Interstitial Cells of Cajal Remodeling as a Mechanistic Insight Into the Natural History of Achalasia: Lessons From 3 Clinical Cases

TO THE EDITOR: We read with great interest recent case-based report in Journal of Neurogastroenterology and Motility describing the dynamic clinical course of achalasia. Taken together from another reports, these cases illustrate not only the progression of esophageal motor dysfunction but also the potential for partial remission, providing a unique window to consider the role of interstitial cells of Cajal (ICC) remodeling in disease evolution.

1. Martín et al¹ – Rapid Progression of Nonspecific Esophageal Motor Disorder to Type II Achalasia and Recovery of Peristalsis After Pneumatic Dilation

This case highlighted a patient who progressed from nonspecific esophageal motor disorder to type II achalasia, with subsequent partial recovery of peristalsis following pneumatic dilation. Importantly, the observation of functional recovery suggests that esophageal motor patterns are not irreversibly lost, raising the possibility of ICC network plasticity that can be re-engaged after therapeutic intervention.

2. Chen et al² – On the Origin of Rhythmic Contractile Activity of the Esophagus in Early Achalasia

This case showed spontaneous rhythmic, non-propulsive esophageal contractions (~7/min), independent of swallows that highlighted intrinsic rhythmic activity even when effective peristalsis is lost, suggest that critical neuromuscular elements—nitrergic neurons and ICC—may remain suppressed but viable in early stages, and could serve as scaffolds for restoring coordinated peristalsis if disease-modifying therapy were available.

3. Ma and Liu³ – A Case Illustrating the Natural Progression of Type III to Type II Achalasia

In this case, a transition from spastic contractions (type III) to pan-esophageal pressurization (type II) was documented. The shift underscores dynamic remodeling of excitatory and inhibitory neural input interacting with ICC networks. The evolving motor pattern suggests that ICC may mediate compensatory mechanisms, shaping clinical manifestations over time.

Integrative Perspective

These 3 reports together support the view that achalasia is not simply a static outcome of irreversible neuronal loss but rather a dynamic process involving remodeling of ICC and their interaction with the enteric nervous system. Table from early rhythmic preservation to functional recovery after dilation, ICC appear central to both the progression and potential remission phases of disease.

ICC remodeling as a mechanistic factor based on above cases is supported by histological studies in patients diagnosed with achalasia, in whom there is a decrease of neurons containing nitric oxide synthase and ICC.^2,4 We take those as a lesson for further mechanistic studies. Understanding ICC plasticity could guide development of therapies beyond purely mechanical approaches such as dilation or myotomy, perhaps targeting pathways of ICC preservation, regeneration, or reactivation.