Childs Nerv Syst DOI 10.1007/s00381-015-2720-8

CASE REPORT

Autistic spectrum disorder, epilepsy, and vagus nerve stimulation Mariam Mettry Hull 1 & Deepak Madhavan 1 & Charles M. Zaroff 2

Received: 6 April 2015 / Accepted: 19 April 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Purpose In individuals with a comorbid autistic spectrum disorder and medically refractory epilepsy, vagus nerve stimulation may offer the potential of seizure control and a positive behavioral side effect profile. We aimed to examine the behavioral side effect profile using longitudinal and quantitative data and review the potential mechanisms behind behavioral changes. Methods We present a case report of a 10-year-old boy with autistic spectrum disorder and epilepsy, who underwent vagus nerve stimulation subsequent to unsuccessful treatment with antiepileptic medication. Results Following vagus nerve stimulation implantation, initial, if temporary, improvement was observed in seizure control. Modest improvements were also observed in behavior and development, improvements which were observed independent of seizure control. Conclusions Vagus nerve stimulation in autistic spectrum disorder is associated with modest behavioral improvement, with unidentified etiology, although several candidates for this improvement are evident.

Keywords Autism . Vagus nerve stimulation . Epilepsy . Stereotypy

* Charles M. Zaroff [email protected] 1

Nebraska Comprehensive Epilepsy Program, Nebraska Medical Center, Omaha, NE 982045, USA

2

Department of Psychology, University of Macau, Avenida da Universidade, E21-3053, FSS, Taipa, Macao, SAR, China

Background Electrographic epileptiform abnormalities are common in autistic spectrum disorders [10, 20], and the disorder itself is associated with an increased risk of epilepsy [46]. Epileptiform abnormalities may correlate with behavioral sequelae of autistic spectrum disorders, such as mental retardation and behavioral regression [43]. Treatment for autistic spectrum disorder generally revolves around behavioral therapies, with a goal of reducing problem behaviors and general distress, while improving social and communication skills [44]. However, in individuals suffering from autistic spectrum disorder and comorbid epilepsy, epilepsy may represent an avenue of treatment, either via (a) an approach focusing on controlling epilepsy itself or (b) treatment of some of the electrophysiological abnormalities that, if not directly causative of autistic spectrum disorder, are nonetheless thought to interfere with cognition and behavior [4]. In fact, it has been suggested that with advances in seizure control, treatment regimens should be geared toward comorbidities [21], especially owing to their ability to exacerbate epilepsy-related quality of life compromise in individuals and their caregivers [40]. Historically, the treatment of epilepsy has focused on seizure control, and antiepileptic medication has commonly been utilized toward this goal. In individuals with epilepsy and comorbid autistic spectrum disorder treated with antiepileptic medication, improvements in communication skills, as well as a lessening of behavioral problems, have been reported [14]. Similar improvements, when present, have been found in children whose treatment consisted of epilepsy surgery [31] or other medication alternatives, such as vagus nerve stimulation [33]. Vagus nerve stimulation is a treatment option for those with medically refractory partial epilepsy [49]. Although the

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mechanisms of action remain poorly understood and treatment effects vary, there are clear benefits evident in seizure control using this approach [32]. Importantly, vagus nerve stimulation would appear in general to be well tolerated, even in difficult to treat populations, such as children with severe intellectual disability and autistic spectrum disorders [38]. Additionally, while results are far from consistent, vagus nerve stimulation has been shown to have positive effects on quality of life [28] and cognition [39], and in some reports, these results have been found to extend to patients with autistic spectrum disorders. Thus, in a study of six children with tuberous sclerosis complex and mental retardation, the one child with an autistic spectrum disorder experienced a greater than 90 % reduction in seizure frequency, and an 80 % reduction in injurious behaviors concurrent with vagal nerve stimulation [33]. In a retrospective study of 16 children and adolescents with mental retardation and refractory epilepsy [30], more than half of the sample experienced a greater than 50 % reduction in seizure frequency, and in the two patients with severe autistic traits, a Bmarked^ decrease of such traits was observed in both. Murphy, Wheless, and Schmoll [49] studied six individuals with hypothalamic hamartomas, medically refractory epilepsy, and (in 75 % of the cases) mental retardation. All four of the patients with an autistic spectrum disorder showed behavioral improvements, and two of the four demonstrated improved learning, changes which were observed both at home and at school. This was observed despite the fact that improved seizure control was only observed in three of these four patients. Other information from this report raises the possibility of a direct effect of vagus nerve stimulation on behavior, independent of seizure control. That is, in one individual, an immediate return of problem behavior was observed after the generator was turned off, while within hours of renewing vagus nerve stimulation, the negative behaviors ceased. In the patient who experienced no change in seizure frequency, significant behavioral improvements were observed nonetheless. Such improvements have also been observed in individuals without comorbid mental retardation. Warwick et al. [48] reported on a 23-year-old male with Asperger’s syndrome and medically refractory epilepsy. While the case in question had numerous developmental risk factors, including epilepsy onset at age 1, intermittent seizure control, and multifocality (and in fact was deemed by study authors to have epileptic encephalopathy), the patient nonetheless possessed average academic performance. However, lifelong and severe impairments in socialization were noted, as were persistent and worsening obsessive-compulsive tendencies, tendencies so fixed that attempts by family members to intervene resulted in violent behavior. After vagus nerve stimulation implantation, frequency and duration of seizures were decreased. When examining the case prior to implantation and 6 months later, the

Yale-Brown Obsessive Compulsive Scale [19] revealed improvements in the Abnormal Nonverbal, Social Interaction, and Emotion areas. The BPhysician Quality of Life Indicators^ captured improvements on physician reports of Mood and Achievement, from Bpoor^ to Bgood,^ and in the area of Memory, from Baverage^ to Bgood.^ The authors also reported that the patient had secured employment and was beginning to date, and at a 1-year follow-up, these positive results were maintained. Vagus nerve stimulation parameters found to be influential in outcome were increased output current, rather than signal frequency or pulse width parameters. Some reports using larger sample sizes have found similar encouraging results behaviorally. Thus, in a retrospective study utilizing a patient registry, Park [34] found that more than half of the 59 patients with an autistic spectrum disorder experienced at least a 50 % reduction in seizure frequency at 1-year follow-up. The majority were more alert after vagus nerve stimulation implantation, at both 3- and 12-month follow-ups. Based on physician observation, more than half of the sample was also reported to have shown improvement in achievement and mood. Levy and colleagues [27] compared a group of patients with refractory epilepsy with (n=77) and without autistic spectrum disorder (n=315). The groups were not equivalent, as more than 90 % of those with an autistic spectrum disorder had mental retardation (although this group was also significantly less likely to have abnormal neuroimaging findings). Nonetheless, seizure outcomes were similar across groups. While it is not clear how specific ratings were determined, no group differences in quality of life outcomes were observed, except that the group with an autistic spectrum disorder demonstrated significantly greater improvement in mood. Furthermore, the majority of patients showed improvement at 3- and 12-month follow-ups in alertness, and to a lesser extent, in BVerbal,^ BMemory,^ and BSchool/ Professional Achievements.^ The case report by Warwick and colleagues [48] made use of a standardized rating scale with adequate psychometric properties. Studies using such methods are often lacking. A notable exception is a report by Aldenkamp et al. [2]. In a study with perhaps the most stringent methodological controls, 16 children with Lennox-Gastaut syndrome with either developmental delay or mental retardation were studied before and after vagus nerve stimulation implantation. Autistic spectrum disorder was not diagnosed, but rather assessed quantitatively, as part of a procedure in which parent or nurse reports were used to measure quality of life variables, which also included independence, behavior, and mood. Cognitive variables were also assessed using observations of behavior, and standardized developmental/intellectual assessments were performed. Quality of life and cognitive variables were subsequently compared to published normative data. Improvements in cognition and quality of life were noted, but these were (a) nonsignificant and (b) not observed in the

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quality of life area pertaining to autistic spectrum disorder symptoms. Nonetheless, the sample exhibited an increase in mental age of nearly 3 months over a 6-month period—which might suggest a positive developmental outcome in a sample of children and adolescents who on average were approximately 11 years of age chronologically, but developmentally possessed a less than 3-year-old age equivalent. Interestingly, in the report by Aldenkamp and colleagues [2], similar to what was found by Murphy et al. [29], the behavioral benefits did not appear directly tied to seizure control. Seizures were reduced, on average, by a little over 25 % after 6 months, although seizure control was the strongest in those with the highest mental age. However, in the group experiencing no change, or a worsening of seizure frequency, a greater than 9-month improvement in mental age over 6 months was observed. Perhaps the least positive results in the use of vagus nerve stimulation for epilepsy in individuals with autistic spectrum disorder were found by Danielsson et al. [12]. Similar to the report by Aldenkamp et al. [2], standardized assessment measures were utilized prior to, and subsequent to, vagus nerve stimulation implantation, in eight children with intractable epilepsy. None of the children experienced a reduction in seizure frequency 2 years later. Standardized measures assessing autistic spectrum disorder diagnoses and symptoms, and an intellectual assessment measure, were utilized at baseline, and at a 2-year follow-up. Diagnoses were unchanged, and no cognitive improvement was observed. Of greater concern, only one participant exhibited a discrete improvement in mental age, suggesting a potential stagnation in cognition, and, potentially, a developmental regression. Quality of life outcomes were variable. Thus, in sum, apart from the report by Danielsson and colleagues [12], results of vagus nerve stimulation in individuals with epilepsy and autistic spectrum disorders on cognition and behavior have generally been encouraging, if modest in effect size, and inconsistent in outcome. We report herein on a case of a child with an autistic spectrum disorder and intractable epilepsy who underwent vagus nerve stimulation.

Methods The patient is a 10-year-old boy with a medical history remarkable for intractable seizures, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) treated with penicillin, and an autistic spectrum disorder. The patient was attending a school for children with developmental difficulties and behavior problems at the time of this report. Prior examinations included negative cytogenetics testing and a negative diagnostic routine for fragile X. Early delays in developmental milestones were noted, and significant and persistent problems in communication and

behavioral control (e.g., hyperactivity, defiance and aggression, deficient social interaction) were observed. At 7 years of age, a significant regression was observed, and the limited repertoire of speech was lost. An MRI of the brain at that time, both with and without contrast, was normal. Concurrently, the patient began exhibiting brief episodes of nonresponsiveness and staring, accompanied by anisocoria. Video EEG monitoring was normal. At 9 years of age, episodes of deep inhalation, pupil dilation, truncal flexion, and upper extremity rigidity, lasting for 30 s, and occurring up to ten times per day, were observed. Video EEG monitoring at that time revealed epileptiform activity arising from the frontal lobes bilaterally, and mild diffuse slowing, with frequent interictal epileptiform activity, manifesting as well defined spike and wave discharges in the left central, right temporal, and right parietal regions. High amplitude polyspike and slow wave discharges were seen arising from bilateral regions in the frontal lobe. During seizures, there were 3-s bursts of poorly formed anteriorly dominant semirhythmic spike and wave discharges. Subsequently, antiepileptic drug therapy was initiated, with lamotrigine. Seizure activity then decreased within a week to three to six per day. After a dosage increase, to maximal dosage, seizure activity decreased to once every 2 days. At that time, problematic behaviors (e.g., hyperactivity, self-injury, stereotypies) became even more pronounced. The patient also remained mute. According to school staff, learning and development appeared to plateau, and little or no improvements were observed in expressive speech, receptive communication (e.g., following directions), social interaction skills, or behavioral control. At 10 years of age, during maintenance on a maximal dosage of lamotrigine, an increase in seizure activity was observed, generally manifested in daily events lasting approximately 30 s. Zonegran was added and subsequently augmented seizure control, although significant side effects, including extreme fatigue, incontinence, and insomnia, were observed. The patient was subsequently weaned off of zonegran and underwent implantation of vagus nerve stimulation (model 105). Implantation was set at an output current of 0.25 mA, an output current frequency of 30 Hz, a pulse width of 500 ms, and an output current on-time of 30 s and off-time of 5 min. The magnet current was 0.50 mA. Magnet on-time was 60 s, and magnet pulse width was 500 ms. Prior to implantation, the patient was having one to two seizures daily, was nonverbal, and was continuing to display difficulties in communication, socialization, and behavior control (e.g., aggression toward others, angry outbursts, severe hyperactivity). The output current was increased in increments of 0.25 mA on a weekly basis, reaching 1.5 mA by 5week postimplantation and remaining at that level for more than 6 months. The magnet current increased in similar steps on a weekly basis, from 0.5 to 1.75 mA by 5 weeks, and

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remained at this level for more than 6 months. During this time, the pulse width remained at 500 ms, and the output current off-time remained at 5 min. During this time, seizures decreased in severity and duration, lasting 10 s or less. The patient simultaneously began making progress in learning, development, and behavior. He became less hyperactive, with decreases in ritualistic behavior, hyperactivity, and aggression, and also demonstrated increased social interactions. Family members also noted improvement in eye contact, increased interaction with siblings, and overall improvement in communication and mood. Six months following vagus nerve stimulation implantation, seizure frequency again increased, ranging from six to ten per day. Nonetheless, no regression was observed, and continued progress was evident, according to parents and school staff (e.g., teachers and counselors). Angry outbursts were no longer evident, and in general, conduct problems ceased. He was able to follow commands and participate in group activities. Nine months after implantation, the output current off-time was changed from 5 to 3 min, and then, 2.5 months subsequent to this, changed again to 1.8 m. Vagus nerve stimulation settings were changed again at approximately 11.5 months. At that time, output current was increased to 1.75 mA, output current frequency was changed to 20 Hz, pulse width was shortened to 250 ms, and magnet current time was increased to 2.0 mA. At approximately 13 months, settings were again changed such that output current was 2.0 mA and magnet current was increased to 2.25 mA. With these changes in settings, seizure activity decreased to three to four per day. Prior to and subsequent to vagus nerve stimulation implantation, counselors at the patient’s school completed a studyinitiated behavior checklist targeting the following areas: (1) aggression, (2) stereotypies, (3) expressive communication, (4) receptive communication, and (5) self-help skills. These areas were assessed at baseline, and at 3 months, 6 months, 9 months, and 12 months post-vagus nerve stimulation implantation. Counselors were instructed to assign values based on the frequency of behaviors. Aggression was classified as physical aggression toward others (e.g., poking others in the eye) and/or self-injurious behavior. Stereotypies were defined as instances of repetitive and purposeless behavior. Stereotypies were monitored using 150-s differential reinforcement of other behavior with a 10-s facial screen, and multiple stimulus without replacement assessment, as well as a 105-s differential reinforcement of other behavior with a 20-s facial screen and multiple stimulus without replacement preference assessment. During this assessment, the patient is seated at a table and given five preferred objects and allowed to choose one and subsequently engage with the item for 20 s. This object is then removed from the five objects, and the remaining objects are presented until each object has been chosen. During this time, the patient is

monitored for stereotypies. If the stereotypy occurs, the therapist conducts a facial screen—this consists of the therapist standing behind the patient with one arm around the patient’s body, holding his arms down to his sides while the other arm is placed so that the patient’s sight is shielded. The patient is given positive reinforcement when exhibiting the desired behavior or when able to be redirected. Expressive communication was defined as either vocalization (e.g., Bhi^), sign language usage, or expressive communication using available electronic devices. Both spontaneous and prompted communications were recorded. Receptive communication skills were defined on the basis of the ability to follow commands. Self-help skills were defined as a variety of activities, e.g., toileting behaviors, tooth brushing, hand-washing, dressing, and wiping spills.

Results After vagus nerve stimulation implantation, aggressive behaviors declined steadily over the course of study (Fig. 1). Stereotypy frequency similarly exhibited a steady decline (Fig. 2). The greatest decrease occurred in the initial 3 months following implantation. Expressive communication skills appeared more variable (Fig. 3). In the 3 months following the procedure, there was a great increase in the ability to follow instruction (Fig. 4). Self-help skills were somewhat variable (Fig. 5).

Discussion We report a case of a 10-year-old boy with an autistic spectrum disorder and developmental delay and superimposed behavioral regression at age seven, concurrent with an onset of episodic staring and anisocoria, with a normal video EEG. At 9 years of age, episodic deep inhalation, pupil dilation, truncal flexion, and upper extremity rigidity were observed, accompanied by electrographic abnormality: bilateral frontal onset, interictal slowing, and multifocal and bilateral focal activity. Following implantation of vagus nerve stimulation, quantitative ratings of autistic spectrum disorder symptoms and cognitive and self-help skills were assessed via school counselor report over 1 year, at 3-month intervals. During this time, improved seizure control was initially observed but not maintained. Nonetheless, considerable improvement in control of aggressive behavior and receptive communication skills were noted and maintained over 1 year. Improvements were also observed in the form of reduced stereotyped behavior, while little if any consistent improvements were observed expressive communication or self-help skills. This case is not overly atypical in that approximately one third of children with autistic spectrum disorder develop

Childs Nerv Syst 3.5 Frequency of aggressive behaviors

Fig. 1 Average frequency of aggressive behaviors. Behaviors were monitored for 4-h periods daily; values were averaged for each of the months of interest (e.g., a value of 3 represents a daily average of 3 aggressive behaviors during a 4-h period during each school day for the respective month listed)

3 2.5 2 1.5 1 0.5 0

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epilepsy [13], and one third of children with an autistic spectrum disorder have a regression in communication skills [46]. As autistic spectrum disorder is among the most common of developmental disabilities [5] and comes with a heavy societal, financial, and familial burden [6], this is clearly an area ripe for further research regarding etiological variables and potential intervention approaches. This report adds to a growing body of evidence suggesting that vagus nerve stimulation can be utilized, and tolerated, in the treatment of epilepsy with comorbid autistic spectrum disorder. However, the results were notable for an apparent discrepancy between the effects of vagus nerve stimulation on seizure control, and on behavior. In the context of the treatment of epilepsy, vagus nerve stimulation has been found to improve quality of life [28], and some beneficial effects on cognition and behavior have been reported [35, 39]. There is some evidence that vagus nerve stimulation can ameliorate some of the problem behaviors in autistic spectrum disorder and/or provide concurrent improvement in developmental areas like language and selfhelp skills. In general, in individuals with an autistic spectrum disorder, vagus nerve stimulation has been found to benefit behavior, whether in individual cases [30, 33, 48], or in larger series [2, 27, 29, 34], and cognitive improvements have also

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been observed [2, 29, 34]. Only one report has been overwhelmingly consistent in showing little or no benefit on behavior and development in this patient population [12]. Thus, the current report would appear to add to a growing body of literature suggesting that the effects of vagus nerve stimulation on behavior in autistic spectrum disorders, when evident, are generally positive, if modest in breadth and depth, and that similarly sized effects on cognition may be observed. The mechanisms by which vagus nerve stimulation could improve behavioral control, and possibly cognition, is unclear. Interictal spikes can disrupt cognitive functioning in a pattern suggestive of neuroanatomical specificity [41], and in individuals with autistic spectrum disorder, epileptiform abnormalities are common, even in the absence of seizure activity [47]. Such abnormalities presumably contribute to at least some of the cognitive difficulties commonly observed in autistic spectrum disorder (e.g., attention and language; [4]). Thus, interventions to reduce seizures and/or epileptiform activity could potentially be expected to improve cognition. In a study of seven children with Bautism or autistic epileptiform regression^ from a larger subset of patients with LandauKlefner syndrome and associated medically refractory epilepsy [31], multiple subpial transections resulted in improvement in all seven patients (defined on the basis of either

5 4.5 4 Stereotypies

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Fig. 2 Average frequency of stereotypies using (1) 150 differential reinforcement of other behaviors, with a 10-s facial screen and multiple stimulus without replacement assessment and (2) 105 differential reinforcement of other behavior with a 20-s facial screen and multiple

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stimulus without replacement reinforcement. Daily monitoring of behaviors occurred and averaged for the months of interest (e.g., a value of 3 represents an average of 3 stereotyped behaviors requiring redirection daily for the respective month listed)

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Fig. 3 One month averaged daily frequency of spontaneous and prompted expressive communication (e.g., a value of 3 represents an average of 3 daily instances of spontaneous or prompted expressive communication)

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electrographic evidence or improved seizure control). These seven individuals also demonstrated Bmoderate^ improvements in language, social skills, and behavior, although these positive outcomes were temporary in nature. In studies of individuals with epilepsy and comorbid autistic spectrum disorder treated with vagus nerve stimulation, results are in general similarly positive, if modest in effect size, and often occur concurrent with improved seizure control [30, 33, 38]. The lack of understanding concerning how vagus nerve stimulation might act to influence cognition and behavior in individuals with autistic spectrum disorder may be due in large part to the lack of knowledge regarding the role of epilepsy and epileptiform activity in the behavior and development of individuals with autistic spectrum disorders [14]. While epileptiform activity may theoretically interfere with cognition and behavior, it has also been theorized that epilepsy and the behavioral phenomena of autistic spectrum disorder are completely separate entities caused by underlying dysfunction in common areas of the brain [4]. Recent and more nuanced views expand on this perspective and consider the possibility that epilepsy itself is a symptom of multiple pathological conditions, and thus itself a comorbidity [21]. Thus, the relationship between epilepsy and other comorbidities like autistic spectrum disorder are potentially bidirectional. The

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prevalence of cognitive and psychiatric sequelae at the time of epilepsy diagnosis lends weight to this view [22, 24, 50]. Interestingly, in the current report, and others [2], behavioral improvements do not necessarily correlate with seizure control. This would appear to suggest potentially independent and individual effects of vagus nerve stimulation on seizure control, on the one hand, and behavior, on the other. These findings would also appear to emphasize the possibility of an underlying pathological process influencing epilepsy and autistic spectrum disorder. In one patient in a study by Murphy and colleagues [29], rage behavior could be aborted by magnet activation. In another patient, turning off the generator as part of a preparatory process for stereotactic surgery was accompanied by a return of injurious and antisocial behaviors, which then resolved within hours of renewing vagus nerve stimulation. While these specific results noted by Murphy and colleagues are perhaps atypical, and information was not provided about the immediate influence on electrographic activity, the rapidity with which behavior changed suggests that behavioral improvement was not wholly tied to electrographic activity. Similarly, the greater extent of such improvements within those having the highest mental functioning in another report [2] would seem to suggest that a simple cessation of static encephalopathy is not responsible for all such changes.

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Fig. 4 Average frequency of receptive communication behaviors. Receptive communication behaviors consisted of the ability to follow directions or redirections during 4-h periods daily; values were

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averaged for each of the months of interest (e.g., a value of 3 represents an average of 3 aggressive behaviors during a 4-h period during each school day for the respective month listed)

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Self help ability

Fig. 5 Average frequency of selfhelp behaviors. The frequency of spontaneous and prompted selfhelp behaviors were averaged for each of the months of interest (e.g., a value of 3 represents an average of 3 daily self-help behaviors during each school day for the respective month listed)

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In fact, it has been suggested that in the absence of seizures, treatment of electrographic abnormalities in autistic spectrum disorder cannot be recommended owing to the lack of definitive evidence for behavioral efficacy [45]. Other variables that could conceivably influence behavior and cognition include those pertaining to antiepileptic medication regimen. However, a simple reduction in side effect profiles with lowered medication regimen post-vagus nerve stimulation implantation is unlikely to be particularly contributory because several studies note little if any changes in antiepileptic medication after vagus nerve stimulation initiation [2, 29, 48]. Additionally, antiepileptic medications can potentially improve behavior [26], or communication and socialization skills, in individuals with autistic spectrum disorder [14]. The discrepancy that may exist between the aforementioned cognitive and behavioral improvements, on the one hand, and seizure control outcomes on the other, points to a potential etiological factor discussed far more often in the literature concerning autistic spectrum disorders than in that pertaining to epilepsy: the vagus nerve itself. The vagus nerve, containing both afferent and efferent fibers innervating most bodily organs [16], influences multiple brain structures, including orbitofrontal cortex, hippocampus, and amygdala [18]. These are regions implicated in social and emotional processing, and potentially, autistic spectrum disorders in particular [1, 3, 8]. While not indicative of a direct causative process, there is much recent data associating vagus nerve variables with autistic spectrum disorders via (1) the role of autonomic functioning in early social development and (2) findings of autonomic dysregulation in children, adolescents, and adults with autistic spectrum disorders. Thus, correlates of vagal activity, such as heart rate variability, have been positively associated with facial expressions of social interest in infants [17]. Longitudinal studies indicate potential predictive value of vagus nerve variables. In a study of at-risk infants, defined on the basis of perinatal variables such as very low birthweight, vagal activity between 33 and 35 weeks of gestational age predicted better social skills 3 years later [15]. When suppression of respiratory sinus

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arrhythmia is utilized as a proxy of vagus nerve activity, abnormalities at age 2 years also correlate with poorer social skills at age 4.5 years [7]. The model of a Bvagal brake^ has been posited, in which difficulty reducing vagal activity during social tasks may be associated with difficulties in reciprocally engaging and disengaging during socialization [36]. In individuals with autistic spectrum disorders, there is clear evidence of autonomic anomaly, although more work is needed to clarify the nature of this relationship. In one report with a sample of children with fragile X syndrome, anomalous physiological arousal (including lower vagal tone) prior to age one appeared to predict the severity of autistic spectrum disorder symptoms at approximately 1 to 3 years of age [37]. Anomalous vagal tone in children and adolescents with autistic spectrum disorders has also been found on the basis of elevated respiratory sinus arrhythmia in response to social cognition tasks [25]. There is even some evidence pointing to the potential use of such vagal tone indices to define autistic spectrum disorder subtypes [11]. As succinctly stated by Cheshire [9], children with autistic spectrum disorders exhibit anomalous autonomic responsiveness on cognitive tasks, including those in areas in which they are deficient, in a manner appearing to suggest a hyper-sympathetic state due to inadequate regulation via vagal parasympathetic factors. Thus, these results suggest that the potential benefits of vagus nerve stimulation on behavior and development in individuals with epilepsy and comorbid autistic spectrum nisorder need not be limited to the effect on epilepsy itself. This finding is consistent with an interpretation of epilepsy as a symptom of an underlying foundational brain pathology. Therefore, the treatment of epilepsy with vagus nerve stimulation may improve autistic spectrum disorder symptoms in a bidirectional fashion, although this need not be the sole mechanism of action. An effect on underlying brain functioning may influence both conditions. Perhaps the very modest effects in behavior and cognition following vagus nerve stimulation in individuals with autistic spectrum disorder reflect the fact that vagus nerve stimulation is often applied mid-development, whereas studies of vagal variables show an influence quite early in development.

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While the current report is suggestive of potential benefits of vagus nerve stimulation on behavior and development in autistic spectrum disorder, several limitations are evident. Children and adolescents with autistic spectrum disorder may be described as Bconsistently inconsistent,^ reflecting problems in persistence and difficult to predict developmental and behavioral peaks, plateaus, and regression [23, 42]. Thus, in a case report such as this, incidental improvement outside of vagus nerve stimulation is possible. Additionally, and most notable, ratings of behavioral symptoms and developmental abilities were obtained using a rating scale constructed specifically for this study, lacking validation for this purpose, and completed by school staff un-blinded to the purposes of the measures. Furthermore, this is a case study, and thus, a control group was not utilized. Nonetheless, this practice has been utilized in several studies in this area of research, in which statistical controls are uncommon, and the results in studies with and without comparison data (either in within or between subjects paradigms) do show trends toward positive outcomes. Additionally, the lack of a uniform improvement in all domains suggests that the ratings were to some extent objective. It is recommended that future research employ larger series with assessment methods sensitive to change effects. Also needed are more reports detailing the specifics of vagus nerve stimulation parameters, as this is one variable almost completely ignored in reports in which individual changes are noted. Regardless, the current results do add to a growing body of literature suggesting that vagus nerve stimulation may be beneficial, if modestly so, in improving behavior and cognition, in individuals with autistic spectrum disorder, and that this effect may not necessarily rest upon resultant improvements in seizure control. Acknowledgments The authors declare no funding for this project. The authors report no conflict of interest. Compliance with ethical standards All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study has been approved by the appropriate institutional research ethics committee. The study was part of a clinically instituted treatment protocol.

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Autistic spectrum disorder, epilepsy, and vagus nerve stimulation.

In individuals with a comorbid autistic spectrum disorder and medically refractory epilepsy, vagus nerve stimulation may offer the potential of seizur...
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