Pathomechanisms, Clinical Features, and Assessment of Urge Urinary Incontinence in Neurogeriatric Patients Abdul Muis Department of Neurology, Dr.

Wahidin Sudirohusodo Hospital/ Faculty of Medicine,Hasanuddin University Makassar-Indonesia Abstract Urge urinary incontinence is define as involuntary urinary leakage accompanied by or immediately preceded by a sensation of an urgent need to urinate. All cases of urge incontinence involve an overactive bladder. This may occur as a result of either some abnormalities of function or of other illnesses of the lower urinary tract. Some conditions that can produce the disorders leading to urge incontinence include benign prostatic hyperplasia (BPH), prostate surgical procedures, hysterectomy, damage to the central nervous system, infections, the aging process, emotional disorders, medications including some sleeping pills, and genetic factors may play a role in some cases. In the elderly patients, urinary incontinence commonly seen in cerebrovascular disease, Alzheimer,s disease, and Parkinson,s disease. The disturbances could be in nerves, smooth muscle, and urothelium of the bladder. In models have been found increased connectivity and excitability of both detrusor smooth muscle and nerves which involved in micturition rely on growth factors that orchestrate neural plasticity. There are changes in both macroscopic structure and ultrastructure of the bladder. In this condition, detrusor become overactive and hypersensitive; urothelial hypersensitive and poor detrusor-sphincter coordination. The main symptom of urge incontinence (also called hyperactive, irritable, or overactive bladder) is the need to urinate frequently. Patients may go to the bathroom more than 8 times over 24 hours, including 2 or more times a night, and have subsequent leakage. The amount of urinary leakage with each episode of incontinence is large. Often have no ability to reach the toilet in time following an urge to void, but no leaking by physical activity. These features distinguish urge urinary incontinence from other type of incontinence such as stress incontinence or mixed type. The first step in the diagnosis of incontinence is a detailed history. The doctor should ask questions about the patient's present and past medical conditions and patterns of urination. The patient might find it helpful to keep a diary for 3 to 4 days before the office visit. One of the important measurements for urinary incontinence is the postvoid residual urine volume (PVR). Ultrasound is useful in determining the volume of urine. Cystometry measures the bladder's ability to retain urine at different capacities and pressures. It uses a catheter and can be performed at the same time as the PVR test. For neurological causes also need certain neurologic procedures. Key words: pathomechanisme, urge urinary incontinence, clinical features, assessment, neurogeriatric patients

Pathomechanisms, Clinical Features, and Assessment of Urge Urinary Incontinence in Neurogeriatric Patients Abdul Muis Department of Neurology, Dr.Wahidin Sudirohusodo Hospital/ Faculty of Medicine,Hasanuddin University Makassar-Indonesia I. Introduction

Patients with an unstable bladder often share common symptoms, including urgency, frequency, urge incontinence, and nocturia, regadless of etiology. Urge urinary incontinence is define as involuntary urinary leakage accompanied by or immediately preceded by a sensation of an urgent need to urinate. All cases of urge incontinence involve an overactive bladder (OAB). This may occur as a result of either some abnormalities of function or of other illnesses of the lower urinary tract. Some conditions that can produce the disorders leading to urge incontinence include benign prostatic hyperplasia (BPH), prostate surgical procedures, hysterectomy, damage to the central nervous system, infections, the aging process, emotional disorders, medications including some sleeping pills, and genetic factors may play a role in some cases. In the elderly patients, urinary incontinence commonly seen in cerebrovascular disease, Alzheimer,s disease, and Parkinson,s disease. (The Merck Manual,2009-2010) Eight to 34% of community-dwelling elderly persons suffer from urinary incontinence; rates are higher in women than in men, and urinary incontinence affects > 50% of elderly patients in hospitals and in nursing homes. Yet, urinary incontinence is abnormal regardless of age, mobility, mental status, or frailty. Moreover, incontinence often causes the affected person to feel embarrassed, isolated, stigmatized, depressed, and regressed; incontinent elderly persons are often institutionalized, because incontinence is a substantial burden to caregivers. Incontinence remains largely a neglected problem despite the fact that it is highly treatable and often curable. (The Merck Manual,2009-2010) The disturbances could be in nerves, smooth muscle, and urothelium of the bladder. Examination of the peripheral innervations and the micturation reflex in models of OAB reveals consistent changes such as patchy denervation of the bladder, enlarged sensory neurons, hypertrophic ganglion cells, and an enhanced spinal micturition reflex. Smooth muscles from unstable bladders often shows enhanced spontaneous contractile activity. Morphologic changes in the detrusor may represent the morphologic correlate to increased electrical coupling in unstable bladders. Neuroplastic changes may result from alterations in activity in the nerves controlling the detrusor and probably involve nerve growth factor.(Steers WD, 2002; Ramundo JM et al) The main symptom of urge incontinence (also called hyperactive, irritable, or overactive bladder) is the need to urinate frequently. Patients may go to the bathroom more than 8 times over 24 hours, including 2 or more times a night, and have subsequent leakage. The amount of urinary leakage with each episode of incontinence is large. Often have no ability to reach the toilet in time following an urge to void, but no leaking by physical activity. These features distinguish urge urinary incontinence from other type of

incontinence such as stress incontinence or mixed type. Quality-of-life issues are signifficant in patient with urge incontinence. They have decreases in quality-of-life scores. The assesment of patient with urge incontinence should include neurologic history, urologic history, psychiatric history, gastrointestinal history, and medication history. Beside that, physical examination such as abdominal, pelvic, and neurological examination are very important to perform, and bladder diary should be done. One of the important measurements for urinary incontinence is the postvoid residual urine volume (PVR). Ultrasound is useful in determining the volume of urine. Cystometry measures the bladder's ability to retain urine at different capacities and pressures. It uses a catheter and can be performed at the same time as the PVR test. For neurological causes also needed certain neurologic procedures. (Ramundo JM et al, Thuroff J et al, 2006). II. Pathomechanism

Continence requires input from the central nervous system (CNS) and integrity of lower urinary tract function, adequate mentation, mobility, and motivation. The role of CNS is complex, integrates control of the urinary tract. The pontine micturition center mediates synchronous detrusor contraction and sphincter relaxation, while the frontal lobe, basal ganglia, and cerebellum as the higher centers exert inhibitory and facilitatory effects. Because lower urinary tract function involves so many CNS centers, the impact of diseases such as stroke and dementia, which commonly involve many centers, is often difficult to predict.(The Merck Manual, 2009-2010). Physiological filling signals from the bladder are conveyed to the spinal cord by the pelvic, hypogastric and pudendal nerves. They comprise thin, myelinated, A -fibres and thinner, non-myelinated C-fibres, the latter exhibiting slower conductance (Marrison J et al,2006). The A -fibre endings are located in the detrusor smooth muscle layer and are the most sensitive nerve endings in the bladder; accordingly, they are referred to as tension receptors and are considered to be the primary mediators of the physiological sensation of bladder fullness. On the other hand, the nerve endings of the C-fibres are found in the urothelium and lamina propria (Marrisson J,1999). The C-fibres are thought to be only activated by distension that is greater than that required to activate A -fibres and are considered to be less sensitive to contraction than to bladder distension. Factors which are considered to be important in pathology including high osmolality, high ambient KCl concentration or inflammation can activate a subgroup of C-fibres. C-fibres may primarily be involved in pathological situations and apparently are less important in the sensation of physiological bladder filling (except close to functional bladder capacity); these properties makes them a better candidate to be involved in the sensation of urgency. The non-neuronal release of neurotransmitters may also have a direct stimulatory effect on C-fibres (Lips KL et al,2007); Yoshida M et al,2008). As they originate largely from the urothelium (Yoshimura N et al,2008), the urothelium may play a specific role in generating urgency. Several lines of evidence support the concept that urgency is a pathological sensation which is sensed by mechanisms which are at least partly distinct from those involved in sensing bladder filling (Fitzgerald MP et al,2005).

In pathologic conditions, the nervous system is able to change transmitters, reflexes, or synaptic transmission; known as neuroplasticity. Plasticity of the neurons may shift the balance toward voiding. However, coexistent conditions such as ischemia may injure the nerves, so sensation is lost or damage to smooth muscle results in impaired contractility.
(Steers WD,2002).

Spinal cord transaction and urethral obstruction produce bladder instability and an increase in size of both the afferent neurons in the pelvic plexus. After spinal injury, central transmission of the micturition reflex become delayed. The micturation pathway is reorganized from a spinobulbospinal loop to a predominantly spinal network. Silent Cfiber afferents can trigger micturation in unstable bladders, although not in normal bladder.(Steers WD,2002). The molecular trigger for changes in the afferents or synaptic transmission in the central nervous system may be nerve growth factor (NGF), in addition to other neurotrophins and cytokines. NGF is responsible for the growth and maintenance of sympathetic and sensory neurons and has been shown to be responsible for neuronal regrowth after injury. In spinal cord injury, pretreatment with antibodies against NGF or its receptors prevent urinary frequency and unstable contractions. Conversely, intravesical NGF causes unstable detrusor contractions.(Steers WD,2002). Increased access to NGF alters membrane conductance and excitability of dorsal root ganglia (DRG). This altered conductance is postulated to result from changes in the structure or combination of protein subunits of sodium (Na+) and potassium (K+) channels in the cell membrane. These changes appear sufficient to change the properties of afferents. NGF is known to lower the threshold for firing of bladder neurons and induced spontaneous and burst firing (hypothetical unstable contractions, urgency). The site of abnormal firing has been determined to e the DRG, and the firing appers to be due to changes in the isoforms for voltage-gated Na+ channels, which causes spontaneous ectopic discharges. Tetrodotoxin (TTX) as a nerve blocking agent can binds to and inactivates this voltage-gated Na+ channels. Most voltage-gated Na+ channels exhibit rapid inactivation kinetics and sensitivity to nanomolar concentration of TTX that known as TTX-sensitive (TTX-S). Small bladder sensory neurons in the L6-S1 DRG show two types of Na+ currents, a rapidly inactivating TTX-S sodium current and a slowly inactivating TTX-resisent (TTX-R). (Steers WD,2002). As neurons switch from a quiescent state to a high-frequency firing, as with reawakening of C-fibers, they use their Na+ channels differently. There is extensive evidence to suggest that subunits forming the pore of the Na+ channel change in response to environmental conditions and changes in accsess to NGF. This scenario has been called environmental plasticity associated with channelopathy. (Steers WD,2002). There is clinical evidence that Na+ channels play a role in OAB and can be manipulated to treat urgency and frequency. The local anesthetic and nonselective Na+ channel blocker lidocaine can be use to reduce the symptoms of OAB in a variety of conditions, including BPH. Intravesical lidocaine blocks sensory nerve transmission from the human bladder, as subcutaneous lidcine , it may preferentially act on C-fibers. (Steers WD,2002).

Insight to the mechanism underying the increased mechanosensitivity of C-fibers after spinal cord injury (SCI) has been gained by examining the DRG cells supplying the bladder. Plasticity in these afferents is manifested by enlargement of these cells and increased electrical excitability. A shift in expression on Na+ channels from highthreshold TTX-resistant type to a low-threshold TTX-sensitive type occurs after SCI. Indeed, prevention of increased NGF levels in SCI rats prevent hyperreflexia. Altertively, glial-derived neurotrophic factor (GDNF) may be especially impotant because a small population of DRG neuros giving rise to C-fibers is nonresponsive to NGF but responds to GDNF. It is noting that other neurogenic disorders associated with urge incontinence respond to intravesical capsaicin therapy, suggesting that plasticity in C-fiber afferents could form the neurogenic basis for bladder overactivity.(Steers WD,2002). Its probably too simplistic to view OAB with urge urinary incontinence as just a myogenic or afferent disorder. Acetylcholine released cause activation of M 3 receptors. The M3 elicited contraction is due to a rise in cytosolic calcium (Ca+2) from intracellular stores. Ca+2 is released from these stores following M 3-coupled activation of G-protein (G-p) mediated phospholipase C (PLC) breakdown. Inositol triphosphate (IP 3) triggers Ca+2 release from sacroplasmic reticulum (SR). M 2 activation causes a fall in cyclic adenosine monophosphate (cAMP), preventing relaxation.( Steers WD, Rev Urol.2002). Circumstantial evidence suggests individual with depression, anxiety, and attention deficit disorder may experience symptoms of OAB more often than general population. Wolfe and colleagues suggested that depression, anxiety, feeding disturbances, pain, irritable bowel syndrome, fibromyalgia, and changes in voiding are associated with disturbances in brain circuits using specific neurotransmitters, in particular serotonin (5-hydroxytryptamine, or 5-HT). In these conditions, the 5-HT is diminished in its function. Serotonin or 5-HT also modulates pain and bladder function. Neurons originating in the brainstem raphe nucleus synapse on visceral afferents and preganglionics in the thoracolumbar and sacral spinal cord. These neurons release 5-HT. Stimulation of raphe nucleus in the brainstem inhibits reflex bladder contractions. The pharmacologic data suggest that descending 5-HT pathways tonically depress bladder afferent input to the sacral spinal cord.(Steers WD,2002). Functional position emission tomography studies have identified areas within the brain which are activated during storage and voiding, and these areas are underperfused in patients with DO (Bulmer P,&Abrams P,2004). Similar studies have identified that different areas of the cortex may be active during the perception of the physiological sensation of urge as compared to urgency (Athwal BS et al, 2001) and there may be significant differences between those with good as compared to bad bladder control (Griffiths D & Tadic SD (2008). With functional MRI examination have been revealed activity in rostral and subgenual anterior cingulate gyrus, insula, inferior frontal gyrus, orbitofrontal cortex, dorsal and posterior cingulate gyrus, parahippocampus, cuneus and parts of parietotemporal lobe correlated positively with daytime incontinence frequency and urine loss. Different brain regions correlated with the psychological burden, and the associations were inverse: precuneus/cuneus and posterior cingulate gyrus, superior temporal, supramarginal, and transverse gyrus. Some drugs such as opioid receptor agonists, gabapentin or GABA receptor ligands (Andersson K-E,(2004) and also muscarinic

antagonists with good penetration into the brain such as oxybutynin (Kono M, Nakamura Y, Ishiura Y et al (2006) may exert beneficial effects on urgency by interfering with these central processing mechanisms. In the elderly patients, urinary incontinence commonly seen in cerebrovascular disease, Alzheimer,s disease, and Parkinson,s disease. With age, bladder capacity, contractility, and the ability to postpone voiding decline, and than uninhibited bladder contractions become prevalent. Postvoiding residual volume increases. Urethral length and sphincter strength decline in women, and prostate size increases in most men. (Merck Manual, 20092010). The disturbances could be in nerves, smooth muscle, and urothelium of the bladder
(Steers WD, 2002; Ramundo JM et al)

III.

Clinical Features and Assessment

The main symptom of urge incontinence (also called hyperactive, irritable, or overactive bladder) is the need to urinate frequently. Patients may go to the bathroom more than 8 times over 24 hours, including 2 or more times a night, and have subsequent leakage. The amount of urinary leakage with each episode of incontinence is moderate to large, sacral sensation and reflexes are preserved, and voluntary control of the anal sphincter is intact. Often have no ability to reach the toilet in time following an urge to void, but no leaking by physical activity. These features distinguish urge urinary incontinence from other type of incontinence such as stress incontinence or mixed type (see Table 1 and 2). The postvoiding residual volume is generally low; a residual volume of > 50 to 100 mL suggests outlet obstruction (although the residual volume may be nil in early obstruction), a large bladder diverticulum, pooling of urine in a cystocele (in women), or detrusor hyperactivity with impaired contractility (DHIC). A large residual volume is often found in patients with Parkinson's disease, spinal cord injury, or diabetic neuropathy.
Postvoiding residual volume can be determined by catheterization or ultrasound. (The Merck Manual, 2009-2010).

Table 1. Storage symptoms of the Lower Urinary Tract Sympto m Stress Urge Mixed Description

Leakage with physical exertion or on sneezing or coughing Leakage with a strong and urgent desire to void Combination of stress and urge

Table 2. Symptoms Differentiate Stress and Urge Incontinence Symptoms Stress Incontinence Yes Urge Incontinence

Leaking during physical activity (eg coughing, sneezing,, liftting etc) Ability to reach the toilet in time, following an urge to void Urgency accompanying Incontinence (strong, sudden desire to void) Waking to urinate at night

Sometimes

Yes

No

Seldom

Often

No

Yes

The assessment of urge incontinence consits of voiding diary, physical, neurologic, pelvic, rectal, and pelvic examinations. The urinalysis, postvoiding residual volume of urie, and assessment of quality of life should be performed. (see Fig. 1,2,3 and 4). A voiding diary, kept by the patient or caregiver for 48 to 72 hours, is a record of the volume and time of each void and incontinent episode (see Table 3). The voiding diary is one of the most important components of the evaluation. It provides important clues to the cause of incontinence and helps in devising a therapeutic plan. (The Merck Manual of
Geriatric,2009-2010).

Table 3 . Sample Voiding Diary of An Incontinent Person

Physical examination is important for excluding causes of transient incontinence, detecting serious underlying conditions and causes of established incontinence, and evaluating comorbid disease and functional ability. Neurologic examination helps identify delirium, dementia, stroke, Parkinson's disease, spinal cord compression, and neuropathy (autonomic or peripheral). Additionally, spinal column deformities or dimples suggestive of dysraphism, bladder distention (indicative of bladder weakness or outlet obstruction), and stress incontinence should be explored.(The Merck Manual of Geriatric,2009-2010).

Fig.1. Initial Management of Urinary Incontinence in Men.(Thuroff J et al. Guidelines on

Urinary Incontinence. EAU. 2006).

Rectal examination should check for fecal impaction, masses, prostate nodules, sacral reflexes, and symmetry of the gluteal creases. Prostate size, as determined by palpation, correlates poorly with outlet obstruction. The rest of the rectal examination is actually a detailed neurourologic examination because the same sacral roots (S2-4) innervate the external urethral sphincter and the anal sphincter. Placing a finger in the patient's rectum, the examiner assesses motor innervation while the patient volitionally contracts and relaxes the anal sphincter. The other hand is placed on the patient's abdomen to check for abdominal straining, which can mimic sphincter contraction. Many neurologically intact elderly patients cannot volitionally contract the sphincter. However, successful sphincter contraction is evidence against a cord lesion. Innervation can be assessed further by testing the anal wink (S4-5) and bulbocavernosus (S2-4) reflexes. However, the absence of these reflexes (especially the anal wink) is not necessarily pathologic, nor does their presence exclude an underactive detrusor (eg, due to diabetic neuropathy). Finally, afferent nerve supply is assessed by testing perineal sensation. (The Merck Manual of Geriatric,2009-2010).

Fig.2. Specialized Management of Urinary Incontinence in Men. (Thuroff J et al. Guidelines

on Urinary Incontinence. EAU. 2006).

Pelvic examination should be performed for all incontinent women. Pelvic muscle laxity may cause a cystocele, enterocele, rectocele, or uterine prolapse. Bulging of the anterior wall when the posterior wall is stabilized indicates a cystocele, whereas bulging of the posterior wall indicates a rectocele or enterocele. Unless severe (in which prolapse can kink the urethra and cause obstruction), pelvic floor muscle laxity indicates little about the cause of incontinence. Detrusor overactivity may exist in addition to a cystocele, and stress incontinence may exist without a cystocele. (The Merck Manual of Geriatric,2009-2010). The vagina should be inspected for signs of atrophic vaginitis, characterized by mucosal erythema, tenderness, friability, petechiae, telangiectasia, or vaginal erosions. Vaginal atrophy (not associated with incontinence) is characterized by loss of rugal folds and a thin, shiny mucosa. A cytologic maturation index showing 100% parabasal cells indicates atrophy but not necessarily atrophic vaginitis. (The Merck
Manual of Geriatric,2009-2010).

Fig.3. Initial Management of Urinary Incontinence in Women .(Thuroff J et al.

Guidelines on Urinary Incontinence. EAU. 2006)

Urinalysis should be performed and blood urea nitrogen and creatinine levels checked. Electrolytes should be measured if the patient is confused, urine culture should be obtained if dysuria is present, and serum concentrations of glucose and calcium (and albumin, to allow calculation of free calcium levels in sick, malnourished patients) should be measured if the voiding record suggests polyuria . (The Merck Manual of
Geriatric,2009-2010).

Urine cytology or cystoscopy should be performed if a patient has sterile hematuria, suprapubic or perineal discomfort, or a high risk of bladder cancer (eg, unexplained recent onset of urgency or urge incontinence, exposure to industrial dyes). (The Merck Manual of Geriatric,20092010).

If the cause of incontinence cannot be determined, urodynamic evaluation should be considered. Urodynamic evaluation includes various tests (eg, cystometry, uroflowmetry, urethral profilometry) as well as x-ray imaging during bladder filling and emptying. The tests required depend on the clinical question. Although its precise role is debated, multichannel urodynamic evaluation is probably warranted when diagnostic uncertainty may affect therapy, when empiric therapy has failed and other approaches may be tried, or when surgery is being contemplated. (The Merck Manual of Geriatric,2009-2010).

Fig.4. Specialized Management of Urinary Incontinence in Women. (Thuroff J et al.

Guidelines on Urinary Incontinence. EAU. 2006)

IV.

Conclusion

Urge urinary incontinence is define as involuntary urinary leakage accompanied by or immediately preceded by a sensation of an urgent need to urinate. Pathomechanism of urge urinary incontinence based on disturbances in nerves both central and peripheral abnormalities, smooth muscle, and urothelium of the bladder. In the elderly patients,

urinary incontinence commonly seen in cerebrovascular disease, Alzheimer,s disease, and Parkinson,s disease. With age, bladder capacity, contractility, and the ability to postpone voiding decline, and than uninhibited bladder contractions become prevalent. The nerves become more sensitive to such stimuli especially the preganglionic C-fibers. There is extensive evidence to suggest that subunits forming the pore of the Na+ channel change in response to environmental conditions and changes in accsess to NGF. This environmental plasticity associated with channelopathy of the Na+ channels results in alteration of C-fibers function and become more sensitive. The central nervous system that play an important role for urge incontinence is serotonin (5-hydroxytryptamine, or 5-HT). Serotonin is released in raphe nucleus and has been diminished in its function in patients with incontinence. Raphe nucleus synapse on visceral afferents and preganglionics in the thoracolumbar and sacral spinal cord. Denervated bladders show increased M3 receptor expression and is activated by acetylcholine release. The M3 elicited contraction is due to a rise in cytosolic calcium (Ca+2) from intracellular stores. Ca+2 is released from these stores following M3-coupled activation of G-protein (G-p) mediated phospholipase C (PLC) breakdown. Inositol triphosphate (IP3) triggers Ca+2 release from sacroplasmic reticulum (SR). M2 activation causes a fall in cyclic adenosine monophosphate (cAMP), preventing relaxation. The clinical feature concists of the need to urinate frequently. Patients may go to the bathroom more than 8 times over 24 hours, including 2 or more times a night, and have subsequent leakage. The amount of urinary leakage with each episode of incontinence is moderate to large, sacral sensation and reflexes are preserved, and voluntary control of the anal sphincter is intact. Often have no ability to reach the toilet in time following an urge to void, but no leaking by physical activity. Clinical assessment for urge urinary incontinence consist of voiding diary, physical, neurologic, pelvic, rectal, and pelvic examinations. Urinalysis should be performed and blood urea nitrogen and creatinine levels checked. Urine cytology or cystoscopy should be performed if a patient has sterile hematuria, suprapubic or perineal discomfort, or a high risk of bladder cancer

V.

References

Andersson K-E. 2004. New pharmacological targets for the treatment of the overactive bladder: an update. Urology 63(Suppl 3A):3241 Athwal BS, Berkley KJ, Hussain I et al. 2001. Brain responses to changes in bladder volume and urge to void in healthy men. Brain 124:369377. Bulmer P, Abrams P. 2004. The unstable detrusor. Urol Int 72:112 Fitzgerald MP, Kenton KS, Brubaker L, 2005. Localization of the urge to void in

patients with painful bladder syndrome. Neurourol Urodyn 24:633637 Griffiths D, Tadic SD. 2008. Bladder control, urgency, and urge incontinence: evidence from functional brain imaging. Neurourol Urodyn 27:466474 Kono M, Nakamura Y, Ishiura Y et al. 2006. Central muscarinic receptor subtypes regulating voiding in rats. J Urol 175:353357 Lips KS, Wunsch J, Sarghooni S et al. 2007. Acetylcholine and molecular components of its synthesis and release machinery in the urothelium. Eur Urol 51:10421053 Morrison J, Birder LA, Craggs M et al. 2006. Neural control. Plymbridge Distributors Ltd, Plymouth, pp 363422 Morrison J. 1999. The activation of bladder wall afferent nerves. Exp Physiol 84:131136 Steers DW.2002. Pathophysiology of overactive bladder and urge urinary Incontinence. Rev Urol 4(Suppl4): S7-S18.
Tadic SD, Griffiths D, Schaefer W, Cheng CI et al. 2010, Brain activity measured by functional magenetic resonance imaging (fMRI) is related to patient treported severity of urgency urinay incontinence. J Urol. 183(1): 221228.

The Merck Manual of Geriatric.2009-2010. Merck Sharp & Dohne Corp. a subsidiary of Merck & Co.Inc. N.J. USA. Thoroff J et al.2006. Guidelines on Urinary Incontinence. European Association of Neurology. Yoshida M, Masunaga K, Satoji Y et al. 2008. Basic and clinical aspects of non-neuronal acetylcholine: expression of non-neuronal acetylcholine in urothelium and its clinical significance. J Pharmacol Sci 106:193198. Yoshimura N, Kaiho Y, Miyazato M et al. 2008. Therapeutic targets for lower urinary tract dysfunction. Naunyn Schmiedebergs Arch Pharmacol 377:437448