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Proceeding of the NAVC

North American Veterinary Conference
Jan. 13-27, 2007, Orlando, Florida

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Reprinted in the IVIS website with the permission of the NAVC

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Published in IVIS with the permission of the NAVC
Small Animal – Nephrology and Urology
FELINE IDIOPATHIC CYSTITIS: CURRENT
INFORMATION AND HOW IT APPLIES TO
TREATMENT
Jodi L. Westropp, DVM, PhD, Diplomate ACVIM
School of Veterinary Medicine
University of California, Davis, CA
PATHOPHYSIOLOGY: WHAT ROLE DOES STRESS
PLAY?
Clinical signs of feline idiopathic cystitis (FIC) can
wax and wane and appear to be exacerbated by
stressful circumstances. In previous studies in cats with
FIC, we found they had a significant increase in tyrosine
hydroxylase (TH) immunoreactivity (IR) in the brainstem
(locus coerules (LC))1 as well as the paraventricular
nucleus of the hypothalamus.2 TH is the rate-limiting
enzyme of catecholamine synthesis. The increased
THIR observed in the LC of cats with FIC may provide a
clue to the observation that clinical symptoms of FIC
follow a waxing and waning course, and can be
aggravated by environmental stressors.
Because of these findings, we prospectively
evaluated various catecholamines in 13 FIC and 12
healthy cats. All cats were subjected to an acute,
moderate stressor for 8 days. During that time period,
we compared serum fluorescein concentrations to
evaluate bladder permeability, and urine coritsol:
creatinine to evaluate the hypothalamic–pituitary–
adrenal axis. In a subset of cats, catecholamine
concentrations were also analyzed. After 8 days of a
moderate stressor, all cats were moved to an “enriched”
environment and testing was once again repeated to
investigate this form of therapy. Our results showed that
plasma fluorescein concentrations were significantly
higher in FIC cats at all times. In the group of cats where
plasma [CCE] were available, plasma
dihydroxyphenylalanine (DOPA), norepinephrine (NE)
(Figure 1), and dihydroxy- phenylglycol (DHPG)
concentrations were significantly increased in FIC cats at
all times (P<0.05); no differences between groups were
identified in cortisol: creatinine. Therefore, we concluded
that FIC cats appear to have altered bladder
permeability, which was worse during the initial stress.
NE
15000
NE (pg/ml)
Healthy
FIC
5000
0 10 20 30 40
Day
Figure Figure
1. Plasma
1 norepinephrine concentrations
were significantly increased in FIC cats (P<0.05).
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The marked increment in [DOPA] suggests the
possibility of a stress-induced increase in activity of TH,
the rate-limiting step in CCE synthesis. In contrast, no
effects on urine cortisol:creatinine were identified,
suggesting an uncoupling of these two parameters of the
stress response.
Enhanced stimulus-induced local NE release from the
bladder3 could lead to a functional desensitization of
central alpha-2 adrenoceptors (α-2 AR) in cats with FIC.4
In the brainstem, α-2 agonists inhibit NE release,
whereas in the spinal cord they inhibit transmission of
nociceptive input to the brain.5 To further test this
hypothesis, we evaluated the functional sensitivity of the
α-2 AR in cats with FIC by evaluating their response to
the selective α-2 AR agonist, medetomidine. These
studies were carried out under the same stress protocol
we used to measure catecholamine concentrations. If
the post-synaptic α-2 ARs are normal, one would expect
a decrease in heart rate (HR) and increase in pupil size
after medetomidine administration. The decline in HR
following medetomidine administration was significantly
greater in healthy cats as compared with cats with FIC,
although this difference was attenuated after
environmental enrichment, which was assessed on day
35 (P = 0.05, Table 1).6 The increase in pupil diameter
following medetomidine administration was significantly
greater in healthy cats as compared with FIC cats. We
did not see any significant differences in post synaptic
α2-AR function when evaluating sedation.7 Electrical
field stimulation studies of bladder strips from FIC cats
revealed that atipamezole, an α2-AR antagonist, did not
alter the relaxing effect of NE, further suggesting that
α2-ARs are downregulated in this disease.8
In addition to the sympathetic nervous system,
abnormalities in the hypothalamic–pituitary–adrenal axis
(HPA) have also been observed in cats with FIC. After a
significant stressor (car ride, flight and transport to our
hospital), a high dose (125 µg) of synthetic ACTH was
administered. Cats with FIC had significantly decreased
serum cortisol responses as compared with healthy cats
(Figure 2).9 Although no obvious histological
abnormalities were identified, the areas consisting of the
zonae fasciculata and reticularis were significantly
smaller in sections of glands from cats with FIC than in
sections of glands from healthy cats. Therefore, it
appears that while the sympathoneural system is fully
activated in this disorder, the HPA axis is not.
Table 1. Percent Change in Heart Rate after
Medtomidine Administration
FIC Cats Healthy Cats
(mean ± SD) (mean ± SD)
Day 1 23% ±1 5%* 34% ± 10%
Day 3 15% ± 14%* 37% ± 12%
Day 8 24% ± 9%* 32% ± 13%
Day 35 20% ± 10% 26%± 16%
711
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ACTH
20 Stimulation
Serum cortisol (ug/dl)
p=0.0007
10
p=0.5
0
0 30
Figure 2
Time
Figure 2. Cats with FIC had significantly decreased
serum cortisol responses as compared with healthy
cats .
The pathophysiology of FIC likely involves complex
interactions between a number of body systems.
Abnormalities are not localized just to the bladder, but
are present in the nervous, endocrine, and even
cardiovascular systems.10 How these systems
communicate and manifest as FIC in some cats, but not
in others remains to be determined. In order to better
treat their patients, it is important for clinicians to
understand that this syndrome is not just a “bladder
disease” amenable to simple diet or drug therapies.
APPROACH TO THE PATIENT DIAGNOSTICS
Because FIC is a diagnosis of exclusion, diagnostics
should be performed to rule out other causes of LUTS
mentioned above. Urolithiasis can occur
approximately 12% to 15%11 of cats with LUTS and an
abdominal radiograph which includes the entire urinary
tract should be performed. Less than 2% of young (<10
years of age) cats have true bacterial cystitis, so urine
culture is a low yield test,11,12 but warranted particularly
in all cats with recurrent (>2 episodes) LUT signs. The
possibility of a urinary tract infection increases with age,
perineal surgery, in the presence of cystic calculi, and
dilute urine.13 A contrast cystourethrogram can be
helpful to better evaluate for the presence of non-
radiopaque calculi and other lesions such as mass
lesions, blood clots, and strictures in those cats with
recurrent episodes. If, despite therapy, clinical signs
continue, an abdominal ultrasound, and/or cystoscopy
can be performed to be sure no other lesions in the
lower urinary tract were missed. These imaging
modalities are especially indicated in elderly cats (>10
years of age) where FIC is not as likely.
TREATMENT OF FIC
When a cat presents with LUTS, analgesic therapy
seems appropriate for the acute management of the
disease. Providing analgesia with nonsteroidal anti-
inflammatory agents such as carprofen and ketoprofen,
or butorphanol or more potent opioids such as fentanyl
(patches) has been suggested, but no studies have been
reported to date, and many drugs are not approved for
712
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The North American Veterinary Conference – 2007
these uses. During acute flare-ups we generally
prescribe some form of analgesia such as butorphanol
or buprenorphine combined with a short-term tranquilizer
p=0.0004
such as acepromazine. In male cats, I will oftentimes
use an alpha antagonist such as phenoxybenzamine or
prazosin.
Normal n=12
MULTIMODAL ENVIRONMENTAL MODIFICATIONS
FIC n=23 (MEMO)
Based on our previous findings where
catecholamines decreased after environemental
60 modifications in research cats, we have evaluated client-
owned cats with idiopathic cystitis implementing
multimodal environmental modification (MEMO) as the
sole management strategy. In this observational study
we evaluated 46 client-owned indoor-housed cats with
FIC. In addition to their usual care, clients were offered
recommendations for MEMO based on a detailed
environmental history. Cases were followed for ten
months by client contact to determine the effect of
MEMO on LUTS and other signs. Significant (P<0.05)
reductions in LUTS, fearfulness, nervousness, signs
referable to the respiratory tract, and a trend (P<0.1)
toward reduced aggressive behavior were identified.14
These results suggest that MEMO is a promising
adjunctive therapy for indoor-housed cats with LUTS.
I generally follow a staged approach to therapy which
begins with client education and MEMO. If a patient
relapses, these topics are thoroughly reviewed and
additional changes are implemented. In multi-cat
houses, cats also interact with each other. Addressing
inter-cat issues seems very important in the
management of this disease as well.
in DIETARY THERAPY
Some dietary modifications may reduce the risk of
recurrence of LUT signs in affected cats. Efforts to
acidify the urine using dry foods have no demonstrated
value in the treatment of cats with FIC. A slightly
acidifying high moisture diet can be used in male cats
that are obstructed with struvite crystalline plugs. We do
encourage increasing water intake, and consumption of
a canned food is one way to accomplish this. To avoid
the potential stress of being confronted with an
unfamiliar diet, we recommend introducing the new
canned food alongside the original diet. In one report,
LUT signs recurred in only 11% of affected cats during
one year of feeding the canned formulation of a dietary
product designed to result in production of slightly acidic
urine. Recurrence occurred in 39% of cats fed the dry
formulation of the same food, suggesting that both
constancy and consistency (ie, increased water intake)
may be important, but the reasons for this effect remain
to be determined.
PHEROMONES AND DRUG THERAPY
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
both the limbic system and the hypothalamus that alter
the emotional state of the animal.15 Feliway® (Ceva
Published in IVIS with the permission of the NAVC
Small Animal – Nephrology and Urology
Sante Animale, Libourne, France), a synthetic analogue
of this naturally occurring feline facial pheromone, was
developed in an effort to decrease anxiety-related
behaviors 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 to these patients and their owners. Increased
grooming and food intake in hospitalized cats16 also has
been reported with the use of Feliway®.
We have used amitriptyline (a tricyclic antidepressant
(TCA)) in uncontrolled trials to successfully decrease
clinical signs of severe, recurrent FIC.17 Amitriptyline
(Elavil®, 2.5–5 mg per cat SID), may provide analgesia
by inhibition of NE reuptake at noradrenergic nerve
terminals,18 and possibly due to inhibition of a wide
range of nociceptive neurons in the spinal trigeminal
nucleus.19 Urine retention through anticholinergic effects
of the TCAs may result. Findings in a series of cats with
severe FIC showed that the clinical signs of some cats
were reduced during amitriptyline treatment during a 12-
month period.
Clomipramine (Clomicalm® 0.5 mg/kg SID, veterinary
label; and Anafranil®, human label) is also a tertiary
amine like amitriptyline, but has more selectivity for
blocking the reuptake of 5-HT. Although not studied in
cats with FIC, I have prescribed this and found
improvements in some patients. Other drugs such as
fuoxetine (Prozac®, 0.5–1.0 mg/kg PO SID) has been
reported to help cats with inappropriate urinations with
variable success rates.20 Fluoxetine was used to help
decrease the rate of urine marking after environmental
alterations such as litter box hygiene and appropriate
cleaning strategies.
We do not recommend amitriptyline for acute
treatment of FIC since it has been shown to have
minimal to no benefit in the short- term resolution of
signs in cats with FIC. All the TCAs as well as the
selective serotonin reuptake inhibitors should be
reserved for recurrent, severe cases. These drugs
should only be used after environmental strategies, diet
changes (if necessary), and behavior modifications have
failed. Furthermore, it is our opinion that these drugs
should then only be used in conjunction with the above-
mentioned therapeutic strategies for optimal effects.
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