The overactive bladder complex: management and case studies

The idiopathic overactive bladder (OAB) is a clinically-diagnosed symptom complex consisting of frequency, urgency and nocturia with or without urge associated urinary continence. This complex assumes no underlying cause as a source of bladder dysfunction. The alternate term of detrusor overactivity on the other hand is a urodynamic diagnosis based on cystometrography (CMG) – previously termed bladder instability – which is characterised by an unprovoked rise in detrusor pressure during the filling phase of a CMG, and is often associated with a clinical feeling of urgency in a normally sensate individual.

There have been challenges in determining what is defined by normal, and the International Continence Society (ICS) now suggests that clinical deterioration is what is perceived by the patient, and leads them to seek medical help. In addition to ‘normal’ voiding patterns during the day, the ICS has qualified this as a “sudden and compelling desire to pass urine, which cannot be deferred”, and may lead to urinary incontinence.¹ Epidemiological studies have found that the prevalence of this condition is rising, and now affects approximately 16% of European and American populations.²

Diagnosis and management are important in minimising OAB’s impact on activities of daily living. The burden of OAB is even heavier in the older population. 

The symptoms can be defined as the following:

• Urgency – sudden, compelling desire to void that is difficult to defer
• Daytime frequency – the need to frequently urinate during the day
• Nocturia – waking up at night to void
• Urgency urinary incontinence may be present but is not necessary for a diagnosis of OAB.

Overactive bladder will become an increasingly prevalent problem as populations age. It is associated with additional health risks in older patients, particularly with falls and fractures. It is associated with increased mortality and may be a predictor of institutionalisation (especially in the presence of urinary incontinence).

Older patients are less likely to discuss their OAB symptoms with their healthcare provider, and are more likely to be untreated or undertreated. OAB may interfere with social and occupational activities.

Assessment

We need to tailor investigations to suit the individual, their environment, lifestyle, age, health, expectations, and the mode of treatment we wish to prescribe. A 20-year-old female with OAB may be particularly bothered by troublesome nocturia as she needs to wake early and work a full day, or by nocturnal enuresis which can affect new relationships. On the other hand, an 80-year-old man might be most upset if he cannot visit friends/relatives without the psychosocial embarrassment of urge associated incontinence.

It is very important however, to exclude urinary tract infections and other associated differential diagnoses before applying a label of an overactive bladder (see Table 1). An important differential for reversible causes of urinary incontinence can be remembered by the mnemonic ‘DIAPPERS’:

• Delirium
• Infection
• Atrophic vaginitis/urethritis (females)
• Pharmaceuticals
• Psychological problems 
• Excess urine output 
• Reduced mobility 
• Stool impaction.

It is important that urinary tract infections be identified and adequately treated prior to the undertaking of further investigations or prescribing pharmacological treatment for OAB. To this end, it is important to consider the fastidious organisms mycoplasma hominis, ureaplasma urealyticum, and chlamydia trachomatis, which are commonly found in both urine and vaginal discharge. As these organisms are fastidious, they must be specifically cultured, and an index of suspicion is required. Treatment for these is low-dose tetracycline (doxycycline) for three months, compared to a standard seven to 10 day course of a broad spectrum antibiotic for bacterial organisms.

Frequency-volume chart

The frequency-volume chart, also known as a bladder or voiding diary, is a valuable tool in assessing OAB symptoms; it identifies voiding patterns and the balance between diurnal and nocturnal urinary frequency. They identify those who are drinking a lot of fluid through the day. If the patient’s symptoms are not explained by the voiding diary, one might need to undergo urodynamic investigations, defined as measurements to quantify the ability of the bladder to store and expel urine.

NICE guidelines recommend use of a diary for a minimum of three days to include a combination of work and leisure days.³

Uroflowmetry

Uroflowmetry is the most simple of the urodynamic tests; it is not invasive and is physiological. In normal individuals, the maximum urinary flow rate should be in the region of > 15mL/s for a voided volume of > 150mL. As a rule, a low flow rate implies voiding difficulties, due either to a hypotonic detrusor or to an obstructed outlet, which cannot be differentiated without further assessment. The importance of uroflowmetry in OAB lies in the tendency of the antimuscarinic agents to impair voiding function. Thus, to avoid the possibility of retention, one needs to know the patient’s pre-treatment flow rate as well as postvoid residual urine volume.

Case study 1

PK is a 70-year-old male who until about a year ago remained quite active. His background history includes an ST-elevation myocardial infarction (seven years ago), and an open radical retropubic prostatectomy two years ago. 

Sensitive subjects can be difficult to discuss. As you enquire about his health and how he is recovering since his surgery, you specifically ask if he has any troubles with his bladder. He mentions that these days he has to make sure that wherever he goes there will be a bathroom. As you reassure PK that this is a common concern and that there are ways to treat it, he begins to open up about how the problem has been affecting him. You learn that he has become increasingly restricted in his activity because of his urinary frequency and urgency. He also has occasional urinary incontinence. He is concerned and upset that he can no longer visit his grandchildren because long excursions from home cause him tremendous anxiety about whether he will be able to reach a bathroom as required. Even short trips away from home for such tasks as going into town to shop for necessities are becoming problematic, and he increasingly relies on his wife to do these things. He is beginning to feel isolated and depressed.

PK’s weight is 78kg and his blood pressure is 121/82. His medications include levothyroxine 50mcg once daily, rosuvastatin 10mg once daily, low-dose aspirin 75mg once daily, amlodipine 5mg once daily, pantoprazole magnesium 40mg once daily, metoprolol SR 50mg twice daily, ramipril 5mg twice daily, and furosemide 40mg twice daily.

There are a number of conditions that can contribute to OAB symptoms, and it is important to consider these during initial workup (see Table 2). In this case, it is important to note that diuretics, especially rapid-acting agents, cause a rapid increase in bladder volume, which may precipitate urgency and detrusor overactivity. Anticholinergic agents, opioids and calcium-channel blockers decrease bladder contractility and may cause urinary retention with a decreased functional bladder capacity. Cholinesterase inhibitors could contribute to detrusor overactivity by increasing acetylcholine levels, and should be suspected in patients in whom symptoms develop after initiation of treatment.

Based on your recommendation following a frank discussion relating to his ideas, concerns and expectations, you have made some adjustments to his medication regimens, as well as some lifestyle changes, including reducing his caffeine intake. 

Behavioural intervention 

Behavioural intervention improves central control, based on the idea that if people can learn to become continent in infancy, they can re-learn it in adult life. This approach avoids the morbidity and mortality associated with surgery, as well as the side-effects of drugs. Bladder ‘drills’ were first described between 1978 and 1980, and following the exclusion of any other relevant pathology, the patient is given an achievable target time for using the toilet, before which they may not do so. The time target is set low enough in order to allow the patient to wait for long enough without wetting. After that goal is met, the target time is increased. The patient maintains a normal fluid intake and keeps their own fluid-balance chart. This works better with continued supervision and encouragement, and exercise compliance rates tend to decrease at home. The relapse rate is high. Other interventions include a reduction in caffeine, weight loss and evening fluid intake.

Despite these drug changes and behavioural interventions, PK has continued to have persistent symptoms and occasional urgency incontinence after three months of good compliance. You are concerned about his lack of progress. Evidence has shown that urinary incontinence in patients > 65 years is associated with a twofold increased relative risk of impaired functioning in activities of daily living. You recommend to PK that he begin pharmaceutical treatment, however he wants to know about what is available and how these work.

Pharmacological treatment

Three classes of treatment are indicated in the management of OAB:

• Clinical guidelines recommend first-line pharmacotherapy with antimuscarinic agents, which have been in use for 30 years 
• A newer treatment option is a selective beta 3 adrenoceptor agonist, mirabegron
• Botulinum toxin type A was approved for intradetrusor injections for the second-line treatment of OAB in adult patients who have an inadequate response to or are intolerant of antimuscarinic medication.

Antimuscarinics 

A major meta-analysis of trials of antimuscarinic agents for OAB found antimuscarinics efficacious compared to placebo.⁴ Differences in the relative efficacy of the agents was not apparent, except that some results showed statistical significance in favour of the higher dosage of fesoterodine and solifenacin over placebo and lower dose antimuscarinics. 

Options for antimuscarinic treatment include darifenacin extended release tablets, 7.5mg or 15mg; fesoterodine extended-release tablets, 4mg or 8mg; oxybutynin, 5mg regular (immediate release) or extended release tablets, 5mg, 10mg, twice weekly dosing, 36mg (3.9mg/day system); solifenacin succinate tablet, 5mg or 10mg; tolterodine regular or extended release capsules, 2mg or 4mg; and trospium chloride coated tablet,20mg.

Antimuscarinics differ in their frequency of administration, receptor selectivity and specificity, binding affinity, and other characteristics. The primary sites of activity are the M2 and M3 receptors of the bladder, which mediate contraction. Selectivity for muscarinic receptors is the main reason for variation in side effects across the antimuscarinic agents. Action on muscarinic receptors in the body beyond the detrusor muscle leads to side effects. The side effect profile of each antimuscarinic differs with possible adverse effects that can, depending on the agent, include dry mouth, constipation, headache, blurred vision, pruritus, tachycardia, somnolence and impaired cognition. 

Mirabegron (beta 3 adrenoceptor agonist)

Mirabegron is an oral, once-daily, selective beta-3 adrenoceptor agonist that has shown similar efficacy to antimuscarinics. Mirabegron seems to act on the storage phase of bladder function to facilitate smooth muscle relaxation, for increased bladder capacity and lengthened interval between voiding. 

Mirabegron extended-release tablets are available in 25mg and 50mg. Mirabegron is generally well tolerated; the most commonly reported adverse reactions (> 3% of patients taking mirabegron 50mg/day) were hypertension, urinary tract infection, headache and nasopharyngitis. The incidence of dry mouth and other side effects was similar in rate to placebo.

Botulinum toxin

Botulinum injections are now indicated for the treatment of OAB when there has been inadequate response to antimuscarinic therapy. Botulinum toxin exerts its effect by cleaving key proteins required for nerve activation. First, the toxin binds specifically to nerves which use the neurotransmitter acetylcholine. Once bound to the nerve terminal, the neuron takes up the toxin into a vesicle. As the vesicle moves further into the cell, it acidifies, activating a portion of the toxin which triggers it to push across the vesicle membrane and into the cell cytoplasm. Once inside the cytoplasm, the toxin cleaves SNARE proteins preventing the cell from releasing vesicles of neurotransmitter. This stops nerve signalling, leading to paralysis. Clostridium botulinum type A, a neurotoxin, is injected into the detrusor muscle via a flexible or rigid cystoscope. The needle is inserted into the detrusor and 20 injections are delivered. Clinical improvement may occur within two weeks. 

Patients may be considered for reinjection when the clinical effect of the previous injection has diminished, but no sooner than three months from the prior bladder injection. The most common adverse reactions with botulinum injections in the first 12 weeks post-op include urinary tract infections (26%), dysuria (11%), bacteriuria (8%), urinary retention (6%), increased residual urine volume (3%), and pollakiuria (daytime frequency) (2%). 

Case study 2

SP is a 54-year-old female with a five-year history of urinary incontinence. She works as a zoo-keeper which is a very active job, and is distressed with the impact this is having on her work and social life. She experiences frequency every 30-60 minutes during the day and wakes up twice at night to urinate. She gets a sudden urge to void and this is associated with an involuntary leakage of moderate amounts of urine, especially at night. Her urgency is triggered by running water and cold temperatures.

She had a hysterectomy at age 45. Her BMI is 29.5kg/m2 (overweight) but she is otherwise healthy, and does not experience any urinary tract infections. Following an initial consultation with her primary care physician, she has restricted her fluid intake (especially after 6pm), has given up caffeine to good effect, and no longer drinks alcohol. Her bladder diary shows a low fluid intake (one cup of water in the early morning and two cups in the evening). She voids 10 times during the day. Her leakage is both diurnal and nocturnal and usually happens on the way to the bathroom. As a result, she has resorted to wearing two to three incontinence pads per day.

SP returns to the office with a completed bladder diary for a further clinical review. These indicate that she still has clinical evidence of urgency incontinence, and her symptoms of urgency and frequency with leakage match the definition of OAB (wet). Following a balanced review, and a frank risk/benefit discussion, you have recommenced her treatment cycle. 

Conservative therapy: This includes fluid adjustment, with an encouraged fluid intake of between six and eight cups with a balanced intake throughout the day but decrease evening intake due to nocturia. She should continue to eliminate caffeine and check for other bladder irritants. One also needs to encourage weight loss, as it may improve urgency symptoms

Behavioural therapy: This includes pelvic floor muscle training, urge suppression and bladder retraining, which will progressively increase sphincter tone, as well as urge suppression and pelvic muscle contractions. Biofeedback training given by a clinical nurse specialist can also help identify voiding issues, and can curtail storage lower urinary tract symptoms

Medication: As described above, if conservative therapies are unsuccessful, a trial of antimuscarinic (anticholinergic) medication (eg. oxybutynin, tolterodine, darifenacin, solifenacin or trospium) should be instigated. A combination of drug and behavioural therapy might act synergistically to improve her symptoms. If incontinence persists, she may be able to use a product suitable for her absorbency requirement. It might be an extra absorbent pad, undergarment or protective underwear. Further discussion should then be had regarding more invasive treatments. 

Case study 3

AD is a 12-year-old male who had closure of a T10 myelomeningocoele as a neonate. He is ambulant with walking aids, and is on long-term bowel management in the form of laxatives. He also complains of recurrent MSU-confirmed UTIs, and urge-associated urinary incontinence. 

In the paediatric population, much of the symptomatology is difficult to elicit directly from patients, and one must rely to an extent on the history presented by a parent/guardian. The definitions remain broadly similar to the adult population, however, children broadly fall into four categories when dealing with voiding dysfunction:

• Voiding dysfunction with or without constipation (bladder bowel dysfunction)
• Neurogenic bladder
• Congenital structural anomalies (ectopic ureter leading to continual incontinence)
• Idiopathic OAB.

By far, the most common of these is the first category of voiding dysfunction with/without constipation. However, the most feared is the accurate diagnosis, and management of the neurogenic bladder. Broadly speaking, congenital neurogenic bladders can be categorised into open or occult neural tube defects (NTD), sacral agenesis, spinal cord lesions and cerebral palsy.

Open NTDs can be subcategorised into (lipo)myelomeningocoele (exposed meninges and neural tissue +/- lipoma of the cord), and meningocoele (exposed meninges only). These are thought to affect 1/1,000 births, and rates vary in different geographic regions with access to prenatal ultrasonographic scanning and differing legislation determining termination. They affect the lumbosacral/sacral regions of the cord in approximately 67% of patients, and are usually closed as a neonate. Interestingly, the severity of symptom complex cannot be predicted as easily as that of a spinal cord injury, however, as a rule of thumb, the higher the lesion, the more likely the degree of severity. Occult NTDs and spinal cord tethering (due to lipomeningocoele, intradural lipoma, dermoid cysts/sinuses, tight filum terminale) are thought to affect 1/4,000 births, and often don’t present clinically until patients demonstrate a failure to achieve continence. 

Urodynamic studies may demonstrate lower tract dysfunction such as large capacity, poorly emptying bladders with associated poor sphincter functions. Neurosurgical correction has been shown to improve outcomes in this cohort, however, there is a paucity of prospective data in this cohort. Sacral agenesis (associated with maternal diabetes mellitus) can be associated with a wide range of neurologic deficits associated with voiding dysfunction, and just over one-third will demonstrate evidence of poor compliance and increased bladder filling pressures on urodynamic studies. 

Management of AD’s condition is quite different from the storage lower urinary tract symptoms described in the adult cases outlined above and, following a careful initial history, physical exam, voiding and stooling diaries, as well as a baseline ultrasound of the abdomen/pelvis, it is also important to involve initial urodynamic studies and long-term follow up for vesicoureteric reflux, incontinence and upper tract deterioration. Those patients with associated detrusor-sphincter dyssinergia (DSD) are more likely to develop poor bladder compliance and worsening upper tracts. Bowel management is also especially important in this cohort. In adolescence and adulthood, management of erections, sexual function and fertility prove a challenging but importance facet to their care. 

Urinary incontinence in women

In 2004, the International Consultation on Incontinence (ICI) devised an algorithm that summarised the proposed initial management of urinary incontinence in women.⁵ This includes an initial history and symptom assessment taking into account co-morbid conditions, lifestyle choices and medications, and following which patients are divided into categories of stress urinary incontinence, mixed urinary incontinence, urge-associated urinary incontinence and/or OAB symptoms. After careful clinical evaluation with physical examination (including a bimanual pelvic exam in women), a presumed diagnosis is made based on initial tests such uroflowmetry. Those with OAB go on to bladder retraining and antimuscarinic drugs. Only when these simple measures fail does one offer specialised management.

Conclusion

In those presenting with the symptom complex of frequency, urgency and nocturia with or without urge associated incontinence, one needs to exclude other pathology including UTIs, before diagnosing OAB. 

Social circumstances and the lifestyle and expectations of the individual patient need to be taken into account in order to tailor appropriate investigations. 

Behavioural therapy and lifestyle interventions should be used as initial treatment for most patients, but there is a high risk of relapse. 

Compliance with antimuscarinic therapy relates to efficacy, but there is significantly reduced compliance over time. Botulinum toxin can be used in those who don’t respond to or who cannot tolerate pharmacological treatment.

References

1. International Continence Society. Fact Sheets. A background to urinary and faecal incontinence. 2015. www.ics.org
2. Irwin et al. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int 2011 Oct; 108(7):1132-8
3. Urinary incontinence in women:management. NICE clinical guideline CG17. September 2013. Updated November 2015 www.nice.org.uk/guidance/cg171/chapter/1-Recommendations#assessment-and-investigation
4. Athanasolpoulos A, Giannitsas K. An overview of the clinical use of antimuscarinics in the treatment of OAB. Adv Urol 2011; 2011: 820816
5. Viktrup L. Addressing the need for a simpler algorithm for the management of women with urinary incontinence. Medscape General Medicine 2005; 7(3):62