Management of Nonobstructive Idiopathic Feline Lower Urinary Tract Disease

DISORDERS OF THE FELINE LOWER URINARY TRACT II

0195-5616/96 $0.00 + .20

MANAGEMENT OF NONOBSTRUCTIVE IDIOPATHIC FELINE LOWER URINARY TRACT DISEASE Jolm M. Kruger, DVM, PhD, Carl A. Osborne, DVM, PhD, and Jody P. Lulich, DVM, PhD

"Too often we think about what drug to prescribe rather than whether or not to prescribe." H. I. WRIGHT

Feline lower urinary tract diseases (LUTDs) are a heterogeneous group of disorders that may result from fundamentally different causes. Though many single or multiple interacting causes of hematuria, dysuria, or urethral obstruction have been identified in affected cats, the exact cause(s) remain unknown in a substantial number of patients. In a prospective clinical study of 141 male and female cats with naturally acquired LUTDs, a diagnosis of idiopathic LUTD was established in 77 (55%) cats by exclusion of other known causes of hematuria and dysuria.38 Similarly, idiopathic disease was identified in a large percentage of patients in a recent unpublished study of 100 cats with naturally occurring LUTDs. 9 Over the past decade, our knowledge of specific causes and the natural course of other feline LUTDs has increased, allowing diagnostic and therapeutic efforts to be directed toward identification and elimina-

From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan (JMK); and the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota (CAO, JPL)

VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 26 • NUMBER 3 • MAY 1996

571

572

KRUGER et al

Table 1. TYPES OF DISORDERS IN 141 CATS WITH HEMATURIA, DYSURIA, POLLAKIURIA, STRANGURIA, AND/OR URETHRAL OBSTRUCTION Group Nonobstructed lemales Nonobstructed males Obstructed males Total

Idiopathic

Urethral Plug

Uroliths

43

25

0

17

47

37

0

8

51

15

30

5

141

77

30

30

#

Uroliths and UTI

UTI 0

0

2 0

2

2

UTI = urinary tract infection. Data from 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.

tion of specific underlying causes. However, consistently effective treatment and prevention of idiopathic LUTD in male and female cats remains an enigma. Because clinical signs associated with this form of the disease are frequently self-limiting and of short duration, considerable debate exists about the efficacy of various symptomatic therapies advocated for management of idiopathic feline LUTD. Any form of therapy might appear to be beneficial, as long as it was not harmful. The selflimiting nature of some forms of idiopathic feline LUTD underscores the need for controlled prospective double-blind clinical studies to prove the value of various forms of therapy. EPIDEMIOLOGY

The incidence of disease is defined as the annual rate of appearance of new cases of disease among the entire population of individuals at risk of the disease. 65 The incidence of idiopathic feline LUTD is unknown. Previous studies have estimated the incidence of LUTD in domestic cats in the United States and the United Kingdom to be approximately 0.5% to 1.0% per year. 39• 65 However, almost all of these studies have used the nonspecific "FUS" concept as the common denominator to group affected cats. Few populations selected for study were defined on the basis of contemporary clinical diagnostic procedures. Consequently, the results of most of these epidemiologic studies must be interpreted in the context of a combination of all types of feline LUTDs rather than a specific disorder. Further understanding of the epidemiologic features of idiopathic forms of feline LUTD depends on contemporary controlled studies designed to evaluate subsets of cats with LUTDs defined on the basis of specific diagnostic criteria. In a prospective clinical study performed at the University of Minnesota from 1982 to 1985, 141 untreated cats with hematuria, dysuria, urethral obstruction, or a combination of these signs were evaluated with contemporary diagnostic methods. 38 Three groups of cats were

MANAGEMENT OF NONOBSTRUCTIVE IDIOPATHIC FELINE LUT DISEASE

573

selected for study: nonobstructed female cats with dysuria, hematuria, or both; nonobstructed male cats with dysuria, hematuria, or both; and male cats with urethral obstruction. Specific diagnoses were established in 64 of 141 (45%) cats (Table 1). However, a specific cause could not be identified for 58% of nonobstructed females, 79% of nonobstructed males, and 29% of obstructed males. Likewise, a high prevalence of idiopathic disease was reported in a recent unpublished study of 100 cats with LUTD. 9 Our observations suggest that nonobstructive idiopathic LUTD occurs in cats of all ages but is most common in young to middle-aged cats (Table 2). Seventy-six percent of patients with nonobstructive forms of idiopathic LUTD were 1 to 6 years of age. Though the mean age at the time of evaluation of cats with nonobstructive idiopathic LUTD was 53 months, over half of these patients had a history of having one or more episodes of LUTD before evaluation (see Table 2). Idiopathic forms of LUTD are uncommon in cats less than 1 year of age.

Table 2. CLINICAL FEATURES OF 62 CATS WITH NONOBSTRUCTIVE IDIOPATHIC LOWER URINARY TRACT DISEASE Feature Breeds Mean age (range) Previous episode(s) of LUTD* Mean urine specific gravity (range) Urine pHt Hematuria:J: Pyuria§ Crystalluria Radiographic findingsll Thickened bladder wall Irregular mucosa Urachal diverticula Urethral narrowing Normal Urine culture Aerobic bacteria Mycoplasma/ureaplasma Viruses

Males (n 37)

=

Females (n 25)

=

Overall (n 62)

Mixed (n = 36) Persian (n = 1) 53 mo (12 to 144 mo) 18(48%) 1.051 (1.006 to 1.077) usually acidic 35 (95%) 6(16%) 20(54%)

Mixed (n = 22) Persian (n = 3) 53 mo (9 to 132 mo) 20(80%) 1.061 (1.027 to 1.114) usually acidic 24(96%) 2(8%) 11 (44%)

Mixed (n = 58) Persian (n = 4) 53 mo (9 to 144 mo) 38(61%) 1.055 (1.006 to 1.114) usually acidic 59 (95%) 8(13%) 31 (50%)

21 (57%) 11 (30%) 4(11%) 4 (11%) 13(35%)

19(76%) 7(28%) 3(12%) 0(0%) 4(16%)

40 (65%) 18(29%) 7(11%) 4(6%) 17(27%)

0(0%) 0(0%) 0(0%)

0(0%) 0(0%) 0(0%)

0(0%) 0(0%) 0(0%)

=

*One or more previous episodes of clinical signs compatible with lower urinary tract disease. tUrine pH as estimated by reagent test strips. tRed blood cells greater than or equal to s per high power field (450X). §White blood cells greater than or equal to 5 per high power field (450X). IIResults of survey abdominal radiography, positive contrast urethrography, and double contrast cystography. LUTD = lower urinary tract disease Data from 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.

574

KRUGER et al

Four of 62 cats in our series were Persians (see Table 2). Specific breed predilections have not, as of yet, been identified in cats affected with idiopathic forms of LUTD. However, Persian cats do appear to have a higher relative risk (odds ratio between 1.4 and 4.3) of LUTD than do domestic shorthair cats. 65 CLINICAL FEATURES

Clinical signs of idiopathic LUTD are indistinguishable from other infectious and noninfectious causes of feline LUTD and may include hematuria, dysuria, pollakiuria, stranguria, urge incontinence, and I or inappropriate urination. In our series of 62 cats with nonobstructive idiopathic LUTD, all affected cats had one or more signs of dysuria, pollakiuria, or stranguria.38 Gross hematuria was observed in more than 80% of affected cats. Unless complicated by other concurrent illness, results of serum chemistry profiles and complete blood counts are usually normal in cats with nonobstructive idiopathic LUTD. Urinalysis findings of hematuria and proteinuria without concomitant pyuria or bacteriuria are characteristic of, but not pathognomonic for, nonobstructive idiopathic LUTD (see Table 2). 38 The prevalence and magnitude of crystalluria in cats with nonobstructive idiopathic disease is variable. In our series of 62 cats, struvite crystalluria was identified in 50% of affected cats; however, the prevalence of crystalluria in cats with nonobstructive idiopathic disease did not differ significantly from that of normal control cats. 38 Cats with nonobstructive idiopathic LUTD typically have concentrated and acidic urine (see Table 2). Results of urine culture for aerobic bacteria, mycoplasma/ureaplasma, or viruses are invariably negative. Survey abdominal radiographs of cats with nonobstructive idiopathic LUTD are usually normal. Contrast urethrocystography may be normal or may reveal various combinations of thickened urinary bladder wall, irregular urinary bladder mucosa, macroscopic vesicourachal diverticula, and/ or urethral narrowing (see Table 2). Radiographic abnormalities were not observed in 17 of 62 (27%) of cats affected with nonobstructive idiopathic disease. 38 BIOLOGIC BEHAVIOR

The biologic behavior of nonobstructive idiopathic LUTD has not been evaluated by prospective studies of suitably large populations of untreated male and female cats. However, our observations and those of others suggest that clinical signs of hematuria, dysuria, and pollakiuria in many untreated nonobstructed male and female cats with acute idiopathic LUTD frequently subside within 5 to 7 days. 3• 37• 51 • 63 These signs may recur after variable periods of time and again subside without therapyY Our impression is that recurrent episodes of acute idiopathic

MANAGEMENT OF NONOBSTRUCTIVE IDIOPATHIC FELINE LUT DISEASE

575

LUTD tend to decrease in frequency and severity over time. Though recurrent clinical signs in patients with idiopathic LUTD are often assumed to be recurrence of the original disease, recurrent signs may also be the result of a delayed manifestation of the original disease (for example, spontaneous or iatrogenic urethral stricture), onset of a different disease associated with clinical manifestations similar to those of the original disorder (such as urolithiasis), or combinations of these. Occasionally, we have encountered cats with signs of hematuria and dysuria that have persisted for weeks to months and for which a specific cause cannot be identified. Whether this chronic form of idiopathic LUTD represents one extreme in the spectrum of clinical manifestations associated with similar etiologic factors or whether it represents an entirely different mechanism of disease than that associated with acute self-limiting idiopathic disease is unknown. We have also encountered idiopathic urethral obstruction in a substantial number of male cats with LUTD. In a prospective clinical study of 141 cats with LUTD, 15 of 77 cats (20%) with idiopathic LUTD had urethral obstruction.38 The specific cause(s) and site(s) of urethral obstruction in these cases were not identified. However, obstruction may have been the result of (1) inflammatory swelling of the urethra, (2) urethral muscular spasm, (3) reflex dyssynergia, (4) intraluminal accumulations of sloughed tissue, inflammatory cells, or red blood cells, or (5) undetected matrix-crystalline urethral plugs. Further studies are necessary to identify the cause(s) and site(s) of urethral obstruction in cats with idiopathic LUTD. ETIOPATHOGENESIS Crystalluria

Struvite crystalluria has been hypothesized to induce cystitis and urethritis in cats. 41 However, our observations and those of others indicate that variability exists in the prevalence, magnitude, and mineral composition of crystals in urine collected from normal cats and from cats with idiopathic LUTD or other forms of naturally occurring LUTD. 38• 56• 58 In a prospective study of 141 cats with naturally occurring LUTDs, crystalluria was observed in 50% of cats with nonobstructive (n = 62) idiopathic LUTD. The prevalence of crystalluria in cats with idiopathic LUTD was not significantly different from that of unaffected control cats. 38 The observation that signs of hematuria, dysuria, and urethral obstruction may occur in the absence of crystalluria suggests other etiologic factors must be involved. Infectious Agents

Infectious agents, especially viruses, have been implicated as potential causative agents in the etiopathogenesis of some forms of naturally

576

KRUGER et ai

acquired feline LUTD. 19 This hypothesis was supported by isolation of a gamma herpesvirus (Bovine Herpesvirus type 4), a calicivirus (feline calicivirus), and a retrovirus (feline syncytia forming virus) from urine and tissues obtained from cats with naturally occurring LUTD. 20• 21 • 28• 46• 55 Similarly, herpesviruses, adenoviruses, polyomaviruses, and retroviruses have been incriminated as causes of hemorrhagic cystitis in humans (see article entitled "Viral Infections of the Feline Urinary Tract" in Part I of this issue [March 1996]). Despite considerable evidence that viral agents can induce LUTD in cats in laboratory settings, reproducible clinical evidence that viruses cause naturally occurring symptomatic feline LUTD is lacking. 19• 36 However, the inability to detect viruses in patients with LUTD must be viewed with caution. Negative findings may represent insensitive or inappropriate virus detection methods, the virucidal nature of feline urine, or improper handling of samples. 36 Recent discovery of viruslike particles tentatively identified as calicivirus in a substantial number of crystalline-matrix urethral plugs obtained from male cats with naturally occurring urethral obstruction is noteworthy. 50 These observations emphasize the need to reexamine the roles of known pathogens as well as to continue the search for other uropathogens. Interstitial Cystitis

Interstitial cystitis is a nonmalignant inflammatory disorder of humans. Its etiologic origin is unknown. The disease is characterized by dysuria, pain above the pubic region that is relieved by voiding, normal urinalyses, and distinctive mucosal lesions detected by cystoscopy (Table 3).34• 47 Proposed causes include viral infections, autoimmune disease, mast-cell mediated disease, lymphatic or vascular obstruction, neurogenic disease, endocrinopathies, and defects in the glycosaminoglycan coating of the mucosal surface of the bladderY No consistently effective therapy exists and complete remission of clinical signs is rare. Some cats with feline LUTD have clinical findings similar to those observed in humans with interstitial cystitis (see the article entitled " Interstitial Cystitis in Cats" in Part I of this issue [March 1996]). They include decreased urine concentrations of glycosaminoglycans, increased urinary bladder permeability, and similar gross and light microscopic changes (see Table 3).7· 8• 26• 49 These similarities have prompted the hypothesis that idiopathic feline LUTD is an analog of human interstitial cystitis. 6• 9• 14 However, further studies are essential to prove or disprove this hypothesis.

MANAGEMENT The following generalities recommended for treatment of nonobstructive forms of idiopathic feline LUTD have not all been substantiated by experimental and / or clinical investigations. In formulating our rec-

MANAGEMENT OF NONOBSTRUCTIVE IDIOPATHIC FELINE LUT DISEASE

577

Table 3. CLINICAL FEATURES OF FELINE IDIOPATHIC LOWER URINARY TRACT DISEASE AND HUMAN INTERSTITIAL CYSTITIS Idiopathic LUTD Signalment Signs

Clinical course Urinalysis

Urine culture Radiography Cystography

Light microscopy

GAGs

Young to middle-aged Male and female Dysuria Pollakiuria Hematuria Urethral obstruction Episodic Self-limiting Hematuria Proteinuria + 1- Pyuria Decreased GAGs? Sterile Irregular mucosa Thickened bladder wall Glomerulations?

Ulceration Hemorrhage Mononuclear cell infiltrate Increased mast cells?

Interstitial Cystitis Middle-aged Predominantly female Pollakiuria +I- Hematuria Nocturia Pelvic pain Chronic Persistent + 1- Hematuria + 1- Pyuria Decreased GAGs? Sterile Unremarkable Glomerulations Reduced bladder capacity Hunner's ulcers Ulceration Hemorrhage Mononuclear cell infiltrate Increased mast cells? Granulation tissue Vasculitis Perineural inflammatory infiltrate

= glycosaminoglycans; LUTD = lower urinary tract disease

ommendations, we may become victims of our own criticism. Some of our suggestions are based on uncontrolled clinical observations and personal opinion. We emphasize the need for continued caution and logical judgment when considering any therapeutic recommendation. We hope that the research required to substantiate or refute our recommendations and those of others will continue to be supported.

Antibacterial Agents

Antibiotics have commonly been used for empiric therapy of idiopathic LUTD (Table 4). However, the infrequency with which bacteria have been identified at the onset of clinical signs of lower urinary tract disorders has been well established.38• 40• 46• 58 The uselessness of antimicrobial agents in the treatment of abacteriuric cats with LUTD has also been documented. 3 Indiscriminate use of antimicrobial agents has undoubtedly been responsible, at least in part, for the emergence of the resistant strains of microbes that populate veterinary hospitals.

578

KRUGERet al

Table 4. HISTORIC PERSPECTIVE OF THERAPEUTIC RECOMMENDATIONS FOR CATS WITH CLINICAL FINDINGS COMPATIBLE WITH IDIOPATHIC FORMS OF FELINE LOWER URINARY TRACT DISEASE Assessment of Therapy Proposed Therapies

Controlled Study?

Efficacy•

Antibiotics Antispasmotics Urinary acidifiers Vitamin A Testosterone Hylauronidase Low Mg and phos diet Antibiotics Urinary acidifiers

No No No No No No No No No

ND ND ND ND ND ND ND ND ND

Antibiotics Urinary acidifiers Lactated Ringer's soln

No No No

ND ND ND

Antispasmotics Urinary acidifiers Sodium chloride Moist food 197563 Nonobstructed males Urinary acidifiers and females; no Lactated Ringer's soln Topical phenol uroliths; no UTI lntravesicular Lugol's soln 197717 Nonobstructed males Antibiotics and females; no Urinary acidifiers uroliths; + /- UTI Curcai-Feline:j: Moist low ash diet 197827 Nonobstructed males Antibiotics and females; no Urinary antiseptics uroliths; no UTI Urinary acidifiers Sodium chloride Megesterol acetate Moist food 198o•• Obstructed males; lntracystic copper coil + / - uroliths; + 1- UTI 1981' 6 Nonobstructed males Antibiotics and females; Urinary acidifiers +1- uroliths; Sodium chloride + 1- UTI FCV/FHV-1 vaccine Moist low ash diet 19823 Nonobstructed males Antibiotics§ and females; no Antispasmoticsll uroliths; + /- UTI Lactated Ringer's

No No No No No No No No

ND ND ND ND ND ND ND ND

No No No No No No No No No No No

ND ND ND ND ND ND ND ND ND ND ND

No No No No No Yes Yes Yes

ND ND ND ND ND not significant not significant not significant

Date

Patient Population

195543 Obstructed and nonobstructed males; + 1- uroliths; +1- UTI

196631 Nonobstructed females; no uroliths; +/- UTI 48 1970 Obstructed and nonobstructed males and females; no uroliths; +/- UTI 197252 Nonobstructed males and females; no uroliths; no UTI

soln~

Table continued on opposite page

MANAGEMENT OF NONOBSTRUCTIVE IDIOPATHIC FELINE LUT DISEASE

579

Table 4. HISTORIC PERSPECTIVE OF THERAPEUTIC RECOMMENDATIONS FOR CATS WITH CLINICAL FINDINGS COMPATIBLE WITH IDIOPATHIC FORMS OF FELINE LOWER URINARY TRACT DISEASE Continued Assessment of Therapy Date

Patient Population

Proposed Therapies

199057 Nonobstructed males Antispasmotics and females; no Urinary acidifiers uroliths; no UTI Sodium chloride Diuretics Corticosteroids DMSO Moist acidifying low-Mg diet 199542 Nonobstructed males Antispasmotics and females; no Potassium chloride uroliths; no UTI Moist food 199551 Nonobstructed males Corticosteroidstt and females; idiopathic LUTD** 19959 Nonobstructed males Amitriptyline and females; Corticosteroids idiopathic LUTD** Urohydrodistention

Controlled Study?

Efficacy*

No No No No No No No

ND ND ND ND ND ND ND

No No No Yes

ND ND ND not significant

No No No

ND ND ND

*Degree of reduction in severity or duration of clinical signs in affected cats treated with a therapeutic agent compared to placebo treated or untreated controls. :j:0.085% tetrasodium ethylenediamine tetraacetic acid (EDTA) and 0.06% sodium tripolyphosphate. §Chloramphenicol 100 mg PO q 8 hrs for five days. IIPropantheline bromide, 7.5 mg PO once. ~Lactated Ringer's solution, 100 ml subcutaneously once. •• A diagnosis of idiopathic LUTD was based on exclusion of all other known causes of hematuria and dysuria. ttPrednisolone 1.0 mg/kg PO q 12 hrs for 10 days. DMSO = dimethyl sulfoxide; FCV = feline calicivirus; FHV-1 = feline herpesvirus type 1; LUTD = lower urinary tract disease; Mg = magnesium; ND = not determined; phos = phosphorous; soln = solution; UTI = urinary tract infection

Urinary Tract Antiseptics

Urinary tract antiseptics are sometimes used as adjunctive agents in the treatment, control, and prevention of urinary tract infections in humans. Though their use is frequently acknowledged in the treatment of bacterial urinary tract infection in dogs and is occasionally mentioned for treatment of lower urinary tract disorders in cats, no studies have substantiated their effectiveness in these species (see Table 4). Methenamine is a cyclic hydrocarbon. In an acidic environment (pH less than 6.0) methenamine hydrolyzes to form formaldehyde, an essential component of its antimicrobial activity. Because of the necessity of acidic urine for formation of formaldehyde, methenamine is usually given in combination with acidifiers such as mandelic acid (methenamine mandelate) or hippuric acid (methenamine hippurate). Methenamine must remain in the urinary tract for a sufficient period to allow generation of effective concentrations of formaldehyde. However, once generated in sufficient concentration, formaldehyde is capable of killing

580

KRUGER et al

microbes at any urine pH. In light of the hypothesis that some forms of lower urinary tract disorders in cats are caused by viruses, the unproved suggestion that methenamine may have virucidal action in urine is of interest-3 2 However, the intracellular location of viruses poses the problem of access of formaldehyde to this location. The lack of definitive proof that viruses are a cause of naturally occurring lower urinary tract disorders in cats and the lack of studies of the efficacy of methenamine in such patients are additional problems. At this time, the use of methenamine to treat cats with feline urinary tract disorders is no more than an idea. Methylene blue (tetramethylthionine chloride) is a weak antiseptic agent that at one time was popularly used in combination products designed to treat lower urinary tract symptoms. Medications containing methylene blue are contraindicated in cats because methylene blue has the potential to cause Heinz bodies and severe anemia. 59 Urinary Tract Analgesics

Phenazopyridine is an azo dye that is commonly used as a urinary tract analgesic in man. Its use alone or in combination with sulfa drugs is contraindicated in cats because it has the potential to cause methemoglobinemia and irreversible oxidative changes in hemoglobin, resulting in formation of Heinz bodies and anemia. Cats have been highly susceptible to dose-related toxicity of this agent. 30 Urinary Acidifiers

Administration of urinary acidifiers has been one of the most common forms of empiric therapy recommended for cats with nonobstructive and obstructive forms of feline LUTD (see Table 4). Rationale for their use is based on the assumption that struvite crystalluria and formation of struvite uroliths and struvite-containing urethral plugs were responsible for most, if not all, cases of feline hematuria, dysuria, and urethral obstruction. 16• 17• 27• 31 • 41 • 43• 48 Several subsequent studies have demonstrated the relative importance of low urine pH in inhibiting struvite crystal formation. 10• 62 Though little doubt exists that struvite uroliths and struvite-containing urethral plugs are important causes of feline LUTD, increasing evidence suggests that crystalluria per se, and struvite crystalluria in particular, are not significant factors in the etiopathogenesis of all nonobstructive idiopathic forms of feline LUTD. In a prospective study of 62 cats with nonobstructive idiopathic LUTD, the prevalence of crystalluria was not different from that of unaffected control cats (see Table 2). 38 Considering that (1) struvite crystalluria does not appear to be a significant risk factor for all forms of nonobstructive idiopathic LUTD, (2) chronic administration of acidifying agents may have detrimental effects on acid/base balance, renal function, bone

MANAGEMENT OF NONOBSTRUCTIVE IDIOPATHIC FELINE LUT DISEASE

581

formation, and mineral balance, and (3) chronic administration of acidifying agents may be a risk factor for formation of calcium oxalate uroliths, we see no logic for generalized use of urinary acidifiers in cats with nonobstructive idiopathic LUTD.6• 13• !5, 22. 51, 53

Smooth and Skeletal Muscle Antispasmotics

Many cats with inflammation of the lower urinary tract develop pollakiuria (frequent voiding of small volumes of urine) and / or urge incontinence (an uncontrollable desire to void that results in involuntary loss of urine). In both cases, inappropriate voiding of urine usually occurs at low volumes of bladder filling and may be associated with sensations of pain, bladder fullness, and urgency. Because the exact mechanisms of pollakiuria and urge incontinence are unknown, details about specific therapy are unavailable. Presumably, pollakiuria and urge incontinence are the result of inflammation-induced stimulation of urinary bladder sacral sensory afferent nerves. 24 Sensations of pain and perceptions of fullness and urgency induce a premature micturition reflex and subsequent inappropriate or involuntary voiding of small quantities of urine. Because cholinergic parasympathetic efferents are largely responsible for detrusor contraction, anticholinergic agents may logically be considered as symptomatic treatment of pollakiuria and urge incontinence. 24 However, the efficacy, if any, of these agents in cats with nonobstructive idiopathic LUTD has not been established by properly controlled clinical trials. The anticholinergic agent propantheline minimizes the force and frequency of uncontrolled detrusor contractions but has negligible effect on urethral sphincter pressure. In a controlled clinical study of the efficacy of propantheline (7.5 mg given orally on one occasion) for treatment of naturally occurring hematuria and dysuria in nonobstructed male and female cats, no difference in rate of recovery was observed between cats treated with propantheline and control groups.3 However, therapy with propantheline of longer duration may have reduced the severity of dysuria; we consider propantheline to reduce the severity and frequency of urge incontinence in nonobstructed male and female cats. It has a rapid onset of action. However, care must be used to prevent urinary retention as a result of excessive doses. Because the smallest tablet is 7.5 mg, the suggested dose is 7.5 mg given orally approximately every 72 hours. Further studies using appropriate doses and maintenance intervals are required to substantiate a beneficial symptomatic effect of propantheline in cats with urge incontinence. Other smooth and skeletal muscle antispasmotics, including aminopromazine, dantrolene, diazepam, phenoxybenzamine, and prazosin, have been recommended for symptomatic management of urethrospasm associated with LUTD. 12• 25• 45• 57• 60• 61 Though some of these pharmacologic agents produce significant decreases in intraurethral pressure in normal

582

KRUGER et al

male cats and cats with naturally occurring urethral obstruction/5• 45• 60• 61 the role of urethral smooth or skeletal muscle spasm in producing clinical signs associated with idiopathic forms of feline LUTD is unknown. In a limited study of 6 male cats with urethral obstruction caused by unspecified causes, intraurethral pressures before administration of antispasmotics were not significantly different from those of normal nonobstructed male cats. 60 Similar studies in cats with idiopathic forms of LUTD have not been performed. Anti-Inflammatory Agents

Assuming that most cats with idiopathic LUTD have an inflammatory lesion of the lower urinary tract is probably reasonable. Hematuria is indicative of (but not pathognomonic of) inflammation; dysuria indicates involvement of the lower urinary tract. The cause of the inflammation in cats with idiopathic disease is unknown. The lack of specific therapy for cats with idiopathic causes of hematuria and dysuria has stimulated many to question the value of antiinflammatory agents to reduce the severity of clinical signs. Success in minimizing the frequency of voiding would not only be beneficial to affected cats, it would eliminate owner frustration associated with the socially unacceptable problem of frequent voiding on floors, carpets, and furniture, Unfortunately, few controlled clinical trials have studied the short- and long-term effectiveness of anti-inflammatory agents in the symptomatic treatment of dysuria and hematuria in cats (see Table 4). We emphasize that hematuria and dysuria in cats with idiopathic LUTD is often self-limiting. Glucocorticoids

Consideration of glucocorticoids to minimize persistent signs associated with inflammation in cats with idiopathic dysuria and hematuria is logical. To test this logic, we conducted a double-blind, controlled therapeutic trial of male and female adult cats with previously untreated idiopathic LUTD (see article entitled "Prednisolone Therapy of Idiopathic Feline Lower Urinary Tract Disease: A Double-Blind Clinical Study" earlier in this issue), Briefly, six symptomatic cats selected randomly were given 1.0 mg/kg of prednisolone orally, twice each day; six symptomatic cats were given a placebo. In both groups, clinical signs subsided in a mean of 1 to 2 days, and in both groups hematuria and pyuria subsided in approximately 2 to 5 days. In one cat with recurrent idiopathic LUTD, treatment with prednisolone and the placebo were given at different times. No detectable difference occurred in response to the two different forms of management. Because of their catabolic effect, glucocorticoids are generally contraindicated in cats with urethral obstruction and postrenal azotemia. They should not be considered in such patients until deficits and excesses in fluid, electrolyte, and acid-base balance have been corrected. Likewise, glucocorticoids are contraindicated in cats with bacterial uri-

MANAGEMENT OF NONOBSTRUCTIVE IDIOPATHIC FELINE LUT DISEASE

583

nary tract infection. The use of glucocorticoids in cats with indwelling catheters is especially apt to be hazardous.2• 4 Dimethyl Sulfoxide

Dimethyl sulfoxide (DMSO) is an analgesic anti-inflammatory agent with weak antibacterial, antifungal, and antiviral activity. 5 It is reportedly effective in the treatment of a variety of genitourinary disorders of humans including interstitial cystitis, radiation cystitis, chronic prostatitis, and female chronic trigonitis.47 Retrograde infusion of 50% solutions of pyrogen-free DMSO into the bladder lumens of humans with interstitial cystitis reportedly minimizes associated clinical signs in some patients. DMSO has been used to treat LUTD in cats, presumably because of its reported efficacy in humans with interstitial cystitis. 2• 35• 57 Intravesicular instillation of 10 to 20 mL of 10% DMSO was associated with amelioration of clinical signs in three cats with chronic LUTD. 57 However, appropriately controlled clinical trials designed to evaluate the effectiveness of local instillation of DMSO into the urinary bladder of cats with signs of lower urinary tract disease have not been reported (see Table 4). In one controlled study of cats with induced cystitis, intravesicular administration of 45% DMSO for 3 days was of no detectable benefit in minimizing bacterial infection or inflammation.2.4 Doses and frequency of administration of DMSO have been entirely empiric. 2• 57 Local instillation of various quantities (up to 25 mL) of solutions containing 25% to 50% DMSO into the urinary bladders of dogs weighing 15 to 40 kg every other week for up to 6 months resulted in no detectable side effects. 54 Use of solutions containing 100% DMSO caused mucosal edema and hemorrhage.2 Licensed products available to veterinarians contain 90% DMSO and are not pyrogen-free; licensed products available to physicians contain 50% DMSO and are pyrogen-free. Side effects of DMSO in cats have apparently not been evaluated. Pending further studies, we discourage its use to treat idiopathic feline LUTD. Amitriptyline

Amitriptyline (Elavil) has recently been advocated for symptomatic therapy of idiopathic feline LUTD. 6• 9 Amitriptyline is a tricyclic antidepressant with anticholinergic, antihistaminic, anti-alpha-adrenergic, anti-inflammatory, and analgesic properties. 1• 29 Amitriptyline is used extensively for treatment of interstitial cystitis in humans. 29 Despite amitriptyline's popularity, its exact mechanism of action and its therapeutic value in managing patients with interstitial cystitis is unknown. In an uncontrolled study of 28 human patients with refractory interstitial cystitis, 18 (64%) patients experienced remission of clinical signs, 5 (18%) patients had unacceptable side effects, and 5 (18%) patients had no clinical benefit. 29 Similarly, anecdotal reports and limited data suggest that administration of amitriptyline to some cats with idiopathic forms of LUTD

584

KRUGER et al

results in amelioration of clinical signs within 24 to 48 hours (DJ Chew, DVM, personal communication, 1995). Consequently, amitriptyline has gained popularity as an agent for symptomatic therapy of idiopathic feline LUTD. 9• 44 As is the case in humans, however, appropriately controlled clinical studies designed to evaluate the effectiveness of amitriptyline in controlling clinical signs of cats with idiopathic forms of LUTD have not been reported (see Table 4). Dose, frequency, and duration of amitriptyline therapy is entirely empiric. 9 Adverse reactions reported in humans treated with antidepressant doses of amitriptyline include urinary retention, dry mucous membranes, blurred vision, hypotension, tachycardia, arrythmias, sedation, weakness, lethargy, thrombocytopenia, agranulocytosis, elevations in liver enzyme activities, and hypersensitivity reactions.1 Sedation, urinary retention, and other anticholinergic side effects have been observed in cats treated with higher doses of amitriptyline (DJ Chew, DVM, personal communication, 1995). Pending further safety and efficacy studies, we urge caution in the use of amitriptyline to treat idiopathic feline LUTD. Urohydrodistention

Controlled distention of the urinary bladder under anesthesia (therapeutic urohydrodistention) has been recognized as having value in alleviating signs of interstitial cyctitis in human patients for over 60 years.n Approximately 30% of human interstitial cystitis patients experience substantial, though temporary, relief of signs after urohydrodistention. 47 Though the exact mechanism of action is unknown, urohydrodistention may induce (1) increased urothelial glycosaminoglycan (GAG) production, (2) depletion of bladder sensory nerve neuropeptides, or (3) ischemic degeneration of sensory nerve endings within the bladder wall.47 Controlled distention of the urinary bladder during cystoscopy reportedly alleviates clinical signs in some cats with idiopathic LUTD.9 As with nearly all forms of symtomatic therapy, however, the efficacy of urohydrodistention has not been evaluated by appropriately controlled clinical trials (see Table 4). Unfortunately, establishing a diagnosis of idiopathic LUTD requires contrast radiography and/ or cystoscopy (both of which distend the urinary bladder). Until other, more specific markers of idiopathic LUTD are identified, differentiating the effects of bladder distention for diagnostic purposes versus those induced by therapeutic urohydrodistention will be difficult. Urothelial Debridement

Cystotomy to lavage and debride the bladder mucosa has been recommended by some to treat patients with cystitis, urethritis, and/ or urethral obstruction. Though this procedure is still used by some veterinarians, no controlled experimental or clinical studies indicate the

MANAGEMENT OF NONOBSTRUCTIVE IDIOPATHIC FELINE LUT DISEASE

585

efficacy of the procedure. In fact, reports of clinical experiences suggest that the technique is of little benefit (see the article entitled, "Treatment of Feline Lower Urinary Tract Disease by Debriding the Bladder Mucosa: First Do No Harm" ). This is not surprising because the urethra and urinary bladder are affected in many cats with dysuria, hematuria, and pollakiuria. If one assumes (and we do not) that debridement of the urothelium is of some therapeutic benefit, removal of the bladder mucosa would have no obvious beneficial effect on the urethra. We do not recommend this procedure. Other Agents

A variety of other agents have been advocated by various authors to treat and prevent feline lower urinary tract disorders (see Table 4). None has been evaluated by appropriate selection of patients for study or by controlled clinical trials. Recommendations for testosterone, castor oil, garlic, megesterol acetate, feline calicivirus/ feline herpesvirus type 1 vaccines, Lugol's solution, Curcal-feline, vitamin A, hyaluronidase, and various homeopathic preparations appear to be based on supposition rather than fact. We do not recommend them. SUMMARY

Despite the fact that idiopathic feline LUTD is the most common cause of hematuria and dysuria encountered in nonobstructed male and female cats, it is the least well understood of all feline urinary tract disorders. Consequently, effective treatment of cats with nonobstructive idiopathic hematuria and dysuria remains an enigma. Because specific therapy for these idiopathic cases is unavailable, symptomatic and supportive care is often initiated using a wide variety of agents. However, our observations and those of others suggest that clinical signs of hematuria, dysuria, and pollakiuria in many untreated male and female cats with idiopathic LUTD are frequently self-limiting. Therefore, we emphasize that appropriate caution be used before advocating any therapy to control signs of LUTD on the basis of what appear to be beneficial responses. For years, drugs such as Chlor-Ethamine (ethylenediamine dihydrochloride), Curcal-feline, antibiotics, and corticosteroids (see Table 4) were commonly used to treat idiopathic disease because signs of dysuria, pollakiuria, and hematuria subsided coincidentally with their administration. For most patients administration of these drugs was an active form of doing nothing. Emphasis has been misplaced on which drugs to prescribe rather than whether or not to prescribe. Acceptance of the value of these drugs was unconsciously reinforced by the fact that many episodes of idiopathic LUTD were, and are, self-limiting. We explain this to clients by using the analogy of the "common cold" that affects humans. In these situations, any form of therapy may appear to be beneficial as long as it is not overtly harmful.

586

KRUGER et al

We also recognize that client-induced self-induced psychologic pressure to "do something" is occasionally overwhelming. Our desire to do something, however, must be evaluated in light of the potential benefits of our therapeutic action. On occasion, the psychologic benefits of some form of therapy may justify the time, expense, and risks involved; however, these should be carefully considered by all concerned. Perhaps if we answer the question, "Am I doing for my patient what I would do for myself or my family?" it might help us decide on a course of treatment. Ultimately, the decision should be based on our commitment to the idea that the unshakable principle that guides our actions is the welfare of our patients-first and last. Toward this end we wholeheartedly support and encourage continued investigations of new therapeutic strategies for management of idiopathic feline LUTDs and join with our colleagues in emphasizing that these studies entail double-blind, placebo-controlled clinical trials. References 1. Baldessarini RJ: Drugs and the treatment of psychiatric disorders. In Gilman A, Rail TW, Nies AS, et al (eds): Goodman and Gillman's The Pharmacologic Basis of Therapeutics. New York, Pergamon Press, 1990, p 383 2. Barsanti JA, Finco DR, Brown SA: The role of dimethyl sulfoxide and glucocorticoids in lower urinary tract diseases. In Bonagura JD, Kirk RW (eds): Current Veterinary Therapy XII Small Animal Practice. Philadelphia, WB Saunders, 1995, p 1011 3. Barsanti JA, Finco DR, Scotts EB, et al: Feline urologic syndrome: Further investigation into therapy. JAm Anim Hosp Assoc 18:387, 1982 4. Barsanti JA, Shotts EB, Crowell WA, et al: Effect of therapy on susceptibility to urinary tract infection in male cats with indwelling urethral catheters. J Vet Intern Med 6:64, 1992 5. Brayton CF, Schwark W: Use and misuse of DMSO. In Bonagura JD, Kirk RW (eds): Current Veterinary Therapy XII Small Animal Practice. Philadelphia, WB Saunders, 1995, p 67 6. Buffington CAT: Lower urinary tract disease in cats: New problems, new paradigms. J Nutr 124:2634S, 1994 7. Buffington CAT, Blaisell JL, Binns SP, et al: Decreased urine glycosaminoglycans (GAG) in cats with idiopathic lower urinary tract disease. J Vet Intern Med 7:126, 1993 8. Buffington CAT, Chew DJ: Presence of mast cells in submucosa and detrusor of cats with idiopathic lower urinary tract disease. J Vet Intern Med 7:126, 1993 9. Buffington CAT, Chew DJ: Idiopathic lower urinary tract disease in cats-is it interstitial cystitis? In Proceedings of the 13th American College of Veterinary Internal Medicine Forum, Orlando, 1995, p 517 10. Buffington CA, Roger QR, Morris JG: Effect of diet on struvite activity product in feline urine. Am J Vet Res 51 :2025, 1990 11. Bumpus HC: Interstitial cystitis: Its treatment by overdistention of the bladder. Med Clin North Am 13:1495, 1930 12. Chew DJ, DiBartola SP, Fenner WR: Pharmacologic management of urination. In Kirk RW (ed): Current Veterinary Therapy IX Small Animal Practice, ed 9. Philadelphia, WB Saunders, 1986, p 1207 13. Ching SV, Feltman MJ, Hamar DW, et al: The effects of chronic dietary acidification using ammonium chloride on acid-base and mineral metabolism in adult cats. J Nutr 119:902, 1989 14. Clasper M: A case of interstitial cystitis and Hunner's ulcer in a domestic shorthaired cat. N Z Vet J 38:158, 1990

MANAGEMENT OF NONOBSTRUCTIVE IDIOPATHIC FELINE LUT DISEASE

587

15. Dow SW, Fettman MJ, Smith KR, et a!: Effects of dietary acidification and potassium depletion on acid-base balance, mineral metabolism, and renal function in adult cats. J Nutr 120:509, 1990 16. Elcock L: Feline urological syndrome. Feline Pract 11:6, 1981 17. Engle GC: A clinical report on 250 cases of feline urological syndrome. Feline Pract 7:24, 1977 18. Fabricant CG: Herpesvirus-induced urolithiasis in specific pathogen-free male cats. Am J Vet Res 38:1837, 1977 19. Fabricant CG: The feline urological syndrome induced by infection with a cell-associated herpesvirus. Vet Clin North Am Small Anim Pract 14:493, 1984 20. Fabricant CG, Gillespie JH, Krook L: Intracellular and extracellular mineral crystal formation induced by viral infection of cell cultures. Infect Immun 3:416, 1971 21. Fabricant CG, King JM, Gaskin JM, et a!: Isolation of a virus from a female cat with urolithiasis. JAm Vet Med Assoc 158:200, 1971 22. Fettman MJ, Coble JM, Hamar DW, et al: Effect of dietary phosphoric acid supplementation on acid-base balance and mineral and bone metabolism in adult cats. Am J Vet Res 53:2125, 1992 23. Finco DR, Kneller SK, Crowell WA: Diseases of the urinary system. In Catcott EJ (ed): Feline Medicine and Surgery, ed 2. Santa Barbara, American Veterinary Publications, 1975, p 251 24. Fletcher TF, Badley WE: Neuroanatomy of the bladder-urethra. J Urol119:153, 1978 25. Frenier SL, Knowlen GG, Speth RC, et al: Urethral pressure response to alpha-adrenergic agonist and antagonist drugs in anesthetized healthy male cats. Am J Vet Res 53:1161, 1992 26. Gao X, Buffington CAT, Au JLS: Effect of interstitial cystitis on drug absorption from urinary bladder. J Pharmacol Exp Ther 271:818, 1994 27. Gaskell CJ, Denny HR, Jackson OF, et al: Clinical management of the feline urological syndrome. J Small Anim Pract 19:301, 1978 28. Gaskell RM, Gaskell CJ, Page W, et al: Studies on a possible etiology for the feline urological syndrome. Vet Rec 105:243, 1979 29. Hanno PM: Amitriptyline in the treatment of interstitial cystitis. Urol Clin North Am 21:89, 1994 30. Harvey JW, Kornick HP: Phenazopyridine toxicosis in the cat. J Am Vet Med Assoc 169:327, 1976 31. Holzworth J: Urolithiasis in cats. In Kirk RW (ed): Kirk's Current Veterinary Therapy 1966-1967 Small Animal Practice. Philadelphia, WB Saunders, 1965, p 410 32. Jackson JW: Methenamine mandelate in feline urological syndrome. Feline Pract 6:10, 1976 33. JacobS: Mode of action and biological effects of DMSO. Vet Med/Small Anim Clinician 77:365, 1982 34. Johannson SL, Fall M: Clinical features and spectrum of light microscopic changes in interstitial cystitis. J Urol143:1118, 1990 35. Koller LC: Clinical application of DMSO by veterinarians in Oregon and Washington. Vet Med/Small Anim Clinician 71:591, 1976 36. Kruger JM, Osborne CA: The role of viruses in feline lower urinary tract disease. J Vet Intern Med 4:71, 1990 37. Kruger JM, Osborne CA: Recurrent, nonobstructive, idiopathic feline lower urinary tract disease: An illustrative case report. J Am Anim Hosp Assoc 31 :312, 1995 38. Kruger JM, Osborne CA, Goyal SM, et al: Clinical evaluation of cats with lower urinary tract disease. JAm Vet Med Assoc 199:211, 1991 39. Lawler DF, Sjolin DW, Collins JE: Incidence rates of feline lower urinary tract disease in the United States. Feline Pract 15:13, 1985 40. Lees GE, Rogers KS, Wolf AM: Diseases of the lower urinary tract. In Sherding RG (ed): The Cat: Diseases and Clinical Management. New York, Churchill Livingstone, 1989, p 1397 41. Lewis LD, Morris ML: Feline urologic syndrome: Causes and clinical management. Vet Med 79:323, 1984

588

KRUGER et al

42. Ling GV: Feline urological syndrome. In Lower Urinary Tract Diseases of Dogs and Cats. St. Louis, Mosby, 1995, p 179 43. Lumb WV: Cystitis and urolithiasis. Vet Med 50:26, 1955 44. Mandelker L: What's hot and what's not. Vet Forum Ouly):54, 1995 45. Marks SL, Straeter-Knowlen IM, Know len GG, et a!: The effects of phenoxybenzamine and acepromazine maleate on urethral pressure profiles of anesthetized, healthy male cats. J Vet Intern Med 7:122, 1993 46. Martens JG, McConnell S, Swanson CL: The role of infectious agents in naturally occurring feline urological syndrome. Vet Clin North Am 14:503, 1984 47. Messing EM: Interstitial cystitis and related syndromes. In Walsh PC, Retik AB, Stamey TA, et al (eds): Campell's Urology, ed 6. Philadelphia, WB Saunders, 1992, p 982 48. Osbaldison GW, Taussig RA: Clinical report on 46 cases of feline urological syndrome. Vet Med / Small Anim Clinician 65:461, 1970 49. Osborn S, Chew DJ, Buffington CA, et al: Cystoscopic identification of glomerulations in cats with idiopathic cystitis. J Vet Intern Med 8:169, 1994 50. Osborne CA, Kruger JM, Lulich JP, et al: Feline matrix-crystalline plugs: A unifying hypothesis of causes. J Small Anim Pract 33:172, 1992 51. Osborne CA, Kruger JM, Lulich JP, et a!: Feline lower urinary tract disorders. In Ettinger SJ (ed): Textbook of Veterinary Internal Medicine, ed 4. Philadelphia, WB Saunders, 1995, p 1805 52. Osborne CA, Low DG, Finco DR: Cystitis-urethral obstruction complex in the cat. In Canine and Feline Urology. Philadelphia, WB Saunders, 1972, p 361 53. Osborne CA, Lulich JP, Thumchai L, et al: Etiopathogenesis and therapy of feline calcium oxalate uroliths. In Proceedings of the 13th American College of Veterinary . Internal Medicine Forum, Orlando, 1995, p 487 54. Osborne CA, Polzin DJ, Klausner JS, et al: Medical management of male and female cats with nonobstructive lower urinary tract disease. Vet Clin North Am Small Anim Pract 14:617, 1984 55. Rich LJ, Fabricant CG: Urethral obstruction in male cats: Transmission studies. Can J Comp Med 33:164, 1969 56. Rich LJ, Kirk RW: The relationship of struvite crystals to urethral obstruction in cats. JAm Vet Med Assoc 154:153, 1969 57. Ross LA: Treating FUS in unobstructed cats and preventing its recurrence. Vet Med 85:1218, 1990 58. Schechter RD: The significance of bacteria in feline cystitis and urolithiasis. J Am Vet Med Assoc 156:1567, 1970 59. Schechter RD: Heinz body anemia associated with use of urinary antiseptics containing methylene blue in the cat. JAm Vet Med Assoc 162:37, 1973 60. Straeter-Knowlen IM, Marks SL, Rishniw M, et al: Urethral pressure response to smooth and skeletal muscle relaxants in anesthetized, adult male cats with naturally acquired urethral obstruction. Am J Vet Res 56:919, 1995 61. Straeter-Knowlen IM, Marks SL, Speth RC, et al: Effects of succinylcholine, diazapam, and dantrolene on the urethral pressure profile of anesthetized, healthy, sexually intact male cats. Am J Vet Res 55:1739, 1994 62. Talon GF, Hamar DW, Lewis LD: Urinary acidification in the prevention and treatment of feline struvite urolithiasis. JAm Vet Med Assoc 184:437, 1984 63. Taussig RA: Cystitis in the female cat: Therapy and prophylaxis. Feline Pract 5:52, 1975 64. Tucker HQ, Keating LK: Use of copper intracystic device to treat urinary obstruction in male cats. Vet Med/Small Anim Clinician 75:435, 1980 65. Willeberg P: Epidemiology of naturally occurring feline urological syndrome. Vet Clin North Am Small Anim Pract 14:455, 1984

Address reprint requests to John M. Kruger, DVM, PhD Department of Small Animal Clinical Sciences Michigan State University College of Veterinary Medicine East Lansing, MI 48824