Interstitial Cystitis

See Also

Definitions

Bladder Pain Syndrome (previously Interstitial Cystitis)
1. At least 6 weeks of intermittent pain localized to the Bladder (esp. with Bladder filling)
2. Not due to other conditions (e.g. Urinary Tract Infection)

Epidemiology

U.S. Prevelance: 450,000 to 700,000 (52-67 per 100,000)
Women account for 80-90% of patients (4:1 ratio to men)
1. Affects 0.8 to 0.9% of women in United States (0.1 to 0.2% worldwide and likely underestimated)
2. Affects 0.06% of men in United States
Ethnicity: White patients account for 90% of cases in studies
Jewish persons account for 15% of patients
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

Pathophysiology

Urothelial damage is the primary underlying problem in Interstitial Cystitis
1. Dysfunction or deficiency of the Glycosaminoglycan protective layer
2. Loss of Glycosaminoglycan layer allows for caustic solutes to injury the Bladder wall
3. Bladder wall injury triggers Nociceptor (pain receptors) and inflammatory response
4. Results in Central Sensitization with Hypersensitivity, smooth Muscle Contraction and neuropathic pain
Glycosaminoglycan deficiency in Bladder mucin layer
1. Urothelial glycosaminoglycan normally provides barrier protection from caustic solutes in the Bladder
  1. Hydrophilic and anionic mucous layer is water barrier for urothelium
2. Glycosaminoglycan deficiency disrupts protection
  1. Dysfunction or loss of the barrier may result from prior Bacterial Urinary Tract Infection
Urinary solutes (especially Potassium) provoke inflammation (when Glycosaminoglycan is deficient)
1. Tissue irritation and injury
2. Sensory Nerve depolarization
3. Mast Cell degranulation and Histamine release
  1. Mast Cells may also be abnormal
Central Pain Sensitization
1. See Central Sensitization,
2. Central Sensitization is an inappropriate response to low level stimuli
  1. Exaggerated stimulus response, with lower thresholds triggering a pain response
  2. Pain persists after trigger is removed
3. Ascending pain signals are amplified and pain inhibitory signals are suppressed
  1. Increased Cytokine concentrations after infections
  2. Sympathetic Nervous System hyperactivity
  3. Endogenous Opioid system changes
  4. Altered brain neuroplasticity
4. Associated syndromes
Hunner Lesions (Hunner Ulcers)
1. Inflamed, red patches in the Bladder wall seen on cystoscopy in 5–20% of Bladder Pain Syndrome patients
2. Pathognomonic for Bladder Pain Syndrome (Interstitial Cystitis)

Types

Non-ulcer type of Interstitial Cystitis (90%)
Severe Interstitial Cystitis with Hunner Leions (10%)

Symptoms

History Log
1. Patient monthly log of symptoms and menstrual periods
2. Patient single 24 hour log of voiding
Validated Symptom Scales
1. O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI)
  1. https://painful-bladder.org/media/archive/pdf/RESOURCES_ICSIICPI_scores.doc.pdf
  2. References
    1. Yoshimura (2022) Int J Urol 29(4):289-96 +PMID: 34929761 [PubMed]
2. Pelvic Pain, Urgency and frequency score (PUF)
  1. https://www.mywtmf.com/documents/microsites/PUF-Questionaire.pdf
  2. References
    1. Parsons (2002) Urology 60(4):573-8 +PMID: 12385909 [PubMed]
3. Pelvic Function Surveys
  1. https://pelvicfunction.com/questionnaires/
Most common Symptoms
1. Dysuria
2. Dyspareunia
3. Suprapubic Pain or Pelvic Pain or pressure Sensation
  1. Relieved with small volume voids
  2. Pain recurs with Bladder filling
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
  4. Includes Nocturia
Provocative factors
1. Dietary changes (see management below for more common food triggers)
2. Emotional stress
3. Intercourse
4. Exercise
Infrequently associated symptoms
1. Gross Hematuria (20%)
Timing
1. Symptoms persist over at least 9 months (no longer required to make diagnosis)
2. Symptoms worse during week before Menses
Consider other diagnosis
1. Symptoms not due to recent Urinary Tract Infection
2. Incontinence suggests other diagnosis

Signs

Pelvic tenderness
1. Suprapubic tenderness overlying the Bladder region
2. Tenderness on bimanual pelvic exam
Vaginal tenderness
1. Especially incolving lateral and anterior wall
2. Painful speculum exam
Rectal Pain
1. Rectal spasms or pain occur on Digital Rectal Exam
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
Exam should also evaluate for findings suggestive of alternative diagnoses
1. Vaginal Atrophy
2. Pelvic Organ Prolapse
3. Infection (e.g. Genital Herpes, Vaginitis, Pelvic Inflammatory Disease)

Differential Diagnosis

See Associated Conditions below
Infection
1. Urinary Tract Infection
2. Active Genital Herpes (Herpes Simplex Virus)
3. Chlamydia Trachomatis infection
4. Yeast Vaginitis
5. Ureaplasma infection
6. Tuberculous cystitis
7. Pelvic Inflammatory Disease
Masses
1. Uterine Fibroids
2. Genitourinary tumor
3. Bladder Cancer (carcinoma in situ)
4. Pelvic Organ Prolapse (Cystocele or other urogenital prolapse)
Irritants and Iatrogenic Conditions
1. Chemical cystitis or Urethritis
2. Radiation cystitis
Other genitourinary pain syndromes
1. Chronic Prostatitis
2. Chronic Urethritis
3. Myofascial Pain Syndrome
4. Vulvar Vestibulitis or Vulvodynia
5. Pelvic Congestion Syndrome
6. Pubic Symphysis pain
7. Endometriosis
  1. Symptoms are worse during Menstruation (Dysmenorrhea)
8. Nerve Entrapment
  1. Pudendal nerve entrapment (pudendal neuralgia)
  2. Lumbosacral Radiculopathy
Other urogenital disorders
1. Urethral Diverticulum
2. Bladder neck obstruction
3. Uerterolithiasis or Bladder stone
4. Neuropathic Bladder dysfunction
5. Overactive Bladder
6. Pelvic Floor Dysfunction
7. Vaginal Symptoms of Menopause (Atrophic Vaginitis)

Associated Conditions

Major Depression (50%)
Suicidal Ideation (Relative Risk: 3-4)
Allergic disease
Irritable Bowel Syndrome
Vulvodynia
Fibromyalgia
Migraine Headache
Endometriosis
Chronic Fatigue Syndrome
Chronic Pelvic Pain (similar mechanisms and associated comorbidity)
1. Chronic Prostatitis
2. Chronic Urethritis
3. Painful Bladder Syndrome may be responsible for 33% of Chronic Pelvic Pain
4. Clemons (2002) Obstet Gynecol 100:337-41 [PubMed]

Labs

Urinalysis and Urine Culture
1. Microscopic Hematuria may be present
2. Pyuria may be present
Consider Urine Cytology
1. Only when Bladder Cancer is suspected

Imaging

Consider imaging for the evaluation of alternative diagnosis (e.g. malignancy, Ureteral Stone)
Imaging options when indicated
1. CT Urogram
2. Bladder and renal Ultrasound
3. Pelvic Ultrasound

Diagnosis

Postvoid Residual Urine
1. Residual urine >100 ml suggests Urinary Retention
Cystoscopy
1. Indications
  1. Interstitial Cystitis refractory to conservative management
  2. Other standard indications for cystoscopy (e.g. Hematuria, Bladder Cancer risks)
2. Direct visualization
  1. May be helpful in evaluating for alternative diagnosis or assessing severity
  2. Not required for Interstitial Cystitis diagnosis
3. 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)
4. Hunner's Ulcers
  1. Mucosal Ulcers on Bladder wall with granulation
  2. Brownish red ulcers involve all Bladder wall layers
5. 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
6. 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)
Urodynamic Studies
1. Indications
  1. Incomplete Bladder emptying
  2. Urinary urgency
  3. Refractory Bladder symptoms to standard Interstitial Cystitis management
2. Not required for Interstitial Cystitis diagnosis
3. Shows decreased Bladder capacity (reduced to <350 in Interstitial Cystitis)
  1. Not specific for Interstitial Cystitis
Other testing
1. AnestheticBladder 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
2. Intravesical Potassium Sensitivity Test (AVOID, not recommended)
  1. No longer recommended dur to low Test Specificity (listed for historical purposes only)
  2. Insert #10 french pediatric Feeding Tube into Bladder
    1. 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)

Management
General

Reassurance
1. Not cancer
2. Not indicator for more severe systemic disease
3. Therapy is symptomatic not curative
Avoid exacerbating foods
1. https://www.icnetwork.org/interstitial-cystitis-diet/the-ic-food-lists/
2. Caffeine
3. Alcohol
4. Carbonated beverages
5. Citrus fruits or beverages
6. Artificial Sweeteners
7. Tomatoes
8. Chocolate
Non-pharmacologic measures
1. Pelvic Floor Exercise (consider physical therapy)
2. Cognitive Behavioral Therapy
3. Yoga
4. Mindfulness
Analgesics as needed
1. NSAIDS
2. Phenazopyridine (Pyridium, azo)
  1. Avoid frequent use (risk of Methemoglobinemia)
3. Hyoscyamine, methenamine, Methylene Blue, and Sodium biphosphate (Urelle, Uribel, Uro-MP, UTA, Urogesic Blue)
  1. Adverse effects include blue urine, and Anticholinergic Symptoms (Dizziness, Tachycardia, confusion)
Manage other associated conditions
1. Treat Vaginal Atrophy in menopausal patients (e.g. Vaginal Estrogen)
2. Consider gynecology referral for broader evaluation
  1. Chronic Pelvic Pain
  2. Pelvic mass
  3. Pelvic Organ Prolapse
  4. Endometriosis
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

Management
First Line Medications (multi-modal therapy)

Pentosan polysulfate (Elmiron)
1. Replaces epithelial function (variable efficacy in studies)
2. Dose: 300-400 mg orally daily divided two to three times daily
3. Risk of Retinal damage (Pigmentary Maculopathy) with prolonged use (typically with years of use)
  1. Obtain baseline ophthalmology exam prior to initiation and then as needed
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
Hydroxyzine (Atarax)
1. Dose: 25-50 mg orally at bedtime
2. May reduce Mast Cell degranulation symptoms
Other measures to consider
1. Gabapentin (Neurontin)
2. Cimetidine (Tagamet) 300 mg orally twice daily

Management
Urology

Indications
1. Bladder Cancer risks
2. Hematuria evaluation
3. Incomplete Bladder emptying or Urinary Retention
4. Prior Bladder surgery or vaginal mesh
5. Structural urologic disorders
6. Complicated or refractory Interstitial Cystitis (Bladder Pain Syndrome)
Cystoscopy-based Procedures
1. Bladder Hydrodistention
2. Hunner Lesions
  1. Fulguration (electrocautery or injection)
  2. Fulguration Refractory lesions may be treated with Triamcinolone or oral Cyclosporine A
    1. Sairanen (2005) J Urol 174(6): 2235-8 [PubMed]
3. Intradetrusor OnabotulinumtoxinA (Botox) Injection
  1. May decrease Bladder pain, urinary urgency and frequency
  2. Jhang (2019) Toxins 11(11):641 +PMID: 31689912 [PubMed]
Neuromodulation Techniques
1. Sacral Neuromodulation (S3 Nerve Root)
  1. Implanted neuromodulation device at S3 Nerve
  2. Reduces pain and symptom scores (esp. with comorbid Overactive Bladder)
  3. Wang (2017) Sci Rep ;7(1):11031 +PMID: 28887515 [PubMed]
2. Pelvic Trigger Point Injections
  1. Adjunct to Pelvic Floor Exercises
  2. Patil (2022) BJUI Compass 3(6):450-57 +PMID: 36267200 [PubMed]
Intravesicular Instillation
1. Instillation Agents
  1. Dimethyl sulfoxide (DMSO, Rimso-50) 50% solution every 1-2 weeks for 6-8 times
    1. Heparin 10,000 Unit 3x/week (may potentiate Rimso-50)
    2. Alkalinized Lidocaine
  2. Hyaluronic acid 40 mg weekly
    1. May help replenish Glycosaminoglycans (GAG) layer
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
Surgical interventions
1. Indications (rare)
  1. Failed all other management strategies and multispecialty Consultation
  2. End-stage small fibrotic Bladder
2. Major surgical interventions
  1. Urinary diversion (with or without cystectomy)
  2. Supratrigonal cystectomy with augmentation cystoplasty

Management
Other systemic medications that have been used for Interstitial Cystitis

Nifedipine XL (Procardia XL) 30-60 mg dailly
Aspirin
Oxybutynin chloride (Ditropan)
Doxycycline

Prognosis

May be severely debilitating
Expect a waxing and waning course

Resources

Interstitial Cystitis (StatPearls)
1. https://www.ncbi.nlm.nih.gov/books/NBK570588/
Interstitial Cystitis Association
1. https://www.ichelp.org/

References