Preoperative Imaging in Patients with 22q11 Deletion Syndrome Undergoing Velopharyngeal Surgery

Abstract

Objective:

To evaluate the utility of preoperative imaging before velopharyngeal dysfunction (VPD) surgery in children with 22q11 Deletion Syndrome (22qDS) in evaluating internal carotid artery (ICA) medialization.

Data Sources:

PubMed, Scopus, and CINAHL

Review Methods:

Following PRISMA guidelines, a systematic review was performed. Studies of children with 22qDS who underwent preoperative imaging (MRA or CTA) to identify ICA anomalies were included. High-risk medialized ICAs were defined as either submucosal, retropharyngeal, Pfeiffer Grade III-IV, or <3mm from the pharyngeal mucosa. Meta-analyses of proportions were performed.

Results:

Eleven studies met inclusion criteria, comprising 398 patients with 22qDS (weighted mean age 7.6 years). In 372 patients with imaging, the rate of ICA medialization on imaging was 47.1% (95%CI 29.2-65.5), of which 46.3% (95%CI 27.4-65.8) were determined high-risk. Operative plans were modified in 19.4% (95%CI 5.7-38.8) of 254 surgeries due to medialized ICA. In studies attempting to use nasopharyngoscopy pulsations to identify medialization for 214 patients, the true-positive rate was 53.9% (95%CI 27.5-79.2), and the false-positive rate was 16.2% (95%CI 7.9-26.8). Nine of eleven studies (81.8%) recommended universal preoperative imaging of the ICAs in children with 22qDS undergoing VPD surgery. No cases of perioperative bleeding secondary to ICA injury were identified.

Conclusion:

While most studies endorse routine preoperative imaging to assess for ICA medialization in children with 22qDS undergoing VPD surgery, only a minority of these cases led to surgical modification. Additional studies are needed to compare outcomes in children with and without preoperative imaging given the low rates of ICA injury in the literature.

Lay Summary:

A meta-analysis evaluated the debated use of preoperative imaging before velopharyngeal surgery to assess for medicalized ICAs in patients with 22qDS. Most studies supported the use of routine preoperative ICA imaging, with low rates of operative modifications and complications.

Introduction

The incidence of 22q11 Deletion Syndrome (22qDS) is one in 2,000 to 7,000 births and encompasses DiGeorge, Velocardiofacial (VCFS), Conotruncal anomaly face, autosomal dominant Opitz G, and Cayler cardiofacial syndromes.^1–9 Compared to the general population, there is a high prevalence of velopharyngeal dysfunction (VPD), or velopharyngeal insufficiency (VPI), in children with 22qDS due to a combination of structural and functional anomalies.^1,4,10 Anatomical anomalies may include shortened palate, palatal and pharyngeal asymmetry, irregular pharyngeal muscle fiber size and distribution, and velopharyngeal disproportion, while functional anomalies include velopharyngeal muscle hypotonia and wall dysmotility.^1,4,10 Without repair, VPD can cause hypernasal speech, inappropriate nasal emission or turbulence, nasal grimacing, poor speech intelligibility, difficulties swallowing, and nasal regurgitation.^1,9,11–14 In addition to being more prevalent in children with 22qDS, VPD is often more severe and refractory to nonsurgical management, and children with 22qDS frequently experience less favorable post-operative outcomes and require revision of VPD repair at higher rates.^{1,4,10,11,15–17}

Furthermore, treating VPD in this population is challenging due to concerns of medialization of the internal carotid artery (ICA).^3,9,18–21 In the usual position, the ICA is 1 to 1.5cm away from the pharyngeal operative field; however, medialization can reduce this distance to millimeters.²² The concern of ICA medialization in 22qDS velopharyngeal procedures was first described in 1987 by Mackenzie-Stepner et al.^9,22,23 During routine preoperative nasopharyngoscopy to assess VPD, three children were noted to have posterior pharyngeal wall pulsations. The authors hypothesized that ICA displacement was causing the pulsations, which was then confirmed by imaging. Surgery was deemed contraindicated in two children who instead received a prosthetic appliance for VPD treatment. The third child underwent a modified narrow pharyngeal flap, which failed and ultimately required a prosthetic. The authors concluded that irregular pulsations on preoperative nasopharyngoscopy warranted a CT followed by arteriogram. Furthermore, the authors stated that velopharyngeal surgery is contraindicated if the ICAs were displaced into the area of the flap.²² Since this article’s publication, many proponents have recommended universal imaging of the ICAs for operative planning and to assess for medialization before velopharyngeal surgery in children with 22qDS.^9,22–24

However, routine imaging for preoperative preparation remains controversial.^3,11,23 Routine imaging was contested in 1998 when Witt et al. advised pharyngeal surgery for VPD would be safe without imaging; however, the article has been criticized due to deficient substantial scientific evidence errors including data based on anecdotes and surveys.^1,21,25,26 Moreover, routine imaging is not benign, as there are concerns of radiation exposure, sedation, and cost-effectiveness.^{3,9,12,19,25,27–29} Instead, some suggest using nasopharyngeal endoscopy to observe for pulsations and assume medial deviation.^21,27 Some propose obtaining imaging only if pulsations are present,³⁰ while other studies question the relationship of pulsations and medialization, as well as whether pulsations and/or medialization is surgically relevant with precise dissection.^{13,24,25,28,31,32}

Although ICA medial displacement is a concern in velopharyngeal surgeries, there is no consensus on whether routine preoperative imaging should be obtained in all children with 22qDS before VPD surgery.^3,11,23 Therefore, we performed a systematic review and meta-analysis to evaluate the role of ICA imaging before VPD surgery in children with 22qDS.

Methods

Search Criteria

Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was performed.³³ No prior reviews of our topic were identified. Comprehensive search criteria were created for the following databases: PubMed (U.S. National Library of Medicine, National Institutes of Health), Scopus (Elsevier), and CINAHL (EBSCO). A search strategy was formed by two authors (K.A.D. and N.S.P.) using a combination of subject headings (e.g., MeSH in PubMed) and keywords around the terms “22q11 Deletion Syndrome”, “imaging”, “surgical procedures”, and “pediatrics”. The strategy used to search PubMed was modified for the two remaining databases by using similar keywords and substituting MeSH terms with appropriate subject headings when available. The three databases were searched from the date of inception through May 17, 2022. Appendix A includes comprehensive search strategies, filters used, and the number of results for each database. Reference lists containing pertinent studies were manually searched to ensure that the search strategy did not miss any vital articles. The articles were selected using the review management software Covidence (Veritas Health Innovation Ltd, Melbourne, Australia).

Selection Criteria

Eligibility criteria for studies were defined utilizing the PEO (participants, exposure, outcome) framework. Studies of children with 22qDS (P) who underwent preoperative imaging (E) to identify ICA anomalies (O) were included. Secondary outcomes were: higher-risk ICA medialization, rates of ICA anomaly in patients without 22qDS, whether surgical plans were modified or abandoned based on ICA findings, presence of surgical complications, and preoperative nasopharyngoscopy prediction of ICA anomaly on imaging. Studies were not required to have a control arm of children without 22qDS to be included in this systematic review. Double- or single-blinded randomized controlled trials, double- or single-blinded randomized comparison trials, non-randomized controlled trials, and prospective or retrospective observational studies were considered for inclusion. All studies included children with 22qDS undergoing workup for surgery to correct VPD. Exclusion criteria consisted of studies that did not evaluate large vessels with imaging, non-English language, non-human studies, review articles, case reports of less than four children, non-pediatric populations, studies without outcome data, and duplicate studies. For comprehensiveness, studies with children and patients older than 18 years old were included in this review.

Two authors (K.A.D. and N.S.P.) evaluated titles and abstracts to identify all articles that initially met the inclusion criteria. Disagreements were resolved by discussion with a third author (P.P.P.). Two reviewers (K.A.D. and N.S.P.) then individually evaluated the full texts of articles to identify those meeting all inclusion and exclusion criteria for the final analysis; conflicts were resolved by a third author (P.P.P.).

The evidence level of included articles was assessed using The Oxford Center for Evidence-Based Medicine criteria.³⁴ The Cochrane Handbook for Systematic Reviews of Interventions Version 6.0 was followed to assess the risk of bias.³⁵ Because all included articles were retrospective reports, the Risk of Bias in Non-Randomized Studies – of Interventions (ROBINS-I) tool was utilized.³⁶ Each study was graded as either “low”, “moderate”, or “serious” risk of bias in the following elements: bias due to confounding, bias in selecting participants, bias in intervention classification, bias due to deviating from intended interventions, bias due to missing data, bias in the measurement of outcomes, and bias in selecting reported results. Two authors (K.A.D. and N.S.P.) individually evaluated three studies and compared results to ensure consistency. Both authors then performed an independent risk assessment on the remaining studies, with all disagreements being resolved by a third author (P.P.P.).

Data Extraction

Two authors (K.A.D. and N.S.P.) individually compiled the data and compared for accuracy. Author, year of publication, and participant demographics, including age and sex, were recorded. The imaging modality (CTA or MRA), type of ICA anomaly, and severity of medial displacement were extracted. First, the presence of all ICA anomalies were collected, which encompassed medialization along with other ICA aberrancies, such as hypoplasia, tortuosity, kinking, and anterior deviation.^{3,23,24,28,29,32} Vessels with a bifurcation at a more cranial or caudal level than expected or asymmetric vessels were not considered an anomaly.³ Then, ICAs with medialization were specifically extracted, defined as deviating from a vertical course parallel with cervical vertebrae and instead aiming toward the pharyngeal midline 25% from normal course or more.²⁴ Furthermore, high-risk medially deviated ICAs were extracted, defined as submucosal, retropharyngeal, abutting the Levator veli palatini muscle, 50% or more deviation, Pfeiffer Clinico-radiological Grade III-IV (high-very high risk for injury based on level of aberrancy and distance from pharyngeal wall),³⁷ or <3mm from the pharyngeal mucosa.^{13,23–25,28,30} The clinical classification system for aberrant ICAs first proposed by Pfeiffer and Ridder ranges from Grade I (which corresponds to a low risk potential for ICA injury with the ICA located at least 10 mm from the pharyngeal wall and the deviation at the level of the nasopharynx or oropharynx) to Grade IV (very high risk, with the ICA 2 mm or less to the pharyngeal wall and deviation within the level of nasopharynx or oropharynx).^37,38 The number of successful procedures and surgical complications were recorded. The number of patients whose operative approach was altered due to imaging-confirmed ICA medialization and patients with surgical cancellation or abandonment due to medialization was also noted. We defined “modifying surgical plans based on imaging” if there was a change in the operative method (e.g., altering the pharyngeal flap location or size) but not canceling the surgery. Preoperative surgical cancellation and intraoperative surgical termination based on medialized ICAs were considered surgical abandonment. Postoperative complication rates were collected and included hemorrhage, obstructive sleep apnea, or readmission directly related to the surgery. Nasopharyngoscopy predictability was described using true-positive, false-positive, and false-negative rates when compared to imaged-confirmed ICA medialization. On nasopharyngoscopy, each patient could have none, one, or both medialized ICAs, with the rates calculated per ICA. Lastly, data were collected on whether each study supported or opposed the use of universal preoperative imaging in children with 22qDS.

Statistical Analysis

Categorical data were summarized by frequencies with percentages, while continuous data were presented by mean ± SD or range (minimum, maximum). Utilizing MedCalc 20.011 (MedCalc Software, Belgium), meta-analysis of proportions was performed. The pooled measures for this analysis included the presence of ICA anomaly, ICA medialization in both patients with 22qDS and controls, high-risk medialization, nasopharyngoscopy predictability, surgical termination, surgical plan modification, and surgical complications. These measures were weighted according to the number of patients in each particular outcome. The Freeman-Tukey transformation was used to calculate the weighted summary proportion from each study included in the meta-analysis.³⁹ If these analyses suggested high heterogeneity (I²>50%), the fixed-effects model was considered invalid, and the random-effects model was deemed more appropriate.^40,41 A random-effect model incorporates both the random variation within and between different studies.^40,41 Additionally, we performed sensitivity analyses in multiple meta-analyses to assure findings were not driven by a few studies with higher likelihood of bias. Lastly, Egger’s tests with funnel plots were performed to assess the risk of publication bias.^42,43 Potential publication bias was evaluated by Egger’s regression test, which statistically examines the asymmetry of the funnel plot.⁴² Visual inspection of the funnel plot was also used, as bias results in an asymmetrical funnel plot. A p-value of <0.05 was considered statistically significant for all statistical tests.

Results

Search Results and Study Characteristics

The literature search generated 677 unique articles; screening titles and abstracts further excluded 640 studies. The remaining 37 articles were reviewed in full text, and 26 additional studies were excluded. A total of 11 articles underwent final data extraction and analysis. Demonstrated in Figure 1 is the PRISMA flowchart detailing the complete search procedure. Critical appraisal of studies indicated an acceptably low risk of bias for most studies (Figure S1). The most prevalent biases were bias due to the selection of participants into the study and bias in measurement of outcomes. A funnel plot with Egger’s test suggested little publication bias; all except two articles were within the funnel with no asymmetry (2.5 95%CI −3.8-8.8, p=0.388) [Figure S2]. As detailed in Table 1, all studies included for data analysis were either level 3b or 4 articles according to the Oxford Level of Evidence and were published between 1996 and 2020 across seven countries.⁴⁴

Figure 1.

PRISMA flow diagram of study selection. PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Table 1.

Description of Included Studies of Children with 22qDS with Preoperative Imaging and Controls without 22qDS

Author (Year)	OLE	Study Design	Total 22qDS Patients (N)	Patient Age Mean, Year (Range)	Patient Male (%)	Patients with Imaging (N)	ICA Anomaly (N)	ICA Medialization (N)	Completed surgery (N)	Total Controls (N)	Controls, ICA Medialization (N)	Type of imaging used	Recommends universal preoperative imaging? (Yes/No)
Álvarez Carvajal (2018)	4	CS	8	9.25 (4-17)	75.0	8	2	2	8	0	NA	CTA	Y
Baek (2013)	3b	CC	23	9.7 (NR)	60.9	23	10	10	23	21	3	MRA*	N
Bois (2017)	4	CS	9	7 (4-11)	55.6	9	9	9	9	0	NA	MRA or CTA	Y
Fallico (2020)	4	CS	40	NR (NR)	47.5	23	7	7	NR	0	NA	MRA	Y
Kimia (2020)	4	CS	90	7.34 (0.85-17.2)	47.8	90	29	23	NR	0	NA	MRA	Y
Lai (2004)	4	CS	7	6.9 (3-11)	42.9	7	5	3	6	0	NA	MRA and/or CTA	Y
Mitnick (1996)	4	CS	20	NR (3-32)	45.0	20	13	12	15	0	NA	MRA	Y
Oppenheimer (2010)	3b	CC	86	8 (3-24)	53.5	86	NR	42	NR	50	5	MRA	Y
Ross (1996)	3b	CC	25	7.6 (4.5-14.1)	56.0	25	25	25	NR	5	0	CTA	N
Stransky (2015)	4	CS	70	6.9 (3-16)	48.6	70	38	10	69	0	NA	MRA or CTA	Y
Tatum (2002)	4	CS	20	6.2 (4-17)	55.0	20	20	13	20	0	NA	MRA or CTA	Y

CC = case-control; CS = case series; CTA = Computed Tomography Angiography; ICA = Internal Carotid Artery; OLE = Oxford Level of Evidence; N = number of participants; NA = not applicable; NR = not reported; MRA = Magnetic Resonance Angiogram; 22qDS = 22q11 Deletion Syndrome;

^*n=1 underwent CTA because imaging was originally to evaluate levator veli palatini muscle hypoplasia

Patient Characteristics

The eleven studies that met inclusion criteria comprised 398 patients with 22qDS and 76 control patients without 22qDS (Table 1). The weighted mean age was 7.6 years (range, 0.9 - 32.0) in the group of patients with 22qDS and 11.5 years (range, 2.0 to 24.0) years in the group of controls. Two studies included patients older than 18 years old; one with twenty patients ranging from 3 to 32 years,²⁸ and another with 86 patients from 3 to 24 years old and a mean age of 8.0 years.²⁵ Within the studies that reported sex, males made up 50.8% of patients with 22qDS and 71.4% of controls. All but one study obtained imaging in every patient, with a total of 381 total patients with 22qDS in our analysis undergoing imaging.²³ Two of the articles with controls included participants who did not have VPD but had accessible oropharyngeal imaging,^2,25 while the third analyzed five controls with VPD.³⁰

Internal Carotid Artery Anomalies

Nine studies (81.8%) reported extractable data on rates of ICA abnormalities of any kind within 286 patients with 22qDS.^{3,9,23,24,28–32} All studies published data on the rate of medialization in the 381 patients with 22qDS who received imaging.^{3,9,13,23–25,28–32} One article with 9 patients was excluded from the medialization rate calculation because only patients with 22qDS who had medialized ICA and deemed ineligible for pharyngoplasty surgery were assessed,¹³ leaving 372 patients included in calculating the medialization rate. In patients with 22qDS, the rate of ICA abnormalities of any form was 57.3% (95%CI 32.5-80.3). The rate of ICA medialization was 47.1% (95%CI 29.2-65.5) [Figure 2]. Seven studies (63.6%) reported rates of high-risk medialization in 273 patients with 22qDS, of which 131 had ICA medialization.^{3,13,23–25,28,30} Of the patients with imaging-confirmed ICA medialization, 46.3% (95%CI 27.4-65.8) were high-risk (29.5% of total patients including those without medialization, [95%CI 13.0-49.4]) [Figure 3]. Three studies (27.3%) recorded extractable data about ICA medial deviation within 76 controls without 22qDS.^9,25,30 The rate of medialized ICA within controls was 11.5% (95%CI 5.4-20.6).

Figure 2.

ICA Medialization in Patients with 22qDS. ICA = internal carotid artery; 22qDS = 22q11 Deletion Syndrome

Figure 3.

High-Risk ICA Medialization in Patients with 22qDS. ICA= internal carotid artery; 22qDS = 22q11 Deletion Syndrome

Procedure modifications and abandonment

Eight studies (72.7%) reported data regarding modifying operative plans based on imaging-discovered medialization.^{3,9,13,23,24,29,31,32} Surgical approaches were modified in 19.4% (95%CI 5.7-38.8) of 254 patients in the entire cohort, including those with normal imaging findings (Figure 4). Surgical approaches were modified in 43.3% (95%CI 15.5-73.7) of 77 patients with medialized ICAs. All studies except three described data on procedure cancellation based on medialization concerns.^{3,9,13,23,24,28,29,31,32} Surgery was abandoned in 1.2% (95%CI 0.3-3.3) of 274 patients overall and 3.6% (95%CI 0.9-9.4) of 89 patients with medialization.

Figure 4.

Surgical Plan Modifications in Patients with 22qDS. 22qDS = 22q11 Deletion Syndrome

Procedure Complications

Postoperative complication rates were described by eight studies (72.7%) consisting of 235 patients with 22qDS.^{3,9,13,24,28,29,31,32} Within those who received surgery, the proportion of patients with postoperative complications of obstructive sleep apnea or readmission was 3.6% (95%CI 1.6-6.8) [Figure 5]. There was no hemorrhage secondary to ICA injury.

Figure 5.

Surgical Complications in Patients with 22qDS. 22qDS = 22q11 Deletion Syndrome

Nasopharyngoscopy Predicting Medialization

Six articles (54.5%) described data on the relationship of pulsations observed on nasopharyngoscopy and imaging-confirmed ICA medialization, with 214 arteries observed on nasopharyngoscopy, 79 being medialized.^{13,24,25,28,31,32} The true-positive rate was 53.9% (95%CI 27.5-79.2), the false-positive rate was 16.2% (95%CI 7.9-26.8), and the false-negative rate was 18.4% (95%CI 4.5-38.7) [Figure 6].

Figure 6.

Nasopharyngoscopy False-Negative Rates in Patients with 22qDS. 22qDS = 22q11 Deletion Syndrome

Sensitivity Analyses

In the sensitivity analysis, excluding the article in which all patients were not imaged,²³ the rate of ICA anomalies in 263 patients was 60.7% (95%CI 32.9-85.1) and the rate of ICA medialization in 349 patients was 49.0% (95%CI 29.3-68.9). Further, in the sensitivity analysis in which two studies with ICA anomaly rates of 100% were removed,^24,30 the rate of ICA anomaly in 241 patients was 37.6% (95%CI 25.6-50.5). In the sensitivity analyses excluding two studies with wide confidence intervals,^31,32 the rate of ICA medialization in 357 patients was 49.6% (95%CI 29.2-70.1), the rate of surgical modifications in 239 patients was 17.1% (95%CI 3.2-38.9), and the rate of postoperative complications in 221 patients was 3.0 (95%CI 0.4-7.7).

Recommending preoperative imaging

Nine of the eleven studies (81.8%) recommended universal preoperative imaging of the ICAs in children with 22qDS undergoing VPD surgery,^{3,13,23–25,28,29,31,32} with two recommending against routine imaging. One article opposing universal imaging supported using nasopharyngoscopy initially then pursuing further imaging if pulsations were observed.³⁰ The other cited concerns regarding cost and complexity of imaging children and instead proposed the use of intraoperative Doppler ultrasonography to assess for ICA position in high risk-patients, as previously suggested by Pfeiffer et al.^9,37

Discussion

Children with 22qDS have a higher incidence of VPD requiring surgical treatment then the general pediatric population.^{1,4,9–11,14–17} The use of preoperative imaging for ICA medialization in VPD surgery planning among children with 22qDS is debated. Concern for ICA medial displacement was first raised when it was proposed that children with 22qDS should not undergo VPD surgery without ruling out ICA medialization.^9,22,23 Since then, more providers began obtaining imaging to evaluate for ICA placement preoperatively via imaging in this population.^22,24 However, some question the utility and cost-effectiveness of universal imaging and consider pharyngeal wall pulsations on preoperative nasopharyngeal endoscopy sufficient to ascertain ICA anomalies, while others question whether pulsations and/or ICA medialization is surgically relevant with precise dissection.^9,21,27 A survey of VPD surgeons caring for patients with 22qDS found variability in preoperative practices between surgeons, and only 29.4% of respondents routinely obtained preoperative imaging for ICA medialization in children with 22qDS.¹¹ This survey demonstrated that surgeons were more likely to obtain imaging in children with 22qDS than those without and that 30.2% would benefit from established guidelines regarding preoperative imaging.¹¹ Due to a lack of consensus, this systematic review and meta-analysis aimed to evaluate the use of routine preoperative imaging for VPD surgery in children with 22qDS and to evaluate the predictability of nasopharyngoscopy in identifying ICA medialization. Half of the patients in this review had one or more medialized ICAs, half of which carried higher surgical risk (i.e., were submucosal or retropharyngeal). Half of the patients with ICA medialization had changes in VPD operative approach. Studies found that nasopharyngoscopy could not reliably predict ICA medialization as an alternative to imaging and most articles supported routine ICA imaging before VPD surgery in children with 22qDS.

Around half of patients with 22qDS and preoperative imaging had an ICA abnormality of any kind. About half of those with ICA medialization were considered high-risk for VPD surgery (29.5% of total patients), with about 1 in 5 patients requiring preoperative changes (43.3% of those with medialization). Most articles (81.8%) in our analysis are proponents of preoperative ICA imaging in all children with 22qDS undergoing VPD surgery, as they felt imaging were crucial in preventing harm. Furthermore, these proponents argue that just a few major operative complications in this population would outweigh the utilization expense associated with imaging.²⁸ This systematic review demonstrated few postoperative complications and no children experienced hemorrhage from ICA injury. Overall, there is a scarcity of data recording perioperative bleeding secondary to injuring a displaced ICA in this population.^29,32 One report of one child with 22qDS and ICA medialization experienced significant intraoperative bleeding during pharyngeal flap elevation, requiring a two-unit transfusion.^23,29,45 The bleeding source was unidentified as the ICA was intact, and authors presumed it was from ascending pharyngeal artery or one of its branches.^29,45

Therefore, the question becomes if the rates of medialization and preoperative plan changes observed in our analyses are sufficient to constitute universal screening with CTA or MRA for all children with 22qDS before undergoing VPD surgery. A similar debate exists regarding children with idiopathic scoliosis undergoing MRI to screen for neurological defects, for which The American College of Radiology (ACR) guidelines advise universal MRI in the age group where abnormalities are present in 13-27% of children.^46,47 Based on these recommendations, one might argue that half of children with 22qDS being at-risk warrants universal imaging in order to prevent harmful and potentially detrimental events secondary to medialization. There is difficulty ascertaining a substantial benefit from universal imaging due to the rarity of reported detrimental complications, low incidence of 22qDS, and absence of a control group of children without imaging, making changing standards based on theoretical risks challenging.²⁹ Furthermore, universal imaging is costly, and barriers regarding obtaining imaging in children are sedation,^3,9 contrast,^9,25 and radiation exposure.^3,25,28,29 One report questioned of the number of small single-center studies required to form or alter standard practice, arguing they should not be changed due to lack of evidence-proven favorable outcomes in universal imaging.¹² They instead proposed that surgeons palpate for pulsations denoting abnormally located vessels intraoperatively before dissecting and avoiding sharp instrumentation in high risk areas.¹² That being said, the current low complication rate in our review could be due to surgeons prophylactically imaging most children or under reporting of complications. This review ultimately displays the crucial role of shared decision making and disclosing possible risks of imaging and surgery in this population.²⁹

Due to concerns associated with preoperative imaging in children such as anesthesia requirement, some articles analyzed the reliability of nasopharyngoscopy, which is regularly utilized in VPD evaluation, to predict ICA medialization. The true-positive rate of using nasopharyngeal endoscopy was 53.9%, with a false-positive rate of 16.2% and a false-negative rate of 18.4%. All six studies that evaluated this found no correlation between pulsations observed on nasopharyngeal endoscopy and imaging-confirmed ICA medialization.^{13,24,25,28,31,32} Proposed explanations of the poor predictability include positioning in which children are being evaluated in a seated position for nasopharyngoscopy yet placed supine with mild neck hyper-extension during VPD surgery, variations in patient blood pressure, and dynamic changes musculature and tension in awake children undergoing the endoscopic procedure.^24,28,32 One article noted on nasopharyngoscopy and MRA that the position of a submucosal medialized ICA was more midline when the child’s head was in neutral position compared to being hyper-extended, and accordingly advised repositioning children’s heads during nasopharyngoscopy to note variations in location and degree of pulsations.²⁸ Data has failed to substantiate that pulsations reliably predict a high-risk ICA, and the false-negative rate from our analysis shows that ICA medialization does not always produce pulsations on nasopharyngoscopy.^{13,24,25,28,31,32} Therefore, our review suggests that detecting pulsations on nasopharyngoscopy does not reliably predict ICA displacement in children with 22qDS.

Limitations

The opportunity for selection bias exists in our review. We only selected studies if a proportion of patients underwent imaging, all of which were retrospective reports. One report noted possible ascertainment bias due to some patients previously being deemed ineligible for surgery due to ICA pulsations.²⁴ Additionally, a publication bias could exist, where surgeons who do not routinely obtain imaging for ICA medialization before VPD surgery in patients with 22qDS do not publish imaging findings and are consequently not included in this analysis. Further, two studies found that 100% of patients included had ICA medialization,^13,30 which could be contributing to selection bias, although one of the studies was proactively excluded from calculating rates of ICA medialization due to concern that all patients were suspected to have ICA medialization. Moreover, our sensitivity analysis that excluded two studies with 100% ICA anomaly rates resulted in a nearly a 20% lower in estimated ICA anomalies, although the rate (37.6%) was still substantial. These factors could allow for our analysis overpredicting medialization rates in patients with 22qDS. Therefore, a prospective trial is needed to predict this rate more reliably. Secondly, there was heterogeneity in imaging modalities used to evaluate ICA abnormalities. Additionally, there were discrepancies in ICA anomaly definitions, which included ICA tortuosity, kinking, or looping, anterior displacement, and ICA hypoplasia. Furthermore, there was no standardization in reporting or defining ICA medialization and high-risk medialization, with some studies using strict definitions and others not disclosing specific criteria for ICA medialization or high-risk deviation. This introduces heterogeneity between subjects that are unable to be accounted for in these analyses. The inability to account for different institutional procedures and protocols of radiological studies and nasopharyngoscopy is another source of bias. Two articles universally imaged patients in a hyper-extended position,^25,28 but others did not report positioning, which could influence ICA deviation. The lack of uniform techniques could contribute to confounding and observer bias. Variability was present in different institutions using pharyngeal flap or sphincter pharyngoplasty as standard VPD operative treatment and how surgeries were modified based on medialization. Finally, all included articles in this review were retrospective analyses, which restricts the external validity of our findings to the general pediatric population.

Conclusion

Nearly 30% of patients with 22qDS in this review had high-risk medial displacement of their ICA noted on imaging and approximately 20% of patients with imaging experienced a change in operative technique. Nasopharyngoscopy was not reported to be reliable in identifying ICA medialization. No complications of perioperative hemorrhage occurred. Most studies endorse the routine use of preoperative imaging to assess for ICA medialization in children with 22qDS undergoing VPD surgery. Outcomes in children who do not undergo routine pre-operative imaging are unknown, so additional studies are needed to compare outcomes in children with and without preoperative imaging. These data would help to form a guideline in the preoperative workup for children with 22qDS undergoing velopharyngeal surgery for VPD.

Supplementary Material

Fig S1

Figure S1. Risk of Bias of Included Studies (ROBINS-I). ROBINS-I = Risk of Bias in Non-Randomized Studies – of Interventions

Fig S2

Figure S2. Funnel Plot to Assess for Publication Bias

Appendix A. Search Strategy

Pubmed (U.S. National Library of Medicine, National Institutes of Health) search strategy:

(“22q11 Deletion Syndrome”[MeSH] OR “22q11 Deletion Syndrome”[tw] OR “DiGeorge syndrome”[MeSH] OR “DiGeorge syndrome”[tw] OR “DiGeorge Anomaly” [tw] OR DGA[tw] OR “Velocardiofacial syndrome”[tw] OR VCFS[tw] OR “VCF syndrome”[tw] OR “Deletion Syndrome, 22q11”[tw] OR “22q11.2 deletion syndrome”[tw] OR 22qDS[tw] OR 22q11.2DS[tw] OR “Conotruncal anomaly face syndrome”[tw] OR CTAF[tw] OR “Third and fourth pharyngeal pouch syndrome”[tw] OR “Thymic Aplasia Syndrome”[tw] OR “Thymus and Parathyroid Hypoplasia”[tw] OR Catch22[tw] OR “Velopharyngeal insufficiency”[tw] OR VPI[tw] OR “Velopharyngeal dysfunction”[tw] OR “Chromosomes, Human, Pair 22”[MeSH] OR “Chromosomes, Human, Pair 22”[tw]) AND (“Diagnostic imaging”[MeSH] OR “Diagnostic imaging”[tw] OR “Medical Imaging”[tw] OR “Radiography”[MeSH] OR Radiography[tw] OR “Radiographic Imag*”[tw] OR Radiograph*[tw] OR “Tomography”[MeSH] OR Tomography[tw] OR “Tomography, X-Ray”[MeSH] OR “Tomography, X-Ray”[tw] OR “Tomography, X-Ray Computed”[MeSH] OR “Computed Tomography”[tw] OR “Computed Tomography Angiography”[tw] OR CT[tw] OR CTA[tw] OR “Angiography”[MeSH] OR Angiography[tw] OR “Magnetic resonance Imaging”[MeSH] OR “Magnetic resonance Imaging”[tw] OR “Magnetic Resonance Angiography”[MeSH] OR “Magnetic Resonance Angiography”[tw] OR MRI[tw] OR MRA[tw] OR Videonasopharyngoscop*[tw] OR “Multiview video fluoroscopy”[tw] OR “Lateral videofluoroscopy”[tw] OR Nasendoscop*[tw]) AND (“Surgical Procedures, Operative”[MeSH] OR “Surgical Procedures, Operative”[tw] OR Surg*[tw] OR “Otorhinolaryngologic Surgical Procedures”[MeSH] OR “Otorhinolaryngologic Surgical Procedur*”[tw] OR “Oral surgical procedures”[MeSH] OR “Oral surgical procedur*”[tw] OR “Pharynx/surgery”[MeSH] OR “Pharynx/surgery”[tw] OR “Sphincter pharyngoplasty”[tw] OR “Reconstructive Surgical Procedures”[MeSH] OR “Reconstructive Surgical Procedur*”[tw] OR “Surgical Flaps”[MeSH] OR “Surgical Flap”[tw] OR “Pharyngeal Surgery”[tw] OR “Pharyngeal flap”[tw] OR “Velopharyngeal Insufficiency/surgery”[MeSH] OR “Furlow palatoplasty”[tw] OR Palatoplasty[tw] OR Procedure[tw] OR “Otorhinolaryngologic Procedur*”[tw] OR “Otorhinolaryngologic Surg*”[tw]) AND (“Child”[MeSH] OR child*[tw] OR “Infant”[Mesh] OR infan*[tw] OR “Adolescent”[MeSH] OR adolescen*[tw] OR preadolescen*[tw] OR “Pediatrics”[MeSH] OR pediatri*[tw] OR paediatri*[tw] OR “Pediatricians”[MeSH] OR “Pediatric Emergency Medicine”[MeSH] OR “Intensive Care Units, Pediatric”[MeSH] OR PICU[tw] OR “Hospitals, Pediatric”[MeSH] OR neonat*[tw] OR newborn*[tw] OR “Intensive Care Units, Neonatal”[MeSH] OR NICU[tw] OR toddler*[tw] OR “school age*”[tw] OR juvenile*[tw] OR teen*[tw] OR youth[tw] OR baby[tw] OR babies[tw]):

• Filters/limits: none

• Date Searched: May 16, 2022

• # of records identified: 421

Scopus (Elsevier) search strategy:

(TITLE-ABS-KEY (“22q11 Deletion Syndrome” OR “DiGeorge syndrome” OR “DiGeorge Anomaly” OR DGA OR “Velocardiofacial syndrome” OR VCFS OR “VCF syndrome” OR “Deletion Syndrome, 22q11” OR “22q11.2 deletion syndrome” OR 22qDS OR 22q11.2DS OR “Conotruncal anomaly face syndrome” OR CTAF OR “Third and fourth pharyngeal pouch syndrome” OR “Thymic Aplasia Syndrome” OR “Thymus and Parathyroid Hypoplasia” OR Catch22 OR “Velopharyngeal insufficiency” OR VPI OR “Velopharyngeal dysfunction” OR “Chromosomes, Human, Pair 22”)) AND (TITLE-ABS-KEY (“Diagnostic imaging” OR “Medical Imaging” OR Radiography OR “Radiographic Imag*” OR Radiograph* OR Tomography OR ”Tomography, X-Ray” OR “Tomography, X-Ray Computed” OR “Computed Tomography” OR “Computed Tomography Angiography” OR CT OR CTA OR Angiography OR “Magnetic resonance Imaging” OR “Magnetic Resonance Angiography” OR MRI OR MRA OR Videonasopharyngoscop* OR “Multiview video fluoroscopy” OR “Lateral videofluoroscopy” OR Nasendoscop*)) AND (TITLE-ABS-KEY (“Surgical Procedures, Operative” OR Surg* OR “Otorhinolaryngologic Surgical Procedures” OR “Otorhinolaryngologic Surgical Procedur*” OR “Oral surgical procedures” OR “Oral surgical procedur*” OR “Pharynx/surgery” OR “Sphincter pharyngoplasty” OR “Reconstructive Surgical Procedures” OR “Reconstructive Surgical Procedur*” OR “Surgical Flaps” OR “Surgical Flap” OR “Pharyngeal flap” OR “Pharyngeal Surgery” OR “Velopharyngeal Insufficiency/surgery” OR “Furlow palatoplasty” OR Palatoplasty OR Procedure OR “Otorhinolaryngologic Procedur*” OR “Otorhinolaryngologic Surg*”)) AND (TITLE-ABS-KEY (Child OR child* OR Infant OR infan* OR Adolescent OR adolescen* OR preadolescen* OR Pediatrics OR pediatri* OR paediatri* OR Pediatricians OR “Pediatric Emergency Medicine” OR “Intensive Care Units, Pediatric” OR PICU OR “Hospitals, Pediatric” OR neonat* OR newborn* OR “Intensive Care Units, Neonatal” OR NICU OR toddler* OR “school age*” OR juvenile* OR teen* OR youth OR baby OR babies)):

• Filters/limits: none

• Date Searched: May 17, 2022

• # of records identified: 492

CINAHL (EBSCOhost) search strategy:

(“22q11 Deletion Syndrome” OR “DiGeorge syndrome” OR “DiGeorge Anomaly” OR DGA OR “Velocardiofacial syndrome” OR VCFS OR “VCF syndrome” OR “22q11.2 deletion syndrome” OR 22q11.2DS OR 22q11.2DS OR “Conotruncal anomaly face syndrome” OR CTAF OR “Third and fourth pharyngeal pouch syndrome” OR “Thymic Aplasia Syndrome” OR “Thymus and Parathyroid Hypoplasia” OR Catch22 OR “Velopharyngeal insufficiency” OR VPI OR “Velopharyngeal dysfunction” OR “Chromosomes, Human, Pair 22”) AND (“Diagnostic imaging” OR “Medical Imaging” OR Radiography OR “Radiographic Image” OR Radiography OR Tomography OR “Tomography, X-Ray” OR “Tomography, X-Ray Computed” OR “Computed Tomography” OR “Computed Tomography Angiography” OR “CT” OR “CTA” OR Angiography OR “Magnetic resonance Imaging” OR “Magnetic Resonance Angiography” OR “MRI” OR “MRA” OR Videonasopharyngoscopy OR “Multiview video fluoroscopy” OR “Lateral videofluoroscopy” OR Nasendoscopy) AND (MH “Surgical Procedures, Operative” OR Surg* OR MH “Otorhinolaryngologic Surgical Procedures” OR MH “Otorhinolaryngologic Surgical Procedur*” OR MH “Oral surgical procedures” OR MH “Oral surgical procedur*” OR MH “Pharynx/surgery” OR MH “Sphincter pharyngoplasty” OR MH “Reconstructive Surgical Procedures” OR MH “Reconstructive Surgical Procedur*” OR MH “Surgical Flaps” OR MH “Surgical Flap” OR MH “Pharyngeal flap” OR MH “Pharyngeal Surgery” OR MH “Velopharyngeal Insufficiency/surgery” OR MH “Furlow palatoplasty” OR Palatoplasty OR Procedure OR MH “Otorhinolaryngologic Procedur*” OR MH “Otorhinolaryngologic Surg*”) AND (MH “Child+” OR child* OR MH “Infant+” OR infan* OR MH “Adolescence+” OR adolescen* OR preadolescen* OR MH “Pediatrics+” OR pediatri* OR paediatri* OR MH “Pediatricians” OR MH “Intensive Care Units, Pediatric+” OR PICU OR MH “Hospitals, Pediatric” OR neonat* OR newborn* OR MH “Intensive Care Units, Neonatal” OR NICU OR toddler* OR school age* OR juvenile* OR teen* OR youth OR baby OR babies)

• Filters/limits: none

• Date Searched: May 17, 2022

• # of records identified: 66