Introduction

Since the initial development of Chicago Classification in 2009, diagnostic evaluation and management of primary esophageal motility disorders have immensely evolved. Given the diverse and complex ways by which esophageal dysmotility can develop, symptoms of esophageal motility disorders can be highly variable. More common symptoms indicating esophageal dysmotility include dysphagia, non-cardiac chest pain, and bland regurgitation. Although symptom presentation alone can be helpful in identifying the etiology of symptoms, the gold-standard for diagnosis of esophageal motility disorders is high-resolution manometry (HRM). Chicago Classification has been revolutionary by establishing diagnostic criteria for esophageal motility disorders based on validated objective HRM data. However, in the absence of symptoms, the clinical relevance of abnormal HRM findings is often unclear, and treatment of asymptomatic manometric dysmotility may not be indicated. Further, abnormal manometric findings alone may be inconclusive for a single primary esophageal motility disorder. As a result, a priority of the Chicago Classification version 4.0 (CCv4.0) update was to limit over-diagnosis of inconclusive manometric dysmotility and improve characterization of primary esophageal motility disorders by incorporating clinical symptoms and additional diagnostic testing to enhance manometric diagnosis.

The Evolution of Chicago Classification

Chicago Classification at its core uses standardized HRM metrics and esophageal pressure topography (EPT) plots to categorize esophageal motility disorders. First published in 2009, Chicago Classification (CCv1.0) was established by the International High-Resolution Manometry Working Group, a collaborative formed in 2007 by three pioneers in esophageal motility [1, 2]. Inspired by the innovative work, Dr. Ray E Clouse, the International HRM Working Group set out to address clinical approach to primary esophageal motility disorders during their inaugural meeting in San Diego, CA in 2008. In developing CCv1.0, the International HRM Working Group introduced the first formal classification scheme of esophageal motility disorders [1, 3, 4]. By incorporating this objective data, CCv1.0 revolutionized clinical practice by establishing a unified systematic approach to esophageal motility based on standard and validated criteria.

Since its initial publication in 2009, clinical application of Chicago Classification has sparked further investigational data that has contributed to updates outlined in subsequent revisions. Developed through deliberations in 2011 in Ascona, Switzerland, the second version of Chicago Classification (CCv2.0) first categorized achalasia into its subclasses: type I (classic), type II (panesophageal pressurization), and type III (spastic) [5]. Delineating between subtypes of achalasia was notable in guiding subsequent management of these disorders [6,7,8,9]. In defining peristaltic abnormalities, CCv2.0 more distinctly distinguished weak peristalsis, frequent failed peristalsis, rapid contractions with normal latency, and hypertensive peristalsis based on published HRM data developed after the publication of CCv1.0 [5]. After CCv2.0 was published in 2012, further study on HRM metrics led to the development of the Chicago Classification version 3.0 (CCv3.0) in 2014. In establishing CCv3.0, the International HRM Working Group set out to refine diagnostic criteria for achalasia and esophagogastric junction (EGJ) outflow obstruction (EGJOO), while focusing on metrics of both EGJ morphology and peristalsis. More specifically, measures of distal contractile integral (DCI) were used to define failed peristalsis (< 100 mmHg•s•cm), weak peristalsis (100–450 mmHg•s•cm), and hypercontractile peristalsis (> 8000 mmHg•s•cm) [4]. In addition, two minor disorders of peristalsis (i.e. ineffective esophageal motility (IEM) and fragmented peristalsis) were described. Similar to CCv2.0, CCv3.0 uses integrated relaxation pressure (IRP) values in defining disorders of lower esophageal sphincter (LES) relaxation such as achalasia and EGJOO. However, it was recognized that mean IRP included in CCv2.0 may misrepresent a true average IRP if significant outlier values exist. As a result, CCv3.0 used median IRP in defining LES dysfunction and related motility disorders [4]. Overall, CCv3.0 further clarified diagnostic criteria for esophageal motility disorders as prior studies have shown reduced rates of indeterminate diagnoses and increased detection of both EGJOO and minor motility disorders using CCv3.0 [10, 11].

Chicago Classification version 4.0

Since publication and clinical application of CCv3.0, new treatment and diagnostic modalities have emerged in the setting of achalasia and other motility disorders. As a consequence, the development of CCv4.0 utilized new clinical data to improve the accuracy of esophageal dysmotility identification and management. Published in January 2021, Chicago Classification version 4.0 was established after a two-year process that focused on protocol standardization, redefinition of esophageal motility disorders and consideration of clinical relevance of esophageal motility diagnoses (Table 1) [12].

Table 1 Summary of Chicago classification version 4.0: diagnosis and management of esophageal motility disorders
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Standard HRM Protocol

CCv4.0 outlines a standardized HRM protocol based on performance and interpretation of HRM findings. In an effort to improve consistency and accuracy of HRM diagnoses, the International HRM Working Group recognized that the initial protocol of 10 supine swallows is often not sufficient in diagnosing certain esophageal motility disorders such as EGJOO. [13, 14]

As such, the updated standardized protocol expanded testing to include wet swallows performed in both supine and upright positions. Testing can begin in either position (supine or upright) as the primary position. Ten wet swallows in the primary position are first performed followed by 5 wet swallows in the secondary position. To further enhance diagnostic yield for indeterminate cases, the proposed protocol includes further testing with at least one supine multiple rapid swallow (MRS) as well as an upright rapid drink challenge (RDC), as these maneuvers can evoke symptoms or elicit manometric disruptions [3]. Although not part of the standardized protocol, additional ancillary testing is further described, including pharmacologic provocation and solid test swallow, when HRM findings remain equivocal or do not explain a patient’s symptoms. However, it is noted that in cases in which the diagnosis is clear-cut, such as in certain cases of achalasia, evaluation in either supine or upright position alone should be sufficient. Further adjunct studies including a timed barium esophagram (TBE) or functional lumen imaging probe (FLIP) may be considered thereafter [12]. Overall, by incorporating additional positional modifications and ancillary tests, the updated standardized protocol aims to enhance diagnostic accuracy and consistency across motility centers.

Disorders of EGJ Outflow:

Achalasia

Generally, the manometric definition of achalasia remains unchanged. As updated in CCv3.0, all subtypes of achalasia require an elevated median IRP rather than mean IRP in supine or upright positions with concurrent 100% abnormal peristalsis. In both type 1 and type II achalasia, all swallows are failed (DCI < 100 mmHg-s-cm), with panesophageal pressurization present in at least 20% of swallows in type II achalasia. Type III achalasia, on the other hand, is akin to spastic achalasia where at least 20% of swallows are spastic (distal latency less than 4.5 s in the setting of a normal DCI) and the remainder of the swallows are failed (Fig. 1) [12]. Importantly, inconclusive patterns of achalasia can be encountered on HRM. These include a pattern of type I or II achalasia in the primary position, however with evidence of peristalsis with position change. Another inconclusive pattern is when a pattern of type I or II achalasia is suspected but the median IRP is at the upper limit of normal. In these scenarios further testing is recommended to evaluate for EGJ outflow with a TBE, preferably with tablet, and/or FLIP. Inconclusive findings for type III achalasia include the presence of esophageal spasm with evidence of normal peristalsis. The presence of an elevated median IRP with spasms and any evidence of normal peristalsis may be more consistent with EGJOO with spastic features. Therefore, ancillary testing with TBE and/or FLIP is recommended. Opioid-induced esophageal dysfunction (OIED) is also highlighted in the updated Chicago Classification. Opioid medications have been associated with elevated median IRP and short distal latency (DL), leading to manometric findings of EGJOO, distal esophageal spasms, and achalasia type III [15, 16]. Given the association between opioids and disorders of EGJ outflow, updated guidelines now recommend that HRM testing be performed off of opioids if possible. Discontinuation of opioid medications should be timed based on medication half-life [12].

Fig. 1
figure 1

The three subtypes of achalasia are all defined by an elevated median IRP and specifically include A) Type 1 Achalasia with 100% failed peristalsis, B) Type 2 Achalasia with 100% failed peristalsis and at least 20% of swallows with panesophageal pressurization, and C) Type 3 Achalasia with at least 20% of swallows with premature contractions and the remainder of the swallows failed or premature. The more stringent criteria for type 3 achalasia is an update in the Chicago Classification version 4.0

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EGJ Outflow Obstruction

If the median IRP is elevated in both positions along with presence of intrabolus pressurization, but there is manometric evidence of peristalsis, then EGJOO is considered. EGJOO in concept represents a primary dysfunction of LES relaxation which may be an achalasia variant or represent early achalasia. However, manometric evidence of EGJOO is not always conclusive for true LES dysfunction. EGJOO often results due to benign secondary causes, including mechanical obstruction, artifact, opioid effects, or central obesity [3, 17]. In these cases, interventions targeting the LES may not be warranted and should be considered carefully in select cases. Evidence of elevated median IRP with preserved peristalsis is therefore subject to overdiagnosis and overtreatment of EGJOO. Thus, one major aim of CCv4.0 was to clarify the diagnostic criteria for EGJOO and specify therapeutic indications as a result.

Based on updated criteria, manometric diagnosis of EGJOO requires an elevated median IRP in both supine and upright positions, and at least 20% of supine swallows with intrabolus pressurization. Per CCv4.0, manometric criteria alone are not diagnostic for EGJOO. Patients must additionally present with obstructive symptoms including dysphagia and/or non-cardiac chest pain, and diagnosis should also be confirmed with ancillary testing, such as FLIP and/or TBE preferably with a tablet. Additional maneuvers, including solid test meal and pharmacologic provocation, can support EGJOO diagnosis by demonstrating manometric evidence of outflow obstruction during each maneuver.

Treatment choice and implications of EGJOO may be highly variable depending on etiology, symptom burden, and anatomical factors. Characterizing EGJOO based on peristaltic pattern can help identify appropriate treatment options. EGJOO is described as having spastic features, hypercontractility, ineffective esophageal motility, or intact peristalsis. As previously mentioned, type III achalasia and EGJOO with spastic contractions are often difficult to discern due to similar clinical and manometric features. The two can be distinguished based on the presence of any intact peristalsis. Therefore, additional supplementary testing is indicated in either case to provide further manometric evaluation and supportive data. EGJOO may represent a variant of achalasia or early achalasia, and thus the two likely lie on a fluid spectrum. Distinguishing EGJOO from achalasia on manometry is key in determining appropriate treatment. While per-oral endoscopic myotomy (POEM) can be considered first-line for type III achalasia, medical management is first-line over endoscopic intervention in the setting of EGJOO due to primary LES dysfunction [14, 18]. Specifying EGJOO based on peristaltic features further expands motility characterization. The clinical relevance of these specifications may warrant further future study in regards to clinical approach [12].

Disorders of Peristalsis

Consistent with prior versions of Chicago Classification, disorders of peristalsis include absent contractility, distal esophageal spasm (DES), hypercontractile esophagus, and IEM. In contrast to CCv3.0, fragmented peristalsis is no longer identified as its own entity, but is instead included in IEM characterization. Disorders of peristalsis are considered when a disorder of EGJ outflow has been ruled out such that the median IRP is within normal limits. Disorders of peristalsis may have overlapping and similar manometric features. As such, a hierarchical diagnostic classification has been proposed that first includes absent contractility, DES, then hypercontractile esophagus, and lastly, IEM.

Absent Contractility

Diagnostic criteria for absent contractility remains unchanged from prior iterations. Absent contractility is defined by a normal median IRP in both supine and upright positions with 100% failed peristalsis (DCI < 100 mmHs-s-cm) [1, 12]. Notably, patients with type I achalasia may have evidence of absent contractility on HRM. Thus, careful evaluation should be performed in patients with absent contractility and a high normal median IRP, as this warrants manometric provocation and/or ancillary testing, such as TBE and/or FLIP, to delineate the motility pattern.

Distal Esophageal Spasm

Diagnostic criteria for DES on HRM is defined by the presence of at least 20% of premature contractions with distal latency less than 4.5 s and a normal DCI (450–8000 mmHg-s-cm) with normal median IRP. Manometric criteria must also be accompanied by the presence of dysphagia and/or non-cardiac chest pain in order for diagnosis of DES to be conclusive. Overall, true DES is rare, as premature contractions may represent a spastic feature. As such, similar to EGJOO with spastic features, DES can be considered along the spectrum of type III achalasia. The greater the proportion of premature swallows that are seen, the higher the pretest probability that DES is the primary disorder of peristalsis. Additional testing with TBE and/or FLIP can increase diagnostic yield.

Hypercontractile esophagus

Manometric diagnosis for hypercontractile esophagus is defined by at least 20% of swallows with hypercontractility (DCI > 8000 mmHg-s-cm) with a normal median IRP (Fig. 2). Further, the presence of dysphagia and/or non-cardiac chest pain must accompany manometric findings for diagnosis of hypercontractile esophagus. Esophageal hypercontractility can occur due to multiple secondary etiologies, including gastroesophageal reflux disease (GERD), EGJ mechanical obstruction, and medications, such as opioids [19]. However, true primary hypercontractile esophagus must occur in the absence of EGJ outflow obstruction (i.e. achalasia and EGJOO). Based on the hierarchical classification of disorders of peristalsis, the presence of DES must also be ruled out prior to diagnosis of hypercontractile esophagus.

Fig. 2
figure 2

Adapted from the Chicago Classification version 4.0 ©. Hypercontractile Esophagus is defined by a normal median IRP and at least 20% or more swallows as hypercontractile (DCI ≥ 8000 mmHg-s-cm). In the Chicago Classification update hypercontractile esophagus is no longer synonymous with Jackhammer esophagus but rather may indicate one of three phenotypes: A) single peak hypercontractile swallow (the most common), B) jackhammer esophagus with repetitive prolonged contractions, or a new entity defined by a C) hypercontractile lower esophageal sphincter

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Given multiple phenotypic patterns observed, three subtypes of hypercontractile esophagus have been identified: single-peaked, jackhammer, and hypercontractile swallows with vigorous LES aftercontraction (Fig. 2). With the establishment of these three subgroups, future research work investigating the clinical application and relevance of each will be important in characterizing each clinically. In this matter, while jackhammer patterns with repetitive prolonged contractions are generally more likely to respond to medical therapies, further investigation in the management of all three hypercontractile subtypes may improve clinical outcomes and symptom control [20, 21]. In general, conservative medical therapies are considered first-line in managing hypercontractile esophagus prior to considering more invasive interventions, such as endoscopic or surgical [12].

Spastic esophageal disorders, including DES and hypercontractile esophagus, can also result due to secondary causes, including opioid-induced esophageal spasms or in response to GERD. As a result, management of these disorders should be directed at the etiology eliciting the spastic response [3].

Ineffective esophageal motility

Previously recognized as a minor motility disorder, IEM diagnosis now involves more strict criteria, requiring that more than 70% of swallows be ineffective (DCI < 450 mmHs-s-cm) or fragmented. Alternatively, IEM is diagnostic if at least 50% of swallows are failed (DCI < 100 mmHs-s-cm). When 50–70% of swallows are ineffective, IEM is considered inconclusive (Fig. 3). Further recommended confirmatory testing includes manometric provocation such as multiple rapid swallow. Poor bolus transit on impedance or on barium esophagram also further supports a diagnosis of IEM. Previously recognized as a minor motility disorder separate from IEM, fragmented peristalsis is no longer classified as its own distinct motility disorder. Instead, fragmented swallow is used to characterize and identify IEM as described. As a result, CCv4.0 eliminates designated major and minor disorders of peristalsis [12].

Fig. 3
figure 3

Ineffective esophageal motility is defined as a normal median IRP with more than 70% of swallows ineffective or at least 50% failed. A) A failed swallow is defined as a DCI < 100 mmHg-s-cm. An ineffective swallow may be B) weak (DCI 100 to 450 mmHg-s-cm) or C) fragmented (peristaltic break > 5 cm)

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Conclusion

The Chicago Classification of esophageal motility disorders has transformed the realm of esophageal dysmotility and management. By establishing systematic criteria for disorders of esophageal motility, Chicago Classification standardized diagnosis and approach to these disorders and has sparked further clinical investigation on esophageal dysmotility patterns, physiology, and clinical outcomes. Growing data has subsequently contributed to the development of new treatments and has evolved Chicago Classification into its multiple versions. Recently published Chicago Classification version 4.0 maintains the categorization of esophageal motility disorders into disorders of EGJ outflow and disorders of esophageal peristalsis. However, key revisions outlined in CCv4.0 focus on the presence of clinical symptoms in diagnosing esophageal dysmotility, establish a modified standard HRM protocol, and address the role of ancillary testing for inconclusive manometric diagnoses (Table 1). Moreover, updated criteria for EGJOO, DES, IEM, and hypercontractile esophagus are more stringent and will hopefully limit overdiagnosis of these disorders. As described by CCv4.0, it is also important to recognize secondary factors affecting esophageal motility, including GERD, mechanical obstruction, and opioid use, when evaluating a patient with manometric abnormalities or obstructive symptoms, as the underlying etiology will ultimately guide treatment and resolution.

Future investigational research will help characterize patterns and pathophysiology of esophageal spasms. This subsequently should improve understanding of the treatment of spastic disorders. Using the refined definition of EGJOO outlined by CCv4.0, future outcomes data will further improve our approach to disorders of outflow obstruction and specify their clinical relevance. Moreover, advances in both the diagnosis and treatment of esophageal motility disorders will provide further future data regarding work-up and management, such as indications and outcomes of per-oral endoscopic myotomy. In summary, Chicago Classification version 4.0 outlines key clarifying modifications that aim to improve diagnostic accuracy of clinically relevant esophageal motility disorders. As a result, these updates will hopefully improve symptom management and clinical outcomes for patients presenting with obstructive symptoms.