Urgency Frequency Syndrome Hann-Chorng Kuo Department of Urology Buddhist Tzu Chi General Hospital Hualien

Lower Urinary Tract Symptoms Storage symptoms -- Frequency, urgency, urge incontinence, nocturia, suprapubic pain Empty symptoms -- Hesitancy, intermittency, dysuria, poor stream, terminal dribble, residual sensation, micturition pain

The Urge Syndrome Sensory urgency – hypersensitivity of bladder or urethra or both, which causes -- a constant desire to void which is unrelieved by voiding -- a desire to void at a low bladder volume Motor urgency – occurrence of involuntary detrusor contractions which make patients urge to void and/or urine leakage

Frequency & Polyuria (Pollakisuria) A number of patients may have large daily urine output >2800ml/day Polydipsia, high water intake Frequency with voided volume >350ml is physiologically normal Should check metabolic status (DM, azotemia, hyperlipidemia, etc.) or diuretics

Sensory Urgency & Frequency Reduced capacity of first desire (<150mL) or urgency (<350mL) subjectively Absence of detrusor instability Absence of urinary tract infection The incidence of sensory urgency has been estimated 6%, compared with an incidence of 31% for detrusor instability

Known Causes of Sensory urgency freqency Urinary tract infection Lower ureteral stone or bladder stone Bladder tumor Irradiation cystitis Interstitial cystitis Chonic cystitis and reduced capacity Foreign body or bladder injury

Etiology of Idiopathic Urgency Frequency Psychological factors Urothelial leak syndrome Reduced bladder compliance Diuresis Learned habit Detrusor instability Occult neuropathy

Sensory Urgency A Psychosomatic Complaint ? Bladder retraining is effective in treating sensory urgency Relaxation training, biofeedback, hypnosis, acupuncture have a 85% initial response, but relapse rate is 50% Cognitive factor to maintain high stress and arousal levels, increase vigilance concerning bladder sensation and fullness

Psychological Social & Psychiatrical Factors High level of distress High level of anxiety Symptoms may worsen in relation to work or stress Belief of relationship with disease – uremia, infection, cancer Overestimate the significance of symptoms

Sensory Urgency Frequency A disease of exclusion Acute symptoms and chronic symptoms? Related to empty symptoms or not? Related to painful syndrome (painful bladder, painful perineum, urethral pain)? Intermittent? Persistent? Waxing & waning? Related to urge or stress incontinence?

Diagnostic Work-up Urinalysis Uroflowmetry & residual urine amount Voiding diary – 3 days KUB or Cystoscopy Ultrasound of bladder and urethra Cystometry & sphincter EMG Pressure flow study or videourodynamics

Pathophysiology of LUTS in 256 Taiwanese Women Normal bladder and urethra 46 Hypersensitive bladder 102 Detrusor instability 44 Low detrusor contractility 77 Poor relaxation of urethral sphincter 76 Genuine stress urinary incontinence 49 Bladder outlet obstruction 21

Urethral sensitivity An etiology of urgency frequency? Increased urethral sensitivity was found in reduced bladder capacity and in women with normal CMG who complain of frequency urgency & dysuria A higher incidence of bladder neck incompetence in patients with urgency frequency than the controls Pelvic floor exercises and bladder neck suspension improves urgency frequency symptoms

Bladder Neck Incompetence in Urgency Frequency Syndromes PVL(cm) PVS(degrees) Resting Straining Increment Bladder neck incompetence 43 (55.1%) 1.99±0.40 2.07±0.46 0.08±0.22 25.7±21.8 51.2±30.4 25.5±18.9 competence 35 (44.9%) 2.12±0.37 2.14±0.39 0.03±0.16 9.4±9.5 20.4±15.0 11.0±11.7 Statistics NS P<0.005

Ultrasound of Bladder neck incompetence in urgency frequency

Bladder Neck Decsent & Incompetence before Pelvic Floor exercises

Improved Bladder neck Incompetence after Pelvic Floor exercises

Detrusor Instability as an etiology of urgency frequency Minute detrusor contraction occur in the normal bladder – C-fiber dominates? Increased perception of bladder fullness during diuresis No significant difference in perception of bladder fullness between sensory urgency and detrusor instability Similar clinical efficacy of oxybutynin in treating sensory urgency (62.5%) and DI (60.4%)

Increased amplitude of detrusor contractions in bladder filling

Sensory nerves of bladder Dual sensory innervation of mammalian bladder Myelinated A-delta fibers – mediate stretch and micturition reflex Unmyelinated C-fibers (capsaicin sensitive sensory fibers) – mediate pain, temperature, noxious stimuli Sensory axons are present in lamina propria

Sensory Innervation of Bladder

Capsaicin sensitive sensory fiber Sensory function – regulating micturition threshold (especially after spinal cord transection), mediating pain, activating cardiovascular responses Efferent function – activating local motor responses, regulating nerve excitability, local control of vascular blood flow and permeability (neurogenic inflammation ?)

Treatment of sensory urgency by intravesical capsaicin Capsaicin in 10 micro-M can effectively treat hypersensitive disorders Transient desensitization of capsaicin-sensitive afferents without interfering motor function Little effect was found in classical Interstitial cystitis Resiniferatoxin may have similar effects

Role of Potassium in pathogenesis of Urgency Frequency Syndrome Chronic diffusion of urinary potassium into bladder interstitium may induce sensory symptoms, damage tissue, and possibly cause interstitial cystitis Intravesical potassium test (40ml, 0.4M) is a reliable method for detecting abnormal urothelium permeability

Potassium test in Urgency Frequency Syndrome

Nerve Growth Factor Increased nerve growth factor levels in the bladder biopsies from sensory urgency, chronic cystitis, and interstitial cystitis than in controls Immunostaining showed increased NGF expression in the urothelium, most marked in idiopathic sensory urgency Anti-NGF treatment may be rational

NGF immunostaining in Idiopathic Sensory Urgency

Urgency frequency associated with Bladder or perineal pain Suprapubic pain or perineal pain at bladder fullness The pain may/not disappear after voiding A tight sphincter EMG at bladder capacity Reduced bladder compliance Urethral obstruction due to stricture or spastic urethral sphincter as etiologies

Reduced bladder capacity and Frequency urgency bladder pain

Frequency urgency & pain Spastic pelvic floor & sphincter

Differential diagnosis of Urgency Frequency Syndrome History – Bladder injury, foreign body Urinalysis – UTI Uroflowmetry – BOO Cystoscopy – bladder tumor, bladder stone, irradiation cystitis, chronic cystitis Ultrasound – bladder neck and/or urethral incompetence Cystometry – low compliance, DI, DESD

Pressure flow study for Urgency frequency syndrome Cystometry can only detect capacity, detrusor instability, compliance, and bladder sensation during filling phase Pressure flow study can diagnose bladder outlet obstruction, low detrusor contractility, poor relaxation of urethral sphincter, and DESD accurately

Urodynamic study in Urgency frequency syndrome- Detrusor overactivity

Urodynamic study in Urgency frequency syndrome- Detrusor underactivity

Urodynamic study in Urgency frequency syndrome- Bladder outlet obstruction

Urodynamic study in Urgency frequency syndrome- Low compliant bladder

Urodynamic study in Urgency frequency syndrome- Pseudodyssynergia

Urodynamic study in Urgency frequency syndrome- Idiopathic Sensory Urgency

LUTS Analysis of Voiding dysfunction Frequency (n=233) Urgency (n=98) Dysuria (n=104) Incontinence (n=129) Bladder pain (n=34) Normal bladder & urethra(n=46) 44 17 20 5 Hypersensitive bladder (n=102) 90 38 47 25 Detrusor instability (n=44) 37 22 18 30 6 Low detrusor contractility (n=77) 68 34 Poorly relaxed sphincter (n=76) 40 28 19 Genuine stress incontinence (n=49) 45 2 Bladder outlet obstruction (n=21) 21 13 9

Treatment of Frequency urgency syndrome & Normal UDS Reassurance Bladder biofeedback Restrict fluid intake Avoid diuretics and certain acid foods Sedatives or mild tranquilizers

Foods to be Avoided Acid foods All alcoholic beverages Guava Apple juice,red and green apples Lemon juice Apricots Nectarines Cantaloupes Peaches Chilis/spicy foods Plums Citrus fruits (lemon,lime, orange,etc) Strawberries Coffee Tea Cranberries Tomatoes Grapes Vinegar

Foods high in tyrosine, typtophan, aspartate, and phenylalanine Avocados Nutrasweet (Aspartame) Chocolate Saccharine Bananas Nuts Corned beef Sour cream Beer Onions Cranberries Soy sauce Brewer’s yeast Pickled herring Fava beans Vitamins buffered with aspartate Canned figs Pineapple Lima beans Wines Champagne Prunes Marmite Yogurt Cheeses Raisins Mayonnaise Chicken livers Rye bread

Bladder biofeedback for Urgency frequency syndrome Urodynamic proven sensory urgency Bladder biofeedback – increased each voiding interval by holding urine for 5 min more Increase fluid intake gradually Improved functional capacity (296 v 96ml) and decreased daytime frequency (5.7 v 15.8) and nocturia (0.3 v 2.3) after treatment

Intravesical Heparin therapy Patients with urgency frequency and a positive potassium test Intravesical Heparin 25000u/10ml saline and holding for 2 hours 2x or 3x per week for 12 weeks 67% patients have improvement in symptoms and increase in bladder capacity

The changes of urodynamic parameters before and after heparin treatment Baseline 3 months Statistics P value FSF(ml) 96.5±46.4 146.1±55.4 0.001 US(ml) 225.4±96.2 264.9±84.2 0.009 Cystometric capacity(ml) 262.0±89.8 304.3±84.8 0.002 PdetQmax(cmH2O) 25.7±9.1 28.3±9.3 0.07 Qmax (ml/sec) 12.9±5.7 15.1±7.7 0.063 Residual urine(ml) 29.4±38.4 14.5±25.7 0.096 IPSS (points) 19.5±4.6 9.0±4.0 Nocturia (times/night) 5.7±2.0 2.3±1.1 Pain scale of KCl (points) 3.2±0.5 0.7±0.7

Urodynamic finding before and after Heparin Therapy

Intravesical Capsaicin Therapy Patients who are refractory to conventional treatment Capsaicin 10 -5 M in 30ml N/S instilled to bladder for 30 minutes Resiniferatoxin 10-8 M in 30ml N/S A burning sensation or urge at instillation Relief of pain and urge in the later days

Cystometric Results after Capsaicin Instillation Hypersensitive Bladder (n=10) IC Before After FSF(ml) 59±21* 27±7.5 75±33* 21±15 FS(ml) 110±28* 55±17 109±32* 34±13 Capacity(ml) 189±30* 82±14 143±31* 59±17 Qmax(ml/sec) 22.8±7.5* 16.5±2.9 19.3±5.4* 12.5±4.7 Corredcted Qmax 1.65±0.5 1.83±0.3 1.62±0.3* 1.63±0.2 *P<0.05

A Cocktail Preparation for Idiopathic Urgency Frequency ? Mixture of Xylocaine, Resiniferatoxin, Heparin, Oxybutynin with certain vehicle To provide local anesthesia, C-fiber desensitization, repair of defected glycosaminoglycan layer, anticholinergic effect together in one instillation Clinical trial is undergoing

Anticholinergics Treatment Oxybutynin – the most effective and safe drug currently available Detrusitol – M3 antagonist, less salivary and GI side effects than ditropan Flavoxate – mild effect in detrusor Imipramine – central and anticholinergics

DDAVP – Alternative for Urgency Frequency Polyuria Baseline Post-treatment Paired t-test Nocturnal frequency (times/night) 5.20±1.16 2.24 ±1.12 P<0.0001 Noctunal urine volume(ml) 955.6±255.9 522.8 ±210.5 Quality of Life 4.47±1.07 1.05 ±0.91 Urine specific gravity 1.012 ±0.007 1.016 ±0.005 P≒0.011 Serum Na (meq/L) 139.5 ±4.34 139.7 ±3.84 P≒ 0.761 Serum K (meq/L) 4.46 ±0.35 4.31 ±0.44 P≒ 0.022

Pelvic Floor Exercises for Urgency frequency syndrome 3 sets of 8 to 12 slow velocity maximal pelvic floor muscle contractions Sustained for 6 to 8 seconds each Performed 3 to 4 times a week Continued for at least 15 to 20 weeks

Results of Pelvic Floor Exercises Increased maximal cystometric capacity Fewer detrusor contractions Less incontinence episodes Expected cure/improvement rates 65-75% About 50% of patients avoid surgery

Changes of Bladder sensation after Pelvic Floor Exercises Pre-treatment Post-treatment Statistics (p value) Qmax (mL/s) Total 22.6 ± 13.0 20.9 ± 10.2 0.390 Successful 26.0 ± 10.77 23.4 ± 10.7 0.236 Failure 18.3 ± 14.9 17.8 ± 9.2 0.881 Voided volume 340.5 ± 123.4 386.1 ± 152.9 0.240 395.4 ± 69.8 414.1 ± 176.3 0.780 273.3 ± 144.5 351.9 ± 119.4 0.021 FSF (mL) 101.0 ± 26.8 128.2 ± 41.6 0.025 96.1 ± 21.1 136.4 ± 45.8 0.027 107.0 ± 32.7 118.1 ± 35.7 0.484 FS (mL) 189.0 ± 47.5 229.5 ± 46.9 0.006 190.4 ± 51.4 245.0 ± 47.4 0.015 187.3 ± 45.2 210.4 ± 40.9 0.218

Increased Voluntary Contractility after Pelvic Floor Exercises

Cystometrographic Biofeedback Under direct visualization of detrusor activity or involuntary detrusor contractions, patients are instructed to hold urine as strongly as possible Pressure flow study with patient sitting on commode with a uroflowmeter

Detrusor instability and Holding urine during involuntary DI

Neuromodulation for Urgency frequency syndrome Surface neuromodulation at suprapubic area Sacral nerve stimulation from sacral foramina Electromagnetic stimulation Interferential current electrostimulation of pelvic floor muscles Other transcutaneous neuromodulation

The Anxious Bladder