck CN, DeGiorgio CM, Apuzzo MLJ: Experience with vagus nerve stimulation for intractable epilepsy: some questions and answers. 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Can J Neurol Sci 27 (Suppl 1):S111 S125, 2000 Manuscript submitted March 31, Accepted March 2, This paper was previously presented at the 55th Annual Meeting of the Congress of Neurological Surgeons, Boston, Massachusetts, in Address correspondence to: Michael L. Levy, M.D., Ph.D., Di vision of Pediatric Neurosurgery, Rady Children s Hospital San Diego, 8010 Frost Street, Suite 502, San Diego, California J Neurosurg: Pediatrics / Volume 5 / June 2010