Introduction

Results of studies over the past 20 years indicate that idiopathic/interstitial cystitis in cats is the result of complex interactions between the bladder, nervous system, adrenal glands, husbandry practices and the environment in which the cat lives. A recent review emphasises that many cats with a diagnosis of feline idiopathic (interstitial) cystitis (FIC) have lower urinary tract (LUT)-predominant clinical signs that are part of a larger systemic disorder referred to as 'Pandora syndrome'. Clinical problems outside the lower urinary tract are common in those with a diagnosis of FIC and include signs related to the gastrointestinal tract, respiratory system, skin, central nervous system, cardiovascular system and the immune system. It has been traditional to refer to cats that have obvious LUT signs as those having 'feline urological syndrome', 'feline lower urinary tract disease' or 'feline interstitial cystitis', but this method of naming the disease focuses on the organ with the predominant clinical sign rather than a thorough evaluation of the entire cat and all of its organ systems. A diagnosis of Pandora syndrome would apply to those cats that exhibit clinical signs in other organ systems (in addition to the LUT), waxing and waning of clinical signs associated with stressful events that presumably activate the stress response system, and undergo resolution of severity of clinical signs following effective environmental enrichment.

There are four possible urinary presentations associated with FIC. An acute seemingly self-limiting episode of FIC is thought to be the most common condition with an estimated relative prevalence of 80–95%; recurrence is likely if stressful situations become severe enough in the future. Frequently recurrent episodes of clinical signs related to FIC is next in occurrence (2–15%), followed by persistent forms of FIC (2–15%) in which the clinical signs never abate. The fourth possibility is for urethral obstruction to develop in male cats suffering from FIC (15–25%). These four types of presentations may represent a spectrum of signs from the same disease process, but this hypothesis has not been tested. Most publications reflect data from cats with frequent recurrences or persistent clinical signs that are presented to referral practices. Clinical signs associated with an initial or recurrent episode of non-obstructive idiopathic cystitis often resolve within about 7 days, with or without treatment. Over 50% of cats with idiopathic cystitis will have recurrent signs within 1 year based on recent studies.

Diagnosis

The diagnosis of FIC requires the exclusion of known causes of LUT signs, especially the presence of urolithiasis, bacterial urinary tract infection (UTI), neoplasia and anatomical abnormalities. There is not presently a clinically available definitive biomarker that identifies cats with FIC. A recent report demonstrated the potential utility of infrared microspectroscopy of dried serum films to diagnose interstitial cystitis in both humans and cats. Cats with FIC, other disorders, and healthy cats were able to be distinguished with this test. Findings from urinalysis are useful, but are neither sensitive nor specific for any particular LUT disorder. The classical positive finding is a preponderance of red blood cells with few neutrophils in the urine sediment. Crystals often are not present when fresh urine is evaluated. If crystals are observed, they usually are present in low numbers. Refrigeration can cause the formation of crystals ex vivo that were not present in vivo. The presence of crystals has no known diagnostic or pathophysiological impact on non-obstructive forms of idiopathic cystitis.

Results from infrared microspectroscopy of dried serum films distinguishes cats with FIC, other disorders, and healthy cats on the basis of tryptophan and its metabolites. Decreased urinary glycosaminoglycan excretion has been demonstrated during active and quiescent phases of FIC compared to normal controls. A deficiency of urinary trefoil factor 2 in FIC has been demonstrated in affected cats compared to controls whereas increased urinary fibronectin has been demonstrated in affected cats compared to controls, cats with UTI, and cats with urolithiasis. A primary role for these compounds in the pathophysiology of FIC or their measurement as a clinical biomarker has yet to be demonstrated.

Pathophysiology

The pathophysiology of chronic idiopathic cystitis appears to involve complex interactions between multiple body systems. Abnormalities have been found in the bladder, nervous system, hypothalamic-pituitary-adrenal (HPA) axis and other body systems in cats with idiopathic cystitis. Histological changes, urothelial abnormalities, and decreased excretion of both total urinary glycosaminoglycan (GAG) and a specific GAG, GP-51, have been identified in the bladders of cats with idiopathic cystitis. Increased bladder permeability is a consistent feature of interstitial cystitis that may in part be attributed to abnormalities in GAG and health of underlying uroepithelium. Histological changes are generally nonspecific, and may include an intact or damaged urothelium with submucosal oedema, dilation of submucosal blood vessels with marginated neutrophils, submucosal haemorrhage and sometimes increased mast cell infiltration. There is a paucity of neutrophilic infiltration, but there may be a minor increase in lymphoplasmacytic cells in the submucosa. Electron microscopy of bladder tissue in FIC reveals missing uroepithelial cells that could account for some of the increased bladder permeability encountered in FIC.

In the brain, a significant increase in tyrosine hydroxylase (TH) immunoreactivity (IR) has been reported in cats with idiopathic cystitis. Chronic activation of the stress response system can increase TH activity in the locus coeruleus (LC), with accompanying increases in sympathetic autonomic outflow. Increased noradrenergic outflow may alter urothelial permeability, increase sensory (C-fibre) activity and activate local neurogenic inflammatory mechanisms. Increased epithelial permeability could permit constituents of urine to gain greater access to sensory afferent neurons in the bladder wall, which could result in increased sensory afferent firing and local inflammation. Neurogenic inflammation affecting the urinary bladder can explain many of the findings in interstitial cystitis. Damage or malfunction of either or both of the uroepithelium and overlying GAG layer may permit constituents of the urine, such as protons, potassium ions, or hyperosmolar (> 2,000 mOsm/l) fluid to activate the sensory fibres. The effects of stress on sensory fibres may be related to descending efferent sympathetic signals inducing peripheral release of neuropeptides.

External environmental events that activate the stress response system (SRS) are termed stressors, including sudden movements, unknown or loud noises, novel and unfamiliar places and objects, and the approach of strangers. Inadequate perception of control and predictability also can activate the SRS in animals because of interference with attempts to cope with their environments. Depending on the frequency, intensity and duration, chronic activation of the SRS can overtax homeostatic regulatory systems, resulting in diminished welfare, abnormal conduct and sickness behaviours. Sickness behaviours refer to variable combinations of vomiting, diarrhoea, anorexia or decreased food and water intake, fever, lethargy, somnolence, enhanced pain-like behaviours, as well as decreased general activity, body care activities (grooming) and social interactions. Evidence also supports the observation that both external (environmental) as well as internal (visceral) events can activate the SRS, leading to activation of variable combinations of neural, hormonal and immune responses. Sickness behaviours were observed in a laboratory study both in healthy cats and in cats with FIC in response to unusual external events for 77 weeks after environmental enrichment. Unusual external events were associated with significantly increased risks for decreases in food intake and elimination, and increases in defecation and urination outside the litter box and expulsion of contents of the upper gastrointestinal tract in both groups. These results suggest that some of the most commonly observed abnormalities in client-owned cats probably occur after unusual external events.

Abnormalities in the HPA axis have also been observed in cats with idiopathic cystitis. An 'uncoupling' of SRS output, with a relative predominance of sympathetic nervous system to HPA activity, appears to be present in patients with FIC and IC. Increased concentrations of corticotropin-releasing factor (CRF) from the hypothalamus and adrenocorticotropic hormone (ACTH) from the anterior pituitary gland have been identified at times of decreased serum cortisol response to ACTH stimulation during periods of stress in cats with idiopathic cystitis, documenting the presence of reduced adrenocortical reserve in this population. Additionally, the adrenocortical response to ACTH stimulation during stressful circumstances is reduced (less increase in circulating cortisol), and cats with FIC often have small adrenal glands. Histopathological examination of these glands identified reduced size of the fasciculata and reticularis zones of the adrenal cortex without other lesions. These data suggest the presence of mild primary adrenocortical insufficiency or decreased adrenocortical reserve in cats with FIC - a genetic or familial susceptibility, a developmental accident or some combination could account for this.

Decreased adrenocorticosteroid activity may adversely affect epithelial permeability, as cortisol is known to enhance tight junction integrity to reduce permeability in other tissues. Urothelial cells can express both alpha- and beta-adrenergic receptors. Adrenergic agonist stimulation of these receptors can lead to altered bladder function. Activation of the SRS can increase epithelial permeability by neural mechanisms, permitting environmental agents greater access to sensory neurons in the bladder wall, which could result in increased afferent firing and local inflammation. The effects of the emotional state of the animal may modulate perceived sensations from peripheral organs, including the bladder, following overactivation of the SRS.

Treatment

The waxing and waning natural history of cats with idiopathic cystitis has made it difficult to determine which treatments, if any, are effective. The goals of treatment are to decrease the severity and duration of signs during an acute episode (intra-episode), to increase the interval between episodes in those with recurrent idiopathic cystitis (inter-episode) and to decrease severity of signs in those with persistent idiopathic cystitis. Based on the pathophysiology described above, it is crucial to reduce the output of the sympathetic nervous system, since enhanced noradrenergic outflow appears to potentiate clinical signs by a variety of mechanisms. Based on the premise that cats with idiopathic cystitis are 'sensitive cats in a provocative environment', one important objective of therapy is to identify and hopefully modify provocateurs (e.g., diet, water, indoor living with humans, suboptimal husbandry, stress and inactivity). Since chronic pain perception can amplify noradrenergic outflow, it is important to consider treatments that provide analgesia. Breaking the pain-inflammation cycle can be an important step in the management of some cats with chronic idiopathic cystitis. Providing analgesia systemically appears to be more important than analgesia within the bladder locally. Resolution of clinical signs occurs in an estimated 85% of cats within 1 week, often without treatment, though the recurrence rate for clinical signs is high within the next 6–12 months with (or without) conventional treatment. Clinical signs for longer than 7 days are beyond the point of spontaneous resolution for most cats so specific recommendations are justified at that time.

What is Multimodal Environmental Modification?

The overarching premise of multimodal environmental modification (MEMO) is that some cats suffer adverse consequences of indoor housing, especially when cats are forced to spend nearly all of their time indoors in association with people and other animals. Ethological and behavioural studies demonstrate that captivity may elicit a stress response in some cats. The indoor environment of some house cats may be monotonous and predictable, which could be stressful. If we are to continue to recommend indoor housing to reduce the risks of exposure to accidents and infectious agents, recommendations to improve the indoor environment from the cat's point of view should be considered. Many indoor-housed cats appear to survive adequately by accommodating to less than perfect surroundings. The neuroendocrine abnormalities in cats with recurrent idiopathic cystitis suggest a sensitised response to stress indicating that these cats may have greater needs for enriched surroundings than do healthy cats. Extensive indoor housing in unenriched environments does not create idiopathic cystitis, but it can contribute to its development and maintenance by unmasking the tendency of a particular cat to develop idiopathic cystitis in response to external risk factors. Successful MEMO may obviate the need for drug therapy in many instances. Based on uncontrolled prospective studies at our hospital, we estimate that 80% of cats with recurrent idiopathic cystitis will have clinically significant reductions in signs during the year following successful implementation of the first level of MEMO. Stressors in an individual cat can emanate from another cat, people, other aspects of environment or combinations of these. MEMO is a package of recommendations designed to reduce environmental or social stressors. A tailored treatment plan for each cat is created, since individual cats and environments vary widely. These include general recommendations for all cats with FIC and then specific recommendations for some cats. It is essential to implement a system of follow-up consultation and encouragement that is often best executed by animal technicians with special interest and training in this area (under the supervision of a veterinarian).

A cat that has been properly diagnosed with FIC will have the propensity to develop recurrent LUT signs for all of its life depending on the magnitude of exposure to external stressors in the face of an altered SRS. We prefer to prevent future episodes of FIC with MEMO than to treat active flares. Treatment of the first episode or a flare during a recurrent episode includes provision of an analgesic and a tranquilliser/urethral antispasomodic for 5–7 days as our standard of care, though it is not known if this impacts the development of future episodes of FIC. We prescribe oral buprenorphine (injectable form aspirated into a syringe and given orally) at 10–20 µq/kg q6–12h depending on the severity of the clinical signs; we also provide oral acepromazine at 2.5 mg q8–12h. MEMO should be attempted before other drug therapy is prescribed since MEMO often is effective without the use of any drugs.

Change to a canned food diet is usually recommended as part of MEMO if this is not too stressful for the cat or the owners. Salutary effects of feeding canned foods may be due to elaboration of more dilute urine due to increased moisture - this could prove less noxious when gaining access to the highly permeable bladder wall of the FIC cat. Alternatively, hedonics or the mouth feel of moist food may change the neurobiology of the cat. A third mechanism that could explain this benefit is the ritual of feeding canned foods is substantially different than that of feeding dry foods and could favourably alter the owner's interaction with the cat.

Litter box hygiene and management may be suboptimal for some sensitive cats, a situation that provides a source of stress for some cats with FIC. We believe this to be the most frequently neglected concern for cats in general and specifically for those with FIC or other litter box issues. Optimal litter box management is often not discussed adequately with cat owners before problems with FIC develop. There are many nuances as to the suitability of the litterbox and substrate to any particular cat, such as adequate number and location, size, depth, shape, hooding and automatic cleaning devices. The goal is to make the litter box a pristine place for the cat to eliminate and not hesitate to do so willingly.

Increased interaction between cats and their owners may increase the quality of life for some cats. This may be accomplished depending on the particular cat during grooming and petting, playing games with laser pointers and simulating hunting of prey activities (feathered or tailed devices). Cats often enjoy playing with toys, particularly those that are small, move and that mimic prey characteristics. Use of containers or toys that intermittently release food during play may provide actions to simulate hunting behaviour. Timing of these activities at dawn or dusk may be helpful since cats are generally more active at these times.

Drug Therapy?

Drug therapy is not attempted until analgesics have been administered and initial environmental modifications have been implemented without adequate resolution of clinical signs (including low-grade persistent signs or frequent recurrence of clinical signs). We always recommend MEMO before further drug therapy is attempted. It is our impression that drug therapy, if necessary to control signs, works better in those in which MEMO has already been implemented. When MEMO has not been effective in reducing LUT signs, we consider the addition of tricyclic drugs such as amitriptyline or clomipramine. When positive effects are seen, we taper the dose of these drugs gradually and stop them whenever possible after at least 3 months of use. Drug therapy sometimes gives the owners an edge to implement more MEMO, which then lessens the need for long-term drug therapy.

Studies to date have not shown a benefit of glucosamine or pentosan polysulfate (PPS) supplementation as a 'GAG replacer' over that of placebo to cats with idiopathic cystitis. Also no benefits for the use of synthetic feline facial pheromones could be shown over that of treatment with placebo. Tricyclic analgesics/antidepressants (TCA) can decrease clinical signs in some cats with recurrent idiopathic cystitis but two recent studies found no benefit of TCA for acute bouts of idiopathic cystitis. We prescribe TCA only when the MEMO treatments described above have not been sufficiently helpful.

References

1.  Buffington CA. Idiopathic cystitis in domestic cats - beyond the lower urinary tract. Journal of Veterinary Internal Medicine 2011;25:784–796.

2.  Buffington CA, Westropp JL, et al. Clinical evaluation of multimodal environmental modification (MEMO) in the management of cats with idiopathic cystitis. Journal of Feline Medicine and Surgery 2006;8:261–268.

3.  Chew DJ, Buffington CA, et al. Amitriptyline treatment for severe recurrent idiopathic cystitis in cats. Journal of the American Veterinary Medical Association 1998;213:1282–1286.

4.  Markwell PJ, Buffington CA, et al. Clinical evaluation of commercially available urinary acidification diets in the management of idiopathic cystitis in cats. Journal of the American Veterinary Medical Association 1999;214:361–365.

5.  Stella JL, Lord LK, et al. Sickness behaviours 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.