Robert J. Washabau, VMD, PhD, DACVIM
Professor of Medicine and Department Chair, Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota
St. Paul, MN, USA
Canine Idiopathic Megaesophagus
Idiopathic megaesophagus is the most common cause of regurgitation in the dog. The disorder is characterized by esophageal hypomotility and dilation, progressive regurgitation, and loss of body condition. Several forms of the syndrome have been described, including congenital idiopathic, acquired secondary, and acquired idiopathic megaesophagus.
Congenital idiopathic megaesophagus is a generalized hypomotility and dilation of the esophagus causing regurgitation and failure to thrive in puppies shortly after weaning. An increased breed incidence has been reported in the Irish setter, Great Dane, German shepherd, Labrador retriever, Chinese Shar-Pei, and Newfoundland breeds, and autosomal dominant inheritance has been demonstrated in the Miniature Schnauzer and Fox terrier breeds. The pathogenesis of the congenital form is incompletely understood, although several studies have pointed to a defect in the vagal afferent innervation of the esophagus. Congenital idiopathic megaesophagus has been reported in several cats, and in one group of cats secondary to pyloric dysfunction. Acquired secondary megaesophagus may develop in association with a number of other conditions. Myasthenia gravis accounts for 25-30% of the secondary cases. In some cases of myasthenia gravis, regurgitation and weight loss may be the only presenting signs of the disease, whereas in most other cases of acquired secondary megaesophagus regurgitation is but one of many clinical signs including peripheral muscle weakness. Acquired secondary megaesophagus has also been associated with hypoadrenocorticism, lead poisoning, lupus myositis, and severe forms of esophagitis. Hypothyroidism has been suggested as a secondary cause of idiopathic megaesophagus but retrospective risk factor analysis has not identified it as an important cause.
Most cases of adult-onset megaesophagus have no known etiology and are referred to as acquired idiopathic megaesophagus. The syndrome occurs spontaneously in adult dogs between 7 to 15 years of age without sex or breed predilection. The disorder has been compared erroneously to esophageal achalasia in humans. Achalasia is a failure of relaxation of the lower esophageal sphincter and ineffective peristalsis of the esophageal body. A similar disorder has never been rigorously documented in the dog. Several important differences between idiopathic megaesophagus in the dog and achalasia in humans have been documented. Although the etiology(ies) has not been identified, some studies have suggested a defect in the afferent neural response to esophageal distension similar to what has been reported in congenital megaesophagus.
Routine hematology, serum biochemistry, and urinalysis should be performed in all cases to investigate possible secondary causes of megaesophagus (e.g., hypoadrenocorticism). Survey radiographs will be diagnostic for most cases of megaesophagus. Contrast radiographs may be necessary in some cases to confirm the diagnosis, evaluate motility, and exclude foreign bodies or obstruction as the cause of the megaesophagus. Endoscopy will confirm the diagnosis and may further reveal esophagitis, a frequent finding in canine idiopathic megaesophagus.
If acquired secondary megaesophagus is suspected, additional diagnostic tests should be considered, for example: serology for nicotinic acetylcholine receptor antibody, ACTH stimulation, serology for antinuclear antibody, serum creatine phosphokinase activity, electromyography and nerve conduction velocity, and muscle and nerve biopsy. Additional medical investigation will be dependent upon the individual case presentation. Hypothyroidism has been cited as an important cause of idiopathic megaesophagus in the dog, although risk factor analysis has not revealed a clear association. Thyroid function testing (e.g., TSH assay, TSH stimulation, free and total thyroid hormones) should be performed in individual suspicious cases.
Animals with secondary acquired megaesophagus should be appropriately differentiated from other esophageal disorders and treated. Dogs affected with myasthenia gravis should be treated with pyridostigmine (1.0-3.0 mg/kg PO BID) and/or corticosteroids (prednisone 1.0-2.0 mg/kg PO or SQ BID), dogs affected with hypothyroidism should be treated with levothyroxine (22 µg/kg PO BID), and dogs affected with polymyositis should be treated with prednisone (1.0-2.0 mg/kg PO BID). If secondary disease can be excluded, therapy for the congenital or acquired idiopathic megaesophagus patient should be directed at nutritional management and treatment of aspiration pneumonia. Affected animals should be fed a high-calorie diet, in small frequent feedings, from an elevated or upright position to take advantage of gravity drainage through a non-peristaltic esophagus. Dietary consistency should be formulated to produce the fewest clinical signs. Some animals handle liquid diets quite well, while others do better with solid meals. Animals that cannot maintain adequate nutritional balance with oral intake should be fed by temporary or permanent tube gastrostomy. Gastrostomy tubes can be placed surgically or percutaneously with endoscopic guidance.
Pulmonary infections should be identified by culture and sensitivity, and an appropriate antibiotic selected for the offending organism(s). This may be accomplished by trans- or endo-tracheal wash or by bronchoalveolar lavage at the time of endoscopy.
Smooth muscle prokinetic (e.g., metoclopramide or cisapride) therapy has been advocated for stimulating esophageal peristalsis in affected animals, however metoclopramide and cisapride will not likely have much of an effect on the striated muscle of the canine esophageal body. Bethanechol has been shown to stimulate esophageal propagating contractions in some affected dogs and is therefore a more appropriate prokinetic agent for the therapy of this disorder. Because of the high incidence of esophagitis in canine idiopathic megaesophagus, affected animals should also be medicated with oral sucralfate suspensions (1 g q8h for large dogs, 0.5 g q 8h for smaller dogs, 0.25 to 0.5 g q8h to q12h for cats).
Animals with congenital idiopathic megaesophagus have a fair prognosis. With adequate attention to caloric needs and episodes of aspiration pneumonia, many animals will develop improved esophageal motility over several months. Pet owners must be committed to months of physical therapy and nutritional support. The morbidity and mortality of acquired idiopathic megaesophagus remain unacceptably high.
Gastric Emptying Disorders
Gastric emptying disorders are fairly common in dogs and cats. They result from disease processes that alter normal gastric functions, i.e., storage of ingesta, mixing and dispersion of food particles, and timely emptying of gastric contents into the small intestine. Disorders of gastric emptying arise from mechanical obstruction, or from defective propulsion. Anatomic lesions (e.g., malignancy, hyperplasia, foreign bodies) cause delayed gastric emptying because of mechanical obstruction. Diagnosis and management of mechanical obstruction is usually straight-forward. Disorders of defective propulsion, on the other hand, cause delayed gastric emptying because of abnormalities in myenteric neuronal or gastric smooth muscle function, or because of abnormalities in antropyloroduodenal coordination. A number of primary conditions have been associated with these functional disorders, including infectious or inflammatory disease, ulcer, and post-surgical gastroparesis. Delayed gastric emptying has also been associated with a number of secondary conditions, including electrolyte disturbances, metabolic disorders, concurrent drug usage (cholinergic antagonists, adrenergic agonists, opioid agonists), acute stress, and acute abdominal inflammation. Recovery from gastric dilation/volvulus is almost always associated with significant myoelectrical and motor abnormalities in the dog. Diagnosis and management of the delayed gastric emptying disorders may not be so straight-forward. Nutritional and medical management, including smooth muscle prokinetic agents (e.g., cisapride, erythromycin, and ranitidine), are important components of therapy.
Small Intestinal Transit Disorders
A number of small intestinal transit disorders have been described in dogs and cats, including enteritis, post-surgical pseudo-obstruction, nematode infection, intestinal sclerosis, and radiation enteritis. Vomiting and diarrhea are the most important clinical signs associated with these disorders. Overgrowth of small intestinal bacteria, a common sequela to disordered motility, contributes to these clinical signs. Transit disorders associated with mechanical obstruction should always be differentiated and treated appropriately. Delayed transit associated with functional disorders should be managed with dietary modification (low fat diets) and prokinetic agents (cisapride, tegaserod, or metoclopramide). Tegaserod, a new 5-HT4 partial agonist, has recently been reported to normalize intestinal transit in opioid-induced bowel dysfunction in dogs.
Colonic Motility Disorders
Constipation, obstipation, and megacolon may be observed in cats of any age, sex, or breed, however, most cases are observed in middle aged (mean = 5.8 years), male cats (70% male, 30% female) of Domestic Shorthair (46%), Domestic Longhair (15%), or Siamese (12%) breeding. Affected cats are usually presented for reduced, absent, or painful defecation for a period of time ranging from days to weeks or months. Some cats are observed making multiple, unproductive attempts to defecate in the litter box, while other cats may sit in the litter box for prolonged periods of time without assuming a defecation posture. Dry, hardened feces are observed inside and outside of the litter box. Occasionally, chronically constipated cats have intermittent episodes of hematochezia or diarrhea due to the mucosal irritant effect of dehydrated feces.
Colonic impaction is a consistent physical examination finding in affected cats. Other findings will depend upon the severity and pathogenesis of constipation. Dehydration, weight loss, debilitation, abdominal pain, and mild to moderate mesenteric lymphadenopathy may be observed in cats with severe idiopathic megacolon. Colonic impaction may be so severe in such cases as to render it difficult to differentiate impaction from colonic, mesenteric, or other abdominal neoplasia. Cats with constipation due to dysautonomia may have other signs of autonomic nervous system failure, such as urinary and fecal incontinence, regurgitation due to megaesophagus, mydriasis, decreased lacrimation, prolapse of the nictitating membrane, and bradycardia. Digital rectal examination should be carefully performed with sedation or anesthesia especially in those cats with recurring bouts of constipation. Pelvic fracture malunion may be detected on rectal examination in cats with pelvic trauma. Rectal examination might also identify other unusual causes of constipation, such as foreign bodies, rectal diverticula, stricture, inflammation, or neoplasia. Chronic tenesmus may be associated with perineal herniation in some cases. A complete neurologic examination with special emphasis on caudal spinal cord function should be performed to identify neurologic causes of constipation, e.g., spinal cord injury, pelvic nerve trauma, and Manx sacral spinal cord deformity.
Several authors have emphasized the importance of considering an extensive list of differential diagnoses (e.g., neuromuscular, mechanical, inflammatory, metabolic/endocrine, pharmacologic, environmental, and behavioral causes) for the obstipated cat. A review of published cases, however, suggests that 96% of cases of obstipation are accounted for by idiopathic megacolon (62%), pelvic canal stenosis (23%), nerve injury (6%), or Manx sacral spinal cord deformity (5%). A smaller number of cases are accounted for by complications of colopexy (1%) and colonic neoplasia (1%); colonic hypo- or aganglionosis was suspected, but not proved, in another 2% of cases. Inflammatory, pharmacologic, and environmental/behavioral causes were not cited as predisposing factors in any of the original case reports. Endocrine factors (obesity, n=5; hypothyroidism, n=1) were cited in several cases, but were not necessarily impugned as part of the pathogenesis of megacolon.
The pathogenesis of idiopathic megacolon has been historically attributed to a primary neurogenic or degenerative neuromuscular disorder. While it seems clear that a small number of cases (11%) result from neurologic disease, the vast majority (>90%) of cases have no evidence of neurologic disease. Some of the idiopathic cases may instead involve disturbances of colonic smooth muscle as suggested by several studies. In vitro isometric stress measurements were performed on colonic smooth muscle segments obtained from cats suffering from idiopathic dilated megacolon. These studies suggested that the disorder of feline idiopathic megacolon is a generalized dysfunction of colonic smooth muscle, and that treatments aimed at stimulating colonic smooth muscle contraction might improve colonic motility.
The specific therapeutic plan will depend upon the severity of constipation and the underlying cause. Medical therapy may not be necessary with first episodes of constipation. First episodes are often transient and resolve without therapy. Affected animals should always be re-hydrated if dehydration has contributed to the onset of clinical signs. Mild to moderate or recurrent episodes of constipation usually require some medical intervention. These cases may be managed, often on an outpatient basis, with dietary modification, water enemas, oral or suppository laxatives, and/or colonic prokinetic agents. Severe cases of constipation usually require brief periods of hospitalization to correct metabolic abnormalities and to evacuate impacted feces using water enemas, manual extraction of retained feces, or both. Followup therapy in such cases is directed at correcting predisposing factors and preventing recurrence. Subtotal colectomy will become necessary in cats suffering from obstipation or idiopathic dilated megacolon. These cats, by definition, are unresponsive to medical therapy. Pelvic osteotomy without colectomy may be sufficient for some cats suffering from pelvic canal stenosis and hypertrophic megacolon.
NEW DEVELOPMENTS IN PROKINETIC THERAPY
Cisapride (Janssen Pharmaceutical)
Cisapride was widely used in the management of canine and feline gastric emptying, intestinal transit, and colonic motility disorders throughout most of the 1990's. Cisapride was withdrawn from the North American and certain Western European in July of 2000 following reports of untoward cardiac side effects in human patients. Cisapride causes QT interval prolongation and slowing of cardiac repolarization via blockade of the rapid component of the delayed rectifier potassium channel (IKr). This effect may result in a fatal ventricular arrhythmia referred to as torsades de pointes. Similar effects have been characterized in canine cardiac Purkinje fibers, but in vivo effects have not yet been reported in dogs or cats. The withdrawal of cisapride has created a clear need for new GI prokinetic agents although cisapride continues to be available from compounding pharmacies. Two new prokinetic agents, prucalopride and tegaserod, are in differing stages of drug development and may prove useful in the therapy of GI. motility disorders of several animal (dog, cat, horse) species.
Tegaserod (SDZ HTF 919-Novartis Corporation)
Tegaserod is a potent partial non-benzamide agonist at 5-HT4 receptors and a weak agonist at 5-HT1D receptors. Tegaserod has definite prokinetic effects in the canine colon. Intravenous doses of tegaserod (0.03-0.3 mg/kg) accelerate colonic transit in dogs during the first hour after intravenous administration. The highest doses of tegaserod (0.1 and 0.3 mg/kg) have no greater efficacy than lower doses (0.03 mg/kg), suggesting the possibility that tegaserod may stimulate canine colonic motility through a receptor-independent mechanism, or that tegaserod may act at sites other than 5-HT4 receptors at higher doses.
The motor mechanisms responsible for tegaserod-induced canine colonic propulsion are unclear. High amplitude propagated phasic contractions are thought to be responsible for mass movements, but they were not observed during tegaserod infusion. Contraction, amplitude, and motility indices were not different postprandially among treatment groups, so the mechanism of the tegaserod effect will require more detailed investigation in the dog.
In vitro studies suggest that tegaserod does not prolong the QT interval or delay cardiac repolarization as has been occasionally reported with cisapride.
Clinical efficacy has been demonstrated in human motility disorders, and new drug approval was rewarded by the U.S. Food and Drug Administration in September 2002. Tegaserod has been marketed under the trade name of Zelnorm in the United States, and under the trade name of Zelmec in the United Kingdom.
Gastric effects of tegaserod have not been reported in the dog, so this drug may not prove as useful as cisapride in the treatment of delayed gastric emptying disorders. Tegaserod at doses of 3-6 mg/kg PO has been shown to normalize intestinal transit in opioid-induced bowel dysfunction in dogs, and it may be useful in other disorders of intestinal ileus or pseudo-obstruction.
Prucalopride (R093877--Janssen Pharmaceutical)
Prucalopride is a potent partial benzamide agonist at 5-HT4 receptors, but is without effect on other 5-HT receptors or cholinesterase enzyme activity. Prucalopride dose-dependently (0.02-1.25 mg/kg) stimulates giant migrating contractions (GMC's) and defecation in the dog. The prucalopride effect is observed most prominently in the first hour after administration, suggesting that the prucalopride effect is a direct effect on the colon rather than on total gut transit time. Oral and intravenous doses appear to be equipotent again implying a high oral bioavailability. Prucalopride also enhances defecation frequency in healthy cats. Cats treated with prucalopride at a dose of 0.64 mg/kg experience increased defecation within the first hour of administration. Fecal consistency is not altered by prucalopride at this dosage.
Prucalopride also appears to stimulate gastric emptying in the dog. In lidamidine-induced delayed gastric emptying in dogs, prucalopride (0.01-0.16 mg/kg) dose-dependently accelerates gastric emptying of dextrose solutions. The prucalopride effect is equipotent following oral and intravenous administration suggesting that prucalopride may have a high oral bioavailability.
Prucalopride has not yet been marketed in the United States or elsewhere.
Prostaglandin E1 analogues
Misoprostol is a prostaglandin E1 analogue that reduces the incidence of nonsteroidal anti-inflammatory drug-induced gastric injury. The main side effects of misoprostol therapy are abdominal discomfort, cramping, and diarrhea. Dog studies suggest that prostaglandins may initiate a giant migrating complex pattern and increase colonic propulsive activity. In vitro studies of misoprostol show that it stimulates feline and canine colonic smooth muscle contraction. Given its limited toxicity, misoprostol may be useful in dogs and cats with severe refractory constipation.
What Does the Future Hold for Companion Animal Prokinetic Therapy?
The 5-HT4 receptor appears to hold the most interest and promise for future drug development. 5-HT4 receptor activation can cause relaxation or contraction depending on the region, cell type, and animal species. In the dog, the effects of selective 5-HT4 receptor agonists suggest that these receptors are present on jejunal mucosa, ileal mucosa, gastric cholinergic neurons, and circular colonic smooth muscle cells. Increased motor activity following 5-HT4 receptor activation results from increased release of acetylcholine from cholinergic neurons, and relaxation results from 5-HT4 receptors on smooth muscle cells.
Development of 5-HT4 ligands is somewhat constrained by the effects these drugs have on cardiac 5-HT4 receptors and the delayed rectifier potassium channel (IKr). Some, but not all, 5-HT4 agonists prolong the QT interval and delay cardiac repolarization. Molecular biology experiments have revealed differences in the carboxyl terminus of smooth muscle and cardiac muscle 5-HT4 receptors, but these amino acids differences are distant from the receptor binding site. Thus, receptor sub-types may exist but they may not be important from a functional or therapeutic standpoint.