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Overactive Bladder: Etiology, Diagnosis and Treatment

Definition

Overactive bladder (OAB) is urinary urgency, with or without urinary incontinence, usually with increased daytime frequency and nocturia, if there is no proven infection or other obvious pathology (Abrams et al., 2002). OAB without urge incontinence is also called dry OAB, with urge incontinence wet OAB. Synonyms used are urge syndrome or urgency-frequency syndrome.

Epidemiology

The prevalence of overactive bladder increases with age. At over 65, the incidence in men is 22% (with urge incontinence 10%), in women 38% (with urge incontinence 19%).

Etiology

Increased afferent signaling:

Increased afferent signaling triggers the urge to urinate, caused by activated stretch receptors in the urothelium and in the adjacent connective tissue. This malfunction can also be caused by detrusor hypertrophy (see BPH) or defects in the GAG layer (see also interstitial cystitis).

Decreased central inhibition:

Afferent signals are physiologically inhibited in the CNS (e.g., thalamus), thus preventing conscious perception. A decreased central inhibition leads to an increased perception of the bladder filling and thus to urge symptoms.

Microbiome of the urinary bladder:

The doctrine that the bladder and urine are sterile is questioned in current research. With the help of modern laboratory methods (e.g., PCR of bacterial DNA, advanced culture techniques such as EQUC), a large number of bacteria can be detected in the urine of women, which is called sterile with common laboratory methods (Hilt et al., 2014). The significance of the microbiome of the urinary bladder is unclear, but some studies which show a relationship to urge symptoms (Pearce et al., 2014).

Signs and Symptoms

Frequency:

Frequency is over eight micturition per 24 hours with normal diuresis (under 2,8 l/24 h).

Urgency:

Urgency is the sudden, compelling desire to void that is difficult to defer, with the risk of urge incontinence.

Nocturia:

Nocturia is the need to void once or more during the night, with or without urgency.

Urge incontinence:

Urge incontinence is urinary incontinence with urgency.

Diagnosis

History and micturition diary:

A micturition diary with documentation of drinking habits, incontinence episodes, pad changes, and voided volumes may help to quantify the severity and bother of OAB. Specific questions help with the differential diagnosis (previous operations, neurological symptoms, medication, bowel function).

Physical examination:

Including vaginal examination, assess pelvic floor insufficiency, rectal examination, prostate size, and a quick neurological examination.

Urine sediment:

To exclude urinary tract infection or hematuria.

Imaging:

Ultrasound imaging of the kidneys and urinary bladder (filled to assess the detrusor thickness and after micturition to determine the residual urine). In the event of abnormalities, cystoscopy, voiding cystourethrography, retrograde pyelography, or intravenous urography may be required to rule out organic causes of LUTS.

Cystoscopy or urine flow rate:

Tests to rule out subvesical obstruction and to measure the functional urinary bladder capacity. Cystoscopy is more invasive but has a higher diagnostic value (excluding bladder carcinoma, urethral diseases and bladder stones).

Urodynamic studies:

Urodynamic studies are indicated in patients after unsuccessful pharmacological therapy or before invasive treatment. Typical urodynamic findings in patients with an overactive bladder are urinary urgency starting from 100 ml, functional urinary bladder capacity below 250 ml, involuntary detrusor contractions, and possibly urge incontinence.

Treatment of Overactive Bladder

Lifestyle interventions:

The amount of drinking and frequency can be optimized using the micturition diary. To a certain extent, the functional bladder capacity can be increased by delaying urination and ignoring urgency symptoms.

Pelvic floor exercises (with electrical stimulation):

Pelvic floor exercises strengthen the sphincter and reduce urinary incontinence. The electrical stimulation via vaginal or anal electrodes leads, comparable to the sacral neuromodulation, to an inhibition of the micturition reflex and the relief of urge symptoms.

Vaginal estrogen therapy:

Vaginal atrophy becomes clinically manifest several years after menopause; subjective complaints such as urgency symptoms, dyspareunia, or increased vaginal pH (>5) are present in up to 50% of all postmenopausal women. Systemic estrogen therapy does not guarantee sufficient vaginal estrogenization (Sturdee et al., 2010). If there are no oncological contraindications, vaginal estrogen therapy is recommended for every perimenopausal or postmenopausal woman with OAB. A Cochrane analysis showed a subjective cure and improvement rate of urge incontinence under estrogens of 57% vs. 28% under placebo (Moehrer et al., 2003). Tablets, vaginal suppositories, ovules, creams, or vaginal rings are available for vaginal estrogen therapy, which differ regarding the application and vaginal discharge. Dosage: 0,03–0,5 mg intravaginal estriol once a week.

Anticholinergic therapy:

Anticholinergics act as antagonists on muscarinic receptors; this leads to a relaxation of the smooth muscles. The force of normal or autonomous detrusor contractions is reduced, and the functional urinary bladder capacity is increased.

Regular micturition is necessary to obtain significant symptomatic improvement. The aim is to urinate before the bladder volume is reached, which induces autonomous detrusor contractions. The high rate of bothersome side effects often leads to termination of drug therapy. The following substances are often used to treat OAB; for a detailed description see the section "Anticholinergics":

• Trospium: 5 mg 1-1-1 to 30 mg 1-1-1.
• Oxybutinine: 2.5 mg 1-0-1 to 5mg 1-1-1-1.
• Tolterodine: 1 mg 1-0-1 to 2 mg 1-1-1. Extended-release 4 mg 1-0-0.
• Fesoterodine: 4–8 mg 1-0-0.
• Propiverine: 15 mg 1-0-1, or increase to 1-1-1.
• Darifenacine: 7.5–15 mg 1-0-0.
• Solifenacine: 5–10 mg 1-0-0.

Adrenergic β3 Receptor Agonists:

Adrenergic β3 receptors occur in the urinary bladder and mediate (hardly) any cardiovascular effects. Selective β3 receptor agonists such as mirabegron and solabegron proved effective for the therapy of OAB in clinical studies with few side effects. The dosage is 50 mg 1-0-0 p.o. A dose reduction to 25 mg 1-0-0 p.o. is recommended for patients with severe renal insufficiency or moderate hepatic insufficiency. Long-term experience regarding the cardiovascular safety of the β3 receptor stimulation is not yet available; see also the section "Pharmacology of mirabegron".

Botulinum Toxin:

Transurethral injections of botulinum toxin A into the detrusor reduce detrusor overactivity lasting several months with increased functional urinary bladder capacity. Botulinum toxin A is indicated in case of failure or intolerance of medical therapy (Cruz et al., 2011); see above. For OAB, the dosage is 100 units of Botox; see also the section "Pharmacology of botulinum toxin A".

Prospects and Experimental Treatment:

Capsaicin or resiniferatoxin are experimental treatment options in OAB. After instillation, repetitive vanilloid receptor stimulation (pain fiber receptors) leads to their inactivation. Pain with instillation is a major drawback of the treatment.

Intravesical Glycosaminoglycans:

Intravesical chondroitin sulfate instillations showed better results than administering anticholinergics in a small randomized study with OAB patients (Gauruder et al., 2006). The therapeutic benefit of intravesical instillation with glycosaminoglycans is controversial.

References

Abrams, P.; Cardozo, L.; Fall, M.; Griffiths, D.; Rosier, P.; Ulmsten, U.; van Kerrebroeck, P.; Victor, A.; Wein, A. & committee of the International Continence Society, S. S. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society.
Neurourol Urodyn 2002, 21, 167-178

Cruz, F.; Herschorn, S.; Aliotta, P.; Brin, M.; Thompson, C.; Lam, W.; Daniell, G.; Heesakkers, J. & Haag-Molkenteller, C. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial.
Eur Urol, 2011, 60, 742-750

Gauruder-Burmester, A.; Wildt, B. & Tunn, R. [Treatment of overactive bladder with sodium chondroitin sulphate].
Zentralbl Gynakol 2006, 128, 336-340

Hilt, E. E.; McKinley, K.; Pearce, M. M.; Rosenfeld, A. B.; Zilliox, M. J.; Mueller, E. R.; Brubaker, L.; Gai, X.; Wolfe, A. J. & Schreckenberger, P. C. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder.
J Clin Microbiol, 2014, 52, 871-876

Moehrer, B.; Hextall, A. & Jackson, S. Oestrogens for urinary incontinence in women.
Cochrane Database Syst Rev 2003, CD001405

Pearce, M. M.; Hilt, E. E.; Rosenfeld, A. B.; Zilliox, M. J.; Thomas-White, K.; Fok, C.; Kliethermes, S.; Schreckenberger, P. C.; Brubaker, L.; Gai, X. & Wolfe, A. J. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence.
MBio, 2014, 5, e01283-e01214

Sturdee, D. W.; Panay, N. & , I. M. S. W. G. Recommendations for the management of postmenopausal vaginal atrophy.
Climacteric 2010, 13, 509-522

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