Recurrent Gastric Dilatation and Intestinal Dysmotility Possibly Resulting from Autonomic Neuropathy in a Great Dane

Introduction

The purpose of this article is to document for the first time an autonomic neuropathy in a dog with recurrent gastric dilatation and intestinal dysmotility. To the authors’ knowledge, such a cause of recurrent gastric dilatation and dysmotility has not been previously explored and could open new directions for study of the pathogenesis of gastric dilatation in this species.

Case Report

A 5 yr old 45.8 kg spayed female Great Dane was evaluated for chronic and episodic gastric dilatation. The dog had been a patient of the clinic since she was 6 mo old and was current on all vaccinations. A prophylactic incisional gastropexy was performed by laparotomy at the time the dog was spayed at 7 mo of age. Beginning at 21 mo of age, the dog presented for five separate episodes of vomiting and small bowel diarrhea. At that time, hematologic and abdominal radiographic analyses were unremarkable and the dog typically responded to supportive treatment on an outpatient basis.

When she was 5 yr, the dog was presented for minor surgical removal of a small dermal mass. On physical examination, a thin body condition was noted (body condition score 2/5), which was reduced compared with previous visits when the dog had been at a more ideal body condition. When concern was expressed about the change in body condition, the owners reported a good appetite without obvious gastrointestinal problems and thought controlled feedings may be the cause. Routine presurgical laboratory screening included a complete blood cell count that was normal and serum biochemical analysis that showed mild elevations in alkaline phosphatase (ALP) (205 μkat/L; reference range, 20–150 μkat/L) and alanine aminotransferase (ALT) (283 μkat/L; reference range, 10–118 μkat/L). In-house pre- and postprandial (2 hr) bile acid tests were unremarkable. Surgical excision of the dermal mass was routine and anesthesia uneventful. Approximately 3 hr after the minor surgical procedure, gastric dilatation was noted. Abdominal radiographs showed a greatly distended stomach with the stomach in a normal position. During preparation for reinduction of anesthesia to relieve the gastric dilatation, a large amount of gas was expelled. Radiographs confirmed a reduction in gastric size. The dog was monitored overnight without further episodes of gastric dilatation before being discharged to the owners the following morning. The histopathologic diagnosis of the dermal mass was fibroadnexal dysplasia with pyogranulomatous dermatitis with complete excision.

Nine days later, the dog was again presented for abdominal distention, and recurrence of gastric dilatation was suspected. Serum biochemical analysis was performed, which revealed further increases in ALP (1,215 μkat/L) and ALT activities (381 μkat/L). The dog was discharged with metoclopramide (10 mg per os [PO] q 12 hr) and a gastrointestinal prescription diet^a. Feeding frequent, small meals was discussed extensively with the owner. The following day, the owner reported that abdominal distention was still present. On examination, a very distended abdomen was noted. Radiographs again confirmed gastric dilatation; however, free gas was additionally noted in the abdomen (Figures 1A, B). An emergency abdominal exploratory surgery was performed and a gastric rupture identified in the body of the stomach was repaired. Surgical biopsy specimens were collected from both the site of the gastric rupture and the liver and were submitted for histopathology.

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Histopathology revealed a lymphocytic-plasmacytic and fibrosing gastritis with myriad intralesional spiral bacteria, consistent with Helicobacter spp.¹ Based on those findings, treatment was initiated with a 2 wk course of triple therapy including amoxicillin (1,000 mg PO q 12 hr), metronidazole (750 mg PO q 12 hr), and bismuth subsalicylate (524 mg PO q 24 hr) based on published Helicobacter spp. treatment protocols.^2,3 Additional treatment included canine-derived probiotic Bifidobacterium animalis strain AHC7^b (one tablet PO q 12 hr). Histopathologic abnormalities in the liver included chronic, moderately severe and diffuse centrolobular hepatic degeneration and central vein fibrosis. Those changes were attributed to vascular damage associated with the 2 day episode of gastric distention. The vascular damage could explain the elevated ALP and ALT.

Two wk following surgery for gastric rupture, sutures were removed and the owner reported the dog was doing very well. On physical examination, the dog was still thin but had gained a small amount of weight (current weight, 46.7 kg). One wk after the triple therapy was discontinued, intestinal peristaltic waves were readily visible through the abdominal wall supporting intestinal dysmotility. A prescription gastrointestinal formula diet was again prescribed. Four days later, the dog was presented to the local veterinary emergency hospital for another episode of gastric dilatation. Radiographs confirmed severe gastric dilation. The dog was hospitalized, anesthetized, and a stomach tube was passed. Stomach contents contained sausage casings in addition to the prescription diet. Due to the dietary change, dietary indiscretion, recurrent gastric dilatation, and what was perceived to be success of the initial course of triple therapy, an additional course of triple therapy was reinstituted, along with the canine-derived probiotic Bifidobacterium animalis strain AHC7.

Referral for advanced diagnostics, including a dynamic fluoroscopic contrast gastrointestinal study, was strongly suggested throughout the course of treatment but declined by the owners. Following consultation with an internist at the local referral center, metoclopramide (15 mg PO q 8 hr) was added to the treatment protocol for potential motility abnormalities that may have been causing the multiple episodes of gastric dilatation. In addition, simethicone was administered PO to effect when episodes of gastric distention occurred. The condition appeared to stabilize for 2 wk but then another episode of gastric distention was noted. The owners administered simethicone at the onset of that episode and it appeared to resolve the condition.

Triple therapy was discontinued after 21 days of treatment with continuation of metoclopramide and the probiotic. The dog continued to have occasional episodes of mild abdominal distention that occurred postprandially. Although the body condition continued to deteriorate, the owners reported that the dog was active, eating well, and only uncomfortable during episodes of gastric distention. The diet was again changed from the gastrointestinal prescription diet^a to a novel protein diet^c in the event that food sensitivity was the cause of postprandial gastric distention. Due to the previously reported success of simethicone during an episode of gastric distention, simethicone was continued on an as-needed basis and eventually was used several times throughout the day as a preventative after feeding. All treatments were initially reported as successful by the owners, but typically gastric distention would occur within 2 wk of implementation.

Three and one-half mo later, the owners recorded a video that demonstrated intense intestinal peristaltic-like waves visible through the abdominal wall. Due to episodes of gastric distention following previous veterinary visits, the dog had not been evaluated in the clinic during the previous 1 mo. Additional diagnostic testing was elected in an attempt to identify an underlying nongastrointestinal cause for the recurrent episodes of gastric distention and intestinal dysmotility. The body weight decreased slightly to 45.4 kg; however, the loss of muscle mass was dramatic. The minimal loss of body weight with dramatic loss of muscle mass may have been a result of large amounts of fluid in the gastrointestinal tract.

Repeat in-house hematologic analysis, including a complete blood cell count and routine serum biochemical analysis showed a persistent mild elevation in ALP (237 μkat/L). Additional blood samples were submitted to an outside laboratory to evaluate the thyroid gland (i.e., total thyroxine, free thyroxine by equilibrium dialysis, and thyroid-stimulating hormone concentration) and adrenal gland (baseline cortisol only) function, serum trypsin-like immunoreactivity, pancreatic lipase immunoreactivity, and cobalamin and folate concentrations. Fecal samples were also submitted for ova and parasites with centrifugation and for Giardia by enzyme-linked immunosorbent assay. Shortly after leaving the clinic following sample collection, the dog had a severe episode of gastric distention, was sedated with propofol (200 mg IV), and a stomach tube was passed. A copious amount of gastric fluid was removed.

Abnormalities noted on endocrine testing included a low free thyroxine by equilibrium dialysis (5.2 pmol/L; reference range, 10.3–41.1), borderline total thyroxine (6.6 pmol/L; reference range, 6.4–41.1) and elevated thyroid-stimulating hormone (35 mU/L; reference range, 0–30) concentrations, suggesting hypothyroidism, although nonthyroidal illness could not be ruled out. Abnormalities noted on gastrointestinal testing included decreased trypsin-like immunoreactivity (4.6 µg/L; reference range, 5.7–45.2) and folate (16.3 nmol/L; reference range 17.4–55.3) concentrations consistent with chronic small intestinal disease.

Based on loss of muscle mass and the possibility of causes of gastric dilatation and intestinal dysmotility not yet investigated in veterinary medicine, an underlying neuromuscular disorder was considered as a potential cause for the dog’s condition. Muscle biopsies are easily performed and can be used to identify an underlying myopathy or neuropathy. A pattern of atrophy consistent with denervation can be identified with fiber typing. Intramuscular nerve branches within the muscle biopsy can also be evaluated for distal nerve fiber loss, which would support a peripheral neuropathy. Thus, unfixed chilled and formalin fixed biopsies were collected from the triceps brachii and vastus lateralis muscles, and submitted to the Comparative Neuromuscular Laboratory, University of California, San Diego. Unfixed biopsies were shipped under refrigeration and evaluated in cryosections by a standard panel of histochemic stains and reactions.⁴ Fixed biopsies were paraffin embedded. A neurogenic pattern of muscle fiber atrophy was evident in both the triceps and vastus lateralis muscles, and nerve fiber loss was observed within the most distal intramuscular nerve branches consistent with a polyneuropathy.

The dog continued to deteriorate, and the owners expressed concern over a change in respiration, including increased inspiratory and expiratory effort and occasional coughing. The generalized weakness progressively worsened. Following receipt of the muscle biopsy report and documentation of polyneuropathy, the owners elected euthanasia and a necropsy was performed. Grossly, the entire intestinal tract was dilated and fluid filled. The gastropexy site, performed at the time of spay, was intact and in the correct location. The lungs appeared hyperemic and were less pliable. A variety of tissues were collected and submitted for standard histopathologic analysis. In addition, the phrenic nerve, the left vagus nerve just caudal to the heart, and the sciatic nerve was fixed in 10% formalin and submitted to the Comparative Neuromuscular Laboratory for further evaluation.

Acute bronchopneumonia was evident on histologic evaluation of the lungs that was most likely a result of aspiration of stomach contents. Focal ulcerative and sclerosing pyloric gastritis was also evident that may have been a result of previous surgery. No other specific abnormalities were identified in other tissues including the colon, small intestine, gastric fundus, spleen, diaphragm, lymph nodes, pancreas, and esophagus. The muscular layers and the myenteric and submucosal plexuses in the stomach, small intestine, and colon were considered normal.

Fixed specimens from the phrenic, vagus, and sciatic nerves were resin embedded and evaluated in 1 µm semithin sections as previously described.⁵ Compared with an age-matched control, the vagus nerve showed severe loss of myelinated fibers with extensive endoneurial fibrosis and only small islands of myelinated nerve fibers remaining (Figures 2A, B). Regenerative changes, such as nerve fiber clusters and sprouts, were not observed. The extensive nerve fiber loss in the vagus nerve together with the denervation atrophy and nerve fiber loss within intramuscular nerve branches in the skeletal muscle biopsies were consistent with polyneuropathy and severe autonomic neuropathy. No specific abnormalities were identified in the phrenic and sciatic nerves (not shown). The absence of pathologic changes in those nerves could be explained by either a variable or multifocal distribution of pathology and severity of nerve involvement in different peripheral neuropathies, distal nerve fiber loss in Wallerian-like (axonal) degeneration with relative sparing of more proximal segments until late in the course of the disease, or selective involvement of specific nerves.

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Discussion

Clinical signs of chronic gastric dilatation and intestinal dysmotility and severe nerve fiber loss within the vagus nerve are consistent with a form of autonomic neuropathy. The autonomic division of the peripheral nervous system has two structural and functional components: the sympathetic and parasympathetic divisions. In addition to innervating the pharynx, larynx, and palate, the vagus nerve supplies parasympathetic motor and sensory fibers to the viscera of the body.⁶ Gastric disorders (vagal indigestion) are common in vagus nerve abnormalities in ruminants and can result in distention.⁷ The enteric division of the peripheral nervous system also exerts effects on digestive processes such as motility, secretion and absorption, and blood flow. The main components of the enteric nervous system are the myenteric plexuses located between the longitudinal and circular layers of smooth muscle and the submuscosal plexuses that innervate esophageal and intestinal smooth muscle. No abnormalities were identified in either the myenteric or submucosal plexuses of the esophagus, stomach, small intestine, or colon in this dog.

To the authors’ knowledge, this is the first report of chronic gastric distention and intestinal dysmotility possibly resulting from vagal neuropathy in a dog. In human medicine, many conditions have autonomic disturbances as one of the clinical symptoms, if not the primary symptom. However, few similar conditions have been described in animals. Selective autonomic disturbances have been recognized clinically in animals, but little is known about the cause.⁸ For example, idiopathic Horner's syndrome or pupillotonia occur with sympathetic and parasympathetic disturbances, respectively.^9,10 Megaesophagus can be a sole manifestation of myasthenia gravis but it can also occur as an idiopathic condition that could represent a selective autonomic neuropathy.^11,12 Diffuse autonomic failure can also occur secondary to a more generalized disease process, such as diabetes mellitus, dysautonomia, malignant neoplasms, or as an idiopathic condition.^8,13 In this dog, clinical signs were generally restricted to the gastrointestinal tract, although generalized weakness was described late in the course of the disease, and a neurogenic pattern of muscle fiber atrophy and distal nerve fiber loss was identified in the muscle biopsies consistent with a polyneuropathy.

In dogs, most studies looking into potential causes of gastric distention have focused on conformational, behavioral, dietary, and hereditary risk factors.^14–17 In this case, the dog exhibited many of the previously identified markers associated with an increased risk of gastric distention, including first-generation relative (sire) with a history of gastric distention, thin and lean body condition, chronic medical problems (such as inflammatory bowel disease with multiple episodes of vomiting and diarrhea), postprandial abdominal distension, and the dog was nervous and easily stressed.^15,16 The significance of possible hypothyroidism in this case is not known.

It is the authors’ opinion that neuromuscular disease and autonomic neuropathy should be considered as a potential cause of recurrent gastric distention in the dog. In this case, late in the course of the disease, severe muscle atrophy was noted that suggested an underlying neuromuscular disorder. Changes in histopathology and histochemistry within limb muscle biopsies were consistent with a distal polyneuropathy. Based on the authors’ findings, electrodiagnostics and peripheral nerve biopsy should be considered in the diagnostic work up of dogs with chronic and recurrent gastric dilatation and intestinal dysmotility. Concomitant sensory and/or motor involvement has been described in human autonomic neuropathies.¹³ The descriptions in human autonomic neuropathies prompted the evaluation of the phrenic and vagus nerves at necropsy leading to the identification of a vagal neuropathy.

Peripheral nerve diseases can be slowly progressive, and this dog lived for 2 yr after the onset of the initial episode of gastrointestinal disease. Recurrent gastric distention continued during the remainder of the dog’s life. At the time of the exploratory surgery (3 wk after the original episode of gastric distention) and again at necropsy, the original gastropexy site remained intact and in the correct position. The gastropexy may have contributed to the dog surviving multiple incidences of gastric distention and life threatening volvulus. Previous studies have looked at the benefit of gastropexy postgastric distention and the theoretical cost savings of a prophylactic gastropexy; however, there are no studies looking at the risks and benefits of prophylactic gastropexy and whether it actually decreases risk of either death or severity of the course of disease if a future episode of gastric distention occurs.^18,19 The dog also lived in a household where it was under 24 hr supervision; therefore, veterinary care could be initiated immediately if the clinical condition changed.

Conclusion

Recognition of a neuromuscular disease as a potential cause of recurrent gastric distention may allow for earlier diagnosis and identification of potential treatments. In this case, identification of an autonomic neuropathy occurred late in the course of the disease, and an underlying etiology could not be identified. Both sensory and motor polyneuropathies are well described in dogs; however, autonomic neuropathy is a previously unexplored cause of gastric dilatation and intestinal dysmotility in this species.²⁰ This likely represents either a failure to look for the signs of autonomic disturbance or dismissal of the signs as unrelated to the primary disease. The authors’ findings should open new directions for exploring pathogenic mechanisms for gastric dilatation in dogs.