Validation of clinically relevant thresholds of esophagogastric junction obstruction using FLIP Panometry

Abstract

Background & Aims:

This study aimed to assess the accuracy of functional luminal imaging probe (FLIP) Panometry to detect esophagogastric junction (EGJ) obstruction assigned by high-resolution manometry (HRM) and the Chicago Classification version 4.0 (CCv4.0).

Methods:

687 adult patients that completed FLIP and HRM for primary esophageal motility evaluation and 35 asymptomatic volunteers (“controls”) were included. EGJ opening was evaluated with 16-cm FLIP during sedated endoscopy via EGJ-distensibility index (DI) and maximum EGJ diameter. HRM was classified according to CCv4.0 and focused on studies with a conclusive disorder of EGJ outflow (i.e. achalasia subtypes I, II, or III; or EGJ outflow obstruction with abnormal timed barium esophagram) or normal EGJ outflow.

Results:

All 35 controls had EGJ-DI >3.0mm²/mmHg and maximum EGJ diameter >16mm. Per HRM and CCv4.0, 245 patients had a conclusive disorder of EGJ outflow and 314 patients had normal EGJ outflow. Among the 241 patients with reduced EGJ opening (REO: EGJ-DI <2.0 mm²/mmHg and max EGJ diameter <12mm) on FLIP Panometry, 86% had a conclusive disorder of EGJ outflow per CCv4.0. Among the 203 patients with normal EGJ opening (NEO: EGJ-DI ≥2.0 mm²/mmHg and maximum EGJ diameter ≥16mm) on FLIP Panometry, 99% had normal EGJ outflow per CCv4.0.

Conclusions:

FLIP Panometry accurately identified clinically-relevant conclusive EGJ obstruction as defined by CCv4.0 in patients evaluated for esophageal motor disorders. Thus, FLIP Panometry is a valuable tool for both independent and complementary evaluation of esophageal motility.

Introduction

The functional luminal imaging probe (FLIP) utilizes impedance planimetry technology to assess lumen dimensions along the length of the esophagus and esophageal distensibility (i.e. the relationship of dimension with distensive pressure) during controlled volumetric distension. In 2014, our group developed a new technique to assess esophageal motility using FLIP and a volume distention protocol: FLIP Panometry.¹ By displaying the esophageal diameter changes along a space-time continuum with associated pressure utilizing FLIP Panometry, esophagogastric junction (EGJ) opening mechanics and the contractile response to distension, i.e. secondary peristalsis, can be assessed.^{1, 2}

Esophageal high-resolution manometry (HRM) classified according to the Chicago Classification is generally considered the primary method to assess for esophageal motility disorders.^{3, 4} An update of the Chicago Classification, version 4.0 (CCv4.0), was recently generated by consensus of the International HRM Working group.⁴ A point of emphasis within this update was to provide a framework for HRM to identify conclusive clinical diagnoses based on HRM when possible (e.g. achalasia), but to also recognize that complementary testing beyond HRM should be applied for inconclusive HRM findings. When HRM findings are inconclusive, such as the HRM classification of EGJ outflow obstruction (EGJOO), the consensus recommendation of CCv4.0 was to obtain complementary testing with esophagram or FLIP to support a conclusive, clinically relevant diagnosis.⁴

The addition of FLIP to the conclusive definition of EGJOO was based on previous studies demonstrating that EGJ distensibility was consistently abnormal among patients with achalasia and also beneficial for identification of EGJOO in equivocal cases based on HRM.^5–7 Thus, normal EGJ distensibility can effectively exclude achalasia. Further, while the majority of patients with normal esophageal motility on HRM have normal EGJ distensibility, abnormal EGJ distensibility can also occur (in 27% of patients in a recent study); however the abnormal EGJ distensibility in this cohort with normal manometry was associated with retention on timed barium esophagram (TBE).^{8, 9}

Although assessment of EGJ opening with FLIP and thresholds were reported in a previous review, this recommendation was based on limited data and the methodology and approaches to FLIP interpretation have subsequently been updated.¹⁰ Additionally, CCv4.0 provides an updated framework to provide conclusive assignments of esophageal motor functions independently of FLIP outcomes. Therefore, the aim of this study was to evaluate diagnostic thresholds using FLIP Panometry to assess for EGJ obstruction (as defined by CCv4.0) among a large cohort of symptomatic patients and asymptomatic controls.

Methods

Subjects

Adult patients (age 18–89) presenting to the Esophageal Center of Northwestern for evaluation of esophageal symptoms between November 2012 and December 2019 who completed FLIP during upper endoscopy and HRM were prospectively evaluated and data maintained in an esophageal motility registry. Consecutive patients that completed FLIP during sedated endoscopy and a corresponding HRM for evaluation for primary esophageal motility disorders were included. Patients with technically limited FLIP or HRM studies were excluded. Patients with previous foregut surgery (including previous pneumatic dilation) or esophageal mechanical obstructions including esophageal stricture, eosinophilic esophagitis, severe reflux esophagitis (Los Angeles-classification C or D), hiatal hernia > 3cm were excluded as these are causes of secondary esophageal motor abnormalities (Figure S1). Additional clinical evaluation (e.g. TBE) was obtained at the discretion of the primary treating gastroenterologist. No endoscopic or surgical treatment occurred between applied FLIP, HRM, or esophagram. Most patients completed a validated dysphagia symptom severity score, the Brief Esophageal Dysphagia Questionnaire (BEDQ), on the day of the FLIP test (supplementary material); greater scores indicate greater symptom severity.¹¹

Additionally, a cohort of healthy, asymptomatic (i.e. free of esophageal symptoms), adult volunteers were included as “controls”.¹² Informed consent was obtained for subject participation; control subjects were paid for their participation. The study protocol was approved by the Northwestern University Institutional Review Board. There is overlap of both the patient and control cohorts with previous publications.^{2, 9, 12} The Standards for Reporting Diagnostic Accuracy Studies checklist is included in supplementary material.¹³

FLIP Study Protocol and Analysis

The FLIP study using 16-cm FLIP (EndoFLIP® EF-322N; Medtronic, Inc, Shoreview, MN) was performed during sedated endoscopy and analyzed as previously described; an expanded description of methods is included as supplementary material.^{2, 9, 12} Briefly, with the endoscope withdrawn and after calibration to atmospheric pressure, the FLIP was placed transorally and positioned within the esophagus with 1–3 impedance sensors beyond the EGJ. Stepwise 10-ml FLIP distensions beginning with 40 ml and increasing to target volume of 70 ml were then performed; each stepwise distension volume was maintained for 30–60 seconds. FLIP data were exported using a customized program (available open source at http://www.wklytics.com/nmgi) to generate FLIP Panometry plots for analysis.^{7, 8} FLIP analysis was performed blinded to clinical details. The EGJ analysis specifically focused on the EGJ distensibility index (DI) at the 60ml FLIP fill volume and the maximum EGJ diameter that was achieved during the 60ml or 70ml fill volume (Figure 1). The EGJ-DI was not calculated if the applied FLIP pressure was <15mm Hg; in these cases (n=10 of this cohort), the maximum EGJ-diameter was applied independently for analysis.

Figure 1. Evaluation of esophagogastric junction (EGJ) opening parameters on FLIP Panometry.

FLIP Panometry output from four patients (A-D) are displayed as length (16-cm) x time x color-coded diameter FLIP topography (top panels) with corresponding intraballoon pressure (bottom panel). EGJ-distensibility index (DI) was calculated as the median value of three measures (dashed vertical lines 1–2-3) obtained during the 60-ml fill volume (dashed box); the maximum EGJ diameters are marked by “*”. When antegrade contractions were present, as in the patients with normal motility on high-resolution manometry (HRM) in A and B, the EGJ-DI was measured at the peak EGJ diameters that occurred in response to the pressure ramp associated with the contraction (black dashed lines). When antegrade contractions were absent, as in the patients in C (type II achalasia on HRM) and D (patient with systemic sclerosis and absent contractility on HRM), the EGJ-DI measures were obtained during expiration and at times without lower esophageal sphincter contractions (black dashed lines). Figure used with permission from the Esophageal Center of Northwestern.

EGJ opening was classified with FLIP using pre-specified thresholds.^{9, 10} Previously described criteria and terminology included defining ‘EGJ outflow obstruction’ by an EGJ-DI <2.0 mm²/mmHg or EGJ-DI 2.0–3.0 mm²/mmHg and maximum EGJ diameter <12mm versus ‘normal EGJ’ as EGJ-DI >3.0 mm²/mmHg or EGJ-DI 2.0–3.0 mm²/mmHg and maximum EGJ diameter >12mm.¹⁰ A separate classification scheme (and terminology) for EGJ opening was also applied that defined reduced EGJ opening (REO) as EGJ-DI <2.0 mm²/mmHg and max EGJ diameter <12mm); borderline reduced EGJ opening (BrEO) as EGJ-DI <2.0 mm²/mmHg or max EGJ diameter <14mm, but not REO; borderline normal EGJ opening (BnEO) as a maximum EGJ diameter 14–16 mm or EGJ-DI <2.0 mm2/mmHg and maximum EGJ diameter ≥16mm; or normal EGJ opening (NEO) as EGJ-DI ≥2.0 mm²/mmHg and maximum EGJ diameter ≥16mm); Figure 2.⁹

Figure 2. Association of FLIP Panometry esophagogastric junction (EGJ) opening parameters with Chicago Classification v4.0 (CCv4.0).

A) Patients with a conclusive disorder of EGJ outflow on high-resolution manometry (HRM), i.e. achalasia subtypes I, II, or III; or EGJ outflow obstruction with an abnormal timed barium esophagram. The triangles within dashed circles indicate two patients with systemic sclerosis that had a classification of type I achalasia via HRM per CCv4.0.⁴ B) Patients with an impression of normal EGJ outflow on HRM and asymptomatic controls. Patients with an inconclusive HRM per the CCv4.0 were not included in this figure.⁴ The FLIP Panometry EGJ opening classifications of reduced EGJ opening (REO), borderline reduced EGJ opening (BrEO), borderline normal EGJ opening (BnEO), and normal EGJ opening (NEO) are reflected by the colored regions of the plots; BrEO and BnEO are separated by the maximum EGJ diameter threshold at 14mm (dashed line). Figure used with permission from the Esophageal Center of Northwestern.

HRM protocol and analysis

After a minimum 6-hour fast, the HRM assembly (36 circumferential pressure sensors at 1-cm intervals; Medtronic Inc, Shoreview, MN) was placed transnasally and positioned to record from the hypopharynx to the stomach with approximately three intragastric pressure sensors. After a 2-minute baseline recording (during which the basal EGJ pressure was measured during end expiration), the HRM protocol was performed with ten, 5-ml liquid swallows in a supine position and with five 5-ml liquid swallows in an upright, seated position.⁵

Manometry studies were analyzed according to the CCv4.0, Table S1.^{4, 14} TBE was applied when available to patients with an HRM classification of EGJOO to reach an assignment of ‘conclusive’ EGJOO (Table S1); patients with an HRM classification of EGJOO that did not complete a TBE were assigned as inconclusive-EGJOO as recommended by CCv4.0.^{4, 14, 15} Thus, strict criteria independent of FLIP were applied for assignment of presence or absence of EGJ outflow obstruction as outlined by CCv4.0. Criteria for ‘inconclusive’ disorders of peristalsis were not applied in this study focused on EGJ obstruction.⁴

Statistical Analysis

Results were reported as mean (standard deviation; SD), or median (interquartile range; IQR) depending on data distribution. Correlation was assessed using Spearman’s rho. Groups were compared using Chi-square test for categorical variables and ANOVA/t-tests or Kruskal-Wallis/Mann-Whitney U for continuous variables, depending on data distribution. Statistical significance was considered at a two-tailed p-value < 0.05. Post-hoc comparison testing, as appropriate, was completed using a Bonferroni correction. Primary analyses focused on patients with conclusive classification of disorders of EGJ outflow versus classifications without EGJ outflow obstruction (Table S1). Receiver operating characteristic (ROC) curves were primarily applied to predict conclusive disorders of EGJ outflow from disorders without EGJ outflow obstruction; i.e. inconclusive EGJ outflow studies were not applied due to diagnostic uncertainty. Secondary analysis with ROC curves was also applied by a) assigning all inconclusive-EGJ outflow as EGJ outflow obstruction and then b) assigning all inconclusive-EGJ outflow as not EGJ outflow obstruction.¹³

Results

Subjects

687 patients, mean (SD) age 54 (17) years, 57% female and 35 controls, mean (SD) age 30 (6) years, 71% female, were included (Table 1). Among the patients, 245 (36%) had a conclusive disorder of EGJ outflow, 314 (46%) had an HRM classification with normal EGJ outflow, and 128 (19%) had an inconclusive HRM for EGJ outflow obstruction. Inconclusive EGJOO classifications were based on incomplete TBE in 84/121 patients (69%), while the remaining 37/121 patients (31%) had a TBE that was not conclusively abnormal. HRM classifications among the controls were normal motility in 32 (91%) and ineffective esophageal motility in 3 (9%). No adverse events occurred related to the FLIP study.

Table 1.

Cohort characteristics.

	Patients	Controls
n	687	35
Age, mean (SD), years	54 (17)	30 (6)
Gender, n (%) female	393 (57)	25 (71)
Indication, n (%)
Dysphagia	622 (90)	0
Reflux symptoms	41 (6)	0
Chest pain	15 (2)	0
Other	10 (2)	35 (100)
Endoscopy findings, n (%)
Erosive esophagitis;
Los Angeles Grade A / B	23 (3) / 18 (3)	0
Non-obstructing ring	15 (2)	0
Diverticulum	21 (3)	0
HRM metrics
Supine IRP, mmHg, median (IQR)	18 (11–28)	10 (8–14)
Upright IRP, mmHg, median (IQR)	16 (9–26)	9 (4–10)
Basal EGJ pressure, mmHg, median (IQR)	21 (12–32)	14 (8–17)
HRM-Chicago Classification, n (%)
Type I achalasia b	57 (8)	0
Type II achalasia b	129 (19)	0
Type III achalasia b	40 (6)	0
EGJOO b	19 (3)	0
Achalasia-inconclusive	7 (1)	0
EGJOO-inconclusive	121 (18)c	0
Hypercontractile esophagus	15 (2)	0
Distal esophageal spasm	15 (2)	0
Absent contractility	17 (3)	0
Ineffective esophageal motility	47 (7)	3 (9)
Normal motility	220 (32)	32 (91)
HRM-EGJ-morphology, n (%)
Type I (no hiatal hernia)	549 (80)	31 (89)
Type II-III (hiatal hernia)	137 (20)	4 (11)
EGJ-distensibility index, mm2/mmHg, median (IQR)	1.8 (0.9–4.0)	5.8 (5.0–6.4)
Maximum EGJ diameter, mm, median (IQR)	13.2 (9.1–18.3)	20.4 (19.5–20.8)

^aDysphagia +/− reflux symptoms or chest pain.

^bConclusive disorders of EGJ outflow.

FLIP Panometry – EGJ opening metrics among controls and patients

The controls had median (5–95^th percentile) EGJ-DI (60ml) of 5.8 (3.2–8.4) mm²/mmHg and maximum EGJ-diameter of 20.4 (16.7–21.9) mm. All of the controls had an EGJ-DI >3.0mm²/mmHg and maximum EGJ diameter >16mm, and thus all were classified as NEO. Controls had greater EGJ-DI and greater maximum EGJ-diameter than patient cohorts with normal EGJ outflow, disorders of EGJ outflow, or inconclusive defined by CCv4.0, (P-values <0.001), Figure 3.

Figure 3. FLIP Panometry metrics by subject cohort.

^†EGJ classification was assigned per Chicago Classification version 4.0.⁴ The ○ and * on the box-and-whisker plots reflect outlier values. Figure used with permission from the Esophageal Center of Northwestern.

Among the patients, the EGJ-DI was negatively correlated with supine IRP (rho = −0.623), upright IRP (rho = −0.620), and basal EGJ pressure (rho= −0.390). The maximum EGJ diameter was also negatively correlated with supine IRP (rho = −0.656), upright IRP (rho = −0.659), and basal EGJ pressure (rho = −0.391). P-values <0.001 for all above correlations.

Patients with conclusive disorders of EGJ outflow had lower EGJ-DI and lower maximum EGJ-diameter than patients with inconclusive EGJ outflow on HRM and inconclusive EGJ outflow had lower EGJ-DI and lower maximum EGJ-diameter than patients with normal EGJ outflow on HRM; P-values <0.001; Figure 3.

Accuracy of FLIP Panometry EGJ opening metrics to detect disorders of EGJ outflow

ROC curves to identify conclusive disorders of EGJ outflow from normal EGJ outflow (i.e. inconclusive EGJOO not included) demonstrated area-under-the-curve (AUC) (5–95% confidence interval, CI) of 0.897 (0.870–0.923) for EGJ-DI and 0.946 (0.928–0.963) for maximum EGJ diameter. Coordinates of the ROC curve (sensitivity and specificity) for detection of conclusive disorders of EGJ outflow obstruction are listed in Table 2. If all inconclusive-EGJOO HRM were included as abnormal, the AUC (5–95% CI) was 0.853 (0.824–0.882) for EGJ-DI and 0.885 (0.860–0.910) for maximum EGJ diameter. If all inconclusive-EGJOO HRM were included as normal, the AUC (5–95% CI) was 0.835 (0.805–0.865) for EGJ-DI and 0.902 (0.880–0.924) for maximum EGJ diameter.

Table 2.

Sensitivity and specificity for detection of esophagogastric junction (EGJ) obstruction.

EGJ-distensibility index					Maximum EGJ diameter
Cut-point (mm2/mmHg)	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Cut-point (mm)	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
0.5	15	99	89	60	8	37	99	95	67
1.0	56	92	84	73	9	53	96	91	72
1.5	80	85	80	84	10	70	94	90	80
2.0	90	77	76	90	11	82	91	87	87
2.5	96	69	71	95	12	89	89	86	91
2.8	97	65	68	96	13	94	85	83	94
3.0	97	62	66	96	14	96	80	78	96
3.5	98	57	64	96	15	97	75	75	97
4.0	99	50	60	98	16	98	66	69	97
					17	99	60	65	99
					18	100	52	62	100

Values are based on point coordinates of receiver operating characteristic curves to detect conclusive disorders of EGJ outflow per the Chicago Classification version 4.0.⁴ PPV – positive predictive value. NPV – negative predictive value.

FLIP Panometry Classification of EGJ opening

Among the 245 patients with a conclusive disorder of EGJ outflow, 85% (n=207) had a FLIP Panometry-EGJ classification of REO, 11% (n=27) had BrEO; 3% (n=8) had BnEO, and 1% (n=3) had NEO (Table 3; Figure 2). 93% (229 patients) had an EGJ-DI <2.0 mm²/mmHg or EGJ-DI 2–3 mm²/mmHg with maximum EGJ diameter <12mm. 7% (n=16) had an EGJ-DI >3.0 mm²/mmHg or EGJ-DI 2–3 mm²/mmHg with maximum EGJ-diameter >12mm.

Table 3.

Chicago Classification by Panometry EGJ opening classification.

	FLIP Panometry Classification				///	Previous thresholds10
	Reduced EGJ opening (REO)	Borderline reduced EGJ opening (BrEO)	Borderline normal EGJ opening (BnEO)	Normal EGJ opening (NEO)	///	EGJ-DI < 2.0	EGJ-DI 2–3 and maximum EGJ diameter <12mm	EGJ-DI 2–3 and maximum EGJ diameter >12mm	EGJ-DI > 3.0
Controls (n, %)	0	0	0	35 (100)	///	0	0	0	35 (100)
Patients (n, %)	294 (43)	80 (12)	80 (12)	233 (34)	///	367 (53)	17 (3)	74 (11)	230 (33)
	n (%)	n (%)	n (%)	n (%)	///	n (%)	n (%)	n (%)	n (%)
Indication, n (%)
Dysphagia	290 (99)*	73 (91)*	69 (83)	188 (81)		357 (97)*	17 (100)*	58 (78)	188 (82)
Reflux symptoms	0*	3 (4)*	8 (10)	30 (13)	///	2 (1)*	0	10 (14)	29 (13)
Chest pain	3 (1)*	2 (3)	0	10 (4)		5 (1)	0	3 (4)	7 (3)
Other	1 (<1)*	2 (3)	3 (4)	5 (2)		3 (1)	0	3 (4)	5 (2)
HRM-CCv4.0 a,b
Type I achalasia b	43 (18)*	11 (20)*	0	3 (2)c		42 (15)*	3 (21)*	6 (11)*	6 (3)c
Type II achalasia b	113 (47)*	13 (24)*	3 (5)*	0		119 (45)*	7 (50)*	1 (2)	2 (1)
Type III achalasia b	32 (13)*	3 (6)*	5 (8)*	0		38 (13)*	1 (7)*	1 (2)	0
EGJOO b	19 (8)*	0	0	0	///	18 (6)*	1 (7)*	0	0
Hypercontractile esophagus	6 (3)	2 (4)*	5 (8)*	2 (1)		8 (3)	0	4 (7)*	3 (2)
Distal esophageal spasm	V (2)	3 (6)	3 (5)	5 (3)		8 (3)	0	0	7 (4)
Absent contractility	0 (0)*	0*	3 (5)	14 (7)		1 (1)*	0	1 (2)	15 (8)
IEM	6 (3)*	7 (13)	11 (18)	23 (11)		14 (5)*	0	9 (16)	24 (12)
Normal motility	18 (8)*	16 (29)*	30 (50)*	156 (77)		39 (14)*	2 (14)*	35 (61)	144 (72)
HRM-Inconclusive
Disorders of EGJ outflow
Achalasia	5 (9)	1 (4)	1 (5)	0	///	5 (6)	0	0	2 (7)
EGJOO-incomplete TBE	40 (76)*	18 (72)*	13 (65)	13 (43)		60 (75)*	2 (67)	12 (71)*	10 (36)
EGJOO-inconclusive TBE	8 (15)*	6 (24)*	6 (30)	17 (57)		15 (19)*	1 (33)	5 (29)	16 (57)
Brief Esophageal Dysphagia Questionnaire Score, median (IQR) [n completed BEDQ]	19 (11–28)* [n=215]	14 (6–21)* [n=60]	13 (4–23) [n=56]	9 (4–17) [n=185]	///	18 (9–26)* [n=274]	22 (14–29)* [n=6]	11 (3–19) [n=55]	9 (4–17) [n=179]

The columns on the left reflects the refined FLIP Panometry classification while the right reflects previously described thresholds.¹⁰

^aHigh-resolution manometry (HRM)/CCv4.0 classification among patients.⁴

^bConclusive disorders of EGJ outflow.

^cIncluded two patients with systemic sclerosis and type I achalasia pattern on high-resolution manometry (HRM).

^*P<0.05 compared with Normal EGJ opening (left) or EGJ-DI >3.0 (right). IEM – ineffective esophageal motility.

Of the 314 patients with a CCv4.0 classification of normal EGJ outflow, 11% (n=34) had REO, 9% (n=28) had BrEO, 17% (n-52) had BnEO, and 64% (n=200) had NEO. 23% (72 patients) had an EGJ-DI <2.0 mm²/mmHg or EGJ-DI 2–3 mm²/mmHg with maximum EGJ diameter <12mm. 77% (242 patients) had an EGJ-DI >3.0 mm²/mmHg or EGJ-DI 2–3 mm²/mmHg with maximum EGJ-diameter >12mm.

The indication for motility testing was more frequently dysphagia and dysphagia symptom severity (BEDQ score) was greater in patients with reduced EGJ opening than in patients with normal EGJ opening (Table 3).

Of note, two patients with NEO (and EGJ-DI >3.0 mm²/mmHg) on FLIP Panometry had systemic sclerosis and an HRM with elevated IRP and absent contractility yielding a classification of type I achalasia; neither were clinically managed as achalasia.

Discussion

The major findings of this study support that assessment of EGJ distensibility using FLIP Panometry was accurate in detecting EGJ obstruction based on this study of a large prospective cohort of 687 symptomatic patients that completed clinical evaluation for primary esophageal motility disorders and 35 asymptomatic healthy controls. The presence (or absence) of conclusive disorders of EGJ outflow obstruction was assigned independently of FLIP per the recommendations of the recent international consensus, CCv4.0, including applying TBE to reach a conclusive assignment when HRM suggested EGJOO.^{4, 14} Among patients classified as REO on FLIP Panometry, defined by EGJ-DI <2.0 mm²/mmHg and maximum EGJ diameter <12mm, 86% (207/241 patients) had a conclusive disorder of EGJ outflow per CCv4.0. Among patients classified as NEO on FLIP Panometry, defined as EGJ-DI ≥2.0 mm²/mmHg and maximum EGJ diameter ≥16mm, 99% (200/203 patients) had a CCv4.0 classification of normal EGJ outflow. Reduced EGJ opening was also associated with greater symptom (dysphagia) severity than normal EGJ opening. Overall, the approach of applying FLIP Panometry findings during endoscopy to support or exclude conclusive EGJ obstruction could be applied to direct management or additional evaluation.

Reduced EGJ distensibility was reported in achalasia as compared with asymptomatic healthy controls in multiple previous studies utilizing FLIP, including studies that represent earlier reports of the present patient cohort.^{2, 5, 16} Impaired LES relaxation, the hallmark of achalasia and the intended assessment of the IRP on HRM, is an etiology (but not the only etiology) for reduced EGJ distensibility as demonstrated by the consistently abnormal EGJ opening parameters among achalasia patients, including >99% of achalasia patients in this cohort. As evident by the correlation between EGJ pressure on HRM and EGJ distensibility on FLIP Panometry, there is a shared physiology of LES relaxation and EGJ distensibility. However, these are different parameters of esophageal function. Other factors may also contribute to reduced EGJ opening in response to distension, such as those related to esophageal wall inflammation or fibrosis, or reactive contraction in response to distension. The role of contraction of the LES in response to distension, with an extreme pattern of this phenomenon previously described as sustained LES contraction, in particular requires additional study.⁹ Overall, diagnostic value may be gained in both concordant and discordant findings. In some scenarios (such as those with borderline or equivocal findings) the two modalities may be viewed as being complementary instead of competitive and the alternate test should be obtained when the results of a single test (FLIP or HRM) yield inconclusive results. When discordance between FLIP Panometry and HRM occurs, TBE may be required as an arbitrating test to clarify the clinical diagnosis.

The present study aimed to advance the application of FLIP Panometry by evaluating a large patient cohort across a full spectrum of heterogeneous esophageal motility diagnoses. Of note, the goal of the present study was not to develop a FLIP Panometry approach to identify an abnormal IRP on HRM (with its inherent limitations) but instead to develop a FLIP Panometry approach to identify a clinically relevant outcome, defined in this study as the presence or absence of a conclusive disorder EGJ obstruction per CCv4.0.⁴ Therefore, with derivation of the FLIP Panometry Classification of EGJ opening, an attempt was made to avert the limitations associated with a dichotomous interpretation of the IRP on HRM.³ The previously described FLIP Panometry criteria for EGJ assessment carried a similar limitation by application of EGJ-DI in isolation.¹⁰ However, application of the multiple FLIP Panometry parameters (EGJ-DI and maximum EGJ diameter) helped avoid potential over reliance on a single metric that may hold inherent limitations (e.g. appearance of ‘normal’ EGJ-DI when low pressures are incorporated). Additionally, application of two thresholds of abnormality leveraged the expected balance of sensitivity for specificity (and vice versa). Therefore, consistent distinctly abnormal or distinctly normal EGJ opening parameters could be associated with a high probability for pathologic (REO) versus physiologic (NEO) function, respectively.

However, a tradeoff was the BrEO and BnEO classifications. While BrEO carries a greater probability for EGJ obstruction than BnEO, akin to the approach applied by the CCv4.0 (and also the Lyon Classification of ambulatory reflux monitoring), recognition of inconclusive findings intends to avoid over reliance on findings that may suggest pathology, but with less diagnostic certainty.^{4, 17} These classifications are intended for assignment into research studies in which certainty of diagnosis is necessary.^{4, 17} Additionally, these proposed FLIP Panometry EGJ classifications and thresholds should not be viewed as firm lines in the sand, but instead as guidance based on best available data. Further, it is worth considering that application of fixed thresholds remains a limitation that could be addressed with application of other techniques to generate diagnostic probabilities applying these parameters. Work to do so by applying machine learning techniques is ongoing. Ultimately, FLIP Panometry findings should be clinically applied in the context of existing clinical data (e.g. endoscopic findings, clinical presentation). If diagnostic uncertainty remains, such as with BrEO/BnEO or if FLIP findings that are discordant with other data (e.g. endoscopic appearance of EGJ), additional clinical correlation with complementary tests (HRM and esophagram) should be pursued before assigning a clinical diagnosis, and particularly prior to pursuing invasive therapies.

While this study carries strengths related to the detailed analysis of a novel application to a large cohort of comprehensively evaluated patients, in addition to asymptomatic controls, there are some limitations as well. The composition of the patient cohort (which reflects an expansion of previously described patient cohorts) reflects a referral bias (quaternary referral center for esophageal motility disorders), and thus patients with achalasia and HRM classification of EGJOO are over-represented in the study cohort.^{2, 5, 6, 9, 12, 18} There may also be a selection bias for use of FLIP when the HRM diagnosis was equivocal, such as EGJOO. While this may somewhat limit direct generalizability of these results to other clinical practices, including application of the positive and negative predictive values, an achalasia diagnosis represents the most important outcome of an esophageal motility evaluation and thus the description of EGJ opening with FLIP Panometry in this large achalasia cohort carries substantial value. Additionally, even though the state-of-the-art, recommendations of the CCv4.0 were applied to assign status of ‘conclusive’ EGJ outflow obstruction, this classification is not perfect, e.g. an HRM pattern of type I achalasia in patients with systemic sclerosis. Further, HRM classifications often resulted in inconclusive assessment for presence of EGJ outflow obstruction, and thus these classifications could not reliably be applied to assess for accuracy of FLIP Panometry to detect EGJ obstruction.⁴ Thus, ongoing work is focused on the inconclusive EGJOO cohort via application of provocative HRM maneuvers and evaluation of longitudinal clinical outcomes.

In conclusion, evaluation of EGJ opening via FLIP Panometry provides a method to accurately identify clinically relevant esophageal obstruction, including achalasia. Because FLIP Panometry is performed at the time of the sedated endoscopy, this assessment can be applied to help improve the diagnostic yield of endoscopy and potential direct intervention (e.g. endoscopic dilation) as well as future evaluation (e.g. pursuing HRM +/− TBE when borderline findings are observed). However, FLIP Panometry reflects a novel technology and thus further evolution based on future investigation is anticipated. Future development of machine learning applications in particular, including those that could potentially be incorporated into real-time analysis software, would further augment this degree of application for clinical decision support and will be a focus of future investigation. Nonetheless, this study demonstrates the clinical utility and validity of the evaluation of EGJ opening via FLIP Panometry and further supports its value for the diagnosis of esophageal motility disorders.

BACKGROUND

The functional luminal imaging probe (FLIP) measures esophagogastric junction (EGJ) opening in response to distension and reduced EGJ distensibility is observed in achalasia.

FINDINGS

Using high-resolution manometry (HRM) and the Chicago Classification v4.0 (CCv4.0) as the reference standard, FLIP Panometry findings of reduced EGJ opening accurately identified patients with CCv4.0 disorders of EGJ outflow and normal EGJ opening on FLIP accurately identified patients with normal EGJ outflow by CCv4.0.

IMPLICATIONS FOR PATIENT CARE

FLIP Panometry provides an accurate method to complement or in some cases substitute HRM for evaluation of esophageal motility disorders.

Abbreviations:

AUC

area-under-the-curve

BEO

borderline EGJ opening

CCv4.0

Chicago Classification version 4.0

CI

confidence interval

DI

distensibility index

EGJ

esophagogastric junction

EGJOO

EGJ outflow obstruction

FLIP

functional luminal imaging probe

IRP

integrated relaxation pressure

IQR

interquartile range

HRM

high resolution manometry

IEM

ineffective esophageal motility

LES

lower esophageal sphincter

NEO

normal EGJ opening

REO

reduced EGJ opening

ROC

Receiver operating characteristic

TBE

timed barium esophagram