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Todd R. Tams, DVM, DAVCIM VCA West Los Angeles Animal Hospital THE VOMITING DOG - DIAGNOSIS
Vomiting refers to a forceful ejection of gastric and occasionally proximal small intestinal contents through the mouth. The vomiting act involves three stages: nausea, retching, and vomiting. Serious consequences of vomiting include volume and electrolyte depletion, acid-base imbalance, and aspiration pneumonia. It is essential that the clinician make a clear differentiation between regurgitation and vomiting at the outset. Regurgitation is defined as passive, retrograde movement of ingested material, usually before it has reached the stomach. Failure to recognize the difference between regurgitation and vomiting often leads to misdiagnosis. Regurgitation may occur immediately after uptake of food or fluids or may be delayed for several hours or more. Clinical Features Of Vomiting Because of the wide variety of disorders and stimuli that can cause it, vomiting may present the clinician with a major diagnostic challenge. A complete historical review with emphasis on all body systems is essential for determining a realistic and effective initial work-up plan and treatment protocol. All too often concentration on only the gastrointestinal tract leads to an incorrect diagnosis and inappropriate treatment. Consideration of the following features is useful in assessing and diagnosing a patient with vomiting: (1) duration of signs, (2) signalment and past pertinent history, (3) environment and diet, (4) systems review (e.g., history of PU/PD, coughing and sneezing, dysuria or dyschezia, etc.), (5) time relation to eating (vomiting of undigested or partially digested food more than 8-10 hours after eating often indicates a gastric motility disorder [more common] or gastric outlet obstruction [less common]), (6) content of the vomitus (food, clear fluid, bile, blood, material with fecal odor), and (7) type and frequency of vomiting (projectile?, chronic intermittent?, cyclic?, morning vomiting only?). Most Common Causes of Acute or Chronic Vomiting in Dogs First need to Rule-Out: Dietary problems
Main Categories: Motility Disorders
Intermittent Chronic Vomiting Chronic intermittent vomiting is a common presenting complaint in veterinary medicine. Often there is no specific time relation to eating, the content of the vomitus varies, and the occurrence of vomiting may be very cyclic in nature. Depending on the disorder, other signs such as diarrhea, lethargy, inappetence, and salivation (nausea) may occur as well. When presented with this pattern of clinical signs, the clinician should strongly consider chronic gastritis, inflammatory bowel disease, irritable bowel syndrome, and gastric motility disorders as leading differential diagnoses. A detailed work-up including gastric and intestinal biopsies is often required for definitive diagnosis in these cases. It is important to note that chronic intermittent vomiting is a common clinical sign of inflammatory bowel disease in both dogs and cats. Vomiting from systemic or metabolic causes may be an acute or chronic sign and generally there is no direct correlation with eating and no predictable vomitus content. Diagnostic Plan Vomiting patients in some cases require an extensive work-up, but an organized approach will help to minimize the tests necessary for an early diagnosis. The most important initial considerations in determining what tests to perform are: (1) signalment, (2) acute (less than 3 to 4 days) versus chronic duration, (3) frequency of vomiting, (4) degree of symptoms (mild versus moderate to severe illness, i.e., life threatening, (5) other clinical signs (e.g., shock, melena, abdominal pain, etc.) and (6) physical examination findings. If reasonable concern is established, then a minimum data base of CBC, biochemical profile (or specific tests for evaluation of liver, kidney, pancreas, electrolytes), complete urinalysis (pre-treatment urine specific gravity extremely important for diagnosis of renal failure), and fecal examination is essential. Survey abdominal radiographs are indicated if thorough abdominal palpation is not possible or suggests an abnormality (e.g. foreign body, pancreatitis, pyometra). Unfortunately these tests are often not done early enough. Even if baseline results are unremarkable they are more than justified because they help to rule out serious problems at the outset (e.g., vomiting due to renal failure, diabetes mellitus, liver disease). Alternatively, any abnormalities provide direction for initial treatment and further diagnostics. The decision for performing more in-depth diagnostic tests is based on ongoing clinical signs, response to therapy, and initial test results. These tests include ACTH stimulation to confirm hypoadrenocorticism in a patient with an abnormal Na:K ratio or to investigate for this disorder if electrolytes are normal, complete barium series or BIPS study (for gastric or intestinal foreign body, gastric hypomotility, gastric outflow obstruction, partial or complete intestinal obstruction), cPLI* or fPLI*(canine and feline lipase immunoreactivity, respectively, for diagnosis of pancreatitis in dogs and cats), and serum bile acids assay (to assess for significant hepatic disease). Barium swallow with fluoroscopy is often necessary for diagnosis of hiatal hernia disorders and gastroesophageal reflux disease. Serum gastrin levels are run if a gastrinoma (Zollinger-Ellison Syndrome) is suspected. One of the most reliable and cost efficient diagnostic tools currently available for evaluation of vomiting is fiberoptic endoscopy. Endoscopy allows for direct gastric and duodenal examination, mucosal biopsy from these areas, and in many cases gastric foreign body retrieval. Endoscopy is considerably more reliable than barium series for diagnosis of gastric erosions, chronic gastritis, gastric neoplasia, and inflammatory bowel disease (a common cause of chronic intermittent vomiting in dogs and cats). It is stressed that biopsy samples should always be obtained from stomach and whenever possible small intestine regardless of gross mucosal appearance. Normal gastric biopsies may support gastric motility abnormalities, psychogenic vomiting, irritable bowel syndrome, or may be noncontributory (i.e., look elsewhere for diagnosis). Many dogs with vomiting due to inflammatory bowel disease have no abnormalities on gastric examination or biopsy. If only gastric biopsies are obtained, the diagnosis may be missed. Ultrasonography can be useful in the diagnostic work-up of a number of disorders that can cause vomiting. Among the problems that may be detected with ultrasonography are certain disorders of the liver (e.g., inflammatory disease, abscessation, cirrhosis, neoplasia, vascular problems), gall bladder (cholecystitis, choleliths), GI foreign bodies, intestinal and gastric wall thickening, intestinal masses, intussusception, kidney disorders, and others. Needle aspirations and/or biopsies can be done at many sites under ultrasound guidance. Abdominal exploratory is indicated for a variety of problems including foreign body removal, intussusception, gastric mucosal hypertrophy syndromes, procurement of biopsies, and for resection of neoplasia. References
The address is: Initial nonspecific management of vomiting includes NPO (in minor cases a 6-12 hour period of nothing per os may be all that is required), fluid support, and antiemetics. Drugs used to control vomiting will be discussed here. The most effective antiemetics are those that act at both the vomiting center and the chemoreceptor trigger zone. Vomiting is a protective reflex and when it occurs only occasionally treatment is not generally required. However, patients that continue to vomit should be given antiemetics to help reduce fluid loss, pain and discomfort. I strongly favor chlorpromazine (Thorazine), a phenothiazine drug, as the first choice for pharmacologic control of vomiting in most cases. Phenothiazine antiemetics have a broad spectrum effect and are effective in controlling vomiting due to a variety of causes. Chlorpromazine acts on the emetic center, chemoreceptor trigger zone, and on peripheral receptors. It is also thought to function as a calcium channel antagonist. This effect decreases cyclic AMP concentrations in intestinal epithelial cells which leads to decreased intestinal epithelial cell secretion. Further, chlorpromazine has minimal anticholinergic effects. The recommended dose is 0.1 to 0.25 mg/lb IM or SC SID - TID as needed to control vomiting. At this dose there is a minimal sedative effect. Any sedation resulting from use of chlorpromazine, unless pronounced, is not considered a deleterious side effect. patient comfort should always be a priority. Chlorpromazine is an excellent choice for control of nausea. A potential side effect of phenothiazine drugs is hypotension which can result from an alpha-adrenergic blocking action, causing arteriolar vasodilation. This is a minor problem and it is readily controlled with intravenous fluid support. If chlorpromazine is ineffective as an antiemetic, metoclopramide (Reglan), a gastric promotility drug that also has central antiemetic effect, can be used. Metoclopramide increases gastric and proximal small intestinal motility and emptying without causing acid secretion and provides inhibition of the chemoreceptor trigger zone. Parvovirus can cause gastric hypomotility and therefore the promotility effects of metoclopramide may prove beneficial. The recommended injectable dose is 0.1 to 0.2 mg/lb IM or SC given TID to QID as needed. Metoclopramide can also be given IV as a constant rate infusion (0.5 - 1.0 mg/lb over 24 hours). Chlorpromazine and metoclopramide are occasionally used together in dogs in which neither drug is effective in significantly reducing the frequency of vomiting when used alone. It is possible, however, that the combination may potentiate side effects that may result from use of either drug individually. Animals that are treated with a combination of chlorpromazine and metoclopramide are observed carefully for nervous-type behavior or significant depression. My preference at this time, if both chlorpromazine and metoclopramide are ineffective when given individually, or if there is severe vomiting that does not respond to whichever of these drugs is used first, is to institute ondansetron (Zofran) therapy (see later discussion). Metoclopramide - Clinical Applications for Chronic Vomiting Several clinical applications for use of metoclopramide in dogs with chronic vomiting have been identified. These include gastric motility disorders, gastroesophageal reflux disease (GERD), primary or adjunctive therapy for antral and pyloric mucosal hypertrophy, and as treatment for nausea and vomiting caused by various other disorders. Gastric motility disorders are being recognized with increased frequency in veterinary medicine. Gastric stasis, characterized by abdominal discomfort, periodic bloating, borborhygmus, nausea and vomiting may be associated with a number of clinical states that include inflammatory disorders (e.g., chronic gastritis), gastric ulcers, gastroesophageal reflux, infiltrative lesions (e.g., neoplasia), and chronic gastric dilatation. Metabolic disturbances that may cause gastric stasis include hypokalemia, hypercalcemia, acidosis, anemia, and hepatic encephalopathy. Short-term continued vomiting that is observed in some cases after apparent recovery from viral enteritis may be due to abnormal gastric motility. Transient (3 to 14 days) gastric hypomotility may also occur after gastric or abdominal surgery. Motility disorders with no organic cause may be best classified as idiopathic. For any of the disorders listed, the primary cause should be treated, and metoclopramide may be a valuable short-term adjunct to therapy in these cases. Metoclopramide alternatively may be used as the primary treatment on a long-term basis for idiopathic hypomotility disorders. Metoclopramide has also been useful in treatment of dogs that have chronic vomiting characterized by episodes occurring routinely in the early morning and containing bilious fluid. In addition, metoclopramide's antiemetic action has proven quite effective in management of chemotherapy induced vomiting. In general, patients less than 10 pounds receive 2.5 mg per dose, 11-40 pounds 5 mg per dose, and greater than 40 pounds 10 mg per dose. Metoclopramide is given 30 to 45 minutes before meals and again at bedtime. Animals that require chronic medication may need only 1 to 2 doses daily. Because of its short half-life, the drug is not effective when given by intravenous or intramuscular bolus injection for purposes other than when only one treatment would be administered (i.e., to aid in evacuating the stomach if an anesthetic procedure in a non-fasted patient becomes necessary, pre-radiologic contrast study). Subcutaneous administration into fat may be of benefit when oral therapy is contraindicated and an intravenous line is not available. Metoclopramide is supplied as 5 and 10 mg tablets and as a cherry flavored liquid containing 5 mg/ml. Injectable metoclopramide is available in 2 ml single dose vials and in 10 ml multiple dose vials (5 mg/ml). Side Effects Some adverse effects may occur if metoclopramide is given in the usual therapeutic doses. Clients should be apprised of these before the medication is prescribed. These effects are uncommon. Motor restlessness and hyperactivity may occur; and when observed, these signs usually begin 20 to 30 minutes after a dose and last 4 to 5 hours. Alternatively, drowsiness and depression occasionally occur. Side effects are infrequent in cats, but clients have reported disorientation, frenzied behavior, and hiding tendencies associated with the medication. These side effects are reversible (Benadryl 1 mg/lb IV or discontinuing the drug) but generally do not subside when lower doses are given. Unless side effects are infrequent, the use of metoclopramide should be discontinued if adverse reactions are seen. In general, metoclopramide should not be given to epileptic patients. Other contraindications include evidence of significant mechanical obstruction, simultaneous use of anticholinergic agents (antagonism of metoclopramide's effects), and pheochromocytoma. Ondansetron - Clinical Applications for Acute Vomiting Ondansetron (Zofran, Glaxo Pharmaceuticals) is a potent new antiemetic drug that holds tremendous promise for use in both human and veterinary medicine. It has been used in human cancer patients undergoing cisplatin therapy, a drug that frequently causes nausea and severe vomiting, with dramatic results. Ondansetron acts as a selective antagonist of serotonin S3 receptors (a principal mediator of the emetic reflex). S3 receptors are found in both the gut in response to a variety of insults (e.g., chemotherapeutic agents, inflammation) from enterochromaffin cells to stimulate receptors in vagal and splanchnic afferent nerves that lead to the emetic center. The chemoreceptor trigger zone may be stimulated as well. High concentrations of serotonin S3 receptors have also been demonstrated in the area-postrema-nucleus tractus solitarii region of the medulla. The principal site of action of ondansetron is in the area postrema, but it also has some peripheral gastric prokinetic activity. In my experience to date, ondansetron has produced dramatic results in either controlling or at least significantly decreasing the frequency of vomiting in dogs with severe parvovirus enteritis. The recommended dose is 0.05 to 0.08 mg/lb IV given as a slow push every 6 to 12 hours (based on patient response). Frequently dogs that appear quite distressed due to nausea and vomiting look much more relaxed and comfortable within 15 minutes of receiving ondansetron. There are no reports of any significant side effects such as diarrhea, sedation, or extrapyramidal signs in human and animal trials. Ondansetron is expensive (currently approximately $180.00 per 20ml multiple dose vial, concentration 2 mg/ml) and so it is not practical for frequent use in animal patients. However, its use should be considered in any patient with intractable vomiting. Cisapride - The Newest GI Promotility Drug Cisapride (Propulsid) is the newest GI prokinetic drug. A great deal of excitement has been generated about this drug because it has broader promotility effects than metoclopramide (e.g., cisapride has demonstrated excellent efficacy in management of colonic inertia). Cisapride is unique among prokinetic agents in that it does not have antidopaminergic properties. Whereas metoclopramide antagonizes the inhibitory effects of dopamine and can cross the blood-brain barrier, cisapride has no effect on the central nervous system. Cisapride is a benzamide derivative that promotes GI motility by increasing the physiologic release of acetylcholine from post ganglionic nerve endings of the myenteric plexus, leading to improved motor activity of the esophagus, stomach, small bowel, and large bowel. In contrast to metoclopramide, which has central effect a the CRTZ in addition to its peripheral effects, cisapride has no known direct antiemetic properties. The onset of pharmacologic action of cisapride is approximately 30 to 60 minutes after oral administration. Cisapride increases lower esophageal pressure and lower esophageal peristalsis compared to placebo and/or metoclopramide. It significantly accelerates gastric emptying of liquids and solids. Small intestinal and colonic motor activity are also significantly enhanced. Cisapride has been approved for treating gastroesophageal reflux disease in humans, but it has also been shown to be effective in treating a variety of other conditions (e.g., gastroparesis, bile reflux gastritis, nonulcer dyspepsia, intestinal manifestations of systemic disorders, postoperative ileus, constipation, irritable bowel syndrome, and in diagnostic studies [radiographic studies, aid in duodenal intubation of motility and suction catheters]). The most relevant uses of cisapride in animal patients include treatment of gastroparesis, especially in patients that experience significant side effects from metoclopramide (e.g., hyperactivity and other dystonic reactions), idiopathic constipation, gastroesophageal reflux disease (if H2-receptor antagonists and dietary management alone are not effective), and postoperative ileus. In my experience to date, cisapride is extremely well tolerated by animal patients. I have used cisapride in dogs and cats that have experienced neurologic side effects from metoclopramide. I have observed no adverse reactions to cisapride in any of these patients, even in those whose side effects to metoclopramide included very bizarre behavior changes. The suggested dose of cisapride is similar to what has been recommended for metoclopramide (0.1 - 0.25 mg/lb orally SID-TID depending on the clinical situation). In general, animals weighing 10 pounds or less receive 2.5 mg per dose, 11-14 pounds 5 mg per dose, and those over 40 pounds 10 mg per dose. The dose can be gradually increased if necessary. As is recommended for metoclopramide, cisapride should be administered no closer than 30 minutes before feeding. Injectable and oral suspension forms are not yet available in the United States. Giardiasis, Clostridium perfringens Enterotoxicosis, and Cryptosporidiosis
Introduction Giardia, Clostridium perfringens enterotoxin, and Cryptosporidium are important causes of diarrhea in dogs and cats. These disorders should be investigated early in the course of diarrhea, whether it is persistent or intermittent, along with evaluation for dietary causes of GI signs, nematode parasites, bacterial and viral causes, and acute idiopathic colitis. This group of disorders constitutes a thorough differential list for animals with acute and intermittent diarrhea (Table 1). The challenge to veterinarians is in making an accurate diagnosis, so that the best therapy can be instituted as early as possible. This will then lead to the best opportunity for successful control of the medical disorder. It is also important to recognize that some animals will have several disorders at the same time, so a thorough diagnostic approach is recommended. This is why it is often best to run tests for these disorders at the same time, through use of a "fecal diagnostics panel" that is now available at many commercial laboratories. A single fecal sample is submitted to the lab, and tests for each of these disorders is done at the same time. This provides a prompt and thorough analysis for important clinical disorders of the GI tract. The clinician then has more clear direction on how to proceed with treatment, or other diagnostic tests in the event that none of these disorders is identified. Table 1: Common Causes of Acute Diarrhea in Dogs and Cats
Giardia is an important cause of diarrhea, and for some patients other GI signs as well. It is an important pathogen in dogs and cats, as well as humans and other species. Accurate diagnosis of Giardia poses a significant challenge to veterinary practitioners. Because of the impact that this organism can have on animals, and also humans because of its zoonotic potential, it is important that veterinarians perform accurate diagnostic testing on animals to determine whether or not an animal is infected with Giardia. These notes will emphasize steps for accurate diagnosis, and also management of giardiasis. Clostridium perfringens enterotoxicosis is a common cause of intermittent diarrhea in dogs and cats. Veterinary practitioners should test for the enterotoxin whenever faced with a patient that has unexplained diarrhea. Although cryptosporidiosis is not a common disorder in dogs and cats, it can cause significant abnormalities, and it has significant zoonotic potential. Cryptosporidiosis can be fatal in people that also are immunosuppressed (e.g., on chemotherapy or corticosteroids, carriers of HIV). Therefore, it is incumbent on veterinarians to test for this disorder, as there are important implications to both the patient as well as to humans who may come in contact with an infected animal. Diagnosis and Management of Giardia
Diagnosis Standard diagnostic tests used in any practice setting should include fresh saline fecal smears and zinc sulfate flotation. Zinc sulfate flotation with centrifugation, rather than flotation alone, is a somewhat more effective means of testing for Giardia. Trophozoites are more likely to be found in loose stools, while cysts are more often found in semi-formed or formed stools. Performing both zinc sulfate concentration with centrifugation and a Giardia antigen test together constitutes the most accurate means of evaluating a patient for the presence of Giardia. This is recognized as the "gold standard" in human medicine, and is true also in veterinary medicine. Direct Saline Smear A fresh saline smear is made by mixing a drop of feces with a drop of saline on a glass slide. A coverslip is applied and the preparation is examined immediately under 40x magnification. Trophozoites are pear-shaped and have a characteristic concave ventral disk. They demonstrate rolling/wobbling motion (e.g., like a falling leaf). Adding a drop of Lugol's solution of iodine on the edge of the coverslip can be done as an optional procedure and this will enhance the morphologic features of the organisms and make them easier to find. The iodine kills the parasite, so motion will no longer be seen if this procedure is used. Differentiation of trichomonads from Giardia is based on a different motion pattern (more forward motion with trichomonads versus rolling motion with Giardia), the absence of a concave disk, a single nucleus, and the presence of an undulating membrane. Identification of Giardia trophozoites is diagnostic, while their absence in fecal samples does not rule out presence of infection. Zinc Sulfate Concentration with Centrifugation Many studies have now shown that zinc sulfate concentration with centrifugation is the most reliable test available for demonstration of Giardia cysts in fecal samples. The test can be done in any practice setting, and the technique is described below. Zinc sulfate concentration is also a very effective method for identifying nematode eggs in feces. It is therefore now used as the standard test for screening for intestinal parasites in most academic and many private practices. Studies have shown that approximately 70 percent of Giardia positive dogs can be identified on a single zinc sulfate concentration test (as opposed to approximately 40 percent of dogs after 3 separate saline smear preparations). Slides should be examined within 10 minutes of preparation because the cysts may begin to shrink. Since animals shed Giardia on an intermittent basis it is recommended that a series of zinc sulfate concentration tests be run over a 3 to 5 day period in order to maximize chances of accurately diagnosing or ruling out Giardia in animals with chronic diarrhea (or, alternatively, an antigen test can be run at the same time to help increase diagnostic efficiency and accuracy). Diagnostic efficiency increases to 95 percent when 3 zinc sulfate examinations are conducted over a 3 to 5 day period.2 A positive result on any of the tests warrants treatment for Giardia. Caution: It is not uncommon for plant spores, yeast bodies, and other amorphous debris to be mistaken for Giardia cysts. In fact, Giardia is frequently misdiagnosed - either it is being diagnosed incorrectly, or the wrong tests are being run and animals with Giardia are being missed. Giardia cysts are 11-13 u in size, and the subtle characteristics of the nuclei, axostyles, and median bodies are often more easily observed under 100X oil immersion magnification. Sometimes there are crescent shaped indentations of the cyst wall. Yeast bodies are similar to Giardia in size, shape, and color. Yeast bodies appear to be far more common than Giardia. Zinc Sulfate Concentration - Summary
Zinc Sulfate Centrifugation Flotation Technique
Initially mixing the sample with water and centrifuging it can remove some of the debris in the fecal sample. Resultant supernatant is discarded, and zinc sulfate solution is added to the pellet and centrifuged as described above. This initial water wash is not necessary on a routine basis. When steatorrhea is present, large amounts of fat float with the Giardia cysts and may complicate reading of the slide. In these situations, an ethyl acetate sedimentation technique can be used: the sample is mixed with water, filtered, and placed in a centrifuge tube with two to three milliliters of ethyl acetate or ether. After centrifuging, the supernatant, including a distinct layer containing the organic solvent and fat, is discarded. The pellet is then resuspended, and a drop is stained with Lugol's iodine and examined. Reference: Zajac, AM: Giardiasis. Compendium on Continuing Education for the Practicing Veterinarian 14(5):606, 1992. Differentiation of Cyst Structures
Giardia
Yeast Bodies
Sarcocystis sp. and Cryptosporidium sp.
Giardia Antigen Testing Other diagnostic tests for Giardia include an enzyme-linked immunosorbent assay (ELISA) test for Giardia antigen in feces, a direct immunofluorescent assay, duodenal aspiration under endoscopic guidance, and the peroral string test. The latter two tests are impractical for routine use in small animal practice, especially when the effectiveness of serial zinc sulfate examinations is recognized. The fecal ELISA test detects Giardia antigen that is produced by dividing trophozoites. The test is very sensitive in humans and reportedly detects 30 percent more cases of Giardia than does zinc sulfate. Studies have now confirmed that this is also an excellent test for use in animals. A rapid assay for in-house use is now available and is technically easy to perform (ProSpecT Giardia Rapid Assay, Alexon). One advantage of the ELISA test is that, since it detects Giardia specific antigen in the feces, it avoids the problem of intermittent cyst excretion in the feces. This test can be a significant aid in accurate diagnosis of Giardia in any private practice setting, and I highly recommend that veterinarians utilize this test in order to more consistently make an accurate diagnosis of giardiasis in their small animal patients. Indications for Running Giardia Antigen Test:
Treatment of Giardia For many years the primary treatment for Giardia in dogs and cats has involved metronidazole. For dogs in which metronidazole proved ineffective, quinacrine was often used in the past. However, although quinacrine has been shown to be more effective than metronidazole, it frequently causes side effects, including lethargy, anorexia, and vomiting. It was also used in cats. Quinacrine is no longer available, however. More recently it was shown that albendazole (Valbazen) is highly effective in controlling Giardia. I recommended albendazole as an effective treatment for Giardia from 1993-1997, but experience with albendazole in dogs and cats has shown that it can cause bothersome side effects; including leukopenia, lethargy, and inappetence. Therefore, I no longer recommend albendazole for treatment for giardiasis in dogs and cats. Fenbendazole (Panacur), well known for its effectiveness against a variety of intestinal parasites, also appears to be very effective against Giardia. In a controlled trial at Cornell University 6/6 dogs were effectively treated in an initial study. The same dose that is used to treat roundworms, hookworms, whipworms, and the tapeworm Taenia pisiformis (50 mg/kg orally once daily for 3 consecutive days) is used to treat Giardia. If the infection is not cleared on this regimen, a longer course of therapy is used (5 to 7 days). Fenbendazole has a proven track record for being very safe and is thought to not have any teratogenic effects. Fenbendazole is therefore the drug of choice for treatment of Giardia in pregnant animals. This is now also the preferred treatment for Giardia in cats. Drontal Plus (Bayer) is also an excellent choice for treatment of Giardia. This product includes febantel in addition to praziquantel and pyrantel pamoate. Febantel is the drug component that treats Giardia. Febantel is metabolized into fenbendazole and oxyfenbendazole after oral administration. Drontal Plus is administered once daily for 3 to 5 consecutive days for treatment of Giardia. Drontal Plus has been approved for use in dogs. Metronidazole is still a useful drug for treating Giardia, and it has the added advantage of having antibacterial as well as antiinflammatory properties. In situations in which it is unclear whether diarrhea is due to giardiasis, bacterial overgrowth, or mild inflammatory bowel disease, metronidazole is an excellent choice, especially when a client requests empirical therapy rather than definitive diagnostic testing. Metronidazole is only 67-74 percent effective in eliminating Giardia from dogs, however, and if a positive diagnosis is made fenbendazole would also be a reasonable choice. Potential side effects of metronidazole include anorexia, vomiting, and neurologic problems (ataxia, vestibular problems, seizures). In my experience these side effects are not common. They are more likely to occur when the anti-Giardia dose is used (25 to 50 mg/kg orally every 12 hours for 5 to 7 days). The total dose of metronidazole should not exceed 65 mg/kg per day (30 mg/lb per day). A lower dose (10 to 20 mg/kg every 12 hours) is used in treatment of intestinal bacterial overgrowth and inflammatory bowel disease. Side effects are infrequent at this dose. In the past, if a 5 to 7 day course of metronidazole failed to eliminate Giardia, a longer follow-up course (10 to 14 days) was often used. With the availability of fenbendazole and Drontal Plus it is recommended that one of these drugs be used instead in this situation. Oral furazolidone has proven to be an effective drug for treating Giardia in cats at a dose of 4 mg/kg (1.8 mg/lb) orally twice daily for 5 to 10 days. Furazolidone causes vomiting and/or diarrhea in some cats. It should not be used in pregnant queens. In addition to use of pharmacotherapy to eradicate Giardia, it is important to consider environmental control so as to minimize chances of reinfection, especially in kennel or cattery situations. Cysts present in a cool environment can remain infective for a long period of time. Cages and runs should be thoroughly cleaned of all solid fecal material. Steam cleaning, or treatment with a quaternary ammonium compound are both very effective measures for killing cysts. Allowing time for thorough drying is important, to desiccate any remaining cysts. Bathing: Steps to prevent reinfection play an important role in resolution of giardiasis in dogs. Dogs may be reinfected with cysts from the hair or the environment, and bathing at the time that rug therapy is concluded, thereby removing cysts that could be licked from the hair coat by the animal, may be a very helpful additional step in decreasing the chances of reinfection. Changing the environment, if possible, can also be beneficial. Zoonotic Potential: Current information indicates that zoonotic potential definitely exists with Giardia. When both animals and humans living in the same environment become infected, a common source of infection rather than direct transmission must also be considered. The question whether animals that are asymptomatic carriers of Giardia should be treated is often asked. Giardia cysts have been found in many animals with well-formed feces. Giardia is clearly not pathogenic in some animals, while in others it causes significant enteritis. Because the public health considerations must still be considered, it is recommended that all animals with fecal samples that contain Giardia be treated. Vaccination: New Giardia Vaccine (GiardiaVax) In 1999 a new vaccine was released by Ft. Dodge for control of Giardia. The vaccine is a killed product containing chemically inactivated trophozoites. Efficacy studies showed that vaccinated dogs were less severely affected clinically and shed cysts for a shorter time following challenge with infective cysts, compared with nonvaccinated dogs. In addition, chronic giardiasis resolved after dogs were vaccinated with this product. In these studies clinical signs of infection were less severe by 21 to 35 days after vaccination, and cysts were no longer detected in the feces by 21 to 70 days. This is not expected to be a Tier 1 or "core" vaccine (i.e., recommended for annual vaccination of all dogs and cats), but there definitely is a place for it in our armamentarium. The vaccine has been approved for use in both dogs and cats. Important Points Regarding Giardia Vaccine:
Which Dogs Should Be Considered Candidates for Vaccination? Pets considered at higher risk of exposure to Giardia (and therefore candidates for vaccination) include dogs that frequently visit parks or play areas frequented by other dogs, dogs in multi-pet households, dogs living in endemic areas, hunting dogs, dogs that travel to pet shows, farm dogs, dogs that board at training kennels, dogs that board frequently at boarding kennels, and dogs that have chronic giardiasis with poor response to therapy. One ml of vaccine is administered subcutaneously and repeated 2-4 weeks later. Annual vaccination is recommended at this time. Reference: Payne, PA, Ridley, RK, Dryden, MD, et al: Efficacy of a combination febantel-praziquantel-pyrantel product, with or without vaccination with a commercial Giardia vaccine, for treatment of dogs with naturally occurring giardiasis. Journal of the American Veterinary Medical Association, Vol 220, No. 3, February 1, 2002. Clostridium Perfringens Enterotoxicosis Over the last 12 years Clostridium perfringens enterotoxicosis (CPE) has emerged as a frequently recognized cause of chronic intermittent diarrhea in dogs. Although it is likely a less common cause of diarrhea in cats it is still diagnosed frequently enough that it should be considered in the diagnosis of diarrhea in cats as well. This is not a new disease. Frequent use of the definitive test (enterotoxin assay performed on feces) for this disorder has revealed that CPE is seen relatively commonly in clinical practice and that CPE is a disorder that should be considered in any dog or cat with intermittent or chronic persistent diarrhea. C. perfringens is a normal vegetative enteric organism. Simply identifying C. perfringens on a fecal culture is meaningless. The pathogenesis of CPE is through an enterotoxin that is produced after certain strains of C. perfringens sporulate. The toxin damages epithelial cells of the distal ileum and colon. Inciting factors that promote sporulation are not clearly understood but may include stress, diet changes, concurrent disease, or inherent immune status. The most common clinical signs are chronic intermittent or persistent diarrhea. In some animals acute diarrhea is the primary sign. In fact, some of the cases of hemorrhagic gastroenteritis (HGE syndrome), characterized by acute bloody diarrhea and an increased packed cell volume that most practitioners have seen over the years, may have been due to CPE. Many animals exhibit signs of large bowel diarrhea, but small bowel signs may be seen as well. In some cases signs may be seen for only a day or two at a time, with persistent recurrences on a weekly, monthly, or on a less frequent basis. Stressful events or diet changes may incite flare-ups of clinical signs. In other cases C. perfringens enterotoxicosis is one of several problems that an animal may have concurrently and diarrhea may be persistent. Diagnosis CPE must be considered whenever more than one animal in the environment has diarrhea (e.g., household, kennel, cattery). Transmission from animal to animal can occur. A presumptive diagnosis may be suggested on fecal cytology in which more than 3-4 spores per high power oil immersion field are observed (the spores have a safety pin appearance and are larger than most bacteria). However, definitive diagnosis is by identification of enterotoxin which is currently done via a fecal assay. Clinicians should be aware that simply seeing spores on fecal cytology does not establish a definitive diagnosis (see JAVMA February 1, 1999). Stool is submitted to the lab for enterotoxin analysis. Fecal samples that will be shipped off from the hospital directly to a laboratory should be sent on ice via overnight express. If a courier service will be picking up samples for transport to the laboratory it is sufficient to keep the sample refrigerated until pick-up. The courier service will keep the sample properly chilled during transport. The minimum amount of stool that should be submitted is the size of a pea. Typically I submit samples in a red top tube, without serum separator. In animals with intermittent diarrhea the chances of a positive toxin finding are greater when abnormal rather than a normal stool is examined. A negative result does not definitively rule-out CPE. Treatment Several antibacterial drugs are effective in controlling CPE. Acute cases often respond well to amoxicillin (22 mg/kg BID) or metronidazole (10-20 mg/kg BID) for 7-28 days. Many clinicians have likely treated CPE with these medications empirically without knowing what they were treating. Chronic cases tend to respond best to tylosin powder. The recommended dose is: Animals greater than 23 kg ¼ tsp BID, 12 to 23 kg 1/8 tsp BID, 5 to 12 kg 1/12 tsp BID, and less than 4.5 kg 1/16 tsp BID (a "pinch"). Cats definitely do not accept the powder well at all, even when it is mixed in very tasty foods. It is best to have the powder reconstituted to capsule form for administration to cats. The medication is very safe. Some animals require treatment for several to many months (3 to12 months or more). Over time the dose may in some cases be successfully reduced to SID and then every other day dosage (after several months or more on a BID schedule). Dietary fiber supplementation may also help control CPE. Probable mechanisms include decreased C. perfringens fecal concentration, lower colonic pH, which prevents sporulation, and increased concentrations of SCFA. Some patients may respond well to dietary fiber supplementation alone. Follow-up testing at 3-6 months can be done to determine if toxin persists. Once daily to every other day tylosin in conjunction with dietary fiber supplementation are used in chronic cases. Cryptosporidiosis Cryptosporidium parvum is a very small coccidia (5u) that has occasionally been associated with diarrhea in cats and neonatal puppies. Because Cryptosporidia are not very host specific they also infect humans, sometimes fatally in the presence of severe immunosuppression. Cats have also been implicated as a cause of infection in humans. Infection is also subclinical in dogs and cats. Acute symptoms may include diarrhea, abdominal pain, vomiting, fever, and listless behavior. Chronic unresponsive diarrhea has been associated with cryptosporidiosis in cats with serious underlying disease as well as in dogs. Studies done at Colorado State University have shown that approximately 5% of the cats and 6% of the dogs with chronic diarrhea are passing Cryptosporidium parvum oocysts in feces. This highlights the importance of testing dogs and cats for cryptosporidiosis. Cryptosporidia oocysts are quite small (as little as one-tenth the size of common Isospora oocysts) and can be very difficult to detect on microscopy. Other diagnostic tests that have been used include Sheather's sugar flotation, Kinyoun's carbolfuchsin negative staining, or modified acid-fast staining. The best tests for Cryptosporidium are fecal IFA and acid fast staining of fecal smears. These tests are readily available at commercial laboratories (acid fast staining can also be done in house). Indications for Testing
The following treatment regimens may be used for cryptosporidiosis:
Inflammatory Bowel Disease in Dogs
Intestinal Disease in Shar-Peis German Shepherd Enteropathy Pythiosis Management of Inflammatory Bowel Disease in Dogs It is important that the clinician formulate a treatment protocol based on a correlation of clinical course, laboratory and gross findings, and histologic findings rather than relying on histologic changes alone. Although treatment principles for cats and dogs with IBD are similar, drug selection and dosage regimens vary between these two species in some situations. Specific treatment recommendations for dogs with inflammatory bowel disease (IBD) are as follows. Corticosteroids are the initial treatment of choice for lymphocytic-plasmacytic and eosinophilic enteritis in most cases. Mild to moderate cases (as determined by clinical signs, normal protein levels, and degree of inflammatory cell infiltrate on biopsy) often respond to prednisone at a dose of 0.25 to 0.75 mg/lb divided twice daily for two to four weeks followed by a gradual decrease in 50% increments at two-week intervals. Alternate day or every third day treatment can often be reached by two to three months. Occasionally treatment can be discontinued altogether by three to six months. Moderate to severe cases and any case in which the total protein is less than 5.5 g/dl should be treated more aggressively using an initial prednisone dose of 1 mg/lb per day for two to four weeks before an attempt is made to decrease the dose. Dogs in this category often require long-term therapy (months to years) on an every other day or every third day basis to maintain remission. Use of combination drug therapy (prednisone and metronidazole) in these cases at the outset is recommended in order to improve chances of controlling clinical signs more quickly and to prevent progression of the disease. If significantly bothersome side effects are caused by prednisone (e.g., severe polyuria/polydipsia, panting, lethargy, etc.), oral dexamethasone can be used instead. In some dogs dexamethasone is much better tolerated and side effects are minimal or nonexistent. If prednisone side effects are judged to be severe it is generally discontinued for 12 to 36 hours in order to allow for adequate metabolism and clearance. Prednisone may then be reintroduced at 25 to 50 percent of the previous dose or alternatively dexamethasone can be instituted at a conservative level (0.005 to 0.01 mg/lb/day orally). Budesonide is a new and recently approved corticosteroid for use in humans. Budesonide is a glucocorticoid that also represents a new alternative for management of IBD in dogs and cats, especially in severe cases that have proven to be refractory to prednisolone, metronidazole, azathioprine, and dietary management; or that are intolerant of the corticosteroids discussed above. It is one of a group of novel corticosteroids that have been in development for use in humans in an attempt to make available alternative preparations that will help limit toxicity associated with corticosteroid use. Others include fluticasone propionate, tixocortol pivalate, and beclomethasone dipropionate. Budesonide undergoes high first pass metabolism in the liver and 90% is converted into metabolites with low corticosteroid activity. It has minimal systemic availability. The potential for typical corticosteroid side effects is significantly reduced as a result of decreased bioavailability and the resulting limited systemic exposure, which makes this a particularly attractive drug for use in humans and animals that are poorly tolerant of other corticosteroids. Budesonide also has a high receptor-binding affinity in the mucosa. It has been referred to as a "locally acting" corticosteroid. Therapeutic results with budesonide have been promising in humans with Crohn's disease, collagenous colitis and lymphocytic colitis, ulcerative colitis, either when administered as a retention enema or in oral form, and primary biliary cirrhosis. Budesonide has been used by some veterinary clinicians in recent years to treat IBD in dogs and cats. Dose recommendations vary. In humans, a range of 6 mg to 9 mg per day has been used during initial therapy. The following general recommendations have been made for dogs and cats. In general, budesonide is administered to cats and small dogs at 1 mg administered once per day. It has been used at higher doses (3 mg per small dog or cat per day), but the lower dose is frequently effective. Large dogs receive 3 mg twice daily initially, and the dose is later tapered to 3 mg once daily, and then to alternate day administration for longer term use. Budesonide can be used in combination with other drugs. Potential adverse effects include PU/PD, when budesonide is used at the high end of the dose range, and GI ulceration. These reactions have been observed in some human patients. These problems would be more likely to occur in dogs than in cats. It appears to be very safe when used at the levels listed above. Metronidazole has both an antibacterial and antiinflammatory effect. It is useful in treatment of IBD in dogs as well as in cats. Metronidazole's mechanism of action includes an antiprotozoal effect, inhibition of cell-mediated responses, and anaerobic antibacterial activity. Metronidazole is administered at 5 to 10 mg/lb two times daily. A major advantage of using combination therapy is that the corticosteroid dose can usually be decreased from the high initial dose in a timely manner, thus decreasing the likelihood of significant corticosteroid-related side effects. Also, I have successfully managed on a long-term basis canine patients with mild to moderate lymphocytic-plasmacytic enteritis that were intolerant to corticosteroids or metronidazole alone. When prednisone and metronidazole are used in combination the dosage level of each drug is generally gradually decreased as the animal's condition improves and laboratory parameters (especially protein levels and white blood cell count) return to normal. Corticosteroids are decreased gradually for several months before any reduction is made on the metronidazole dose. If there has been an excellent response it is possible that metronidazole can be discontinued after several months. Alternatively, if chronic therapy is required, metronidazole can often be administered on a once daily and eventually on an every other day basis. If it is not possible to discontinue medication altogether due to recurrence of symptoms when no medication is given control can be maintained with prednisone and/or metronidazole given on an alternate day basis. If both drugs are used, I often recommend giving prednisone on one day and metronidazole on the alternate day. Occasionally in dogs with moderate to severe IBD or in a case where both IBD and chronic bacterial overgrowth are present it is necessary to continue metronidazole on a long-term (months to years) basis (5 to 10 mg/lb twice daily). I have observed no instances of significant complications when this protocol has been used. Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. There are reports of humans with Crohn's disease who have been treated with high doses of metronidazole for prolonged periods of time and who subsequently developed breast or oral cancer. A cause and effect relationship has not been established. To date I am aware of no cases of GI or mammary cancer that have occurred in dogs or cats in conjunction with metronidazole use. I consider it to be a safe drug for prolonged use (months to years) in patients with chronic disorders for which long-term therapy is required. Dogs with marked hypoproteinemia (total protein less than 4.5 g/dl) caused by lymphocytic-plasmacytic enteritis often respond well when an aggressive therapeutic course is undertaken (prednisone, metronidazole, and azathioprine used in combination). This aggressive approach has led to control of clinical signs and return to a total protein level of greater than 6.0 g/dl (by 2 to 4 months) in a number of cases. One exception to this approach, in my experience, is that animals with hypoproteinemia resulting from eosinophilic enteritis often respond well to corticosteroids alone. Combination drug therapy is used early in severe cases or if a side effect to one drug requires that it be used at a lower dose. If corticosteroids are poorly tolerated (e.g., excessive polyuria/polydipsia, listlessness, panting, inappetence associated with steroid hepatopathy) or if corticosteroids and metronidazole are unable to achieve remission, then azathioprine should be added to the regimen. Azathioprine is started early in the course for cases of lymphocytic-plasmacytic enteritis that cause a protein-losing enteropathy with a total protein level less than 4.5 g/dl. The canine dose is 1 to 1.25 mg/lb once daily (note significant difference in dose between cats [0.15 mg/lb once every other day] and dogs). If azathioprine is used at the outset, the prednisone dose is decreased by 50% from 1mg/lb per day after three to four weeks or based on clinical improvement (i.e., remission of signs and increase in protein levels) and degree of tolerance of this dose of prednisone. Subsequent decreases in the prednisone dose can usually be made at monthly intervals until an alternate day schedule is reached. If azathioprine is started in any type of IBD case because of significant corticosteroid side effects, the prednisone is initially decreased by 50% to 75% but is not stopped completely unless absolutely necessary because loss of remission might result. Azathioprine is generally used for three to nine months in dogs. Once adequate control is achieved, the daily dose is decreased by 50%, and subsequently alternate day therapy is used. Side effects are uncommon in dogs but may include anorexia, jaundice (hepatic damage), poor hair growth, and bone marrow suppression. In addition, it is suspected that azathioprine has the potential to induce pancreatitis. This is an uncommon occurrence, however, in my experience. A complete blood count should be run to monitor for evidence of anemia or leukopenia at three week intervals for the first two months and then once every several months. Routine monitoring also includes periodic (once every 4 to 6 weeks initially) evaluation of hepatic enzyme levels (increases may be due to corticosteroids and occasionally azathioprine) and protein levels. IBD that is initially graded as moderate to severe usually can be managed quite successfully and can be maintained in remission but not often cured. Sometimes follow-up biopsies in severe cases reveal only slight to moderate histologic resolution of inflammatory infiltrates despite excellent clinical control even on lower drug doses. Alternatively, dramatic histologic resolution has been noted in other cases. Treatment decisions (e.g., can treatment be discontinued completely?) ideally are based on a thorough review of clinical response to date (control of clinical signs, levels of medication required, and resolution of hypoproteinemia if it was initially present) and follow-up endoscopic biopsy information. As a general clinical rule of thumb an attempt can be made to discontinue therapy after two to three months of successful control on twice weekly medication. If signs recur then medication is resumed on a daily basis for 7 to 14 days before a gradual reduction program is started. In some dogs with severe lymphocytic-plasmacytic enteropathy and marked hypoproteinemia, therapy can be successfully discontinued as early as six months to one year. In others, lifelong treatment is required. Dietary Management of IBD In some animals with mild lymphocytic-plasmacytic enteritis or eosinophilic enteritis dietary modification may lead to partial or complete resolution of clinical signs and even improvement in histologic lesions. In others dietary therapy may be an important adjunct to pharmacotherapy in the control of clinical signs related to chronic IBD. It is also possible that dietary management used on a long-term basis will effectively help maintain control once drug therapy is discontinued. Potential benefits of dietary therapy include reduction of hypersensitivity reactions to dietary antigens, alteration of bowel motility, and effects on composition of the bowel flora and mucosal morphology and function. Dietary therapy for IBD may involve use of a strict elimination diet or a balanced commercial diet that contains minimal additives. In most cases, diets that are highly digestible and low-residue work best for small intestinal disease. If a decision is made to initially manage an animal with dietary therapy alone the dietary trial should be conducted for a minimum of three to four weeks. Some animals require six weeks or more before clinical improvement occurs. If biopsies reveal moderate to severe IBD and/or if there is any degree of patient compromise pharmacotherapy should be included in the treatment regimen along with dietary management. In my experience, animals with this degree of disease rarely respond to dietary manipulation alone. Diets that often work well include those that supply a single source of protein to which the animal has not previously been exposed (i.e., "novel" proteins). These may include lamb, rabbit, venison, duck, or low-fat cottage cheese. A single digestible carbohydrate such as boiled rice should be added to home prepared diets. Many of the premium commercial diets now include optimum levels of omega-6 and omega-3 fatty acids. These agents may be useful in reducing inflammation in the intestine. Baby food or boiled chicken are often well tolerated in cats that will not eat commercial foods. Dividing feedings into two to three meals per day will help maximize dietary assimilation. Chronic Enteropathy in Shar Peis Shar Peis with chronic diarrhea frequently have moderate to severe inflammatory bowel disease and intestinal bacterial overgrowth. Typical signs in Shar Peis often include persistent diarrhea weeks to months in duration, weight loss, and an increased to ravenous appetite. There is almost always evidence of small bowel diarrhea, but in some dogs large intestinal signs such as hematochezia, mucoid feces, and dyschezia are evident as well. Energy level often remains normal or nearly normal until the disease is severe. There is also intermittent vomiting in some dogs. The prognosis for successful clinical control of symptoms is excellent, as long as a definitive diagnosis is made before the disease becomes too severe. Clinicians are reminded that, although a great majority of Shar Peis with chronic diarrhea have IBD and IBO, an occasional case of intestinal lymphoma, histoplasmosis, etc. may still be found in this breed. Clinical signs and baseline laboratory parameters may be similar in all of these disorders. Therefore, it is always best to make every effort to establish a definitive diagnosis, rather than simply assuming that the most common problem is indeed present and subsequently administering empirical therapy. This issue should be thoroughly discussed with clients who may initially be reluctant to support the diagnostic testing that is necessary to make a diagnosis. The most consistent laboratory parameters are panhypoproteinemia (usually ranging from 2.8 to 5.0 g/dl), indicating significant small intestinal involvement, and low cobalamin (vitamin B12) levels, which is most consistent with intestinal bacterial overgrowth. Folate levels are usually either normal or mildly elevated (increased folate is also consistent with bacterial overgrowth). There may be leukocytosis (often 20,000 to 40,000 cells/ul) with mature neutrophilia, and mild anemia (most consistent with anemia of chronic disease, and rarely blood loss). Eosinophilia is occasionally present. Despite the fact that the triad of signs of chronic diarrhea, weight loss, and ravenous appetite is strongly suggestive of exocrine pancreatic insufficiency, I have found this disease to be quite uncommon in Shar Peis (based on trypsin-like immunoreactivity assays). In addition to a complete blood count, serum biochemical profile, fecal examinations for parasites, fecal cytology, fecal analysis for Clostridium perfringens enterotoxin, TLI assay for exocrine pancreatic insufficiency, and cobalamin and folate assays for intestinal bacterial overgrowth, Shar Peis with chronic diarrhea should undergo upper and lower GI endoscopy in order to obtain biopsies from the stomach, duodenum, jejunum (if it can be reached) ileum, and colon. Even if there are no clinical signs consistent with large bowel disease colonoscopy is still done because it is important that biopsies be obtained from the ileum. Usually there is diffuse involvement of the small intestine. However, occasionally histologic lesions will be found only in the lower small intestine (this highlights the importance of doing both upper and lower GI endoscopy). Other findings may include esophagitis (grossly evident at endoscopy), gastric hypomotility, and colitis. Treatment Treatment of Shar Peis usually includes management of IBD and IBO (prednisone, metronidazole, and amoxicillin which is administered for one month if there is laboratory evidence of IBO). In severe cases of IBD it may be necessary to use azathioprine (see guidelines described earlier). It may be useful to administer tylosin powder if the diarrhea is poorly responsive to initial therapy (reasons for poor response may include persistent bacterial overgrowth or Clostridium perfringens Enterotoxicosis that did not respond to metronidazole and/or amoxicillin). Esophagitis is managed with a restricted fat diet, H2-blocker therapy (e.g., famotidine once daily 30 minutes before food), and metoclopramide. Treatment for gastric hypomotility includes a restricted fat diet provided in divided feedings two to three times daily and a promotility drug (metoclopramide or cisapride). Colitis is managed with metronidazole and in some cases sulfasalazine is used as well. Anemia often resolves as the inflammatory disease comes under control. Dietary therapy guidelines previously described for IBD are followed. Most Shar Peis can be managed on a long-term basis, once remission has been achieved, with maintenance doses of prednisone (every two to three days) and metronidazole (once daily to every other day). In some cases medication can be discontinued altogether after 6 to 24 months. Hematologic parameters and overall clinical condition should be consistently back to normal before all medication is stopped. Dogs with gastric motility disease (hypomotility) may require lifelong promotility therapy. If there are periodic flare-ups of large intestinal signs sulfasalazine is used as needed, generally for 7 to 21 days at a time (dose and frequency of administration depends on severity of clinical signs). German Shepherd Dog Enteropathy German shepherd dogs appear to be predisposed to an increased incidence of GI diseases such as IBD and SIBO. Practitioners who see German shepherds with any frequency no doubt recognize that these dogs have an increased incidence of diarrhea and sometimes weight loss and other symptoms. It is not known for sure why German shepherds are predisposed to IBD and SIBO, but there are several theories, and perhaps there are at least several factors involved concurrently. Possible factors include:
It is possible that IBD and SIBO in German shepherds are part of a single disease syndrome. It is also possible that, given that SIBO is more common in young animals and IBD is more common in older dogs, that SIBO can predispose to IBD. There is currently no substantiation of this hypothesis, but studies are ongoing. Clinical signs in German shepherds are variable. The most common signs of SIBO are diarrhea and weight loss or failure to thrive. Signs of IBD are more variable and in addition to diarrhea and weight loss may include vomiting, flatulence, decreased appetite, and other signs. German shepherd dogs with GI signs should be investigated in the same manner as has been described for intestinal disease earlier in this chapter. Problems other than SIBO and/or IBD may be present, so a thorough diagnostic work-up should be recommended. In addition to a baseline of a CBC, biochemical profile, and urinalysis, other tests should include fecal tests for nematode parasites, Giardia, Cryptosporidium, and Clostridium perfringens enterotoxin, TLI if exocrine pancreatic insufficiency has not already been ruled out, serum cobalamin, folate, and SUCA or other currently recommended indirect test for SIBO, and upper and lower GI endoscopy for procurement of intestinal biopsies. Alternatively, if there are minimal signs and the dog's condition remains good overall, a trial with antibiotics (see treatment section below) for 4 to 6 weeks may be tried. A positive response would be suggestive of SIBO. It will then need to be determined if antibiotics need to be continued long-term or on an intermittent basis. Treatment If it is thought that the problem is limited to SIBO and/or IBD, it is generally recommended that antibiotics alone be used initially, unless there is a moderate or of course severe degree of IBD present, in which case immunosuppressive therapy is also indicated. Antibiotics may include oxytetracycline, metronidazole, or tylosin. Initially a course of 4 to 6 weeks in prescribed, and then if there has been a good response the medication can be discontinued. The dog is then observed for relapse, and if this occurs the antibiotic therapy should be reinstituted. Again, it is important that other causes of diarrhea be ruled out, if they have not been already, and an effort to look for evidence of Clostridium perfringens enterotoxicosis (CPE) must be made. CPE sometimes responds to metronidazole, and more consistently, especially in chronic cases, to tylosin. Fiber supplementation is also very beneficial in management of CPE. For SIBO and IBD, a highly digestible low residue diet is generally preferred, so dietary trials may be necessary, along with a thorough diagnostic effort, to determine which type of diet is most indicated. If there is an excellent response to antibiotics and the diarrhea recurs when they are discontinued, antibiotics can be used either continuously on a low dose basis (I prefer to use tylosin in this situation as a first choice, and metronidazole as a second choice) or pulse therapy may be used, in which case antibiotics are administered once daily two to three times a week. In some dogs this is sufficient to maintain control. If IBD is present and not responsive to antibiotics and dietary management, immunosuppressive drugs are used following the guidelines described earlier in this chapter. In general, I rarely find it necessary to use a prednisone dose greater than 0.5 mg/lb per day in German shepherd dogs. Pythiosis Pythiosis is a severe and often fatal cause of chronic GI or cutaneous disease in dogs living mostly in tropical or subtropical climates. In the United States, most cases are seen in the Gulf Coast states region, but it has been seen as far north as southern Indiana, Missouri, Kentucky, and North Carolina. There are also rare cases in cats that involve mostly invasive subcutaneous lesions. Pythiosis is caused by the aquatic oomycete Pythium insidiosum. The infective stage of Pythium insidiosum is thought to be the zoospore, which is released into warm water environments. Infection is caused either through encystment in the skin or through ingestion. GI pythiosis causes severe segmental transmural thickening of the GI tract with variable mucosal ulceration and mesenteric lymphadenopathy. There are other fungal agents of the class Zygomycetes that can cause severe intestinal and skin disease. It is difficult to differentiate some of the agents, however, and so the general term zygomycosis is often used. Dogs with zygomycosis oftentimes are undifferentiated from those cases with pythiosis. These infections were formerly misnamed phycomycosis (outdated name that should no longer be used). Historically definitive diagnosis of pythiosis and zygomycosis has been difficult because of the challenges inherent in obtaining a culture-based confirmation of these organisms. Therefore, a presumptive diagnosis has often been made, i.e., "suspected pythiosis," based on histopathologic findings. Newer tests are now available which are making specific diagnosis somewhat easier. Clinical signs include chronic intractable diarrhea and vomiting, loss of appetite, depression, and chronic weight loss. The diarrhea may become bloody due to intestinal necrosis and ulceration. Extensive granulomatous reaction may cause palpable enteromesenteric masses to develop. There may eventually be spread to other abdominal viscera. Baseline laboratory tests may reveal mild to moderate nonregenerative anemia, neutrophilic leukocytosis, and panhypoproteinemia. Survey abdominal radiography may reveal a mass effect and barium contrast radiography may identify an area of obstruction. Abdominal ultrasonography can identify intestinal thickening and lymphadenopathy. Rectal scraping cytology may reveal organisms as may a fecal culture. Historically diagnosis has been dependent on histologic identification of characteristic hyphae in biopsy samples of stomach, intestine, or abdominal lymph nodes. Diagnostic tissue samples are best obtained surgically, as endoscopic biopsy techniques do not reliably harvest adequate tissue in all cases for diagnosis of pythiosis. Extensive tissue reaction may be evident at laparotomy, and this should not be mistaken for neoplasia. It is best to obtain tissues and await a histologic diagnosis rather than making assumptions based on visual inspection alone. The clinical faculty at Louisiana State University has extensive experience in diagnosis and management of pythiosis and zygomycosis, and some promising new tests have recently been developed in their laboratory. These include PCR-based assays and serology. There is now a PCR test available for identification of P. insidiosum. This assay can be applied to DNA extracted either from cultured isolates or from appropriately preserved infected tissue samples. The test will reliably differentiate P. insidiosum from other Pythium species. A new highly specific and sensitive mycelial antigen-based ELISA assay for the detection of anti-P insidiosum antibodies is also now available for use on samples from both dogs and cats. This test provides an excellent means for making an early, non-invasive diagnosis, and also provides an excellent means for monitoring response to therapy. This is especially important with regard to the GI form of the disease because, unlike with skin lesions, the owner cannot visually monitor the lesions. Treatment The treatment of choice for pythiosis is aggressive surgical removal of lesions. Complete resection provides the best chance for long term cure. For intestinal lesions, the goal is to resect infected tissues with 4 to 6 cm margins. Post-operative medical management is also necessary, as there is always a chance for local recurrence. Medical management utilizing either itraconazole with or without terbinafine is recommended for a period of 2 to 4 months after surgery. Drug cost is a significant concern for some owners. If medical management cannot be afforded, then ELISA serology is recommended at several month intervals for up to a year after surgery to monitor for evidence of recurrence. Medical management alone is often unrewarding, but this is the only choice in patients that have diffuse nonresectable disease. The internal medicine service at Louisiana State University has reported that in recent years about 15% of their cases of pythiosis in dogs have responded to either itraconazole at 5 mg/lb every 24 hours for 3 to 6 months or amphotericin B lipid complex (Albecet) 1 to 1.5 mg/lb administered IV over several hours, every other day to a cumulative dose of 11 to 12.5 mg/lb. The drugs can also be used in combination, or alternatively, itraconazole and terbinafine (2.5 to 5 mg/lb per 24 hours) can be used in combination. Combination has been shown to achieve a better response overall, although the prognosis still remains very guarded. References Grooters AM, Leise BS, Lopez MK, et al. Development and evaluation of an enzyme-linked immunosorbent assay for the serodiagnosis of pythiosis in dogs. J Vet Intern Med 2002; 16:142-146. Grooters AM. Phycomycosis revisited: new developments in canine pythiosis. ACVIM Annual Forum Proceedings 2002; 479-481. Lymphocytic-Plasmacytic Enteritis of Basenjis Lymphocytic-plasmacytic enteritis (LPE) of Basenjis is an immunoproliferative process involving primarily the small intestine. This is a potentially severe form of IBD that is thought to result from a genetic disorder of immune regulation. There is an intense infiltration of lymphocytes and plasma cells in the intestinal mucosa. Other changes often include gastric rugal hypertrophy, lymphocytic gastritis and/or gastric mucosal atrophy, blunting and widening of intestinal villi, and mild dilation of lacteals. LPE of Basenjis is often progressive in nature. Clinical signs may tend to be intermittent for a period of time before they worsen and become more persistent. Gastrointestinal signs may be exacerbated by episodes of "stress" such as traveling, boarding, or other medical disorders. Clinical signs usually include small intestinal diarrhea which may become intractable, vomiting, and/or inappetence. Weight loss can become significant as the disease progresses. Ulcerative dermatitis of the pinnae occasionally occurs in conjunction with this disease. Most affected Basenjis demonstrate clinical signs by 3 to 4 years of age. Basenji enteropathy is commonly associated with hypoalbuminemia and hyperglobulinemia, especially in advanced cases. Neutrophilic leukocytosis and mild non-regenerative anemia are commonly present as well. Early in the disease course Basenji enteropathy may mimic other forms of IBD (mild symptoms, no significant laboratory abnormalities, etc.). As the disease becomes more advanced signs and laboratory parameters are characteristic, however, clinicians should be aware that other forms of intestinal disease such as lymphoma, lymphangiectasia, or histoplasmosis may be present and the symptoms of any of these diseases can mimic Basenji enteropathy. Therefore, it is always best to confirm the diagnosis by doing intestinal biopsies before instituting aggressive immunosuppressive therapy. Treatment of Basenji enteropathy is based on control of the inflammatory bowel component (see guidelines for treatment of IBD in dogs described earlier in this chapter), management of intestinal bacterial overgrowth if it is present, and feeding a controlled or hypoallergenic diet. Since the disease is often progressive Basenjis with this disorder should be carefully monitored. Over time treatment may need to include combination immunosuppressive drugs and use of long-term antibiotics (e.g., metronidazole, tylosin). If there is evidence of gastric hypomotility, a promotility drug (metoclopramide or cisapride) is also used. Most Basenjis die within 2 to 3 years of diagnosis, while some affected dogs can be maintained for a period of years with careful monitoring and ongoing therapy. Affected dogs should not be bred. Inflammatory Bowel Disease and Intestinal Lymphoma in Cats
Inflammatory Bowel Disease Inflammatory bowel disease (IBD) currently is recognized as a common and important medical problem in cats. Three general types of clinical presentations have been identified in cats with idiopathic IBD: (1) a clinical course characterized primarily by vomiting, (2) a clinical course characterized primarily by diarrhea, and (3) a clinical course that includes both vomiting and diarrhea as primary signs. Associated clinical signs can include change in appetite (anorexia, inappetence, or ravenousness), weight loss, and lethargy. In some cats, the clinical signs are cyclic; they seem to flare up and then abate in a predictable pattern. Vomiting, one of the most frequent clinical signs of IBD in cats, is most often recognized as an intermittent occurrence for weeks, months, or years. Affected cats are frequently misdiagnosed as having hairballs as the primary problem. As the disorder progresses, an increased frequency of vomiting often leads the owner to seek veterinary attention. In addition to vomiting, diarrhea is a common sign observed in feline IBD and most likely is due to derangement of normal mechanisms of absorption and motility caused by mucosal inflammation. In most cases, diarrhea is intermittent early in the course of the disorder, and there may be a transient response (weeks to several months) to dietary manipulation or any of a variety of medications. Later, the diarrhea becomes persistent and usually responds only to specific treatment, which is determined after a definitive diagnosis is made. Signs of small bowel diarrhea predominate, but signs of large bowel diarrhea may be evident as well if there is generalized intestinal tract involvement. Appetite changes in cats with idiopathic IBD vary from decreased appetite to complete anorexia to ravenousness. Inappetence seems to occur more commonly in cats that have vomiting as the primary clinical sign and usually occurs during exacerbation of clinical signs, and vomiting or diarrhea is not observed until later or not at all. The three leading differential diagnoses for a cat with a ravenous appetite, diarrhea, and weight loss are IBD, hyperthyroidism, and exocrine pancreatic insufficiency (uncommon). A definitive diagnosis of IBD can be made based only on intestinal biopsy. Further tests are run to evaluate the overall health status of the patient and to rule out other disorders. Recommended baseline tests include a complete blood count, biochemical profile, urinalysis, fecal exams for parasites, serum thyroxine test, and a feline leukemia virus test. Testing for feline immunodeficiency virus should be considered in cats with chronic wasting disease. Treatment It is important that the clinician formulate a treatment protocol based on a correlation of clinical course, laboratory and gross findings, and histologic findings rather than relying on histologic changes alone. Corticosteroids are the cornerstone of treatment for idiopathic inflammatory bowel disorders. Mild to moderate cases often respond to prednisone or prednisolone at a starting dose of 0.5 to 1 mg/lb divided twice daily for two to four weeks followed by a gradual decline in 50% increments at two week intervals. Cats with inflammatory changes graded as mild usually respond quite well to the lower dose and alternate day or every third day treatment can often be achieved by two to three months. Occasionally treatment can be discontinued altogether by three to six months. If biopsies reveal disease that is moderate to severe a prednisolone dose of 1 to 2 mg/lb divided twice daily is used for the first 2 to 8 weeks or until clinical signs resolve. I do prefer to use prednisolone over prednisone in cats with inflammatory disorders of a moderate to severe nature, as there may be improved bioavailability in some cats with prednisolone. This dose of corticosteroid is usually well tolerated in cats. In these cases a dose of 0.5 to 1 mg/lb per day may be necessary long term (months to years) to maintain clinical remission. Use of combination drug therapy may also be required at the outset to control clinical signs and prevent progression of the disease. Cats with hypoproteinemia and histologic changes graded as severe often respond quite well when an aggressive therapeutic course is undertaken. Budesonide is a glucocorticoid that represents a new alternative for management of IBD in dogs and cats, especially in severe cases that have proven to be refractory to prednisolone, metronidazole, azathioprine, and dietary management; or that are intolerant of the corticosteroids discussed above. Budesonide is a new and recently approved corticosteroid for use in humans. It is one of a group of novel corticosteroids that have been in development for use in humans in an attempt to make available alternative preparations that will help limit toxicity associated with corticosteroid use. Others include fluticasone propionate, tixocortol pivalate, and beclomethasone dipropionate. Budesonide undergoes high first pass metabolism in the liver and 90% is converted into metabolites with low corticosteroid activity. It has minimal systemic availability. The potential for typical corticosteroid side effects is significantly reduced as a result of decreased bioavailability and the resulting limited systemic exposure, which makes this a particularly attractive drug for use in humans and animals that are poorly tolerant of other corticosteroids. Budesonide also has a high receptor-binding affinity in the mucosa. It has been referred to as a "locally acting" corticosteroid. Therapeutic results with budesonide have been promising in humans with Crohn's disease, collagenous colitis and lymphocytic colitis, ulcerative colitis, either when administered as a retention enema or in oral form, and primary biliary cirrhosis. Budesonide has been used by some veterinary clinicians in recent years to treat IBD in dogs and cats. Dose recommendations vary. In humans, a range of 6 mg to 9 mg per day has been used during initial therapy. The following general recommendations have been made for dogs and cats. In general, budesonide is administered to cats and small dogs at 1 mg administered once per day. It has been used at higher doses (3 mg per small dog or cat per day), but the lower dose is frequently effective. Budesonide can be used in combination with other drugs. Since cats tolerate corticosteroids very well, there is little indication to use budesonide as initial therapy for IBD. However, this may be a very attractive option for use in diabetic cats that also have IBD, or in patients where conventional therapies have not been sufficiently effective. Potential adverse effects include PU/PD, when budesonide is used at the high end of the dose range, and GI ulceration. These reactions have been observed in some human patients. These problems would be more likely to occur in dogs than in cats. It appears to be very safe when used at the levels listed above. When combination therapy is indicated metronidazole (Flagyl) is usually the first choice to be used in conjunction with prednisone. Metronidazole's mechanism of action includes an antiprotozoal effect, inhibition of cell-mediated immune responses, and anaerobic antibacterial activity. A dosage of 5 to 10 mg/lb two times daily is used for IBD. Ideally, at least several months of metronidazole therapy is given once it is started. In some cats with severe disease long term consecutive use or one to two month cycles of treatment may be required. Side effects to metronidazole at this low dose are uncommon in cats. Occasionally nausea or vomiting may be seen. Methylprednisolone acetate (Depo-Medrol, Upjohn) can be used as sole treatment for cats with mild to moderate IBD or as adjunctive therapy when oral prednisone and/or metronidazole are used as the primary treatment and flare-ups of clinical signs occur. Consistent control of clinical signs in cats with moderate to severe IBD is more difficult to maintain when methylprednisolone acetate is used alone, however. It is recommended that sole use of methylprednisolone acetate be reserved for situations in which the owner is unable to consistently administer tablet or liquid prednisolone preparations. Initially 20 mg is given subcutaneously or intramuscularly and is repeated at 2-week intervals for 2 to 3 doses. Injections are then given every 2 to 4 weeks or as needed for control. If remission cannot be maintained with use of corticosteroids and metronidazole then azathioprine (Imuran) should be used. Azathioprine is an immunosuppressive drug with a nonspecific effect. Replication of rapidly dividing cells, including immunoblasts, is inhibited. Azathioprine is usually used in cats only when the previously discussed therapeutic measures fail to control the disease. The most important side effect of azathioprine in cats is bone marrow suppression. I use a maximum starting dose in cats of 0.15 mg/lb once every other day. At this low dose side effects are extremely uncommon. Alternatively if clinical signs of IBD do not resolve on the initial azathioprine dose the dose can be increased slightly if there is no evidence of bone marrow suppression. Because of a lag effect, beneficial therapeutic results from azathioprine often are not apparent until 2 to 3 weeks after treatment is started. Azathioprine is generally used for 3 to 9 months in cats. A majority of cats with IBD do not require azathioprine treatment. A complete blood count should be run to monitor for anemia and leukopenia at 3 to 4 week intervals for the first 2 months and then once monthly. Significant side effects are most often identified during the first 3 to 6 weeks of treatment with azathioprine. There is usually no physical evidence of early azathioprine toxicity in cats. Mild leukopenia (e.g., 3000 - 4000 cells/mm) is usually the first abnormality that is identified. Azathioprine is currently only available as 50 mg tablets. The low dosage used in cats requires that the tablet be broken into small fragments (i.e., 1/30 - 1/50 tablet depending on body weight). Since this is a very inaccurate and potentially dangerous way of administering azathioprine to cats, this drug must be administered in suspension form. A suspension preparation can be made by a compounding pharmacy service. A major advantage of administering azathioprine in this manner is that any required increase in dosage can be done very accurately. If azathioprine is well tolerated and there has been inadequate clinical improvement the dosage can be increased form 0.15 mg/lb to 0.2 to 0.25 mg/lb once every 48 hours. Another immunosuppressive drug that is used in some cats with severe IBD is chlorambucil (Leukeran). Some clinicians use chlorambucil as an alternative to azathioprine (they are not used in conjunction). Chlorambucil is an alkylating agent. Alkylating agents alter DNA synthesis and inhibit rapidly proliferating cells. Chlorambucil is administered initially at 0.05 to 0.1 mg/lb/day in conjunction with prednisolone at 1 mg/lb/day. The small pill size of chlorambucil (2 mg) allows for easy dosing. Most cats receive one-half tablet (1 mg) per day. Various dosage schedules for cats have been published. An alternate schedule is 0.07 to 0.15 mg/lb every 72 hours. Toxicities are uncommon in cats but may include anorexia, vomiting, and diarrhea, but these problems generally resolve rapidly when chlorambucil is reduced from daily to every other day administration. Bone marrow suppression is possible but uncommon, and is mild and rapidly reversible when it does occur. Once the desired clinical response is achieved, chlorambucil is gradually tapered over several months while prednisolone is continued as the primary maintenance drug. Cobalamin therapy in cats: Significant tissue level cobalamin deficiency is present in some animals with GI disease. This is usually secondary to reduced cobalamin absorptive capacity. Therapy involves administering injectable cobalamin at the following schedule for cats: 250 ug subcutaneously once a week for 6 weeks, then every 2 weeks for the next 6 doses, then dose monthly. Most generic cobalamin preparations contain 1 mg/ml (1000 ug/ml). It is important to note that multi-vitamin and B-complex injectable formulations contain significantly lower concentrations of cobalamin and they also cause pain when injected. Therefore, it is recommended that these preparations not be used for cobalamin supplementation. Unless the intestinal disease is totally resolved, long-term and perhaps lifelong supplementation with cobalamin may be necessary. The frequency of injections on a long-term basis is determined by regular measurement of serum cobalamin concentration. Because dietary allergens may play a role in the cause if IBD, specific dietary therapy may be beneficial. Often, moderate to severe degrees of IBD are either temporarily responsive or only minimally responsive to careful dietary manipulations. However, long term control of IBD with as minimal a drug administration schedule as possible may be aided by specific dietary management. This should be started as soon as a diagnosis is made and continued as drug therapy is decreased later. Chicken, duck, lamb, or venison based diets are often tried initially. A gradual change to commercial diets that are low in additives and that are formulated with chicken or lamb as their primary ingredient is then attempted. Diets such as IVD Select Care Neutral or IVD Limited Ingredient Diets, Iams Feline, Hill's Prescription Diet c/d or w/d, or Waltham select protein diets are generally recommended. Poor responses to treatment of cats with IBD usually result from:
Lymphoma is the most common feline neoplasm. It is also the most common form of gastrointestinal neoplasia in cats. Gastrointestinal lymphoma is often referred to as either well differentiated (low grade or lymphocytic), poorly differentiated (high grade, lymphoblastic, or immunoblastic), and intermediate (or mixed). Endoscopy has been shown to be a very useful modality for diagnosis of intestinal lymphoma in cats, especially when multiple biopsies are obtained using proper technique and instruments that can procure adequate size tissue samples. Full thickness intestinal biopsies may be required in a very limited number of cases in order to establish the correct diagnosis. Many cats respond favorably to treatment for intestinal lymphoma, especially with the low grade or chronic lymphocytic type. Clinical signs can be very similar to cats with IBD. Therefore, it is strongly recommended that cats with chronic GI signs undergo a biopsy procedure as early as possible, so that the correct diagnosis can be established and the best course of therapy be made available for each individual cat. Multi-agent chemotherapy is recommended for all cats with GI lymphoma. Surgery is done only if there is an isolated mass that is causing some degree of luminal obstruction. Survival times in excess of 12 to 18 months are not unusual. In some cats the response is somewhat shorter (three to six months). The prognosis for longer survival time is much better if the diagnosis is made before clinical signs become chronic and debilitation results. One study has reported excellent results in cats with chronic lymphocytic lymphoma using a protocol of prednisone (10 mg PO per cat per day) and chlorambucil (Leukeran) at a dosage of 15 mg/m2 PO, once every day for 4 days, repeated every 3 weeks. Sixty-nine percent of the cats with lymphocytic lymphoma treated with this regimen achieved a complete remission. The median disease free interval for cats that achieved complete remission was 20.5 months (range, 5.8-49 months). The median survival for all cats with lymphocytic lymphoma treated with chemotherapy was 17 months (range, 0.33-50 months). Cyclophosphamide (Cytoxan) was used for rescue in some of the cats that were entered in this protocol (225 mg/m2, PO, every 3 weeks). For further reference on this protocol, see Richter,K: Feline gastrointestinal lymphoma, ACVIM Proceedings 2001, p. 547-549. The protocol that I have used most often was originally published by Cotter in 1983. Dosage levels have been modified slightly since that time. This protocol utilizes cyclophosphamide, oncovin, and prednisone or prednisolone (COP). This protocol can be easily managed in any practice setting. Vincristine is administered intravenously at a dose of 0.5-0.75 mg/m2 once weekly for 4 consecutive weeks and then once every 3 weeks. The initial doses are often decreased by approximately 25 percent for cats that are inappetent or debilitated. If well tolerated the dose can then be gradually increased. Care is taken to ensure that none of the vincristine is given extravascularly. The average volume that is administered is quite low (0.1 to 0.15 ml for many cats, using a vincristine concentration of 1 mg/ml). Cyclophosphamide is given orally at a single dose of 225 mg/m2 every 3 weeks (50 mg tablets are used with dosage adjusted to the nearest 25 mg on the low side of the calculated dose). Prednisone or prednisolone (preferred) is given orally at 10 mg per cat per day. Although cyclophosphamide and vincristine can be given on the same day I often prefer to have the owner administer the cyclophosphamide 2 to 3 days after the oncovin. A CBC is done several times during the first month and then every 3 weeks to be sure that adequate granulocytes are present before treatment. At least 3,000 granulocytes/ul must be present before cyclophosphamide is given. If the granulocyte count drops to less than 1,000/ul 5 to 7 days after cyclophosphamide, the dose for subsequent treatments is reduced by 25 percent. The highest non-toxic dose is most likely to result in the greatest tumor cell kill. The COP protocol is generally well tolerated, although side effects may occur and dosage or interval adjustments may be necessary. Side effects of COP in cats may include anorexia, vomiting, lethargy, and severe tissue irritation if any vincristine is given extravascularly. Also, the haircoat may become thinner, but complete hair loss does not occur. Cats do tend to lose whiskers. Cats should be carefully observed for sepsis especially during the induction phase. Prophylactic antibiotics are not indicated, but any infections that occur should be treated aggressively. Advantages of this protocol include hospital visits at only 3 week intervals after the first 4 weeks, lower cost to the owner, and a treatment interval that allows recovery of normal cells between treatments. I would like to emphasize that with careful monitoring and use of a dosage schedule that is tailored to each individual cat few problems are encountered It is my general practice to encourage owners of most cats with GI lymphoma to pursue treatment that includes chemotherapy. Nutritional and metabolic support are also important. If inappetence is a problem cyproheptadine can be administered as an appetite stimulant (1 to 2 mg PO every 12 to 24 hours) on an as needed basis (long-term if necessary). If there is concurrent renal disease with azotemia or if dehydration is a problem owners are taught how to administer subcutaneous fluids at home (e.g., lactated Ringer's 100 to 150 ml every 24 hours to 48 hours, based on each individual cat's needs). Injections of B complex vitamins are sometimes helpful as well. Rarely chemotherapy can be discontinued after one year. This is done only if follow-up endoscopic intestinal biopsies indicate that there is no remaining lymphoma. Most cats remain on treatment for the remainder of their lives. If chemotherapy is poorly tolerated and reduced dosages and increased intervals between treatment times are unsuccessful in adequately decreasing side effects chemotherapy should be suspended. Prednisone should be continued however because it may help maintain remission for a period of time. L-asparaginase can also be used if cyclophosphamide and vincristine are poorly tolerated. Doxorubicin (Adriamycin) can also be used in cats. For clinicians who are inexperienced in administering chemotherapy, nor who have not treated many cats with intestinal lymphoma, it is recommended that a veterinary oncologist or internist be consulted for guidance on protocol selection and ongoing management. Many cats with intestinal lymphoma can be managed successfully for some period of time! Diagnosis and Management of Large Intestinal Disorders in Dogs
History Large bowel disorders are common in dogs. These disorders can usually be managed very successfully. It is useful in any patient with diarrhea to begin by attempting to differentiate between primarily small bowel and large bowel diarrhea, based on presenting signs and characteristics of the stool. Tests and treatment often vary for small and large intestinal disorders, making this initial characterization very important. Because large bowel - type problems occur so commonly, I often begin by asking questions relative to this area of the intestinal tract when presented with a patient with diarrhea. Specifically, the presence or absence of mucus, fresh blood, straining, and any change in frequency of defecation are discussed. Small bowel diarrhea is often characterized by an increased frequency of defecation with evacuation of larger than normal amounts of soft stool. Dyschezia and tenesmus are not characteristics of a small bowel disorder and are apparent only if a large bowel disorder is present as well (this is an important historical point, indicating probable diffuse intestinal involvement). Urgency may be present in acute small bowel disorders or in those associated with cramping. Generally, rapid evacuation of a large volume of watery diarrhea ensues (as opposed to large bowel problems in which only a small volume is passed). Presence of undigested food indicates maldigestion, which is generally due to either EPI or rapid bowel transit time. The presence of weight loss and inappetence in conjunction with chronic diarrhea suggests a significant small intestinal disorder (e.g., inflammatory bowel disease, lymphangiectasia, histoplasmosis, neoplasia), and their presence should hasten the clinician's efforts toward making a definitive diagnosis. The combination of chronic diarrhea, weight loss, and increased appetite in cats suggests hyperthyroidism, inflammatory bowel disease, EPI (rare in cats), and occasionally lymphosarcoma (some cats with GI lymphoma actually have an increased rather than decreased appetite). This combination of signs in dogs is most consistent with EPI. Characteristics of diarrhea in animals with EPI include voluminous soft consistency stools that are often rancid in nature. Coprophagy is an ancillary sign that frequently occurs in dogs with EPI. Weight loss and inappetence rarely occur in dogs and cats with intestinal disorders limited to the large bowel. Physical Examination Along with the history, physical findings help direct the clinician regarding what specific tests, if any, should be done and how quickly a work-up should be expedited. Particular attention is paid to the animal's attitude, hydration, and posture. Abnormal posture (e.g., arched back) may indicate abdominal pain that can be associated with acute or chronic disorders. Body weight and overall physical stature should be noted. The act of defecation, especially if there is a history of dyschezia or tenesmus, should be observed by the clinician whenever possible. Careful abdominal palpation is done to examine for thickened bowel (inflammatory or neoplastic infiltration), intussusception, presence of a mass that could be causing partial intestinal obstruction with resultant diarrhea, and lymphadenopathy (benign or neoplastic). The caudal dorsal abdominal region should be palpated in dogs with signs of large bowel diarrhea in order to see if there is evidence of discomfort. A rectal examination is always done in dogs with diarrhea, of any type, to examine for increased mucosal sensitivity, presence of narrowing (e.g., infiltrative disease, stricture), foreign body, or mass effect and to obtain a fresh stool sample for gross examination. Diagnosis In mild cases a diagnosis is often established based on fecal parasite examination (e.g., whipworms, hookworms, coccidia, and Giardia); positive response to empirical treatment for difficult-to-diagnose parasite problems (Giardia and whipworms); response to dietary trials (fiber augmented diet, elimination diets); or response to empirical treatment for acute colitis. Diagnostic tests for chronic large bowel diarrhea principally involve:
Complete colonoscopy with examination of the rectum, descending, transverse, and ascending colon, cecum, and ileocolic orifice area is preferred. Although examination and biopsy of the descending colon with a rigid colonoscope is commonly diagnostic in animals with large bowel diarrhea, such problems as occult trichuriasis in which whipworms may be grossly evident in the cecum but not in the descending colon, ileocolic or cecocolic intussusception, typhlitis, or neoplasia that is localized in the transverse or ascending colon may be missed unless a complete examination of the colon is done with a flexible endoscope. Another advantage of using a flexible endoscope is that ileoscopy may be accomplished in after complete colonoscopy. Biopsy samples should always be obtained during colonoscopy, regardless of gross appearance. The primary indications for performing colonoscopy are for chronic recurrent large intestinal ñ type diarrhea, suspected chronic small intestinal disease in patients in which both upper and lower small intestinal biopsies are desired (both duodenum and ileum), and for evaluation of dyschezia, hematochezia without abnormal stool consistency, and for evaluation of a mass or possible intussusception (cecocolic or ileocolic). Clostridium Perfringens Enterotoxicosis Over the last 9 years Clostridium perfringens enterotoxicosis (CPE) has emerged as a frequently recognized cause of chronic intermittent diarrhea in dogs. Although it is likely a less common cause of diarrhea in cats it is still diagnosed frequently enough that it should be considered in the diagnosis of diarrhea in cats as well. This is not a new disease. Frequent use of the definitive test (enterotoxin assay) for this disorder has revealed that CPE is seen relatively commonly in clinical practice and that CPE is a disorder that should be considered in any dog or cat with intermittent or chronic persistent diarrhea. C. perfringens is a normal vegetative enteric organism. Simply identifying C. perfringens on a fecal culture is meaningless. The pathogenesis of CPE is through an enterotoxin that is produced after certain strains of C. perfringens sporulate. The toxin damages epithelial cells of the distal ileum and colon. Inciting factors that promote sporulation are not clearly understood but may include stress, diet changes, concurrent disease, or inherent immune status. The most common clinical signs are chronic intermittent or persistent diarrhea. In some animals acute diarrhea is the primary sign. In fact, some of the cases of hemorrhagic gastroenteritis (HGE syndrome), characterized by acute bloody diarrhea and an increased packed cell volume that most practitioners have seen over the years, may have been due to CPE. Many animals exhibit signs of large bowel diarrhea, but small bowel signs may be seen as well. In some cases signs may be seen for only a day or two at a time, with persistent recurrences on a weekly, monthly, or on a less frequent basis. Stressful events or diet changes may incite flare-ups of clinical signs. In other cases C. perfringens enterotoxicosis is one of several problems that an animal may have concurrently and diarrhea may be persistent. CPE must be considered whenever more than one animal in the environment has diarrhea (e.g., household, kennel, cattery). Transmission from animal to animal can occur. A presumptive diagnosis can be made on fecal cytology in which more than 3-4 spores per high power oil immersion field are observed (the spores have a safety pin appearance and are larger than most bacteria). Definitive diagnosis is by identification of enterotoxin which is currently done via a reverse passive latex agglutination assay. Clinicians should be aware that simply seeing spores on fecal cytology does not establish a definitive diagnosis (see JAVMA February 1, 1999). Stool is submitted to the lab for enterotoxin analysis. Laboratories that run the assay include Antech Diagnostics, Colorado State University, Cornell University, and the University of California Davis. Fecal samples that will be shipped off from the hospital directly to a laboratory should be sent on ice via overnight express. If a courier service will be picking up samples for transport to the laboratory it is sufficient to keep the sample refrigerated until pick-up. The minimum amount of stool that should be submitted is the size of a pea. Typically I submit samples in a red top tube, without serum separator. In animals with intermittent diarrhea the chances of a positive toxin finding are greater when abnormal rather than a normal stool is examined. A negative result does not definitively rule-out CPE. Several antibacterial drugs are effective in controlling CPE. Acute cases often respond well to amoxicillin (10 mg/lb BID) or metronidazole (5-10 mg/lb BID) for 7-28 days. Many clinicians have likely treated CPE with these medications empirically without knowing what they were treating. Chronic cases tend to respond best to tylosin powder. The recommended dose is: Animals greater than 50 pounds 1/4 tsp BID, 26-50 lb 1/8 tsp BID, 11-25 lb 1/12 tsp BID, and less than 10 lb 1/16 tsp BID (a "pinch"). Cats definitely do not accept the powder well at all, even when it is mixed in very tasty foods. It is best to have the powder reconstituted to capsule form for administration to cats. The medication is very safe. Some animals require treatment for several to many months (3-12 or more). Over time the dose may in some cases be successfully reduced to SID and then every other day dosage (after several months or more on a BID schedule). Dietary fiber supplementation may also help control CPE. Probable mechanisms include decreased C. perfringens fecal concentration, lower colonic pH which prevents sporulation, and increased concentrations of SCFA. Follow-up testing at 3-6 months can be done to determine if toxin persists. It is best to continue treatment if the test remains positive, even if there is no diarrhea. Once daily to every other day tylosin in conjunction with dietary fiber supplementation are used in chronic cases. Management of Large Intestinal Diarrhea Treatment of large intestinal diarrhea frequently involves dietary manipulation, specific anthelmintic therapy for parasite infections, antibacterial drugs or antifungal agents for infectious disorders, and antiinflammatory therapy for large intestinal inflammatory bowel disease (sulfasalazine and metronidazole are the most common drugs used to control inflammation of the large intestine in dogs). Symptomatic therapy for acute non-complicated diarrhea includes bowel rest and dietary manipulation. The treatment for Clostridium perfringens enterotoxicosis has already been described above. If pharmacotherapy is deemed necessary for acute large intestinal diarrhea, metronidazole is often the most indicated drug and is frequently used for 5 to 7 days on an empirical basis. It is emphasized that some animals with chronic diarrhea may have several disorders at the same time (e.g., inflammatory disease, Clostridium perfringens enterotoxicosis, and small intestinal bacterial overgrowth). A thorough work-up will lead to diagnosis of each disorder, with subsequent development of a comprehensive treatment plan. The likelihood of more rapid resolution of symptoms is much greater when each existing problem is properly treated. Sulfasalazine (Azulfidine) is a drug that is commonly used for colitis in dogs. It is used somewhat less commonly in cats, primarily because corticosteroids are very effective in controlling colitis in cats, whereas corticosteroids are rarely effective in dogs with colitis (unless the disorder is primarily eosinophilic colitis, which is very uncommon in my experience). Sulfasalazine is a combination of 5-aminosalicylic acid (ASA) and sulfapyridine tied together by an azo bond that prevents significant absorption of the drug before it reaches the colon. Once in the colon, where the bacterial count is considerably higher than the small intestine, bacteria split the bond and release the 5-ASA for its local effect. Olsalazine (Dipentum), Asacol, and Pentasa are drugs that contain only 5-ASA combined by an AZO bond. These drugs can reach the colon in higher concentration that Azulfidine. They are more expensive, however, and dosage preparations are limited. I still use Azulfidine in most dogs in which use of a 5-ASA containing drug is desired. The starting dose of Azulfidine in dogs is generally 10-15 mg/lb TID. In more chronic or severe cases a dose of 15-25 mg/lb TID is recommended. The dose should not exceed a total of 5 grams per day. Side effects are uncommon, but may include keratoconjunctivitis sicca (KCS), allergic dermatitis, nausea and vomiting, and cholestatic jaundice. In my experience, KCS occurs quite uncommonly in dogs on sulfasalazine. I do, however, routinely take the precaution of doing a Schirmer tear test on middle age to older dogs before instituting sulfasalazine. Duration of therapy is quite variable. In mild colitis cases, 7-14 days of therapy with sulfasalazine may be sufficient, while in others several months may be required. In some dogs with chronic unrelenting colitis sulfasalazine may be needed for months to years. In these cases the lowest possible frequency is used. For example, the dose may be gradually reduced to a BID and then SID schedule, and in some cases a single dose given every other day may be effective on a long-term basis. Sulfasalazine works well in combination with metronidazole. If clinical signs suggest significant patient discomfort and/or biopsies reveal moderate to severe large intestinal disease I will frequently administer both drugs in combination. Metronidazole has both an antibacterial and antiinflammatory effect. It is useful in treatment of both small and large intestinal inflammation. Metronidazole's mechanism of action includes an antiprotozoal effect, inhibition of cell-mediated responses, and anaerobic antibacterial activity. Metronidazole is administered at 5 to 10 mg/lb two times daily. Also, I have successfully managed some canine patients with mild to moderate lymphocytic-plasmacytic colitis on a long-term basis with metronidazole. Irritable Bowel Syndrome The irritable bowel syndrome (IBS) is a chronic disorder characterized by variable signs of gastrointestinal dysfunction or distress in the absence of underlying structural causes for the symptoms. It has also been termed spastic colon, nervous colon, spastic colitis, and mucous colitis. IBS has been well recognized in man for many years and is classified as a functional bowel disorder. The term functional disorder indicates disordered or abnormal physiologic function in the absence of pathologic lesions. IBS in humans is characterized by intermittent disturbances of intestinal function with unpredictable periods of exacerbation and remission. Sometimes bouts occur in response to nonspecific emotional stresses or other psychologic factors. Clinical experience, based on detailed patient evaluation (including negative enteroscopies and colonoscopies) and no evidence of organic disease in a number of patients with compatible signs, strongly suggests that a similar syndrome occurs in small animals, especially dogs. The clinical presentation in dogs with IBS most often involves signs of a large bowel disorder. Intermittent passage of small amounts of mucoid stool, with or without dyschezia, and increased frequency of defecation are commonly observed. Hematochezia may occur but is infrequent. There are occasional episodes of urgency to defecate, perhaps because of a sensation of incomplete evacuation. Stools may be soft but formed or watery. Unlike the situation in humans, in my experience, constipation does not commonly occur in dogs with IBS. Often, other signs occur, with or without diarrhea, that heighten the clinician's suspicions that IBS may be present. Intermittent bloating, nausea, vomiting, and abdominal pain may also be present. There may be evidence of significant distress (e.g., reluctance to move, groaning, pacing) associated with cramping. It is emphasized that IBS is a chronic disorder characterized by an intermittent or cyclic pattern of symptoms. The clinician should evaluate the history carefully, with particular interest in determining what, if any, stressful or disruptive events occur in close association with clinical signs. Stressful factors may include being left alone for a longer period of time than the animal is accustomed to, household conflict between humans, or other environmental stimuli, such as work details for police or other performance dogs. Pecking order problems with other dogs in the immediate environment may also be a factor. While some dogs with IBS are timid and reserved or, alternatively, hyperactive, many other dogs seem to be well adjusted, and stressful factors cannot be reliably implicated as a cause. In these situations, distinct periodic aberrations in normal motility patterns (involving either small or large bowel or both) may be involved, and stress may play no role at all. Alternatively, perhaps over-responsive, "doting" owners may themselves represent a significant "stress" factor. There is no known sex or breed predilection for IBS. I have examined a number of both large breed dogs (police, guard, seeing eye) and small to medium-size dogs in which clinical signs were consistent with IBS and in which detailed diagnostic evaluations failed to provide any positive diagnostic information for the presence of organic disease. It is strongly suggested that a diagnosis of IBS be limited to patients that have undergone detailed diagnostic evaluation, lest the term be used too loosely to describe conditions with a provable cause for which the clinician has failed to investigate thoroughly. Diagnosis The diagnosis of IBS is complicated by the fact that similar clinical signs can be caused by a number of gastrointestinal disorders (i.e., functional disorders may resemble the presentation of organic disorders) potentially involving any area of the gastrointestinal tract. Since there are no histologic changes identifiable in patients with IBS, no hematologic or biochemical abnormalities, and no pathogens to identify on culture or serology, IBS is truly a diagnosis of exclusion. The clinician can only be confident of a diagnosis of IBS once all other conditions have been excluded. In my experience, abnormal gastric motility, inflammatory bowel disease, and chronic idiopathic colitis are the most commonly encountered disorders that must be differentiated from IBS. As the treatment course and prognosis for these disorders can vary considerably, it is strongly recommended that patients with chronic signs be thoroughly evaluated so that the best possible therapeutic regimen can be instituted. If clinical signs are poorly responsive to initial treatments, the clinician should undertake a more detailed investigation, including a complete blood count, biochemical profile, and fecal cytology. (Increased numbers of neutrophilic leukocytes suggest inflammatory small or large bowel disease or invasive bacterial enteritis.) Since chronic Clostridium perfringens enterotoxicosis can cause chronic signs very similar to those of IBS, fecal toxin analysis should be done to evaluate for this problem. Contrast radiographic studies (food mixed with barium or radiopaque markers - BIPS) should be considered if a gastric motility disorder is suspected (stomach should be empty by 8 to 10 hours after a meal). Contrast studies are gener |