Definitions of IC: U.S. perspective Edward Stanford MD MS FACOG FACS Western Colorado
PURPOSE OF A DEFINITION? Identifies with specificity those patients who are most likely to have the disease. Identifies those patients eligible for selective treatments. Allows us a way to follow patients for diagnosis of other possible disorders and to adjust treatments (early or late).
PURPOSE OF A DEFINITION? How effective are current definitions? How effective are current treatments? What
Micturition normal Afferent signals from the LUT A delta mechanosensitive, myelinated, both nociceptive and non-nociceptive C-fibers does not respond to distention, unmyelinated, activated by cold, heat, chemical irritation
Micturition normal Control neural circuits in the brain and spinal column Coordination of activity of smooth muscle in the urethral sphincter and pelvic floor muscles Involves sympathetic, parasympathetic, and somatic neurons Sensation of bladder filling = stimulation of mechano-sensitive axons alerts brain of capacity
Micturition normal Sympathetic during filling relaxes detrusor stimulates urethral sphincter Parasympathetic during micturition contracts detrusor relaxes urethral sphincter Somatic innervation maintains active tone of PFM stimulation of the striated muscle of the external urethral sphincter
Micturition normal Cortex inhibitory Brain stem facilitatory Pontine on-off switch to LUT between storage and emptying
Micturition normal Receptors Muscarinic (M3)
IC Purinergic neurotransmission via - adenosine 5 triphosphate (ATP) pathway - vanilloid and purinergic (P2X3) pathway Confirming inflammatory role - increased numbers of - substance P (released by C-fibers) containing neurons - substance P receptors (neurokinin-1) mrna - increased NGF (nerve growth factor)
DEFINITIONS - NIH Originally to enroll patients in research trials and relied upon cystoscopic findings (1988) Now symptom based Syndrome pain, urgency, frequency, no infection Chronic, fluctuating symptoms No specific treatments Exact causation unknown Most often diagnosed as a UTI (Porru)
DEFINITIONS ESSIC 2007 Bladder pain syndrome (BPS) Chronic (>6 months) pelvic pain, pressure or discomfort perceived to be related to the urinary bladder accompanied by at least one other urinary symptom like persistent urge to void or frequency Confusable diseases - exclude Cystoscopy with hydrodistension Bladder biopsies Cognitive, behavioural, emotional and sexual symptoms should be addressed
ESSIC 2007 Cystoscopy with hydrodistension Not done Normal Glomerulations2 Hunner s ulcer3 Not done XX 1X 2X 3X Normal XA 1A 2A 3A Biopsy Inconclusive XB 1B 2B 3B Positive3 XC 1C 2C 3C 1 cystoscopy: glomerulations grade II-III 2 with or without glomerulations 3 histology showing inflammatory infiltrates and/or detrusor mastocytosis and/or granulation tissue and/or intrafascicular fibrosis
ESSIC Definition only diagnosed 74% of 156 patients diagnosed with BPS/IC 53% of 150 CPP patients (Cheng 2012)
DEFINITIONS Classic ulcerated Non-ulcer Invasive cystoscopy with hydrodistention Hunner s ulcers relatively uncommon (3-10%) Glomerulations seen in asymptomatic patients (32% Cheng et al 2012)
PATHOGENESIS Changes in urothelial permeability Sensory nerve stimulation Mast cell activation
DIFFERENTIAL DIAGNOSIS Urinary UTI (30 patients) 60%? hematuria Gyn GI Endometriosis 38 85% Vulvar vestibulitis 20% IBS 35%
Coexistence of Pathology Bladder Epithelial Dysfunction: IC 64 patients: 69% IC 64% adhesions 28% endometriosis 20% vulvar vestibulitis Vulvar Vestibulitis 7 1 28 9 1 2 14 Pelvic Pathology: biopsy-proven endometriosis, adhesions Stanford et al JMIG 2006
Stanford et al AJOG 2008 IC: Database
Misdiagnosis ICD-9 Diagnosis N % 1 789.0 Abdominal pain 1,169 31 2 599.0 UTI 912 24 3 595 Cystitis 565 15 4 788.1 Dysuria 542 14.4 5 788.41 Frequency 510 13.6 6 625.9 Pelvic pain, 468 12.5 NOS 7 599.7 Hematuria 411 10.9 8 616.1 Vaginitis 375 10 9 724.2 Lumbago 325 8.7 10 723.1 Cervicalgia 184 4.9
Misdiagnosis ICD-9 Diagnosis N % 11 788.3 Incontinence, NOS 165 4.4 12 617 Endometriosis* 160 4.3 13 625.6 SUI 159 4.2 14 729.1 Myalgia/Myositis 150 4 15 788.31 Urge 128 3.4 incontinence* 16 616 Cervicitis 120 3.2 17 788.9 Urinary 113 3 symptoms, NOS 18 625.8 Female Genital 101 2.7 symptoms, NOS 19 597.8 Urethritis 100 2.7 20 788.43 Nocturia 97 2.6 21 788.33 Mixed 94 2.5 incontinence 22 788.2 Urinary retention 84 2.2 23 596.8 Bladder 83 2.3 symptoms, NOS 24 598.9 Urethral stricture 65 1.7 25 789.3 Abdominal swelling 65 1.7
Concomitant disorders Concomitant disorder N Mean SD p value Age seen None 37 43.7 16.4 Age at initial diagnosis One 54 42.7 16.3 One 31 33.2 9.1 0.007 None 37 40.9 16.2 PUF score at diagnosis One 54 40.9 16.6 >One 31 28.5 8.2 0.001 None 32 15.7 6.8 Stanford SGS 2009 One 52 17.9 5.5 > One 28 20.1 5.98 0.021
TESTING THE DEFINITIONS
DIAGNOSIS Symptoms pain, urgency, frequency PST UD Markers Questionnaires
PAIN Reportedly affects 100% 11% may not have pain Usually with bladder filling The bladder fills are different rates during the day Suprapubic 80% Perineal 70% Genital 40% Overlapping mechanisms functional pain syndromes Pelvic visceral pain Sacral neuromodulation Hydrodistension Resinaferatoxin (RTX)
UTI Recurrent UTI 204 patients, IC diagnosis 24 months Actual recurrent UTIs, 7% Most common diagnosis in patients with recurrent UTI stone 93% have sterile urine with symptoms of recurrent UTI Stanford EJ, McMurphy C Int Urogyn J 2007
HEMATURIA Benign microscopic hematuria 100 women, IC, prospective, low risk of GU malignancy 24% with MH, no gross hematuria PUF 17 (mean) PST positive in 92%, 8 with cysto pos findings Likelihood of a pos PST or pos cysto findings with MH same PST correlated with cysto findings MH likely an incidential finding in IC patients Stanford et al Urology 2006
UROTHELIAL PERMEABILITY PST not recommended Only test for IC pain on an awake patient GAG hyaluronic acid and chondroitin
Results vary URODYNAMICS
MARKERS None useful in diagnosing IC APF
QUESTIONNAIRES ICSI PUF
INTERSTITIAL CYSTITIS Syndrome Unknown etiology Commonly associated with concomitant disorders No test to confirm diagnosis Definitions are not supported