Gastro Hep Advances 2023;2:701–710

NARRATIVE REVIEW
Advances in the Diagnosis and Management of Achalasia
and Achalasia-Like Syndromes: Insights From HRM and FLIP
Peter J. Kahrilas, Dustin A. Carlson, and John E. Pandolfino

Department of Medicine, Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University,
Chicago, Illinois

High-resolution manometry, Chicago Classification v4.0, therapeutics over the last 2 decades. High-resolution
the functional lumen imaging probe, Panometry, and per- manometry (HRM) is now firmly entrenched in motility lab-
oral endoscopic myotomy (POEM) are all now integral oratories around the world and the Chicago Classification,
parts of the landscape for managing achalasia or, more now in v4.0, is uniformly accepted as the consensus state-
precisely, achalasia-like syndromes. This narrative review
ment on HRM interpretation.1 Per Oral Endoscopic Myot-
examines the impact of these innovations on the manage-
omy (POEM) has largely replaced laparoscopic Heller
ment of achalasia-like syndromes. High-resolution
manometry was the disruptive technology that prompted myotomy (LHM) and pneumatic dilation (PD) as first-line
the paradigm shift to thinking of motility disorders as therapy for achalasia, especially spastic achalasia, in esoph-
patterns of obstructive physiology involving the esoph- ageal tertiary care centers.2–4 Intraoperative functional
agogastric junction and/or the distal esophagus rather lumen imaging probe (FLIP) measurements are being used
than as siloed entities. An early observation was that the to calibrate the myotomy for achalasia.5,6 FLIP panometry
cardinal feature of achalasia—impaired lower esophageal is being adopted as a diagnostic tool used in conjunction
sphincter relaxation—can occur in several subtypes: with endoscopy to diagnose achalasia and achalasia-like
without peristalsis, with pan-esophageal pressurization, syndromes both on its own and to clarify equivocal HRM
with premature (spastic) distal esophageal contractions, findings.1,7–9 All of this is relatively new. A mere 15 years
or even with preserved peristalsis (esophagogastric junc-
ago, ‘experts’ were still debating the merits of HRM verses
tion outlet obstruction). Furthermore, there being no
three-channel line-tracing manometry, a technology now
biomarker for achalasia, no manometric pattern is
perfectly sensitive or specific for ‘achalasia’ and there is as obsolete as a typewriter.
also no ‘gold standard’ for the diagnosis. Consequently,
complimentary physiological testing with a timed barium Achalasia-like syndromes
esophagram or functional lumen imaging probe are
employed both to improve the detection of patients likely A fundamental innovation of HRM was changing the
to respond to treatments for ‘achalasia’ and to characterize presentation format of motility data from line tracings to
other syndromes also likely to benefit from achalasia pressure topography or Clouse plots.10 Pressure topography
therapies. These findings have become particularly rele- plots use a coordinate system of time on the x-axis, sensor
vant with the development of a minimally invasive tech- position on the y-axis, and pressure values as spectral color
nique for performing a tailored esophageal myotomy, within that grid. This elegantly condenses an enormous
POEM. Now and in the future, optimal achalasia manage- dataset of 36 pressure sensors sampling at a rate of 40 Hz
ment is to render treatment in a phenotype-specific into a single image that makes sphincters, propagated or
manner, that is, POEM calibrated in a patient-specific nonpropagated contractions, luminal pressure gradients,
manner for obstructive physiology including the distal
and isobaric regions within the esophagus visually obvious.
esophagus and more conservative strategies such as a
Hence, in a way never achieved with line-tracing manom-
short POEM or pneumatic dilation for obstructive physi-
ology limited to the lower esophageal sphincter. etry, HRM revealed patterns of obstructive physiology, both

Abbreviations used in this paper: BOM, blown out myotomy; CI, confi-
Keywords: Dysphagia; Achalasia; Functional lumen imaging dence interval; DI, distensibility index; EGJ, esophagogastric junction;
probe; Manometry; Esophagus EGJOO, EGJ outflow obstruction; FLIP, functional lumen imaging probe;
HRM, High-resolution manometry; IRP, integrated relaxation pressure;
LES, lower esophageal sphincter; LHM, laparoscopic Heller myotomy; OR,
odds ratio; PD, pneumatic dilation; POEM, per-oral endoscopic myotomy;
RAC, repetitive antegrade contraction; RCT, randomized control trial.
Most current article
Introduction
Copyright © 2023 The Authors. Published by Elsevier Inc. on behalf of the

T he universe of esophageal motility disorders

has seen a series of major changes in conceptuali-
zation, diagnostic instruments, diagnostic algorithms, and
AGA Institute. This is an open access article under the CC BY-NC-ND
license ([Link]
2772-5723
[Link]
702 Kahrilas et al Gastro Hep Advances Vol. 2, Iss. 5

Figure 1. Achalasia subtypes and achalasia-type esophagogastric (EGJ) outflow obstruction. A. Type I achalasia: integrated
relaxation pressure (IRP) is elevated (> 15 mmHg) with 100% failed peristalsis (distal contractile index [DCI] < 100
mmHg
s
cm), and without panesophageal pressurization. B. Type II achalasia: IRP is elevated with 100% failed peristalsis and
panesophageal pressurization to > 30 mmHg observed in  20% of test swallows. Note that this recording was obtained with
an impedance-manometry catheter with the impedance signal (evident by the purple shading) showing retained fluid in the
distal half of the esophagus. On timed barium esophagram, the level of barium retention would correspond to the level of
purple shading. C. Type III achalasia: IRP is elevated with a normal DCI (> 450 mmHg
s
cm), and premature contractions
(distal latency < 4.5s). D. EGJ outflow obstruction: IRP is elevated with preserved peristalsis and compartmentalized pres-
surization between the peristaltic contraction and the EGJ. Note the differences between the spatial pressure variation (SPV)
plots to the right of the type III achalasia and EGJ outflow obstruction panels. The SPV plots illustrate the top-to-bottom
pressure profile within the Clouse plot at the time indicated by the black dashed line. In type III achalasia this has multiple
peaks indicating multiple points of luminal closure, often reported as a ‘corkscrew’ or ‘rosary bead’ on an esophagram and
interpreted as distal esophageal spasm, while with compartmentalized pressurization, the zone of pressurization is a flat
plateau, indicating pressurization within a chamber sealed at both ends. This would also be the case with type II achalasia
except the plateau extends from the upper sphincter to the lower sphincter making it panesophageal pressurization.
Figure used with permission from the Esophageal Center at Northwestern.

at the esophagogastric junction (EGJ) and along the esoph- single test will ever be perfect. After all, there are no bio-
ageal lumen. An early outcome of this revolutionized visu- markers of esophageal motility disorders and, in the
alization was the subtyping of achalasia based on the 3 absence of a biomarker, there can be no ‘gold standard’ for
major patterns of esophageal pressurization associated with diagnosis. Motility disorders are diagnosed based on ab-
outflow obstruction at the EGJ11 (Figure 1). However, it has normalities of esophageal function, not on the etiology of
since become clear that obstructive physiology also occurs that dysfunction. Although we recognize that in pathology
in syndromes besides achalasia involving the EGJ and/or specimens sourced from advanced cases of achalasia, the
distal esophagus. In fact, obstructive physiology is increas- underlying pathology is of a myenteric plexopathy,13,14 the
ingly recognized as the fundamental abnormality leading to diagnosis is rarely, if ever, established by neuropathology.
the perception of dysphagia with esophageal motility dis- Instead, the diagnosis is established using physiological
orders.12 This concept of obstructive physiology as the tests to demonstrate that symptomatic esophageal
fundamental abnormality has substantially morphed the dysfunction (potentially dysphagia, regurgitation, or chest
clinical management of esophageal motility disorders. pain) is occurring as a result of esophageal obstruction that
Classification schemes are important in clinical man- cannot be attributed to a stricture, tumor, prior surgery,
agement and the Chicago Classification has gone a long way vascular structure, implanted device, infection, or inflam-
in objectifying the diagnosis of achalasia. However, the fact matory process. Rather, the obstruction is caused by
that it has now gone through 4 iterations since 2008 em- abnormal contractility, the impairment of normal neuro-
phasizes that this is a work in progress and that no classi- nally mediated inhibition, or both. For achalasia-like syn-
fication scheme of esophageal motility disorders based on a dromes, the contractile obstruction can be located at the
2023 Insights Into Achalasia From HRM and FLIP 703

lower esophageal sphincter (LES) or the LES along with the measures EGJ distensibility, defined as EGJ opening diam-
adjacent distal esophagus. The objective of physiological eter as a function of distending pressure. The FLIP device
testing is to identify and localize the physiological obstruction uses impedance planimetry to measure luminal cross-
so as to optimize treatment. Furthermore, it is noteworthy sectional area within a 15-cm span of the esophagus. The
that most, but not all, muscularis propria biopsy specimens of probe has a cylindrical, highly compliant bag at its distal end
these patients obtained in the course of a therapeutic myot- enclosing multiple impedance planimetry electrodes and a
omy exhibit the myenteric plexopathy described in advanced single pressure sensor. During a FLIP study, usually done in
achalasia cases.15,16 In one of those series, 3 of the 46 cases conjunction with endoscopy and using the same sedation as
treated with a surgical myotomy exhibited apparently normal for the endoscopy, the probe is positioned across the EGJ,
histopathology and one case had predominantly eosinophilic protruding slightly into the stomach. In some cases, endo-
inflammation.15 Similarly, it is now widely recognized that scopic manipulation is needed to obtain proper positioning.
chronic opioid use can cause dysphagia and abnormal HRM The probe is then progressively filled with 50, 60, and 70 mL
patterns often mimicking type III achalasia.17 Hence, the of saline to distend the distal esophagus and EGJ. The
terminology ‘achalasia-like syndromes’. resultant distention-induced esophageal contractility is dis-
Given the diagnostic limitations discussed above, it is played topographically, analogous to pressure topography
important to recognize the limitations of HRM with respect displays of HRM.19 The difference between FLIP and HRM is
to the diagnosis and management of achalasia: (1) some that FLIP topography (Panometry) is a dynamic topographic
patients with achalasia have an integrated relaxation pres- plot of esophageal diameter along the length of the probe as
sure (IRP) < 15 mmHg, the widely accepted upper limit of opposed to HRM which is a dynamic topographical plot of
normal; (2) there can be instances in which some peristalsis resting and contractile pressure along the sensing catheter.
is preserved making the criterion of ‘absent peristalsis’ Pressure is also recorded from within the FLIP probe but
somewhat subjective; (3) the IRP performs poorly as an only from a single sensor which then allows for calculations
assessment of treatment outcome; (4) HRM is inherently of distensibility (mm2/mmHg), a critical metric for assessing
better at quantifying contraction than detecting inhibition, outflow obstruction. Hence, assessing esophageal motility
which is an equally important determinant of normal with FLIP is based on characterizing distention-induced
esophageal motility; and (5) the distinction among achalasia contractility in the distal esophagus and EGJ distensibility.
subtypes can be blurred when underlying spastic contrac- The bag encasing the FLIP sensors is flaccid to a fill
tility is obscured by panesophageal pressurization. Basically, diameter of z2 cm and then essentially noncompliant. It is
the threshold for diagnosis and the distinction among made of a noncompliant plastic material, much like plastic
achalasia subtypes (or between achalasia and nonachalasia) wrap. Consequently, fluid moves easily within the FLIP
can be difficult and some cases have features of more than probe and peristalsis progresses along the probe such that
one subtype. Furthermore, as the disease develops over an the topography display characterizes both its rate of pro-
unknown period of time, there is a transition from normal gression and the extent of associated luminal occlusion in a
peristalsis and normal EGJ relaxation to absent peristalsis real-time plot. With progression of a normal secondary
and impaired EGJ relaxation; at intermediate time points in peristaltic contraction, the distal end of the probe (situated
the development of the disease, these abnormalities might in the stomach) fills to capacity and eventually pressurizes
or might not achieve the requisite diagnostic thresholds. to a value more than that of the advancing contraction, at
Textbook cases will always be easy to diagnose, but no which point the fluid escapes retrograde back into the
matter what your level of expertise, there will always be proximal segment of the probe, again distending the
‘borderline’ cases in which clinical judgment rather than esophagus, and thereby stimulating another secondary
adherence to dichotomous numerical thresholds ends up peristaltic contraction. Hence, the normal pattern of
being the final arbiter. contractility during FLIP Panometry is of repetitive ante-
grade contractions (RACs), defined as 6 repetitive contrac-
tions spanning at least 6 cm of the FLIP probe and occurring
FLIP in the diagnosis of achalasia-like syndromes at a frequency of 6  3 per minute. Among 35 normal
One approach to clarifying inconclusive or equivocal volunteer subjects tested, 89% exhibited RACs while the
HRM findings is to add provocative maneuvers such as other 11% also exhibited antegrade contractions but not
multiple rapid swallows (5 sequential 2-mL swallows less sufficiently repetitive to meet the ‘rule of 6’, which was
than 4 seconds apart) or a rapid drink challenge (200 mL devised as an objective definition of RACs.20,21 Notably,
swallowed within 30 seconds) to the HRM protocol as esophageal contractions can be detected with Panometry
advocated in Chicago Classification v4.0.1,18 This is in even when they are not lumen occluding making them un-
recognizing that the cardinal abnormality in achalasia is detectable by HRM and explaining the ‘recovery’ of peri-
obstructive physiology at the EGJ and that there can be stalsis often observe in HRM studies after achalasia
relevant EGJ obstruction with a normal or even low IRP on treatments.22,23 In actuality, the weak peristaltic contrac-
HRM in the setting of absent contractility. An alternative (or tions were always there but they were masked by the
additional) approach to an equivocal HRM diagnosis is to greater values of panesophageal pressurization attributable
compliment the HRM study with a FLIP study. The FLIP to EGJ outflow obstruction.
704 Kahrilas et al Gastro Hep Advances Vol. 2, Iss. 5

Figure 2. Contractile response (CR) patterns observed in FLIP Panometry. The topographic images are of time (x axis), position
along the probe (y axis) and luminal diameter (color). Hence, contractions appear much as they do in HRM with the distinction
being that it is luminal diameter rather than pressure that is being portrayed. The normal CR (A) is of repetitive antegrade
contractions (RACs) observed at some time during the 50, 60, or 70 mL distention volumes, each of which is maintained for at
least 60 seconds. With a borderline CR (B), antegrade contractions are observed but not meeting RAC criteria. With an
impaired/disordered CR (C), contractions are observed but without any distinct antegrade contractions. No contractility is
observed with absent CR (D) usually seen with non-spastic achalasia or an HRM pattern of absent contractility. With the
spastic/reactive CR (E) sustained occluding contractions (SOC), sustained LES contraction (sLESC), or repetitive retrograde
contractions (RRCs) are seen, any one of which constitutes a spastic reactive CR. Figure used with permission from the
Esophageal Center at Northwestern.

The FLIP correlate of impaired EGJ relaxation on HRM broadens the definition of a high IRP to include evidence of
(IRP > 15 mmHg) is impaired EGJ opening as assessed with obstructive physiology gained from wet swallows in a sec-
the distensibility index (DI) at the 60-mL fill volume and the ondary testing position (sitting vs supine or vice versa),
maximal EGJ opening diameter achieved at the 60-mL or 70- during multiple repetitive swallows, or during a rapid drink
mL fill volumes. The conceptual advantage of FLIP over challenge.1,18 With FLIP, diagnosing an achalasia-like syn-
HRM lies in the distinction between sphincter relaxation and drome requires reduced EGJ opening and something other
sphincter opening. HRM measures relaxation; the FLIP than a normal contractile response (RACs). The RAC pattern
quantifies opening. Although these are usually related, it is is uniformly lost in achalasia, seen in 0 of 224 patients with
sphincter opening that determines the volume of bolus flow treatment naïve achalasia as defined by HRM (55 type I, 129
through the EGJ. Normal EGJ opening is defined as EGJ-DI  type II, 40 type III).9 Instead, the achalasics had either a
2.0 mm2/mmHg and maximum EGJ diameter  16 mm. weak contractile response, absent contractile response, or a
Reduced EGJ opening is defined as EGJ-DI < 2.0 mm2/ spastic-reactive contractile response (Figure 2). Further-
mmHg and maximum EGJ diameter < 12 mm. Patients not more, when antegrade or retrograde repetitive contractions
meeting either of these definitions are categorized as are observed in achalasia, they occur at a faster frequency
borderline opening.24 that the 6  3 per minute of the normal RAC pattern. The
Following from the above, both HRM and FLIP Pan- differing frequency of repetitive contractions and the
ometry have criteria for defining obstructive physiology at occurrence of retrograde repetitive contractions remains to
the EGJ, a prerequisite for diagnosing achalasia or achalasia- be explained but is potentially related to diminished inhib-
like syndromes. With HRM, a diagnosis of achalasia requires itory myenteric plexus function, loss of connectivity to a
a high IRP and absent primary peristalsis, albeit often with central pattern generator linked to respiration, or even the
other patterns of esophageal pressurization. Chicago Clas- intrinsic refractoriness of the esophagus after a contrac-
sification v4.0 differs from earlier versions in that it tion.21 One could speculate that the pathophysiological
2023 Insights Into Achalasia From HRM and FLIP 705

difference between achalasia subtypes is the complete loss low-density barium in an upright posture followed by
of myenteric neuron function in nonspastic achalasia as frontal x-rays 1, 2, and 5 minutes afterward. The degree of
opposed to a selective loss of inhibitory myenteric neuron esophageal emptying is then estimated by measuring the
function in spastic achalasia. Agangionosis leads to a flaccid, height of the residual barium column in the esophagus. The
dilated esophagus with persistent LES contraction attribut- most robust outcome measure is the height of the barium
able to residual myogenic tone. On the other hand, the se- column at 5 minutes with the proposed critical threshold
lective loss of inhibitory myenteric neuronal function results ranging from 2–5 cm.26,28 When a 12-mm barium tablet is
in rapidly propagated contractions (even retrograde con- used in conjunction with the timed barium esophagram, a
tractions on Panometry) along with greater LES pressure secondary criterion of abnormality is for the tablet to
because of unopposed excitatory neuron stimulation. become lodged at the EGJ. A positive timed barium
Whatever the explanation, FLIP distinguishes 2 subtypes of esophagram is strong supportive evidence of functionally
achalasia: spastic achalasia (with spastic-reactive contractile significant EGJ outflow obstruction and a completely normal
response) and nonspastic achalasia (with weak contractile study makes an achalasia diagnosis highly unlikely.29 Anal-
response or absent contractile response). Do HRM and FLIP ogous data can be obtained using HRM with impedance in
identify the same patients as having achalasia? Pretty much; an upright posture and using the impedance electrodes to
in a study of 687 symptomatic patients evaluated with both ascertain the height of retained fluid in the esophagus at a 5-
tests and interpreted in a blinded fashion, HRM conclusively minute interval.30 However, these tests are not as definitive
diagnosed achalasia in 224 and 223 (99.5%) of these had in evaluating EGJOO as they are for achalasia because bolus
reduced EGJ opening on FLIP Panometry.20 Evident by this clearance may not be compromised in EGJOO. FLIP, on the
concordance, there is a shared physiology between impaired other hand, yields an assessment of EGJ obstructive physi-
LES relaxation on HRM and reduced EGJ opening on FLIP. ology that is independent of the esophageal contractile
response making it more useful in this circumstance.
The Chicago Classification v4.0 working group tasked
Esophagogastric junction outflow obstruction with evaluating the EGJOO conundrum formulated a tech-
HRM unquestionably advanced our understanding of nical note on the topic along with a series of recommen-
esophageal motility disorders and certainly improved our dations to guide management.27 Recommendations required
ability to diagnose achalasia as evidenced by a study sug- agreement by  80% of the working group and were
gesting that the adoption of HRM in a motility laboratory led assigned a strength of recommendation along with an
to a 3-fold increase, the estimate of the disease incidence in evaluation of the quality of supportive evidence. The most
the surrounding area.25 Furthermore, HRM seemed to noteworthy conclusion from the working group was that an
detect cases of an achalasia-like syndrome characterized by isolated manometric diagnosis of EGJOO should always be
obstructive physiology at the EGJ (usually defined as an IRP considered clinically inconclusive. To become actionable
> 15 mmHg) along with sufficiently preserved peristalsis to that findings must be supported by the presence of clinically
exclude a diagnosis of achalasia.26 In the Chicago Classifi- relevant symptoms (chest pain or dysphagia) and at least
cation, this entity was labeled EGJ outflow obstruction one of the other testing modalities (timed barium esopha-
(EGJOO), a heterogenous group including cases of ‘variant’ gram, preferably with a tablet, or FLIP) that confirmed EGJ
achalasia, obstructive hiatus hernia, manometric artifact, obstructive physiology. Basically, there is no ‘gold standard’
opiate effect, abdominal obesity, and normal individuals. for a conclusive (actionable) EGJOO diagnosis and it takes at
Laboratories around the world reported the prevalence of least 2 positive complementary studies to establish the
EGJOO to range between 5% and 24% of all HRM studies in diagnosis. In instances when all 3 studies (HRM, FLIP, and
a multitude of published cohorts.27 Given that only a frac- timed barium esophagram) are available and there is
tion of these individuals actually had clinically relevant discordance, the majority rules, potentially negating the
obstructive physiology at the EGJ, caution has always been findings from any one of them.
advised in the management of EGJOO patients, avoiding The recommendations of the Chicago Classification v4.0
achalasia treatments in most of them because published working group on EGJOO were subsequently tested in an
series concluded that anywhere from 32% to 94% of EGJOO observational study of a 139 EGJOO patient cohort who
patients did not require any therapy.27 However, in the era were all evaluated with both HRM and FLIP.8 A substantial
of Chicago Classification v3.0, this cautionary advice was fraction of the cohort also had data available from timed
often ignored leading to the inappropriate treatment of barium esophagram and/or a rapid drink challenge as part
many EGJOO patients as ‘variant’ achalasia. In fact, such of their HRM study. The corresponding FLIP Panometry EGJ
overdiagnosis and overtreatment was a major impetus for opening classifications in this EGJOO ‘inconclusive’ cohort
formulating Chicago Classification v4.0. were reduced EGJ opening in 48%, borderline EGJ opening
Apart from using provocative maneuvers during the in 30%, and normal EGJ opening in 22%. The FLIP con-
HRM study, Chicago Classification v4.0 advocates using tractile response patterns were normal in 6%, borderline in
ancillary testing with FLIP or timed barium esophagram to 21%, impaired/disordered CR in 43%, absent contractile
clarify the significance of EGJOO on HRM. With a timed response in 17%, and spastic-reactive in 14%. Applying
barium esophagram, the patient drinks 200 mL of both the EGJ and contractile response classifications, the
706 Kahrilas et al Gastro Hep Advances Vol. 2, Iss. 5

final FLIP Panometry classifications were ‘normal’ in 21%, potential patient-specific predictors of treatment outcome,
thereby refuting the HRM classification of EGJOO. On the the meta-analysis concluded that most putative predictors
other hand, the FLIP Panometry was supportive of either were inconsistent among studies and only age (younger
EGJ obstruction with weak contractile response or spastic- patients did worse), manometric subtype (type III did
reactive contractile response supporting a clinically rele- worse), and the presence of sigmoid-shaped esophagus (did
vant diagnosis of conclusive EGJOO in 49% of the cohort but worse) were classified as predictors with a strong level of
still leaving 29% as ‘inconclusive’. Notably, 77% of the cumulative evidence. Poor outcomes with sigmoid esoph-
conclusive EGJOO patients reported significant clinical agus are understandable as these patients often have
improvement following achalasia-type treatments as judged chronic esophageal retention with a sink-trap deformity at
by an improved Eckhardt score. This compared to no sig- the distal end. In that circumstance, simply eliminating the
nificant improvement in 12 of 12 patients; such patients outflow obstruction might not suffice to facilitate esopha-
managed with a ‘non-achalasia’ treatment approach. geal emptying, especially when the chronic esophageal
Figure 3 details the comprehensive evaluation of this patient retention is combined with the complete absence of distal
cohort emphasizing the complimentary nature of these esophageal contractility. Alternatively, poor treatment out-
function tests and that, even using the updated criteria in comes with type III achalasia are attributable to persistent
Chicago Classification v4.0, EGJOO remains an entity asso- obstructive physiology in the distal esophagus that may be
ciated with clinical heterogeneity and, ultimately, still some inadequately addressed with LES-targeted treatment. Also,
instances of diagnostic uncertainty. of course, none of these trials included patients with
achalasia-type EGJOO. Taken together, all of these consid-
erations enhance the appeal of phenotype-directed
Personalized, phenotype-directed treatment treatment.
With the widespread adoption of POEM, it now joins PD To date, there are no RCT data on achalasia management
and LHM as a highly efficacious and durable treatment that prospectively consider achalasia subtype in their design
approach for achalasia. However, it has also complicated the or in their assessment of treatment efficacy. However,
discussion of which therapy is optimal for which patient. retrospective analysis of RCT data exemplified by the Eu-
There are published randomized control trials (RCTs) ropean achalasia trial31 suggests that achalasia subtypes are
comparing LHM to POEM,3 LHM to PD,31–34 and POEM to of great relevance in forecasting treatment effectiveness.
PD2,35 but no 3-armed RCT. In these trials, the efficacy of Indeed, in the European achalasia trial, the efficacy of PD for
LHM or POEM was uniformly in the 90% range while that of treating type II achalasia was 100%, significantly better
PD ranged from 54%35 to 86%.31 The variable response to LHM (93%, P ¼ .03), whereas treatment success in type 3
PD speaks to the nonstandardized protocols by which it is achalasia was 40% and 86% for PD and LHM, respectively
done, variable employing dilators to a maximum or 35-mm (although this difference was not statistically significant
or 40-mm diameter and variably allowing for repeated di- because of small numbers of patients, n ¼ 10 and 8,
lations with recurrence of dysphagia as part of the PD respectively).39 Subsequently, an excellent meta-analysis
protocol or not. This variability in PD protocol necessarily was published identifying all relevant articles reporting
weakens the findings of a network meta-analysis seeking to clinical outcomes of patients with achalasia classified by
integrate the entire dataset of RCTs because the PD arms are manometric subtype after botulinum toxin injection, PD,
not comparable from one trial to another. Nonetheless, a LHM, and POEM.4 Data from that meta-analysis summarized
recent attempt at doing just that concluded that POEM and in Figure 4 concluded that (1) POEM was more successful
LHM have equal efficacy and both are more effective than than LHM for both type I (oods ratio [OR] 2.97, P ¼ .03) and
PD.36 Other limitations of the RCT data are that advanced type III achalasia (OR 3.50, P ¼ .007), (2) POEM was the
achalasia cases were variably included or excluded from the most efficacious treatment across the entire achalasia
study populations and, most significantly, that there was no spectrum with pooled response rates of 95%, 97%, and
prospective subtyping of achalasia. 93% for type I, II, and III achalasia, respectively, (3) PD had
All subtypes of achalasia share the common element of a lower but not significantly different success rate compared
impaired EGJ relaxation and reduced EGJ opening, but the with POEM or LHM in type II achalasia, and (4) botulinum
associated pattern of esophageal contractility varies from toxin injection was inferior in all subtypes.
absent contractility at one extreme to spastic contractions The widespread adoption of POEM in esophageal ter-
involving the entire smooth muscle esophagus at the other. tiary care centers around the world has clearly been a major
An immediate observation with the description of achalasia development in achalasia therapeutics.42 The POEM pro-
subtypes in 2008 was that treatment outcome varied with cedure involves making a submucosal tunnel from the mid-
subtype such that the best treatment outcomes were seen in esophagus to the gastric cardia and then performed a cir-
type II and the worst in type III.11 Those observations were cular muscle myotomy from within the submucosal tunnel,
subsequently confirmed by a number of other studies37–40 beginning at the gastric cardia and progressing proximally
and by a systematic review and meta-analysis exploring a across the LES.43 Therein lies the key advantage of POEM
multitude of potentially factors relevant to treatment over LHM; the myotomy performed with POEM can be
outcome.41 After assessing 117 relevant citations for longer if desired, potentially extending along the entire
2023 Insights Into Achalasia From HRM and FLIP 707

Figure 3. Results of further evaluation of EGJ outflow obstruction (EGJOO) obstruction patients using provocative maneuvers,
FLIP panometry, and timed barium esophagram (TBE) as proposed in Chicago Classification v4.0. Initially, all EGJOO diag-
nosed are considered inconclusive but with the addition of FLIP panometry 49% became conclusive and 22% were deemed
normal, leaving 29% still inconclusive. Note that while all of the patients had both HRM and FLIP panometry only a portion of
them had TBE and the rapid drink challenge (RDC) as indicated in the Figure. The associated finding from RDC and TBE are
shown to emphasize the value of complimentary testing and the potential for inconsistency in diagnosis among testing
modalities. PEP, panesophageal pressurization. Figure used with permission from the Esophageal Center of Northwestern.

length of smooth muscle esophagus, whereas in LHM it is achalasia subtype but can be attributable to post-treatment
limited to the length of esophagus that can be safely reflux, recurrent dysphagia, the development of esophageal
accessed from below the diaphragm. This benefit is most hypersensitivity, formation of a pseudodiverticula at the
apparent in treating patients with distal esophageal myotomy site (also known as a blown out myotomy or
obstructive physiology such as type III achalasia. Supportive BOM),46 or progression of esophageal dilatation. In extreme
of that hypothesis, in a meta-analysis of uncontrolled POEM cases of treatment failure, often after multiple LES-targeted
series, Khan et al. reported a weighted pooled response rate interventions, esophagectomy may be required in patients
of 92% (95% CI 84%–96%) in type III achalasia with a mean with end-stage achalasia to restore alimentary transit,
length of myotomy of 17.2 cm (range 13.0–19.7 cm).44 reverse nutritional deficiencies, prevent recurrent aspira-
Furthermore, treatments effective for type III achalasia tion pneumonia, or because of the development of squa-
should also be effective for other disorders characterized by mous cell cancer, the incidence of which has been estimated
obstructive physiology of the distal esophagus, notably distal to be about 3 per 1000 patient-years follow-up.47 A sys-
esophageal spasm and hypercontractile esophagus. The meta- tematic review and meta-analysis of esophagectomy for
analysis by Khan et al. reported a weighted pooled response end-stage achalasia identified 8 published series inclusive of
rate of 72% (95% confidence interval [CI] 55%–83%) in 1307 patients.48 The most common indication for esoph-
‘jackhammer’ esophagus and of 88% (95% CI 61%–97%) in agectomy was of severe symptoms with radiographic find-
distal esophageal spasm, only 4% less than in type III acha- ings of a sigmoid esophagus. The stomach was used as a
lasia. However, it must be emphasized that these data are conduit in 95% of these cases with a colonic interposition
from short-term uncontrolled studies without standardiza- being the main alternative. Postoperative morbidity ranged
tion of how the appropriate myotomy length was determined. from 19% to 50% with pneumonia and anastomotic leaks
Although we have come a long way in the diagnosis and being the most reported complications. Mortality ranged
treatment of achalasia, no current treatment is curative and from 0% to 5.4% among series.
the overall treatment efficacy declines over time regardless
of which treatment is rendered. Long-term treatment failure
rates following LHM or PD have been reported to range Post-treatment reflux
from 18%–35%.40,45 The likelihood and mechanism of It stands to reason that surgical myotomy of the LES can
treatment failure varies with the specific treatment and result in problematic acid reflux. With LHM, this risk is
708 Kahrilas et al Gastro Hep Advances Vol. 2, Iss. 5

patients reported that symptomatic GERD (19% vs 8.8%),

abnormal pH-metry (39% vs 16.8%), and erosive esopha-
gitis (29.4% vs 7.6%) were all more common after POEM
than LHM.49 However, the clinical significance of this has
been questioned given that despite 47% of 2373 post-
POEM patients having abnormal pH-metry, only 8.5%
were symptomatic.50 Similarly, most post-POEM esopha-
gitis is mild (Los Angeles A or B) and in the RCT comparing
LHM to POEM, there was no significant difference in the
occurrence of Los Angeles C or D esophagitis.3 Nonethe-
less, modifications to the intraoperative POEM technique
such as shortening the myotomy, avoiding dividing the
gastric sling fibers by orienting the myotomy along the
lesser curve, and using intraoperative FLIP to calibrate the
myotomy have all been suggested as a way of minimizing
post-POEM reflux.51

Conclusion
HRM and analysis algorithms recently updated in the
Chicago Classification v4.0 have led to a paradigm shift to
thinking of motility disorders as patterns of obstructive
physiology involving the EGJ and/or the distal esophagus
rather than as siloed entities. The cardinal feature of acha-
lasia, impaired LES relaxation, is now recognized to occur in
several disease phenotypes: with absent contractility, with
premature (spastic) distal esophageal contractions, with
pan-esophageal pressurization, or with some preserved
peristalsis. An immediate effect of this advance has been
Figure 4. Meta-analysis of studies reporting clinical out- increased detection of achalasia, challenging previous
comes of achalasia patients that were classified by mano- epidemiological estimates of the incidence and prevalence
metric subtype after treatment with botulinum toxin injection, of this disorder. Furthermore, without a disease-specific
pneumatic dilation (PD), laparoscopic Heller myotomy (LHM), biomarker, no manometric pattern is absolutely sensitive
or per-oral endoscopic myotomy (POEM). The major con- or specific for idiopathic achalasia caused by a myenteric
clusions from the meta-analysis were that: (1) POEM was plexopathy and physiological testing reveals other syn-
more successful than LHM for both type I (OR 2.97, P ¼ .03)
dromes involving physiological obstruction but not meeting
and type III achalasia (OR 3.50, P ¼ .007), (2) POEM was the
Chicago Classification criteria for achalasia, which also
most efficacious treatment across the entire achalasia
spectrum with pooled response rates of 95% 97% and 93% benefit from therapies formerly reserved for achalasia.
for type I, II, and III achalasia, respectively, (3) PD had a lower Complimentary assessment with timed barium esophagram,
but not significantly different success rate compared with FLIP, or provocative maneuvers done in conjunction with
POEM or LHM in type II achalasia, and (4) botulinum toxin HRM can be useful in defining these syndromes. The utility
injection was inferior in all subtypes. Data from Andolfi C and of these additional clinical assessment techniques has
Fisichella PM, 2019.4 become particularly relevant with the development of the
POEM procedure, an endoscopic technique for performing a
calibrated myotomy of the esophageal circular muscle that
mitigated by pairing the myotomy with a partial fundopli- can be done on outpatients. Hence, with HRM and the Chi-
cation, be that a posterior 270 Toupet fundoplication or an cago Classification v4.0, we have come to conceptualize
anterior 180 Dor fundoplasty. Initially, it was hoped that esophageal motility disorders by specific aspects of physi-
GERD would be infrequent following a POEM procedure ological dysfunction, potentially involving the LES and/or
given the absence of hiatal dissection or gastric mobiliza- obstructive physiology of the distal smooth muscle esoph-
tion. However, subsequent studies have suggested that agus. A major implication of this approach is a shift in
GERD is more common following POEM compared with PD management strategy toward rendering treatment in a
and LHM. Indicative of this, a multicenter RCT of 221 pa- phenotype-specific manner, for example, POEM calibrated to
tients with achalasia found that erosive esophagitis was patient-specific physiology as defined by HRM for the
more common following POEM from LHM at 3 months spastic disorders and more conservative strategies such
(57% vs 20%) and 24 months (44% vs 29%).3 Similarly, a as a short POEM or PD for obstructive physiology limited
meta-analysis comparing 1542 POEM and 2581 LHM to the LES.
2023 Insights Into Achalasia From HRM and FLIP 709

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39. Rohof WO, Salvador R, Annese V, et al. Outcomes of Address correspondence to: Peter J. Kahrilas, MD, Northwestern University,
treatment for achalasia depend on manometric subtype. Feinberg School of Medicine, Division of Gastroenterology and Hepatology,
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[Link].
40. Costantini M, Salvador R, Capovilla G, et al. A thousand
and one laparoscopic Heller myotomies for esophageal Authors’ Contributions:
Peter J. Kahrilas: Concept and design, acquisition of data, analysis and
achalasia: a 25- year experience at a single tertiary interpretation of data, drafting of the manuscript, critical revision of the
center. J Gastrointest Surg 2018;23:23–35. manuscript for important intellectual content, and final approval of the manu-
41. Oude Nijhuis RAB, Prins LI, Mostafavi N, et al. Factors script. Dustin A. Carlson: Acquisition of data, analysis and interpretation of
data, critical revision of the manuscript for important intellectual content, and
associated with achalasia treatment outcomes: system- final approval of the manuscript. John E. Pandolfino: Analysis and interpreta-
atic review and meta-analysis. Clin Gastroenterol Hep- tion of data, obtained funding, critical revision of the manuscript for important
atol 2020;18:1442–1453. intellectual content, and final approval of the manuscript.
42. Kahrilas PJ, Katzka D, Richter JE. The use of Per-Oral Conflicts of Interest:
Endoscopic Myotomy (POEM) in achalasia: expert re- These authors report the following: John E. Pandolfino, Peter J. Kahrilas, and
Northwestern University hold shared intellectual property rights and ownership
view and best practice advice from the American surrounding FLIP Panometry systems, methods, and apparatus with Medtronic
Gastroenterological Association. Gastroenterology 2017; Inc. Peter J. Kahrilas: Ironwood (Consulting); Reckitt (Consulting), Phathom
153:1205–1211. (consulting). Dustin A. Carlson: Medtronic (Speaking, Consulting); Phathom
Pharmaceuticals (Consulting). John E. Pandolfino: Sandhill Scientific/Diversa-
43. Inoue H, Sato H, Ikeda H, et al. Per-oral endoscopic tek (Consulting, Speaking, Grant), Takeda (Speaking), Astra Zeneca (Speaking),
myotomy: a series of 500 patients. J Am Coll Surg 2015; Medtronic (Speaking, Consulting, Patent, License), Torax (Speaking, Consul-
221:256–264. ting), Ironwood (Consulting).
44. Khan AK, Kumbhari V, Ngamruengphong S, et al. Is Funding:
POEM the answer for management of spastic esopha- This work was supported by P01 DK117824 (JEP) from the Public Health
Service.
geal disorders? A systematic review and meta-analysis.
Dig Dis Sci 2017;62:35–44. Ethical Statement:
45. Zerbib F, Thetiot V, Richy F, et al. Repeated pneumatic This study did not require the approval of an institutional review board.
dilations as long-term maintenance therapy for esopha- Reporting Guidelines:
geal achalasia. Am J Gastroenterol 2006;101:692–697. Not applicable for this article type.