The role of stereotactic neurosurgery as a symptomatic treatment for autism spectrum disorders: a systematic review

doi:10.21203/rs.3.rs-2186734/v1

Download PDF

Research Article

The role of stereotactic neurosurgery as a symptomatic treatment for autism spectrum disorders: a systematic review

https://doi.org/10.21203/rs.3.rs-2186734/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 30 Apr, 2023

Read the published version in Asian Journal of Psychiatry →

Version 1

posted

You are reading this latest preprint version

Although stereotactic neurosurgery has been applied in autism spectrum disorders (ASD), its safety and efficacy remain elusive due to the limited sample size. We aimed to investigate the safety and efficacy of stereotactic neurosurgery for ASD by systematically reviewing the literature through the PubMed, EMBASE and Cochrane databases. A total of 11 studies with 36 patients were included. 16 patients (44.44%) received deep brain stimulation (DBS), 10 patients (27.78%) underwent radiofrequency ablation (RA), and 10 patients (27.78%) underwent gamma knife radiosurgery and RA. The therapeutic targets of 11 patients (42.31%) were the amygdala, and the surgical indication of 10 patients was aggression; the ventral anterior limb of the internal capsule or medial forebrain bundle was regarded as the target for 6 patients (23.08%), and the surgical indication was OCD. The mean Yale-Brown-Obsessive-Compulsive Scale (Y-BOCS) score of 19 patients was 31.37 at baseline. After a median follow-up time of 48 months, the mean Y-BOCS score decreased to 18.32, and the mean improvement rate was 42.74%. After a median follow-up duration of 48 months (range: 2-120), the mean Overt Aggression Scale score of 15 patients was reduced from 11.20 to 4.40, and the mean improvement rate was 59.59%. There were a total of 8 patients whose cardinal symptoms benefited from the surgery. Seven patients (19.44%) suffered adverse events after stereotactic neurosurgery. Stereotactic neurosurgery is an effective and safe therapy to alleviate the symptoms of aggressive behaviors and OCD in ASD patients. DBS has the potential to improve the social contact difficulty and communication disorders of ASD.

autism spectrum disorders

stereotactic neurosurgery

deep brain stimulation

safety

efficacy

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders whose cardinal symptoms include social communication deficits, verbal or nonverbal communication barriers and repetitive or unusual sensory–motor behaviors^[19]. With the advancement of diagnostic techniques and the gradual attention of families and society, the prevalence of ASD reached approximately 1.00-1.85%^{[20, 36]}, and males were more susceptible to ASD. As a comorbid aggressive behavior, obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD) and so on, ASD has a serious impact on the quality of life of patients and imposes a huge burden on society. A fair number of interventions have been applied in children and adult patients with ASD, including early parent-mediated interventions, naturalistic behavioral developmental interventions, behavioral and social treatments and so on^[19]. However, due to differences in economic level, treatment technology and parental cognition, intervention modalities vary from region to region, and the results of the therapy are limited. No breakthroughs have been made in the treatment of ASD, and exploring new therapies for ASD has become a top priority. Stereotactic neurosurgery has a history of more than half a century, in which deep brain stimulation (DBS) and radiofrequency ablation (RA) are commonly used. It has satisfactory efficacy in movement disorders, intractable psychiatric disorders, chronic pain, epilepsy and so on. Recently, growing interest exists for stereotactic neurosurgery in ASD, and several scholars have implemented stereotactic neurosurgery. However, there is not sufficient evidence to determine how effective and safe stereotactic neurosurgery is for ASD due to the limited sample size in the literature review. Thus, to elucidate the safety and efficacy of stereotactic neurosurgery for ASD, we conducted a systematic review of the related literature.

We performed this systematic review in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the process of literature research was depicted in Fig. 1.

Literature selection

We searched the PubMed, EMBASE and Cochrane databases using the following key words: autism spectrum disorder OR autism spectrum disorders OR autistic spectrum disorder OR disorder, autistic spectrum AND deep brain stimulation OR electrical stimulation of the brain OR radiofrequency ablation OR ablation, radiofrequency OR radio frequency ablation OR radio-frequency ablation OR ablation, radio-frequency, covering the period from the inception of the database to June 10, 2022. References in the related literature was screened to identify additional eligible articles. Study screening was conducted independently by three researchers (WY, SYF and LJM). Disagreements were resolved after discussion, and other reviewers were involved (GY and XYY). The inclusion criteria were as follows: (1) the subjects of the study were diagnosed with ASD; (2) studies reported the safety or efficacy of stereotactic neurosurgery for ASD in the form of case reports or cohort studies; and (3) articles published in the English language. The exclusion criteria were as follows: (1) diseases other than ASD, (2) studies involving nonhuman subjects, and (3) studies with no original data. For the same case series reported in more than one study, the study with the most complete or recent data set was included.

Data extraction

We collected data on the study, including research characteristics (authors, publication year, country, study design and sample size), patient characteristics (age at surgery, sex, disease duration, follow-up duration, symptoms, diagnosis, medication history and so on), parameters of the treatment (type of surgery, indication for surgery, therapy target, stimulus parameter and so on), efficacy (change in symptoms, the results of the neuropsychological scale during follow-up and so on), and adverse events during and after the operation.

Quality assessment and data analysis

The methodological quality of each included study was determined according to methodological index for non-randomized studies (MINORS). A descriptive synthesis of the extracted data was performed. Statistical analyses were performed for several characteristics, such as the age at surgery, follow-up duration, and the results of several scales, using SPSS version 23 (IBM Corp, Armonk, New York). Several studies have applied the Yale-Brown-Obsessive-Compulsive scale (Y-BOCS) to analyze the efficacy. A decrease of 35% or more was defined as a full response, whereas a decrease below 25% was defined as a nonresponse, and a decrease between them was classified as a partial response^[14].

Search result

A total of 589 studies were generated using the database and reference search. After screening the titles and abstracts, 11 studies were excluded due to duplication, 428 studies were excluded due to irrelevant content, and 91 studies were excluded for clinical trials. Of the 48 studies excluded after screening the full text, 15 studies were viewpoints rather than original data, 7 studies were animal trials, 6 studies were related to diseases other than ASD, 17 studies were not relevant to DBS, 1 study was a clinical study protocol, and 2 studies were the same case series. Finally, a total of 11 studies with 36 patients were included in this systematic review (Fig. 1).

Study quality

We assessed the quality of the studies using MINORS guidelines^[31], which are displayed in Table 1. All studies had clear research objectives, and 10 studies assessed the outcome using standardized scales unbiasedly^{[3, 7, 8, 10, 12, 21, 24, 30, 32, 33]}. Seven studies were case reports^{[7, 8, 16, 24, 30, 32, 33]}, and one was a case series^[12]. Three studies were original research^{[3, 10, 21]}.

Table 1

Quality assessment according to MINORS.
Author(year)	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Total
Strurm (2013)	2	0	0	1	2	2	2	0	9
Stocco (2014)	2	0	0	1	2	2	2	0	9
Benedetti-Isaac (2015)	2	2	0	2	2	2	2	0	12
Segar (2015)	2	0	0	1	2	2	2	0	9
Park (2017)	2	0	0	1	2	2	2	0	9
Kakko (2018)	2	0	0	0	0	0	2	0	4
Doshi (2019)	2	0	0	1	2	0	2	0	7
Gouveia (2020)	2	2	0	2	2	2	2	0	12
Davis (2021)	2	0	0	1	2	2	2	0	9
Graat (2022)	2	2	0	2	2	2	2	0	12
Roberto (2022)	2	2	0	2	2	2	2	0	12
“The items are scored 0 (not reported), 1 (reported but inadequate), or 2 (reported and adequate)”. “The global ideal score is 16. Q1 to Q8 are from methodological items for nonrandomized studies of MINORS”. Q1: a clearly stated aim; Q2 inclusion of consecutive patients; Q3 prospective collection of data; Q4 endpoints appropriate to the aim of the study; Q5 unbiased assessment of the study endpoint; Q6 follow-up period appropriate to the aim of the study; Q7 loss to follow-up less than 5%; Q8 prospective calculation of the study size.

Study characteristics

The included studies were published from 2013 to 2022 with patients from North America^{[7, 10, 30, 32]}, Europe^{[12, 16, 21, 33]}, Asia^{[8, 24]} and South America^[3]. Strurm et al. reported the first study about DBS for ASD in 2013^[33]. Gouveia et al. and Roberto et al. reported the largest series about RA for ASD containing 10 patients^{[10, 21]}. We pooled these cases into one cohort because most of the included studies were case reports. Twenty-nine of the 36 patients (80.56%) were male. The median age of surgery was 23 years old, and the range was from 11 to 54. All patients were diagnosed with ASD and had coexisting diseases: 21 patients suffered from OCD, 5 patients suffered from seizures, 4 patients suffered from depression, and 2 patients suffered from Tourette syndrome. Of 21 patients, 19 patients were low function, and only 2 patients were high function.

The type of therapy

Of the 36 patients, 16 patients (44.44%) received DBS, 10 patients (27.78%) underwent RA, and 10 patients (27.78%) underwent gamma knife radiosurgery (GKRS) and RA. The surgical indication of 3 studies with 12 patients (33.33%) was OCD and aggression^{[8, 10, 21]}. Five studies^{[3, 10, 16, 24, 33]} with 14 patients (38.89%) reported that the indication for surgery was aggression, and 2 studies^{[7, 12]} with 7 patients (19.45%) considered OCD to be an indication. The indication for surgery for a patient in Segar et al.’s study was OCD and Tourette syndrome (TS)^[30]. Stocco et al. reported that the indication was aggression and tardive dystonia for a female and stereotypies for a male^[32]. Ten studies with 26 patients reported the type of surgery in detail for each patient (Fig. 2)^{[3, 7, 8, 10, 12, 16, 24, 30, 32, 33]}. Among the 26 patients, the therapeutic targets of 2 studies with 11 patients (42.31%) was amygdala, and the surgical indication of 10 patients was aggression while one was OCD and aggression^{[10, 33]}; Graat et al selected ventral anterior limb of the internal capsule (vALIC) or medial forebrain bundle (MFB) as the target for 6 patients (23.08%) and the surgical indication was OCD^[12]; 2 studies with 2 patients (7.70%) reported the target was the nucleus accumbens (NAc) and the indication of operation was OCD and aggression for one and self-mutilation for another^{[8, 24]}; the target of 2 studies with 2 patients (7.70%) was ventral capsule/ventral striatum (VC/VS) and the surgical indication was OCD for one and OCD and TS for another^{[7, 30]}; 2 studies with 2 patients (7.70%) reported the target was internal globus pallidus nucleus (GPi) and the surgical indication was aggression and tardive dystonia for one and aggression for another^{[16, 32]}; Benedetti-Isaac et al selected posteromedial hypothalamus (pHyp) as the therapeutic targets for 2 patients^[3] (7.70%) and the surgical indication was aggression; Stocco et al selected ALIC and globus pallidus internus (GPi) for a male and the indication of operation was stereotypies^[32]. Of the 10 patients with ASD who underwent GKRS and RA reported by Roberto et al., 8 patients received two surgeries, and 2 patients underwent three surgeries^[21]. All patients underwent GKRS at the first surgery, while 6 patients received RA, and 4 patients underwent GKRS at the second surgery^[21].

Treatment efficacy

OCD and aggressive behavior

To quantify the improvement in symptoms of ASD following stereotactic neurosurgery, various clinical symptom scales were applied in the included studies (Table 2). Five studies with 19 patients reported the results of Y-BOCS score before and after surgery in detail^{[7, 8, 12, 21, 24]}. The mean Y-BOCS score of 19 patients was 31.37 ± 5.04 (range: 19–39) at baseline. After a median follow-up time of 48 months (range: 8-120), the mean Y-BOCS score decreased to 18.32 ± 8.15 (range: 0–32), and the mean improvement rate was 42.74% (Fig. 3A). A total of 63.16% of patients were full responders, 21.05% of patients were partial responders, and 15.79% of patients were non-responders. Three studies with 15 patients reported the outcomes of the overt aggression scale (OAS) before and after surgery in detail^{[3, 10, 21]}. After a median follow-up duration of 48 months (range: 2-120), the mean OAS score of 15 patients was reduced from 11.20 ± 1.70 (range: 8–14) to 4.40 ± 2.20 (range: 0–8), and the mean improvement rate was 59.59% (Fig. 3B).

Table 2

The patient characteristics and treatment outcomes for 36 ASD patients.
Author (year)	Pa	Gender	Age of surgery	Diagnosis	HF or LF	F-U duration	Indication of surgery	Type of therapy	Target	Parameters	Baseline	Last	Adverse event
Davis (2021)	1	M	46	ASD, OCD, TS, depression, seizure	HF	40 mo	OCD	DBS	VC/VS	Fre:130 Hz Wid:100us Amp:5-6.5 V	YGTSS:81 Y-BOCS:39 MARDS:32	YGTSS:29 Y-BOCS:22 MARDS:5	None
Doshi (2019)	2	Fe	42	ASD, OCD, seizure	LF	NA	OCD, aggression	DBS	NAc	NA	Y-BOCS:19 HAMA:30 HAMD:20 SCQC:26	Y-BOCS:5 HAMA:18 HAMD:15 SCQC:16	None
Gouveia (2021)	3	M	19	ASD, ID	LF	12 mo	aggression	RA	amygdala	NA	CARS:55 OAS:13	OAS:2	None
	4	M	27	ASD, ID	LF	12 mo	aggression	RA	amygdala	NA	CARS:53 OAS:10	OAS:2	None
	5	M	29	ASD, OCD, ID	LF	12 mo	aggression OCD	RA	amygdala	NA	CARS:48 OAS:12	OAS:0	None
	6	M	20	ASD, ID	LF	12 mo	aggression	RA	amygdala	NA	CARS:54 OAS:10	NA	None
	7	M	21	ASD, ID	LF	12 mo	aggression	RA	amygdala	NA	CARS:47 OAS:9	NA	None
	8	M	19	ASD, ID	LF	12 mo	aggression	RA	amygdala	NA	CARS:51 OAS:11	NA	None
	9	M	11	ASD, ID	LF	12 mo	aggression	RA	amygdala	NA	CARS:48 OAS:7	NA	None
	10	M	24	ASD, ID	LF	12 mo	aggression	RA	amygdala	NA	CARS:54 OAS:12	NA	None
	11	M	13	ASD, ID	LF	12 mo	aggression	RA	amygdala	NA	CARS:53 OAS:9	NA	None
	12	M	20	ASD, ID	LF	12 mo	aggression	RA	amygdala	NA	CARS:54 OAS:7	NA	None
Author (year)	Pa	Gender	Age of surgery	Diagnosis	HF or LF	F-U duration	Indication of surgery	Type of therapy	Target	Parameters	Baseline	Last	Adverse event
Graat (2021)	13	Fe	39	ASD, OCD depression	NA	62 mo	OCD	DBS	vALIC /MFB	NA	Y-BOCS:33 HAMD:27	Y-BOCS:12 HAMD:7	None
	14	Fe	54	ASD, OCD	NA	51 mo	OCD	DBS	MFB	NA	Y-BOCS:38 HAMD:30	Y-BOCS:18 HAMD:4	Infection; suicide attempt
	15	M	32	ASD, OCD, ADHD	NA	11 mo	OCD	DBS	vALIC /MFB	NA	Y-BOCS:31 HAMD:18	Y-BOCS:23 HAMD:12	pain
	16	Fe	31	ASD, OCD, depression, AN	NA	10 mo	OCD	DBS	vALIC /MFB	NA	Y-BOCS:34 HAMD:30	Y-BOCS:32 HAMD:27	None
	17	M	51	ASD, OCD	HF	11 mo	OCD	DBS	vALIC /MFB	NA	Y-BOCS:34 HAMD:5	Y-BOCS:0 HAMD:2	stimulation-related
	18	Fe	30	ASD, OCD depression, Anxiety	NA	8 mo	OCD	DBS	vALIC /MFB	NA	Y-BOCS:34 HAMD:23	Y-BOCS:22 HAMD:22	None
Park (2017)	19	M	14	ASD, OCD	LF	24 mo	self-mutilation	DBS	NAc	Fre:130 Hz Wid:90us Amp:3–5 V	Y-BOCS:22 C-GIS:6 ABC:106 K-ARS:54 SRS:101	Y-BOCS:7 C-GIS:4 ABC:40 K-ARS:36 SRS:98	None
Stocco (2014)	20	Fe	19	ASD, ID, TD, monosomy 2q and trisomy 20p	LF	13 mo	self-mutilation ; TD	DBS	GPi	Fre:80 Hz Wid:120us Amp:3.3 V	JHMRS:46	JHMRS:4	None
	21	M	17	ASD; ID; anxiety	LF	6 mo	stereotypies	DBS	ALIC +GPi	Fre: 40–200 Hz Wid:100-210us Amp:2–5 V	JHMRS:67	JHMRS:67	None
Author (year)	Pa	Gender	Age of surgery	Diagnosis	HF or LF	F-U duration	Indication of surgery	Type of therapy	Target	Parameters	Baseline	Last	Adverse event
Strurm (2013)	22	M	13	ASD; Spastic paraparesis	LF	24 mo	self-mutilation	DBS	amygdala	NA	CGI-S:6 ADI-R: 46	CGI-S:4 ADI-R: 40	None
Benedetti-Isaac (2015)	23	M	23	ASD, ID, TBI, seizure	LF	48 mo	aggression	DBS	pHyp	Fre:185 Hz Wid:90us Amp:2.7 V	OAS:9	OAS:1	secretion from the scar
Benedetti-Isaac (2015)	24	M	16	ASD, ID, seizure	LF	2 mo	aggression	DBS	pHyp	Fre:185 Hz Wid:90us Amp:2.8 V	OAS:8	OAS:8	None
Roberto (2022)	27	M	25(15–36)	ASD, OCD	NA	120 mo	aggression OCD	RA and GKRS	capsule/ amygdala/ cingulate gyrus/ stria terminalis.	24Gy for amygdala; 120Gy for cingulate gyrus; twice surgery for all; thrice for 2 patients.	Y-BOCS:36 OAS:10	Y-BOCS:26 OAS:5	edema for 1 patient; local infection for 1 patient.
	28	M		ASD, OCD	NA	120 mo	aggression OCD	RA and GKRS			Y-BOCS:34 OAS:14	Y-BOCS:28 OAS:5
	29	M		ASD, OCD	NA	48 mo	aggression OCD	RA and GKRS			Y-BOCS:34 OAS:12	Y-BOCS:27 OAS:5
	30	M		ASD, OCD	NA	120 mo	aggression OCD	RA and GKRS			Y-BOCS:32 OAS:12	Y-BOCS:22 OAS:6
	31	M		ASD, OCD	NA	48 mo	aggression OCD	RA and GKRS			Y-BOCS:32 OAS:12	Y-BOCS:21 OAS:6
	32	M		ASD, OCD	NA	48 mo	aggression OCD	RA and GKRS			Y-BOCS:30 OAS:11	Y-BOCS:19 OAS:6
	33	M		ASD, OCD	NA	120 mo	aggression OCD	RA and GKRS			Y-BOCS:32 OAS:12	Y-BOCS:18 OAS:5
	34	M		ASD, OCD	NA	120 mo	aggression OCD	RA and GKRS			Y-BOCS:28 OAS:11	Y-BOCS:14 OAS:5
	35	M		ASD, OCD	NA	48 mo	aggression OCD	RA and GKRS			Y-BOCS:28 OAS:13	Y-BOCS:16 OAS:6
	36	M		ASD, OCD	NA	48 mo	aggression OCD	RA and GKRS			Y-BOCS:26 OAS:9	Y-BOCS:16 OAS:4
Author (year)	Pa	Gender	Age of surgery	Diagnosis	HF or LF	F-U duration	Indication of surgery	Type of therapy	Target	Parameters	Baseline	Last	Adverse event
Segar (2015)	25	Fe	24	ASD, TS, OCD	LF	36 mo	OCD; TS	DBS	VC/VS	Fre:130 Hz Wid:90us Amp:2–8 V	GAF:20	GAF:60	lead fracture
Kakko (2018)	26	M	19	ASD, tardive dyskinesia, Seizure	LF	NA	aggression	DBS	GPi	NA	NA	symptom recovered	None
HF: high function; LF: low function; SD: social disorders; CD: communication difficulty; FIB: fixed interest or behavior; F-U: follow-up; OCD: obsessive-compulsive disorder; ASD: autism spectrum disorders; AN: intellectual disabilities; TS: Tourette syndrome; ID: intellectual disabilities; TD: tardive dystonia; SCQC: Social Communication Questionnaire Current version for autism; MARDS: Montgomery Asberg depression rating scale; CGI-S: The Clinical Global Impression-Severity score; ABC: Antecedent, Behavior, Consequence; SRS: Social responsiveness scales; K-ARS: Korean attention deficit hyperactivity disorder rating scale; JHMRS: John's Hopkins motor stereotypy rating scale; GAF: Global Assessment of Functioning; ADI-R: Autism Diagnostic Interview-Revised; CARS: Childhood Autism Rating Scale.

Social contact difficulty (SCD) and communication disorders (CD)

The improvement of SCD and CD in ASD was reported after DBS as well. Strum et al. reported a 13-year-old boy whose autism diagnostic interview-revised (ADI-R) score was decreased from 46 to 40 after DBS^[33]. The symptoms of anxiety, emotional tensions, sleep disorder and impaired processes in response to auditory and visual stimulation were relieved to a certain extent^[33]. The language function of the patient was improved slightly as well, and the patient could use single words, which was impossible before surgery^[33]. Two studies with 2 patients reported the outcome of social skill before and after the operation^{[8, 24]}. Doshi et al. reported a middle-aged female whose social communication questionnaire current version for autism (SCQC) score decreased from 26 to 16^[8]. Park et al. reported a young male whose SRS score decreased from 101 to 98^[24]. Two years after surgery, the patients’ expression and comprehension improved, and they had better eye contact with others^[24]. In addition, 4 studies with 5 patients described the improvement of social interaction ability^{[7, 12, 16, 30]}. Davis et al. reported a middle-aged male who found a job and received positive feedback from his supervisor and peers after DBS^[7]. Graat et al. reported a 54-year-old female who participated in volunteer work and improved her relationship with her husband. Meanwhile, they also reported a 51-year-old male who became more confident and less social shyness after DBS^[12]. Segar et al. reported a 24-year-old female whose speech and social interaction ability was improved after DBS^[30]. Kakko et al. reported a 19-year-old male whose communication ability gradually recovered after DBS^[16]. One study with 10 patients reported the results of childhood autism rating scale (CARS)^[10]. The median CARS score was 53.00 (range: 47.00–55.00) before surgery, but the result of CARS after surgery was not reported.

Other symptoms

Two studies with 7 patients reported Hamilton depression scale (HAMD) score before and after surgery, and the mean HAMD score decreased from 21.86 ± 8.78 to 12.71 ± 9.30. Stocco et al. assessed the improvement of stereotyped behavior for 2 patients via John's Hopkins motor stereotypy rating scale (JHMRS), and the JHMRS score decreased from 46 to 4 and 67 to 67, respectively^[32].

Safety

Among the 36 patients, 7 patients (19.44%) suffered adverse events after stereotactic neurosurgery. Of three patients reported in Graat et al.’s study^[12] (Table 2), one suffered infection of the DBS device and required removal of the system; meanwhile, due to the disappointment with the initial efficacy of DBS, the patient had a suicide attempt; one suffered transient pain in the region of drill holes and cables, and the patient suffered hallucinations (hearing people having sex), which was resolved after changing the parameter of stimulation; one suffered transient light-headedness after increasing setting. Benedetti-Isaac et al. reported a patient who presented a slight serous secretion from the scar but without evidence of pathogenic microbial infection^[3]. Segar et al. reported a patient whose lead had fractured and then underwent a second operation to replace the lead^[30]. Of the two patients who suffered complications after surgery in Roberto et al.’s report^[21], one suffered from self-limited postoperative edema and presented with transient headache, incontinence and bradypsychia; another suffered local infection and recovered after therapy.

This is the first systematic review to investigate the safety and efficacy of stereotactic neurosurgery for ASD. A total of 36 patients harboring ASD underwent stereotactic neurosurgery until now. Herein, we considered that the purpose of stereotactic neurosurgery for ASD was to minimize the impairments of the co-occurring disease, including OCD and aggressive behavior, to try to improve the symptoms of SCD and CD and then to create favorable conditions for facilitating learning and acquisition of adaptive skills to improve functional independence^[15]. In general, stereotactic neurosurgery could improve the symptoms of ASD patients with satisfactory safety.

OCD is a common comorbid disease among individuals with ASD and accounts for 17.40%^{[17, 35]}, while stereotactic neurosurgery can effectively alleviate OCD. Across our studies, the outcome of Y-BOCS was recorded in more than half of the patients during the operation, and nearly two-thirds achieved a full response. The vALIC was a common target for OCD therapy and was a point of convergence for key white matter fibers. It connects the prefrontal and anterior cingulate cortex with the hippocampus, amygdala, and thalamus and together forms a core limbic network in the human brain^[22]. Graat et al. reported a cohort including 50 patients with treatment-refractory OCD who underwent vALIC-DBS^[13]. They found that the symptoms of OCD, anxiety and depression were improved significantly after DBS. Graat et al. reported that 6 patients with refractory obsessive OCD and ASD benefited from vALIC-DBS, which was included in this systematic review. They considered that for patients with OCD and ASD, DBS was an effective therapy and should not be regarded as a contraindication. Repetitive behavior is a typical characteristic both in OCD and ASD, and it is extremely difficult to differentiate between them. The repetitive pattern of behavior in ASD was egosyntonic and even was the source of pleasure and satisfaction, which meant patients were content with the present situation without negative judgment about themselves^{[8, 25]}. In addition, patients with ASD were less likely to experience thoughts about aggressive, contamination, sexual, or religious content and had a high probability of hoarding obsessions^{[25, 27]}. However, individuals with OCD experienced higher levels of repetitive behavior and greater symptom severity than patients with ASD and suffered fierce unwanted and unpleasant distress^{[22, 26, 28]}. Murray et al. conducted a study to compare cognitive behavior therapy (CBT) for OCD outcomes among youth with and without ASD^[23]. Although they found that the response to CBT for OCD patients with ASD was inferior to that for OCD patients without ASD, both OCD patients with and without ASD benefited from CBT^[23]. Although it has been considered that DBS could alleviate the repetitive behavior of OCD (ego-dystonic obsessions) but not the repetitive behavior of ASD (ego-syntonic obsessions), the Y-BOCS was decreased significantly after stereotactic neurosurgery in this study. It seems to show that stereotactic neurosurgery is an effective therapy for the repetitive behavior of ASD.

Although the amygdala has been regarded as a satisfactory target for aggression behavior for more than 50 years, the neurobiological mechanisms explaining this behavioral change are not known. The amygdala is a key structure of the limbic system in charge of integrating signal inputs from the sensory systems and projecting this information to specific brain regions to monitor emotional responses^[10]. In addition, the amygdala is involved in facial processing and participates in socioemotional processes, which can process and store the information necessary to navigate social contexts^{[6, 34]}. It seems that amygdala damage could trigger fear recognition and abnormal reductions in eye gaze^[1]. Rutishauser et al. considered the amygdala’s vital role in abnormal face processing by people with ASD at the cellular level, and it appears that the dysfunction of a specific subpopulation of neurons for the amygdala altered selectivity for the features of faces^[29]. In this study, the indication for surgery for 11 patients who underwent DBS or RA targeting the amygdala was aggression, and those patients gained satisfactory results. Stereotactic neurosurgery targeting the amygdala improves aggression, possibly by reducing the activity of the nucleus to restore homeostatic patterns of the brain^{[4, 9]}.

It seems that DBS may alleviate social contact difficulty and communication disorders. There were a total of 8 patients whose cardinal symptoms of ASD benefited from DBS in this study. According to limited data, we found that DBS could ameliorate the difficulty in social contact and emotional disorder, improving verbal expression and comprehension and social function. Although the results were based on nonstandardized assessment or subjective descriptions from limited case reports, we cannot neglect the potential efficacy of DBS for the core symptoms of ASD. In addition, a basic study confirmed the efficacy of DBS in core symptoms of ASD. Lin et al. elevated the efficacy of DBS in an ASD rat offspring model^[18]. They found that DBS activated several brain regions, including cortical areas, limbic-related areas, and the dorsal striatum, and significantly decreased the level of dopamine D2 receptor^[18]. Meanwhile, they observed that DBS increased social interaction and decreased social avoidance in an ASD rat model^[18]. In addition, study associated with DBS applied in other psychiatric disorders suggested that DBS could improve attention, memory and executive functioning^[5]. Prospective studies with a standardized neuropsychological assessment battery should be performed to analyze the efficacy of stereotactic neurosurgery in the core symptoms of ASD.

DBS and RA were both applied in ASD, but there were some differences in the type of complications. Gouveia et al. considered that the risk of complications, including infection, skin erosion, and lead fracture, would increase for ASD patients with severe self-aggressive behavior to receive DBS^[11]. Therefore, RA, without device-related and stimulation-related adverse events, had better safety for such patients than DBS. In addition, studies have shown that school-age ASD patients with intellectual disabilities (intelligence quotient < 70) accounted for 11–65%^{[2, 19]}. It was extremely difficult to require ASD patients with low function to cooperate during surgery; hence, sleep DBS seemed to be safer than awake DBS for ASD patients. The postoperative management of patients with low function will be a great challenge for clinicians, and it requires clinicians to take more energy and patience in patients with ASD.

There are certain limitations in this systematic review. Firstly, ASD is often accompanied by other diseases. In fact, among this study, ASD was not the principal diagnosis for several patients of the included studies, which means that we analyzed the efficacy of stereotactic neurosurgery for ASD in an indirect way. Secondly, although all patients in the included studies were diagnosed with ASD, several included studies did not report whether the diagnosis was based on standardized diagnostic criteria (e.g., DSM-Ⅴ). Besides, we drew a conclusion based on a limited sample size, most included studies were case report, which could influence the study quality. In addition, data from several studies could not be acquired completely, which could affect the accuracy of the results.

Stereotactic neurosurgery is an effective therapy to alleviate the symptoms of OCD and aggression for ASD patients with satisfactory safety based on the review. DBS has the potential to improve the social contact difficulty and communication disorders of ASD. Further investigation of the efficacy and safety of stereotactic neurosurgery in ASD using a standardized neuropsychological scale is needed.

Funding: This work has been supported by grants from Clinical Research Incubation Project, West China Hospital, Sichuan University (2022HXFH024).

Competing interests: All authors declare that they have no competing interests.

Availability of data and material: Not applicable.

Code availability: Not applicable.

Ethics approval: Not applicable.

Consent to participate: Not applicable.

Consent for publication: Not applicable.

Supplement data: The dataset used in this study is available in this article and its Additional file: Dataset.

Authorship statement: YW and WW proposed the conception and designed of the study. YW, YFS and MJL conducted the literature search and study screening. YG, YYX, RT, JJH and DHL conducted data extraction and the quality assessment. YW, HD, LLX, BTX, WZ and MQW were involved in the analysis and interpretation of data. YW wrote the first draft of the manuscript and all authors revised it under the guidance of WW.

Adolphs R, Gosselin F, Buchanan TW, Tranel D, Schyns P, Damasio AR. A mechanism for impaired fear recognition after amygdala damage. Nature 2005; 433(7021):68–72.
Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord 2001; 31(1):5–17.
Benedetti-Isaac JC, Torres-Zambrano M, Vargas-Toscano A, Perea-Castro E, Alcalá-Cerra G, Furlanetti LL, et al. Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior. Epilepsia 2015; 56(7):1152–1161.
Blair RJ. The Neurobiology of Impulsive Aggression. J Child Adolesc Psychopharmacol 2016; 26(1):4–9.
Bouwens van der Vlis TAM, Duits A, van de Veerdonk M, Mulders AEP, Schruers KRJ, Temel Y, et al. Cognitive Outcome After Deep Brain Stimulation for Refractory Obsessive-Compulsive Disorder: A Systematic Review. Neuromodulation 2022; 25(2):185–194.
Bzdok D, Langner R, Schilbach L, Engemann DA, Laird AR, Fox PT, et al. Segregation of the human medial prefrontal cortex in social cognition. Front Hum Neurosci 2013; 7:232.
Davis RA, Winston H, Gault JM, Kern DS, Mikulich-Gilbertson SK, Abosch A. Deep Brain Stimulation for OCD in a Patient With Comorbidities: Epilepsy, Tics, Autism, and Major Depressive Disorder. J Neuropsychiatry Clin Neurosci 2021; 33(2):167–171.
Doshi PK, Hegde A, Desai A. Nucleus Accumbens Deep Brain Stimulation for Obsessive-Compulsive Disorder and Aggression in an Autistic Patient: A Case Report and Hypothesis of the Role of Nucleus Accumbens in Autism and Comorbid Symptoms. World Neurosurg 2019; 125:387–391.
Gouveia FV, Germann J, de Morais R, Fonoff ET, Hamani C, Alho EJ, et al. Longitudinal Changes After Amygdala Surgery for Intractable Aggressive Behavior: Clinical, Imaging Genetics, and Deformation-Based Morphometry Study-A Case Series. Neurosurgery 2021; 88(2):E158-e169.
Gouveia FV, Germann J, Devenyi GA, Fonoff ET, Morais R, Brentani H, et al. Bilateral Amygdala Radio-Frequency Ablation for Refractory Aggressive Behavior Alters Local Cortical Thickness to a Pattern Found in Non-refractory Patients. Front Hum Neurosci 2021; 15:653631.
Gouveia FV, Hamani C, Fonoff ET, Brentani H, Alho EJL, de Morais R, et al. Amygdala and Hypothalamus: Historical Overview With Focus on Aggression. Neurosurgery 2019; 85(1):11–30.
Graat I, Balke S, Prinssen J, de Koning P, Vulink N, Mocking R, et al. Effectiveness and safety of deep brain stimulation for patients with refractory obsessive compulsive disorder and comorbid autism spectrum disorder; A case series. J Affect Disord 2022; 299:492–497.
Graat I, Mocking R, Figee M, Vulink N, de Koning P, Ooms P, et al. Long-term Outcome of Deep Brain Stimulation of the Ventral Part of the Anterior Limb of the Internal Capsule in a Cohort of 50 Patients With Treatment-Refractory Obsessive-Compulsive Disorder. Biol Psychiatry 2021; 90(10):714–720.
Huys D, Kohl S, Baldermann JC, Timmermann L, Sturm V, Visser-Vandewalle V, et al. Open-label trial of anterior limb of internal capsule-nucleus accumbens deep brain stimulation for obsessive-compulsive disorder: insights gained. J Neurol Neurosurg Psychiatry 2019; 90(7):805–812.
Hyman SL, Levy SE, Myers SM. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics 2020; 145(1).
Kakko K, Bjelogrlic-Laakso N, Pihlakoski L, Lehtimäki K, Järventausta K. Tardive Dyskinesia Should Not Be Overlooked. J Child Adolesc Psychopharmacol 2019; 29(1):72–74.
Kanne SM, Mazurek MO. Aggression in children and adolescents with ASD: prevalence and risk factors. J Autism Dev Disord 2011; 41(7):926–937.
Lin TC, Lo YC, Lin HC, Li SJ, Lin SH, Wu HF, et al. MR imaging central thalamic deep brain stimulation restored autistic-like social deficits in the rat. Brain Stimul 2019; 12(6):1410–1420.
Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J. Autism spectrum disorder. Lancet 2018; 392(10146):508–520.
Maenner MJ, Shaw KA, Baio J, Washington A, Patrick M, DiRienzo M, et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2016. MMWR Surveill Summ 2020; 69(4):1–12.
Martínez-Álvarez R, Torres-Diaz C. Surgery of autism: Is it possible? Prog Brain Res 2022; 272(1):73–84.
Mithani K, Davison B, Meng Y, Lipsman N. The anterior limb of the internal capsule: Anatomy, function, and dysfunction. Behav Brain Res 2020; 387:112588.
Murray K, Jassi A, Mataix-Cols D, Barrow F, Krebs G. Outcomes of cognitive behaviour therapy for obsessive-compulsive disorder in young people with and without autism spectrum disorders: A case controlled study. Psychiatry Res 2015; 228(1):8–13.
Park HR, Kim IH, Kang H, Lee DS, Kim BN, Kim DG, et al. Nucleus accumbens deep brain stimulation for a patient with self-injurious behavior and autism spectrum disorder: functional and structural changes of the brain: report of a case and review of literature. Acta Neurochir (Wien) 2017; 159(1):137–143.
Paula-Pérez I. Differential diagnosis between obsessive compulsive disorder and restrictive and repetitive behavioural patterns, activities and interests in autism spectrum disorders. Rev Psiquiatr Salud Ment 2013; 6(4):178–186.
Postorino V, Kerns CM, Vivanti G, Bradshaw J, Siracusano M, Mazzone L. Anxiety Disorders and Obsessive-Compulsive Disorder in Individuals with Autism Spectrum Disorder. Curr Psychiatry Rep 2017; 19(12):92.
Russell AJ, Mataix-Cols D, Anson M, Murphy DG. Obsessions and compulsions in Asperger syndrome and high-functioning autism. Br J Psychiatry 2005; 186:525–528.
Ruta L, Mugno D, D'Arrigo VG, Vitiello B, Mazzone L. Obsessive-compulsive traits in children and adolescents with Asperger syndrome. Eur Child Adolesc Psychiatry 2010; 19(1):17–24.
Rutishauser U, Tudusciuc O, Wang S, Mamelak AN, Ross IB, Adolphs R. Single-neuron correlates of atypical face processing in autism. Neuron 2013; 80(4):887–899.
Segar DJ, Chodakiewitz YG, Torabi R, Cosgrove GR. Deep brain stimulation for the obsessive-compulsive and Tourette-like symptoms of Kleefstra syndrome. Neurosurg Focus 2015; 38(6):E12.
Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, Chipponi J. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J Surg 2003; 73(9):712–716.
Stocco A, Baizabal-Carvallo JF. Deep brain stimulation for severe secondary stereotypies. Parkinsonism Relat Disord 2014; 20(9):1035–1036.
Sturm V, Fricke O, Bührle CP, Lenartz D, Maarouf M, Treuer H, et al. DBS in the basolateral amygdala improves symptoms of autism and related self-injurious behavior: a case report and hypothesis on the pathogenesis of the disorder. Front Hum Neurosci 2012; 6:341.
Van Overwalle F. Social cognition and the brain: a meta-analysis. Hum Brain Mapp 2009; 30(3):829–858.
van Steensel FJ, Bögels SM, Perrin S. Anxiety disorders in children and adolescents with autistic spectrum disorders: a meta-analysis. Clin Child Fam Psychol Rev 2011; 14(3):302–317.
Zeidan J, Fombonne E, Scorah J, Ibrahim A, Durkin MS, Saxena S, et al. Global prevalence of autism: A systematic review update. Autism Res 2022; 15(5):778–790.

No competing interests reported.

Dataset.xls

Download PDF

Journal Publication

published 30 Apr, 2023

Read the published version in Asian Journal of Psychiatry →

Version 1

posted

You are reading this latest preprint version

The role of stereotactic neurosurgery as a symptomatic treatment for autism spectrum disorders: a systematic review

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Materials & Methods

Data extraction

Quality assessment and data analysis

Results

Search result

Study quality

Study characteristics

The type of therapy

Treatment efficacy

Safety

Discussion

Limitations

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1