Normal micturition control and reflexes

Normal lower urinary tract function

Aetiology of neuropathic bladder dysfunction

• diseases above the mid brain
• diseases primarily affecting the spinal cord
• peripheral neural pathology

Lower urinary tract dysfunction

• classification
• neurologic evaluation

Treatment

• common modalities

Neuromodulation

These have been determined largely through lesional studies, electrical and pharmacological stimulation, pseudorabies injection in cats, rats and dogs, cordotomies for chronic pain and more recently by PET scans in human volunteers. There are 6 areas involved:

1) Suprapontine Region
The frontal lobe of the cerebral cortex, hypothalmus, basal ganglia and cerebellum have a modifying influence on the pontine micturition centre.

2) Pontine Micturition Centre (PMC)/Barrington's Nucleus/Nucleus Locus Coerulus
This is located in the ventral peri-aqueductal grey area of the pons and is the area of integration and control of afferent and efferent impulses from the urinary bladder. It has 2 associated areas located dorsally in the pontine tegmentum - the M area (for micturition) and the L area (for storage).

3) Sacral Spinal Cord/Parasympathetic Motor Nucleus S2,3,4.
This is located in the intermediolateral horn of the spinal cord and provides the major motor innervation to the detrusor. There is also purinergic innervation of the detrusor which may be important in pathological states.

4) Onuf's Nucleus S2,3,4
This is located in the anterolateral horn of the sacral spinal cord and provides the motor innervation of the rhabdosphincter. The fibres travel through the pudendal nerve.

5) Sympathetic Supply T10-L2
This outflows from the intermediolateral horn and nucleus intercalus. The fibres include both pre- and post-ganglionic fibres. They pass through the superior hypogastric plexus, then the right or left hypogastric nerves to the pelvic plexus where they either interact with parasympathetic fibres, or synapse with post-ganglionic neurons. The majority of the supply is stimulatory to the BN and urethral smooth muscle via a-receptors. The supply to the detrusor is inhibitory via b-receptors.

6) Afferent nerves of the bladder originate from mechanoreceptors that respond to stretch. The impulses travel through A-d fibres in the pelvic nerves and relay on the interneurons in the posterior horn of the spinal cord from where the secondary neuron travels through the spinothalamic tract to the PMC. Other afferent impulses originate at the trigone and urethra and relay mostly to the c/cortex.

Up to 12 micturition reflexes have been described but only 4 are considered important in health:

• the afferent impulse routed up to the pons to cause parasympathetic efferent contraction of the bladder
• reciprocal relaxation of the intrinsic rhabdosphincter to allow unobstructed voiding
• the local spinal reflex increase in urethral pressure during bladder filling
• sympathetic inhibition of parasympathetic ganglionic transmission in the pelvic plexuses during more advanced bladder filling

The micturition cycle involves 2 relatively discrete processes and bladder dysfunction results from abnormality of one of them:

Bladder filling and storage - this requires accommodation at low pressure (compliance), closed bladder outlet at rest and with increased intra-abdominal pressure and the absence of involuntary bladder contractions.

Bladder emptying - requires co-ordinated contraction of the detrusor of sufficient amplitude and duration, a concomitant lowering of resistance at the smooth and striated sphincter and the absence of anatomical obstruction.

Mechanisms underlying the 2 phases of micturition: filling and voiding.

• Filling Phase is dependent on
  • the viscoelastic/stress relaxation/receptive relaxation property of the bladder i.e. stretch without tension
  • increased urethral pressure through the action of pudendal efferents to the rhabdosphincter
  • inhibition of sacral parasympathetics by inhibitory interneurons during subthreshold stimuli-gating
  • urinary continence during abdominal pressure increases may depend on intra-abdominal urethra, the hammock hypothesis (Delancy 1994 Am. J. Obs. & Gynae. vol 170) and/or reflex increase in intrinsic sphincter activity.
• Voiding Phase
  • initiated by increased intravesical pressure of a full bladder producing a sensation of distension
  • second, the micturition reflex is activated, co-ordinated in the brain stem (pons).
  • finally, co-ordinated contraction of the detrusor and a decrease in outlet resistance

Diseases at or above the brain stem:

• Cerebrovascular Disease (CVA)
• Dementia
• Parkinson's Disease
• Cerebral Palsy (CP)
• Shy-Drager Syndrome (Multiple System Atrophy)

1. Cerebrovascular Disease

Epidemiology	prevalence of 60 per 1000 in >65 years, third most common cause of death
Pathology	brain stem ischaemia or infarction secondary to thrombosis, empolic occlusion or haemorrhage of variable size, location and degree of recovery
Lesion	upper motor neuron lesion (UMN)
Clinical features	hemiplegia/paresis, facial palsy etc., urinary retention from 'cerebral shock' for days to months secondary to detrusor areflexia
Detrusor activity	normal or overactive
Compliance	normal
Smooth sphincter	synergic
Striated sphincter	synergic
Comment	the most common long term expression of lower urinary tract dysfunction after CVA is detrusor hyperreflexia

2. Dementia

Pathology	atrophy of grey and white matter especially of the frontal lobes of the cerebral cortex associated with intellectual impairment. The awareness of desirability of voluntary control of urine may be lost even though the ability may be present. It may be associated with widespread cerebrovascular disease - Alzheimer's, Pick's or Creutzfeldt-Jakob disease
Clinical features	urinary incontinence
UDS	there may be detrusor hyperreflexia but this may not be responsible for the incontinence
Management	difficult - anticholinergic is contraindicated in Alzeimer's disease because theory of aetiology is cortical cholinergic deficiency

3. Parkinson's Disease

Pathology	degenerative disorder primarily of the dopaminergic substantia nigra-corpus striatum (extra pyramidal) pathway in a relative dopaminergic deficiency and cholinergic predominance. There is also loss of pigmented neurons in the substantia nigra and associated intracytoplasmic inclusions (Lewy bodies)
Lesion	UMN
Clinical features	bradykinesia, tremor, skeletal rigidity. LUTS occur in 35-70% of patients
Detrusor activity	normal, impaired or overactive
Compliance	normal
Smooth sphincter	synergic
Striated sphincter	synergic/pseudodyssynergic/bradykinesic
Comments	urodynamic assessment is essential in suspected prostatic obstruction as symptoms may be due to the neurologic disease on the bladder and sphincter function. Also demonstration of poor voluntary sphincter control during videourodynamics identifies those with a high risk of post-prostatectomy incontinence. Subcutaneous apormorphine (dopamine receptor agonist) improves motor activity and helps in urodynamic differentiation of obstructed patients from those with voiding dysfunction due to the condition itself

4. Cerebral Palsy

Pathology	non-progressive brain injury in the prenatal, perinatal or early infancy that produces neuromuscular disability caused by infection, hypoxia or hyperbilirubinaemia
Lesion	UMN
Clinical features	delayed gross motor development, abnormal motor performance, altered muscle tone, abnormal posture and exaggerated reflexes. Most children and adults with only CP have normal control, normal filling and emptying
Detrusor activity	normal or overactive
Compliance	normal
Smooth sphincter	synergic
Striated sphincter	synergic
Comments	in those patients that exhibit significant dysfunction, the type of deficit that one would suspect from the UDS is localised above the brain stem and manifests by detrusor hyperreflexia and co-ordinated sphincters. However, spinal cord damage can occur and may account for CP patients who have evidence of striated sphincter dyssynergia

5. Shy-Drager Syndrome

Pathology	cell loss and gliosis in the cerebellum, substantia nigra, globus pallidus, caudate, putamen, inferior olives, intermediolateral columns of spinal cord and Onuf's nucleus. It is a progressive condition with poor prognosis. Incidence is uncommon (males=females)
Clinical features	orthostatic hypotension, anhydrosis, ataxia, voiding and sexual dysfunction
Detrusor activity	impaired/hyperreflexic
Compliance	normal or decreased
Smooth sphincter	open
Striated sphincter	synergic or denervated

Summary

In suprapontine lesions, there is detrusor activity of sufficient amplitude and duration for normal voiding through a synergically relaxed sphincter. This synergy is only altered where there is associated caudal lesion(s) that may not be clinically obvious. The only common urodynamic abnormality found is hyperrflexia.

Diseases primarily involving the spinal cord:

• Multiple Sclerosis
• Spinal Cord Injury (SCI) and Disease
• Spina Bifida
• Other

1. Multiple Sclerosis

Epidemiology	a disease of young and middle aged adults with a prevalence of 6-122 per 100,000 and females are more affected than males
Pathology	focal demyelination of white matter with axonal sparing that results in delayed nerve conduction. The posterior and lateral columns of the cervical spinal cord are mostly affected. The cerebral cortex and mid brain may also be affected.
Clinical features	50-90% have voiding symptoms at some stage during the disease. 10% may present solely with LUTS or as a part of a symptom complex e.g. acute urinary retention in a young woman of unknown cause.
UDS	detrusor hyperrflexia (DH) is the commonest abnormality detected. Three patterns of voiding dysfunction have been described in MS patients: DH with striated sphincter synergia (38%), DH with striated sphincter dyssynergia (29%) and detrusor areflexia (26%).
Comments	the main determinants of urologic complications in MS are: DSD in men, high detrusor filling pressure (>40 cm H2O) and indwelling catheter.
Management	anticholinergics and CISC (57%), anticholinergics alone (13%), CISC alone (15%), behavioural therapy and surgical management only (7-10%).

2. Spinal Cord Injury and Disease

• Spinal shock
• Suprasacral SCI
• Sacral SCI
• Autonomic dysreflexia/hyperreflexia

The spinal column vertebrae have a different relationship to the spinal cord segmental levels at different locations. The sacral spinal cord is located at T12-L1 vertebral level. The spinal cord terminates in the corda equina at L2 level of the spinal column.

SCI may occur at multiple levels and even a single level may evolve cephalad, caudad or both. Leading causes of SCI are: RTA (50%), falls (21%), violence (14%) and sporting injuries (14% in US). The male to female ratio is 4:1.

The four main groups at the time of hopital admission are:

- 28% incomplete quadriplegics
- 26% complete paraplegics
- 24% complete quadriplegics
- 18% incomplete paraplegics

In the past, urinary system complications were the major cause of death in paraplegics. However, more recent reviews show that the leading causes of death now are pneumonia, accidents, suicide septicaemia, PE's and cancer indicating an improvement in the urological management of these patients.

Bladder contractility and reflex contractions depend on an intact spinal cord (SSC) and its afferent and efferent connections. Therefore, complete lesions above the SSC but below the area of sympathetic outflow result in detrusor hyperreflexia, absent sensation below the level of the lesion, smooth sphincter synergia and striated sphincter dyssynergia. Lesions above spinal column T6 (cord segments T7,8) i.e. above sympathetic outflow to the pelvis may result in smooth sphincter dyssynergia as well.

Spinal Shock

A period of decreased spinal cord excitability lasting days to months following significant SCI characterised at the level of injury and below by:

- absent somatic reflex activity
- flaccid muscle paralysis, but the anal and bulbocavernosus (most peripheral) reflexes may not disappear or may return within minutes/hours
- autonomic activity is suppressed
- bladder is acontractile or areflexic
- BN is closed and competent unless injury involves the pelvis sympathetics
- striated sphincter EMG is low
- MUCP is low
- if the sacral cord is intact but isolated from higher influences, reflex bladder activity and contractility returns in 6-12 weeks initially by involuntary voiding, but bladder recovery may sometimes take up to 2 years.

Suprasacral SCI
Neurological examination distal to the lesion shows skeletal muscle spasticity, hyperreflexic DTR, abnormal plantar response and impairment of superficial and deep sensation. UDS for complete cord lesion shows normal compliance, detrusor hyperreflexia, smooth sphincter synergia (lesions below sympathetic outflow) and striated sphincter dyssynergia resulting in functional obstruction. There are also both storage and emptying problems.


Sacral SCI
After the period of spinal shock there is detrusor areflexia, normal or high compliance later resulting in poor compliance (spastic bladder). The smooth sphincter is competent but non-relaxing and the striated sphincter has low fixed tone and is not under voluntary control. Voiding is only possible by crede manouvre or straining with obstruction at the BN if closed or at the sphincter with a fixed tone.

Neurologic and urodynamic findings in suprasacral and sacral spinal cord injuries do not exactly correlate. Complete or incomplete injuries as clinically defined may not be exact, multiple level SCI may be present but clinically only a single level is usually defined, complete somatic injury may not be associated with the same degree of autonomic injury. Therefore, urodynamics should form the basis of rational therapy.

Autonomic Dysreflexia/Hyperreflexia
(Trop & Bennett 1991, J. Urol. 146, 1461)

This is an acute massive disordered autonomic (primarily sympathetic) response to specific stimuli in patients with SCI above cord level T6-8 in the sympathetic outflow. It is more common in cervical SCI (60%) compared with thoracic SCI (20%). The onset is after the period of spinal shock. Distal cord viability is essential.

Clinical features

These include a pounding headache, hypertension, flushing of face and body with sweating above the level of the SCI, bradycardia, tachycardia or arrhythmia all as a result of excessive sympathetic discharge.

Pathophysiology

The evoking stimuli usually arise from the bladder or rectum but also from bone or pressure sores. Nociceptive impulses to the SC elicit reflex motor outflow causing arteriolar, pilomotor and pelvic visceral spasm and sweating. Stimuli that precipitate attacks include instrumentation, catheter blockage, clot retention and faecal impaction etc. Withdrawal of the stimulus leads to quick resolution.

Prevention

Endoscopy in susceptible patients should be performed under spinal or carefully monitored GA: oral nifedipine 10-20 mg 30 minutes before the procedure (e.g. flexi, UDS) and Terazosin (selective a-1 blocker) for longterm management and prevention.

Treatment of acute episode - relieve or discontinue the precipitating condition or procedure and administer parenteral alpha adrenergic or ganglionic blockade or parenteral chlorpromazine.

3. Spina Bifida (Neurospinal Dysraphism)

Pathology shows congenital spinal and neural tube defects of varying severity e.g. spina bifida occulta - meningocele - meningomyelocele - syringocele with associated myelodysplasia. Typical UDS include detrusor areflexia or hyperreflexia, open bladder neck, fixed external sphincter pressure and therefore stress incontinence. DSD is found in 10-15%. Continence may improve after puberty.

4. Other Spinal Cord Conditions

Tabes Dorsalis - Syphilitic myelopathy affects the dorsal columns and posterior sacral roots leading to loss of bladder sensation and a large residual (sensory neurogenic bladder).

Pernicious Anaemia - this also causes classic sensory neurogenic bladder because of subacute combined degeneration of the dorsal columns of the spinal cord.

Poliomyelitis - the incidence of voiding dysfunction varies from 4-42% and produces a typical neurogenic bladder with urinary retention because the viral infection has a predilection for the anterior horn cells.

Disc Disease - most disc protrusions compress the spinal roots at L4/5 or L5S1 interspaces and there may be associated voiding dysfunction in 1-18%. Consistent UD findings are normal compliance, detrusor areflexia with normal innervation or incomplete denervation of perineal floor muscles. Patients typically present with back pain. Voiding dysfunction mainifests with difficulty in voiding, straining or urinary retention. Laminectomy may not improve bladder function and pre-op UDS is desirable.

Spinal Stenosis - compression can involve the SC at any level or the nerve roots at the root canal or intervertebral canal with different manifestations. UDS would be the basis for rational therapy.

Peripheral Nerve Involvement

• Radical pelvic surgery
• Diabetes mellitus
• Guillain Barre Syndrome

1. Radical Pelvic surgery

Voiding dysfunction commonly occurs with A-P resection and radical hysterectomy due to pelvic plexus injury with reported incidence of 10-60% but only 15-20% of these are permanent.

Injuries occur due to:

• denervation
• tethering of nerves or encasement in scar
• direct bladder or urethral injury
• bladder devascularisation
• adjuvant treatment, chemotherapy, DXT
• parasympathetic decentralisation may result in synaptic re-organisation in the bladder wall or sympathetic hyperinnervation.

Urodynamic results:

• acontractile or hypocontractile detrusor
• open non-functional smooth sphincter
• fixed striated sphincter tone without voluntary control
• decreased compliance - overall, storage and emptying failure and risk of upper tract damage
• betanechol supersensitivity test is positive

The therapeutic goal is to reduce bladder storage pressure and institute periodic emptying with CIC, resist the temptation to perform TURP (risk of incontinence) unless obstruction at this level is demonstrated on UDS.

2. Diabetes Mellitus

This is the most common cause of peripheral neuropathy in Europe and N. America

Mechanisms:
a) Polyol (sorbitol) theory - chronic hyperglycaemia leads to an increase in the accumulation of polyols via the aldolase reductase pathway leading to a decrease in NA-K ATPase activity with the loss of myelinated and unmyelinated fibres, Wallerian degeneration and blunted nerve reproduction.
b) Formation of advanced glycosylation end product from glucose.
c) Acute hyperglycaemia leading to impaired nerve function.

The term diabetic cystopathy has been used and it classically presents as sensory neuropathic bladder resulting in overdistension and loss of contractility. There is now evidence of motor neuropathy also.

UDS

• impaired bladder sensation
• increased cystometric capacity
• decreased detrusor contractility
• impaired Qmax and later increased PVR
  

Treatment includes timed voiding in early phases and CIC.

3. Guillain Barre Syndrome

Inflammatory demyelination of peripheral nerves from viral infection or demyelination. Ascending paralysis starting with LL. There is polyradiculopathy with autonomic involvement. The incidence of retention is 11-30%. Treatment includes CIC.

Non-neuropathic conditions

Bladder Neck Dysfunction
This occurs in young and middle aged men with longstanding voiding and storage symptoms. Videourodynamics shows BOO localised at the BN, secondary DI may result and striated sphincter may be dyssynergic resulting in 'trapped prostate'. Treatment includes BNI ± small TURP.

Low Pressure Low Flow/Anxious Bladder
The patient has prolonged hesitancy when attempting voiding in the presence of others - usually in young patients (men). No consistent improvement with drugs or surgery.

Non Neurogenic Bladder/Hinman's Syndrome
Dysfunctional voiding with urodynamic evidence of detrusor striated sphincter dyssynergia in the absence of any demonstrable neurogenic disease.

Post-operative Urinary Retention
Contributing factors include:

• traumatic instrumentation
• bladder oversdistension
• diminished awareness of bladder sensation
• decreased bladder contractility
• increased outlet resistance
• decreased micturition reflex activity
• nociceptive inhibition reflex via sympathetic stimulation
• pre-existent outlet pathology
• anaesthesia and analgesia can contribute
  

Prophylaxis and treatment
Bladder decompression for 18-24 hours post-op decreased the incidence of retention in joint replacement patients (52% vs. 27%) (Michelson et al. 1988 N. Eng. J. Med.).
Phenoxybenzamine (alpha-blocker)compared to a placebo has also been shown to reduce the incidence of retention by 29% in a metanalysis of randomised, controlled studies (Velanovich 1988 Infect-Urol.).

Main objectives:

• upper tract preservation or improvement
• absence or control of infection
• adequate storage at low intravesical pressure
• adequate emptying at low intravesical pressure
• adequate control
• no catheter or stoma
• social acceptability and adaptability

Hyperreflexia management
This includes behavioural therapy such as timed bladder emptying and pharmacotherapy with anticholinergics (e.g. probanthin), musculotropics (e.g. oxybutynin), Ca++ antagonists (e.g. detrunorm), tricyclic antidepressants (e.g. imipramine) with central, anticholinergic and sedative effects and others such as K+ channel blockers, PG inhibitors and beta-adr antagonists. Also bladder distension, denervation, detrusor myectomy, acupucture, neuromodulation and augmentation cystoplasty.

Incontinence management - increasing outlet resistance
Physiotherapy and biofeedback (PFE) and pharmacotherapy with alpha adrenergic agonists leading to increased MUCP (has CNS and CVS side effects). Estrogens can be used in postmenopausal patients. Also vesico-urethral suspension and compression procedure (peri-urethral injections, urethral plugs and clamps. Surgical management includes sling procedures, BN closure, AUS, urinary diversion and neuromodulation.

Hypocontractility/acontratility/increased outlet resistance management: facilitation of bladder emptying.
CIC, Crede/Valsalva manouvre, trigger zones activation and pharmacotherapy with alpha blockers and skeletal muscle relaxants (e.g. baclofen, dantrlene). Also, neuromodulation, sphinterotomy, continuous catheterisation and urinary diversion.

Neuromodulation is a term used to imply modification of the sensory and/or motor functions of the bladder through electric stimulation

Pre-requisites are:

• a co-operative patient
• preservation of the lower urinary tract morphology
• intact sacral cord (reflex centre)
• low degree of peripheral denervation of pelvic floor
• ability to empty voluntarily or by CIC

Principles

1. Prolonged stimulation of sacral roots induces increased urethral resistance through the activation of the striated sphincter and induces hypertrophy and histochemical changes to make it fatigue resistant.
   
   
2. Stimulation of the anterior sacral root produces bladder contraction and voiding.
   
   
3. Stimulation of the striated sphincter has a reflex inhibitory effect on the detrusor which is useful for the management of DI and hyperreflexia.
   
   
4. There is a pain free window that allows application of the stimuli.
   
   
5. Posterior root rhizotomy may be combined to improve compliance by bladder de-afferentation.

Methodology

• all patients are initially tested by UDS
• responses to percutaneous S2, S£ and S4 stimulation unilaterally and bilaterally are recorded
• if desired responses are obtained, the wire is left in place for temporary percutaneous stimulation over a few days so that the patient can assess potential benefits
• if improvement is 50% or more, the patient is considered for permanent electrode implant

Results

In 27 children between 6 and 16 years, 19 with meningomyelocele, 6 with voiding dysfunction and 2 with neonatal hypoxia the overall response rate was 70-75%. The viability of the nerves was maintained after 6000-12000 hours of stimulation (Tanagho 1992 J. Urol. vol. 148).

Everaert et al. (1997 BJU vol. 79) assessed neuromodulation effects urodynamically. In 27 patients, 17 responded well (all had hypocontractile detrusor and sphincter hypertonicity) and 9 out of 10 with spastic pelvic floor syndrome responded well. There was no response in those with acontractile detrusors.

TENS and temporary S3 neuromodulation for severe refractory idiopathic DI resulted in significant changes in urodynamic parameters and symptoms (Hassan et al. 1996 J. Urol.).