Autism spectrum disorder (ASD) is a group of neurodevelopmental dysfunctions characterized by impaired social communication and restricted, repetitive patterns of behavior, interest, or activities (1, 2). Standardized screening for ASD is recommended at 18 and 24 months of age in primary care, but diagnosis later than 6 years of age is reported in one-third to half of children (3). Epilepsy is another common neurologic disorder in children (4). The rate of seizures among people with ASD in clinically ascertained samples has been reported to as high as 46% (5). Vagus nerve stimulation (VNS) is a widely used therapy for patients over 4 years old with drug resistant epilepsy (DRE) (6–8). Children candidate for VNS are at higher risk of behavioral comorbidities or other chronic illnesses, including ASD, compared with those in the general population (9–12).

Vagus nerve is a key component of regulating autonomic nervous system, social emotional function and adaptive behaviors (13). Numerous studies have reported that VNS remarkably improves the quality of life in children with DRE by improving alertness, communication, independence, memory, mood, and sleep (14–19). However, the effects of VNS on autistic behavior in children with DRE is inconsistent. Some case reports supported positive improvements with VNS on autistic behavior in children with DRE and comorbid ASD (20, 21), while other studies have reported the opposite effects (22, 23). Although several studies have observed that the effect of VNS on autistic behavior are independent of seizure control (21–23), within 2 years of VNS implantation, the proportion of pediatric DRE responders (≥50% reduction in seizure frequency) gradually increases from 20 to 60% (24–27). Subsequently, the efficacy of VNS tends to stabilize (27–29). Whether the benefits of autistic behavior improvements are due to VNS or seizure control is still unclear.

Here, we assessed the effects of VNS on autistic behaviors between two follow-ups in ten children with DRE, who achieved stable seizure control. This was the first study to observe the effects of VNS on autistic behavior in children with severe epilepsy at stable seizure control.

Previous studies indicated that the responder rate of VNS for DRE was similar between adults and children (28, 32). Fang et al. recently reported that the response rates of 213 children with DRE were 57.1, 69.2, and 70.7% at 12, 18, and 24 months, respectively (25). Muthiah et al. also reported that the overall response to VNS therapy of 59 patients aged 4–6 years in a single center at 1, 2 and 4 years after VNS implantation was 55, 60, and 52%, respectively (27). These studies showed that the efficacy of VNS gradually increased and was basically stable after 2 years. In our study, the median age of our children at VNS surgery was 4.6 years, and the age ranged from 3.6 to−5.4, which was relatively concentrated at the younger age of children. Seven children (70%) became responders at follow-up 1 (mean 2.16 years) and six (60%) were responders at follow-up 2 (mean 2.98 years). Among the responders, six were stable from follow-up 1 to 2, and two children were stable seizure-free. Our results of chronic VNS for 10 DRE children were consistent with previous studies on seizure control.

In our study, a decrease in ABC score was observed after children achieving stable seizure control, and two of four children changed their diagnosis from “autism” to “suspected autism” under stable seizure control, suggesting the possible positive effects of VNS for autistic behaviors. Moreover, significant reduction of autistic behaviors was observed in language, social and self-help, which were consistent with the enhancement of VNS stimulation in neurocognitive function, including executive functions and language (17, 33, 34). Besides, resent studies reported that the transcutaneous auricular VNS (taVNS) has been demonstrated the positive effects on the regulation of mood and visceral state associated with ASD (13, 35, 36). The taVNS was one of the branches of the vagus nerve (23, 37). As stimulating the vagus nerve directly, VNS shared the similar mechanisms with taVNS at activating the brain regions, triggering neuroimmune modulation and producing treatment effects (23, 36, 38–40). However, the effects of VNS for ASD or comorbid disorders of ASD have been not completely proved, which might be its invasive feature of less application.

It was worth mentioning that the improvements of autistic behaviors over time might be associated with the earlier interventions (including educational practices, or developmental therapies, or behavioral interventions) or getting older (41, 42). Actually, our 10 children haven't gone to school and didn't receive training interventions during the two time points. Besides, these DRE children were with seriously developmental delay. Although the effects of interventions and age cannot be ruled out completely, the improvements in autistic behaviors in these ten children might be partly due to VNS therapy.

Moreover, in addition to VNS, the 10 children also received antiseizure medications (ASMs). In seizure treatments, several evidence pointed to valproate, lamotrigine, and levetiracetam as the most effective and tolerable ASMs for epilepsy in individuals with ASD (43). However, no medications are currently proved to treat core autistic symptoms, including the abnormal language development, impairments in reciprocal social interactions, behavioral inflexibility and repetitive and ritualized behaviors. At present, a major consideration in the ASM therapy of children with ASD is its side effects. The first generation ASMs, such as barbiturates, benzodiazepines, carbamazepine, ethosuximide, phenytoin and valproate, have adverse side effects that in some children could result in or exacerbate epilepsy comorbidities (44). Although some of the second and third generation ASMs have fewer adverse effects, it can't completely be ruled out that in any individual child the ASM could contribute to the comorbidity. In our 10 children, the valproate is a commonly used medicine. Under the circumstances, chronic VNS highly likely contributed to the improvements of language and social and self-care in these children.

In addition, the CBCL assessment showed no significant reduction in autistic behaviors in our study. The CBCL was an emotional/behavioral problems scale that completed by parents (45). It had weaknesses, including biases in assessment and voluntary reporting by relatives of the patients (46). More objective measures or professional reporting will be needed to assess the benefits of VNS for autistic behaviors.

There were still several limitations in our study. First, there was a lack of preoperative baseline assessments of autistic behaviors in these children with DRE, which could better elucidate the role of VNS or seizure control on autistic behaviors. Second, it was not enough for these 10 children to assess their autistic behaviors using ABC alone. Thirdly, the sample size was small. In the future, we will design more rigorous clinical trials to confirm the effects of VNS, medications, and age on autistic behaviors.

In all, our study firstly reported that the VNS had positive effects on autistic behaviors in younger DRE patients at stable seizure control, which suggested that younger children with DRE comorbidity ASD may benefit from VNS therapy. Recently, pairing bursts of VNS with specific movements or sensory events has been shown to improve the rehabilitation of stroke, tinnitus, traumatic brain injury, spinal cord injury, and posttraumatic stress disorder (47). Moreover, behavioral therapies have led to significant gains in intelligence, communication, and social skills in a proportion of children with autism (48–50). In the future, new forms of VNS stimulation or VNS combined with behavioral therapy might be potential better approaches for improving the functional outcomes of individuals with DRE comorbidity ASD, even ASD itself.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the Medical Ethical Committee of Affiliated Hospital of Zunyi Medical University, the Medical Ethical Committee of Peking University First Hospital, and the Medical Ethical Committee of Shenzhen Children's Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.

LL and YW contributed to conception and design of the study. XY, QZ, TJ, and JW collected the data. YJ, YW, XS, JL, and HH organized the database. ZW performed the statistical analysis and wrote the first draft of the manuscript. TC and XQ wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (Grant Number 82101549) and Shenzhen International Cooperative Research Project (GJHZ20180930110402104).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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