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Pathophysiology of urinary relevant anatomy, physiology, neural control and biochemistry
of the lower urinary tract. In this article we will explore the

incontinence pathophysiological mechanisms underlying urinary incontinence
but also revisit the relevant normal anatomy and physiology, as
pertains to continence, before describing the abnormal.
Arjun K Nambiar
Malcolm G Lucas Bladder wall physiology and neuromuscular control
The bladder wall and interstitial cells
Abstract The main purpose of the urinary bladder is to receive urine from
Urinary incontinence is a condition with multi-factorial aetiology and a the kidneys and act as a compliant pouch to store that urine, until
complex pathophysiological basis. However, the underlying principles such time as it is socially appropriate and convenient to void.
are relatively simple. In this article we consider these pathophysiological Structurally it is made up of interwoven fibres of detrusor muscle
elements in separate sections to emphasise how they interact to effect a that make up the body of the bladder, and specialized smooth
change in lower urinary tract pressures during different phases of the muscle fibres within the detrusor that arise from a distinct
micturition cycle. embryological source. The muscle layers are lined internally by
The interstitial cells have a key sensory role in the bladder, with much an inner urothelium that acts as a protective layer. The bladder
research currently taking place to investigate their exact function. Neural urothelium is distensible along with the bladder muscle and
pathways, by comparison, are relatively well established and interactions forms an effective bloodebladder barrier to prevent uraemia.3
between the pontine micturition centre (PMC) in the brain stem and the Deep to the urothelium are found the interstitial cells, which
sacral micturition centre (SMC) in the sacral spinal cord, with voluntary have recently been proposed to be the cells responsible for ‘pace-
control from higher centres, provide neurological control of the lower uri- making’ activity in the bladder.4,5 Two types of interstitial cells
nary tract. Depending on the level of a neurological deficit or injury, have been identified e the sub-urothelial interstitial cells (or
certain recognizable patterns of bladder dysfunction can be identified. myofibroblasts) and the intra-detrusor interstitial cells. These
Mechanical factors e the pelvic floor, striated sphincter muscles and cells differ in molecular constitution and neurotransmitter
smooth muscles of the bladder and urethra e also play a major role in content, but M2 and M3 muscarinic receptor activity of sub-
maintaining normal continence. urothelial interstitial cells have been found to correlate with
Dysfunction of any of these elements can cause, to varying degrees, a urgency scores in humans,6 and their position makes them
loss of urethral pressure, a rise in bladder pressure, or both. This imbal- ideally situated to modify feedback mechanisms of ATP and
ance results in incontinence. An understanding of this principle, and the acetyl choline (ACh) between the urothelium and nerve end-
pathophysiological mechanisms behind it, will help guide investigation ings.7 The intra-detrusor interstitial cells can be spontaneously
and treatment choices to best manage patients with this unfortunate active, so possibly have the pacemaker role, and they also
condition. demonstrate cGMP activity.
Keywords Bladder; lower urinary tract; neuro-urology; pathophysiology; Neurophysiology
pelvic floor; pressure; urinary incontinence The bladder and urethra are influenced by all three neural sys-
tems e sympathetic, parasympathetic and somatic (Figure 1).
They innervate the bladder through the pelvic plexus, formed by
Introduction contributions of the hypogastric (sympathetic) (T10-L2) and
Urinary Incontinence (UI) is defined by the International Conti- pelvic (parasympathetic) (S2eS4) nerves as well as somatic
nence Society as the complaint of any involuntary leakage of nerves. Sympathetic nerves release noradrenaline and innervate
urine.1 There are a number of factors that may influence the the external urethral (rhabdo) sphincter, the excitatory a-adren-
reported prevalence of UI, including sampling frame, response ergic response resulting in an increase in muscular tone and
rates, threshold definitions, types of UI and survey methods. But thereby outlet resistance. Being a striated muscle this external
broadly speaking the prevalence of UI in the general population sphincter is under a degree of voluntary control. There is also
appears to be in the range of 30e60% in middle-aged and older evidence of a sympathetic reflex whereby bladder stretch results
women, with the condition being twice as prevalent in women as in stimulation of b-adrenergic receptors in the detrusor that
in men.2 enhance bladder relaxation and inhibit parasympathetic activity.
The cause of UI can be multi-factorial, and understanding the The parasympathetic nerves innervate the detrusor and via ACh
pathophysiological mechanisms requires an understanding of the release stimulate detrusor contraction. Autonomic nerves are both
under higher control, mainly from the excitatory pontine micturi-
tion centre (PMC), located in the brain stem, which causes detrusor
contraction by parasympathetic excitation and simultaneous
external sphincter relaxation through sympathetic inhibition. The
Arjun K Nambiar MBBS MRCS PG Cert (Clin Res) is a Clinical Research
PMC is normally under inhibitory influence from the frontal lobes
Registrar in Urology at Morriston Hospital, ABM University LHB, UK.
and cingulate gyrus via the peri-aqueductal grey (PAG), and these
Conflicts of interest: none declared.
centres are responsible for determining the ‘socially acceptable and
Malcolm G Lucas FRCS (Urol) ChM is a Consultant Urologist at Morriston convenient’ aspect of normal initiation of voiding.
Hospital, ABM University LHB, Hon. Senior Lecturer, Swansea The main control centres of bladder function are the pontine
University, UK. Conflicts of interest: none declared. micturition centre (PMC) mentioned above, and the sacral

SURGERY 32:6 279 Ó 2014 Elsevier Ltd. All rights reserved.

Neural switches are reset at the end of the void to revert substances present in the urine it holds. The clinical effects of tetanic contractions that are seen in other smooth muscles neurological lesions affecting bladder function can largely be of the gastrointestinal tract and uterus. between PMC and SMC. and the poor electrical coupling between the muscle cells It also has afferent inputs via the pelvic nerves as well as motor results in the visco-elasticity of the bladder and absence of output via parasympathetic nerves. All rights reserved. but activation of smooth muscles and relaxation of striated basically it serves to store a convenient amount of urine without muscles causing detrusor contraction. The SMC is located at S2eS4 spinal  Compliance e the net-like arrangement of detrusor fibres levels and communicates with the PMC via spinothalamic tracts. and protects the inner SMC and lower pathways. layers of the bladder wall from the toxic effects of prolonged contact with urine. and sphincter relaxation to effect void- acceptable to void. SURGERY 32:6 280 Ó 2014 Elsevier Ltd. To be able to do this it to baseline striated muscle tone (contracted sphincter) and has some inherent properties and features. The normal filling and voiding cycle  Co-ordinated neuronal control e resulting in synchronous The bladder performs a number of physiological functions. relaxed smooth muscle (bladder neck and wall). BASIC SCIENCE Ennervation of the bladder Pre-frontal cortex Pontine micturition centre Inferior T10 mesenteric Hypogastric T11 ganglion nerve T12 L1 L2 β Sacral S2 Pelvic micturition S3 S4 plexus centre Pudendal Levator nerve ani External sphincter Afferent via pudendal and pelvic nerves Figure 1 micturition centre (SMC). and without itself being damaged by the toxic ing. . bladder neck open- significant rise in pressure until such time as it is socially ing and funnelling. or involves the bladder barrier alluded to earlier.8 determined by assessing whether the main lesion affects the  Protective urothelium e which forms the effective bloode pathway above the PMC.

proximal urethra and form a circumferential ring at the internal itory effect on these reflex pathways resulting in voluntary con. PMC and higher centres (frontal lobes. This stimulates further reflex bladder contractions via spinal reflex and somatic/supraspinal mechanisms. This stimulates para. length. External to increase in bladder pressure and expulsion of urine. The penile urethra has normal filling and voiding cycles work remarkably well in most very little muscular tissue and hence plays a minimal role in people. is controlled largely by reflex activity through the PMC and SMC. BASIC SCIENCE Figure 2 The inner lining of the urethra. Parasympathetic In males e at the commencement of the membranous urethra excitation occurs simultaneously. Neural circuits con.10 (Figure 2). loss of The inner lining of the urethra e the mucosa (urothelium) is inhibition of PMC to SMC signals occur. Afferent signals pass from the bladder base and where the detrusor surrounds the trigonal ring bladder to the SMC and PMC. tween the urethra and bladder e when the bladder pressure In the female urethra the urethral smooth muscle. cingulate gyrus any other time will result in incontinence. the fixity of the membranous urethra. and hence Despite the complexity of the physiological mechanisms. and mixed bladder and urethral dysfunction. the bladder pressure. continence apart from the passive resistance provided by its Urinary incontinence is largely due to a pressure imbalance be. The vesical neck refers to an area at the bladder base where During the normal filling phase the bladder fills with urine the urethral lumen passes through the thick muscle of the due to its compliant property. Smooth muscles from the bladder trigone continue down into the With maturing of neural circuitry higher centres exert an inhib. these fibres lie the striated fibres of the pelvic floor. Bladder afferent ac. We have already seen that the bladder is controlled mainly by leak through.9 The functional importance of this brings bladder sensation to consciousness. lies SURGERY 32:6 281 Ó 2014 Elsevier Ltd. Hence the ‘reflex bladder’ of infancy. augmenting sphincter relaxation there is a layer of circular striated fibres anteriorly in a horse- and bladder smooth muscle contraction resulting in exponential shoe configuration that forms the rhabdosphincter. and Abnormalities causing a loss of urethral pressure bladder filling sensations are also transmitted rapidly through afferent pathways in the spinal reflex arc to efferent neurons that The urethra and sphincter cause bladder emptying.9 voluntary signals pass from higher centres to the PMC. All rights reserved. Hence based on the and basal ganglia) through inter-linked neural pathways pathophysiological mechanisms urinary incontinence can be involving the peri-aqueductal grey (PAG). PMC inputs are predominantly excitatory to the SMC. ized arteriovenous anastomosis9. area lies in its sympathetic innervation e selective damage to tivity also causes reflex sympathetic firing through the pudendal this nerve supply results in the vesical neck remaining open at nerve (the guarding reflex) through a spinal reflex arc and hence rest. which can result in poorer outcomes following stress in- promotes continence by increasing rhabdosphincter tone. as with any body system. gradually reaching a threshold that and internal urinary meatus. Once continence surgery. those abnormalities resulting in high bladder pressures. but at the SMC. folded in longitudinal layers allowing for considerable distensi- sympathetic excitation and simultaneous excitation of inhibitory bility and also provides space for a rich sub-mucosal plexus that inter-neurons that synapse with sympathetic motor neurons of may act as a cushion to promote co-aptation by way of special- Onuf’s nucleus (in the SMC).9 trol over micturition. However. Sympathetic inhibition results in relaxation of the urethral The muscular layers of the urethra are considerably different sphincter and hence entry of a small amount of urine into the ure. contin- exceeds urethral pressure there will be a tendency for urine to uous with the smooth muscle from the bladder trigone. In infancy. divided into: those abnormalities resulting in loss of urethral trolling bladder function mature with age. things can go wrong. This is the normal situation during voiding. . in males and females: thra. meatus.

such as post-menopause. puboanal muscle. or floor. anchored to the viscera. the levator ani under neural control) and co-aptive forces of the urethral lumen. can result in dryness of the fascial component can have no mechanical effect without being mucosa and loss of urethral co-aptation resulting in loss of ure. All rights reserved. From reference 10 with kind permission.9 Co-aptive forces can be hampered by any condition that results in Broadly speaking. vagina and rectum have been resected just above the pelvic floor. while in the distal segment it compresses the urethra The pelvic floor antero-posteriorly. urinary incontinence. together. is maintained mainly by the pelvic peritoneum and the vulvar skin: from inside to outside two factors e muscular tone of the sphincter (which is largely the peritoneum. if not cause. perineal body uniting the two ends of the puboperineal muscle. Therefore similar effect. dispose to. these can be grouped together into a loss of the rich sub-mucosal plexus of the urethra and can pre. muscular component. as can trauma and pelvic surgery. hence these two layers are sometimes thral closure pressure and stress urinary incontinence (SUI). The outer layer is part of the pudendal nerve therefore can result in loss of sphincter formed by the striated urogenital sphincter. and a visceral component. inside the striated urogenital sphincter muscle and consists of Muscular tone of the sphincter is maintained at rest by sym- inner longitudinal (shortens and funnels urethra during voiding) pathetic activity through the pudendal nerve. Damage to the motor and thin outer circular (constricting) layer. known. can ferentially in the upper two-thirds but distally extends to encircle predispose to this type of injury which explains the preponderance the vagina as the urethrovaginal sphincter. of the abdominal cavity against a firm surface to be effective. iliococcygeal muscle and puborectal muscle. as the viscero-fascial layer. external anal sphincter. or urethral tone. which runs circum. The urethra. on it from above. The urethra and vagina have been transected just above the hymenal ring. and in the case of urethral and has to withstand the variable pressures that can be exerted compression this firm structure is the pelvic floor. It consists of several components lying between Urethral pressure. Motor neuropathies can also have a pubic ramus as the compressore urethra9 (Figure 3a). (b) The levator ani muscle seen from above looking over the sacral promontory showing the pubovaginal muscle. viscera and endopelvic fascia. Hormonal in. muscles. in the proximal segment the striated muscle probably constricts the urethra. a connective tissue and fascial component. tone and SUI. especially instrument-assisted. perineal membrane and external genital muscles. Vaginal delivery. BASIC SCIENCE Figure 3 (a) The levator ani muscles from below after the vulvar structures and perineal membrane have been removed showing the arcus tendineus levator ani. . or along the inferior of SUI in post-partum females. Compressive forces usually need to be exerted The pelvic floor forms the base. The visceral and fascial (endopelvic fluences play a large role here and especially in women oestrogen fascia) components are inextricably linked in so much as the deficiency. This layer consists SURGERY 32:6 282 Ó 2014 Elsevier Ltd.

have all the answers. SURGERY 32:6 283 Ó 2014 Elsevier Ltd. with radical prostectomy being the most common sur- parasympathetic neurons synapse in the bladder wall gical cause. but neurogenic detrusor the abdominal cavity and low external atmospheric pressure.g. multiple sclerosis.g. but detrusor over- keeps the hiatus closed and compresses the vagina and urethra activity can also result from neurogenic overactivity e loss of against the pubic bone. e. compliance. During a transient rise in (referred to as detrusor-sphinctre dyssynergia). neurokinin. like most connective tissues. adren- circumferentially from the pelvic wall. The degree of incontinence These can be very difficult to diagnose and extremely high varies depending on the degree of residual sphincter function but risk bladders can be missed due to a lack of overt symp- it is not uncommon for these men to have very poor urethral toms. and This results in involuntary spasm of bladder muscle resulting in the opening in the diaphragm through which the urethra and transient. As a result continence is maintained by mainly  Lesions of the peripheral nerves or nerve roots can cause a the rhabdosphincter.  Disease of the frontal lobe/cingulate gyrus leads to a loss Another factor we must consider when talking about urethral of inhibition of the PMC and results in a regression to an pressure is that it is not constant even during the filling phase. but almost IAP the urethra is compressed against the pelvic floor muscles and inevitably neurogenic detrusor overactivity due to a hyper- effectively closed off. by extension. cular sphincter. closure pressures and consequently severe SUI. All rights reserved. and also to Depending on the level of the lesion the effect on bladder the levator ani muscle itself. prolonged and repeated stress. spina bifida.g. as wall and ischial spine). These layers are made up of connective we have already seen. is a result of the unique structural tissue that. as the bladder is sphincter weakness and pelvic floor weakness are neuropathic or not completely denervated because the post-ganglionic surgical. . It is thought that interstitial cells may play The levator ani is a complex of three muscles arising almost a key role in bladder sensitivity through muscarinic. pre-prostatic and prostatic urethra along with the proximal cir- prolapsed inter-vertebral disc. BASIC SCIENCE mainly of parametrium (attaching the uterus to the pelvic side Abnormalities causing high bladder pressures wall) and paracolpium (attaching the vagina to the pelvic side Bladder pressure is a function of compliance. In case parasympathetic activity. areflexic or non-contractile bladder) and possibly a loss of In men the common causes of pudendal nerve damage. nitric oxide and cGMP pathways.  Lesions of the sacral spinal cord can lead to a flaccid pa- assisted delivery and perineal tears all predispose to pelvic floor ralysis of the bladder with sensory loss (referred to as an weakness post-partum and therefore increase the risk of SUI. cauda equina injury. laterally by the le- pressure and result in incontinence (urgency urinary inconti- vator ani muscles and posteriorly by the perineal body and nence or UUI). the para- in NDO there is a tendency for these patients to have high resting colpium. cerebral tain continence and this is achieved through the physical system trauma or severe epilepsy. however keeping in mind our the ATFP or levator ani can result in both a loss of urethral sup- earlier discussion on neuromuscular control certain patterns of port and a loss of the base upon which the urethra is compressed dysfunction can be identified (Figure 4). The nature of the surgery necessitates removal of the and hence may still retain some activity. cord lesions anatomy as a result of pelvic organ prolapse can upset this (paraplegics) mechanism and hence cause SUI. attaches to the arcus tendineus fascia pelvis (ATFP) that bladder pressures that can endanger kidney function. If these in front and continuing along ridges of dense connective tissue cells do in fact play a role in bladder ‘pacemaker’ activity then called the arcus tendineus fascia pelvis (ATFP) and arcus tendi- they could well be the key to understanding the entity we neus levator ani (ATLA) (Figure 3b). This. discussed in the anatomy of the pelvic floor e the paraurethral  Lesions below the brain stem but above the conus can result supports in the lower third of the urethra keep it relatively fixed in a loss of co-ordination between the detrusor and sphincter while the upper third is relatively mobile. The extent of this can vary. gery can result in sphincter weakness. prolapse and predisposing to stress urinary incontinence. e.g. The hiatus therefore is pressure that can occasionally overcome urethral closure bounded anteriorly by the pubic symphysis. cerebro- abdominal pressure (IAP) (and hence bladder pressure) to main- vascular accidents (stroke). will stretch if exposed to composition of the bladder coupled with effective neural control. In normal healthy individuals Biochemical signalling pathways in the bladder wall are a these forces are usually absorbed by the muscular components of subject of intense study at the moment and we still do not yet the pelvic floor e the levator ani and perineal membrane. Parkinson’s disease. and often neuropathic damage during sur- mixed picture depending on the nerve roots involved. in turn attaches to the pubic bone and ischial spine. to maintain continence during a rise in intra-abdominal pressure. The levator ani along with its currently refer to as ‘idiopathic detrusor overactivity’ (IDO). leading to pelvic organ bladder resulting in detrusor spasms and high bladder pressures. results in no or little inhibition from supra-sacral centres resulting in reflex spasms of tension on the ligamentous supports of the pelvic organs. Due to the complexity of neural control of damage to the pelvic floor the ligaments have to bear the strain and the different patterns of neurological disease the effects on of holding the pelvic organs in place between the high pressure of bladder function can be vastly varied. Prolonged third stages of labour. starting from the pubic arch ergic. e. sometimes sustained and intense. The ‘infant bladder’ whereby voiding occurs without any re- urethra must be able to withstand transient rises in intra- gard for social circumstance or convenience. rises in bladder vagina pass is called the urogenital hiatus. e. external anal sphincter. Pelvic floor weakness or distortion of pelvic reflexic bladder. Therefore it follows that any defect in function can vary immensely. Normal baseline activity of the levator ani These originate from afferent pathways. In overactivity (NDO) is a well-recognized phenomenon that results such a situation it is only a matter of time before the ligaments in increased efferent firing parasympathetic neurons to the become overloaded and are over-stretched. and compliance. Due to the more persistent nature of the parasympathetic activity The ligamentous support of the paraurethral tissue. fascial coverings is often referred to as the pelvic diaphragm.

biochemical. 2009. 35e111. The standardisation of terminology In this situation treating the main cause (low urethral pressure) in lower urinary tract function: report from the standardisation sub- may be all that is required to resolve (or at least significantly committee of the International Continence Society. vary depending on the underlying disease. symptoms of IDO. endocrine factors. All rights reserved. Therefore the investigation and treat- (paraplegia. Intervention can then be planned to either reduce pressures to co-exist. Indeed it has been demonstrated that 37e49. therefore the pattern These cases can be difficult to evaluate and require careful of bladder involvement can also vary dramatically with combi. stimulation of the urethra by flow of urine into its proximal the balance. resulting in a mixed picture of incontinence bladder pressure or augment urethral pressure to try and restore that is more difficult to evaluate. Neurological ment pathways of lower urinary tract dysfunction follow this diseases that cause relatively low risk bladders include MS. This Mixed bladder and urethral dysfunction coupled with a careful history and examination can very often provide adequate evidence of the dysfunction in an individual It is not uncommon for high bladder pressures and low urethral patient. Thom D. 61: improve) the situation. patients with no overt symptoms of bladder dysfunction to have The pathophysiology of urinary incontinence involves the significant underlying bladder pathology that may pose a risk to interplay of anatomic. Nelson R. tetraplegia) and cauda equina injuries. but the Conditions that commonly result in high risk bladders are end result simply involves an alteration in the balance of bladder congenital cord injuries and spina bifida. CVA basic principle e to identify the pressure imbalance and try to and Parkinson’s disease. compounding the problem. These interactions are highly complex. 1 Abrams P. Fall M. As we have already discussed. SURGERY 32:6 284 Ó 2014 Elsevier Ltd. A segment can lead to reflex stimulation of the bladder. In: Abrams. spinal cord injuries versus urethral pressures. Paris: Health Publications Ltd. correct it. BASIC SCIENCE Causes of bladder and urethral dysfunction Bladder/urethral dysfunction Risk Examples category Reflex bladder CVA Pre-frontal cortex Cortical injury Co-ordinated sphincter relaxation Low Cerebral trauma Complete emptying Epilepsy Peri-aqueductal grey Parkinson’s Pontine micturition centre (PMC) Supra-sacral injury Reflex bladder Cord injury Detrusor sphincter dyssynergia (DSD) High Transverse myelitis Poor emptying/high pressure MS Sacral injury Non-contractile bladder Spina bifida Poor emptying High Prolapsed disc SUI Sacral micturition Poor compliance centre (SMC) Nerve root injury Mixed picture Cauda equina injury Varies depending on root involvement Variable Peripheral neuropathy Figure 4 Neurological lesions are very often incomplete and patterns causes of low urethral pressure. Therefore in patients with low urethral pressures this constant reflex REFERENCES stimulation can cause bladder overactivity and detrusor spasms. treatment of SUI through surgery often improves or even cures 2 Milsom I. Altman D. Urology 2003. Cardozo L. neurological and even the upper tracts due to very high storage pressures or reflux. It is also not uncommon for the problem. investigation before deciding on the appropriate strategy to fix nations of the above three pictures.3 Epidemiology of urinary (UI) and Faecal (FI) incontinence and pelvic On the other hand all the aforementioned causes of high organ prolapse. Wein A. . Kouhry S. eds. Urodynamic evaluation can give a snapshot of varia- tions in pressure during a given filling and voiding cycle. Cardozo L. bladder pressures could simply occur simultaneously with Incontinence. Lapitan MC. Sillen U. et al.

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