Memorias XXXV Congreso Nacional AMMVEPE 2017

AMMVEPE 1968 - 2017

MEMORIAS DE LAS PONENCIAS EN EL XXXV CONGRESO NACIONAL AMMVEPE 2017 Mayo 18, 19 y 20 Resort Mundo Imperial Acapulco Guerrero

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

AMMVEPE 1968 - 2017

MEMORIAS DE LAS PONENCIAS EN EL XXXV CONGRESO NACIONAL AMMVEPE 2017 Hypercalcemia and Primary Hyperparathyroidism (PHP) in Dogs Edward C. Feldman, DVM, DACVIM (SAIM) Diagnosis of Hyperadrenocorticism (Cushing’s Syndrome) in Dogs Which Test are Best?

Edward C. Feldman, DVM, DACVIM (SAIM) Feline Acromegaly Edward C. Feldman, DVM, DACVIM (SAIM) Hypoadrenocorticism Edward C. Feldman, DVM, DACVIM (SAIM) Clinical Pearls not necessarily found in textbooks John C. Angus, DVM, DACVD Top Five Reasons Dogs itch - an 8 week plan John C. Angus, DVM, DACVD Pseudomonas Otitis - What to do when nothing else works John C. Angus, DVM, DACVD

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

feldman HYPERCALCEMIA AND PRIMARY HYPERPARATHYROIDISM (PHP) IN DOGS Edward C. Feldman, DVM, Diplomate ACVIM, Emeritus Professor of Small Animal Internal Medicine Department of Medicine and Epidemiology School of Veterinary Medicine, University of California Davis, California 95616-8737, U.S.A. Email: ecfeldman@ucdavis.edu

DIFFERENTIAL DIAGNOSIS & DIAGNOSTIC APPROACH TO HYPERCALCEMIA Differential Diagnosis Hypercalcemia is an abnormality usually serendipitously identified on serum biochemical analysis. Since hypercalcemia is almost always unsuspected, it would not be a mistake to obtain a second blood sample to rule out laboratory error, which in our experience is extremely rare.

Disorders associated with hypercalcemia in dogs, in an approximate order of incidence at the University of California, include lymphosarcoma, acute and chronic kidney disease (CKD), primary hyperparathyroidism (PHP), hypoadrenocorticism (Addison’s Disease), vitamin D toxicosis, apocrine gland carcinoma of the anal sac, multiple myeloma, rarelly associated with a variety of carcinomas (lung, mammary, nasal, pancreas, thymus, thyroid, vaginal, and testicular), and in certain granulomatous diseases (blastomycosis, histoplasmosis, schistosomiasis). History, physical examination, CBC, urinalysis, serum biochemistry analysis, thoracic and abdominal radiographs, abdominal ultrasound, and examination of cytology and biopsy specimens usually provide adequate information to establish a diagnosis in dogs.

History and Physical Examination Once hypercalcemia is identified, the veterinarian should review the signalment and history with the owner to identify any clues to a definitive diagnosis that may not have been noted initially. From the history, one can attempt to identify possible exposure to toxins

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feldman containing vitamin D (rodenticides; inappropriate supplementation of food, etc), evidence of pain or change in behavior due to a lytic bone lesion (multiple myeloma or mammary tumor), or a waxing/waning course of illness sometimes noted with hypoadrenocorticism. Duration of illness and signs of disease are important. In general, the more ill the dog, the less likely the diagnosis will be primary hyperparathyroidism. More than a third of the owners of dogs in our series did not notice any worrisome concerns. The majority of owners who did observe clinical signs, thought the changes were due to simple aging and were not considered overly worrisome.

Owners of hypercalcemic dogs that had conditions other than hyperparathyroidism usually were quite concerned about abnormalities and their progression.

The physical examination should also be repeated in an attempt to identify a tentative explanation for hypercalcemia. The spine, ribs, and long bones should be palpated to identify bone pain due to a lytic lesion, the mammary chain evaluated for neoplasia, the abdomen to assess size and shape of the kidneys and a general assessment for masses or organomegaly, the rectal and perineal area for apocrine gland carcinoma of the anal sac or other tumor, the heart rate (slow) and pulse quality (poor) for abnormalities consistent with hypoadrenocorticism, and the peripheral lymph nodes for enlargement suggestive of lymphoma (most hypercalcemic lymphoma dogs have a mediastinal mass and unremarkable peripheral nodes). Dogs with PHP commonly have a physical examination that does not contribute to a diagnosis (parathyroid masses are almost never palpable).

Routine “Data Base�

A thorough review of the CBC, serum biochemistry profile and urinalysis should be completed. The urine specific gravity is commonly <1.020 in hypercalcemic dogs with renal disease, hypoadrenocorticism, and primary hyperparathyroidism. Urinary tract infection is

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feldman common in each of these disorders. The CBC may demonstrate a normocytic normochromic non-regenerative anemia which is relatively common in CKD, hypoadrenocorticism (sometimes masked by dehydration), chronic disease and various neoplasias. The serum biochemistry profile should also be assessed for increases in BUN, creatinine, and serum phosphate consistent with CKD or vitamin D toxicosis; increase in BUN, decrease in cholesterol, hyperkalemia and/or hyponatremia suggestive of hypoadrenocorticism; hyperglobulinemia consistent with myeloma; and hypophosphatemia consistent with primary hyperparathyroidism. To this point, the only â&#x20AC;&#x153;newâ&#x20AC;? expense incurred would be the repeated serum total calcium concentration (if obtained), since these recommendations are talking with the owner, repeating a physical examination, and reviewing laboratory results already obtained in order to have identified the hypercalcemia.

Imaging: Radiographs and Ultrasonography If review of the history, physical examination and data base does not define the cause for hypercalcemia, thoracic radiographs are important. The primary purpose for radiographs is to assess the cranial mediastinum for a mass consistent with lymphoma. If a mass is present, fine needle aspiration (FNA) or tissue obtained via biopsy should be evaluated. Since lymphoma is highly exfoliative, diagnosis is usually straight-forward. Thoracic radiographs also provide an opportunity to evaluate the perihilar area and lungs for evidence of lymphadenopathy, neoplasia or systemic mycoses, the spine and ribs for lytic lesions caused by neoplasia, and the heart for microcardia of hypoadrenocorticism.

Abdominal radiographs can be assessed, although ultrasound examination of the abdomen is preferred. The size and consistency of the liver, spleen, and mesenteric and sublumbar lymph nodes can be evaluated for abnormalities suggestive of malignancy (lymphoma) or other conditions. Malignancy can be located in virtually any organ, but tumors other than lymphoma

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feldman are less common causes of hypercalcemia. When possible, any area considered suspicious for neoplasia should be aspirated or biopsied. On ultrasound imaging, the size and consistency of the adrenals can be assessed. Dogs with primary hypoadrenocorticism usually have small and thin adrenals. Small irregular kidneys would be consistent with CKD. The kidneys, ureters, bladder and urethra should be evaluated for the presence of calculi, which develop in about 30% of dogs with primary hyperparathyroidism and could develop in any hypercalcemic dog.

If these assessments fail to confirm or strongly suggest a diagnosis, the index of suspicion increases for primary hyperparathyroidism. Until a specific cause for hypercalcemia is confirmed, however, lymphoma should never be ruled out. Cervical ultrasonography (discussed in a later section) has become an extremely valuable screening test in dogs with hypercalcemia and should be considered the next diagnostic step in attempting to define cause.

SIGNALMENT and HISTORY IN DOGS WITH PHP Dogs with primary hyperparathyroidism are usually 6 years of age or older. The mean age from our series of 335 dogs with primary hyperparathyroidism was 10.7 years. Dogs of both genders are equally affected, about 14% of affected dogs are Keeshonds (a breed demonstrated to be genetically predisposed to this condition) but a huge number of breeds and mixed-breeds have been represented. The mean body weight of the 335 dogs was 24 kg.

Dogs with PHP, unlike those afflicted with most other diseases that cause hypercalcemia, are usually not ill or â&#x20AC;&#x153;not as ill.â&#x20AC;? Owners of 124 of 335 the dogs with primary hyperparathyroidism (37%) in our series had observed no abnormalities in their pet related to hypercalcemia. The reason that blood had been obtained from these dogs was usually part of a routine geriatric evaluation, part of a pre-anesthesia screen prior to a dentistry procedure, or for an unrelated condition. Even when owners were told about hypercalcemia and its likely

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feldman symptoms, most owners continued to suggest that their dog was not ill. However, once treated, virtually all owners notice improvements in activity, muscle strength, and appetite. Most gain weight and have reduced water intake and urine output.

The

most

common

owner-observed

abnormalities

in

dogs

with

primary

hyperparathyroidism were polyuria and polydipsia (57% of dogs), lethargy / weakness / decreased activity (43%), decreased appetite (30%), weight loss or muscle wasting (10%), shivering or trembling (7%), and vomiting (5%). It is important to remember that even when clinical signs are observed, they are often relatively mild. When signs were observed, they had been present for as little as a few days to as long as 2+ years. Not all dogs with urolithiasis or urinary tract infection had appropriate clinical signs (ie, straining to urinate, increased frequency of urination, and hematuria) thus the strong recommendation for abdominal imaging in any hypercalcemic dog is emphasized.

PHYSICAL EXAMINATION IN DOGS WITH PHP In 254 of 335 dogs with primary hyperparathyroidism (76%), the medical record stated that no abnormalities relative to that diagnosis were noted on physical examination. When abnormalities were seen, they included muscle wasting, slow to rise, obesity in some and thin body condition in others. Each of these problems was seen in <10% of dogs with PHP. LABORATORY ABNORMALITIES IN DOGS WITH PHP Hypercalcemia (ie, serum total calcium concentrations >12 mg/dl; reference range of 9.9 to 11.6 mg/dl) was identified in all 335 dogs with primary hyperparathyroidism in our series.

This â&#x20AC;&#x153;sensitivityâ&#x20AC;? (100%) may be misleading since we do not evaluate dogs for hypercalcemia unless this criterion is met. The mean total serum calcium concentration was 14.5 mg/dl with a range of 12.1 to 24.2 mg/dl. About 50% of PHP dogs had serum total calcium concentrations

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feldman >12 and <14 mg/dl; about 33% had values >14 and <16 mg/dl, about 10% had values >16 and <18 mg/dl, and slightly more than 10% had values >18 mg/dl. The mean plasma ionized calcium concentration in the 335 dogs with PHP was 1.76 mmol/L (range: 1.22 to 2.87; reference range 1.12 to 1.41 mmol/L). Just under 4% of the dogs with PHP had a serum ionized calcium concentration within the reference range, almost 33% had values between 1.42 and 1.65 mmol/L, and almost 50% had concentrations between 1.66 and 1.90 mmol/L, with more than 10% having concentrations >1.91 mmol/L. It may be of interest to point out a common reason for referral of dogs ultimately diagnosed with primary hyperparathyroidism: concern on the part of the referring veterinarian that if not treated, hypercalcemia would place dogs at risk for developing acute kidney injury or CKD. However, this is not the case. Of 335 dogs with PHP, their mean BUN concentration (~18 mg/dl) was at the low end of the reference range of 18 to 28 mg/dl, their mean serum creatinine concentration (0.9 mg/dl) was well within the reference range (0.5 to 1.6 mg/dl) and their mean serum phosphate concentration (2.7 mg/dl) was below the reference range (3.0 to 6.5 mg/dl). All these values were significantly less than values from 200 age and body-weight-matched control dogs that were examined at our hospital within a month of the time that the dogs with primary hyperparathyroidism were seen. In other words, dogs with primary hyperparathyroidism seem protected from kidney damage rather than predisposed to it. Duration of hypercalcemia was also not a factor, since some dogs went years without treatment. Owner observed polyuria and polydipsia was well supported by finding a mean urine specific gravity in 335 dogs with PHP of 1.012. 30% of these dogs had urinary tract infection and about 30% had cystic calculi (some had both). Kidney damage is rare and not a reason for treating a dog with primary

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feldman hyperparathyroidism. However, infection and calculi are common and certainly should be among the reasons for recommending therapy.

CONFIRMATION OF PRIMARY HYPERPARATHYROIDISM (USE OF SERUM PTH AND PTHrP CONCENTRATIONS) Are PTH Assay Results Vital?

The differential diagnosis for hypercalcemia is relatively short and veterinarians should be able to rule in or rule out most conditions using the diagnostic approach recommended earlier.

The need for sophisticated and relatively expensive studies, such as assaying serum PTH and PTHrP concentrations take on less importance in this context. Serum PTH concentrations have been assessed on a large number of dogs with PHP that we have treated since the early 1980â&#x20AC;&#x2122;s.

However, to be fair, many of these results were available days-to-weeks after treatment had been completed. In other words, diagnosis was confirmed and treatment completed without need for these assay results. Employing a logical approach in determining the cause of hypercalcemia in dogs (not cats) should lead to a diagnosis. This is not to suggest that the assays have no value.

Rather, it is to suggest that a logical practical approach to differential diagnosis out-weighs specific tests and, in this context, the assay results are not vital.

Serum Parathyroid Hormone (PTH) Concentrations The parathyroid glands and their primary product: parathyroid hormone (PTH) are responsible for maintaining serum calcium concentrations within narrow limits. PTH controls minute-to-minute circulating calcium concentrations as well as being responsible for control over periods of days, weeks and months. Serum PTH concentrations can be measured commercially and assays are widely available. Reference range-to-increased concentrations confirm the

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feldman diagnosis of primary hyperparathyroidism in non-kidney-failure hypercalcemic dogs. Dogs with CKD may also have increased serum PTH concentrations but within the context of the renal parameters, the serum phosphate concentration, ionized serum calcium concentration (increased in primary hyperparathyroidism while results may be reference range or decreased in dogs with CKD) and other pertinent information, dogs with primary hyperparathyroidism can usually be readily distinguished.

As serum calcium concentrations rise in healthy individuals, serum PTH concentrations should become undetectable. The term “normal range” can be misleading, since the average dog with primary hyperparathyroidism has a seemingly counter-intuitive serum PTH concentration that is “normal.” We prefer using the term “reference range,” which improves the ability to understand this condition. Since increasing serum calcium concentrations should decrease serum PTH concentrations below the reference range, values within the reference range are physiologically abnormal. Using a reference range for serum PTH concentrations of 2 to 13 pmol/L, 198 of 335 (~60%) dogs with PHP had serum PTH concentrations within the reference range; 36% had results of 2.3 to 7.9 pmol/L, 24% had results of 8.0 to 13.0 pmol/L, 16% had results between 13 and 20 pmol/L, and 24% had results >20 pmol/L. Serum Parathyroid Hormone-related-Protein (PTHrP) concentrations Certain cancers, particularly some lymphomas and apocrine carcinomas of the anal sac, have the capacity to synthesize chains of amino acids that are quite similar in appearance and in action to natural PTH. Since this protein is not true PTH, it is called parathyroid-hormone-related protein (PTHrP). Increased serum PTHrP concentrations in hypercalcemic dogs would be most consistent with a diagnosis of lymphoma, apocrine gland carcinoma of the anal sac, or another malignancy. Increased PTHrP concentrations should lead to aspiration or biopsy of any

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feldman suspicious mass, lymph node, spleen, and/or liver, in an attempt to establish a diagnosis of malignancy, including lymphoma. Lymphoma is emphasized because it is a common condition which can, on occasion, be a difficult diagnosis to confirm, especially after glucocorticoids have been administered.

LOCALIZING PARATHYROID TISSUE CAUSING HYPERPARATHYROIDISM Cervical Ultrasound Ultrasound examination of the cervical area is generally available, noninvasive and relatively cost efficient. The reader is reminded that the value of an ultrasound examination, as much as any diagnostic tool utilized in veterinary medicine, is "operator dependent." The skill and experience of the individual performing the examination and the equipment available for ultrasonography are major factors in the value of this diagnostic aid.

Parathyroid tumors are typically round-to-oval hypoechoic masses that measure 4 to 8 mm in greatest length and are closely associated with a thyroid lobe. The largest parathyroid adenoma in our series was 21 mm in greatest diameter. Most masses are 4 â&#x20AC;&#x201C; 6 mm in greatest diameter. Cervical ultrasound was performed in 255 of the dogs in our series. In 221 of these 255 dogs, a solitary parathyroid mass was visualized. In 218 of these 221 dogs, the diagnosis was correct. In 15 of these 221 dogs, the diagnosis of a solitary parathyroid mass and a single (or multiple) thyroid mass was correct. One dog, at the time of diagnosis, had 2 parathyroid masses identified and removed at surgery while only one had been reported on the ultrasound examination. In each of 2 dogs, ultrasound diagnosis of both solitary thyroid and parathyroid masses was later confirmed to have been 2 parathyroid adenomas. About 5% of the dogs with primary hyperparathyroidism in our series have thyroid cysts, thyroid adenomas or thyroid carcinomas seen as a thyroid mass on cervical ultrasonography. Ultrasound examination

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feldman suggesting 2 parathyroid masses in each of 12 dogs was correct in 9. One dog had only 1 parathyroid mass and 2 dogs each had a solitary parathyroid and a solitary thyroid mass.

Ultrasound examination failed to identify a parathyroid mass in 5 dogs, each of whom had a solitary parathyroid tumor removed at surgery. Each of 31 dogs (9% of the 335) had 2 parathyroid masses correctly identified via ultrasonography at the time that PHP was diagnosed.

Cervical ultrasonography has become a routine component of evaluating hypercalcemic dogs. Failure to identify at least one enlarged parathyroid gland in a dog suspected as having primary hyperparathyroidism would not eliminate that diagnosis. However, failure to visualize a mass is reason to re-consider the diagnosis or to repeat the ultrasound examination.

Other Tests Abnormal parathyroid tissue has been localized in humans using Tc99 sestamibi nuclear scintigraphy. Results in dogs with PHP have been inconsistent at best and the procedure is not recommended. Recent attempts to localize abnormal parathyroid tissue utilizing selective venous sampling to measure the serum concentrations of PTH were not satisfactory.

TREATMENT OF PRIMARY HYPERPARATHYROIDISM Pre-Treatment Considerations â&#x20AC;&#x201C; Candidates for Percutaneous versus Surgical Treatment Treatment options for primary hyperparathyroidism include surgical removal and percutaneous, ultrasound-guided, heat or ethanol ablation. Several factors should be considered prior to suggesting a treatment recommendation. If a male dog has cystic or urethral calculi, surgery or urohydropulpulsion is recommended to remove all calculi. A majority of the dogs in our series with cystic calculi were managed successfully with urohydropulpulsion. The decision to perform surgery on dogs with renal or ureteral calculi must be considered on an individual basis, but those undergoing surgery for calculi in the urinary tract should have their parathyroid

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feldman mass surgically removed during the same anesthesia. Dogs with evidence of both a parathyroid mass and a thyroid mass should probably undergo surgery. Candidates for ultrasound-guided ablation treatment must not have a mass too closely associated with one of the carotid arteries nor can the mass be too small to confidently have a needle placed percutaneously. Masses >12 mm in greatest diameter are not common and should be surgically removed. For dogs with 2 contralateral parathyroid masses, surgery is recommended or the percutaneous treatment should be â&#x20AC;&#x153;stagedâ&#x20AC;? at least 30 days apart to avoid any possibility of iatrogenic laryngeal paralysis, an uncommon but possible problem with heat ablation. Transient laryngeal paralysis was a side effect of ethanol ablation and is the primary reason for abandoning that protocol in favor of radiofrequency heat ablation.

Pre-Treatment Considerations â&#x20AC;&#x201C; Serum Calcium Concentrations Dogs are not at risk for developing worrisome hypocalcemia and tetany in the first 48 hours after successful surgical or percutaneous therapy for primary hyperparathyroidism, regardless of the pre-treatment serum calcium concentration or duration of disease.

Hypocalcemia following successful treatment usually occurs 3 to 8 days later. If the pre-treatment serum calcium concentration is >12 but <14.5 mg/dl, vitamin D therapy is usually withheld. In these dogs, serum total or ionized calcium concentrations should be monitored once or twice daily for 5 to 7 days after treatment. It is our opinion that most dogs should remain hospitalized for about 5 days for monitoring and to decrease their activity. Vitamin D therapy is only instituted if the total serum calcium concentration decreases below 9.5 mg/dl, the ionized calcium decreases below 1.00 mmol/L, or clinical signs of tetany are observed.

If the total serum calcium concentration prior to therapy is >14.5 mg/dl, the ionized calcium >1.70 mmol/L, or if a dog has more than one parathyroid mass, the incidence of

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feldman post-treatment worrisome hypocalcemia is greater. In these dogs, vitamin D therapy is usually initiated (calcitriol: 10 to 20 ng/kg daily) the morning of the treatment day. Whenever vitamin D therapy is utilized, serum calcium is monitored as described earlier and parenteral calcium is only administered if tetany occurs or is thought to be imminent. Vitamin D is then tapered to ever decreasing dosages over a 2 to 6 month time period (usually over 2 to 4 months). Once the serum calcium concentrations plateau at a safe concentration (total calcium >9.5 mg/dl; ionized calcium >1.1 mmol/L), the dog should be returned to the owner with instructions regarding keeping the dog quiet and monitoring recommendations. No dog should be given vitamin D without being monitored carefully. Serum calcium concentrations can be checked frequently initially and then usually every 2 weeks. Calcium concentrations should always be measured immediately prior to any dose reduction. Vitamin D dose reduction is usually about 50% every 2 weeks.

Percutaneous Ultrasound-Guided Heat Ablation Approximately 55% of the dogs we diagnose as having primary hyperparathyroidism have surgery and about 45% undergo percutaneous ultrasound-guided ablation. Both procedures have excellent results. Dogs that meet the inclusion criteria for percutaneous therapy are placed under anesthesia and, with ultrasound guidance, have an insulated needle placed into the parathyroid mass. The needle is attached to a radio-frequency unit (radio frequency waves are naturally converted to heat at the needle tip). The wattage is started at a low level and increased based on observing a â&#x20AC;&#x153;bubblingâ&#x20AC;? appearance to the tissue. The needle tip is repositioned several times to insure, as much as possible, that the entire parathyroid mass has been ablated.

Percutaneous ultrasound guided heat ablation requires less than 30 minutes of anesthesia and is

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feldman significantly less expensive than surgery. Post-heat ablation management of the dog is identical to the management following surgical removal of a parathyroid mass.

Percutaneous Ultrasound-Guided Ethanol Ablation Ethanol is caustic and when delivered into a mass, can destroy that tissue. However, ethanol can also leak out of any target, causing unintended damage. For example, leaking ethanol from parathyroid adenomas likely resulted in unilateral laryngeal paralysis in some of our treated dogs. For this reason, percutaneous ethanol ablation is no longer recommended. The procedure used was similar to that described for the heat ablation except the needle is connected to a syringe containing a volume of ethanol similar to the calculated volume of the parathyroid nodule. Ethanol was infused slowly in an effort to expose all tissue to ethanol and the needle tip was repositioned several times to aid in accomplishing this goal, perhaps increasing risk of leakage.

Surgery Complete exploration of both thyroid lobe areas is recommended for dogs with primary hyperparathyroidism having surgery, with both ventral and dorsal surfaces of both thyroid lobes examined. In most dogs with PHP, the abnormal parathyroid tissue is solitary, off-color, larger than normal parathyroid tissue, easily recognized and easily extirpated. Only abnormal parathyroid tissue is removed if possible, although when a parathyroid tumor lies within a thyroid lobe, that thyroid lobe is usually removed. If no parathyroid mass is observed and the diagnosis is thought to be correct, one thyroid/parathyroid complex should be removed and examined histologically. If 2 abnormal parathyroids are observed, both should be removed.

POST-TREATMENT CARE Use of Calcitriol

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feldman We have recently completed a planned retrospective / prospective study regarding posttreatment hypocalcemia in dogs with primary hyperparathyroidism. Fifty-four dogs with primary hyperparathyroidism were arbitrarily divided into 4 groups based on their pre-treatment plasma ionized calcium (iCa) concentration (reference range: 1.20 – 1.42 mmol/L). Twelve dogs had pre-treatment iCa of 1.45 – 1.61 (group 1); 15 had iCa of 1.62 – 1.71 (group 2); 14 dogs had iCa of 1.72 – 1.81 (group 3); and 13 dogs had iCa >1.81 mmol/L (group 4). All dogs were monitored daily for at least 5 days following treatment. Ten of the 54 dogs had documented serum iCa concentrations <1.0 mmol/L: 1/12 group 1 dogs; 1/15 group 2 dogs; 2/14 group 3 dogs; and 6/13 group 4 dogs. Thus, hypercalcemic dogs with pre-treatment serum iCa <1.72 mmol/L had a 7% chance of developing worrisome hypocalcemia. However, 30% of dogs with pre-treatment iCa concentrations >1.71 mmol/L developed worrisome hypocalcemia. Moreover, dogs with pretreatment iCa concentrations >1.81 mmol/L had a 47% chance of developing worrisome hypocalcemia! After reviewing the retrospective data, the prospective aspect of this study was abandoned for ethical reasons. No dog in this study had a serum total calcium concentration as high as 16.0 mg/dL and only 2 of the 54 dogs had severe ionized hypercalcemia (iCa >2.0 mmol/L). It can be assumed that had more dogs with severe hypercalcemia been included, the results would have been more dramatic in support of dogs with the highest pre-treatment calcium concentrations being at greatest risk for worrisome post-treatment hypocalcemia and tetany. Our current recommendations are to administer calcitriol prophylactically, beginning the morning of planned surgery or percutaneous ablation, to any dog whose total serum calcium concentration is >14.5 mg/dL or whose plasma iCa concentration is >1.70 mmol/L. General

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feldman Dogs are kept in-hospital for 5 to 7 days after treatment to monitor serum calcium concentrations and, more importantly, to keep them quiet. Since most dogs are quiet in-hospital, it can be appreciated that the quiet hypocalcemic dog is less prone to clinical tetany than would be the case if the dog is active. Dogs that are unusually active in-hospital, are sent home for this reason. We usually monitor serum total calcium concentrations twice daily until release from the hospital.

HISTOLOGY Parathyroid tumors have been histologically classified as adenoma, hyperplasia or carcinoma. These classifications have not had use clinically, since all parathyroid masses act biologically similar. We have not experienced a dog with local tumor invasion nor with distant metastasis. Recurrence rate is about 10% regardless of the histology.

HYPOCALCEMIA Causes Some of the more common causes of hypocalcemia include post-whelping eclampsia, acute kidney injury, and acute pancreatitis. The most common cause of hypocalcemia in dogs in our hospital population is post-treatment for primary hyperparathyroidism. Remember that total calcium decreases with decreases in serum albumin concentrations but that ionized calcium is not affected.

Clinical Signs Reviewing the clinical signs associated with hypocalcemia is worthwhile. Some of the earliest signs include rubbing the muzzle and chewing at the paws. Also early signs can include nervousness, anxious / restless behavior. More worrisome signs include muscle twitching or fasciculations that are often worsened by excitement. Lameness, stiff gait, and reluctance to be

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feldman handled are often seen. Tetany culminates with seizure-like activity, extreme sensitivity to sound and touch, and can be terminal.

References and Suggested Reading Feldman EC, Hoar B, Pollard R, et al: Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004). J Am Vet Med Assoc 227:756, 2005

Pollard RE, Long CD, Nelson RW, et al: Percutaneous ultrasonographically guided heat ablation for treatment of primary hyperparathyroidism in dogs. J Am Vet Med Assoc 218:1106, 2001

Skelly, BJ: Hyperparathyroidism. In: Mooney CT and Peterson ME (editors); BSAVA Manual of Canine and Feline Endocrinology, 4th edition. British Small Animal Veterinary Association, 2012.

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DIAGNOSIS OF HYPERADRENOCORTICISM (CUSHING'S SYNDROME) IN DOGS WHICH TESTS ARE BEST? Edward C. Feldman, DVM Diplomate, ACVIM, Emeritus Professor of Small Animal Internal Medicine School of Veterinary Medicine, University of California Davis, CA 95616 U.S.A. Email: ecfeldman@ucdavis.edu CAUSES The most common cause of Cushing’s syndrome in dogs is iatrogenic. Glucocorticoids are used in treating many conditions. The anti-inflammatory and immune-suppressive effects of glucocorticoids in dogs can be dramatic. However, not only are these beneficial effects common, but dogs demonstrate their sensitivity to this class of hormone by consistently exhibiting a number of progressive, sometimes alarming, clinical signs. These same clinical signs are common in naturally occurring hyperadrenocorticism in dogs, in whom about 85% have pituitary dependent hyperadrenocorticism (PDH) and the remaining 15% have a solitary functioning adrenocortical tumor (FAT). Dogs with PDH have an autonomously functioning, ACTH-secreting, adenoma. Chronic excess ACTH secretion leads to excess circulating glucocorticoids and bilateral adrenocortical hyperplasia. Cortisol-secreting adrenocortical tumors are usually soliary, can be either an adenoma or carcinoma, but in either case, the tumor autonomously secretes excessive quantities of glucocorticoids.

Other causes for Cushing’s syndrome have been recognized and are rare. In all cases, the final common denominator is the chronic and excessive exposure of dogs to glucocorticoids that causes signs, physical changes, laboratory test abnormalities, and need for imaging. Iatrogenic Cushing’s is easily treated: stop giving the drug. Naturally occurring Cushing’s is a more complicated diagnosis and treatment is never inexpensive nor is it ever without risk. These notes focus on the naturally occurring syndromes.

HISTORY

Dogs chronically exposed to excess cortisol usually develop a classic combination of clinical signs, some of which may be dramatic. These common signs include polydipsia, polyuria, polyphagia, abdominal enlargement, alopecia, pyoderma, panting, muscle weakness, thin skin, and lethargy. It must be remembered, however, that not all dogs with hyperadrenocorticism develop the same signs. From this long list of potential signs (plus others), most dogs exhibit several (but not all) of these problems.

Hyperadrenocorticism is a clinical disorder, and animals afflicted with this disease must have at least some of these clinical signs or the diagnosis must be questioned. Clinical signs result from the combined gluconeogenic, lipolytic, protein catabolic, anti-inflammatory, and immunosuppressive effects of glucocorticoids. Dogs are uniquely sensitive to glucocorticoid, such that a â&#x20AC;&#x153;sub-clinicalâ&#x20AC;? is not likely.

Typically, the course of the disease is insidious and slowly progressive. Owners usually report observing some alterations typical of hyperadrenocorticism in their pet for 6 months to as long as 6 years before they seek veterinary attention for their animal, since these changes are quite gradual in onset and are often believed to be a result of simple "aging." Commonly, only after signs become intolerable to the client or after abnormalities are pointed out by people who see a pet infrequently (therefore objectively noting obvious changes that have developed so slowly the owners do not observe them) that professional opinion is sought. The most common reasons that owners give for finally seeking veterinary help are usually polydipsia/polyuria, polyphagia, lethargy, panting, and/or hair coat changes. It should be pointed out that dogs with Cushingâ&#x20AC;&#x2122;s syndrome should not have vomiting, diarrhea, anorexia, weight loss, or other signs that would cause many owners to quickly seek veterinary care.

PHYSICAL EXAMINATION The physical examination on a typical "Cushing's" dog reveals an animal that is stable, hydrated, has good mucous membrane color and is not in distress. Veterinarians will usually observe,

during the physical examination, many of the signs seen by owners. Among these abnormalities are abdominal enlargement (truncal obesity), panting, bilaterally symmetrical alopecia, thin skin, skin infections, and comedones. Hyperpigmentation, testicular atrophy, and hepatomegaly are commonly noted. Ectopic calcification (calcinosis cutis), clitoral hypertrophy, and easy bruisability are much less common. Sites where previously clipped hair coats may not have grown back normally are common.

There is, however, remarkable variation in the number and severity of abnormalities noted. Afflicted dogs may have a single dominant sign or 10 signs.

SENSITIVITY AND SPECIFICITY (WHICH TEST IS BEST?) Test sensitivity refers to the number of patients with a condition whose test results are abnormal and consistent with that diagnosis. Test specificity refers to the number of patients that do not have a condition but their test results are positive for that diagnosis, incorrectly. Medicine would be much easier if our tests were 100% sensitive and 100% specific. Since this is never the situation, the most commonly asked question regarding testing to confirm naturally occurring hyperadrenocorticism is: “which test is best?” There is no doubt that the most specific and sensitive tests for the diagnosis of Cushing’s syndrome in dogs are history and physical examination. Therefore, all test interpretations must be done in the context of these two parameters.

"ROUTINE" DATA BASE Any dog suspected of having hyperadrenocorticism from the history and physical examination should be thoroughly evaluated before specific endocrine testing is undertaken. These initial tests should include laboratory testing, blood pressure measurement, and imaging studies. Laboratory assessments should include a CBC, urinalysis with culture, and a serum chemistry profile. It is not common to “routinely” recommend urine culture, however, about 50% of dogs with naturally occurring Cushing’s syndrome have a urinary tract infection. However, many of those with infection do not have the typical signs of straining nor do they have evidence of inflammation on urinalysis. In

addition to blood and urine testing, abdominal ultrasonography (preferred over radiography) should be completed.

Finding a large percentage of abnormalities on initial screening tests that are consistent with hyperadrenocorticism further allows the veterinarian to move toward a definitive diagnosis, which should have initially been based on history and physical examination. Typical abnormalities include hypertension, increases in serum alkaline phosphatase activity (sometimes dramatic), mild-to-moderate increases in ALT and serum cholesterol, low-normal or low BUN, urine specific gravity <1.020 on a sample caught by the owner at home, and bacteriuria. Thoracic radiographs should also be obtained.

Most dogs with hyperadrenocorticism have age-appropriate changes on thoracic imaging. However, one should look for the unexpected before embarking on expensive tests specific to the diagnosis of Cushing’s syndrome.

The more expensive and sophisticated studies needed to "confirm" a diagnosis and to localize the cause of Cushing’s syndrome can be recommended to the client if still indicated. Initial data base results not only ensure that the veterinarian is pursing the correct diagnosis but also might alert the clinician to any concomitant medical problems. These problems may be common for hyperadrenocorticism (urinary tract infection) or unexpected (renal failure), but in any case may require specific therapy.

"SCREENING" TESTS (separating dogs with Cushing’s syndrome from those who do not have this condition) Background After establishing a presumptive diagnosis of canine hyperadrenocorticism from a review of owner observations, physical examination, and laboratory data base, one usually proceeds to attempt “confirmation” of the diagnosis. When necessary, and if possible, an attempt can also be made to determine whether the dog has PDH or FAT. Choosing a screening test for Cushing's syndrome is

important because that test result may determine whether or not a dog is treated. Routinely used screening tests include ACTH stimulation, low dose dexamethasone, and the urine cortisol : creatinine ratio.

The decision to treat a dog for Cushing's syndrome should never be based solely on laboratory information. Cushing's syndrome is a clinical disorder with clinical signs. If a dog has no clinical signs of Cushing's syndrome, treatment is not recommended. This concept gains importance when it is understood that the goal of treating dogs for Cushing’s syndrome is to resolve their clinical signs.

Further, no screening test is correct all of the time, i.e., as previously stated, sensitivity and specificity is never 100%. Some dogs with non-adrenal disease and many with polyuria and polydipsia due to a condition other than Cushing’s syndrome can have false positive screening test results for hyperadrenocorticism. Because false-positive test results have been observed with every commonly used screening test, definitive diagnosis of Cushing's syndrome should never be solely on screening test results, especially in dogs without classical clinical signs or in those with known non-adrenal disease. In our experience, the most sensitive, specific, and reliable screening test for hyperadrenocorticism in dogs is the history and physical examination. The most sensitive, specific, and reliable hospital study is the low dose dexamethasone test.

Low Dose Dexamethasone Test (LDDS) The protocol utilized for this test is obtaining serum or plasma samples for cortisol before and 4 and 8 hours after I.V. administration of 0.01 mg/kg dexamethasone. The 8-hour cortisol is used as a screening test for hyperadrenocorticism. Concentrations >1.0 or >1.4 µg/dL are consistent with, not confirming, the diagnosis of Cushing's syndrome. This test is relatively sensitive and specific, but not perfect. Approximately 90% of dogs with Cushing's syndrome have an 8 hour post-dexamethasone cortisol concentration >1.4 µg/dl and another 6 to 8% have values of 0.9 - 1.3 µg/dl.

ACTH Stimulation (NO LONGER RECOMMENDED)

The ACTH stimulation test has been popular for decades in veterinary medicine. It is simple to complete and takes little time. Results of ACTH stimulation are the only tests which reliably demonstrate the effects of o,p'-DDD, trilostane, or other therapy on the adrenal cortex. Further, test results are relatively easy to interpret. Some veterinarians believe that results of an ACTH stimulation test prior to initiating medical therapy may aid in determining treatment needs and the "baseline" information can be used for comparison purposes as therapy continues. This is not a valid reason for conducting an ACTH stimulation test, as pre-treatment results have no bearing on therapy chosen, protocol or prognosis.

Regardless of the protocol chosen, it must be appreciated that as many as 40% of dogs with Cushing's syndrome have test results within the reference range (in our laboratory: post-ACTH plasma cortisol concentrations: 6 to 17 µg/dl). An additional 20% of dogs with Cushing's have test results described as "borderline" (plasma cortisol concentrations >17 but <22 µg/dl). Therefore, the test is not considered sensitive but is relatively specific, i.e., those dogs with plasma cortisol concentrations >22 µg/dl frequently have Cushing's. However, specificity of an exaggerated response to ACTH is also not perfect. Therefore, test results should never be interpreted without knowing results of history, physical examination, and routine data base testing. There are no features of ACTH stimulation test result that reliably allow discrimination between PDH and FAT. As ACTH for these tests has become more expensive, its value is being scrutinized closely.

Protocols to monitor dogs being treated for Cushing’s syndrome have been developed without use of ACTH stimulation. Neither form of ACTH is consistently available to veterinarians. ACTH gel is effective but has a history of not being consistently potent. Synthetic ACTH can be given at 0.05 mg/kg (IV or IM) instead of using .25 mg (one vial) per dog. Excess re-constituted ACTH can be frozen and maintain potency for about 6 months. Excesses can be stored in one-tenth mL aliquots and easily used later.

Lack of ACTH stimulation test sensitivity makes it a test that the profession should abandon as a screening test for dogs suspected as having naturally occurring hyperadrenocorticism. ACTH stimulation testing continues to be indicated for monitoring Cushing’s therapy, to aid in the diagnosis of iatrogenic Cushing’s syndrome (an Addisonian response), and it remains the “gold standard” for the diagnosis of naturally occurring hypoadrenocorticism (Addison’s disease).

Urine Cortisol: Creatinine Ratio (UC:CR) The urine UC:CR ratio is easily performed: simply have the owner collect and deliver urine to the hospital and submit it to the laboratory. It is usually less expensive than other screening tests. Most dogs (~98%) with naturally occurring Cushing’s syndrome have an abnormal result (the test is sensitive) but a significant percentage of dogs with polyuria / polydipsia due to other conditions and those with non-endocrine illness may also have abnormal results (the test is not specific). It has been suggested that the UC:CR be routinely performed only on urine collected by an owner at home, rather than having it collected in-hospital. Since this protocol eliminates travel or hospital stress from altering test results, it seems reasonable to follow this concept. We do not utilize this test with the same degree of confidence with which we use the low dose dexamethasone screening test. However, a normal result is quite uncommon in a dog with Cushing’s syndrome while an abnormal result could be used to prompt further testing. Therefore, this test can be used as a prompt to recommend abdominal ultrasonography and a low dose dexamethasone test to an owner.

17 HydroxyProgesterone (17OHP) Testing The use of 17OHP has been recommended as a screening test for dogs with “atypical Cushing’s syndrome.” The definition of “atypical” is a dog with clinical signs and routine laboratory testing consistent with hyperadrenocorticism but with normal low dose dexamethasone screening test results, normal ACTH stimulation test results, and normal urine cortisol : creatinine ratio test results.

People, dogs and cats with adrenocortical tumors have been reported in which the primary hormone

secreted has been 17OHP. Adrenocortical tumors have long been known to synthesize and secrete a myriad of steroids and it is not surprising to learn that some primarily produce steroids other than cortisol. Such dogs and cats, in our experience, do not have “normal” screening tests results, but their results may be relatively low in cortisol. It is extremely rare for a dog or cat with PDH to produce only 17OHP. Some recommend assaying 17OHP before and after ACTH stimulation. Our recommendation would be to repeat a low dose dexamethasone test if results are <0.9 µg/dl at the 8-hour sample, since the most common explanations for such a result would be administration of 0.1 instead of 0.01 mg/kg of dexamethasone or simple fluctuation in circulating cortisol concentrations. If one is convinced that a dog has naturally occurring hyperadrenocorticism, and if that dog persistently has a non-diagnostic low dose dexamethasone test result, use of ACTH stimulation and assessment of 17OHP can be considered. This is an extremely unusual scenario.

Hair Cortisol Hair samples have been used successfully separate dogs without hyperadrenocorticism from those with the condition. This holds promise as a simple, inexpensive, sensitive, specific, and reliable screening test. Future studies will be of interest.

Recommended Reading Behrend, E.N.: Canine Hyperadrenocorticism, in Feldman, E.C., Nelson R.W., Reusch C.E., Scott-Moncrieff J.C.R., and Behrend E.N.: Canine and Feline Endocrinology, Fourth Edition, Elsevier Saunders, St Louis, USA; 2015 Herrtage M.E. and Ramsey I.K.: Canine hyperadrenocorticism, in Mooney, C.T., Peterson M.E.: BSAVA Manual of Canine and Feline Endocrinology, Fourth Edition. British Small Animal Association, Gloucester, England; 2012 Perez-Alenza, M.D., Melian, C.: Canine hyperadrenocorticism, in Ettinger, S.J., Feldman, E.C., Cote, E: Textbook of Veterinary Internal Medicine, Eighth Edition. Elsevier Saunders, St Louis, USA; 2017

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

FELINE ACROMEGALY Edward C Feldman, DVM, DACVIM (SAIM) Emeritus Professor of Small Animal Internal Medicine University of California, Davis Email: ecfeldman@ucdavis.edu Definitions Acromegaly is a condition caused by chronic and persistent excesses in circulating growth hormone (GH) concentrations. This once “rare” disorder in cats appears to have been significantly under estimated and now thought to “commonly cause diabetes mellitus in cats.”

Excess GH causes insulin resistance and subsequent DM by reducing insulin receptor numbers, interfering with post-insulin-receptor processes, and other mechanisms. Acromegaly should be considered a possible complicating condition in any middle-aged to older cat with diabetes mellitus. While not all cats with acromegaly have diabetes, the diagnosis is currently far more difficult to initially suspect in non-diabetics. Further, not all diabetic cats with acromegaly have obvious insulin resistance, again suggesting that remaining open to this possible diagnosis is sometimes the only reason a veterinarian may have for pursuing testing.

Incidence It has been estimated that 20 to 33% of diabetic cats have concurrent acromegaly. This incidence is greater than that of urinary tract infection or pancreatitis among newly diagnosed diabetic cats, two conditions commonly tested for. There is potential for geographic differences.

One large United Kingdom screening study was conducted on more than 1200 cats. Samples from each cat were assayed for insulin-like growth factor-1 (IGF-1). With an arbitrary value of >1000 ng/ml being considered suspicious, more 300 cats (>25%) were identified as suspects and about 95% of those cats were confirmed to have acromegaly! Thus, it is reasonable to

recommend screening all cats recently diagnosed with diabetes for acromegaly.

Causes Overview. The form of acromegaly in cats discussed in these notes is caused by an autonomously functioning, GH-secreting tumor, usually an adenoma, in the anterior pituitary. A small number of cats have had pituitary carcinomas and others have had non-neoplastic hyperplasia. It is assumed that cats with naturally occurring acromegaly, like humans with this form of acromegaly, likely have chronic and persistent increases in both the frequency and amplitude of pituitary GH secretory patterns. An underlying cause has not yet been identified, but environmental and genetic factors have been implicated.

Environmental Causes (From: Niessen, Textbook of Veterinary Internal Medicine, 8th ed). Organohalogenated contaminants (OHCs) have been implicated in the oncogenesis of various tumor-related endocrine conditions in various species, including people and cats. OHCs are persistent bio-accumulative chemicals found in organochlorine pesticides and industrial chemicals. Polychlorinated biphenyls (PCBs) and brominated flame retardants (BFRs) are commonly added to materials used in furniture and bedding and these chemicals are frequently identified in house dust and some foods. Dust may be especially relevant in cats with their intense grooming behavior. In one report, significantly higher levels of such contaminants were identified in cats with acromegaly as compared to cats without an endocrine disorder or to cats with primary diabetes mellitus. Data also suggested that acromegaly may, in turn, reduce a catâ&#x20AC;&#x2122;s capacity to metabolize some of these chemicals. Similar contaminants have been implicated in the emergence of feline hyperthyroidism.

Genetic Causes. Pituitary adenomas in people were considered the result of an acquired single cell monoclonal somatic mutation. It was later demonstrated that a contributing

mechanism for development of GH-secreting pituitary adenomas involved germline mutations that inactivate tumor suppressor genes in as many as 40% of people with GH secreting adenomas. This protein has a range of effects that include activation of xenobiotic metabolizing enzymes, making the previously discussed link with exposure and accumulation of environmental OHCs even more interesting.

Clinical Signs of Acromegaly “Non-Diabetic” Signs. Most cats with acromegaly have concurrent diabetes mellitus.

Only rarely have non-diabetic cats been diagnosed with acromegaly. These cats may have phenotypic acromegalic changes, described later in this section. Initial clinical signs in cats with acromegaly are likely to be subtle and, to owners, consistent with aging. Owner observed signs noted in the literature, are from groups of affected cats whose signs are determined in part by the timing of an owner’s concern. Since the diagnosis of this condition has been uncommon, those cats initially described are likely to have had the most obvious signs. As the condition becomes better recognized, variations in clinical presentation will be better understood. In one study of more than 300 cats suspected as having acromegaly, their mean age (11 years; range 4 – 19), gender (a majority were neutered males), breed (most were Domestic Short Hair cats) were not unique. Certainly, these ages, the bias to males, and the breeds seen were all similar to cats with diabetes mellitus in general and, therefore, not useful in raising the suspicion of acromegaly.

Cats with acromegaly can be thin or obese, they are not all “large.”

Signs of Diabetes Mellitus. Most cats currently diagnosed as having acromegaly are first brought to a veterinarian due to signs of diabetes mellitus. The most common signs in diabetic cats are polyuria and polydipsia (PU/PD) secondary to the osmotic effects of glucose in the urine. Some of these cats are profoundly polyphagic. Insulin treatment is usually initiated and

can lead to successful amelioration of clinical signs in some cats. Diabetic remission, usually transient, can occur. However, gaining reasonable carbohydrate control is difficult in most cats with concurrent acromegaly and diabetes mellitus. If weight gain is noted in a cat with suboptimal diabetic control or if unexplained insulin resistance is encountered, acromegaly should be suspected.

Signs of Chronic Acromegaly. As the condition becomes chronic, more cats have what are considered “classic” clinical signs. The classic signs are in addition to those associated with diabetes mellitus (polyuria, polydipsia, polyphagia) or weight gain despite suboptimal diabetic control reported (although weight loss has been seen in a few). Polyphagia independent of diabetes or of diabetic control can be extreme. The classic signs of chronic disease include inspiratory stridor (snoring), broad facial features, prognathia inferior (protrusion of lower jaw), large distal limbs or paws, abdominal enlargement with organomegaly, mobility issues due to arthropathy and/or diabetic neuropathy, insulin resistance (unfortunately, these last two are quite vague), heart murmur and congestive heart failure, and, if the cat develops a “macro” pituitary tumor: obtundation, inappetence, circling, blindness, and seizures.

More than half of cats diagnosed as having acromegaly have had upper respiratory stridor, due to tissue swelling. The narrowed nasopharynx often causes an owner to notice their cat “snoring.” Increased width of the head and broad facial features might be the most obvious feature on physical examination. However, these changes can be subtle and difficult to appreciate because of facial hair, breed-related conformational variation and the tendency for owners not to notice changes that have develop quite gradually over an extended time period.

The organomegaly and arthropathy issues are due to abnormal growth of these tissues stimulated by the excesses in circulating GH concentrations over time. For example, abnormal cardiac

growth can cause murmurs and failure while abnormal growth in and around joints, cause arthritis.

Diagnosis Using Serum or Plasma IGF-1 Each Laboratory Must Have Independent Reference Ranges. For most veterinarians, serum total IGF-1 assessment represents the most feasible and accessible means of screening cats for acromegaly. While the positive predictive value of an IGF-1 > 1000 ng/ml was shown to be about 95% with one particular radioimmunoassay, readers are warned to only use validated assays with independent laboratory-generated reference ranges. Serum IGF-1 concentrations have been useful for judging treatment success post-hypophysectomy, but assays have not yet been adequately sensitive to document the less pronounced GH decreases that might occur following radiotherapy.

Weaknesses of IGF-1. The weakness of randomly obtained blood samples for IGF-1 concentrations as a screening test for acromegaly is that hepatic IGF-1 synthesis is dependent on adequate concentrations of portal insulin. Since insulin concentrations can be deficient in cats with diabetes mellitus (newly diagnosed or those with chronic disease), false-negative IGF-1 results can be expected. One study demonstrated false negatives in about 10% of untreated diabetic cats. Also confounding the issue are the increased IGF-1 concentrations reported in some diabetic cats who have no evidence of acromegaly. Thus, IGF-1 results can never be considered perfectly specific nor sensitive (similar to all endocrine testing).

Diagnosis via Assessing GH Commercially available GH assays remain elusive. In one group, all tested acromegalic cats had results above the reference interval. However, 100% sensitivity has never existed in endocrinology. Use of a readily available assay would be appreciated, but has not yet become

reality. GH suppression tests (often using oral glucose), often considered the gold standard for the diagnosis of human acromegaly, have thus far not been found useful in the cat.

Alternative Blood Tests Relative to the tissue growth associated with acromegaly, one group studied serum type III pro-collagen pro-peptide (PIIIP), a peripheral indicator of collagen turnover. Results in diabetic cats with acromegaly were five times higher than those in cats with diabetes mellitus but no evidence of acromegaly. Serum ghrelin concentrations, a GH secretagogue, were lower in acromegalic versus healthy cats, but results were similar to those from cats with diabetes mellitus and no evidence of acromegaly.

Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) Scans Imaging confirmation of acromegaly is currently recommended and often helpful by demonstrating pituitary enlargement via contrast-enhanced CT or MRI scans. Absence of a mass or of enlargement should not, however, be interpreted as excluding the diagnosis. Remember that only about 50% of pituitary tumors are visible with CT or MRI scanning at the time of diagnosis of hyperadrenocorticism in dogs. Microadenomas and acidophil hyperplasia can occur and must be more common than currently appreciated. As cats are diagnosed earlier in the course of disease, the number of visible masses on advanced imaging should be expected to decline. In longer-standing cases, CT may demonstrate acromegaly-related prognathia inferior (about 25% of affected cats), temporomandibular-joint malformations, and increased thickness of the skin, SQ tissues and calvarium bone.

Treatment with Hypophysectomy As veterinary experience with hypophysectomy continues, it is recognized as the definitive â&#x20AC;&#x153;gold-standardâ&#x20AC;? treatment for dogs and cats with pituitary tumors causing illness.

Contraindications are inevitable and may include tumor size and significant comorbidities. The financial commitment for surgery can be an obstacle, although it is important for the owner to be educated about the cost of ineffective insulin therapy or radiation treatment.

I have no experience with surgically treated cats. In hospitals that employ surgery, as many as 85% of cats enter diabetic remission within 2 months of surgery while the remainder attain good glycemic control with more traditional doses of insulin. The peri- and postoperative mortality rate has been about 10%. This is an acceptable risk for most cat owners, especially given the paucity of effective treatment alternatives. After surgery, cats require glucocorticoid and thyroid replacement therapy, both life-long. DDAVP, synthetic anti-diuretic hormone, is usually required in the immediate post-surgical period but can be discontinued in most cats. GH replacement therapy is not deemed necessary.

Medical Management Somatostatin (SST) analogues and dopamine agonists have not been effective.

Pasireotide (SigniforÂŽ, Novartis, Basel, Switzerland), a novel multi-receptor ligand SST analogue with high binding affinity for SST receptor subtypes 1, 2, 3 and 5 has recently been shown to effectively suppress the somatotrophinoma in cats with acromegaly. Treated cats had significant decreases in serum IGF-1, average 12-hour blood glucose, fructosamine and insulin requirements. A short-acting BID injectable form and a once-monthly long-acting injectable form have been tested. About 25% of cats treated with the once monthly form entered diabetic remission. Disadvantages include mild GI side effects (loose stools/diarrhea) and cost.

Radiotherapy Although radiation therapy was initially believed to provide an optimal alternative to medical or surgical treatments, even results after use of stereo-tactical or gamma-knife

technology has failed to rival results of hypophysectomy. Following radiation therapy, it has been difficult to predict response. Many cats have had no response, but others have had responses at variable times after completion of radiation. Thus, no consensus is available regarding when a response should be expected, how insulin requirements may change, or how long radiation effects persist. Lack of response in terms of IGF-1 normalization in several studies puts further doubt over the efficacy of radiation therapy, even in cats who required less insulin.

Acromegalic changes have been shown to progress in some cats even after diabetic improvement or resolution was achieved. Radiation treatment may be valuable for shrinking a macro-tumor.

Diabetes Mellitus Treatment Only If definitive treatment for acromegaly is declined by owners, one should treat the diabetes mellitus. Treatment should begin as with any diabetic cat. While high insulin doses may be anticipated, the cat should dictate dose. Some suggest insulin doses should not exceed a certain level, but the experience of others indicates that use of extremely high doses is sometimes the only way to achieve an acceptable quality of life. Use of high dose insulin therapy does mean owners need to be prepared for, and indeed need to accept, the possibility of iatrogenic hypoglycemia, but it seemed to have been rare. The pituitary tumor does retain its pulsatile GH secretory patterns, which may explain episodes of increased insulin sensitivity. Appropriate insulin dose should be determined by gradually increasing the amount as required, usually increasing by no more than 1 unit/injection/cat /week. Ideally, periodic blood glucose curves are obtained along with careful assessment of the clinical condition. If insulin doses increase too quickly, there is increased risk of encountering Somogyi phenomena. Negative sequelae of the progressive acromegalic changes may require attention: including treatment for arthropathies, congestive heart failure, or chronic kidney disease. Central nervous system signs (e.g. seizures,

blindness, depression) due to an expanding pituitary mass are rare, given their slow-growing nature. However, signs can occur.

Hypoadrenocorticism Definition A. “Hypoadrenocorticism” typically refers to a severe deficiency of both glucocorticoids & mineralocorticoids B. Primary adrenal insufficiency a. A failure of the adrenal glands to synthesize and secrete the 2 main classes of “steroids” (glucocorticoids and mineralocorticoids) i. Normally, the hormones are synthesized, in several steps, from cholesterol ii. Glucocorticoids from the adrenocortical zonae fasciculata and reticulosa iii. Mineralocorticoids from the outermost cortex area: zona glomerulosa b. Some dogs exhibit a deficiency in one class of hormone (glucocorticoids or mineralocorticoids) days to months before the other deficiency becomes clinically obvious and important. c. The synonym for condition resulting from destruction of the adrenal cortices (thought to represent >90% loss of function) is “Addison’s Disease” C. Insufficient pituitary secretion of ACTH results in glucocorticoid deficiency a. This is called “secondary” adrenal insufficiency. b. The renin-angiotensin-aldosterone system: i. should either not be affected or be affected minimally ii. serum Na+ and K+ concentrations should be within reference limits Incidence A. Relatively rare B. Incidence increasing? a. Possible …. b. More likely: i. veterinarians are increasingly aware of the condition & its clinical signs (both severe and subtle) ii. easy and inexpensive to screen with a simple basal cortisol check iii. those with low cortisol are often correctly diagnosed with another condition iv. those still candidates are now being “caught” or “identified” C. Just curious: do you think a client who refuses to pay for testing would be likely to pay for medication and its monitoring ? i.e. how hard should we persuade someone to test?

Causes A. Primary adrenal insufficiency = destruction or atrophy of all 3 layers of the adrenal cortex a. Vast majority of dogs with naturally occurring hypocortisolism have primary dz. b. Usually never determine because we treat them & they do GREAT! c. thus, we do not have many post-mortems d. common: idiopathic destruction with some evidence for an auto-immune condition: i. familial in certain breeds (see below) ii. histology and serology studies are suggestive e. infiltrative neoplastic or infectious/granulomatous or vascular conditions possible f.

a common cause is iatrogenic! But the natural are far more fun! i. Acutely stopping chronically given glucocorticoid medication ii. o,p’-DDD (mitotane): overdose of drug used for hyperadrenocorticism iii. trilostane (vetoryl): overdose of drug used for hyperadrenocorticism iv. o,p’-DDD and Vetoryl most commonly cause glucocorticoid deficiency, but either can cause transient or permanent complete adrenocortical failure

B. Deficient ACTH a. Is considered by most to be “extremely rare” b. Idiopathic destruction (probably immune-mediated, probably auto-immune) c. Also can follow infectious, infiltrative (cancer), or vascular conditions of pituitary Pathophysiology A. A few results of glucocorticoid deficiency include: a. Decreased gluconeogenesis, decreased glycogenolysis b. Impaired energy metabolism c. Inability to maintain vascular tone or endothelial integrity d. Increase in vasopressin secretion which can exaggerate hyponatremia B. A few results of mineralocorticoid deficiency include: a. Renal wasting of sodium, chloride and water …. i. causing hypovolemia and hypotension ii. causing hyponatremia iii. leading to hyperkalemia b. Renal retention of potassium and hydrogen c. Decreased myocardial excitability, poor cardiac output, poor tissue perfusion

C. The resulting metabolic derangements are seen with varying degrees of severity: a. Hypotension and decreased cardiac output b. Poor tissue perfusion that clinically causes weakness, lethargy, obtundation, vomiting, diarrhea, anorexia, pre-renal azotemia, shock c. Hyperkalemia and/or hyponatremia (either of which can be severe) d. Acidosis which is usually mild and not in need of treatment Signalment A. Has been reported in: a. Dogs 2 months to 14 years of age, most are young-to-middle-aged (mean ~4 yrs) b. Perhaps more common in females, but this is not consistent in the literature B. A few breeds are predisposed: Standard Poodles, Portuguese Water Spaniels, Bearded Collies, Nova Scotia Duck Trolling Retrievers, Leonbergers, West Highland White Terriers, and a few others ………….. but this disease can affect any dog at any age either gender C. The disease is extremely uncommon-to-rare in cats Clinical Signs A. Most signs are non-specific and similar to those seen in numerous other conditions B. Acute, end-stage insufficiency a. Inappetence-to-Anorexia, Weight Loss, Vomiting, Diarrhea, Abdominal Pain, b. Weakness, Obtundation, Collapse c. Hypothermia d. Bradycardia despite hypovolemia, nice when present e. Incidence of hyperkalemia-related cardiac arrhythmias increases as K+ increases f.

Death if not treated quickly

C. Subacute or more chronic adrenal insufficiency (becoming a more common diagnosis) a. Sometimes a dog that simply is “not well” in the opinion of the owner b. Chronically underweight, inactive, “often not interested in food” c. Intermittent vomiting, diarrhea, hematochezia, melena, poor appetite d. Weakness, slow, not playful, shivering on occasion, e. Polyuria / Polydipsia is an extremely uncommon concern, but these patients do lose the ability to concentrate their urine due to their sodium deficiency f.

Positive response to non-specific fluid therapy or steroid therapy

g. Inability to “respond to stress” …. A classic observation in people

Initial Suspicion of Hypoadrenocorticism A. History and clinical signs: a. Sometimes so vague that one must maintain an “index of suspicion” b. Other conditions that cause vague signs like these are far more common (G.I.; kidney; heart; liver; pancreatitis; etc) B. Hemogram a. Absolute eosinophilia and lymphocytosis: i. nice but not common ii. eos & lymphs in an extremely ill dog should be decreased or absent b. Dehydration and hypovolemia may mask a chronic NNN anemia c. Sometimes the anemia can be profound secondary to G.I. hemorrhage C. Serum biochemistry a. The “Classic”: decreased serum sodium and increased serum potassium i. Most dogs with Addison’s have a serum Na <135 mmol/L ii. Most dogs with Addison’s have a serum K >5.5 mmol/L iii. (Na of 135 and K of 5.5 = a ratio of 24.5) iv. Ratios of Na+ / K+ <27, <25, <24, or <23 “are suggestive” 1. About 25% of dogs with a ratio <25 had Addison’s in one study 2. Almost 2/3 of dogs with a ratio <20 had Addison’s in one study 3. Please see “Differential Diagnosis” below for low Na+ &/or high K+ v. Cut-off values for any ratio should be independently determined by your laboratory, not the literature vi. Really, any ill dog that is hyponatremic or hyperkalemic should be a suspect, regardless of the ratio, until proven otherwise vii. 10 – 30% of dogs with Addison’s have serum electrolyte concentrations within reference ranges at diagnosis, likely a reflection of 1. early recognition in some 2. transient continued function of the zona glomerulosa 3. these dogs tend to be older, have a longer history of illness, and more likely to be anemic and have low cholesterol and albumin 4. progression to having electrolyte issues is unpredictable, is not common, and usually occurs within a year of diagnosis

viii. Remember: 1. Red Blood Cells of some Japanese breeds (Akita, Shiba Inu) contain large quantities of K+. Hemolysis will cause increases, sometimes large increases, in measured K+ on blood chemistries, called: pseudohyperkalemia since it occurs in vitro, not in vivo 2. almost any condition causing metabolic acidosis, remarkable thrombocytosis or leukocytosis can have associated hyperkalemia 3. hyperkalemia has been described in a dog receiving heparin Rx b. Azotemia i. pre-renal: due to dehydration, hypovolemia, and poor perfusion ii. often, increase in BUN is greater than predicted by the creatinine 1. G.I. bleeding is the primary culprit 2. Some dogs are quite thin, lowering their creatinine iii. urine concentrating ability decreased due to Na loss (see below) c. Calcium i. Total and iCa increased in about 25% 1. related to decreased renal excretion, acidosis, hyperkalemia?

2. Usually mild, clinically insignificant 3. not caused by PTH or Vitamin D ii. Total Ca may be low due to hypoalbuminemia, iCa should be normal d. Hypoglycemia is i. uncommon but, when present, related to loss of gluco-corticoids ii. some estimate as many as 30% of Addisonian dogs were hypoglycemic e. Liver i. Some hypoadrenal dogs have a small liver, increased enzyme activities, low cholesterol, low albumin, and, rarely, ascites ii. Do some of these dogs have immune-mediated or other hepatopathy? iii. More common in dogs without hyperkalemia and/or hyponatremia? iv. Changes related to glucocorticoids being needed for fat absorption? v. Are some changes due to protein-losing enteropathy?

D. Blood Pressure a. Expected to be dramatically low due to hypovolemia and poor cardiac output

b. In one study: i. 53 hypo adrenal dogs mean systolic BP = 90 mm Hg, (range 40 – 150) ii. 110 dogs with other illness, mean systolic BP = 140, (range 50 – 210) E. Urine a. Usually specific gravity of 1.10 – 1.025 despite severe dehydration b. Renal loss of sodium lowers the concentration gradient F. Electrocardiogram changes are due to hyperkalemia & when present can be helpful a. Widening, flattening and then disappearance of P waves; increased P-R interval b.

Decreased amplitude & increased duration of QRS complexes, spiked T waves

c. Bradycardia, atrial standstill G. Imaging a. Thoracic radiographs i. Microcardia & narrow vena cava due to hypovolemia ii. Small liver due to hypovolemia? iii. Megaesophagus in association with Addison’s?: rare b. Abdominal ultrasonography i. adrenals may appear “thin” but of normal “length” ii. little overlap with normal-sized glands H. Basal plasma or serum cortisol concentration a. Basal cortisol >2 µg/dL (>50 mmol/L): Addison’s quite unlikely b. Basal cortisol <2 µg/dL (>50 mmol/L): i. Virtually all Addisonian dogs will have this result ii. Non-specific, however, with non-adrenal illness diagnosed most commonly Confirming the Diagnosis A. ACTH stimulation test a. This is the “gold standard” test for ruling in or out this diagnosis b. While only assessing cortisol, it is assumed to reflect mineralocorticoid status i. Pets should not receive steroids of any kind before or during the test ii. Hydrocortisone et al may cross-react with assays iii. Dexamethasone does not cross-react with assays but still may alter results iv. Glucocorticoids rarely needed to save a life, rather it is fluids that save lives c. protocol:

i. obtain blood, give ACTH (IM or IV), 5 micrograms/kg IV or IM ii. take 2nd sample 1 hr post using synthetic ACTH (cosyntropin, tetracosactide) iii. take 2nd sample also @ 1 hr if using a depot formulation of ACTH d. In Addison’s: results not usually vague, easy to interpret (pre and post are low) i. Basal cortisol concentration almost always <2 µg/dL (>55 mmol/L) ii. Post-ACTH cortisol concentration almost always: <2 µg/dL (>55 mmol/L) iii. Differential?: inactive ACTH, iatrogenic Cushing’s or iatrogenic Addison’s B. Other Tests Evaluated (some assays not always available & some may be expensive) a. Cortisol : ACTH ratio (CAR), discriminated healthy from Addison’s but some overlap i. Only 1 blood sample ii. Negates dependence on ACTH administration b. Aldosterone : Renin ratio (ARR), clearly discriminated healthy from Addison’s c. Urine Cortisol : Creatinine Ratio, will be decreased, but i. Does not “confirm” Addison’s ii. Does not assess adrenocortical reserve d. Cortisol-induced alkaline phosphatase (CiALP): cannot be used alone e. Combining: eosinophil count, Na:K ratio, CiALP, BUN, and CK, excellent to discriminate Addison’s from diseases mimicking Addison’s D. Endogenous ACTH concentrations (samples handled as directed by laboratory: important!) a. Results in primary adrenal failure should be i. Obviously and remarkably increased 1. Lack of negative feedback to pituitary 2. Concentrations often higher in dogs with primary adrenal failure than in dogs with ACTH-secreting pituitary tumors ii. ACTH concentrations are similar when comparing dogs with Addison’s and electrolyte disorders and dogs with Addison’s without electrolyte disorders b. In “secondary” adrenal insufficiency i. Obviously low ii. No ACTH is the cause of the condition Differential Diagnosis ….

A. “Every” illness a. causes anorexia, vomiting, diarrhea, weight loss, depression, etc

b. most are far more common than Addison’s B. This is a partial list and depends on results of history, physical examination and initial tests a. Primary G.I. disease b. Kidney disease: AKI, CKD, other urinary tract issues (rupture, blockage, etc) c. Pancreatitis d. Neurologic, Cardiovascular, Muscular, Metabolic conditions e. Hepatopathies (usually failure) f.

Causes of hypercalcemia

g. Effusions, pleural or peritoneal h. Cancers i.

Iatrogenic (excess fluid supplementation, heparin Rx, K-sparing diuretics, ACE inhibitors, NSAIDS)

Treatment A. Life is made easier by obtaining as much information as possible prior to giving hormones a. because treatment invariably “might” alter subsequent test results b. because Addison’s is a life-long condition, expensive to monitor and treat B. Acute Severe Crisis a. The Addisonian dog in crisis is dying of: i. Hypovolemia ii. Hypotension iii. Hyperkalemia iv. Hyponatremia v. Is there 1 therapy to save this patient’s life? IV saline fixes each of the above vi. Some believe saline has too much Na, that Ringer’s-type solution is better b. After testing is complete: Glucocorticoids: i. dexamethasone (0.1 – 2.0 mg/kg IV) 1. My choice is the lower end of the dose range 2. Subsequent doses every 6 - 8 hours ii. Hydrocortisone hemisuccinate or hydrocortisone phosphate c. After testing is complete Mineralocorticoids: i. Desoxycorticosterone Pivalate (DOCP) 1. 2.2 mg/kg IM (first dose),

2. Next dose is in 25 days ……….. ii. However, K usually decreases 1. just with saline IV to safe or reference concentrations 2. improved renal perfusion enhances this result 3. With saline IV …. Can Na rise too quickly? iii. Use of Ca, Insulin, Glucose 1. for severe hyperkalemia?

2. Feldman has never used these drugs on an Addionian iv. Other mineralocorticoids: hydrocortisone sodium succinate 1. 0.5 mg/kg/hour IV, separate container, until well enough for oral Rx 2. Has glucocorticoid and mineralocorticoid activity 3. Negates need for separate gluco- and mineralocorticoid medication d. Glucose if hypoglycemic, not often needed e. Bicarbonate if acidotic, not often needed C. Long term mineralocorticoid replacement a. DOCP, extremely effective, few side effects, ideal for this condition i. can be quite precise & objective, begin at 2.2 mg/kg, SQ, Q25days ii. determined by periodic assessment of serum Na and K iii. most dogs can be tapered 1. 1 – 1.4 mg/kg, SQ, Q25days (decrease 10% / month as allowed) 2. Final Range in older study: 0.8 – 3.4 mg/kg/dose, Q 14 – 35 days iv. owners can easily learn to give SQ injections to save $ v. assess Na and K about 15 days post-DOCP to assess dose after first few injections vi. assess Na and K at about 25 days post-injection to assess frequency requirements after first few injections vii. DOCP has no glucocorticoid activity, therefore separate glucocorticoid therapy is needed b. Fludrocortisone Acetate (florinef), oral, drug of choice for people i. Given daily, 0.01 – 0.03 mg/kg/day, divided ii. 10 X glucocorticoid activity & 125 X the mineralocorticoid activity of cortisol iii. Not as effective a mineralocorticoid as DOCP, plus ……..

iv. Glucocorticoid-related negative side effects are common v. Dose requirements remain stable over time vi. This drug is not recommended by most in the U.S. D. Long term glucocorticoid replacement a. Dose Requirements: i. In contrast to DOCP, NOT objectively determined, but subjectively ii. Do not recommend using leukogram to replace detailed owner observations for determining the ideal dose for their pet iii. Determined by owner perception of need, so is completely subjective 1. Too much, unwanted side effects of cortisol excess 2. Too little, poor appetite and other signs of Addison’s b. Prednisone or prednisolone are fine and often the dose is quite low as compared with doses used for other conditions (about 0.1 – 0.2 mg/kg) c. Cortisone Acetate i. Equal glucocorticoid and mineralocorticoid activity, brief half-life ii. 0.5 – 1.0 mg/kg/day or divided BID iii. Iatrogenic Cushing’s not common d. Prednisolone Prognosis …………………….. EXCELLENT (owners should have emergency glucocorticoids always available)

Clinical Pearls not necessarily found in textbooks John C. Angus, DVM, DACVD Animal Dermatology Clinic Pasadena, California, USA Collecting Skin Cytology and Culture I know this doesnâ&#x20AC;&#x2122;t sound very exciting, but there are a few things that dermatologists do every day that improve the diagnostic value of skin cytology. First, the edge of the glass slide is your new favorite tool. There is no need for a spatula that needs to be cleaned/sterilized between patients. Each patient gets their very own fresh clean slide; this substantially decreases the risk for exchange of resistant strains of bacteria between patients. For pustules, use the edge to pop the top off and collect the purulent exudate without contaminating from the skin. More importantly in the case of epidermal collerettes, use the edge of the glass slide to peel back the collerette to reveal the glistening moist surface underneath. This greatly increases the yield.

However where the edge of the glass slide really shines is on dry, lichenified skin. Normal impression does not transfer much in the way of bacteria or yeast, but by using the edge of the glass slide to abrade the surface first, then pressing the slide to the skin a greater number of organisms will be transferred. I personally never heat fix slides prior to staining.

The edge of the glass slide is also used in the same way to prepare the skin for a swab for culture and sensitivity, culture the pustule first, if not available then the glistening surface under the superficial spreading collerette, and finally if that is not available, abrade the dry erythematous and lichenified surface then roll the culture swab across the surface.

My Dog Keeps Licking Her Paws: Malassezia or Salivary Staining Many dogs present to the veterinarian for paw licking. Even with successful management of generalized pruritus due to Atopic Dermatitis, sometimes the last and most difficult area to improve is the paws. First question, do they lick the top of the paw or the bottom? If bottom, then flip the paw over and examine the haired skin between the main pad and the digital pad. Is there hair? If hair is absent there is a high probability of bacterial or yeast infection. Collect cytology with the edge of the glass slide (if possible), a moistened swab, or clear adhesive tape. Make a note in the record if hair is absent or present each visit. Observing hair growing back after treatment is a very important sign of successful therapy. Observing loss of hair or failure to regrow hair is a sign of failed therapy and a need to adjust protocol.

If the top of the paw is the focus examine the claws, the claw bed, and interdigital haired area on top of the paw. In many cases there is mild erythema at the claw bed and small amount of exudate. Sometimes the claw itself is stained brown in the claw material itself. This reddish-brown stain is almost always an indication of the presence of Malassezia deep in the claw fold and a significant need for systemic imidazole therapy. To sample the claw fold, I recommend using a disposable wooden tooth pick. If you do not have a toothpick then break a wooden cotton tip applicator to create a narrow sharp point. Gently wipe the point across the top of the claw just inside the claw fold. This can be painful for some dogs so be sure to observe good restraint techniques. A small amount of debris is present on the tip of the tooth pick; apply this to the glass slide, stain and observe the wonders of yeast/bacteria colonizing the patient. I frequently dose Ketoconazole at 5-10mg/kg every 24 hours for 30 days. Give with food for best results. For dogs that rapidly relapse then administer a pulse dose of Ketoconazole, 2 consecutive days per week (for example, give on Saturday and Sunday, off Monday to Friday).

Effective management of claw fold infection will dramatically improve patientâ&#x20AC;&#x2122;s comfort, and you will appear to be a genius to the owner.

How can you tell if the reddish brown staining of hair is from Salivary Staining or Malassezia infection? Simple, where does the staining start on the hair. If the proximal part of the hairshaft near the follicle root is white and normal and the longer portion towards the surface is red then Salivary Staining is most likely. If the hair shaft is stained all the way into the follicle then most assuredly this is evidence of Malassezia overgrowth and infection.

Nares, Lip Fold and Perivulvar Dermatitis in German Shepherd Dogs These lesions are characterized by painful, depigmenting, erosive/ulcerative changes on the non-haired areas of the lateral nares, the mandibular lip near the commissure of the mouth, sometimes extending onto haired area of the lip fold, and of course the perivulvar fold. In the past many of these cases were inappropriately diagnosed as mucocutaneous pyoderma. This made sense because in fact many of these patients have significant Staphylococcal overgrowth on the lips and mixed bacterial infection around the vulva. Additionally

when placed on antibiotics clinical signs improve, then relapse later after antibiotics are discontinued. In the case of perivulvar dermatitis some dogs are sent to surgery. The problem is, like in so many other conditions this is not a primary pyoderma. This is not the same as intertrigo or even perivulvar dermatitis in other breeds.

This is a manifestation of immune-mediated dermatitis known as Mucocutaneous Lupus Erythematosus (MCLE) a variant of discoid lupus erythematosus. Unlike the nasal planum disorder it does not seem to be exacerbated by sun-light but rather by exotoxins produced by the bacteria. Treatment of the current bacteria is important, but treatment of the underlying lupus interface dermatitis is critical to long term success. In severe cases a short course of prednisone at 1mg/kg twice daily is appropriate to reduce inflammation then transition to Doxycycline/Niacinamide for long term maintenance. If poor response to Doxycycline/Niacinamide, Microemulsified Cyclosporin is an effective alternative.

Topical Sucralfate Cream Sucralfate is a sulfate-sucrose-aluminum compound, well-known for use in management of gastric ulceration.

The effectiveness of the product is due to the affinity for defective mucosa and barrier formation by forming polyvalent binding with positively charged peptides in erosive epithelium. In particular Sucralfate forms insoluble complexes with fibrinogen. This inhibits binding by damaging bacteria that also bind to fibrinogen.

Recently antimicrobial activity against Staphylococcus, including MRSP, has also been demonstrated during in vitro laboratory experiments. Additionally, Sucralfate stimulates production of epidermal-growth factor, basic fibroblast growth factor; both of which are important to reform basement membranes and promote wound healing. Several reports in humans also demonstrate reduction of pain after application to cutaneous ulcers. In veterinary dermatology Sucralfate can be used topically on erosive-ulcerative skin lesions, particularly those associated with MCLE in German Shepherds. Applied to painful perivulvar ulcerations there is observed clinical benefit. I have also used it on ulcerated intertriginous fold dermatitis, lip fold erosions/ulcers, thermal burns, caustic injury, and postoperative laser surgery sites. There are commercial products as well as recipes for crushing the tablets and mixing with other bases such as Aquaphor (petrolatum/glycerin ointment).

Not all scooting is due to Anal Sacculitis The observed behavior â&#x20AC;&#x201C; scooting â&#x20AC;&#x201C; is a manifestation of pruritus. Most veterinarians and clients associate this behavior with dilated, obstructed, inflamed, or infected anal sacs. Occasionally scooting does result in selfexpression of anal sacs and occasionally dogs experience relief of symptoms after manual expression of anal sacs. However, there are other causes for scooting behavior. In female dogs the most common cause is pruritic perivulvar fold dermatitis, particularly Malassezia and to a lesser extent Staphylococcus. Both male and female dogs may also scoot due to Malassezia or bacterial overgrowth around the anus. Other primary diseases of pruritus such as Atopic Dermatitis, Cutaneous Adverse Food Reaction, Ischemic Dermatopathy, Drug Eruption, and Vasculitis can cause scooting to variable degrees.

What to do when anal sacculitis is the cause and does not resolve with manual expression? Perhaps there is a degree of infection in the sac or other inflammation of the epithelial lining. Think about it this way, the anal sac is like a bowl of oatmeal, you cannot simply shake out the oatmeal and put the bowl back on the shelf as if it were clean. Similarly material is always left behind in the anal sac after expression. Many dogs will tolerate cannulation and flushing of the anal sac awake or with light sedation. I prefer to use a curved irrigation syringe filled with Douxo Micellar ear solution. Other gentle, cerumenolytic, neutral pH ear solutions could be substituted. Fill the gland and allow to stay filled for 3-5 minutes, then express. By using a cerumenolytic rather than saline, a much larger amount of material is loosened and removed. Repetition is sometimes necessary. Following irrigation and cleaning, instill oil based otic ointments that contain an antibiotic-antifungalglucocorticoid. Most dogs will experience substantial relief without relapse for many months or years following this procedure.

TOP FIVE REASONS DOGS ITCH: AN 8 WEEK PLAN John C. Angus, DVM, DACVD Animal Dermatology Clinic Pasadena, California, USA

What is pruritus? Pruritus is medical term derived from the latin prurire meaning itch. 340 years ago Samuel Hafenreffer defined pruritus as “an unpleasant sensation provoking the desire to scratch.” If you feel an itchy sensation, you scratch near it in order to change your perception of that sensation. This is distinctly different from pain – which is an unpleasant sensation provoking the desire to move in the opposite direction and say ouch. There are many clinical diseases that are associated with pruritus; however, many are uncommon and rare for even dermatologists to encounter. When entering an exam room for a 15-20 minute appointment with a patient presented for pruritus it is important to have a coherent, consistent approach to diagnosis and management.

Top 5 essential reasons dogs itch (1) Atopic Dermatitis (2) Adverse Food Reaction (3) Parasite hypersensitivity (Fleas, Sarcoptes, Cheyletiella, or Otodectes) (4) Malassezia dermatitis (5) Staphylococcal pyoderma To make it even easier, (4) Malassezia dermatitis and (5) Staphylococcal pyoderma are almost always complications of (1 – 3) Atopy, Food allergy, or Parasite hypersensitivity.

First Visit Talk about the 5 major causes for itch, but really focus on parasites, bacteria, and yeast. If the patient has any of these three cause, effective management will have the biggest impact on the patients quality of life. Indeed, managing only yeast and bacteria can cause a reduction in pruritus as much as 60-70% within two weeks.

Granted the bacterial or yeast infections may be secondary to Atopic Dermatitis or Food Allergy, but it really doesn’t matter how good you are at managing Atopic Dermatitis or Food Allergy if you under treat infections.

Therefore evaluating for infection and parasites is critical on the first visit, while you lay the ground work for diagnosis and management of primary allergic diseases.

History: None of the top 5 causes for pruritus can be definitively ruled in or out by history, but they can be ordered differently based on history. Age of onset can be useful. Patients less than one year are most likely parasite hypersensitivity or demodicosis, but can rarely have atopy or food. Between 1 and 4 years of age, anything is possible, but atopy is most common. Over 6 years of age, food allergy becomes more likely than atopy. Over 8 years of age start thinking about endocrinopathy with secondary yeast/bacterial overgrowth.

Patients with definite seasonality are usually atopy or flea allergy dermatitis. Year round pruritus does not eliminate atopy or flea allergy, but add food allergy. Ask about recent additions to the household, high risk parasite environment, if other animals or people in the house are itching.

Breed: Not particularly useful, but can lead you astray, convincing you that commonly atopic breed, such as French Bulldog or West Highland White Terrier is atopic, when it really just has sarcoptes. Breed predisposition lists are over long, change based on breed popularity, geography, and time. Any dog can be atopic, food allergic, acquire parasites, or become overgrown by Malassezia and/or Staphylococcus. Ignore breed and approach all itchy dogs the same.

Physical Examination: Atopy and food allergy can look identical in the exam room. Resist the temptation to rule in or rule out either based on body distribution sites. Flea allergy tends to affect the back half of the dog worse, with classic signs of alopecia, erythema, papular dermatitis at dorsal tail head, also check the umbilicus; many dogs with flea hypersensitivity have lesions here as well. Sarcoptes is most commonly associated with the pinna, elbows, flank; but not always. Never rule out Sarcoptes based on PE, any dog that itches can be a sarcoptes dog. Cheyletiella usually has heavy dry scale on the dorsum. Check for a pinnal-pedal reflex by rapidly scratching the leading edge of the pinna. If the ipsilateral leg starts stratching, then positive. Positive in majority of sarcoptes dogs, while negative with most other pruritic diseases. A rough tool, but if positive a parasite treatment trial is always indicated. Don’t rule out Sarcoptes based on negative pinnal-pedal reflex.

Diagnostic testing: Every patient gets cytology, skin scraping, and a parasite treatment trial.

Perform cytology for bacteria and yeast. Major cause of pruritus complicates diagnosis of allergic disease.

May be primary cause of pruritus in patients with hypothyroidism, etc. Skin scrape for Sarcoptes, Cheyletiella, Demodex. Negative scraping does not rule out either; however, if you get lucky and find mites then no need to keep going with other diagnostic testing.

Parasite treatment trial is an essential part of logical diagnostic plan for pruritus. Rule out the possibility of parasite as cause. Author prefers isoxazoline parasite prevention: sarolaner (Simparica, Zoetis), afloxolaner (Nexgard, Merial), or flurolaner (Bravecto, Merck) These three products are very effective against fleas, ticks, sarcoptes, and demodex at the label dose and frequency. Alternatives include Milbemycin at 2mg/kg once weekly for 4 weeks or Ivermectin 300mcg/kg once weekly for 4 weeks. Since any breed can be ivermectin sensitive, always titrate up to full dose. Lime sulfur dip is an excellent and safe miticide, that also happens to help with dermatophytosis, but kinda smelly.

Additional Diagnostics Based on Suspicion • Dermatophyte Culture: Hey, not a top 5 cause in my clinic, but in your region it may be a common enough diagnosis that you want to perform a screening culture for all patients presenting for pruritus. In many regions of the country this is considered an essential test as part of the “minimum dermatology database.”

• 8-week elimination diet trial followed by challenge feeding may be appropriate on the first visit, if not at least discuss the methodology with owners, so they are prepared if bacteria/yeast/pruritus continues to relapse.

• Antifungal treatment trial. Usually yeast and bacteria are easily found on cytology, however, in some practices yeast is tricky to find consistently. First, work on improving your cytology technique; however, if there is significant odor and no evidence of bacteria on cytology, then you may consider treating for yeast empirically. Recommend Ketoconazole or Fluconazole 5mg/kg once daily for 30 days. Combine with Weekly antiseptic shampoo: Chlorhexidine, Ketoconazole, Miconazole, Benzoyl Peroxide.

• Biopsy is diagnostic test of choice for any pruritic patient that just doesn’t look right. If you have a patient with any sort of unusual appearing lesions associated with pruritus biopsy early. Consider biopsy on later visits, if the patient is not responding or skin disease is progressing in spite of therapy.

Two or Four Week Recheck At Two weeks verify that the bacterial and yeast infection are resolved or resolving. If not responding to therapy and cytologic evidence for bacteria is present, then perform a bacterial culture and sensitivity to screen for methicillin-resistent Staphycloccus species. Verify parasite prevention is being used properly. Reinforce good behavior in the owner and encourage them to keep going. If at 4 weeks, bacteria, yeast, and parasites are fully resolved, whatever itch is left over is due to food allergy or atopic dermatitis. Approach the owner about performing an elimination diet trial while continuing topical antiseptic shampoo therapy AND parasite prevention.

8-week elimination diet trial Key components of an effective diet trial is (1) avoidance of any possible trigger for 8-weeks and (2) provocative challenge feeding at the end of the trial. There is no magical property to novel proteins or hydrolyzed diets that reduce itch. These diets are simply providing nutrition while the owner avoids all previously fed proteins. If your patient is allergic to chicken there is no value to the owner feeding a 99% chicken free diet. Additionally the diagnostic value is not in evaluating how much better the patient gets while on the new diet, but rather do they get worse when challenged with the original diet at the end of 8-weeks.

Fewer than half of patients with food allergies show any improvement during the first 4 weeks on the new diet, and 20% may still have some level of pruritus as late as 8-weeks. However, when you challenge a patient to the allergen after an 8-week break, they will show relapse of more intense clinical signs. If the patient flares up, congratulations you have diagnosed food allergy, return to test diet. If the patient does not flare up, congratulations you have ruled out food allergy. Clearly this is a simplified discussion of food trials and more detailed discussion is appropriate, please consult texts or other lectures for nuanced approach to diet testing.

Visit after 8-week diet trial If you have ruled out food, eliminated parasites, and managed secondary bacteria and yeast infections, then whatever itch is left over is likely due to Atopic Dermatitis. At this stage continue parasite prevention, antiseptic topical therapy, and focus your attention on both short and long term maintenance for Atopic Disease. This may include corticosteroids for temporary relief of inhumane levels of itch, antihistamines, omega III fatty acids,

topical emollient therapy, topical antipruritic therapy, cyclosporine, oclacitinib, or allergen specific immunotherapy. Regardless of your preferred approach, I promise you that this atopic patient will be easier to manage now than patient with atopy AND concurrent food allergy, fleas, bacteria and yeast.

Atopic Dermatitis: Current Concepts and Therapy When I was a student I was taught that Atopic Dermatitis (AD) was the most common disease I would treat as a veterinarian in practice. That was probably only thing true about those lectures 25 years ago. At the time Malassezia was only just being recognized as a potential cause of skin disease in dogs. Everything has changed. In the last 5-10 years there has been rapid and widening increase of our understanding of the pathophysiology of Atopic Dermatitis in dogs, the neuronal mechanism of pruritus, and completely new therapeutic interventions. What I learned as a student, how I managed pruritus in practice, and how I understood Atopy during my residency are completely upside down and backwards now.

What is Atopic Dermatitis?

What I was taught in school was that AD in dogs is an IgE-mediated disease similar to respiratory allergies in people. I was caused by inhalant allergens triggering mast cell degranulation, release of histamine, and subsequent itching and scratching. I was taught that there were no primary lesions of AD (in latin, pruritus sin material). All the clinical changes to the skin were the consequence of scratching: excoriations, erythema, salivary staining, and alopecia. Secondary bacterial infections caused the clinical signs of papules, pustules, seborrhea, alopecia, odor, and hyperpigmentation. So what has changed? First, I recognize several primary clinical lesions associated with AD: periocular erythema, as well as erythema of the convex surface of the pinna, the flexural surface of the elbow and the palmar surface of the carpus between the main pad and the accessory carpal pad. These areas may rapidly develop worsening of the signs due to rubbing, licking, scratching and secondary bacterial or yeast overgrowth, but erythema occurs first and can be observed to worsen during intradermal skin tests while the patient is sedated and unable to rub, lick, or scratch, and in a time frame too rapid to be explained by secondary infection.

Two Key Defects and Two Key Microbes in Canine Atopic Dermatitis In the late1990s and early 2000s, several very interesting research papers in human atopic dermatitis without concurrent allergic rhinitis or respiratory disease began to focus on transcutaneous route for allergens rather than by inhalation route (Ohnishi Y, et al, Clin Diag Lab Immunol 1999:6:101-4). Intuitively, this made more sense, since pollens and other antigens large enough to be bound by IgE and T-cell receptors were too large to cross respiratory tissue, be transported by capillaries past the liver and spleen and back out to the skin where cutaneous mast cells would be triggered by cross-linkage to release histamine. If AD was caused by inhalation of allergens, why didnâ&#x20AC;&#x2122;t mast cells in the nasal passages and lungs respond first? Several studies were performed to demonstrate the transdermal route was indeed the primary mechanism for exposure to antigens in dogs as well (Marsella R, et al, Vet Dermatol 2006:17:111-20 and 306-12). These observation coincided with the concept that intrinsic epidermal barrier defects in atopic dogs and humans are key events in both the sensitization phase and the elicitation phase of the disease.

Epidermal Barrier Defect describes both genetic and environmental changes in the effectiveness of the epidermis to act as a barrier to environmental antigens. This can be measured in research settings as alteration in the rate of transepidermal water loss. Theoretically this also correlates with increased absorption and deeper penetration of allergens across the superficial stratum corneum into the deeper layers of the stratum spinosum where the antigens are sampled and processed by Langerhans cells (sensitization). Further as the stratum corneum loses continuity and function, this predisposes the patient to increased colonization and overgrowth of potential pathogens, Staphylococcus pseudintermedius and Malassezia. In human AD, several genetic defects have been identified that correlate two abnormal function of the key protein of the stratum corneum (filaggrin) and the key lipids (cerumides). Since the structure of the stratum corneum is basically protein and lipid, defects in filaggrin and cerumides result in abnormal function, poor barrier and abnormal desquamation. Additional findings below the stratum corneum have also been described, principally gaps between keratinocytes due to abnormalities in tight junctions and adhesion molecules.

In addition to genetic differences, several environmental factors contribute to worsening of epidermal barrier function. First, house dust mites, a major allergen in humans and dogs, produce proteases that disrupt proteins. Malassezia produces lipases that disrupt lipids. And Staphylococcal exfoliative exotoxins increase desquamation and further disrupt junctions between keratinocytes.

When I was in school, most discussions of the inflammatory reaction to allergens centered on IgE-mediated Mast Cell degranulation. More recently, IgE has been demoted, to AD being an IgE-associated disease rather than an IgE-mediated disease. Even that assertion may be on shaky ground as numerous studies have demonstrated that classic Atopic Dermatitis disease can occur in both human and canine patients that are incapable of producing IgE. Basically, current thinking is that antigen-specific IgE production in AD patients is actually the consequence of T-lymphocyte and cytokine differences rather than the cause of the disease.

T-cell imbalance or T-cell tilt describes the observation that dogs with AD produce a different cytokine profile than non-atopic dogs sensitized and exposed to allergens. There are two major categories of cytokines (and a bunch of others, but for this lecture we focus on the two big categories: Th1 and Th2. Th1 cytokines are inflammatory mediators produced by T-lymphocytes in response to stimulation; this group of cytokines are associated with strong antiviral responses (shift to production of IgG by B-cells, interferon and education and survival of memory T-cells) as well as bone marrow production, recruitment and activation of neutrophils and macrophages at the site of injury, bacterial infection, and fungal infections. Th2 cytokines are those produced

by T-cells in response to stimulation associated with parasites, including increase production of IgE by B-cells and increase bone marrow production, recruitment and activation of eosinophils, mast cell activation, expansion and survival, as well as increase production of IL-31, the recently discovered cytokine that triggers an itch response when bound to unmyelinated nerve fibers in the skin. Guess which way dogs with AD tilt?

That is correct, there is an observed T-cell imbalance favoring Th2 cytokine production in response to antigenic stimulation in dogs with Atopic Dermatitis.

A third and fourth player in the march towards Atopic Dermatitis is the presence of Staphylococcus and Malassezia on the skin of dogs. Both are considered normal resident microbes that can under appropriate conditions act as pathogens. Veterinary Dermatologists have long recognized that dogs are more prone to Staphylococcal pyoderma and Malassezia dermatitis than humans and other veterinary species. Many theories were proposed to explain this, including the acid-mantle theory (human skin is more acidic than canine skin), the absence of a sebum plug in the canine hair follicle, etc etc. But increasingly it has become obvious that dogs get lots of skin infections because a large number of dogs have Atopic Dermatitis. Indeed the most common cause of relapsing or recurring skin infections is AD, followed by cutaneous adverse food reactions, parasite hypersensitivity, hypothyroidism, and hyperadrenocorticism. However, in the context of Atopic Dermatitis there is a direct relationship between epidermal barrier function and colonization by Staphylococcus and Malassezia. In 2003, a Japanese study of AD in humans (Arikawa J, et al. JID 2002; 119:433-439), identified a key defect in the enzymes involved in production of Sphingosine, a key ceramide for normal epidermal barrier function. This ceramide also has direct antimicrobial activity and is a component of the innate (passive) immune function of the skin. In this study there was an inverse correlation between ceramide levels and colonization by Staphylococcus, meaning that the lower sphingosine content was in the epidermis of the patient the higher the count of Staphylococcus was on their skin. This was true in both lesional and nonlesional skin. These observations match closely with what has long been recognized: dogs with AD are prone to overgrowth and infection by Staphylococcus and Malassezia as a complication of their disease, and that these organisms contribute substantially to clinically relevant pruritus. Treating infections is an essential component to management of atopic dogs and is critical to reducing the dose and frequency of corticosteroids to manage the pruritus.

However, Staphylococcus and Malassezia are more important than as simple complications of AD, they are also implicated in the pathogenesis and progression of disease. Remember that Malassezia produces lipases that can disrupt lipid function in the stratum corneum. Additionally, exfoliative exotoxins produced by Staphylococcus can disrupt normal desquamation. Both of these events can result in worsening epidermal barrier function and therefore facilitate deeper penetration of environmental antigens, such as pollens, molds, and house dust mite antigen, to a level in the skin where immune surveillance cells (Langerhans cells) reside.

This is where it gets very exciting to dermatologists and immunologists; under normal circumstances absent any co-stimulation by danger signals Langerhans cells will down-regulate response to these antigens; that is induce tolerance. However because of the presence of Staphylococcus, Malassezia and their microbial peptides, DNA, RNA, and lipids that are recognized as foreign by Toll-like receptors in the skin. These toll-like receptors in the skin sound the alarm, recruit neutrophils, activate macrophages, and upregulate inflammatory cytokine production. This results in the harmless environmental antigens (pollens, molds, and house dust mite antigens) being processed by Langerhans cells in the presence of costimulatory cytokines and danger signals.

The result is the adaptive immune system is trained to interpret future exposure to these antigens as a threat and respond accordingly.

Putting these three concepts together the current theory for the pathogenesis of Atopic Dermatitis in dogs. First a genetic defect in the epidermal barrier that leads to deeper penetration of normally harmless environmental antigens, such as house dust mite, ragweed, oak pollen, etc. This exposes Langerhans cells in the deep stratum spinosum to antigens that otherwise would have been excluded by a normal functioning epidermal barrier. Because these Langerhans cells are being co-stimulated by danger signals associated with microbial pathogens Staphylococcus and Malassezia, the immune system is sensitized to these harmless environmental antigens as if they are also threats to the body. Over time the epidermal barrier worsens due to drying, additional insults from Staphylococcal exfoliative exotoxins and Malassezia origin proteases, as well as licking and scratching. Then the following year the patient is exposed to the same seasonal environmental antigens across the same surface the patient was sensitized (the skin, not the respiratory tract), the immune surveillance system sounds the alarm and upregulates the adaptive immune response, effector T-lymphocytes.

However, because this patient also has a tendency to produce excessive Th2 cytokines when stimulated, there is upregulation of IgE, eosinophils, mast cell expansion, mast cell survival, and release of cytokine mediators of itch. With each passing year the epidermal barrier function worsens, the patient is increasingly susceptible to Staphylococcus and Malassezia overgrowth and infection, and progressive inflammation and pruritus.

Clinically we observe this as the well-recognized pattern of the march towards Atopic Dermatitis: a normal appearing puppy with maybe a mild superficial impetigo but no real problems; a 1 to 3 year old dog with seasonal pruritus, dermatitis, episodic otitis, pyoderma, or yeast dermatitis; then finally to a > 3 year dog with progressively worsening signs, and perhaps developing year round chronic pruritus, dermatitis, and otitis.

Pruritus Another leap forward in our understanding of the clinical condition Canine Atopic Dermatitis is greater clarity on the neuronal mechanism of pruritus. Pruritus is the most consistent clinical sign of Atopic Dermatitis and is of utmost importance to clients, therefore alleviating pruritus is of utmost importance to treatment of our patients.

Classically, pruritus has been defined as an unpleasant sensation that elicits the desire to scratch; or in the case of dogs. While we have a great deal of information about things that stimulate pruritus (allergy, infection, parasites) and we recognize the response in our patients (scratching, rubbing, licking, biting, chewing, rolling, scooting, shaking, or dragging their body against the floor), the understanding of the process that mediates between stimulus and response is not as well known. We know that it involves activation of peripheral nerve fibers in the skin and signaling to the brain a sensation we interpret as itch, eliciting the scratch response. But so does pain; and pain is certainly interpreted by the brain differently than pruritic sensations and elicits a very different response. We have also identified many peptides and biological mediators that when injected in the skin create an itch response rather than pain. Histamine is the best studied of these mediators, but seems to be less clinically relevant due to the observation of poor clinical response to traditional antihistamines.

However, this may change after the recent discovery of a fourth histamine receptor (H4), perhaps therapy that specifically blocks H4 receptors would have a greater clinical impact on pruritus associated with allergic dermatitis.

The recently discovered cytokine IL-31 has received the majority of attention during the last 5 years. Canine IL-31 is produced primarily by Th2 lymphocytes and can be measured in large quantities in dogs with naturally occurring Atopic Dermatitis. IL-31 receptors are present on peripheral nerve fibers and when bound trigger a Janus-kinas cell signal event. When injected into normal dogs the patient is observed to scratch in the same manner as pruritic dogs. When JaK inhibitor is given to naturally pruritic dogs, they stop scratching. This makes IL-31, JaK-stat inhibitors attractive targets for therapeutic intervention.

Management: Steroid Sparing Strategies Pruritus is one of the most common reasons owners present their dog to a veterinarian. In many cases, pruritus is chronic and recurrent, resulting in high levels of frustration for owners, veterinarians, and of course extended misery for the patient. There is a very long list of diseases that can manifest as pruritus in dogs; however, a much shorter list consisting of atopy, food allergy, parasite hypersensitivity, pyoderma, and malassezia dermatitis represents the majority of clinical cases managed by veterinarians. For the purposes of this presentation, I will focus only on symptomatic management of atopy.

What is â&#x20AC;&#x153;symptomatic managementâ&#x20AC;?

In addition to identifying and treating the underlying disease, most clients prefer that we provide comfort and relief from pruritus right now. Nobody wants to wait around for 6-12 months for allergen specific

immunotherapy to work. Therefore any treatment plan for an atopic patient must include strategies to reduce the clinical signs of pruritus. These strategies are referred to collectively as symptomatic management.

Systemic Glucocorticoids are the most effective method of providing immediate, substantial relief from pruritus. Evidence supports good to excellent response in 75-97% of atopic patients, using various study designs, drugs, and dosages. The goal of steroid therapy is temporary humane relief from refractory pruritus; however, steroids should never be used as a substitute for diagnosis. Nor should steroids be first choice for mildly affected patients. Overall steroids are safe and effective for short courses; however, even at low doses long term exposure can have disastrous consequences, including recurrent pyoderma, demodicosis, dermatophytosis, poor wound healing, recurrent bacteruria, calcium urolithiasis, hypertension, muscle atrophy, ligament injury, congestive heart failure, and pulmonary thromboembolism. How much is too much? Depends on the patient, but if they start to look cushingoid or suffer any significant morbidity associated with the above listâ&#x20AC;Ś.too much steroid.

What steroid you use is a matter of personal preference and experience. For severely itchy dogs, I prefer to use an intravenous injection of dexamethasone 0.05 to 0.1 mg/kg followed by oral prednisone at 0.5mg/kg twice daily for 2-3 days, then one time daily for 2-3 days, then twice daily for 10-20 days. For moderately itchy dogs I skip the IV injection. For most patients, punctuated short courses such of this can be implemented several times a season with a month or two off steroids in between. For other patients prolonged courses are required to maintain symptomatic relief. Some where between short, punctuated exposure for 10-20 days and prolonged exposure for 10 years is when most patients get into trouble. In order to avoid complications the overall goal is to reduce the total amount of steroids used in a life time of the patient to the lowest achievable level by combining systemic steroid therapy with other strategies that reduce pruritus. I aim for a total annual prednisone dosage of 30mg/kg/year.

Number one steroid-sparing strategy: PREVENT INFECTION! I consider antiseptics to be the most important steroid sparing agents in our pharmacy. Recognizing and eliminating recurrent pyoderma or malassezia dermatitis in an atopic patient is critical for reducing the lifetime total amount of steroid required to maintain a happy dog. If owners report a sudden flare in pruritus (i.e. call for a refill of pred), suspect bacteria or malassezia. The key question is odor (do they smell again right after a bath); the key physical exam traits are erythema, seborrhea, folliculitis, lichenification; the key diagnostic test is cytology.

Number two steroid-sparing strategy: FREQUENT BATHING! Bathing accomplishes multiple goals that are all high value for reducing pruritus. First, dry skin is itchier than normal skin. Water is a good moisturizer and emollients that we add help normalize the epidermal barrier. In the stratum corneum, Sphingosine is the single most important molecule after keratin and has been shown to be deficient in atopic humans. Phytosphignosine in the Douxo line of products should improve barrier function of abnormal epidermis to help restore moisture barrier. Second, bathing removes allergens and irritants from the skin. Humans inhale their allergens, but evidence in dogs overwhelmingly points towards absorption across the skin. Do not underestimate the tremendous value of bathing for overall reduction of allergen exposure and therefore reduction of prednisone requirement. One colleague recently stated that if a patient doesnâ&#x20AC;&#x2122;t improve with daily bathing for two weeks, then they probably have food allergy not atopy. Finally, bathing helps prevent infection by reducing bacterial colonization of abnormal skin; I use antiseptic shampoo long term in all my atopic patients. Chlorhexidine 2-4%, benzoyl peroxide, miconazole, and/or ketoconazole are all high value products. Leave on conditioners that contain emollients, antiseptics, and hydrocortisone are additionally beneficial.

Steroid-sparing Strategy No. 3: TOPICAL SPRAYS Topical sprays can be employed to apply anti-pruritic ingredients in between bathing. Some ingredients focus on cooling (witch-hazel, menthol, etc), antihistamine (diphenhydramine), or anesthesia (pramoxine).

Topical steroids, such as Genesis spray (0.015% aqueous triamcinolone) are useful for short term relief of pruritic dermatitis. However, excessive application of potent topical steroids can alter adrenocorticol access and will cause cutaneous thinning and milia if over used by clients. Recommend strict adherence to label recommendations. Steroid ointments and potent steroid sprays have limited benefit except in the most focal pruritus and high risk for problems if used long term. Mild hydrocortisone sprays are less risky and may reduce systemic steroid usage in patients that respond favorably.

Douxo Microemulsion and Calm sprays are takes a unique approach to steroid-sparing topical products. The primary active ingredient, Phytosphingosine, improves barrier function, normal desquamation, and has a suppressive effect against both Staphylococcus and Yeast organisms. Since preventing infection is steroidstrategy number one, any product that improves barrier and makes the skin less hospitable to excess colonization by bacteria and yeast should be beneficial in the overall goal of reducing pruritus. Douxo Calm contains two additional ingredients: hinokitiol and rasberry seed oil. Hinokitiol is a plant based extract with antimicrobial, antifungal, and anti-inflammatory properties. Raspberry seed oil is high in Omega III fatty acids which may locally modify the aracadonic acid inflammatory cascade in a similar fashion to oral supplementation of high dose Omega III fatty acids. In a multicenter study evaluating two antipruritic shampoos and Douxo Calm spray in allergic dermatitis in dogs, all treatment groups experienced similar 20-30% reduction in pruritus and 40-46% reduction in clinical lesion scores. In this study, maintenance with spray alone (after 3 baths) was as effective as continuous bathing, providing a useful alternative for owners that have difficulty bathing their dogs frequently.

Other strategies: Flea and mite prevention is a must for all atopic dogs. Nothing tips a humanely itchy atopic over into an inhumane state like a flea. The only reason parasite prevention is not listed as the number one steroid-sparing agent for atopic dogs is because my assumption is that veterinarians are already aggressively recommending comprehensive flea control. If not, please make this happen in your hospital, so my assumption is correct. The key method to flip unconvinced owners is to focus on the concept of prevention. Better to prevent a problem rather than treat a problem after damage is done.

Omega III fatty acids and antihistamines may be directly beneficial in mild pruritus, but are less likely to provide satisfactory results in severely affected patients. The dosage of EPA (eicosapentanoic acid) should be approximately 40 mg/kg/day. Alone fatty acids are not likely to substantially reduce pruritus, however in combination with other therapies fatty acids can be beneficial, even reducing the amount of corticosteroid required. Antihistamines are very safe, with minimal side-effects or contraindications. Failure to respond does not mean the patient wouldnâ&#x20AC;&#x2122;t respond to a different antihistamine. Try several for two week trial before abandoning hope. The key to successful intervention with fatty acids and antihistamines is not asking them to do too much. Let the steroids and antibiotics do the heavy lifting, while fatty acids and antihistamines are used in conjunction with steroids during flares in pruritus to reduce the amount of steroid necessary to bring the flare under control, then are used during mild phases to extend the duration good times before the next flare.

Microemulsified Cyclosporin(CsA) has multiple mechanisms of action: Inhibits T-cell activation, mast cell survival, response, histamine release, prostaglandin production, cytokine production, eosinophil migration, survival, and degranulation. Independent research demonstrates that CsA works for controlling pruritus in atopic dogs. Atopica (Elanco) has been approved for use in dogs for 15+ years and there is a large body of knowledge regarding safety and efficacy. The major drawback in dogs is nausea, vomiting, and diarrhea that can occur during the starting period. The GI symptoms are typically dose dependent and do not last once the patient is acclimated to the drug, therefore I start my patients at half dose (2.5mg/kg/day) for 2 weeks, then if doing well move up to 5.0mg/kg/day. The second drawback is delay before onset of relief, often 2-4 weeks (although I tell owners 4-6 weeks to get some cushion before they get antsy). Veterinarians can use corticosteroids, Apoquel, or Cytopoint to provide short term relief while waiting for Atopica to kick in. Long term many patients can be maintained successfully every 48 hours.

Most common long term side effect is gingivial hyperplasia/advancement of gums over the crowns of the teeth. This may require dental cleaning, laser ablation of the excess gum tissue and reduction or discontinuation of therapy. Generally Atopica is a medication used to treat corticosteroid dependent Atopic dogs that do not respond to immunotherapy or other treatment modalities.

Allergen-specific immunotherapy provides a non-drug option for long term treatment of atopy. While not directly anti-pruritic, ASIT modulates response to allergens and diminishes severity of hypersensitivity reactions. The precise mechanism of action is not known; however the safety record is very good and there is excellent evidence for efficacy. Response rates as high as 70% have been reported for ASIT in veterinary patients. The earlier you start the better. In human children, ASIT has been shown to alter or even stop progression of disease when used early. Evidence in dogs demonstrates best response when started earlier than 5th year of clinical signs. ASIT has a great safety record in dogs with only one

reported anaphylaxis (knock wood) in a dog. In humans, severe life-threatening reactions can occur, but are almost always people with respiratory disease, not atopic dermatitis. Facial edema, urticaria, lethargy, anxious behavior are reported in dogs, but uncommon. Increased pruritus and local injection site reactions are more common.

Targeting IL-31:. Zoetis has been focused on developing therapy around new the neuronal mechanisms of pruritus: IL-31. IL-31 is a cytokine messenger molecule produce by allergic T-lymphocytes in the skin when exposed to antigens. IL-31 binds to IL-31 receptors in on peripheral nerves triggering a JAK-stat intracellular signal cascade. Our brain perceives this as itch. So if I inject a dog with IL-31 they start scratching. However, if you treat the dog with a JAK-Stat inhibitor prior to injection of IL-31 they donâ&#x20AC;&#x2122;t start scratching. More relevant to clinical situations if a dog with naturally occurring itch is given oclacitinib (Apoquel) that blocks the specific JAK-stat involved in the peripheral nerves of dogs â&#x20AC;&#x201C; they stop itching. The majority of patients experience relief from pruritus equivalent to use of corticosteroids in as short as 24 hours after initiation. A small fraction of dogs do not respond or exhibit only partial response. Some patients respond very well at twice daily dosing, but one time daily dosing does not provide a full 24 hours of relief. When this drug becomes more widely available there are several important clinical points. First, do not use in dogs less than 12 months of age. Safety has not been established; development of generalized demodicosis has been observed in young dogs treated with Apoquel and there is a theoretical concern regarding interference the developing immune system. If an adult dog experiences a break of of demodex while on Apoquel I typically start. Second, do not use in dogs with deep infection (pneumonia, sepsis, septic abdomen, deep tissue infections, etc). I have personally observed one patient that developed a retrobulbar abscess while on Apoquel; which resolved with discontinuation and treatment with appropriate antibiotics. I have also had a patient develop pyometra while on Apoquel and a third patient that died of septic abdomen following enterotomy for a gastrointestinal foreign body; in this case the surgeon did not discontinue the Apoquel. I recommend stopping Apoquel prior to any surgery that has associated risk for infection. Certainly, discontinue if patient has post-operative infections. Superficial skin infections are not of a concern. Third, do not use in patients with neoplasia and discontinue in patients that develop neoplasia while on Apoquel. Too the best of my knowledge and according to currently available literature patients on Apoquel are at no greater risk for neoplasia than patients treated by other methods; however, some veterinarians have raised concerns based on anecdotal observations. Apoquel can be used in conjunction with prednisone safely for short periods (2 weeks); longer periods have not been evaluated. Vaccination is safe and effective.

Newer still than Apoquel (oclacitinab) is Cytopoint (lokivetmab), also by Zoetis. This is a canine-specific monoclonal antibody therapy that binds and eliminates Canine IL-31 in the tissues. By reducing available IL-31 prior to attachment to receptors in the peripheral nerves, Cytopoint reduces the perception of pruritus by the patient. 85-90% response rate within 24-72 hours and average duration of benefit for 4-8 weeks. Because of the unique mechanism of action Cytopoint has several advantages over traditional drugs â&#x20AC;&#x201C; first and foremost is safety. There are no known contraindications and no drug interactions.

Cytopoint is eliminated by normal protein metabolism. There are no issues with compromised liver disease, renal disease, and no toxic metabolites. Cytopoint is not immune suppressive and can be used in patients where Apoquel or Corticosteroids were not acceptable (deep infection, systemic fungal infection, demodicosis, neoplasia, etc). Cytopoint can also be used in dogs less than 1 year of age. For refractory pruritus due to Atopic Dermatitis, Cytopoint can be combined with corticosteroids, Apoquel or Atopica without risk. The only significant downside is that it is for use in dogs only and cannot be used in cats.

SUMMARY: Atopy is really common. Pruritus is really miserable for the patients and alarming to owners. Steroids work really well to manage the symptoms of pruritus but can cause problems for owners (excess urination, food seeking, panting) and can be harmful to the patient if used in excess over long periods.

Developing an arsenal of strategies gives veterinarians multiple options for managing pruritus with the goal of reducing the total lifetime amount of prednisone prescribed to an atopic patient. The best strategies involve minimizing infection, preventing parasites, bathing frequently, and application of topical antipruritic products in between baths provides additional options.

Suggested Reading • • • •

Marsella, R., Olivry, T., Carlotti, D.-N. and for the International Task Force on Canine Atopic Dermatitis (2011), Current evidence of skin barrier dysfunction in human and canine atopic dermatitis. Veterinary Dermatology, 22: 239–248.

Santoro, D., Marsella, R., Pucheu-Haston, C. M., Eisenschenk, M. N. C., Nuttall, T. and Bizikova, P. (2015), Review: Pathogenesis of canine atopic dermatitis: skin barrier and host–micro-organism interaction.

Veterinary Dermatology, 26: 84–94.

Pucheu-Haston, C. M., Bizikova, P., Marsella, R., Santoro, D., Nuttall, T. and Eisenschenk, M. N. C. (2015), Review: Lymphocytes, cytokines, chemokines and the T-helper 1–T-helper 2 balance in canine atopic dermatitis. Veterinary Dermatology, 26: 124–132.

Gonzales, A. J., Humphrey, W. R., Messamore, J. E., Fleck, T. J., Fici, G. J., Shelly, J. A., Teel, J. F., Bammert, G. F., Dunham, S. A., Fuller, T. E. and McCall, R. B. (2013), Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Veterinary Dermatology, 24: 48–53.

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx

PSEUDOMONAS OTITIS: WHAT TO DO WHEN NOTHING ELSE WORKS John C. Angus, DVM, DACVD Animal Dermatology Clinic, Pasadena, CA Clinically significant otitis externa occurs in 10-20% of the dog and cat population. The majority of cases result from common underlying problems, such as atopy, food allergy, or ectoparasites. Less commonly foreign objects, neoplasia, non-neoplastic masses, endocrinopathies, immune-mediated disorders are the primary cause. Bacteria and Malassezia overgrowth occur secondarily when normal local microenvironment is altered and passive immunity is disrupted. Overgrowth of resident organisms contribute directly to inflammation and perpetuation of clinical signs. Over time infection may extend to the middle ear or chronic physical changes alter the external canal, resulting in recurrence and increased severity of disease. Under appropriate conditions, opportunistic organisms such as Pseudomonas aeruginosa, Proteus mirabilis, E. coli and others replace resident organisms. Repeated exposure to antibiotics selects for resistant organisms. Although not the most common bacterial infection, Pseudomonas aeruginosa stands out as the most painful, smelly, frustrating, and difficult to manage. Frustration with Pseudomonas results from (1) severity of inflammatory response, (2) unpredictable antimicrobial susceptibility patterns, and (3) frequent treatment failure.

Role of Pseudomonas in ear disease Pseudomonas is an opportunistic bacteria found primarily in water, decaying vegetation, and only occasionally on or in animals. In order to colonize the ear canal or other animal tissues, Pseudomonas must first establish firm adhesion to epithelial cells. Under normal circumstances the adhesion points are occupied by the normal microflora, protected by passive immunity in the form of immunoglobulins and other antimicrobial peptides found in normal cerumen. For Pseudomonas to colonize the canine ear, two events are required: (1) presence of organism (water) and (2) disruption of normal microflora and healthy epithelial barrier. Once Pseudomonas has a foothold it is an excellent competitor, suppressing other bacteria and yeast, producing collagenases, protease, and exotoxins; which cause further disruption, eventually resulting in ulceration and tissue breakdown, including the tympanic membrane. To make matters worse the gram negative cell wall and extracellular slime resists immune response. Vast numbers of neutrophils and macrophages are attracted to Pseudomonas infections. Although only partially effective against the bacteria, these WBC produce collagenases and proteases, which worsens tissue damage. In fact, serine proteases produced by neutrophils may actually enhance the ability of Pseudomonas to invade tissue. Clinically the result is an external ear canal characterized by severe inflammation, erythema, ulceration, pain, and large quantity of purulent exudate.

DIAGNOSIS History is useful to help rank likely differential diagnoses for primary cause of otitis. For example, determine the “age of onset” of very first episode. If, less than 1 year, parasites are most likely. Food also possible. If between 1-4 years, this is consistent with Atopy, but any cause is possible. If greater than >6 years, atopy is less likely, but any cause is possible. Seasonality strongly suggests Atopy. Non-seasonal disease can be atopy or food. If household affected or recently introduced, always consider parasites hypersensitivity, even if none are found on examination. Ask about prior medications. If the patient initially got better then suddenly worsened think about contact reactions. If current infection is of long duration (> 6 months) or more than 3 episodes a year then concurrent otitis media is very likely.

Physical Examination characterizes current state of infection and helps develop likely differential diagnoses for primary cause. A whole body dermatologic examination should be performed to find evidence of concurrent disease such as Atopy, Food, Parasites, Pemphigus, Hypothyroidism, etc. Begin with palpation of external canal and parotid region Record findings such as pain, edema or soft-tissue swelling. Is the canal flexible or rigid due to fibrosis, mineralization? Is cerumen present on pinna? Normal clearance of debris should deposit this debris on the pinna. Absence of debris could indicate failure of epithelial migration.

Excessive erythema, erosions, pain could indicate contact reaction or more generalized dermatologic diseases.

Finally, check palpebral reflex. Reflex is diminished in some cases of otitis media cases or end-stage disease.

Otoscopy may be futile during initial examination of awake patient. Canal is often too painful, too ulcerated, or too full of pus to permit a satisfactory evaluation. However, otoscopy should be attempted to satisfy the owner’s expectations and to evaluate for obvious problems such as a mass in the vertical canal. Recommend diagnostic evaluation under anesthesia, combine with therapeutic flush to remove debris. If the canal is too

edematous and stenotic to advance the scope into the vertical canal, then postpone. Treat with oral and topical steroids (prednisone 1 – 2 mg/kg/day) until edema is diminished. This will add value to the procedure.

Otic Cytology is a mandatory diagnostic test for every patient presenting with otitis. Cytology is necessary to characterize type and number of organisms seen. Mixed infections are common: >3 species present in 3060% of cases. Cytology allows you to identify current organisms, characterize the severity of disease, better interpret culture and susceptibility results, and make rational decisions regarding therapy. Use cytology to differentiate overgrowth from infection. Overgrowth occurs when native organisms take advantage of changes in the microenvironment. Overgrowth contributes to severity of disease, but is more easily managed with topical therapy alone. True infection results from either native or opportunistic organisms penetrating tissue, extending into middle ear, or creating severe inflammatory response resulting in purulent exudate. The presence of white blood cells almost always indicates true infection rather than overgrowth. Cytology is performed by direct smear and in-house stain, such as Diff-Quik. Examine on all objectives including oil immersion 100x. Be sure to record findings in the medical record for comparison with later cytology during reevaluation: (1) Malassezia: presence/absence, estimated numbers (2) Bacteria: presence/absence, rod or coccoid morphology, estimated number, phagocytosis by neutrophils, (3) White blood cells: presence/absence; which organisms are they targeting, and (4) Parasites: presence/absence.

Culture and Susceptibility testing of bacteria in otitis externa is of questionable value. Susceptibility breakpoints used by the laboratory don’t correlate to achievable concentrations in external canal. Organisms present in the external ear canal are usually very different than those found in the tympanic cavity (89.5% of cases had different species or susceptibility patterns in one study). Laboratory results are not repeatable even when obtained from same ear canal collected submitted the same time. Variability between commercial laboratories methodology and reporting can yield very different results. Do not think of antibiotic susceptibility results as rock solid fact. Culture should never be used to monitor response to therapy. Culture only tells you presence or absence of organism, but provides little information regarding response to therapy, changing numbers, changing presence of white blood cells, etc. Culture and sensitivity is only indicated for antibiotic selection against bacteria with unpredictable susceptibility patterns, or if poor response to appropriate therapy.

Other diagnostic procedures • Food trial – 8 weeks with provocative challenge at the end • Parasite treatment trial – Eliminate the possibility of parasites with simple therapy. o Selemectin every 2 weeks for 3 treatments (95-100% effective) o Ivermectin 0.3mg/kg weekly for 4 weeks (gradual step up to target dose in all breeds).

• Allergy testing – Intradermal Allergy Testing, Allergy serology • Thyroid profile – T4, free T4, TSH is much better screen than T4 alone • Discontinue all prior topical or systemic therapies in case of contact or adverse drug reaction THERAPY Specific therapy for the underlying primary disease is essential for long term success. Simply chasing bacteria will ultimately result in treatment failure and progression to more severe disease. That said, anesthesia for otoscopy and deep ear flush is the most valuable diagnostic test and indispensable therapeutic procedure for Pseudomonas otitis. Flushing of mucopurulent, septic exudates from the middle ear is necessary for relief.

Even the most spectacular antibiotic in the world cannot exceed the value of physical removal.

Preparation: You may need to postpone until decrease inflammation in the canal. Prednisone 1.02.0mg/kg/day for 4-7 days with a topical corticosteroid, such as flucinolone is very useful prior to deep ear flush under anesthesia. The day of the procedure, be sure to collect a sample for cytology before flushing. Always always always use an endotracheal tube with a good cuff! Anesthestized or heavily sedated dogs lack a gag reflex and may aspirate irrigation fluid with microorganism and debris. The fluid can easily run through the ruptured tympanum, through the tympanic bulla, down the Eustachian tube, into the oropharynx, down the trachea and into the lower respiratory tract. Also, be sure to protect the eyes with excessive amounts of sterile lubricant. Tilt the head to prevent irritating irrigation fluids with debris, bacteria, and bacterial proteases from running over the eye and damaging the cornea. Finally, be sure to warm the sterile saline or other flush solution prior to cleaning. Large volumes of room temperature fluid should not to be used! You are very close to the brain and the brain is at body temperature. Cool or room temperature fluid will be very painful over time.

Procedure: Collect samples for cytology and culture prior to flush. If debris is thick and tenacious use ceruminolytic to break up debris. Never leave ceruminolytics in the tympanic bulla, since they can damage the

more sensitive respiratory epithelial lining. Only use ceruminolytics at the beginning to do the heavy lifting, then irrigate with warm water or sterile saline for the detail work and large volume flushing. You will finish with a drying agent so don’t worry about leaving a wet canal at this stage. Bulb syringes, catheters and 12ml syringes, or mechanical flush/suction devices are all useful. Use a lot of fluid, keep flushing until debris is cleared. Use buck curette to remove any adherent debris. Do not use cotton-tipped swabs.

Advantages of video-otoscopy vs. standard operating head scopes: (1) Superior optics provide significantly higher degree of magnification and detail resolution, (2) permits continuous viewing during irrigation, (3) avoids light reflecting off fluid interface, (4) decreases problem of blocking view by instrumentation, (5) increases precision, (6) decreases risk of injury to fragile structures, and (7) creates photographic record.

Assess the tympanum: Otitis media may be present even if the tympanum appears intact. In one study, the tympanum appeared intact with standard hand-held operating head otoscope in 27 of 38 cases of otitis media.

Video-otoscopy enhances opportunity for accurate diagnosis by increasing detail of image and permitting visualization under fluid. Hand held otoscopes require suctioning of the ear canal. Typically the tympanum will appear opaque, sclerotic or discolored if the tympanic cavity contains fluid, mucus, or pus rather than air, or if healing from a prior rupture. Suspect otitis media if: (1) large numbers of leukocytes on cytology, (2) characteristic changes in color or consistency of membrane, (3) vestibular signs, deafness, or Horner’s syndrome, (4) poor palpebral or corneal reflex, (5) clinical signs of otitis externa greater than 6-months, (6) tympanum may be entirely absent, or (7)notice flush fluid emerging from nostrils.

Flushing of the tympanic cavity: If the tympanum is ruptured and otitis media is present the cavity is often filled with purulent exudates. Any debris or infection is very irritating to the respiratory epithelium, which responds by producing more mucus and pus. Failure to adequately remove material during the flush will result in persistent otitis media, inability of the tympanic membrane to heal, and ultimately treatment failure regardless of follow-up. Warm sterile saline is excellent for breaking up mucus and is not ototoxic. Do not use ceruminolytics, chlorhexidine, or other ototoxic substances in this region. If using a catheter in the tympanic bulla, aim caudoventrally to avoid fragile structures such as the auditory ossicles, the corda tympani (a branch of the facial nerve), the round window and the oval window. Also, the largest portion of the tympanic bulla is ventral to the opening from the external canal. Be sure to avoid excessive pressure. Potential complications include: pain, vestibular signs, facial nerve injury, deafness, Horner’s syndrome (cats in particular are predisposed). When flushing is complete suction the tympanic cavity as dry as possible. Rinse with drying agent or astringent that is “safe” in the tympanic cavity. (e.g. Oticalm, Epiotic, Burotic-HC). Instill 50:50 mixture of Baytril injectable and Dexamethasone SP directly into the tympanic bulla. Steroid suppresses inflammation of respiratory epithelium and the injectable antibiotic should have a high enough concentration to overcome antibiotic resistance mechanisms. Dr. Craig Griffin reports success using Amikacin and Dexamethasone in this manner, without observing ototoxic reactions; however, aminoglycosides are reported as ototoxic agents, so proceed with caution unless peer reviewed publications support usage of Amikacin in this manner.

To go home therapy: Prescibe awake ear flush at home after patient has recovered. The goal is to remove debris, dry the canal, and kill microorganisms. Avoid irritating, ototoxic, or wet solutions. If the patient is too painful to permit at home ear cleaning, treat with steroids and medicated drops only until able to tolerate cleaning. Product selection can be challenging. Recommend acidifying flushes for yeast infections to inhibit growth; however, in bacterial infections these products may decrease efficacy of topical antibiotics. Both fluoroquinolones and aminoglycosides function better at a neutral pH than acidic pH. Virtually any Pseudomonas can adapt to a constant acidic environment. TrisEDTA containing product are the preferred solution for Pseudomonas or resistant bacteria. pH = 8.0 is ideal for fluoroquinolones or aminoglycosides. The EDTA punches holes in bacterial cell wall by chelating calcium and magnesium. In high concentrations and prolonged contact TrisEDTA is directly bactericidal. At a minimum, it is synergistic with antibiotics and may help to overcome many resistance mechanisms. Soak ear 10 minutes before topical antibiotic.

Topical medication is typically prescribed to follow ear cleaning. In general thin liquids preferred over thick ointments. Several choices exist. Zymox is a gentle triple enzyme formulation that is very well tolerated by patients, even those with ulceration. Recent study in human burn patients demonstrated that lactoferrin inhibited binding of Pseudomonas to epithelium. This drug is my first choice if patient is too painful to tolerate anything else. Antibiotic/Antifungal/Steroid combinations are also a good choice. Fluoroquinolones are best if there is a lot of debris building up in the ear canal. Veterinary Baytril otic™: 0.5% Baytril + 1% Silver Sulfadiazine or the human product Cipro HC otic can be used. A marbofloxacin otic formulation is available in Europe (Aurizon). A home-made solution of Baytril inj + + Dexamethasone SP in TrisEDTA-Ketoconazole base

in a 1:1:4 ratio can be useful. Aminoglycosides have excellent anti-Pseudomonas activity, but are inactive when large amounts of organic debris or in low oxygen tension environment. Use only when after exudates are resolved. A home-made Tobramycin solution combinines two 5ml bottles of Tobramycin ophthalmic + 4ml Dexamethasone injectable. There is no commercial amikacin product, however, injectable Amikacin + TrisEDTA or Sterile saline with a target concentration of 30-50mg/ml has been recommended. Gentamicin is available in many commercial ointments, but thickness of ointment may prevent penetration to deep canal.

Ticarcillin, Ticarcillin/Clavunate have great anti-Pseudomonal activity. Unfortunately stability after reconstitution minimizes usefulness. If sending home, reconstitute with sterile saline, divide into aliquots, and keep frozen.

The owner then thaws each aliquot prior to application. Ceftazidime has brilliant anti-pseudomonal activity, but internists and criticalists will throttle anyone using Ceftazidime for Pseudomonas otitis.

New products containing micronized silver have shown promise in use against bacteria that produce biofilm and may be most useful for maintenance therapy to prevent recolonization in patients prone to relapse.

Systemic steroids are ESSENTIAL for managing severe Pseudomonas otitis. You must shut down neutrophils proteases, edema, and stenosis. Recommend Prednisone 1-2 mg/kg/day until recheck in 7-14 days combined with topical dexamethasone or flucinolone.

Systemic antibiotics are controversial. Resistance is high, concentration in the external canal is low. Use systemic antibiotic only for otitis media. There is limited selection of effective antibiotics available for oral administration. SQ or IV administration of injectable antibiotics may not provide any substantial benefit and may select for resistance to drugs that should be preserved for use in dogs with life-threatening systemic infections (i.e. don’t use imipenem to treat ear disease). If using systemic antibiotics, ears require higher doses than other body systems because of difficulty penetrating into external and middle ear canal. As a general guideline use a dose and duration as if treating an osteomyelitis. Fluoroquinolones remain the best empirical choice for Pseudomonas however, resistance is on the rise! enrofloxacin 10-50% of isolates are susceptible, ciprofloxacin fairs better at 75-90% susceptibility, marbofloxacin >90% susceptible. If using a fluoroquinolone aim for the highest achievable dosage: enrofloxacin – minimum acceptable dose is 15mg/kg SID, Ciprofloxacin – limited studies in dogs. Suggested dose 20mg/kg BID, Marbofloxacin – 5mg/kg SID. Combination therapy may be needed, since mixed infections with highly fluoroquinolone resistant streptococcus, enterococcus, corynebacteria, or anaerobes are common. Recommend marbofloxacin with mlindamycin or Clavamox for mixed bacterial infections. Note: enrofloxacin and clindamycin have been shown to concentrate in WBC and therefore may be more effective in purulent otitis than other antibiotics. Treat for 6-12 weeks depending on severity of disease, the organism present, response to therapy, and healing of the ruptured tympanum.

Pain management is appropriate, since ear pain can be extreme in Pseudomonas otitis. Steroids decrease pain causing events, but do not provide direct analgesic effects. NSAIDS provide the best analgesia for ear pain, but cannot be used in conjunction with high dose prednisone. Opiod analgesics such as Tramadol can be used in conjunction with steroids, but have more variable pain control.

Follow- up to assess progress with PE and cytology. Cytology is the best method for monitoring response to therapy. Evaluate for decreasing numbers of organism, change in dominant organism, and change in WBC. Ideally at two weeks there are no WBC and substantial reduction of bacterial numbers. Repeat deep ear flush if significant mucopurulent exudate and debris remains. If responding continue with current course of therapy for additional 4-6 weeks, then recheck prior to discontinuation of therapy.

Long term plan. Outline ideal management of primary disease (avoidance of food allergy, treating parasites, allergen-specific immunotherapy, cyclosporin, etc). Keep ears dry. Flush with astringent ear solutions once or twice weekly; especially after swimming or bath. Avoid using water, dilute vinegar, or hydrogen peroxide.

Monitor frequently for recurrence and treat all infections aggressively at the earliest sign. Surgical intervention with total ear canal ablation is appropriate for end-stage ears: chronic pain, no chance for response to medical management. Lateral ear canal resections except are of limited benefit and are not recommended.

Suggested reading 1) Angus JC. Diseases of the Ear. In: Campbell KL, editor. Small Animal Dermatology Secrets.

Philadelphia: Hanley & Belfus; 2004. p. 364-384.

2) Gotthelf LN Small Animal Ear Diseases: An Illustrated Guide. 2nd Ed, 2005.

3) Matousek JL (ed) Ear Disease. Vet Clin North Amer Sm Anim Pract March 2004

4)

Scott DW. External ear diseases. In Scott DW, Miller WH, Griffen CE (eds) Muller and Kirkâ&#x20AC;&#x2122;s Small Animal Dermatology, 6th edition, Philadelphia, W.B. Saunders, 2001, pp 1203-1232.

Asociación Mexicana de Médicos Veterinarios Especialistas en Pequeñas Especies, S. C. www.ammvepe.com.mx