Nonobstructive Idiopathic or Interstitial Cystitis in Cats

Chapter 10 Nonobstructive Idiopathic or Interstitial Cystitis in Cats



Terminology



Feline Urological Syndrome (FUS) and Feline Lower Urinary Tract Disease (FLUTD)





1. Previously used terminology is confusing and reflects a lack of understanding of the etiopathogenesis of this syndrome.

2. These terms originally were used to describe a syndrome in cats characterized by pollakiuria, stranguria, hematuria, and inappropriate urination.

3. They are nonspecific terms and do not indicate if clinical signs arise from the bladder, urethra, or both.

4. In private practice, cats with idiopathic cystitis account for 1.5% to 6.0 % of all feline visits.


Feline Idiopathic Cystitis (FIC)





1. Describes signs of abnormal or irritative voiding behavior associated with absent or minimal cellular inflammation in the lower urinary tract. This type of inflammation is called neurogenic and is characterized by vasodilatation, edema, vascular leakage, diapedesis of red blood cells, but minimal inflammatory cellular infiltration.

2. FIC is a diagnosis of exclusion made after ruling out urolithiasis, bacterial urinary infection, anatomic abnormalities, behavioral disturbances, and neoplasia.

3. The disease process is multifactorial and involves interactions among the bladder, other organs (e.g., adrenal glands), the central nervous system (CNS), husbandry practices, and the environment.

4. It can be an acute or chronic condition.

5. In severe cases, affected cats may have a variety of comorbid disorders, and lower urinary tract signs are a manifestation of some underlying disorder.

6. Most male cats with urethral obstruction have lower urinary tract signs related to FIC after relief of the obstruction.


Interstitial Cystitis





1. Originally used to describe a bladder pain syndrome in humans that is very similar to FIC.

2. Original guidelines for diagnosis required visualization of glomerulations (submucosal petechial hemorrhages) by cystoscopy, but these findings are no longer required for diagnosis.

3. Interstitial cystitis refers to a chronic condition that waxes and wanes in severity and often is exacerbated by stress. Flares are acute episodes of clinical signs superimposed on the underlying chronic condition.

4. The term feline interstitial cystitis was coined to include cats with FIC that had undergone cystoscopic evaluation for the presence of glomerulations (submucosal petechial hemorrhages).



Pathophysiology




A. The pathophysiology of chronic FIC is not completely understood, but appears to involve abnormalities in many body systems including the bladder, nervous system, hypothalamic-pituitary-adrenal (HPA) axis, and possibly other body systems. Bladder lesions observed in cats with FIC may be a result of abnormalities in other body systems and not the actual cause of the disease.

B. Little is known about the acute pathophysiology of FIC because clinical signs often spontaneously resolve in <5 to 7 days even without treatment. Most studies have focused on cats with recurrent FIC.

C. Subclinical systemic abnormalities persist in cats with recurrent FIC even when clinical signs are not present.
1. Urothelial integrity, bladder permeability, glycosaminoglycan (GAG) excretion, adrenal function during stress, and CNS function are all abnormal in cats with FIC even when detectable clinical signs are not present.

2. No correlation exists among clinical signs, cystoscopic appearance of the bladder, and histologic findings. Cystoscopy often reveals severe changes in the bladder mucosa of cats currently in remission.

D. Histopathologic lesions in the bladder of affected cats are nonspecific (Figure 10-1).
1. Urothelium may be damaged or intact.

2. Submucosal edema.

3. Dilatation of submucosal blood vessels with marginated neutrophils.

4. Submucosal hemorrhage.

5. Increased mast cell infiltration.

6. Minor increases in numbers of lymphocytes and plasma cells in the submucosa.

7. Neutrophilic infiltration is not common.

8. Fibrosis.

9. Increased sensory nerve fiber density (identified by special stains).

E. Urothelial integrity is compromised in chronic FIC, and this change may be an initiating or perpetuating factor in the disease process (Figure 10-2).
1. In a normal bladder, GAG (specifically GP-51) contributes to the mucous layer that coats the intact urothelium and provides a barrier that inhibits bacterial attachment and repels noxious substances in urine, thus preventing urothelial damage.

2. Chronic FIC is characterized by a decrease in urinary GAG excretion. In some but not all studies, this is seen to occur as a result of decreased GAG synthesis or increased GAG adherence to damaged uroepithelial cells. The underlying reason for these changes in GAG and the uroepithelium is unknown. Whether the change is a primary abnormality or secondary to other changes in the bladder remains to be determined.

3. Decreases in the urothelial GAG layer may lead to an increase in bladder permeability allowing noxious substances in urine to permeate the bladder wall, causing tissue irritation and activation of the nervous system.
a. Urine can be damaging because of its high osmolality, low pH, and the presence of noxious waste products.

b. No single urinary component has been identified as the cause of irritation to the bladder mucosa.

c. Sensory neurons in the bladder wall are stimulated by urine and may contribute to nervous system abnormalities.

d. Sensory neuron stimulation also initiates pelvic pain.

F. Sensory neuron abnormalities.
1. C-fiber sensory neurons in the bladder are more sensitive in cats with FIC than in normal cats and contribute to altered activation of neural pathways.
a. Sensory neurons innervate the bladder via the pelvic and hypogastric nerves, which originate from the dorsal horn of the sacral and lumbar spinal cord, respectively.

b. These nerves include unmyelinated, nociceptive fibers referred to as C-fibers.

c. These fibers are more sensitive to bladder distension in cats with FIC than in normal cats.

d. There are increased numbers of these sensory fibers in addition to increased sensitivity to pain stimulation in cats with FIC.

2. Changes in sensory neuron excitability are not limited to the bladder and appear to represent a general neurologic malfunction, which, in turn, may explain why clinical signs of FIC are not necessarily limited to the bladder.

G. CNS alterations in FIC are associated with increased sympathetic nervous system activity.

image

FIGURE 10-1 Histopathologic lesions in the bladder of cat with FIC. Note predominantly hemorrhagic inflammation in the submucosa just below the uroepithelium. The submucosa is also edematous. Substantially lacking is any identifiable infiltration with neutrophils.


image

FIGURE 10-2 A, Normal bladder. Urine is repelled by the normal uroepithelium of the bladder and the glycosaminoglycan (GAG) layer. B, Chronic FIC showing increased bladder permeability. The GAG layer (1) or the GAG layer and the uroepithelium (2) have been damaged, allowing urine to permeate the bladder wall. Increased permeability in chronic FIC cats has been demonstrated even when cats were not showing signs of active inflammation. Infiltration with mast cells and increased numbers of sensory nerve fibers are a result. (Drawn by Tim Vojt.)



image Increased sympathetic nervous system outflow from the brain stem is a pivotal event in the neurogenic model of inflammation in FIC.




1. Altered activity in the locus coeruleus (LC), Barrington’s nucleus, and the paraventricular nucleus of the hypothalamus increase sympathetic outflow.

2. The LC is the most important source of norepinephrine in the feline CNS.
a. Perception of threat or bladder distension stimulates activity in the LC.

b. The LC increases sympathetic nervous system output to the periphery, including the bladder.

c. Chronic activation of this pathway increases levels of tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of catecholamines, in the LC.

d. Increases in TH contribute to increases in norepinephrine in cerebrospinal fluid and nervous tissue, bladder and colon, plasma, and urine in cats with FIC.

e. Cats with FIC have increased tyrosine hydroxylase immunoreactivity (THIR) in the LC.

H. Stress, inflammation, and bladder pain are key components of FIC that are integrated at the level of the sympathetic nervous system.
1. Stress, inflammation, and pain all activate the sympathetic nervous system.

2. Environmental stressors combined with increased sympathetic activity play a key role in the disease process.
a. Even in healthy animals, stress activates the sympathetic nervous system, which may initiate and perpetuate inflammation.

b. Norepinephrine contributes to vigilance, arousal, analgesia, and visceral responses to stress in cats.

c. In FIC, increased THIR and the corresponding increase in plasma norepinephrine concentration indicate an exaggerated sympathetic response even in the absence of stress.

d. This finding may explain why cats with FIC often exhibit a disease course that waxes and wanes and why environmental stressors intensify clinical signs.

e. Development of clinical signs of FIC seems to result from a sensitive cat in a provocative environment as depicted in Figure 10-3.

I. Increased sympathetic nervous system activity potentiates clinical signs in several ways.
1. Increased sympathetic nervous system activity promotes release of inflammatory mediators throughout the body, and these mediators are linked with pain that is not limited to the bladder. Norepinephrine also initiates the release of prostaglandins.

image

FIGURE 10-3 Interactions among environmental stimuli, the central nervous system, and the bladder can produce clinical signs of FIC when a sensitive cat is exposed to a provocative environment. Over activation of the brain stem from sensory nerve stimulation from the bladder activates adrenergic outflow from the locus coeruleus (LC) to the spinal chord, dorsal root ganglia, and the bladder wall, which upregulates the inflammatory response. The LC also can be activated directly from external stressors or through input from the cerebral cortex. (Drawn by Tim Vojt.)



image Increased sympathetic nervous system activity enhances the inflammatory potential of the bladder and urethra.




2. image Increased sympathetic outflow to the bladder alters urothelial permeability and initiates neurogenic inflammation via C-fibers (Figure 10-4).
a. Increased urothelial permeability allows noxious components of urine to gain access to the bladder wall and activate C-fibers.

b. Increased C-fiber activity initiates local inflammatory pathways that lead to vasodilatation and mast cell infiltration.

c. Chronic C-fiber activation may overload the brain with sensory information, which over time causes an increase in the density of C-fibers in the bladder.

3. Alpha 2-adrenoceptors also appear to function abnormally in cats with FIC in ways that may enhance inflammation.
a. Alpha 2-adrenoceptors are found throughout the CNS, including in the LC and spinal cord. Receptors in the brain function to prevent catecholamine release and those in the spinal cord dampen nociceptive input to the brain.

b. Peripheral alpha 2-adrenoceptors can be found in the bladder and urethral mucosa, where they regulate blood flow.

c. Alpha 2-adrenoceptors in the bladder and in the spinal cord of cats with FIC appear to be relatively desensitized.
(1) In the bladder, there is an increase in the inflammatory response, because of changes in blood flow.

(2) Nociceptive input to the brain increases, because the receptors in the spinal cord no longer dampen sensory input.

J. Abnormalities in the HPA axis help explain increased sympathetic activity.
1. Activity of the HPA axis in the healthy cat.
a. Corticotropin releasing factor is released by the hypothalamus and communicates with the pituitary to initiate the release of adrenocorticotrophic hormone (ACTH) and also activates the sympathetic nervous system in the brain stem.

image

FIGURE 10-4 Neurogenic inflammation in FIC. Sensory neurons (C-fibers) transmit action potentials via the dorsal root ganglia (DRG) to the spinal cord (SC) and brain. These signals may be interpreted as pain by the brain. Sensory fibers also can propagate a local axon reflex without central transmission. The local 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 result in the submucosal petechial hemorrhages (i.e., glomerulations) observed at cystoscopy. Receptors for SP also are present on smooth muscle. Also shown are the uroepithelium and glycosaminoglycan (GAG) layer overlying the mucosa. Damage to either or both of these layers permits hyperosmolar (>2000 mOsm/L) urine and its constituents (e.g., protons, potassium ions) to activate the sensory fibers. Stress may result in descending efferent sympathetic (SNS) signals stimulating the DRG and inducing peripheral release of neuropeptides. Local release of neurotransmitters by bladder sympathetic fibers also may stimulate sensory fibers. (Drawn by Tim Vojt.)



image Feline stressors often are unappreciated by the owner and attending veterinarian. Stress is a powerful stimulus for increased sympathetic nervous system activity and subsequent neurogenic inflammation.





b. ACTH stimulates the release of cortisol and other corticosteroids from the adrenal cortex.

c. Cortisol participates in a negative feedback loop to decrease production of ACTH and limit activation of the sympathetic nervous system.

2. Increased concentrations of corticotropic-releasing factor and ACTH and an impaired cortisol response have been identified during periods of stress in cats with FIC (Figure 10-5).

3. Decreased adrenal corticosteroid production may be involved in the pathogenesis of FIC.
a. During stressful situations in FIC cats, a disproportionate activation of sympathetic outflow may occur because of the deficient adrenocortical response.

b. Epithelial permeability may be adversely affected because, normally, cortisol enhances tight junction integrity.

4. Glucocorticoid therapy does not provide any long-term benefit to cats with FIC, indicating that inadequate production of other adrenal steroids may play a role in the pathophysiology. Only cortisol has been studied thus far.

5. Decreased adrenal gland volume per kilogram of body weight was found in cats with FIC compared with healthy cats.
a. No histologic abnormalities were identified in the adrenal glands of FIC cats.

b. The zona fasciculata and zona reticularis of the adrenal cortex (areas responsible for corticosteroid production) were significantly smaller in FIC cats compared with healthy cats.

c. The adrenal medulla (the area responsible for catecholamine production) was slightly larger in FIC cats compared with healthy cats.

image

FIGURE 10-5 Imbalances in the neuroendocrine system in FIC.. A, Normal stress response. B, Abnormal stress response. Excitatory sympathetic nervous system (SNS) outflow is inadequately restrained by cortisol and other adrenal corticosteroids. This enhanced sympathetic activity can increase tissue permeability, resulting in increased sensory afferent activity. Feedback inhibition at the level of the anterior pituitary and hypothalamus also is decreased, which perpetuates release of corticotrophin releasing factor (CRF). Neurosteroid production by the adrenal cortex, which normally enhances central nervous system (CNS) inhibitory tone during chronic stress, also may be reduced. The bold solid arrows indicate stimulation, and the dotted arrows indicate inhibition. Line thickness indicates signal intensity.



Signalment



Age





1. Range: 1 to 10 years of age.

2. Peak occurrence: 2 to 7 years of age.

3. Decreased risk in cats younger than 1 year of age.


Sex





1. No difference in occurrence between males and females.


Breed





1. Persian cats may be at increased risk.

2. Siamese cats may be at decreased risk.


Behavioral Characteristics of Affected Cats





1. Over-reactive to their environment.

2. Nervous, fearful, defensive, or aggressive.

3. May have a neurotic attachment to their owners.


Factors That Have Been Associated With Increased Risk





1. Neutered (versus intact).

2. Indoor housing.

3. Use of a litter box for urination and defecation.

4. Diet consisting of 75% to 100% dry food.

5. Obesity.

6. Sedentary lifestyle.

7. Multi-cat household.

8. Decreased water intake.

9. Stressful interactions with owners or environment.

10. Recent moves or changes in routine.

11. Genetics and epigenetic modulation.


Clinical signs




A. We use the acronym “FISH” to describe the principal lower urinary tract signs associated with idiopathic cystitis:
1. Increased frequency.

2. Inappropriate urinations. Also called periuria (i.e., urinating outside the litter box). This is the most common clinical sign reported by owners, and in some cases may be the only reported sign.

3. Stranguria.

4. Hematuria and howling (vocalization) during urination.

B. Clinical signs may be acute or chronic.
1. An attempt should be made to determine if the problem has been chronic.

2. Chronic recurrent signs mandate a more extensive diagnostic evaluation and treatment plan.

3. Urethral obstruction may be a sequela to FIC in male cats.

C. The development of clinical signs appears to require the presence of predisposing internal abnormalities (i.e., brain, bladder, adrenal glands) as well as external factors (i.e., stressors) that bring the cat to a threshold at which clinical signs will be exhibited.

D. Recent studies have shown that 50% or more of cats with FIC will develop episodic or persistent signs within 1 year of the first episode.


Differential diagnoses



Cats Younger Than 10 Years of Age





1. FIC accounts for 60% to 70% of cats presented for clinical signs of irritative voiding (Figure 10-6).
image

FIGURE 10-6 Distribution of diagnoses in young cats presented for signs of lower urinary tract distress.


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



image FIC is the most common diagnosis in cats younger than 10 years of age with signs of irritative voiding.


2. Urolithiasis accounts for 10% to 20%.

3. An anatomic abnormality (e.g., urachal diverticulum, urethral stricture) accounts for 10%.

4. A behavioral disorder accounts for 10%.

5. Bacterial urinary infection accounts for <2%.

6. Neoplasia accounts for <1%.


Cats Older Than 10 Years of Age





1. FIC accounts for only 5% of cats presented for clinical signs of irritative voiding.

2. Bacterial urinary tract infection (UTI) accounts for more than 50%. Bacterial UTI in older cats often occurs in association with urolithiasis or chronic kidney disease (with production of submaximally concentrated urine).


History




A. See Figure 10-7 for lower urinary tract (LUT) Environmental and Resource Questionnaire.

B. Effective client communication will facilitate accurate diagnosis and increase the likelihood of successful treatment.

C. Establish a bond with the client, ask open-ended questions, practice reflective listening, and provide empathic statements to obtain a thorough history and build client confidence.

D. Ask questions about early adverse events the cat may have experienced and that may serve as vulnerability factors (e.g., maternal stress, orphaned, bottle-fed, early neutering).

E. Attempt to identify comorbid conditions that may be present:
1. Gastrointestinal disturbances.
a. Regurgitation.

b. Vomiting (hair or food).

c. Soft stool.

d. Diarrhea.

2. Skin lesions (e.g., a diagnosis of flea allergy dermatitis with no fleas present).

3. Behavior problems (e.g., frightened, withdrawn, hiding, aggressive, overly attached).

4. Cardiac conditions.
a. Heart murmur.

b. Gallop rhythm.

c. Cardiomyopathy.

F. Gather information about litter box use and maintenance.
1. Number and location.
a. Cat owners should have one litter box for each cat (or cat group) in the household plus one additional box.

b. Boxes should be easily accessible and kept away from noisy household appliances that may frighten the cat and keep it from using the litter box.

2. Size and depth.
a. Boxes may be too small for large cats or too deep for arthritic cats to easily enter.

b. As a rule of thumb the litter box should be as long as the cat.

3. Hooded or uncovered.

4. Automatic cleaning. Although these devices keep litter boxes clean, some cats are frightened by the noise created by the machine.

5. Type of litter used and how often the owner changes the litter.
a. Clumping versus nonclumping.

b. Scented versus nonscented.

c. Cats sometimes demonstrate definite substrate preferences.
(1) Substrate preference can be determined by testing different substrates in separate boxes and allowing the cat to choose.

(2) The type of substrate should not be changed frequently, because doing so may induce stress, unless the new substrate is provided in a separate litter box.

6. Cleaning schedule.
a. How often is the box scooped for urine and feces (i.e., once daily, twice daily, every other day, weekly)?

b. How often is the litter completely removed and the box refilled?

7. Does the cat fully cover its urine and feces in the box? Failure to do so suggests an unsatisfactory litter box environment.

G. Ask detailed questions about inappropriate eliminations to identify periuria.
1. The location, number, and size of urine spots may help determine if FIC or a behavioral problem is more likely.
a. Large spots may indicate polyuria with overflow.

b. Small spots in numerous locations may indicate increased urgency and pain from cystitis.

2. Distinguish litter box problems from inappropriate eliminations associated with FIC. Toileting (defined as the deposition of normal urine and feces outside the litter box without signs of irritative voiding) suggests litter box management problems.

image image image image

FIGURE 10-7 Detailed Environmental History and Assessment Forms for use in cats with FIC. Results from these forms are designed to assist the attending veterinarian in a comprehensive assessment of the cat’s living environment. A, Clinical Signs History Form.


B, “9-Lives” Checklist.


C, Resource Checklist and Client Action Plan.


(Developed by the Indoor Cat Initiative, The Ohio State University [www.vet.ohio-state.edu/indoorcat.htm] and used by permission.)



image Determine if inappropriate urinations are normal toileting events or related to irritation of the lower urinary tract.





a. Characterized by the presence of a moderate amount of urine in one spot.

b. Paw markings on the carpet around the urine spot suggest an attempt to cover the area (a normal behavior associated with urination).

c. The cat may prefer the substrate in the area in which it is toileting (e.g., carpet texture).

d. Toileting problems indicate the litter box must be cleaned more frequently.

e. Toileting problems may indicate the cat has developed an aversion to the current litter. Aversion to a particular litter type can develop during acute episodes of FIC, after which the cat may associate a particular litter type with painful attempts at urination. Toileting in only one location suggests litter box avoidance.

f. Urinations on vertical locations (e.g., walls) indicate spraying or marking behavior.

g. Litter box problems should be considered likely if the owner reports deposition of both feces and urine outside of the litter box.

3. Irritative voiding results in deposition of small volumes of urine in multiple places.

H. Stress in the cat’s or owner’s life should be identified if possible during the history because stress can play an important role in initiating and perpetuating clinical signs. Determination of the degree of stress in an individual cat’s life can be difficult.
1. Moving to a new living space or a change in the owner’s schedule are very stressful experiences for a cat.

2. Many other stressors are possible and may arise from other animals, humans, the living space itself, and husbandry (e.g., diet, water, litter box).

3. Earthquakes and dramatic changes in weather conditions (as seasons change) also have also been reported to increase risk for episodes of FIC.

4. The amount of activity in the cat’s environment can affect the stress response.


Physical Examination




A. Perform a complete physical examination of all other body systems before focusing on the urinary tract to ensure identification of all comorbid conditions that may be present.

B. Evaluate the cat for pain on abdominal palpation of the bladder or elsewhere.

C. A thickened bladder wall may be identified in some cats with chronic disease. During flares of FIC, the bladder will be small due to irritative voiding.

D. The remainder of the physical examination usually is normal.

E. Excessive grooming or biting of the hair on the caudal abdomen may be a sign of referred pain in some cats (so-called barbering). Some cats also will pull hair out in clumps from the flanks and tail base.

F. Gallops, murmurs, hypertrophic cardiomyopathy, obesity, odontoclastic resorptive dental lesions, gastrointestinal disease, and nervousness potentially are comorbid conditions that occur with increased frequency in cats with FIC.
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Related posts:

  1. Familial Renal Diseases of Dogs and Cats
  2. Diseases of the Glomerulus
  3. Acute Renal Failure
  4. Disorders of Micturition and Urinary Incontinence

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Jul 10, 2016 | Posted by in INTERNAL MEDICINE | Comments Off on Nonobstructive Idiopathic or Interstitial Cystitis in Cats

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