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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 urgeincontinence 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 prostatichyperplasia (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 theelderly 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 involvedin 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 poordetrusor-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 than8 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 ofincontinence 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 theoffice 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 andpressures. 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


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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 incontinenceinvolve 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 centralnervous system, infections, the aging process, emotional disorders, medications

including some sleeping pills, and genetic factors may play a role in some cases. In theelderly 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 causesthe 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 problemdespite 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 nervegrowth factor.(Steers WD, 2002; Ramundo JM et al)

The main symptom of urge incontinence (also called hyperactive, irritable, or overactivebladder) 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 noability 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


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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 theimportant 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 andcan 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 iscomplex, 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 -fibresand thinner, non-myelinated C-fibres, the latter exhibiting slower conductance (Marrison Jet 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 astension 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 -fibresand 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-fibresmay 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 sensationof 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 apathological sensation which is sensed by mechanisms which are at least partly distinct

from those involved in sensing bladder filling (Fitzgerald MP et al,2005).


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In pathologic conditions, the nervous system is able to change transmitters, reflexes, orsynaptic 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 C-

fiber afferents can trigger micturation in unstable bladders, although not in normalbladder.(Steers WD,2002).

The molecular trigger for changes in the afferents or synaptic transmission in the centralnervous 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 dueto 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 exhibitrapid 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 slowlyinactivating 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 withchannelopathy.(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).


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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 andincreased electrical excitability. A shift in expression on Na+ channels from high-

threshold 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 incontinencerespond 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 M3 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 M3-coupled activation of G-protein

(G-p) mediated phospholipase C (PLC) breakdown. Inositol triphosphate (IP 3) triggers

Ca+2 release from sacroplasmic reticulum (SR). M2 activation causes a fall in cyclicadenosine 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 brainwhich 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 differencesbetween those with good as compared to bad bladder control (Griffiths D & Tadic SD

(2008). With functional MRI examination have been revealed activity in rostral andsubgenual anterior cingulate gyrus, insula, inferior frontal gyrus, orbitofrontal cortex,dorsal and posterior cingulate gyrus, parahippocampus, cuneus and parts of parieto-

temporal lobe correlated positively with daytime incontinence frequency and urine loss.

Different brain regions correlated with the psychological burden, and the associationswere 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


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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, 2009-

2010). 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 8times 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, sacralsensation 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). Thepostvoiding 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 detrusorhyperactivity 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 orultrasound. (The Merck Manual, 2009-2010).

Table 1. Storage symptoms of the Lower Urinary Tract

Sympto

m

Description

Stress Leakage with physical exertion or on sneezing or coughing

Urge Leakage with a strong and urgent desire to void

Mixed Combination of stress and urge


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Table 2. Symptoms Differentiate Stress and Urge Incontinence

Symptoms Stress

Incontinence

Urge Incontinence

Leaking during physical

activity (eg coughing,

sneezing,, liftting etc)

Yes Sometimes

Ability to reach the toilet

in time, following an

urge to void

Yes No

Urgency accompanying

Incontinence (strong,

sudden desire to void)

Seldom Often

Waking to urinate at

night

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 ofGeriatric,2009-2010).

Table 3 . Sample Voiding Diary of An Incontinent Person


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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


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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).


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Fig.2. Specialized Management of Urinary Incontinence in Men.(Thuroff J et al. Guidelineson 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 MerckManual of Geriatric,2009-2010).


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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 ofGeriatric,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,2009-2010).


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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 ofurge urinary incontinence based on disturbances in nerves both central and peripheral

abnormalities, smooth muscle, and urothelium of the bladder. In the elderly patients,


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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 nervesbecome 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. Thisenvironmental 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, or5-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. Inositoltriphosphate (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 thebathroom 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 toiletin 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 andblood urea nitrogen and creatinine levels checked. Urine cytology orcystoscopy 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


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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 receptorsubtypes regulating voiding in rats. J Urol 175:353357

Lips KS, Wunsch J, Sarghooni S et al. 2007. Acetylcholine and molecularcomponents of its synthesis and release machinery in the urothelium.

Eur Urol 51:10421053

Morrison J, Birder LA, Craggs M et al. 2006. Neural control. PlymbridgeDistributors 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 urinaryIncontinence. Rev Urol 4(Suppl4): S7-S18.

Tadic SD, Griffiths D, Schaefer W, Cheng CI et al. 2010, Brain activitymeasured by functional magenetic resonance imaging (fMRI) is relatedto 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 inurothelium and its clinical significance. J Pharmacol Sci 106:193198.

Yoshimura N, Kaiho Y, Miyazato M et al. 2008. Therapeutic targets for lowerurinary tract dysfunction. Naunyn Schmiedebergs Arch Pharmacol

377:437448

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Pathomechanisms.doc Bali 2010.Doc Revisi