Loss of Interstitial Cells of Cajal and Patterns of Gastric Dysrhythmia in Patients With Chronic Unexplained Nausea and Vomiting

Abstract

Background & aims: Chronic unexplained nausea and vomiting (CUNV) is a debilitating disease of unknown cause. Symptoms of CUNV substantially overlap with those of gastroparesis, therefore the diseases may share pathophysiologic features. We investigated this hypothesis by quantifying densities of interstitial cells of Cajal (ICCs) and mapping slow-wave abnormalities in patients with CUNV vs controls.

Methods: Clinical data and gastric biopsy specimens were collected from 9 consecutive patients with at least 6 months of continuous symptoms of CUNV but normal gastric emptying who were treated at the University of Mississippi Medical Center, and from 9 controls (individuals free of gastrointestinal disease or diabetes). ICCs were counted and ultrastructural analyses were performed on tissue samples. Slow-wave propagation profiles were defined by high-resolution electrical mapping (256 electrodes; 36 cm(2)). Results from patients with CUNV were compared with those of controls as well as patients with gastroparesis who were studied previously by identical methods.

Results: Patients with CUNV had fewer ICCs than controls (mean, 3.5 vs 5.6 bodies/field, respectively; P < .05), with mild ultrastructural abnormalities in the remaining ICCs. Slow-wave dysrhythmias were identified in all 9 subjects with CUNV vs only 1 of 9 controls. Dysrhythmias included abnormalities of initiation (stable ectopic pacemakers, unstable focal activities) and conduction (retrograde propagation, wavefront collisions, conduction blocks, and re-entry), operating across bradygastric, normal (range, 2.4-3.7 cycles/min), and tachygastric frequencies; dysrhythmias showed velocity anisotropy (mean, 3.3 mm/s longitudinal vs 7.6 mm/s circumferential; P < .01). ICCs were less depleted in patients with CUNV than in those with gastroparesis (mean, 3.5 vs 2.3 bodies/field, respectively; P < .05), but slow-wave dysrhythmias were similar between groups.

Conclusions: This study defined cellular and bioelectrical abnormalities in patients with CUNV, including the identification of slow-wave re-entry. Pathophysiologic features of CUNV were observed to be similar to those of gastroparesis, indicating that they could be spectra of the same disorder. These findings offer new insights into the pathogenesis of CUNV and may help to inform future treatments.

Keywords: Gastroparesis; High-Resolution Mapping; ICC; Slow-Wave.

Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Normal gastric slow wave propagation in a control. (A) Position of the array. (B) Electrograms from positions indicated in C (frequency, 2.8 ± 0.1 SD cycles/min). (C) Isochronal activation map of ‘Wave 1’ indicated in B, demonstrating normal antegrade propagation. Black dots represent electrodes, with white dots outlined red representing electrodes where activity was interpolated. Each color band shows the area of slow wave propagation per 2 seconds. (D) Velocity map of Wave 1, showing the speed (color spectrum) and direction (arrows) of the wavefront at each electrode. (E,F) Isochronal activation and velocity field maps of ‘Wave 2’ in B, demonstrating consistency of the antegrade propagation. See Supplementary Video 1 for animation.

Figure 2

(A,B) Representative images showing depletion of the ICC network in the gastric smooth muscle in a CUNV patient (A) compared to control (B). The red signal is Kit immunoreactivity marking ICC; the blue signal is 4’,6’-diamidino-2-phenylindone counterstain marking cellular nuclei. (C,D) Electron microscopy images showing mild ultrastructural abnormalities in a CUNV patient (C) compared to control (D). Labeled structural components: thick basal lamina (small astericks), nerve endings (NE), smooth muscle cells (SMC), lamellar body (LB), ICC-SMC contact (arrows), and peg-and-socket junction (large astericks).

Figure 3

Comparison of ICC density between CUNV patients and healthy controls. Data from a recent gastroparesis (GP) cohort (in grey) are also displayed for comparison.

Figure 4

Classification and occurrence of slow wave dysrhythmias mapped in CUNV patients. ‘N’ signifies normal frequency. There was one additional case (ID #5) of tachygastria of indeterminate origin, and a further case (ID #1) of apparent slow wave quiescence (see text).

Figure 5

Abnormal slow wave initiation and conduction; isochronal intervals = 1.5 seconds. (A) Position of the array. (B) Representative electrograms from positions indicated in C; propagation sequences are labeled based on their corresponding waves 1–4, shown in panels C–F. (C) Isochronal activation map. Slow wave activity propagated onto the array from the greater-curvature, colliding with an unstable focal activity on the distal portion of the array. (D) The unstable focal activity was consistent over a second cycle. (E) A new stable ectopic pacemaker emerged in the distal portion of the array (represented by a star), initiating retrograde propagation that collided with the uncoupled antegrade wavefront. Circumferential propagation was out-of-phase with distal activity that was propagating in the opposite direction circumferentially, resulting in a complete functional conduction block (thick black line). (F) Propagation repeated as described in E, with stability of the ectopic pacemaker and distal block that remained consistent through the end of the recording period. A frequency increase occurred between the unstable focal activity of C&D (bradygastric, 2.0 ± 0.1 cycles/min) and the stable ectopic activity of E&F (normal frequency, 3.2 ± 0.2 cycles/min). See Supplementary Video 2 for animation.

Figure 6

Slow wave re-entry; isochronal intervals = 2 seconds. (A) Position of the array. (B) Representative electrograms from positions indicated in C; electrode 1 is repeated at the bottom of the electrograms to illustrate the continuity of the re-entrant circuit. (C–E) Isochronal activation maps. Activation propagated in a circuit around a linear conduction block (thick black line), re-activating that same circuit over successive cycles, thereby establishing re-entry (frequency, 3.3 ± 0.2 cycles/min). Slow wave activity propagated outward from the re-entrant circuit, in part colliding with an uncoupled antegrade-propagating wavefront. See Supplementary Video 3 for animation.