Evolution of esophageal function testing in achalasia: Linking new technology to treatment outcome

Achalasia, meaning “failure to relax” in Greek, is the most investigated primary esophageal motility disorder involving the smooth muscle of the esophageal body and lower esophageal sphincter (LES). Recent decades have witnessed a great stride toward better understanding and management of this old but rare disease. However, the exact etiology and pathogenesis of achalasia remain elusive. Lines of evidence show that an initial insult, such as HSV-1 infection, to the esophagus and esophagogastric junction might trigger an inflammatory process in the myenteric plexus, which may be followed by autoimmune responses, resulting in neurodegeneration with loss of inhibitory neurons. The histopathology of achalasia further demonstrates degeneration of ganglion cells, especially inhibitory neurons, in the myenteric plexus of the esophageal body and LES. It has been proposed that dysfunction of the nitrergic pathway might cause LES hypertension and impaired relaxation in achalasia [1] .

With progressive dysphagia to both solid and liquid food, achalasia affects patients not only physically but also psychologically. Chest pain, heartburn, regurgitation and weight loss may also occur. Abnormal food intake is usually accompanied by behavior accommodation such as slow eating, water/soup drinking after meals, stereotactic movements and social avoidance. Endoscopy is commonly the initial modality used to search for the causes of dysphagia. However, the esophagus may show minimal change or appear to be completely normal. Therefore, the diagnosis of achalasia is usually delayed until typical findings of the “bird-beak” appearance of the LES and marked dilated esophagus are shown on barium esophagogram. Currently, esophageal manometry, which demonstrates the characteristic aperistalsis, LES hypertension and poor LES relaxation, remains the gold standard in the diagnosis of achalasia. Recently, multichannel intraluminal impedance (MII) monitoring has gained popularity not only as a reflux detection tool but also as a novel method for examining esophageal bolus transport without radiation exposure. Esophageal impedance monitoring measures the difference in impedance (resistance) to alternating electrical currents generated between pairs of electrodes mounted on a non-conductive catheter. Luminal content with high ionic concentration has low impedance and air has high impedance. Therefore, the impedance level drops when a liquid bolus passes and increases when air passes. The direction of movement of intra-esophageal material can thus be identified as antegrade or retrograde. When MII and esophageal manometry are integrated into the same diagnostic device—combined “MII-EM”—the new technique not only assesses the peristaltic patterns of the esophagus but also better characterizes the actual bolus movement. Several different features of bolus transport can be obtained with combined MII-EM, including patterns/parameters of bolus transport and swallow-related events. Taking advantage of these functions, MII-EM provides better evaluation of global esophageal function than conventional standard esophageal manometry, which mainly assesses pressure changes in the esophageal body and LES [2] .

In this issue of the Journal, Lei et al. [3] report the first observational study of combined MII-EM in Taiwanese patients with achalasia. Although the case number was relatively small, the authors confirmed that patients with achalasia were characterized by poor esophageal contraction and absent esophageal bolus clearance. They also clearly demonstrated a low baseline impedance level in the distal esophagus and air entrapment in the proximal esophagus in all achalasia patients. Since intraluminal impedance is inversely related to the electrical conductivity of the luminal contents and the cross-sectional area, an extremely low impedance level was invariably found in the markedly dilated and fluid-accumulated esophagus. Such findings of low baseline impedance level and air trapping were consistent with several previous studies and suggest that the utility of combined MII-EM in the evaluation of esophageal motility in achalasia patients may be limited [4] ; [5]  ;  [6] . A retrospective review of 73 MII-EM tracings from patients with achalasia showed that most patients have elevated LES residual pressure, normal LES pressure, and low baseline impedance. Nonetheless, the authors suggested that low impedance values identified chronic fluid retention in the lower esophagus and help to confirm the diagnosis [7] . In another retrospective analysis comparing MII-EM tracings from patients with achalasia and scleroderma, Mainie et al. confirmed that combined MII-EM could characterize the difference in segmental bolus stasis in these two groups of patients by detecting impaired bolus transit [8] . Both studies highlight the clinical value of MII-EM in the evaluation of achalasia. Although treatment outcomes were not assessed by Lei et al. [3] , another important finding was that low baseline impedance levels and incomplete bolus transit were still noted in both patients who had undergone Heller myotomy. At present, management of primary achalasia focuses on the disruption or weakening of the LES to lower LES pressure. Treatment options include pharmacotherapy, botulinum toxin injection, endoscopic pneumatic dilation and surgical myotomy of the LES, which has been extensively reviewed elsewhere [9] . Among them, endoscopic pneumatic dilation and myotomy have been proposed as effective first-line therapeutic modalities for achalasia, with similar efficacy [10] . However, both interventions for achalasia mainly disrupt the LES without affecting the esophageal body, and whether or not they have beneficial effects on the regaining of esophageal function remains widely debated. Some restoration in peristalsis as well as improved bolus clearance after Heller myotomy for achalasia has been described by Tatum et al. [11] . More studies are needed to clarify this important issue.

The recent introduction of high-resolution manometry (HRM), assembled with 36 solid-state sensors at much shorter intervals (1 cm), provides a more convenient and comprehensive evaluation of esophageal motor function. Moreover, according to the updated Chicago classification criteria of esophageal motility disorders, achalasia can be further categorized with HRM into three subtypes: achalasia with minimal esophageal pressurization (type I, classic), achalasia with esophageal compression (type II), and achalasia with spasm (type III) [12] . These subtypes are closely related to the treatment outcomes of medical or surgical therapies [13] . Although the impedance technique alone seems to be less suitable for the clinical evaluation of achalasia, combined HRM and impedance (HRIM) has been found to have excellent agreement with timed barium esophagogram for assessing bolus retention at 5 minutes, and has been suggested as a single test to assess bolus retention and motor function in the management of achalasia [14] . A recent study further showed that the addition of automated integrated analysis of impedance and pressure signals was more sensitive in detecting subtle abnormalities in esophageal function in patients with non-obstructive dysphagia and normal manometry compared with conventional pressure-impedance assessment [15] .

A vast amount of knowledge on the basic and clinical aspects of primary achalasia, mostly from observations of human and animal mutant models, has accumulated in recent decades. Since achalasia is a chronic and progressive disease, early diagnosis and intervention before the clinical onset of esophageal dysmotility to ameliorate the deterioration in esophageal function is the goal of future research. Although combined MII-EM seems to add little further information for the management of achalasia, it remains a useful tool for simultaneously assessing bolus transit and associated muscular peristaltic patterns in many other esophageal motility disorders. With advances in technology, many novel techniques have been developed and applied in the diagnosis and evaluation of various esophageal motility disorders. Nonetheless, several technical aspects may still need to be refined and standardized, such as study algorithms, test substances (volume, viscosity) and body position (supine, upright). In the future, more outcome studies to test the feasibility and predictability of these new techniques are warranted before they can be applied in our daily practice.

Conflicts of interest

The authors declare that they have no potential, perceived, or real conflicts of interest.

References

1. [1] G. Di Nardo, C. Blandizzi, U. Volta, R. Colucci, V. Stanghellini, G. Barbara, et al.; Review article: molecular, pathological and therapeutic features of human enteric neuropathies; Aliment Pharmacol Ther, 28 (2008), pp. 25–42
2. [2] H.N. Nguyen, G.R. Domingues, F. Lammert; Technological insights: combined impedance manometry for esophageal motility testing—current results and further implications; World J Gastroenterol, 12 (2006), pp. 6266–6273
3. [3] W.Y. Lei, W.L. Lo, C.H. Yi, T.T. Liu, C.L. Chen; Assesment of esophageal motor function using combined multichannel intraluminal impedance and manometry in patients with achalasia; Adv Dig Med, 1 (2014), pp. 43–49
4. [4] H.N. Nguyen, G.R. Domingues, R. Winograd, F. Lammert, J. Silny, S. Matern; Impedance characteristics of esophageal motor function in achalasia; Dis Esophagus, 17 (2004), pp. 44–50
5. [5] J.M. Conchillo, M. Selimah, A.J. Bredenoord, M. Samsom, A.J. Smout; Assessment of oesophageal emptying in achalasia patients by intraluminal impedance monitoring; Neurogastroenterol Motil, 18 (2006), pp. 971–977
6. [6] N.G. Burgess, J.W. Wyeth; An audit of combined multichannel intraluminal impedance manometry in the assessment of dysphagia; J Gastroenterol Hepatol, 26 (Suppl. 3) (2011), pp. 79–82
7. [7] A. Agrawal, A. Hila, R. Tutuian, D.O. Castell; Manometry and impedance characteristics of achalasia. Facts and myths; J Clin Gastroenterol, 42 (2008), pp. 266–270
8. [8] I. Mainie, R. Tutuian, A. Patel, D.O. Castell; Regional esophageal dysfunction in scleroderma and achalasia using multichannel intraluminal impedance and manometry; Dig Dis Sci, 53 (2008), pp. 210–216
9. [9] S.K. Chuah, C.H. Chiu, W.C. Tai, J.H. Lee, H.I. Lu, C.S. Changchien, et al.; Current status in the treatment options for esophageal achalasia; World J Gastroenterol, 19 (2013), pp. 5421–5429
10. [10] S.K. Chuah, T.H. Hu, K.L. Wu, P.I. Hsu, W.C. Tai, Y.C. Chiu, et al.; Clinical remission in endoscope-guided pneumatic dilation for the treatment of esophageal achalasia: 7-year follow-up results of a prospective investigation; J Gastrointest Surg, 13 (2009), pp. 862–867
11. [11] R.P. Tatum, J.A. Wong, E.J. Figueredo, V. Martin, B.K. Oelschlager; Return of esophageal function after treatment for achalasia as determined by impedance-manometry; J Gastrointest Surg, 11 (2007), pp. 1403–1409
12. [12] A.J. Bredenoord, M. Fox, P.J. Kahrilas, J.E. Pandolfino, W. Schwizer, A.J. Smout; Chicago classification criteria of esophageal motility disorders defined in high resolution esophageal pressure topography; Neurogastroenterol Motil, 24 (Suppl. 1) (2012), pp. 57–65
13. [13] J.E. Pandolfino, M.A. Kwiatek, T. Nealis, W. Bulsiewicz, J. Post, P.J. Kahrilas; Achalasia: a new clinically relevant classification by high-resolution manometry; Gastroenterology, 135 (2008), pp. 1526–1533
14. [14] Y.K. Cho, A.M. Lipowska, F. Nicodeme, E.N. Teitelbaum, E.S. Hungness, E.R. Johnston, et al.; Assessing bolus retention in achalasia using high-resolution manometry with impedance: a comparator study with timed barium esophagram; Am J Gastroenterol (2014 Apr 8) https://doi.org/10.1038/ajg.2014.61 [Epub ahead of print]
15. [15] N.Q. Nguyen, R.H. Holloway, A.J. Smout, T.I. Omari; Automated impedance-manometry analysis detects esophageal motor dysfunction in patients who have non-obstructive dysphagia with normal manometry; Neurogastroenterol Motil, 25 (2013), pp. 238–245 e164