C. Prakash Gyawali1, Jin Ye Yeo2
1Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA; 2AOE Editorial Office, AME Publishing Company
Correspondence to: Jin Ye Yeo. AOE Editorial Office, AME Publishing Company. Email: aoe@amegroups.com
This interview can be cited as: Gyawali CP, Yeo JY. Readers’ Choice: Author Interview with Dr. C. Prakash Gyawali. Ann Esophagus. 2024. Available from: https://aoe.amegroups.org/post/view/readers-rsquo-choice-author-interview-with-dr-c-prakash-gyawali.
Expert introduction
Dr. Gyawali is currently the Director of Neurogastroenterology and Motility, at the Division of Gastroenterology, Washington University School of Medicine, St. Louis, USA. He completed his internal medicine training first at Calicut Medical College in South India, and later at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, where he also completed his fellowship training in gastroenterology. Dr. Gyawali’s academic interests include esophageal motility disorders, gastroesophageal reflux disease, and functional disorders. He directs gastrointestinal motility centers affiliated with Washington University and is involved in motility testing using high-resolution manometry, esophageal ambulatory esophageal pH and impedance monitoring, wireless pH monitoring, and endoscopic functional lumen imaging probe (FLIP). Dr. Gyawali is also actively involved in clinical research involving neurogastroenterology and motility and has over 300 original publications. He has mentored a generation of medical students, internal medicine residents, and gastroenterology fellows in his career thus far.
Dr. Gyawali’s article, “Pathophysiology of achalasia”, published in our journal, has received an outstanding readership and entered the journal’s Most Read Article List.
Figure 1 Dr. C. Prakash Gyawali
Interview
AOE: What inspired you to pursue a career in gastroenterology, and how did you develop an interest in gastrointestinal motility disorders?
Dr. Gyawali: I have always been interested in the evaluation of symptoms and using new tools and tests to try and explain clinical symptoms in order to provide the most appropriate and personalized patient management. Gastroenterology offers a unique patient evaluation paradigm, where both clinical presentation and new tests are needed to provide a clinical opinion and to develop a management plan, and this is what drew me to gastroenterology. When I first arrived at Washington University in St. Louis, my mentor, Ray Clouse, was in the process of developing and testing high-resolution manometry (HRM). My work with Ray Clouse and his mentorship piqued my interest in gastrointestinal motility disorders, particularly esophageal disorders, and this is what initiated my career interest in benign esophageal disease.
AOE: Your article on the pathophysiology of achalasia garnered significant attention. What motivated you to write about this topic?
Dr. Gyawali: Achalasia has always been an intriguing clinical condition, and diagnosis as well as management are closely linked to pathophysiology. Besides, with the advent of HRM, diagnosis and subtyping of the condition have drastically changed. I was offered the opportunity to develop a review article describing the pathophysiology by one of the associate editors of AOE, and I was delighted to accept the invitation and write the article.
AOE: Achalasia can be difficult to diagnose due to its varied presentation and overlap with other esophageal disorders. Could you provide a brief overview of how the diagnostic approach to achalasia evolved over the years?
Dr. Gyawali: HRM has made an important contribution to the precision diagnosis of achalasia and the recognition of high-resolution manometry-based subtypes. More recently, the development of the functional lumen imaging probe (FLIP) has improved the sensitivity and specificity of the identification of obstructive motor disorders. With these two advances and the increasing use of the timed barium esophagogram (TBE) and barium pill swallow for evaluation of esophageal emptying in the upright position, the sensitivity and specificity of achalasia diagnosis have improved. In recent years, the fact that there may be under- and over-diagnosis of obstruction using HRM alone is better recognized, and the value of complementary evaluation using FLIP and/or TBE when the clinical picture suggests achalasia but HRM is inconclusive has improved our ability to diagnose achalasia.
From a management perspective, the introduction of peroral endoscopic myotomy (POEM) has revolutionized achalasia management. The utilization of this minimally invasive procedure has introduced precision and personalization in achalasia management. For instance, achalasia phenotypes with absent esophageal body peristalsis on the one hand, and phenotypes with intact esophageal body peristalsis on the other hand (so-called esophagogastric junction outflow obstruction, after confirmation of the diagnosis) can be offered a short POEM that only targets the abnormally relaxing lower esophageal sphincter (LES). At the other end of the spectrum, when there is premature or especially hypercontractile esophageal body peristalsis in addition to abnormal LES relaxation, a long POEM that targets the entire smooth muscle esophagus has the best chance of resolving esophageal transit symptoms. A short POEM has also been found to reduce the incidence of post-POEM reflux disease. Laparoscopic Heller myotomy and pneumatic dilation continue to be offered in scenarios where POEM is not available or feasible, and botulinum toxin injection remains an option in patients with poor surgical risk, but even these options can be offered on a personalized basis depending on the phenotype of the disorder.
AOE: You also discuss the role of inflammation in achalasia. How significant is the evidence linking chronic inflammation to disease progression, and do you anticipate any new therapeutic strategies targeting inflammation in achalasia treatment?
Dr. Gyawali: While there is definitive evidence that inflammation from an autoimmune basis is the starting point for the development of achalasia in predisposed individuals, this cannot be targeted for management since this occurs months to even years prior to the first clinical manifestation of achalasia. At present, there are no biomarkers that would diagnose an early achalasia phenotype, even in patients with minimal symptoms. Therefore, strategies directly targeting inflammation are not at the point of actionable clinical management of achalasia in the present day.
There is one important exception – where esophageal mucosal or muscle eosinophilia is demonstrated on biopsy. There are patients with an esophageal mucosal histological profile identical to eosinophilic esophagitis (EoE) who may have an obstructive motor disorder that fits one of the achalasia phenotypes. In such patients, treatments similar to those offered for EoE have the potential to improve symptoms by suppressing eosinophil-driven inflammation. Research continues in better identification of eosinophilic inflammation in achalasia and a better understanding of how eosinophilic inflammation can lead to achalasia.
While Chagas disease could also be considered a chronic inflammatory phenotype, by the time this manifests clinically, managements similar to traditional achalasia are needed in addition to treating the organism that causes Chagas disease (Trypanosoma cruzi).
AOE: What do you believe are the most promising areas of research that could lead to breakthroughs in the diagnosis or treatment of achalasia?
Dr. Gyawali: Better identification of the genotypes that are predisposed to achalasia and more precise recognition of how the etiopathogenesis of achalasia unfolds from seemingly unconnected viral infection to the destruction of myenteric neurons may lead to breakthroughs in the early diagnosis, and consequently the early management of achalasia. We also do not fully understand how chronic opioid medication use can cause an achalasia-like motor pattern in the esophagus, which may be reversible upon discontinuation of opioids. It is not clear why this only occurs in some but not all chronic opioid users and why agents that block opioid effects in the lower bowel (for management of opioid-induced constipation) do not impact opioid-induced esophageal dysmotility.
From a management standpoint, better precision in the identification of the pathophysiologic mechanism in each achalasia patient will lead to better utilization of POEM, particularly in tailoring POEM length in achalasia management. To this day, we do not have a pharmaceutical option that consistently blocks esophageal smooth muscle contraction and LES tone. While phosphodiesterase inhibitors have been studied for this role, the effects are not consistent and symptoms do not always improve.
AOE: As a leading researcher and clinician in the field of gastroenterology, what do you think are the most pressing unmet needs in the field of motility disorders?
Dr. Gyawali: We do not have a good understanding of which esophageal motility disorders are actionable in that something permanent done to the esophagus (similar to achalasia treatments) has the potential to improve symptoms, and which disorders benefit from treatments targeting symptoms rather than the underlying motor pattern. This distinction becomes particularly important when there is no evidence of abnormal LES relaxation or esophageal outflow obstruction on testing in the symptomatic patient. This is because esophageal hypersensitivity and hypervigilance can be the underlying mechanism of many patients with esophageal symptoms, and non-achalasia motility disorders, in particular, may be bystanders rather than the direct cause of symptoms. Research to better define the reason why obstructive esophageal symptoms sometimes develop even in the absence of demonstrable obstruction, and how to best manage symptoms in this context are sorely needed.
Finally, we do not have good therapeutics for esophageal motility disorders beyond the management of achalasia and obstructive phenotypes.
AOE: What are your current research projects, and what goals do you hope to achieve in your ongoing studies?
Dr. Gyawali: My research centers on using modern diagnostic tools to better characterize and explain esophageal symptoms, and on defining disease phenotypes using these modern tools. My group continues to work on developing clinical scores calculated from metrics from esophageal tests to simplify the utilization of these diagnostic tests by the average clinician, particularly within the reflux realm. We have several multi-center studies designed to understand the role of esophageal hypervigilance and affective disorders in symptomatic patients, and if targeting these can improve symptoms. We continue to study targeted and personalized management of esophageal disorders, including achalasia, gastroesophageal reflux disease, and functional esophageal disorders.