Felipedia

Feline idiopathic cystitis (FIC) has been characterised as a chronic lower urinary tract syndrome of unknown cause and with no widely accepted treatment. The clinical signs of FIC include variable combinations of dysuria, pollakiuria haematuria and periuria (inappropriate urination). FIC may be the most common cause of lower urinary tract signs. It affects two thirds of the 1.5% of cats that present to primary veterinary care with lower urinary tract signs.

FIC is not thought to be a single disease entity, since it presents with a comorbidity of a variety of unexplained clinical conditions in some patients with FIC. Recent studies in cats with severe FIC reveal the presence of an underlying neuroendocrine abnormality.

Human patients with idiopathic cystitis appear to suffer from a wide variety of comorbid conditions and the data suggests the same is true in cats. For example, lower urinary tract signs have been reported to be a comorbid condition in cats with separation anxiety syndrome, hypertrophic cardiomyopathy and obesity. These findings suggest that FIC may not be a disease process localised to the bladder. Further research in cats with FIC supports this hypothesis. Clinicians must obtain a thorough history and physical examination of cats with lower urinary tract signs to identify other abnormalities and to help prepare specific therapeutic protocols for individual cats with FIC.

One important challenge to any hypothesis for a non-bladder etiology for FIC is 'Why are clinical signs related to the urinary bladder?' A more illuminating question may be 'Why can so many organ systems be affected in patients with FIC?' The answer to this question may be related to alterations in the two primary stress response systems in the body: the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis.


Normal urinary system in the male cat	FIC in the male cat

In FIC in cats, there appears to be an enhanced activation of the stress response system, primarily the sympathetic nervous system limb. Once stimulated by higher brain structures responding to the perception of a threat, corticotrophin-releasing factor (CRF) is released from the hypothalamus, which acts as a hormone to stimulate the anterior pituitary gland to release ACTH. CRF also acts as a neurotransmitter to stimulate neurones in the brainstem, including the locus coeruleus, to activate the sympathetic nervous system. Under mild stress conditions, cats with FIC had significantly higher plasma levels of dihydroxyphenylalanine (DOPA), norepinephrine (NE), and other catecholamine metabolites compared with healthy cats. These results support previous work documenting elevated tyrosine hydroxylase, the rate limiting step in catecholamine synthesis in the brainstem of cats with FIC.

Activation of the SNS can increase epithelial permeability and permit environmental agents greater access to sensory afferent neurones, which could result in increased sensory afferent firing and local inflammation. Altered bladder permeability has been reported in cats with FIC and may be mediated via the SNS. Sympathoneural-epithelial interactions apparently play an important role in permeability. For example, it has been shown that application of NE to bladder strips induces release of nitric oxide from uroepithelium. Application of capsaicin results in release of nitrous oxide from epithelium in addition to nervous tissue in the urinary bladder. In light of reports that nitrous oxide may increase urothelium permeability, these results suggest that some of the sympathetically mediated alterations in permeability may be mediated by norepinephrine via this mechanism. The increased permeability related to increased SNS activation does not require direct interaction with epithelial cells, nor is it restricted to the urinary bladder.

However, the presence of inflammation and altered permeability is not well correlated with pain, as anyone who has had a superficial bruise will know. In the bladder, we have reported the presence of submucosal petechial haemorrhages in cats with no signs of referable to the lower urinary tract, and other investigators have identified urothelial disruption and increased presence of inducible nitric oxide synthase (and presumable increased permeability) in painless bladder conditions. Moreover, emotional and environmental factors such as stress or depression can modulate the experience of pain through descending pathways from the midbrain. Therefore, even the increased activity of afferent nerves noted in FIC cats could result in different perceived bladder sensations at any given time, depending on the emotional state of the animal.

If similar mechanisms are at work in patients with FIC, and the evidence to date suggests that they are, it could provide an explanation for the association of symptom flares with stressful circumstances. Conversely, drugs or environmental manipulations that promote improved emotional status, or are perceived to do so, are likely to reduce flare-ups. Such a mechanism also could explain the high placebo response (approximately50 per cent) observed in interstitial cystitis in humans and FIC trials. Knowledge of this placebo response could be useful for the clinician, because maximising it through environmental enrichment strategies described below could result in a more successful outcome for the patient.


The interaction between sensory and inflammatory pathways in the urinary bladder	The layers of the adrenal gland

In contrast to the elevated SNS in some FIC cats, we found that the cortisol response to ACTH stimulation was reduced during stressful periods in cats with FIC. We also found that adrenal gland size was significantly smaller in cats with FIC than in healthy cats. Microscopic examination of the adrenal glands did not reveal any obvious fibrosis, haemorrhage, inflammation, infection or necrosis as causes of the reduced size; the primary abnormality identified was a reduced size of the zona fasciculata and zona reticularis (the zones responsible for cortisol and other steroid hormone secretions). These results, when combined with our observations of increased concentrations of CRF and ACTH in response to stress, in the absence of a comparable increase in plasma cortisol concentration, strongly support the presence of decreased adrenocortical reserve in cats with FIC. Cortisol mainly restrains SNS outflow from the locus coeruleus and inhibits its own release by feedback inhibition at the level of the anterior pituitary gland and hypothalamus to terminate the stress response. The lack of cortisol (and possible other neurosteroids) might contribute to the elevated SNS. Adrenocortical steroids tend to antagonise the effects of the SNS. For example, glucocorticoids play a role in epithelial permeability, with cortisol primarily enhancing tight junction integrity to reduce permeability. This and other adrenocortical steroid-related protective mechanisms may be less efficient in hypocortisolemic states.

To explain this paradoxical combination of increased CRF, ACTH and SNS activity is difficult in the presence of reduced adrenocortical response and small adrenal fasciculata and reticularis zones. One current hypothesis involves a genetic disorder or developmental anomaly affecting the fetus (or some combination of the two). A number of recent reviews have explored the consequences of subjecting pregnant females to threatening stressors for the developing foetus. If the stressor is sufficiently harsh, the hormonal products of the ensuing stress response may cross the placenta and affect the course of fetal development. A reduction in adrenal size may result from glucocorticoid-mediated suppression of release of ACTH by the fetal anterior pituitary gland. It has been shown that glucocorticoid injections during the last trimester of pregnancy in baboons inhibited fetal pituitary ACTH release and adrenal cortical ACTH receptor expression. This effect blocked development of the fetal transitional (cortisol producing) zone. Prenatal and postnatal stressors also can result in persistently increased central CRF activity. Regardless of the cause, decreased biological activity of glucocorticoids may have a variety of adverse effects on bodily function, possibly related to their role in restraining activation of the immune system and other components of the stress response, including the SNS and CRF.

Although cortisol responses are subnormal in these severe FIC cats, cortisol replacement with prednisolone has not been demonstrably useful in this clinical syndrome. The apparent lack of long-term benefit of glucocorticoid therapy in patients with FIC suggests that inadequate production of other steroids also may play a role in the pathophysiology of this disease. The adrenal cortex is responsible for many different hormones, and the only one sufficiently investigated is cortisol. Preliminary studies in humans with interstitial cystitis have suggested alterations in the relationships between adrenal hormones, particularly the cortisol / dehydroepiandrosterone sulfate (SHEAS) ratio. Adrenocortical function also has been evaluated in human patients with other chronic, waxing and waning pain conditions (e.g. chronic fatigue syndrome) by measuring the cortisol / DHEAS ratio. This ratio was twofold to threefold higher in chronic fatigue patients than in controls. It has been suggested that serum levels of DHEAS may be low in patients with inflammatory and noninflammatory diseases because of an activate SNS. Sympathetic hyperactivity may be a common denominator for low levels of DHEAS in both inflammatory and noninflammatory diseases. Currently we have not investigated this in cats with FIC. In the meantime, we cannot advocate the use of steroids as a sole treatment for FIC, and based on clinical experience, cats do not seem to improve with the current antiinflammatory doses of prednisolone commonly administered.

The sensitivity of cats to their surroundings has long been recognised. Recent ethological studies in zoos, research laboratories and boarding facilities have documented that cats subjected to impoverished or unpredictable environments have decreased activity levels and increased hiding behaviour. The indoor environment of some house cats also may be monotonous and predictable, which could be stressful. The effects of indoor housing on disease risk in domestic cats recently has been reviewed. Although it reduces the risk of infectious disease and accidental injury, indoor housing has been associated with increased risk for development of FLUTD, calcium oxalate urolithiasis, odontoclastic resorptive lesions, obesity and hyperthyroidism.

Currently, the HPA axis abnormalities found in cats with FIC are not fully understood, and our current therapy is aimed at alteration of the SNS in hopes of decreasing sympathetic tone and neurogenic inflammation and altered permeability. Any treatment strategy to decrease SNS outflow may be important in reducing these abnormalities. Our clinical experience with cats with severe FIC suggests that environmental enrichment to attempt to reduce the cat's perception of threat often is sufficient to eliminate recurrence of signs. We have reported recently that environmental enrichment strategies that consisted of owner education about their cat's disease, proper litterbox management strategies, dietary alterations, modification of the indoor environment to reduce anxiety and cooperation with owners in multicat households to reduce conflict resulted in highly statistically and clinically significant remission of FLUTD and abnormal behavioural signs. Changes to the cat's environment were implemented slowly, and alterations were tailored for each individual cat according to limitations of each owner and household. See www.indoorcat.org for more information.

Another strategy for treating cats with FIC includes application of feline pheromones. Pheromones are fatty acids that seem to transmit highly specific information between animals of the same species. Although the exact mechanisms of action are unknown, pheromones reportedly induce changes in the limbic system and the hypothalamus, which alter the emotional state of the animal. Feliway, a synthetic analogue of this naturally occuring feline facial pheromone was developed in an effort to decrease anxiety-related behaviours of cats. Although not specifically tested in cats with FIC, treatment with this pheromone has been reported to reduce the amount of anxiety experienced by cats in unfamiliar circumstances, a response that may be helpful for FIC patients and their owners.The spray can be used to treat areas of the house where the cat is urinating by use of a single spray to the affected spot daily for 30 days.