**1. Introduction**

188 Urinary Incontinence

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Overactive bladder (OAB) is a symptomatic complex affecting both men and women. The overall incidence is above 10% but may exceed 40% in the elderly population (Irwin et al., 2006; Irwin et al., 2009; Sexton et al., 2009a). OAB is defined by the International Continence Society (ICS) as a clinical syndrome characterized by urinary urgency, with or without incontinence, usually with frequency and nocturia (Abrams et al., 2002, 2003; Hashim & Abrams, 2007). Urgency, which is a storage symptom defined as a sudden compelling desire to pass urine difficult to defer, is the hallmark symptom as it is the only one that must be present in order to establish the diagnosis of OAB (Abrams et al., 2002, 2003). Several comorbidities are very common among OAB patients, including depression, insomnia and fractures (Coyne et al., 2008; Sexton et al., 2009a; Sexton et al., 2009b). The economic costs of OAB, associated with medical consultations, therapy and diminished productivity at work, may reach billions of dollars (Irwin et al., 2009) and will certainly increase with the demographic shift of an ageing population.

The true causes of urgency/OAB remain poorly understood. The difficulty in establishing animal models that accurately represent urgency/OAB still holds. It was originally thought that the origin of OAB could be ascribed to anomalies in the neuromuscular junction and myocites. More recent data indicate a strong involvement of bladder sensory mechanisms involving the urothelium and suburothelial afferent nerves. In addition, dysfunction of central nervous system centres that control the micturition reflex, including the Periaqueductal Gray (PAG) and pontine micturition centre, has been implicated in the genesis of OAB (Fowler et al., 2008; Drake et al., 2010; Fowler & Griffiths, 2010).

No cure exists for OAB. Management is initiated by exclusion of confounding diseases and by the introduction of conservative measures, including limiting fluid intake, avoiding caffeinated, acidic and carbonated drinks, weight reduction, smoke avoidance and bladder training. If bothersome OAB symptoms persist, patients are initiated on antimuscarinic

<sup>\*</sup> Corresponding Author

Biomarkers in the Overactive Bladder Syndrome 191

and successful outcome of OAB treatment impedes the routine use of urodynamic assessment for the majority of OAB patients. In a recent study, investigators tried to identify the presence of involuntary detrusor contractions through near-infrared spectroscopy (NIRS), a noninvasive method (Farag et al., 2011a; Farag et al., 2011b). NIRS is an imaging technique that can be used to monitor haemodynamic events. As the name indicates, it uses light in the nearinfrared area, which is able to penetrate the skin. It is absorbed by oxyhaemoglobin and deoxyhaemoglobin, the levels of which can reflect oxygen consumption. In those studies, investigators were able to demonstrate that detrusor contractions were accompanied by changes in those chromophores (Farag et al., 2011a; Farag et al., 2011b). The overall specificity of NIRS to detect DO was 86% when measuring oxyhaemoglobin, 80% for deoxyhaemoglobin and 72% for the sum of both chromophores. Despite obvious limitations, such as the inclusion

of more men than women, results are interesting and deserve further investigation.

In patients with bladder outlet obstruction, the thickness of the total bladder wall or simply the thickness of the detrusor layer was shown in several studies to be significantly increased in OAB patients when compared with healthy volunteers (Hakenberg et al., 2000; Oelke et al., 2006; Oelke et al., 2007). Hence, it was forwarded that BWT/DT could be influenced by the work overload of the bladder wall introduced by DO. Indeed, some authors have reported a trend of increasing DT associated with the severity of urgency as reported by Panayi and coworkers (Panayi et al., 2010). Khullar and co-workers analysed the total BWT via transvaginal ultrasound in a group of female patients with idiopathic DO (Khullar et al., 1996). They found that 58.7% of all analysed subjects had a mean BWT greater than 5 mm, 94% of which had DO. Only 1.6% of subjects had DO with a BWT of 3.5 mm or less. The authors proposed that the measurement of mean BWT by transvaginal ultrasound, with a cut-off of 5mm, is a suitable screening method (Khullar et al., 1996). In addition, by determining BWT also with transvaginal ultrasound, Kuhn and co-workers were able to differentiate between women suffering from stress urinary incontinence or bladder outlet obstruction (Kuhn et al., 2011). In OAB patients, DWT was reduced after anti-muscarinic treatment (Liu et al., 2009b; Kuo et al., 2010b). In addition, a positive correlation has been found between the presence of OAB and high BWT/DT(Robinson et al., 2002; Kuo, 2009).

However, the reliability of DT as a marker for DO or OAB is still debatable. BWT/DT are typically measured by ultrasound. One particular problematic issue is the well-known bias associated to the different operators of ultrasound. Another unsolved issue regards the best way to measure BWT/DT. Should the bladder be empty of filled? If filled, at which volume? Should one use an abdominal or transvaginal approach? Which are the costs? In addition, several studies failed to demonstrate significant differences between healthy controls, patients with DO, bladder outlet obstruction or with increased bladder sensation (Blatt et al., 2008). More recently, Liu et al measured the DT in normal controls and patients suffering from OAB or interstitial cystitis (Liu et al., 2009b). They found a wide variation amongst all groups of individuals with a trend of higher BWT/DT in OABwet patients that did not reach statistical significance. In another study, no differences in the BWT/DT were found between OAB patients and individuals with no OAB symptoms

**2.2 Bladder wall thickness/Detrusor thickness (BWT/DT)** 

(Chung et al., 2010).

therapy, the current mainstay for pharmacological management of OAB (Henderson & Drake, 2010; Athanasopoulos & Cruz, 2011). Nevertheless, despite significant improvement, antimuscarinics still produce important side-effects that may lead patients to discontinue treatment (Andersson, 2004; Andersson et al., 2009; Gulur & Drake, 2010). Moreover, antimuscarinics are contra-indicated for patients with narrow angle, may interfere with cognitive function and aggravate constipation (Gulur & Drake, 2010), all of which commonly occur in the typical OAB age group. More recently, the administration of vanilloids and botulinum toxin have been proposed as a possible treatment for OAB but these approaches should be taken with care as they are off-label procedures (Cruz & Dinis, 2007; da Silva & Cruz, 2009).

The key symptom in OAB, urgency, may often be confounded with urge to void. Urge is a normal bladder sensation, the intensity of which is proportional to the degree of bladder filling and allows the subject to fully control bladder function. Differentiation between urge and urgency may not always be an easy task for the caregiver or patients, particularly those who are cognitively impaired by age or disease (Michel & Chapple, 2009a, b). In addition, grading urgency is a difficult task to be accomplished by the clinician, even with the use of standardized questionnaires (Nixon et al., 2005; Starkman & Dmochowski, 2008). Currently, there is no objective test to diagnose OAB although several attempts have been made in order to overcome this. Here, we will review recent data proposing new biomarkers for a better characterization of OAB patients. The value of a biomarker in medicine is considerable and lies in its ability to identify the disease, back diagnostic and therapeutic decisions and establish a valuable prognosis to the condition. In addition, it will positively influence the outcome of the condition. In OAB, investigators have focused on bladder parameters (the presence of detrusor overactivity and the thickness of the bladder wall), serum proteins (the C reactive protein) and urinary elements (prostaglandins, cytokines and neurotrophins).
