PRIMER

Achalasia
Edoardo Savarino   1,2 ✉, Shobna Bhatia   3, Sabine Roman   4,5,6, Daniel Sifrim7,
Jan Tack8, Sarah K. Thompson9 and C. Prakash Gyawali10
Abstract | Achalasia is a rare disorder of the oesophageal smooth muscle characterized by
impaired relaxation of the lower oesophageal sphincter (LES) and absent or spastic contractions
in the oesophageal body. The key pathophysiological mechanism is loss of inhibitory nerve func-
tion that probably results from an autoimmune attack targeting oesophageal myenteric nerves
through cell-mediated and, possibly, antibody-mediated mechanisms. Achalasia incidence
and prevalence increase with age, but the disorder can affect all ages and both sexes. Cardinal
symptoms consist of dysphagia, regurgitation, chest pain and weight loss. Several years can pass
between symptom onset and an achalasia diagnosis. Evaluation starts with endoscopy to rule out
structural causes, followed by high-resolution manometry and/or barium radiography. Functional
lumen imaging probe can provide complementary evidence. Achalasia subtypes have manage-
ment and prognostic implications. Although symptom questionnaires are not useful for diagno-
sis, the Eckardt score is a simple symptom scoring scale that helps to quantify symptom response
to therapy. Oral pharmacotherapy is not particularly effective. Botulinum toxin injection into
the LES can temporize symptoms and function as a bridge to definitive therapy. Pneumatic
dilation, per-oral endoscopic myotomy and laparoscopic Heller myotomy can provide durable
symptom benefit. End-stage achalasia with a dilated, non-functioning oesophagus may require
oesophagectomy or enteral feeding into the stomach. Long-term complications can, rarely,
include oesophageal cancer, but surveillance recommendations have not been established.

The oesophagus is a hollow muscular tube that forms a LES with absent or spastic contractions in the oesopha-
conduit for the transmission of ingested food from the geal body in the absence of structural obstruction in the
mouth to the stomach. A sphincter controls each end oesophageal body or oesophagogastric junction (EGJ)1,2.
of the oesophagus: the upper oesophageal sphincter The clinical manifestations of achalasia are a conse-
(UES) separates the oropharynx from the oesophagus, quence of obstruction in oesophageal transit owing to
and the lower oesophageal sphincter (LES) forms a abnormal swallow-induced LES relaxation3. Incomplete
barrier between the intrathoracic and intra-abdominal LES relaxation and abnormal oesophageal body peristal-
compartments of the gut (Fig. 1). Volitional initiation of sis can also be seen in pseudoachalasia, which needs to
a swallow in the skeletal muscle oropharynx results in be distinguished from achalasia4.
UES opening and transmission of the ingested bolus into At its core, the pathophysiological abnormality in
the oesophagus. The bolus travels through the oesopha­ achalasia is loss of inhibitory nerve function in the
gus primarily by gravity in the upright position, and smooth muscle oesophagus. The main hypothesis is
an oesophageal stripping wave from circular muscle that it results from an autoimmune reaction that targets
contraction forms a peristaltic sequence that clears any oesophageal myenteric neurons through a cell-mediated
remnant content into the stomach. This peristaltic wave and a, possibly antibody-mediated, attack against an
starts in the proximal skeletal muscle oesophagus and is antigen, which has not yet been fully identified, in
transmitted into the distal smooth muscle oesophagus genetically predisposed patients 5–8. Infectious and
through the muscle fibres themselves, and through inter- degenerative hypotheses have also been postulated,
mediary ganglia that control excitation and inhibition but no definitive evidence has been reported9–11. Three
within the oesophageal smooth muscle. The LES relaxes subtypes of achalasia can be distinguished on the basis
concurrently with UES opening, and regains its closed of manometric assessment of oesophageal motility pat-
✉e-mail: edoardo.savarino@ resting tone when the peristaltic sequence arrives at the terns. Achalasia type 1 is characterized by 100% failed
unipd.it level of the lower sphincter. contractions and no oesophageal pressurization; type 2
https://doi.org/10.1038/ Achalasia is defined as the presence of oesophageal is defined as pan-oesophageal pressurization occurring
s41572-022-00356-8 outflow obstruction due to impaired relaxation of the with at least 20% of swallows; and type 3 is defined as

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Author addresses was used18. However, these epidemiological changes

cannot be attributed solely to the adoption of HRM, as
1
Gastroenterology Unit, Azienda Ospedale Università di Padova (AOUP), Padua, Italy. a true increase in disease incidence, an increased dis-
2
Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, ease awareness related to the introduction of modern
Padua, Italy. diagnostic tools and the availability of new therapeutic
3
Department of Gastroenterology, Sir HN Reliance Foundation Hospital, Mumbai, India.
modalities could also have contributed22.
4
Hospices Civils de Lyon, Digestive Physiology, Hopital E Herriot, Lyon, France.
5
Université Lyon 1, Villeurbanne, France.
6
Inserm U1032, LabTAU, Lyon, France. Mechanisms/pathophysiology
7
Wingate Institute of Neurogastroenterology, Queen Mary University of London, In achalasia, the pharyngeal swallow effort and prox-
London, UK. imal oesophageal peristalsis are generally normal,
8
Division of Gastroenterology, University Hospital of Leuven, Leuven, Belgium. as the disease primarily affects LES relaxation, with
9
Discipline of Surgery, College of Medicine and Public Health, Flinders University, compromising consequences on coordination and
Bedford Park, South Australia, Australia. strength of distal oesophageal circular muscle func-
10
Division of Gastroenterology, Washington University School of Medicine, St. Louis, tion and impaired contractility of longitudinal muscle
MO, USA. layers. Thus, swallowed boluses traverse the pharynx
and upper part of the oesophagus without difficulty,
the presence of premature contraction for at least 20% arriving in the non-functioning lower two-thirds of
of the swallows with premature contraction defined as the oesophagus, which dilates and retains content
distal latency <4.5 s. In terms of neuronal dysfunction, because of insufficient contractile emptying force and
achalasia types 1 and 2 are both characterized by loss of an obstructing non-relaxing LES. In early achalasia,
ganglion cells (aganglionosis)12, with a gradient of more retained oesophageal muscle tone and hydrostatic
severe loss in type 1 achalasia13, whereas in type 3, inhib- forces generated by the ingested bolus can overcome
itory neuron function is impaired without clear neuronal the sphincteric resistance such that LES obstruction
loss, possibly mediated by cytokine-induced alterations is incomplete and adequate nutrition is maintained;
in gene expression. however, the oesophagus never completely empties. In
In this Primer, we discuss the epidemiology, patho- later disease stages, emptying comprises only a small
physiology, diagnosis and management of achalasia. stream of fluid seeping through the obstructed, closed
We also summarize effects of this disorder on patient sphincter23.
quality of life and research areas that are in need of
further study. Abnormal neural control of motor function
Failing neural inhibition of oesophageal motility is the
Epidemiology prime reason for abnormal peristalsis and incomplete
The annual incidence of achalasia is estimated at LES relaxation in achalasia24 (Fig. 2). An inverse relation-
1–5 cases per 100,000 individuals with a prevalence of ship exists between the extent of neural inhibition and
7–32 cases per 100,000 individuals14–17. Incidence rates the propagation velocity of oesophageal peristalsis dur-
are comparable across countries and regions using sim- ing swallowing: the lower the inhibition, the faster the
ilar epidemiological methodology and do not differ by propagation. In the extreme case of near absent or absent
ethnicity18–20. A 2021 US study using commercial insur- inhibition as in achalasia, non-peristaltic simultaneous
ance and Medicare claims data suggested that incidence oesophageal body contractions occur that eventually
and prevalence could be higher than previously thought, lead to aperistalsis25.
with incidence of 10 and 26 per 100,000 individuals, and Deglutitive inhibition can be evaluated using mul-
prevalence of 18 and 162 per 100,000 individuals in the tiple rapid swallows (MRS), an adjunctive provocative
two databases, respectively20. On the basis of these data, manoeuvre routinely performed during oesophageal
the economic burden of achalasia exceeded $408 million HRM. Under normal circumstances, repetitive swal-
in 2018 in the USA. lowing during MRS inhibits oesophageal smooth muscle
Achalasia can occur at any age, but incidence and contractions and induces complete LES relaxation. The
prevalence increase with age, and the mean age at final swallow of the MRS series is followed by a pow-
diagnosis is >50 years17,19,20. Incidence (2.2 per 100,000 erful peristaltic sequence in the oesophageal body and
persons) and prevalence (15.3 per 100,000 persons) in re-establishment of LES tone26 (Fig. 3). In patients with
men and women are similar15; however, in the US study, achalasia, during MRS, LES relaxation can be incom-
the incidence was higher (21.0 per 100,000 person) in plete. Discoordinated or simultaneous oesophageal
women aged 45–64 years than in men of similar age, body contractions can occur in early-stage achalasia,
but no sex-specific difference was observed in younger and aperistalsis and oesophageal pressurization occurs
patients20. in late stages of achalasia27,28.
The delay between onset of the first symptoms and Both in vivo and in vitro experiments have evaluated
a diagnosis of achalasia can be as long as several years, the mechanisms that underlie abnormal neural control
although use of high-resolution manometry (HRM) in achalasia. In vivo, intravenously administered recom-
may facilitate an earlier diagnosis21. For example, the binant haemoglobin, which inactivates nitric oxide, pro-
incidence of achalasia in the Chicago area was twofold duces simultaneous oesophageal body contractions and
to threefold higher in 2004–2014, after the introduc- failed LES relaxation similar to that seen in achalasia29,
tion of HRM for achalasia diagnosis, compared with establishing a role for nitric oxide in inhibitory neural
previous estimates when conventional manometry transmission. In vitro, in LES specimens from patients

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with achalasia, inhibitory neurons containing vasoactive provokes paradoxical LES contraction in achalasia33. By
intestinal peptide (VIP) and nitric oxide synthase were contrast, excitatory cholinergic nerves were found to be
found to be reduced or absent30,31. Circular LES mus- partially preserved in achalasia34.
cles strips showed an abnormal contractile response
to electrical field stimulation owing to lack of activa- Aetiopathogenesis
tion of nitric-oxide-containing inhibitory neurons32. Achalasia is an autoimmune disease that affects
Furthermore, cholecystokinin, which normally relaxes oesophageal myenteric neurons with confirmed
the LES through activation of inhibitory nerves, cell-mediated and possible antibody-mediated mech-
anisms. Autoimmune disorders, including Sjögren
syndrome, type 1 diabetes mellitus and hypothy-
Lower cranial nerves roidism, are frequently encountered in patients with
from brain stem nuclei
achalasia, supporting autoimmune mechanisms in acha-
Direct innervation
Upper through lower lasia pathophysiology35–38. In a large European cohort of
oesophageal Proximal cranial nerves patients with idiopathic achalasia, comorbid allergic and
spincter skeletal autoimmune disorders, as well as viral infections (in par-
muscle
ticular with varicella zoster virus) before symptom onset,
were observed39. Genetic predisposition also has a role,
as an eight-amino-acid insertion in the cytoplasmic tail
of HLA-DQβ1 is a risk factor for achalasia40,41. This is
more prevalent in type 1 achalasia than other subtypes
and less common in northern European patients (around
6–7%) than in southern Europeans (~16%)42. Thus, loss
of myenteric plexus neurons involves autoimmunity,
viral infection and genetic predisposition (Fig. 4).

Cell-mediated autoimmunity. Oesophageal biopsy

samples in achalasia demonstrate myenteric plexus
Outer
longitudinal neurons surrounded by inflammatory cells, predom-
Distal
muscle smooth inantly T cells, eosinophils, plasma cells, B cells, mast
muscle cells and macrophages 6,43,44. Immunohistochemical
Inner circular
muscle
staining indicates that the T cells are CD3+, cytotoxic
CD8+ and tumour necrosis factor (TNF)-positive (TNF
Ganglia in
is a cytokine able to promote the killing of various intra-
intermuscular Excitatory innervation cellular infectious viruses, bacteria and parasites) rather
Auerbach’s to longitudinal muscle than a regulatory phenotype45. Inflammation is seen in
plexus
all regions of the oesophagus and in all three achalasia
Excitatory innervation subtypes. Other immune cells, including eosinophils
to circular muscle and mast cells, also contribute to the inflammatory
response46. Eosinophils infiltrate both the muscula-
Inhibitory innervation ris externa and the muscularis propria47, and degran-
to circular muscle
ulating eosinophils release toxic proteins capable of
destroying myenteric neurons, leading to impaired
oesophageal motility as hypothesized in patients with
eosinophilic oesophagitis, who showed an increase in
Lower
oesophageal
Intrinsic tone achalasia diagnoses48. Infiltration of mast cells, both at
Vagal stimulation
sphincter Vagal inhibition
the LES muscle and in the myenteric plexus49, leads to
a decrease in interstitial cells of Cajal, neuronal nitric
oxide synthase-positive cells and S-100-positive cells of
Stomach neural crest origin50. The observation of these specific
cells involved in extracellular matrix turnover, apoptosis
and fibrosis, as well as the systemic inflammatory auto-
Fig. 1 | Normal oesophageal physiology and innervation. The upper oesophageal immune component (increased numbers of circulating
sphincter and the proximal third of the oesophagus consist of skeletal muscle under T helper 22 (TH22), TH17, TH2 and TH1 cells), associated
volitional control through direct cranial nerve innervation. The remainder of the tubular with the presence of specific anti-myenteric autoanti-
oesophagus consists of smooth muscle, with an outer longitudinal layer and an inner bodies and herpes simplex virus 1 (HSV-1) infection,
circular layer. A nerve plexus (Auerbach’s plexus) between the two muscle layers has all support the concept of autoimmune mechanisms that
cranial input, and both excitatory and inhibitory post-ganglionic neurons innervate the
target the oesophageal myenteric plexus in achalasia5.
circular muscle, but only excitatory neurons innervate longitudinal muscle. Excitation
induces contraction via cholinergic neurotransmitters, and inhibition via nitric oxide
as the predominant neurotransmitter is crucial for the timing of peristalsis as well as Antibody-mediated autoimmunity and serum cytokines.
relaxation of the lower oesophageal sphincter (LES). The LES has resting pressure that The immune attack on the myenteric plexus is associ-
keeps the lumen closed at rest, determined by a combination of intrinsic tone and vagal ated with the production of antineuronal antibodies by
stimulation. plasma cells and B cells51–53. Antibodies to myenteric

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Normal Early achalasia Established achalasia End-stage achalasia

oesophagus Symptoms may type 1 or 2* type 1 or 2*
not be classic Abnormal oesophageal Oesophageal retention,
and may be emptying leading to symptoms abnormal emptying, aspiration
Immune-mediated mistaken for GERD of dysphagia, regurgitation, pneumonia, symptoms persist
inflammation weight loss and chest pain despite disruption of LES

Gradual destruction
of myenteric plexus
ganglion cells Abnormal Dilated,
body sigmoid
peristalsis oesophagus
Loss of inhibitory
innervation mediated
via nitric oxide

Oesophagus
Abnormal Open LES
LES from past
relaxation therapy
Stomach

Normal myenteric plexus (left) Depleted myenteric plexus (left) Extreme loss of myenteric plexus (left)
and normal ganglion cell (right) and inflamed ganglion cell (right) and destroyed, fibrosed ganglion cell (right)

Fig. 2 | Oesophageal manifestations and natural history of achalasia. The core pathophysiological abnormality in
achalasia is loss of predominantly inhibitory nerve control of the oesophagus, leading to oesophageal outflow obstruction
from loss of swallow-induced relaxation of the lower oesophageal sphincter (LES), and loss of or abnormal oesophageal
body peristalsis. Symptoms are a consequence of this obstructive effect, which leads to progressive dilation of the oesoph-
ageal lumen over time. Histopathological analysis shows inflammation and depletion of oesophageal ganglia and neurons
in early achalasia and replacement with fibrosis in later stages of achalasia. End-stage achalasia results in a dilated,
sigmoid-shaped oesophagus that may not empty even if the LES is open from adequate therapeutic disruption. GERD,
gastro-oesophageal reflux disease. *Achalasia type 3 may not manifest oesophageal dilation, and its natural history is
largely unknown.

neurons can be found in patients with achalasia with activation that damages oesophageal enteric neurons
HLA-DQA1*0103 and HLA-DQB1*0603 alleles 51. only when triggered by a yet unknown factor and only in
However, the specificity of antineuronal antibodies genetically susceptible individuals57. Thus, not all patients
for achalasia has been questioned, as these antibod- infected with predisposing viruses develop achalasia, indi-
ies do not selectively target oesophageal myenteric cating the potential role of genetic factors to make some
neurons and have also been detected in patients with individuals more susceptible to achalasia than others58.
gastro-oesophageal reflux disease (GERD)8. Thus, these
antibodies may be a consequence of the inflammatory Genetics. Immunogenetic studies report an association
process and nonspecific rather than a causative factor in between HLA-DQw1, HLA-DQA1 and HLA-DQB1,
achalasia pathogenesis. and achalasia, with HLA-DQB1 being the most com-
monly reported53,59. Antibodies to myenteric neurons
Viral infection. Viral DNA and virus-targeted antibodies have been found in serum samples from patients with
have been found in oesophageal tissue and in the serum, achalasia, particularly those with HLA-DQA1*0103
respectively, of patients with achalasia54,55, involving and HLA-DQB1*0603 alleles51. As achalasia has asso-
HSV-1, measles virus and human papillomavirus11,54. ciations with HLA genes, affected siblings and parents
HSV-1 is a neurotropic virus with a predilection for are occasionally encountered60, although familial acha-
squamous epithelium. Viral DNA from HSV-1 was demon- lasia is uncommon61. Achalasia can be part of a genetic
strated in oesophageal tissue from patients with achala- syndrome, such as the Algrove syndrome (also termed
sia, and T cells from that tissue proliferated and released AAA syndrome, which involves achalasia, alacrimia
cytokines following exposure to HSV-1 antigens11,55. and adrenal insufficiency) from missense or trunca-
However, other investigators did not find HSV-1 or other tion mutation on chromosome 12 (ref.62). Achalasia can
viruses in achalasia oesophageal specimens56. HSV-1 occur in individuals with intellectual disability owing
DNA has also been found in oesophageal tissue from to chromosome 2 mutations and in those with Down
individuals without achalasia. These findings have led to syndrome63. Genetic syndromes may be identified more
the hypothesis that HSV-1 can cause a persistent immune often in children with achalasia.

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Furthermore, in some studies, signalling pathway and upregulated expression of INPP4B, the latter being
abn­ormalities have been reported in idiopathic acha- linked to AKT pathway regulation66.
lasia, which might be related to the underlying patho-
logical neuronal mechanism and reduced activity of Achalasia subtypes
interstitial cells of Cajal64,65. Transcriptomic analysis Pathophysiology. Achalasia is a heterogeneous disor-
of achalasia tissues identified dysregulated expression of der and the aetiopathogenesis, pathophysiology and
specific genes, such as downregulated expression of KIT symptomatic profiles of achalasia subtypes vary 67.

a Normal pattern Type 1 achalasia Type 2 achalasia Type 3 achalasia mmHg

150
UES 140

120
Intact Absent body Absent body Abnormal body
oesophageal peristalsis peristalsis with peristalsis with 100
body without pan-oesophageal premature
Oesophageal peristalsis pressurization pressurization contraction
80
body
60

40

EGJ (LES 20
and CD)
5s Impaired LES relaxation Impaired LES relaxation Impaired LES relaxation 0
–5
Definition • IRP < upper limit of normal • IRP > upper limit of normal • IRP > upper limit of normal • IRP > upper limit of normal
• Normal peristalsis or • 100% absent peristalsis • 100% absent peristalsis • 100% abnormal peristalsis
≤30% ineffective or • No pressure • ≥20% pan-oesophageal • ≥20% premature peristalsis
<50% failed swallows compartmentalization pressure
compartmentalization

LES Normal Impaired Impaired Impaired

relaxation

Smooth Both circular and Circular and longitudinal Circular muscle does not Circular and longitudinal
muscle longitudinal muscles muscles do not contract contract but longitudinal muscle contraction are
dysfunction contract and oesophagus is dilated muscle contraction discoordinated and
is retained asynchronous

Oesophageal Normal oesophageal Very limited; by gravity and by Suboptimal; Emptying may be adequate,
emptying empyting unique patient manoeuvres to by pan-oesophageal but peristalsis is segmented
increase intrathoracic pressure pressurization and compartmentalized

mmHg
b Normal MRS response MRS in type 1 achalasia MRS in type 2 achalasia MRS in type 3 achalasia 150
140
UES
5s 120
No Absent
pan-oesophageal oesophageal 100
Augmented Pan-oesophageal Absent Abnormal Augmented
pressurization body pressurization oesophageal oesophageal oesophageal
oesophageal 80
Oesophageal contraction body body body
Normal body
body oesophageal contraction contraction inhibition contraction 60
body inhibition 40
20
EGJ (LES Normal LES relaxation Impaired LES relaxation Impaired LES relaxation Impaired LES relaxation 0
and CD) –5

Fig. 3 | Achalasia subtypes based on high-resolution manometry. rapid swallows (MRS) for assessment of deglutitive relaxation in achalasia26–28.
a | High-resolution manometry (HRM) patterns identifying oesophageal During repetitive swallowing in the healthy oesophagus, there is profound
achalasia during liquid swallows and according to Chicago classification inhibition of oesophageal body contraction and relaxation of the lower
v4.0 (ref.3). The common manometric abnormality on HRM is an abnormal oesophageal sphincter (LES). After the last swallow of the sequence, there
integrated relaxation pressure (IRP) above the upper limit of normal for the is an augmented contraction sequence and re-establishment of LES tone.
HRM system used. However, IRP may be within normal limits in type 1 Inhibitory dysfunction manifests as varying degrees of incomplete
achalasia. The oesophageal body motor pattern determines the three LES relaxation during MRS in the achalasia subtypes. In type 3 achalasia, LES
subtypes. In type 1 achalasia, peristalsis and pressurization are absent. relaxation is intermittent. Oesophageal body contraction is absent in type 1
In type 2 achalasia, pan-oesophageal pressurization occurs in at least 20% and type 2 achalasia, but with pan-oesophageal pressurization in type 2
of swallows. In type 3 achalasia, non-peristaltic oesophageal body achalasia. In type 3 achalasia, incomplete inhibition may manifest as a
contractions are observed with ≥20% premature contractions (with distal breakthrough contraction during repetitive swallowing. CD, crural
latency <4.5 s). The patterns of smooth muscle contractility and mechanisms diaphragm; EGJ, oesophagogastric junction; UES, upper oesophageal
of oesophageal emptying also differ between the three subtypes. b | Multiple sphincter.

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Genetic predisposition emptying, generated by a combination of preserved

proximal striated muscle contraction, longitudinal mus-
cle contraction and non-occlusive distal circular muscle
Environmental trigger (possibly viral infection)
contraction against augmented EGJ outflow obstruction
(EGJOO)69. Interestingly, impedance recordings suggest
Autoimmune myenteric plexitis that oesophageal transit can be adequate but segmented
and discoordinated in type 3 achalasia69,70. When chal-
Inflammation lenged with MRS, type 1 achalasia exhibits no LES relax-
ation, type 2 may augment LES pressure and type 3 may
manifest LES relaxation to a near normal extent27,28.
Aganglionosis and Imbalance between
neuronal cell death inhibition and excitation
Aetiopathogenesis. The prevailing hypothesis is that
both type 1 and type 2 achalasia are the consequence
Type 1 Type 2 Type 3 of a cytotoxic immune attack leading to progressive
achalasia achalasia achalasia EGJOO myenteric plexus neuronal death without selectivity
among subsets of myenteric plexus neurons5–11 (Fig. 2). By
Fig. 4 | Two possible pathways of pathogenesis differen-
contrast, patients with type 3 achalasia have an immune
tiate achalasia subtypes. In genetically predisposed indi-
viduals, an environmental trigger, perhaps a viral infection,
response that affects neuronal function but without
is thought to initiate a cell-mediated immune response as causing neuronal death12,13. Serum from patients with
well as an antibody-mediated response that preferentially type 3 achalasia can induce downregulation of nitric
attacks inhibitory ganglia and neurons in the oesophageal oxide synthase expression and increased cholinergic
neural plexi. If complete loss of ganglia and neurons results, sensitivity without affecting the number of neurons71.
abnormal lower oesophageal sphincter (LES) relaxation Circulating IL-8 can mediate this response, suggesting
coexists with absent contraction in the oesophageal body, that local cytokine release could induce an imbalance
characterizing potentially type 2 achalasia in early stages, between inhibitory and excitatory post-ganglionic neu-
and type 1 achalasia as the disease progresses. If inflamma- ronal function in type 3 achalasia. Finally, a progressive
tion ensues without complete loss of inhibitory control,
plexopathy is also recognized, evolving from achala-
imbalance between inhibition and excitation results in pre-
mature or spastic oesophageal body contractions charac-
sia with preserved peristalsis, to type 2 achalasia and,
terizing type 3 achalasia or even intact oesophageal body subsequently, to type 1 achalasia68.
contractions in conjunction with abnormal LES relaxation
characterizing oesophagogastric junction outflow Diagnosis, screening and prevention
obstruction (EGJOO). Clinical presentation
The most common symptoms reported by patients with
achalasia consist of dysphagia for both solids and liq-
Abnormal LES relaxation is a prerequisite finding, but uids, and regurgitation of undigested food and saliva,
oesophageal body motility patterns differ between the especially while lying flat at night, which can result in
three achalasia subtypes defined with HRM3. Impairment weight loss and, less frequently, bronchitis or relapsing
of LES relaxation occurs in association with absent peri- pneumonias72. Although counterintuitive, achalasia can
stalsis (type 1 achalasia), pan-oesophageal pressurization also exist in individuals with morbid obesity, likely due to
(type 2), premature (spastic) distal oesophageal contrac- associated oesophageal hyposensitivity, which may limit
tions (type 3) (Fig. 3), or even preserved peristalsis, all of the sensation of dysphagia73. Regurgitation of undigested
which are compatible with achalasia68. food can be misidentified as vomiting, leading to sus-
During normal peristalsis, circular and longitu- picion of a gastric disorder rather than an oesophageal
dinal smooth muscle in the oesophageal body con- process. Chest pain may also be reported in all subtypes
tracts synchronously. Both circular and longitudinal of achalasia, but particularly type 3 achalasia23,68. The
muscle contraction are substantially compromised exact mechanism underlying chest pain remains unclear
in type 1 achalasia, with minimal to no longitudinal but could include fermentation of food retained in the
muscle contraction. By contrast, in type 2 achalasia, oesophagus to acidic by-products that stimulate chemo­
strong longitudinal muscle contraction, part of the receptors, stasis-related oesophageal inflammation,
basis for pan-oesophageal pressurization, is preserved. spastic and discoordinated smooth muscle contraction
Considerable discoordination between contracting and/or oesophageal hypersensitivity1,2,68. Presenting
circular and longitudinal muscles characterizes type 3 symptoms in children are similar to those in adults
achalasia69. Thus, smooth muscle contraction, particu- with achalasia. Additionally, coughing and/or choking
larly longitudinal muscle contraction patterns, differ during eating, recurrent aspiration pneumonias, feed-
between the three achalasia subtypes. ing difficulties, food refusal and failure to thrive may
Mechanisms of oesophageal emptying are also dis- be present74,75. The Eckardt score quantifies the four
tinct. In type 1 achalasia, oesophageal emptying occurs cardinal achalasia symptoms (dysphagia, regurgitation,
with gravity and from unique measures that the patient chest pain and weight loss) using a 4-point grading
develops to increase intrathoracic pressure above the system76 (Table 1), in which a score of ≤3 quantifies ade-
LES closing pressure. By contrast, in type 2 achalasia, quate treatment outcome. Despite lack of validation as a
pan-oesophageal pressurization against a closed LES patient-reported outcome (PRO) measure, it is useful to
is the main mechanism of intermittent oesophageal record the Eckardt score at initial achalasia diagnosis as

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a measure of symptom severity77,78. Of note, patients can for this assessment and is easier to perform than con-
rarely present with symptoms that mimic GERD, such as ventional manometry, with good to excellent inter-rater
heartburn, chest pain and regurgitation, and may even and intra-rater agreement for achalasia subtypes, and it
be referred for anti-reflux surgery79,80. This may lead to is preferred by learners as well as experts84,85. HRM uses
disease progression and a more severe impairment of a classification scheme termed the Chicago classification
oesophageal anatomy and peristalsis from misdiagnosis to define disorders of EGJ function and oesophageal per-
and mismanagement as GERD79. istalsis, which was revised and updated in 2021 (ref.3).
Other benign disorders, including GERD, benign This classification is based on the hierarchical assess-
oesophageal strictures, eosinophilic oesophagitis, dif- ment of adequacy of LES–EGJ relaxation followed by
fuse oesophageal spasm, hypercontractile oesophagus evaluation of oesophageal body peristalsis. By using spe-
and neoplastic oesophageal diseases are more com- cific HRM metrics, clinically relevant motor patterns can
mon causes of dysphagia and regurgitation than of true be reliably identified, including achalasia, EGJOO, distal
achalasia. Thus, oesophageal evaluation for achalasia is oesophageal spasm, hypercontractile oesophagus, inef-
usually undertaken after upper endoscopy and/or bar- fective oesophageal motility and absent contractility3.
ium radiography have ruled out alternative structural or Thus, the application of HRM using the Chicago classi-
mucosal mechanisms for symptoms. Presentation with fication in clinical practice increases the diagnostic yield
chest pain or heartburn in combination with regurgi- and emphasizes the role of HRM in selecting the optimal
tation may prompt a diagnosis of GERD, and trials of therapeutic approach in achalasia, with the ultimate goal
anti-reflux medications are common. In fact, achala- of improving patient outcome86,87. Whenever possible,
sia is diagnosed in up to 2.5% of patients undergoing HRM should be performed in the absence of opioid or
manometry before anti-reflux surgery80, indicating other medications that may alter oesophageal motility.
that testing for achalasia needs to be performed when The key metric for adequacy of LES relaxation is the
reflux-like symptoms do not improve despite anti-reflux integrated relaxation pressure (IRP), which describes
medications. nadir LES pressures over 4 s during a 10 s window that
includes swallow-induced LES relaxation. The sensitivity
Diagnostic modalities of the IRP over the upper limit of normal was 98% for
Diagnosis of achalasia requires recognition of presenting a diagnosis of abnormal LES relaxation, with a speci-
symptoms as well as appropriate use and interpretation ficity of 96%88. Compared with conventional manome-
of diagnostic testing (Fig. 5). The tests commonly used for try, use of the IRP from HRM increased the diagnostic
reaching a correct diagnosis include upper endoscopy, yield from 12% to 26% in patients with dysphagia in a
manometry and oesophagography. randomized multicentre study21. The median IRP from
10 swallows of 5 ml of water in the supine position dur-
Upper endoscopy. Endoscopy has a low diagnostic yield ing HRM is the current standard, and the upper limit of
in the identification of achalasia and its primary role is in normal differs depending on the HRM system used3,89.
ruling out alternative mechanisms for oesophageal In addition to abnormal LES relaxation, oesophageal
obstruction2. However, the procedure might provide smooth muscle contraction is considerably altered in
clues to the presence of achalasia, including the presence achalasia, including absence of peristaltic contractions,
of fluid or food residue within a dilated oesophagus, and although premature or spastic contractions can also
a puckered, tight EGJ that resists but does not obstruct occur. The pattern of pressurization or contraction within
the passage of the endoscope (Fig. 6). Other endoscopic the smooth muscle oesophageal body determines acha-
signs include the oesophageal rosette sign and the lasia subtypes (Fig. 3), which has implications for disease
champagne glass sign81,82. Frothy saliva and candidiasis management87. Absence of peristalsis without pressuri-
within a non-dilated oesophagus may raise suspicion for zation is seen in type 1 achalasia, in which the IRP may
achalasia83. be manometrically normal in some instances, and alter-
native tests are needed to confirm achalasia in the pres-
Manometry. Achalasia is diagnosed on the basis of ence of compatible symptoms90 (Fig. 5). Pan-oesophageal
manometric demonstration of abnormal LES relaxation pressurization in ≥20% of supine water swallows defines
and aperistalsis (Fig. 5). HRM is the modern standard type 2 achalasia, which has the best management out-
comes among all achalasia subtypes86,87. Contractility is
Table 1 | Eckardt score retained in type 3 achalasia, but peristalsis is not nor-
Symptom Score mal; premature and/or spastic contractions are seen in
≥20% of the swallows3. Response to standard therapy can
0 1 2 3 be substandard in type 3 achalasia86, although tailored
Dysphagia None Occasional Daily Every extended per-oral endoscopic myotomy (POEM) may
meal provide improved symptom relief 91.
Regurgitation None Occasional Daily Every Some patients can present with achalasia-like symp-
meal toms that respond to achalasia treatment, but with intact
Chest pain None Occasional Daily Every oesophageal body peristalsis and evidence of oesoph-
meal ageal outflow obstruction in the form of an abnormal
Weight loss (kg) None <5 5–10 >10 IRP (termed EGJOO)92. Conceptually, EGJOO could
Scores are added up to generate a total score between 1 be related to compromised deglutitive EGJ relaxation
and 12. Adapted with permission from ref.76, Elsevier. (motor EGJOO) or to structural EGJ abnormalities

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Compatible symptoms
• Dysphagia • Bland regurgitation
• Chest pain • Reflux-like symptoms without improvement on PPI therapy
• Weight loss • Recurrent aspiration pneumonia

Short duration symptoms? Initial investigation

Significant weight loss? Oesophagogastroduodenoscopy and/or barium radiography
Normal or suggestive
Consider pseudoachalasia of motor obstruction
High-resolution manometry On chronic opiate medication?
• Cross-sectional imaging
• Endoscopic ultrasonography
• FLIP Consider opiate-induced
• Serological tests oesophageal dysmotility

• IRP below upper • IRP above upper limit • IRP above upper
limit of normal of normal limit of normal
• Absent peristalsis • Abnormal oesophageal • Intact oesophageal
body peristalsis body peristalsis

• Timed barium • Timed barium

oesophagram oesophagram
• FLIP • FLIP

Type 1 achalasia Type 2 achalasia Type 3 achalasia Motor EGJOO

• LHM • LHM
Standard • POEM • POEM • POEM
• PD • PD

• LHM
Optional • LHM, long myotomy • POEM
• PD

Unsuitable
for surgery or • Botulinum toxin
• Botulinum toxin • Botulinum toxin • Sildenafil • Botulinum toxin
bridge therapy

End stage • Oesophagectomy • Oesophagectomy

• Enteral feeding • Enteral feeding

Fig. 5 | Diagnostic and management algorithm for achalasia. In the presence of compatible symptoms (particularly
dysphagia, regurgitation, chest pain and weight loss), upper endoscopy serves to exclude structural aetiologies, as well
as pseudoachalasia from distal oesophageal or proximal gastric neoplastic processes. Opioid use can mimic achalasia,
particularly type 3 achalasia and oesophagogastric junction outflow obstruction (EGJOO). The gold standard for diagnosis
of achalasia is high-resolution manometry (HRM). HRM findings can also subtype achalasia, with management implications.
Type 1 achalasia needs to be suspected even when the integrated relaxation pressure (IRP) is within normal limits on HRM,
and adjunctive tests (timed barium oesophagram, functional lumen imaging probe (FLIP)) can be valuable in this regard.
These adjunctive tests can also help to differentiate motor EGJOO, which can respond to achalasia treatments, from struc-
tural EGJOO or artefact. Definitive achalasia management requires disruption of the lower oesophageal sphincter (LES),
using forceful dilation (pneumatic dilation (PD)) or myotomy (laparoscopic Heller myotomy (LHM) or per-oral endoscopic
myotomy (POEM)). Botulinum toxin injection is an option for patients who are unsuitable for surgical intervention, and
as a bridge to definitive therapy. Oesophagectomy or enteral feeding through a gastrostomy tube may be needed in
end-stage achalasia with a dilated, non-functioning oesophagus that may not empty despite an open LES. PPI, proton
pump inhibitor.

associated with mechanical obstruction (that is, fundo- remains under debate92,93. Clinically, it is imperative that
plication or bariatric surgery, cancer or other infiltrative structural mechanisms and artefactual IRP elevations
processes, luminal stricture or extraluminal compression are ruled out before considering achalasia-like manage-
due to para-oesophageal hernia). Whether confirmed ment for EGJOO. Persistence of IRP elevation on upright
motor EGJOO without mechanical obstruction repre- swallows, compartmentalization of intrabolus pressure
sents early achalasia in which oesophageal body features in the distal oesophagus and obstructive features on
have not yet developed or whether it is a different entity provocative tests during HRM support a diagnosis of

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EGJOO. When available, amyl nitrite inhalation during non-achalasia mechanisms94,95. However, supporting
HRM can demonstrate LES relaxation in achalasia or evidence from barium radiography or functional lumen
motor EGJOO, which can help distinguish achalasia imaging probe (FLIP) is essential for a conclusive diag-
from opioid-induced EGJOO or IRP elevation due to nosis of EGJOO3. When the diagnosis is inconclusive,
a therapeutic trial of botulinum toxin injection into the
Endoscopy Timed barium oesophagram LES during endoscopy can be useful96, as a symptom
response might indicate motor obstruction that could
respond to achalasia treatment for durable symptom
Tight relief (Fig. 5).
LES
Barium
column Barium radiography. Barium radiography, particularly
Barium >2 cm the timed barium oesophagram (TBE), has diagnostic
column and prognostic value in achalasia. A standard barium
>2 cm
swallow may demonstrate a dilated oesophagus with
a tapered ‘bird’s beak’ EGJ, but has suboptimal per-
formance characteristics for diagnosis of oesophageal
motility disorders97. In patients with achalasia, a 13 mm
diameter barium pill may become trapped and obstruct
Sigmoid the EGJ. In a study comparing swallows of liquid barium
oesophagus
alone with swallows of a combination of liquid barium
Bird’s beak
Tight sign plus a 13 mm barium pill, combined liquid barium and
LES Bird’s beak
sign tablet increased diagnostic yield from 79.5% to 100% in
patients with untreated achalasia and from 48.9% to 60%
Functional lumen imaging probe in patients with EGJOO, highlighting the complemen-
100
tary role of the barium pill in identifying achalasia as
80 Pressure (mmHg) well as mechanical obstruction at the EGJ98. For TBE, the
60 Volume (ml)
40 patient rapidly drinks 200 ml of low-density barium sul-
20
0 Estimated Distensibility fate while upright, and X-ray films are obtained 1, 2 and
diameter (mm) (P > 5mmHg) 5 min thereafter98,99 (Fig. 6). In an analysis of TBE data
1
20.1 3.9 from a large cohort of patients with confirmed acha-
2 Topographical depiction
of cross-sectional area 22.0 4.7 lasia and individuals without achalasia but dysphagia
3
22.9 5.1
4 presentations, a barium column height of 5 cm at 1 min
22.5 4.9
5 Oesophageal body 21.5 4.5 showed the highest sensitivity of 86% and specificity
6 aperistalsis of 71% in differentiating achalasia from non-achalasia
Electrode number

22.3 4.8
7 21.1 4.3 oesophageal disorders, whereas a height of 2 cm at 5 min
8 19.2 3.6 had a sensitivity of 80% and specificity of 86%98. TBE
9 15.3 2.3 findings are reproducible with excellent inter-observer
10 6.5 0.4
11 LES agreement, and can predict the likelihood of future
4.8 0.2
12
symptom recurrence after achalasia therapy99,100. Thus,
10.0 1.0
13 16.5 2.6
TBE can be used to adjudicate inconclusive HRM find-
14 21.9 4.6 ings, especially in the context of EGJOO, and to assess
15 23.3 5.2 adequacy of achalasia management (Fig. 5).
16 22.7 5.0
0 5 10 15 Functional lumen imaging probe. In the past 5 years, the
Time (s) FLIP, an endoscopic device consisting of a distensible bal-
loon containing a catheter with several pairs of electrodes
Fig. 6 | Adjunctive tests in the diagnosis of achalasia. Endoscopy may demonstrate
and a pressure sensor that simultaneously measures the
a dilated oesophagus with food or frothy saliva residue and a tight and puckered lower
oesophageal sphincter (LES) that offers modest resistance to endoscope passage2. cross-sectional area and pressure within a hollow viscus,
A timed barium oesophagram (TBE) reveals abnormal oesophageal emptying, typically has become a valuable complementary tool in the diagno-
measured as a barium column >2 cm in the upright position 5 min after administration of sis of EGJ obstruction101. This advanced imaging system
200 ml of low-density barium sulfate98–100. The bird’s beak sign of the oesophagus is used is able to study the biomechanical properties of luminal
to refer to the tapering of the inferior oesophagus in achalasia. In the advanced stage organs, in particular, the oesophagus and the EGJ. EGJ
of achalasia, a TBE may show a sigmoid-shaped oesophagus, in which the oesophageal distensibility measured using FLIP can reliably diagnose
lumen is substantially dilated, swerved and rotated. Functional lumen imaging probe achalasia even when EGJ relaxation is manometrically
(FLIP) uses impedance planimetry to measure cross-sectional areas within the oesopha- normal90,102. FLIP may detect an abnormal response to
geal lumen101. The ratio between cross-sectional area and distending pressure at the oesophageal distension in 50% of patients diagnosed
level of the LES determines the distensibility index, which is typically <2 mm2/mmHg in
with ineffective oesophageal motility (IEM) or normal
obstructive processes. Topographical depiction of cross-sectional area in the oesopha-
geal body can be used to demonstrate secondary peristalsis, termed FLIP panometry. HRM findings103. EGJ metrics (distensibility index and
The oesophageal body demonstrates no contraction (aperistalsis) in achalasia type 1 diameter) from FLIP studies outperform both supine
and type 2 (as shown here). By contrast, spastic contractions and retrograde contractions and upright IRP measurements when compared with bar-
may be seen in type 3 achalasia. A normal contraction pattern consists of anterograde ium retention on TBE in detecting obstruction104 (Fig. 6).
contractions occurring at the rate of six contractions per minute. Furthermore, FLIP can characterize achalasia subtypes

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Box 1 | Features of pseudoachalasia Chagas disease, an infection of the protozoan para-

site Trypanosoma cruzi, which causes damage to the
The term pseudoachalasia has traditionally been applied to neoplasia-induced oesophageal myenteric plexus that results in partial or
achalasia-like manifestations. However, structural changes and processes at the absent LES relaxation and mega-oesophagus, can mimic
oesophagogastric junction (EGJ), such as tight fundoplication or hiatus hernia repair, achalasia111,112. Opioid use can result in manometric
laparoscopic gastric band or bariatric surgical procedures, can also result in similar
patterns with obstruction, including EGJOO and type 3
achalasia-like manifestations.
Characteristics that can be associated with pseudoachalasia achalasia, and amyl nitrite inhalation during HRM
can be used to differentiate opioid-related syndromes
• Manometric pattern can mimic type 1, type 2 or type 3 achalasia, or EGJ outflow
obstruction from true achalasia94. Eosinophilic oesophagitis can
overlap with achalasia in rare instances, and achalasia
• Incomplete patterns are common
management may be needed to complement traditional
• Occurrence at >55 years of age
eosinophilic oesophagitis treatments113,114. Congenital
• Short duration of symptoms (<1 year) oesophageal stenosis in adults is an extremely rare disor-
• Substantial weight loss (>10 kg), der that can present as achalasia115. Finally, some patients
• Difficulty in negotiating endoscope through EGJ with spastic oesophageal body motility (hypercontractile
• Evidence of neoplasia on biopsy from EGJ or gastric cardia oesophagus and distal oesophageal spasm) may have an
• Abnormal, irregular wall thickening on endoscopic ultrasonography or CT obstructive component similar to achalasia, and case
• Positive serological tests (antineuronal nuclear antibodies (ANNAs; also known as reports exist of these spastic disorders transitioning to
anti-Hu antibodies)) achalasia over time116.
• Detection of distant cancers (such as lung, kidney or pancreatic cancer) on CT
• History of previous surgery at hiatus (for example, laparoscopic fundoplication or Screening and prevention
laparoscopic gastric band) As achalasia is extremely rare, population-based screen-
ing is not feasible. Early diagnosis can be facilitated
by maintaining a high index of suspicion, particularly by
by detecting non-occlusive oesophageal contractions performing HRM, TBE or FLIP when oesophageal symp-
that are not observed with HRM to varying degrees in toms do not improve with symptomatic management, or
achalasia subtypes, enabling additional subclassification when persisting symptoms do not have a clear explana-
of patients with oesophageal obstruction105,106. Thus, tion. However, there is an inherent delay in diagnosis, as
FLIP has value as a complementary test for diagnosis of clinical manifestations take time to develop to the degree
achalasia and EGJ obstruction, especially when HRM is that prompts patients to present for medical evaluation.
inconclusive97 (Fig. 5). No preventive measures for achalasia are known.

Exclusion of pseudoachalasia Management

Local distal oesophageal cancer and proximal gastric The oesophageal motor dysfunction in achalasia is irre-
cancer, as well as distant cancer (for example, small versible. Thus, repair of the defective oesophageal body
cell lung cancer) can cause oesophageal symptoms and contractility is unrealistic, and therapeutic efforts are
motor findings similar to achalasia, prompting use of focused on relief of EGJ obstruction to restore oesopha­
the term pseudoachalasia to describe these oesophageal geal emptying, relieve oesophageal symptoms, improve
manifestations. Short duration of dysphagia (typically quality of life and reduce the risk of end-stage achala-
<1 year), substantial weight loss and old age are sugges- sia. Several options are available, from pharmacological
tive of pseudoachalasia4,107, and warrant cross-sectional approaches to endoscopic or surgical myotomy, which
imaging (for example, CT and/or MRI), or endoscopic have varying levels of symptom benefit and adverse
ultrasonography as part of the evaluation107,108 (Box 1). effects. In late stages of achalasia, a dilated and sigmoid
Serological tests, such as antineuronal nuclear anti- oesophagus may not be salvageable, and oesophagectomy
bodies (anti-ANNA 1 and 2 antibodies, also termed and/or enteral feeding are sometimes necessary.
anti-Hu antibodies) have high sero-positivity rates
in patients with small cell lung cancer and are some- Medical therapy
times performed when pseudoachalasia is suspected109. Oral pharmacological therapy. Calcium channel block-
Compared with achalasia, HRM findings in pseudo­ ers, nitrates, anticholinergics and phosphodiesterase
achalasia can be atypical or incomplete and may not inhibitors have been used for treating achalasia in small
fit achalasia subtypes4. The term pseudoachalasia was and often uncontrolled studies117–120. Although these
initially applied only to neoplasia mimicking achalasia, agents can reduce LES pressure and temporarily relieve
but it is now recognized that structural EGJ processes dysphagia, they do not improve oesophageal peristalsis
can also result in HRM patterns identical to those of or enhance LES relaxation121. Furthermore, prominent
achalasia4,107. Endoscopy may reveal mucosal obstruc- adverse events, such as headache, hypotension and
tive lesions, reduced EGJ compliance or stricture when peripheral oedema, can occur, limiting continued use
local cancer is the mechanism for pseudoachalasia, and and resulting in poor compliance of agents such as cal-
endoscopic biopsy can confirm the diagnosis. Structural cium channel blockers122. As the clinical response to oral
obstruction from a tight fundoplication/hiatus hernia pharmacological agents is inconsistent, incomplete and
repair, gastric band placed for weight loss, extrinsic short-lived, their use should be reserved for patients who
compression or para-oesophageal hernia can also result are not candidates for invasive endoscopic or surgical
in manometric findings similar to those of achalasia110. therapy, or those who decline invasive therapy.

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Botulinum toxin injection. Injection of botulinum toxin a mucosal incision is created in the middle to distal
into the LES is a short-term option for symptom relief or oesophagus, and the endoscope is advanced within the
until more-durable therapies can be administered123,124. oesophageal submucosal layer using blunt dissection130.
Botulinum toxin impairs acetylcholine release, leading A tailored myotomy of the oesophageal and LES circu-
to inhibition of contraction of LES smooth muscle fibres, lar muscle is performed using a cautery device, and the
thereby lowering LES tone. A statistically significant mucosal incision is subsequently closed using endoscopic
decrease in average LES pressure from 38.23 mmHg clips. The length of myotomy can be tailored to the indi-
(range 34.40–42.06 mmHg) before the procedure to vidual’s unique motor pattern and can be extended from
23.30 mmHg (range 20.79–25.81 mmHg) after botuli- the upper oesophagus to the proximal stomach, which is
num toxin injection (P < 0.01) has been demonstrated125. particularly relevant with pan-oesophageal spastic con-
Usually, botulinum toxin is injected into the four LES tractions in achalasia type 3 where a long myotomy is
quadrants. Botulinum toxin injection can improve acha- preferred, in contrast to achalasia types 1 and 2 where a
lasia symptoms by decreasing LES pressure and improv- short myotomy can suffice131,132.
ing oesophageal emptying126, but the duration of benefit POEM results in a significant reduction in LES pres-
is short (median 6–9 months), necessitating repeated sure with associated improvement in dysphagia symp-
injection to maintain benefits. A systematic review toms, and an efficacy of 82–98% over a follow-up of
and meta-analysis of 22 uncontrolled studies involving 3 months to 3 years133. In a large series of 500 patients
730 patients with achalasia treated with botulinum toxin with achalasia treated between 2008 and 2013, the mean
injection showed that therapeutic success, defined by Eckardt score decreased from 6 to 1; however, 21.3% of
an Eckardt score of ≤3, was achieved in 77% of patients patients developed GERD manifestations at the 3-year
during a follow-up period of 1–6 months125. Adverse time point134. In a meta-analysis of 36 studies with a total
events, including chest pain, heartburn and oesophageal of 2,373 patients, 98% of procedures were considered
perforation with mediastinitis, have been reported, but successful with reduction in Eckardt score to ≤3. By con-
they are rare127. When successful, botulinum toxin injec- trast, abnormal oesophageal acid exposure on pH testing
tions can be offered to patients with other diseases that was observed in 47%, suggesting a high rate of GERD
preclude other invasive management options. after POEM135.
Although no long-term follow-up data from ran-
Endoscopic and surgical therapy domized controlled trials are yet available, several
Pneumatic dilation. Pneumatic dilation (PD) is an cohort studies have demonstrated that POEM can be
endoscopic procedure in which LES fibres are disrupted effective even after 10 years of follow-up136. Although
through pressurized distension of a stiff balloon centred higher grades of reflux oesophagitis are uncommon
across the LES, typically under fluoroscopic guidance. after POEM137, one study reported moderate-to-severe
Graded balloons of 30 mm, 35 mm and 40 mm diameter oesophagitis in 40% of patients with GERD symptoms,
are generally used, always starting with a 30 mm bal- and endoscopic oesophagitis even in those without
loon to reduce the risk of perforation. Progression to a symptoms138. Caution should be adopted in evaluat-
larger diameter is reasonable if response is suboptimal, ing young patients, as POEM may expose them to life-
and most patients tend to undergo a 30 mm followed long reflux with potential for peptic strictures, Barrett
by a 35 mm PD for sustained symptom response, which oesophagus and even oesophageal cancer.
reduces the risk of perforation to 1%, compared with
9% if a 35 mm PD is performed initially128. In a system- Laparoscopic Heller myotomy. Heller myotomy was
atic review and meta-analysis of 52 uncontrolled trials introduced as an open surgery more than a century ago,
of PD in 4,166 patients with achalasia, clinical success but the procedure has evolved to laparoscopic Heller
(Eckardt score ≤3) was achieved in 83% of patients myotomy (LHM), which comprises an anterior cardio­
over a follow-up period of 3–6 months125. The rate of myotomy that disrupts both circular and longitudinal
symptomatic GERD, the most common adverse effect muscle fibres up to 5–7 cm proximally from the EGJ
of any intervention to disrupt the EGJ, was relatively low, and at least 2 cm onto the gastric cardia139. Robotically
occurring in 9% of the patients after 6 months. PD is assisted Heller myotomy has also been described, but sys-
a useful treatment option particularly in patients with tematic review and meta-analysis has not shown any sig-
type 2 achalasia, but also in those with type 1 achalasia; nificant advantage over the laparoscopic approach with
caution is needed when offering PD to patients younger the exception of a decrease in the rate of intraoperative
than 40 years, with baseline chest pain, male sex, and oesophageal perforation140. Of note, a partial anterior or
those with basal LES pressures of >30 mmHg, as repeat partial posterior fundoplication is routinely performed as
procedures are often needed129. It is particularly useful in part of LHM, primarily because a randomized controlled
patients who present with recurrent symptoms after one study found objective reflux in 48% of patients without
of the other treatment modalities, especially in regions a fundoplication compared with 9% with a partial fun-
without access to advanced endoscopic skills, such as doplication at LHM after 3–5 months of follow-up141.
those required for POEM (Fig. 5). There does not seem to be any significant difference in
long-term outcomes for dysphagia and reflux, provided
Per-oral endoscopic myotomy. POEM is an innovative the fundoplication is partial and not total142. LHM has
technique that has gained popularity since its first descrip- excellent efficacy, with an improvement in symptom
tion in 2007 as an effective and safe treatment modality scores in >90% and high satisfaction in >90% of patients
in achalasia. During upper endoscopy under sedation, for up to 5 years after the procedure139,143.

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The procedure has a high safety profile in care- Salvage therapy with symptom recurrence. As none of
fully selected patients. Potential complications include the treatment options for achalasia is uniformly effec-
mucosal perforation, splenic injury, pneumothorax tive, and the underlying motility disorder is not curable,
and incisional bleeding. A large single-centre series of salvage therapy is often required when symptoms recur.
400 patients reported morbidity and mortality rates Objective evaluation of symptom recurrence can include
of 2% and 0%, respectively, and an initial failure rate of endoscopy, HRM, TBE or FLIP; symptom assessment
10%144. In a long-term follow-up study, satisfaction alone, even with use of validated measures such as the
rates decreased to 75% at 15 years, owing to both dys- Eckardt score may not provide enough data to recom-
phagia and reflux, even though pathological reflux was mend repeat invasive management. PD has been demon-
documented objectively in only 14% of 149 patients143. strated to be safe after LHM failure in a systematic review
Similarly, erosive oesophagitis was seen on endoscopy in involving 87 patients with failed LHM, with a success
only 25% during a 5-year follow-up period after LHM rate of 89%156. Limited available data suggest safety and
with partial fundoplication145. efficacy of PD following POEM as well157. Case series
exist in which patients with failed PD and POEM have
Comparison of procedures. Various therapeutic options been managed successfully with LHM157,158, which can
with high levels of clinical efficacy are now available for be offered before oesophagectomy even when a sigmoid
achalasia management, which makes selection of the oesophagus is encountered in these failures159. Finally,
optimal approach difficult. Thus, several comparative POEM is emerging as a safe and effective option after
studies have been published in the past decade to help failure of LHM, with 94% efficacy in a multicentre case
prioritize management options. series160. Small case series also document improvement
A single series of PD procedures is as effective as of barium column height and symptoms after POEM
LHM in relieving symptoms at 1-year follow-up146, but following failed PD161,162. Thus, any of the other two
less effective than POEM147, without differences in safety options is feasible when achalasia symptoms persist or
or risk between the options. In studies in which PD was recur despite LHM, PD or POEM, but the available lit-
repeated owing to symptom recurrence, efficacy and erature does not provide guidance on the optimal option
safety between PD and LHM were similar129. In the past in each clinical setting.
3 years, hydraulic dilation using a stiff 30 mm dilating
balloon in conjunction with FLIP has been used as an End-stage achalasia and oesophagectomy
alternative to PD without the need for fluoroscopy, with Despite adequate disruption of the LES, achalasia pro-
comparable symptomatic outcomes in retrospective and gresses to end-stage disease in ~5% of patients, which is
open label studies148,149. However, a 35 mm dilating bal- characterized by a dilated (>6 cm) and tortuous sigmoid
loon is not available using this approach, and randomized oesophagus on barium swallow163,164. A key consequence
comparisons with PD have not been performed. is the formation of a ‘sump’ in the lower oesophagus,
No long-term follow-up data from randomized con- leading to pooling of food and fluid. End-stage acha-
trolled trials are available yet, but POEM seems to be as lasia can lead to considerable morbidity, including
effective as LHM as a first-time treatment of patients malnutrition, aspiration and pulmonary complications
with achalasia120,150. In 2019, a randomized trial showed such as pneumonia, and chronic severe oesophagitis165.
that POEM was non-inferior to LHM with Dor fundo- International guidelines suggest trialling all invasive
plication in controlling achalasia symptoms at 2 years, options (PD, POEM, LHM) in end-stage achalasia166,
but GERD was more common in patients who under- but an oesophagectomy with gastric pull-up or colonic
went POEM than in those who underwent LHM151. interposition may be indicated in patients who are can-
By contrast, another randomized clinical trial found didates for surgical removal of the dilated, functionless
that treatment success was significantly better with oesophagus2. Morbidity and mortality with oesophagec-
POEM than with PD (95% versus 54%, respectively) tomy are high at 50% and 0.9%, respectively 166–168.
after a 2-year follow-up period147. POEM is particu- Enteral feeding to bypass the oesophagus is an option
larly effective in type 3 achalasia (Fig. 5), which is asso- for patients unfit for oesophagectomy2.
ciated with a higher likelihood of treatment failure of
botulinum toxin injections, PD and LHM than type 2 Quality of life
achalasia120,152,153. A multicentre retrospective cohort Symptom questionnaires
study of 75 patients with type 3 achalasia demonstrated Standardized questionnaires are helpful to assess symp-
a higher clinical response rate with POEM (98%) than tom severity, symptom response to therapy and qual-
with LHM (81%, P = 0.01), reflecting the longer tailored ity of life in achalasia. The Eckardt score is a 4-item
myotomy length possible with POEM154. Thus, POEM self-report scale that is easy to use, with short, simple
is a safe and effective therapy for achalasia, with infre- questions, evaluating the most common achalasia
quent serious adverse events. Of note, GERD is a more symptoms169. Each of dysphagia, regurgitation, chest
frequent adverse effect after POEM than after LHM pain and weight loss is graded from 0 to 3, with a max-
or PD120. imum possible score of 12 (Table 1). The Eckardt score
LHM achieves similar achalasia-related symptomatic was initially developed to assess efficacy of achalasia
control to PD and POEM in type 2 achalasia, and is the management, with a post-treatment score ≤3 being
preferred approach in type 1 achalasia, as it performs considered optimal. The score demonstrates fair relia-
particularly well in patients with pre-treatment LES bility and validity170, mainly from questions on dyspha-
pressures >30 mmHg (ref.155). gia and regurgitation. However several limitations exist,

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Box 2 | Experience of an anonymous patient with severe achalasia Quality of life

Achalasia symptoms negatively affect eating, quality of
During my adolescence in 1996, I was struck with the inability to eat. It felt like food was life and productivity (Box 2). Owing to the substantial
stuck in my chest beating a drum vigorously, a sensation that I could not quiet or stop. effects on eating function, patients with achalasia can
When I tried to swallow a morsel of food, pain radiated in my chest for 30 minutes.
be misdiagnosed with anorexia nervosa with or without
My condition worsened when I started experiencing severe chest spasms without
bulimia176. Anxiety and hypervigilance can be predic-
eating that were mistaken for heart attacks. After several normal endoscopies and
taking ineffective medication for acid reflux, I was told all symptoms were psychoso- tors of dysphagia severity in patients with oesophageal
matic. Months later, following barium studies and manometry, I was diagnosed with motility disorders177. Similarly, depression is a frequent
achalasia, a rare disease with no known cause or cure. Watching everyone around me comorbidity in achalasia owing to the impairment of
eat, feeling the pangs of hunger, feeling like an alien is going to pop out of my chest at quality of life178. Thus, in addition to individual symp-
any moment, my teenage years became a boot camp for how to conceal pain. toms, measuring quality of life is important to guide
Various treatments were unsuccessful, including oesophageal botulinum toxin injec- treatment and evaluate treatment response in achalasia.
tions and pneumatic dilations. On a liquid diet, my weight decreased and I constantly A 10-item achalasia-specific quality of life question-
managed alienating pain. My first open surgery in 1997, a Heller myotomy, failed. naire (ASQ) measures disease-specific health-related
The second myotomy succeeded insofar that I could eat again. The chest spasms,
quality of life taking into account food tolerance,
my greatest foe, persisted. I carried in me an indiscriminate ticking time bomb that
dysphagia-related behaviour modifications, pain, heart-
exploded often and in any situation imaginable (driving, flying, hiking). I was prescribed
psychotropic medication for oesophageal hypersensitivity. When medication and burn, distress, lifestyle limitation and satisfaction 78.
water failed to temporarily calm my symptoms, I routinely visited the emergency room. ASQ scores demonstrate that quality of life correlates
In my wallet, I carried a letter from my doctor explaining what achalasia is to help other poorly with objective testing in achalasia179, indicating
physicians treat me. At this point, I had normalized the ‘near-death’ experience. that quality of life assessments are complementary to
In the mid-2000s, eating became more arduous again. My oesophagus was enlarging, objective tests and need to be considered when planning
becoming S-shaped, like a flat tyre folding on itself. Drinking 3.5 litres of water was nec- management. Management of achalasia improves quality
essary to push a meal down my uncooperative, winding oesophagus. In 2012, I faced the of life180,181, but a diagnosis of achalasia in childhood is
inevitable, an oesophagectomy. I have lived two lives: one with an oesophagus and one associated with continued impairment of quality of life
without. The latter has been easier. My relationship with food remains complicated, but I
into adulthood182.
can eat and the chest spasms have been vanquished. I can’t lay flat on my back or stom-
ach, my chest burns when I reach down to tie my shoes, I don’t love eating in public
(especially in nice restaurants with small cups for water), splitting the bill at a tapas res- Prognosis
taurant is laughably against my favour, I get passive-aggressive looks when I turn down Morbidity and mortality in achalasia, and consequently
food at social gatherings, but all of this barely registers in me because life with an the prognosis, are influenced by the complications of the
oesophagus was a nightmare, as if I was alone in space and no one could hear me scream. disease. Before the institution of effective treatment,
half of the patients with achalasia are at risk of malnu-
trition regardless of their weight183. Compared with the
mainly because diet restriction and food avoidance general population, there is an increased risk of aspira-
could lead to reduced scores in patients who restrict tion pneumonia (incidence rate ratio (IRR) 13.38, 95%
eating to lessen symptoms, which can explain the sub- CI 1.66–107.79), lower respiratory tract infection (IRR 1.33,
optimal reliability observed in some studies170,171. The 95% CI 1.05–1.70), oesophageal malignancy (IRR 5.22,
Eckardt score is also limited by a recall period, by equal 95% CI 1.88–14.45) and mortality (IRR 1.33 95%
weighting of all symptoms and by a lack of psychomet- CI 1.17–1.51)16.
rically validated cut-off thresholds for success or fail- The risk of oesophageal malignancy is hypothesized
ure. Other dysphagia scores used in achalasia include to be related to two factors. The first is poor oesoph-
the Achalasia Severity Score146, Vantrappen Dysphagia ageal clearance that promotes bacterial growth, chem-
Score172 and Watson Dysphagia Score173, but the sim- ical irritation and mucosal inflammation leading to
plicity of the Eckardt score makes it popular despite its dysplastic changes and development of squamous cell
limitations. carcinoma184. Additionally, increased oesophageal acid
The Brief Oesophageal Dysphagia Questionnaire exposure after achalasia treatment can lead to Barrett
(BEDQ) explores frequency and severity of dysphagia mucosa and oesophageal adenocarcinoma185. However,
for food of various consistencies (liquid, solid, soft) on the exact risk of oesophageal malignancy is not fully
5-point Likert scales addressing six items during the known, partly because of differences in study design
previous 14 days174. Two items measure the frequency and setting186. Although the absolute risk of oesophageal
of pain and coughing during swallowing in the previous cancer is low, the risk ratio of squamous cell carcinoma
14 days, again on 5-point Likert scales. The final two is estimated to be 72 times, and that of oesophageal ade-
items evaluate the number of food impactions last- nocarcinoma six times higher than that in the general
ing longer than 30 min and the number of emergency population185–188. Most malignancies are observed more
department visits over the previous year. The BEDQ is than 10 years after achalasia diagnosis. Male sex and
a rapid, reliable and validated tool to assess oesopha- Chagas disease are known to confer an increased risk
geal dysphagia regardless of the underlying mechanism. of malignancy, and the type of treatment and number of
The BEDQ may also be more sensitive than the Eckardt re-interventions continue to be debated as potential risk
score for manometric diagnoses175. Although the BEDQ factors189,190. Finally, the increased mortality in patients
is more precise than the Eckardt score in assessing dys- with achalasia reported by some studies16,17 remains
phagia, the Eckardt score is more inclusive, as it assesses controversial, as other studies did not find differences
regurgitation, chest pain and weight loss, which are in causes of death and life expectancy compared with
important achalasia symptoms. the general population18,165.

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Box 3 | Areas in need of further research of achalasia status (manometry, TBE, FLIP measure-
ments, oesophageal diameter and length) is highly var-
• Improved understanding of achalasia pathogenesis iable, future definitions of clinical response or success
• Detailed study of oesophageal biopsy, serum, DNA and RNA samples will preferably be based on a combination of PRO and
• Suitable animal model of achalasia objective measures. A validated ASQ for achalasia is
• Development of modern patient-reported outcome (PRO) questionnaire already available78.
• Predictors of non-response to initial treatment Although recent controlled trials showed high suc-
• Assessment of treatment response in childhood achalasia cess rates and low rates of adverse events in short-term
and medium-term evaluation, management of patients
• Improved objective evaluation of treatment response using modern tools
who do not respond to initial therapy remains a
• Evaluation of long-term consequences of per-oral endoscopic myotomy
challenge129,147. An increasingly common trend, espe-
• Screening and surveillance for dysplasia and cancer cially in centres with expertise in all therapeutic modal-
ities for achalasia, is the establishment of a benign
Outlook oesophageal motility multidisciplinary team (MDT) to
In view of the rarity of the condition, an international discuss complex cases192. Analyses of the currently avail-
and multicentre approach is essential for advancing our able data have failed to establish reliable predictors of
understanding of achalasia14–17 (Box 3). In the past dec- non-responsiveness to available treatments, and future
ade, several international multicentre trials have estab- international cohort studies will need to study objective
lished considerable efficacy of diverse available treatment measures from HRM, TBE and novel approaches, such
modalities129,147. Nevertheless, unanswered questions as FLIP, to establish clinically evaluable predictors of
remain, which will also require multicentre approaches. (poor) outcome. There is a relative paucity of outcome
A better understanding of the pathogenesis and predis- data in type 3 achalasia, which seems to be less respon-
position for achalasia, and evaluation of novel treatment sive to PD, especially in paediatric populations. Both
approaches, such as variants of POEM and robotically childhood and adult achalasia groups will benefit from
assisted oesophagocardiomyotomy, are needed120,166. international cohort studies, with or without a prede-
The pathogenesis of achalasia remains poorly fined treatment strategy (for example, surgical myotomy
understood. Evidence for genetic predisposition and compared with POEM in type 3 achalasia).
immune-mediated destruction of myenteric neurons, Achalasia is a lifelong disease and, therefore,
possibly triggered by a viral infection, exists, but a detailed long-term follow-up data are needed, especially when
understanding of disease triggers, insights into mecha- considering cancer risk of incompletely resolved achala-
nisms and pathways, and a suitable animal model are all sia and risk of GERD and its complications from POEM.
lacking191. A large-scale collection of biological samples The controlled clinical trials already preformed as well as
from patients with achalasia at different stages of the dis- new prospective cohort series need to aim for follow-up
ease is required to enhance our understanding, includ- periods beyond the range of 5 years129,147, which may also
ing serum and DNA samples and neuromuscular biopsy elucidate areas with lack of clarity or consensus in exist-
specimens obtained during POEM or LHM. Studying ing guidelines, such as the utility of endoscopic surveil-
biopsy specimens will be crucial to evaluate the presence lance for the detection of squamous carcinoma120,166. The
of viral material and to characterize involved immune increasing use of POEM generates a large population of
cell subtypes and their roles. Pathways that are activated patients at risk of GERD and its complications, including
near the myenteric plexus can be studied using bulk RNA Barrett oesophagus and adenocarcinoma, which could
sequencing, cytokine and other immune signalling medi- justify endoscopic follow-up assessments in their own
ator expression assessment and more-targeted single-cell right. Finally, one of the long-term treatment goals of
RNA sequencing. These insights are essential before achalasia is the prevention of deterioration to a dilated
immune-targeted or neuronal stem cell approaches can and tortuous oesophagus. For all these reasons, endo-
be considered for managing achalasia early in the disease scopic interval follow-up could be needed, but needs to
and in the long term. be supported with evidence. Prospective studies can add
The primary outcome variable for evaluation image enhancement for detection of squamous carci-
of achalasia treatment efficacy in all recent trials is noma and FLIP or other techniques to quantify oesoph-
symptom based, using the Eckardt score129,147. This ageal diameter, enabling identification of the achalasia
long-established score was not developed or validated population with the highest screening yield and the
according to current standards for PRO generation, and appropriate screening interval. Specifically for POEM,
there is a clear need to develop a modern PRO ques- the role of maintenance proton pump inhibitor therapy
tionnaire for achalasia, for application in future trials. and the risk of developing oesophagitis, strictures or
This process is probably best coordinated through an Barrett oesophagus needs prospective follow-up data193.
international scientific organization. Moreover, as the
relationship between symptoms and objective measures Published online xx xx xxxx

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