From FUS to Pandora Syndrome - The Role of Epigenetics and Environment in Pathophysiology, Treatment, and Prevention
Tufts' Canine and Feline Breeding and Genetics Conference, 2013
C.A. Tony Buffington, DVM, PhD, DACVN
The Ohio State University Veterinary Hospital, Columbus, OH, USA

Introduction

In an accurate clinical description of cats with lower urinary tract (LUT) disease published in 1925,1 the disorder was reported to be very common, the roles of confinement and highly nutritious food were discussed, and the common occurrence of the problem in Persian cats was identified. In 1970, the term feline urologic syndrome (FUS) was coined by Osbaldiston and Taussig to describe a problem "characterized by dysuria, urethral obstruction, urolithiasis (although no stones were reported) and hematuria."2 They concluded from a review of 46 cases, "the condition may not be a single disease entity, but rather a group of separate urologic problems."

During the 1980s, Osborne, et al. suggested that FUS should be considered synonymous with feline lower urinary tract disease (FLUTD).3 Then, in 1995, the group4 suggested that the acronym FUS be redefined as feline urologic signs to emphasize that FUS is not an etiologic diagnosis of any particular LUT disease. They proposed that "when possible, refined diagnoses of lower urinary tract disease should encompass descriptive terms pertaining to the site (e.g., urethra, bladder), pathophysiologic mechanisms (e.g., obstructive uropathy, reflex dyssynergia), morphologic features (e.g., inflammation, neoplasia), and causes (e.g., anomalies, urolithiasis, bacteria, fungi)," and suggested that confirmed and suspected causes of LUT diseases in domestic cats be categorized as anatomic, iatrogenic, idiopathic, inflammatory (infectious and noninfectious), metabolic, neoplastic, neurogenic, or traumatic. The terms FUS and FLUTD have since been superseded by the ability of veterinarians to diagnose many distinct causes of the well-known clinical signs of dysuria, stranguria, pollakiuria, hematuria, and inappropriate urination (periuria) that, either individually or in some combination, cause clients to seek further evaluation of their cats.5

Retrospective studies suggest that the majority of non-obstructed cats with LUT signs have an idiopathic disorder, and that this percentage has not changed appreciably during the past 4 decades.2,6-9 The importance of LUT disorders to feline health is emphasized by the finding that elimination disorders (the vast majority of which are urinary) result in destruction of millions of cats in animal shelters in the United States every year.10 We defined idiopathic cystitis as an acute or chronic disease of waxing and waning signs of irritative voiding (dysuria, pollakiuria, hematuria, periuria), sterile urine, absence of cellular abnormalities suggesting neoplasia, and failure to identify an alternative cause for these signs after appropriate lower urinary tract (LUT) imaging procedures (combination of plain radiography, contrast radiography, contrast urethrography, ultrasonography) in the absence of cystoscopic evaluation.8 Feline interstitial cystitis (FIC), a subcategory of idiopathic cystitis, was defined as a chronic condition describing cats that have frequent recurrences or persistence of clinical signs and cystoscopic documentation of submucosal petechial hemorrhages (glomerulations) after bladder distension to 80 cm water pressure in the absence of an alternative explanation for these findings.9

Based on a series of studies conducted during the past two decades, a variety of problems beyond the urinary tract have been identified in cats with chronic, severe, recurrent LUT signs.11 These include epithelial, neurological, endocrine, immune, and behavior abnormalities, as well as a variety of comorbid disorders (which often precede development of LUT signs) affecting many body systems. Enhanced central sympathetic drive in the face of inadequate adrenocortical restraint, which seems to be related to maintaining the chronic disease process, also has been identified. These systems appear to be driven by tonically increased activity of the central stress response system, which may represent the outcome of a developmental accident that durably sensitizes this system to the environment, possibly through epigenetic modulation of gene expression.12 The repeated observation that most of these problems resolve after exposure to an enriched environment provided additional evidence for a disorder of the central nervous system resulting in a chronic multisystem illness variably affecting the bladder and other organs, as opposed to a peripheral, organ-based problem.13-15

Diagnosis

Based on the evidence outlined above, I believe that some cats with chronic LUT signs may have a "Pandora syndrome" (named for the Pandora myth, which reflects my experience in studying this problem and my optimism that hope for effective treatment remains).16

Based on the currently available evidence, provisional criteria for diagnosis of a "Pandora syndrome" might include:

1.  Chronicity - persistence or recurrence of the condition(s) over months to years

2.  Comorbidity - evidence of problems in other body systems (particularly preceding the presenting LUTS in the case of idiopathic cystitis. These may include behavioral, endocrine gastrointestinal, respiratory, dermatological, etc.

3.  A history of early adverse experience (orphaned, bottle fed, rescued)

4.  Evidence of familial involvement; that is, parents and/or littermates have a similar illness profile

Information about early experience and family members often cannot be obtained from owners, and none of these criteria can be considered pathognomonic for anything. They may serve only to raise one's "index of suspicion" that a more systemic problem may be present. By taking the time to obtain a comprehensive review of the cat's history and conduct a thorough physical examination before assuming that the cat has an isolated bladder (or other) disease, one may find that some cats appear to have a disease affecting more than the organ attributed to the presenting signs, which can helpfully inform one's therapeutic recommendations. I urge others to test this hypothesis for themselves.

Treatment

Based on current understanding of the role of the environment in chronic illness in cats, environmental enrichment is the first line of therapy to reduce the risk of recurrence of whatever clinical signs are present.13-15 Environmental enrichment for indoor-housed cats means provision of all "necessary" resources listed below, refinement of interactions with owners, a tolerable intensity of conflict, and thoughtful institution of change(s).5,17,18 The following areas all are considered based on their influence on the health and welfare of indoor-housed cats.

1. Food

Cats prefer to eat individually in quiet locations 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 some cats 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 permits the cat to express its preferences. 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. Specific ingredients or nutrients have been found to be of minor significance to patient outcome when an enriched environment is provided.13-15

2. 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.

3. 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.19

4. 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 may be useful, and videotapes to provide visual stimulation are available.

5. 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 when 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.

6. Conflict Management

When cats' perception of safety becomes threatened, they appear to respond by attempting to restore their "perception of control."20 During such responses, some cats become aggressive, some become withdrawn, and some become ill.13 In our experience, intercat conflict commonly is present when multiple cats are housed indoors together and sickness behaviors are present in some of them.13 Signs of conflict between cats can be open or silent. Cats in open conflict may stalk each other, hiss, and turn sideways with legs straight and hair standing on end up to make themselves look larger. In contrast, signs of silent conflict can be easily missed; threatened cats may avoid other cats, decrease their activity, or both. They often spend increasingly large amounts of time away from the family, stay in areas other cats do not use, or attempt to interact with family members only when the assertive cat is elsewhere. Signs can result from two types of conflict: offensive and defensive. In offensive conflict, the assertive cat moves closer to the other cats to control the interaction. In defensive conflict situations, the threatened cat attempts to increase the distance between itself and the perceived threat. Although cats engaged in either type of conflict may spray or eliminate outside the litter box, we find that threatened cats are more likely to develop elimination problems.

A common cause of conflict between indoor-housed cats is competition for resources: space, food, water, litter boxes, perches, sunny areas, safe places where the cat can watch its environment, or attention from people. There may be no limitation to access to these resources apparent to the owner for conflict to develop; the cat's perceptions of how much control it wants over the environment or its housemates' behaviors determine the outcome of the situation.

Open conflict is most likely to occur when a new cat is introduced into the house and when cats that have known each other since kittenhood reach social maturity. Conflict occurring when a new cat is introduced is easy to understand, and good directions are available from many sources for introducing the new cat to the current residents.21 Clients may be puzzled by conflict that starts when one of their cats becomes socially mature, or when a socially mature cat perceives that one of its housemates is becoming socially mature. When cats become socially mature, they may start to exert some control of the social groups and their activities. This may lead to open conflict between males, between females, or between males and females. And although the cats involved in the conflict may never be "best friends," they usually can live together without showing signs of conflict or conflict-related illness. In severe cases, a behaviorist can be consulted for assistance in desensitizing and counter-conditioning cats in conflict so they can share the same spaces more comfortably if this is desired.

Treatment for conflict between cats involves providing a separate set of the listed resources for each cat, in locations where cats can use them without being seen by other cats, if possible. This lets the cats avoid each other if they choose to without being deprived of any essential resource. Cats may 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 three-dimensional 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 when combined with environmental enrichment, but it cannot replace it. Conflict also can be reduced by neutering all of the cats and by keeping all nails trimmed as short as practicable. 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 space should contain all necessary resources for the cat staying in 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, including dogs. Regardless of how sure the client is that their dog will not hurt the cat, to the cat the dog may represent a predator. To ensure the cat's safety, it must be provided avenues of escape that can be used 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 in which the affected cat lives. To cats, windows offer no protection from a threatening cat outside. If outside cats are the source of the problem, a variety of strategies to make one's garden less desirable to them are available.

7. Pheromones

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, and their effectiveness is not universally demonstrated,22 pheromones appear to effect changes in the function of both the limbic system and the hypothalamus to alter the animal's emotional state. Feliway®, which contains a synthetic analogue of naturally occurring feline facial pheromone and valerian, was developed to decrease anxiety-related behaviors of cats. Use of this product 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 have been reported subsequent to its use. Feliway is not a panacea for unwanted cat behaviors; its effectiveness may be improved by using it in combination with environmental enrichment and/or drug therapies.

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.

Followup

One of the critical keys to any successful therapy program is to follow the progress of the patient, which we generally delegate to a trained technician introduced to the client during the clinic appointment. We tell clients what our followup schedule is and ask them to agree to a preferred method and time to be contacted. Our first contact with the client occurs within a week after initial recommendations are made usually over the telephone, followed by repeat in-house "check-ins" at 3–6 weeks, 3 months, 6 months, and 1 year in uncomplicated cases (which need less followup). This allows one to monitor the patient's progress, to make adjustments as needed, and to continue to coach the client. It also helps to determine when the owner is becoming frustrated or is having problems with the plan so that encouragement or suggestions to help them can be offered.

Conclusions

Many indoor housed cats appear to survive perfectly well by accommodating to less-than-perfect surroundings. The neuro-endocrine-immune systems of some cats, however, do not seem to permit the adaptive capacity that healthy cats enjoy, 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. My current approach is to let the client choose the most appropriate intervention for their particular situation and to let trained technicians do the enrichment implementation and followup (under veterinary supervision as appropriate).

Finally, the question of the relative merits of indoor housing to promote the welfare of cats (and the different opinions on what constitutes animal welfare in general) is beyond the present scope and is a subject of controversy among experts. I hope to encourage extension of the welfare efforts of individuals working in zoos, who have recognized the effects of the quality of housing on the health of animals in their care and work to enrich the environments of these animals, to all "captive" animals in our care. I believe that chronic idiopathic cystitis and a variety of related chronic health problems in cats may be better prevented than treated, and that we have a great opportunity to encourage this husbandry approach in veterinary clinical practice. Further information about environmental enrichment for indoor housed cats is available at: http://indoorpet.osu.edu/.

References

1.  Kirk H. Retention of urine and urine deposits. In: Kirk H, ed. The Diseases of the Cat and Its General Management. London: Bailliere, Tindall and Cox; 1925:261–267.

2.  Osbaldiston GW, Taussig RA. Clinical report on 46 cases of feline urological syndrome. Vet Med Sm Anim Clin. 1970;65:461–468.

3.  Osborne CA, Johnston GR, Polzin DJ, et al. Redefinition of the feline urologic syndrome: feline lower urinary tract disease with heterogeneous causes. Vet Clin N Am Small Anim Pract. 1984;14:409–438.

4.  Osborne CA, Kruger JM, Lulich JP, et al. Feline lower urinary tract diseases. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 4th ed. Philadelphia, PA: WB Saunders; 1995:1805–1832.

5.  Westropp J, Buffington CAT. Lower urinary tract disorders in cats. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7th ed. St. Louis, MO: Elsevier-Saunders; 2010:2069–2086.

6.  Kruger JM, Osborne CA, Goyal SM, et al. Clinical evaluation of cats with lower urinary tract disease. J Am Vet Med Assoc. 1991;199:211–216.

7.  Barsanti JA, Brown J, Marks A, et al. Relationship of lower urinary tract signs to seropositivity for feline immunodeficiency virus in cats. J Vet Intern Med. 1996;10:34–38.

8.  Buffington CA, Chew DJ, Kendall MS, et al. Clinical evaluation of cats with nonobstructive urinary tract diseases. J Am Vet Med Assoc. 1997;210:46–50.

9.  Buffington CAT, Chew DJ, Woodworth BE. Feline interstitial cystitis. J Am Vet Med Assoc. 1999;215:682–687.

10. Patronek GJ, Glickman LT, Beck AM, et al. Risk factors for relinquishment of cats to an animal shelter. J Am Vet Med Assoc. 1996;209:582–588.

11. Buffington CA. Idiopathic cystitis in domestic cats - beyond the lower urinary tract. J Vet Intern Med. 2011;25:784–796.

12. Buffington CAT. Developmental influences on medically unexplained symptoms. Psychother Psychosom. 2009;78:139–144.

13. Stella JL, Lord LK, Buffington CAT. Sickness behaviors in response to unusual external events in healthy cats and cats with feline interstitial cystitis. J Am Vet Med Assoc. 2011;238:67–73.

14. 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.

15. Buffington CAT, 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.

16. Buffington CAT. Idiopathic cystitis in domestic cats - beyond the lower urinary tract. J Vet Intern Med. 2011;25(4):784–796. doi: 10.1111/j.1939-1676.2011.0732.x.

17. Herron ME, Buffington CAT. Environmental enrichment for indoor cats. Compend Contin Educ Pract Vet. 2010;32:E1–E5.

18. Herron ME, Buffington CA. Environmental enrichment for indoor cats: implementing enrichment. Compend Contin Educ Pract Vet. 2012;34:E1–E5.

19. Herron ME. Advances in understanding and treatment of feline inappropriate elimination. Top Comp Anim Med. 2010;25:195–202.

20. Moesta A, Crowell-Davis S. Intercat aggression - general considerations, prevention and treatment. Tierarztliche Praxis Kleintiere. 2011;39:97–104.

21. Overall KL, Rodan I, Beaver BV, et al. Feline behavior guidelines from the American Association of Feline Practitioners. J Am Vet Med Assoc. 2005;227:70–84.

22. Gunn-Moore DA, Cameron ME. A pilot study using synthetic feline facial pheromone for the management of feline idiopathic cystitis. J Feline Med Surg. 2004;6:133–138.

  

Speaker Information
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C.A. Tony Buffington, DVM, PhD, DACVN
The Ohio State University Veterinary Hospital
Columbus, OH, USA


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