Diagnosing and managing idiopathic cystitis in cats (Proceedings)

Feline idiopathic cystitis (FIC) is a sterile, inflammatory process causing signs of lower urinary tract disease (LUTD). It affects 1.5% of cats presented to primary care veterinarians.21 It is the most common diagnosis for young cats with LUTD (the second most common being urolithiasis). FIC is important not only because of the pain and distress it causes patients, but also because it is highly associated with house soiling, the leading cause of relinquishment of cats to shelters.

FIC appears to be a modern disease, having first been mentioned in the early 1990s when it was discovered that no specific diagnosis could be made in over 50% of cats with LUTD.19 Diet and environment play important roles.

Terminology can be confusing with this disease. "Interstitial cystitis" is a term best reserved for that subset of FIC patients with chronic or frequent signs and cystoscopic findings similar to humans with interstitial cystitis. FIC is a more generic, umbrella term for those cats with acute or chronic signs of LUTD where cystoscopy has not been performed or has not revealed changes associated with interstitial cystitis.

Prevalence

Approximately 60-70% of cats under 10 years of age with signs of LUTD have no specific cause, and are referred to as having FIC. In one study of 109 cats with signs of LUTD, 64% were determined to have FIC.5 Urolithiasis affects about 10-20% of cats presenting with LUTD. Several studies have shown that less than 2% of cats with LUTD signs have bacterial urinary tract infection (UTI). Recently, however, a study of 134 Norwegian cats with clinical signs of lower urinary tract disease found 33% had bacteriuria.13 Cats with FIC are generally young to middle-aged when diagnosed; FIC is less likely as a new diagnosis in geriatric cats and other causes of LUTD should be pursued aggressively in this age group.

Patient Signalment and Risk Factors

Most patients are 2-6 years of age at diagnosis; FIC is uncommon in cats under 1 year of age. Certain factors have been associated with increased risk in several studies:

      o Breed: lower in Siamese, higher in Persians

      o Gender: neutered male and spayed female

          • Age at neutering not important

      o Increased body weight, decreased activity

      o Multiple cat households

      o Exclusive dry food diet 6

      o Indoor lifestyle

In one questionnaire-based study of 31 cats with FIC compared to 24 normal housemates and 125 other normal cats8 , certain risk factors were identified: male gender, being overweight, pedigreed breed, and stress factors, especially conflict with another cat in the home.

Clinical Signs

The most common sign associated with FIC is urination in inappropriate places (periuria). Other common clinical signs include:

      o Pollakiuria

      o Dysuria

      o Vocalizing during attempts to urinate

      o Hematuria

      o Bilateral inguinal alopecia, often with self-excoriation

These clinical signs are not specific to FIC, and can also be seen in cats with other causes of LUTD disease, such as cystic calculi, UTI, crystalluria, mass lesions, etc. The clinical signs typically wax and wane, and are usually self-limiting and of short duration (3-7 days). Some cats will have chronic persistent clinical signs or frequent recurrences. It is unknown if this represents an extreme on the spectrum of cats with FIC, or whether it is due to another etiology. Some male cats with FIC will suffer a urethral blockage due to mucus plug that may include serum proteins, crystals, cells and debris.

Pathophysiology

The pathophysiology of FIC is not well understood, although advances have been made in recent years. It is thought that FIC involves complex interaction between the central nervous system and the endocrine system. Cats with FIC are described by the team at Ohio State University as "sensitive cats in a provocative environment." These cats may be unusually sensitive to changes in their environment and diet.

The sympathetic nervous system plays an important role by releasing catecholamines such as norepinephrine (NE) and epinephrine. Stress and pain stimulate increased sympathetic nervous system outflow. Cats with FIC have an increased release of NE and other catecholamine metabolites during stress compared to normal cats.30 This appears to upregulate the inflammatory response. Neurotransmitter substance P and substance P receptors are increased in the bladder of cats with FIC, further fueling the inflammatory response. In addition, cats with FIC have significantly decreased serum cortisol responses compared to normal cats and have smaller adrenal glands.31

Essentially, FIC is an exaggerated sympathetic nervous system response to stress with a blunted endocrine response. Stress appears to be a very important factor in flare-ups of FIC and often precedes a cat's first episode. The involvement of the central nervous system may explain why therapies directed only at the bladder have a high failure rate.

Many similarities between FIC and interstitial cystitis in humans have been found:4,5,25

      o Cystoscopic changes such as submucosal hemorrhage, edema

      o Decreased urinary glycosaminoglycan excretion

      o Increased bladder permeability, allowing constituents of urine to access bladder submucosa and cause inflammation

Diagnosis

FIC is essentially a diagnosis of exclusion. The minimum initial work up should include a complete history including environmental and diet history, a thorough physical examination, and urinalysis. A variety of abnormal findings may be revealed on urinalysis, none of which are specific for any particular bladder disease. Hematuria is commonly found, although it may be present in one sample and not in another from the same cat. Hematuria may also be induced by the sample collection method (manual expression, cystocentesis, and catheterization). Proteinuria and crystalluria may also be found in some cats. Mild crystalluria may be found in normal cats, so over interpretation of this finding must be avoided. Urine specific gravity is often very high with FIC, especially in cats fed exclusively on dry foods. A low urine specific gravity (under 1.035) should prompt investigation for systemic disease. Some normal cats fed only a canned diet may have urine specific gravity as low as 1.030.

Proper interpretation of urinalysis samples takes into account changes induced by collection method and other factors.26 It is important to evaluate urine samples within 60 minutes of collection. Storage for longer periods of time, especially with refrigeration, may cause in vitro formation of struvite or calcium oxalate crystals.1,28 Urine pH and specific gravity are generally not affected by storage. In vitro formation of struvite crystals is especially a risk in stored urine samples from cats fed dry food diets.28

While not a first line diagnostic test, a urine culture should be performed for any cat with recurrent LUTD, or with an identified risk factor. The likelihood of bacterial UTI increases with age, the presence of cystic calculi, with polyuria and with certain concurrent diseases, such as diabetes mellitus, chronic renal disease, and hyperthyroidism. Additionally, in one study, Persians, females, and decreasing body weight were all associated with positive urine cultures2. However, it appears occult lower urinary tract infections may be more common than previously thought. A recent report found 29% of 132 urine samples from cats with no history of lower urinary tract signs, inappropriate urination, or previous urinary tract infection were culture positive.20 The most common bacterial isolates were E. coli and Enterococcus faecalis. Positive cultures were more likely to come from older female cats.

Bladder imaging is useful for recurrent cases of LUTD. About 15-20% of cats with LUTD have cystic calculi.6 Cystography is relatively easy to perform in clinical practice, with few complications.14 Double contrast cystography may be useful as certain findings have been associated with FIC:27

      o Focal or diffuse bladder wall thickening

      o Irregularities of the bladder mucosa

      o Altered ureteral opacity

Ultrasonography may also be used to evaluate cats for cystic calculi, mass lesions, and abnormalities such as blood clots.

Cystoscopy is recommended for cats with recurrent bouts of LUTD when available and when other diagnostics have failed to find a cause. Cystoscopy allows for visualization of the bladder wall and evaluation for abnormalities such as edema and petechial hemorrhages (glomerulations). The bladder wall can be biopsied if necessary. Cystoscopy is also useful for identification of ectopic ureters and bladder masses.

Environmental Modification

Environmental enrichment is proving to be a powerful tool to help decrease sympathetic overdrive, reduce stress, and prolong time between episodes of FIC. Indoor and high density cat populations are a risk factor for FIC.3 Indoor cats need places to climb, scratch, sleep and hide. Many cats do not like to complete for resources (food, water, hiding and sleeping places). Other stressful factors for cats include the presence of other cats in the household, as well as changes in environment, weather, activity in the household, the owner's work schedule, additions or removals of animals or people from the household and changes in diet. Litter boxes should be in a quiet and easily accessible area, and should be scooped daily and cleaned weekly. Clumping, unscented litters and those containing activated carbon are preferred by most cats.24 Citrus-scented litters should be avoided. Ideally, owners should provide a minimum of one more litter box than the number of cats in the household. Cats also seem to prefer large or jumbo sized boxes.

In a recent study of 46 client-owned cats, multimodal environmental modification (MEMO) was instituted and the cats were followed for 10 months.7 The components of MEMO are available for owners and veterinarians on the website of the Indoor Cat Initiative (http://vet.osu.edu/indoorcat.htm. Significant decreases were documented in signs of LUTD, fearfulness, nervousness and aggressive behavior. As well, owners reported decreases in clinical signs referable to the respiratory and gastrointestinal tracts.

Feliway® (Ceva) is a synthetic analogue of feline facial pheromone, available as both a spray and a room diffuser. This pheromone is released when cats feel comfortable in their environment and is used for facial marking. Pheromones induce changes in the limbic system and hypothalamus that alter emotional states in cats.16 In one study, 9 cats completed a randomized, double-blind, placebo-controlled crossover pilot study of the effect of Feliway® on cats with FIC.17 While there were no statistical differences between the treatment groups, there was a trend for cats exposed to Feliway® to show fewer days with clinical signs.

Dietary Therapy

Diet appears to be important in the management of FIC. In one study, 54 client-owned cats with FIC were monitored for 1 year.22 The cats were fed either dry or canned Waltham Veterinary Diet Feline pH Control (now called Urinary SO). Signs of FIC did not recur in 16/18 cats on the canned diet and 17/28 cats fed the dry diet. The increased water content of canned foods may dilute noxious components in urine that irritate the bladder mucosa, thereby decreasing pain and inflammation. The treatment goal should be to decrease the cat's urine specific gravity below 1.030.10 Acidifying diets are of no value in treating FIC unless struvite crystalluria is involved. Dietary change is a stress in itself. Owners should be instructed to offer old and new foods side by side in similar dishes, allowing the cat to become accustomed to the new diet before withdrawing the old diet.

If the FIC patient will not change to a canned diet, increased water intake can be accomplished by various other means:

      o Mix water with dry diets 1:1

      o Flavor water with frozen cubes of meat or fish broth

      o Try distilled or filtered water, especially if the tap water supply is heavy in minerals or chlorine

      o Ensure water is fresh every day, and provide multiple water bowls

      o Ensure the water bowls are kept clean

      o Keep food and water bowls away from the litter box

      o Feed multiple smaller meals instead of one or two larger meals

A common recommendation to increase water consumption is to use a pet water fountain. However, one study of 13 cats found no difference in water consumption when water was offered in a fountain versus a bowl.15

Drug Therapy

Many drug therapies have been recommended for FIC, but few controlled studies have been performed. Antibiotics are not routinely needed in the treatment of cats with LUTD, given the low rate of bacterial UTI in young to middle-aged healthy cats. Signs of LUTD often appear to respond to antibiotic therapy, but most cats have self-limiting clinical signs of short duration.

FIC is a painful disease so analgesics should be prescribed for acute episodes. It is important to break the cycle of pain-inflammation-pain. A common choice is the injectable form of buprenorphine given orally (5-20 mcg/kg, PO, BID-QID) for three to five days.10 Other analgesics that have been recommended include fentanyl patch, butorphanol (1 mg/cat, PO, BID-TID), oxymorphone, and non-steroidal anti-inflammatories (NSAIDS).

NSAIDS must be used with caution in cats due to their potential adverse effects on the gastrointestinal tract and kidney. Ketoprofen is approved for use in the cat in Canada under the brand name Anafen® (Merial). It is considered one of the safest NSAIDS due to its rapid plasma elimination. The label dose is 2 mg/kg (IV, IM, SC) for the first dose, followed by 1 mg/kg, PO, for up to 5 days. A suggested chronic oral dose is 0.25 mg/kg/day. Tolfenamic acid is also approved for use in cats in Canada under the brand name Tolfedine® (Vetoquinol). It has a good safety profile, with uncommon reports of adverse effects. The label dose is 4 mg/kg/day for 3-5 days. Meloxicam® (Metacam, Boehringer Ingelheim) is commonly used in cats for chronic musculoskeletal pain at a dose of 0.1 mg/cat/day given 2-3 times weekly.

Male cats with FIC may benefit from antispasmodics to relax the urethra. Many of these drugs also have sedative properties which may be beneficial. Phenoxybenzamine (Dibenzyline®, Wellspring) is a non-selective alpha adrenoceptor antagonist dosed at 2.5-10 mg/cat, PO, once daily. Prazosin (Minipress®, Pfizer) is an alpha-1 adrenoceptor antagonist dosed at 0.25-0.50 mg/cat, PO, SID-BID. Dantrolene (Dantrium®, Procter & Gamble) is a direct-acting skeletal muscle relaxant dosed at 0.5-2.0 mg/kg, PO, TID.

Amitriptyline has anticholinergic, anti-inflammatory and analgesic properties and has been recommended for severe FIC cases where environmental enrichment and diet change have not provided relief. In one study, 15 cats with severe recurrent FIC were treated with 10 mg/cat, PO, in the evenings.11 Clinical signs were eliminated in 73% of cats for the first 6 months of the study, and in 60% of cats for the full 12 months of the study. However, cystoscopic abnormalities persisted despite clinical remission. Side effects noted included weight gain, lethargy, and decreased grooming. Cystic calculi were noted in 4 cats, and resolved spontaneously in 3 of the cats. Amitriptyline is not useful for acute treatment of FIC as the drug takes weeks to months to exert maximal effect. It appears to be a safe drug, having been prescribed by behaviorists for many years, often at a lower dose (5 mg/cat/day). Transdermal formulations of amitriptyline have poor systemic absorption and cannot be recommended.23

Glycosaminoglycan (GAG) therapy is used successfully in about 10-20% of human cases of interstitial cystitis. The rationale is to help repair the bladder mucosa, as well as provide analgesic and anti-inflammatory effects. One study showed decreased urinary concentrations of GAG in cats with FIC compared to normal cats.4 The significance is unclear, as the decreased GAG excretion could be due to changes in synthesis, metabolism or bladder permeability. There is one case report in the veterinary literature on apparent successful use of sodium pentosan polysulfate in a cat with biopsy-diagnosed interstitial cystitis12, although a two studies of groups of cats showed no difference between cats receiving placebo and cats receiving treatment.9,29

Various GAG formulations are available, such as the human product pentosan polysulfate (Elmiron®, Baker Norton; 50 mg/cat, PO, BID) and veterinary polysulfated GAGs, such as Adequan® (Luitpold; 5 mg/kg, IM, twice weekly x 4-6 weeks, then weekly or less). Most are not labeled for use in the cat.

Glucosamine is a natural substrate for the biosynthesis of GAGs and is available combined with the GAG chondroitin sulfate as Cosequin® (Nutramax). In a recent study, oral glucosamine was compared to placebo in a randomized, double-blind, placebo-controlled study of 40 patients with FIC over 6 months.18 Owners kept a diary of FIC-related events and graded the severity of the cat's clinical signs at the start and at the end of the trial. There was no significant difference between the two groups when considering the owners' assessment of mean health score, the average monthly clinical score, or the average number of days with clinical signs. Most cats in the study did improve clinically, but this was attributed to a change to a canned food diet in 90% of the cats. Despite this, clinical signs recurred in 65% of the cats, so dietary therapy alone was not sufficient. It is difficult to recommend GAG therapy given the low rate of success in humans, and the lack of any veterinary studies demonstrating efficacy in FIC.

References

1.Albasan H, Lulich JP, Osborne CA et al: Effects of storage time and temperature on pH, specific gravity, and crystal formation in urine samples from dogs and cats, J Am Vet Med Assoc 222:176, 2003.

2.Bailiff NL, Westropp JL, Nelson RW et al: Evaluation of urine specific gravity and urine sediment as risk factors for urinary tract infections in cats, Vet Clin Pathol 37:317, 2008.

3.Buffington CA: External and internal influences on disease risk in cats, J Am Vet Med Assoc 220:994, 2002.

4.Buffington CA, Blaisdell JL, Binns SP, Jr. et al: Decreased urine glycosaminoglycan excretion in cats with interstitial cystitis, J Urol 155:1801, 1996.

5.Buffington CA, Chew DJ, DiBartola SP: Lower urinary tract disease in cats: is diet still a cause?, J Am Vet Med Assoc 205:1524, 1994.

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

7.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 8:261, 2006.

8.Cameron ME, Casey RA, Bradshaw JW et al: A study of environmental and behavioural factors that may be associated with feline idiopathic cystitis, J Small Anim Pract 45:144, 2004.

9.Chew D, Bartges JW, Adams LG et al: Randomized, placebo-controlled clinical trial of pentosan polysulfate sodium for treatment of feline interstitial (idiopathic) cystitis (abstract), J Vet Intern Med 23:690, 2009.

10.Chew DJ, Buffington CA: Managing cats with nonobstructive idiopathic interstitial cystitis, Vet Med 104:568, 2009.

11.Chew DJ, Buffington CA, Kendall MS et al: Amitriptyline treatment for severe recurrent idiopathic cystitis in cats, J Am Vet Med Assoc 213:1282, 1998.

12.Clasper M: A case of interstitial cystitis and Hunner's ulcer in a domestic shorthaired cat, N Z Vet J 38:158, 1990.

13.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 9:458, 2007.

14.Essman SC: Contrast cystography, Clin Tech Small Anim Pract 20:46, 2005.

15.Grant DC: Effect of water source on intake and urine concentration in healthy cats, Journal of Feline Medicine & Surgery In Press, Corrected Proof, 2010.

16.Griffith C, Steigerwald E, Buffington C: Effects of a synthetic facial pheromone on behavior of cats, J Am Vet Med Assoc 217:1154, 2000.

17.Gunn-Moore D, Cameron M: A pilot study using synthetic feline facial pheromone for the management of feline idiopathic cystitis, J Feline MedSurg 6:133, 2004.

18.Gunn-Moore D, Shenoy C: Oral glucosamine and the management of feline idiopathic cystitis, J Feline Med Surg 6:219, 2004.

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

20.Litster A, Moss S, Platell J et al: Occult bacterial lower urinary tract infections in cats-urinalysis and culture findings, Vet Microbiol 136:130, 2009.

21.Lund E, Armstrong P, Kirk C et al: Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States, J Am Vet Med Assoc 214:1336, 1999.

22.Markwell PJ, Buffington CA, Chew DJ et al: Clinical evaluation of commercially available urinary acidification diets in the management of idiopathic cystitis in cats, J Am Vet Med Assoc 214:361, 1999.

23.Mealey KL, Peck KE, Bennett BS et al: Systemic absorption of amitriptyline and buspirone after oral and transdermal administration to healthy cats, J Vet Intern Med 18:43, 2004.

24.Neilson JC: The latest scoop on litter, Vet Med 104:140, 2009.

25.Pereira DA, Aguiar JA, Hagiwara MK et al: Changes in cat urinary glycosaminoglycans with age and in feline urologic syndrome, Biochim Biophys Acta 1672:1, 2004.

26.Reine NJ, Langston CE: Urinalysis interpretation: how to squeeze out the maximum information from a small sample, Clin Tech Small Anim Pract 20:2, 2005.

27.Scrivani PV, Chew DJ, Buffington CA et al: Results of double-contrast cystography in cats with idiopathic cystitis: 45 cases (1993-1995), J AmVet Med Assoc 212:1907, 1998.

28.Sturgess C, Hesford A, Owen H et al: An investigation into the effects of storage on the diagnosis of crystalluria in cats, J Feline Med Surg 3:81, 2001.

29.Wallius BM, Tidholm AE: Use of pentosan polysulphate in cats with idiopathic, non-obstructive lower urinary tract disease: a double-blind, randomised, placebo-controlled trial, J Feline Med Surg 11:409, 2009.

30.Westropp JL, Kass PH, Buffington CA: Evaluation of the effects of stress in cats with idiopathic cystitis, Am J Vet Res 67:731, 2006.

31.Westropp JL, Welk KA, Buffington CA: Small adrenal glands in cats with feline interstitial cystitis, J Urol 170:2494, 2003.