WHAT IS THE PATHOGENESIS OF FIC?

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Emory Carroll
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1 Urine Agny: Feline Lwer Urinary Tract Disease Je Bartges, DVM, PhD, DACVIM, DACVN Crnell University Veterinary Specialists, Stamfrd, CT, USA Prevalence f lwer urinary tract disease is mre cmmn in cats between 1 and 10 years f age; whereas in dgs, the prevalence increases with advancing age. In cats greater than 10 years f age, bacterial urinary tract infectin is mst cmmn. In yung cats, idipathic lwer urinary tract disease ccurs mst cmmnly. Urinary tract infectins and urlithiasis has been discussed previusly in this cnference; therefre, this discussin will fcus n feline idipathic cystitis (FIC). WHAT IS THE PATHOGENESIS OF FIC? By definitin, FIC is an idipathic disease and therefre the underlying cause is unknwn. As nted earlier, it is entirely pssible (and perhaps even prbable) that FIC is nt a single entity, but rather a syndrme that may have mre than ne underlying cause. This, fr example, is evident in the nging search fr a ptential viral rle in sme cases f FIC. Nevertheless, in a number f different studies, bth lcal bladder abnrmalities and/r neurhrmnal changes have been bserved in at least a prprtin f cats affected by FIC. While these changes are hard t interpret, and again it can be difficult t differentiate cause frm effect (and smetimes even incidental bservatin), they d supprt the cncept f cmplex underlying abnrmalities and predispsitins that may cntribute t the develpment f FIC. There are several prpsed lcal bladder abnrmalities in the pathgenesis f FIC. Studies in cats with idipathic cystitis have shwn that as in humans with interstitial cystitis, there is a decreased cncentratin f glycsaminglycans (GAGs) in the urine f affected cats Other lcal bladder factrs have als been identified that may have a rle t play in the pathgenesis f FIC. These include: an altered tissue r and/r urine cncentratin f inflammatry r ther biactive mlecules such as cmplement c4a, thiredxin, NF-κB p65, galaectin-7, I-FABP, fibrnectin, and trefil factr 2; mucsal muscarinic receptrs have been reprted t have increased sensitivity in cats with FIC, which culd ptentially enhance smth muscle spntaneus cntractin, althugh evidence f an veractive bladder has nt been fund in assciatin with FIC; increased bladder tissue cncentratins f nrepinephrine and an increase in maximum urethral pressures and urethral clsure pressures in affected cats; histlgical changes in the bladder wall including edema, haemrrhage, vasdilatin, ccasinally ulceratin, and a variable increase in the number f mast cells; there is evidence t supprt the presence f neurgenic inflammatin and mediatrs f pain and inflammatin in the bladder, with evidence f increased expressin f transmitters such as ATP and nitric xide, altered expressin f purinergic receptrs, increased numbers f substance P cntaining neurns, increased expressin f high affinity substance P

2 receptrs, and increased excitability f afferent bladder neurns, with evidence that urthelial cells themselves may be invlved in the prcess. As in humans with interstitial cystitis, a number f neur-hrmnal abnrmalities have been detected in cats with FIC that might have a rle t play in the pathgenesis f the cnditin. These bservatins include: an increase in plasma nrepinephrine and dihydrxylphenylalanine in FIC cats cmpared with nrmal cats, but withut a cncmitant increase in crtisl r adrencrtictrphic hrmne (ACTH); an increase in tyrsine hydrxylase immunreactivity in the lcus ceruleus f the brain f cats with FIC (during apparent quiescent perids), further supprting a rle fr increased sympathetic activity in cats with FIC; ptential adrenal insufficiency in cats with FIC evidenced by significantly reduced respnses t ACTH cmpared with healthy cats, and reduced vlume f their adrenal glands; differences in respnses t the α2-adrenergic agent medetmidine in FIC cats cmpared with nrmal cats. Cllectively, these findings (althugh perfrmed in a limited number f cats) lend supprt t the fact that FIC appears t be assciated with a stress respnse in many cats, but als suggests an uncupling f the nrmal stress respnses with increased sympathetic stimulatin but suppressed adrencrtical respnses. CLINICAL SIGNS OF LOWER URINARY TRACT DISEASE Causes f lwer urinary tract disease in cats present with similar clinical signs including, but nt limited t pllakiuria, hematuria, stranguria, and inapprpriate urinatin. WHAT ARE RISK FACTORS FOR FIC? Data frm studies are cnflicting fr the mst part. Sme studies shw a higher risk in males while thers shw n gender predispsitin. Mst studies d nt shw a breed predilectin; hwever, ne study did shw a predispsitin in lng-haired cats. In anther study, the fllwing factrs were fund t be assciated with develpment f FIC: being mre fearful than ther cats in the same husehld, being mre nervus than ther cats in the husehld, having a lwer water intake, partaking in less hunting activity, having lwer activity levels, using a litter bx, mving huse, hiding when unknwn visitrs are in the huse, having a higher bdy cnditin scre, and having less access t an utdr envirnment. Additinally, it is nt uncmmn fr cats with FIC t have ne r mre ther chrnic diseases such as inflammatry bwel disease, respiratry disease, and behaviral disrders. DIAGNOSTIC TESTING WITH LOWER URINARY TRACT SIGNS CBC and bichemical analysis are nrmal unless urethral bstructin is present. Urinalysis reveals hematuria; hwever, pyuria and bacteriuria may be present with UTI. Urine culture is negative unless UTI is present. Abdminal radigraphy and ultrasngraphy may be nrmal unless urliths are present. In cats with FIC, cystscpy reveals small pin-pint hemrrhages called glmerulatins and bladder wall bipsy ften reveals submucsal edema, mucsal ulceratin, pssible submucsal inflammatin, and pssible fibrsis. FIC is a diagnsis f exclusin. TREATMENT OF LOWER URINARY TRACT DISEASE Urethral Obstructin Urethral bstructin may ccur frm urliths r urethral plugs. Matrix-crystalline urethral plugs are fund nly in male cats and apprximately 84% f matrix-crystalline plugs cntain a mineral cmpnent with struvite being the mst cmmn mineral present. Urliths have been discussed previusly. Urethral bstructin results in dehydratin, aztemia, metablic acidsis, hyperphsphatemia, hyperkalemia, and eventually death. Treatment invlves rehydratin, relieving the urethral bstructin, and managing hyperkalemia. After relieving urethral bstructin, an indwelling urinary catheter may be required. If inserted, use a clsed cllectin system, d nt administer antimicrbial agents, and d administer urethral relaxants (alpha adrenergic blckers).

3 Nn-Obstructive Idipathic Lwer Urinary Tract Disease There have been dzens f prpsed treatments fr cats with lwer urinary tract disease; very few have undergne evaluatin in a randmized cntrlled clinical trial. Antimicrbial Agents The rle f micrbial agents in feline lwer urinary tract disease is cntrversial. In yung adult cats evaluated at university referral hspitals, the incidence f bacterial urinary tract infectin is 1% r less; hwever, apprximately 1 in 3 cats seen at primary care facilities in Nrway had bacterial urinary tract infectin. Furthermre, lder adult cats are mre likely t have a bacterial urinary tract infectin and as many as 50% f lder cats with lwer urinary tract signs have a bacterial urinary tract infectin. Unless a UTI is present, administratin f an antimicrbial agent is nt warranted. Urinary Tract Antiseptics and Analgesics Methenamine and methylene blue are nt indicated in cats as they may induce metablic acidsis and Heinz bdy anemia. Phenazpyridine is an ver the cunter preparatin available fr use by wmen with recurrent vaginitis/cystitis that causes Heinz bdy anemia in cats. Smth Muscle and Skeletal Muscle Relaxants Many cats with FIC have urge incntinence and inapprpriate urinatin. Prpantheline, an antichlinergic agent, minimizes frce and frequency f uncntrlled detrusr cntractins and may be beneficial in sme cats; hwever, ne study did nt dcument a benefit. Phenxybenzamine and prazsin are sympathlytic agents that decrease urethral tne and spasm and may help sme cats. Cats with FIC have been fund t have a dysregulatin in their stress respnse with an increase in sympathetic autnmic nervus tne and a decreased hypthalamic-pituitary-adrenal respnse. Prazsin has mre systemic effects than phenxybenzamine and, therefre, may have benefit in cats with FIC t decrease the increased sympathetic nervus system activatin. Diazepam and dantrlene are skeletal muscle relaxants that may decrease tne and spasm f the distal urethra. Anti-Inflammatry and Analgesic Agents Gluccrticids have been used t decrease inflammatin; hwever, studies have shwn n benefit in cats with FIC. They are cntraindicated in cats with urethral bstructin r thse that have indwelling urinary catheters because they increase risk f UTI. Nnsteridal anti-inflammatry drugs (NSAID) may decrease inflammatin and pain; hwever, they are cntraindicated with aztemia and dehydratin. Buprenrphine and Trbugesic d nt have anti-inflammatry prperties, but d decrease pain and appear t make cats with FIC mre cmfrtable. Amitriptyline Amitriptyline is a tricyclic antidepressant that may have analgesic prperties, stabilize mast cells, and decrease inflammatin. In ne uncntrlled study, 9 f 15 cats with idipathic lwer urinary tract disease imprved with amitriptyline. One cntrlled study f cats with active lwer urinary tract disease shwed n benefit and cats receiving amitriptyline had a higher incidence f recurrence f lwer urinary tract signs. The gal is t find a dse that will have a calming effect. Glycsaminglycans (GAGs) Cats with FIC have decreased cncentratins f GAGs in their urine. GAGs may have a prtectant rle at the mucsal-urine interface. Tw cntrlled study\ies, failed t shw a difference in clinical signs between a GAG and placeb in cats with idipathic lwer urinary tract disease. There is ne pilt study f intravesical instillatin f a GAG (A-CYST) in cats presenting with urethral bstructin that shwed reductin in repeated urethral bstructin (0% recurrence in GAG treated cats versus 43% in placeb treated cats); hwever, it was nt statistically different. Dietary Mdificatin In cats with matrix-crystalline plugs r with struvite crystalluria, feeding a struvite preventative diet may have sme benefit. In ne study f cats with idipathic lwer urinary tract disease, cats fed a canned diet had fewer recurrences than thse fed a dry diet. In a mre recent randmized cntrlled clinical trial, cats

4 with FIC had an 89% reductin in recurrences when fed a diet enriched with mega-3 fatty acids and anti-xidants als cntaining L-tryptphan and alpha-caszepine. Marpitant Marpitant is used as an anti-emetic because it is a neurkinin inhibitr. It has been suggested that may aid in treating cats with FIC by reducing spasticity; hwever, n studies have been perfrmed t validate this hypthesis. Stress Reductin and \Multi-Mdal Envirnmental Mdificatin (MEMO) The rle f stress in eliciting clinical signs in cats predispsed t FIC is well dcumented. Decreasing stress by mdifying envirnment may be beneficial. Cats d nt respnd t frce, are territrial, and like t be in cntrl f their envirnment. Minimizing stress and cnflict may help sme cats with FIC. Litter bxes and fd shuld be away frm nise and distractins. Cats like t climb, hide, scratch, and hunt; therefre, vertical and hrizntal space shuld be prvided. One fd dish, water bwl, and litter pan shuld be available fr each cat in the husehld with ne additinal f each. Additinal infrmatin can be fund at the Indr Cat Initiative: <VIN editr: link updated May 1, 2015>. Additinally, the urinary stress diet that was shwn t decrease recurrences by 89% is frmulated t nt nly be anti-inflammatry but t als have a calming effect. Clmipramine and Fluxetine These drugs are used fr urine spraying / marking behavir. They appear t mdify behavir may have sme analgesic effects. Phermnes Feline facial phermnes may calm a cat; hwever, in ne study f cats with FIC, n benefit was fund. HOW DO I TREAT CATS WITH LOWER URINARY TRACT DISEASE? Yung Cat, First Episde Urethral bstructin Unbstruct Radigraphs, UA (ther lab wrk?) Indwelling catheter? Trbugesic? Diet change (likely)? Antibitics (peri-catheterizatinmemo? If persists r recurs, diagnsticsn urethral bstructin Urinalysis (minimum) MEMO Trbugesic? Diet change? Likely - usually stnes r plugs) If persists r recurs D additinal diagnstics Diet? Amitriptyline? Glycsaminglycans? Old Cat, First Episde Urethral bstructin Unbstruct Radigraphs, UA (ther lab wrk?) Indwelling catheter? Trbugesic? Diet change (likely) - stnes r plug? Others?

5 Antibitics (peri-catheterizatin) If persists r recurs - diagnsticsn urethral bstructin Diagnstics MEMO Trbugesic? Diet change? Likely - urlithiasis - calcium xalate) If persists r recurs D additinal diagnstics Trbugesic as needed Diet? Amitriptyline? Glycsaminglycans? REFERENCES 1. Buffingtn CA, JL Blaisdell, Binns SP Jr, Wdwrth BE. Decreased urine glycsaminglycan excretin in cats with interstitial cystitis. J Url. 1996;155(5): Buffingtn CA, Westrpp JL, Chew DJ, Blus RR. Clinical evaluatin f Multimdal Envirnmental Mdificatin (MEMO) in the management f cats with idipathic cystitis. J Feline Med Surg. 2006;8(4): Kruger JM, Lulich JP, et al. Evaluatin f an anti-xidant and mega-3 fatty acid diet n recurrence f feline idipathic cystitis. ACVIM Frum Pressler B, Bartges JW. Urinary tract infectin. In: Ettinger SJ, Feldman EC, eds. Textbk f Small Animal Internal Medicine. St. Luis: Elsevier-Saunders; 2010: Westrpp JL, Buffingtn CA. In viv mdels f interstitial cystitis. J Url. 2002;167 Pt 1(2): Westrpp JL, Kass PH, Buffingtn CA. Evaluatin f the effects f stress in cats with idipathic cystitis. Am J Vet Res. 2006;67(4):731 6.

5.1. What do we need to know before we start planning a canine rabies control programme?

5.1. What do we need to know before we start planning a canine rabies control programme? 5.1. What d we need t knw befre we start planning a canine rabies cntrl prgramme? Yu need t knw abut: The epidemilgy f rabies in yur area The reservir species in yur area Hw rabies is transmitted. This