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Myotomy that alleviates the esophagogastric junction (EGJ) outflow obstruction in achalasia might improve peristalsis.
Two tertiary hospitals (Chicago, USA and Lyon, France)
Thirty patients (18 males; mean age 43 years, range 17-78) were included from 2004 to 2012: 8 type 1 achalasia (27%), 17 type 2 (57%) and 5 type 3 (16%) according to the Chicago Classification.
Esophageal high resolution manometry (HRM) before and after laparoscopic or endoscopic myotomy.
The integrity of peristalsis was characterized as intact, weak, frequent failed, absent, or premature contractions.
Whereas peristaltic fragments were evident only in patients with type 3 achalasia before treatment, intact, weak, or frequent failed peristalsis was encountered in 63% of type 1, 47% of type 2 and 80% of type 3 achalasia after myotomy. One type 3 patient had distal esophageal spasm after treatment. In patients with a post-myotomy integrated relaxation pressure (IRP) <15 mmHg, only 10 (40%) persisted in having absent peristalsis. Panesophageal pressurization disappeared after myotomy in 16 of 19 patients. In the 5 patients with post-myotomy IRP >15 mmHg, 4 had weak peristalsis and one had absent peristalsis.
Reduction or normalization of the EGJ relaxation pressure achieved by myotomy in achalasia patients was associated with partial recovery of peristalsis in some patients suggesting that the disease process progresses from the EGJ to the esophageal body. Whether or not the return of peristalsis is predictive of an improved therapeutic outcome requires further study.
Achalasia is characterized by impaired esophagogastric junction (EGJ) relaxation, absence of normally propagated peristaltic contractions, and absence of a structural explanation for these abnormalities 1. The pathogenesis of achalasia involves inflammation and dysfunction of the myenteric plexus within the lower esophageal sphincter (LES) and esophagus, particularly among post-ganglionic inhibitory neurons 2. This reduction in inhibition is responsible for impaired LES relaxation and may contribute to the peristaltic abnormalities also seen with this disorder.
Esophageal manometry is essential for the diagnosis of achalasia with the hallmark features being impaired deglutitive LES relaxation and the absence of normal peristalsis. The introduction of high resolution manometry (HRM) with esophageal pressure topography (EPT) has improved the sensitivity for diagnosing achalasia by improving the accuracy of measurement and reducing confounding recording artifacts, particularly, esophageal shortening and ‘pseudorelaxation’ 3. Moreover, what has become very apparent with EPT is that the defining criterion of absent normal peristalsis need not equate to the absence of pressurization in the esophagus. Rather, three clinically relevant subtypes of achalasia were recognized based on the pattern of esophageal contractility and pressurization associated with impaired deglutitive EGJ relaxation 4. Type 1 is characterized by absence of contractile activity and absence of pressurization, type 2 by panesophageal pressurization, and type 3 by premature contractions. Logistic regression analysis found that the presence of pan-esophageal pressurization was associated with good treatment response whereas type 3 was predictive of a relatively poor treatment response. These findings have been subsequently been confirmed by other investigators 5, 6.
As there is no treatment to restore normal function of the myenteric plexus, achalasia treatment aims to relieve dysphagia by alleviating EGJ obstruction7. Surgically, this can be achieved by myotomy, done laparoscopically or, more recently, by per-oral endoscopic myotomy (POEM) with promising results 8, 9. While myotomy is intended to eliminate EGJ outflow obstruction, its effect on distal esophageal contractility is less defined. Older literature suggests that peristalsis may return in some cases after achalasia treatment 10-12. For instance, Parilla et al reported the return of peristalsis in the mid esophagus in 24% and in the distal esophagus in 9% of patients after myotomy, especially with a more acute onset of dysphagia, less preoperative esophageal dilatation, and more contractility of the esophageal body 10. However, this issue has always been controversial. Patti et al. reported no relationship between the return of peristalsis and the timing of surgery. Moreover, this issue has not yet been addressed with respect to EPT and achalasia subtypes. Certainly, one would anticipate that markedly reducing EGJ outflow obstruction by myotomy would modify achalasia subtyping in some cases and result in patients no longer meeting diagnostic criteria for achalasia in others. The demonstration of type 2 achalasia, for instance, depends upon the existence of an EGJ outflow resistance of at least 30 mmHg, a condition that should not often occur after myotomy. Hence, the aim of this study was to characterize post-myotomy esophageal contractility in achalasia patients grouped according to their pre-treatment achalasia subtype.
We identified 30 patients with idiopathic achalasia who had high resolution manometry studies before and after myotomy from a consecutive series of clinical EPT studies conducted between August 2004 and January 2012 at two tertiary centers (Northwestern University, Chicago, USA, and Edouard Herriot Hospital, Lyon, France). Twenty patients from Chicago and 10 patients from Lyon were included. None of the patients had received any endoscopic or surgical treatment for achalasia prior to the first HRM. Patients were treated with surgical myotomy (Heller with or without fundoplication) or POEM. Patient characteristics at baseline are summarized in Table 1. A second HRM study was performed with a median delay of 2.4 months after myotomy (range 1-32 months). EPT studies and patients’ charts were reviewed retrospectively.
The study protocol for the retrospective analysis of EPT findings was approved by the Northwestern University Institutional Review Board (JEP). No ethical committee approval was required in France.
EPT studies were done with a 4.2 mm outer diameter solid-state assembly with 36 circumferential sensors spaced at 1-cm intervals (Given Imaging, Los Angeles, CA). Before recording, transducers were calibrated at 0 and 300 mmHg using externally applied pressure. Studies were done in a supine position after at least a 6-hour fasting period. The manometry catheter was placed transnasally and positioned to record from the hypopharynx to the stomach with about 3 intra-gastric sensors. The catheter was fixed in place by taping it to the nose. The manometry protocol included at least a 30-s period to assess basal sphincter pressure and ten 5-ml water swallows.
EPT studies were analyzed using ManoView™ analysis software (Given Imaging, Los Angeles, CA) before and after myotomy. EGJ pressures were analyzed during the resting period without swallowing for mean and expiratory pressure. EGJ relaxation pressure was evaluated using the integrated relaxation pressure (IRP) 13 and nadir pressure. The IRP quantifies EGJ relaxation both in completeness and persistence, reporting the mean EGJ pressure for the 4 seconds of most complete relaxation in the 10-second window after swallowing. The upper limit of normal for the IRP with this instrumentation is <15 mmHg 13.
Peristalsis distal to the transition zone was characterized by the integrity of the 20-mmHg isobaric contour 14. In pre-myotomy studies, peristalsis was considered failed if there was minimal (<3 cm) or absent 20 mmHg isobaric contour integrity. In instances that esophageal contractile activity was present distal to the transition zone, distal latency (DL) was measured from upper esophageal sphincter (UES) relaxation to the contractile deceleration point, demarcating the onset of contraction just proximal to the sphincter15,16. Pan-esophageal pressurization was defined as uniform 30-mmHg pressurization extending from the UES to the EGJ 17. Type 1 (classic achalasia) was defined by mean IRP >15 mmHg and 100% failed peristalsis; type 2 (achalasia with compression) defined by mean IRP >15 mmHg, no normal peristalsis, and pan-esophageal pressurization with ≥20% of swallows; type 3 as mean IRP >15 mmHg, no normal peristalsis, and rapid or premature (spastic) contractions with ≥20% of swallows 4. Although mean IRP <15 mmHg was the threshold for diagnosis, achalasia was diagnosed with an IRP of <15 mmHg if other investigations (barium swallow, endoscopy) were consistent with achalasia.
In studies done after myotomy, distal esophageal contractile activity was similarly assessed according to the integrity of the 20 mmHg isobaric contour. Peristalsis was absent if there was <3 cm integrity, scored as having a large defect if there was a break of >5 cm in the 20-mmHg isobaric contour, as having a small defect if there was a break >2 cm but <5 cm, and as intact if there was no break or a break of <2 cm. When contractile activity was present, the distal contractile integral (DCI) 18 and contractile front velocity (CFV) 16 were measured. The DCI summarizes the contractile vigor of the distal esophagus and is calculated as the product of the mean amplitude (greater than 20 mmHg) and the area of a box drawn to contain the distal contraction, expressed as mmHg-s-cm 19. The CFV, the velocity at which the contraction progresses in the distal esophagus, was estimated as the slope of a tangent drawn to skirt contractile segment between the transition zone and the contractile deceleration point 16. The criterion for pan-esophageal pressurization was that it be seen in at least 20% of swallows. Finally, the Chicago Classification was applied to the post myotomy EPT findings 17.
Pre-operative symptoms were collected by the surgeons during the pre-operative visit. Pre-operative barium esophagrams were available for 22 patients and graded as a non-dilated, dilated, or sigmoid esophagus.
Heller myotomy was performed laparoscopically in 24 patients and by open surgery in one patient who had previous abdominal surgery. Partial fundoplication (Dor or Toupet) was coupled with the myotomy in 16 patients (15 patients from Chicago and 1 from Lyon) whereas no fundoplication was done in 9 patients from Lyon. POEM was performed in 5 patients from Chicago.
Data were expressed as median (interquartile range) unless otherwise specified. Pre and post myotomy data were compared using the paired t-test. Categorical data among groups were compared using the Chi square test and continuous data were compared using the Mann Whitney or Kruskall Wallis tests. A p-value of less than 0.5 was considered as significant.
Pre and post treatment EGJ pressures are shown in Table 2. At baseline, resting expiratory EGJ pressure was greater in the Chicago patients (29 mmHg (23-33) vs 20 (15-22), p=0.02), whereas the other EGJ pressure metrics including IRP and nadir pressures were similar between the two centers. At baseline, the IRP was elevated (>15 mmHg) in all but 4 patients (2 type 1, 1 type 2, and 1 type 3).
After myotomy, the resting expiratory EGJ pressure decreased in all patients whereas mean resting EGJ pressure increased by 18% and 16% in two patients with type 2 achalasia whose Heller myotomy was associated with a fundoplication. Post-myotomy IRP was <15 mmHg in all but 5 patients. The IRP and nadir EGJ relaxation pressure decreased after myotomy in all patients. The decrease of EGJ pressures (resting or relaxation) did not differ among achalasia subtypes or treatment modalities (p>0.05, Kruskall Wallis test).
Prior to myotomy, esophageal contractility was present in the distal two-thirds of the esophagus only in the five patients with type 3 achalasia. In 3 cases, this contractile activity exhibited a reduced distal latency (DL<4.5 s) and in the other two cases the latency could not be measured because the contraction did not extend to the most distal esophagus.
After myotomy, esophageal contractility was observed in the distal two-thirds of the esophagus in seventeen patients (57%): 63% of type 1 patients, 47% of type 2 patients, and 80% of type 3 patients. Figure 1 illustrates examples of pre and post myotomy EPT studies of a patient with type 3 achalasia (panel A) and type 2 achalasia (panel B). Examples of different patterns of post-operative contractile activity are illustrated in Figure 2. In the context of Chicago Classification, these contractile patterns included ‘failed peristalsis’, ‘weak contractions with large breaks in the 20 mmHg isobaric contour’ and ‘premature contractions’. The median percentage of failed peristalsis per subject was 65 (0-100) and the median percentage of swallows with weak contractions with large breaks in the 20 mmHg isobaric contour was 5 (0-73). Breaks were predominantly localized in the distal esophagus, likely reflecting the proximal extent of the myotomy. Two patients had premature contractions: one with type 1 achalasia treated with Heller and fundoplication exhibited a single premature contraction and one had premature contractions with 50% of test swallows (type 3 treated with Heller and fundoplication). When a post-myotomy contraction was present, the average DCI per patient was 309 mmHg-s-cm (200-487). Having a dilated esophagus on the pre-operative esophagram was not predictive of post myotomy absent peristalsis (33% of patients with non-dilated esophagus vs 38% with dilated esophagus had absent peristalsis, p=0.58).
Before treatment, pan-esophageal pressurization was observed in all type 2 patients and concurrently with the defining contractility in two type 3 patients. After treatment, only 3 patients exhibited pan-esophageal pressurization. One patient treated with Heller myotomy without fundoplication exhibited panesophageal pressurization with 50% of swallows before and after myotomy. He had a post myotomy IRP of 7.5 mmHg, 40% of swallows with weak contractions (large breaks), 40% failed peristalsis, and 20% weak contractions with small breaks. The second patient (Heller with fundoplication) had 90% of swallows with pan-esophageal pressurization after treatment versus 100% before. The post-myotomy IRP was 16.3 mmHg and 100% of swallows were associated with weak contractions (large breaks). Finally, the third patient (Heller myotomy without fundoplication) had 30% of swallow with pan-esophageal pressurization after treatment versus 100% before, a post-myotomy IRP of 18.8 mmHg, 50% of swallows with weak contractions (large breaks), and 50% with failed peristalsis. With the caveat that only 3 patients had post-myotomy pan-esophageal pressurization, post-treatment mean EGJ pressure was greater in patients with persistent panesophageal pressurization than in patients without (median 28 vs 17, p=0.02). Expiratory EGJ pressure, IRP, and nadir EGJ relaxation pressure were not different in patients with or without pan-esophageal pressurization. The presence of a fundoplication did not influence the occurrence of pan-esophageal pressurization. Finally, none of the patients without pan-esophageal pressurization before treatment had pan-esophageal pressurization after myotomy.
Post-myotomy motility was classified according to the Chicago Classification 17. If the post myotomy IRP was >15 mmHg, patients were classified as an achalasia subtype or EGJ outflow obstruction pattern. The patients with IRP <15 mmHg but pan-esophageal pressurization were classified as having EGJ outflow obstruction. The distribution of post-myotomy esophageal motility is shown in Figure 3. The pattern of post-myotomy motility was not associated with a specific modality of treatment as evidenced in Figure 4.
The aim of this study was to characterize the effect of surgical or endoscopic myotomy on the esophageal contractility of achalasia patients who were subtyped prior to treatment according to the Chicago Classification. The major finding was than more than half of the twenty-six patients analyzed exhibited either some intact peristaltic contractions or some remnants of distal esophageal peristalsis in their post-treatment EPT study. Whether this resulted in their post-treatment classification as frequent failed peristalsis or weak peristalsis as opposed to EGJ outflow obstruction depended on how effectively the EGJ was obliterated by the myotomy. These findings suggest that EGJ outflow obstruction might play a role in occurrence of failed peristalsis in some achalasia patients.
Recovery of esophageal peristalsis after relieving EGJ obstruction provides an interesting perspective on achalasia pathogenesis. Degeneration of the myenteric plexus is a pathological feature of achalasia 20. This degeneration involves neurons localized both at the LES and in the smooth muscle esophagus. However, the pattern and intensity of inflammation is variable and the observation of functional recovery in the distal esophagus after myotomy suggests neuronal dysfunction limited to the LES might dominate in some achalasia patients. Indeed ‘short segment achalasia’ had been reported prior to the advent of HRM with EPT 21, but findings from the current study suggest that this is, perhaps, more common than previously recognized. In these cases the absent peristalsis observed prior to myotomy would be a consequence of EGJ obstruction. This phenomenon has been demonstrated in an animal model by Mittal et al. by placing calibrated ligatures around the LES of cats causing failed peristalsis with increasing degrees of outflow obstruction 22. Again in a cat model, Schneider at al observed a prompt return of peristalsis after ligature removal 23. In humans, the gastric Lap-Band might represent an analogous model of EGJ obstruction. Manometric features of achalasia have been observed in patients after implant of this device and normal peristalsis has been restored in some cases after band deflation or removal 24, 25 making another argument for the reversible effect of EGJ obstruction on esophageal peristalsis.
The persistence of absent peristalsis as opposed to partial recovery might also indicate progressive stages of the achalasia disease process. Supportive evidence for this hypothesis can be found in a pathological study by Goldblum et al 20. In what is still the most definitive analysis of achalasia neuropathology, those investigators reported that with ‘vigorous’ achalasia (preserved esophageal contractility) myenteric inflammation was associated with a normal numbers of ganglion cells without neural fibrosis. On the other hand, patients with classic achalasia had few or no ganglion cells with neural fibrosis. They concluded that inflammation was an early change in the evolution of the disease, eventually followed by loss of ganglion cells and neural fibrosis. Within this construct, recovery of peristalsis after myotomy might indicate myenteric plexus inflammation in the distal esophagus whereas persistent absent peristalsis might be observed in patients who had progressed toward or achieved aganglionosis. In support of this hypothesis, although demonstrable, post-myotomy peristalsis was usually characterized as weak with large breaks in the 20 mmHg isobaric contour and by a low DCI.
Pre-treatment achalasia subtype also had some bearing on the observed pattern of post-myotomy contractility. All of the type 3 patients exhibited either some intact peristalsis or premature contractions after myotomy. On the other hand, only three of seventeen type 2 patients and three of eight type 1 patients exhibited any post-treatment intact peristalsis. Although the numbers are small, these observations suggest that the type 3 patients have a different pattern of neuropathology, either more limited to the LES leading to some intact peristalsis after myotomy or more specifically selectively targeting inhibitory ganglionic neurons leading to distal esophageal spasm after myotomy.
Another consequence of myotomy was the complete disappearance of the type 2 pattern of achalasia. Panesophageal pressurization, the hallmark feature of type 2 achalasia, occurs secondary to contraction of the muscularis propria longitudinal muscle 26 in association with EGJ outflow obstruction leading to substantial intrabolus pressure spanning from the UES to the LES. A similar pattern of contraction may persist post-myotomy but if so, it would rarely be associated with the requisite 30 mmHg intrabolus pressure to qualify as panesophageal pressurization in the Chicago Classification because of the decreased EGJ pressure. Ascertaining whether or not that is the case and, for that matter, whether patients with type 1 and 3 achalasia exhibit a similar motor pattern would require further investigation.
This study had some important limitations. Due to its retrospective design, it was not possible to determine whether or not recovery of peristalsis was associated with an improved symptomatic outcome because there was no systematic pre and post-operative symptom evaluation. A study using impedance manometry showed that patients with some restoration of peristalsis after myotomy exhibited improved bolus clearance suggesting that might be the case 27. Future studies are planned to address this issue. Finally we did not observe an influence of pre-operative esophageal dilatation or surgical procedure on the return of esophageal contractile activity. However, the numbers of patients in each group were small and these findings will need to be reassessed in a larger series.
In conclusion, this study demonstrated that some degree of peristaltic contraction, not manometrically evident prior to myotomy, was frequently demonstrable in post-myotomy achalasia patients. The degree to which this is observed might be reflective of unique pathogenetic features, especially in type 3 achalasia, or might be reflective of the extent to which the neurodegenerative process has progressed. Alternatively, in some patients, the disease process may uniquely target the LES such that recovery of peristalsis is a consequence of relieving the outflow obstruction. Whether partial or complete recovery of peristalsis is associated with an improved therapeutic outcome will require further research using a prospective study design with systematic symptom evaluation using utilizing disease-specific validated instruments and that remains to be accomplished.
SR, FM, JEP, PJK designed the study and drafted the manuscript; SR, FM, GP, NS, EH acquisition of the data; SR, TN, FN analyzed the data; SR, FM, GP, JEP, PJK, TN, FN, NS, EH critically reviewed the manuscript and approved the final version
This work was supported by R01 DK56033 (PJK) and R01 DK079902 (JEP) from the National Institutes of Health, USA
Potential competing interests
SR and JEP have served as consultant for Given Imaging