Interstitial Cystitis

1. Epidemiology
   1. U.S. Prevelance: 450,000 to 700,000 (52-67 per 100,000)
   2. Women account for 90% of patients
   3. Jewish persons account for 15% of patients
   4. Age Distribution
      1. Less commonly occurs in children
      2. Onset between ages 30 to 70 years old
      3. Patients under age 30 account for 25% of cases
      4. Median age: 40 to 43 years old
2. Cause
   1. Unknown
3. Pathophysiology
   1. Urothelium damage is the primary underlying problem in Interstitial Cystitis
   2. Glycosaminoglycan deficiency in Bladder mucin layer
      1. Hydrophilic and anionic mucous layer is water barrier for urothelium
      2. Glycosaminoglycan deficiency disrupts protection
      3. Possible response to prior bacterial Urinary Tract Infection
   3. Allows urinary solutes (especially potassium) to provoke inflammation
      1. Tissue irritation and injury
      2. Sensory Nerve depolarization
      3. Mast cell degranulation
         1. Mast cells may also be abnormal
4. Types
   1. Non-ulcer type of Interstitial Cystitis (90%)
   2. Severe Interstitial Cystitis with Hunner's Ulcers (10%)
5. Symptoms
   1. Most common Symptoms
      1. Dysuria
      2. Dyspareunia
      3. Suprapubic Pain or Pelvic Pain
         1. Relieved with small volume voids
         2. Pain recurs with Bladder filling
   2. Other common symptoms
      1. Excessive urinary urgency
         1. Uncomfortable constant urge to void
         2. Not relieved with voiding
      2. Urinary Frequency
         1. More than 8 voids per day
         2. Average: 16 voids per day
         3. Reported as high as 40 voids per day
      3. Nocturia
   3. Infrequently associated symptoms
      1. Gross Hematuria (20%)
   4. Timing
      1. Symptoms persist over at least 9 months (no longer required to make diagnosis)
      2. Symptoms worse during week before Menses
   5. Consider other diagnosis
      1. Symptoms not due to recent Urinary Tract Infection
      2. Incontinence suggests other diagnosis
6. Signs
   1. Pelvic tenderness
      1. Suprapubic tenderness
      2. Tenderness on bimanual pelvic exam
   2. Vaginal tenderness
      1. Especially incolving lateral and anterior wall
      2. Painful speculum exam
   3. Rectal Pain
      1. Rectal spasms or pain occur on Digital Rectal Exam
   4. Decreased Bladder capacity
      1. Bladder capacity under 350 ml (normal adult maximal capacity is ~1150 ml)
      2. Urge to void occurs if Bladder distended >150 ml
7. Differential Diagnosis
   1. Tuberculous cystitis
   2. Radiation cystitis
   3. Genitourinary tumor
   4. Chemical cystitis or Urethritis
   5. Active Genital Herpes
   6. Chlamydia trachomatis infection
   7. Yeast Vaginitis
   8. Ureaplasma infection
   9. Herpes Simplex Virus
   10. Vulvar Vestibulitis
   11. Urethral diverticulum
   12. Bladder neck obstruction
   13. Uerterolithiasis or Bladder stone
   14. Neuropathic Bladder dysfunction
   15. Pudendal nerve entrapment
   16. Pelvic floor dysfunction
   17. Overactive Bladder
   18. Cystocele or other urogenital prolapse
   19. Endometriosis
       1. Contrast: Symptoms worse during menstruation
   20. Chronic Prostatitis
   21. Bladder Cancer (carcinoma in situ)
8. Associated Conditions: Similar mechanisms and associated comorbidity
   1. Chronic Prostatitis
   2. Chronic Urethritis
   3. Chronic Pelvic Pain
      1. May be responsible for 33% of Chronic Pelvic Pain
      2. Clemons (2002) Obstet Gynecol 100:337-41
9. Associated Conditions: Other
   1. Major Depression (50%)
   2. Suicidal Ideation (relative risk: 3-4)
   3. Allergic disease
   4. Irritable Bowel Syndrome
   5. Vulvodynia
   6. Fibromyalgia
   7. Migraine Headache
   8. Endometriosis
   9. Chronic Fatigue Syndrome
10. Labs
    1. Urinalysis
       1. Microscopic Hematuria may be present
       2. Pyuria may be present
    2. Urine Culture
    3. Consider Urine Cytology
11. Diagnosis
    1. Intravesical Potassium Sensitivity Test
       1. Insert #10 french pediatric Feeding Tube into Bladder
       2. Slowly instill 40 ml sterile water over 2-3 minutes and rank urgency and pain on scale of 0 to 5
       3. Drain Bladder
       4. Instill 40 ml of 40 meq KCL in 100 ml sterile water and rank urgency and pain on scale of 0 to 5
          1. No pain: Reassess after 5 minutes, then drain Bladder
          2. Pain: Drain Bladder, irrigate with 60 ml sterile water, followed with Bladder anesthetic (see below)
    2. Anesthetic Bladder Challenge
       1. Consider immediately after the intravesical potassium sensitivity test (see above)
       2. Insert #10 french pediatric Feeding Tube into Bladder
       3. Instill Lidocaine 2% (10 ml) with bicarbonate 8.4% (4 ml) and Heparin 40,000 Units
       4. Assess pain relief
12. Evaluation: Others
    1. Careful examination including pelvic exam
    2. Patient keeps 24 hour log of voiding
    3. Urodynamic Studies
       1. Shows decreased Bladder capacity (reduced to <350 in Interstitial Cystitis)
       2. Not specific for Interstitial Cystitis
    4. Cystoscopy
       1. Direct visualization
          1. May be helpful in evaluating for alternative diagnosis or assessing severity
          2. Not required for Interstitial Cystitis diagnosis
       2. Hydrodistention (not required for Interstitial Cystitis diagnosis)
          1. Requires anesthesia
          2. Identifies reduced Bladder capacity (normal approaches 1150 in healthy adults)
             1. Not specific for Interstitial Cystitis
          3. Risk of Urethral tears and Bladder perforation (rare)
       3. Hunner's Ulcers
          1. Mucosal Ulcers on Bladder wall with granulation
          2. Brownish red ulcers involve all Bladder wall layers
       4. Glomerulations on hydrodistention with saline
          1. Multiple petechial-like hemorrhages in mucosa
          2. May be seen in asymptomatic patients
          3. Blood tinged fluid occurs in 90% of patients
       5. Biopsy
          1. Not routinely done in U.S. unless concerns regarding possible Bladder Cancer
          2. Evaluate for neoplasia, dysplasia or Tuberculosis
          3. Confirms Bladder wall inflammation and may identify subgroups (e.g. Eosinophil excess)
13. Management: General
    1. Reassurance
       1. Not cancer
       2. Not indicator for more severe systemic disease
       3. Therapy is symptomatic not curative
    2. Avoid exacerbating foods
       1. Coffee
       2. Alcohol
       3. Carbonated beverages
       4. Citrus fruits or beverages
       5. Artificial Sweeteners
       6. Tomatoes
       7. Chocolate
    3. Chronic Pain Management adjuncts
       1. Support groups (See resources below)
       2. Transcutaneous electrical nerve stimulation (TENS)
       3. Sacral nerve stimulation or pudendal nerve stimulation
       4. Physical Therapy with biofeedback
          1. Pelvic floor relaxation Exercises
14. Management: First Line Medications (multi-modal therapy)
    1. Pentosan polysulfate (Elmiron)
       1. Replaces epithelial function
       2. Dose: 300-400 mg orally/daily divided bid to tid
    2. Tricyclic Antidepressants
       1. Inhibits neuron activation
       2. Amitriptyline (Elavil) or Nortriptyline (Pamelor)
       3. Dose start: 10-25 mg orally at bedtime
       4. Titrate to 50-75 mg orally at bedtime
    3. Hydroxazine (Atarax)
       1. Dose: 25-50 mg orally at bedtime
       2. May reduce mast cell degranulation symptoms
15. Management: Other systemic medications that have been used for Interstitial Cystitis
    1. Nifedipine XL (Procardia XL) 30-60 mg dailly
    2. Cimetidine (Tagamet) 300 mg PO bid
    3. Aspirin
    4. Oxybutynin chloride (Ditropan)
    5. Phenazopyridine (Pyridium)
    6. Gabapentin (Neurontin)
    7. Doxycycline
    8. Cyclosporine A
       1. Sairanen (2005) J Urol 174(6): 2235-8
16. Management: Intravesicular Instillation
    1. Instillation Agents
       1. Dimethyl sulfoxide (Rimso-50) 50% solution every 1-2 weeks for 6-8 times
          1. Heparin 10,000 Unit 3x/week (may potentiate Rimso-50)
       2. Hyaluronic acid 40 mg weekly
       3. Bacillus Calmette-Guerin (BCG) weekly for 6 weeks
    2. Administration
       1. Initially performed in clinic via Urinary Catheter
       2. Patient may learn to self-catheterize for home
    3. Efficacy
       1. Long-term remission seen in >50% of patients
17. Prognosis
    1. May be severely debilitating
    2. Waxing and waning course
18. Resources
    1. Interstitial Cystitis Association
       1. http://www.ichelp.org
19. References
    1. Evans (2007) Urology 69(4 suppl): 64-72
    2. French (2011) Am fam Physician 83(10): 1175-81
    3. Jensen (1989) Urol Int 44:189-93
    4. Metts (2001) Am Fam Physician 64(7):1199-1206
    5. Mobley (1996) Postgrad Med 99:201-14
    6. Moldwin (2007) Urology 69(4 suppl): 73-81
    7. Parsons (2004) J Reprod Med 49(3 Suppl):235-42