Bilateral Ectopic Ureters in a 6-month-old Labrador Retriever Jennifer Lach April 9th, 2014 Clinical Advisor: Dr. Marina McConkey Basic Science Advisor: Dr. Antonia Jameson Jordan Hi, I’m presenting a case of: ________

The Patient 6 month old intact female Labrador Retriever Referred for persistent urinary incontinence Our patient is a 6 month old intact female lab retriever, who was referred to Cornell’s soft tissue surgery service for persistent urinary incontinence. *used with permission

Past Medical History Leaking urine since acquired at age 2 months Day and night Urine culture at referring veterinarian: urinary tract infection (UTI); treated with 6-week course of cefpodoxime, then ciprofloxacin Resolution of infection, but no resolution of clinical signs She had been leaking urine consistently since acquired from a breeder when she was two month old. Soon afterwards, she was evaluated by the rDVM, who diagnosed her with a UTI, which was treated with two courses of antibiotics before the infection resolved, but there was no change in her clinical signs Google Images: http://www.greatdogsite.com/

History Otherwise healthy, up-to-date on vaccines, only medication: Advantage excellent appetite, and owners report no vomiting/diarrhea/sneezing/coughing Patient otherwise had been healthy, up to date on vaccines, only current medication was Advantage *used with permission

On presentation Bright, alert and responsive Temperature: 99.5 degrees F Pulse: 116 beats/min Respiration: 28 breaths/min On presentation, the patient was BAR, with vital parameters all within normal limits. Google Images: http://hdwallpaperia.com/

Physical Exam: Abnormalities Genitourinary: Urine-soaked hindquarters Dribbled urine around exam room Integument: Vulvar and caudal abdominal skin: multiple pink plaques- flat and cup shaped Rest of physical exam was unremarkable A complete physical exam was performed, and showed that her hindquarters were soaked with urine, and during the course of her appointment, she dribbled urine non-stop around the exam room. She also had these pink plaques, or wart-like nodules, all over her vulva, and caudal abdominal skin, didn’t seem painful on manipulation

Problem List Urinary Incontinence Cutaneous Plaques So our problem list: urinary incontinence, and cutaneous plaques Google Images: http://daytonanimallady.blogspot.com/

Differential Diagnoses: Urinary Incontinence Neurologic Non-Neurologic Functional Anatomic The causes of urinary incontinence can be broadly divided into neurologic and non-neurologic causes, to understand why, need a brief anatomy review

Normal Urinary Tract bladder kidney ureter In the normal urinary tract, the ureters carry urine from the kidneys to the trigone of the bladder, out the urethra. The trigone of the bladder is a triangular area distinguished by the openings to the ureters and urethra, in the dorsal aspect of the bladder right near the neck. ureter Evans HE, de Lahunta A. Figure 4-12. In: Guide to the Dissection of the Dog, 7th ed. St. Louis(MO): Saunders, Elsevier Inc. 2010:148. Fossum TW. Ectopic Ureter. In: Small Animal Surgery, 3rd ed. St. Louis(MO): Elsevier Health Sciences 2006:646-654.

Normal Lower Urinary Tract Internal urethral sphincter ureter Urethra Bladder Bladder surrounded by smooth muscle, detrusor muscle Sphincters surrounding the proximal urethra, which exits the neck of the bladder: internal- smooth, external- skeletal Innervation of these muscles gives us control of urination, prevents incontinence http://vanat.cvm.umn.edu/LUTeBook/LUTeBook.pdf

Bladder Filling Bladder Relaxation ureter Bladder Internal urethral sphincter Relaxation -inhibition of pelvic nerve (parasympathetic, S1-S3) -stimulation of hypogastric nerve (sympathetic, L1-L4) Normally, urine is able to be stored in the bladder through coordination of different nerves; relaxation of the detrusor muscle occurs through inhibition of the parasymp innerv (pelvic n), and stim of symp innerv (hypogastric n) http://vanat.cvm.umn.edu/LUTeBook/LUTeBook.pdf

Bladder Filling Bladder Contraction ureter Bladder Internal urethral sphincter -filling also requires contraction of the internal urethral sphincter, also innerv by the hypogastric n, Contraction -stimulation of hypogastric nerve (sympathetic, L1-L4) http://vanat.cvm.umn.edu/LUTeBook/LUTeBook.pdf

Bladder Filling Bladder Contraction ureter Bladder Internal urethral sphincter And the external urethral sphincter, under voluntary control and innerv by the pudendal n -this is all coordinated by the micturition center in the brainstem, and can be inhibited or stimulated by the forebrain -so, Loss of innervation to any of these muscles can cause incontinence Contraction -stimulation of pudendal nerve (somatic; S1-S3) http://vanat.cvm.umn.edu/LUTeBook/LUTeBook.pdf

Differential Diagnoses: Urinary Incontinence Neurologic Non-Neurologic Functional Anatomic -based on her normal neuro exam and absence of any other relevant clinical signs, ruled neuro causes lower on our list of ddx

Differential Diagnoses: Urinary Incontinence Functional Urethral Sphincter Mechanism Incompetence Congenital Hormonal Inflammation/Infection Anatomic Congenital: ectopic ureter, ureterocele, persistent paramesonephric duct remnant, etc. Acquired: stones, neoplasia So for non-neuro causes: -functional, meaning a problem with the act of urination itself, USMI is where the urethral sphincter fails to contract properly around the urethra; can be a congenital problem seen in puppies, esp huskies; also can be a hormonal problem seen secondary to spaying female dogs due to the drop in estrogen -the hormonal cause doesn’t make sense in our case since she’s intact, but a primary congenital abnormal sphincter was a possibility Urge incontinence is seen secondary to inflammation of the bladder lining, this was unlikely in our patient’s case, since her infection had recently resolved, with no effect on her CS   That then brings us to anatomic , or structural, abnormalities -the number one congenital abnormality causing incontinence, esp in female dogs, is ectopic ureters. There’s quite a list of other possibilities, including ureterocels, patent urachus, vaginal stricture, intrapelvic bladder -paradoxical incontinence- which results when there’s an obstruction to urine flow, such as from bladder stones or a tumor, which causes the bladder to get huge, and back pressure on the urethra can cause incontrollable leaking; this couldn’t be ruled out without imaging,

Differential Diagnoses: Urinary Incontinence Functional Urethral Sphincter Mechanism Incompetence Congenital Hormonal Inflammation/Infection Anatomic Congenital: ectopic ureter, ureterocele, persistent paramesonephric duct remnant, etc. Acquired: stones, neoplasia But due to our patient’s signalment and history, we were ranking congenital abnormalities such as primary USMI, and ectopic ureters, highest on our list of DDX at this point

Diagnostics and Results CBC: unremarkable Chemistry Panel: unremarkable Cystocentesis Urinalysis: urine specific gravity of 1.007 Urine Culture: pending Dermatology Consult: DDX: cutaneous inverted papillomavirus, recommended biopsy Focal Urinary Tract Ultrasound

Ultrasound Bilateral Ectopic Ureters and Ureteromegaly ventral Ultrasound Bilateral Ectopic Ureters and Ureteromegaly ventral dorsal U/S found that she had moderate to severe ureteromegaly, with the left being larger than the right; -both ureters were ectopic; they extended caudally to the bladder, tracking closely along the ventral urethra all the way to the pelvic inlet, at which point U/S can’t see through bone  top- ventral, bottom- dorsal, hypoechoic tubular structure is ureter The renal pelvices were mildly enlarged in both kidneys, attributed to the ectopic ureters, or secondary to an infection -and although both kidneys were of normal size, they had irregular contours and mildly poor corticomedullary definition- nephropathy could be attributed to individual variation, scarring from infection, or renal dysplasia Bilateral, Mild Renal Pyelectasia Bilateral, Questionable Nephropathy dorsal

Bilateral Ectopic Ureters!! Diagnosis Bilateral Ectopic Ureters!! Now that we have a cause of her incontinence, what are ectopic ureters?

Why Urinary Incontinence? Ectopic Ureter: inserts distally to the trigone of the bladder Ectopic ureter Bladder Because ectopic ureters insert somewhere caudally to the trigone, bypassing the normal control of urination Internal urethral sphincter http://vanat.cvm.umn.edu/LUTeBook/LUTeBook.pdf

Abnormal Embryologic Development Bladder and urethra arise from urogenital sinus Ureters develop from ureteral bud (metanephric diverticulum) off mesonephric duct Urogenital sinus enlarges, ureters migrate caudally → ureter incorporated into sinus wall → Trigone Caudal migration of ureter → Ectopic ureter Ectopic ureters are the result of abnormal embryologic development. The bladder and urethra develop from a primitive structure called the urogenital sinus. Ureters develop from the ureteral bud off mesonephric ducts (which become the ductus def in males, and regress in females) -as the urogenital sinus enlarges, the ureters migrate caudally and are incorporated into the sinus wall at the level of the trigone; if they migrate too far caudally, then they end up beyond the future urethral sphincter http://vanat.cvm.umn.edu/LUTeBook/LUTeBook.pdf

Ectopic Ureters Intramural vs Extramural Ectopic ureters can be intramural or extramural. Intramural, which is shown in the first image, A, means that the ureters do enter the serosa at the bladder wall, but they tunnel through the submucosa before emptying into the urethral lumen; Extramural ureters, shown in B, travel completely outside the bladder wall, before emptying into the urethra Fossum TW. Ectopic Ureter. In: Small Animal Surgery, 3rd ed. St. Louis(MO): Elsevier Health Sciences 2006:646-654.

Ectopic Ureters >95% intramural More common in female dogs, median age of diagnosis 6-10 months The vast majority of ectopic ureters- more than 95%, are intramural,. They are most commonly diagnosed in female dogs, with a median age of diagnosis of 10mo

Treatment Treatment options: Cystoscopic –guided laser ablation of ectopic ureters (CLA-EU) Surgery Medical management Treatment options vary with the type of ectopic ureter. Laser ablation is the treatment of choice for intramural ureters, whereas surgery is necessary for extramural ureters. Surgery involves ligating and resecting the ureter, and then reimplanting it into the bladder lumen. Medical management typically is only minimally effective, is more often used as an adjunctive treatment if one of the above procedures is not successful. Google Images: http://denverchiropractor.com/

Cystoscopic-Guided Laser Ablation ventral -So now, a little bit about laser ablation. It requires general anesthesia, and the patient is placed in dorsal or sternal recumbency. An endoscope is passed retrograde through the vulva and vestibule; an assistant pinches the vulvar skin closed around the scope, so that sterile saline can be infused throughout the procedure, to aid in visualization of the urinary tract. -these 2 images showing normal female anatomy -The scope can be passed into the urethra or vagina, to look for the ectopic ureter openings. -shorten, reference dorsal Figure: Normal view from vestibule, dog in dorsal recumbency Evans HE, de Lahunta A. Figure 4-24. In: Guide to the Dissection of the Dog, 7th ed. St. Louis(MO): Saunders, Elsevier Inc. 2010:158. http://www.gsvs.org/articles/article.asp?id=40

Cystoscopic-Guided Laser Ablation ventral Figure: Endoscopic images of a dog with ectopic ureters in dorsal recumbency urethra guide wire bladder lumen Here are some endoscopic images of a dog with ectopic ureters in dorsal recumbency. Yellow asterix is marking the urethral lumen, opening seen dorsally is the ectopic ureteral opening At this point, a Guide wire is passed through the endoscope into that ureter, shown in B; in this image, the black arrow is guide wire Scope is then removed so that the laser wire is threaded through the scope and introduced into the urethra C shows the diode laser, marked with a Red arrow, breaking down/cauterizing the wall between the ectopic ureter and the urethra, up until the bladder lumen is reached; the Guide wire protect dorsal and lateral walls of the ureter from the laser D. in D, the final image, a Yellow asterix now marking the bladder lumen, showing that the ureter now patent with the inside of the bladder guide wire guide wire diode laser dorsal http://www.amcny.org/node/1029

Why Cystoscopic-Guided Laser Ablation? Similar success rate to surgery Eliminates need for abdominal surgery and its risks Risks of procedure: anesthesia, UTI, perforation of bladder/urethra/ureter, iatrogenic stricture formation, bleeding Limits of procedure: intramural only; specialized equipment, steep learning curve Laser ablation has several key advantages over surgery -it has a similar success rate, but eliminates the risk of open abdominal surgery Still has risks: still need GA, perforation of any part of the lower urinary tract is possible, iatrogenic inflamm/stricture form, bleeding Has limits: specialized equipment and training, can’t tx extramural ureters

Prognosis Guarded-poor prognosis 25-58% success rate with surgery or CLA-EU Success: partial or complete resolution of urinary incontinence Half of patients that don’t respond to surgery, may respond to medical management unfortunately, regardless of the type of ectopic ureter, or the procedure performed, the success rate is only about 25-50%. Success is defined as either a partial or complete resolution of urinary incontinence. Half of the patients that do not respond to surgery, respond to medical management. Therefore, that means that 75% of cases will have partial or complete resolution of incontinence with surgery +/- medication, and 25% of cases will not have any improvement despite surgical and medical management.

Back to Our Patient Owners elected laser ablation therapy if possible Patient admitted into hospital for cystoscopy +/-laser ablation following morning After a discussion regarding the overall guarded-poor prognosis, and the different treatment options, it was decided to pursue cystoscopy and laser ablation the following day. Our patient was admitted into the hospital, with the procedure scheduled for the following morning.

Cystoscopic-Guided Laser Ablation dorsal Patient was anesthetized, clipped and prepped for cystoscopy Cystoscope was passed retrograde through the vulva and vestibule At this point (in vestibule) instead of two openings, saw five openings *PPMD **Insert image of patient’s vestibule *urethra *left ectopic ureter The following day, Patient was anesthetized, clipped and prepped for cystoscopy in dorsal recumbency. -Cystoscope was passed retrograde through the vulva and vestibule -At this point (in vestibule) instead of two openings, saw five openings: 2 to the vagina, separated by a thick septum (paramesonephric duct remnant) 2 ureteral openings ventral to the double vagina Normal opening to the urethra *scope in right ectopic ureter ventral

Cystoscopic-Guided Laser Ablation Both ureters were intramural Procedure performed as previously described Laser pulsations used to break down membranes between both ectopic ureters and the urethra to the level of the bladder neck dorsal Good news was both ureters were intramural, so procedure performed as previously described, with Laser pulsations being used to break down membranes between both ectopic ureters and the urethra to the level of the proximal urethra ventral

Laser Ablation of PPMD *1 vaginal opening *2 vaginal openings dorsal *1 vaginal opening *2 vaginal openings *1 vaginal opening The caudal-most aspect of the thick intervaginal septum was then broken down with the laser. The endoscope was passed into the opening of the vagina, and at that time it was seen that two vaginal openings, each led to their own cervix. Image on left is again showing a normal vestibule; image on top right shows a vestibule similar to our patients, with the thick PMDR, and bottom image shows the same vestibule post-laser ablation *urethra *urethra *2 ectopic ureters *urethra A. Normal Vestibule B. Before C. After ventral A: http://www.gsvs.org/articles/article.asp?id=40

Last but not least.. Three of the perivulvar plaques were biopsied with a 6mm punch biopsy and submitted for histopathology Patient recovered uneventfully from anesthesia. Three of the perivulvar plaques were biopsied with a 6mm punch biopsy and submitted for histopathology. Patient recovered uneventfully from surgery. *used with permission

Post-Op Plan Discharged on carprofen and tramadol Recheck with referring veterinarian in 1 week for repeat urine culture and sensitivity She was discharged the following day on carprofen and tramadol, to recheck with her rDVM in 1wk for a repeat urine culture and sensitivity

Outcome 3 days post-op continent! Urine culture negative Dilute urine: incidental or early kidney dysfunction? Recommended regular monitoring of urinalysis, blood urea nitrogen, creatinine Histopathology of Skin Plaques: Moderate, multifocal, lichenoid lymphoplasmacytic interface dermatitis most consistent with contact dermatitis secondary to chronic urinary incontinence Immunohistochemical stains for papillomavirus were negative Good news, patient was continent 3 days post-op!! -Urine culture performed pre-op was negative leading us to conclude that her dilute urine was either an incidental finding or early kidney dysfunction. although she had normal renal values, her abnormal appearing kidneys on AUS made us concerned about renal dysplasia -we recommended regular monitoring of U/A, BUN, creatinine Histopathology of Vulvar Plaques: Moderate, multifocal, lichenoid lymphoplasmacytic interface dermatitis -in a nutshell is most consistent with contact dermatitis secondary to chronic urinary incontinence -Immunohistochemical stains for papillomavirus were negative

Outcome Nine Months Later: Patient still doing well; occasionally leaks when excited but owners very happy Nine Months Later: Patient still doing well; occasionally leaks when excited but owners very happy Successfully spayed- rDVM reported that her uterus appeared perfectly normal, but did comment on her abnormal looking kidneys *used with permission

Cost Cystoscopy and Laser Ablation Procedure $444.80 Hospitalization and Exam Fees $421 Diagnostics $383.91 CBC $42.56 Chemistry Panel $48.89 Ultrasound $140 Cystocentesis $21 Urinalysis $23.22 Urine Culture $28.14 Skin Biopsy $80.10 Anesthesia $300.44 Medications $72.72 ------------------------------------------------------------------------- TOTAL BILL: $1622.87 Here’s a summary breaking down the costs of the procedure and hospitalization; total client bill was: $1622.87 Google Images: http://amarillocollege.info/

References Berent AC. Endoscopic Treatment of Ectopic Ureters: Short & Long Term Outcomes Using Cystoscopic-Guided Laser Ablation (CLA-EU). ACVS Vet Symposium Proceedings 2011:392-395. Berent AC, Weisse C, Mayhew PD, et al. Evaluation of cystoscopic-guided laser ablation of intramural ectopic ureters in female dogs. J Am Vet Med Assoc 2012;240(6):716-725. Cote E. Cystoscopy. In: Clinical Vet Advisor, 2nd ed. St. Louis(MO): Mosby Inc, Elsevier 2011:1239-1241. Cote E. Incontinence, Urinary. In: Clinical Vet Advisor, 2nd ed. St. Louis(MO): Mosby Inc, Elsevier 2011:599-601. Cote E. Urethral Sphincter Mechanism Incompetence. In: Clinical Vet Advisor, 2nd ed. St. Louis(MO): Mosby Inc, Elsevier 2011:1134-1135. Fossum TW. Ectopic Ureter. In: Small Animal Surgery, 3rd ed. St. Louis(MO): Elsevier Health Sciences 2006:646-654. Fletcher TF. Applied Anatomy & Physiology of Dog-Cat Lower Urinary Tract. CVM U Minnesota May 2012: http://vanat.cvm.umn.edu/LUTeBook/LUTeBook.pdf. Fletcher TF, Weber AF. Veterinary Developmental Anatomy (Veterinary Embryology). CVM 6903 2013:41-48. http://vanat.cvm.umn.edu/vanatpdf/EmbryoLectNotes.pdf. Full A. Neurology and Neuropharmacology of Urination. VTMED 5510 Fall 2012:1-7. Reichler IM, Specker CE, Hubler M, Boos A, et al. Ectopic Ureters in Dogs: Clinical Features, Surgical Techniques and Outcome. Vet Surg 2012;41:515-522. Smith AL, Radlinsky MG, Rawlings CA. Cystoscopic diagnosis and treatment of ectopic ureters in female dogs: 16 cases (2005-2008). J Am Vet Med Assoc 2010; 237(2):191-195. Here are my references

References: Images Only Google Images, Accessed Feb 2014. Patient’s owners, used with permission Berent AC, Weisse C. Figure 1 and 3. In: Case Study: Cystoscopic-guided Laser Ablation for Ectopic Ureters. Accessed Feb 2014: http://www.amcny.org/node/1029. Evans HE, de Lahunta A. Figure 4-12. In: Guide to the Dissection of the Dog, 7th ed. St. Louis(MO): Saunders, Elsevier Inc. 2010:148. Evans HE, de Lahunta A. Figure 4-24. In: Guide to the Dissection of the Dog, 7th ed. St. Louis(MO): Saunders, Elsevier Inc. 2010:158. Henderson A. Figure 1. Normal View from Vestibule. In: Advances in Veterinary Cystoscopy. Feb 2007: http://www.gsvs.org/articles/article.asp?id=40.

Thank You to: My patient and her owners Advisors, Drs. McConkey and Jameson Jordan Support network – friends, family Class of 2014! And I want to thank_______ *used with permission

Questions? Are there any questions? *used with permission