The lower urinary tract and its neurological control

Optimal patient management requires an understanding of the physiology of the lower urinary tract, and its derangement in neurological disease. The lower urinary tract consists of the bladder and urethra and has just two roles: storage of urine and voiding at appropriate times. To regulate this, a complex neural control system acts like a switching circuit to maintain a reciprocal relationship between the reservoir (storage) function of the bladder and the continence (voiding) function of the urethra (figure 1). The pontine micturition centre is responsible for switching between the ‘storage’ phase and ‘voiding’ phase. It in turn receives input from other centres, particularly the periaqueductal grey of the midbrain, hypothalamus and cortical areas such as the prefrontal cortex.

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Figure 1

Innervation of the lower urinary tract. (A) Sympathetic fibres (blue) originate in the T11–L2 segments of the spinal cord and run through the inferior mesenteric ganglia (inferior mesenteric plexus, IMP) and the hypogastric nerve (HGN) or through the paravertebral chain to join the pelvic nerves at the base of the bladder and the urethra. Parasympathetic preganglionic fibres (green) arise from the S2–S4 spinal segments and travel in sacral roots and pelvic nerves (PEL) to ganglia in the pelvic plexus (PP) and in the bladder wall; this is where the postganglionic nerves that supply parasympathetic innervation to the bladder arise. Somatic motor nerves (yellow) that supply the striated muscles of the external urethral sphincter arise from S2–S4 motor neurons and pass through the pudendal nerves. L₁, first lumbar root; S₁, first sacral root; SHP, superior hypogastric plexus; SN, sciatic nerve; T₉, ninth thoracic root. (B) Efferent pathways and neurotransmitter mechanisms that regulate the lower urinary tract. Parasympathetic postganglionic axons in the pelvic nerve release acetylcholine (ACh) which produces bladder contraction by stimulating M₃ muscarinic receptors in the bladder wall smooth muscle. Sympathetic postganglionic neurons release noradrenaline (NA) which activates β₃ adrenergic receptors to relax bladder wall smooth muscle and activate α₁ adrenergic receptors to contract urethral smooth muscle. Somatic axons in the pudendal nerve also release ACh which produces contraction of the external sphincter striated muscle by activating nicotinic cholinergic receptors. Reproduced with permission from Fowler et al (Nat Rev Neurosci 2008;9:453–66).

Storage phase

• In health, the bladder is in the storage phase for 99.8% of the time, achieved by inhibition of parasympathetic activity and so relaxation of the detrusor muscle of the bladder wall. This results in ‘bladder compliance’ so that intravesical pressure remains below 10 cm H₂O.

• Simultaneously, sympathetic and pudendal nerve mediated tonic contraction of the urethral sphincters ensures continence.

• Functional imaging suggests that the pontine micturition centre is tonically inhibited during bladder filling by signals arising from the periaqueductal grey. Other areas that show ‘activation’ during bladder filling include the anterior cingulate gyrus and right insula.

Voiding phase

• When it is consciously deemed appropriate to void, the periaqueductal grey no longer exerts tonic inhibition on the pontine micturition centre. This results in relaxation of the pelvic floor muscles as well as the external and internal urethral sphincters, along with parasympathetic mediated detrusor contraction.

• Intact neural pathways between the bladder and the pontine micturition centre are essential for the coordinated activity between the detrusor and urethral sphincters.

• The prefrontal cortex is responsible for complex cognitive and socially appropriate behaviours, including voiding.

Neurogenic bladder dysfunction

Storage phase dysfunction most commonly results from lesions of the spinal or suprapontine pathways controlling micturition. This results in involuntary spontaneous or induced contractions of the detrusor muscle (detrusor overactivity) which can be identified during the filling phase in urodynamic studies (figure 2).

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Figure 2

Filling cystometry demonstrating detrusor overactivity. Red trace (Pabd), intra-abdominal pressure recorded by the rectal catheter; dark blue trace (Pves), intravesical pressure recorded by the bladder catheter; pink trace (Pdet), subtracted detrusor pressure (Pves−Pabd). Green traces represent volume infused during the test (Vinf) and volume voided (Vura) while the orange trace represents urinary flow (Qura). Black arrows indicate detrusor overactivity and black arrowhead indicates incontinence.

Voiding phase dysfunction usually results from lesions of the spinal or infrasacral pathways. In myelopathy, this is due to simultaneous contraction of the external urethral sphincter and detrusor muscle—detrusor–sphincter dyssynergia—which can result in both incomplete bladder emptying and abnormally high pressures in the bladder. Impaired detrusor contractions due to reduced parasympathetic drive from the descending bulbospinal pathways may also contribute to incomplete bladder emptying. In lesions affecting the infrasacral pathway, such as of the cauda equina (or occasionally a peripheral neuropathy), voiding dysfunction results from poorly sustained detrusor contractions and possibly non-relaxing sphincters.

Complications arising from the neurogenic bladder

• Detrusor overactivity and reduced bladder wall compliance result in raised intravesical pressure which can in turn lead to structural changes in the bladder wall such as trabeculations and diverticuli.

• The upper urinary tract (kidney and ureter) can also show changes such as vesicoureteric reflux and hydronephrosis, predisposing to renal impairment and even end stage renal disease.

• For reasons that are unclear, upper urinary tract damage and renal failure are surprisingly unusual in multiple sclerosis (MS).

• On the other hand, patients with spinal cord injury are prone to upper tract damage and renal disease, and have five times the age standardised risk for renal failure compared with the general adult population.

• Similarly, the risk is higher in adults with spina bifida, who have an eight times risk for developing renal failure, and this may be a leading cause of death.

• Risk of renal failure is highest in patients who have raised intravesical pressure due to detrusor overactivity, low bladder compliance and a competent bladder neck.

• Patients are prone to various genitourinary tract infections such as cystitis, pyelonephritis and epididymo-orchitis and also to bladder stones.

Diagnostic evaluation

History

As ever, history taking is the cornerstone of evaluation and should assess both the storage and voiding phases of micturition.

• Patients with storage dysfunction complain of frequency of micturition, nocturia, urgency and urgency incontinence.

• Patients with voiding dysfunction complain of hesitancy, straining for micturition, slow and interrupted stream or may be in urinary retention. Unfortunately, the history of voiding function is often unreliable as more than 50% of patients may be unaware of incomplete bladder emptying. The history should therefore be supplemented by a bladder scans (see below).

• The bladder diary records the time and volume of each voiding, urinary output and episodes of incontinence and urgency, and is an extension of the history (figure 3).

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Figure 3

Bladder diary over 24 h demonstrating daytime and night-time frequency, low volume voids and incontinence, in a patient with detrusor overactivity.

Screening for urinary tract infections

Combined rapid tests of urine, using reagent strips for urinalysis (‘dipstick’ test), is advisable for patients presenting with new bladder symptoms or at follow-up if there are unexplained changes in bladder symptoms. The negative predictive value for excluding urinary tract infection is 98% but the positive predictive value for confirming infection is only 50%.

Measurement of postvoid residual urine

Because the extent of incomplete bladder emptying cannot be predicted from the history or clinical examination, it is often important to estimate postvoid residual urine by ultrasonography, most commonly using a portable bladder scanner, or by ‘in–out’ catheterisation.

Ultrasonography is helpful to exclude complications such as bladder stones and should be performed periodically to assess the integrity of the upper urinary tract in patients known to be at risk of damage.

Urodynamics

Urodynamic tests assess detrusor and bladder outlet function.

• Uroflowmetry is a non-invasive assessment of voiding (figure 4).

• Filling cystometry and pressure–flow studies are more invasive tests that measure pressure–volume relationships during bladder filling and voiding (figure 2).

• Urodynamic evaluation also helps to identify concomitant local disorders that may contribute to lower urinary tract dysfunction such as bladder outlet obstruction due to prostate enlargement in men and stress incontinence in women, and their relative contribution to bladder symptoms.

• Videourodynamics uses fluoroscopic x-ray monitoring during urodynamics and allows demonstration of vesicoureteral reflux and any structural abnormalities of the bladder and bladder neck.

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Figure 4

Uroflowmetry, a non-invasive test for voiding functions, demonstrating urinary flow with a normal bell shaped curve and a maximum flow rate of 21 ml/s.

The need for a complete urodynamic study in every patient with neurogenic bladder symptoms is the subject of debate. Patients with spinal cord injury, spina bifida and possibly advanced MS should undergo urodynamic studies because of their higher risk of upper tract involvement and renal impairment, although ultrasound of the upper tract is a less invasive method for monitoring structural changes. In early MS, urodynamics should be carried out only in those whose urinary symptoms are refractory to conservative treatment or who are bothered by their symptoms and wish to undergo further interventions.

The pattern of bladder symptoms, and results of these various tests, depend on the level of the neurological lesion (table 1).

Causes of neurogenic lower urinary tract dysfunction

Dementia

Incontinence is often a prominent symptom and it tends to occur early in normal pressure hydrocephalus, dementia with Lewy bodies, vascular dementia and frontotemporal dementia but later on in the course of Alzheimer's disease and Parkinson's disease with dementia. Bladder dysfunction and increasing cognitive impairment tend to be related.

• Patients may have detrusor overactivity as a result of the underlying neurodegenerative changes affecting the suprapontine centres responsible for bladder control

• Cognitive and behavioural problems, urological/urogynaecological causes, immobility and cholinesterase inhibitors may contribute to incontinence

• On the other hand, incontinence, urinary tract infections and several of the antimuscarinic medications used for treating detrusor overactivity may worsen cognitive and behavioural problems.

Stroke

More than 50% of stroke patients have urinary incontinence during the acute phase. Risk factors for incontinence include lesion size, concomitant illnesses such as diabetes and increasing age. Lesions in the anteromedial frontal lobe and putamen are more commonly associated with incontinence. The burden of white matter hyperintensities causing leukoariaosis is as powerful a risk factor for urinary incontinence as damage in specific regions. Incontinence is independently associated with the severity of neurological disability and institutionalisation.

Parkinson's disease and multiple system atrophy

The severity of lower urinary tract dysfunction in Parkinson's disease is correlated with the stage of the disease, suggesting a relationship between dopamine loss and bladder dysfunction. Urgency and frequency are the commonest symptoms, resulting from detrusor overactivity.

Bladder symptoms in multiple system atrophy often precede other clinical manifestations; in the early stages, incontinence usually arises from detrusor overactivity but incomplete bladder emptying and urinary retention become the predominant problems as the disease progresses. An open bladder neck on videourodynamics is often seen in men with multiple system atrophy.

MS and other demyelinating disorders

Problems with micturition are very common in MS, generally correlating with the severity of the disease and lower limb pyramidal dysfunction. Most commonly, patients report storage symptoms such as urgency and frequency. Voiding symptoms depend on the degree of spinal cord involvement. Bladder dysfunction is also common in acute disseminated encephalomyelitis and may persist after the other neurological impairments have resolved.

Spinal cord injury

Patients may initially be in retention during the acute stage of spinal shock but they then develop the typical pattern of detrusor–sphincter dyssynergia and detrusor overactivity as spinal reflexes return.

Spina bifida

More than 90% of children with spina bifida have bladder dysfunction, through deficits in the somatic as well as the autonomic innervation of the bladder. Symptoms generally start in infancy or childhood but occasionally in adulthood. Urodynamic studies demonstrate a variety of findings: detrusor overactivity, detrusor underactivity or low bladder compliance with ineffective contractions. The bladder outlet may show detrusor–sphincter dyssynergia or it may be incompetent with a static or fixed distal sphincter. Young patients with normal bladder function can develop lower urinary tract dysfunction later on in life as a result of spinal cord tethering and bladder symptoms should be regularly reviewed.

Cauda equina syndrome

Lower motor neuron disturbance affecting the sacral nerve roots can result in voiding dysfunction and chronic urinary retention due to reduced or absent detrusor contractions. Patients may notice reduced sensation of bladder filling, inability to initiate micturition voluntarily and eventually bladder distension to the point of overflow incontinence. However, some patients may occasionally have detrusor overactivity.

Urinary retention

Iatrogenic causes from medications are often missed—opiates, medications with anticholinergic properties (eg, antipsychotic drugs, antidepressants and anticholinergic respiratory agents), α-adrenoceptor agonists, benzodiazepines, non-steroidal anti-inflammatory drugs and calcium channel antagonists may all cause urinary retention.

Neurologists are sometimes referred patients in urinary retention after a urological evaluation has excluded a ‘structural’ lesion obstructing the lower urinary tract. Once history, examination and relevant investigations such as spinal MRI, clinical neurophysiology and perhaps lumbar puncture have excluded a neurological cause, various functional disorders need to be considered (box 1 and 2).

Management

The goals are to achieve continence, improve quality of life, prevent urinary tract infections and preserve upper urinary tract function.

Voiding dysfunction

Before starting treatment, the postvoid residual volume should be measured; in patients with impaired voiding, more than 100 ml is likely to contribute to bladder dysfunction. A single measurement is not representative and, when possible, several should be made over 1–2 weeks. Complete bladder emptying is important for avoiding recurrent urinary tract infections, maintaining upper urinary tract function and optimising the management of storage symptoms. As there are no effective medications for improving voiding, catheterisation is usually the best option.

Clean intermittent self-catheterisation is preferred as it avoids the long term complications associated with a permanent indwelling catheter. However, the patient's cognitive state, motivation, manual dexterity and visual acuity are important factors to consider. Frequency of catheterisation depends on the postvoid residual volume, detrusor pressure and fluid intake.

Reflex voiding using trigger techniques, and Credé's manoeuvre (non-forceful, smooth even pressure from the umbilicus towards the pubis), are usually not recommended as they may result in high detrusor pressures and incomplete bladder emptying during voiding.

Suprapubic vibration using a mechanical ‘buzzer’ has been demonstrated to be effective in MS patients with incomplete bladder emptying and detrusor overactivity, but its effect is limited.

α-Blockers relax the internal urethral sphincter in men and there is evidence that they improve bladder emptying and reduce postvoid residual volumes. However, this is not consistently seen in clinical practice unless there is concomitant bladder outlet obstruction.

Botulinum toxin injections into the external urethral sphincter may improve bladder emptying in patients with spinal cord injury and significant voiding dysfunction.

Storage dysfunction

Non-pharmacological measures are generally effective in the early stages when symptoms are mild.

• Fluid intake of around 1–2 l a day, although this should be individualised and it is often helpful to assess fluid balance by means of a bladder diary.

• Caffeine reduction may reduce urgency and frequency in people who drink plenty of coffee and tea.

• Bladder retraining, whereby patients void by the clock and voluntarily ‘hold on’ for increasingly longer periods, aims to restore the normal pattern of micturition.

• Pelvic floor exercises and neuromuscular stimulation may have a role, if voiding dysfunction has been excluded, for ameliorating mild symptoms.

Antimuscarinic medications competitively inhibit acetylcholine at muscarinic receptors and improve urgency, frequency and incontinence; their effect is by relaxing the detrusor muscle. Since the introduction of oxybutynin, several newer agents have been marketed (table 2) but the only significant difference between them is their adverse effect profile.

Adverse effects resulting from the non-specific anticholinergic action include dry mouth, blurred vision for near objects, tachycardia and constipation. These drugs can also block central muscarinic M1 receptors and cause impairment in cognition and consciousness in susceptible individuals; this might be mitigated by medications with low selectivity for the M1 receptor such as darifenacin or restricted permeability across the blood–brain barrier such as trospium.

Postvoid residual urine may increase following treatment and should be monitored by repeat bladder scans, especially if initial beneficial effects are short lasting. In many patients, there may also be underlying voiding dysfunction and often it is the judicious combination of antimuscarinic medication with clean intermittent self-catheterisation which provides the most effective management for neurogenic bladder dysfunction (figure 5).

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Figure 5

Algorithm for the management of neurogenic bladder dysfunction. Reproduced with permission from the BMJ Publishing Group (J Neurol Neurosurg Psychiatry 2009;80:470–7). CISC, clean intermittent self-catheterisation; PVR, postvoid residual volume; UTI, urinary tract infection.

Desmopressin, a synthetic analogue of arginine vasopressin, temporarily decreases urine production and volume determined detrusor overactivity by promoting water reabsorption at the distal and collecting tubules of the kidney. It is useful for the treatment of frequency or nocturia in conditions such as MS and spina bifida, providing symptom free periods of up to 6 h. It is also helpful in managing nocturnal polyuria which may be seen in Parkinson's disease and dysautonomia. However, it should be prescribed with caution in patients over the age of 65 years or with dependant leg oedema, and should not be used more than once in 24 h for fear of hyponatraemia and heart failure.

Botulinum toxin type A injected into the detrusor muscle under cystoscopic guidance appears to be a highly promising, although as yet unlicensed, treatment for intractable detrusor overactivity. Although patients often have to perform clean intermittent self-catheterisation afterwards, the effect lasts 9–13 months and it significantly improves storage symptoms and quality of life. Patients have fewer urinary tract infections and reduced urethral leakage when using an indwelling catheter (catheter bypassing).

Sacral neuromodulation and posterior tibial nerve stimulation can help manage neurogenic detrusor overactivity. The exact mechanism of action remains unclear.

Surgical options such as augmentation cystoplasty or urinary diversion are guided by discussions in the setting of a multidisciplinary team, considering the degree of disability of the patient.

Appliances and equipment

A range of continence aids such as penile sheaths and disposable body worn pads may be helpful for containing incontinence when other measures are unsatisfactory. Men should be assessed and fitted with external drainage systems if needed, and be reviewed periodically. When appropriate, reuseable products such as pants and bed pads should also be offered, as well as the full range of toileting equipment such as hand held urinals, aids and portable commodes.

Urine infection

• Urine should not be routinely tested unless there are symptoms suggesting infection; asymptomatic bacteriuria alone in a patient performing clean intermittent self-catheterisation is not an indication for antibiotics.

• Antibiotics should be limited to symptomatic urinary tract infections.

• Unrestricted use of prophylactic antibiotics can lead to drug resistance; however, in individuals with proven recurrent urinary tract infections in whom no urological structural abnormality has been identified and whose intermittent catheterisation technique cannot be improved, it is reasonable to start prophylactic low dose antibiotics; this decision should be taken in consultation with a urology specialist team.

• The value of cranberry juice in preventing urinary tract infections is debatable.

Stepwise approach to a patient with neurogenic bladder dysfunction

The treatment options should reflect the severity of the symptoms which generally parallel the extent of the neurological disease (figure 6). However, beyond a certain point, the symptoms may become refractory to all treatments and it is at this stage that a long term indwelling catheter should be offered. This should be a suprapubic rather than a urethral catheter because of the impact of the latter on urethral integrity, perineal hygiene and sexuality. Intermittent bladder drainage with a catheter valve, as opposed to continuous drainage into a leg bag, depends on whether the bladder has a reasonable capacity to store urine.

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Figure 6

Stepwise approach to neurogenic bladder dysfunction management with progressing disability.

Although most patients can be managed along these lines, there are specific situations where specialist urology or urogynaecology services should be involved (box 3).