Diabetes Mellitus Remission in Cats: Strategies to Enhance the Possibility of Remission

Transcription

1 Diabetes Mellitus Remission in Cats: Strategies to Enhance the Possibility of Remission Edward C. Feldman, DVM, Diplomate, ACVIM (Internal Medicine) University of California, Davis Abstract Diabetes mellitus is a relatively common endocrine condition in cats and dogs. While virtually all dogs with diabetes require life-long administration of insulin injections, diabetes can be transient in cats and in many cases may go into remission. Is there an optimum treatment regimen for diabetic cats to enhance the possibility of their hyperglycemia resolving and elimination of their need for insulin administration via injection? This article reviews the insulin, dietary, and ancillary treatments that can be used to improve the chances of remission in diabetic cats. Key Concepts Type of diabetes in cats is derived from people and applied similarly to cats. There is no test to differentiate between type 1 and type 2 diabetes mellitus in cats. Type 1 diabetes mellitus is defined in people as an absolute insulin deficiency that is permanent (life-long) and requires insulin administration for long-term survival. Remission is extremely rare in Type 1 diabetes. Type 2 diabetes mellitus is defined as a relative insulin deficiency, typically associated with both insulin resistance and an inability to synthesize and secrete sufficient insulin to maintain glycemic control. Insulin resistance is most commonly associated with obesity, lack of exercise, and consumption of a diet too high in carbohydrates and too low in fiber. Remission of this type of diabetes mellitus in cats is relatively common. The pathogenesis of diabetes mellitus in insulin-resistant cats is believed to involve a cycle that includes insulin resistance in tissues, increased insulin secretion, hyperglycemia, and, ultimately, beta cell loss with reduced concentrations of insulin secretion. It is believed that remission occurs through reduction and stabilization of blood glucose concentrations in cats that have recoverable beta cell function. Insulin s role involves controlling hyperglycemia to a degree that allows recoverable (viable) pancreatic beta cells to produce sufficient endogenous insulin to maintain normoglycemia. While control of hyperglycemia enhances the possibility of achieving remission of diabetes mellitus in cats, remission is associated as much or more with the introduction of a low-carbohydrate, high-protein diet than with a particular type of insulin. From Chronic Diseases, Proceedings of a Symposium sponsored by Intervet/Schering-Plough Animal Health. Copyright 2010 The Gloyd Group, Inc. All Rights Reserved. The opinions expressed in this article are those of the author and do not necessarily reflect the official label recommendations and point of view of the company or companies that manufacture and/or market any of the pharmaceutical agents referred to.

2 No single type of insulin is more likely than others to induce remission of diabetes mellitus. Remission rates in cats treated with porcine insulin zinc suspension (Vetsulin, Intervet/Schering-Plough Animal Health) ranged from 13% to 41% in diabetic cats that were not on a controlled diet. Based on the evidence that dietary control in conjunction with Vetsulin treatment promotes remission, it is reasonable to expect that remission rates may exceed 50% when Vetsulin treatment is combined with other management factors, including early diagnosis, good glycemic control, diet, and frequent at-home testing. Diabetic cats that no longer require exogenous insulin are not generally considered cured, and have the potential for recurrence. Feline diabetes mellitus is a disease that requires lifelong care and monitoring, even during phases of remission that may last for years. Pathogenesis of Diabetes Mellitus in Cats Sixty to 80% of cats with diabetes appear to have a condition similar to type 2 diabetes in people based on data from clinical trials and histologic evidence of islet amyloidosis and beta cell loss. The clinical similarities between people and cats with diabetes mellitus include a higher incidence of type 2 versus type 1 diabetes in both species; onset in middle age; an association with obesity, inactivity, and improper diet; and the potential for not needing exogenous insulin therapy with use of proper treatment strategies. Some diabetic cats, like people, have been shown to develop insulin resistance, defined as a reduced capacity of tissues to respond to insulin. Cats with intrinsically low insulin sensitivity are at increased risk of developing glucose intolerance with weight gain. In addition, male cats develop diabetes mellitus more commonly than female cats, perhaps in part because males have lower insulin sensitivity. The most common cause of insulin resistance in people is obesity and it is also considered a likely cause for resistance in cats. As the numbers of obese people (and cats) have increased, here has been a parallel increase in the incidence of type 2 diabetes. Adipose tissue, central visceral stores in particular, is an active endocrine organ and part of the innate immune system. Adipose tissue in lean people secretes relatively high levels of the adipocytokine adiponectin, which has anti-inflammatory action, is associated with increased insulin sensitivity and, therefore, a favorable metabolic status. With obesity, adiponectin secretion decreases and large amounts of non-esterified fatty acids, leptin, and pro-inflammatory cytokines are secreted by adipocytes and/or activated macrophages within the adipose tissue. These factors impair insulin signaling and induce or worsen insulin resistance. It is important to note, however, that not all obese cats become diabetic and not all diabetic cats are obese. It was estimated in one report that at the time of diagnosis, about 50% to 60% of diabetic cats are obese, 30% to 40% are normal in weight, and 5% to 10% are underweight. Insulin resistance is also commonly associated with infection or inflammatory conditions. Chronic Diseases Symposium Proceedings 2

3 Beta cell dysfunction is also crucial in the development of type 2 diabetes mellitus. The exact nature of the underlying mechanisms leading to beta cell dysfunction is unclear. Islet cell mass in individuals with type 2 diabetes mellitus is reduced by 40% to 60% due to apoptosis (a form of cell death). Apoptosis is likely triggered by a combination of genetic and acquired factors, such as glucose toxicity, lipotoxicity, and increased deposition of amyloid in islets. Chronic hyperglycemia (glucose toxicity) impairs insulin secretion and contributes to insulin resistance, whereas acute hyperglycemia stimulates insulin secretion and glucose utilization. Interestingly, one of the first experiments on glucotoxicity was performed in cats. In a study in 1948, researchers administered large doses of glucose to normal cats and induced permanent hyperglycemia, degeneration of islets, and ketonuria. In more recent studies, chronic hyperglycemia in previously normal cats resulted in insulin concentrations consistent with type 1 diabetes mellitus within 5 days. Another factor in the pathogenesis of diabetes mellitus is lipotoxicity, specifically the deleterious effects that fatty acids can have on beta cells. It is likely that hyperglycemia must be fully manifested for lipotoxicity to have this effect. Amyloid is likely to be a contributing but not the primary cause of beta cell failure. Islet amyloid is derived from amylin, a hormone co-secreted with insulin from the pancreas. In a state of chronic increases in insulin secretion, as occurs with resistance, there is also increased secretion of amylin. This, in turn, can lead to increased islet deposition of amyloid that contributes to beta cell apoptosis. Amyloid deposition is found in 65% to 90% of cats with diabetes mellitus but is also common in non-diabetic older cats. The pathogenesis of diabetes mellitus in insulin-resistant cats is believed to involve a cycle that includes insulin resistance in tissues (ie, insulin receptors that are less responsive than normal), increased insulin secretion, hyperglycemia, and, ultimately, beta cell loss with reduced concentrations of insulin secretion. Remission is thought to occur through reduction and stabilization of blood glucose concentrations in cats that have recoverable beta cell function. Good diabetic control is often difficult to achieve, however. It is important to avoid significant under- or overdosing of insulin, as either can result in hyperglycemia, apparent resistance, and further beta cell damage. Factors Involved in Remission of Diabetes in Cats Early diagnosis of diabetes mellitus gives cats a better chance of achieving remission because those cats are more likely to have recoverable beta cells compared with cats that have more chronic disease. The extent of beta cell damage is a critical factor; some cats are unable to achieve remission even with treatment because their beta cells lack the capacity to recover and produce insulin. Cats may have persistent insulin resistance due to consumption of a less-than-ideal diet, obesity, inactivity, chronic inflammation, chronic infection, or any of a wide variety of other conditions. Inability to Chronic Diseases Symposium Proceedings 3

4 achieve diabetes remission could also be caused by irreversible beta cell damage simply from chronic type 2 diabetes or destruction of cells by other causes. Further, some cats appear to progress from type 2 to type 1 diabetes mellitus regardless of the level of care provided, perhaps as a result of ongoing immune-mediated destruction of pancreatic beta cells. Effective insulin treatment ideally should maintain blood glucose concentrations between 120 and 300 mg/dl. Attempts at maintaining blood glucose concentrations within the standard laboratory reference range (~75 to 110 mg/dl) are not recommended because attempts to maintain normoglycemia are often associated with overdosing, which can lead to severe life-threatening hypoglycemia or severe hyperglycemia, or both. Under-dosing, however, results in continuing significant hyperglycemia and must also be avoided. Change of diet alone, particularly to one that is low in carbohydrates and high in protein, may allow remission in about one third of cats on insulin therapy according to some authors, while others claim remission rates in excess of 50%. A diet that is also high in fiber would likely be beneficial. Low-stress or at-home blood glucose monitoring is preferred as an aid in effective glycemic control. The answer to the question of how often diabetic cats should be monitored remains elusive, but the appropriate monitoring schedule likely depends at least in part on individual cats and their owners. The duration of therapy may have an effect on remission. Many cats that enter remission do so within 16 weeks of initiating insulin treatment; however, remission has been reported to occur as long as 30 months after diagnosis and initiation of exogenous insulin therapy. Although remission may last for years, diabetic cats that no longer require exogenous insulin are not generally considered cured. Many cats that go into remission are likely to have ongoing subclinical pathology and the potential for recurrence. The exception would be cats that are misdiagnosed with diabetes mellitus when they actually have temporary stress-induced hyperglycemia. Feline diabetes mellitus is a disease that requires lifelong care and monitoring, even during phases of remission. The onset of clinical disease in cats can be associated with events that increase insulin resistance, most notably: Indoor confinement Physical inactivity Obesity Feeding a high-carbohydrate, low-protein diet The second tier of contributors to chronic insulin resistance includes: Chronic infection (especially periodontal disease and urinary tract infection) Chronic Diseases Symposium Proceedings 4

5 Chronic inflammatory conditions (especially periodontal disease and pancreatitis) Certain medications (eg, glucocorticoids) known to cause insulin resistance Other chronic illnesses (eg, kidney disease, heart failure) Much less common but still important causes of insulin resistance include diseases associated with excess production of insulin antagonistic hormones, such as acromegaly (growth hormone) and hyperadrenocorticism (glucocorticoids). The cornerstones of type 2 diabetes management in people include weight loss, switching to a diet lower in carbohydrates and higher in fiber, and exercise. Prevention and/or treatment of concurrent diseases (especially infection and/or inflammation) can assist in stabilizing blood glucose concentrations and reduce the need for insulin. Because diabetes mellitus in some cats is similar to type 2 diabetes in humans, management of the disease should also be similar. The Role of Diet in Achieving Remission Diet is one of the understated factors in reported remission rates among cats with diabetes mellitus. Switching diabetic cats that are already being treated with insulin to a low-carbohydrate, high-protein diet can have a significant influence on the likelihood of remission. This is true in as many as 50% of afflicted cats. Cats are metabolically adapted to consume primarily protein and fat, and diets high in carbohydrate appear to be unfavorable. It has been shown that using a low-carbohydrate, high-protein diet results in better clinical control and increased rates of diabetic remission. According to data from the University of Zurich (1), remission rates are 15% to 25% when diets with variable compositions are fed whereas remission rates increase above 50% when highprotein, low-carbohydrate diets are fed. Recent Studies on Remission of Diabetes Mellitus in Cats The use of porcine, bovine, and human insulins and the importance of their differing amino acid sequences as compared with natural cat insulin has been discussed. Dog and porcine insulin are similar while cat and bovine insulin are similar. Amino acid differences are not critical, however, in determining the insulin type used. Rather, it is dose, frequency of administration, diet, and many other factors that determine success or failure in therapy or in the achievement of remission. In addition, any cat may respond better to one insulin than to another. Therefore, having several choices is always an advantage. Porcine Insulin Zinc Suspension without Dietary Restrictions The use of porcine insulin zinc suspension (Vetsulin [US] and Caninsulin [rest of world], Intervet/Schering-Plough Animal Health) in the management of diabetic cats has been evaluated in several studies. Porcine insulin zinc suspension is classified as a lente insulin (intermediate-acting). Most studies include both cats with newly diagnosed diabetes mellitus and those with previously diagnosed and treated diabetes mellitus. Chronic Diseases Symposium Proceedings 5

6 Further, cats were not required to be on a specific diet to be entered into some studies. This information is useful, especially considering the potential variation among cats with diabetes and the variability of success in controlling their diet. The largest studies of insulin therapy without dietary modification carried out in the United States are the field trials whose data supported the addition of the feline claim to the Vetsulin label. Reported remission rates in two field trials were 33% (4 of 12) and 13% (8 of 61) of the cats studied, respectively. The generally tighter serum glucose control, based on fructosamine and mean glucose concentrations, achieved in the first trial may have been responsible for the higher percentage of remissions. These remission rates were achieved without changes in diet. Remission rates might have been higher if low-carbohydrate diets (with or without increased fiber) had been required in all cats. Other studies that grouped newly diagnosed and previously treated diabetic cats and that had no dietary requirements identified similar numbers of cats going into remission with porcine insulin zinc suspension treatment. Porcine Insulin Zinc Suspension in Cats with Diabetes Mellitus and Severe Ketoacidosis A retrospective study of cats presented to the veterinary teaching hospital at the University of Zurich, Switzerland, was conducted by Sieber-Ruckstuhl and associates (1) from 2003 to Cats newly diagnosed with documented diabetes and ketoacidosis (DKA) were studied. Once DKA resolved via treatment with a standardized protocol that included the use of short-acting insulin, insulin therapy was changed to porcine insulin zinc suspension. This insulin was given at a starting dose of 0.25 to 0.5 U/kg every 12 hours. The cats were also fed a commercial low-carbohydrate, highprotein diet. Seven of 12 (58%) cats that were initially ketoacidotic achieved remissions lasting as long as 3 years. These cats had more pancreatic disease, bacterial urinary tract infection, and cardiomyopathy than cats at the same hospital with newly diagnosed uncomplicated diabetes mellitus achieving remission. Thus, DKA, once thought to occur only in cats with type 1 diabetes, has been documented in cats with type 2 disease as well. These data demonstrate that cats with DKA can eventually achieve remission from diabetes through appropriate insulin and dietary therapy. Lente Insulin versus Insulin Glargine in Cats Fed a Low-Carbohydrate, High-Protein Diet A randomized, open study by Weaver and colleagues (2) investigated human recombinant lente insulin (0.5 U/kg every 12 hours; n = 7) versus insulin glargine (0.5 U/kg every 24 hours; n = 6). There were three newly diagnosed cats in the lente-treated group and five in the glargine-treated group; the other five cats had been previously treated, with poor glycemic control. All the cats were given low-carbohydrate, highprotein diets and they were monitored for 12 weeks. Three of the lente-treated cats (43%) and one of the insulin glargine treated cats (17%) went into remission. Reports of diabetic cats fed a low-carbohydrate, high-protein diet include a study by Boari et al (3) that investigated five newly diagnosed and previously treated diabetic cats administered insulin glargine at an initial dose of 0.25 to 0.5 U/kg twice daily. They Chronic Diseases Symposium Proceedings 6

7 reported that two of five cats (40%) went into remission within 12 weeks. Roomp and Rand (4) looked primarily at previously treated cats (50 of 55 cats) and began treatment with glargine twice a day (dose not specified) with the addition of home monitoring via daily glucose curves (another glycemic control factor); 64% of the cats (35 of 55) achieved remission. A study by Hall and colleagues (5) suggested that diet did not have the intended effect on feline metabolism. Their study was designed to differentiate between the effects of a maintenance diet (six cats) and a low-carbohydrate, high-protein diet (six cats) in diabetic cats. The authors noted that their maintenance diet may have been too low in carbohydrates to serve as a control. In addition, obese cats did not lose weight and cats that were not overweight at the beginning of the study became overweight during the study. Half the cats were newly diagnosed with diabetes mellitus, and all received insulin glargine at an initial dose of 0.25 U/kg twice daily. Two cats (17%) one from each diet group went into remission within 10 weeks. Lente Insulin, Protamine Zinc Insulin, or Insulin Glargine in Newly Diagnosed Cats on a Low-Carbohydrate, High-Protein Diet The results of a prospective clinical study limited to newly diagnosed diabetic cats fed a low-carbohydrate, high-protein diet were reported by Marshall and Rand in Although this study is commonly cited, it has only been published as an abstract. Inclusion criteria and randomization technique used in the study were not reported and this study should remain outside of decision processes until appropriate review and publication. Cats were treated with lente insulin, protamine zinc insulin, or insulin glargine at an initial dose of 0.25 to 0.5 U/kg twice daily. In this study, 25% (two of eight) of lente-treated cats, 38% (three of eight) of protamine zinc insulin treated cats, and 100% (eight of eight) of insulin glargine treated cats went into remission within 16 weeks. The high level of remission observed in the insulin glargine treated cats has not been replicated in other studies. Porcine Insulin Zinc Suspension versus Insulin Glargine No statistical difference in remission rates can be shown between lente insulin (Vetsulin) and insulin glargine when diet is controlled. A meta-analysis of the available data regarding cats fed a low-carbohydrate, high-protein diet demonstrates no statistically significant difference (P = 0.196) in remission rates among diabetic cats treated with lente insulin (44.4%) and those treated with insulin glargine (58.8 %). The achievement of good glycemic control in any diabetic cat, regardless of insulin type used, improves the chances for achieving remission when used in combination with other factors known to contribute to remission in cats. Conclusions from These Studies Based on the studies reviewed here, porcine insulin zinc suspension (Vetsulin) is effective in achieving remission in diabetic cats that are not on a controlled diet, with Chronic Diseases Symposium Proceedings 7

8 remission rates ranging from 13% to 41%. These results are similar to those achieved with the use of other insulin types under comparable conditions. In addition, porcine insulin zinc suspension is effective in achieving remission in cats that have had severe DKA (58%). No statistical difference in remission rates can be shown between lente insulin (including Vetsulin) and insulin glargine when diet is controlled. Nearly all of the studies reporting remissions with insulin types other than porcine insulin zinc suspension (Vetsulin) also included other diabetes management strategies (eg, dietary control) in their design; therefore, simple comparison of remissions achieved without considering these factors can be misleading. For example, with the exception of one study, the data available for insulin glargine treated cats are from studies performed in cats fed a low-carbohydrate, high-protein diet. Switching to this type of diet led to remission in three of nine cats that were already being treated and stabilized with insulin. Such a switch also increased the number of remissions in a study by Bennett and associates (7) in which diabetic cats were being treated with various insulins; 68% of cats on a low-carbohydrate, high-protein diet achieved remission compared with 41% of cats on a moderate-carbohydrate, high-fiber diet. The wide range of remission rates reported in the literature with insulin glargine treatment reinforces the influence of multiple factors in achieving remission. In the often-cited Marshall and Rand study (6), of eight newly diagnosed cats on a lowcarbohydrate, high-protein diet treated with lente insulin, the percentage of cats achieving remission (25%) is similar to that reported in several other studies without such dietary requirements, 13% to 41%. Based on the evidence that dietary control in conjunction with Vetsulin treatment promotes remission and that remission is more likely in newly diagnosed cats, it is reasonable to expect that remission rates may exceed 50%, as reported by Sieber-Ruckstuhl (1), when Vetsulin treatment is combined with other management factors including early diagnosis, good glycemic control, diet, and frequent at-home testing. This is evident from the summary of studies in which remission rates reached 44.4% when only one management factor (ie, dietary control) was added to insulin therapy. Additional research will likely continue to add supporting evidence that newly diagnosed cats on a total diabetes management program, including dietary control, can achieve remission rates with porcine insulin zinc suspension treatment that are comparable to rates associated with other insulin types. Acknowledgment This article has been adapted from an article by the author that was previously published as a Supplement to the Compendium Continuing Education for Veterinarians, Volume 31, Number 7(A), July References 1. Sieber-Ruckstuhl NS, Kley S, Tschuor E, et al. Remission of diabetes mellitus in cats with diabetic ketoacidosis. J Vet Intern Med. 2008;22(6): Chronic Diseases Symposium Proceedings 8

9 2. Weaver KE, Rozanski EA, Mahony O, et al. Use of glargine and lente insulins in cats with diabetes mellitus. J Vet Intern Med. 2006;20(2): Boan A, Aste G, Rocconi F et al. Glargine insulin and high-protein, low-carbohydrate diet in cats with diabetes mellitus. Vet Res Commun. 2008;32(Suppl 1):S243-S Roomp K, Rand J. Intensive blood glucose control is safe and effective in cats using home monitoring and treatment with glargine. J Feline Med Surg. 2009; 5. Hall TD, Mahony O, Rozanski EA, et al. Effects of diet on glucose control in cats treated with twice-daily insulin glargine. J Feline Med Surg. 2009;11(2): Marshall RD, Rand JS, Treatment with glargine results in higher remission rates than lente or protamine zinc insulins in newly diagnosed diabetic cats (abstract). Proc 23 rd ACVIM Forum. 2005, p Bennett N, Greco DS, Peterson ME, et al. Comparison of a low carbohydrate-low fiber diet and a moderate carbohydrate-high fiber diet in the management of feline diabetes mellitus. J Feline Med Surg. 2006;8; Additional references are available from the author upon request. Chronic Diseases Symposium Proceedings 9

10 Lyme Disease 2010: Diagnosis, Treatment, and Prevention Richard E. Goldstein, DVM, Diplomate, ACVIM and ECVIM-CA Cornell University Abstract Despite the large number of clinical and nonclinical Lyme cases seen in small animal practice in Lyme-endemic areas, the veterinary practitioner faces many unanswered questions regarding this disease. Practical aspects of the diagnosis, management, and prevention are discussed in this article, which highlights new research on whether to treat nonclinical Lyme-positive dogs and new data on optimal protocols for canine Lyme vaccines. Key Concepts The classic Lyme signs arthritis, pain, fever, and lethargy are observed only in approximately 5% to 10% of infected cases, tend to occur 2 to 5 months after the infection, and typically resolve within approximately 3 days with antibiotic therapy. The SNAP 4Dx is an excellent test for screening dogs for Lyme infection. This can be done as part of a screening program for nonclinical dogs or when Lyme disease is suspected. A positive result is indicative of active Lyme infection. Tick control is crucially important and is an indispensable part of any Lyme prevention strategy. Three canine Lyme disease vaccines are commercially available, all of which produce borreliacidal antibodies in the dog in response to vaccinal outer surface protein A (OspA). The antibodies work in the gut of the tick to bind the bacteria during the blood meal, thus sterilizing the gut of the tick and preventing the transmission of the bacteria into the dog. While OspA is expressed in the tick s gut, OspC is the main immunogenic protein exhibited by the tick in its salivary glands and in the dog s body during natural infection. A recently launched vaccine (Nobivac Lyme; Intervet/Schering-Plough Animal Health) contains two inactivated Borrelia isolates, one OspA-producing isolate and one unique OspC-producing isolate, both of which stimulate the production of borreliacidal antibodies, perhaps adding an additional layer of protection. Concerns have been raised whether vaccination can contribute to clinical signs of Lyme disease or to the syndrome known as Lyme nephritis. While vaccination of Lyme-negative dogs raises very little concern, there may be some risk when vaccinating Lyme-positive dogs, especially if the C6 antibody titer is very high. In these cases, modifications to the standard protocol of testing and vaccinating, such as a course of treatment with doxycycline prior to vaccination, may be warranted. From Chronic Diseases, Proceedings of a Symposium sponsored by Intervet/Schering-Plough Animal Health. Copyright 2010 The Gloyd Group, Inc. All Rights Reserved. The opinions expressed in this article are those of the author and do not necessarily reflect the official label recommendations and point of view of the company or companies that manufacture and/or market any of the pharmaceutical agents referred to.

11 The alternative not vaccinating Lyme-positive dogs and risking additional infections is likely to be more detrimental than the possible negative effects of vaccination. A current recommendation based on experimental data and a growing number of field studies suggest that there may be some benefit in treating Lyme-positive dogs that have no clinical signs but exceed a certain C6 quantitative titer. Treatment should be with doxycycline for 4 to 6 weeks. Titers should then be rechecked 6 months later to evaluate treatment. This strategy has not been proven to prevent disease later on but appears to be reasonable based on our level of knowledge today. Lyme disease and its causative tick-borne agent Borrelia burgdorferi have become a extremely common in many areas of the United States and Europe over the last 20 years in both humans and dogs (1). Anecdotally, it appears that 2009 stood out in terms of the emergence of high concentrations of Lyme-positive dogs in areas that previously were thought to have only occasional cases. Despite the large number of clinical and nonclinical Lyme cases seen in small animal practice in Lyme-endemic areas, the veterinary practitioner faces many unanswered questions regarding this disease. These include even the most basic question how to treat a clinical case of Lyme disease or even how to recognize infection with Borrelia burgdorferi in a sick dog? Additional questions most practitioners struggle with, perhaps even more often, are if, when, and then how to monitor nonclinical dogs for evidence of Borrelia burgdorferi infection? And perhaps most important of them all is how to prevent Lyme disease? How good is tick control? Should we or should we not vaccinate? Who should we vaccinate and do vaccines prevent or promote the most severe manifestation of Lyme disease Lyme nephritis? After a brief overview of Borrelia burgdorferi pathogenesis necessary for the understanding of these issues, this discussion will revolve around the ways that veterinarians can answer these questions best in their practice. Clinical Signs of Lyme Disease The lack or apparent lack of clinical signs in most dogs with active Lyme infection makes both the diagnosis and the study of this disease very difficult. In dogs, overt clinical signs are observed only in approximately 5% to 10% of infected cases (2). These signs tend to occur 2 to 5 months after the infection and include lameness (monoarthritis or polyarthritis, Figure 1), lymphadenopathy, lethargy, and fever (3). Unlike in humans with acute infections, skin lesions are uncommon in dogs. The classic Lyme signs of arthritis, pain, fever, and lethargy typically resolve within approximately 3 days, in some cases only with antibiotic therapy (1). Some questions remain regarding more serious, less common syndromes that have been associated with Lyme infection in dogs including renal disease (Lyme nephritis), cardiac disease (myocarditis), and neurologic disease. Another question yet to be answered is whether some dogs get the devastating chronic recurrent disease seen in some infected humans. Chronic Diseases Symposium Proceedings 2

12 Figure 1 Typical acute non weight-bearing monoarthritis in a dog with clinical Lyme disease. Diagnosis What diagnostic tools are available? (Table 1) Bacterial Culture or Identification This is very difficult in the case of Borrelia due to the small number of infecting organisms and the complicated techniques involved in their successful culturing. Serology Clinically we must rely on serology in conjunction with clinical signs to diagnose this disease. There are currently three types of serologic tests commercially available: nonspecific or kinetic enzyme-linked immunosorbent assay (ELISA), or KELA; C6 antibody testing; and Western blot. Nonspecific or Kinetic ELISA (KELA) This is a very sensitive test aimed at identifying any antibodies produced against Borrelia whole cell antigen. It does NOT differentiate between antibodies produced in reaction to Lyme infection versus Lyme vaccination and will be positive in both instances. Since we can usually not be sure of infection status and many times of vaccination status, a positive nonspecific ELISA should ideally be followed up with an additional test that would confirm infection, such as a Western blot (4) or a C6 antibody test (5). Chronic Diseases Symposium Proceedings 3

13 Table 1. Diagnosis, Prevention, and Treatment of Canine Lyme Disease Diagnostics Bacterial culture and identification Unfortunately not clinically useful today Serologic tests: Nonspecific (kinetic) ELISA Western blot C6 antibody testing Prevention Tick control Numerous approved products available, including topical spot-on products, sprays, powders, dips, shampoos, collars Vaccines Three approved vaccines available (see text) Treatment Dogs with clinical signs of Lyme disease Dogs with Lyme nephritis Doxycycline, 10 mg/kg/day (divided 5 mg/kg twice daily or given as a once daily dose), for 4 to 6 weeks Amoxicillin, 20 mg/kg twice daily for 4 to 6 weeks Consider treating any dogs positive for both Lyme and proteinuria or microalbuminuria with 4 to 6 weeks of doxycycline. If proteinuria persists or worsens (based on urine protein/creatinine ratio): o Continue doxycycline o Consider a low-protein diet and an angiotensin-converting enzyme (ACE) inhibitor o Consider renal biopsy o If the renal biopsy is consistent with immune-mediated glomerulonephritis, consider immunosuppression with drugs such as mycophenolate, azathioprine, chlorambucil, cyclophosphamide or cyclosporine in consultation with a veterinary internist. C6 Antibody Testing There are currently two commercially available tests for canine antibodies against the Lyme C6 peptide. This peptide is expressed only during infection; therefore, these tests are meant to be positive only in the event of natural exposure and negative in naive dogs or dogs vaccinated for Lyme (6). These tests include the in-house SNAP 3Dx or SNAP 4Dx Tests and the quantitative C6 antibody test available through IDEXX. Chronic Diseases Symposium Proceedings 4

14 The SNAP 4Dx is an excellent test for screening dogs for Lyme infection. This can be done as part of a screening program for nonclinical dogs or when Lyme disease is suspected. A positive result is indicative of active Lyme infection (7). The quantitative C6 antibody test checks for similar antibodies as the 4Dx but in a quantitative fashion. We still have a lot to learn about the value of knowing the quantitative C6 titer in all cases of Lyme infection, but we do know that the quantitative C6 titer does drop with therapy (8) and we have shown that the titer also correlated very well with circulating anti-lyme immune complexes (9) and is likely in the future to be a useful tool in treatment decisions of nonclinical dogs. Western Blot This technique involves a blot smeared with Lyme antigens located in known locations. This is a relatively expensive and labor-intensive type of test and its interpretation requires expertise, and therefore this will never be in-house technology. As we have learned more about the 4Dx and quantitative C6 assays, they have taken over some of the role of the Western blot as a confirmatory assay. At this time I would recommend using the Western blot only in dogs where the vaccinal status is important to the veterinarian. Lyme Prevention Tick Removal It takes time for an infected tick to transmit Borrelia to a dog; this typically can happen no sooner than 48 hours from the beginning of the blood meal (1). Therefore, daily tick removal especially immediately after possible tick exposure is beneficial. People should handle possibly infected ticks with care though, since there is the potential for transmission to the person from the tick. Tick control is crucially important and is an indispensable part of any Lyme prevention strategy. A recent study demonstrated that tick control with fipronil was successful in preventing Lyme infection in dogs when exposed to infected ticks compared with nontreated control dogs (10). Should We Vaccinate?? Whenever contemplating the use of a vaccine one needs to weigh the pros and cons. These are the considerations that, in my opinion, should be evaluated in such cases: How common is the pathogen? How common is the disease? How severe is the disease? How treatable is the disease? How good is the natural immunity? How expensive, reliable, and safe is the vaccine? Is there a zoonotic potential? Chronic Diseases Symposium Proceedings 5

15 For canine Lyme disease vaccines: Common? The disease is very common. Even though most dogs are asymptomatic, the infection rate is so high in the Northeastern United States that it is a very common disease. Ten percent of infected dogs showing clinical signs out of 50% to 75% of the dogs in some areas is a lot!. Severity? Lyme disease is not that bad in most cases. What we do not know is the prevalence and significance of more severe syndromes such as Lyme nephritis and chronic recurrent disease. Treatable? Lyme disease is relatively treatable in most cases in terms of eliminating clinical signs. But in many dogs, based on experimental studies, we may never get rid of the bacteria even with antibiotic therapy (11). So perhaps Lyme diseases is not that treatable. And then of course there is Lyme nephritis, which at best seems very hard to treat. Natural immunity? Not very good, because the immune response appears to dampen over time. This is likely a result of the bacteria hiding themselves from the immune system, mainly in tissue such as synovial membranes, and down-regulating their immunogenic surface proteins (12). How expensive, reliable, and safe is the vaccine? Three kinds of vaccines currently are commercially available; two are whole cell bacterin based and the other a recombinant outer surface protein A (OspA) single antigen vaccine. All appear to be relatively inexpensive. While there is very little published safety data, all three vaccines are USDA licensed for dogs and so have been through safety testing. All three types of vaccine are likely to be effective. How do these vaccines work? One mechanism of action common to all three vaccines is via production of anti-ospa antibodies. These antibodies produced in the dog in response to vaccinal OspA antigen work in the gut of the tick to bind the bacteria during the blood meal (13), thus sterilizing the gut of the tick and preventing the transmission of the bacteria into the dog. Until recently that was the only likely mode of action for all canine Lyme vaccines. In June 2009, a new vaccine was launched (Nobivac Lyme; Intervet/Schering-Plough Animal Health). This vaccine is unique in that instead of being a conventional bacterin, the typical strain of Borrelia that produces OspA in culture, this vaccine contains two isolates, one OspA-producing isolate and one unique OspC-producing isolate (14). OspC is the main immunogenic protein exhibited by the tick in its salivary glands and in the dog s body during natural infection (15). Thus, for the first time, a vaccine reliably induces the production of borreliaciadal OspC antibodies in dogs, the theory being that the borreliacidal OspC antibodies could bind and eliminate Borrelia that have managed to slip through the anti-ospa barrier and are transmitted from the tick into the vaccinated dog. This borreliacidal effect of the anti-ospc antibodies induced by the vaccine has been shown to occur in vitro; additional studies will need to be performed to verify the role of OspC in vivo. Chronic Diseases Symposium Proceedings 6

16 Zoonosis? Not really, although there is some risk to people from infected ticks that are removed before finishing the blood meal. When given a choice, the ticks tend to only feed on one species at a time. Safety of Lyme vaccines? There are different aspects to this question: Regarding acute vaccine reactions, one could assume that all the dogs in the vaccine studies seemed fine so the vaccine must be safe. Obviously that is not a definitive answer. The vaccine studies are too small to pick up uncommon reactions, are too short in duration, are invariably conducted by the vaccine manufacturers, and many of these studies are never published. While safety studies that are much larger are conducted on every vaccine, these are typically looking for acute reactions and most often not published. The more pressing question is: Do vaccines contribute to clinical signs associated with Lyme disease or to the syndrome known as Lyme nephritis? There is a large amount of new and exciting data to try to answer this question, and it is a good question because we now know that Lyme nephritis is not caused by an inflammatory response to renal invasion of Borrelia burgdorferi organisms (16). Lyme nephritis is a condition associated with an accumulation of immune complexes in the kidney. We have shown that all Lyme-positive dogs have a measurable level of Lyme-specific circulating immune complexes in their blood (9). Recently we have also been able to purify renal immune complexes from kidneys of dogs that died of Lyme nephritis and to identify Lymespecific antibodies present within those immune complexes. Studies are still ongoing regarding possible co-infections or other antigen antibody complexes in those kidneys. Other evidence for the lack of a key role for vaccine-induced antibodies in Lyme nephritis is the fact that, despite looking very closely, we have yet to identify a dog with Lyme nephritis with solely vaccinal antibodies within the renal immune complexes. Vaccinal antibodies in the immune complexes are also fairly rare in dogs that have been infected as well as vaccinated against Lyme disease. To answer the question directly, though, we have just completed a large study at Cornell assessing the possible effects of vaccination with either a whole cell bacterin or recombinant OspA vaccines on immune complex formation in dogs. Lyme-negative as well as Lyme-positive dogs were included in different groups in the study. Briefly, the study suggests that there is very little cause for concern when vaccinating Lymenegative dogs. When vaccinating Lyme-positive dogs, there may be cause for some concern, especially if the C6 antibody titer is very high and possibly if the whole cell bacterin vaccine is being used. Alternative protocols involving treatment prior to vaccination and the use of recombinant vaccines in Lyme-positive dogs are currently being studied and are summarized below. My recommendations (based on the above criteria): Vaccinate in endemic areas? Yes, to prevent infection from ticks. What defines an endemic area? That is a good question. Through screening the prevalence should be determined in each practice. In an area with high prevalence (over 20%?), it may be Chronic Diseases Symposium Proceedings 7

17 logical to vaccinate all dogs. In an area with lower prevalence, identifying dogs at increased risk may be a smarter way to do it. Vaccinate Lyme-negative dogs? Yes. Vaccinate positive dogs? Yes, to prevent re-infection from ticks as the immune system may or may not be able to prevent active disease even if the dog is Lyme positive. This is the most relevant scenario for the concern over the immune complex issue. Based on what we know to date, including the most recent studies, that is my recommendation. The alternative not vaccinating and risking additional infections is likely to be more detrimental than the possible negative effects of vaccination. In some cases, especially those with apparent high C6 titers, because of concern of postvaccinal increase in circulating immune complex, modifications to the standard protocol of testing and vaccinating may be warranted. Possible modifications include a course of treatment with doxycycline prior to vaccinating a positive dog, especially a dog with a high quantitative C6 titer. Even without such treatment it appears that the benefits of vaccinations far outweigh the risks as we know them today. How often to vaccinate? Annually, with the currently available vaccines. Even in vaccinated dogs, tick control must be stressed to the owners since a very heavy Lyme burden may override vaccinal protection. Treatment I believe there is little question about treating Lyme-positive dogs with clinical signs. What should we use? There is definitely no proven benefit in vaccinating a dog with clinical Lyme disease from a therapeutic standpoint and that is not recommended. That leaves antibiotics: amoxicillin and doxycycline both work well and should be used for 4 to 6 weeks. Doxycycline will also likely be better at treating additional organisms that may have co-infected our patient along with Lyme disease and is therefore the therapy of choice (17). The more difficult question is what about the nonclinical majority, that is, Lyme-positive dogs with nor clinical signs? Why not treat them all? Although it is hard to look the concerned owner of a young Lyme-positive golden retriever in the eye and refuse to treat a possibly fatal disease, theoretically we should approach the treatment question from a risk/cost-benefit standpoint. At this time I am not sure we have enough information to make an informed choice in this matter. What do we know? Every Lyme-positive dog should be tested for proteinuria and if proteinuric (urine protein-creatinine ratio [UPC] > 0.5 1), these dogs should be treated as clinical cases. They should be given antibiotics and should not be vaccinated, at least not until after being treated. Lyme-positive dogs may remain infected with Lyme at low numbers with or without treatment (11). Chronic Diseases Symposium Proceedings 8

18 There is good evidence to show that treatment tends to lower Lyme titers faster than they would decline without treatment (especially C6 antibody titers)(8). This is also true for circulating immune complexes (18) and therefore may be true for bacterial load as well. Based on experimental and a growing number of field studies data, IDEXX Laboratories is currently recommending treatment above a certain C6 quantitative titer and then rechecking titers 6 months after the initial positive test (or 5 months after the treatment has ended) later to evaluate the success of the treatment.. The more we gain experience with this approach, and as more controlled field studies are published, the better this looks. We hope to have a more definitive answer in the near future for this pivotal question. Lyme Nephritis Current Recommendations for Screening and Treatment of Dogs with Suspected Lyme Nephritis These recommendations are based on limited experience and theory, and not yet on strong clinical data (17):. Monitor dogs in endemic areas for Lyme infection. Screen all positive dogs for signs of proteinuria or microalbuminuria. Screen all dogs that present with proteinuria or microalbuminuria for Lyme. Consider treating any dogs positive for both Lyme and proteinuria or microalbuminuria with 4 to 6 weeks of doxycycline. If proteinuria persists or worsens (based on urine protein/creatinine ratio): o Continue doxycycline o Consider a low-protein diet and an angiotensin-converting enzyme (ACE) inhibitor o Consider renal biopsy o If the renal biopsy is consistent with immune-mediated glomerulonephritis, consider immunosuppression with drugs such as mycophenolate, azathioprine, chlorambucil, cyclophosphamide or cyclosporine in consultation with a veterinary internist. Chronic Diseases Symposium Proceedings 9

19 References 1. Greene CE, Straubinger RK. Borreliosis. In: Greene CE (ed): Infectious Diseases of the Dog and Cat, 3 rd ed. Philadelphia: WB Saunders Co, 2006, pp Levy SA, Magnarelli LA. Relationship between development of antibodies to Borrelia burgdorferi in dogs and the subsequent development of limb/joint borreliosis. J Am Vet Med Assoc. 1992;200: Appel MJG, Allen S, Jacobson RH, et al. Experimental Lyme disease in dogs produces arthritis and persistent infection. J Infect Dis. 1993;167: Lindenmayer J, Weber M, Bryant J, et al. Comparison of indirect immunofluorescentantibody assay, enzyme-linked immunosorbent assay, and western immunoblot for the diagnosis of Lyme disease in dogs. J Clin Microbiol. 1990;28: Levy S, O Connor TP, Hanscom JL, et al. Utility of an in-office C 6 ELISA test kit for determination of infection status of dogs naturally exposed to Borrelia burgdorferi. Vet Therap. 2002;3: Liang FT, Jacobson RH, Straubinger RK, et al. Characterization of a Borrelia burgdorferi VlsE invariable region useful in canine Lyme disease serodiagnosis by enzyme-linked immunosorbent assay. J Clin Microbiol. 2000;38: Bacon RF, Biggerstaff BJ, Schriefer ME, et al. Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2-tiered testing using whole-cell lysates. J Infect Dis. 2003;187: Levy SA, O'Connor TP, Hanscom JL, et al. Quantitative measurement of C6 antibody following treatment of Borrelia burgdorferi antibody-positive nonclinical dogs. Clin Vaccine Immunol. 2007;Nov 14 [Epub ahead of print]. 9. Goldstein RE, Atwater DZ. Serologic and circulating immune complex analysis in dogs naturally infected with Borrelia burgdorferi (abstract). ACVIM Forum Jacobson R, McCall, J, Hunter J, et al. The ability of fipronil to prevent transmission of Borrelia burgdorferi, the causative agent of Lyme disease to dogs. J Appl Res Vet Med. 2004;2: Straubinger RK, Straubinger AF, Summers BA, et al. Status of Borrelia burgdorferi infection after antibiotic treatment and the effects of corticosteroids:an experimental study. J Infect Dis. 2000;181: Straubinger RK. PCR-based quantification of Borrelia burgdorferi organisms in canine tissues over a 500-day postinfection period. J Clin Microbiol. 2000;38(6): Gipson CL, de Silva AM. Interactions of OspA monoclonal antibody C3.78 with Borrelia burgdorferi within ticks. Infect Immun. 2005;73(3): LaFleur RL, Dant JC, Wasmoen TL, et al. Bacterin that induces anti-ospa and anti- OspC borreliacidal antibodies provides a high level of protection against canine Lyme disease. Clin Vaccine Immunol. 2009;16(2): Grimm D, Tilly K, Byram R, Stewart PE, et al. Outer-surface protein C of the Lyme disease spirochete: a protein induced in ticks for infection of mammals. Proc Natl Acad Sci USA. 2004;101(9): Chronic Diseases Symposium Proceedings 10

20 16. Hutton TA, Goldstein RE, Njaa BL, et al. The search for Borrelia burgdorferi in kidneys of dogs with suspected Lyme nephritis. J Vet Intern Med. 2008;22(4): Littman MP, Goldstein RE, Labato MA, et al. ACVIM small animal consensus statement on Lyme disease in dogs: diagnosis, treatment, and prevention. J Vet Intern Med. 2006;20(2): Goldstein RE, Atwater DZ. Serology and circulating immune complexes in dogs naturally infected with Borrelia burgdorferi before and after doxycycline therapy (abstract). ACVIM Forum Chronic Diseases Symposium Proceedings 11

21 Approach to Chronic Otitis: Diagnostic and Therapeutic Options Wayne Rosenkrantz, DVM, Diplomate, ACVD Animal Dermatology Clinic, Tustin, California Abstract Otitis externa is a common problem of dogs and cats that often presents a diagnostic and therapeutic challenge. Inadequate treatment and management of primary and secondary causes and perpetuating factors often leads to treatment failures and chronic cases. This article provides the information you need to improve your diagnostic and therapeutic approach to the problem ear, including cytology, culture and sensitivity, otoscopic examination, cleaning and ear flushing, and treatment with the appropriate topical and systemic agents. Key Concepts Treatment of otitis externa is dependent on identifying and controlling the predisposing factors, primary and secondary causes, and perpetuating factors whenever possible. Inadequate treatment and reversal of the progressive pathologic responses, tympanic membrane alterations, and otitis media often leads to treatment failures or recurrences. While the ears may seem better externally and to the client, the success of treatment can only be determined by otoscopic examination and follow-up cytologic examination of material from the ear canal. Culture and sensitivity testing should never be done without cytology. If the cytology reveals suppurative inflammation with rods or no visible organisms and the animal has not responded to appropriate topical and systemic antibiotic therapy, then a culture and sensitivity may be indicated. Once an ear has been properly cleaned, a variety of topical drying agents and/or disinfectants can be applied into the ear. Some of these agents can serve as primary or sole treatments and in other situations they will be part of a treatment plan or serve as a longer-term maintenance program to control relapses. Topical antibacterial agents are only one aspect of treating secondary or primary bacterial otitis; these agents are often used in conjunction with cleansers, disinfectants, and systemic antibiotics. Most topical antibacterial products also contain glucocorticoids, which decrease the formation of exudate, glandular secretions, and inflammation and swelling. Systemic antibiotics are used whenever otitis media or moderate or marked proliferative changes are present or when appropriate topical therapy and cleansing was not effective. Initial antibiotic selection is usually made empirically based on cytologic findings. From Chronic Diseases, Proceedings of a Symposium sponsored by Intervet/Schering-Plough Animal Health. Copyright 2010 The Gloyd Group, Inc. All Rights Reserved. The opinions expressed in this article are those of the author and do not necessarily reflect the official label recommendations and point of view of the company or companies that manufacture and/or market any of the pharmaceutical agents referred to.

22 Glucocorticoid therapy is indicated in markedly inflamed edematous otitis and when chronic pathologic changes cause marked stenosis of the canal lumen. Some cases of allergic otitis may be treated with systemic glucocorticoids, allowing the initial topical therapy to be a low-potency glucocorticoid product. Otitis externa is a common problem of dogs and cats that often presents a diagnostic and therapeutic challenge. Learning to effectively manage otitis and especially chronic otitis is an important part of small animal practice and can be a major area of practice business or growth. Management of otitis externa is dependent on identifying and controlling the primary and secondary causes and predisposing and perpetuating factors whenever possible. Inadequate treatment and reversal of the progressive pathologic responses often leads to treatment failures or recurrences. Even though outwardly the client perceives that the ears seem better, the success of treatment can only be determined by otoscopsy and follow-up with diagnostic cytologic examination of material from the ear canal. The treatment of otitis externa often requires a comprehensive plan that involves the use of proper cleaning and topical and systemic treatments. Diagnostic Considerations One of the most important approaches to dealing with chronic ear disease management is identifying and controlling the underlying etiologies. The etiology of otitis externa includes the primary and secondary causes, complicating factors such as bacterial and yeast infections, and perpetuating and predisposing factors (1). All of these variables need to be addressed to clear and prevent relapse of otitis cases. Primary Causes Primary causes usually are an actual inciting agent or condition that directly causes damage to the ear canal skin. These can occur alone and induce otitis externa without any other cause or factor. The primary cause may be very subtle and may often go unrecognized by the owner or even the veterinarian until a secondary complicating factor occurs. Once a primary cause alters the aural environment secondary complicating factors, such as infections, often develop. The vast majority of cases will have a primary cause. The most common primary causes seen in a dermatology referral practice are atopic disease, food allergy, epithelialization or metabolic disorders, and ear mites (Figures 1, 2, 3 and 4). For successful long-term management it is critical that a primary cause be found and either eliminated or control be secured. Secondary Causes The secondary causes do not create disease in a normal ear; they contribute to or cause pathology only in the abnormal ear. As such, they occur in combination with primary causes or predisposing factors. The most common secondary causes are infections (Figure 5).Secondary causes of otitis externa generally are easy to eliminate Chronic Diseases Symposium Proceedings 2

23 once identified and when they are chronic it is usually because primary causes or perpetuating factors have not been adequately addressed. Figures 1 and 2 Atopic dermatitis in a mixed-breed dog showing not only the classic facial periocular patterns, but also classic otitis externa. Figure 3 A Labrador retriever with adverse food reaction and severe acute otitis externa with secondary bacterial and Malassezia infections. Chronic Diseases Symposium Proceedings 3

24 Figure 4 A cocker spaniel with primary idiopathic seborrhea with concurrent ceruminous otitis and secondary bacterial overgrowth. Figure 5 Golden retriever with atopic dermatitis and Malassezia otitis. Chronic Diseases Symposium Proceedings 4

25 Perpetuating Factors Perpetuating factors are changes in the anatomy and physiology of the ear that occur in response to otitis externa. These factors may be subtle at first but over time can develop into the most severe component of chronic ear disease. These factors are not disease specific and are most commonly seen in chronic cases. Once present, they accentuate or permit the development of secondary causes, such as infection, by providing environments and microscopic niches that favor their persistence. In many cases, perpetuating factors prevent the resolution of otitis externa when treatments are only directed at primary and secondary causes. The most common examples of perpetuating factors include ear canal proliferation, scarring, stenosis, and calcification (Figure 6).Perpetuating factors are the most common reason otitis externa cases require surgery. Figure 6 Labrador retriever with chronic proliferative otitis externa due to inadequate control of underlying atopic dermatitis and secondary infections. Predisposing Factors Predisposing factors alone do not cause otitis externa but increase the risk of development and persistence of chronic infection. These factors work in conjunction with either primary or secondary causes to become a significant problem. Examples of predisposing factors include conformation issues, excessive moisture in ears, and side effects of previous treatments (Figure 7). Chronic Diseases Symposium Proceedings 5

26 Figure 7 Standard poodle with contact reaction from an ear cleanser/disinfectant. Basic Diagnostic Testing Cytology Cytologic examination of discharge usually does not establish a definitive diagnosis, but it is valuable in determining which infectious agents, if any, are present. The material for cytologic examination is best collected by ear loop or tube passed deep into the canal and should be representative of the discharge in the deeper levels of the canal. If not, additional samples may be collected by an ear loop passed through a cone to allow visualization down the ear canal so the material selected is representative of the deeper discharge. Even with this technique the results of a prospective study indicate that cytology from the middle ear may reveal different organisms than those detected in the external ear canal (2). Your cytology sample should be smeared onto a glass slide, heat fixed, and stained with Diff-Quik or Gram stain. You should describe the presence of any inflammatory cells as well as the number per oil immersion field (oif) of each type of bacteria and yeast. Cytologic evaluation is the preferred method to ascertain the role of Malassezia and in many situations bacteria (Figures 8 and 9). The author generally considers yeast counts greater than 3 yeasts/oif and bacteria counts greater than 5 cocci/oif or 1 rod/oif as being abnormal. Even more important is the presence of inflammatory cells, which is highly suggestive that secondary infection is present (Figures 10 and 11). Chronic Diseases Symposium Proceedings 6

27 Figure 8 Tremendous Malassezia overgrowth is seen on this Diff-Quik stain (1000x) from the golden retriever shown in Figure 5. Figure 9 Overgrowth of a mixture of rods, cocci, and a large segmented normal resident bacteria (Simonsiella) is seen on this Diff-Quik stain (1000x) from the cocker spaniel shown in Figure 4. Chronic Diseases Symposium Proceedings 7

28 Figure 10 Refractory otitis externa associated with a resistant bacterial infection is seen in this mixed-breed dog. Figure 11 Rods, cocci, and polymorphonuclear cells (PMNs) with macrophages are seen on this Diff-Quik stain (1000x) from the mixed-breed dog shown in Figure 10. Rods were ultimately cultured as Pseudomonas spp. Chronic Diseases Symposium Proceedings 8

29 Culture and Sensitivity Culture and sensitivity is indicated if resistant strains of bacteria are suspected (history of chronic topical therapy; bacteria persist on cytologic examination in spite of apparently appropriate therapy) or in the presence of severe proliferative changes or otitis media. It has been noted that the spectrum of bacteria seen in the middle ear versus the canals may differ and that the sensitivity pattern of the same organisms from the canals versus the middle ear may also differ. In one study different organisms were cultured from the middle and external ear and even when Pseudomonas spp was cultured twice from the same ear, different strains were seen based on the sensitivity pattern exhibited (2). Originally this was interpreted as different strains in different parts of the ear but it appears variation occurs even from the same sample site (3,4). Ideally, cultures should be taken after discontinuing topical or systemic antibiotic therapy for 3 to 5 days. When rods are seen on cytology (suggesting the presence of Pseudomonas), sensitivities to polymyxin B, ticarcillin, and third-generation cephalosporins should be routinely requested in addition to those routinely offered. The correlation between culture and sensitivity results and response to topical therapy does not always correspond as well as we would like. This likely has to do with the fact that when resistance is noted on sensitivity testing utilizing the Kirby-Bauer disc diffusion system, it is resistance to microgram/milliliter concentrations of the antibiotic. Topical antibiotics are routinely used at milligram/milliliter concentrations. These higher concentrations may prove efficacious, even when resistance has been suggested to lower concentrations of antibiotic. It is still recommended to perform cultures when you suspect resistance, even if you think you will be using only topical therapy. Culture and sensitivity data appear to be of more value in choosing antibiotics when a decision has been made to use systemic therapy for otitis media or deeper soft-tissue infections of the ear canal. Disc diffusion sensitivity should be performed with minimum inhibitory concentrations (MICs). The MIC data may suggest that higher dosages of antibiotics might still be efficacious. Culture and sensitivity testing should never be done without cytology. If the cytology reveals suppurative inflammation with rods or no visible organisms and the animal has not responded to appropriate topical and systemic antibiotic therapy then a culture and sensitivity may be indicated (Figures 12, 13, 14, 15, and 16). The laboratory should also be sent a cytology slide and/or any information regarding the organisms seen at time of collection so they know whether multiple organisms should be identified. Chronic Diseases Symposium Proceedings 9

30 Figures 12 and 13 Cocker spaniel with medially nonresponsive otitis media and head tilt secondary to idiopathic seborrhea, with progressive proliferative and secondary mixed infections. Figure 14 Heavy mixed rods and some cocci infection, requiring culture and sensitivity are seen on this Diff-Quik stain (1000x) from the cocker spaniel shown in Figure 12. Chronic Diseases Symposium Proceedings 10

31 Figure 15 Another cocker spaniel currently being treated for pemphigus foliaceus with immunosuppressive drug therapy who developed a concurrent methicillin-resistant staphylococcal infection (MRSI) requiring culture and sensitivity for antibiotic selection. Figure 16 Degenerating polymorphonuclear cells (PMNs), intracellular and extracellular cocci, and single acantholytic cell are seen on this Diff-Quik stain (1000x) from the cocker spaniel shown in Figure 15. Chronic Diseases Symposium Proceedings 11

32 Basic Equipment Otoscopes must have a strong light and power source combined with at least 10x magnification that allows focusing within the normal length of the ear canal. If any of these components is not present otoscopic examinations may not be totally effective. Many practitioners use diagnostic otoscope heads. In general, I prefer the surgical otoscope head, which allows more manipulation and angulation as well as easier use with cleaning and therapeutic procedures that require passing instruments or tubes into the ear canal with concurrent visualization. One of the most common mistakes made in practice is the use of hand-held battery-operated otoscopes that no longer have enough power to adequately light the deep ear canal. Every clinic should have at least one plugin otoscope that is not dependent on having fresh fully charged batteries. Various sizes of otoscope cones are needed to be able to examine the different sizes and breeds of dogs and cats seen in practice. The advent of fiberoptics, improved lighting, and miniaturization of video cameras combined with a rigid endoscope designed for use in the external ear canal has led to the development of fiberoptic video-enhanced otoscopy (FOVEO). This equipment is connected to a video monitor, printer, digital recorder, or video camera. The fiberoptic tip with camera also magnifies and with a focal length of several centimeters can improve the visualization of the ear canal. In addition to improving visualization it allows permanent recordings of what is present as well as allowing clients or other veterinarians to see the pathology of the ear canal. In some cases small tears of the tympanic membrane not readily seen with the normal 10x magnified otoscope will be apparent. In addition, filling the ear canal with water or saline is often performed with FOVEO as it further enhances magnification and keeps the tip of the camera lens from fogging. This cannot be done with normal otoscopes. With water or saline in the ear canal tears not even visible with FOVEO alone will sometimes be found and are recognized by the air bubbles coming from the middle ear cavity. This equipment is relatively expensive but considering the improved diagnostics and more importantly the client education and impact as a tool for gaining client support for recommended procedures is well worth the investment in a busy practice. Other equipment needed for diagnostic or therapeutic procedures includes bulb syringes and cleaning solutions for initial cleaning of ear canals. Ear curettes or loops are used to break up concretions or remove small pieces of ear wax, debris, and foreign bodies especially when they are near the tympanum. Several types are available although my favorites are Buck and Billeau ear loops. A narrow alligator forceps is an essential tool for removing debris, hair, and foreign bodies. A small biopsy forceps is also a valuable piece of equipment to sample tissue within the ear canal for histopathology. The biopsy forceps need to be small enough to pass through the FOVEO if one is used. Long needles that can be passed through the otoscope cone and reach the deep ear canal are used to perform intralesional injections or for myringotomy and middle ear flush cytology; 22-gauge is preferred. Tomcat catheters may also be used for flushing, and if cut sharp can be used for myringotomy. Feeding tubes (Sovereign feeding tube and urethral catheter) in various sizes, especially 5 and Chronic Diseases Symposium Proceedings 12

33 10 French, are cut short with the end still large enough to fit over the hub of a syringe. Intravenous tubing and a three-way stopcock are helpful especially with the use of FOVEO equipment. Cleaning and Ear Flushing Patient restraint is required for examination and adequate cleaning and flushing, and sedatives or general anesthesia is often required. Anesthesia also allows for the placement of an endotracheal tube that precludes the aspiration of fluids that may pass through the middle ear into the auditory canal and then into the posterior pharynx. Many clients are reluctant to have their pet anesthetized but are often more understanding if the need for getting the ears cleaned and completely examined is explained in detail. It also helps to explain the potential problems that might occur it the patient moves while instruments are in the ear and that some procedures are painful. There are a variety of techniques to clean and flush the ears. Initial evaluation of the canal should be performed to determine the severity of disease, the type and amount of debris in the canal, and the best initial approach to use to remove the debris. Use of a combination of cleaning techniques often facilitates more rapid removal of debris from the canal. Alligator forceps and ear curettes can be used through a conventional surgical otoscope head to remove larger debris. Flushing with or without ceruminolytics using a 12-mL syringe attached to an open-ended Tomcat catheter or cut infant feeding tubes can be quite effective. The infant feeding tubes can be used in a variety of diameters and lengths to reach the desired location and to accommodate the size of the material to be suctioned and removed. Larger diameter tubes can be used in the ear canal and smaller diameter tubes can be passed into the middle ear cavity. These techniques also allow for more rapid re-direction of the flushing and suction. The video-otoscope can also be used for cleaning the ear. Common problems such as lens fogging or obstruction with debris are best dealt with by removing the probe and wiping the lens with a cotton ball soaked in 70% isopropyl alcohol or simply using the video-otoscope submerged in warm saline or water. In a liquid medium there is less fogging and often better magnification and visualization. A picture may be taken at the initiation of the cleaning to document before and after improvement. A sample of debris can also be aspirated from the depths of the ear for both cytologic examination and possibly for culture and sensitivity testing. Flushing and suctioning can be done through the working channel utilizing a 16-gauge, 5.5-inch Teflon catheter (Abbot Hospital Inc.) or a 4½-inch, open-ended Tomcat catheter. Procedures usually begin after larger debris is removed from the canal. The channel can be used for passage of biopsy or grabbing forceps or an appropriately modified ear curette. Treatment As mentioned above treatment of otitis externa depends on identifying and controlling the predisposing factors, primary and secondary causes, and perpetuating factors whenever possible. Inadequate treatment and reversal of the progressive pathologic Chronic Diseases Symposium Proceedings 13

34 responses, tympanic membrane alterations, and otitis media often leads to treatment failures or recurrences. While the ears may seem better externally and to the client, the success of treatment can only be determined by otoscopic examination and follow-up cytologic examination of material from the ear canal. The treatment of otitis externa often requires a complete plan that will involve the use proper cleaning and topical and systemic treatments. Once an ear has been properly cleaned, a variety of topical drying and/or disinfectants can be applied into the ear. Some of these agents can serve as primary or sole treatments and in other situations they will be part of a treatment plan or serve as a longer term maintenance program to control relapses. Topical Therapy Drying Agents Drying agents are used after the ear is cleaned and relatively dry. Most drying agents contain isopropyl alcohol and one or more of the following: acetic acid, boric acid; benzoic acid; malic acid, salicylic acid, silicone dioxide, or sulfur. Veterinary products of this type include CleaRx Treatment Dryer (DVM Pharmaceuticals); OtiCare B (ARC Laboratories); Otic Clear (Butler), and MalAcetic Otic (DermaPet). These products can be used at home for prophylactic treatment of swimmer s ear and as a deodorizer. Alcohol and higher concentrations of the acids may be irritating or cause a burning sensation in ulcerated ears. Disinfectants Disinfectants such as chlorhexidine and iodophors are commonly used but are considered by some investigators to be contraindicated with a ruptured tympanum (5). Other studies, however, suggest that clinical concentrations of chlorhexidine may not be as ototoxic as previously thought (6). Using ceruminolytics and flushing with water or saline may decrease the development of ototoxicity when chlorhexidine is used. Acetic acid is also a very good disinfectant that has been shown to be very effective in the treatment of otitis externa in humans. It is believed that its activity is not completely due to the ph because other acidic products are not as effective in killing Pseudomonas and Staphylococcus. Acetic acid is most effective against Pseudomonas, with a 2% solution being lethal within one minute of contact. Staphylococcus and Streptococcus can be killed within 5 minutes of contact with 5% acetic acid; however, at this concentration there is often more irritation. When an acetic acid product is needed, the author will commonly use MalAcetic Otic, which is combined with 2% boric acid. Tetrasodium Edetate has also been used as a potent disinfectant and can be very effective in cases of Pseudomonas. It has value when used by itself or in conjunction with other disinfectants and antimicrobials. When combined with low concentrations of chlorhexidine 0.15% (TrizEDTA Plus, DermaPet), it can have synergistic effects to control Pseudomonas infections (7). In another study, TrizEDTA was shown to have a sparing effect on the MIC of enrofloxacin against ciprofloxacin-resistant Pseudomonas. This may benefit treatment of both susceptible and resistant Pseudomonas bacteria (8), and is available commercially as T8 Solution (DVM Pharmaceuticals) and TrizEDTA. Chronic Diseases Symposium Proceedings 14

35 Combination Products with Drying and/or Disinfectant Agents Combination products are another group of ear cleansers that also have some drying and/or disinfectant agents. These products are utilized most effectively in the mild waxy and inflamed ears that are noted on examination but are not the presenting complaint. These products also help ears that have a mild objectionable odor to the client. They are not indicated for clinical otitis externa. These products can also be utilized for longterm management of milder cases of recurrent waxy otitis externa after the otitis is controlled. They tend to be modified drying products with fewer drying ingredients and more antimicrobial properties and mild ceruminolytic agents. Some are primarily mild cleansers with some disinfectant and drying agents added. A variety of ingredients are combined with drying agents to achieve these effects, including propylene glycol; lanolin; glycerin; lactic acid, and parachlorometaxylenol chlorhexidene. Some of the products in this category include Epi-Otic and Epi-Otic Advanced Ear Cleansers (Virbac), OtiClens A (ARC Laboratories), and Oti-Fresh (Pan American). Epi-Otic has the advantage of being alcohol free. A newer product that utilizes phytosphingosine (0.02%) is Douxo Micellar Solution (Sogeval), which consists of a micellar solution that enables delivery of phytosphingosine (lipophilic) as well as soothing moisturizing agents (hydrophilic); it removes cellular debris, removes sebum, and has anti-inflammatory and antimicrobial properties. An advantage of these combination products is the lack of antibiotics and glucocorticoids, which may induce bacterial resistance or adrenal suppression. These products are often used at home as part of maintenance for cases that have higher rates of relapse or as part of other topical and systemic therapy programs. Glucocorticoids Numerous topical preparations for the external ear canal are available. Most of the ear products contain various combinations of glucocorticoids, antibiotics, antifungals, and parasiticidals. Active ingredients that are found in these medications are very important. Most cases of otitis externa benefit from topical glucocorticoids. Glucocorticoids have antipruritic, anti-inflammatory effects and decrease exudation and swelling. In addition, they cause sebaceous atrophy and decrease glandular secretions. Glucocorticoids may reduce scar tissue and proliferative changes, which helps to promote drainage and ventilation. Many different types and potencies of topical glucocorticoids are available. It is best to choose several products of different potencies and become familiar with them. Otic products containing triamcinolone acetonide (Panolog, Pfizer Animal Health) or dexamethasone (Tresaderm, Merial) can be absorbed systemically (9). Treated dogs have elevated liver enzymes and suppressed adrenal response to adrenocorticotropic hormone (ACTH) stimulation. Other studies show more variable absorption but in general dexamethasone- and triamcinolone-containing products were more likely to be associated with some systemic absorption (9 11). In the most recent study, a more Chronic Diseases Symposium Proceedings 15

36 potent glucocorticoid, momentasone (Mometamax, Intervet/Schering-Plough Animal Health), showed no adrenal suppression after one week of therapy (11). In cases of allergic otitis externa long-term topical glucocorticoids may be required. Products with weaker-strength glucocorticoids should be used in these situations, such as those containing 1.0% or 0.5% hydrocortisone (Bur-Otic HC, Virbac; or Burrows solution, generic). Some hydrocortisone 1% gels and sprays may also be helpful in long-term management (CortiCalm Lotion, CortiSpray, DVM Pharmaceuticals; ResiCORT, Virbac). Triamcinolone at a low concentration can also be utilized in or on the ear (0.015% triamcinolone spray (Genesis, Virbac); however, it is not the best for extended use as localized cutaneous atrophy reactions have been seen when used long term. A new product, hydrocortisone aceponate (Cortavance, Virbac), which is converted to HC17-propionate, is a highly active anti-inflammatory with a potency equivalent to that of dexamethasone. Further absorption through the skin causes the drug to become deactivated, allowing it to be excreted without causing systemic effects. Therefore, the manufacturer claims that there are no local or systemic effects, such as the immune suppression and skin thinning that are associated with other topical glucocorticoids. It has been used in one long-term cutaneous study in which it was applied daily for 8 weeks with no cutaneous atrophy or other outward body changes (12). The author has no first-hand experience using this new product as it is not yet available in the United States. Until further studies are evaluated I would be hesitant to use this product for any length of time on or in the ear. Clients should be cautioned not to have their own skin contact the more potent topical glucocorticoids. At the very least clients should wash their hands after coming in contact with these topical medications. Human facial skin is especially sensitive to the potent topical glucocorticoids and clients should be cautioned against allowing these products to contact their face. To prevent any contact, topicals can be applied with applicators or protected fingers. Gloves or Saran wrap can be used to cover the fingers. Antibacterials Topical antibacterial agents are indicated when infection, whether primary or secondary, is present; however, these agents are only one aspect of treating secondary or primary bacterial otitis. It should be emphasized topical antibacterial agents are many times used in conjunction with cleansers, disinfectants, and systemic antibiotics. Most topical antibacterial products also contain glucocorticoids. The glucocorticoids are beneficial in most cases because they decrease the formation of exudate, glandular secretions, and inflammation and swelling. First-line antibiotics most commonly utilized include products containing neomycin or neomycin in combination with other agents, such as Tresaderm. Products typically used in methicillin-resistant staphylococcal infections (MRSI) and methicillin-resistant Staphylococcus aureus (MRSA), staphylococcal, or Pseudomonas infections contain gentamicin, such as Mometamax or Otomax (Intervet/Schering- Chronic Diseases Symposium Proceedings 16

37 Plough Animal Health), or fluoroquinolones. Although ototoxicity has been reported with all gentamicin topical agents, this concern, similar to chlorhexidine, may be overstated. A study showed no vestibulotoxic or ototoxic effects from 21 days of otic gentamicin applied twice a day to ears with ruptured tympanic membranes (13). Baytril Otic (Bayer), which combines enrofloxacin with silver sulfadiazine, is a commonly used enrofloxacin-based otic product. There is no glucocorticoid in the product and some practitioners find the silver sulfadiazine messy, both of which are drawbacks in some cases. Homemade products are another option, using enrofloxacin (Baytril Injectable, Bayer) as a 25% mixture of injectable enrofloxacin (22.7 mg/ml diluted with water, saline, or other active agents with variable concentrations of dexamethasone, not exceeding 0.1 1%). Polymxyin can be a highly effective topical antibiotic and often is effective in many resistant Pseudomonas infections. In the US, however, there are no currently marketed veterinary polymyxin-based topical otic products; the author commonly uses a human product, Cortisporin Otic (Burroughs Welcome). Polymyxin will be inactivated by purulent exudates. In some cases home cleaning by the client each day or every other day may be required when using this product. Other more potent aminoglycosides are occasionally needed for more resistant infections, particularly in Pseudomonas infections. Selection is often based on culture and sensitivities. Other choices include tobramycin, injectable amikican mixed with saline at a final concentration of 25 mg/ml, and ticarcillin. Ticarcillin when reconstituted into a 6% solution and refrigerated remained effective up to 28 days when tested in vitro for susceptible strains of Staphylococcus intermedius and Pseudomonas aeruginosa (14). Care needs to be taken with certain topical aminoglycosides; in a recent study, ototoxicity based on BAER (brainstem auditory evoked response) testing occurred more commonly in dogs treated with amikacin and tobramycin-based topicals (15). Recently the author has also used mupirocin diluted in sterile saline as a topical antibacterial in cases of MRSI in the ear; the product is mixed as one tube of product (30 g) to 30 ml of sterile saline. To date no significant topical reactions or ototoxicity have been seen based on clinical observations, not BAER testing. Antifungal Agents Antifungal agents are required in any case complicated or caused by the yeasts, Malassezia or Candida, or dermatophytes. Some products that appear effective in vitro are not always clinically effective for Malassezia. This can be seen most commonly with nystatin (Panolog) and to a lesser degree thiabendazole (Tresaderm). Clotrimazole is one of the most commonly used antifungal/antiyeast agents and is found in many brand name products, such as Otomax and Mometamax. It is often highly effective but on occasion there will nonresponsive Malassezia cases. The author finds topical 1% miconazole (Conofite Lotion 1%, Intervet/Schering Plough Animal Health) to be very effective. Even more resistant Malassezia cases can be treated by adding a crushed 200-mg tablet of ketoconazole to the miconazole products. Chronic Diseases Symposium Proceedings 17

38 Miconazole usually should be combined with a topical glucocorticoid, as straight miconazole can be irritating when applied into the ear. A 1% dexamethasone solution can be made by removing 7 ml from a 30-mL bottle of Conofite Lotion and replacing it with 7 ml of dexamethasone NaPO 4 (4 mg/ml). Acetic acid (MalAcetic Otic) can be an effective treatment for Malassezia. When acetic acid is found to be irritating to the ear canal, milder Malassezia cases can be treated with boric acid solution, without the presence of acetic acid (Zinc Otic, Addison Biological Laboratory). A relatively new product combines TrizEDTA with ketoconazole and can also be used in milder cases and in maintenance situations (T8 Keto Solution, DVM PHarmaceuticals). Systemic Therapy Antibiotics Systemic therapy is indicated if otitis media is present and in many cases where proliferative changes are marked or in cases that are nonresponsive to topical therapy. Systemic antibiotics are used whenever otitis media or moderate or marked proliferative changes are present or when appropriate topical therapy and cleansing were not effective. Initial antibiotic selection is usually made empirically based on cytological findings. Commonly used antibiotics and dosages are listed in Table 1. When cocci predominate then cephalosporins or potentiated amoxicillin are often prescribed. In mixed infections with cocci present in large numbers, potentiated sulfonamides are often prescribed. Studies in both normal and diseased middle ear canals in dogs suggest that not only aerobic but also anaerobic bacteria can be cultured and are important in the pathogenesis of disease (16,17). Based on these findings combination antibiotics may be needed. Fluoroquinolones usually are prescribed when rod-shaped bacteria predominate on cytology. The most common fluoroquinolones used for otitis include enrofloxacin at 5 mg/kg up to 20 mg/kg every 24 hours, marbofloxacin at 2.75 to 5.5 mg/kg every 24 hours, orbifloxacin (Orbax, Intervet/Schering-Plough Animal Health) at 2.5 to 7.5 mg/kg every 24 hours, and ciprofloxacin at 10 to 15 mg/kg every 24 hours. Ciprofloxacin is not an approved fluoroquinolone in small animals and its use should be limited and other approved fluoroquinolones should preferentially be used. In cats the maximum dose of enrofloxacin is 5 mg/kg once daily because retinal disease and possibly blindness may occur with doses of 20 mg/kg daily, within 21 days of therapy. Marbofloxacin and orbifloxacin have not been reported to cause these problems in cats even dosed at twice the high-recommended range. Some laboratories have been using disk diffusion susceptibility testing (DDT) to assess all fluoroquinolone sensitivities. In one study, ciprofloxacin DDT results were not an accurate indicator of the in vitro susceptibility of enrofloxacin for bacteria isolated from the middle-ear tissue of dogs with end-stage otitis, with 14 of 82 (17.1%) having discrepancies (18). The author strongly recommends individual sensitivity testing by Chronic Diseases Symposium Proceedings 18

39 Table 1. Systemic Antibiotics Commonly Used in Treating Infectious Otitis Drug Trade Name Dose Amoxicillin trihydrateclavulanate Clavamox (Pfizer Animal Health) 22 mg/kg, q12h potassium Cefadroxil Cefa-Tabs, Cefa-Drops mg/kg, q12h (Boehringer Ingelheim) Cephalexin Generics (various) mg/kg, q12h Cephradine Generics (various) mg/kg, q12h Cefpodoxime proxetil Simplicef (Pfizer Animal Health) 5-10 mg/kg q 24h Chloramphenicol Generics (various) 50 mg/kg q 8h Ciprofloxacin Generics mg/kg q 24h Clindamycin hydrochloride Antirobe (Pfizer Animal Health) 11 mg/kg, q12h or 15-20mg/kg q 24h Difloxacin Dicural (Boehringer Ingelheim) mg/kg, q24h Enrofloxacin Baytril (Bayer) mg/kg, q24h Marbofloxacin Zeniquin (Pfizer Animal Health) mg/kg, q24h Ormetoprim-sulfadimethoxine Primor (Pfizer Animal Health) 55 mg/kg the 1 st day then 27 mg/kg q24h Orbifloxacin Orbax (Intervet/Schering-Plough mg/kg, q24h Animal Health) Trimethoprim sulfadiazine- Generics 30 mg/kg, q24h or Trimethoprimsulfamethoxazole Generics (various) divided q12h mg/kg, q12h way of MIC testing. Controlled comparisons of the fluoroquinolones for otitis have been limited but some have suggested there are differences in response. I have seen cases that failed to respond to one fluoroquinolone but did respond to another, but in some cases this can reflect relative differences in dose given. A study performed at the author s practice showed differences in fluoroquinolone resistance. In 15 Pseudomonas isolates where resistance to one or more fluoroquinolone was present, none were susceptible to enrofloxacin, 5 of 15 (33.3%) were susceptible to marbofloxacin, and 9 of 15 (60%) were susceptible to ciprofloxacin. Ear isolates were significantly less susceptible to enrofloxacin than to ciprofloxacin (P<0.001) and marbofloxacin (P=0.014) when resistance to at least one fluoroquinolone was present (19). In some cases injectable aminoglycosides are required to eliminate more resistant infections such as Pseudomonas. Gentamicin and amikacin are only used when a culture indicates their requirement. These drugs can now be given once daily subcutaneously (SC) which has made their use easier for clients. Gentamicin at 6 to 8 mg/kg once daily is less expensive and causes fewer subcutaneous abscesses than amikacin at 15 to 20 mg/kg. Chronic Diseases Symposium Proceedings 19

40 In rare cases, ticarcillin at 15 to 25 mg/kg every 8 hours intravenously (IV) has been needed when resistance to aminoglycosides is seen or when aminoglycosides are contraindicated. In multi-drug resistant Pseudomonas aeruginosa infections, other systemic beta-lactam antibiotics, such as ticarcillin disodium-clavulante potassium, imipenem, meropenem, and ceftazidime sodium, may be options, but are very expensive, are administered parenterally, and should only be considered after aggressive topical cleaning and other antimicrobial agents have been ineffective. Potential side effects of imipenem and meropenem include seizures; these drugs should be used cautiously in patients prone to seizures. The aminoglycoside antibiotics have the potential for nephrotoxicity. Animals must be monitored with periodic urinalysis (protein, casts) and serum blood urea nitrogen (BUN) and creatinine levels. Antifungal Agents Systemic treatment for Malassezia otitis requires oral ketoconazole, fluconazole, or itraconazole. All are dosed at 5 to 10 mg/kg once or divided twice daily initially with many cases controlled at lower alternate-day dosages. Itraconazole has been shown to be effective when pulsed two consecutive days each week (20) due to its longer half-life compared with ketoconazole. Hepatotoxicity is rarely seen at this dosing protocol with ketoconazole; however, occasional anorexia and gastrointestinal problems can be seen. Terbinafine has also been used with similar success to ketoconazole at 30 mg/kg a day (21). Glucocorticoids Glucocorticoid therapy is indicated in markedly inflamed edematous otitis and when chronic pathologic changes cause marked stenosis of the canal lumen. Some cases of allergic otitis may be treated with systemic glucocorticoids, allowing the initial topical therapy to be a low-potency glucocorticoid product. Injectable dexamethasone is useful if only 2 to 3 day s action is required. In more severely inflamed ears, especially when combined with other systemic symptoms, anti-inflammatory dosages of prednisone or prednisolone (1 mg/kg/day) can be used initially and then tapered to the minimum alternate-day dosage that controls the symptoms. For the uncommon case with severe stenosis, primarily of the vertical canal, intra-otic/intralesional triamcinolone acetonide (2 mg/ml) may be helpful. Triamcinolone acetonide is particularly effective for inhibiting fibroblasts and reducing collagen. When longer-term treatment is expected, then alternate-day short-acting glucocorticoid therapy is indicated as outlined earlier. The intralesional treatment is accomplished by injecting numerous small amounts of triamcinolone into the dermis of the canal wall. A long spinal needle (4 6 inches) is passed through the otoscope cone. A ring of injections is made; then the cone is withdrawn and another ring of injections is made. Typically two to three injections per depth are given trying to inject the medial, lateral, anterior, and posterior aspect of the canal wall. Each injection is typically 0.1 to 0.2 ml. A total of 2 to 4 mg can be injected into a single ear canal. Hemorrhage may be extensive and repetitive flushing may be required for continued visualization. Chronic Diseases Symposium Proceedings 20

41 One study looked at oral cyclosporine as another medical option for cases with severe proliferative otitis externa. In a pilot study, five client-owned dogs were treated with oral cyclosporine at 5 mg/kg twice daily for a minimum period of 12 weeks. All dogs were reevaluated clinically every 4 weeks to monitor progress. All five cases showed significant clinical improvement based on owner and clinical assessments. Individual owners also commented on their dog s improved disposition, hearing, and quality of life (21). The author has seen limited benefits with oral cyclosporine in end-stage disease but has seen moderate responses in cases with less severe disease. References 1. Griffin CE. Otitis externa and media. In: Griffin CE, Kwochka KW, MacDonald JM (eds): Current Veterinary Dermatology, The Science and Art of Therapeutics. St Louis: Mosby Year Book, 1993, pp Cole L, Kwochka KW, Kowalski JJ, Hillier A. Microbial flora and antimicrobial susceptibility patterns of isolated pathogens from the horizontal ear canal and middle ear in dogs with otitis media. J Am Vet Med Assoc. 1998;212: Schick A, Angus JC, Coyner K. Variability of laboratory identification and antibiotic susceptibility reporting of Pseudomonas spp. isolates from dogs with chronic otitis externa. Vet Dermatol. 2007;18(2): Graham-Mize C, Rosser EJ Jr. Comparison of microbial isolates and susceptibility patterns from the external ear canal of dogs with otitis externa. J Am Anim Hosp Assoc. 2004;40(2): Igarashi Y, Oka Y. Vestibular ototoxicity following intratympanic applications of chlorhexidine gluconate in the cat. Arch Otorhinolaryngol. 1988;245(4): Merchant SR, Neer TM, Tedford BL, Twedt AC. Ototoxicity assessment of a chlorhexidine otic preparation in dogs. Progr Vet Neurol. 1993;4: Ghibaudo GL, Cornegliani L, Martino P. Evaluation of the in vivo effects of Tris- EDTA and chlorhexidine digluconate 0.15% solution in chronic bacterial otitis externa: 11 cases. Vet Dermatol. 2004;15(s): Gbadamosi S, Gotthelf LN. Evaluation of the in vitro effect of Tris-EDTA on the MIC of enrofloxacin against ciprofloxacin resistant Pseudomonas aeruginosa. Proc 18th Annu Mtg Am Acad Vet Dermatol and Am Coll Vet Dermatol. Monterey, CA, 2001, p Moriello KA, Fehrer-Sawyer SL, Meyer DL, Feder B. Adrenocortical suppression associated with topical otic administration of glucocorticoids in dogs. J Am Vet Med Assoc. 1988;193: Ghubash R, Marsella R, Kunkle G. Evaluation of adrenal function in small-breed dogs receiving otic glucocorticoids. Vet Dermatol. 2004;15(6): Reeder CJ, Griffin CE, Polissar NL, Neradilek B. Comparative adrenocortical suppression in dogs with otitis externa following topical otic administration of four different glucocorticoid-containing medications. Vet Therap. 2008;9(2): Reme CA, Dufour P. Repeated daily application of % hydrocortisone aceponate spray for 8 consecutive weeks in dogs: impact on the skin thickness. Vet Dermatol. 2008;19(Suppl.1):47. Chronic Diseases Symposium Proceedings 21

42 13. Strain GM, Merchant SR, Neer TM, Tedford BL. Ototoxicity assessment of a gentamicin sulfate otic preparation in dogs. Am J Vet Res. 1995;56: Robson DC, Moss SM, Trott DJ, Burton GG. Degradation of in vitro efficacy of refrigerated ticarcillin-clavulanic acid solution against susceptible Pseudomonas aeruginosa and Staphylococcus intermedius isolates over a four-week period. Vet Dermatol. 2008;19(Suppl.1): Patterson S. Ototoxicity. Proc World Congr Vet Dermatol 6, Hong Kong, 2008, pp Angus J, Campbell K, Maddox CW. Anaerobic microbial flora and fluoroquinolones susceptibility of aerobic isolates from the horizontal ear canal and tympanic cavity of dogs undergoing total ear canal ablations. 20th Proc North Am Vet Dermatol Forum, Sarasota, FL, 2005, p Defalque V, Rosser EJ Jr, Peterson AD. Aerobic and anaerobic bacterial microflora of the middle ear cavity in normal dogs. 20th Proc North Am Vet Dermatol Forum, Sarasota, FL, 2005, p Cole L, Kwochka KW, Hillier, A, Kowalski, JJ. Ciprofloxacin as a representative of disk diffusion in vitro susceptibility of enrofloxacin for bacterial organisms from the middle-ear tissue of dogs with end-stage otitis externa. Vet Dermatol. 2005;17(2): Wildermuth B, Griffin CE, Boord, MJ, Rosenkrantz WS. Comparison of ear and skin Pseudomonas spp sensitivities to enrofloxacin, marbofloxacin and ciprofloxacin. 21th Proc North Am Vet Dermatol Forum, Palm Springs, CA, 2006, p Pinchbeck LR, Hillier A, Kowalski JJ, Kwochka, KW. Randomized, single blind evaluation of the efficacy of once daily and pulsed dosing with itraconazole for the treatment of Malassezia sp infections in dogs (abst). Vet Dermatol. 2001;12: Guillot J, Bensignor E, Jankowski F, Seewald W. Comparative efficacies of oral ketoconazole and terbinafine for reducing Malassezia population sizes on the skin of Basset Hounds. Vet Dermatol. 2003;14(3): Hall J. Oral cyclosporine in the treatment of end state ear disease: A pilot study. Proc 18th Annu Mtg Am Acad Vet Dermatol and Am Coll Vet Dermatol. Monterey, CA, 2003, p 217. Chronic Diseases Symposium Proceedings 22

43 Treatment of Refractory Urinary Incontinence Larry G. Adams, DVM, PhD, Diplomate, ACVIM Purdue University Abstract Identification of the cause of urinary incontinence is critical to effective management, and dogs with refractory incontinence may be challenging to manage. Diagnosis and management of refractory urinary incontinence caused by urethral incompetence, detrusor instability, and ectopic ureters are considered in this article. Treatment options for refractory urethral incompetence include combination medical management, surgical procedures, and cystoscopic injection of bulk-enhancing agents. Key Concepts Urinary incontinence occurs either when intravesicular pressure is greater than urethral pressure (eg, decreased urethral pressure or decreased detrusor compliance) or because of anatomic abnormalities which bypass the normal continence mechanisms (eg, ectopic ureters). The diagnostic evaluation of dogs with refractory urinary incontinence should include medical history, physical examination, serum biochemistry profile, urinalysis, urine culture, abdominal radiographs, and ultrasonography, and, if available, cystoscopy and urodynamic testing. Urethral incompetence (or urethral sphincter mechanism incompetence) is the most common cause of incontinence in adult female dogs; it is usually "hormonally responsive" and typically occurs months to years after neutering. Therapeutic options include phenylpropanolamine and estrogen therapy. Because estrogen therapy up-regulates the alpha-adrenergic receptors that phenylpropanolamine stimulates, combination therapy with these medications is synergistic. Therefore female dogs that are refractory to either medication alone may respond to combination therapy. Periurethral injection of collagen narrows the urethral lumen and allows for more effective closure of the urethra by existing urethral pressure; repeat cystoscopic injections may be required in some dogs months to years after initial injections to maintain continence. Dogs with refractory incontinence due to detrusor instability and urge incontience can be treated with anticholinergic medications (oxybutynin, imipramine or dicyclomine) to decrease detrusor contractions during storage of urine. Ectopic ureters are a common cause of urinary incontinence in young dogs and may also be diagnosed in adult dogs with refractory urinary incontinence. Traditionally ureteral openings have been moved into the bladder by various surgical techniques. From Chronic Diseases, Proceedings of a Symposium sponsored by Intervet/Schering-Plough Animal Health. Copyright 2010 The Gloyd Group, Inc. All Rights Reserved. The opinions expressed in this article are those of the author and do not necessarily reflect the official label recommendations and point of view of the company or companies that manufacture and/or market any of the pharmaceutical agents referred to.

44 A new technique for treatment of intramural ectopic ureters is laser ablation of the wall between the urethra and parallel ureter which moves the ureteral opening into the urinary bladder. Urinary incontinence is defined as loss of voluntary control of urination resulting in leakage of urine. Urinary incontinence must be differentiated from inappropriate urination associated with dysuria and pollakiuria. Diagnosis and management of the majority of cases in dogs are routine; however, treatment of refractory urinary incontinence may present a challenge to the clinician. Physiology of Micturition Understanding of the mechanisms of urinary incontinence requires understanding of the anatomy and physiology of the lower urinary tract. The innervation of the lower urinary tract includes sympathetic, parasympathetic, and somatic innervation. The internal urethral sphincter is innervated by sympathetic (alpha-adrenergic) innervation from the lumbar spinal cord (L1 L4 in dogs, L2 L5 in cats) via the hypogastric nerve. The internal urethral sphincter is not an anatomically distinct sphincter; rather, it is a functional sphincter involving the proximal urethral and bladder neck. The external urethral sphincter is skeletal muscle and receives somatic innervation from the sacral (S1 S3) spinal cord via the pudendal nerve. The detrusor muscle of the urinary bladder receives parasympathetic innervation from the sacral (S1 S3) spinal cord via the pelvic nerve (causing contraction) and sympathetic innervation (beta-adrenergic) from the hypogastric nerve (facilitating relaxation). Afferent (sensory) information from stretch receptors in the bladder travels to the spinal cord via the pelvic nerve and also via the hypogastric nerve with bladder overdistension. Afferent information from the urethra is transmitted to the spinal cord via the pudendal nerve. Micturition encompasses both storage and voiding phases. The storage phase of urination is characterized by increased sympathetic tone. The hypogastric nerve provides alpha-adrenergic input to the urethra, resulting in increased tone of the internal urethral sphincter. Beta-adrenergic input to the detrusor muscle causes relaxation to allow low pressure filling of the bladder. Increased sympathetic tone also inhibits parasympathetic input to the detrusor preventing bladder contraction. When the animal is awake, the external urethral sphincter augments the function of the internal urethral sphincter as needed by voluntary and reflex stimulation. When the animal falls asleep, continence is maintained primarily by the internal urethral sphincter. The voiding phase of urination occurs by relaxation of the internal and external urethral sphincters and by contraction of the detrusor muscle. The voiding phase is characterized by increased parasympathetic tone to the bladder, decreased sympathetic input to the internal urethral sphincter, and voluntary relaxation of the external urethral sphincter. Although voiding is a local spinal reflex, it is under control of higher centers including the micturition center in the pons. Urinary incontinence occurs either when intravesicular pressure is greater than urethral pressure (eg, decreased urethral pressure or Chronic Diseases Symposium Proceedings 2

45 decreased detrusor compliance) or because of anatomic abnormalities which bypass the normal continence mechanisms (eg, ectopic ureters). Diagnostic Approach to Refractory Urinary Incontinence A thorough physical examination of dogs with refractory urinary incontinence should be performed, including a rectal examination and a neurologic examination focusing on the rear limbs and perineal reflexes. Dogs with severe urinary incontinence may have urine scald around the vulva or prepuce (Figure 1). The diagnostic evaluation of dogs with refractory urinary incontinence should include a medical history, physical examination, serum biochemistry profile, urinalysis, urine culture, abdominal radiographs, and ultrasonography. If available, cystoscopy and urodynamic testing should be also performed. Urodynamic tests include urethral pressure profile (UPP) and cystometrogram (CMG). The UPP permits evaluation of urethral function during the storage phase and the CMG evaluates detrusor function during the storage and voiding phases. Figure 1 Urine scald of the perivulvar area in a golden retriever with severe urinary incontinence secondary to ectopic ureters. Urethral Incompetence Urethral incompetence (or urethral sphincter mechanism incompetence) is the most common cause of incontinence in adult female dogs. Urethral incompetence is usually "hormonally responsive" and typically occurs months to years after neutering. Congenital anatomic or functional abnormalities of the urethra may result in urethral incompetence prior to neutering. Chronic Diseases Symposium Proceedings 3

46 The pathogenesis of urethral incompetence after neutering is controversial but likely involves the effects of estrogen on alpha-adrenergic receptors. Estrogen has a permissive effect on alpha-adrenergic receptors of the internal urethral sphincter, thereby promoting increased urethral tone and continence. With decreased estrogen concentration, alpha-adrenergic receptors require greater stimulation to maintain urethral tone. This forms the basis of treatment with alpha-adrenergic agonists or estrogen. While the dog is awake, continence may be maintained by the external urethral sphincter. When the dog is sleeping or with muscle relaxation, the internal sphincter fails maintain continence resulting in incontinence. The alpha-adrenergic agonist phenylpropanolamine ( mg/kg orally [PO] every 8 hours) is effective in approximately 85% of female dogs with urethral incompetence (Table 1) (1,2). Clinical response to another alpha-adrenergic agonist, pseudoephedrine, is inferior to response to phenylpropanolamine (3). The dose-related side effects of phenylpropanolamine in dogs include excitability, panting, restlessness, irritability, and hypertension. Phenylpropanolamine should not be used in patients with pre-existing hypertension. Estrogen therapy increases urethral closure pressure by increasing the density and responsiveness of alpha-adrenergic receptors in urethral smooth muscle. Estrogen therapy (diethylstilbestrol) was effective in approximately 65% of female dogs with urethral incompetence (4). Excessive doses of estrogen may cause severe bone marrow suppression; therefore, owners should be cautioned not to exceed recommended doses and complete blood counts (CBC) should be monitored in dogs receiving estrogen therapy. Diethylstilbestrol is administered at 0.1 to 0.2 mg/kg PO daily (maximum dose 1 mg/dog) for 5 days followed by the same dose once to twice a week. The maximum maintenance dose of diethylstilbestrol is 0.1 mg/kg/week. The minimum effective dose should be used for maintenance therapy. Low-dose daily estrogen using estriol is an alternative to diethylstilbestrol (5). Estriol is administered at a dose of 2 mg PO daily for a week; the dose is then reduced at weekly intervals to the minimal effective dose ( mg/dog given daily or every other day). Estriol therapy resulted in continence in 61% of dogs with an additional 22% considered improved (5). In this study of 129 dogs, there was no evidence of bone marrow toxicity when estriol was administered for 42 days (5). Estriol has been marketed for veterinary use in Europe since 2000, and the incidence of adverse effects associated with use of this product appears to be quite low. Estriol therapy increased urethral pressure in normal dogs, but the effects of estriol on urodynamic parameters have not been reported in dogs with urinary incontinence (6). Treatment of Refractory Urethral Incompetence Because estrogen therapy up-regulates the alpha-adrenergic receptors that phenylpropanolamine stimulates, combination therapy with these medications is synergistic. Therefore, female dogs that are refractory to either medication alone may respond to combination therapy (see Table 1). For dogs that are refractory to Chronic Diseases Symposium Proceedings 4

47 Table 1. Treatment of Refractory Urinary Incontinence Diagnosis Urethral incompetence Refractory urethral incompetence Detrusor instability and urge incontinence Ectopic ureters Treatment Options Alpha-adrenergic agonists Phenylpropanolamine ( mg/kg PO q 8 h) Estrogen therapy Diethylstilbestrol: 0.1 to 0.2 mg/kg PO daily (maximum dose 1 mg/dog) for 5 days followed by the same dose once to twice a week Maximum maintenance dose: 0.1 mg/kg/week Use minimum effective dose for maintenance therapy. Estriol: 2 mg PO daily for a week, then reduce dose at weekly intervals to minimal effective dose ( mg/dog given daily or every other day). Combination therapy with alpha-adrenergic agonists and estrogen therapy Cystoscopic injections of bulk-enhancing agents (glutaraldehyde cross-linked collagen) Surgery: Colposuspension, urethropexy with concurrent administration of phenylpropanolamine Anticholinergic medications: Oxybutynin (0.2 mg/kg PO q 8 12 h) Imipramine Dicyclomine Surgery, including cystoscopic-guided laser ablation combination therapy, urodynamic evaluation is recommended. Alternative therapies for dogs with refractory urinary incontinence due to confirmed urethral incompetence include cystoscopic injections of bulk-enhancing agents (glutaraldehyde cross-linked collagen) or surgical methods to increase urethral resistance (7 10). Periurethral injection of collagen narrows the urethral lumen and allows for more effective closure of the urethra by existing urethral pressure (Figure 2). Results of two studies showed that periurethral injection of collagen resolved urinary incontinence in 53% to 69% of dogs without medication. Overall, 75% to 93% of these dogs were improved after peri-urethral collagen injection with or without concurrent administration of phenylpropanolamine (8,10). The mean duration of continence following peri-urethral collagen injections was 17 months (10). Repeat cystoscopic injections of collagen are required in some dogs months to years after the initial injections to maintain continence (10). Chronic Diseases Symposium Proceedings 5

48 Figure 2 Submucosal periurethral collagen injections. Cystoscopic view of the urethra before (A) and after collagen injections (B). Surgical methods for treatment of refractory urinary incontinence include colposuspension and urethropexy (7,9,11). Surgery resolves incontinence in approximately 50% of dogs with an additional 25% to 40% being continent with concurrent administration of phenylpropanolamine (7,9,11). A potential novel approach to the surgical management of urinary incontinence that has been described in a cadaveric model is the placement of a hydraulic urethral sphincter (12). Preliminary trials of this procedure for treatment of clinically affected dogs with incontinence have shown promise. An initial report from Europe indicated that treatment with gonadotropin-releasing hormone (GnRH) analogues may resolve refractory urinary incontinence in female dogs (13). The exact mechanism is unknown. In subsequent studies response has been reported to be quite variable, with some dogs responding well and others not (14). Detrusor Instability and Urge Incontinence Although urethral incompetence is the most common cause of urinary incontinence, incontinence may also occur due to detrusor contraction during storage of urine or due to low compliance of the detrusor muscle, which may be confirmed by cystometrography. When decreased detrusor compliance occurs secondary to inflammatory conditions affecting the lower urinary tract (eg, urolithiasis, urinary tract infection [UTI]), this is termed urge incontinence. Clinical signs of dogs with urge incontinence may also include pollakiuria, stranguria, and dysuria. If no identifiable cause of decreased detrusor compliance is identified, this is termed idiopathic detrusor instability. Chronic Diseases Symposium Proceedings 6

49 Treatment of detrusor instability is by anticholinergic medications (oxybutynin, imipramine, or dicyclomine) to decrease detrusor contractions during storage of urine (15). Although oxybutynin (0.2 mg/kg PO every 8 12 hours) has been most commonly recommended, in one study dicyclomine appeared to have a greater effect on detrusor compliance in normal dogs than oxybutynin (15). Clinical effectiveness of dicyclomine has not been reported in dogs with idiopathic detrusor instability. Imipramine is a tricyclic antidepressant medication that has anticholinergic effects to facilitate urine storage and also increases urethral closure pressure. Therefore, imipramine may be effective for dogs with mixed incontinence due to detrusor dysfunction and concurrent urethral incompetence. Ectopic Ureters Ectopic ureters are a common cause of urinary incontinence in young dogs. Ectopic ureters may also be diagnosed in adult dogs with refractory urinary incontinence, especially the dog with ectopic ureters located in the proximal urethra. Most canine ectopic ureters are intramural in location, meaning the ureter enters the serosal surface of the bladder wall in the correct location, but the intramural ureter tunnels in the wall of the bladder and urethral submucosa with one or more openings in the urethra or vaginal vestibule. Extramural ectopic ureters connect to the urethra or vagina without first tunneling through the bladder and urethral wall. Although ectopic ureters have traditionally been diagnosed by contrast radiography, cystoscopy may be the preferred technique for diagnosis provided the clinician is experienced with the procedure (Figure 3). In studies comparing the diagnostic accuracy of excretory urography, contrast-enhanced computed tomographic (CT) scans, and cystoscopy for detection of ectopic ureters, contrast-enhanced CT scans and cystoscopy were the most accurate diagnostic methods (16,17). During cystoscopy, the anatomy of the urethra and vaginal vestibule are also evaluated. Most dogs with ectopic ureters have an abnormality of the vaginal vestibule called paramesonephric septal remnant, which is a broad band dividing the vaginal opening into two parts and lifting the urethral opening dorsally (Figure 4) (16). Urethral incompetence frequently occurs concurrently with ectopic ureters and can result in treatment failure after repair of ectopic ureters (18,19). Because UPP results can be used to predict postsurgical continence, urodynamic testing should be performed prior to surgical or laser correction of ectopic ureters (18). Traditionally ureteral openings have been moved into the bladder by various surgical techniques. A new technique for treatment of intramural ectopic ureters is cystoscopicguided laser ablation of the wall between the urethra and parallel ureter which moves the ureteral opening into the urinary bladder. (Figures 4, 5, and 6) (20,21). Berent et al reported that laser ablation of intramural ectopic ureters resulted in resolution of urinary incontinence in 5 of 8 female dogs after laser correction using a diode laser (20). Additionally, 2 of 8 female dogs were continent with medication or periurethral collagen injections for concurrent urethral incompetence. Likewise, laser ablation of ectopic ureters resolved urinary incontinence in 4 of 4 male dogs (21). The author has also Chronic Diseases Symposium Proceedings 7

50 successfully treated urinary incontinence in dogs by laser ablation of intramural ectopic ureters using a holmium:yag laser. Dogs with concurrent urethral incompetence require medical management of the concurrent urethral incompetence or cystoscopic injections of collagen to resolve incontinence. Figure 3 Cystoscopic view of a paramesonephric remnant dorsal to the urethral orifice within the vaginal vestibule. Dorsal portion of the vestibule is located at the top of the image. Figure 4 Cystoscopic view of an opening of an ectopic ureter in the middle of the urethra. Dorsal portion of the urethra is located at the top of the image. Chronic Diseases Symposium Proceedings 8

51 Figure 5 Cystoscopic view of the urethra from a dog with bilateral ectopic ureters before (A) and during (B) laser ablation of an ectopic ureter. The open ended ureteral catheter and guide wire (not seen) have been passed up the ureter. Because the dog is positioned in dorsal recumbency, dorsal is located at the bottom of the image. Figure 6 Diagram of laser ablation an intramural ectopic ureter. A) The tissue to be incised via laser ablation is indicated by the arrows. B) Opening of the ureter is located within the bladder lumen after laser ablation. (Figure by Dr. David Williams, Purdue University). References 1. Richter KP, Ling GV. Clinical response and urethral pressure profile changes after phenylpropanolamine in dogs with primary sphincter incompetence. J Am Vet Med Assoc. 1985;187: Chronic Diseases Symposium Proceedings 9