With: C.A. TONY BUFFINGTON, DVM, MS, PHD, DACVN

Chicago Veterinary Medical Association Shaping the Future of Veterinary Medicine - Promoting the Human-Animal Bond. Proudly Presents: FELINE URINARY/NUTRITION With: C.A. TONY BUFFINGTON, DVM, MS, PHD, DACVN MAY 10, 2017

Table of Contents The AAHA Nutrition Assessment Guidelines... 4 Nutritional Screening Risk Factor... 5 Some new information about protein needs in cats... 7 Feeding Factors... 8 Useful websites... 10 References... 11 From FUS To Pandora Syndrome Introduction, Pathophysiology, & Diagnosis... 12 Diagnosis... 13 Recent Research Findings... 14 Conclusions... 16 References... 16 From FUS to Pandora Syndrome Treating the Environment, and Prognosis... 20 Environmental Enrichment 1-3... 20 Additional approaches... 22 Conclusions... 23 References... 23 From FUS to Pandora Syndrome Treating The Owner And The Cat... 24 Treating the Client... 24 Treating the Cat Acute Care... 26 Physiological parameters:... 30 Behavioral parameters/body postures:... 30 Responses to Enrichment... 31 How to fill in the Response to Enrichment form... 31 Additional resources:... 32 Treating the Cat Chronic Care... 34 References... 36 Making Sense of all the Pet Foods on the Market... 38 Premium Isn t Always Better... 38 Don t Confuse Marketing w/ Nutrition, Contaminats and No Need for Confusion 40 What you need to know about pet foods... 42 References... 45 Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 2 of 56

Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 3 of 56

C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) The AAHA Nutrition Assessment Guidelines drbuffcat@gmail.com The American Animal Hospital Association (AAHA) developed Nutritional Assessment Guidelines (NAGs)1 to help enhance pets quality and quantity of life. Incorporating nutritional assessment into regular patient care probably helps maintain pets' health, as well as their response to disease and injury. The specific goals of the NAGs are to: Increase awareness of the value of nutritional assessment in dogs and cats, Provide guidelines for nutritional evaluation of patients to promote optimal health and response to disease, and to offer evidence and tools to support recommendations. The positive impact of satisfactory nutrition on health promotion and disease prevention and treatment is well established. Appropriate feeding throughout all life stages can help prevent diet-associated diseases, as well as assist in the management of other diseases. For example, diets formulated for dogs and cats with chronic kidney disease have been shown to provide significant benefits. Nutritional assessment considers several factors. It is an iterative process, (as shown in the Circle of Nutrition figure at right, assessing each factor affecting the animal's nutritional status in turn, and reassessing as often as required to provide a thorough nutritional assessment of the patient. The factors to be evaluated include the animal, the diet, and feeding management and environmental factors, as described below. Animal-specific factors - include the age, physiological status and activity of the pet. Problems related to animal factors are referred to as nutrient sensitive disorders (e.g., intolerances, allergies, and organ specific diseases). Diet choice for these patients should be restricted to those formulated to meet the disease-associated nutritional limitations of the specific patient. Diet-specific factors - include the safety and appropriateness of the diet fed to that animal in question. Problems related to diet factors are referred to as diet-induced disorders (e.g., nutrient imbalances, spoilage, contamination, adulteration). Feeding a diet known to be appropriate for the patient treats these problems. Feeding management and environmental factors - include the frequency, timing, location and method of feeding, while environmental factors include space and quality of the pet s surroundings. Problems related to feeding and environmental factors are referred to as feedingrelated and environment-related disorders (e.g., over- or underfeeding, excessive use of treats, poor husbandry, competitive eating in dogs, or lack of appropriate environmental stimulation). These situations require effective communications to produce the appropriate behavioral changes in the client. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 4 of 56

Nutritional assessment is a two-part process. Screening Evaluation is performed on every patient. Based on this screening, pets that are healthy and without risk factors need no additional nutritional assessment. Extended Evaluation is performed when one or more nutrition-related risk factors are found or suspected based on the screening evaluation. A person trained to elicit necessary information from the caregiver most knowledgeable about the pet(s) should obtain a detailed nutritional history. A variety of forms are available for recording these findings (some listed under resources). Screening Evaluation - Nutritional screening is part of routine history taking and physical examination of every animal; it includes assessment of each of the parameters of the circle of nutrition. Extended evaluation generally is not necessary for healthy neutered adult pets. Low or high activity level, multiple pets in the home, gestation, lactation, or age < 1 year or > 7 years, all may suggest the need for closer scrutiny. Although these factors by themselves may not trigger an extended evaluation, they should cause the veterinarian to scrutinize the pet s situation more closely. When features are identified that raise one s index of suspicion for a nutrition-related problem, an extended nutritional evaluation may be performed. The value of an extended nutritional evaluation increases as the number of risk factors and their severity increases. Moreover, sufficient concern about any one parameter may be enough to warrant an extended evaluation. If no concerns are raised by the screening evaluation, then the nutritional assessment is complete. Nutritional Screening Risk Factor History Altered gastrointestinal function (e.g., vomiting, diarrhea, nausea, flatulence, constipation) Previous or ongoing medical conditions / diseases Currently receiving medications and/or dietary supplements Unconventional diet (e.g., raw, homemade, vegetarian, unfamiliar) Snacks, treats, table food > 10% of total calories Inadequate or inappropriate housing Check ( ) if present Physical Examination Body condition score 5-pt scale: any score other than a 3 9-pt scale: any score less than 4 or greater than 5 Muscle condition score: Mild, moderate, or marked muscle wasting Unintended weight loss of > 10% Dental abnormalities or disease Poor skin or hair coat New medical conditions / diseases Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 5 of 56

BCS and MCS - Use a consistent method and scale to measure body weight (BW), body condition score (BCS), and muscle condition score (MCS), to assess current status and changes over time. Although different scoring systems may have situation-specific merits, the panel recommends that practices choose, and all doctors and staff consistently use, one system and record the total points on which it is based (i.e., the denominator). The BCS evaluates body fat; a variety of BCS systems are used to evaluate dogs and cats (e.g., scales of 5, 6, 7, or 9). The goal for most pets is a BCS of 2.5 to 3 out of 5, or 4 to 5 out of 9, based on a limited number of studies in dogs and cats, as well as those from other species. Disease risk associations with higher BCS in adult animals appear to increase above 3.5 of 5 (6 of 9). Similar risk associations for other life stages in client-owned pets have not been reported, but may occur at low BCS in growing puppies based on studies of laboratory-housed animals. Additional research in dogs and cats is needed to more fully evaluate the effects of body condition on disease prevention. The MCS differs from the BCS in that it evaluates muscle mass; evaluation of muscle mass includes visual examination and palpation over the temporal bones, scapulae, lumbar vertebrae and pelvic bones. Assessing muscle condition is important as muscle loss is greater in patients with most acute and chronic diseases (i.e., stressed starvation) compared to healthy animals deprived of food when primarily fat is lost (i.e., simple starvation). Muscle loss adversely affects strength, immune function, wound healing, and, is independently associated with mortality in humans. The MCS scale recommended by the Guidelines has never been validated, and it is well known in humans that anatomic MCS does not predict muscle function very well, so both muscle mass and muscle function need to be taken into consideration. Clinically, BCS and MCS may not be directly related. An animal can be overweight but still have significant muscle loss. This can make a moderate MCS look relatively normal if not carefully evaluated. In these cases, although some of the areas of the body may appear relatively normal or even to have excessive fat stores (especially over the ribs or in the abdominal region), muscle wasting is readily felt over bony prominences. Palpation is required for accurately assessing BCS and MCS, especially in animals with medium to long hair coats. Extended nutritional evaluation of animal, diet, feeding and environmental factors is indicated for patients identified to be at risk for any nutrition-related problems from the screening evaluation, and is described in detail in the NAGs. Interpretation, analysis and action - Following the nutritional assessment, interpret and analyze the information that has been gathered to devise an action plan based on the animal, diet, feeding, and environmental factors. Monitoring Healthy animals - Adults in good body condition should be reassessed regularly. Decisions regarding specific frequency of visits are made appropriately on an individual basis, based on the age, species, breed, health, and environment of the pet. Healthy pregnant, lactating, senior, and growing animals require more frequent monitoring. Pet owners should monitor their pet at home including food intake and appetite, BCS and BW, gastrointestinal function (e.g., fecal consistency and volume; vomiting), and overall appearance and activity Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 6 of 56

Client education Effective client communication and rapport is important for achieving desired outcomes. Technicians should be involved in the nutrition evaluation process when they have knowledge and skills in both nutritional concepts and in communication. Engage the client in decision-making and defining expectations. Recommendations may be modified by the client s time, lifestyle, and financial limitations. Use communication techniques that include a variety of forms based on client preferences. Use a variety of educational approaches and tools. Demonstrating and teaching the client to evaluate the BCS and MCS is effective in engaging the client in their pet s care. Expectations and goals should be specific, achievable, and include specific follow-up in order to monitor progress and compliance and to adjust recommendations. Inform clients about specific foods, and potential advantages, risks and concerns. Include recommendations on amount and frequency of diet fed, accounting for snacks, treats, table food, foods used for medication administration, and dietary supplements. Clients may enrich their pet s nutritional experience by interacting with them at feeding, providing food toys and playing and exercising with their pet. Some new information about protein needs in cats A 2011 study 2 published in the Journal of Experimental Biology (open access) added to our understanding of the factors that influence cat s feeding behavior, The study found that carnivores, like herbivores and omnivores, regulate their macronutrient protein, fat and carbohydrate - intake. Establishing that mesopredators such as cats can adjust their intake of these nutrients is a fundamental issue for nutritional ecology. Over 100 adult domestic cats weighing approximately 5 kilograms were enrolled in a series of nine feeding studies over the course of two years. In these studies, the cats were able to select food from three bowls, each containing a different diet that had varying amounts of protein, fat and carbohydrate. The results showed that cats have a daily intake target that they will consistently select if given the opportunity; approximately 26 gm protein (~5.2 gm/kg BW), 9 gm fat and 8 gm carbohydrate. This equates to approximately 52% of their daily calorie intake from protein, 36% from fat and 12% from carbohydrate. These are similar to values reported for feral cats, indicating that domestic cats have retained the capacity to regulate macronutrient intake to closely match the natural diet of their wild ancestors. It was also found that cats have a carbohydrate ceiling of approximately 20 gm per day and decrease their food intake once this amount is reached. In 2013, LaFlamme and Hannah 3 reported a study of the minimum protein intake needed to maintain nitrogen balance or lean body mass (LBM) in adult cats using 24 adult, neutered male cats. They found that approximately 1.5 g protein/kg body weight was needed to maintain nitrogen balance, whereas 5.2 g protein/kg body weight was needed to maintain LBM. This study provided evidence that nitrogen balance studies are inadequate for determining optimum protein requirements. Animals, including cats, can adapt to low protein intake and maintain nitrogen balance while depleting LBM. Loss of LBM and an associated reduction in protein turnover can result in compromised immune function and increased morbidity. Current Association of American Feed Control Officials (AAFCO) and National Research Council (NRC) standards for protein adequacy may not provide adequate protein to support LBM. The minimum daily protein requirement for adult cats appears to be at least 5.2 g/kg body weight, Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 7 of 56

well in excess of current AAFCO and NRC recommendations, but the same as found by Hewson-Hughes, et al. Further research is needed to determine the effect, if any, of body condition, age and gender on protein requirements. Diet Factors these will be discussed in the following lecture Feeding Factors These include how much, how often, when, where, and how to feed cats and dogs. How much is (conceptually) easy; whatever amount is necessary to sustain a body condition score (BCS) appropriate to the pet s life stage (2/5 for growth cats, 3/5 for adults). I recommend the BCS approach because of the variation among pets in measured energy needs. For example, in a recent review article, the average daily Calorie intake for adult cats was reported to be 223, with a range of 104-380! With such a range, it is clear that only an initial estimate can be provided, along with instructions to feed more or less as needed to maintain the desired BCS. The amount to be eaten can be estimated from the pet s current intake, label directions, or from the nutrition calculators provided by the Pet Nutrition Alliance. For cats, one also must ensure that the cat receives 5 gm protein per kilogram healthy body weight in the number of Calories they consume. For example, a 4 kg cat needs (4*5)=20 grams of protein each day contained in the amount of food they need to meet their Calorie needs to maintain a healthy body weight. For example, if the cat eats 223 Calories per day, she needs a food that contains 20 grams/223 Calories=0.09 grams per Calorie, or 9 grams per 100 Calories. To calculate the amount of protein in cat food on a gram per 100 Calorie basis, one can follow the steps below (adapted from: http://todaysveterinarypractice.navc.com/wp-content/uploads/2016/09/t1301f05.pdf.) 4 Step Calculation Dry Food Canned Food 1 Add 1.5 to the label % protein. 35%+1.5=36.5% 10%+1.5%=11.5% 2 Divide Calories (C) per kilogram diet by 1,000. a 4000/1000=4 1000/1000=1 3 Divide Step 1. By Step 2. 36.6/4=9.1 gm/100 C 11.5/1=11.5 gm/100 C a obtained from manufacturers, found online, or in product guides. Based on these calculations, one can quickly see that the dry food barely meets the cat s daily protein needs, whereas the canned food has about 25% more than needed. Pets can be fed from once a day to continuously, depending on the wishes of the owner and the response of the cat. Cats appear to be opportunistic feeders, predating small prey whenever the opportunity presents itself. If meal fed, the amount need not be the same at each meal; for example, feeding a larger meal late in the day to cats that wake their owners up to be fed may be tried, with a smaller morning meal fed before the owner leaves for the day. If cats are fed from a bowl, the bowl should be located in a safe quiet place away from machinery that could come on unexpectedly and scare the cat, or where the cat could be startled (or trapped) by other animals (including humans). Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 8 of 56

One the most interesting recent developments in nutrition for confined pets is the availability of food puzzles, which offer the opportunity for both physical and mental stimulation enrichment. A variety of products are available for sale, as an Internet search for - cats or dogs and puzzle feeders - will demonstrate, and owners also can make simple feeders. Both dry and canned (by freezing it in the feeder) food can be fed using these methods. Because animals have an intrinsic drive to eat, these are a primary form of environmental enrichment. I recommend that feeders be introduced at mealtime, with a portion of the usual meal in the feeder, which is placed next to the usual food source. I recommend that owners choose a puzzle they like from a local pet store to increase their buy-in, although I am happy to recommend ones I have had experience with. I suggest that they introduce the feeder on a day when they can stay around the home to observe the cat s reaction to the feeder. For owners concerned about the feeder leaving food particles around the house, the toy can be confined to a single room with an uncarpeted floor (like the kitchen or bathroom), or placed in a bathtub of large sweater box to restrict its access to the rest of the home. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 9 of 56

Summary - Nutritional assessment is an important aspect of optimal patient care. This document provides guidance for appropriate, effective assessment, evaluation, action monitoring and education. With little practice, this approach can be efficiently incorporated into daily practice without additional time or expense. Stay tuned for further developments and expanding knowledge. Useful websites Association of American Feed Control Officials (AAFCO) American Animal Hospital Association (AAHA) American College of Veterinary Nutrition (ACVN) Academy of Veterinary Nutritional Technicians (AVNT) Pet Nutrition Alliance pet nutrition-related resources. WSAVA Nutrition Toolkit another source of nutrition-related resources Nutritional History Form Example FDA Animal & Veterinary Information (regulatory and safety issues, adverse event reporting, meetings, industry information) FDA Pet Food Site Indoor Pet Initiative (Comprehensive recommendations for environmental enrichment for dogs and cats.) National Research Council (NRC) Nutrient Requirements of Dogs and Cats NRC Downloadable booklets. Your Cat s Nutritional Needs and Your Dog s Nutritional Needs Pet Food Institute United State Pharmacopeia Dietary Supplement Verification Program (voluntary program) National Animal Supplement Council USDA Food and Nutrition Information Center (General supplement and nutrition information, links to a variety of dietary supplement websites) USDA Nutrient Database (full nutrient profiles on thousands of human foods) http://www.aafco.org www.aahanet.org http://www.acvn.org http://nutritiontechs.org/ http://petnutritionalliance.org/ http://www.wsava.org/nutrition-toolkit http://www.acvn.org/wp- content/uploads/2016/01/acvn-diet-history- Form.pdf https://www.fda.gov/animalveterinary/default. htm http://www.fda.gov/animalveterinary/products /AnimalFoodFeeds/PetFood/default.htm https://indoorpet.osu.edu// http://www.nap.edu/catalog.php?record_id=106 68#toc http://dels.nas.edu/global/banr/petdoor http://www.petfoodinstitute.org/ http://www.usp.org/dietarysupplements/overview http://nasc.cc/ https://www.nal.usda.gov/fnic http://www.nal.usda.gov/fnic/foodcomp/search/ Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 10 of 56

References 1. Baldwin K, Bartges J, Buffington T, et al. AAHA nutritional assessment guidelines for dogs and cats. J Am Anim Hosp Assoc 2010;46:285-296. 2. Hewson-Hughes AK, Hewson-Hughes VL, Miller AT, et al. Geometric analysis of macronutrient selection in the adult domestic cat, Felis catus. J Exp Biol 2011;214:1039-1051. 3. Laflamme DP, Hannah SS. Discrepancy between use of lean body mass or nitrogen balance to determine protein requirements for adult cats. J Feline Med Surg 2013;15:691-697. 4. Shmalberg J. Beyond the guaranteed analysis -comparing pet foods. Today's Veterinary Practice 2013;3:43,45. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 11 of 56

From FUS To Pandora Syndrome Introduction, Pathophysiology, & Diagnosis Introduction Signs referable to the lower urinary tract (LUT) are one of the most common reasons cats in the USA are presented for care to veterinarians. These signs can include variable combinations of dysuria, hematuria, periuria, pollakiuria, and stranguria. Many causes for these clinical signs have been identified; the most common causes appear to include idiopathic disease, urolithiasis, infection, neoplasia, and anatomic abnormalities of the LUT. The name for this group of diseases has gone through several changes over the past 50 years. Osborne, et al., 1,2 have repeatedly recommended replacement of the term Feline Urologic Syndrome (FUS) 3 with descriptive terms pertaining to the site, causes, and pathophysiologic mechanisms whenever possible to permit the same terminology and approach to diagnosis and treatment used for other species to be used for cats. Unfortunately, their 1984 chapter, subtitled Feline Lower Urinary Tract Disease with Heterogeneous Causes, resulted in replacement of one acronym (FUS), with another (FLUTD). Such vague, obsolete, urocentric terms have lost their clinical utility as more recent research has provided accurate diagnostic methods for the causes of many if not most of these signs. Moreover, research has demonstrated that these signs also can sometimes reflect a disease elsewhere that is affecting the LUT rather than a problem intrinsic to the LUT itself. 4 These findings have revealed that researchers and clinicians now must look beyond the LUT to consider the whole individual when evaluating cats with LUT signs. This change has come in part as the result of studies using cats with severe, recurrent idiopathic LUT signs and variable comorbidities that have demonstrated that these cats provide a naturally occurring disease analog of a chronic pain syndrome in humans called interstitial cystitis (IC). 5 As in veterinary medicine, the names to describe this syndrome also are in flux in human medicine, with (also urocentric) suggestions including painful bladder syndrome/ic, bladder pain syndrome/ic, bladder hypersensitivity syndrome, and bladder pain syndrome. Thus, names such as FUS or FLUTD to describe recurrent LUT signs over simplify the problem and focus on the end organ rather than reflecting current understanding of the various causes of these signs. I have proposed use of Pandora Syndrome to describe cats with chronic LUT and other clinical signs, for at least two reasons; 1) this term does not identify any specific cause or organ, and 2) it seems to capture the dismay and dispute associated with the identification of so many problems outside the organ of interest of any particular subspecialty. 4 Clinical research on IC in humans has expanded to include both genetic 6 and epigenetic influences 7, to show that comorbid disorders often occur before the onset of LUT signs 8, and to document the extent of systemic involvement that occurs in most patients. 9 Similar to humans, evidence has accumulated that additional problems outside the LUT commonly are present in cats with chronic LUTS. 4 This evidence has led to reconsideration of the cause(s) of the syndrome in these individuals, as well as to considerable debate about the most appropriate nomenclature, diagnostic approach, and treatment recommendations. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 12 of 56

Diagnosis LUTS Acute Idiopathic Cystitis/Urethritis History, PE, UA, Micro, Imaging, Biopsy Neurogenic Urolithiasis Incontinence (No Urge) Recurrent LUTS Urethal Obstruction Iatrogenic Behavioral Neoplasia (TCC) Trauma Self-Limiting UTI FIC Frequently Recurrent Pandora Syndrome? Persistent Urethral Obstruction (males) Stressed Healthy Pandora Syndrome? YES No Figure 1. Some possible causes of LUTS in cats after appropriate diagnostic evaluation. PE physical examination; UCS- quantitative urine culture (cfu/ml); Imaging some combination of radiography, contrast urography, ultrasonography, and/or uroendoscopy. Not all tests are appropriate for every cat, so diagnostic evaluations tailored to each individual cat are most likely to arrive at the correct diagnosis. Cats can be presented for an initial occurrence of idiopathic LUT signs and may not return for care due to (an often presumed) improvement in the condition, or can return with recurrent LUT signs. Both genders appear to be affected equally. Although FIC can be obstructive or nonobstructive in its presentation, urethral obstruction is far more common in male cats, with no difference reported between intact and castrated males. 10 In addition to genetic and possible early adverse life events, other factors associated with an increased risk for chronic LUT signs have been reported, and include excessive body weight, decreased activity, multiple cat households, indoor housing, and a variety of environmental stressors such as conflict with another cat in the household. 11,12 Recommendations for diagnosis and treatment for the most common current causes of LUT signs currently identified in unobstructed cats, (Figure. 1; although some 30 distinct causes of LUT signs have been described 13 ) are widely available. When presented with a cat with LUT signs, clinicians also need to consider whether they are seeing the cat s initial episode, or whether the cat has chronic, recurrent disease, and what other health problems the cat may have. 14 This information permits one to judiciously utilize resources by choosing appropriate diagnostic tests to tailor treatment protocols to each individual cat. Recent research further complicates the diagnostic challenge, however, because cats may have multiple reasons for their clinical signs as well as other medical and environmental conditions that need to be addressed. For example, some cats with severe, chronic LUT signs seem to have YES No Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 13 of 56

a functional rather than a structural lower urinary tract disorder, 4 and periuria has been found to occur in apparently healthy cats exposed to stressful circumstances. 15 Recent Research Findings Infectious disease etiologies Although microorganisms in the LUT have not been identified as a common cause of (F)IC or associated with chronic LUT signs in the USA, a 2007 study from Norway of 134 cats with a variety of obstructive and non-obstructive causes of LUT signs found a surprisingly high number of cats with bacteriuria exceeding 10 3 CFU/mL in 44 (33%) cats, and exceeding 10 4 in 33 (25%), either alone or with variable combinations of crystals and uroliths. 16 These percentages are much greater than those reported from other studies. Interpretation of the general significance of findings from this study is complicated by the proportions of the samples that were obtained from voided midstream (46%) or catheterized urine samples (21%) rather than from the gold standard of cystocentesis (21%; in 10% of cases the method of urine collection was not recorded). In samples cultured on the same day they were collected, bacteria > 10 3 cfu/ml were isolated from 44 of 118 cats. In 33 of these 44 samples, growth was > 10 4 cfu/ml and in 20 growth was > 10 5 cfu/ml. The authors speculated that this higher rate for discovery of UTI in cats with LUT signs might have resulted from differences between cases diagnosed at primary and tertiary care facilities, though geographical differences in occurrence in the development of UTI cannot be excluded. Quantitative growth from midstream voided samples from healthy cats also can be substantial; one study found > 10 3 cfu/ml in cultures from 55% of males and 40% of females. 17 In human beings, one recent study found evidence of UTI within the past 2 years in 38% of the patients with IC they studied, although they reported that, 9...the infection domain was not associated with any increased symptoms. It also has been speculated that intrinsic abnormalities of the LUT make it more vulnerable to microbial colonization, 18 which could be consistent with the observation of increased risk for bacterial UTI in patients with (F)IC. The potential role of viruses in FIC also continues to be investigated. 19 The feline caliciviruses, FCV-U1 and FCV-U2, have been the most studied. Feline calicivirus (FCV) viruria has been detected in cats with chronic LUT signs and in cats with upper respiratory infections; however, its etiologic significance has not been determined. 20 Serologic results suggested increased FCV exposure in cats with FLUTD compared with controls. A weak association between seropositivity for Bartonella spp. and FIC also has been reported. 21 What, if any, role these agents play in the etiopathogenesis of chronic LUT signs, or in the systemic manifestations of the syndrome, remains unknown at this time. Lund, et al., 22 recently reported the prevalence of various viral infections in client-owned cats, 102 with clinical signs of FLUTD and 73 healthy control cats, recruited from the Department of Companion Animal Clinical Sciences at the Norwegian School of Veterinary Science from 2006 to 2009. Urine samples were tested for the presence of FCV, feline coronavirus (FCoV) and feline herpesvirus-1 (FHV-1) by polymerase chain reaction. All urinary samples were negative for FCV and FCoV. Only one percent of urines from cats diagnosed with FLUTD were found to be positive for FHV- 1, indicating that the viral infections examined were not associated with signs of FLUTD in the study sample. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 14 of 56

Bladder and Systemic abnormalities in FIC A variety of abnormalities have been reported in the urine, bladder and sensory apparatus of cats with chronic LUT signs (reviewed in 4 ). What is far less clear is what role(s) these abnormalities might play in the etiopathogenesis and progression of the syndrome, which are results of it, and which are unrelated bystander findings. In humans presenting with chronic LUT signs, urodynamic evaluations often are performed to rule out other LUT diseases, such as overactive bladder, that could account for the clinical signs. Although a decrease in bladder compliance has been reported in cats with FIC, a recent study found no urodynamic evidence for spontaneous bladder contractions (overactive bladder) in female cats with FIC. 23 However, increased urethral closure pressures were noted in cats with FIC compared to healthy cats, despite a lack of clinical signs at the time the studies were performed, suggesting the possibility of enhanced sympathetic tone. Alterations in autonomic function of the urethra of cats with FIC in vitro previously have been reported. 24 Another recent study reported that the acoustic startle response, a brainstem reflex in response to unexpected loud stimuli, appears to be amplified in cats with FIC. The startle response was greatest and most different in cats with FIC from that of healthy cats during stressful situations, but was still greater in affected than in healthy cats even when adapted to enriched housing conditions. 25 Epigenetic Studies A range of studies support the concept that the central stress response of patients with (F)IC is unusually sensitive. Recent research suggests that one mechanism underlying the sensitization of the stress response system involves a process called epigenetic modulation of gene expression. 26 Epigenetic modulation of gene expression is a prominent candidate mechanism for the exaggerated stress responsiveness found in cats with FIC because it has been shown to occur in the offspring of pregnant females exposed to stressors, and to result in long term neuroendocrine abnormalities. 27 Importantly, research in both rodents 28 and cats 29-31 also has demonstrated that effective environmental enrichment can mitigate much of the effect of early life adversity, possibly also by epigenetic modulation of gene expression. 32 Comorbidities A recent study of healthy cats and cats with FIC found that environmental stressors resulted in increased number of sickness behaviors (e.g., vomiting, lethargy, anorexia) in cats with FIC when the results were controlled for other factors. 15 Furthermore, cats with FIC have variable combinations of co-morbid disorders, 11,12,31,33-35 such as behavioral, endocrine, cardiovascular, and gastrointestinal (GI) problems. Most human beings with IC also suffer from variable combinations of comorbid disorders that affect a variety of other body systems. 36 That patients with FIC and IC have variable combinations of other comorbid disorders, and the observation that no temporal relationship has been identified among them raises the question of the extent to which a different etiology affects each organ versus the extent to which some common disorder affects all organs, which then respond in their own characteristic ways. Regardless of the eventual explanation(s), the breadth and consistency of these findings makes it imperative that clinicians evaluating cats presented for chronic LUT signs perform a thorough history and physical examination rather than focusing exclusively on the bladder, and obtain a detailed environmental history from owners of all cats with FIC, and for that matter all cats with chronic Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 15 of 56

disease syndromes to avoid missing comorbidities that may suggest the presence of other manifestations of Pandora Syndrome. Some obvious candidates include type-2 diabetes mellitus, asthma, behavioral inappropriate elimination, and upper and lower gastrointestinal dysfunction. Conclusions Clinical and basic science investigations over the past three decades have resulted in a more complex view of chronic LUT signs, both in human beings and domestic cats, challenging the traditional view that the bladder is always the perpetrator of LUT signs, in contrast suggesting that the bladder also can be one victim of a systemic process associated with a sensitized central stress response system. An overarching principle is that LUT signs and a variety of other signs can occur as a consequence of placing a sensitive cat into a provocative environment. The relationship between the environment and health also is quadratic rather than linear, with both deficient and threatening environments leading to poor health outcomes. 5 With current technology, we have the opportunity to develop collaborative strategies to learn far more about FUS, FLUTD, FIC, Pandora Syndrome, or whatever one s preferred term is; potentially enough to come up with a truly evidence-based nosology, and treatment(s) based on this understanding. Finally, one must keep in mind that even presumably healthy cats can develop sickness behaviors related to the LUT when exposed to sufficiently provocative environments, 15 and meeting the environmental needs of all pet cats to ensure their health and well-being is an animal husbandry responsibility we shoulder when we keep them as pets. While the cats studied to date appear to be more sensitive to their surroundings than healthy cats are, they just seem to be further along on a continuum that likely includes all pet cats. References 1. Osborne CA, Johnston GR, Polzin DJ, et al. Redefinition of the feline urologic syndrome: feline lower urinary tract disease with heterogeneous causes. Vet Clin North Am Small Anim Pract 1984;14:409-438. 2. Osborne CA, Kruger JM, Lulich JP. Feline lower urinary tract disorders. Definition of terms and concepts. Veterinary Clinics of North America - Small Animal Practice 1996;26:169-179. 3. Osbaldiston GW, Taussig RA. Clinical report on 46 cases of feline urological syndrome. Vet Med/Small Anim Clin 1970;65:461-468. 4. Buffington CA. Idiopathic cystitis in domestic cats-beyond the lower urinary tract. J Vet Intern Med 2011;25:784-796. 5. Buffington CAT, Westropp JL, Chew DJ. From FUS to Pandora Syndrome; Where are we, How did we get here, and Where to Now? Journal of Feline Medicine and Surgery 2014;16:385-394. 6. Dimitrakov J, Guthrie D. Genetics and phenotyping of urological chronic pelvic pain syndrome. J Urol 2009;181:1550-1557. 7. Buffington CA. Developmental influences on medically unexplained symptoms. Psychother Psychosom 2009;78:139-144. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 16 of 56

8. Warren JW, Howard FM, Cross RK, et al. Antecedent nonbladder syndromes in casecontrol study of interstitial cystitis/painful bladder syndrome. Urology 2009;73:52-57. 9. Nickel JC, Shoskes D, Irvine-Bird K. Clinical phenotyping of women with interstitial cystitis/painful bladder syndrome: a key to classification and potentially improved management. The Journal of Urology 2009;182:155-160. 10. Hostutler RA, Chew DJ, DiBartola SP. Recent Concepts in Feline Lower Urinary Tract Disease. Veterinary Clinics of North America-Small Animal Practice 2005;35:147-1170. 11. Buffington CAT. External and internal influences on disease risk in cats. Journal of the American Veterinary Medical Association 2002;220:994-1002. 12. Buffington CAT, Westropp JL, Chew DJ, et al. A case-control study of indoor-housed cats with lower urinary tract signs. Journal of the American Veterinary Medical Association 2006;228:722-725. 13. Osborne CA, Lulich JP, Kruger JM. Disorders of feline lower urinary tract I Etiology and Pathophysiology: WB Saunders, 1996. 14. Westropp J, Buffington CAT. Lower Urinary Tract Disorders in Cats In: Ettinger SJ,Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7 ed. St. Louis: Elsevier- Saunders, 2010;2069-2086. 15. Stella JL, Lord LK, Buffington CAT. Sickness behaviors in response to unusual external events in healthy cats and cats with feline interstitial cystitis. Journal of the American Veterinary Medical Association 2011;238:67-73. 16. Eggertsdottir AV, Lund HS, Krontveit R, et al. Bacteriuria in cats with feline lower urinary tract disease: a clinical study of 134 cases in Norway. J Feline Med Surg 2007;9:458-465. 17. Lees GE. Epidemiology of naturally occurring feline bacterial urinary tract infections. Veterinary Clinics of North America 1984;14:471-479. 18. Keay SK, Warren JW. Is interstitial cystitis an infectious disease? Int J Antimicrob Agents 2002;19:480-483. 19. Larson J, Kruger JM, Wise AG, et al. Nested Case-Control Study of Feline Calicivirus Viruria, Oral Carriage, and Serum Neutralizing Antibodies in Cats with Idiopathic Cystitis. J Vet Intern Med 2011;25:199-205. 20. Kruger JM, Osborne CA. The role of viruses in feline lower urinary tract disease. J Vet Intern Med 1990;4:71-78. 21. Sykes JE, Westropp JL, Kasten RW, et al. Association between Bartonella species infection and disease in pet cats as determined using serology and culture. J Feline Med Surg 2010;12:631-636. 22. Lund HS, Rimstad E, Eggertsdottir AV. Prevalence of viral infections in Norwegian cats with and without feline lower urinary tract disease. Journal of Feline Medicine and Surgery 2012;14:895-899. 23. Wu CH, Buffington CA, Fraser MO, et al. Urodynamic evaluation of female cats with idiopathic cystitis. Am J Vet Res 2011;72:578-582. 24. Buffington CAT, Teng BY, Somogyi GT. Norepinephrine content and adrenoceptor function in the bladder of cats with feline interstitial cystitis. Journal of Urology 2002;167:1876-1880. 25. Hague DW, Stella JL, Buffington CA. Effects of interstitial cystitis on the acoustic startle reflex in cats. Am J Vet Res 2013;74:144-147. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 17 of 56

26. Jensen P. Transgenerational epigenetic effects on animal behaviour. Progress in Biophysics and Molecular Biology 2013;113:447-454. 27. Reynolds RM, Labad J, Buss C, et al. Transmitting biological effects of stress in utero: implications for mother and offspring. Psychoneuroendocrinology 2013;38:1843-1849. 28. Russo SJ, Murrough JW, Han MH, et al. Neurobiology of resilience. Nat Neurosci 2012;15:1475-1484. 29. Westropp JL, Kass PH, Buffington CA. Evaluation of the effects of stress in cats with idiopathic cystitis. Am J Vet Res 2006;67:731-736. 30. Westropp JL, Kass PH, Buffington CA. In vivo evaluation of alpha(2)-adrenoceptors in cats with idiopathic cystitis. Am J Vet Res 2007;68:203-207. 31. Buffington CA, Westropp JL, Chew DJ, et al. Clinical evaluation of multimodal environmental modification (MEMO) in the management of cats with idiopathic cystitis. J Feline Med Surg 2006;8:261-268. 32. Sale A, Berardi N, Maffei L. Environment And Brain Plasticity: Towards An Endogenous Pharmacotherapy. Physiological Reviews 2014;94:189-234. 33. Buffington CAT. Comorbidity of Interstitial Cystitis with other Unexplained Clinical Conditions. Journal of Urology 2004;172:1242-1248. 34. Freeman LM, Brown DJ, Smith FW, et al. Magnesium status and the effect of magnesium supplementation in feline hypertrophic cardiomyopathy. Canadian Journal of Veterinary Research 1997;61:227-231. 35. Rush JE, Freeman LM, Fenollosa NK, et al. Population and survival characteristics of cats with hypertrophic cardiomyopathy: 260 cases (1990-1999). Journal of the American Veterinary Medical Association 2002;220:202-207. 36. Warren JW, Wesselmann U, Morozov V, et al. Numbers and types of nonbladder syndromes as risk factors for interstitial cystitis/painful bladder syndrome. Urology 2011;77:313-319. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 18 of 56

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From FUS to Pandora Syndrome Treating the Environment, Follow-up, and Prognosis Environmental Enrichment 1-3 Environmental enrichment is primary therapy for prevention of recurrence of Pandora Syndrome (PS). This opinion is based on the documented neuroendocrine abnormalities suffered by cats with PS, and on our clinical experience. We define environmental enrichment for indoor-housed cats to mean provision of all necessary resources, refinement of interactions with owners, a tolerable intensity of conflict, and thoughtful institution of change(s). Although we are not aware that a particular resource list has been validated for indoor-housed cats, some recommendations are available in the many excellent publications about cat housing and behavior that currently are available. We also recommend extending the 1+1 rule traditionally applied to litter boxes (1 for each cat in the home, plus 1 more) to all pertinent resources (particularly food water and litter containers) in the household. Food - Cats prefer to eat individually in a quiet location where they will not be startled by other animals, sudden movement, or activity of an air duct or appliance that may begin operation unexpectedly. Although canned food may be preferable for cats with PS due to the increased water content or a more natural mouth feel, some cats may prefer dry foods. If a diet change is appropriate, offering the new diet in a separate, adjacent container rather than removing the usual food and replacing it with the new food will permit the cat to express its preference. Natural cat feeding behavior also includes predatory activities such as stalking and pouncing. These may be simulated by hiding small amounts of food around the house, or by putting dry food in a container from which the cat has to extract individual pieces or move to release the food pieces, if such interventions appeal to the cat. Also, some cats seem to have specific prey preferences. For example, some cats prefer to catch birds, while others may prefer to chase mice or bugs. Identifying a cat s prey preference allows one to buy or make toys that the cat will be more likely to play with. Water - Cats also seem to have preferences for water that can be investigated. Water-related factors to consider include freshness, taste, movement (water fountains, dripping faucets or aquarium pump-bubbled air into a bowl), and shape of container (some cats seem to resent having their vibrissae touch the sides of the container when drinking). As with foods, changes in water-related factors should be offered in such a way that permits the cat to express its preferences. Additionally, food and water bowls should be cleaned regularly unless individual preference suggests otherwise. Litter boxes - Litter boxes should be provided in different locations throughout the house to the extent possible, particularly in multiple cat households. Placing litter boxes in quiet, convenient locations that provide an escape route if necessary for the cat could help improve conditions for normal elimination behaviors. If different litters are offered, it may be preferable to test the cat s preferences by providing them in separate boxes, since individual preferences for litter type have been documented. For cats with a history of urinary problems, unscented clumping litter should be considered. Litter boxes should be cleaned regularly and replaced; some cats seem quite sensitive to dirty litter boxes. Litter box size and whether or not it is open or covered also may be important to some cats. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 20 of 56

Space - Cats interact with both the physical structures and other animals, including humans, in their environment. The physical environment should include opportunities for scratching (both horizontal and vertical may be necessary), climbing, hiding and resting. Cats seem to prefer to monitor their surroundings from elevated vantage points, so climbing frames, hammocks, platforms, raised walkways, shelves or window seats may appeal to them. Playing a radio to habituate cats to sudden changes in sound and human voices also has been recommended and videotapes to provide visual stimulation are available. Play - Some cats seem to prefer to be petted and groomed, whereas others may prefer play interactions with owners. Cats also can be easily trained to perform behaviors ( tricks ); owners just need to understand that cats respond much better to praise than to force, and seem to be more amenable to learning if the behavior is shaped before feeding. Cats also may enjoy playing with toys, particularly those that are small, move, and that mimic prey characteristics. Many cats also prefer novelty, so a variety of toys should be provided, and rotated or replaced regularly to sustain their interest. Conflict - When cats perception of safety becomes threatened, they appear to respond in an attempt to restore their perception of control. During such responses, some cats become aggressive, some become withdrawn, and some become ill. In our experience, intercat conflict commonly is present when multiple cats are housed indoors together and health problems are present. Conflict among cats can develop because of threats to their perception of their overall status or rank in the home, from other animals in the home, or from outside cats. With a little practice, one can recognize the signs of conflict and estimate its potential role in exacerbation of signs of PS. If it is, owners usually can identify the causes after the signs of conflict are explained to them. Once this has been done, clients often are well on their way to reducing the intensity of conflict. Of course, some conflict between housemates is normal, regardless of species. Our goal is to reduce unhealthy conflict to a more manageable level for the cats involved. Treatment for conflict between cats involves providing a separate set of resources for each cat, preferably in locations where the cats can use them without being seen by other cats. This lets the cats avoid each other if they choose to without being deprived of an essential resource. Neutering all of the cats also can reduce conflict, and keeping all nails trimmed as short as practicable reduces the risk of fight wounds. Whenever the cats involved in the conflict cannot be directly supervised, they may need to be separated. This may mean that some of the cats in the household can stay together, but that the threatened cat is provided a refuge from the other cats. This room should contain all necessary resources for the cat staying in it. Cats generally require and use more space than the average house or apartment affords them. The addition of elevated spaces such as shelves, kitty condos, cardboard boxes, beds, or crates may provide enough space to reduce conflict to a tolerable level. In severe situations, some cats may benefit from behavior-modifying medications. In our experience, however, medication can help only after environmental enrichment has occurred, it cannot replace it. Conflict with other animals, dogs, children, or adults is relatively straightforward. In addition to being solitary hunters of small prey, cats are small prey themselves for other carnivores, Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 21 of 56

including dogs. Regardless of how sure the client is that their dog will not hurt the cat, to the cat the dog represents a predator. If the cat does not assert dominance over the dog, as often happens, it must be provided ways to escape at any time. For humans, it usually suffices to explain that cats may not understand rough treatment as play, but as a predatory threat. Most cats in urban areas in the United States are housed indoors and neutered, so conflict with outside cats can occur when a new cat enters the area around the house the affected cat lives in. To cats, windows are no protection from a threatening cat outside. If outside cats are the source of the problem, a variety of strategies to make ones garden less desirable to them are available. Because of the dearth of controlled trials, it currently is not possible to prioritize the importance of any of these suggestions, or to predict which would be most appropriate in any particular situation. Appropriately designed epidemiological studies might be able to identify particularly important factors, after which intervention trials could be conducted to determine their efficacy in circumstances where owners successfully implemented the suggested changes. Additional approaches Once environmental enrichment strategies have been implemented, additional treatments may be considered. In our experience, these approaches are more likely to succeed after the environment has been enriched to the extent possible by the client, and more likely to fail in the absence of environmental enrichment. They are listed in the order in which we consider them. Pheromones - A novel aspect of environmental enrichment that recently has become available is application of pheromones to the living space. Pheromones are chemical substances that seem to transmit highly specific information between animals of the same species. Although the exact mechanism of action is unknown at this time, pheromones appear to effect changes in the function of both the limbic system and the hypothalamus to alter the emotional status of the animals. Five facial pheromones have been isolated from cats; cats deposit the F3 fraction on prominent objects (including humans) by rubbing against the object when the cat feels safe and at ease. The function of this secretion is not only to mark objects, but also as an antagonist for urine marking and scratching. Feliway a synthetic analogue of this naturally occurring feline facial pheromone, was developed to decrease anxiety-related behaviors of cats. Although not specifically tested in cats with FIC, treatment with this pheromone has been reported to reduce the amount of anxiety experienced by cats in unfamiliar circumstances, a response that may be helpful to these patients and their owners. Decreased spraying in multi-cat households, decreased marking, and a significant decrease in scratching behavior also has been reported subsequent to its use. Although, Feliway is not a panacea for unwanted cat behaviors or PS, we have used it successfully in combination with environmental enrichment, and/or drug therapies. Feliway is sold as both a spray and room diffuser. The spray can be used to treat areas of the house where the cat is urinating by use of a single spray to the affected spot for 30 days. We also have found Feliway to be beneficial to decrease anxiety associated with traveling. Clients can spray the cat carrier at least 15 minutes prior to the trip and then place the cat in the carrier to help decrease the stress and anxiety most cats associate with travel. The treated areas should be sprayed at least 15 minutes prior to the cat encountering the area because the vehicle (ethanol) the pheromone is carried in is offensive to most cats. The room diffuser can be placed in a room Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 22 of 56

where the cat inappropriately urinates. One room diffuser is reported to cover approximately 650 square feet and last for 30 days. This method of administration of the pheromone is new and we have little experience with its use. A recent study reported that some cats may enjoy other scents, including catnip, silver vine, Tatarian honeysuckle and valerian (a constituent of Feliway). 4 Another recent study reported that pet cat s preferences were owner social interaction with the owner (50%) = food (37%) > toys (11%) > scent (2%). Preference for food was not different from toys, but greater than for scent. 5 Although social interaction with humans was the most-preferred stimulus category for the majority of cats, followed by food, there was clear individual variability among the cats in preference, demonstrating once again the importance of asking the cat by offering changes as choices. Conclusions Many indoor-housed cats appear to survive perfectly well by accommodating to less than perfect surroundings. The neuroendocrine abnormalities in the cats we treat, however, do not seem to permit the adaptive capacity of healthy cats, so these cats may be considered a separate population with greater needs. Moreover, veterinarians are concerned more with optimizing the environments of indoor cats than with identifying minimum requirements for indoor survival. Additional information about environmental enrichment is available at: http://indoorpet.osu.edu/ References 1. Herron ME, Buffington CA. Environmental enrichment for indoor cats: implementing enrichment. Compend Contin Educ Vet 2012;34:E1-5. 2. Herron ME, Buffington CAT. Environmental enrichment for indoor cats. Compend Contin Educ Pract Vet 2010;32:E1-E5. 3. Ellis SL, Rodan I, Carney HC, et al. AAFP and ISFM feline environmental needs guidelines. J Feline Med Surg 2013;15:219-230. 4. Bol S, Caspers J, Buckingham L, et al. Behavioral responsiveness of cats (Felidae) to silver vine (Actinidia polygama), Tatarian honeysuckle (Lonicera tatarica), valerian (Valeriana officinalis) and catnip (Nepeta cataria). BMC Vet Res 2017;submitted. 5. Shreve KRV, Mehrkam LR, Udell MA. Social interaction, food, scent or toys? A formal assessment of domestic pet and shelter cat (Felis silvestris catus) preferences. Behavioural Processes 2017. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 23 of 56

From FUS to Pandora Syndrome Treating The Owner And The Cat Signs referable to the lower urinary tract (LUTS) resolve spontaneously in most cats with idiopathic cystitis within a few days days, with or without treatment. Unfortunately, as many as 50% of these cats suffer another episode within 12 months; 39% recurred in one recent study. It is not yet possible to predict which cats will relapse; some have multiple recurrences, whereas clinical signs never resolve in a small population of severely affected cats. In my opinion, the most important consideration for a successful outcome is good communication with the owner. After performing a diagnostic evaluation of the cat and concluding that the disease is idiopathic, an appointment can be scheduled with only the owners present to thoroughly review the disease process, discuss short and long-term treatment options, and be certain the owners have an understanding of this disease process in their cat. No cure is currently available for idiopathic cystitis, so treatment options are aimed at keeping the cat s clinical signs to a minimum and increasing the disease free interval. Treating the Client Owners of cats with Pandora Syndrome (PS) may go to a veterinarian to get a diagnosis for the cause of the signs. A diagnosis of PS means that we have identified a chronic pain syndrome, and excluded (to the extent possible) other causes for the signs. The clinician also can answer the following common patient questions (adapted from 1 ) Table 1. Common client questions about cats with LUTS presentation of PS Are the urinary signs caused by a precisely No, although current research suggests that the understood medical entity? signs may be the result of a problem that occurred during development Is this life threatening? No, it is definitely not life threatening in itself Does a definitive cure exist? Not yet Can symptoms be ameliorated? Is this likely to plateau or progress? If so, over what period? Are there attendant complications? If so, can these be mitigated, or better still, prevented? If that is a possibility, at what compromise in living? Will a change in lifestyle make a substantial difference in outcome in relation to the cat s well being? Usually yes, and quite effectively Yes, in fact, it usually has reached its plateau by the time the veterinarian sees the patient, although symptoms may wax and wane around this plateau. Stress-exacerbated symptoms, which may be reduced, can occur. Some work to learn to identify and cope with sources of stress may be necessary. Absolutely! Once the diagnosis of PS is made, the veterinarian can explain to the client that PS is not a syndrome commonly treatable by drugs or surgery, is manageable with a combination of analgesic medications (acutely) and environmental modification (chronically), and that most care can be provided in collaboration with their technician. The clinician also should listen to the client s (often frustrated) story of the effects of having a cat with PS, provide a satisfactory Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 24 of 56

explanation for the sources of the signs (I often liken it to a chronic migraine ), express care and concern for the situation, and enhance the client s sense of control. Effective doctor-patient interactions appear to enhance patient adherence to treatments, and quality of life outcomes of therapy. 2 Open-ended questions are those that do not result in a black or white, yes or no, answer. They invite the client to describe what happens to their individual pet in their unique environment. Using open-ended questions may require a bit more time, but they allow the client to provide information by painting a picture you might not otherwise be able to see. Asking open-ended questions also avoids the temptation for client to provide answers they think you may want to hear. Actively listening to clients employs our own body language to indicate that we are really hearing what they have to say. Body language that tells the client we are open and ready to listen include facing them nearly squarely, smiling and making eye contact, nodding our head up and down as we listen, standing or sitting with arms unfolded and palms open, and leaning forward toward them. Actively listening also means responding in a way that tells the client you have heard what they said. Active responses include clarifying (asking another question if the client s response was unclear), paraphrasing (putting the client s information into your own words to make sure you ve got the right perspective or angle), reflecting (repeating what was said to show support) and/or summarizing (bringing disjointed events/information into focus or bringing closure to an interview). Active listening skills require some measure of compassion, as well as practice. Providing clear, unambiguous instructions often is more difficult that it sounds. Ask most people who garage their car how they get to work and most will forget to tell you they open the garage door before driving out! We can apply the same concept to giving go-home instructions to clients. Clients remember information given during the first third of any communication longest, so organize what you need to say and how you want to say it. For common recommendations, consider preparing a written handout with clear, concise instructions that the client can read and follow once they get home. Having the owner write down the instructions you give and review them with you also works well. Other guidelines for information giving include the following: Limit the amount of information given at any one time; most important FIRST Give specific, concrete and simple instructions; Use oral and written material together (draw stick figures or use pictures from wall charts, books or brochures); Check the client s comprehension by asking them to restate the key features of your instructions; Don t assume your client can read, write or do simple math; Don t assume that clinical terms, such as vomiting and diarrhea, mean the same things to you and the client clarify exactly what you mean and what you want them to look for; Ask for and discuss the client s feelings (and biases) about the information you provide; Repeat important information; Whenever possible, involve all members of the household, or significant others, in the therapeutic process. Successful client communication skills are interwoven throughout effective care. Although some natural talent at interviewing or expressing empathy helps if you have it, even the best practitioners and technicians mindfully practice these skills on a daily basis. Regardless of the Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 25 of 56

point at which you enter the iterative process, there are a few key questions to consider when considering the best strategy for effectively communicating with an individual client about their pet: Why is the client here? Is the problem the client describes all or only part of the problem? What are the problems and related concerns that I can address? Since PS is not presently curable, this approach may be one of the most effective strategies for caring for these patients, since they validate the client s reality. We also prescribe analgesic and other pharmacological therapies as appropriate. The appointment concludes with introduction to the technician or other staff member trained in caring for cats with FIC who will take over the adjunctive care of the patient. The formality of this introduction should demonstrate that the veterinarian intends to sustain the partnership with the client toward control of the patient s clinical signs. Treating the Cat Acute Care Pharmacotherapy 3 - Antibiotics are rarely indicated for most cats that present with LUTS0); unless a cat has a documented bacterial urinary tract infection, empiric use of antibiotics is not warranted. Analgesic therapy seems appropriate for the acute management of the disease. Breaking the chronic pain-inflammation cycle may be important in the management of at least some cats with severe signs. Providing analgesia with narcotics such as oral buprenorphine (my preference), butorphanol, or a fentanyl patch can be used depending on the severity of the pain. Non-steroidal anti-inflammatory agents such as carprofen, or meticam also have been recommended, and tramadol has been used anecdotally in cats with this disease as well; no controlled studies support of refute use of these compounds as far as I am aware. We provide buprenorphine for approximately 5 days, and if clinical signs have not significantly improved or resolved, we pursue further diagnostic evaluation. We most commonly use buprenorphine at 5 to 20 micrograms/kg orally BID to QID for 3 to 5 days. We have used the injectable preparation successfully in many cats it appears to be odorless and tasteless to cats. Although butorphanol has been recommended, its effects apparently are not as potent, and do not last as long as those of buprenorphine. It is not known whether or not providing analgesia during acute episodes impacts the development of future episodes. Some also suggest use of antispasmodics such as phenoxybenzamine, prazosin and dantrolene to relax the urethra of male cats, but to my knowledge, no controlled studies of the safety or effectiveness (or lack thereof) of any of these drugs for this syndrome has been reported. Although anecdotal evidence of their use exists, chronic NSAIDS treatment can predispose cats to the development of acute intrinsic renal failure. Also, NSAIDS have been ineffective in pain management of interstitial cystitis in humans. Antispasmodics also are not effective for human beings with the disorder. If the clinician is working with a patient that has chronic signs, analgesics can be dispensed for the cat with instructions for the owner to medicate the cat if clinical signs develop, and then to contact the veterinarian. Oftentimes, this treatment will be successful and the cat will not need to be returned to the veterinary hospital. If the clinician chooses to manage some cats in this manner, they must be confident that other causes of lower urinary tract signs have been excluded, and that the cat has idiopathic cystitis. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 26 of 56

Housing - Enriching the Places we Keep Cats a 4-6 - Although hospitalization can be threatening for any patient, cats with idiopathic cystitis seem particularly sensitive. For these patients especially, housing in areas away from heavily trafficked areas, dogs and other animals, and excessive light and noise seems helpful. If the cat can be kept in its carrier in the cage, or at least housed with familiar articles (e.g., blankets, toys) and its usual food, and cared for by as few individuals as possible, its experience, and clinical course, may be improved. What does Effective Environmental Enrichment for Confined Cats Mean? - As a broad generalization, cats form attachments to places, whereas dogs tend to form attachments to others (dogs, people, etc.). Because of this, confinement in places where cats don t feel safe can adversely affect their behavior and physiology. Fortunately, effectively enriching their living places can improve their behavior, health and welfare. Effective environmental enrichment for confined cats means creating conditions that permit the cat to perceive its surroundings, its place, as safe, predictable, and interesting. These conditions permit cats perception of control over their lives to exceed their perception of threat, which allows them to cope with their surroundings and feel safe in their place. How can we evaluate cats environments to determine what, if any, changes are needed? - Here is a brief summary of factors that can affect the welfare of cats housed in confinement - in shelters, research facilities, veterinary hospitals, or boarding facilities (the same principles also can be applied to indoor housed cats to ensure optimal environmental conditions for them in such places). Please refer to the resource list at the end of the document for more information. Inside the cage - Every cat should have these resources at its disposal. Litter box- any type of litter box and any type of litter can potentially be used; the choice depends on the resources available to the caretaker, and the cat s preferences. Important points to keep in mind when selecting a box and litter: Provide a box that is big enough for the cat (preferably 1.5 times the length of the cat) Ensure the litter is deep enough; cats prefer to dig around (without hitting the bottom of the litter pan) and then bury their eliminations. Empty the box frequently- twice a day is optimal for caged cats Clean with mild dish soap weekly *If the cat isn t using the box then try something different! Food and water- be consistent in type, presentation (location of bowl), and timing of feeding and watering. If feeding canned food, offer it in a separate bowl. Consider using stationary or mobile food puzzles if and as appropriate. Hide- cats use boxes to keep warm, to escape threats, and to scratch and perch on. Cardboard boxes work well, and they are cheap and disposable. Bedding- needs to be large enough to provide comfort (e.g., large towel). Change bedding only when soiled, rather than daily because most cats prefer familiar bedding. Toys- Offer different types and textures. Rotate toys at least weekly. Other things that can be offered as enrichment include music (played softly), food treats, playtime out of the cage with other cats (if they like other cats and being out of the cage), and extra attention like brushing or playing from a familiar, dedicated person. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 27 of 56

Outside the Cage - These factors may be stressful for confined cats. Put Lights on a timer that is constant from day to day if natural light is not provided. If a timer isn t possible, then turn lights on and off manually at the same time each day. Do NOT turn lights on and off each time someone goes in and out of the room. Keep Noise levels to a minimum (<60 db quiet conversational level can be measured with a smartphone app). Have people speak in quiet voices when in the presence of cats, and conduct conversations outside of the cat room. House barking dogs as far from cats as possible, and play music below 60dB. Close cage and room doors quietly. Avoid sudden and unexpected noises, which are especially disturbing to cats. Be aware of noises such as water from hoses, newspaper being unfolded, trash bags, etc., and avoid to the extent possible. Avoid Odors from dogs, other cats, alcohol (from hand rubs), cigarettes, cleaning chemicals (including laundry detergent), etc.; all can be aversive and stressful to cats, especially when confined in a cage where they can t move away from the odor. Minimize odors that are threatening. Temperature: Cats prefer warm, 85-100 degrees F, temperatures. Most cat housing areas are not this warm, so be sure to provide bedding that allows cats to get warm if they choose. If using towels, make sure they are large enough for the cat to get under or to make a nest from. Shredded paper in a box also can be used. Daily routine - A consistent, predictable (by the cat!) daily routine is essential. Most animals, including cats, prefer consistency in their daily routines. Conduct cleaning and feeding procedures at the same time each day, performed by the same person. Clean cages in the same order, and in exactly the same way, each day. Provide cage furnishings in the same place, and house cats in the same cage throughout their stay. Routine cleaning can be stressful for confined animals, and this level of temporal detail helps them to cope. Keep all cat-related activities as consistent as possible, and minimize non-essential traffic in and out of the cat area. Familiar person- Cats adapt better to new places when they see the same friendly person each day. Given time constraints, quality may be more important than quantity of interactions. Have the familiar person visit each cat daily, open the cage door, talk, pet, play with the cat and offer food treats. The cat will look forward to the visit and become active and/or interactive when the person comes into the room. The person will become familiar with the usual affect and behavior of each cat and quickly recognize any changes in behavior. The familiar person also handles the cat during any medical procedures or other potentially stressful situations to comfort the cat. Low stress handling- Cats are both predator and prey animals. They have weapons (teeth and claws) that they can and will use if they feel threatened. They will choose to run or hide if they can when threatened, and even though we may have only the best intentions when performing husbandry and medical procedures, the cat often perceives them as threatening. We define Low stress handling techniques as those that minimize activation of the cat s stress response system (SRS). Low stress handling is important to both the handler and the cat. Cats are much easier (and more fun) to work with when they look forward to being handled. During husbandry this Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 28 of 56

may be accomplished by letting the cat out of its cage during cleaning for a little fun and exercise, or by training the cat to get on a perch by rewarding with treats and praise. Cats can be fed high value food such as baby food or tuna, or be gently restrained using clipnosis, during medical exams, treatments, nail trims or grooming procedures. Having a familiar person handle the cat during threatening procedures also helps minimize the stress associated with the procedure. Remember: less is more when handling cats; both fewer people and less restraint. Never yell at or punish a cat; they only perceive these as threats. Red Flags- These behaviors signal that something may be wrong in the cat area. Their presence warrants investigation of the environment and closer monitoring of the cats to identify and resolve any problem(s) identified. Cats resting in their litter boxes. Cats will do this when they want to hide, but are not provided with an appropriate box, when they are sick, cold, or when they are having trouble coping with the place they are housed in. Cage Condition- Cages that show no use since the last cleaning or are in disarray may indicate anxiety and/or fear. Aggressive behavior. Cats are not generally aggressive, so this may indicate fear or pain. Behavior change. Anytime a cat s behavior changes (particularly in a negative way) one should monitor the individual closely. Sickness behaviors. These include vomiting, diarrhea or soft stool, no eliminations in 24 hours, urinating or defecating out of the litter box, anorexia or decreased appetite, lethargy, and/or not grooming. Caretakers must record each cat s appetite, eliminations, and sickness behaviors daily to ensure proper monitoring. ** Remember to always offer new things (food, litter, litter box, playtime, etc.) as a choice. Let the cat choose whether or not to use any new resource at its own pace. Most importantly, get to know your cats. What do they like, don t like? How do they normally greet you? Are they vocal or rarely talk? Where is their favorite place to be scratched? What is their favorite toy or treat? How much do they normally eat? How often do they urinate, defecate each day? When something about their usual routine changes, monitor the cat and investigate the environment. If you know your cats, you can ensure they are happy cats! How can you tell when a cat feels threatened? - Feeling threatened can activate an animal s SRS. We can recognize this by observing changes in cats physiology and behavior, recognizing that the changes in one cat might be different from those of another that is similarly fearful. We can evaluate any housing situation or handling technique by assessing physiological and behavioral parameters for the state of activation of the SRS in the cat before and after the handling technique is applied. Physiological and behavioral parameters associated with threat include (however many can be obtained or observed): Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 29 of 56

Physiological parameters: Increase in: Presence of: Pupil diameter Sweaty paws Respiratory rate Excessive shedding Temperature Flushing Heart rate Anxious lip-licking Blood pressure Behavioral parameters/body postures: Increases in withdrawal behaviors: Immobility- presence of hiding, cowering, or freezing behaviors. Attempts to run away or avoid handlers. Defensive aggression (hissing, growling, spitting, tail twitching, ear flicking, scratching, biting) Decreases in affiliative ( approach ) behaviors: Friendly approach to caregivers Purring, kneading, rubbing, etc. Interest in food relaxed body postures Normal eliminations Increased effectiveness of the technique with repeated use How should I implement needed changes? Beyond providing an enriched cage, offer enrichments one at a time to avoid overwhelming confined cats. And always offer changes in resources as a choice, so the cat can express its preferences. Carefully observe the cat s reaction and discontinue or remove anything that causes them to avoid the new resource or show any of the threat parameters listed above. How can I assess if my efforts are effective? You can learn if your enrichment and low stress handling efforts are effective by documenting changes in the cat s behavior and physiology. You can use table below to record your observations of the cats before and after your efforts. Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 30 of 56

Responses to Enrichment Physiological Pupil diameter Respiratory rate Temperature Heart rate Blood pressure Sweaty paws Excessive shedding Flushing Anxious lip-licking Behavioral Immobility Attempts to run away or avoid handlers Defensive aggression Friendly approach to caregivers. Purring, kneading, rubbing, etc. Interest in food Relaxed body postures Normal eliminations Before After Change How to fill in the Response to Enrichment form Physiological Before After Change Pupil diameter Constricted, normal, Larger, smaller, no dilated change Respiratory rate Breaths per min Temperature Degrees F (or C) Heart rate Beats/min Blood pressure mmhg Sweaty paws Present? (yes, no, ND 1 ) Excessive shedding Present? (yes, no, ND) Flushing Present? (yes, no, ND) Anxious lip-licking Present? (yes, no, ND) Behavioral Immobility Increase? Attempts to run away or avoid Present? (yes, no, ND) Decrease? handlers No change? Defensive aggression Present? (yes, no, ND) Friendly approach to caregivers. Present? (yes, no, ND) Purring, kneading, rubbing, etc. Present? (yes, no, ND) Interest in food Present? (yes, no, ND) Relaxed body postures Normal eliminations 1 ND not done Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 31 of 56

a Thanks to Dr. Judi Stella and Ms. Traci Shreyer for their invaluable contributions to these recommendations! Additional resources: Enrichment resources for veterinarians at the Indoor Pet Initiative: https://indoorpet.osu.edu/veterinarians Enrichment Strategies for Laboratory Animals from the Viewpoint of Clinical Veterinary Behavioral Medicine: Emphasis on Cats and Dogs. Available at: http://tinyurl.com/jlt8jpu Stella JL, Croney CC: Environmental Aspects of Domestic Cat Care and Management: Implications for Cat Welfare. The Scientific World Journal 2016. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5059607 AAFP Guidelines http://www.catvets.com/guidelines/practice-guidelines/environmentalneeds-guidelines http://www.catvets.com/guidelines/practice-guidelines/handlingguidelines Here is a link to help shelter and clinic personnel better observe, care for, and handle cats in cages: http://vet.osu.edu/assets/shelter/index.html Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 32 of 56

Feline Urinary / Nutrition C.A. Tony Buffington DVM, PhD, Diplomate ACVN (emeritus) Page 33 of 56