Managing idiopathic cystitis in cats for successful outcomes--parts 1 and 2 (Proceedings)

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 emphasizes that many cats with a diagnosis of FIC have lower urinary tract- predominant clinical signs that are part of a larger systemic disorder referred to as “Pandora Syndrome” (Buffington CA. Idiopathic cystitis in domestic cats-beyond the lower urinary tract. J Vet Intern Med 2011;25:784-96.).  Clinical problems outside the lower urinary tract are common in those with a diagnosis of FIC and include signs related to the GI 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 to 95%(Lulich ACVIM Forum Proceedings Anaheim 2010)  – 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 to 15%), followed by persistent forms of FIC (2 to 15%) in which the clinical signs never abate. The fourth possibility is for urethral obstruction to develop in male cats suffering from FIC (15 to 25%).

These 4 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 one year based on recent studies.  It appears that most cats with recurrence have episodic signs of idiopathic cystitis, but some have persistent clinical signs that do not abate.

Differential diagnosis

In cats less than 10 years of age, idiopathic cystitis accounts for clinical signs of irritative voiding in 60 to 70% of cats.  Urolithiasis is encountered in 10 to 20% of cases with most, being associated with either calcium oxalate or struvite.  About 10% may have an associated structural abnormality such as urachal diverticulum or urethral stricture, another 10% have what appears to be a behavior disorder, less than 2 % of cases will be associated with bacterial infection, and less than 1% can be expected to have bladder or urethral neoplasia.

In cats older than 10 years of age at first presentation, only about 5% can be expected to be idiopathic.  More than half of cats in this age category will have bacterial urinary tract infection, either alone or in association with urolithiasis.  Many of these cats with positive quantitative bacterial cultures will have renal disease and sub-maximally concentrated urine.

Diagnosis

Owners report some combination of LUT signs that include hematuria, dysuria, pollakiuria, periuria, and urethral obstruction (male cats) in those with FIC. The diagnosis of FIC requires the exclusion of known causes of LUT signs, especially the presence of urolithiasis, bacterial 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 IC in both humans and cats. Cats with FIC, other disorders, and healthy cats were able to be distinguished with this test. Differences in the concentration of tryptophan and its metabolites were demonstrated between healthy and affected cats (Rubio-Diaz DE, Pozza ME, Dimitrakov J, et al. A candidate serum biomarker for bladder pain syndrome/interstitial cystitis. Analyst 2009;134:1133-7).

Non-obstructive idiopathic cystitis affects males and females equally, although neutered males and females are at increased risk compared to their intact counterparts. An affected cat (non-obstructive) typically is 1 to 10 years of age (peak risk 2-6 years), spends all or nearly all of its time living indoors with humans, is expected to use a litter pan for urination and defection, and eats 75 to 100% dry food. Obesity and a variety of other comorbid conditions may be associated with idiopathic cystitis.

Owners sometimes note that affected cats are unusually nervous, fearful, or aggressive, and are overreactive to their environment compared to healthy cats.  Cats with access to the outdoors still can be affected, especially when the cat population in the outdoor area is dense. Abdominal palpation may reveal pelvic organ pain and/or thickening of the bladder wall in some affected cats.  The bladder is usually small during active bouts of cystitis. The rest of the examination is often normal. Rarely, barbering of hair in the caudal abdomen may represent referred pain. It is our impression that cats with IC have more heart murmurs and gallop rhythms than cats with other disorders.

Urinary tract imaging is recommended for all cats with recurrent LUT signs. Survey radiographs are helpful to identify radiodense calculi such as calcium oxalate or struvite, which usually are observed if ≥ 2-3mm in size.  In those cats with multiple recurrences or persistence of clinical signs, advanced urinary imaging should be pursued to exclude radiolucent calculi and anatomical defects if the survey radiographs were normal.

Abnormalities that can be identified during double-contrast cystography include focal or diffuse thickening of the bladder wall, permeation of contrast agent into the bladder wall or through the bladder and into the abdomen, and filling defects in the contrast pool (blood clots and cellular debris). Ultrasonography (ULS) can be a useful, less invasive alternative to contrast urethro-cystography. The proximal urethra can be examined with ULS, but ULS is not a good method to image the urethra, as most of the urethra cannot be examined.

Cystoscopy (uroendoscopy) provides excellent visualization of the mucosal surfaces of the bladder and urethra in female cats (less reliable for adequate visualization of the bladder mucosa of male cats). The bladder of idiopathic cystitis cats will often display a varying degree of increased vessel density and tortuosity, edema, and sub-mucosal petechial hemorrhages (glomerulations).  Increased number or size of glomerulations and increasing edema can be observed when higher bladder filling pressure (~80 cm water) is used during the scoping, findings that do not happen in cats with normal bladders.

Findings from urinalysis are useful, but are neither sensitive nor specific for any particular LUT disorder. The classical findings of hematuria and proteinuria in cats affected with idiopathic cystitis often wax and wane between days and even within the same day.  Additionally, it is impossible to know with certainty that red cells and protein in the urine did not enter during collection when cystocentesis is performed. The classical positive finding is “hemorrhagic inflammation”, which means that there 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.  Regardless, the presence of crystals has NO known diagnostic or pathophysiologic impact on non-obstructive forms of idiopathic cystitis. Struvite or calcium oxalate crystals do not damage a healthy urothelium. Conventional wisdom previously held that crystals formed and subsequently caused damage to the lower urinary tract, but it is more likely that sterile (neurogenic) inflammation occurs first, plasma proteins exude into urine, urinary pH increases, and then struvite crystals precipitate as a secondary event.

It is physiologically normal to observe a few crystals in urinary sediment, especially when the urine is highly concentrated.  The urine specific gravity (USG) in healthy cats should be greater than 1.025 in those eating mostly canned foods, and greater than 1.035 in those eating exclusively dry foods.  In cats with LUTS and USG less than 1.025, some systemic disease (renal disease, renal failure, hyperthyroidism, diabetes mellitus) may be present that is interfering with the formation of more concentrated urine. Though not specifically studied, our impression is that cats with extremely high USG (1.060-1.080) are at higher risk for perpetuation of idiopathic cystitis once initiated if not transitioned to a therapy that produces a lower USG.

Pathophysiology

The pathophysiology of chronic idiopathic cystitis appears to involve complex interactions between multiple body systems.  Factors that initiate FIC may be different from those that maintain this condition. It may be useful to divide risk factors for the development of FIC into external abnormalities (in the urine), intrinsic abnormalities (bladder tissue itself) and internal abnormalities (nervous and endocrine systems). 

The presence of toxic substances in the urine (irritants, anti-proliferative factor), absence of protective factors in the urine (Tamm Horsfall mucoprotein), or the effects of microorganisms are examples of external abnormalities. A single toxic substance in the urine has never been found that can account for the development or maintenance of FIC. The “toxic” substance could be urine itself, which could be highly irritating should it gain access to the bladder wall (as is thought to happen when bladder permeability is increased).

Microbes could cause FIC or be associated with FIC in a noncausal way. A role for viral infection in development of FIC remains unclear. Recent studies in humans failed to show persistence of viral or bacterial DNA in bladder tissue excluding a chronic infecting etiology (Al-Hadithi J Urol 174:2005). Intrinsic abnormalities associated with FIC may make the LUT more vulnerable to bacterial colonization. Recent studies of Norwegian cats have suggested a much higher frequency of bacterial UTI in cats with LUT signs than previously reported (EggertsdottirJFMS 9:2007).

Abnormalities have been found in the bladder, nervous system, hypothalamic-pituitary-adrenal axis, and other body systems in cats with idiopathic cystitis.  Histological changes, urothelial abnormalities, and decreased excretion of both total urinary 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 generally are nonspecific, and may include an intact or damaged urothelium with submucosal edema, dilation of submucosal blood vessels with marginated neutrophils, submucosal hemorrhage, 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.  Tyrosine hydroxylase is the rate-limiting enzyme of catecholamine synthesis. Chronic activation of the stress response system can increase TH activity in the LC, with accompanying increases in sympathetic autonomic outflow. The increased THIR observed in the LC of cats with idiopathic cystitis may provide a clue to the observation that clinical signs follow a waxing and waning course in animals with this disease, and can be aggravated by environmental stressors.

Increased plasma norepinephrine (NE) and CSF catecholamine concentrations and their metabolites have been documented in cats with idiopathic cystitis when measured during stressful situations. Increased noradrenergic outflow may alter urothelial permeability, increasing sensory (C-fiber) 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. Unmyelinated sensory neurons (C-fibers) seem to play a central role in transmission of nociceptive action potentials via the dorsal root ganglia (DRG) to the spinal cord (SC) and brain.  These signals may be perceived as painful by the brain.  Sensory fibers also can propagate a local axon reflex without transmission of an axon potential. The axon reflex results in release of peptide neurotransmitters such as substance P (SP) by the nerve endings.

Interaction of SP with receptors on vessel walls results in vascular leakage, which can be augmented by SP-induced release of histamine by mast cells. These actions may give rise to the submucosal petechial hemorrhages (glomerulations) observed at cystoscopy. Receptors for SP also occur on smooth muscle, which when activated stimulate muscle contraction. Damage or malfunction of either or both of the uroepithelium and overlying glycosaminoglycan (GAG) layer may permit constituents of the urine, such as protons, potassium ions, or hyperosmolar (>2,000 mOsm/L) fluid to activate the sensory fibers. 

The effects of stress on sensory fibers may be related to descending efferent sympathetic (SNS) signals stimulating the DRG and inducing peripheral release of neuropeptides.  Local release of neurotransmitters by bladder sympathetic fibers also could stimulate sensory fibers.  Another factor probably involved in chronic, neurogenic inflammation of the bladder is local and systemic release of nerve growth factors, which may promote sensory fiber terminal sprouting to increase the size of sensory fiber receptive fields.

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 behaviors.

Sickness behaviors refer to variable combinations of vomiting, diarrhea, anorexia or decreased food and water intake, fever, lethargy, somnolence, enhanced pain-like behaviors, 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 behaviors 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 likely occur after unusual external events.

Abnormalities in the hypothalamic-pituitary–adrenal axis (HPA) also have been observed in cats with idiopathic cystitis.  An ‘‘uncoupling''of SRS output, with a relative predominance of sympathetic nervous system to hypothalamic-pituitary-adrenalactivity, appears to be present in patients with FIC and IC.  Increased concentrations of corticotropin releasing factor (CRF) from the hypothalamus and 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.

CRF stimulates both the release of ACTH from the anterior pituitary and activation of the sympathetic nervous system in the brainstem. During chronic stress in cats with idiopathic cystitis, there appears to be a disproportionate activation of noradrenergic outflow in the absence of a parallel increase in outpouring of adrenocortical steroids (ACS).  This phenomenon may be important since cortisol and other ACS normally restrain sympathetic nervous system outflow, and also inhibit their own release by feedback inhibition at the level of the anterior pituitary and hypothalamus to terminate the stress response.

Additionally, the adrenocortical response to adrenocorticotropic hormone (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 excluded the presence of hemorrhage, inflammation, infection, fibrosis or necrosis, and morphometric evaluation identified reduced size of the fasciculata and reticularis zones of the adrenal cortex. These data suggest the presence of mild primary adrenocortical insufficiency or decreased adrenocortical reserve in cats with FIC.

Potential mechanisms underlying the stress-related reductions in circulating adrenocortical steroid concentrations include endocrine, neural, and developmental influences on the adrenal gland. Increased corticotrophin-releasing factor and ACTH in the presence of reduced adrenocortical response and small adrenal gland size without other apparent abnormalities suggest a genetic or familial susceptibility, a developmental accident, or some combination. Hormonal products during the SRS may cross the placenta and affect the course of fetal development. The timing and magnitude of exposure to maternal hormones can influence the maturation of various body systems during gestation and early postnatal development. 

Adrenal development might be reduced if exposure occurs during the critical period when the adrenocortical maturation program is operational. Postnatal stressors also can result in persistently increased central CRF activity in animals. It appears that events experienced during development may permanently affect visceral sensory systems, representing an additional potential cause of chronic idiopathic disorders. It should be noted that cats with idiopathic cystitis do not appear to experience long-term benefit from current glucocorticoid therapy regimens.

Decreased adrenocorticosteroid activity (ACS) 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 over-activation of the SRS.

The pathways that transduce activation of the SRS into cellular dysfunction likely involve induction of the transcription factor nuclear factor-kB in tissues. Norepinephrine can induce this response in circulating mononuclear cells and is abolished by both a(1)- and b-adrenergic inhibitors. It appears that norepinephrine-mediated activation of nuclear factor-kB represents a downstream effector of the response to stressful psychosocial events. Cytokines and a variety of other inflammatory and metabolic signals also can activate nuclear factor-kB by binding to different cell surface receptors. Adrenocortical steroids tend to inhibit activation of nuclear factor-kB. This and other adrenocortical steroid-related protective mechanisms might be less efficient in hypoadrenocortical states such as FIC.

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, sub-optimal 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 one week, often without treatment, though the recurrence rate for clinical signs is high within the next 6 to 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 (memo)?

The overarching premise of 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 behavioral 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 sensitized 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.

Environmental enrichment refers to housing conditions that facilitate enhanced sensory, cognitive and motor stimulation. We define MEMO as the implementation of changes in the cat's environment to attempt to reduce the likelihood of activating the SRS.  It is not currently possible to identify the importance of any single factor implemented, so MEMO attempts to exploit as many enrichment opportunities into the environment as possible (and appropriate) in a step-wise manner.  Plans for MEMO are developed after analysis of results of a detailed environmental questionnaire (available at The Indoor Cat Initiative The Ohio State University). Identification of stressors in general and those that act as specific triggers for a flare of clinical signs of recurrent FIC help identify specific MEMO opportunities.

A tailored treatment plan for each cat is created, since individual cats and environments vary widely. Some cats are extremely sensitive to what many owners and primary care veterinarians would consider trivial stressors, while other cats are able to adapt to severe stress without manifesting clinical signs. Decreased activity levels and increased hiding behaviors have been observed in cats living in impoverished (barren environments lacking in appropriate novelty and complexity) or unpredictable environments – we interpret this as part of the stress response.

Some environments are chaotic, which also imposes an element of stress into a sensitive cat's life. Finding a balance between a barren and chaotic environment is a key MEMO objective. It is important to remember that cats are not pack animals like dogs and people; cats are not asocial (as are reptiles), but they have evolved as relatively independent creatures in hunting and general living arrangements.

MEMO is a package of recommendations designed to reduce environmental or social stressors. These include general recommendations for all cats with FIC and then specific recommendations for some cats. It is important to remind owners that cats respond better to praise and treats than punishment. The objectives of MEMO are to empower the owner to understand how their efforts can contribute to reduction in LUT and other illness signs, provide guidelines the owner can use to manage the cat's environment, and reduce the cat's perception of threat from multiple potential environmental sources.

These are achieved using effective, empathetic communications skills and regular follow-up during the change process.  Providing owners resources and recommendations is essential for the success of any MEMO program. Information for the owner can be provided verbally during the in-clinic consultation, but reading materials are recommended to provide reinforcement of the principals of good animal husbandry.

We routinely recommend that owners read “From the Cat's Point of View” by Gwen Bohnenkamp and to visit the Indoor Cat Initiative website as resources to consult during the change process. Also essential is 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). After the initial in-clinic consultation has established a diagnosis of FIC, we recommend telephone follow-up approximately one week and one month later to determine how MEMO implementation is proceeding, and to suggest alternative or additional implementations. Monthly telephone rechecks are recommended for owners of particularly difficult FIC cases. Owners need to be made aware that a few months may be needed to implement the number of changes that may be necessary for their particular cat.

It is important to not overwhelm the owner or cat with too many changes at one time. Usually one or at most two changes are attempted at the same time. It is our job to help the owner select which changes they feel the most comfortable making initially, and to adjust the plan as changes are found to work or not for this particular owner-cat pair. Appointments with the veterinarian or facilitating technician can be scheduled without the cat to facilitate goal planning and to decrease stress to the cat from an in-clinic visit.

Forty-six cats with recurrent FIC treated by MEMO were studied for 10 months.  These cats went from a median of weekly LUTS to a median of 0 at the end of the study.  No signs were referable to the lower urinary tract in 70 to 75% of these cats for the 10 months of this study (p < 0.001); improvement is some other organ systems was also noted. The MEMO recommendations most commonly followed were to read the prescribed client educational materials, increase the time spent with the cat, change to a canned diet, and add another litter box. The multi-system benefits encountered following implementation of MEMO were consistent with a reduced output of the SRS in these cats.

Mechanisms for the benefits in this study were not determined, but psychosocial stress is known to increase epithelial permeability by decreasing the integrity of tight junctions between the cells; FIC cats have been shown to have increased uroepithelial permeability. Laboratory studies revealed that environmental enrichment was associated not only with reduction in LUT signs, but also with normalization of circulating catecholamine concentrations, bladder permeability, and cardiac function, and reduced responses to acoustic startle.

When and how should memo be instituted?

MEMO should be discussed and the first steps taken after the first episode of FIC. A cat that has been properly diagnosed with FIC will have the propensity to develop recurrent LUTS 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 tranquilizer/urethral antispasomodic for 5 to 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 PO) at 10 to 20 micrograms per kg BID to QID depending on the severity of the clinical signs; we also provide oral acepromazine at 2.5 mg BID to TID. MEMO should be attempted BEFORE other drug therapy is prescribed since MEMO often works in cases, as described above, 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 favorably alter the owner's interaction with the cat.

Adding additional water or broth to food from cans or pouches can provide additional water intake for some cats. Failure to ingest enough water therapeutically would be documented by a consistently very high urinary specific gravity (above 1.030 but often well above 1.050).  MEMO is still often effective in our practice in cats in which diet change was not able to be implemented; diet change as the only environmental enrichment failed to prevent recurrence of clinical signs of FIC in 65% of the cases of a recent study.

Litter box hygiene and management may be sub-optimal 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 in specific 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.

When FIC has been diagnosed, a detailed discussion about litterbox management is absolutely essential.  An enhanced cleaning schedule should be prescribed, usually for scooping twice daily and to change the entire litter once weekly to ensure proper hygiene that will encourage cats to use the box. Some cats have an aversion to the litter that they associate with their painful urinary bladder and others have a preference for a particular litter substrate.

It can be difficult at times to identify the best litter substrate for FIC cats – it requires sequential testing of the new candidate substrate compared to the old substrate in litter boxes next to each other to see if the cat has a preference or not.  We recommend clumping unscented litter – clumping litter is more manageable for scooping and unscented litter is less aversive for some cats. Cats that enjoy a particular litter use it, stay a while, paw in the litter, and usually cover both their feces and urine deposits. We recommend the “rule of 1+1” for the number of litter boxes that should be available out of sight of each other for cats in the household, in that there should be one for each cat plus one more; this rule also applies for other resources such as food and water bowls.

As or more important may be the location of the litterboxes – they should be available at several locations if there is a large living space. Litterboxes should be placed in accessible locations that allow for some privacy and away from noise and dogs. There are many nuances as to the suitability of the litterbox to any particular cat – such as number, 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.

Cats generally prefer more space than the average house or apartment provides. 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 undisturbed.  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.

Stress is likely increased for cats living in close confinement with small square footage for roaming. Available square footage can be increased for small living spaces by providing vertical places to climb and rest (perches to climb, view, and rest). Chaperoned visits to fenced in back yards or enclosed patios can also help with increased opportunity to explore novel spaces that may provide more interest to bored cats. Audio and video sensory stimulation (TV monitors and sound systems with music) may be useful to entertain and engage some cats while the owner is not present.

Increased interaction between cats and their owners may increase the quality of life for those 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 behavior. Timing of these activities at dawn or dusk may be helpful since cats are generally more active at these times.

Unrestricted outside activity is a controversial recommendation that we sometimes make – it may be the only change that will work to improve some cats with their FIC and use of the litterbox. Indoor restriction leads to increased length of life for cats, but not necessarily an increase in the quality of life for all cats, especially in they are living in un-enriched environments. The indoor environment for some house cats can be monotonous and predictable which can inappropriately activate the SRS. 

Medically acquired illnesses are dose related to the amount of time that cats spend indoors, including hypertrophic cardiomyopathy, diabetes mellitus, obesity, hyperthyroidism, urolithiasis, odontoclastic resportive lesions, and FIC.   Access to the outdoors seems to reduce stress in some cats, but stress can be increased for other sensitive cats, especially if the cat is released into an outdoor environment in which the density of cats nearby is high. The increased risk of death from infectious diseases, trauma, and toxins encountered during life outside must be balanced against the quality of life issues for some cats living indoors with medical diseases including FIC.

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 the cat's perception of their overall status in the home, from other animals in the home, or from outside cats. The goal is to reduce conflict to a more manageable level for the cats involved. Treatment for conflict between indoor 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.

If implementation of initial strategies for MEMO at Level 1 does not adequately reduce signs of idiopathic cystitis, it is important to go back and review what was implemented and what was not, and why.  Alternative approaches should be suggested for those that were not initially implemented based on collaboration with the client to address reasons for failure. Additional modifications also may be added at this time. Increased exposure to the outdoors can be helpful in the management of some cats.

Drug therapy?

         I.            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 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 LUTS, we consider addition of tricyclic drugs such as amitriptyline or chlomipramine. 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. The use of fluoexetine has proven useful in some cats with FIC. Specifics about this kind of drug therapy are beyond the scope of these notes. Drug therapy sometimes gives the owners an edge to implement more MEMO, which then lessens the need for long-term drug therapy.

Most studies of FIC have found a high placebo-response rate. It may be possible to take advantage of this high placebo response by prescribing treats in the form of something like pill pockets. A positive interaction between the owner and the cat could occur during these “treatments” that could decrease stress. If there is no improvement after several weeks of providing the placebo treatment, a drug could be added to the treat vehicle.

       II.            Synthetic feline facial pheromones are marketed to reduce urine marking or spraying behaviors in cats (Feliway;  Ceva Sante Animale, Libourne, France). These pheromones reduce the vigilance of the cat so that the cat's need to mark or spray its territory is reduced. Since vigilance of cats is maintained largely by activity of the sympathetic nervous system, it is possible that use of these pheromones contributes to decreased adrenergic outflow from the brainstem in some cats.

If so, they could be useful for treatment of chronic idiopathic cystitis in cats. A statistically significant effect could not be demonstrated in a study comparing facial pheromones and placebo in cats affected with idiopathic cystitis, though there appeared to be a positive trend.  There appears to be a salutary effect of these pheromones in some cats (personal observations) and we continue to prescribe their use in combination with MEMO.

     III.            Tricyclic analgesics/antidepressants (TCA) can decrease clinical signs in some cats with recurrent idiopathic cystitis. Possible mechanisms include stabilization of mast cells (which may infiltrate the bladder wall during idiopathic cystitis), reduced contractions of detrusor muscle from anticholinergic effects, decreased sensory nerve pain fiber sensations from the bladder, effects on sodium, potassium, and glutamate channels, and downregulation of norepinephrine outflow from the brain.

Two recent studies found no benefit of TCA for acute bouts of idiopathic cystitis; abrupt cessation of TCA administration after 7 days increased the severity of clinical signs and frequency of recurrence in one study.  Prescription of amitriptyline was associated with resolution of clinical signs in 60 % of cats with severe recurrent idiopathic cystitis for one year during administration of 10 mg once daily by mouth at the owner's bedtime. 

Despite the decrease in clinical signs, no improvement in the cystoscopic appearance of the bladder mucosa was observed.. We prescribe TCA only when the MEMO treatments described above have not been sufficiently helpful. Cats may have a marked decrease in clinical signs of idiopathic cystitis during such treatment with amitriptyline, the TCA with which we have had the most experience. Despite the improvement in clinical signs, behavior of these cats may change, and weight gain and poor grooming may be noted by clients. We sometimes prescribe TCA while environmental modifications are being implemented. If MEMO is successful in reducing the cat's stress, it may be possible to taper the dose of TCA gradually and in some instances to stop this form of medication. Due to possible effects on liver enzymes or function during administration of TCA, we recommend a serum biochemical panel prior to starting the drug and again at 1,3 and 6 months during treatment. A complete blood count (CBC) is also recommended to ensure no adverse effects of chronic treatment are occurring (thrombocytopenia and neutropenia).  TCA should be used cautiously if at all in cats with serious heart disease. 

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. Whether GAG supplementation has a benefit in combination with other treatments, such as TCA or environmental modification, has not been investigated in cats. Diarrhea at routine doses and coagulopathy at high doses are possible side effects of GAG supplementation, but are rare.

Nonspecific therapeutic responses might occur during treatment of cats with FIC, possibly by altering their perception of their surroundings as part of a placebo-response.  The effectiveness of environmental enrichment suggests that pharmacological or other therapeutic interventions face an important barrier to demonstrate efficacy in the presence of the large therapeutic response to this approach in cats with the syndrome.

Currently available evidence suggests that many cases of chronic idiopathic LUT signs presently diagnosed as having FIC actually may have a ‘‘Pandora'' syndrome. The syndrome might result from early adverse experiences that sensitize the neuraxis to sensory input, increasing the frequency and duration of activation of the SRS when the individual is housed in a provocative environment. The chronic ‘‘wear and tear'' of persistent activation of the SRS can upregulate the inflammatory response in a variety of tissues including the bladder.

Suggested Reading

Buffington CA. Idiopathic cystitis in domestic cats-beyond the lower urinary tract. J Vet Intern Med 2011;25:784-96.

Stella JL, Lord LK, Buffington CA. 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.