Interventional therapy of extracranial arteriovenous malformations of the head and neck-A systematic review.

OBJECTIVES: The primary aim of this study was to conduct a meta-analysis of the literature on interventional treatment for patients with extracranial AVM of the head and neck to identify a superior treatment. The secondary aim was to evaluate the methodological quality of associated articles published between 2000-2020.
METHODS: The literature search was conducted on PubMed, Embase, the Cochrane Library, and scholar.google.com. Studies, meeting the acceptable reference standard underwent meta-analysis. All identified literature underwent methodological quality analysis.
RESULTS: Of 1560 screened articles, 56 were included in the literature review. Appropriate diagnostic tests were reported in 98% of included articles. 13% of included articles did not specify the embolization agent. Outcome analysis varied throughout. 45% of the authors used radiographic imaging for follow-up. 77% specified the span of follow-up of their entire patient collective. Two articles met the inclusion criteria for meta-analysis. Curing rate of transarterial ethanol embolization for intraosseous AVM was 83% with a complication rate of 58%. Curing rate of ethanol combined with NBCA or Onyx in soft tissue AVM was 18% with a complication rate of 87%.
CONCLUSION: Our literature review revealed an absence of treatment or reporting standards for extracranial AVM of the head and neck. The meta-analysis is comprised of two articles and methodological quality is heterogeneous. We recommend implementing consistent reporting standards to facilitate comparability of studies and to provide robust data for the development of an evidence-based treatment strategy. ADVANCES IN KNOWLEDGE: Meta-analysis showed a favorable radiological outcome for intraosseous AVM when treated with intraarterial ethanol embolization. Our analysis demonstrated that the published data on extracranial AVMs of the head and neck is lacking in consistency and quality, prompting agreement for the need of standardized reporting on AVM treatments.

Introduction

Cutaneous vascular anomalies are rare conditions that can be very demanding for treating clinicians. The spectrum of cutaneous vascular malformations includes high-flow lesions such as arteriovenous malformations (AVM) and low-flow lesions such as venous malformations (VM) and lymphatic malformations (LM). AVM, which are discussed in this work, present with a wide range of symptoms and variable progression. Misdiagnosis and recurrence are not uncommon [1] and can lead to life-threatening situation with serious hemorrhages [2] or congestive heart failure [3]. Additionally, inconsistent nomenclatures [4] and treatment modalities lend confusion in deciding on an approach for resolution or palliation of these lesions that may considerably limit the patients’ quality of life [5].

In 2018, the International Society for the Study of Vascular Anomalies (ISSVA) released a comprehensive classification catalogue [6] subdividing vascular malformations into simple and combined capillary, lymphatic, venous and arteriovenous malformations, according to their vascular architecture (Table 1). AVMs are characterized by an abnormal vascular network directly connecting arteries and veins to form a fast flow lesion that lacks a capillary bed [7].

Table 1

Overview of ISSVA-Classification for vascular malformations.

Vascular Tumors	Vascular Malformations
Benign Locally (aggressive/ borderline) Malignant	Simple	Combined
	Capillary Malformations Lymphatic Malformations Venous Malformations Arteriovenous Malformations Arteriovenous Fistula	CVM, CLMLVM, CLVMCAVMCLAVMother

CVM = Capillary-Venous-Malformation, CLM = Capillary Lymphatic Malformation, LVM = Lymphatic Venous Malformation, CLVM = Capillary Lymphatic Venous Malformation, CAVM = Capillary Arteriovenous Malformation, CLAVM = Capillary Lymphatic.

In this review we focused on the analysis of articles covering the treatment of extracranial AVMs of the head and neck with the use of sclerotherapy and embolization. An illustrative example of an intraarterial embolization procedure is given in Fig 1.

Fig 1

Illustrative example of 4D-MR angiography in patient with extracranial AVM.

Patient in his forties with a progressive pulsating mass on his left upper lip. Magnetic resonance imaging using a dynamic 4D-MR angiography sequence (Fig 1A, sagittal reconstruction in mixed phase) reveals a dense vascular mass (arrow) on the upper lip with arteriovenous shunts. Diagnosis of arteriovenous malformation (AVM) was established. Catheter angiography with selective injection of the left external carotid artery (Fig 1B, lateral view) confirmed the diagnosis. The AVM (short arrow) was fed through the facial artery (long arrow) and drained predominantly into the facial vein. The facial artery was selectively catheterized using a microcatheter and embolized with microparticles (150–250 μm). At the end of the embolization procedure (Fig 1C, selective injection of the left external carotid artery in lateral view) the AVM is completely eliminated. The other branches of the external carotid artery are preserved.

Prior to the initial research, we developed the inclusion criteria for eligibility for meta-analysis (or acceptable reference standard). Methodological quality standards for analyzing the remaining articles were developed during the review process.

We address caregivers of all stages of experience and all disciplines managing these vascular malformations, with the goal of better understanding the results of the different AVM management methods used over the last two decades. Using the PICO approach, we performed a systematic review of relevant literature published between 2000 and 2020 to assess these interventions and their results [8].

Methods

PICO database search

Population

In March 2020 we identified suitable studies using the online search engines PubMed, Embase, the Cochrane Library and scholar.google.com. All clinical studies targeting diagnosis, treatment, outcome, complication rate and recurrence of AVMs, venous malformations, and lymphatic malformations, as well as mixed lesions of the head and neck were included in the primary review [6]. Further publications identified in citations and quotes throughout the initial literature review were included in scope and underwent the same review process, with the last addition made in August 2020. Retrospective and prospective English studies, as well as case reports published between January 2000 and March 2020 were included. This studied timeline marks a rapid progression in the evolution of interventional radiology. There were no restrictions as to the country of origin, clinical setting or size of the institution in which the treatments were performed. We did not set a minimum sample size of the studies, as any clinical findings or experience in treatment might be of value to clinicians or future studies. Management of capillary malformations, vascular tumors, and vascular malformations associated with syndromic diseases were not discussed in this literature review.

For a broad overview, we searched various English medical terms for the description of vascular malformations, their subclassification and possible anatomical sites of interest identified in previous database searches and previewed articles. Medical subject headings (MeSH) items were added to the database research, accordingly. We intentionally included obsolete search terms (such as “hemangiomas”) to ensure inclusion of older publications [4]. A full disclosure of the search terms used, according to the PICO strategy, is shown in S1 Table. The full search string for PubMed is enclosed in S1 Appendix.

Only publications targeting AVMs of the head and neck region underwent quality analysis, irrespective of their anatomical location (intramuscular, intraosseous, and subcutaneous). As details on gender, age, and ethnic background of the treated patients were inconsistently reported, they did not undergo analysis.

Intervention

We focused on treatment of soft tissue AVMs of the head and neck with sclerotherapy and embolization as primary therapy. This includes interventions with any applied sclerosant agent and either pharmaceutical embolization or mechanical embolization with coils, balloons, and vascular plugs through direct lesion puncture or endovascular transarterial or transvenous approach. Where sclerotherapy or embolization were part of the treatment scheme, studies targeting surgical resection were also included in the primary search. To ensure we did not overlook any alternative methods and treatment options, we expanded the search with general MeSH terms and items for any other sclerotherapeutic intervention, and did not specify substance and generic names for utilized agents in our search.

Comparison

Leveraging meta-analysis, we compared radiological outcome and complication rates of the different treatment options for extracranial AVMs with the goal of identifying a superior treatment method within the existing literature.

Outcome

We included publications that documented the progression of treated patients in terms of resolution, palliation, and recurrence measured by clinical inspection, radiological imaging, and subjective patients’ or physicians’ description. The database search also included any aesthetic results and quality of life records conducted by questionnaires or interviews.

Qualitative analysis of methodology

All initial diagnostic tests evaluating the vascular architecture of the lesion were deemed to be of sufficient quality if they were applied in all patients, regardless of whether or not criteria for the choice of method was defined. We considered angiographic imaging to be the gold standard.

To be considered for inclusion, the outcome for each patient had to be measured by comparable tests with reproducible results and re-test reliability.

The post-treatment follow-up was deemed of adequate quality if it was reported for all individuals in the study, with the ideal follow-up time spanning one year between evaluation and the last treatment session [9]. Additionally, description of symptoms and location, as well as details on complications that arose had to be comprehensively reported.

Instrument-based assessment and analysis of the risk of bias were planned but not conducted, since the analyzed studies were retrospective, non-randomized, non-comparative clinical trials and case studies and thereby hold the inherent potential for confounding, selection bias, reporting bias as well as information bias [10].

Inclusion criteria for meta-analysis (Acceptable reference standard)

1) Quality of description of diagnostic measures

Only studies that used angiographic imaging (e.g., magnetic resonance imaging (MRI), computed tomography (CT), digital subtraction angiography (DSA) or fluoroscopic angiography) were included. Ultrasonography was excluded due to inconsistent presentation of AVMs and user-dependence of ultrasound examinations [11]. Clinical examination and clinical history alone were considered insufficient for a reliable diagnosis.

2) Quality of description of therapy

All publications covering sclerotherapy and/or embolization with and without surgical interventions on extracranial AVM of the head and neck were accepted. Information on the sclerosant or embolic agent had to be given.

3) Quality of description of results

To eliminate the risk of a group classification error, we only included studies that defined cure or resolution as devascularization rates of more than 99% compared to baseline. Hence, angiographic imaging had to be performed before and after the intervention to demonstrate the results of the treatment.

4) Quality of follow-up

For cerebral AVM, a minimum follow-up period of one year is recommended to detect lesion recurrence after therapy [9]. Analogously, a follow-up time of at least one year was considered necessary for inclusion in our meta-analysis. As mean or median time of follow-up of the study group (as well as maximum) time do not yield information on the individual minimum follow-up time, that data alone was considered insufficient, and the related literature was excluded from analysis.

Statistical analysis

For statistical analysis we used cross-table and Pearson’s Chi-Square calculations. All statistical analyses were performed with SPSS 25 software (IBM, Armonk, NY).

Results

Overview

Using the selection process outlined in Fig 2, we identified 1520 articles that went into primary title and abstract review, 151 of which fulfilled the criteria for our full text review. Screening their references yielded another 7 publications, for the total of 158. Of the total articles identified, 33 addressed AVMs. An additional search made using the PICO strategy without the link between items identified a further 23 articles, resulting in a total of 56 articles to qualify for full text review. The full text review of 56 articles identified 910 patients. Of the articles reviewed, 52% (29/56) were case reports or case series. Only two articles with a total of 57 patients stood up to our inclusion criteria for meta-analysis [12,13], A summary of the qualitative synthesis of the methodology of items of all 56 articles is given in S2 Table.

Fig 2

PRISMA flow diagram.

* Exclusion if not: AVM of head and neck, English language, published 2000–2020, Interventional treatment applied. ** More than one may apply.

The summary represents the authors’ conclusion about the quality of each item.

A comprehensive overview of each article is provided in the supplemental S3 Table. S2 Appendix shows the full list of excluded studies on full article assessment level.

Quality of description of diagnostic measures

All but one of the 56 publications reported an appropriate diagnostic test for initial diagnosis. Nine authors described using only one singular imaging modality to confirm the clinically discovered type of lesion; all other articles reported two or more imaging modalities for diagnosis. Details of the imaging modalities are outlined in Table 2.

Table 2

Imaging modalities used.

Imaging modality	Ratio of modality usage
Conventional angiography	30/56 (53.6%)
Computed tomography	29/56 (51.8%)
Magnetic resonance imaging	28/56 (50.0%)
Digital Subtraction Angiography	9/56 (16.1%)
Doppler-Ultrasound	5/56 (8.9%)
Other *	2/56 (3.6%)

* Scintigraphy and Time-Of-Flight-MRI.

Quality of description of therapy

All 56 authors used sclerotherapy or embolization as part of the therapy plan. Twenty-seven used sclerosant agents and/or pharmaceutical embolization without surgical interventions. (Table 3).

Table 3

Ratio of therapeutic agents used.

Most used Embolization Agent	Number of Authors to use the agent
N-Butylcyanoacrylate	20/48 (42%)
Polyvenylalcohol	15/48 (31%)
Coils	13/48 (27%)
Ethanol	10/48 (21%)
Onyx	8/48 (17%)
Bleomycin	4/48 (8%)

Articles may have reported multiple agents.

The remaining 29 studies included a surgical procedure as part of their treatment plan, either compulsory, optional, or as an escalation of treatment.

Seven out of 56 authors (13%) did not specify the pharmaceutical agent used [14-20].

Overall, there is a noticeable disparity of treatment algorithms. For instance, Kansy et al. [21] showed a clear treatment algorithm which showed the indication for the therapy applied. All other authors lacked an explanation for their individual treatment decision.

Quality of description of results

Pre- and post-treatment imaging analysis were deemed the measurement of choice for evaluation of therapy outcome, with 45% (25/56) of authors reporting imaging parameters for outcome analysis. Stratification of outcome ranged as shown in Table 4.

Table 4

Outcome stratification.

Authors	Defined devascularization rate for ‘cure’
Kitagawa et al. [22], Su et al. [12], Wang et al. [23], Han et al. [24], Pompa et al. [25,26], Fan et al. [27], Bhandari et al. [28], Zheng et al. [29]	100%
Kim et al. [13]	>99%
Meila et al. [14], Gupta et al [30], Zhao et al. [31]	>90%

Defined devascularization rate (%) authors refer to as ‘cure’ (best outcome possible). The remaining authors did not use devascularization as measurement of outcome.

Some authors refrained from using quantitative stratification for their evaluation and instead used wording such as ‘notable reduction’ (Chelliah et al. [15]), ‘no newly developed nidus’ (Kim et al. [13]), or ‘retention within the vascular lesion’ (Hsiao et al. [32]). Also, descriptions of clinical outcomes were limited to the physicians’ examination and patient report and included domains such as ‘no recurrence’ (Shobeirian et al. [33]), ‘stable condition’ (Ermer et al. [34]), ‘reduction in size’ (Fujita et al. [35]) or ‘symptoms were found to subside’ (Ishimaru et al. [35]). Richter et al. [36] used an interview to evaluate the quality of life of the patients before and after the intervention. A standardized questionnaire, however, was not provided. Kaji et al. [37] used visual evaluation of photographs and the appearance of the lesions alongside a volumetric response calculation based on MRI taken before and after treatment. [38] Saito et al. [39] described their findings to be the ‘desired result’ in cosmetic appearance. Gegenava et al. [39] used a telephone interview to ask for any recurrent bleeding episodes. In studies that addressed multiple types of vascular lesions (AVM, LM, VM) (Churojana [39]) or multiple locations of the AVM (head, neck, trunk, limbs) (Kitagawa [39]), it was not possible to differentiate the outcome for each type of lesion.

Quality of follow-up

Forty-three of 56 articles (77%) reported the time of minimum follow-up for their whole patient collective, averaging to 488.5 days (range 7 days to 2880 days, SD 577.1 days). The remaining 13 articles did not include adequate follow-up data. One article documented ‘ongoing’ follow-up while the remaining four articles reported either mean or maximum follow-up time, with no mention of individual timelines. Eight authors recorded no follow-up information whatsoever.

Meta-analysis

Two articles fulfilled our inclusion criteria for meta-analysis.

In the first study, Su et al. [12] have described the management of 12 patients with AVMs of the maxilla and mandible, admitted with a history of recurrent hemorrhaging and an acute bleeding episode with the need for emergency treatment. Using direct puncture and transarterial ethanol embolization with intravenously deployed coils, they had a curing rate (defined as 100% devascularization of the nidus) of 83% (10/12 patients). Two patients had partial remission and were waiting for additional treatment. Patients went through a mean number of 1.25 treatment sessions (range 1 to 2 sessions).

In the second study, Kim et al. [13] reported the interventional treatment of 45 patients with soft tissue AVMs in the head and neck region using transarterial or direct-puncture ethanol sclerotherapy, and additional surgical resection in 23 of the 45 patients. NBCA (N-Butyl Cyanoacrylate), Onyx (ev3 Neurovascular, Irvine, California, USA) or coils were used as adjunctive material. The AVM was completely eradicated in 18% (8/45) of patients (confirmed in angiography). Their patients were treated 2.93 times on average (range 1 to 9 sessions).

Complete resolution, defined as 100% devascularization of the AVM, was significantly more likely in the series of Su et al. [12], who used ethanol with coils in intraosseous AVM of the jaw, compared to ethanol along with NBCA or Onyx in soft tissue AVM in the series of Kim et al. [13] (p<0.001). There was no significant difference concerning treatment failure, defined as devascularization below 50% of the baseline with failure rates of 0% and 6.7% in the series of Su et al. [12] and Kim et al. [13] respectively (p = 0.358).

Overall complication rates differed significantly between the two treatment approaches (p = 0.006). Using Ethanol alone, Su et al. [12] reported complications in 50% of cases. Using a combination of Ethanol and NBCA or Onyx, Kim et al. [13] reported complications in 87% of cases. There, too, was a significant difference between the mean amount of treatment sessions each patient went through. Patients in the study of Su et al. [12] underwent 1.25 sessions, versus 2.93 sessions in the study of Kim et al. [40] (p = 0.004). Considering the small number of studies, we refrained from using visualization of the meta-analysis. The overview of the meta-analysis is outlined in Table 5.

Table 5

Overview of meta-analysis.

	Su et al. [12]	Kim et al. [13]	P-Value
n Patients	12	45	-
Resolution	83%	18%	<0.001
Mean sessions	1.25	2.93	0.004 (r = 0.38)
Failure	0%	6.7%	0.358
Complications	58.3%	86.7%	0.027

r = medium effect size.

Discussion

A major finding of our analysis was that therapeutic approaches for the management of AVMs vary considerably, not yielding treatment or reporting standards. Our literature review identified 56 articles with sclerotherapy and embolization as the primary treatment modality for AVMs of the head and neck. None of these used the same approach. Remarkably, none of these studies was prospective, hinting towards a publication bias. To our surprise, only two articles fulfilled the acceptable reference standard for meta-analysis. Hence, we were not able to reach our primary aim: to conduct a meta-analysis of interventional treatment for patients with extracranial AVM of the head and neck to identify a superior treatment.

The two articles included in the meta-analysis used ethanol applied by direct puncture of the nidus and transarterial injection (Su et al. [12]), or both direct nidus injection and transarterial application of ethanol with adjuvant use of either NBCA or Onyx (Kim et al. [13]). The approach of Su et al. [12] in the treatment of intraosseous AVMs of the jaw yielded a higher chance for beneficial outcome. They reached complete devascularization in 83% of patients which is superior to 18% of patients in the series of Kim et al. [13], who treated soft tissue AVMs (p<0.001). Kim et al. [13] performed additional surgical resection in 23 of 45 cases to correct residual cosmetic problems or to remove residual fistulas. In addition, Su et al. [12] needed significantly fewer treatment sessions than Kim et al. [13] (1.25 sessions versus 2.93 sessions) (p = 0.004) and had a significantly lower complication rate (50% versus 87%) (p = 0.006).

Given the low number of included cases, the varying reporting standards, and the heterogenous cohorts, the results of our qualitative analysis of the methodology must be interpreted with great care. For instance, the reviewed articles (excluding case series and case reports) included varying numbers of pre-treated patients with a range of 10% (6/62 patients)(33) to 90% (9/10 patients) [36]. Only 52 articles provided details on lesion extent and location, with varying accuracy. For example, Kim et al. [13] used the Schobinger system [41] to describe the characteristics of the AVM but did not report on the exact location in the head and neck region. Most articles summarized the location of the lesions with macroscopic expressions such as ‘cheek’, ‘temporal’, or ‘forehead’. Zou et al. [42] noted a difference between ‘localized’ or ‘diffuse’ lesions, depending on the tissue planes through which the AVM extended. AVM location, however, may have an impact on outcome rates, as has been suggested by Chen et al. [43], who found that intraosseous AVM of the jaw had a higher rate of complete involution in comparison to soft tissue lesions (89.3% and 60.7% respectively). With regard to this, Su et al. [12] reported of intraosseous AVM, which makes it questionable whether management and outcome of these AVM can be compared to that of cutaneous or soft tissue AVMs as studied by Kim et al. [13].

Furthermore, analysis of the results is impeded by the variety of treatment approaches and their combinations. Approaches to AVM obliteration include percutaneously and intravascularly applied sclerosants such as Ethanol, STS (Sodium Tetradecyl Sulfate), OK432 (Picibanil), and Bleomycin. These agents stimulate local inflammation of the endothelia causing thrombosis which occlude the vessel [44-46]. The risk of systemic or distal reactions to the agent has to be thoroughly assessed. Additionally, applied agents (NBCA, Polyvenylalcohol (Onyx), or galantine microspheres) block collaterals or outflow veins of the nidus [47]. Mechanical occlusion with coil depletion into the nidus is also reported [24]. In AVMs with multiple feeding arteries and a single draining vessel, direct puncture embolization may result in a more favorable outcome than the transarterial approach [48]. Adjuvant surgical interventions may be necessary to facilitate cosmetic reconstruction or restore essential structures.

Aside from interventional treatment options, targeted drug therapy has been the subject of recent research [49]. With vascular anomalies showing somatic mutations, cellular signaling pathway inhibitors such as Sirolimus may have a positive effect [50].

The side effects and complications arising from the use of sclerosants and embolization agents has been well-reported [51-56]. Forty-three of the 56 articles included a description of the complications arising during or after the procedures. Considering all reported complications, the mean complication rate amongst all articles, including case reports, was 31% -ranging from 0% to 100% (SD 36.8%). Complications were, however, inconsistently described. One author presented complications according to the Society of Interventional Radiology (SIR Table 6) [57] but did not provide any further details on the nature or management of the adverse effects.[58] Some implemented their own categorization, similar to the SIR, and gave further details on presentation and management [12,35]. Several authors did provide a statement as to whether or not complications had occurred, but did not specify what the complications were [13,22,59]. All others provided a detailed description of adverse effects and the management.

Table 6

Society of Interventional Radiology (SIR) classification system for complications and outcome.

Minor Complications
A.	No therapy, no consequence
B.	Nominal therapy, no consequence; includes overnight admission for observation only.
Major Complications
C.	Require therapy, minor hospitalization (<48 hours)
D.	Require major therapy, unplanned increase in level of care, prolonged hospitalization (>48 hours)
E.	Permanent adverse squelae
F.	Death

When looking at the complications in our meta-analysis group, we identified a significant difference between the occurrence of adverse effects. The high complication rate of 50% (Su et al. [12]) and 86.7% (Kim et al. [13]) in the usage of ethanol is, however, consistent with existing literature. Ethanol is known to cause necrosis, skin ulceration, nerve damage [60] and hemoglobinuria [61] as well as pulmonary hypertension if serum levels are too high [55]. Amongst the 56 articles, minor and reversible treatment side effects were extensively reported. They included skin ulcerations, discoloration, pain, and transient swelling and were conservatively managed. Major complications were reported by Kim et al. [13] and Pekkola et al. [59] and included swelling with the need for surgical decompression, one cerebral infarction and one retinal ischemia. In one study the patient died due to soft tissue necrosis and septicemia [62].

Lastly, varying outcome assessments and definitions make comparisons difficult. For instance, a devascularization above 90% is considered “complete” by three authors, but only considered as “partial” by nine others (Table 4). Additionally, non-standardized subjective outcome parameters impair comparability. In their systematic review, Horbach et al. [63] analyzed the quality of instruments for used for peripheral vascular lesions in patient- and physician-reported outcomes. They found few reliable and adequate measurement instruments that reflect the outcome of therapeutic interventions. They suggested that new specific instruments need to be developed to cover all relevant outcome domains. However, their work did not review the quality of radiologic assessment of vascular malformations.

Overall, research on treatment options for peripheral AVMs lack prospective, randomized trials and the reporting standards necessary to develop evidence-based management of these complex lesions. Therefore, we suggest the implementation of reporting standards for publications that include 1) a dynamic and/or angiographic imaging modality confirming the AVM and distinguishing it from other vascular entities, 2) a detailed description of the therapeutic management, 3) the definition of a devascularization of greater than 99% for complete resolution 4) a follow-up time of at least one year, with post-treatment imaging.

Strengths and limitations

This literature review has its strengths, particularly in the methods. The literature research was conducted in a very broad manner and articles on all vascular lesions, including AVM as well as VM and LM, were included in the initial search. After primary literature review, further relevant references were identified, adding to the integrity of the literature collection. The research was conducted using publicly open sources and is therefore reproducible. There are, however, several limitations. The initial literature research was conducted by only one individual which poses a risk of biases and errors. This risk was minimized by thorough assessment and consultation of experienced authors of medical publications. The inclusion criteria for meta-analysis were decided on within our institution, potentially leading to reporting and confirmation bias. Moreover, the identified articles focus on different localizations of AVM in the body, like intraosseous or soft tissue lesions. This leads to a heterogenic sample group which makes generalization difficult. Finally, some of the studies have a small sample size or are case reports and may therefore not be representative of the target population.

Conclusion

Our meta-analysis implies that intraarterial ethanol embolization result in high rates of complete devascularization of extracranial AVMs of the head and neck located in the bone tissue. However, our qualitative literature analysis revealed that only a small number of articles fulfil a level of methodological quality that allows comparison of treatment effects. Current literature is missing a standardized reporting system for diagnosis, management, and outcome of extracranial AVM, impairing comparability. Despite a considerably large number of publications on the topic, we conclude that to-date there is no robust evidence for a superior treatment strategy. Therefore, we recommend the implementation of standardized criteria for publications that include 1) a dynamic and/or angiographic imaging modality confirming the AVM and distinguishing it from other vascular entities, 2) a detailed description of the therapeutic management, 3) the definition of a devascularization of greater than 99% for complete resolution 4) a follow-up time of at least one year with post-treatment imaging.

(DOC)

Click here for additional data file.

PICO search terms.

Complete list of terms used for database search.

(DOCX)

Click here for additional data file.

Summary of the qualitative synthesis of methodology.

(DOCX)

Click here for additional data file.

Overview of meta-analysed studies: Su et al. [12].

(DOCX)

Click here for additional data file.

Overview of meta-analysed studies: Kim et al. [13].

(DOCX)

Click here for additional data file.

Comprehensive overview of reviewed articles not eligible for meta-analysis.

(DOCX)

Click here for additional data file.

Complete PubMed search string.

(DOCX)

Click here for additional data file.

Complete list of excluded studies.

(DOCX)

Click here for additional data file.

29 Dec 2021

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Stephan Meckel, MD, PhD

Academic Editor

PLOS ONE

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please use an established tool for the quality assessment of non-randomized interventional studies (e.g. the ROBINS-I https://www.bmj.com/content/355/bmj.i4919), which is also recommended in the reference #10 cited in your manuscript. Thank you for your attention to this request.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overall

Thank you for all of your efforts in this work. There is a clear rationale and introduction of the void in our knowledge of AVMs. The writer is up to date in technical and anatomic jargon of the topic. Most tables and supporting data are complete and of value.

I do have major concerns in the methodological set up of the paper. Throughout the review different objectives are stated and it seems if the main goal was altered in the process of writing the manuscript. In addition various adapted risk of bias tools are available for non-RCT studies, these could be easily applied to the present review. Although the writers are critical and aware of the potential biases in the selected articles and opted to critically appraise in Table S2, I believe among others study design and sample size should be included (e.g. assessing the papers on directness of evidence and risk of bias). At this point the review lacks an easily assessable overview (i.e. flowchart or supporting figure) of the various treatments performed and its outcome in terms of for example success or complication rate, which I believe is the main objective of the review. Plenty of published reviews have coped with heterogeneity in results and alternatively analysed (e.g. semi-quantitative) and visualized these results in various supporting manners.

I would also strongly advise to re-write the paper with a native English speaker as the paper contains multiple errors which decreases the joy of reading.

Abstract

Objective: I believe the secondary aim is obsolete as a methodological assessment of the selected papers is one of the key elements of performing a systematic review.

Methods: “Criteria for meta-analysis were implemented.” I think you are meaning to say that a meta-analysis was performed?

Results: “Outcome analysis 38 varied with 45% of the authors using imaging parameters and 77% indicating the span of 39 follow-up of their entire patient collective” > this sentence is very vague for a new reader who was not involved in the research process, please re-write.

Conclusion: This conclusion is not clear from the results section, please align these paragraphs.

Advances in knowledge: Please add “data on AVMs /reporting standards addressing treatment of AVMs”, in this manner it seems you are referring to all data available.

Introduction:

Lines 69 -70: This objective is different of the objective in the abstract, even though outcome is a consequence of a treatment, you should define what is “most effective treatment” ? What outcome are you interested in?

Lines 70-71: See previous comment: evaluating the methodological quality of these papers is part of the systematic review.

Line 73: Why are you only addressing the papers from 2000? Perhaps due to interventional developments? Please add your rationale.

Methods

Lines 90-92: Consider to only mention your search in August 2020, it is OK to update your search once it gets outdated during the writing process, though only if it is performed in a similar fashion. I would recommend to add a second reviewer in the primary selection of eligible articles (or a substantial percentage of the eligible articles)

Lines 112-113: In this statement you are narrowing your research question and this should be used throughout your manuscript.

Line 123: To my opinion comparison in the PICO structure should be the other invention group you are comparing with, so that would be any primary treatment other than “sclerotherapy and embolization” or any patient in need of a secondary treatment and so on. At this point the paragraph after “Comparison” is just a brief sentence of your “Outcome” paragraph and does not give any additional information.

Line 142: The authors should seek to another approach to adequately assess directness of evidence and risk of bias in the selected articles. They could also consider to discuss the case reports separately from the other articles with a sample size of e.g. >15 or >20 patients.

Results

Line 252: “four articles reported either mean of maximum follow-up time only” > if this FU was longer than 1 year I guess these articles could still be included (as is stated in the methods). If so, please add why these papers were excluded.

For a meta-analysis, Pearson Chi square and Mann Whitney U tests are not appropriate.

Discussion

Another goal “representative meta-analysis” is added for the first time in the discussion part. The objectives should be similar throughout the manuscript.

The discussion shows that the authors do have substantial knowledge of the subject as they are able to discuss and reflect on the different treatment options. It would be of interest if the authors could add their view on what the suggested reporting standards should contain or focus on.

Nevertheless all information on the meta-analysis is hazardous to me, since I doubt if the authors have used the appropriate statistical approach.

Line 367-369: To my opinion a long list of Author et al is not reader-friendly, please re-write.

Conclusion

All recommendations for reporting standards should be placed in the discussion. In addition please explain why >99% (why not 90%?) devascularisation is used and how this should be measured.

Also the strengths and limitations should be placed in the discussion.

Fig 1 PRISMA flowchart

- Please take note of the “simple” PRISMA set up of the flowchart in other published systematic reviews. This flowchart is quite chaotic and hard to follow for an interested reader.

Supporting data:

- Please add all supplemental data to one document to help the reader find the information they need to comprehend the message of your paper

- It would be better to give an summary score / rating to the separate articles in the table S2 in order to see which articles are the most appropriate to answer your research question. Also the table should stand on its own, meaning the table should be informative enough to fully understand independently of the paper. In my opinion the legend is too brief for a reader which is not as familiar with the subject as the writers.

- I understand the length of the Table S5 makes it unfavorable to add in the main body of the text, but as this table may be the most important finding of the study I would recommend the writers to think of another way to add this information to the main manuscript. Perhaps a clean flowchart with roughly categorized treatments and their success or complication rate would be of interest.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: Review PLOS ONE 19-05-21.docx

Click here for additional data file.

12 Feb 2022

Review Notes

Note #1

I do have major concerns in the methodological set up of the paper. Throughout the review different objectives are stated and it seems if the main goal was altered in the process of writing the manuscript.

Response: We would like to thank the reviewer as he/she accurately points out that in writing the manuscript, the description of the objects of the review are stated in a varying fashion. We have identified the inaccuracy in the text and changed the phrasing accordingly.

The following section was changed in the Abstract section:

“The primary aim of this study was to conduct a meta-analysis of the literature on interventional treatment for patients with extracranial AVM of the head and neck to identify a superior treatment. The secondary aim was to evaluate the methodological quality of associated articles published between 2000 - 2020.” (Clean Copy Line 25-28)

The following paragraph was changed in the Introduction:

“In this review we focused on the analysis of articles covering the treatment of extracranial AVMs of the head and neck with the use of sclerotherapy and embolization”. (Clean Copy Line 74-75)

The following sections was changed in the Discussion:

“A major finding of our analysis was that therapeutic approaches for the management of AVMs vary considerably, not yielding treatment or reporting standards.” (Clean Copy Line 303-304)

“Given the low number of included cases, the varying reporting standards, and the heterogenous cohorts, the results of our qualitative analysis of the methodology must be interpreted with great care.” (Clean Copy Line 324-326)

The following section was changed in the Conclusion:

“Our meta-analysis implies that intraarterial ethanol embolization result in high rates of complete devascularization of extracranial AVMs of the head and neck located in the bone tissue. However, our qualitative literature analysis revealed that only a small number of articles fulfil a level of methodological quality that allows comparison of treatment effects.” (Clean Copy Line 417-420)

Having set the criteria for eligibility for the meta-analysis before conducting the initial literature research, we were hesitant to change these in the process. This ensures a transparent and robust research and analysis procedure. However, the heterogeneous reporting quality of the publications prompted the authors to add appropriate objectives to yield results that may be of interest to the reader and maintain a credible meta-analysis eligibility.

Therefore, the reviewer is correct when mentioning this change of objectives throughout the process of writing.

It appears, that the fact that the criteria for eligibility for meta-analysis were developed by the authors themselves has not been described adequately throughout the manuscript. As seen above, we modified these sections accordingly.

Note #2

In addition, various adapted risk of bias tools are available for non-RCT studies, these could be easily applied to the present review.

We thank the reviewer for this remark. Risk of bias assessment is a crucial aspect in the evaluation of the quality of scientific literature and we have long discussed this issue during the process. As mentioned in the methods section lines 148-151 we found utilization of risk of bias tools obsolete for the identified articles as none of them compare different interventions. In line 148 to 151 we have outlined the possible biases that may be relevant in the literature. To date there is no appropriate tool for the assessment of the risk of bias available. In 2018 Bero et al. analyzed a tool for studies of exposure (ROBINS-E) but have identified practical concerns with it and concluded that it does not meet the standard for evaluation. (The risk of bias in observational studies of exposures (ROBINS-E) tool: concerns arising from application to observational studies of exposures. DOI: 10.1186/s13643-018-0915-2

Note #3

Although the writers are critical and aware of the potential biases in the selected articles and opted to critically appraise in Table S2, I believe among others study design and sample size should be included (e.g. assessing the papers on directness of evidence and risk of bias).

We would like to thank the reviewer for this remark. We did include details on all evaluated articles in Table S5 which can be found in the appendix. The amount of detailed information in that table was not deemed practical to be included in the manuscript as interested readers can easily access this additional information.

Note #4

At this point the review lacks an easily assessable overview (i.e. flowchart or supporting figure) of the various treatments performed and its outcome in terms of for example success or complication rate, which I believe is the main objective of the review. Plenty of published reviews have coped with heterogeneity in results and alternatively analyzed (e.g. semi-quantitative) and visualized these results in various supporting manners.

The reviewer rightfully points out another important aspect. A clear and simple overview of applied methods and reported results such as outcome and complications is a desirable asset to the readability of a review. After discussing the results of our review, the authors had to acknowledge the vast heterogeneity of the articles in terms of applied therapy, reported characteristics of the study groups and display of results. As this heterogeneity is one of the major findings of the review the authors decided not to design such an overview to prevent the suggestion of comparability of articles. The methodological shortcomings of the reviewed articles unfortunately prohibit such an overview.

Note #5

I would also strongly advise to re-write the paper with a native English speaker as the paper contains multiple errors which decreases the joy of reading.

We would like to thank the reviewer to bring up this issue. We have corrected the manuscript with the help of a native speaker to improve the readability of the text and enhance the joy of reading. All changes are traceable in the markup version attached. However, changes in formatting are not documented.

Abstract

Note #6

Objective: I believe the secondary aim is obsolete as a methodological assessment of the selected papers is one of the key elements of performing a systematic review.

We thank the reviewer to point out this inaccuracy. The section was corrected accordingly. Please see reviewers note #1.

Note #7

Methods: “Criteria for meta-analysis were implemented.” I think you are meaning to say that a meta-analysis was performed?

The reviewer brings out an important point. With the background of existing literature and clinical experience, the authors have agreed on criteria for articles to be eligible for meta-analysis. Those criteria are referred to in the above sentence. We thankfully corrected this confusing phrase and hope to improve comprehension.

We changed the following paragraph in Methods in the Abstract section:

“The literature search was conducted on PubMed, Embase, the Cochrane Library, and scholar.google.com. Studies, meeting the acceptable reference standard underwent meta-analysis. All identified literature underwent methodological quality analysis.” (Clean Copy Line 31-33)

Note #8

Results: “Outcome analysis 38 varied with 45% of the authors using imaging parameters and 77% indicating the span of 39 follow-up of their entire patient collective” > this sentence is very vague for a new reader who was not involved in the research process, please re-write.

We thank the reviewer for pointing out the vague phrasing. We have re-written the section in Results in the Abstract section:

“Outcome analysis varied throughout. 45% of the authors used radiographic imaging for follow-up. 77% specified the span of follow-up of their entire patient collective.” (Clean Copy Line 38-40)

Note #9

Conclusion: This conclusion is not clear from the results section, please align these paragraphs.

We would like to thank the reviewer for highlighting this issue of confusion. Results of meta-analysis and the methodological quality should not be confused and should not imply unrepresentative results. We have aligned these sections and added details where appropriate.

We changed the following paragraph in Conclusion in the Abstract section:

“Our literature review revealed an absence of treatment or reporting standards for extracranial AVM of the head and neck. The meta-analysis is comprised of two articles and methodological quality is heterogeneous. We recommend implementing consistent reporting standards to facilitate comparability of studies and to provide robust data for the development of an evidence-based treatment strategy.” (Clean Copy Line 46-50)

We changed the following paragraphs in the Discussion:

“A major finding of our analysis was that therapeutic approaches for the management of AVMs vary considerably, not yielding treatment or reporting standards.” (Clean Copy Line 303-304)

“Given the low number of included cases, the varying reporting standards, and the heterogenous cohorts, the results of our qualitative analysis of the methodology must be interpreted with great care.” (Clean Copy Line 324-326)

Note #10

Advances in knowledge: Please add “data on AVMs /reporting standards addressing treatment of AVMs”, in this manner it seems you are referring to all data available.

We have thankfully corrected this confusing phrase and added the necessary information.

We changed the following phrasing in the Advances in knowledge in the Abstract:

“Our analysis demonstrated that the published data on extracranial AVMs of the head and neck is lacking in consistency and quality, prompting agreement for the need of standardized reporting on AVM treatments.” (Clean Copy Lines 54-56)

Note #11

Introduction:

Lines 69 -70: This objective is different of the objective in the abstract, even though outcome is a consequence of a treatment, you should define what is “most effective treatment” ? What outcome are you interested in?

We thank the reviewer for showing this poor phrasing and have specified the outcome.

We changed the following section in the Introduction:

“In this review we focused on the analysis of articles covering the treatment of extracranial AVMs of the head and neck with the use of sclerotherapy and embolization.” (Clean Copy Line 74-75)

Note #12

Lines 70-71: See previous comment: evaluating the methodological quality of these papers is part of the systematic review.

See previous correction. We changed the following paragraph in the Introduction:

“Prior to the initial research, we developed the inclusion criteria for eligibility for meta-analysis (or acceptable reference standard). Methodological quality standards for analyzing the remaining articles were developed during the review process.” (Clean Copy Line 75-78)

Note #13

Line 73: Why are you only addressing the papers from 2000? Perhaps due to interventional developments? Please add your rationale.

We thank the reviewer for asking this important question. We have indeed considered this time frame since development of interventional radiology has been most remarkable during that time. We have thankfully added the rational in the methods section.

We changed the following section in the Methods:

“This studied timeline marks a rapid progression in the evolution of interventional radiology.” (Clean Copy Line 102-103)

Note #14

Methods

Lines 90-92: Consider to only mention your search in August 2020, it is OK to update your search once it gets outdated during the writing process, though only if it is performed in a similar fashion. I would recommend to add a second reviewer in the primary selection of eligible articles (or a substantial percentage of the eligible articles)

This sentence was phrased in a confusing manner. We did not perform additional research during the process of the review. Instead, we have added articles found in quotes and citations. This was done to ensure that results from the entirety of existing literature was analysed. The applied search string and keywords might have been missing vital aspects of the topic. By doing so we tried to reduce this possibility to a minimum.

We have rephrased the sentence from the Methods section to reduce the misunderstanding.

“Further publications identified in citations and quotes throughout the initial literature review were included in scope and underwent the same review process, with the last addition made in August 2020.” (Clean Copy Line 98-100)

Note #15

Lines 112-113: In this statement you are narrowing your research question and this should be used throughout your manuscript.

We thank the reviewer for this comment and have used the narrowing of the research question throughout the manuscript.

Note #16

Line 123: To my opinion comparison in the PICO structure should be the other invention group you are comparing with, so that would be any primary treatment other than “sclerotherapy and embolization” or any patient in need of a secondary treatment and so on. At this point the paragraph after “Comparison” is just a brief sentence of your “Outcome” paragraph and does not give any additional information.

We thank the reviewer for the remark that correctly points out the rationale for the comparison of treatment options. One of the findings of our work was that to date there is no treatment standard for extracranial AVM and no superior treatment option has been identified. A comparison to an established treatment would make sense, as has been stated by the reviewer. The authors have opted to aim to identify a superior treatment option within the already implemented options. This information was humbly put in the manuscript.

We added the following paragraph in the Comparison section in the Methods:

“Leveraging meta-analysis, we compared radiological outcome and complication rates of the different treatment options for extracranial AVMs with the goal of identifying a superior treatment method within the existing literature.” (Clean Copy Line 132-134)

Note #17

Line 142: The authors should seek to another approach to adequately assess directness of evidence and risk of bias in the selected articles.

As mentioned in note #2 the authors have planned to implement risk of bias tool before conducting the initial research. It was deemed obsolete to implement these tools for all articles, but the authors indeed took up this suggestion for articles that were meta-analysed and used the ROBINS-I tool. The directness of evidence of all articles is outlined in the manuscript in the result section. As mentioned above, the authors have refrained from further assessment as results may yield wrongly suggestive results.

Note #18

They could also consider to discuss the case reports separately from the other articles with a sample size of e.g. >15 or >20 patients.

This suggestion by the reviewer is valuable for the discussion of the setup of the review. The authors designed the review without a limit to the sample size in order not to miss data and results. Considering the low incidence of extracranial AVM of the head and neck, results from any published treatment option may be of benefit. Thus, publication bias for the analysed literature can be limited. Furthermore, if the authors altered study groups or developed sub-groups in the process, results that may wrongfully suggest superior therapies can emerge. The authors tried to prevent this effect by purposefully leaving the sample size unrestricted.

Results

Note #19

Line 252: “four articles reported either mean of maximum follow-up time only” > if this FU was longer than 1 year I guess these articles could still be included (as is stated in the methods). If so, please add why these papers were excluded.

We would like to thank the reviewer for this comment. In designing the study, the authors agreed to limit the minimum time of follow-up to one year. This means that all included individuals from the study groups must have a minimum follow-up time of one year or 360 days. If articles only stated, the mean follow-up time there is a possibility that not all individuals have had that minimum requirement. The same applies for the maximum follow-up time. The authors do agree with the reviewer that the phrasing was unclear and have corrected the sentence in the Quality of follow-up section in Methods:

“For cerebral AVM, a minimum follow-up period of one year is recommended to detect lesion recurrence after therapy.(9) Analogously, a follow-up time of at least one year was considered necessary for inclusion in our meta-analysis. As mean or median time of follow-up of the study group (as well as maximum) time do not yield information on the individual minimum follow-up time, that data alone was considered insufficient, and the related literature was excluded from analysis.” (Clean Copy Line 180-185)

Note #20

For a meta-analysis, Pearson Chi square and Mann Whitney U tests are not appropriate.

This is an important remark that we implemented in the manuscript. We have now applied Chi-square for the calculation of a significance in difference. In general, we would have liked to apply regression tables to perform a more precise calculation in the meta-analysis and visualization with forest-plots. Since we could only identify two studies to undergo these calculations, we decided to use Chi square as straight forward and solid approach for this statistical issue. As this does indeed show a limitation of the quantitative analysis, we gave explanation in the limitation section.

Discussion

Note #21

Another goal “representative meta-analysis” is added for the first time in the discussion part. The objectives should be similar throughout the manuscript.

We thank the reviewer for pointing this issue out. We have revised all sections of the manuscript regarding the phrasing and details on the objectives of the study. Particularly the discrimination between the implementation of the acceptable reference standards, the conducted meta-analysis, and the qualitative analysis of the methodology of the articles was verified and corrections were made.

Note #22

The discussion shows that the authors do have substantial knowledge of the subject as they are able to discuss and reflect on the different treatment options. It would be of interest if the authors could add their view on what the suggested reporting standards should contain or focus on.

We appreciate the reviewer’s interest in the authors’ suggestions for reporting standards. To emphasize the subjective character of these suggestions the authors added four aspects for future reporting standards at the end of the Discussion and in the Conclusion.

Note #23

Line 367-369: To my opinion a long list of Author et al is not reader-friendly, please re-write.

We thankfully received the suggestions and changed the section in Discussion accordingly.

“Lastly, varying outcome assessments and definitions make comparisons difficult. For instance, a devascularization above 90% is considered “complete” by three authors, but only considered as “partial” by nine others (Table 4).” (Clean Copy Line 383-385)

Conclusion

Note #24

All recommendations for reporting standards should be placed in the discussion. In addition please explain why >99% (why not 90%?)a devascularisation is used and how this should be measured.

Regarding suggestions for reporting standards, please see note #20 above.

For radiographic extinction of an AVM lesion, proof of complete devascularization is necessary. When suggesting a 90% devascularization as adequate, the reader may come to believe that the status “cure” may also be obtained with the detection of a residual nidus. This can lead to misunderstanding when looking at the results of the qualitative analysis of the articles, where “cure” is a vague term. Therefore, the nidus must not be detectable in DSA while leaving the chance of missing that 1% of contrast volume with the naked eye in DSA.

Note #24

Also the strengths and limitations should be placed in the discussion.

We thank the reviewer for this valuable point and have changed the sections accordingly.

Note #25

Fig 1 PRISMA flowchart

- Please take note of the “simple” PRISMA set up of the flowchart in other published systematic reviews. This flowchart is quite chaotic and hard to follow for an interested reader.

This is a very helpful suggestion by the reviewer and has helped us to redesign the graph in hopes to show a clearer picture of the research process. (Please see attached Fig1_Revised)

Supporting data:

Note #26

Please add all supplemental data to one document to help the reader find the information they need to comprehend the message of your paper

When submitting the manuscript and the supporting data, we held on to the submission guidelines outlined on the PLOS webpage. If there is need to change the layout or order of the submitted data, we are more than happy to do so.

Note #27

It would be better to give an summary score / rating to the separate articles in the table S2 in order to see which articles are the most appropriate to answer your research question. Also the table should stand on its own, meaning the table should be informative enough to fully understand independently of the paper. In my opinion the legend is too brief for a reader which is not as familiar with the subject as the writers.

This comment is very helpful to recognize the importance of clear and brief overviews and has been a point of discussion for the authors in the past, as seen in Note #4. A scoring system or any other form of ranking of the articles may suggest to the reader that reporting standards were maintained by the authors of the literature to a varying extend. Yet, there are no standards, and such ranking may wrongfully imply the superiority of the quality of one article over another. Therefore, we would rather not consider such a method at this point. If, however, the application of other symbols or coloring were of help for readability, we would be happy to improve the table in the desired way.

Note #28

I understand the length of the Table S5 makes it unfavorable to add in the main body of the text, but as this table may be the most important finding of the study I would recommend the writers to think of another way to add this information to the main manuscript. Perhaps a clean flowchart with roughly categorized treatments and their success or complication rate would be of interest.

This important issue has been pointed out by the review and is addressed in note #4 and #27. We would like to refer to the answers there. However, we are happy to consider changes in this regard if the reviewer still deems this of utmost importance.

10 May 2022

Interventional therapy of extracranial arteriovenous malformations of the head and neck – A systematic review

PONE-D-21-11556R1

Dear Dr. Nikoubashman,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

In your final version please add an example figure as outlined by reviewer 1 of an AVM pre and post embolization!

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Stephan Meckel, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All comments have been successfully addressed and I am pleased with the revised manuscript and supportive rationale. One last remark as cherry on top of the manuscript; it would be interesting to add an example figure of i.e. DSA before and after treatment of the AVM. Best wishes in future research

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Constance JHCM van Laarhoven, MD PhD

20 May 2022

PONE-D-21-11556R1

Interventional therapy of extracranial arteriovenous malformations of the head and neck – A systematic review

Dear Dr. Nikoubashman:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Prof. Dr. Stephan Meckel

Academic Editor

PLOS ONE