Introduction

The normal adult human bladder is under voluntary control and does not contract, except during micturition. Conversely, an overactive bladder is one which contracts involuntarily or can be provoked to do so. Raised bladder pressure was first reported in certain neurological conditions over 70 years ago (Rose 1931, Langworthy et al 1936), but its clinical significance was not appreciated until 1963 when Hodgkinson et al demonstrated urinary incontinence as a result of detrusor contractions in 64 neurologically normal women. They called this condition ‘dyssynergic detrusor dysfunction’. Various other names have been used, including ‘detrusor instability’, ‘detrusor reflex instability’, ‘overactive bladder’ and ‘detrusor hyperreflexia’. The terminology of lower urinary tract dysfunction has been revised and standardized by the International Continence Society in order to clarify understanding of patient symptoms and diagnosis (Abrams et al 2002).

Overactive Bladder

The term ‘overactive bladder’ (then ‘unstable bladder’) was first used by Bates et al (1970) to describe ‘the objectively measured loss of ability to inhibit detrusor contraction even when it is provoked to contract by filling, change of posture, coughing, etc.’ More recently, overactive bladder has been redefined as the symptom-based diagnosis of ‘urgency, with or without urge incontinence usually with frequency and nocturia’ (Abrams et al 2002).

Detrusor Overactivity

The symptoms of overactive bladder are due to involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle. These involuntary contractions are termed ‘detrusor overactivity’ (Abrams et al 2002) and are mediated by acetylcholine-induced stimulation of bladder muscarinic receptors (Andersson 1997). However, overactive bladder is not synonymous with detrusor overactivity, as the former is a symptom-based diagnosis whilst the latter is a urodynamic diagnosis. It has been estimated that 64% of patients with overactive bladder have urodynamically proven detrusor overactivity, and 83% of patients with detrusor overactivity have symptoms suggestive of overactive bladder (Hashim and Abrams 2006).

Incidence

Epidemiological studies have reported the overall prevalence of overactive bladder in women to be 16.9%, suggesting that there could be 17.5 million women in the USA who suffer from the condition. The prevalence increases with age, being 4.8% in women under 25 years of age and 30.9% in those over 65 years of age (Stewart et al 2001). This is supported by recent prevalence data from Europe in which 16,776 interviews were conducted in a population-based survey (Milsom et al 2001). The overall prevalence of overactive bladder in individuals aged 40 years and above was 16.6%, and this increased with age. Frequency was the most commonly reported symptom (85%), whilst 54% complained of urgency and 36% complained of urge incontinence. When considering management, 60% had consulted a physician, although only 27% were currently receiving treatment.

More recently, a further population-based survey of lower urinary tract symptoms in Canada, Germany, Italy, Sweden and the UK has reported on 19,165 men and women over the age of 18 years (Irwin et al 2006). Overall, 11.8% were found to complain of symptoms suggestive of overactive bladder and 64.3% reported at least one urinary symptom. Nocturia was the most prevalent lower urinary tract symptom, being reported by 48.6% of men and 54.5% of women.

Aetiology

No specific underlying cause for overactive bladder has been identified, but possible aetiologies include idiopathic, psychosomatic and neurogenic causes in addition to incontinence surgery and outflow obstruction (men).

During infancy, prior to toilet training, it is normal for the bladder to contract uninhibitedly at a critical volume, and overactive bladder may be the result of poorly learnt bladder control. Zoubek et al (1990) studied 46 toilet-trained children, all of whom developed isolated urinary frequency. In 40% of cases, a ‘trigger’ was identified prior to the onset of symptoms. This often involved problems at school. All cases were self-limiting or resolved following counselling or removal of the ‘trigger’. In addition, there is a strong association between childhood nocturnal enuresis and overactive bladder presenting in adult life (Whiteside and Arnold 1975).

The psychoneurotic status of women with overactive bladder has been assessed by several authors, with conflicting results. Walters et al (1990) evaluated 63 women with incontinence and 27 continent controls using formal psychometric testing. They reported no difference in the test results between women with urodynamic stress incontinence and those with overactive bladder. Women with overactive bladder scored significantly higher than controls on the hypochondriasis, depression and hysteria scales. They concluded that these abnormalities may be related to incontinence in general and not to the specific diagnosis. Norton et al (1990) psychiatrically assessed 117 women prior to urodynamic investigation. There was no increased psychiatric morbidity in women with detrusor overactivity compared with women with urodynamic stress incontinence. Interestingly, women in whom no urodynamic abnormality could be detected had the highest scores for anxiety and neuroticism. These levels were comparable with those of psychiatric outpatients.

Neurological lesions such as multiple sclerosis and spinal cord injuries may cause uninhibited bladder contractions, which play an aetiological role in a small group of women with neurogenic detrusor overactivity.

In addition, following incontinence surgery, there is an increased incidence of detrusor overactivity (Cardozo et al 1979, Steel et al 1985, Brown and Hilton 1999) for which no specific cause has been found, but it may be due to extensive dissection around the bladder neck as it is more commonly seen after multiple previous operations. Alternatively, it may be failure to diagnose the abnormality prior to surgery or relative outflow obstruction caused by the operation itself. Outflow obstruction is rare in women and does not seem to cause detrusor overactivity in the same way that prostatic hypertrophy does in men. The increased incidence of detrusor overactivity in the elderly may be due to the onset of occult neuropathy (e.g. senile atherosclerosis or dementia).

Muscarinic Receptors

Molecular cloning studies have revealed five distinct genes for muscarinic acetylcholine receptors in rats and humans, and it has been shown that five receptor subtypes (M₁–M₅) correspond to these gene products (Caulfield and Birdsall 1998). In the human bladder, the occurrence of mRNA encoding M₂ and M₃ subtypes has been demonstrated, although not for M₁ (Yamaguchi et al 1996). The M₃ receptor is thought to cause a direct smooth muscle contraction (Harris et al 1995). Whilst the role of the M₂ receptor has not yet been clarified, it may oppose sympathetically mediated smooth muscle relaxation (Hegde et al 1997) or result in the activation of a non-specific cationic channel and inactivation of potassium channels (Hegde and Eglen 1999). In general, it is thought that the M₃ receptor is responsible for the normal micturition contraction, although in certain disease states, such as neurogenic bladder dysfunction, the M₂ receptors may become more important in mediating detrusor contractions (Braverman and Ruggieri 1998).

Pathophysiology

A detrusor contraction is initiated in the rostral pons. Efferent pathways emerge from the sacral spinal cord as the pelvic parasympathetic nerves (S2, 3 and 4) and run forwards to the bladder. Whilst preganglionic neurotransmission is predominantly mediated by acetylcholine acting on nicotinic receptors, transmission may also be modulated by adrenergic, muscarinic, purinergic and peptidergic presynaptic receptors.

Acetylcholine is released by the postganglionic nerves at the neuromuscular junction, and results in a coordinated detrusor contraction mediated through muscarinic receptors. However, adenosine triphosphate (ATP) also has a role (Burnstock 2001) mediated through non-adrenergic, non-cholinergic receptors (O’Reilly et al 2002).

Conversely, sympathetic innervation is from the hypogastric and pelvic nerves acting on β-adrenoreceptors causing relaxation of the detrusor muscle. Thus, a balance between sympathetic and parasympathetic stimulation is required for normal detrusor function.

The pathophysiology of detrusor overactivity remains unclear. In-vitro studies have shown that in cases of idiopathic detrusor overactivity, the detrusor muscle contracts more than normal. These detrusor contractions are not nerve mediated and can be inhibited by the neuropeptide vasoactive intestinal polypeptide (Kinder and Mundy 1987). Other studies have shown that increased α-adrenergic activity causes increased detrusor contractility (Eaton and Bates 1982). There is evidence to suggest that the pathophysiology of idiopathic and obstructive overactive bladder is different. From animal and human studies on obstructive overactivity, it seems that the detrusor develops postjunctional supersensitivity, possibly due to partial denervation (Sibley 1997), with reduced sensitivity to electrical stimulation of its nerve supply but greater sensitivity to stimulation with acetylcholine (Sibley 1985). If outflow obstruction is relieved, the detrusor can return to normal behaviour and reinnervation may occur (Speakman et al 1987).

Relaxation of the urethra is known to precede contraction of the detrusor in a proportion of women with detrusor overactivity (Wise et al 1993a). This may represent primary pathology in the urethra which triggers a detrusor contraction, or may merely be part of a complex sequence of events which originate elsewhere. It has been postulated that incompetence of the bladder neck, allowing passage of urine into the proximal urethra, may result in an uninhibited contraction of the detrusor. However, Sutherst and Brown (1978) were unable to provoke a detrusor contraction in 50 women by rapidly infusing saline into the posterior urethra using modified urodynamic equipment.

Brading and Turner (1994) suggest that the common feature in all cases of detrusor overactivity is partial denervation of the detrusor, which may be responsible for altering the properties of the smooth muscle, leading to increased excitability and increased ability of activity to spread between cells, resulting in coordinated myogenic contractions of the whole detrusor (Brading 1997). They dispute the concept of neurogenic detrusor overactivity (i.e. increased motor activity to the detrusor) as the underlying mechanism in detrusor overactivity, proposing that there is a fundamental abnormality at the level of the bladder wall, with evidence of altered spontaneous contractile activity consistent with increased electrical coupling of cells, a patchy denervation of the detrusor and a supersensitivity to potassium (Mills et al 2000). Charlton et al (1999) suggest that the primary defect in the idiopathic and neuropathic bladders is a loss of nerves accompanied by hypertrophy of the cells, and an increased production of elastin and collagen within the muscle fascicles.

Clinical Presentation

Quality of Life

Quality of life (QoL) has been defined as including ‘those attributes valued by patients including their resultant comfort or sense of well being; the extent to which they were able to maintain reasonable physical, emotional, and intellectual function; the degree to which they retain their ability to participate in valued activities within the family and the community’ (Naughton and Shumaker 1996). This helps to emphasize the multidimensional nature of QoL, and the importance of considering the patient’s perception of their own situation with regard to non-health-related aspects of their life (Gill and Feinstein 1974).

QoL is assessed by the use of questionnaires completed by the patient alone or as part of the consultation, and its measurement allows the quantification of morbidity and the evaluation of treatment efficacy. It also acts as a measure of how lives are affected and coping strategies adopted. It is estimated that 20% of adult women suffer some degree of life disruption secondary to lower urinary tract dysfunction (Burgio et al 1991).

Generic questionnaires, such as the Short Form 36 (Jenkinson et al 1993), are general measures of QoL and are therefore applicable to a wide range of populations and clinical conditions, whilst disease-specific questionnaires have also been designed to focus on lower urinary tract symptoms. Generic questionnaires are not specific to a particular disease, treatment or age group and hence allow broad comparisons to be made. Consequently, they lack sensitivity when applied to women with lower urinary tract symptoms, and may be unable to detect clinically important improvement.

The King’s Health Questionnaire is a reliable, validated, disease-specific tool used to assess women with lower urinary tract dysfunction (Kelleher et al 1997a). Experience using this questionnaire has shown that incontinence impact scores were significantly worse for women with detrusor overactivity than for those with urodynamic stress incontinence, and significantly better in women with normal urodynamics.

Investigations

Frequency/volume chart

It is the authors’ practice to send all patients a frequency/volume chart with their appointment for urodynamic investigations, so that their fluid intake and voiding pattern can be evaluated. As well as the number of voids and incontinence episodes, the mean volume voided over a 24-h period can also be calculated as well as the diurnal and nocturnal volumes. They are asked to complete the chart (Figure 53.1) for 5 days, but are told that they need not measure their voided volumes when at work if this proves difficult. In addition, there is now evidence that 3- and 4-day frequency/volume charts are as accurate as 7-day diaries (Brown et al 2003). Some women find that this is a useful exercise, similar to home bladder drill.

Figure 53.1 Frequency/volume chart from a woman with overactive bladder.

Cystometry

The urodynamic diagnosis of detrusor overactivity is made when detrusor contractions are seen on a cystometrogram. Detrusor overactivity is defined as ‘a urodynamic observation characterised by involuntary detrusor contractions during filling which may be spontaneous or provoked’ (Abrams et al 2002). The recorded detrusor pressure rise may take different forms on the cystometrogram trace. Most commonly, uninhibited systolic contractions occur during bladder filling (Figures 53.2 and 53.3). Not all cases of detrusor overactivity will be diagnosed on supine filling alone (Turner-Warwick 1975). Some show an abnormal detrusor pressure rise on a change of posture and may void precipitately on standing (Figure 53.4), or there may be detrusor contractions provoked by coughing which manifest as stress incontinence. Sometimes, a steep detrusor pressure rise occurs during bladder filling. This usually represents low compliance of the detrusor, but may be due to involuntary detrusor activity in some cases. It can be difficult to differentiate between systolic (phasic) detrusor overactivity and low compliance, which may coexist. Both conditions usually produce similar symptoms.

Figure 53.2 Cystometrogram showing severe systolic and provoked detrusor contractions during filling.

Figure 53.3 Cystometrogram showing neurogenic detrusor overactivity during filling in a patient with multiple sclerosis.

Figure 53.4 Cystometrogram showing low compliance with a high isometric contraction (Piso) during bladder filling.

During the cystometrogram, it is important to ask the patient about her symptoms and relate them to the recorded changes. Most patients will complain of urgency when a detrusor contraction occurs, or urge incontinence if the detrusor pressure exceeds the urethral pressure. Thus, in order to diagnose or exclude detrusor overactivity, subtracted provocative cystometry must be employed. Other common, although not universal, features of the cystometrogram in women with detrusor overactivity are early first sensation, small bladder capacity and inability/or difficulty in interrupting the urinary stream. The latter may be associated with a high isometric detrusor contraction (Figure 53.4) or, if videocystourethrography is performed, slow or absent ‘milk-back’ of contrast medium from the proximal urethra into the bladder.

Ambulatory urodynamics

There are three main components to an ambulatory urodynamic system: the transducers, the recording unit and the analysing system. The transducers are solid state and are mounted on 5 French and 7 French bladder and rectal catheters. It is the authors’ practice to use two bladder transducers in order to reduce artifact. The recording system should be portable in order to allow freedom of movement, with a digital memory aiding compression and expansion of the traces which are obtained. An event marker is attached to the recording unit allowing the patient to mark episodes of urgency and also to document voids. In addition, the recording unit is attached to an electronic (Urilos) pad to document episodes of leakage during the study, and should have the facility to attach to a flow meter in order to record pressure flow voiding studies. The ambulatory protocol at Kings College Hospital consists of a 4-h period during which time the patient is asked to drink 200 ml of fluid every 30 min and also to keep a diary of events and symptoms. On completion of the test, the trace is analysed with the patient using a personal computer and the urinary diary. Detrusor overactivity should only be diagnosed if there is a detrusor contraction noted on both bladder lines in the presence of symptoms (Figure 53.5).

Figure 53.5 Cystometrographic recording obtained during ambulatory monitoring. A detrusor contraction (Pdet) is associated with pressure rises in both bladder lines (Pves, Pura) and leakage of urine (loss).

The clinical usefulness of ambulatory urodynamics is limited by the high prevalence of abnormal detrusor (38–69%) contractions in asymptomatic volunteers (van Waalwijk van Doorn et al 1992, Robertson et al 1994, Heslington and Hilton 1996). However, the diagnosis of detrusor overactivity is highly dependent on interpretation of the results; in a prospective study of 26 asymptomatic women, the incidence of detrusor overactivity varied from 11.5% to 76.9% depending on the criteria used (Salvatore et al 1998, 2001). If the criteria for defining abnormal detrusor contractions are a simultaneous pressure rise on both bladder lines in addition to patient-reported symptoms of urgency or urge incontinence, the findings are normal in 90% of women; this is similar to that reported in laboratory urodynamics. In order to improve the diagnostic discrimination of ambulatory urodynamic studies, a standardization document has been published (van Waalwijk van Doorn et al 2000).

Videocystourethrography

Additional information may be acquired by undertaking videocystourethrography with pressure and flow studies, rather than subtracted cystometry, and this may also increase the diagnostic accuracy. Bladder diverticulae (Figure 53.6) and trabeculation (Figure 53.7) may be observed during videocystourethrography, and vesicoureteric reflux may be observed when severe detrusor overactivity has caused upper urinary tract damage.

Figure 53.6 Multiple bladder diverticulae.

Figure 53.7 Trabeculated bladder secondary to longstanding overactive bladder, with bladder diverticulae and bilateral vesicoureteric reflux. The bladder neck is open during a detrusor contraction with associated leakage.

Treatment

Not all women with overactive bladder require treatment. Once the problem has been explained to them, some will be able to control their own symptoms by behavioural modification, such as drinking less and avoiding tea, coffee and alcohol (which are bladder stimulants).

However, most women with overactive bladder request treatment, and although many different therapies have been tried, none have proved universally satisfactory. The major therapeutic interventions which are currently in use attempt to either improve central control, as in behavioural intervention, or alter detrusor contractility using drugs or surgical denervation techniques. When these measures fail to control the patient’s symptoms adequately over a long period of time, more invasive treatment may be employed. Conventional bladder neck surgery (as is used to treat urodynamic stress incontinence) rarely cures women with detrusor overactivity and may make the symptoms of urgency and frequency worse.

Methods of treatment currently employed are behavioural intervention, drug therapy, intravesical botulinum toxin and neuromodulation. For patients with intractable overactive bladder who are resistant to therapy, surgical procedures such as augmentation cystoplasty and urinary diversion may have a role.

Historically, other types of treatment which have been tried include vaginal denervation (Hodgkinson and Drukker 1977, Warrell 1977, Ingleman-Sundberg 1978), caecocystoplasty, selective sacral neurectomy (Torrens and Griffiths 1974), cystodistension (Ramsden et al 1976, Higson et al 1978, Pengelly et al 1978) and bladder transection (Mundy 1983). All give some short-term benefit in carefully selected cases, but may produce significant morbidity. None have stood the test of time.

Pharmacology

Drug therapy has an important role in the management of women with urinary symptoms caused by overactive bladder, although there are no drugs which act specifically on the bladder and urethra and do not have systemic effects. The large number of drugs available is indicative of the fact that none are ideal, and it is often their systemic adverse effects which limit their use in terms of efficacy and compliance (Kelleher et al 1997b). The pharmacology of drugs and recommendations for usage have been reviewed recently by the 4th International Consultation on Incontinence (Andersson et al 2009) (Table 53.1).

Table 53.1 Drugs used in the treatment of overactive bladder

*^,# See Appendix.

Antimuscarinic drugs

The detrusor is innervated by the parasympathetic nervous system (pelvic nerve), the sympathetic nervous system (hypogastric nerve) and by non-cholinergic, non-adrenergic neurones. The motor supply arises from S2, 3 and 4 and is conveyed by the pelvic nerve. The neurotransmitter at the neuromuscular junction is acetylcholine, which acts upon muscarinic receptors. Antimuscarinic drugs should therefore be of use in the treatment of detrusor overactivity. Atropine is the classic non-selective anticholinergic drug with antimuscarinic activity; however, its non-specific mode of action makes it unacceptable for clinical use because of the high incidence of side-effects. All antimuscarinic agents produce competitive blockade of acetylcholine receptors at postganglionic parasympathetic receptor sites. They all, to a lesser or greater extent, have the typical side-effects of dry mouth, blurred vision, tachycardia, drowsiness and constipation. Unfortunately, virtually all the drugs which are truly beneficial in the management of overactive bladder produce these unwanted systemic side-effects.

Tolterodine

Tolterodine is a competitive muscarinic receptor antagonist with relative functional selectivity for bladder muscarinic receptors (Ruscin and Morgenstern 1999). Whilst it shows no specificity for receptor subtypes, it does target the muscarinic receptors in the bladder rather than those in the salivary glands (Nilvebrant et al 1997). Several randomized, double-blind, placebo-controlled trials have demonstrated a significant reduction in incontinent episodes and micturition frequency (Jonas et al 1997, Hills et al 1998, Millard et al 1999), whilst the incidence of adverse effects has been shown to be no different to placebo (Rentzhog et al 1998). When compared with oxybutynin in a randomized, double-blind, placebo-controlled, parallel-group study, it was found to be equally efficacious and to have a lower incidence of side-effects, notably dry mouth (Abrams et al 1998). A pooled analysis of the safety, efficacy and acceptability of tolterodine in 1120 patients in four randomized, double-blind, parallel, multicentre trials found that both tolterodine and oxybutynin decreased incontinent episodes significantly, although tolterodine was associated with fewer adverse events, dose reductions and patient withdrawals than oxybutynin (Appell 1997).

Tolterodine has also been developed as an extended-release, once-daily preparation. A double-blind, multicentre trial of 1235 women compared extended-release tolterodine with immediate-release tolterodine and placebo. Whilst both formulations were found to reduce the mean number of urge incontinence episodes per week, the extended-release preparation was found to be significantly more effective (Swift et al 2003). In addition to increased efficacy, extended-release tolterodine has been shown to have better tolerability. In a double-blind, multicentre, randomized placebo-controlled trial of 1529 patients, extended-release tolterodine was found to be 18% more effective in the reduction of episodes of urge incontinence, whilst having a 23% lower incidence of dry mouth (van Kerrebroeck et al 2001).

Extended-release oxybutynin and extended-release tolterodine were compared in the OPERA (Overactive bladder: Performance of Extended Release Agents) study, which involved 71 centres in the USA. Improvements in episodes of urge incontinence were similar for the two drugs, although extended-release oxybutynin was significantly more effective than extended-release tolterodine in reducing the frequency of micturition. Significantly more women taking oxybutynin were also completely dry (23% vs 16.8%; P = 0.03), although dry mouth was significantly more common in the oxybutynin group (Diokno et al 2003).

In summary, the available evidence suggests that tolterodine is as effective as oxybutynin; in addition, as it has fewer adverse effects, patient tolerability and compliance are improved.

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