The exact pathogenesis of DES is not fully understood. Current high-resolution manometric studies suggests impairment of inhibitory neurons. These inhibitory neurons use nitric oxide (NO) as neurotransmitter.

The exact pathogenesis of DES is not fully understood. However, current high-resolution manometric studies suggest impairment of inhibitory myenteric plexus neurons in DES.^[1] These neurons use nitric oxide (NO) as neurotransmitter.^[2] Hence, these patients may also have dysregulation of endogenous NO synthesis or/and degradation. Inhibitory neurotransmitters are nitric oxide (NO), vaso-active intestinal peptide (VIP) and ATP whereas excitatory neurotransmitter are acetyl choline (ACh), glutamate and substance P.^[3] Anti-ganglionic acetylcholine receptor antibodies (anti-gAChR-Abs) are reported in some cases.^[4] The final result is premature and rapidly propagated or simultaneous contraction of smooth muscles of distal esophagus.

There are reports of families with Achalasia and esophageal spasm which supports the hypothesis that genetic traits may play role in pathogenesis of DES as well as association between the two disorders.^[5] However, genetic inheritance is not fully established.

DES occurs in association with other motility disorders of esophagus like achalasia. Esophageal epiphrenic diverticulum is also commonly associated with DES.^[6]

On gross pathology, gross thickening of muscularis propria layer and LES than normal subjects are characteristic findings of DES.^[7] This gross thickening is due to hyperplasia (not hypertrophy).

On microscopic histopathological analysis, degeneration of vagal fibres, inflammatory infiltration of myenteric plexus, and hyperplasia of smooth muscles are characteristic findings of DES. Data on microscopic pathology of DES are limited due to rarity of disease and even less common need of surgery as a treatment.