Interstitial Cystitis Painful Bladder Syndrome

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Interstitial Cystitis
Painful Bladder Syndrome


            Hann-Chorng Kuo
          Department of Urology
 Buddhist Tzu Chi General Hospital Hualien
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Interstitial cystitis
   A syndrome of mystery in urology
   A diagnosis of exclusion
   Triad diagnostic characteristics –
    Suprapubic pain at full bladder and
    relieved after voiding, with severe
    frequency and nocturia
    Sterile urine
    Characteristic cystoscopic findings
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Diseases associated with IC
  Allergies, autoimmune diseases, rheumatic
   disease,irritable bowel syndrome
  A common pathophysiology mediated by
   immune, endocrine & neurologic dysfunction
  Systemic lupus erythematosus
  The role of mast cell (increase histamine
   release from bladder biopsies) in IC
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Epidemiology of IC
  In a survey of USA Nurse’s health Study,
   self-reported IC was 0.4% (357 in
   91155 NHSI) and 1.4% (1354 in
   993428 NHSII)
  NIDDK criteria is too restrictive, about
   60% excluded patients may have IC
  The prevalence of IC was estimated to
   be 52 per 105 (NHSI) and 67 per 105
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Possible pathogenesis of IC
  Post-infection autoimmune process
  Mast cell activation – inflammation, toxin,
   stress
  Urothelial dysfunction – increased
   permeability of urothelium
  Neurogenic inflammation – K diffusion- mast
   cell activation – upregulation of sensory
   fiber – release of neuropeptide (substance
   P) – neurogenic inflammation – pain in IC
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Characteristic cystoscopic
findings after hydrodilatation
  Classical IC – contracted bladder,
   Hunner ulcer
  Early IC – glomerulation, petechial
   hemorrhage, mucosal fissure
  Recent investigations revealed classical
   IC may be misleading, chronic IC may
   be more accurate to describe pathology
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Interstitial cystitis
     1915 Hunner – an elusive ulcer after secondary
      bladder hydrodilation
     1949 Hand – Female tomale ratio 11:1
     1975 Oravisto – incidence about 18/105
     1978 Messing – Glomerulation after hydrodilatation
     1982 Larsen – mast cell quantitative assessment in IC
     1983 Parsons – a defect in bladder GAG layer
     1987 Holm-Bentzen – painful bladder syndrome
     IC remains a syndrome of unknown etiology, difficult
      to diagnosis and treatment
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IC patient accrual form –NIDDK
1987 automatic exclusion
    Less than 18 years old
    Benign or malignant bladder tumor
    Irradiation cystitis
    Tuberculous cystitis
    Bacterial cystitis
    Vaginitis
    Cyclophosphamide cystitis
    Symptomatic urethral diverticulum
    Uterine, cervical, vaginal, or urethral cancer
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IC patient accrual form
-- automatic exclusion
    Active herpes
    Bladder or lower ureteral calculi
    Waking frequency < 5/12 hours
    Nocturia <2/night
    Symptoms relieved by antibiotics, urinary
     antiseptics, analgesics
    Involuntary detrusor contractions
    Capacity > 400ml, no sensory urgency
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IC patient accrual form
-- automatic inclusions
    Hunner’s ulcer
    Positive factors –
    Pain on bladder filling relieved by emptying
    Pain (suprapubic, pelvic, urethral, vaginal,
     perineal)
    Glomerulation on endoscopy
    Decreased compliance on cystometry
    Bladder distention by 80 cm water x 1 min,
     two positive factors are necessary
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Cystoscopic Hydrodilatation
  Intravenous general anesthesia or spinal anesthesia
  Inserting cystoscopy lightly, do not evacuate bladder
   completely
  Inspection the whole bladder for vasculature and
   lesions
  The fluid level is set at 80 cm water above symphysis
   pubis
  Fully distended the bladder
  Evacuation of the bladder slowly and observe any
   glomerulation, petechial, splotch hemorrhage or
   mucosal laceration
  Refilled the bladder and check ulceration
  Take bladder biopsy if necessary
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Glomerulation and petechia
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Increased vasculature in
a man with IC
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Interstitial cystitis in Men
   Less than 10% of IC are men
   35/60 (58%) men with non-bacterial
    prostatitis or prostatodynia had
    petechiae following cystoscopic dilation
   In 29 men with IC, misdiagnosis
    wasmade as prostatitis (48%), BPH
    (38%)
   Carcinoma in situ should be ruled out
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Management after cystoscopic
Hydrodilatation for IC
  Indwelling a Foley catheter especially
   after bladder biopsy
  Adequate hydration
  Hemorrhage is usually not a problem
  Analgesics for severe irritative
   symptoms
  Remove the catheter after fully
   awakened
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Basic urodynamic abnormalities
  Sensory urgency
  Intolerance to increments of bladder
   volume
  Decrease in bladder compliance
   <30ml/cm water (16/30 v 3/17 PBS,
   p<0.025)
  Smaller maximal capacity under
   anesthesia (548 v 612, p<0.05)
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Urodynamic findings in IC
  50 patients with painful bladder
   underwent urdynamic study and
   cystoscopic hydrodilation
  30 (28 F & 2 M) had characteristic IC,
   20 non-IC
  Symptomatology was indifferent
   between IC & non-IC
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Symptomatology of 30 IC
                                     IC(N=30) Non-IC(n=20)
Frequency                              30          20
Urgency                                14          7
Nocturia(>two/night)                   30          20
Small urine amount                     28          17
Dysuria                                25          13
Suprapubic pain on bladder filling     28          14
Pain relieved after voiding            25          13
Lower abdominal discomfort              2          6
Gross hematuria                         2          -
Other somatic complaints                3          11
Duration of symptoms > two years       29          20
Treated as cystitis                    25          13
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Uroflowmetry in IC patients
                                     IC (n=28)   Non-IC (n=16)   Statistics*

Voided volume             ≦ 350         20            9
     (mL)                 >350          8             7           P>0.1
                          mean       277±101       319±124        P >0.1

Maximal flow rate         ≦ 20          16            10
   (mL/sec)
                          >20           12            6           P >0.1
                          mean       18.8±6.9      20.7±8.2       P >0.2
Corrected max.flow rate   mean       1.15±0.42     1.19±0.38      P >0.3
Flow pattern              normal        6             5
                          abnormal      22            11          P >0.1
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Various Types of Abnormal
Uroflowmetry in IC (1)
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Various Types of Abnormal
Uroflowmetry in IC (2)
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Various Types of Abnormal
Uroflowmetry in IC (3)
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Uroflowmetry in IC
  Most IC patients present with abnormal
   flow pattern
  With or without a low maximal flow rate
   (22/28), but this feature also can be
   found in non-IC (11/16)
  Can rule out other hypersensitive
   bladder and bladder outlet obstruction
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Urodynamic results in IC
                                     IC (n=30)     Non-IC (n=17)   Statistics*

First sensation of filling   ≦ 100   20            9
 (mL)                        >100    10            8               P>0.1
                             mean    100.9±38      112.4±45.7      P >0.1
Tolerable capacity
                             ≦ 400   25            15
  (mL)
                             >400    5             2               P >0.1
                             mean    307.4±89.2    303.1±79.7      P >0.4
Compliance                   ≦ 30    16            3
  (mL/cmH2O)                 >30     14            14              P <0.025
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Urodynamic parameters in IC
    Bladder hypersensitivity FSF <100ml
    A trend toward smaller capacity in chronic
     cases
    Most have normal compliance in early IC and
     decreased compliance in classic IC
    Most have a normal flow rate
    Urethral pressure profile has no clinical value
    As prognostic indicators and surgical results
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Normal and abnormal
cystometry in IC
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Abnormal cystometry in IC (1)
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Abnormal cystometry in IC (2)
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Abnormal cystometry in IC (3)
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Pathological findings in IC
pathology                      IC (n=24)
                      Absent    Mild       Marked
Mucosal erosion         2        12         10
Submucosal edema        3        19          2
Vascular dilation       6        13          5
NMC infiltration        2        21          1
Intravascular PMN       9        10          5
Plasma cell            21        2           1
Granulation tissue
Endothelial cell       23        -           1
Fibroblast
 proliferation         22        1           1
Squamous metaplasia    23        -           1
Mast cell count         -        19          5
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Microscopic finding in early IC
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Microscopic findings in
Chronic IC
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Microscopic findings in IC
  Classical IC – mucosal ulceration with
   granulation tissue; marked mononuclear cell
   infiltration; increased mast cell in lamina
   propria and detrusor; presence of
   intraurothelial mast cell; perineural
   inflammatory cell; significant fibrosis
  Early IC – mucosal rupture; suburothelial
   hemorrhage; scanty inflammation and mild
   submucosal edema
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Detrusor Mastocytosis in IC
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Physiology of Micturition
  Bladder sensation: first sensation 150ml,
   full sensation 250-350ml, urge
   sensation 400-500ml
  Sensory afferents – reflex center S2-4 –
   micturition center (pons) – cerebral
   cortex
  Voiding pressure in women 20-40 cm
   water, men 30-50 cm water
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Bladder mucosa and
vasculature
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Vesical Blood Urine barrier
  Urothelium appears to be a functional
   extension of renal collecting duct
  Absence of barrier allows recirculation
   of renal waste and deteriorate function
  13:1 mucosal to muscular blood flow in
   bladder wall ratio imply a barrier
   function for blood-urine compound
   exchange and equilibrium
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Increased bladder mucosal
permeability
  Acute bacterial cystitis
  Chronic cystitis
  Foreign body, calculi, tumor
  Overdistension
  Acidic fluid or toxin substance
  Surgical trauma or instrumentation
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Increased permeability of
Bladder epithelium
  Bladder capacity was decreased by K,
   hyperosmolar, and PH5; while increased by
   hypoosmolarity electrolyte free media,
   furosemide, and PH8
  Normal subjects absorbed 4.3%, IC 25% of
   concentrated urea from bladder
  Frequent voiding reduced urinary contact
   time, protecting from urine recirculation
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Pathophysiology of Leaky
epithelium and cystometry
  Impairment of blood urine barrier led to a
   decrease in compliance and capacity
  Isotonic KCl and hyperosmolar NaCl induced
   an immediate onset of voiding contraction in
   rat bladders
  CMG in normal bladder revealed no such
   effects of KCl & hyperosmolar NaCl
  Urge sensation and pressure are elicited in
   diseased human bladder after intravesical K
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Potassium and Bladder control
  Bladder sensory afferent pathway relative to
   submucosal K and intramuscular
   proprioceptor to to intravesical pressure and
   tension
  Intravesical K or hyperosmolarity affects
   exteroception resulting in reflective storage
   pressure elevation and urge proprioception
  Local or perimuscular K enhancement
   facilitates onset of voiding contraction
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Glycosaminoglycan &
Frequency urgency syndrome
  A subset of frequency urgency syndrome has
   a leaky epithelium and cations (K) can diffuse
   subepithelially and provoke urgency
   frequency
  Intravesical KCl (0.4M) provoked symptoms in
   4.5% normal, 70%IC, 18% heparin treated
   IC, 100% irradiation cystitis
  Intravesical sulfated polysaccharide can
   restore injured urothelium to normal
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Pathophysiology of
Leaky Epithelium
  Hyperosmolar NaCl concentration decreased
   more rapidly in over-distension, retention,
   bacterial and chronic cystitis
  Serious water inflow and recirculation of renal
   waste occurred in urine retention
  In experimental cystitis, slow blood flow rate
   resulted in maximal hyperosmolar
   suburothelial urea accumulation (maximal
   exchange)
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Treatment of Interstitial Cystitis
     Cystoscopic hydrodilatation
     Intravesical heparin therapy
     Intravesical DMSO instillation
     Intravesical capsaicin or resiniferatoxin
     Sodium pentosan polysulfate (PPS, Elmiron)
     Amitriptynin
     Supratrigonal cystectomy augmentation
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Medical treatment of IC
    Cyclosporine
    Methotrexate
    Tice strain BCG– 60% response rate vs 27%
     in placebo
    Elmiron (PPS 100mg tid) – 6.2% to 18.7%
     response rate
    Electromotive administration of intravesical
     lidocaine & dexamethasone – 62% effective
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Inravesical 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
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Urodynamic finding before and
after Heparin Therapy
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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         0
  Nocturia (times/night)    5.7±2.0      2.3±1.1         0
  Pain scale of KCl         3.2±0.5      0.7±0.7         0
  (points)
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Intravesical Capsaicin Therapy
  Capsaicin in 10 uM concentration
   instilled intravesically 1/week to 10
   women with hypersensitive bladder(HSB)
   and 10 with interstitial cystitis, a total 6
   weeks
  8 HSB responded for 3-5 days, 2 IC
   responded for 2-3 days
  No reported side effects
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Cystoscopic hydrodilatation
  Under general or spinal anesthesia, at
   pressure of 80cm water, the bladder
   was distended for 30min
  Effective in relieving symptoms after
   hydrodilatation
  The increased bladder capacity was
   limited
  Regular hydrodilatation is needed
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Cystectomy & augmentation
  Supratrigonalor subtrigonal cystectomy
   plus enterocystoplasty are effective
  Major operation with complication
  Residual LUTS including pain persist in
   30% of patients
  Only suitable in severe classical IC
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Bladder autoaugmentaton
  A minor operation to relieve intravesical
   pressure
  Myomectomy or detrusectomy and open
   bladder wall
  Increased bladder capacity and pain at
   full bladder can be relieved
  Covering of omentum or de-epithelial
   bowel musculature will be helpful
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Bladder autoaugmentaion
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Improved in bladder capacity but not Voiding
  pressure after autoaugmentation for IC
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Conclusions
  Interstitial cystitis is more prevalent
   than previously realized
  A multiplicity of dynamic
   pathophysiological processes in bladder
  Vicious circle of increased urothelial
   permeability, inflammation, and nerve
   sensitization leads to chronicity of IC

				
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