**5.3.2 Sacral neuromodulation (SNM)**

SNM uses mild electrical pulses to stimulate the sacral nerves that innervate the pelvic floor and lower urinary tract. InterStimTM therapy was developed by Medtronic (Minneapolis, Minn, USA) for use in humans. This technology utilizes an implanted unilateral lead stimulating the S3 nerve root. This electrode is attached to a small pacemaker placed within a subdermal pocket in the buttock region. It is FDA approved for refractory urge incontinence, refractory urgency frequency, and idiopathic nonobstructive urinary retention. "Off-label uses of the technology include for treatment of interstitial cystitis and pelvic pain syndrome. (Al-Shaiji et al, 2011)

Implantation of the device usually proceeds in 2 steps: a test phase and implantation or lead removal based on test response. The initial test phase can be performed in the office or

Neuromodulation can be utilized to increase pelvic muscle contraction and decrease detrusor contractions. The use of neuromodulation is assumes that OAB results from an imbalance of inhibitory and excitatory control systems of the detrusor that leads to the symptoms of OAB during the filling phase. (Fall and Lindstrom ,1991) Neuromodulation is gaining popularity because it bridges the gap between conservative treatments and highly invasive options. Currently, the methods used include sacral nerve modulation (SNM) via surgically implanted electrodes and other newer methods that deliver percutaneous

The exact mechanism of action for neuromodulation is not well understood. However,

 Sensory input through the pudendal nerve has been shown to inhibit detrusor activity. Pudendal nerve stimulation and enhancement of external sphincter tone may serve to

 Stimulation of afferent sacral nerves in the pelvis or lower extremities has been shown to increase the inhibitory stimuli to the efferent pelvic nerve thus reducing detrusor

 Neuromodulation affects the "neuroaxis" at various levels and restores the balance between excitatory and inhibitory regulation at various locations within the peripheral

There are several devices on the market to provide noninvasive electrical stimulation to the pelvic floor. The removable device is placed in the. Its mechanism of action in the treatment of OAB is thought to be secondary to reflex inhibition of the detrusor muscle by stimulation of the pudendal nerve. There is some evidence that this therapy has some efficacy in the

SNM uses mild electrical pulses to stimulate the sacral nerves that innervate the pelvic floor and lower urinary tract. InterStimTM therapy was developed by Medtronic (Minneapolis, Minn, USA) for use in humans. This technology utilizes an implanted unilateral lead stimulating the S3 nerve root. This electrode is attached to a small pacemaker placed within a subdermal pocket in the buttock region. It is FDA approved for refractory urge incontinence, refractory urgency frequency, and idiopathic nonobstructive urinary retention. "Off-label uses of the technology include for treatment of interstitial cystitis and

Implantation of the device usually proceeds in 2 steps: a test phase and implantation or lead removal based on test response. The initial test phase can be performed in the office or

control bladder overactivity and facilitate urine storage. (Vodusek et al, 1986) The bladder responds to neural stimulation initially with rapid contraction. This is then followed by slow, longer-lasting relaxation. With recurrent, repetitive electrical stimulation, there is a downregulation of the bladder's response, thus reducing the

many theories have been proposed as follows. (Al-Shaiji et al, 2011)

detrusor muscle overactivity. (Appell & Boone, 2007)

and central nervous system. (Van Der Pal, 2006)

treatment of OAB. (Berghmans et al., 2000; Goode et al., 2003)

contractility. (Fall & Lindstrom, 1991)

**5.3.1 Noninvasive electrical stimulation** 

**5.3.2 Sacral neuromodulation (SNM)** 

pelvic pain syndrome. (Al-Shaiji et al, 2011)

**5.3 Neuromodulation** 

stimulation of the peripheral tibial nerve.

operating room allowing for placement of the lead with a test period of 1 to 2 weeks; full implantation can be performed under local or general anesthesia. Response is objectively evaluated by pre- and postvoiding diaries assessing various urinary parameters.

The test phase of the procedure consists of implantation of tined quadripolar leads, under intravenous (IV) sedation, local anaesthesia, or general anaesthesia. Under fluoroscopy with a C-arm the right or left S3 foramen is identified and the permanent tined lead is passed through the foramen needle. The lead is then tested for a response. Correct placement in the S3 foramina includes bellows contraction of the pelvic floor and plantar flexion of the great toe. Once the appropriate side and position is selected, the lead is connected to an external pulse generator and taped to the skin surface. A 7- to 14-day home test period is used to determine which patients meet criteria to have the IPG implanted. Patients who respond favorably and demonstrate a 50% symptom improvement from baseline have the permanent generator implanted. (Al-Shaiji et al, 2011)

The most common adverse events include lead migration, implant site pain, bowel dysfunction, and infection. Infection usually resolves with antibiotics and the lead adverse events can usually be corrected by reprogramming, reinforcing the lead, or inserting a new lead contralaterally.

There is now convincing evidence for the success of SNM for refractory OAB. Several studies including RCTs and long-term observational studies reported fair clinical response between 64 and 88% of all patients (Leong et al, 2010).

#### **5.3.3 Percutaneous stimulation of the tibial nerve**

In addition, percutaneous stimulation of the tibial nerve (PTNS) has shown promise in the treatment of patients with refractory urge incontinence. PTNS is a minimally invasive, office-based procedure that involves percutaneous placement of a 34-gauge (ga) needle over the medial malleolus of the ankle to provide stimulation of the posterior tibial nerve. The procedure is repeated in 30-minute treatment sessions over a period of 12 weeks. PTNS in patients with OAB has been shown to significantly reduce in symptoms and improvement in health-related quality of life. (Yoong et al, 2010) However, one multicenter randomized trial of 100 patients with OAB symptoms did not show a reduced rate of urinary frequency when PTNS was compared to tolterodine extended release, 4mg daily. (Peters, 2009)

#### **5.4 Surgery**

In general most patients with OAB symptoms can be treated with medical and behavioral therapies. Generally, augmentation cystoplasty is only considered when patients have small volume bladders and are debilitated by their symptoms.

#### **5.4.1 Augmentation cystoplasty**

Augmentation cystoplasty (AC) is a surgery where a portion of the bowel is removed and patched to the bisected bladder. This procedure increases bladder capacity and decreases bladder pressure caused by unstable detrusor contractions. Considered a procedure of last resort, the risks of the surgery include recurrent UTI's, renal or bladder infections, metabolic changes and mucus production. (Khastgir et al., 2003) reviewed outcomes associated with

Diagnosis and Treatment of Overactive Bladder 181

average daily number of urgency episodes was significantly reduced, as were the average daily number of urgency incontinence and total urinary incontinence episodes. The authors concluded that NK1 receptor antagonism holds promise as a potential treatment approach

Overactive bladder (OAB) is a common medical condition, yet often undetected and undertreated despite the substantial impact on a woman's quality of life. The etiology of OAB is unclear, but several mechanisms may interplay and interconnected in contributing to the multi-symptom condition. Despite symptoms that often interfere with work, daily life, intimacy, and also cause embarrassment and diminished self-esteem, less than half of

A working clinical diagnosis of OAB can usually be made simply by utilizing proper urinary questionnaires, urinary diaries or a thorough medical history and physical examination. Confirmation of diagnosis is most often achieved via a post-void residual,

The primary goal of treatment of OAB is simply a reduction in urinary incontinence episodes. First-line therapy for OAB should include conservative options such as timed voiding and alterations in types and amount of fluid intake. Counseling patients on dietary and lifestyle modification will often improve their acute symptoms and decrease the number of voiding episodes per day. Other non surgical first line options include pelvic floor muscle training and/or biofeedback, both of which center around exercises designed to improve the function of the pelvic floor muscles. The primary limitations of behavioral

Antimuscarinic (anticholinergic) drugs are the cornerstone of pharmacological treatment of OAB and provide a favorable efficacy/tolerability/safety profile. These result in decreased bladder contractions and thus reduced the symptoms of OAB. For patients who are not candidates for antimuscarinic (anticholinergic) therapy or have failed previous trials of other medical therapy, noninvasive electrical stimulation to the pelvic floor via neuromodulation may increase pelvic muscle contractions and decrease detrusor contractions . More aggressive nerve modulation and stimulation therapies include, sacral nerve stimulation or peripheral nerve stimulation , which can be considered in patients with refractory urge incontinence. Lastly, surgical options, including augmentation cystoplasty and detrusor myectomy have been developed for those in which all other treatment

Lastly, there are promising new receptor-specific medical alternatives emerging and future

Despite the prevalence of OAB, and the patients' lack of willingness to report their life altering symptoms, screening for OAB should be part of every woman's annual well woman visit. Health care providers need not shy away from urinary incontinence questionnaires, as straightforward diagnosis and OAB treatments are available. Although the primary treatment goal of OAB is the reduction in urinary incontinence episodes, to the patient, the

therapy is the required long term patient commitment required for effectiveness.

for OAB.

**6. Summary** 

sufferers seek treatment from a licensed provider.

alternatives have been exhausted.

most important measure is quality of life.

studies will determine their place in the therapeutic arsenal.

simply cystometry or multichannel urodynamic testing.

augmentation cystoplasty. This group emphasized clinical outcomes (e.g. maximum detrusor pressure and bladder volume capacity) and patient symptoms (e.g. incontinence episodes and number of pads). Other outcomes included a questionnaire that measured quality of life, and the evaluation of complications from the surgery.

Using a definition of success as a > 50% reduction in symptoms, one group found a 97% success rate for AC. (Blaivas et al., 2005)

#### **5.5 Future therapies**

#### **5.5.1 Beta adrenoreceptor agonists**

The human detrusor muscle contains B2 and B3-adrenoceptors. Both receptors are thought to be involved in detrusor relaxation. Currently, there are a number of [beta] 3-adrenoceptor selective agonists being evaluated as potential treatment for OAB, including YM178 (mirabegron). Chapple et al (Chapple et al., 2008) conducted a clinical trial with mirabegron versus tolterodine and placebo in patients with OAB. Patients in the treatment arm had a statistically significant reduction in mean micturition frequency when compared to placebo. In addition, mirabegron was superior to placebo in regard to mean volume voided per micturition, mean number of incontinence episodes, nocturia episodes, urgency incontinence episodes, and urgency episodes per 24 hours. The drug was well tolerated, and the most commonly reported adverse effects were headache and gastrointestinal adverse effects. Further randomized trials will be needed to prove efficacy.

#### **5.5.2 Centrally acting drugs**

#### **5.5.2.1 Tramadol**

Many parts of the brain are activated during storage and voiding and there is increasing interest in centrally acting drugs which modulate the micturition reflex. (Andersson & Pehrson, 2003) Tramadol is an analgesic that is a weak μ-receptor agonist; however, it is metabolized to several different compounds, which inhibit serotonin (5-HT) and noradrenaline reuptake. (Grond & Sablotzki, 2004;Safarinejad & Hosseini, 2006) Both μreceptor agonist and amine reuptake inhibition are useful in the treatment of OAB. In a double-blind, placebo-controlled, randomized study, 76 patients were given 100 mg tramadol sustained release every 12 hours for 12 weeks. Tramadol significantly reduced the number of incontinence periods by 50% per 24 hours. The authors concluded that tramadol provided beneficial clinical and urodynamic effects.

#### **5.5.2.2 Tachykinins**

Tachykinins such as substance P, neurokinin A (NKA), and neurokinin B (NKB) may play a role in OAB. Substance P has a specific receptor (NK1) that is expressed in the dorsal horn of the spinal cord and may play an important role in detrusor overactivity. (Grond & Sablotzki, 2004; Safarinejad & Hosseini, 2006)

Aprepitant, an NK1 receptor antagonist, has been shown to significantly improve symptoms of OAB in postmenopausal women with a history of urgency incontinence or mixed incontinence in a small pilot. (Green et al., 2006) Aprepitant significantly decreased the average daily number of micturitions (−1.3 ± 1.9) compared with placebo (−0.4 ± 1.7). The average daily number of urgency episodes was significantly reduced, as were the average daily number of urgency incontinence and total urinary incontinence episodes. The authors concluded that NK1 receptor antagonism holds promise as a potential treatment approach for OAB.
