AJG Red Section: The tailored approach to manometric esophagogastric junction outflow obstruction (EGJOO): Treat the clinical diagnosis, not the manometry pattern

Esophagogastric junction outflow obstruction

Esophagogastric junction (EGJ) outflow obstruction (EGJOO) is defined on high-resolution manometry (HRM) per the Chicago Classification (CC) by abnormally elevated pressure across the EGJ in response to swallow as well as the presence of esophageal peristalsis such that a distinct diagnosis of achalasia (subtypes I, II, or III) is not met.¹ However, challenges arise with this ‘diagnosis’ because it does not reflect a distinct, clinical disease entity (i.e. EGJOO is not a disease). Instead, manometric EGJOO can represent broad clinical differential diagnoses (Table 1) that includes an achalasia-variant, mechanical obstruction, or pressure recording artifact (e.g. occurring from HRM catheter angulation or thermal drift, and thus not truly reflecting EGJ pressure) yielding a false-positive HRM.^2–5 Given this broad clinical differential, there is not a single universal treatment for EGJOO. Instead, efforts, often using complementary testing beyond HRM, are necessary to better define the esophageal disease state and thereby inform therapeutic options.

Table 1.

Differential diagnosis for manometric pattern of esophagogastric junction outflow obstruction (EGJOO)

EGJOO: Differential diagnosis
Achalasia (evolving; variant; early) Subtle (or unappreciated) mechanical obstructiona Hiatal herniaa Extrinsic esophageal compression Infiltrative diseases Opioid effect Pressure artifact (i.e. false positive HRM)

^aNote that the Chicago Classification is intended for diagnosis of primary esophageal motility disorders and thus for application to patients with normal esophageal anatomy and without previous foregut surgery, large hiatal hernia or paraesophageal hernia, or overt mechanical obstruction.

EGJOO: Diagnostic criteria

Recognizing the clinical challenges posed by “EGJOO”, the recent CC update (CCv4.0) aimed to refine the EGJOO diagnosis, seeking to identify patients with clinically relevant pathology.^{1, 4} Updated HRM criteria for EGJOO include an elevated median integrated relaxation pressure (IRP; a measure of EGJ relaxation pressure) in both supine and upright HRM positions (compared to the reliance on an elevated IRP in a single position from previous CC versions) and intrabolus pressurization in at least 20% of supine test swallows, as well as presence of appreciable peristalsis such that a diagnosis for achalasia is not achieved (Figures 1 and 2; Table 2). Also new to CCv4.0 is the inclusion of symptomatic criteria such that obstructive esophageal symptoms (dysphagia or non-cardiac chest pain) are required to reach a diagnosis of EGJOO. In addition to these more robust criteria for EGJOO, CCv4.0 further asserts that a diagnosis of EGJOO based on HRM alone is considered clinically “inconclusive”, and that corroboration of EGJ obstructive physiology on additional testing using timed barium esophagram (TBE) and/or functional lumen imaging probe (FLIP) is required to meet a clinically relevant ‘conclusive’ diagnosis of EGJOO. Establishing a clinically relevant conclusive diagnosis of EGJOO is particularly pertinent prior to pursuing achalasia-type treatments such as pneumatic dilation or lower esophageal sphincter (LES) myotomy.^{1, 3}

Figure 1. Esophagogastric junction (EGJ) outflow obstruction (EGJOO).

Examples of two patients (A and B) that were evaluated for non-obstructive dysphagia are included with high-resolution manometry (HRM) at top, timed barium esophagram (TBE) bottom-left, and functional lumen imaging probe (FLIP) Panometry bottom-right. On HRM, both patients (A and B) had integrated relaxation pressure (IRP) greater than the upper-limit of normal during both supine (left panels) and upright (right panels) test swallows, as well as intrabolus pressure >20mmHg (white arrows; note the isobaric contour is set at 20mmHg) during supine swallows. A) Had a normal TBE and FLIP with normal EGJ opening (EGJ-distensibility index 7.0mm²/mmHg and maximum EGJ diameter 20 mm), as well as normal 96-hour wireless pH testing. The patient was reassured and dysphagia resolved after several months and dietary modification. B) Had an abnormal TBE with a 20cm column height at 5 minutes, as well as corkscrew configuration and narrowed-appearing EGJ. FLIP demonstrated reduced EGJ opening with EGJ-distensibility index 0.6 mm²/mmHg and maximum EGJ diameter 8 mm. The patient was initially treated with botulinum toxin injection with resolution of dysphagia lasting 6-months; peroral endoscopic myotomy (POEM) was then performed with resolution of dysphagia at follow-up. Figure used with permission of the Esophageal Center of Northwestern.

Figure 2. Examples of manometry cases no longer considered EGJ outflow obstruction (EGJOO) in Chicago Classification (CC) v4.0.

Representative swallows (left panel = supine; right panel = upright) from two patients (A and B). Patient A was evaluated for heartburn and regurgitation and patient B was evaluated for post-prandial cough; both had unremarkable findings on upper GI endoscopy. In both cases, integrated relaxation pressure (IRP) was elevated in the supine position, but normalized during upright swallows. In prior iterations of CC this study would have been consistent with EGJOO. Now with the current CCv4.0 definitions for manometric EGJOO, these studies do not meet criteria for EGJOO and do not require further testing to evaluate EGJ physiology. Figure courtesy of University of San Diego Center for Esophageal Diseases.

Table 2. Checklist of criteria for diagnosis of esophagogastric junction outflow obstruction (EGJOO).

Manometric pattern of EGJOO is always considered clinically inconclusive. A diagnosis of conclusive EGJOO is met when all listed criteria are met. TBE – timed barium esophagram. FLIP – functional lumen imaging probe.

EGJOO: Diagnostic criteria
Manometric EGJOO = Inconclusive
Elevated median IRP in supine swallowsa Elevated median IRP in upright swallowsa Elevated intrabolus pressure (>20mmHg) in ≥20% of supine swallows Presence of peristalsis (supine swallows)
Clinically Relevant EGJOO = Conclusive
Meeting all above criteria for Inconclusive EGJOO Presence of dysphagia or non-cardiac chest pain Abnormal TBE and/or FLIP supportive of EGJ obstructive physiology

^aThe threshold for upper limit of normal of integrated relaxation pressure (IRP) is dependent on the high-resolution manometry (HRM) assembly manufacturer and patient position.

Also notable is that CC is intended for the evaluation of non-obstructive dysphagia and to diagnose a primary esophageal motility disorder, and thus applicable to patients with normal esophageal anatomy and without previous foregut surgery, large hiatal hernia, paraesophageal hernia, or overt mechanical obstruction (Table 1). These conditions all can result in an EGJOO-pattern on HRM, underscoring the importance of a careful endoscopic and/or radiographic evaluation and clinical history taking prior to pursuing HRM.

Complementary evaluation of EGJOO (Table 3)

Table 3. Complementary evaluation of manometric esophagogastric junction (EGJ) outflow obstruction (EGJOO).

Of note, equivocal (i.e. ‘suggestive, but inconclusive’ abnormal findings) may occur on complementary testing thus prompting consideration for additional testing, i.e. obtaining timed barium esophagram (TBE) and functional lumen imaging probe (FLIP), in addition to high-resolution manometry (HRM).

Complementary test	Description	Supportive of conclusive EGJOO	Suggestive (but inconclusive) abnormal findings
HRM provocative maneuvers	Rapid drink challenge (RDC): 200ml liquid rapidly drank in upright position Solid test meal: 200g soft, solid meal (e.g. rice) eaten at normal patient rate Pharmacologic challenge: Amyl nitrite: 4–5 sniffs in supine position Cholecystokinin (CCK): 40ng/kg IV push in supine position		Premature or hypercontractile swallows during standard 5ml liquid test swallows Elevated IRP or panesophageal pressurization during RDC or solid test meal Symptom-association during solid test meal Amyl nitrite response: Reduction in IRP >10mmHg below IRP during standard supine test swallows CCK response: paradoxical LES contraction >50mmHg
TBE	200–236ml thin barium ingested in upright position with images obtained 1, 2, and 5 minutes later Ingestion of 12.5–13mm barium tablet	5-minute column height >5cm Impaction of barium tablet	1 minute column height >5cm Beaked appearing EGJ Corkscrew or rosary bead appearance
FLIP	Stepwise volumetric distension while FLIP positioned across EGJ during sedated endoscopy	Reduced EGJ opening (REO) EGJ-DIa <2.0 mm2/mmHg and maximum EGJ diameter <12mmb	Borderline EGJ opening EGJ-DIa <2.0 mm2/mmHg or maximum EGJ diameter <16mmb, but not REO Spastic-reactive contractile response

^aEGJ-distensibility index (DI) measured at 60ml fill volume using 16cm FLIP catheter or 40ml using 8cm FLIP catheter.

^bMaximum EGJ-diameter measured at 60ml or 70ml fill volume using 16cm FLIP catheter or 40ml or 50ml using 8cm FLIP catheter

Provocative HRM maneuvers

While additional testing beyond HRM is recommended to reach a diagnosis of a conclusive EGJOO, other features and maneuvers on HRM can lend support as well. Among these, an abnormal peristaltic/contractile pattern during the standard, supine test swallows (e.g. premature, hypercontractile, or even severe ineffective motility) may support a clinically relevant motility disorder (while also recognizing that peristaltic response can be impacted by outflow obstruction, e.g. hypercontractility occurring secondarily to mechanical obstruction). Conversely, normal peristalsis may be more suggestive of a subtle mechanical obstruction or a false positive from pressure artifact than an achalasia-variant. Further, provocative HRM test maneuvers, such as the rapid drink challenge (RDC) or a solid test meal (Table 3), can provide insight on the evaluation of EGJOO.^{6, 7} Elevated IRP, panesophageal pressurization, and/or reproduction of symptoms during these maneuvers is supportive of relevant EGJOO, though risk of pressure-artifact impacting the IRP measures remains a consideration (thus lending caution with interpretation) during these maneuvers as well. Pharmacologic provocation using amyl nitrate or cholecystokinin has also been described with findings that can support relevant EGJOO.⁸

Timed barium esophagram (TBE)

Barium esophagram can provide evaluation of esophageal retention and esophageal anatomy. Utilization of the TBE protocol (Table 3) helps provide a consistent, standardized measure of esophageal retention via measurement of the column heights at the defined image times.⁹ Additionally, utilization of a 12.5–13mm barium tablet may further enhance the functional evaluation provided by TBE. Conclusively abnormal findings on TBE have been considered as a 5-minute column height >5cm or impaction of the barium tablet, though noting that lesser degrees of retention may also reflect abnormal function. Additional anatomic information can also be useful such as appearance of the EGJ (e.g. beaked appearance suggestive of achalasia) or esophageal body dilatation or ‘corkscrew’ appearance.

FLIP

FLIP is performed in a sedated patient at the time of endoscopy and measures esophageal lumen (EGJ in particular) cross-sectional area and distensibility. Reduced EGJ opening on FLIP, defined by an EGJ-distensibility index <2.0 mm²/mmHg and a maximum EGJ diameter <12mm, supports a true physiologic EGJ obstruction.¹⁰ Other FLIP findings, such as an abnormal contractile response involving ‘spastic-reactive’ contractions may also support an EGJOO, also suggesting coexisting spasm. On the other hand, a normal FLIP in the context of EGJOO on HRM may effectively rule-out a clinically relevant motility disorder.¹¹ Further, FLIP during the initial endoscopy for dysphagia may preclude need for HRM (e.g. if FLIP is normal) or may also direct targeted intervention (e.g. dilation).

Additional imaging/Endoscopic ultrasound

Obstruction related to extrinsic esophageal compression or intramural pathology, including tumors (both benign and malignant), may also account for manometric EGJOO. While universal application of endoscopic ultrasound (EUS) or computed tomography (CT) to EGJOO patients was demonstrated as low yield in several studies, we generally have a low threshold to consider imaging in EGJOO patients, especially if concerning clinical features (e.g. significant weight loss, smoking history).¹² EUS may also facilitate injection of botulinum toxin under visualization into the LES.

Tailored treatment approach

Overall, the comprehensive diagnostic evaluation aims to reach a distinct clinical diagnosis to facilitate appropriate tailored treatment. Importantly, if a conclusive EGJOO diagnosis is not reached with complementary testing, the diagnosis of EGJOO remains inconclusive and definitive achalasia therapies should not be pursued. If FLIP and/or TBE are normal, an initial conservative approach is recommended, such as optimizing treatment for reflux and/or a functional esophageal syndrome, as appropriate. If symptoms persist or progress, repeat motility testing may be considered to objectively assess for progression of dysmotility.

If hiatal hernia is considered as the possible etiology for manometric EGJOO and obstructive symptoms, hiatal hernia repair may be considered; ambulatory reflux monitoring provides further complementary testing in this scenario. If an opioid-induced EGJOO is considered, a pragmatic recommendation is to work with pain managing providers to reduce or cease opioids, with potential for repeat testing if obstructive symptoms persist. Opioid minimization is not possible for all patients, in which case a conservative step-up approach as described below may be considered.

In the case that complementary testing yields supportive (but not conclusive) findings for EGJ obstruction (Table 3) and even in some cases of conclusive complementary findings, distinguishing between achalasia-variant and other etiologies for the EGJ obstruction (such as subtle mechanical obstruction) can pose a challenge. Thus, treatment strategies generally involve a graded, step-up approach initially utilizing less-invasive and reversible options prior to pursuing definitive (irreversible) achalasia-type treatments (Figure 3). Among these, off-label use of esophageal smooth muscle relaxants (e.g. hyoscyamine (anticholingeric), nitrates, or sildenafil) may be considered (if there are no medical contraindications). This recognizes that only a short trial may be needed to gauge response and that medication effects are reversible with medication cessation (though also that supporting clinical evidence is limited). Further, endoscopic treatments with dilation (i.e. ≤20mm) may uncover a subtle stricture, such as if heme is elicited by dilation. If there is not a notable endoscopic response to dilation, LES botulinum toxin may be considered, even during the same endoscopic encounter as dilation. The response to botulinum toxin (and among other initial treatment trials) can be integrated with additional clinical data and test results to help formulate the global clinical impression. Though if symptoms persist, repeat HRM on or after initial treatment(s) may help to distinguish between a resolved versus ongoing manometric EGJOO.

Figure 3. Graded, stepwise treatment approach to manometric esophagogastric junction (EGJ) outflow obstruction (EGJOO).

The extent to which treatment is escalated should be based on the degree of support on complementary testing for a relevant EGJOO. Particular scrutiny should be applied (“”) regarding the support for a clinical diagnosis of an achalasia-variant prior to progressing to invasive, achalasia-type treatments, such as botulinum toxin and particularly prior to definitive (irreversible) treatments: pneumatic dilation, peroral endoscopic myotomy (POEM), or laparoscopic Heller’s myotomy. Repeat, follow-up testing to assess for progression of motility disorder should be considered to support such escalation of treatment. *Possibly during same endoscopy session (during which endoscopic ultrasound may be considered) if no heme or endoscopic response is appreciated after dilation. PPI – proton pump inhibitor. LES – lower esophageal sphincter.

When consistent abnormal findings are observed on complementary testing such that the global clinical impression (i.e. also incorporating clinical history and course, endoscopy findings, and additional HRM features) is of achalasia, treatment with pneumatic dilation, peroral endoscopic myotomy (POEM) or laparoscopic Heller’s myotomy may be considered for definitive treatment, tailored to the clinical impression.

Ultimately, the manometric diagnosis of EGJOO is inconclusive in isolation and a comprehensive clinical evaluation is necessary to reach a clinical diagnosis to which targeted treatment can be applied. Conservative treatment approaches and observation for objective progression are often reasonable considerations, as well as graded escalation of invasive options. Cautious utilization of definitive achalasia treatments are limited to scenarios where clinically relevant EGJ outflow obstruction is confirmed by complementary tests and supported by the global clinical impression.